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PMC9875318_01

Male

A 70-year-old patient with primary open-angle glaucoma was implanted with a second-generation EYEMATE-IO device during cataract surgery in the right eye as part of a clinical trial in 2015. At that time, he had been diagnosed with glaucoma for 29 years. He had not undergone previous eye surgery at the time of EYEMATE-IO implantation. Glaucoma was mild in both eyes, with a mean visual field defect of 4.8 and 2.4 dB in the right and left eye, respectively. The IOP was well regulated with local latanoprost and brimonidine. We followed the patient regularly until the outbreak of the COVID-19 pandemic in 2020. During that time, visits to the clinic were highly restricted, and the patient was seen only twice per year. In addition, the patient's wife had a serious illness and was in constant need of care, so the patient was additionally restricted in his visits the Eye Hospital. In May 2021, the EYEMATE-IO recorded an increase in the IOP in the right eye. During a visit arranged at short notice, the EYEMATE-IO measurements revealed IOP values between 24.8 and 26.6 mmHg, which were verified by three GAT measurements showing values between 26.0 and 28.0 mmHg in the right eye. The antiglaucoma medication was changed to a preservative-free combination of bimatoprost/timolol and dorzolamide; however, severe allergic eczema of the eyelids and the periocular skin developed. In December 2021, the patient's GAT IOP values were between 34.0 and 37.0 mmHg (three measurements). Self-measurements obtained via the EYEMATE-IO during the same visit showed IOP values between 41.3 and 42.0 mmHg (three measurements). On gonioscopy, the anterior chamber angle was Shaffer grade IV in all quadrants, with normal pigmentation of the trabecular meshwork. Furthermore, there was no change in the position of the EYEMATE-IO , which could have explained the IOP elevation. Several mechanisms might have caused the increase in IOP, including the course of the disease, loss of IOP reduction capacity of the antiglaucoma medications, and loss of adherence to therapy due to the adverse effects caused by the medications. In addition, optical coherence tomography (OCT) demonstrated progressive loss of the retinal nerve fiber layer of 2.9 microm per year in the last 2 years. Because the glaucoma was progressive on OCT and the IOP was elevated on maximal-tolerated medication, the decision was made to perform minimally invasive bleb surgery in the right eye with the PreserFlo MicroShunt. Antiglaucoma medications were stopped in the right eye 2 weeks prior to surgery, and systemic acetazolamide 250 mg twice daily was given instead. Unpreserved dexamethasone eye drops were given three times daily in the right eye 1 week before surgery. The surgery was uncomplicated, and the postoperative care was unremarkable. Moxifloxacin eye drops were given for 1 week four times daily, and unpreserved dexamethasone eye drops were tempered over 6 weeks. The patient continued to conduct IOP self-measurements with the EYEMATE-IO postoperatively. At 3-month follow-up, we observed a moderately elevated, posterior, well-functioning filtering bleb in the right eye. The IOP was 14.5 mmHg (mean of two measurements) with GAT and 15.5 mmHg (mean of two measurements) with the EYEMATE-IO . The patient was medication free in the operated eye. A further follow-up was scheduled in 6 months, and the patient was instructed to continue the IOP self-measurements. The patient was prompted to contact the clinic immediately if his IOP increased over 20.0 mmHg to arrange an earlier visit. The telemetrically obtained IOP data between January 2021 and the time of publication of this report are presented in Figure 1. Statistical analysis was performed to compare the mean IOP values collected by the EYEMATE-IO during follow-up. IOP decreased significantly from 28.7 +- 8.3 mmHg at baseline (range = 13.5-49.1 mmHg, 76 measurements) to 14.6 +- 2.7 mmHg at 3 months (range = 8.1-22.4 mmHg, 137 measurements), 12.7 +- 2.2 mmHg at 5 months (range = 6.8-17.9 mmHg, 120 measurements), 14.1 +- 2.2 mmHg at 7 months (range = 8.6-19.7 mmHg, 81 measurements), and 14.6 +- 2.7 mmHg at 9 months after surgery (range = 8.4-22.3 mmHg, 73 measurements), respectively. The self-measured IOP values during the preoperative month and postoperative months 3, 5, 7, and 9 - depending on the time of the day - are presented in Tables 1 and 2 and Figure 2. In addition, the 24-h IOP fluctuations were considerably lower at all follow-up time points compared with the fluctuations recorded during the preoperative month (Figures 2 and 3).

argos, iop sensor, preserflo microshunt, glaucoma, intraocular pressure sensor, minimally invasive glaucoma surgery

PMC5751031_01

Male

A 26-year-old Caucasian male with no significant past medical history presented with fatigue, pruritus, jaundice, dark urine and clay colored stools for 1 month. The patient had been taking methyl-1-etiochoenolol-epietiocholanolone, an androgenic anabolic steroid (AAS). Initially, at an outpatient clinic he was found to have a total bilirubin (Tbili) of 6 mg/dl. He was advised to discontinue the AAS. He discontinued the AAS but the patients' symptoms worsened. Repeat blood work 2 weeks later showed a Tbili of 32.5 mg/d, which prompted inpatient management. The patient denied use of other hepatotoxic drugs, herbal supplements, tobacco, illicit drugs or alcohol. He had a similar episode 5 years ago; he had been taking a similar AAS and developed mild jaundice, which resolved spontaneously once he discontinued the AAS. On exam, his vital signs were normal. He was extensively jaundiced, had a normal mental status without asterixis, and normal cardio-respiratory and abdominal exam without ascites or hepatomegaly. Liver biochemistries revealed aspartate aminotransferase (AST) 67 U/l, alanine transaminase (ALT) 106 U/L, alkaline phosphatase 166 U/l, Tbili 36 mg/dl, and international normalized ratio (INR) 0.95. Complete blood cell count (CBC) and Renal Function Panel (RFP) were normal. An extensive infectious, autoimmune, and metabolic work was negative. His abdominal ultrasound was normal. At this stage, he was initiated on a 4-day trial of MARS therapy due to refractory hyperbilirubinemia after standard medical therapy (SMT). By day 3 of MARS therapy his pruritus, fatigue, hemoglobinuria and jaundice improved. Liver biochemistries at that time revealed AST 95 U/l, ALT 147 U/l, alkaline phosphatase 166 U/l, Tbili 24.3 mg/dl and INR 1.01. CBC and RFP remained normal. Over the course of his therapy, he remained hemodynamically stable, clinically improved and his Tbili decreased to 20.7 mg/dl. A percutaneous liver biopsy was performed showing severe cholestasis with bile duct injury/inflammation and hepatocyte injury without steatosis (Fig. 1), consistent with DILI. Patient was discharge with outpatient follow-up. At 2 months follow-up he ceased taking AAS and noted a resolution of his fatigue, jaundice, pruritus, and abnormal stool and urine color. Labs showed AST 56, ALT 104 and Tbili 3.3 mg/dl.

PMC8077664_01

Female

In June 2019, a 70-year-old woman was referred to our hospital due to pain in the chest and back. Chest computed tomography (CT) revealed a tumor in the upper left lobe involving the left hilum and mediastinum (Fig. 1A, E). Moreover, multiple metastatic sites were suspected at mediastinal lymph nodes, ribs, liver, and left adrenal gland (Fig. 1I). The pathological result of biopsy of liver metastases showed adenocarcinoma originating from the lung. After complete inspection, the patient was diagnosed as stage IV NSCLC (adenocarcinoma). The gene detection of biopsy tissue by amplification refractory mutation system (ARMS) showed deletion in exon19 at the EGFR gene. Rearrangement in the anaplastic lymphoma kinase (ALK) and c-Ros oncogene 1 receptor kinase (ROS1) fusions were negative. Afterwards, the patient started to receive targeted therapy of icotinib (125 mg, per os, t.i.d.). Re-examination by radiological scans in 1-month intervals demonstrated the primary lung cancer mass had no obvious change but the remaining metastasis of the liver, adrenal gland, and mediastinal lymph nodes had decreased in size significantly (Fig. 1B, F, J). According to the Response Evaluation Criteria in Solid Tumors v.1.1 (RECIST 1.1), a stable response in pulmonary lesions and partial response in extrapulmonary metastasis were confirmed. In November 2019, the patient received two cycles of chemotherapy with pemetrexed on the basis of targeted therapy. However, the pulmonary tumor remained stable after combination therapy (Fig. 1C, G). In order to clarify the different responses between the primary pulmonary lesion and other metastasis, electronic bronchoscope was performed, which revealed an ulcer at the left main and superior lobar bronchus. Also, a biopsy specimen revealed chronic inflammation with necrosis. A nucleic acid test of respiratory pathogens in the sputum was positive for mycobacterium TB complex. The patient was then transferred to the TB hospital. GeneXpert MTB/RIF detection showed a positive result but a TB smear was negative. After the diagnosis of TB in January 2020, the patient received anti-TB treatment with an HRZE fixed dose combination composed of isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months. Meanwhile, she continued targeted therapy. In May 2020, chest and abdomen CT demonstrated that the pulmonary mass had shrunk significantly but metastases of the liver and adrenal gland had enlarged markedly, which was assessed as disease progression (Fig. 1D, H, L). Re-biopsy of the liver metastasis showed the same pathological pattern as before. The gene detection by ARMS revealed deletion in exon19 and a point mutation in exon20 (T790M) at the EGFR gene. Hence, the patient received osimertinib treatment.

egfr, lung cancer, pulmonary tuberculosis

PMC6033244_01

Male

A 30-year-old male, with no significant past medical history, came to the emergency department with complaints of fever and chills for a duration of 3 days. He also complained of myalgia and abdominal pain for the same duration. He reported diffuse abdominal pain, which was 6/10 in severity, nonradiating, and not related to food. He also reported 2 episodes of diarrhea without any blood or mucous, brown in color. He denied cough, shortness of breath, chest pain, night sweats, weight loss, history of trauma, extreme exercise, or any history of travel. His abdominal examination was significant for abdominal tenderness in all four quadrants, but was soft and nondistended and bowel sounds were present. The rest of his examination was unremarkable. Triage vitals were significant for a temperature of 103.3 F, heart rate of 88 beats per minute, respiratory rate of 18 breaths per minute, blood pressure of 109/49, and pulse oximetry of 99% on room air. Admission laboratory workup revealed leukocyte count of 6.1 x 103 microL (reference range 4.5-11.0 x 103) with 72% neutrophils, hemoglobin of 16.2 g/dL (reference range 13.0-17.0), hematocrit of 48.2% (reference range 39-53), platelet count of 149 x 103 microL (reference range 130-400 x 103), ESR of 4 mm/hr (reference range 0-20), BUN of 34 mg/dL (reference range 8-20), creatinine of 1.8 mg/dL (reference range 0.4-1.3), potassium of 4.7 mmol/L (reference range 3.6-5.1), phosphorous of 3.0 mg/dL (reference range 2.4-4.7), aspartate aminotransferase of 1,146 IU/L (reference range 15-41), alanine aminotransferase of 243 IU/L (reference range 17-63), and creatinine kinase of 39,125 IU/L (reference range 38-398). Urinalysis was significant for large blood, and urine red blood cells were 0-2. In view of the high-grade fever, we attempted to find an infectious source to explain his history and presentation. Chest X-ray (Figure 1) and CT scan were obtained and showed no signs of pneumonia. Urinalysis and influenza rapid antigen test were performed and did not reveal any abnormalities. CT of the abdomen and pelvis was obtained and did not reveal any focal sources. Stool culture with ova and parasites, blood cultures, urinary toxicology including synthetic THC (K2), HIV, herpes simplex virus, hepatitis panel, Mycoplasma pneumoniae IgM antibody, urine Legionella antigen, QuantiFERON test for tuberculosis, and TSH were all performed as well. All the test results were negative except immunoglobulin M antibodies for Mycoplasma pneumoniae that were detected by enzyme-linked immunosorbent assay. The antibodies were initially 781 U/mL, which is considered a low positive (reference range 770-950). Our patient was empirically started on levofloxacin and metronidazole for possible gastroenteritis initially while culture and laboratory results were pending. He was managed for his acute renal failure and rhabdomyolysis with aggressive parenteral hydration. However, he continued to spike fevers during days 1-4 of the admission, but his diarrhea, abdominal pain, and myalgia resolved by day 3. One week later, mycoplasma antibody was recorded again and it was 976 U/ml, which is considered a true positive (reference range 950+). The fact that the antibody titer was trending up was clinically significant for a recent Mycoplasma pneumoniae infection. After mycoplasma was found to be positive, metronidazole was discontinued and he was continued with levofloxacin. His creatinine, liver function tests, and CK trended down to normal reference ranges (Figure 2), and he was discharged on day 9 with planned outpatient follow-up.

PMC3256991_01

Female

A 42 year old woman was brought to an outside facility after a fall from a motorcycle. She had a 15 minute loss of consciousness. Following this, her Glasgow Coma Scale (GCS) was 15. CT brain revealed a small amount of traumatic subarachnoid hemorrhage. Imaging revealed non-displaced fractures of the transverse processes on the right side of the second, third, fourth and seventh cervical vertebrae (C2, C3, C4 and C7) extending into the foramen transver-sarium (Fig.1). Imaging also revealed compression fractures of sixth and eighth thoracic vertebrae (T6 and T8) without impingement on the spinal canal. She was also found to have a fracture of the distal right radius, dislocation of the left elbow and a grade 2 splenic laceration on imaging. She underwent closed reduction and external fixation of the right forearm. Following the surgery, she was neurologically intact. The next day she abruptly became mute with deviation of the head and gaze to the left with right hemiparesis. She was emergently transferred to our facility for management of acute stroke. A non-contrast CT of the brain revealed loss of grey-white differentiation in a left middle cerebral artery distribution and a CT angiogram revealed dissection of both carotid arteries immediately proximal to the skull base as well as dissection of the left vertebral artery in the neck. On the left side the distal cervical internal carotid artery was found to be nearly occluded (Fig.2) with only a string sign in the carotid canal, with patency of the distal left intracranial internal carotid artery and middle cerebral artery. On the right side, a raised intimal flap with early signs of pseudoaneurysm formation was seen with >50% narrowing of the lumen of the vessel (Fig. 3). The left vertebral artery demonstrated luminal narrowing of >50% just prior to entering the foramen transversarium of the sixth cervical vertebra (C6) and also demonstrated an intimal flap with narrowing of the lumen >25% at the level of the first cervical vertebra (C1). Magnetic Resonance Imaging (MRI) of the brain confirmed a large left middle cerebral artery territory infarct (Fig. 4). The patient was not considered to be a candidate for anticoagulation with heparin in view of the splenic laceration and endovascular management was not performed in view of the completed infarct on the left side. She was started on Aspirin 81mg a day. She remained globally aphasic and right hemiparetic for the duration of the Intensive Care Unit (ICU) stay. The Intracranial Pressure (ICP) via CodmanTM monitor was briefly elevated to 20-30mmHg and the patient was successfully treated with osmotherapy rather than decompressive surgery. The patient was transferred out of the ICU after several days and seen in clinic follow up 3 months later at which time significant neurological improvement was seen. The patient was able to communicate and follow commands although a significant expressive aphasia remained. She was able to ambulate with assistance although she had very limited function of her right arm. A repeat CT angiogram at 3 months revealed significant healing of the dissection on the left side to <50% (Fig. 5) while on the right side there was progression of the pseudoaneurysm to 18mm in length (Fig. 6). The left vertebral lesions were unchanged. The patient was maintained on 81mg of Aspirin to decrease the risk of thromboembolism and referred for endovascular management in view of the progressive nature of the pseudoaneurysm. An estimated 1.5 million head injuries occur every year in the United States and Traumatic Brain Injury (TBI) is the leading cause of death and disability in children and adults from ages 1 to 44. Blunt cerebrovascular injury (BCVI), or injury to the carotid and vertebral arteries in the setting of blunt trauma, was originally reported to be very uncommon, occurring in 0.08% of patients. More recent studies, however, report a prevalence ranging from 1.1-1.6% of all patients with blunt trauma, with a prevalence of 2.7% in the most severely injured (injury severity score>=16). This increased prevalence is almost certainly a consequence of screening protocols instituted at several institutions. BCVI results in significant disability and morbidity- 32-67% for carotid injury and 14-24% for vertebral injury. While patients with BCVI often die because of other injuries (particularly severe TBI), there appears to be significant attributable mortality to BCVI itself, with one study reporting attributable mortality up to 38%. The more wide-spread use of screening for BCVI using CT or catheter angiography is mostly driven by the awareness that a significant number of these injuries are initially asymptomatic, prior to presenting with symptoms of cerebral ischemia/ infarction, and that detecting these lesions when they are asymptomatic may provide an important window of opportunity to prevent ischemic strokes. The mechanism of blunt injury to the carotid appears to be through longitudinal stretch of the vessel, often against the transverse processes of C1/ C2 in the context of hyperextension and contra-lateral rotation, thereby accounting for the usual location of these injuries in the distal cervical internal carotid artery, just proximal to the skull base. Carotid BCVI also occurs with fractures of the skull base, particularly those involving the carotid canal. Vertebral artery injuries occur in the context of spinal subluxation/ dislocation and fractures running through the transverse foramen resulting in stretching of the otherwise fixed vertebral artery against the surrounding bony structures or dural margin. Other mechanisms of BCVI include direct trauma to the anterior neck (as with hanging), intraoral injuries and displacement/ fracture of the mandible. Thromboembolism likely results from platelet aggregates that form when the intima is disrupted or within pseudoaneurysms, resulting in distal embolism or luminal narrowing/occlusion and limitation or obstruction of flow. Stroke may also occur when intramural hematomas and intimal flaps cause hemodynamic compromise. Available data suggests that the majority of patients with carotid artery dissections suffer brain injury more consistent with a thromboembolic mechanism. Less common mechanisms of stroke include complete transection and venous hypertension with arterio-venous fistulas (AVF). It is clear that while some cases of BCVI present early with focal neurological signs/ symptoms or active arterial bleeding and others never become symptomatic, there is a significant group of patientswith BCVI who demonstrate a latent period, lasting from hours to days, before suffering an ischemic stroke. In different case series, 23-50% of patients with BCVI who develop symptomatic cerebral ischemia do so after a period of 12 or more hours after the injury, sometimes up to 7 days. This latent period may be a window in which therapeutic intervention can be initiated to prevent subsequent cerebral ischemia. Knowledge of the traumatic injuries that are most commonly associated with BCVI, including asymptomatic BCVI, has led some authors to propose screening criteria based on certain clinical or radiological findings. The most widely used screening criteria for BCVI were developed in Denver, Colorado, based on the work of Biffl and Cothren et al. The Denver criteria are listed in Table 1. In addition to these criteria, the presence of major chest trauma also seems to predict the presence of BCVI. It is important to note that 20-24% of patients with BCVI will not be picked up by the aforementioned screening criteria and may present with neurological signs and symptoms despite a policy of screening for BCVI. Interestingly, our patient described above, who was not screened for BCVI, did not have any of the classical risk factors for carotid injury (base of skull fracture, diffuse axonal injury, Le Fort 2 or 3 fracture) but did have a risk factor for vertebral artery injury (fractures passing through the transverse foramen, Fig. (1)) and therefore would have fit screening criteria for BCVI. It is useful to note here that multi-vessel injury, as seen in our patient, is common, occurring in 18-38% of BCVI and should be actively looked for when any one vessel injury is detected. The diagnostic tool most appropriate for screening for BCVI is a matter of debate. Four vessel digital subtraction angiography (DSA) is widely accepted as the gold standard, but does involve the small but definitive (generally <1%) risk of procedural thromboembolism and stroke, as well as minor or major bleeding into the thigh or retroperitoneum. More recently, multidetector Computed Tomographic Angiography (mdCTA) has seen widespread use as a less invasive screening tool for BCVI. The frequent need for CT scanning of other parts of the body makes this particularly expedient, with some institutions including CT angiography of the neck as part of a whole- body rapid multidetector spiral CT scan, involving one spiral data acquisition and one contrast injection for the entire body. While whole-body scanning is much more frequently associated with the presence of artifacts, it does seem to detect clinically significant BCVI with accuracy comparable to focused md CTA of the neck. Two studies have looked at the use of mdCTA as a screening tool for BCVI with DSA performed only to confirm positive findings on CTA, No patients with negative mdCTAs (who did not undergo DSA and were followed clinically) suffered clinical neurological decline in either study. Two studies have directly compared 16-channel mdCTA to DSA. The earlier study performed both mdCTA and DSA in all patients who met screening criteria for BCVI. The sensitivity and specificity of mdCTA compared to DSA were 98% and 100% respectively. A subsequent study that also performed mdCTA and DSA in all patients meeting screening criteria reported very different results, with sensitivity and specificity of only 74% and 84% respectively. Of note, though, when only the second half of enrolled patients were analyzed, the sensitivity and specificity jumped to 100% and 86%, suggesting that the presence of a significant learning curve for radiologists in the use of mdCTA to diagnose BCVI. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA) are frequently used in the context of ischemic stroke for the diagnosis of cervical artery dissection. A retrospective comparison of 18 patients with ischemic stroke associated with cervical artery dissection evaluated with both mdCTA and MRI/ MRA suggested that CTA may be superior for the depiction of dissection, particularly in the vertebral artery. MRI and MRA have not been systematically evaluated for the diagnosis of BCVI. The use of MRImay, at several institutions, pose logistical problems in terms of availability, time taken for the study and the ability to monitor potentially unstable trauma patients while in the scanner. Duplex ultrasound has been used as a non-angiographic method to screen for BCVI. Carotid duplex ultrasound appears to have very poor sensitivity in comparison to 4-vessel or CT angiography. One retrospective study compared 407 trauma patients screened with mdCTA for BCVI with an earlier group of 1471 patients screened with carotid duplex sonography. Carotid duplex detected five cases of BCVI but missed another eight cases associated with ischemic stroke. Sensitivity and specificity of carotid duplex were 38.5% (95% Confidence Interval [95%CI]: 13.9-68.4%) and 100% (95%CI, 99.7-100%), respectively. In contrast, CT angiography detected BCVI in 11 patients, with a sensitivity of 100% (95%CI 71.5-100%), but produced one false-positive result. In order to standardize the reporting of BCVI, Biffl and coworkers have proposed an angiography based grading system for BCVIs (Table 2). The risk of stroke appears to be directly correlated with angiographic grade (Table 2) in carotid BCVI, while in vertebral BCVI, interestingly, the highest risk of stroke appears to be with Grade II injuries (luminal narrowing >25%, intraluminal thrombi or AVF) and least with Grade III (pseudoaneurysm). Medical treatment with antithrombotic agents appears to be the mainstay of management of BCVI. A number of retrospective studies have shown a large reduction in the rate of neurological sequelae with the use of antithrombotic therapy compared to patients who, for any reason, were not treated with anticoagulant or antiplatelet therapy. In one such study by Cothren et al., BCVI was diagnosed in 244 patients using the Denver screening criteria. Of 187 patients eligible for and treated with antithrombotic therapy, one (0.5%) suffered a stroke while 21% of patients not treated (generally because of the presence because of a contraindication such as bleeding risk) suffered a stroke. Patients who suffered strokes had a significantly higher BCVI-attributable mortality (21% in carotid BCVI, 18% in vertebral BCVI) compared to those who did not suffer a stroke (0% for both carotid and vertebral BCVI). In another study by the same group, over a 7 year period in which prospective screening criteria for angiography were used, 643 patients were screened and 114 patients found to have blunt carotid injury. Of these, 73 were treated with either anticoagulation (n=56) or antithrombotic agents (n=17) and the rest were not treated, most commonly because of the presence of contraindications. None of the treated patients developed an ischemic stroke while 46% of the untreated patients suffered "ischemic neurologic events". There are no randomized controlled trials comparing anticoagulation with Heparin to the use of antiplatelet agents in BCVI. The large number of patients who would likely need to be enrolled to obtain a meaningful result makes such a trial challenging. Most studies that have performed subgroup analysis of non-randomized and retrospective studies to address this question have found no difference between the two groups. In the absence of data from randomized controlled trials, some experts, including the Denver group, do preferentially recommend the use of Heparin in patients without major bleeding risk on the basis of some studies that have demonstrated a trend toward reduction in stroke rates with Heparin as compared to Aspirin. One study by Biffl et al. showed a 1% vs. 9% rate of stroke (p=0.07) with Heparin vs. Aspirin. Serious bleeding complications can, however, complicate the use of anticoagulation. In the same study from the Denver group by Biffl et al., bleeding requiring transfusion or cessation of Heparin was seen in 54% of patients, on the basis of which the authors recommend a more conservative Partial Thromboplastin Time target of 40-50 seconds while using Heparin. Worsening of intracranial bleeding has also been reported with the use of anticoagulation to treat BCVI. Our patient was treated with Aspirin instead of Heparin- despite the presence of a symptomatic near-occlusion of the left carotid and a Grade 2 injury of the right carotid- because of the presence of a concomitant splenic laceration. No data currently exists on when antithrombotic therapy should be discontinued. Some authorities recommend making a decision based on follow-up imaging after 7-10 days. Antithrombotic therapy is stopped if the injury has healed, while if persistent injury is seen, therapy with an antiplatelet or Warfarin is continued for another 3 months at which time a DSA or mdCTA is repeated. The role of open surgery appears to be very limited in BCVI. Most carotid injuries are close to the skull base and not easily accessible. In patients with surgically accessible injuries, however, patients who do not have a dense neurological deficit who undergo reperfusion appear to do better than those who undergo ligation. Patients with a dense neurological deficit, however, seem to do poorly regardless of the specific surgical treatment chosen. The role of endovascular techniques in the management of BCVI is not clearly defined. Several case series have indicated the safety and feasibility of emoblization of pseudoaneurysms and stenting of intimal injuries. One retrospective study from the Denver group, however, reported a much higher rate of carotid occlusion in patients who underwent stenting than those who underwent medical management with a consequently higher rate of symptomatic complications (21% vs. 5%). The retrospective nature of this study and the likelihood of selection bias makes it difficult to draw meaningful conclusions from this study, however, and other studies have reported very good results with endovascular procedures performed in patients with dissections. Advances in endovascular techniques and devices have made stenting and coiling of distal extracranial as well as intracranial lesions feasible. Ansari et al. have reported excellent results with the use of the neuroform stent to treat distal extracranial as well as intracranial dissections. Kadkhodayan et al. reported a case series of 26 patients with carotid dissections, with or without associated pseudoaneurysm, treated with angioplasty and stenting. After stenting, only one patient was left with significant vessel lumen stenosis (50%). Three patients experienced procedural TIAs, and there were no procedural strokes. One patient developed a new intimal flap, resulting in termination of the procedure. At mean follow-up of 14.6 months, two patients experienced angiographic occlusion of the treated vessel (one at 22 days and the other at 3.4 months). One was asymptomatic, while the other experienced a stroke contralateral to the treated side. Two patients experienced recurrent ipsilateral Transient Ischemic Attacks, at 2.7 months and 12 months, respectively. The use of endovascular stents in patients with multi-system trauma can be problematic because of the need for dual antiplatelet therapy, often for several months, in patients at high risk for bleeding. BCVIs are dynamic lesions and both treated and untreated injuries can either heal or progress. Most authorities recommend obtaining follow-up imaging after 7-10 days in patients with BCVI, since this appears to frequently influence management. As an example, Biffl et al. reported the results of follow up imaging at 7-10 days in 114 patients with carotid BCVI and 79 patients with vertebral BCVI. 57% of grade 1 and 8% of grade 2 injuries healed, allowing cessation of antithrombotic therapy. 8% of grade 1 and 43% of grade 2 lesion demonstrated progression, requiring referral for endovascular management. Patients with grade 3 and 4 injuries, however, rarely showed much change, remaining stable 93% and 82% of the time. Interestingly, in our patient, both healing and progression was seen in different vessels, with the symptomatic left carotid near-occlusion demonstrating significant healing; and the right carotid BCVI demonstrating progression from a grade 2 to a sizeable grade 3 injury, requiring referral for endovascular management. No prospective, randomized controlled trial has validated a policy of aggressively screening blunt trauma patients for BCVI. Many non-randomized studies, including the previously mentioned studies by the Denver group, however, strongly suggest a large reduction in the risk of stroke when asymptomatic patients with BCVI are treated with antithrombotic agents. In a more recent study by Schneidereit et al., 8-channel mdCTA was used to screen patients with prospectively identified risk factors for BCVI. 170 patients were screened over a year and the prevalence of BCVI rose from 0.17% to 1.4%, while, more significantly, the BCVI related stroke rate as well as BCVI-specific mortality dropped to 0% from 67% and 38% respectively. While there may significant expenditure with the widespread use of screening for BCVI, the increasing use of whole- body mdCTA contrast imaging with a single spiral acquisition and a single contrast injection means that less expenditure may be required for dedicated screening for BCVI. Screening for BCVI may be cost-effective even when DSA is used to screen for BCVI. In the study by Cothren et al., 187 patients with asymptomatic BCVI were detected, preventing 32 strokes in the authors' estimation. The authors concluded that at $6500 per DSA, the expense per stroke avoided was about $154,000 and that screening with DSA was therefore cost-effective.

cerebrovascular trauma, brain ischemia, carotid artery diseases, craniocerebral trauma, spinal injuries

PMC9233227_01

Male

A 63-year-old Caucasian male was referred from a local emergency centre as an outpatient with weight loss, chronic cough and blood-stained sputum. A chest radiograph done two weeks prior showed a round opacity in the posterior left lower lobe. This was treated as a bacterial pneumonia with oral levofloxacin with symptom progression prompting representation. The patient recalled that no previous travel history had been taken. Background history included relapsed atrial fibrillation with a previous atrial ablation, on sotalol and rivaroxaban. Social history included distant cigarette use. Travel history included a work-related trip to the United Kingdom, as well as a trip to Angola six months prior, which included recreational cave-exploration activities. The patient had several months of chronic fatigue and headache, a non-productive cough and intermittent fever. This led to multiple primary care visits and repeated sputum testing for tuberculosis (TB) with negative results. More recent symptoms included unintentional weight loss of more than 10 kg and anorexia for 4 - 6 weeks, progressive chronic headaches without visual disturbance, 2 weeks of streaky haemoptysis and night sweats. No reported skin lesions, or urological or gastrointestinal symptoms. The initial outpatient examination revealed an acutely unwell, afebrile, cachectic male patient. On general inspection, there was no clubbing, pallor or lymphadenopathy. Chest findings were unremarkable, except for a respiratory rate of 22 bpm (without hypoxia). On neurological examination, no nuchal rigidity or papilledema was present. The patient was admitted to the hospital from the outpatient clinic and isolated in the medical ward pending an infectious disease screen. A repeat radiograph showed a well-defined mass in the posterior basal region of the left lower lobe. On biochemistry, the white cell count was elevated at 9.92 x 109 (3.9 - 9.8 x109) with a normal haemoglobin, and renal and liver function. Sputum for acid-fast bacilli and TB Gene Xpert was negative. Two HIV 4th generation ELISA tests were non-reactive. Computed tomography (CT) showed a lobulated mass of 38 x 44x42 mm in the posterior basal segment of the left lower lobe, abutting the pleural space. Features included a hypodense lesion with necrotic areas and an inferior pleural-based nodule of 21 x 20x25 cm and no cavitation. Sub-centimetre pre-carinal lymph nodes of 5 x 7 mm and mild central bronchiectasis were noted. Imaging of the brain with a contrast CT was normal. The presumptive diagnosis was that of a malignant lung mass with superimposed infection, however, pulmonary TB and atypical infections needed to be excluded. The patient developed an in-hospital fever of 38.5 C and neck stiffness with severe headaches after 72 h in the hospital. The rest of the neurological examination, including fundoscopy, was normal. A repeat CT brain was normal, showing no evidence of raised intracranial pressure or a space-occupying lesion. A lumbar puncture (LP) was performed for cerebrospinal fluid (CSF) collection and empiric antimicrobial therapy was started with ceftriaxone pending the results. The opening pressure was 49 cmH2O. Results of the lumbar puncture was total white cells = 560 cells/uL, polymorphs = 0 cells/uL, mononuclear cells = 560 cells/uL, total protein = 1115 mg/L (140 - 450 mg/L) and glucose = 2.7 mmol/L (2.2 - 3.9 mmol/L). The following day, a fine needle aspiration biopsy (FNAB) was performed on the pulmonary lesion with rapid onsite cytology (ROSE). The pathologist detected numerous fungal yeasts with budding, which were strongly positive for mucin, and positive on PAS and Grocott stains, suggestive of Cryptococcus species. Cryptococcal latex agglutination test (CLAT) was positive on serum and CSF. Microbiological culture of the lung mass, blood culture and CSF confirmed Cryptococcus gattii species and a diagnosis of disseminated cryptococcal disease was made. The patient was commenced on induction amphotericin B (AmBd) and fluconazole 400 mg daily, in discussion with an infectious disease specialist from the nearest Tertiary centre. The ophthalmological and urological assessment was normal. Subsequent fungal cultures detected Cryptococcus gattii species from the pulmonary lesion, the CSF and blood culture. The patient experienced significant drug-related toxicities due to the AmBd, including renal failure up to 285 micromol/L (45 - 90 micromol/L), hypokalaemia and hypomagnesaemia) which was managed with aggressive fluid rehydration and intravenous (IV) electrolyte replacement. During the induction phase, thrombophlebitis was managed initially with peripheral access and subsequently with central venous access. Intractable headaches occurred within the first 15 days, leading to near-daily LPs and opioid analgesia. Transfusion rigors were managed with IV paracetamol and a reduced rate of the AmBd and fluid rehydration. Ongoing monitoring for drug interactions between fluconazole and sotalol was continuous cardiac monitoring and measurement of QTc. Ongoing intolerance by day seven, prompted a Section 21 application for Liposomal Amphoteracin B (LFAmB) and oral flucytosine (5-FC) with the South African Health Products Regulatory authority (SAHPRA). This application took nearly 10 days for approval, with an additional four days for the arrival of the LFAmB from the supplier. The patient had completed approximately two weeks of interrupted Amphoteracin B and fluconazole therapy when the LFAmB was commenced. The LFAmB was better tolerated by the patient, but there were ongoing problems with renal impairment, cholangitis and transfusion reactions, requiring discontinuation for up to 48 h at a time. The patient also experienced oesophagitis and vomiting, related to the pill burden of flucytosine at a dose of 6000 mg per day (12 tablets per day in divided doses every 6 h), which was managed with pantoprazole and metoclopramide. Recurrent anaemia required the transfusion of packed RBC every two weeks. After a protracted hospital stay with treatment interruptions and treatment-related complications, the patient completed six weeks of induction therapy and was successfully discharged home. Treatment comprised of induction with AmBd+fluconazole and later LFAmB + 5-FC totalling six weeks. Repeat Chest CT at the end of induction, demonstrated a reduction in the size of the pulmonary mass to 30 x 32x33 mm. The creatinine remained mildly elevated at 105 micromol/L (45 - 90 micromol/L), but all other biochemical parameters had returned to normal. All symptoms had resolved on discharge. The consolidation phase of treatment was oral fluconazole 400 mg daily for 8 weeks, with a biochemical and clinical review every two weeks, followed by maintenance phase treatment of fluconazole 200 mg daily for 6 months, with a monthly review. At the 6 & 12- month review, no relapse occurred and the CT chest only had a residual pulmonary nodule that will be followed annually.

aids, acquired immune deficiency syndrome, aki, acute kidney injury, ambd, amphotericin b deoxycholate, cdc, centre for disease control, clat, cryptococcal latex agglutination tests, ct, computed tomography, cryptococcus gattii, disseminated, ecg, electrocardiogram, elisa, enzyme-linked immunosorbent assay, fnab, fine needle aspiration biopsy, hiv, human immunodeficiency virus, icp, intracranial pressure, immunocompetent, kg, kilogram, lfamb, lipid-formulation amphoteracin b, lp, lumbar puncture, morbidity, pas, periodic acid-schiff, qtc, corrected qt time on electrocardiogram, rbc, red-blood cell, rose, rapid onsite cytology examination, sahivsoc, southern africa hiv clinicians society, tb, tuberculosis, toxicity

PMC9340840_01

Female

The subject of this case report and her parents were informed that the data concerning the case would be submitted for publication and provided consent. A 15-year-old United States of America Gymnastics (USAG) level 9 gymnast presented with right hamstring pain after regular practice. She had been diagnosed with isolated GHD at age 4 and treated with growth hormone replacement therapy until age 14. After cessation of the HGH intervention, she continued to have normal physical growth, as indicated by records from her pediatric endocrinologist. She had delayed menarche at 16 years and had a history of secondary amenorrhea despite normal weight for her age. Six months before presentation, she experienced the insidious onset of dull, aching pain in her right hamstring, near the junction of the thigh and buttocks, that was believed to be the result of a chronic hamstring strain. The pain increased gradually over a year and was relieved with rest, massage, and dry needling. Two days before presentation, she felt a "snap" and pain while performing a switch leap during regular practice. She had sharp localized pain in the proximal hamstring with walking and sitting. Upon physical examination, the subject had tenderness over the ischial tuberosity and painful restriction of right hip flexion, especially with knee extension in this position. Although radiographs were normal, computed tomography showed an asymmetric 6-mm widening in the right ischial tuberosity epiphysis compared with the other side (Figure 1). Magnetic resonance imaging of the pelvis showed edema of the ischium near the origin of the hamstring tendon at the fracture site (Figure 2). She was diagnosed with a Type 2 avulsion fracture of the ischial tuberosity (displacement of 0-2 cm) according to the classification system proposed by McKinney et al. She chose nonoperative treatment and was subsequently treated with rest, ice, and non-weightbearing ambulation with crutches. Her serum growth hormone level (327 pmol/L) was within normal range. Radiography indicated a bone age of 13 years, but her chronologic age was 15 years 4 months. The subject was advised to continue to be non-weightbearing until she was pain-free with radiographic fracture healing, which occurred three months after the injury. The subject underwent rehabilitation with the athletic trainer. Starting three months post injury, her rehabilitation was focused on gaining hip range of motion for two weeks followed by strengthening of hip, lower extremity and core muscles, and gait training. Patient also underwent training for proprioception, running, and sprinting. She was then allowed to begin vault training at four months, and running at five months, after her injury. She could perform switch leaps and splits seven months after injury. She participated in a USAG level 9 competition 12 months after the initial injury. At a three-year follow-up, she continued to practice gymnastics and compete in level 10 USGA competitions without any symptoms related to her avulsion fracture of the ischial tuberosity.

avulsion, gymnast, ischial tuberosity, nonoperative treatment

PMC2822819_01

Female

In this very rare case of 43 years-old female, refugee from Kosovo, was admitted as an outpatient to the Department of pulmonary diseases in 2003. because of erythema nodosum and dry cough. She was without fever during admission, smoked up to 30 cigarettes daily and was healthy most of her life. She suffered only of head injury and face trauma acquired during the war (during 1995.) by shelling. Three years before the outbreak of erythema nodosum, two small red subcutaneous tubercles were found on her forehead, in the left eyebrow area. The biopsy test showed chronic granulomatous infection that was described as a reaction to a foreign body. Laboratory analysis revealed ESR 37 (normal range 0-15 mm/h), WBC 9.030/mm3, RBC 3,7/mm3 and C-reactive protein 9.8 mg/L, AST 60 U/L, ALT 76 U/L, GGT 86 U/L, AP 79 U/L, while urea, creatinine, calcium in serum and 24 hours urine were within normal range. Angiotensin-converting enzyme (ACE) was elevated 108 U/l (normal 0-56). Tuberculosis test (2 IU) was 14 mm of induration in diameter. The result of spirometry measured 85% vital capacity (VC), 94,5% of forced vital capacity (FCV), 77% of forced expiratory volume (FEV),82,4% of forced expiratory volume in first second (FEV1) and FEV1/FCV 87,2% from referral values. Arterial blood gases were pO2 9,8 kPa, pH 7.45 and diffusing capacity of carbon monoxide (DLCO) 72%. Chest radiogram showed fibroindurative changes in the area of both upper lobes with lung traction. In upper lobes subpleurally and more to the left there was a focus with <<round glass>> pattern. Mycronodular interstitial infiltrations were found bilateral on chest radiogram with fibrous changes of hilus (Figure 1). High-resolution computed tomography (HRCT) of thorax showed interlobar and peribronchial thickness in upper lung lobes with subpleural fibroses and deformation of bronchi. There were minor areas of fresh infiltrations in apices on both sides, suggesting a new pathological process. There was a cavity 8 x 12 mm large in apical-posterior segment of the upper left lobe. Hilar lymph nodes were more then 2 cm in diameter, some of them had fibrous changes and some were calcificated. High resolution thorax CT with hilar lymph nodes enlargement and granulomas with reticular interstitial pattern in the lower respiratory part is present on the Figure 2(a, b). Fiberbronchoscopy revealed slightly edematous and hyperemic mucous membrane of bronchi on both sides, while purulent secrete was seen in bronchus left upper lobe and in lingul. The routine bacteriological culture of bronchial aspirate was sterile. Direct smear microscopy examination of the sample for the presence of acid-resistant bacilli by using Ziehl-Neelsen method was negative. Pathohistological findings of lung (Figure 3) and bronchial walls biopsy showed chronic granulomatous infection without caseous necroses. In bronchoalveolar lavage (BAL) CD4+ lymphocytes and alveolar macrophages were predominantly. The ratio of CD4+ and CD8+ lymphocytes was 5.5:1. All relative findings, including pathohistological examination indicate lung sarcoidosis. The patient was stared corticosteroid therapy (out of hospital-out-hospital patient) according to usual scheme for lung sarcoidosis, prednisolone 1 mg/kg body weight. Three weeks after introducing corticosteroid therapy, culturing the sample on Lowenstein-Jensen solid medium by using liquid culture method MGIT (Mycobacterium Growth Indicator Tube), Mycobacterium tuberculosis was isolated. The sensitivity test was performed by using the proportion method on solid Lowenstein-Jansen culture according to CLSI (Clinical and Laboratory Standards Institute) standards. All the four routine tested antituberculotics (isoniazid, rifampicin, ethambutol and streptomycin) responded well to sensitivity test and the susceptibility of pyrasinamide was confirmed in the referral national laboratory. A previous diagnosis was corrected to microbiological confirmed lung tuberculosis. Corticosteroid therapy was excluded after three weeks of treatment and antituberculotic therapy (ATL) was introduced. The patient was treated with rifampicin 600 mg, isoniazid 400 mg, etambuthol 1200 mg and pyrazinamide 1500 mg, on a daily basis during two months, after pyrazinamide was excluded and triple therapy was continued for one month. After three months from the beginning of ATL treatment, ethambuthol was excluded and rifampicin and isoniazid were continued for the next 3,5 months (entirely 6,5 months) with controlling regular hematological and biochemical analysis. The patient was in good clinical condition. However, ACE was continuously raised, 80-100 U/l. After four months of ATL therapy chest radiogram was made showing complete regression of tiny infiltrates in both upper lobes and small regression of nodular infiltrates which was described as unsatisfactory. During ATL therapy new nodes on face and nose, similar to those on the forehead appeared (Figure 4). The biopsy of skin changes was made and the pathohistological confirmation for sarcoidosis is evident on the Figure 5. Antituberculotic therapy was preceded for next two months until negative mycobacterium culture in new collected sputum was obtained. In course of the last month of TB therapy novel bigger, firm nodes appeared on ear lap. Pathohistological tests indicate sarcoidosis of the skin. Microbiological examinations of the skin substrata in direct microscopy and polymerase chain reaction (PCR) with specific primer had not confirmed presence of M. tuberculosis. After 6 months of the beginning of ATL treatment, the patient received corticosteroid (prednisolone 40 mg daily) and colchicine therapy (200 mg daily) for lung and skin type of sarcoidosis. After four months of the corticosteroid therapy chest radiogram showed almost complete regression of nodular infiltrates in lung parenchyma. The skin changes were considerably smaller, dry on surface, and there were no new lesions on the skin while ACE was in normal rate (30 U/l).

Thorax CT with hilar lymph nodes enlargement.

PMC8636697_01

Male

Case 1 was a 63-year-old man who presented with a 4-month history of productive cough and started to deteriorate after having a fever for a week. The patient had an 8-year history of cigarette smoking, and his father had been diagnosed with lung cancer. Repeated antibiotic treatment had been used since he started coughing, which produced a small amount of yellow sputum, and on January 6, 2018, he was diagnosed with community-acquired pneumonia. Unfortunately, his condition did not improve, and he gradually developed persistent right chest pain and shortness of breath after activity. He was admitted to our hospital on March 19th, and chest computed tomography (CT) showed an irregular solid nodule in the anterior segment of the upper lobe of the right lung and lamellar density shadows in the lower lobe of the right lung (Figure 1A and B). A bronchoscopic examination showed that the bronchi were unobstructed, slightly congested and had a mild amount of purulent exudate. A transbronchial lung biopsy (TBLB) was performed in the posterior basal segment and dorsal segment. Galactomannan (GM) of bronchoalveolar lavage fluid (BALF) was 1.068. No fungus, interstitial fibroblastic proliferation, incrassation or fibrosis was seen in the lung tissue biopsy, but acid-fast staining and PAS negativity suggested organizing pneumonia; the patient was then diagnosed with organizing pneumonia. The patient was started on prednisone 30 mg orally once a day on March 27, and he was discharged after his symptoms of cough, chest pain and shortness of breath had gradually improved. He took prednisone as prescribed after discharge. However, his condition worsened with a fever that developed on May 8, and he was admitted to the hospital on May 15. On examination, his body temperature was 39.6 C, and his superficial lymph nodes were not swollen. A small moist rale was detected in the lower right lung. Routine blood tests revealed a leukocyte count of 15.85x109/L, a red blood cell count of 4.18x1012/L, a hemoglobin level of 110.70 g/L, and a neutrophil percentage of 83.0%. His hypersensitive C-reactive protein was 171.23 mg/L, the erythrocyte sedimentation rate was 70 mm/h, and serum procalcitonin was 0.707 ng/mL. The serum was positive for AIGAs. His plasma HIV antibody, blood culture, beta-D-glucan, GM and Cryptococcus latex agglutination tests were all negative. The lesion in the right upper lobe was still present, and the high-density lesions in the posterior and outer basal segments of the lower lobe of the right lung were slightly smaller on May 16. A percutaneous lung biopsy was performed on May 21, 2018. The right lower lung biopsy showed a chronic inflammatory lesion but no granuloma or neoplastic lesion. Immunohistochemistry with PAS and acid-fast staining showed that the chronic inflammatory lesions were negative. After the admission of the patient and after considering an infection in the lung, the dosage of prednisone was gradually reduced and ultimately discontinued on May 24. The patient was successively treated with imipenem-cilastatin, voriconazole, compounded sulfamethoxazole and linezolid but still had a fever, with the highest temperature being 39.1 C. On May 30, his symptoms, including difficulty breathing, gradually worsened, and he developed type I respiratory failure. Therefore, he was transferred to the intensive care unit (ICU) for endotracheal intubation for salvage treatment. After admission to the ICU, the patient had scattered herpes in his right anterior chest wall and posterior chest wall. Herpes zoster was clinically diagnosed, and acyclovir sustained release tablets were given as oral antiviral treatment. T. marneffei was cultured from lung biopsy tissue performed on June 4, and chest CT showed growth of the two lung lesions (Figure 1C and D). Liposomal amphotericin B was started on June 6 as an antifungal agent; the patient's temperature returned to normal, and the patient's cough and shortness of breath improved after 3 days. He was transferred back to the general ward. Unfortunately, liposomal amphotericin B was discontinued due to progressive renal impairment and was replaced by voriconazole 0.2 g twice daily starting on June 19. He was discharged after a chest CT showed that the lung lesions were significantly smaller (Figure 1E and F) on June 25. He was started on a course of itraconazole after discharge. He developed another episode of cough and fever with a maximum temperature of 40 C on December 25, 2020. A chest CT showed that the nodules in the right upper lobe of the lung were significantly larger and that the lesions in the lower lobes of both lungs were stable on January 15, 2019 (Figure 1G and H). Bronchoscopy revealed that the mucosa in the anterior segment of the right upper lobe had lost its normal structure, and the lumen was narrow. The pathology from the TBLB performed in the anterior segment of the right upper lobe showed primary adenocarcinoma (Figure 2A-D). The patient was confirmed to have right lung adenocarcinoma and TSM. However, he was discharged after refusing treatment and died in February 2019.

talaromyces marneffei, adult immunodeficiency, anti-interferon-γ antibodies, lung adenocarcinoma

PMC8636697_02

Male

Case 2 was a 57-year-old male from Guangxi Province who presented with cough and fever for a week. He had a 40-year history of smoking, and his father had nasopharyngeal cancer. He was admitted to the hospital with a temperature of 38.5 C but with no abnormalities in the other physical examination parameters on January 22, 2018. His white blood cell count was 15.68x109/L, hemoglobin was 91.90 g/L, and neutrophil percentage was 74.0%. His serum albumin was 27.5 g/L. His hypersensitive C-reactive protein was 163.71 mg/L. HIV antibody testing was negative. No abnormalities were found in renal function, blood glucose, autoantibody spectrum or T lymphocyte subsets. A chest CT showed multiple nodules in the upper lobe of the left lung, a mass in the left hilar lung and a mass in the middle lobe of the right lung with mediastinal and left hilar lymph node enlargement (Figure 3A and B). Fiber bronchoscopy revealed that the trachea, main bronchus and bronchi segmentales were unobstructed, and no necrotic material or tumor was observed. TBNA of the right paratracheal lymph node and subcarinal lymph node was conducted. The pathology of those lymph nodes revealed purulent exudate and hemorrhage. He was given cefoperazone tazobartan at 2.25 g every 8 hours and vancomycin at 500 mg every 12 hours a week, but the patient had a recurrent high fever. A chest CT on January 31 showed that the pulmonary lesions had increased in size (Figure 3C and D). T. marneffei was isolated from TBNA tissues on February 4 (Figure 4A and B). Thus, voriconazole at 200 mg orally every 12 hours and amphotericin B at 30 mg/day intravenously were prescribed. However, amphotericin B was discontinued due to the development of renal impairment noted on February 13. The lung lesions were smaller 2 weeks later on February 22, 2018. He was discharged with voriconazole orally 200 mg every 12 hours. However, he repeatedly developed a cough and increased sputum in August 2018, and AIGAs were identified in his serum. There were no intracavitary neoplasms seen during tracheoscopy. TBLB was performed in the posterior segment of the upper lobe of the left lung, and TBNA of the subcarinal lymph node was repeated. TBLB revealed acute and chronic inflammation of the mucous membranes accompanied by local hemorrhage, but no cancer cells were observed. No tumor cells were found in the TBNA. We considered that the patient might have T. marneffei combined with a nontuberculosis mycobacteria (NTM) infection. Therefore, rifampin at 450 mg/day, ethambutol at 750 mg/day, moxifloxacin at 400 mg/day, and clarithromycin at 500 mg/day were started. Meanwhile, cefoperazone tazobartan 2.25 g every 8 hours + linezolamide 0.6 g every 12 hours and voriconazole 200 mg every 12 hours were used for antibacterial treatment and antifungal therapy, respectively. After one week, cefoperazone tazobartan and linezolamide were discontinued, and chest CT on August 27, 2018 showed that the lesion in the upper lobe of the left lung was larger, but the mass of the left hilum was smaller (Figure 3E and F). The patient was discharged after his temperature gradually recovered. After discharge, he continued anti-NTM and antifungal therapy. However, he presented with left-sided chest pain without fever in October 2018. A chest CT showed that the lesion in the upper lobe of the left lung had enlarged, and on November 6, 2018, the mass of the left hilar was the same as before (Figure 3G and H). An ultrasound-guided lung puncture biopsy was performed on November 12. The pathology was confirmed as infiltrating adenocarcinoma, and no epidermal growth factor receptor mutation was observed (Figure 5A-D). The anti-TNM drugs were discontinued. A positron emission tomography/computed tomography showed lung cancer in the upper lobe of the left lung with metastasis in the lower lobe of the left lung, the left hilum and mediastinal lymph node, the left 3rd and 4th ribs, and the cervical, thoracic and lumbar spine. The final diagnosis was confirmed as primary lung adenocarcinoma (cT4N2M1 stage IV) with metastasis to the lower lobe of the left lung, ribs, thoracic and lumbar vertebrae and a T. marneffei infection. He took itraconazole capsules orally at 100 mg twice a day for antifungal therapy but refused chemotherapy and chose icotinib for antitumor treatment. We did not recommend this treatment because his EGFR status was negative, and he died in April 2019.

talaromyces marneffei, adult immunodeficiency, anti-interferon-γ antibodies, lung adenocarcinoma

PMC3212969_01

Female

A 26-years old lady presented with progressive weakness and fever for 3 months, and was found to have pancytopenia (hemoglobin 6.5g/dl, total leukocyte count 2.8x109/l, neutrophils 12% and lymphocytes 88% and platelet counts 13x109/l). Bone marrow biopsy revealed cellularity of 5%. She was diagnosed severe aplastic anemia and had HLA matched sibling. She underwent allogenic peripheral blood stem cell transplantation (PBSCT) from the matched sibling donor, with conditioning regimen including fludarabine 30mg/m2 for 6 days (from day -10 to day -5) and cyclophosphamide 60mg/m2 for 2 days (day -6 and day -5). The CD34+ cell dose given was 4.8x106/kg. Graft versus host disease (GVHD) prophylaxis included horse anti-thymocyte globulin (ATGAM Pfizer) 30mg/kg/day for 4 days (day -4 to day -1), methotrexate (10mg/m2) on day+1, +3 and +6, and cyclosporine 100mg twice daily intravenously from day -1 with dose adjusted according to plasma cyclosporine levels (between 150-300ng/ml). She was given oral levofloxacin 500mg daily, fluconazole 400mg daily, aciclovir 400mg twice daily and trimethoprim-sulfamethoxazole 480 mg q12 hours on alternate days as prophylaxis. She developed fever on day +4 of transplant and was started on piperacillin plus tazobactum (4.5g i.v. q 6 hours) and amikacin (750mg i.v. q 24 hours). Chest radiograph was normal, and blood and urine cultures were sterile. She became afebrile on day +7. She engrafted on day +10 (absolute neutrophil count >0.5x109/l and unsupported platelet count > 20x109/l). On day + 17 she developed fever with dry cough and left sided chest pain. Computerized tomography (CT) scan of the chest showed left upper lobe consolidation with surrounding ground glass opacity. (Figure 1) Oral voriconazole (400mg twice daily on the first day followed by 200mg twice daily) was emperically started and fluconazole was stopped. Bronchoalveolar lavage showed the presence of acid fast bacilli suggestive of mycobacterium tubercular infection (Figure 2). On day +19 she was started on anti-tubercular therapy (ATT) (isoniazid 300mg, rifampicin 450mg, ethambutol 1000mg and pyrizinamide 1500mg daily). Considering high risk of fungal infection and interactions of voriconazole with anti-tubercular drugs, lung biopsy was performed 3 days later, which revealed broad aseptate hyphae branching at a right angle suggestive of mucormycosis (Figure 3). She was started on liposomal amphotericin B (3mg/kg/day) and voriconazole was stopped. With continued liposomal amphotericin B along with anti-tubercular drugs, the lesion started decreasing in size, and surgical resection was deferred. Patient became afebrile 2 weeks latter and follow-up CT scan and sequential chest radiographs showed a significant reduction in the size of the lesion. On day +28 of transplant, patient developed renal dysfunction (serum creatinine 1.8mg/dl) and peripheral smear showed schistocytes. Cyclosporine was stopped in view of drug induced microangiopathy and mycophenolate mofetil 1000mg twice daily was started which she tolerated well. She was continued on liposomal amphotericin B for 8 weeks and had nearly complete resolution of lung lesion. ATT was stopped 6 months later. Mycophenolate mofetil was stopped 18 months post transplant. She did not develop acute GVHD but had onset of limited chronic skin GVHD in 7th month which was controlled with steroids (prednisolone 1mg/kg/day for 4 weeks and then in tapering doses for next 2 months), without reactivation of tuberculosis or mucormycosis. Patient is now 2 years post stem cell transplant with hemoglobin 12.5g/dl, total leukocyte count 8.6x109/l and platelet counts 192x109/l, with no sequele related to chest infection or GVHD. Mucormycosis is rare in allogenic transplant recipients with an incidence of 1.9% reported in a series of 263 patients. The incidence of mycobacterial infection among stem cell transplant recipients has been estimated to be 0.6%-9.7% in United States but the incidence in developing countries may be even higher where tuberculosis is endemic. Our case highlights certain important facts. First, a high index of suspicion of tuberculosis should be kept in patients with upper lobe consolidations. Second, invasive fungal infections, particularly aspergillosis and rarely mucormycosis may occur in post transplant immunocompromised state and distinction between the two is very important as treatment differs. Voriconazole is the treatment of choice for aspergillus but is ineffective against mucormycosis which responds to amphotericin and may even require surgical debridement. Posaconazole has also been shown to be effective against mucormycosis. Thirdly, drug-to-drug interactions are very common when antitubercular drugs (e.g. rifampicin) are being used with antifungal (voriconazole) and immunosuppressive drugs (cyclosporine). Infection has to be treated adequately and simultaneously immunosuppression has to be maintained to prevent graft rejection. Bronchoalveolar lavage and lung biopsy both helped in detecting the causative organisms in our case leading to appropriate treatment. Both tuberculosis and mucormycosis have been reported as late complications following transplantation but our patient developed these infections early after transplantation. Rifampicin increases the metabolism of cyclosporine and so dose of latter has to be modified according to plasma levels. Toxicity of multiple drugs, particularly affecting renal and hepatic functions, can occur and requires careful monitoring of these organs. With increasing number of patients undergoing transplantations in developing countries, the endemic diseases also need to be considered while looking for the usual infections in immunocompromised post transplant recipients and mixed infections are a possibility. Diagnosis of mixed infections is challenging and requires a high index of suspicion and adequate management for better outcome, particularly when there is an emerging trend of fungal infections in patients with pulmonary tuberculosis.

Axial CT chest showing left upper lobe consolidation with surrounding ground glass opacity (shown by arrow).

PMC6597736_01

Female

A 53-year-old Japanese female with a history of cervical cancer and vocal cord papilloma visited to our hospital for evaluation of three weeks history of progressive dry cough and dyspnea. She was a past smoker (1 pack/day for 8 years) and had no history of environmental exposure. Although she was treated with azithromycin as an outpatient, she presented with right chest pain, fever and hemoptysis on three days after the first visit and admitted to our hospital. On hospital admission, her vital signs were as follows: heart rate 125 bpm, blood pressure 114/81 mmHg, body temperature 39.0 C. Percutaneous arterial blood oxygen saturation was 94% on room air and respiratory rate was 24/min. Chest examination revealed unilateral coarse crackles in the right lower lung fields. Skin rash, joint pain and swelling, muscle weakness, and other physical findings suggestive of connective tissue disease were not observed. Laboratory testing on admission showed a white blood count of 11,180/muL, hemoglobin of 14.2 g/dL and platelet count of 327,000. Erythrocytes sedimentation rate was 98 mm/h and C-reactive protein was 5.3 mg/dL. Lactate dehydrogenase, Krebs von den Lungen-6 and surfactant protein D were within the normal range. Work up for respiratory disease including sputum cultures, urinary pneumococcal and Legionella antigen were all negative. Serologic studies for connective tissue disease, vasculitis were also unrevealing. High-resolution computed tomography (CT) of the chest revealed unilateral focal consolidation with halo sign in the right lower lobe (Fig. 1A-D). Despite that ceftriaxone and minocycline were started on the first day, her clinical condition did not improve. On the third day of admission, the patient underwent flexible bronchoscopy with bronchial wash and TBLC from the right lower lobe B9 and B10. The biopsy specimens of 4 mm x 5 mm size were collected by TBLC. Histological study of these specimens showed intra-alveolar fibrin balls, involving more than three quarters of alveolar space and mononuclear cells infiltration without eosinophils and formation of hyaline membranes (Fig. 2A-C), indicating AFOP. Bacterial culture was negative. After TBLC, high dose of methylprednisolone was initiated, resulting in rapid clinical improvement. On the twenty five day of admission, she was discharged home on 25 mg prednisone daily. She has remained free of pulmonary symptoms and finished taking prednisone ten months later. There was no evidence of collagen tissue disease, vasculitis, and other etiology during the disease course. We diagnosed her with idiopathic AFOP.

acute fibrinous and organizing pneumonia, cryobiopsy, cryptogenic organizing pneumonia

PMC6566467_01

Male

A 76-year-old man was referred to the hospital in September 2016, due to bilateral edema in his lower extremities and general fatigue. He had pancreaticoduodenectomy against pancreatic cancer in November, 2015, and had Tegafur, Gimeracil, Oteracil Potassium as postoperative chemotherapy which was discontinued because of the occurrence of pancytopenia. From April, 2016, nivolumab treatment at the dose of 0.5 mg/kg was started and continued until July, three times in total, which improved his symptoms for a certain period. However, from the beginning of September, 2016, he re-developed edema and fatigue. At visit, his serum creatinine (SCr) level increased from 0.8-0.9 mg/dL to 3.08 mg/dL, and he was hospitalized for further investigation. His past medical history was not remarkable, except for the history of treatment against lung tuberculosis in his 20's. Among his medication, rabeprazole 10 mg/day, Furosemide 10 mg/day, and spironolactone 25 mg/day were started recently. Other than that, he was taking levocarnitine 1500 mg/day and sennoside 24 mg/day. On physical examination, vital signs were unremarkable except for an increase of 5 kg in body weight in 4 months. His lungs were clear to auscultation, and bilateral pitting edema was noted in his lower extremities. His skin was dry, but no eruption nor rash were noted. Laboratory findings on admission are shown as Table 1. His SCr level was 3.08 mg/dL, and urinary protein or occult blood were both negative, although pyuria was evident without any eosinophil in urine cytology. Urinary excretion of beta2-miroglobulin and alpha1-microglubulin were high. A renal ultrasound showed hyperechoic parenchyma of bilateral kidneys without an evidence of hydronephrosis or enlargement of the both kidneys. Gallium scintigraphy showed increased gallium-67 uptake in both kidneys, which was compatible with the inflammation of AIN. A percutaneous renal biopsy was performed. Of 15 glomeruli, six were collapsed; however, no increase of mesangial matrix nor hypercellularity were represented. There was severe interstitial inflammation along with tubulitis in some parts. Among infiltrate lymphocytes, CD3+ T-lymphocytes were dominant, and infiltration over the basement membrane of CD8+ lymphocytes were seen. Some nuclei of tubular epithelial cells were variably sized, massively enlarged, irregularly shaped, and abnormally hyperchromatic occasionally. These morphological findings were indicative of those of karyomegalic changes. These epithelial cells were positive for Ki-67 in immunostaining, which suggested the regenerative changes in renal tubular epithelium. Interstitial fibrosis and tubular atrophy were observed in approximately 20% of the cortical area, according to the result of the Masson-trichrome staining. Overall, the changes represented drug-induced tubulointerstitial nephritis with karyomegalic epithelial changes. After the discontinuation of nivolumab treatment, his renal function had recovered gradually from 3.08 mg/dL to SCr level 1.84 mg/dL in 5 months. His renal function continued to partially improve, to which SCr level 1.42 mg/dL, approximately 1 year after the discontinuation of nivolumab treatment.

acute interstitial nephritis, immune checkpoint inhibitor, karyomegalic epithelial cell, nivolumab

PMC7862762_01

Unknown

In Hong Kong, it was estimated that the incidence of autism spectrum disorder (ASD) is at 5.49 per 10,000, and the prevalence rate of ASDs is at 16.1 per 10,000 for children <15 years old. According to the government's recent mental health review, ASD was the main type of mental disorders among young children, comprising >60% of caseload of the child and adolescent services in public hospitals in 2015-2016, and the number of children with ASD seeking medical services from public hospitals had doubled between 2011 and 2016. Generally, the government has provided various support from early diagnosis to medical intervention and education. Through allying various institutions such as child assessment center, social welfare department, and education bureau (EDB), the government aims to improve the well-being of children and adolescents through developing a holistic support system. According to the EDB, the services for children with ASD cover assessment and identification, training and intervention, family support services, home-school cooperation, cross-sector collaboration, public education, and counseling and consultation. Many of these services are in "face-to-face" format, and the waiting time to receive any assessment through certified governmental agencies is, on average, 13-19.6 months. In January 25, 2020, the Hong Kong Government had raised the response level under the "Preparedness and Response Plan for Novel Infectious Disease of Public Health Significance (the Plan, hereafter)" to the emergency level. This plan was developed after the SARS epidemic in 2003 to allow Hong Kong to be much more prepared for future epidemics. The main goal of the plan is to ensure that a well-planned and fully integrated emergency management response can be implemented by all bureaus of the Hong Kong government with the support of the multisectors in the society. The plan includes three response levels: alert, serious, and emergency. These response levels are based on risk assessment of the novel infectious disease that may affect Hong Kong and its health impact on the community. Emergency response level corresponds to a situation where the risk of health impact caused by the novel infection on local population in Hong Kong is high and imminent. Generally, it depicts a high risk of serious human infections caused by the novel infectious agent in Hong Kong, and serious infections may be widespread. It generally applies to situation when there is evidence or imminent risk of sustained community level outbreaks. Accordingly, since late January, several preventive public health measures including surveillance, quarantine, social distancing, the use of face masks, and school closures have been implemented to suppress the transmission of COVID-19. On January 25, the education bureau announced the deferral of class resumption after Chinese New Year holiday for all schools, which marked the beginning of school suspension in response to the COVID-19 development in Hong Kong until further notice. Many nonurgent health care and social services were delayed or reduced. Previous studies found that the outbreak of a novel virus was associated with the onset of psychiatric symptoms in mentally healthy individuals, exacerbated conditions of individuals with mental illness, and elevated burden for caregivers. The anxiety, fear, and stress experienced by the general public was associated with strong sense of insecurity, triggering off widespread panic buying of food and other basic necessities in at least two international cities. The prolonged closure of public services, quarantine, and impaired economic and social activities at the later stage further worsen the situation. A worry for further spread of COVID-19, distrust toward the government in their ability to contain the outbreak, anticipated economic downturn, and increased unemployment rate are associated with intensified negative emotions in the society. Under such a problematic situation, parents had to handle multiple stressors simultaneously. Many parents struggle to secure enough resources, such as food and masks, to ensure home schooling of their children, taking care of the elderly, and going to work without contamination of their household. Limited data in the United States suggested the COVID-19 outbreak negatively affected vulnerable families more, including lower-income families and families of children with ASD. Under the COVID-19 outbreak, families of children with ASD might face a particular difficult situation for at least three reasons. First, because of the ASD condition of their children, the parents might not be able to obtain enough tangible necessities. In particular, the closure of schools and child day-care centers shifted back the day-to-day caretaking role back to the parents while they were running here and there to fetch all kinds of daily necessities. Having limited patience and various vulnerabilities, children with ASD could not line up in the queue for long. As a result, these families often failed to get the necessities. The constant lack of resources causes stress and tension within families of children with ASD. Second, numerous research already showed that parents of children with ASD often suffered from elevated stress, lowered quality of life, and heightened psychological distress. Third, because of the rigidity nature of people with ASD, the heavily disrupted daily routine has negatively affected their well-being. Realizing the needs of parents of children with ASD, social service professionals fight against the odds to offer continued support and services for these families. Theoretically, social service professionals underwent the processes of resiliency as service providers. Resiliency of social service professionals can be conceptualized as the dynamic process in which social service professionals work with service users in encompassing positive adaptation within the context of significant adversity. In the time of COVID-19, Hong Kong social service professionals adopted a strength-based approach to mobilize community resources and empower service users to address their needs. It is necessary to document and summarize Hong Kong social service professionals' innovation, practice wisdom, and lessons learned for at least four reasons. First, "COVID-19 is not the first virus to threaten humanity, and it will not be the last". The Hong Kong social service professionals' experiences can help to develop the practice guide and conceptual model for the future. Second, studies on social service professionals' view on the families of children with ASD under the period of COVID-19 pandemic are scarce. The document fosters the understanding of experiences of the families of children with ASD and serves as an expression of concern of academia toward these families in the time of uncertainty. Third, some service users mistakenly perceived that social service professionals might not be able to provide any kind of services in the period of COVID-19 outbreak. Our documentation helps to make social service professionals' work and the related challenges more visible and accountable. Fourth, up to date, parenting-related studies under the period of COVID-19 pandemic only present scholars' views [e.g., ]. Little is known from frontline practitioners' perspectives. The current study can address this gap. Based on a focus group interview with the social service professionals serving families of children with ASD, the current study aims to address the following research questions: What are the needs of families of children with ASD and other developmental issues under the period of COVID-19 pandemic? What are the services provided to families of children with ASD and other developmental issues under the period of COVID-19 pandemic? What are the challenges social service professionals encountered? What are the solutions to these challenges?

covid-19 pandemic, hong kong, children with autism or development delays, service needs, social service providers

PMC6302579_01

Male

A 22-year-old man visited a sexual health clinic for symptomatic urethritis with purulent urethral discharge and pain while urinating. Clinical examination showed no other signs or symptoms, including fever. His last sexual intercourse (including orogenital contacts) occurred 3 weeks before with his stable, unique, asymptomatic male partner. Both men reported that they had not had any other sexual partner before and since their first intercourse together <1 year before. Meningococcal vaccination statuses were unknown. Results of nucleic acid amplification testing for N. gonorrhoeae and Chlamydia trachomatis in urine, pharyngeal, and anal samples, and serologic testing for HIV, hepatitis B and C viruses, and syphilis were negative for the patient and his partner. Urethral culture yielded growth with oxidase and Gram stain results consistent with gonococcus, but matrix-assisted laser desorption/ionization time-of-flight mass spectrometry identified N. meningitidis (isolate TUR1). A pharyngeal swab specimen was collected from the partner of the patient to identify a potential source of contamination. This specimen also grew N. meningitidis (isolate CHA1). Isolates were nongroupable by slide agglutination serogrouping. We purified genomic DNAs by using a NucleoSpin Tissue Kit (Macherey-Nagel, http://www.mn-net.com), prepared DNA libraries by using the Nextera Library Construction Kit (Illumina, https://www.illumina.com), and sequenced these DNAs by using a MiSeq sequencer (Illumina), which yielded 62x coverage for isolate TUR1 and 66x coverage for isolate CHA1. We assembled the genomes of CHA1 and TUR1 isolates by using SPAdes version 3.10.1 (http://bioinf.spbau.ru/spades), which resulted in assemblies consisting of 395 contigs for TUR1 and 636 contigs for CHA1 and yielded draft genomes of 2.19 Mb. We performed genome annotation by using the MicroScope Platform (http://www.genoscope.cns.fr/agc/microscope), which yielded 2,597 coding sequences, including protein-encoding genes and RNAs. We analyzed high-throughput sequencing data by using the PubMLST website (https://pubmlst.org) for typing the CHA1 and TUR1 isolates. These 2 isolates belonged to the clonal complex sequence type (ST) 11 and had fine-type PorA 1.5,2; FetA F1-1. DNA sequence analysis of the csw gene of these isolates showed an open reading frame of 3,114 bp that had 99.9% nucleotide identity with that of the N. meningitidis W:2a:P1.7-2,4 ST11 strain (GenBank accession no. EU164779), which was consistent with genogroup W (,). We used CSI Phylogeny version 1.4 (https://cge.cbs.dtu.dk/services/CSIPhylogeny) for phylogenomic analysis on the basis of single-nucleotide polymorphisms (SNPs) and called among core genomes of CHA1 and TUR1 isolates and 3 other ST11 N. meningitidis strains (NM3688 from Brazil [Bioproject PRJNA264543], COL-201505-31 from the United States [BioProject PRJNA324131]), and LNP27256 from France [Bioproject PRJNA215157]). Analysis showed that the CHA1 and TUR1 isolates differed by only 3 SNPs, thus demonstrating their clonal relationship. Conversely, these isolates differed by >890 SNPs from the other strains. Nucleotide sequence accession numbers for whole-genome shotgun projects have been deposited at DNA Data Bank of Japan/European Molecular Biology Laboratory/GenBank under accession nos. MULP000000001 (Bioproject PRJNA369721) and MULO000000001 (Bioproject PRJNA369166). The patient recovered quickly after receiving single doses of intramuscular ceftriaxone (500 mg) and azithromycin (1 g). His partner received a single dose of intramuscular ceftriaxone (500 mg) as a decontamination strategy. Albeit rare, N. meningitidis-associated urethritis is emerging worldwide among men (,). These infections can be highly symptomatic and mimic gonococcal urethritis. Orogenital transmission is often suspected but rarely proven. In our study, use of whole-genome sequencing strongly supported the hypothesis that the oropharyngeal carriage of N. meningitidis by the man who performed oral sex was the source of the urethritis. Moreover, whole-genome sequencing showed that the strains belonged to the ST11 clonal complex. Several studies reported nongonococcal urethritis caused by N. meningitidis ST11 in Japan and the United States (,,). These worldwide descriptions suggest that N. meningitidis S11 might represent an emerging urethrotropic clade. This case is notable because the patient had highly symptomatic urethritis without risky sexual behavior. In fact, he reported that he and his only sexual partner had not had sex with others before they met. Since 2010, several clusters of serogroup C invasive meningococcal disease have been reported among men who have sex with men, and sexual transmission is suspected to be involved (-). These infections led to an extension of the meningococcal vaccine recommendations to men who have sex with men who are engaged in risky behavior in some outbreaks areas. Our case highlights that sexual transmission of N. meningitidis should be considered for all men. Finally, although systematically collected information is limited, meningococcal urogenital infections are potentially increasing and raising public health concerns. These infections need to be monitored, and bacteriological culture of purulent exudate should always be considered when available. Also, because fidelity might be contested between partners when a sexually transmitted disease is being diagnosed, identification of meningococcal urethritis and its transmission might have a strong psychological effect on the couple.

neisseria meningitidis, st11, bacteria, clonal complex, men who have sex with men, monogamous couple, orogenital transmission, sequence type 11, sexually transmitted infections, urethritis, whole-genome sequencing

PMC8096437_01

Female

A 32-year-old female non-smoker was found to have abnormal lung shadows on a chest x-ray during an annual check-up. A computed tomography (CT) scan at the previous hospital showed a small cavitary nodule in the left upper lobe and diffuse tiny nodules throughout both lungs. The serum tuberculosis-specific IFN-gamma test was negative, and tumor marker levels were not elevated. Transbronchial lung biopsy specimens obtained bronchoscopically showed suspected miliary metastasis by a lung cancer. The patient had a slight cough and no history of respiratory disease, and her Eastern Cooperative Group Performances Status (ECOG-PS) was 0. Blood examinations demonstrated none of the significantly increased tumor markers levels (CEA 1.6 ng/mL, CYFRA 0.6 ng/mL, Pro GRP 54.5 pg/mL), but her serum amylase levels were elevated (total amylase 584 IU/L, pancreatic amylase 76 IU/L). A chest X-ray showed bilateral diffuse shadows at our hospital (Figure 1A). A CT scan revealed a 19 mm cavitary nodule in the left upper lobe and multiple small nodules with a random distribution throughout both lung fields, swollen mediastinal lymph nodes, and spinal metastasis (L4 and L5) (Figure 1B). No CT findings were detected in the salivary glands or pancreas. Magnetic resonance imaging (MRI) of the brain revealed multiple skull metastases but no evidence of brain metastasis (cT4aN2M1c, Stage IV). She underwent both transbronchial lung biopsy (TBLB) from the left upper lung and endobronchial ultrasound-guided trans-bronchial needle aspiration (EBUS TBNA) from the mediastinal lymph nodes. Hematoxylin and eosin (HE) staining revealed adenocarcinoma cells in the EBUS TBNA specimens (Figure 2A). In addition, ALK protein was confirmed to be positive by D5F3 ALK immunohistochemistry assay (Roche, Arizona, USA) of the TBLB samples (Figure 2A and C). The OncomineTM Dx Target test (Thermo Fisher Scientific Inc., Waltham, MA, USA) showed no EGFR, ROS1 rearrangement, KRAS, BRAF, or other NSCLC driver mutations. The PD-L1 tumor proportion score (TPS of 10%) was a low expression. The patient was treated with alectinib (300 mg daily), and a CT scan after three months of the treatment showed a marked improvement in the miliary pulmonary metastasis in both lungs, and the patient's total serum amylase level had decreased (Figure 1C). A Grade 2 skin rash according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 appeared, but it rapidly responded to treatment with an antihistaminic agent. No severe adverse drug reactions have occurred at any time during treatment.

alk rearrangement, alectinib, miliary pulmonary metastasis, non-small-cell lung cancer

Chest X-ray and CT findings. (A) Chest X-ray at the first visit to our hospital revealed bilateral diffuse shadows and a small cavity in the left lung.

PMC8096437_01

Female

A 32-year-old female non-smoker was found to have abnormal lung shadows on a chest x-ray during an annual check-up. A computed tomography (CT) scan at the previous hospital showed a small cavitary nodule in the left upper lobe and diffuse tiny nodules throughout both lungs. The serum tuberculosis-specific IFN-gamma test was negative, and tumor marker levels were not elevated. Transbronchial lung biopsy specimens obtained bronchoscopically showed suspected miliary metastasis by a lung cancer. The patient had a slight cough and no history of respiratory disease, and her Eastern Cooperative Group Performances Status (ECOG-PS) was 0. Blood examinations demonstrated none of the significantly increased tumor markers levels (CEA 1.6 ng/mL, CYFRA 0.6 ng/mL, Pro GRP 54.5 pg/mL), but her serum amylase levels were elevated (total amylase 584 IU/L, pancreatic amylase 76 IU/L). A chest X-ray showed bilateral diffuse shadows at our hospital (Figure 1A). A CT scan revealed a 19 mm cavitary nodule in the left upper lobe and multiple small nodules with a random distribution throughout both lung fields, swollen mediastinal lymph nodes, and spinal metastasis (L4 and L5) (Figure 1B). No CT findings were detected in the salivary glands or pancreas. Magnetic resonance imaging (MRI) of the brain revealed multiple skull metastases but no evidence of brain metastasis (cT4aN2M1c, Stage IV). She underwent both transbronchial lung biopsy (TBLB) from the left upper lung and endobronchial ultrasound-guided trans-bronchial needle aspiration (EBUS TBNA) from the mediastinal lymph nodes. Hematoxylin and eosin (HE) staining revealed adenocarcinoma cells in the EBUS TBNA specimens (Figure 2A). In addition, ALK protein was confirmed to be positive by D5F3 ALK immunohistochemistry assay (Roche, Arizona, USA) of the TBLB samples (Figure 2A and C). The OncomineTM Dx Target test (Thermo Fisher Scientific Inc., Waltham, MA, USA) showed no EGFR, ROS1 rearrangement, KRAS, BRAF, or other NSCLC driver mutations. The PD-L1 tumor proportion score (TPS of 10%) was a low expression. The patient was treated with alectinib (300 mg daily), and a CT scan after three months of the treatment showed a marked improvement in the miliary pulmonary metastasis in both lungs, and the patient's total serum amylase level had decreased (Figure 1C). A Grade 2 skin rash according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 appeared, but it rapidly responded to treatment with an antihistaminic agent. No severe adverse drug reactions have occurred at any time during treatment.

alk rearrangement, alectinib, miliary pulmonary metastasis, non-small-cell lung cancer

Chest X-ray and CT findings. (B) CT at the time of EBUS-TBNA showed small, discrete, rounded pulmonary nodules of uniform size diffusely distributed throughout both lung fields. A suspected cavitary primary lesion was identified in the left upper lobe.

PMC9831644_01

Female

A 24-year-old farmer female was admitted to the Department of Neurosurgery with low back pain, no fever, cough, motor deficit, or any symptoms. Medical, surgical, family histories and physical examinations were unremarkable. The laboratory findings showed a white cell count of 9.8 x 103/muL, C-reactive protein concentrations of 20, erythrocyte sedimentation rate of 50 mm/1 h, 90 mm/2 h and tuberculin skin test was positive. X-ray films showed the collapse of the L1, L2 vertebrae, and L1-2 intervertebral space (Fig. 1). An abscess was observed at the L1-L2 vertebral level in lumbar magnetic resonance imaging (MRI) (Fig. 2). Chest X-rays and Sputum smear were negative. The patient was treated with anti-TB treatment (Isoniazid, Rifampicin, Ethambutol, Pyrazinamide) due to spinal TB findings on MRI (Fig. 3). After 40 days, the patient was diagnosed with grade 1/5 lower limb weakness, and bladder and bowel dysfunction, with no impairment in sensation, which predicts spinal infection. MRI confirmed these abnormalities and showed typical findings such as vertebral endplate destruction, bone marrow and disk signal abnormalities, and paravertebral or epidural abscesses (Fig. 3). Due to clinical manifestations and MRI spinal TB findings (Fig. 3), the patient underwent surgical debridement, interbody fusion and internal fixation with fibular autografting and supplemental posterior spinal stabilisation using a posterior-only approach. On post-operative follow-up, the treatment continued for 9 months, in addition to physical therapy for lower limb weakness. In the end, the patient returned to full motion with grade 5/5 in the lower limb, normal sensation, and no bladder or bowel incontinence. No recurrence was observed in the grafting area. Radiologically 2, 6 and 12 months, 14 years' post-operation, the patient had achieved full bony graft spinal fusion (Figs 4-6).

mycobacterium tuberculosis, pott’s disease, fibula autografting, posterior-only approach, psoas abscess, spinal tb, tuberculosis, tuberculous spondylitis

PMC5548684_01

Male

A 62-year-old man who had been treated for severe persistent asthma for 10 years at a local hospital presented to our hospital with a 1-month history of wheezing and exertional dyspnea. At his local hospital, he had been treated with high-dose inhaled corticosteroid, an inhaled long-acting beta2-agonist, leukotriene receptor antagonist, xanthine and intermittent systemic corticosteroids at least once a month for half a year. At our hospital, his wheezing disappeared after the administration of oral corticosteroid, but his exertional dyspnea did not improve. He was admitted to our hospital for the investigation of dyspnea and pulse oximeter desaturation. A physical examination was normal despite hypoxemia. Chest sounds were normal, and expiratory wheezing was no longer heard after bronchodilator administration. There were no skin lesions, lymphadenopathy or neurological findings. Laboratory findings showed elevated serum lactic dehydrogenase (LDH) (1,482 IU/L), aspartate aminotransferase (AST) (39 IU/L) and C-reactive protein (CRP) (1.6 mg/dL) levels. An arterial blood gas analysis at rest while breathing room air showed hypoxemia (PaO2 53.9 Torr) with an elevated alveolar-arterial oxygen difference (AaDO2) (60.9 Torr). The serum tumor markers were within normal limits, except for an elevated soluble interleukin-2 receptor level (sIL-2R) (1,570 U/mL). Although chest X-ray showed no abnormal findings, chest CT showed diffuse multiple small nodules in the lung fields, no mass and no lymphadenopathy in the thorax or the abdominal cavity (Fig. 1A). Respiratory function testing showed a decline in the pulmonary diffusing capacity for carbon monoxide (DLCO). Pulmonary blood flow scintigraphy showed decreased accumulation in both middle-lower lung fields. A diffuse pulmonary 18F-FDG PET-CT scan showed an increased diffuse FDG uptake in both middle-lower lung fields (Fig. 1B). The existence of malignant lymphoma, such as IVLBCL, without clinical findings was suspected because of the hypoxemia, the high levels of LDH and sIL-2R, the increased AaDO2, the decreased DLCO and the scintigraphic, CT and PET-CT findings. A random skin biopsy and TBLB were performed, and the pathological findings revealed atypical lymphoid cells located within the intravascular space of the capillary vessels and pulmonary artery. In immunohistochemical staining, these atypical lymphoid cells were positive for CD20 and CD79a, which are B-cell markers (Fig. 2), and demonstrated a high proliferation index, as revealed by MIB-1 (Ki-67) (data not shown). Based on these results, the patient was diagnosed as having IVLBCL with pulmonary involvement. After transfer to the Department of Hematology, the patient was treated with prednisolone and vincristine to reduce the pulmonary tumor burden due to his worsening respiratory condition. After one week, his respiratory condition improved. Following prednisolone and vincristine administration, he was treated with R-CHOP chemotherapy, consisting of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone. He achieved complete remission after eight cycles of R-CHOP chemotherapy with no severe adverse events, and the LDH and sIL-2R levels, the AaDO2 and chest CT and FDG-PET findings subsequently revealed no signs of lymphoma involvement (Fig. 3).

asthma, intravascular large b-cell lymphoma, positron emission tomography, transbronchial lung biopsy

18F-FDG PET-CT. scans at the initial presentation, showing diffuse multiple small nodules in the lung fields and an increased diffuse FDG uptake in both middle-lower lung fields. FDG: fluorodeoxyglucose, PET: positron emission tomography.

PMC5548684_01

Male

A 62-year-old man who had been treated for severe persistent asthma for 10 years at a local hospital presented to our hospital with a 1-month history of wheezing and exertional dyspnea. At his local hospital, he had been treated with high-dose inhaled corticosteroid, an inhaled long-acting beta2-agonist, leukotriene receptor antagonist, xanthine and intermittent systemic corticosteroids at least once a month for half a year. At our hospital, his wheezing disappeared after the administration of oral corticosteroid, but his exertional dyspnea did not improve. He was admitted to our hospital for the investigation of dyspnea and pulse oximeter desaturation. A physical examination was normal despite hypoxemia. Chest sounds were normal, and expiratory wheezing was no longer heard after bronchodilator administration. There were no skin lesions, lymphadenopathy or neurological findings. Laboratory findings showed elevated serum lactic dehydrogenase (LDH) (1,482 IU/L), aspartate aminotransferase (AST) (39 IU/L) and C-reactive protein (CRP) (1.6 mg/dL) levels. An arterial blood gas analysis at rest while breathing room air showed hypoxemia (PaO2 53.9 Torr) with an elevated alveolar-arterial oxygen difference (AaDO2) (60.9 Torr). The serum tumor markers were within normal limits, except for an elevated soluble interleukin-2 receptor level (sIL-2R) (1,570 U/mL). Although chest X-ray showed no abnormal findings, chest CT showed diffuse multiple small nodules in the lung fields, no mass and no lymphadenopathy in the thorax or the abdominal cavity (Fig. 1A). Respiratory function testing showed a decline in the pulmonary diffusing capacity for carbon monoxide (DLCO). Pulmonary blood flow scintigraphy showed decreased accumulation in both middle-lower lung fields. A diffuse pulmonary 18F-FDG PET-CT scan showed an increased diffuse FDG uptake in both middle-lower lung fields (Fig. 1B). The existence of malignant lymphoma, such as IVLBCL, without clinical findings was suspected because of the hypoxemia, the high levels of LDH and sIL-2R, the increased AaDO2, the decreased DLCO and the scintigraphic, CT and PET-CT findings. A random skin biopsy and TBLB were performed, and the pathological findings revealed atypical lymphoid cells located within the intravascular space of the capillary vessels and pulmonary artery. In immunohistochemical staining, these atypical lymphoid cells were positive for CD20 and CD79a, which are B-cell markers (Fig. 2), and demonstrated a high proliferation index, as revealed by MIB-1 (Ki-67) (data not shown). Based on these results, the patient was diagnosed as having IVLBCL with pulmonary involvement. After transfer to the Department of Hematology, the patient was treated with prednisolone and vincristine to reduce the pulmonary tumor burden due to his worsening respiratory condition. After one week, his respiratory condition improved. Following prednisolone and vincristine administration, he was treated with R-CHOP chemotherapy, consisting of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone. He achieved complete remission after eight cycles of R-CHOP chemotherapy with no severe adverse events, and the LDH and sIL-2R levels, the AaDO2 and chest CT and FDG-PET findings subsequently revealed no signs of lymphoma involvement (Fig. 3).

asthma, intravascular large b-cell lymphoma, positron emission tomography, transbronchial lung biopsy

18F-FDG PET-CT. scans after the completion of eight courses of R-CHOP. Diffuse multiple small nodules and the diffuse FDG uptake disappeared completely in the lung fields on CT and FDG-PET/CT findings, respectively. FDG: fluorodeoxyglucose, PET: positron emission tomography.

PMC5902110_01

Male

A 50-year-old immunocompetent Hispanic male patient presented in April 2017 to the California Hospital Medical Center in Los Angeles with dizziness, nausea, headache, and a 2-week history of flu-like symptoms. Routine chest radiograph showed no abnormalities. Suspected bacterial meningitis was treated with vancomycin and ceftriaxone. Neurological examination revealed cranial nerves II through XII intact, no sensory or motor deficits, stable gait, DTRs 2+ bilaterally, and a negative Babinski sign. Serum lab results showed white blood cell count of 17,000/mm3. The patient had lumbar puncture done which revealed xanthochromic CSF fluid with a lymphocytic pleocytosis: WBC count of 234/mm3 (94% lymphocytes), glucose of 17 mg/dL, and CSF protein of 90 mg/dL. CT of the head showed ventricular enlargement and hydrocephalus with basal cistern patterns, but he did not require a shunt. Also, mild volume loss with small chronic ischemic disease was noted. Considering the CT of the head, dexamethasone was initiated, and the evaluation to establish the etiology of the meningitis was performed. Initial negative laboratory results were as follows: influenza A or B virus; CSF cryptococcal antigen; HIV-1/2 Ag/Ab screen; blood cultures; CSF cultures; and PCR for Mycobacterium tuberculosis. However, 6 days later the patient's condition worsened, and he was transferred to the ICU. The patient was not responding to the antibiotic and corticosteroid treatment, and his condition deteriorated rapidly over the next few days. Coccidioidal meningitis was confirmed with CSF Coccidioides complement fixing antibody titer of 1:2048. Treatment with IV fluconazole 1200 mg daily was then initiated. Neurological assessment demonstrated altered mental status; the patient was alert, oriented x1, responding to his name only, unable to follow commands, was able to move all extremities but had decreased grip strength bilaterally, held arms in flexion, and had difficulty feeding himself. Blunted left nasolabial fold was noted as a new manifestation. CT of the head demonstrated slightly improved hydrocephalus when compared to the previous exam. MRI of the brain showed meningeal enhancement in the basilar cisterns suggestive of basilar meningitis or a granulomatous process and 9 mm acute infarct in the right globus pallidus. Several days after initiation of fluconazole, follow-up neurological exam exhibited no improvement; the patient's motor strength gradually decreased with intact sensation and withdrawal to stimuli. MRI of C-spine (Figure 1) and T-spine without contrast revealed areas of signal changes in the cord secondary to myelitis and inflammation. MRI of L-spine without contrast showed crowding of the nerve roots in the lower lumbar spinal canal, suggestive of arachnoiditis, and explained the cause of the patient's significant neurological decline. The patient's motor strength decreased to 3/5 in proximal upper extremities and 0/5 in distal upper extremities with very poor hand grasp bilaterally. The patient lost bladder control, and his lower extremities were paralyzed completely even though his mentation improved.

PMC5925101_01

Male

A 46-year-old man with a history of heroin use presented to the emergency room with right hand pain, redness, and swelling four days after attempting to inject heroin into his vein but missing. The wound had progressively worsened to the point of severely limiting hand motion. The patient also reported fevers and chills. He was actively injecting heroin till the day of presentation but denied sharing needles. The past medical history was relevant for uncontrolled diabetes mellitus, hypertension, chronic hepatitis C infection, and chronic kidney disease stage III. Upon presentation, the patient was afebrile (temperature: 100.3 F) with a pulse of 96 beats per minute (bpm), blood pressure of 177/96 mm Hg, respiratory rate of 13/min, and had 98% saturation on room air. Physical exam was unremarkable except for generalized erythema and swelling of the right hand with decreased gross sensation and power in the right hand. White blood cell count was 10,800/microL with 80.8% neutrophils. Lactate was 2.8 meq/l. Blood cultures were sent, and the patient was started on intravenous (IV) vancomycin, piperacillin-tazobactam, and fluids for sepsis management. X-ray of the right hand showed dorsal soft tissue swelling without any other acute abnormalities or radiopaque foreign body. Urine drug screen was positive for heroin, opiates, and benzodiazepines. HIV screen was negative. Plastic surgery performed 2 incisions on the dorsum of the right hand which drained clear fluid without pus. Counterincision was made on the distal part on the dorsal aspect of the hand (Figure 1(a)). Cultures were taken from the deep wounds, and the wounds were packed. The patient left against medical advice but was called back after a day when 1 of his 2 blood cultures was positive for methicillin-susceptible Staphylococcus aureus (MSSA). His wound culture was also positive for MSSA. Upon return, he was afebrile (temperature: 97.9 F) with a pulse of 100 bpm, blood pressure of 177/96 mm Hg, respiratory rate of 13/min, and had 99% saturation on room air. He had persistent pain but was able to move his fingers. He acknowledged inhaling heroin before coming in. He was started on intravenous ampicillin/sulbactam, and blood cultures were sent on day 1 of second admission. White count was 11,400/microL with 70.5% neutrophils. Transthoracic echocardiogram was negative for vegetation. Seven days after initial presentation to the hospital, blood cultures from the first day were reported to be positive for acid fast bacilli (AFB). Repeat cultures from day 1 of second admission also came back positive for AFB. TB QuantiFERON (negative), CD4 count (610/microL), chest X-ray (negative for consolidation), and HIV viral load (negative) were done. On day 10, M. phocaicum was identified preliminarily via best match (CPAL: Central Pennsylvania Alliance Laboratory). Unfortunately, no wound cultures were sent for AFB testing. IV amikacin and cefoxitin with probenecid were started, and intravenous ampicillin/sulbactam was discontinued. Questioning to determine a source of infection revealed that the patient had used tap water and phenol as a solvent for heroin. Repeat blood cultures were negative. Mycobacterium was later confirmed as M. mucogenicum. Amikacin was stopped due to acute kidney injury, and the patient was instead put on meropenem and cefoxitin for 2 weeks followed by doxycycline 100 mg twice daily and trimethoprim-sulfamethoxazole (TMP-SMX) daily for 6 weeks. On follow-up, he had completed full course of antibiotics and his hand had improved significantly (Figure 1(b)).

PMC5742016_01

Male

A 30-year-old male laborer with no significant past medical history presented to our hospital October 2016 with chronic sinus discharge from his left thigh. He mentioned that his problem started two months ago when he started complaining of pain in his left thigh, associated with swelling, redness and hotness, and noticed a small boil with intermittent serous discharge at his thigh, which was diagnosed as a subcutaneous abscess by a general practitioner, that was treated in a primary health care center with local drainage and multiple short courses of antibiotics (Cloxacillin 500 mg TID for 14 days, then Ciprofloxacin 500 mg BID for another 14 days) with no benefit. The drainage was not sent for culture by the treating physician. During this period, the patient's pain used to improve temporarily after each drainage, however, after few days, the pain and local symptoms recur. Therefore, he kept visiting the emergency department with tender indurated skin at the posterior aspect of the thigh, where an Ultrasound was performed showing a 10 cm homogenous anechoic collection, with surrounding subcutaneous edema. Again, a needle aspiration was attempted, but no pus came out. And for two months the patient kept suffering until he was referred to orthopedics service in our institution. At presentation, the patient was afebrile with no constitutional symptoms and with chronic sinus discharge at the posterior aspect of his left thigh (Fig. 1). Initial lab investigations were normal with normal inflammatory markers; WBC = 9.3*10^3/ul, ESR = 21 mm/hr, CRP < 5 mg/dl. Left femur radiographs and MRI showed features of chronic osteomyelitis with sinus tract communicating with skin at the posterior thigh type II-A according to Cierny-Mader classification of osteomyelitis (superficial osteomyelitis in a normal host) (Fig. 2, Fig. 3, Fig. 4). Swab from the discharge was taken for gram stain and culture, and the patient was started on cefazolin empirically. Quantiferon test for TB was negative, and serology tests for Malaria, Brucella, Salmonella, Aspergillus, and CMV were negative. Several days later, the Gram-stained smear of colonies revealed gram-negative coccobacilli. The isolate was oxidase positive and did not oxidize glucose. Following 16S ribosomal RNA sequencing identified the organism as Moraxella oselensis. And as in-vitro susceptibility testing for this organism is not routinely done in our hospital, the patient continued Cefazolin 1 g TID for another ten days. Then antibiotic was changed to intravenous Ampicillin-Sulbactam every 6 h, and posted for bone debridement and biopsy as recommended by ID team as sinus discharge did not stop. Sinogram showed two sinus tracts, one is superior and another one is inferior, with no contrast connected to the intramedullary cavity of the femur (Fig. 5). A 3 cm skin incision, and excision of the upper sinus tract and curettage for the lower tract were done. Afterwards, drilling for the two bony sinuses in the femur was performed, no intramedullary pus was appreciated. Bone biopsy was sent for culture and histopathology. The tissues were washed with copious amount of normal saline, and Vacuum dressing was applied. The surgical pathology specimen culture report was ready after 7 days post-operatively, which showed no growth; this might be explained as the patient had already been on antibiotics for around 16 days (Cefazolin for 10 days, and Ampicillin-Sulbactam for 6 days). Manual sensitivity for Moraxella oseolensis from the previous specimen was tested and showed it was very sensitive to Amoxicillin, Ceftriaxone, and Trimethoprim-Sulphamethoxazole. Post-operatively, the patient was started on intravenous Ceftriaxone and Vacuum dressing was changed every 3 days, with only minimal serosanguinous collection. After seven days, the wound became dry, the Vacuum dressing was removed, sterile dressing was applied, and the patient was discharged home on daily intravenous 2 g Ceftriaxone to be given in a special clinic for outpatient intravenous drugs administration, to complete a total duration of six weeks of treatment. The patient sinus discharge stopped, and complete wound healing was observed and documented on his visit to the outpatient clinic after 21 days post-operatively. He was followed up clinically for more than 3 months, the inflammatory markers maintained their normal range values during the post-operative period (WBC = 8.8*10^3/ul, ESR = 6 mm/hr, CRP <5 mg/dl), and the patient stayed asymptomatic during this period.

case report, moraxella osloensis, osteomyelitis

PMC9883691_01

Female

A 37-year-old female patient was admitted to the Emergency Department of Tianjin Medical University's General Hospital due to complaints of palpitations and fatigue for 1 week, which worsened over the last 4 days. One week before admission, the patient started having palpitations and fatigue, and occasionally with urinary frequency, without dysuria, fever, headache, dizziness, cough, abdominal pain, or diarrhea. She underwent a blood routine examination in another hospital, and the result showed an increase in the white blood cell count and the neutrophil percentage, a slight increase in procalcitonin (PCT), and five white blood cells/high power in urine. After 3 days of treatment with cephalosporin, the symptoms of palpitations and fatigue did not improve. Since the onset of this illness, the patient had low energy levels, average appetite, good sleep, normal bowel movements, normal urination, and insignificant weight loss. There was no history of hypertension, diabetes, or coronary heart disease. The patient denied any history of hepatitis, tuberculosis, other infectious diseases, or any food allergies. The patient presented at our hospital for further diagnosis and treatment. The white blood cell count and the percentage of neutrophils were high. The illness was still considered to be an infection, and the patient was treated with oral levofloxacin hydrochloride tablets. After administering the tablets for 3 days, the white blood cell count increased from 13.18 x 109/L to 19.0 x 109/L, and there was no change in the symptoms of palpitations or fatigue. The patient was admitted for further treatment. At the time of admission, the patient's body temperature was 36.2 C, pulse rate was 68 bpm, breathing rate was 17 bpm, and blood pressure was 120/72 mmHg. The patient showed mental anxiety, answered questions correctly, had a soft neck, no resistance, no thyroid enlargement, clear breath sounds in both lungs, no rales, good heart sounds, regular heart rhythms, a soft abdomen, no tenderness, rebound pain, and muscle tension. She had no percussion pain in the liver area, negative Murphy sign, no pain in the kidney area, bowel sounds four times per min, normal muscle strength in the limbs, and no swelling of the lower limbs.

case report, leukocytosis, pituitary adenoma, silent corticotropin adenomas, subclinical cushing's disease

PMC7388897_03

Unknown

The validity and psychometric properties of the DSM-5 version of the UCLA-PTSD-RI have been validated in the pediatric population. The UCLA-PTSD-RI is a self-report questionnaire that assesses trauma history and diagnostic criteria for PTSD based on frequency of symptoms. Symptoms are reported in five clusters: (1) intrusive symptoms such as unwanted upsetting memories, flashbacks, nightmares (cluster B); (2) avoidant symptoms such as avoidance of thoughts, feelings, or reminders (cluster C); (3) negative cognition/mood symptoms such as inability to recall the trauma, negative affect and thoughts, culpability, decreased interest (cluster D); (4) hyperarousal symptoms such as irritability, angry outbursts, risky behavior, hypervigilance (cluster E); and (5) dissociative symptoms such as depersonalization, derealization (cluster A). The scale has been validated for children over 6 years old. A cut-off was fixed at >=38. This cut-off showed the greatest sensitivity and specificity for detecting PTSD. The sleep score is an added subscale to the UCLA-PTSD-RI to monitor for sleep problems, summing questions 10 and 21 from the UCLA-PTSD-RI, with a score range of 0 to 8. The CGI provides a brief assessment of the clinician's view of the patient's global functioning prior to and after initiating a treatment. The CGI-S is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment: 1 = Normal, not at all ill; 2 = Borderline mentally ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; 7 = Among the most extremely ill patients. All assessments except UCLA-PTSD- RI (self-questionnaire) were performed and reviewed by senior child and adolescent psychiatrists (MS and VF) with expertise in pediatric PSTD. Prazosin was initiated at 1 mg per day at bedtime, consistent with previous studies. The dosage was then increased by 1 mg every week until clinical improvement, as long as tolerance was acceptable. No other treatments targeting PSTD features besides prazosin were introduced during the trial. We defined the response to treatment by a reduction >=25% of the UCLA-PSTD-RI global score in accordance with other reports and the remission of PTSD could be considered from a score less than 38 (UCLA-PTSD index cut off). As prazosin has been reported to have a significant effect on symptoms during the first weeks in adults, the duration of the study was 4 weeks. For clinical purpose, maintenance treatment was proposed to patients at the end of the study in cases of significant improvement. Most of our admitted patients were admitted while taking others agents such as antidepressants, antipsychotics and psychostimulants for comorbid psychiatric disorders (MDD, anxiety disorders, ADHD) or symptoms of PTSD. As part of the treatment protocol, we maintained treatments without changing dosage at the time of initiating prazosin and during prazosin dosage adjustment. Common side effects associated with prazosin therapy include: i) dizziness, drowsiness, headache, faintness, and syncope for the nervous system; ii), palpitations, hypotension (reported as rare) for the cardiac-vascular system; iii) constipation, diarrhea, dry mouth, nausea, vomiting for the gastrointestinal system; iv) urinary frequency for the renal and urinary system; and v) reduced response to environmental allergens for the immune system. Blood pressure (BP) and heart rate were manually monitored, measured, and recorded on a daily basis twice a day during the first week of treatment and during the week after each dose increase. BP was manually measured in two positions, first in supine position and after in seated still position in a quite nursing room, in order to capture orthostatic hypotension. Heart rate was manually measured following seated BP. After initial close monitoring, BP, and heart rate were manually measured once a week in the morning until the end of the hospitalization. All other known adverse events (headache, enuresis, hypotension, ...) were systematically evaluated and, when present, monitored by senior physicians through a checklist (part of the medical file) on a weekly basis through a general clinical work up and a full side effect clinical interview. Any new side effect that could be imputable to prazosin was recorded and reported to pharmacology-toxicology department, as our standard procedure requires. Statistical analyses were conducted using SPSS software (IBM SPSS Statistics for Windows, Version 24, IBM Corp., Armonk, NY). Kolmogorov Smirnov tests identified that changes in the UCLA and sleep scores did not follow a normal distribution. Due to the small number of participants and the impossibility to assume a normal distribution, non-parametric tests were used. Differences in the mean of the clinical scores were compared to zero (null hypothesis) using a Wilcoxon's test. Comparisons between two groups were tested using a Fisher's exact test and tests between more than two groups were examined with a Kruskal-Wallis's test. Correlations were tested using both Pearson's and Spearman's tests. A bilateral alpha-risk of 0.05 was assumed. Graphical representations were done using SPSS.

nightmares, post-traumatic stress disorder, prazosin, sleep disorder, youth

PMC5994559_01

Female

A 41-year-old female patient was admitted to a local hospital abroad with a 4-week history of lower respiratory tract infection that had been refractory to antibiotic treatment. Several weeks after initial clinical improvement after intravenous antibiotics against pathogens commonly associated with community acquired pneumonia she developed headache, back pain, and fever. Due to an acute onset of spinal cord symptoms with paraparesis accompanied by bladder and bowel dysfunction she was transferred to our neurological department. Spinal magnetic resonance imaging (MRI) showed multiple contrast enhanced nodular masses along the leptomeninges in the cervical, thoracic, and lumbosacral segments of the spinal cord including the cauda equine and a myelopathy in the thoracic segment (Figures 1A1,A2). A lumbar puncture was performed and revealed an elevated cerebrospinal fluid (CSF) cell count (314 cells/mul), highly increased levels of protein (45,300 mg/l), a severe blood-CSF barrier dysfunction (Q-Albumin 694), and increased lactate concentration (7 mmol/l). Initially, neither bacterial (conventional cultural growth, mycobacterial cultures, Borrelia burgdorferi, and Treponema pallidum antibodies test), nor viral (herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, enteroviruses, measles virus, rubella virus, tick-borne encephalitis, and JC virus), or fungal (cultural growth and antigen test to Aspergillus and Cryptococcus neoformans) pathogen could be detected in CSF. Laboratory testing for autoimmune causes such as connective tissue diseases (antinuclear antibodies, anti-DNA antibodies, antiphospholipid antibodies, antineutrophil cytoplasmic antibodies, and rheumatoid factor) was unremarkable. Computed tomography (CT) of the chest showed findings suggestive for tuberculosis (Figure 1C) and tuberculostatic therapy with ethambutol, rifampicin, isoniazid, and pyrazinamide was started. Histopathological examination of lung tissue obtained by bronchoscopic transbronchial biopsy revealed granulomas compatible with tuberculosis (Figures 1G,I). Another spinal MRI after 2 weeks of treatment exhibited a slight progress in the extension of the nodular masses but a regress of myelopathy. CSF examination revealed a decreased cell count (195 cells/mul) accompanied by an unchanged severe blood-CSF barrier dysfunction (Q-Albumin 742). Further analyses by using the polymerase chain reaction (PCR) technique detected the atypical Mycobacterium genavense in the lung tissue, while this was considered a possible contamination since retesting and cultural growth were negative for this pathogen. Cultural growth of sputum and bronchoalveolar lavage fluid revealed Serratia marcescens and Aspergillus fumigatus. Thereupon, cotrimoxazole, azithromycin, and voriconazole were added to patient's treatment. In addition, the patient was medicated with high-dose methylprednisolone to suppress inflammatory bystander reaction, which is considered responsible for developing granulomas.

cerebrospinal fluid, chronic granulomatous disease, immunodeficiency, infectious diseases, spinal cord diseases

PMC6885207_01

Male

A 37-year-old primigravida at 24 + 0/7 gestational weeks was involved a single-car accident at a speed of approximately 50 km/h. She was traveling in the left front passenger seat, had worn a three-point seatbelt restraint, and had the supplemental restraints and airbag system deployed. She was transported to our hospital by ambulance 1 h after the event. On examination, her vital signs were as follows: Glasgow Coma Scale, E4V5M6; blood pressure level, 90/50 mmHg; and heart rate, 90 beats/min. She suffered seatbelt injuries to her right thorax and entire lower abdomen and presented such severe pain to her lower abdomen that she was unable to move her body. Fetal heart rate monitoring indicated bradycardia of 80-90 beats/min with loss of variability that led to rapid demise. Whole-body computed tomography revealed intraperitoneal bleeding due to vessel injury around the uterus and placental lacerations over the seatbelt-compressed region (Figure 1). Blood tests revealed D-dimer coagulopathy of 31.7 microg/mL (normal level, <1 microg/mL) and fibrinogen degradation product of 58.0 microg/mL (normal level, <10 microg/mL). Rapid and massive blood transfusion therapy, insertion of an intra-aortic balloon occlusion catheter, and emergency laparotomy under the stabilization of maternal hemodynamics were immediately performed. Bleeding occurred all across the uterine surface during the operation (Figure 2). After delivery of a deceased male baby weighing 640 g via uterine incision, the extensive bleeding surrounding the uterine vessels was stopped using sutures. The total intraoperative hemorrhage was 2500 mL, and total 12 units of red blood cells, 12 units of fresh frozen plasma, and 20 units of platelets were transfused. The mother was admitted to the intensive care unit and discharged after 2 weeks of hospitalization. The placenta was macroscopically lacerated into several parts (Figure 3), and ischemic changes were microscopically noted. Written informed consent was obtained from the patient prior to publication of this case report and the accompanying images.

PMC4020897_01

Male

A ten-year-old Qatari boy, of Arab ethnicity, presented to our emergency department with a history of intermittent lower back pain of 12 months' duration. The pain was reported by the child as severe in nature, intermittent, restricting his daily routine activity, and with partial response to anti-inflammatory medications like 200 mg of ibuprofen. There was no history of joint involvement. The child's family had sought medical advice repeatedly in the past on an outpatient basis, without any specific work up or diagnosis. The family denied any history of fever, trauma, vigorous excercise, weight loss, or any gastro-intestinal symptoms. There was also a negative history of any raw milk ingestion, chronic cough, or contact with patients known to have tuberculosis. The patient had no previous hospitalizations or blood transfusions. Despite parental consanguinity, there was no family medical history suggestive of sickle cell disease symptoms in any of the first or second degree relatives, nor were the parents aware of any known carrier for Hemoglobin S or thalassemia in the family. On examination, the child was noted to be in pain that was assessed by numerical rating scale as 8/10. General examination did not show any signs of pallor or jaundice. The patient was afebrile and hemodynamically stable with a temperature of 37.5C orally, heart rate of 100 beats per minute, respiratory rate of 20 breaths per minute, and blood pressure of 120 mmHg/85 mmHg. The patient's height and weight were at the 50th percentile for his age and sex. Muskuloskeletal examination revealed tenderness upon palpation of the entire lumbo-sacral area, with no other external signs of inflammation such as erythema or swelling. He had limited movement of the trunk, with pain elicited during forward and lateral flexion. There was no spine deformity. There was no hepatosplenomegaly or lymphadenopathy, and the rest of the physcial exam was unremarkbale. The patient was admitted to the general pediatric ward for pain management and investigation of his recurrent back pain. The admitting differential diagnosis included chronic osteomyelitis involving the lumbosacral vertebrae, primary and secondary bone neoplams, and possible undiagnosed rheumatological conditions. The patient was started on regular intravenous acetaminophen along with oral ibuprofen to manage his pain, to which he responded rapidly. Initial laboratory results were as follows: white blood cells 9,500/uL (neutrophils 90%; lymphocytes 6.1%; monocytes 3.8%; and basophils 0.1%); hemoglobin 12.5 g/dL; platelets 217,000/uL, mean corpuscular volume of 70.8 fL and mean corpuscular hemoglobin of 23.6 picograms/cell, with a normal reticulocyte count. The peripheral smear showed microcyic hyppochromic red blood cells with mild neutrophil leukocytosis, with rare immature granulocytes and some toxic features. C-reactive protein was less than 5 mg/L, and erythrocyte sedimentation rate was 9 mm/hour. Serum electrolytes were normal. Urine and blood culture were negative as well as the QuantiFERON test, salmonella, and brucella serology. Antero-posterior spine radiograph revealed straightening of the lumbar lordosis with multiple fish mouth-appearing vertebral bodies from L2-L5, diffusely porotic bone with accentuated medullary pattern, and normal intervertebral spaces with slight widening of the sacro-iliac joint space. AP chest radiograph was essentially normal, with no mediastinal mass or hilar lymphadenopathy. Magnetic resonance imaging (MRI) of the spine (Figure 1) and pelvis with contrast was requested on the second day post-admission. It showed multiple bone marrow-replacing lesions involving the thoracic, lumbar, and sacral vertebrae extending from T2 vertebral level downwards to the lower sacral segment. These displayed a predominantly low signal intensisty in T1-weighted images and high signal intensity in T12 fluid-attenuated inversion recovery-weighted images, with a patchy homogenous pattern of enhancement. There was an associated reduction of the height of the vertebral bodies, mainly in L3, L4, L5, and S1 levels. The MRI findings prompted a consultation with the pediatric hematology and oncology services to discuss the possibility of malignant inflitration, such as with leukemia and lymphoma. A bone marrow biopsy and an aspirate were conducted, both of which were normal. MRI of the abdomen was conducted to exclude the possibility of an underlying malignancy. The image showed mild hepatomegaly, with a liver span of 15 cm with moderate splenomegaly, no focal lesions, and no evidence of any abdominal lympahdeopathy or mass lesion in the retroperotenium or adrenal glands. On day 7 post-admission, the result of the hemoglobin electrophoresis that was requested on admission revealed HbF =2.9%, HbA2 =2%, HbA =0%, HbS =66.8%, and HbE =28.3%, which confirmed the diagnosis of sickle cell disease with HbSE component. Our patient was discharged with a diagnosis of sickle cell disease (HbSE subtype) on oral folic acid 1 mg once a day and ibuprofen 400 mg per mouth every six hours if needed. In addition, our patient was started on oral penicillin VK 250 mg every 12 hours at the hematologist's discretion, although there are no specific guidelines clarifying the need for penicillin prophylaxis in HbSE disease. The patient's parents refused hemoglobin electrophoresis for themselves as well as for the patient's siblings. The patient was seen in the pediatric out patient clinic after 2 months and was in a stable condition. In addition, he has been seen twice since then in the pediatric hematology clinic and reportedly has good pain control with ibuprofen as needed. The patient's parents stated that patient had used ibuprofen only twice in 2 months.

hbse, case report, hemoglobin, pediatrics

PMC4716643_01

Male

A previously healthy 64-year-old Sri Lankan man was admitted to the general medical unit because of progressive impairment of his memory regarding recent events that had occurred during the previous 3 weeks. The memory impairment was associated with irritability and confusion. He had been a smoker for 15 pack-years. Physical examination revealed no fever, and his Glasgow coma scale score was 12/15 with alternating irritability and drowsiness. His pupils were equal in size and reactive to light, and no significant neck stiffness was noted. Focal neurological signs were absent. The patient was not cooperative enough to conduct a proper mini-mental examination. His presentation was suggestive of delirium. Basic hematological investigations and renal and liver profiles were not suggestive of an extracranial cause. Before performing lumbar puncture, we carried out noncontrast CT of the brain to exclude any pathology causing increased intracranial pressure. CT revealed a hyperdensity in the hypothalamic region surrounded by hypodensities extending toward the temporal lobes bilaterally; these findings were consistent with a possible hypothalamic tumor with perilesional edema (Fig. 1a and b). Electroencephalography showed generalized slowing that was maximal in the bitemporal regions. On the second day of admission, his serum biochemistry parameters became abnormal with a rising serum sodium level (>160 mEq/L) and normal serum potassium level. We noticed a significant increase in his urine output (average of 5.5 L/day) and lowering of his urine osmolality (190 mOsm/kg). Based on the hypovolemic hypernatremia and low urine osmolality associated with the radiological abnormalities in the hypothalamus, we suspected underlying cranial diabetes insipidus in this patient. He was treated with rehydration and intranasal desmopressin, to which he showed only a partial response. The patient was then transferred to the intensive care unit for close monitoring. Once the patient was stable, gadolinium-enhanced MRI of the brain and brain stem was carried out. The transverse section of the brain showed increased T2-weighted signals in the deep temporal lobes, suggesting the involvement of the limbic system (Fig. 2a). The coronal section of the brain showed increased T2-weighted signals in inner mesial regions (Fig. 2b). Interestingly, the mass lesion had disappeared during the previous 3 days. Therefore, viral or autoimmune encephalitis was considered as a more probable diagnosis than a mass lesion. Lumbar puncture was performed at this point, and samples were sent for screening of viral markers (herpes simplex virus, cytomegalovirus, and Japanese encephalitis virus) and tuberculosis polymerase chain reaction; all results were negative. Cytology of the CSF was negative for any malignant cells; however, lymphocytosis was present, suggesting an underlying inflammatory process. Based on the clinical and radiological picture, PLE with associated predominant hypothalamitis was suspected in this patient. Unfortunately, autoimmune markers were not available, and the patient had financial limitations that prevented further investigation. His condition deteriorated with the development of acute kidney injury caused by severe intravascular hypovolemia due to resistant diuresis. Considering the possibility of an associated malignancy, a chest radiograph was obtained and showed a mass lesion in the right hilum. The patient was not fit enough to undergo contrast-enhanced axial CT of the thorax because of his rising serum creatinine level. However, bronchoscopy was performed, and histological examination of the hilar mass showed a SCLC of the "oat cell" variety. Unfortunately, the patient died before the oncology referral while being treated in the intensive care unit.

PMC9054449_01

Male

A 4-year seven-month-old, Tunisian boy was referred to the Pediatric Dentistry Department at the Faculty of Dental Medicine of Monastir (Tunisia) complaining of pain related to poor oral and dental condition. The patient' medical history revealed that the young boy was initially diagnosed with SSS by his pediatrician who relied on clinical features, consanguineous factor, and biochemical measures to confirm the diagnosis. The patient was born to consanguineous parents and had no other siblings. He had history of full-term birth by caesarean section with a birth weight of 2 kg, a birth height of 42 cm, and a head circumference of 31 cm. The patient's medical history reported also episodes of tetany and convulsions associated with signs and symptoms of hypocalcemia from the 15th day of birth. The seizures lasted a few minutes and were resolved without intravenous antiepileptic drug administration. The initial patient's biochemical examinations showed hyperphosphatemia (2.5 mmol/L), hypocalcemia (1.8 mmol/L), and very low levels of parathyroid hormone (4.2 pg/L) (Table 1). Vitamin D and oral calcium preparations were prescribed by the patient's pediatrician during clinical follow-ups, but due to recurrence of hypocalcemia, second episodes of seizures were observed at the age of 13 months. A16 months, the pediatrician general examination revealed characteristic facial dysmorphism with microcephaly (-3 standard deviation [SD]) and severe growth retardation (-4 SD for height, -3 SD for weight). At this age, the patient height was 80 cm and weight was 14 kg. The general examination demonstrated also intrauterine growth retardation (IUGR), oligohydramnios, and fetal distress. His hands and feet were small with thin and short digits, which gave him a very short stature. No congenital heart abnormality was reported. The genetic testing revealed 12 bp (155-166 del) within the TBCE gene in exon 3 confirming the diagnosis of SSS. The neurological examination revealed an intellectual disability, with a mental retardation, a psychomotor delay, and a severe speech delay which made the dental examination and treatment very difficult to perform. Extraoral head and neck examination confirmed the diagnosis of SSS and reported typical craniofacial features of this syndrome such as microcephaly, large set ears, deep-set eyes, prominent forehead, beaked nose, thin lips, and marked philtrum (Figure 1). Intraoral examination revealed micrognathic mandible and maxilla, an arched palate, and small dental arches with an open bite. All the maxillary and mandibular teeth were severely decayed due to the poor oral hygiene, the plaque accumulation, and the enamel hypoplasia (Figure 2). Radiographic examinations were not possible due to the patient behavior. The proposed treatment plan was discussed and approved by the patient's parents. Written informed consent was obtained from the child's parents for all imaging exams, treatment modalities, and data publications. The full dental treatment was planned and summarized in Table 2. A pulpotomy was performed on teeth #62 and #52 after removal of the coronal pulp using a sterile excavator. The pulp chamber was then rinsed with normal saline, and the bleeding was controlled using a small cotton pellet. A zinc oxide-eugenol mixed to a thick consistency was then applied and condensed over the imputed pulp of the prepared cavity. Finally, the rest of the cavity was partially filled with type IX glass ionomer cement (GIC) (Riva self-cure, SDI Australia) and then restored with resin composite (3M FZ100 MP-USA). A root canal therapy was performed on teeth #51, #61, #54, #55, #64, #65, #74, #75, #84, and #85, by the same pediatric dentist using the same procedure. After administration of local anesthesia, coronal access was performed with a #02 round high-speed carbide burr without isolation using a rubber dam since isolation was difficult to perform for this patient. Then, after identification of the canal orifices, the root canals were manually prepared using stainless steel manual K-files (Dentsply-Maillefer, Ballaigues, Switzerland) in a step back manner through size #35 by quarter-turn-pull technique. The root length was determined approximately given the impossibility of taking X-rays. The pulp chamber was abundantly irrigated with 2.5% sodium hypochlorite. All the root canals were dried using paper points and sealed using zinc oxide-eugenol. Finally the access cavities were restored with type IX GIC (glass ionomer cement) (Riva self-cure, SDI Australia). Composite resin restorations (3M FZ100 MP-USA) were placed on the maxillary and mandibular incisors and stainless-steel crowns (3M ESPE -USA) on all maxillary and mandibular primary molars. All the dental treatments were carried out over several sessions under local anesthesia because the patient's parents refused categorically general anesthesia. Figure 3 shows the postoperative restorative treatments. Dietary advice with instructions on oral hygiene was given for the parents, and regular follow-up visits were scheduled every 6 months and showed a very satisfactory clinical condition of all the restorative treatments. Regular follow-up visits were scheduled, and dental prophylaxis was performed at each visit.

PMC8216685_01

Male

A 51-year-old male patient, who lives in a rural area, was first taken to the emergency department of another hospital with a 3-month history of headaches associated with gait alterations due to weakness of the lower limbs, instability, difficulty to climb stairs without support, memory loss and behavioral changes. The initial computed tomography (CT) of the head, according to his medical record and the radiology report, did not reveal any evident lesion and a lumbar puncture was performed showing hyperproteinorrachia, hypoglycorrhachia and mild lymphocytic pleocytosis. However, fungal and bacterial cultures, cryptococcus latex agglutination test, Mycobacterium tuberculosis (MT) polymerase chain reaction and MT culture were negative. Due to the lymphocytic pleocytosis and the high prevalence of tuberculosis in our country, empiric anti-tuberculosis treatment was started. Nevertheless, the patient was evaluated again three months after his initial visit due to the persistence of symptoms and the onset of urinary incontinence, drowsiness, emesis and fever. The physical examination revealed that the patient was disoriented in time and space and had short-term memory difficulties. Acalculia was noticed. The examination of the eye fundus revealed bilateral papilledema without any other pathological finding. Physical examination did not reveal tremors or asymmetric pronation of hands. Rapid alternating movements and finger-to-nose movements were normal. However, the pull test was positive, and an ataxic gait was noticed. Meningeal signs were absent. Blood tests were carried out showing leukocytosis and neutrophilia without eosinophilia and a new lumbar puncture was performed with similar results to the previous, once again, all the infectious diseases investigations were negative. Due to the lack of response to the initial treatment, the diagnosis of meningeal tuberculosis was ruled out and treatment was suspended. Serological tests for Histoplasma, Cryptococcus and Aspergillus were negative. A head CT scan revealed ventricular dilation and the presence of a cerebellar cyst (Figure 1); the magnetic resonance imaging (MRI) of the brain showed a left cerebellar cyst along with severe dilation of the ventricular system compatible with hydrocephalus (Figure 2), so that a ventriculoperitoneal shunt was performed. Due to the clinical deterioration of the patient and the lack of a clear diagnosis, a biopsy of the cyst was performed with evidence of a cysticercus cyst (Figure 3). Racemose neurocysticercosis with cerebellar involvement was considered and 8 mg of intravenous dexamethasone every 8 h in conjunction with albendazole at the maximum dose (30 mg/kg/day/) was started, as Praziquantel is not commercially available in Colombia. While hospitalized, the patient evolved with a progressive improvement of symptoms with subsequent discharge from the hospital. However, the follow-up visits were scheduled in another institution, and the patient was lost to follow up.

PMC4897020_01

Male

A 47-year-old man presented to the emergency department complaining of left testicular swelling and pain for 3 weeks. Additional symptoms included intermittent lower abdominal pain and nausea without episodes of emesis. There was no dysuria, hematuria, urinary retention, urgency, frequency, or hesitancy with urination. Furthermore there was no weight loss, loss of appetite, night sweats, hemoptysis, night fevers, or cough. A chest radiograph was normal. Past medical history was relevant for a positive PPD in 2002, with no subsequent treatment. On physical exam, the patient was afebrile, with normal heart rate, blood pressure of 159/127, and normal respiratory rate and oxygen saturation. His height was 5 feet 8 inches with a BMI of 20.83 kg/m^2. Head and neck exam was normal. There was no temporal artery tenderness. There was no meningismus. Palpation elicited reproducible pain at the left occipital insertion of the trapezius. The skin was warm and dry, with no rash, no laxity or noted thinning. His cardiac, pulmonary, and abdominal exams were unremarkable. His neurological exam revealed clear and fluent speech, intact cranial nerves II-XII, 5/5 strength throughout, and intact sensation. Gait was normal, and there was no nystagmus. He was alert and oriented. Laboratory investigations revealed complete blood count and chemistries within normal limits. On physical examination the left testis seemed smoothly enlarged. There was associated boggy swelling of the left spermatic cord. The right testis was unremarkable. A firm right extratesticular mass, suspected to be epididymal, was present. Laboratory findings revealed: HCG 0; AFP less than 4.13; no pyuria. A urine AFB was performed based on the patient's history of a positive PPD. His urine was negative for AFB smear and culture. Scrotal ultrasound was performed as part of the initial evaluation. Images demonstrated the presence of a 1.3 x 1.0 x 0.9 cm, well-defined predominantly, hypoechoic lesion in the upper pole of the right testicle (Fig. 1). This area was not tender to probe palpation. The lesion has slightly increased peripheral vascularity upon color Doppler interrogation. There was also noted edema with increased blood flow and small amount of fluid between the right epididymis and upper pole of the testicle. The remainder of the right testicle was normal measuring 4.4 x 2.1 x 2.5 cm. The left testicle and left epididymis were normal. Images of the upper left scrotal sac and distal inguinal canal demonstrated a serpiginous 3.0 x 1.8 cm structure with heterogeneous echogenicity which could not be separated from the left spermatic cord (Fig. 2). No abnormal vascularity was seen upon color Doppler interrogation. No peristalsis was present on real time imaging. Small bilateral hydroceles were noted. The patient was referred for surgical management of a testicular mass. Preoperative diagnosis was right testicular tumor probable seminoma, and possible left patent processes vaginalis with omental herniation versus spermatic cord lesion. Postsurgical pathology revealed caseating granulomata in the upper pole of right testicle (Fig. 3) and also caseating granuloma in the left spermatic cord (Fig. 4). The right epididymis was normal. Cultures were positive for Mycobacterium tuberculosis.

ct, computed tomography

PMC1151652_01

Male

A 19-year-old male, semi-elite Australian Rules footballer presented with left sided hamstring pain that occurred during a game two weeks prior. The patient had not played a game or been able to train for two weeks since the injury. He had been treated with cryotherapy, NSAID's, slump stretching, lumbar spine mobilizations, ultrasound and massage to the hamstrings. He had a history of mild osteitis pubis 12 months previously that was treated with rest and modified activity. There had been no prior history of hamstring or low back injury. On physical examination the patient was standing with an apparent lumbar spine hyperlordosis, anterior pelvis tilt, flexed knees and increased thoracic kyphosis. There was tight (reduced range of motion) bilateral hip flexors (modified Thomas position* +15 ) and hamstring muscles (45 straight leg raise [SLR]), hypertonicity of the gluteii, hamstring, lumbar and psoas muscles and general mid thoracic and lumbar spine motion restriction, determined by inter-segmental motion palpation and observation of range of motion (ROM). (*Modified Thomas testing requires the patient to sit at the edge of the table and to bring one knee to their chest to firmly flatten their back. They then assume the supine position, allowing the testing leg to extend off the table. An angle is formed between the femur and a line drawn parallel to the tabletop. A positive angle means the femur is projecting upwards. A negative angle means the femur hangs downwards). There was weakness of the left hamstring and gluteus maximus graded 4/5. Hamstring tenderness could not be localized on palpation. Other physical examination findings, including Trendelenburg, valsalva, neurological, slump, extension leg raise and hip and sacroiliac joint motion palpation and orthopedic testing were unremarkable. The patient was given a working diagnosis of back-related hamstring injury as a result of lumbar-pelvic myofascial pain referral, mimicking a grade one hamstring strain. Differential diagnoses included pain referral from gluteal trigger points. Treatment involved long-lever SMT to the lumbar spine, short-lever SMT to the mid thoracic spine, drop piece knee manipulation, active release soft tissue massage techniques (ART) to the psoas, gluteal, lumbar and hamstring muscles and proprioceptive neuromuscular facilitation (PNF) stretching of the hamstring and psoas muscles. Post treatment, modified Thomas position bilaterally was +5 , SLR 60 bilaterally and muscle strength was graded 5/5. The patient received 3 treatment sessions that week and played a match the next week without re-injury. He was put on a maintenance program for the rest of the 12 weeks of the season including finals (one visit per week for a month, one visit per fortnight thereafter) which included the above treatment and strengthening and muscle activation work (to improve hip extension and abduction motor patterns) to the gluteus maximus and medius, multifidus, transversus abdominus and internal oblique muscles. Maximum medical improvement (MMI) was reached after 7 treatments. The patient finished the season without re-injury. Posture and muscle length changes continued to improve over this period (bilateral modified Thomas position -5 , SLR 85 ).

PMC1151652_02

Male

A 25 year old male, semi-elite Australian Rules footballer felt a 'twinge' in his right hamstring during a game. He presented to us the day after, complaining of tightness in his medial right hamstring and a stiff low back. He had no previous history of hamstring injury but had suffered episodic low back pain over a 5-year period. On physical examination, the right pelvis was low compared to the left in standing position; there were tight right (45 SLR) and left (55 SLR) hamstrings and tight left hip flexors (+10 modified Thomas position). There was palpable hypertonicity through the right hamstring, left psoas, lumbar and gluteal muscles, thoracolumbar spine and right sacro-iliac joint (SIJ) motion restriction, positive Gillett's (standing S-I joint motion palpation) and extension leg raise testing for the right SIJ and weakness of the right hamstring and gluteus maximus muscles rated 4/5. Hamstring tenderness could not be localized on palpation but mild discomfort was reproduced in resisted muscle testing. Other physical examination findings and testing procedures, including Trendelenburg, valsalva, neurological, slump, lumbar ROM and hip joint motion palpation and orthopedic testing were unremarkable. The patient was diagnosed with a back-related hamstring injury on the basis of his apparent right SIJ motion restriction and pain referral. Differential diagnoses included pain referral from lumbar-pelvic myofascial structures, gluteal trigger points or a grade 1 hamstring injury with concurrent lumbar-pelvic dysfunction. Treatment involved high velocity low amplitude (HVLA) SMT to the right SIJ and thoracolumbar spine, long axis manipulation to the right hip joint, ART to the right hamstring, left psoas, lumbar and gluteal muscles, PNF stretching of the right hamstring and left psoas and hamstring cryotherapy. Post treatment, modified Thomas position was 0 on the left, SLR 55 on the right and 65 on the left. Muscle strength was graded 5/5. The patient did not participate in training during the week and received 2 more treatment sessions. He played a match the next weekend without re-injury. He was seen twice the next week and put on a maintenance program for the 16 weeks remaining in the season (one visit per week for a month, one visit per fortnight for a month, one visit per month thereafter). This included the above treatment plus strengthening and muscle activation work (to improve hip extension motor patterns and running technique) to the gluteus maximus, multifidus, transversus abdominus and internal oblique muscles and home advice including flexibility and stability work. MMI was reached after 10 treatments. No re-injury occurred during this period and muscle length changes continued to improve (bilateral modified Thomas position 0 , SLR 75 ).

PMC7448128_01

Unknown

Almost half a million children 1 to 14 years old suffer from TBI each year in The United States. While these occur from various mechanisms, the most frequent causes are falls, being struck by a motor vehicle, or abusive injuries. Mild TBI is often accompaniedby long term behavioral and neuropsychological defects. Mild TBI usually occurs with head trauma due to contact and/or acceleration or deceleration forces. The type of mechanical forces may determine the nature of the resultant injury. What effect this injury has on the developing brain is unclear. Despite the fact that mild TBI seems to be associated with significant morbidity, there is very little data in the literature on long term sequelae related to mild traumatic injury unrelated to sports injuries. An interesting study by Manley et al reviewed potential long-term effects of sports related concussion looking at sequelae 10 years after injury. However, this was inclusive of professional athletes as well as high school athletes. It was also not specific regarding exact type of concussive injury. It did find that some former athletes in contact, collision, and combat sports suffer from depression and cognitive deficits later in life, and there is an association between these deficits and a history of multiple concussions. This would suggest that children with mild TBI would be at such risk with repetitive injury. The exact relationship with the repetitive injury and progression to chronic traumatic encephalopathy is unclear. Our review of the current literature did not show any article regarding children that was similar to this paper. Our current study focused on TBI occurring from non-sports related injuries, and long-term sequelae related to TBI. In this study we extended our data to a period of time much further than our previous study which went only to 14 months' post injury. Weaknesses of our study are that we are unable to verify pre-existing mental conditions even though we asked about pre-existing issues, and as our survey was self-reported, we are unable to formally attach a diagnosis to our patients. With regard to pre-existing neurologic issues prior to the mild TBI, we were unable to find any such issues in our patient population. We found once again that persistent sequelae are present after seemingly innocuous TBI. Unlike our previous study which showed persistence of headaches, this study shows a persistence of anxiety and depression which once again suggest post-traumatic stress disorder (PTSD). As suggested in our previous paper, learning disabilities and memory loss are very problematic to patients and families. Since the persistence of neuropsychiatric issues beyond 5 years is significant in our population, perhaps routine neuro-psychiatric testing of all patients with mild TBI should be considered. Because we identified many patients with long term sequelae, we were able to guide them to our neurology colleagues to follow up and address these issues. Unfortunately, due to the retrospective and self-reported nature of our study no association between initial data and persistent sequelae was found. Further studies looking at non-sports related mild TBI are needed with specific data looking into objective data on neuro-psychological issues. Mild TBI clearly has a profound long-term impact on the developing brain. We also understand that comparing issues such as anxiety in a child aged 4 may not be comparable to a child of age 14. We made the assumption that, as the survey was being answered by the parent or guardian, we could make a general comparison. We also did a statistical analysis between each of the age groups (age 1-14) and because our numbers were small, we found no difference, hence we decided to combine age groups so as to look for any difference, which was also not present. The earlier identification and more detailed analysis of patients at risk may yield better outcomes in child with mild TBI. We conclude that significant sequelae are present in our pediatric patients that suffer, non-sports related, seemingly mild TBI.

traumatic brain injury, pediatrics, residual sequealae, telephone survey

PMC9428010_03

Unknown

As far as we know, this is the first measles outbreak caused by imported D8 genotype in Jiangsu province, and the fourth in China. Further epidemiological investigation showed that neither of the two patients reported herein had received measles vaccination. The first D8 case was an eight-month old child from Shanghai in 2012, with no previous measles vaccination, and the second outbreak was in Beijing in 2013, with two adult cases, for whom no information on measles vaccination could be gathered. All of these reports suggest that an immunity gap among all imported D8 genotype cases, which is still an important factor for transmitting measles virus. It is therefore necessary to implement supplement activity of measles immunization target adult with immunity gap. Population density is a major determinant of attack rates and transmission of measles virus. In China, almost of all imported measles cases occurred in economically developed regions and border regions. Frequent migration and higher population density make these regions more vulnerable than others in China, as all adults got imported measles virus infection in venues with higher population density such as school, hospital, and fabric market. Therefore, more attention should be drawn to measles surveillance in regions and venues with high population migration and density, especially in epidemic seasons.

imported d8 genotype, measles virus, outbreak

PMC5959028_01

Female

We present the case of a 42-year-old female patient with no significant pathological history. She presented at the Department of Emergency Ophthalmology, claiming a drop of vision in the left eye (LE), which gradually installed during the last 48 hours before she presented at the Emergency Department. There was no history of ocular trauma or surgery. The ophthalmic evaluation at the time of admission revealed a well-contoured and normally colored optic disc, retinal hemorrhage radiating from the inferotemporal optic disc margin with a flame shaped aspect, dot-spot retinal hemorrhages and low foveolar reflex, at the right eye (RE). At the left eye (LE), an elevated optic disc with moderate retinal oedema marked retinal hemorrhages, and preretinal hemorrhage with no foveolar reflex. The slit lamp examination of the anterior segment was normal for the RE and delayed RFM for the LE. The visual acuity (VA) for the RE was 0.9 with correction and for the LE was counting fingers at 1 meter, not correctable. In the first stage of biohumoral status assessment, we performed blood tests such as CBC, erythrocyte sedimentation rate, C-reactive protein, fibrinogen, blood glucose test, lipid profile, total serum protein and thyroid markers. The results of blood test showed a severe pancytopenia with 1.43 X 103/ microl leukocytes, 24 X 103/ microl thrombocytes and severe low levels of Hb 5 g/ dl, inflammatory markers were high, erythrocyte sedimentation rate ESR 60 mm/ h, CPR 17.63 mg/ l, lower fibrinogen levels 94.77 mg/ dl. Given the analyses, we suspected disseminated intravascular coagulation and we performed D- Dimeri test with positive result. Interdisciplinary medical evaluations were made by colleagues from internal medicine, cardiology and hematology departments. In the multidisciplinary team, we decided to complete the investigations with Hemostasis Analyzer Markers (Pts, Ptr, INR, and APTT), which suggested a hemostasis disorder. Lactate dehydrogenase test, Polymerase chain reaction (PCR) and ferritin were on high levels, serum iron was on low levels, negative serology for HIV, Hepatitis B and Hepatitis C, anti-thyroid peroxidase antibodies (anti-TPO antibodies) and the thyroid hormones within normal limits. At the time of admission, the CT for head segment did not indicate pathological changes. A bone marrow aspiration and biopsy were made. Leukocyte concentrate, cytological blood smear test, and the cytological examination of the spinal cord were inconclusive because they showed a low percentage of promyelocytes of approximately 8% and blasts of approximately 6%. Due to the patient's general condition changing with the onset of fever we decided to transfer her to the intensive care unit. Given the unfavorable evolution, we repeated the CT for head segment, which showed multiple supratentorial lesional processes predominantly in the white matter and calf body and a few isolated thalamic lesions that raised the suspicion of brain microabscesses in a septic context (Fig. 1). The head CT also revealed a modulation of signal diffusion in the left eye-viewable on the hemosiderin-susceptible sequence in moderate hyposignal, which almost totally interests the vitreous body, possibly hemorrhagic. At the CT for thorax and abdomen, we found multiple pulmonary outbreaks spread in both lungs, parapneumonic pleurisy of 6 mm on the right and 5 mm on the left, pelvic ascites fluid with infiltrative appearance around the genitals. Blood culture test was negative; RT-PCR Sepsis test was negative for S. aureus, Enterococcus faecalis, Streptococcus agalactiae, Enterobacteriaceae, Candida spp and Pseudomonas aeruginosa. The examination of the posterior pole revealed marked changes of the retina and optic disc with massive hemorrhages that practically covered a large part of the posterior pole for the LE and for the RE extensive retinal hemorrhage, marked papillary edema, both eyes with vitreous condensation (Fig. 2,3). It was difficult to determine the patient's VA given the general altered status. The patient was transferred to the hematology department having an extended mucosal cutaneous hemorrhage syndrome (Fig. 4), hepatic cytolysis syndrome and started the specific treatment for LAM3 with Vesanoid 45 mg/ m2 - 80 mg/ day. The general status of the patient worsened, becoming confused, jaundice with haematological status in the collapse with WBC=55.76 X 103/ microl, Neutrophils 0.00 X 103/ microl, Lymphocytes 0.00 X 103/ microl, Monocytes 0.00 X 103/ microl, Eosinophils 0.00 X 103/ microl, Basophils 0.02 X 103/ microl, she had PLT=8 X 103/ microl, Hb=7.7 g/ dl. In the hematology department, the test battery was extended with flow cytometer, PML RAR alpha transcript t 15, 17, and immunohistochemistry. The result of PML RAR alpha screening transcript (15;17) was positive. The patient received antibiotics, red blood cell transfusion, freshly frozen plasma platelets, cryoprecipitate, corticosteroid, and haemostatic. Due to severe coagulopathy and severe fibrinogenemia, she received treatment with Haemocomplettan fibrinogen concentrate. Thirteen days after admission, the patient suffered a respiratory cardiac arrest and died. Later on, after the patient died, the result of Bone Marrow Biopsy revealed a hypercellularity with intertrabecular infiltration of blastic cells with cytoplasmic granulations and Auer rods, about 80-90% of the total cells.

lam3-acute promyelocytic leukemia, all-trans retinoic acid, bone marrow aspiration and biopsy, disseminated intravascular coagulation (dic), leukemic retinopathy, sepsis

PMC3425249_01

Male

A 26-year-old male, an unmarried rickshaw puller working temporarily in a jute mill in Nodakhali, southern West Bengal, presented to the psychiatry outpatient department with persistent fear for 2-3 days that his penis was shrinking into his abdomen which was making him progressively weak. He became intensely anxious and was unable to sleep well at night and repeatedly brooded over the thought. He denied any addiction or habitual intake of any psychotropic drugs, while his informant and medical records failed to show any premorbid psychiatric illness. He thought his symptom was due to his recent nocturnal emission and masturbatory practices. He promptly reacted by immersing himself in a nearby pond for 14-16 hours overnight which resulted in symptomatic chest infection in his lungs. His action quickly gained recognition in the inhabitants of the nearby worker's quarters. Two days following the event, six laborers presented with similar symptoms and they promptly followed similar preventive measure as well. None of the cases could qualify for any other codable Axis I diagnosis. The occurrence led us to arrange for a small medical camp in the vicinity to spread awareness and group psychotherapy, and the outbreak subsided after 5-6 days.

koro, culture bound syndrome, jute mill

PMC3425249_02

Male

A 53-year-old divorced senior worker, who was show caused by the authority recently for irregularities in his professional commitment, working as a mechanic in the same jute mill suddenly noticed his penis growing smaller and shrinking into his abdomen. This resulted in a panic, and he frantically reached for help in the emergency department of the hospital. He had learnt that a similar occurrence had occurred 1 week back nearby his quarter, which caused the victims to immerse themselves in ice-cold water. He admitted taking country liquor at least on two to three occasions per week, amounting to 1-2 pints each time on an average, though he was abstinent for the last 15 days. There were no other significant premorbid medical or psychiatric illnesses. He was given chlordiazepoxide 80 mg in divided doses and thiamine and was reassured. His condition caused his nephew, who had been on a vacation in Bihar, to come back to the state. In 2-3 days, the nephew started having similar complaints that resulted in intense panic and had to be admitted to surgery observation ward following abrasive injury over the glans which reportedly occurred as he tried to pull out his penis from the abdomen, which he thought was retracting. He recovered within 3 days but the news was followed by an outbreak of similar illness among 11 workers in the same jute mill and they resorted to immersing themselves in a pond nearby. They believed that the disease was occurring due to increased heat accumulated within the body that needed to be cooled down. Another medical camp was arranged, and assurance followed by group psychotherapy resulted in reduction of symptoms within 6-7 days. Close individual psychiatric interviewing revealed most of the cases to be unmarried. Immediately prior to the outbreak, there was a prolonged cease work in the jute mill discussed and the workers were not getting their salaries for the last 1 year which led to financial instability. The demographics and other relevant particulars of the two case clusters discussed herewith are briefly summarized in [Table 1].

koro, culture bound syndrome, jute mill

PMC6425318_01

Female

A 34-year-old woman gravida 5, para 3, abortion 1 presented to the ER of our hospital, at 29 weeks' gestation, due to uterine contractions that increased in frequency and intensity in the last 5 hours, with no other symptomatologies added (Figure 1). Her past medical history was unremarkable with O + hemotype; she had an abortion due to an anembryonic pregnancy that required curettage, which was performed without complications. The patient had 3 healthy previous pregnancies which resulted in 3 healthy living children. Currently in her fifth pregnancy, she denies pregnancy care; only one obstetric ultrasound performed at 24 weeks' gestation in another clinic reported the following: harmonic fetal growth and no fetal malformations; however polyhydramnios was present. During her observation in the ER, a new ultrasound examination was ordered, which revealed an apparently large placenta with approximate weight of 1,800 gr, suggestive of placental edema; the fetus appeared with polyhydramnios, and no heartbeats nor fetal movements were registered; she was then referred to the high risk obstetric department, where she was found to have normal vital signs, mild edema of the ankles without fovea, and a gravid uterus occupied by a single longitudinal cephalic fetus with lateralized back to the left; fetal heart rate was not detected with doptone; she had regular uterine dynamics palpable at a rate of 3 contractions lasting 60 seconds each, within a time frame of 10 minutes; at vaginal examination the cervix was softened with 4 cm of dilation and 70% thinned, intact amniotic membranes, without bleeding or leucorrhoea. Laboratory tests reported the following: hemoglobin 11.5 g/dl, hematocrit 34.8%, and no other abnormal results including normal renal and hepatic function. Due to increased frequency of contractions, she was immediately sent to the expulsive room, where a single female sex without vitality was spontaneously delivered, with data of hydrops and macerated skin, weight: 1,730 gr, with a grayish and hemorrhagic sacral mass (Figure 2). After resection of the tumor and pathologic examination the following report was made: An 820 gr Type I sacrococcygeal teratoma (SCT) with mature and immature elements as well as blood sequestration areas, partially encapsulated with extensive areas of coagulation and necrosis. Placenta was grossly edematous and weighed 1,280 gr with a marked hydropic change of the villi, with an area of intervillous fibrinoid infarct was noticed. Amnion and chorion had no alterations. The umbilical cord had three blood vessels with marked edema of Wharton's jelly. The patient received counseling and was discharged 3 days after delivery without edema or any other physical alteration.

PMC6260906_01

Male

A 77-year-old-man was admitted to our respiratory department for an organized, unilateral pleural effusion. He reported a severe former smoking habit (150 pack/years). He worked mainly as a tailor and, for some years, as a metalworker; he is currently retired, and he spends his time in his garden. His medical history demonstrated that he suffered from arterial hypertension, treated with 10 mg of Olmesartan once daily. He underwent partial gastrectomy some years before for a peptic ulcer. In the month before the admission, he reported a stroke, which led to slight dysarthria; because of this, he is currently on therapy of 300 mg Aspirin once daily. He denied any clinical history of ischaemic heart disease, heart failure, or diabetes. No apparent sources of asbestos exposure were known. In the month of April 2018, he came to the emergency department of our hospital for acute dyspnoea and tachyarrhythmia (166 beats/min) with a normal arterial pressure (120/80 mmHg). He had a partial arterial oxygen pressure (PaO2) of 57 mmHg with normal partial arterial carbon dioxide pressure (PaCO2) and pH. The patient also complained of exertional dyspnoea from a few months. He denied fever, cough, and chest pain in the previous months. Blood tests showed macrocytic anaemia (haemoglobin 11 g/dL, mean cell volume 104 fL), a slight value of inflammatory response (leucocytes 10.5 x 109/L with 80% neutrophils, C-reactive protein 28.70 mg/L). The electrocardiograph showed a paroxysmal atrial fibrillation, which was treated with amiodarone and oral anticoagulation therapy. The chest X-ray showed a unilateral, organized pleural effusion (Fig. 1). A chest CT scan showed a right, organized pleural effusion and a thickening of the right parietal and mediastinal pleura, suggestive of malignant pleural disease, without mediastinal lymph node involvement but with a compressive atelectasis of the adjacent lung parenchyma (Fig. 1). On the suspicion of pleural mesothelioma or a pleural localization of a lymphoproliferative disease, the patient underwent medical thoracoscopy, in which multiple biopsies were performed and a pleural drainage was performed, with a removal of 850 mL of pleural fluid. Physical examination of the pleural fluid showed a corpusculated, orange-coloured liquid with many cords of fibrin; chemical analysis showed an acid pH (7.18) and lactate 9.9 mmol/L, with pleural fluid lactate dehydrogenase (LDH) of 7849 IU/L and total proteins of 5.7 g/dL. Light's criteria were positive for an exudative pleural effusion. Cytology showed a relevant inflammatory pattern, mainly composed of neutrophils (60.9% of total) and lymphocytes (36.5% of total); no neoplastic cells were described. The research of mycobacteria tuberculosis through in vitro culture was negative. A peripheral lymphocyte subset typing method by cytofluorometry excluded lymphoid malignancies. Histological exam performed on biopsies and pleural fluid showed a "purulent pleuritis" with evidence of Bacillus megaterium infection, which was sensible to all antibiotics tested, except for clindamycin. Therapy with meropenem of 3 g/day and levofloxacin of 500 mg/day was started, with benefits. A chest CT scan after two weeks of the antibiotic therapy showed a significant improvement (Fig. 2) with normality of blood exams. The patient was no longer dyspnoeic, without a need for oxygen. The patient achieved completed resolution.

bacillus megaterium infection, pleural effusion, pleuritic

PMC4285284_01

Male

In 2013, a 71-year-old man came to the Tropical Medicine Clinic at Heidelberg University Hospital (Heidelberg, Germany) with suspected dengue fever 3 days after returning from West Africa to Germany. The patient had traveled for 6 weeks from mid-September through mid-October 2013 to Togo (Lomie, first 3 weeks), Benin (Ouidah, 1 week), back to Togo (Lomie, 1 week), and Burkina Faso (Ouagadougou, 3 days). Tests results for DENV nonstructural protein 1 and IgM against DENV were positive. The result of a real-time reverse transcription PCR for DENV 1-4 was also positive. A serotype-specific real-time reverse transcription PCR identified DENV-3. To obtain the sequence of a 1,479-nt fragment of the complete gene of the envelope glycoprotein gene, we designed generic primers specific for all complete DENV-3 genomes available from GenBank (alignment was performed by using Geneious version 6.1; http://www.geneious.com), which were then sequentially adapted to sequences obtained (primers and protocol available upon request). Sequencing of the complete envelope glycoprotein gene of the virus isolated from the patient identified DENV-3 genotype III (GenBank accession no. KJ922394). For phylogenetic comparison, we chose all DENV-3 sequences available from Africa and neighboring regions and a set of global sequences that represented different genotypes; DENV-1 was used an outgroup. Sequences were aligned on the basis of translated nucleotide sequences, and a neighbor-joining tree with p-distance was inferred with 1,000 bootstrap replicates in MEGA version 5.2.1 (http://www.megasoftware.net/) for a 1,479-nt fragment spanning the complete gene of the envelope glycoprotein and a smaller fragment of 220 nt (Figure). We observed clustering of the virus sequence with those of strains from Cote d'Ivoire and Benin. Genetic identity was 99% with strains from Cote d'Ivoire (AB447989) (1,472/1,479 nt) and Benin (AB690858) (1,469/1,479 nt). Because of limited availability of only 4 complete envelope glycoprotein gene sequences from Africa, an additional phylogenetic analysis was performed with a smaller fragment of 220 nt to include more sequences of African origin. A total of 7 sequences, including additional sequences from Senegal and Cameroon, were available. Clustering of sequences of African origin was confirmed in this analysis; highest sequence identity of virus isolated from the patient was with viruses isolated in Cote d'Ivoire, Benin, and Senegal. Nearly all sequence data for DENV-3 from Africa originate from returning travelers, such as reports of imported cases in 2006 from Cameroon to Spain, from Senegal to Spain in 2007 and to Italy in 2010, from Cote d'Ivoire to France and Japan in 2008, from Benin to Japan and France in 2010, and from Eritrea to Finland in 2010. Phylogenetic analysis of virus strains identified in these cases shows clustering with sequences of African origin, as observed for our patient. However, because only a small number of sequences of DENV-3 strains from Africa are available (and not all sequences refer to the same genomic region), a comparative phylogenetic analysis of strains from Africa is limited. A recent investigation of febrile patients from Gabon showed not only circulation of DENV-3, but simultaneous circulation of 3 DENV serotypes (DENV-1, DENV-2, and DENV-3) in West Africa. Molecular data for travelers are useful in areas where DENV diagnosis and surveillance are not routinely performed. The case-patient reported here highlights sustained transmission of DENV-3 genotype III strains or closely related strains during recent years. Increasing numbers of reports on local outbreaks and available phylogenetic information support ongoing DENV-3 transmission in West Africa. If one assumes a maximum incubation time of 14 days, our case-patient was most probably exposed to DENV in Togo or Burkina Faso. These 2 countries have not been considered as areas to which DENV is endemic. Our findings indicate that further systematic evaluation of the risk and disease burden of dengue in Africa is urgently needed. Dengue fever should be considered in travelers returning from Africa with acute febrile illness.

PMC5394216_01

Male

A 71-year-old man visited our hospital for a second opinion on his worsening dyspnea, recurrent for more than 6 months. 6 months ago, he had started to present dyspnea on exertion, which eventually worsened; he was admitted at a tertiary hospital. At the hospital, pulmonary function test results were normal except for the diffusing capacity for carbon monoxide, at 22.4 mL/mmHg/min (29%). Chest CT showed diffuse GGOs in the both lungs and consolidation at the left lower lobe (Fig. 1A). Echocardiography showed a mildly thickened left ventricle wall and moderate resting pulmonary hypertension (The maximal tricuspid regurgitation velocity 3.6m/sec). Heart biopsy was done to rule out amyloidosis, which came out negative. Bronchoscopic alveolar lavage (BAL) procedure was carried out; the fluid cell count included a total of 640 white blood cells, 64% alveolar macrophages, 12% neutrophils, and 24% lymphocytes. Additionally BAL culture provided no definite finding, as no pathogens were detected, including Mycobacterium tuberculosis and nontuberculosis mycobacteria. Transbronchial lung biopsy was not performed because of hypoxemia during the examination. These results, supplemented by others, prompted his attending physician at that hospital to explain to the patient that he was diagnosed as having suspected cryptogenic organizing pneumonia. Thus, the attending physician decided to treat him with 50 mg of intravenous methylprednisolone, as an empirical therapy. Initially, therapy was effective; however, upon gradual tapering of the steroid, recurrence of dyspnea on exertion occurred. Upon conducting a follow-up chest CT scan, newly developed multiple nodules were found to have been superimposed on GGOs in the both lungs (Fig. 1B). Subsequently, the patient visited our hospital for further evaluation and management of the worsening dyspnea. The patient had type 2 diabetes mellitus, dyslipidemia, a duodenal ulcer, and benign prostatic hyperplasia. The patient stated that before the dyspnea occurred, he had smoked 15 cigarettes per day for 50 years, totally 37.5 pack years. His family history and alcohol history were nonspecific. His vital signs showed blood pressure of 110 mmHg over 70 mmHg, heart rate of 93 beats per minute, respiratory rate of 22 breaths per minute, and body temperature of 36.4 C. His lung sounds were diffusely coarse in both sides. He had no cervical neck vein engorgement, organomegaly, or palpable mass. In laboratory examinations, he had a white blood cell count of 5990/mm3 of blood (neutrophil 80.9%), hemoglobin concentration of 11.8 g/dL, platelet count of 71,000/mm3, 306 mOsm/kg serum osmorality, 128 mEq/L sodium, 4.1 mEq/L potassium, 97 mEq/L chloride, 3.6 g/dL total protein, 2.1 g/dL albumin, 566 mg/dL glucose, 0.5 mg/dL total bilirubin, 28 mg/dL blood urea nitrogen, 1.4 mg/dL creatinine, 32 IU/L aspartate aminotransferase, 31 IU/L alanine transaminase, 1.9 mg/L c-reactive protein, and 1707 IU/L LDH. Blood gas analysis showed pH 7.41, PaCO2 25 mmHg, PaO2 61 mmHg, and oxygen saturation level was 96% at receiving oxygen 3L/min via nasal prong. Upon review of sequential chest CT at the previous hospital (Fig. 1) and high LDH level, we decided to perform SLB through VATS. On hematoxylin and eosin staining, pulmonary interstitium was filled with several atypical lymphocytes in the capillaries (Fig. 2). Immunohistochemical staining showed tumor cells were positive for CD20 (Fig. 3) and negative for CD3, S-100, HMB45, Pan-CK, CEA and CD31. Finally he was diagnosed as IVLBCL of lung. We referred him to Seoul St. Mary's hospital. Before treatment, positron emission tomography-computed tomography (PET-CT) was done as a baseline study. We found no abnormal 18-fluorodeoxyglucose (FDG) avid lesion (Fig. 4). Thus, we could confirm him as IVLBCL of lung without any other organic involvement. He was treated with R-CHOP chemotherapy for six cycles. One month later, he came back to the outpatient clinic of the hematology of Seoul St. Mary's hospital after completion of the chemotherapy. He said that he could climb mountain just like a few years ago and had no dyspnea at all. His lung sounds were clear without crackles. In laboratory examinations, he had a white blood cell count of 15,770/mm3 of blood (neutrophil 81.0%), hemoglobin concentration of 10.2 g/dL, platelet count of 281,000/mm3, 26.0 mg/dL blood urea nitrogen, 1.24 mg/dL creatinine, and 726 IU/L LDH. In radiologic findings, the comparison of sequential chest CT images before and after R-CHOP treatment were also compatible with complete remission of IVLBCL (Fig. 5). He went back home looking forward to his next visit to the hospital.

intravascular large b-cell lymphoma, lactate dehydrogenase, video-assisted thoracoscopic surgery

PMC9023043_01

Female

Focusing on the case of a Japanese-born celebrity athlete who resides in the United States and has attained global fame as a highly successful tennis player on the world stage, the theme of this study has both a domestic and a comparative-transnational component. Naomi Osaka was born in Chuo-ku, Osaka in 1997 as the daughter of a (Black) Haitian father and a Japanese mother (Cheng,; Lock,; Natividad,; O'Malley,). At age three, she moved with her family to the United States to live with her father's parents. Her father was inspired by the success of Serena and Venus Williams to guide his two daughters, Naomi and one-year older sister Mari, towards a successful tennis career. In 2006, the family moved to Florida so that the two sisters could have access to better training opportunities. Naomi became a professional player in 2013, and gradually rose in the world rankings. Her breakout year was 2018, when she won the U.S. Open tournament, becoming the first Japanese woman to win a grand slam. While sister Mari retired from tennis in March 2021, Naomi Osaka has continued to gain world-wide fame and recognition as one of the most successful tennis stars and one of the richest women athletes in the world today (Badenhausen,; Fendrich,; Natividad,). Although the focus of this paper is situated within a distinctly American framework, especially concerning the racial dimensions of criminal justice, the impact of Osaka's criminal justice activism is transnational in scope. To some extent, the wide reach of celebrity activism goes hand in hand with the spread of celebrity culture as a global phenomenon, but in the case of Naomi Osaka it also relates to the tennis player's unique background as a bi-national athlete. Although Osaka has lived most of her life in the United States, in tennis she officially represents Japan, in which country she also holds sole citizenship since 2019 (Lock,). As such, the tennis sensation culturally reflects an intrinsic measure of duality and interconnectedness between American and Japanese society. It is in the United States that Osaka has been most prolific in her activism on matters of criminal justice, but her appeal, as will be shown, extends well beyond the country's borders. While celebrities in Japan and in other Asian nations have generally not been as involved in activism, the differences across cultures are remarkably reflected in the case of Osaka, because, as the biracial daughter of a Haitian father and a Japanese mother, she has attained success and fame in a global context. Besides its transnational reach, Osaka's activism has also been peculiarly successful, not so much in bringing about effective change, as in being widely discussed and favorably received among the public at large and in the news media that shape popular opinion (Gomez,; Lawrence,; Maine,; O'Malley,). Along with an appreciation of her athletic prowess, Osaka is today widely embraced as one of the key figures in the world of celebrity (and sports) activism, even though her advocacy has started only recently. As part of the recognition of Osaka's activism and standing as a celebrity, several scholarly contributions have already been devoted to the tennis star, particularly concerning her racial identity and advocacy on racial justice, both in the form of short commentaries (Allen & Brown,; Montez de Oca,) and in-depth analyses (Calow,; Deflem,; Razack & Joseph,). Centered on Osaka's criminal justice activism, I will adopt a constructionist framework to investigate the interplay between the (subjective) motives and objectives and the (inter-subjective) reception of her efforts. This inquiry should demonstrate the criminological value of the study of celebrity as an important element of contemporary culture. The specialty area of cultural criminology has advanced very well in recent decades as a valued field of theorizing and research (Ferrell,; Ilan,). Moreover, celebrity and fame have for some years now become topics of considerable scholarly attention (Ferris,; van Krieken,). However, the relevance of celebrity culture for the study of crime, deviance, and social control has not yet received due attention in the field of criminology. There exists a body of literature on celebrity culture and crime, but it focuses mostly on famous criminals and cops in lore and legend (Penfold-Mounce,; Steenberg,). Similarly, with respect to celebrities in the world of sports, a small but interesting specialty area of sports criminology focuses largely on crime and social control in sports (Atkinson & Young,; Groombridge,) rather than on sports as an arena for activism on matters of crime and criminal justice. This paper seeks to fill the void in the criminology of celebrity culture by examining the activism of Naomi Osaka on matters of police and criminal justice. I will investigate Osaka's criminal justice activism from the viewpoint of the development and criminological relevance of contemporary celebrity culture during the COVID-19 pandemic. In a first section, I will explain my theoretical perspective to conceive of celebrity as a cultural phenomenon and clarify the data and methodology used in this paper to investigate the case of Osaka. Next, I provide a brief descriptive account of the development of celebrity culture during COVID-19, in which context I will subsequently present a detailed overview of Osaka's activism and its focus on police and criminal justice. Thereafter, I will separately analyze the dynamics of this activism in terms of its motives and objectives, on the one hand, and the impact and public reception thereof, on the other. The relationship between these subjective and inter-subjective dimensions is important to consider given the intrinsically mediated nature of celebrity. Theoretically this study will lead me to substantiate two related arguments. First, grounded in the case of Osaka's criminal justice activism, I will develop a model on the conditions for celebrity activism to be positively embraced. Second, with respect to the implications of celebrity activism, I will argue that the case of Osaka shows that her (and other celebrities') activism has brought about that critical dimensions of criminal justice, specifically police reform and charges of racial inequity, have themselves become subject to a process of celebritization. More broadly, these findings suggest the value of treating celebrity activism on matters of criminal justice as an exponent of a celebrity culture that is intruding in on, rather than emanating from within, ongoing debates in the wider culture of criminal justice. Celebrity and fame can be conceptualized in terms of a relationship that is mediated in various ways between the public and the object(s) of its attention. Fame (being well-known) and celebrity (being known or celebrated for being well-known) are therefore relational terms rather than qualities of a person or persons. These conceptual clarifications are uncontested as the subject matter in the sociology of celebrity (and the interdisciplinary field of celebrity studies), but disagreements exist concerning the nature and role of celebrity (Deflem,, pp. 17-23; Rojek,; Turner,; van Krieken,). Broadly, two competing theoretical perspectives divide the scholarly study of celebrity. One, a political economy approach emphasizes the political and economic functions of celebrity culture in capitalist societies to appease the public and divert attention from market contradictions and potential political conflicts. Rooted in C. Wright Mills' famous study of the power elite, this perspective understands celebrity as being "created from above" in order to provide entertainment as a "shadow of money and power" (Mills,, pp. 71, 83). In this sense, some contemporary scholars argue that celebrity culture serves a mechanism "for mobilizing abstract desire" to serve capitalist goals (Rojek,, p. 189). Two, a constructionist perspective, within which my work is situated, critiques political-economic theories of celebrity as reductionist and instead focuses on the study of celebrity as culture, comprised of the whole of meaningful beliefs and corresponding practices surrounding the spectacle of fame in society (Deflem,, pp. 19-22). This perspective understands celebrity as a form of cultural esteem or prestige that is constructed between the public, as the onlookers, and a society's celebrities, as the focal points of the public's attention. As such, celebrity relates intimately to the media through which it is established. In today's age, these media have greatly diversified and become ever-present in social life, especially because of the expansion of the internet and the popularity of social media. Operated on held-hand devices, a wide range of media now allow for a multitude of ways to create celebrity, whether by embracing or critiquing the stars of fame and infamy. Among its sociologically relevant characteristics, celebrity is associated with various forms of privilege (Kurzman et al.,). Celebrities typically enjoy a measure of economic privilege (to garner monetary wealth), legal privilege (to protect their acquired status), interpersonal privilege (to engage, horizontally, with other celebrities, as well as vertically, with the public), and normative privilege (to function as role models). As part of the latter form of privilege, celebrities can rely on their elevated position in the cultural sphere to take on various advocacy causes. The activism of celebrities has an inevitably unique feature in readily relying on special access to the media through which their fame is constituted, which can be used to promote their causes with great visibility towards a large audience. The consequences of celebrity activism on the part of the public, however, cannot be predetermined on the basis of media access or any self-stated motives and objectives, but need to be examined from case to case. In this paper, I will therefore investigate the criminal justice activism of Naomi Osaka in terms of the tennis star's proclaimed motives and objectives, on the one hand, and the impact and reception thereof in the news media and among the public at large, on the other. A clarification is in order about the methodology adopted in this paper and what this study accordingly can and cannot accomplish. Conceived as a case study, this paper cannot make strong claims to generalize from Osaka's criminal justice activism to cases of advocacy undertaken by other celebrities in sports and elsewhere. Such an inquiry would have to be made on the basis of a systematic study of the whole of celebrity activism or a sample thereof. Suffice it to say that the case of Osaka does not stand alone and that it can be situated within a broader trend towards the adoption of activism among celebrities that developed over the course of the COVID-19 pandemic. While not claiming Osaka's activism to be representative of the whole of celebrity culture, the adopted case study approach allows for an in-depth analysis of Osaka's activism as illustrative of a peculiarly successful case against which other cases can be measured in further research. Thus, the methodology used in this paper does not seek to test a proposition of specifically interrelated variables but, instead, will develop a well-grounded proposition on the factors that promote the reception of celebrity activism. In no small part because of her activism, Naomi Osaka is today widely embraced and placed at the center of celebrity culture, both as an accomplished athlete as well as with respect to activist causes, especially on matters of race and criminal justice (Dator,; Lawrence,). To make sense of this success of Osaka's activism, this inquiry relies on an interpretive strategy, communicated in narrative form, which further research can examine more systematically on a large number of cases. This approach does not adopt the hypothesis-testing strategy of the quantitative method of Content Analysis as introduced by Klaus Krippendorff, but instead relies on the theory-generating qualities which a thick description, to use Clifford Geertz' term, can provide. This approach is not merely descriptive, however, as it is theoretically guided and centered on specific questions of research. Guiding this examination of the roots and trajectory of Osaka's criminal justice activism from May 2020 onwards will be the following three questions: 1) (Objective) Actions: Which kinds of activist conduct on which thematic issues has Osaka engaged in?; 2) (Subjective) Motives and Objectives: How has Osaka defined and justified these actions in her own terms and by her own understanding?; and 3) (Inter-Subjective) Response: How has Osaka's advocacy been responded to in the news media and among the public? Given the centrality of media in the construction of celebrity, the analysis in this paper will rely on sources available on the internet, specifically news articles and social media posts. These data were retrieved through targeted searches conducted in Google News. This method not only allowed to retrieve a multitude of news sources but also relevant social media posts as the latter are typically discussed and linked into the former. When judged useful in terms of the research objectives, more targeted internet searches were conducted, specifically concerning Osaka's criminal justice activism, its actions, and reactions. This study's reliance on internet sources is all the more appropriate because of conditions brought about by the COVID-19 pandemic, specifically the limits that were placed on face-to-face gatherings because of social-distancing policies and the resulting increased reliance on virtual means of communications. During the pandemic, indeed, celebrity activism has predominantly taken place, and has been reported on, in the virtual world of the internet. The news sources relied upon in this paper, it should be noted, are primary sources of analysis because it is through these media that the fame between the public and its celebrities is constituted. Data were analyzed to retrieve the motives and objectives of Osaka's activism in matters of criminal justice as well as the reception thereof. Importantly, the reactions to Osaka's activism are not measured instrumentally in terms of whatever changes it may have brought about in the criminal justice system, but in terms of the effects it has had on public perceptions about criminal justice. As such, the focus will be on the culture of criminal justice as referring to the whole of popular beliefs and associated practices relating to the administration of justice. In view of certain high-profile events in the first year of the COVID-19 pandemic, especially the police killing of George Floyd in May 2020, the sentiments and actions of contemporary criminal justice culture have largely revolved around policing and police violence as well as alleged problems of racial (in)justice associated therewith. As explained in the next section, it is in the context of this broader move towards celebrity activism over the course of the COVID-19 pandemic that Naomi Osaka's criminal justice activism can be situated. In the present era, celebrities are everywhere, and everybody is exposed to the interventions of celebrities via the privileged access they enjoy in the media. Today's celebrities have increasingly been involved in a multitude of activist causes, bringing about the development of celebrity activism as a central component within the broader sphere of celebrity culture (Atkinson & DeWitt,; Katayama,). In recent years, celebrity activism has greatly expanded quantitatively and has also qualitatively broadened in scope to become more diverse in its orientation towards a wide variety of advocacy issues (Deflem,). Whether celebrities are sincere in these efforts or not should not preclude a scholarly examination of their actions and how these are received by the public in more or less favorable ways. Following the outbreak of COVID-19 pandemic in the spring of 2020, celebrity activism initially concentrated on relief efforts in the fight against the coronavirus (Billboard,). As the pandemic went on, however, celebrity involvements in activist causes diversified well beyond COVID-19 towards other social and political issues, including matters of racial justice, especially in response to certain high-profile incidents (Deflem,). Most important in this transformation was the video-taped police killing of George Floyd on May 25, 2020, which led to widespread protests and social unrest. Throughout June 2020, celebrities accordingly shifted their attention from virus-related concerns to discussions on policing and racial justice under the heading of the Black Lives Matter movement (Crawford,). Originally formed as an organization with a specific political intent, Black Lives Matter has since propelled a broad movement with global appeal and representation that focuses on racial justice concerns, especially regarding criminal justice and police violence. Throughout the pandemic in 2020 and the first half of 2021, celebrity activism continued and further expanded to include an increasing number of justice causes and political issues. Concentrating on the police killing of Breonna Taylor on March 13, 2020, celebrity activism additionally focused on gender inequality, particularly after September 23, 2020 when a grand jury decided not to bring charges against the police officers involved in the shooting of the Black woman (Musumeci,). Celebrity activism eventually turned towards politics in the leadup towards the U.S. Presidential elections in November 2020. However, since the victory of Democratic candidate Joe Biden, which was widely applauded by the largely left-leaning American celebrity elite (Long,), celebrity activism has diminished considerably, as shown from a sharp decline in news reports (retrieved through Google News) about celebrity activism and celebrity reactions to the ongoing pandemic. When media attention focused on incidents of anti-Asian violence across the United States in the spring of 2021, celebrities stayed noticeably silent, some exceptions notwithstanding (Carras,). Following the conviction of Derek Chauvin, one of the police officers involved in the killing of George Floyd, on second-degree murder on April 20, 2021, celebrities took to social media to express their satisfaction with the verdict. Since then, however, celebrities have mostly returned to a 'new normal' that began with the growing availability of the COVID-19 vaccines in the summer of 2021 (Chatterjee,). Although the appearance of later variants of the coronavirus, especially Delta (in the summer and fall of 2021) and Omicron (in the fall and winter of 2021), subsequently extended the pandemic, celebrities did by and large not return to the activism they had engaged in during the first year of the pandemic. Celebrity activism has since then not completely disappeared but has again become one of the routine elements characterizing contemporary celebrity culture. The activism Naomi Osaka engaged in over the course of the COVID-19 pandemic generally fits the turn towards the adoption of advocacy causes among celebrities at large. Remarkable about Osaka's activism is that it has already gone through various stages despite the relative short time since both the tennis star's athletic career and her celebrity status have been unfolding. In the following pages, I will provide an overview of this development, before examining its dynamics in the subsequent section. In line with the criminological focus of this paper, attention particularly goes to Osaka's activism in matters concerning policing, police violence, and other aspects of criminal justice, issues that have indeed been at the forefront of tennis star's activities and reception as an activist. Naomi Osaka's athletic career began blossoming from 2016 onwards when she entered the ranks of the world's best women's tennis players (Cheng,; Maine,; O'Malley,). After a relatively stagnant period in 2017, Osaka steadily improved her game over the course of 2018, leading to her first grand-slam victory at the U.S. Open. In the months that followed, she continued to be successful on the court. By the summer of 2020, Osaka had won an additional grand slam (the Australian Open) among other tournaments, was for some time ranked No. 1 by the Women's Tennis Association, and had become the highest-paid woman athlete of all time (Badenhausen,). Having garnered a large fan base in a sport where fans tend to have relatively high levels of income and in which women players, unlike many other sports, are closer to being as popular as their men counterparts, Osaka was particularly attractive for brand sponsorship. Most all of the $37 million earnings she had amassed in the 12-month period before May 2020 came from endorsement deals (Badenhausen,). It was very soon after Osaka had attained financial success and her newfound status as a global tennis star that she also began to engage in activism. Osaka's earliest forms of activism included using social media concerning matters of police violence and, especially, its impact on people of color in the United States. On May 29, 2020, Osaka first posted a tweet reacting to the George Floyd killing, albeit indirectly, stating "Just because it isn't happening to you doesn't mean it isn't happening at all" (Osaka,). She thereafter continued to use social media to express her concerns, posting images on Instagram showing her in Minneapolis participating at protests related to the killing of George Floyd (Carayol,). With respect to the motives of her advocacy, Osaka spoke to media outlets and on her social media platforms why she felt that it was important for her to engage in criminal justice activism and, more generally, why it would be appropriate for athletes to engage in advocacy. Osaka said she believed that her voice could reach and persuade many people who might otherwise not hear or care about events like George Floyd's murder and, ultimately, she hoped to bring about change (Tarrant,). She further stated that she found it telling that people who are successful in other careers, such as music, literature, and the arts, are more readily accepted, even expected, to speak out, while she and other athletes "are often met with criticism for expressing our opinions" (Osaka,). Osaka's earliest expressions of activism generally met with a positive reception, but there was some resistance against her actions as well. When a fan commented negatively on Osaka's Instagram post, claiming "Martin Luther King would be disappointed in you people," Osaka reacted by calling out the racially insensitive tone of the comment, remarking "You people? Who is you people? Just for clarification" (Carayol,). She responded to other criticisms in a similar rebuking fashion (Tarrant,). Although her statements calling out racism in Japan, in particular, met with some resistance from the Japanese public, reactions in the country of her birth were generally nonetheless mostly favorable as well (The Japan Times,). In the period leading up to and during the U.S. Open in the fall of 2020, Osaka more resolutely took on her newly acquired role as a criminal justice activist, extending her efforts to more media outlets and bringing them to the tennis court as well. She chose to be explicit and publicly communicate about what she was advocating and why. In an op-ed published in Esquire Magazine on July 1, 2020, Osaka explained that she decided to speak publicly after seeing the video of police killing George Floyd. "When I saw the horrific video of George Floyd's murder and torture at the hands of a cop and his three colleagues," she wrote, "my heart ached. I felt a call to action. Enough was finally enough. I flew to Minneapolis with my boyfriend days after the murder to pay our respects and have our voices heard on the streets. When I came back to Los Angeles, I signed petitions, I protested, and I donated, like many of us. But I kept asking myself what can I do to make this world a better place for my children? I decided it was time to speak up" (Osaka,). Osaka framed her actions explicitly in terms of her identity as a multi-ethnic woman, who answered the question if she is "Japanese," "American," "Haitian," "Black," or "Asian" by stating she considers herself "all of these things together at the same time" (Osaka,). In relation to criminal justice, Osaka therefore drew attention to alleged Black victimization by police and voiced support for the idea to defund the police. "By that, I don't necessarily mean to eradicate them altogether," she explained, adding instead that "Some of their funding :like payment plans to cops who have been convicted of crimes: should be re-allocated to social measures within the community: Education, housing and youth programs, which are so often neglected" (Osaka,).

celebrity activism, celebrity culture, criminal justice culture, naomi osaka, police violence, popular culture

PMC9023043_02

Male

In protest against the (non-lethal) police shooting of 29-year-old Black man Jacob Blake on August 23, 2020, Osaka took a next action in her burgeoning activism by announcing she would withdraw from her upcoming semifinal match at the Western & Southern Open tennis tournament in Cincinnati (Harvey,). Although Osaka was the only tennis player at the tournament who had decided not to play, athletes in other professional sports such as basketball, soccer, and baseball that day also withdrew from their athletic events (Dator,). Osaka again took to social media to explain her decision, posting a statement on Twitter written in both English and Japanese (Osaka,) in which she argued that her racial and gender identity superseded her standing as a tennis player. "Before I am an athlete," Osaka wrote, "I am a black woman. And as a black woman I feel as though there are much more important matters at hand that need immediate attention, rather than watching me play tennis" (Osaka,). As to the objectives of her actions, Osaka hoped that her decision not to play would turn the public's attention on the problem of police violence. "I don't expect anything drastic to happen with me not playing," she explained, "but if I can get a conversation started in a majority-white sport, I consider that a step in the right direction" (Osaka,). Following Osaka's decision not to play, the Cincinnati tournament organizers postponed all matches scheduled for that day. When the semifinal eventually took place, Osaka entered the court wearing a 'Black Lives Matter' t-shirt. She would go on to win the match, but later had to exit the tournament because of an injury (Srikanth,). The reactions to Osaka's decision to withdraw were mostly positive, but a few commentators criticized her. A reporter writing in the National Review, for instance, accused Osaka of being "misguided" and making "irresponsible claims" concerning racism and police violence (Seminara,). Taking advantage of the popularity of the U.S. Open that began on August 31, 2020, Osaka intensified her activism against police violence. In a very visible fashion, Osaka participated at the New York tennis tournament wearing facemasks, mandated in view of the COVID-19 pandemic, that carried the names of Black victims of police violence and other alleged injustices. Having prepared seven different masks, each carrying the name of a Black victim of police and vigilante violence (Breonna Taylor, Elijah McClain, Ahmaud Arbery, Trayvon Martin, George Floyd, Philando Castile, and Tamir Rice), Osaka planned to wear a different mask for every day she could play at the tournament (Black Voice News,; Lampen,). Using the facemasks as an additional motivation to play well, Osaka eventually wore all seven masks as she made it to finals and also won the tournament. Asked during a post-game interview what message she was meaning to send wearing the facemasks, Osaka said that she hoped that people who were unfamiliar with displayed names would go on to find out more about them and become more concerned about racism and police violence (Lampen,). Osaka further reiterated that she aspired more people to talk about the issue as a result of her actions (Black Voice News,; Srikanth,). As with many of Osaka's activities on and off the court, Osaka's actions and statements at the U.S. Open garnered a lot of media coverage and public reactions, mostly praising the tennis star for her willingness to speak out (Dator,; Lampen,; The Japan Times,). The parents of Trayvon Martin and Ahmaud Arbery posted videos thanking Osaka for publicly displaying their respective son's names (Tucker,). Osaka's Coach, Wim Fissette from Belgium, also supported the tennis star's activism, noting that she had a "great attitude on court" and also was a "role model off court" (The Japan Times,). While Osaka herself reiterated that her primary goal was to bring awareness about the unjustified killings and offered to help the families if they needed anything (Lampen,), her family came out in support of her actions as well (The Japan Times,). At the finals, Osaka had also been cheered on by her boyfriend, Black rap musician Cordae, who sat in the stands in a t-shirt that read 'Defund the Police' (Bryant,). Cordae had been among the 87 people arrested in Louisville, Kentucky, in July 2020 while protesting at the home of attorney general Daniel Cameron to pressure him to arrest the police officers who had killed Breonna Taylor (McDonald,). The rap star's opinions and conduct did not stand alone as several celebrities, in the aftermath of the police killing of George Floyd, expressed support to defund the police (Willen,) and some were arrested while engaging in protest (Gonzales,). Following the U.S. Open, the increasing media coverage about Osaka, as the newest star of women's world tennis, began to more broadly reflect on her role and standing as an activist, positioning the tennis champion in the tradition of sports activism, especially among Black athletes (Lawrence,; Sawyer,). The vast majority of this coverage was positive, with commentators lauding Osaka for her justice advocacy and comparing her to other famous sports activists, such as Lebron James, Serena Williams, and Billie Jean King (Gomez,; Reyes,). In December 2020, Osaka was named Female Athlete of the Year by the Associated Press (Fendrich,). With Lebron James having been chosen as Male Athlete of the Year, the two sports stars received the honor not only because of their athletic achievements, but also and explicitly because of their activism (Sawyer,). Osaka had thus reached not only the top of tennis, but the top of activism among celebrity athletes as well. By the beginning of 2021, Osaka had acquired global success and fame both in and beyond the world of sports, leading her once again to step up her activism. Similar to how she had justified the beginning of her activism in an op-ed in Esquire, in December of 2020 Osaka clarified her continued actions in the form of an op-ed published in The New York Times under the title "Athletes, Speak Up" (Osaka,). In it, she countered the idea that athletes should not speak about social issues and injustices. Lauding the activism of other athletes, such as LeBron James, Colin Kaepernick, and fellow tennis players Venus Williams, Coco Gauff, and Billie Jean King, Osaka argued that athletes not only have a right to publicly express opinions they deem important, but, in fact, "have a greater responsibility to speak up" (Osaka,). By the beginning of 2021, Osaka had become not only a global tennis star and widely respected activist, she had also greatly expanded her wealth by continuing to secure a multitude of brand partnerships (Fendrich,; Uwumarogie,). Among the lucrative deals were endorsements for watchmaker Tag Heuer and fashion brand Louis Vuitton (O'Malley,) and participation in Levi's campaign 'Beauty of Becoming' to produce advertisements that were designed as both marketing tools and inspirational videos (Rivas,). In preparation of the Australian Open tournament in February 2021, there had been some negative reaction against the fact that Osaka and a select number of other tennis players could practice in a location with fewer COVID-19 restrictions than other tennis players (Zaczek,). Yet, most of this criticism was targeted at the organizers of the tournament, not at Osaka, who would go on to win the tournament, making her only the 9th woman to win at least one grand slam in four consecutive years (Fendrich,; Gaillot,). Following her success at the Australian Open, Osaka again broadened the scope of her activism, specifically by adding an attention to gender inequality. When the tennis star became part owner of the professional women's soccer team North Carolina Courage, for instance, she justified the decision because of her self-understanding as a role model for women to seek leadership positions and work towards closing the gender pay gap in sports (Gaillot,). Considering her reasons for taking up various roles besides playing tennis, Osaka stated that part of what inspires her to play well is that she seeks to inspire others, especially young women, in the same way that the Williams sisters had been an inspiration to her (Fendrich,). In a February 2021 interview, Osaka reiterated the personal motive of her activism as a person who is "not half anything" but feels "both Japanese and Haitian fully" (Gaillot,). She clarified her objectives to end police violence and racial injustice by contributing to raise awareness among her fans "about what was going on in America and encourage them to have those hard conversations" (Gaillot,). Throughout the spring of 2021, Osaka continued to receive endorsement deals and win awards, while her activism expanded as well. Taking her activism to Japan, Osaka launched a project called "Play Academy with Naomi Osaka" aimed at helping girls get involved in tennis. Justifying the initiative, she stated that she seeks to be a role model for other young women to also take on both athletics as well as activism (Warner,). Osaka also continued using social media to share her concerns. Following a violent attack involving Asian-American women in late March of 2021, she lamented how people who enjoy Asian culture can have so little respect for Asian lives (Goodwin,), echoing a concern she had earlier raised about Black cultural appropriation without regard for Black lives and the Black experience (Carayol,). Osaka's fans and followers on Twitter overwhelmingly expressed approval of her actions (Ciotti,). Criminal justice concerns continued to motivate Osaka as well. On April 20, 2021, the day when former Minneapolis police officer Derek Chauvin was found guilty of the (second-degree unintentional) murder of George Floyd, Osaka was one among many celebrities and athletes to express her thoughts. She stated that although she was glad that Chauvin was convicted, she was upset that his fate had been in doubt at all (Kyodo News,). Osaka's comments, like those of other celebrities, received widespread and favorable media attention (Hatzipanagos,; Lawrence,; Lutz,; Tarrant,; The Japan Times,). Over the summer of 2021, Osaka's career and standing as a successful celebrity activist continued on. On May 2, 2021, Osaka was announced as the winner of the Sportswoman of the Year award from the Laureus World Sports Awards (Harris,). Again, she received the award not only for her athletic skills but also for her role as an activist. Tweeting the announcement of the award, the Laureus organization mentioned Osaka winning two US. Open titles and that off the court "she demonstrated incredible activism and support for the Black Lives Matter movement" (Laureus Sport,). For the same combined reasons of athletics and activism, Osaka was also included in Time magazine's 2020 list of most influential people in the world and was featured among the athletes gracing the cover of Sports Illustrated when the magazine chose 'The Activist Athlete' as the 2020 Sportsperson of the Year (Fendrich,). On a commercial level, Osaka continued to be very successful as well. Among other ventures, she began a partnership with Bodyarmor sports drink (Uwumarogie,), invested in restaurant chain Sweetgreen (Harris,), and created a swimwear line and skincare products company geared towards people of color (Badenhausen,; Trinh,). On May 25, 2021, the one-year anniversary of the killing of George Floyd was commemorated with public demonstrations across the United States. However, most celebrities remained silent, and Osaka was no exception (Yasharoff,). Instead of commenting on the Floyd killing, Osaka that day tweeted a funny video of her falling on her behind during tennis practice for the upcoming French Open (Osaka,). On the same day, it was reported that Osaka was the year's highest-earning woman athlete, having earned $55 million in the prior 12 months (Badenhausen,). The next day, Osaka tweeted that she would not hold press conferences at the French Open (Osaka,), soon followed by her decision, posted on Twitter on May 31, to withdraw from the tournament altogether (Osaka,). Citing "long bouts of depression" and "social anxiety" (Osaka,), the singular tweet brought about an avalanche of attention and support, thereby almost instantly turning Osaka into a mental health advocate (Mitchell,), a position she has been able to retain and strengthen since (Gillen,). The sociological study of culture, including popular culture and celebrity, should always examine relevant structures and processes as part of the broader social order in which they are situated. This comprehensive focus should at the same time also allow for an examination of the relationship between celebrity culture and other social institutions. One immediate observation on the relevance of Naomi Osaka's criminal justice activism for criminology and the study of criminal justice is that her fame and popularity readily imply that her activism, no matter its validity, is relevant to criminal justice and how it is perceived. The criminal justice activism practiced among celebrities is criminologically relevant inasmuch as it can and does affect criminal justice culture by influencing popular beliefs and attitudes concerning crime and criminal justice. This influence can be analyzed in terms of the interplay between the celebrity's motives and objectives, on the one hand, and its impact and public reception, on the other. What is readily noticeable about Osaka's criminal justice activism is that she defines her actions not primarily in terms directly associated with crime or policing, but on the basis of her racial identity as a Black woman. As recent discussions on police violence in the United States have primarily been framed in racial terms, Osaka could successfully rely on her minority status, which she also visibly amplifies by means of dress and style (Midkiff,). Contemporary popular sentiments are generally also respectful of people's racial identity, so that Osaka's (subjective) presentation of self has generally also been (inter-subjectively) well received among the public at large (Nayak,). The sincerity of Osaka's motives and objectives, "to make people start talking" (Osei,), need not be questioned to observe that she has in this respect been successful in fostering awareness by bringing matters of policing and police violence to people's attention. In an August 2020 interview, Osaka explained that she initially thought her opinion would not matter, but she changed her mind upon visiting Minneapolis after the George Floyd killing. "Just going there and seeing how the whole city was at that moment," she said, "I just started thinking, 'Even if one person cares about what I say, then maybe that person will show another person'" (Cheng,). Osaka also understood that her success as a tennis champion had brought about a measure of celebrity status that gave her a powerful platform from which to voice her opinions. "Today, given the television coverage we receive and our prominence on social media," she wrote, "athletes have platforms that are larger and more visible than ever before" (Osaka,). Relying on her acquired status as a successful athlete, Osaka thus realized that she, like many other (minority) athletes before her, was uniquely placed to speak on activist causes. In an age of generally increased concern over discriminatory practices, moreover, Osaka's explicit presentation as a woman athlete made her advocacy work be as respected as, if not even more so than, that of the successful men in sports among whom activism has historically been more prevalent (Gomez,; The Japan Times,). In line with her self-understanding (as a Black woman) and her acquired position (as a star athlete), Osaka has framed her criminal justice activism as part of a broader racial justice activism (Deflem,). In her Esquire op-ed, Osaka especially highlighted and criticized the racial injustices she claimed to exist in the United States as "oppression" against which, she wrote, "Being 'not racist' is not enough. We have to be anti-racist" (Osaka,). Likewise, Osaka critiqued the silence of (non-Black) people who, she said, can be fond of engaging with Black culture while refusing to take a stand against racism (Carayol,). Following the video-taped police shooting of Jacob Blake, Osaka went as far as to speak of "the continued genocide of Black people at the hands of the police" (Osaka,). In her New York Times op-ed, she similarly framed the matter in terms of the nexus between "systemic racism, inequality and police brutality" (Osaka,). Thus, rather than relying on considerations related to crime control and methods of policing, Osaka focuses on the Black victims of police violence and other incidents that have via their media exposure, especially during the coronavirus pandemic, attained great symbolic significance. In this sense, Osaka practices what could be called a 'Black liberation criminology' inasmuch as she understands the problems associated with criminal justice in terms of racial identity and racial (in)justice affecting Black life and seeks to contribute to an emancipation from these conditions. To be sure, the tennis star does not construct her ideas systematically as a criminologist would, but justifies her thoughts and actions on the basis of her (minority) standing as a Black woman who takes advantage of the opportunities afforded to her to speak out because of her (elevated) standing as a tennis champion. In terms of the consequences of criminal justice activism, it is of course too soon to say if any ongoing or future changes in policing and other aspects of criminal justice might be attributed to, or at least said to have been aided by, the activism of Osaka and other athletes and celebrities. Such instrumental considerations need also not be the sole focus of a scholarly examination. Instead, Osaka's criminal justice activism can also be examined in terms of the impact it has had on her career and social standing as well as its reception by others. In this respect it can be straightforwardly observed that the tennis star has been able to establish a highly successful career and garner enormous wealth, especially by means of endorsements (Badenhausen,; Natividad,). Endorsements are an important and concrete sign of success and impact as companies interested in profit will choose to work with athletes who have great public appeal. In terms of its impact on Osaka's standing as a celebrated athlete and cultural icon, the tennis player's activism on criminal justice (and other matters, especially mental health) has generally been very well received in the news media and by the public (Black Voice News,; Lawrence,). Osaka's activist efforts directly contributed to her receiving numerous awards and positively influenced her financial standing by means of endorsements. Her success as a tennis player has gone hand in hand with, and has at times even been superseded by, her success as an activist and a brand, to wit her continued high earnings and positive standing as an activist throughout 2021 despite a decline in success on the tennis court (Mitchell,). When Osaka plays (or refuses to play) tennis and when she wins (or loses) tournaments, she always makes sure to place a spotlight on advocacy issues. When she is given awards, both her activism and her athletics are explicitly noted. And whenever Osaka is discussed in the media, she is routinely placed at the center of sports activism. Strikingly, even when the primary topic of a news story is Osaka's tennis, her activism and ideas about policing, race, and criminal justice are often also discussed (Maine,; Osei,). In today's lucrative world of professional sports, it is useful to examine the financial and other effects of activism on athletes who express opinions in matters that resonate strongly with public sentiments, such as crime and policing. Most (in)famous in this respect is the career of former NFL football player Colin Kaepernick (Nugent,). During the 2016 NFL season, Kaepernick sought to draw attention to alleged racist police violence by taking a knee while the national anthem was being played before games. The following year, he was released from his contract, presumably for athletic reasons, although he and others have claimed he was let go (and remained unsigned) because of his actions against police violence. Regardless of differing opinions about his conduct, Kaepernick has become an important test case to measure the impact of sports activism (Allen & Williams,). Some observers have argued that athletes who engage in advocacy have typically been in danger of losing money and other rewards as a result of their actions (Bryant,). However, following several much publicized high-profile incidents of police violence (most notably, the video-taped police killing of George Floyd), indications are that the situation today has reversed as justice advocacy goals and company profit objectives now tend to go hand in hand. Among the beneficiaries of changing attitudes concerning criminal justice in the post-Floyd era has been Colin Kaepernick himself, whose actions have most recently become more readily accepted, especially in the media and in the corporate world (Boykoff & Carrington,). Although the former NFL quarterback has not been re-instated as a professional athlete, he has in the meantime acquired the status of a civil-rights advocate, contributed to making protest against police violence almost routine, and been able to profit from various lucrative sponsorship deals (Marston,). In March 2022, Kaepernick teamed up with Naomi Osaka by joining the board of directors for the tennis star's skincare brand Kinlo (Trinh,). In the post-Floyd era, the changed atmosphere of collective sentiments in criminal justice culture, readily expressing concerns about racial injustice and other assumed inequities in criminal justice, also contributed positively to the reception of Osaka's activism. "Now, everybody talks about brands taking a stand," as a sports marketing expert explains, so that Osaka's activist efforts are more readily perceived as reasonable and her speaking out publicly "comes across as very real" (Badenhausen,). With additional credence given because of her identity as a young biracial Black Japanese woman, Osaka has thus benefited from the post-Kaepernick climate of public opinion that implied a sharp reversal of the skepticism traditionally voiced against athlete activism towards a ready embrace thereof. In terms of the impact of Osaka's criminal justice activism, Osaka herself has expressed that, while she realizes that drastic changes are needed to "take on systemic racism head-on, that the police protect us and don't kill us," to bring about such change, she said, "I am proud, too, of the small part I have played in changing perceptions and opinions" (Osaka,). While Osaka understands that organizational changes are needed for her activism to be truly consequential, she thus conceives of her impact on public opinion as a first step in that direction. "Watching the police injustices like George Floyd, Breonna Taylor and Jacob Blake (to name just a few)," Osaka stated in an interview, "broke my heart. I am proud of my U.S. Open victory, but more so that I got people talking about the real issues" (Fendrich,). Given the nature of contemporary celebrity being constituted primarily through social network sites and news outlets, any impact of celebrity activism on a societal level must take place via the media. Shaping public opinion about Osaka, the role of professional news media cannot be overstated as they function as a powerful vehicle through which both her career and her criminal justice activism are known to the public. In that respect, a first observation is that the news media have not only spent a lot of attention to Osaka's activism, on criminal justice as well as other issues, but also that they have generally treated it very positively (e.g., Lawrence,; Maine,; Mitchell,; Reyes,; Warner,). Osaka is now routinely referred to, not as just a tennis player, but as an 'activist-athlete,' right alongside of other influential athletes who took many years to acquire that status (Fendrich,). Remarkable indeed has been the ease and swiftness for Osaka's activism to be (inter-subjectively) very well received when it (objectively) consisted of relatively few concrete actions, mostly tweets, opinion pieces, and an expression of sentiments in interviews. The widespread favorable attention that has been given to Osaka's activism in the media and by the public extends well beyond the borders of the United States to include her native Japan and many other parts of the world. Osaka is among the few biracial Japanese athletes to have publicly addressed issues of racial diversity and social justice, topics that are not as commonly discussed in Japan as they are in the United States, and she has done so with a measure of success that has fostered debate in the country of her birth (Henson,; The Japan Times,). This transnational reach of Osaka's activism is not altogether obvious inasmuch as her activism is largely focused on conditions pertaining to the United States. The criminal justice issues addressed by Osaka might even be said to be distinctly American because of their relationship with racial conditions, guns, and the dynamics of U.S. law enforcement. However, apart from the fact that tennis is an essentially global sport with tournaments in many parts of the world, Osaka was able to draw attention to problems of police violence and racial injustice on a geographically larger scale than many other athletes before her because of the manner in which she framed the issues of her advocacy. Osaka is not only a biracial woman with Japanese and American nationality and self-identity, she also deliberately sought to have an international impact, taking advantage of the growing awareness of the issues she addressed across the world. As Osaka wrote in her Esquire op-ed, she observed that the protest movement against police brutality and racial injustice had "gone global :from Oslo to Osaka, from Tallahassee to Tokyo... There were even Black Lives Matter marches in Japan -something many of us would never have expected or imagined possible" (Osaka,). Osaka's agent Stuart Duguid also explained the tennis star's global aspirations, noting that his client "has appeal in every continent -Asia obviously as her home nation; America as the place she was born and raised and probably most identifies with the culture; Europe where they are tennis-mad; and Australia where she is a recent grand slam champion" (Chammas,). Osaka herself has commented that her identification as a biracial athlete and her activism have also been favorably received in Japan. Although she noted an "ignorance of a few," she stated that she and other Black-Japanese athletes "have been embraced by the majority of the public, fans, sponsors, and media" (Osaka,). When she retweeted a post about a Black Lives Matter demonstration in the city of Osaka, the tennis star commented, "that was cool, because I've never seen a Black Lives Matter protest anywhere in Japan" (Cheng,). Osaka also argued such protest efforts to be necessary in Japan, because the country would have its own problems with racism, which she claimed to have experienced herself in the form of alleged racist attitudes from the Japanese media (Nugent,). Although she understood that the ethnic homogeneity of Japanese society makes the country different from the United States, she also found that the vast majority of Japanese people have embraced her along with other biracial Japanese athletes (Osaka,). While more in-depth research would be needed to examine the public response to Osaka's activism in different nations, there are reasons to understand her claim about its positive reception in Japan (and possibly elsewhere) as more aspirational than realized. Celebrity activism is in Japanese society not nearly as developed as it is in the United States. It is also not as acceptable nor accepted for celebrities and athletes to speak out on public matters. Osaka realized that in Japan there "were some people really upset with me" (Cheng,). Looking at the reception of Osaka's criminal justice activism in Japan, some reactions have indeed been very negative. Especially some of the Japanese-language comments in response to the (otherwise favorably received) tweets by the tennis player in May 2020 harshly condemned her activism. Among the negative posts were claims that Osaka "isn't really Japanese," that "Boycotting the matches doesn't do anything," and even that "The guy who got shot by police deserved it" (Thompson,). Offsetting the occasionally harsh negativity, other people in Japan have shown their support for Osaka, including several notable positive comments from Japanese politicians who have said to stand "in solidarity with the protest against all structural racism" (Thompson,). Compared to the United States, the reaction to Osaka's activism in Japan can be said to be more ambivalent. As a Black Japanese woman, Osaka is in Japanese public opinion caught between a measure of pride over her tennis success (as the first grand slam-winning Japanese) and a reluctance to accept her racially motivated criminal justice advocacy (or, at best, to understand it as an issue that pertains to the United States). Over the course of the spread of the COVID-19 pandemic since the spring of 2020, celebrity culture has witnessed an increasing intensification and diversification of celebrity activism that had been going on for some years (Deflem,). In this relative short period time, as this paper has shown, Naomi Osaka emerged as a much admired activist addressing problems in criminal justice. Osaka framed her criminal justice activism as part of a broader focus on social justice, especially in matters of racial inequality and oppression. In terms of its impact, Osaka's activism has received a lot of attention in the form of news coverage and social media engagements. Her statements on criminal justice, police, and race are favorably received and have even been described in terms of a "racial reckoning" to which she is said to have contributed (Gunia et al.,). Osaka won numerous prestigious awards explicitly because of her combined efforts in tennis and activism, including her efforts on matters of criminal justice which she has undertaken with a more effective global appeal than any comparative criminologist could hope to achieve. Irrespective of whether Osaka's motives are sincere and whether her positions are valid, her criminal justice activism plays a role in shaping public perceptions because, as a celebrity, the tennis star enjoys a high measure of visibility that commands attention. Celebrities represent a category of privileged people who have taken advantage of existing societal institutions, including those which are argued to have contributes to injustice, for which reason the public can turn against them when it is thought that they lack sensitivity or are unaware of their elevated position. Yet, Osaka has managed to avoid such unintended consequences by relating her criminal justice activism to racial justice issues on the basis of her biracial background and identity as a Black Japanese woman. Noteworthy from the viewpoint of celebrity culture, moreover, is that Osaka's success in tennis and her acquired celebrity not only facilitated her activism, but that it, in turn, has also contributed to her continued standing as a celebrity icon. Two theoretical arguments emerge from this research. First, although based on a singular case study, this inquiry of the criminal justice activism of Naomi Osaka suggests a model of the conditions for celebrity activism to be successfully embraced. In the case of Osaka's criminal justice activism, the tennis player could rely on her athletic achievements as a champion, along with the wealth and opportunities it generated, as well as her identity as a young Japanese-American Black woman to authentically express her motives and goals of seeking to bring about racial justice and equity. She was thereby able to communicate her ideas through various media and become widely respected as an activist in a cultural climate that, in the post-Floyd era of Black Lives Matter, has been generally accepting of celebrity (sports) activism, especially when it involves minority athletes discussing racial justice concerns. In sum, the case of Osaka thus suggests that celebrity activism is more likely to be successful when it is based on: 1) certain objective characteristics of celebrities' measure of acquired fame and aspects of their personal identity; 2) that can be relied upon, through various media, to subjectively present the motives and objectives of their activism as genuine within a given cultural climate; 3) in order to be inter-subjectively received as intended in the news media and by the public. Conceiving of celebrity in relational terms, this model differentiates objective, subjective, and inter-subjective conditions of celebrity activism. This theory suggests the value of a constructionist perspective while also acknowledging that certain objective conditions of self and society have to be present for any subjectively motivated actions to be intersubjectively well received (Deflem,). Further research is needed to test this model more systematically on a larger number of cases of celebrity activism. Second, the effectiveness of celebrity activism, as in the case of Osaka's advocacy on matters of criminal justice, cannot be narrowly understood solely, nor even primarily, in instrumental terms of bringing about changes in the criminal justice system. Instead of simply accepting its stated objectives to bring about certain changes, celebrity activism should always be situated in relation to its role and function vis-a-vis the development of celebrity culture itself. As such, it can be seen that the adoption of matters related to criminal justice as causes worthy of attention among celebrities ironically brings about a celebritization of those issues. Not to be confused with celebrification (as the transformation from obscurity to celebrity), celebritization is the process whereby certain events or issues become 'celebrated' in the sense of being subject to presentation and reception in the terms of celebrity culture (Driessens,). Because of their treatment by celebrities, important societal phenomena and social problems, such as police violence and racial justice, then become slogans that are used by celebrities (and accordingly marketed by companies) at their convenience. Celebritization can have ironic implications that are inherently counterproductive to the goals of activism. Irrespective of the sincerity of the motives with which celebrities present their advocacy and regardless of how celebrity activism is received, the celebritization of activist causes creates its own dynamics in a world of celebrity that is far removed from the reality of the social problems it sought to address. In the case of criminal justice activism practiced by Osaka and other celebrities, statements about police violence and racial inequity in the criminal justice system are then discussed in terms that have little if any resemblances to how these problems are perceived by those who are directly involved, whether it be as alleged victims or accused perpetrators. These unintended implications of celebritization are rooted in the fact that celebrities are by definition privileged, even when, as in the case of minority athletes such as Naomi Osaka, they are intersectionally positioned in complicated ways related to gender, race, class, culture, and nationality. As with the suggested model on the conditions of successful celebrity activism, the celebritization of activist causes needs further examination and elaboration. The findings from the present study should at least have demonstrated that the theoretical arguments on the conditions and implications of celebrity activism are empirically substantiated in the case of Osaka's criminal justice activism.

celebrity activism, celebrity culture, criminal justice culture, naomi osaka, police violence, popular culture

PMC5776002_01

Male

A 38-year-old gentleman presented to us for fever and weight loss of two months duration. He had a significant background history of having multiple sex partners and had no other co-morbidities. His vitals were normal, systemic and general physical examinations were normal except for low body mass index (BMI) of 17.5 kg/m2. On subsequent evaluation, he was found to have acquired immune deficiency syndrome (AIDS) with cluster of differentiation 4 (CD4) cell count of 50 cells/mm3. He was started on highly active antiretroviral therapy (HAART) comprising of tenofovir, lamivudine, and efavirenz. His fever subsided with improvement in general well-being till one month back, when he again presented to us, this time with generalised lymphadenopathy and low-grade fever. On examination, he was febrile with the temperature of 100oF, had normal blood pressure (112/74 mmHg) with a heart rate of 96/min and respiratory rate of 18/min. He was malnourished with body mass index (BMI) of 18 kg/m2. General physical examination showed pallor with multiple, bilateral, cervical and inguinal lymphadenopathy. The lymph nodes were non-tender, mobile, firm in consistency and maximum 3x3 cm in size. Examination of the respiratory system, cardiovascular, per-abdominal and central nervous system were within normal limits. Complete blood count showed normocytic, normochromic anaemia (10.4 g/dl) with mild neutropenia (32x109/L) and normal platelet count (180x109/L). Chest X-ray showed miliary infiltration in bilateral lung fields. Lymph nodal biopsy showed spindle-shaped histiocytes, filled with acid-fast bacilli on Ziehl-Neelsen (ZN) stain, suggestive of MSP (figures 1A-1C). Immunohistochemical (IHC) stains were positive for CD68, S-100 and negative for CD31, which were consistent with MSP (figures 1D, 2A, and 2B). Polymerase chain reaction (PCR) of the biopsy tissue was positive for MTB. Subsequently, he underwent bone marrow biopsy, which also showed epitheloid granuloma suggestive of tubercular marrow infiltration. Hence, HAART was continued and anti-tubercular therapy (ATT) was started with isoniazid, rifampin, ethambutol, and pyrazinamide along with pyridoxine supplementation. Fever resolved 2 weeks after the initiation of ATT and there was a resolution of lymph nodal swelling by 6 weeks.

acquired immunodeficiency syndrome, biopsy, hiv, mycobacterium tuberculosis (mtb), spindle cell

PMC3342021_01

Female

A 58 year-old woman entered our hospital, with symptoms of constipation, excessive urine secretion (over 2 liter/day:polyouria) and severe muscle fatigue. She had a negative medical history and she hadn't used alcohol or drugs of any type. She complained of persistent dry cough and anorexia: her body weight had decreased 10 kgs during the last two months period. On evaluation, the patient looked sick; she was pale, her temperature was 36.1 C, her blood pressure was 100/60 mmHg, and her pulse rate was 70 bpm. The clinical examination revealed total muscle fatigue of arms and legs, without specific neurological signs. The patient couldn't walk or stand without help. She said that she had remained in bed during the main part of the day for the last week. The initial laboratory data were: Hct =31%, Hb =10.9 g/dL, Wbc =20.250 k/muL; (91% were granulocytes and 9% were lymphocytes), Platelets =438.000/muL, Glu =140 mg/dL, BUN =44 mg/dL, Creatine =0.9 mg/dL, K =1.9 meq/L, Na =140 meq/L, Ca =9.6 mg/dL, SGOT =11 IU/L, SGPT =15 IU/L, ALP =85 IU/L, LDH =147 IU/L, CPK =53 IU/L, Bill =0,4 mg/dL. Her arterial blood gasses were pH =7.48, pO2 =73 mmHg, pCO2 =44 mmHg, HCO3 =36.5, SpO2 =94%. All these demonstrated metabolic alkalosis. The chest X-ray that was performed, demonstrated opacity without cavitation to the left upper lung lobe (Fig. 1). During next day, the patient was extremely tired, febrile and her breath frequency exceeded 22 per minute (tachypnea). Finally, she got intubated because of severe respiratory (hypercapnic- elevated PCO2) acidosis. The measurement of 24 hour-urine secretion of sodium (108,2 mEq/L) and potassium (34,8 mEq/L), showed extensive hyperkaliurea. On the contrary, urine 5-HIAA was normal (5 mg; normal range: 5-100 mg). After 3 days, the patient extubated, without respiratory muscle weakness, while she had received intravenously high amount of solutions with potassium. The patient remained with low serum potassium (hypokaliemia), despite the extensive intravenous replacement. We measured the serum levels of aldosterone, aldolase, cortisone, and renin in order to find out a responsible specific disease for this condition. The laboratory data are presented in Table 1. We considered as possible the existence of paraneoplasmatic syndrome. The CT scanning of the thorax revealed a lung nodule, at the upper anterior left lung lobe, without collateral lymphadenopathy (Fig. 2). The CT scanning of the brain, and upper and lower abdomen departments, were negative for any kinds of lesions (secondary metastatic sites) and excluded the coexistence of juxtaglomerular tumors. The values of tumor markers were within normal range. Urine examination was also normal. Smear examination and sputum culture were negative for Mucobacterium tuberculosis and the tuberculin skin test was negative too. The patient underwent a fiberoptic bronchoscopy. We found a highly vascular endobronchial mass with a reddish smooth-looking surface, into the right anterior sub segmental bronchus of the left upper lung lobe. The bronchial biopsy revealed numerous membrane-bound neurosecretory granules characteristic of neuroendocrine tumor (pulmonary carcinoid tumor). Three days later, we planned the surgical wedge resection of the carcinoid. The extended histopathology study revealed the pattern of the typical carcinoid tumor of the lung, because of the absence of necrosis. (Fig. 3). Two weeks after the surgical procedure, the patient's blood pressure was measured and was found normal and the renin activity-levels serum were found normal, too (Table 1).

hypokaliemia, neurosecretory pulmonary tumor, pulmonary carcinoid, renin

Thorax CT scanning revealed a left lung nodule (diameter 21 x14 mm), at the upper anterior lung lobe without collateral lymphadenopathy.

PMC7328483_04

Female

The remaining case was a 45-year-old female patient who presented with extensive extramedullary hematopoiesis, which aggravated severe neurological complications such as blindness and paraplegia, with ECOG performance grade 4 and HCT-CI score 4. The patient was diagnosed as polycythemia vera (PV) with JAK2 exon 12 mutation accompanying splenomegaly in 2002, and treated with intermittent phlebotomy until 2007. Progressive thrombocytopenia and huge splenomegaly with a longest diameter of 25 cm was identified in 2012, and a follow-up BM study showed MF-3 fibrosis with normal karyotype. Splenectomy was conducted in 2014 due to severe pain. After splenectomy, thrombocytopenia and constitutional symptoms improved transiently but she complained of intermittent headache and diplopia at 5 months after splenectomy. Brain MRI showed diffuse meningeal thickening along parieto-temporal regions (Figure 1A), and dura biopsy revealed an increased number of hematopoietic precursors of all lineages. Diplopia was aggravating, with visual disturbance, and back pain and paraplegia developed despite radiation therapy (Figure 1B). We planned a RIC allo-HCT but the patient's performance status was getting worse due to progressive paraplegia and development of pneumonia. Although we explained that she was not a proper candidate for allo-HCT due to the high expectation of fatality, we finally decided to conduct allo-HCT using NMA conditioning regimen with patient consent and willingness. The patient received a CD34+ stem cell infusion of 18.9 x 106/kg from her younger brother on September 2015. CBC recovered on day 13 and the patient discharged without early complications. Although herpes zoster infection occurred, no GVHD developed, follow-up BM showed improved fibrosis with MF-2 grade, and meningeal lesions on follow-up MRI totally disappeared at 6 months post-HCT (Figure 1C). Despite improved performance status with stable blood counts, WB and donor T-cell chimerism declined progressively; 66% and 62% at 6 months, and 37% and 41% at 18 months post-HCT, respectively. Mutation of JAK2 exon 12 became undetectable at 6 months post-HCT, but re-appeared at 11 months post-HCT. She was scheduled for additional stem cell infusion when the chimerism fell to 47% at 14 months post-HCT, and infusion was conducted at 19 months post-HCT (CD34+ and CD3+, 11.0 x 106/kg and 230.0 x 106/kg, respectively). At 8 months after second stem cell infusion, both WB and T-cell chimerism became 99% and she is alive with full donor chimerism and no evidence of BM fibrosis at 52 months post-HCT. However, her neurological complications still remain. She experienced only mild oral GVHD, which was soon resolved with low dose of prednisolone. Patients with MF frequently exhibit accompanying extramedullary hematopoiesis within the liver, spleen, or any sites at advanced stage. However, involvements in vital organs, such as cardiovascular system or central nervous system (CNS), are rare manifestations and can sometimes be fatal. Although these manifestations are not included as an adverse-risk parameter in a prognostic scoring system, uncontrolled extramedullary hematopoiesis might be an emergency complication and should be treated by urgent radiation therapy or with allo-HCT in progressive cases. Although RIC regimens allow allo-HCT for patients ineligible for a myeloablative conditioning regimen, we still confront high TRM after transplantation. Therefore, we should cautiously consider NMA conditioning regimens for MF with progressive extramedullary hematopoiesis that aggravates a patients' comorbidities. Among several NMA regimens, low dose TBI plus alemtuzumab for sickle cell anemia showed stable mixed-donor chimerism with reversal of hemoglobinopathy without significant GVHD and TRM. Our experience also showed this NMA regimen can be applied safely in MF patients with severe comorbidity, without producing acute or chronic complications. However, severe viral or fungal infection due to alemtuzumab and poor graft function are the problems most expected, and these should be considered and closely monitored for survival outcome. Thus, a meticulous search for potential focus of infection should be performed prior to HCT. We think the critical difference in treatment outcome between patient #3 and #4 may be the difference in the number of infused stem cells (CD34+, 10.9 x 106/kg and 2.5 x 106/kg, respectively). In addition, our experience also suggested that the time and appropriate procedure for additional stem cell infusion should be studied more, and that NMA conditioning regimen followed by stem cell infusion from unrelated or mismatched donor should be tried cautiously due to poor immune reconstitution and infectious complications. We expect that MF patients with severe comorbidity might be treated successfully with alemtuzumab-based NMA regimen from MSD followed by additional stem cell infusion without significant fatalities.

allogeneic, hematopoietic cell transplantation, myelofibrosis, non-myeloablative conditioning

PMC8669953_01

Male

A 9-year-old boy was outborn at term without complications as the first child of non-consanguineous and healthy parents after a complicated course of pregnancy (vaginal bleeding on gestational week 12, gestational diabetes). Postpartum weakness of the left arm was noted. He was first presented to our Center for Chronically Sick Children at 2.6 years of age. He had spastic hemiparesis affecting particularly the left arm, hemineglect, and intermittent spontaneous nystagmus. A cranial MRI revealed a cystic parenchyma defect of the right parietotemporal side due to an ischemic stroke of his middle cerebral artery (Figure 1A). At this point, he had no reported seizures. At the age of 9 years, the patient presented again because of global developmental delay, hemiparesis, and drug-refractory epilepsy with persistent seizures. ASM treatment with VPA (18.75 mg/kg/day) and lamotrigine (LTG) (0.95 mg/kg/day) failed to control the seizures. First focal-onset seizures had occurred at 4 years of age. Over time, these gradually shifted to focal-onset seizures with increasingly impaired awareness. At presentation, he had focal to tonic-clonic seizures every 8 weeks. He showed appropriate engagement during social contact with a slight decrease in proximity-distance regulation. In neuropsychological examination, difficulties in attentional control, impulse control, and inhibition, as well as slightly increased motor agitation could be observed. Furthermore, he showed reduced stress resilience and frustration tolerance in the presence of excessive emotions. Because of highly increased emotional stress of the parents, it was not possible to examine neuropsychological data via questionnaires. We classified the patient as drug-resistant and included him in our epilepsy surgery program. Further investigations with congruent findings in MRI and EEG led to the indication for hemispherotomy. A vertical parasagittal hemispherotomy on the right side was performed without complications. Since then, the patient has remained seizure-free (Figure 1B). Two weeks after surgery, he showed an acute increase in psychological problems. He showed an acute aggravation of neuropsychological issues: hyperactivity, inhibition, and attentional control. The patient was restless and hardly controllable during medical examinations. Furthermore, the parents and teachers reported an increased tendency to aggressive behavior, which led to an exclusion from school. Overall, the symptoms had a high impact on the well-being of the family and the patient. An EEG showed no evidence of leftward transition with no evidence of clinical seizure signs (Figure 2A). We considered these behavioral problems to be related to the postoperatively changed neuronal networks of the brain. This working hypothesis was based on clinical experience by one of the senior authors (CE) on VPA-induced behavioral disturbances after epilepsy surgery that has not been reported previously. Already after VPA reduction from 18.75 to 14 mg/kg/day, the behavioral problems decreased. Once VPA was tapered-off, the behavioral problems were back at the preoperative level. Serum levels of the ASM of the patient were not measured. An EEG performed 6 months post-operatively showed no evidence of seizures (Figure 2B). A standardized neuropsychological follow-up assessment 6, 12, and 24 months postoperatively revealed a significant improvement in attention span, inhibitory skills, and frustration tolerance. Aggressive behavior was not detected during the medical examinations. The parents reported them to be absent during everyday life.

behavioral problems, children, drug resistant epilepsy, epilepsy surgery, hemispherotomy, pediatrics, valproic acid

PMC9425258_01

Male

A 49-year-old previously healthy man was admitted to the hospital with a 10-day history of chills, fever, and dyspnea in August 2011. He had no history of surgery or intravenous drug use, and had no notable medical record. At the time of hospital admission, physical examination revealed a pulse rate of 62 beats per min, respiratory rate of 20 breaths per min, and blood pressure of 125/83 mmHg. A systolic murmur was best heard at the apex. He was febrile (40.7 C) and he had a minor abrasion on left foot. The rest of his physical examination was unremarkable. Pertinent laboratory investigations revealed white blood cell count of 23,100/mm3, with 94.5% neutrophils, 3.2% lymphocytes, and 2.3% mononuclear cells, platelets of 40,000/mm3 and C-reactive protein of 58.6 mg/L. The patient was hospitalized for a presumptive diagnosis of septicemia. Empirical antibiotics were started with vancomycin and levofloxacin (0.5 g q8 h) therapy. During the next two days, echocardiography revealed large vegetation on the anterior mitral valve leaflet (3 cm x 3 cm) with moderate mitral valve regurgitation (Fig. 1A) Spiral computed tomography (CT) showed renal and splenic infarction (Fig. 1B). CT scans of the brain demonstrated multiple low-density bilateral lesions of the temporal lobes, right parietal lobe and occipital lobe, suggestive of cerebral embolism. Preliminary blood cultures grew S. aureus susceptible to ciprofloxacin, rifampicin, linezolid, vancomycin, tetracycline, sulfamethoxazole, levofloxacin and fosfomycin but resistant to penicillin, oxacillin, clindamycin, cefazolin, cefoxitin, cefuroxime, and erythromycin, as determined on the basis of CLSI disc diffusion standards. A diagnosis of acute infective endocarditis with systemic embolism caused by CA-MRSA was thus considered. Because of his impaired renal function and bacterial susceptibility profile, the patient was treated with intravenous linezolid (600 mg q12 h) and fosfomycin (8.0 g q12 h). On day 10, his clinical status worsened with episodes of tachypnea, pink frothy sputum and oxygen saturation (SpO2) decreased rapidly to 83% with ventilator support. Furthermore, renal function deteriorated, oliguria and right lower extremity tissue necrosis appeared. Embolization of the right common iliac artery and right internal and external iliac arteries was seen on echocardiography (Fig. 1C). He subsequently developed a coma with a Glasgow Coma Scale (GCS) score of 6. His clinical condition deteriorated such that he was transferred to the ICU, and replacement of the mitral valve was accomplished with a 29-mm Carbomedics mechanical valve. Considering the presence of coma and fever (39.8 C) postoperatively, brain CT was obtained and showed multiple low-density lesions in temporal lobes, right parietal lobe, and occipital lobe, suggestive of cerebral embolism (Fig. 1D). Levofloxacin (0.75 g qd) was added to his antibiotic regimen. After 10 days of intravenous antibiotics, the patient regained consciousness (GCS score of 9) and made a good clinical recovery. On day 35, he was transferred to a secondary hospital, and linezolid therapy was continued for eight weeks. He recovered uneventfully and was well at the last follow-up in November 2013. The isolate recovered from the vegetation was first identified by the VITEK 2 system and then identified with MicroFlex LT instrument (Bruker Daltonics). Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) based fingerprint analysis of extracted proteins yielded a pattern similar to that of confirmed S. aureus isolates, Flexcontrol 3.0 software and Biotyper 2.0 database (Bruker Daltonics) identified the isolate as S. aureus with a maximum score value of 2.166 (data not shown). In addition to MALDI-TOF-MS analysis, 16S rRNA sequencing was performed in order to identify the origin of the bacteria in the vegetation. The sequence of the PCR product was compared with sequences of closely related species in GenBank by using BLAST. Sequencing of the 16S rRNA gene of the isolates showed that there was 100% identity with the 16S rRNA gene sequence of the isolate of S. aureus (GenBank accession no. JN102565), confirming that the isolate was S. aureus. To further investigate the genetic basis of the strain, multilocus sequence typing (MLST), a method that uses seven housekeeping genes (arcC, aroE, glpF, gmk, pta, tpi and yqiL) for genetic identification, and result was assigned by comparison with the S. aureus MLST database (http://www.mlst.net/). The staphylococcal chromosomal cassette (SCC) mec type (I-V) was also determined. The spa type was analyzed by sequencing of the PCR product of the spa gene, and the spa type was assigned using an online spa database (http://www.spaserver.ridom.de/). Detection of the accessory gene regulator (agr) allele group was according to PCR and sequencing. Likewise, the antimicrobial drug resistance genes (mecA, msrA, msrB, ermA, ermB, ermC and blaZ) were determined. The presence of gene encoding PVL (lukF/lukS) and other virulence related genes (sea, seb, sec, sed, see, seg, seh, sei, sej, sem, sen, seo, sek, sel, sep, seq, hla, hlb, hld, hlg, hlg2, eta, etb, lukE, lukM, bsaA and edin,) were investigated by PCR. The presence of adhesion genes (cna, clfA, clfB, fnbA, efb and icaA) were also determined by PCR and sequencing. The CA-MRSA isolate was typed as sequence type (ST) 630 SCCmecV with spa-type t4549, agrI/IV and was PVL-negative. We confirmed the presence of mecA, ermC and blaZ genes by PCR and sequencing. The genome of the MRSA isolate encoded three hemolysin genes (hlb, hld and hlg2) and five adhesion genes (clfA, clfB, fnbA, efb and icaA) (Fig. 1E).

community-acquired mrsa, infective endocarditis, st 630, surgical therapy

PMC9251371_01

Male

A 53-year-old man visited our clinic complaining of quickly worsening hair loss in the scalp, eyebrows, beard, armpit hair, groin, and nearly his entire body 5 months ago, seriously affecting his appearance and increasing his psychological burden. Other than these outcomes, he was healthy without any medical history or family history of similar diseases except for transient urticaria 3 months ago. No previous treatments were administered to the patient. Skin examination showed hair loss in the scalp, eyebrows, beard, and the rest of his body ( Figure 1 ). The Severity of Alopecia Tool (SALT) score and the Alopecia Areata Investigator Global Assessment (AA-IGA ) score was used to assess his hair loss. His SALT score was 100, and AA-IGA score was 4, which suggested that his condition was severe. Routine analysis of hemogram, hepatic and renal function, corticosteroid hormone, serum IgE, and T-SPOT.TB tests (T-SPOT) were all normal. We also examined his peripheral blood T-cell subsets, which showed that CD3+ T cells, CD3+CD4+ T cells, and CD4+/CD8+ T cells were normal except for CD3+CD8+ T cells, which were slightly increased. Simultaneously, peripheral blood cytokines were examined using a commercial multiple cytokine detection kit [multiple microsphere flow cytometry] (qdraisecare, China) to examine the cytokine level. The normal values of the cytokine level were defined based on the serum cytokine level of 198 healthy people. Results showed that IL-6, IL-17, and IL12p70 increased, while IL-4, IL-10, IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha) levels were within the normal range ( Figure 2 ). According to the typical clinical manifestation and medical history, the patient was diagnosed with AU. After written informed consent was obtained, the patient was administered 5 mg of oral tofacitinib daily. Fortunately, a rapid and significant therapeutic effect was observed after the treatment, and his hair regrew gradually, although the color of the hair was white. No systemic side effects were found after treatment except slightly elevated glutamic-pyruvic transaminase (ALT) levels and blood lipid levels. Twenty-four weeks after tofacitinib treatment, the SALT and AA-IGA scores decreased significantly to zero ( Figure 2 ). We reexamined his peripheral blood T-cell subsets and found these values returned to normal. However, his peripheral blood cytokines were significantly increased, including Th1 cytokines IFN-gamma, TNF-alpha, IL12p70, Th2 cytokines IL-4, IL-6, IL-10, and Th17 cytokines IL-17. IFN-gamma was found to have increased 72 times compared with the baseline before tofacitinib treatment ( Figure 2 ). Considering the patient's safety and benefits observed with the patient's regrown hair, oral tofacitinib was discontinued, and Diprospan (7 mg/ml, 1 ml, contains betamethasone disodium phosphate 2 mg and betamethasone dipropionate 5 mg) intramuscular injections were administered once every 4 weeks to sustain the effect. Twenty-four weeks after Diprospan treatment, his hair growth was maintained. We reexamined his peripheral blood cytokines and found that all the cytokines decreased to normal, with only IL12p70 remaining slightly above the standard level. However, this value still decreased compared to the baseline ( Figure 2 ). The patient was very satisfied with both tofacitinib and Diprospan treatment, and the frequency of the Diprospan treatment was decreased gradually. No adverse effects were reported during the treatment or the follow-up.

janus kinase inhibitor, alopecia universalis, cytokines, hair loss, tofacitinib

PMC5509175_01

Male

The index case (Case 1) was an aboriginal man who was a tunnel worker. He lived in the village of Wan-Rong, Taiwan which had a TB incidence of 512.5 cases per population of 100,000 in 2006. He was first diagnosed with pulmonary TB in November 2000, when he was 43 years old. Sputum smears were positive for acid-fast bacilli, and sputum cultures grew Mycobacterium tuberculosis. This isolate was sensitive to all first-line drugs. The patient was cured after 8 months of standardized treatment, but due to a relapse in February 2002, antituberculosis treatment was restarted. During the second treatment course, the patient showed poor compliance with the treatment regimen. Sputum cultures were again positive in April 2004, and chest radiography revealed worsening of left lung infiltrations and cavitations (Fig. 1A). The results of a drug-susceptibility test (DST) of the sputum culture 2 months later revealed resistance to isoniazid (H) and rifampicin (R), so the patient's regimen was changed to ethambutol (E), pyrazinamide (Z), streptomycin (S), prothionamide (Pto), and moxifloxacin (Mfx). In September 2005, sputum cultures still grew M. tuberculosis, and repeated DST showed resistance to HERS. The patient was enrolled in a directly observed therapy program (DOT-plus) in 2007, and continued treatment with E, Z, Pto, Mfx, para-aminosalicylic acid, and rifabutin (Rfb). However, this sputum cultures remained positive. Despite the use of Group I:V antitu- berculosis drugs, the patient's sputum cultures remained positive at the time of this report. He was diagnosed to have chronic MDR- TB in 2009 and was placed in long-term isolation in a negative- pressure room. Case 2 is the third daughter of the index case. In 2002, she was diagnosed with pulmonary TB at the age of 19 years. At that time, the isolated strain was sensitive to HERS. She completed 8 months of treatment with HERZ and was cured in June 2003. However, in November 2006, a follow-up chest radiograph (Fig. 1B) and sputum cultures confirmed recurrent disease. DST showed resistance to HR, so she was treated with E, Z, S, Pto, and Mfx. Streptomycin was used for 6 months, and she completed an 18-month treatment course and was cured in September 2008. Case 3 is the index patient's older son. He was diagnosed with pulmonary TB in May 2005, at the age of 14 years, during a regular health checkup. A chest radiograph revealed infiltrations in the left upper lobe (Fig. 1C). He was treated with HERZS, but 2 months later DST showed HER resistance. The regimen was switched to Z, S, Pto, Rfb, and Mfx. Streptomycin was used for 7 months. He completed 18 months of treatment and was cured in January 2007. Case 4 is the index patient's younger son. He was first diagnosed in November 2006, at the age of 13 years. A chest radiograph revealed infiltrations and cavitations over the left upper lobe (Fig. 1D). The first M. tuberculosis isolate was fully drug susceptible, and he was treated with HERZ. However, due to persistent positive sputum cultures 3 months after starting treatment, DST was repeated and revealed resistance to HERS. The regimen was switched to Z, kanamycin, para-aminosalicylic acid, Pto, Rfb, and Mfx. He was cured in March 2009 after sputum conversion for 18 months. All four patients were tested for antibodies to HIV by enzyme immunoassay, and all were found to be negative (Fig. 2). Drug susceptibility testing was performed by the indirect proportion method. M. tuberculosis isolated from all four patients revealed similar multiple drug resistance to first-line HER and second-line ofloxacin. Fortunately, the strains were sensitive to kanamycin (Table 1). Isolates of MDR-TB stains from the four patients showed identical genotypes indistinguishable from each other by spoligotyping and Mycobacterium interspersed repetitive units:variable-number tandem-repeat (MIRU-VNTR) typing (Table 2).

aboriginal family, multidrug-resistant tuberculosis, mycobacterium interspersed repetitive units—variable-number tandem repeat, outbreak, spoligotyping, taiwan

PMC3884181_01

Female

A 53-year-old Caucasian woman presented with a 40-year history of severe plaque psoriasis. The patient had recalcitrant psoriasis that was unresponsive to multiple conventional therapies such as methotrexate and acitretin. The patient also had a 20-year history (>800 treatments) of psoralen plus ultraviolet A (PUVA) therapy. Her past medical history was notable for a benign compound nevus on the left anterior thigh, which was completely excised in January 2011. In January 2012, the patient was screened (including physical examination, baseline laboratory studies, and screening for latent tuberculosis and chronic viral infections) and began etanercept therapy (50 mg subcutaneously twice weekly). After 3 months, the patient was responding insufficiently to etanercept and was switched to infliximab (5 mg/kg at weeks 0, 2 and 6, and then every 8 weeks thereafter). This treatment resulted in the complete disappearance of her psoriasis. Twelve months after beginning the infliximab treatment, the patient developed palpable lymphadenopathy in the left inguinal region. Given the suspect nature of the palpable mass, the patient underwent an inguinal lymph node biopsy. The histology of the biopsy specimen showed a metastatic melanoma. Positron emission and computed tomography scans were negative for distant metastatic disease. Infliximab was discontinued and a complete inguinal lymph node dissection was performed, which revealed no additional nodal involvement. A full skin evaluation did not reveal any suspicious lesions, but 4 cm below the metastatic lymph node, the scar from the previously removed nevus could be seen (fig. 1). The histopathologic slides of the excised nevus were reviewed along with immunohistochemical studies, which led to the definite diagnosis of nevoid melanoma (Breslow thickness 1.44 mm; fig. 2). A BRAF V600E mutation was detected and the patient was enrolled in a clinical trial of combined adjuvant therapy with dabrafenib and trametinib.

diagnostic pitfalls, infliximab, metastasis, nevoid melanoma, tumor necrosis factor-α

PMC7843435_01

Female

A 59-year-old woman with no past medical history presented with 1-week symptoms of atypical chest pain and mild dyspnea. Upon physical examination, her heart rate, respiration rate, blood pressure, and body temperature were 102 beats per minute (bpm), 22 breaths per minute, 110/60 mm Hg, and 36.1 C, respectively. No moist rales or wheezing sound in lungs and no cardiac murmur or pericardial rub were detected. Laboratory tests showed the level of d-dimer as 6,440 mug/L (reference range, 0-550 mug/L) and brain natriuretic peptide as 107.52 ng/L (reference range, 0-100 ng/L). Arterial blood gas analysis in room air showed severe hypoxemia (pH 7.393, Pao2 = 60 mm Hg, Paco2 = 43.3 mm Hg, = 25.8 mmol/L). Myocardial enzymes, tumor markers, thyroid function tests, T-SPOT, tuberculosis antibody, hepatitis virus, human immunodeficiency virus, syphilis, and autoimmune panel were all negative. An electrocardiogram showed a fast sinus rhythm of 102 bpm, with flat T-wave in precordial leads. Computed tomography pulmonary angiography (CTPA) showed multiple embolisms of bilateral pulmonary arteries and a mild-sized pericardial effusion (Figure 1A). Color Doppler ultrasound showed left calf muscular venous thrombosis. Upon clinical examination and tests, the patient was diagnosed of acute pulmonary thromboembolism (PTE) (intermediate risk) and left muscular calf vein thrombosis (diagnosed on December 16, 2019). First line of treatment included hypodermic injection of low-molecular-weight heparin as anticoagulation therapy. However, 2 days posttherapy, the patient complained of progressive development of dyspnea, fatigue, chest tightness, and palpitations, to later experience transient loss of consciousness. Her heart rate increased to 125 bpm, whereas blood pressure and pulse pressure were slightly decreased (96/69 and 27 mm Hg, respectively). Jugular venous distention and muffled heart sounds were present. Both transthoracic echocardiogram (TTE) and thoracic CT were significant for severe large-scale pericardial effusion (Figure 1B). No obvious mass was identified either in the pericardium or heart. Therefore, acute pericardial tamponade was considered as a differential diagnosis. Emergency pericardiocentesis and drainage were performed, draining 210 mL of bloody effusion in total. Repeated thoracic CT the following day was significant for bilateral pleural effusion, which was greatly increased in amount (Figure 1C). Further left thoracentesis and thoracic drainage were performed, draining another 710 mL of pleural effusion (the first two times, collected effusion was bloody; the third time, effusion was examined as pale yellow). Symptoms of dyspnea and palpitations were also immediately improved after a third round of drainage. Additional pericardial effusion cultures for bacteria and acid-fast bacilli were repeated twice, obtaining negative reports each time. Repeated cytological examination of the pericardial effusion did not show any malignant cells. Repeated thoracic CT prior to discharge showed mild bilateral pleural effusion and pericardial effusion (documented on December 30, 2019; Figure 1D). Patient was followed up in the outpatient department. Half a month later (January 15, 2020), although she was asymptomatic, her levels of d-dimer were spiked to 10,740 mug/L. TTE showed a mild pericardial effusion. Given that PTE is prone to relapse, she suffered an acute pericardial hemorrhage after anticoagulation, where low-dose rivaroxaban (10 mg every day) was later administered from January 15, 2020, onward. The levels of d-dimer were decreased significantly (1,450 mug/L) after 2 months of oral rivaroxaban, and there were no bleeding events recorded during this period. Four months later, the patient complained of progressive hemoptysis and dyspnea (May 2, 2020). She did not stop taking the administered oral rivaroxaban until the embolisms were absent by CTPA on May 18, 2020. However, CTPA also showed a large mixed mass, occupying the right pericardium (4.5 x 8.5 cm; Figure 1E), and she was readmitted. On physical examination, mucocutaneous color was pale, and medium moist rales in lungs was detected. The levels of CA-125 and neuron-specific enolase (NSE) were markedly elevated (117.5 U/mL [reference range, 0-35 U/mL]; 46.96 ng/mL [reference range, 0-24 ng/mL], respectively). The hemoglobin content was 68 g/L (reference range, 115-150 g/L); the plasma d-dimer level was 4,160 mug/L; arterial pressure of oxygen was 56 mm Hg (reference range, 80-100 mm Hg). Dual-source coronary CT angiography (CCTA) showed the mass infiltrated and communicated with the RA, with heterogeneous thickened pericardium and localized moderate pericardial effusion (Supplementary Movie 1). No stenosis was seen in the coronaries, and there was no communication of the tumor with the coronaries. CCTA also showed a mild left pleural effusion, enlarged mediastinal and hilar lymph nodes, multiple and scattered ground-glass opacity [diffuse alveolar hemorrhage (DAH)] nodules over bilateral lung field, and multiple bipleural nodules (Figure 1F, May 21, 2020). TTE showed a huge mass in the pericardium, surrounding and compressing the RA and right ventricle. Mild blood flow signals were also observed in the mass (Figure 2A) (May 20, 2020). The tumor was significantly larger than before with a strip-like hyperechoism within the RA (Figure 2B, recorded on June 18, 2020). Contrast-enhanced ultrasound showed the mass and chamber were filled with contrast agent almost simultaneously (Figures 2C1-C3 and Supplementary Movie 2). Axial Fiesta (Figure 2D) and 4CH-2D (Figure 2E) of cardiac magnetic resonance (CMR) showed an irregular, large tumor (size up to 10 x 5.5 cm) with heterogeneous distinction diffusely within the pericardium (10 x 5.5 cm), mainly located outside the right cardiac chamber system, compressing the right heart. Positron emission tomography scan exhibited a heterogeneous mass located at the right margin of pericardium, poorly demarcated from the RA and superior vena cava (Figures 3A-C). Distant metastases were found in both lungs and bilateral pleura (Figures 3B,D), nodules in hilar and mediastinal lymph nodes (Figures 3E,F). Ultrasound-guided biopsy was performed for a definitive diagnosis. The biopsy specimen showed a malignant tumor in histopathologic examination (Figure 4A) and positive immunohistochemical staining for CD31 (Figure 4B) and CD34 (Figure 4C), but negative for CEA, CK, CK5/6, CR, D2-40, desmin, and MC, indicating poorly differentiated angiosarcoma. Surgery was not a suitable option for the patient because of metastasis. Unfortunately, she refused treatment with radiotherapy, chemotherapy, or immunotherapy, where the clinical condition of the patient deteriorated rapidly after. She died on June 28, 2020, while waiting for the pathologic results due on June 29, 2020. The patient survived for 6 months from the first episode of PTE. The progression and examination of the clinical course are shown in Figure 5.

cardiac angiosarcoma, cardiac tamponade, hemoptysis, pulmonary metastasis, pulmonary thromboembolism

Progression and examination of the clinical course. PTE, pulmonary thromboembolism; BNP, brain natriuretic peptide; CTPA, computed tomography pulmonary angiography; TTE, transthoracic echocardiogram; CMR, cardiac magnetic resonance; PET, positron emission tomography; CCTA, coronary computed tomography angiography.

PMC5266394_01

Female

A 22-year-old woman (gravida 1, para 0) presented at the local hospital complaining of dyspnea. The patient described a cough, palpitation, and generalized myalgia. The patient had no prior medical history. She denied the use of tobacco products and said she consumed alcohol only occasionally. Her menstrual history revealed that she had experienced menarche at age 14, irregular cycles in the past, and occasional vaginal spotting in last two cycles. The chest radiographs revealed bilateral diffuse nodularity and a left pneumothorax. She was treated for pulmonary tuberculosis and pneumothorax with tuberculosis medications and the insertion of a chest tube; however, her symptoms worsened. A pulmonary thromboembolism was suspected, and chest enhanced computed tomography (CT) showed a filling defect in the left inferior pulmonary artery (Fig. 1A). Rivaroxaban was administered for the treatment of the pulmonary thromboembolism. Two weeks after starting treatment with rivaroxaban, the patient presented with aggravated dyspnea and massive hemoptysis and was urgently referred to the emergency department (ED). Upon arrival at the ED, the patient was afebrile, with a heart rate of 138 beats per minute, blood pressure (BP) of 90/80 mm Hg, respiratory rate of 18 breaths per minute, and oxygen saturation of 100% in room air. She was alert and oriented. The chest examination for the breath sounds and auscultation revealed coarse crackles from the right lung and no sounds from the left. The arterial blood gas levels under oxygen mask inhalation (5 L/min) were as follows: pH, 7.51; PaO2, 81 mm Hg; and PaCO2, 25 mm Hg. Her hemoglobin level was 13.1 g/dL, white blood cell count was 7,520/mL, and platelet count was 273,000/mL. The D-dimer was 2.72 mug/mL, and the troponin level was elevated slightly, at 0.01 ng/mL. Her chest radiograph revealed a normal cardiac field, diffuse nodularity in both lung fields, and a pneumothorax with chest tubing in the left lung zone. While repositioning the chest tube into the pneumothorax, she became mentally confused, and the laboratory results showed a partial pressure of oxygen (pO2) of 38 mm Hg. She was intubated, started on mechanical ventilation, and admitted to the intensive care unit for further evaluation. On the second day after admission, her mean BP was decreased gradually. The patient remained hypotensive despite the intravenous fluid boluses that escalated the inotropic infusion with the maximum dose. VA ECMO was initiated to restore hemodynamic stability. An echocardiogram revealed a severe left ventricular systolic dysfunction with an ejection fraction of 29% and a D-shaped left ventricle. Bronchoscopy revealed diffuse alveolar hemorrhage but no evidence of an endobronchial lesion. Therefore, the administration of rivaroxaban therapy was stopped. Pulmonary angiography was performed and showed a large filling defect in the left pulmonary artery (Fig. 1B). The patient underwent a pulmonary embolectomy in the presence of ECMO. At the site of the main pulmonary artery near its opening to the left pulmonary artery, a whitish tumor embolus was found in the left pulmonary artery. The tumor embolus was removed to the extent possible. Histologically, the pulmonary tumor embolism specimen revealed a malignancy consistent with choriocarcinoma (Fig. 2). After a diagnosis of choriocarcinoma was made, the serum beta human chorionic gonadotropin (hCG) level was measured, and a gynecologic examination was performed. The serum beta hCG values were 260,000 mIU/mL. A metastatic workup revealed no lesions in the liver, spleen, kidney, pelvic cavity, and brain (International Federation of Gynecology and Obstetrics [FIGO] stage III, FIGO prognostic score 6). Although she was under an ECMO insertion state and her platelet level was below 75,000/muL, chemotherapy was started with the following conventional regimen after receiving fully informed consent: etoposide, 100 mg/m2 on days 1 and 2 ; methotrexate, 100 mg/m2 via intravenous bolus on day 1 and 200 mg/m2 via intravenous infusion over 12 hours on day 1; actinomycin D, 0.5 mg via intravenous bolus on day 1 and 2; cyclophosphamide, 600 mg via intravenous infusion on day 8; and vincristine, 1.0 mg/m2 on day 8 (EMA-CO). After the initial chemotherapy, her beta hCG level decreased to 2,296 mIU/mL, and the ECMO was removed as her heart function was restored. The second cycle of chemotherapy was postponed because of a poor general condition and grade 4 neutropenia. After a 2-month period of chemotherapy, the follow-up CT showed dissolved emboli in the pulmonary artery. The patient was discharged from hospital with a normal beta hCG level.

choriocarcinoma, extracorporeal membrane oxygenation, pulmonary embolism

(A) A chest enhanced computed tomography, demonstrating a filling defect in the left inferior pulmonary artery.

PMC2815824_01

Female

A 43-year-old woman was referred to our hospital for cardiomegaly on chest X-ray (Fig. 1). Physical examinations revealed a healthy appearing woman except for distant heart sounds. All laboratory findings were within the normal range. The patient had no history of trauma, congenital heart disease, thoracic surgery or tuberculosis. Transthoracic echocardiography revealed a large amount of pericardial effusion without hemodynamic compromise. Diagnostic pericardiocentesis was performed with 500 mL of a milky-colored pericardial fluid aspirated. Routine examination of the pericardial fluid revealed pH 6.8, protein 5.0 g/dL, and LDH 234 IU/L. WBCs and RBCs were uncountable due to cell clumping. Routine bacterial and tuberculous cultures were subsequently reported as negative, as was the cytological examination, and the adenosine deaminase level was 15.5 U/L. Considering these clinical and laboratory findings, the initial clinical impression was of nonspecific chronic pericarditis with effusion. We did not diagnose chylopericardium because we overlooked the clue offered by the color of the pericardial fluid. After pericardiocentesis, follow-up echocardiography revealed that minimal pericardial effusion remained. She was regularly followed up at our outpatient clinic after discharge. However, echocardiography one month later revealed a large amount of pericardial effusion without evidence of hemodynamic compromise (Fig. 2), and she was readmitted to our hospital for further evaluation. The patient, who was afebrile on admission, complained only of mild substernal discomfort. Her blood pressure was 90/60 mmHg and pulse rate 72 beats per minute. On physical examination neck veins were distended and peripheral pulses were normal. Her breathing sound was clear without rale, though heart sounds were slightly decreased and pericardial friction rub was inaudible. The chest X-ray showed marked enlargement of the cardiac shadow with a globar shape, and an electrocardiogram demonstrated a sinus rhythm, with low voltage QRS complexes in the precordial leads. The laboratory examination showed; white cell count 7,740/mm3, hemoglobin 13.0 mg/dL, hematocrit 39%, and platelets 238,000/mm3. The ESR was 17 mm/hr and CRP 6.7 mg/dL. Blood chemistry revealed; BUN 12.9 mg/dL, creatinine 0.6 mg/dL, total protein 7.0 g/dL, albumin 4.7 g/dL, AST/ALT 21/17 IU/L, total cholesterol 196 mg/dL, triglyceride 111 mg/dL, HDL-cholesterol 46 mg/dL, and LDL cholesterol 138 mg/dL. Urinalysis was normal. Antinuclear antibody and anti-viral antibodies including HIV were all negative. beta2-microglobulin and CEA were within the normal range. Repeated pericardiocentesis was performed, and an immediate gushing out of 700 mL of a milky-yellowish fluid ensued (Fig. 3). An examination of the pericardial fluid showed pH 6.8, protein 7.0 g/dL, glucose 98 mg/dL, LDH 560 IU/L, cholesterol 97 mg/dL, and triglyceride 1078 mg/dL. RBCs and WBCs were uncountable due to cell clumping. The adenosine deaminase level was 17.0 U/L and the CEA level 1.15 ng/mL. Routine cultures for bacteria and tuberculosis were subsequently reported as negative and a cytologic examination showed no tumor cells. These findings with inappropriately elevated triglyceride in the pericardial fluid sufficed to diagnose chylopericardium. The patient underwent extensive investigations to determine the secondary causes. Chest computed tomography revealed a suspicious small cystic lesion on the left neck and mediastinal haziness. The possibility of cystic hygroma with mediastinal extension was highly suggested by radiologists. Neck sonography also showed a 1.9 cm sized multilocular, compressible cystic lesion between the sternocleidomastoid muscle and the internal jugular vein of the left neck. These findings were compatible with cystic hygroma (Fig. 4). The cystic lesion could not be aspirated due to patient's refusal. To demonstrate the presence of any anomalous communication between the lymphatic channels and the pericardial sac, we performed a direct lymphangiography. However, no direct communication between the pericardial sac and the thoracic duct could be definitely established. Follow-up echocardiography was performed 10 days after the pericardiocentesis and showed a massive reaccumulation of pericardial effusion. 11 days after pericardiocentesis, the patient underwent pericardiostomy. Using the subxyphoid approach, a pericardial window was made with 32 Fr draining tube insertion in an attempt to prevent pericardial fluid reaccumulation and cardiac tamponade. Incision of the pericardium resulted in the extrusion of 600 mL or more of milky fluid. The pericardial fluid analysis showed that it had the same nature as the previous sample. When the patient was placed on total parenteral nutrition for 30 days and a subsequent low fat diet enriched with medium-chain triglycerides for 15 days, the drainage reduced to 30-40 mL per day. On the 45th day after pericardiostomy, drainage tube was removed and she was discharged from the hospital on a low fat diet. She remained totally asymptomatic without interval changes of heart size on chest X-ray (Fig. 5) or clinical signs of cardiac tamponade at the 6 month follow-up.

PMC8214888_01

Male

A 41-year-old male patient presented with swelling associated with pain of the right leg, which gradually increased over the last two and a half years. There was no previous history of trauma, tuberculosis, or any other significant comorbidity. Overall, the patient's health status was good except for the leg swelling and associated pain. The clinical examination revealed a firm and tender swelling on the right leg's anterolateral surface of 20 cm in its longest axis. The overlying skin appeared normal. The remaining systemic examination was normal. All the hematological and biochemical parameters were within the normal range. The X-ray of the leg showed a cortical erosion in the tibia diaphysis and associated soft tissue involvement. The biopsy histomorphology showed a biphasic tumor comprising fibrous stroma with cords and glandular pattern of epithelial cells exhibiting a central discohesion (Figures 1A, 1B). Some areas show fibrous components (Figure 1C). The high-power examination showed round to oval epithelial cells with bland nuclear features and mild to moderate cytoplasm, and no pleomorphism (Figure 1D). The immunohistochemistry showed a Pan CK positivity, MIB proliferation index (KI 67) 20-30%, SMA-negative, S100-equivocal (Figures 2A, 2B, 2C, and 2D). CD34 was negative. The computed tomography (CT) study of the right leg revealed multiple patchy cortical erosions/irregularities in the right tibia in the diaphysis and contiguous involvement of adjacent upper metaphysis. There were adjoining soft tissue thickenings. Streak artifacts are noted due to postoperative changes (screws) (Figure 3A). The MRI sagittal section of the right leg reveals cortical erosions/ irregular outlines of the tibia with altered signals in the adjoining bone marrow and soft tissue. Susceptibility artifacts are noted due to postoperative metallic screws (Figure 3B). The patient was followed for 3 years, with no signs of metastasis or local relapse.

adamantinoma, diaphyses, tibia

PMC5220135_01

Male

A 52-year-old male was diagnosed with stage IV angioimmunoblastic T-cell lymphoma with bone marrow involvement in 2011. He was originally treated with CHOP x6. Owing to refractory lymphoma, he received salvage ifosphamide, carboplatin, etoposide x2, a clinical trial with high-dose cyclosporine discontinued due to seizures, and reached a partial response with seven cycles of romidepsin before matched unrelated donor hematopoietic cell transplant (HCT). His conditioning regimen was reduced intensity with rabbit anti-thymocyte globulin, 2.5 mg/kg from day -9 to -7 followed by TBI to a total dose of 4.5 Gy, delivered in three 1.5 Gy fractions on day -1 to 0. For GvHD prophylaxis, he received tacrolimus and mycophenolate. His post-transplant course was uncomplicated by day +180. His days +60 and +100 bone marrow, blood and T cells were 100% donor and no evidence of disease recurrence was found on radiographic imaging. Pulmonary function testing day +100 revealed a FEV1 of 93% and DLCO of 78% pre-transplant FEV1 and DLCO were 93 and 80%, respectively. The patient had mild classic chronic GvHD of skin and eyes treated with topical hydrocortisone and Refresh eye drops. He was off immunosuppression by day +168. He started his vaccination protocol on day +240 for meningococcal, haemophilus influenza type B, influenza, pneumococcal 13, Hepatitis A and B, inactivated polio and Dtap. On day +325 after transplant he presented to the outpatient bone marrow transplant clinic with subacute cough, dyspnea, hypoxemia and no other clinical symptoms of GvHD. Pulse oximetry showed oxygen saturations of 68% on room air. Computed tomography (CT) of the chest showed rapidly progressive pulmonary infiltrates (Figure 1a). He was admitted to the inpatient bone marrow transplant floor, started on broad-spectrum antimicrobials, and subsequently underwent bronchoscopy that was non-diagnostic. Over the next 2 days he developed worsening hypoxemia requiring transfer to the medical intensive care unit for hypoxemic respiratory failure. High-dose methylprednisolone 125 mg every 6 h was initiated. On day +328 he underwent video-assisted thoracoscopic surgery (VATS) and left upper lobe/left lower lobe wedge resection. He was extubated on day +329, but remained hypoxic, requiring non-invasive ventilation. On day +331 the pathology from the wedge resections showed Acute organizing fibrinous pneumonia (AFOP) (Figure 2a). Given the lack of clinical improvement, methylprednisolone was increased from 125 to 250 mg every 6 h, tacrolimus was continued (goal trough level 10) and we started etanercept 25 mg SC twice weekly for a total of eight doses. After the initiation of etanercept the patient had significant improvement in respiratory status. His hypoxemia improved, he was off non-invasive ventilation after two days and supplemental oxygen was rapidly weaned. He completed 8 doses of etanercept; continued tacrolimus and steroids were tapered off over 2 weeks. His VATS was complicated by pneumothorax and pneumomediastinum, which required small bore thoracostomy placement and eventually mechanical pleurodesis due to persistent air leak. On day +364 he was discharged home off supplemental oxygen with significant clinical and radiographic improvement (Figure 1b). His post hospitalization FEV1 was 72% and DLCO was 58%. Currently, the patient is 2.5 years from HCT and remains in remission from his lymphoma; he is on tacrolimus and twice weekly every other week extracorporeal photopheresis for GVHD as a steroid sparing agent that was started after day +364 upon discharge from the hospital. Prednisone was discontinued at day +393. He has had no other symptoms of GVHD except for an erythematous rash on day +519. He was started on 20 mg of prednisone, which was tapered off by day +756. He is off supplemental oxygen and recent CT scans reveal mild air trapping, however, a significant improvement from prior CT scans and his spirometry is normal, FEV1 (96%) and DLCO 89. AFOP has been reported post allogeneic HCT and has two subtypes, one indolent and one very aggressive that carries a high morbidity (as in our patient). The pathogenesis of AFOP is unknown, but our patient's response to etanercept suggests a role of TNF-alpha as part of a cytokine-modulated immune response causing inflammation and fibrosis. Hara et al. report two cases of AFOP in non-HCT transplant patients. They demonstrated overexpression of heme oxygenase-1 (HO-1) in the macrophages within the fibrin balls and type II pneumocytes. In another study, Terry et al. demonstrated that the inflammatory cytokines IL-1 and TNF-alpha are effective inducers of HO-1 in vascular endothelial cells and oxidative stress is implicated in the pathogenesis of many pulmonary diseases associated with inflammation, including acute respiratory distress syndrome. Therefore, the initial insult/injury could have led to increased TNF-alpha and HO-1 that have been described in AFOP. Murine models of induced pluripotent stem (IPS) after HCT, suggest the lung is a target of immune-mediated injury by two distinct and related pathways involving soluble inflammatory effectors including TNF-alpha and the other driven by antigen specific donor T-cell effectors, which synergize to cause inflammation and cellular injury. Etanercept has been used as a treatment in transplant-related lung injury after HCT with 24% of patients surviving hospital stay. Yanik et al. studied the TNF inhibitor, etanercept, combined with corticosteroids in treating 15 patients with IPS after HCT. Etanercept was administered SC at a dose of 0.4 mg/kg (maximum 25 mg) twice weekly, for a maximum of eight doses. Therapy was well tolerated and 10 of 15 patients had a complete response, defined as the ability to discontinue supplemental oxygen support during study therapy. The 28-day survival was 73%. The combination of etanercept and corticosteroids is safe and is associated with high response rates and improved survival in patients with IPS after HCT. To our knowledge this is the first case AFOP after HCT, successfully treated with etanercept. Although, there is a lack of clinical evidence to support the use of entanercept in patients with AFOP. Our rational for the use of etanercept in this critically ill patient with a non-infectious lung injury was that AFOP may be driven by oxidative stress, which may be modulated by TNF-alpha. Interestingly, the lung biopsy was positive for both HO-1 and TNF-alpha (Figure 2b). This supports our hypothesis that AFOP may be driven by oxidative stress induced by TNF-alpha. Therefore, we propose that etanercept may be responsible for the marked clinical improvement in the patient because with high-dose steroids and tacrolimus the patient was requiring non-invasive ventilation and high-flow oxygen 15 L nasal canula until the addition of etanercept. We speculate that AFOP is a manifestation of GvHD, and that TNF-alpha is implicated in its pathogenesis. Until more information is available on the pathogenesis of AFOP after HCT, we recommend early use of etanercept in patients with AFOP post HCT because of rapidly progressive respiratory failure and high mortality. The authors declare no conflict of interest.

PMC4531965_01

Female

A woman, 76 years old, was admitted to our hospital for fatigability, puffy face and leg edema in August, 1992. In 1985, she had suffered from a right thyroid tumor. The data of thyroid function tests are shown in Table 1. The 99mTc and 123I thyroid scintigraphy indicated large functioning thyroid nodule in right thyroid lobe [123I uptake: 37.6% (3h), 40.6% (6h) (normal range 6h. 8-25%)] with suppresstion of left lobe. In the following year, she got an operation of the thyroid gland for functioning follicular adenoma of the right lobe and nodular hyperplasia (adenomatous goiter) of the left one. The right lobe of the thyroid had been totally resected and only half of the left lobe remamed. Before and after the operation, free T4 and TSH levels were below normal range and desiccated thyroid was administered. The thyroid evaluation, performed after three months following the operation, was hypothyroid state as follows; T3 (66ng/dl), T4 (5.3mug/dl), F-T4 (0.29mug/dl) and TSH (32.3 muU/ml) (Table 1). The dosage of desiccated thyroid was increased to 60mg and serum TSH level became low level. In May, 1991, thyroid function test showed normal serum total thyroid hormone, suppressed TSH and low free T4 levels. Thereafter her compliance of taking drugs was insufficient. On admission, (in August, 1992), she appeared clinically to be myxoedematous because of puffy face and non-pitting leg edema. On physical examination, the body temperature was 36.5 C, pulse rate 72 beats per minute and regular, and blood pressure 132/70mmHg. The hair and skin were normal. Thyroid gland which remained was not palpable. Urinalysis, hemogram, levels of electrolytes, blood urea nitrogen, blood glucose, uric acid, cholesterol and liver function were within normal limits. The roentogram of the chest revealed an enlarged heart. Electrocardiogram showed left ventricular hypertrophy. To evaluate the pituitary-thyroid function, the administration of desiccated thyroid was discontinued for one week after this admission. TSH was still suppressed despite low level of T4 (1.6mug/dl), T3(15ng/dl), free T4(0.15ng/dl) and free T3 (below 0.4). Serum TBG level was 20.5mug/ml and anti-thyroglobulin, microsome antibodies, TSH receptor antibody and anti-TSH antibody were negative. As shown in Table 2, a significant increase in serum TSH levels did not occur after drip infusion (2mg) of TRH for 30 minutes. After repeated injection of TRH (2mg/day) for 4 consecutive days, serum TSH levels were still suppressed (maximum level: 1.45muU/ml in 120 minutes of final injection day). With the final TRH injection, combined pituitary stimulation test by intravenous injection of 0.1 units/kg reglar insulin, 0.1mg LH-RH was performed. Growth hormone (GH), LH, FSH, prolactin (PRL) and cortisol kept almost normal responses (Table 2). The pituitary MRI and CT did not show any abnormality. These results were consistent with secondary hypothyroidism derived from the isolated deficiency of TSH.

PMC5925152_01

Male

A previously healthy 38-year-old gentleman began to experience episodes of intermittent abdominal pain five days prior to presentation. The abdominal pain was predominantly in the epigastrium, nonradiating, and occasionally associated with nausea. He did not have any episodes of vomiting or diarrhea. Over the course of next five days, he noticed yellowing of his eyes and urine which prompted him to visit the emergency room. Patient denied any history of fever, night sweats, weight loss, or decreased appetite. Family history was unremarkable. He migrated to the United States at the age of 33 from the Philippines. He had received BCG vaccination during childhood but had no previous history of treatment for tuberculosis. He denied any sick contacts or travel within the last few years. He worked as a pharmacist. He denied smoking and alcohol or intravenous drug use. The patient appeared well nourished with icteric sclera. Physical examination revealed a temperature of 38 C, blood pressure 110/55 mmHg, heart rate 85 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 95% on room air. Cardiopulmonary examination was normal. Abdominal examination revealed tenderness in the epigastric region with no guarding or rigidity. However, no palpable mass could be appreciated. Routine laboratory investigations showed normochromic normocytic anemia with Hb 12.3 gm/dl. Total bilirubin was 2.9 mg/dl while aspartate aminotransferase 167 U/L, alanine aminotransferase 443 U/L, and alkaline phosphatase were 424 U/L, respectively. Serum lipase and amylase were not elevated. The chest radiograph at the time of admission was normal. Subsequently, he underwent an abdominal computed tomography (CT) scan which revealed a 3.8 x 2.7 cm solid mass posterolateral to the pancreatic head, suggestive of peripancreatic lymphadenopathy. Magnetic resonance imaging (MRCP) showed a 4.1 x 2.6 cm mass in the pancreatic head encasing the portal vein with multiple central areas of nonenhancement (Figure 1). There was a 1.5 cm segment of narrowing in the mid common bile duct with mild dilation of the intrahepatic ducts. The pancreatic duct was not dilated. The differential diagnosis included malignant pancreatic tumor, autoimmune pancreatitis, neuroendocrine tumor, and gastrointestinal stromal tumor. Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) was performed which showed a heterogeneous hyperechoic pancreatic lesion which on histopathology revealed areas of coagulation necrosis, lymphocytes, and epithelioid histiocytes suggestive of granulomatous inflammation (Figure 2).

PMC6195231_01

Male

The case describes the presumed diagnosis of miliary tuberculosis (TB) in an 11-year-old, immunocompetent boy based on chest X-ray changes and clinical symptoms. The high incidence of TB in Namibia and hence high pretest probability made the diagnosis likely, despite consistently negative cultures. Failure of clinical response should have made the treating doctors question the diagnosis much earlier. Only upon referral to a specialist service with scrutinizing of the history followed by diagnostic opportunities of high resolution computed tomography (HR-CT), bronchoscopy and trans-bronchial biopsy made the alternative diagnosis of idiopathic pulmonary hemosiderosis (IPH) possible.

pulmonary tuberculosis, idiopathic pulmonary haemo-siderosis, respiratory services

PMC6195231_02

Male

An 11-year-old boy who presented with a four-year history of hypoxemia, ongoing hemoptysis and easy fatigability. His chest X-ray showed diffuse nodular infiltrates, resembling a pattern interpretable as miliary tuberculosis (Figure 1, Figure 2). The patient was repeatedly treated for pulmonary TB for a total period of three years, without treatment response. TB cultures and smears remained negative. Upon referral to a recently established specialist respiratory service, a HR-CT scan showed diffuse ground glass infiltrates (Figure 3, Figure 4). Consecutive bilateral alveolar lavage showed diffuse pulmonary hemorrhage (Figure 5), while histology of trans-bronchial biopsy demonstrated iron loaded pulmonary macrophages (Figure 6, Figure 7). The findings confirm the diagnosis of IPH. During his course of disease, the boy was admitted and investigated several times at his local hospital. This included treatment in an ICU in 2008, where he was diagnosed with severe pneumonia, pulmonary edema and respiratory failure. History reported an ongoing non-productive cough for one week, shortness of breath, hemoptysis and generalized weakness. On presentation severe respiratory distress, hypoxemia and pyrexia were reported. Treatment included a course of broad spectrum antibiotics, furosemide and steroids. The patient was started on TB treatment after discharge (he had a positive TB contact) despite that TB smear, microscopy and repeated cultures remained negative. He had received a blood transfusion after laboratory investigations revealed a hemoglobin (Hb) level of 6.60 g/dl, with a mean cell volume (MCV) 65fl and mean cell hemoglobin (MCH) 17.4 pg, in keeping with iron deficiency anemia. Further investigations showed normal liver function, renal function, serum electrolytes and clotting profile. HIV serology, auto-immune screen (ANA, anti-DS DNA, RF) and TB Mantoux test were negative. After discharge from ICU he continued TB treatment, but without substantial improvement of symptoms and more admissions to the local hospital. After three years he was referred for a second opinion to a pediatrician and onwards to a specialist respiratory service, which allowed the diagnosis of IPH. At referral the patient had an acute episode with deterioration of oxygen saturation from above 85% to the 60-75%. The chest X-ray demonstrated a miliary picture (Figure 1). After establishing the diagnosis, hypoxia and X-ray changes resolved after a week of high dose steroids (2mg/kg prednisolone) and he was discharged home without home oxygen. Outpatient treatment included milk-free diet, tapered doses of steroids for two months, followed by inhaled budesonide 400 mcg BD and hydroxychloroquine which was discontinued after his eyesight deteriorated at six months. One year after diagnosis he remains in remission on inhaled corticosteroids and milk-free diet.

pulmonary tuberculosis, idiopathic pulmonary haemo-siderosis, respiratory services

HR-CT scan showing diffuse ground glass opacities indicative of alveolar haemorrhage and thickened interlobar septae.

PMC6195231_02

Male

An 11-year-old boy who presented with a four-year history of hypoxemia, ongoing hemoptysis and easy fatigability. His chest X-ray showed diffuse nodular infiltrates, resembling a pattern interpretable as miliary tuberculosis (Figure 1, Figure 2). The patient was repeatedly treated for pulmonary TB for a total period of three years, without treatment response. TB cultures and smears remained negative. Upon referral to a recently established specialist respiratory service, a HR-CT scan showed diffuse ground glass infiltrates (Figure 3, Figure 4). Consecutive bilateral alveolar lavage showed diffuse pulmonary hemorrhage (Figure 5), while histology of trans-bronchial biopsy demonstrated iron loaded pulmonary macrophages (Figure 6, Figure 7). The findings confirm the diagnosis of IPH. During his course of disease, the boy was admitted and investigated several times at his local hospital. This included treatment in an ICU in 2008, where he was diagnosed with severe pneumonia, pulmonary edema and respiratory failure. History reported an ongoing non-productive cough for one week, shortness of breath, hemoptysis and generalized weakness. On presentation severe respiratory distress, hypoxemia and pyrexia were reported. Treatment included a course of broad spectrum antibiotics, furosemide and steroids. The patient was started on TB treatment after discharge (he had a positive TB contact) despite that TB smear, microscopy and repeated cultures remained negative. He had received a blood transfusion after laboratory investigations revealed a hemoglobin (Hb) level of 6.60 g/dl, with a mean cell volume (MCV) 65fl and mean cell hemoglobin (MCH) 17.4 pg, in keeping with iron deficiency anemia. Further investigations showed normal liver function, renal function, serum electrolytes and clotting profile. HIV serology, auto-immune screen (ANA, anti-DS DNA, RF) and TB Mantoux test were negative. After discharge from ICU he continued TB treatment, but without substantial improvement of symptoms and more admissions to the local hospital. After three years he was referred for a second opinion to a pediatrician and onwards to a specialist respiratory service, which allowed the diagnosis of IPH. At referral the patient had an acute episode with deterioration of oxygen saturation from above 85% to the 60-75%. The chest X-ray demonstrated a miliary picture (Figure 1). After establishing the diagnosis, hypoxia and X-ray changes resolved after a week of high dose steroids (2mg/kg prednisolone) and he was discharged home without home oxygen. Outpatient treatment included milk-free diet, tapered doses of steroids for two months, followed by inhaled budesonide 400 mcg BD and hydroxychloroquine which was discontinued after his eyesight deteriorated at six months. One year after diagnosis he remains in remission on inhaled corticosteroids and milk-free diet.

pulmonary tuberculosis, idiopathic pulmonary haemo-siderosis, respiratory services

HR-CT scan showing diffuse ground glass opacities indicative of alveolar haemorrhage and thickened interlobar septae, indicating extent of disease.

PMC9480580_01

Female

On October 16th, 2018, a 54-year-old married female patient, who was postmenopausal for 7 years and had 2 children, initially visited our hospital due to a pelvic mass accidentally found for 2 weeks. She underwent a resection of the left temporal skin basal cell carcinoma in September 2018, and her father died of brain metastases from lung cancer. Except for those, no other notable medical histories were present. Results of physical examinations were generally normal. Transvaginal ultrasound in our hospital showed a heterogeneous hypoechoic mass with a size of 11.9x9.3 x 9.0 cm in the pelvic cavity, and an ultrasound-guided needle biopsy of the mass was performed. The carbohydrate antigen 125 (CA125) is 517.3 U/mL. The patient was primarily diagnosed with ovarian cancer based on a pathological report of intrapelvic adenocarcinoma and results of immunohistochemistry. The results showed that ER(+), PMS2(+80%), MLH1(+80%), MSH2(+90%), MSH6(+90%), PR(-), P16(+), WT-1(+), p53(+90%), Ki-67(+80%), HER-1(EGFR)(+), HER-2(1+), CDX-2(small focal+), Villin(-). On admission, gynecological examination suggested that the pelvic range of motion was poor and closely related to the rectum, and the risk of rectal injury was greater, and there was ascites, it was difficult to achieve R0 in surgery. After adequate evaluation and discussion, the patient was given two-course neoadjuvant chemotherapy with paclitaxel and cisplatin (TP). The neoadjuvant treatment time was October 30, 2018, and November 29, 2018 respectively. On January 4, 2019, the patient underwent open abdominal cytoreductive surgery for ovarian cancer. Then she was diagnosed with stage IIIC moderately differentiated ovarian endometrioid adenocarcinoma based on postoperative pathology. The patient received satisfactory cytoreductive surgery and achieved R0. From January 13, 2019, to June 20, 2019, the patient was given six-course TP chemotherapy after surgery. Due to tumor recurrence suggested by imaging, bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, was combined since the 4th course of TP chemotherapy. At the end of treatment in June 2019, the ultrasound showed a hypoechoic nodule with a size of about 1.4 x 2.1 x 1.6 cm above the vagina. Follow-up regular reexaminations detected a slow growth of the vaginal hypoechoic nodule to 3.2 x 2.6 x 3.3 cm and new multiple small nodules in the pelvic cavity. In combination with biopsy pathology, it was considered to be tumor recurrence with metastasis, and the disease progressed. The patient was diagnosed with PROC and unable to be treated promptly due to coronavirus outbreak, no maintenance treatment and pelvic lesions persisted and progressed. On August 9, 2020, the patient was enrolled in a phase II study for PROC patients (ChiCTR1900027114) and treated with combination treatment of fuzuloparib (100mg PO BID), apatinib (250mg PO QD), and camrelizumab (200mg IV Q3W) for every 3-week cycle. From August 9, 2020, to November 23, 2021, twenty-one cycles of therapy have been administered. CT scans revealed a partial response. At baseline, the diameter of target lesions at the vaginal stump and in front of rectum was 44 mm (Figure 1), and multiple lymph nodes below 8 mm in the internal iliac vessel region were observed for non-target lesions (Figure 2). After the 4th cycle of treatment, non-target lesions disappeared and did not recur (Figure 3). At the end of the 11th cycle, the diameter of target lesions reduced to 3.9 mm without significant change thereafter (Figure 4). Target lesions sharply decrease by 91.14%. No new lesions were found. The incidence of grade 3 and above adverse reactions was 0. After the 4th cycle of treatment (November 5, 2020), grade 2 hypothyroidism gradually occurred. The main symptoms included serum-free T4 level gradually decreased to a minimum of 4.63 pmol/L, and serum thyroid-stimulating hormone level gradually increased to a maximum of 108.15 mU/L, accompanied by fatigue, weight gain, ECG ST-T changes, and other symptoms. The patient was given regular oral administration of levothyroxine sodium tablets (75ug QD) till now. Related symptoms were gradually relieved with good control. Reexamination of thyroid function was within the normal range. Another adverse reaction was a grade I red blood cell count decreased, which was fluctuating between 3.38 x 1012/L and 3.8 x 1012/L. The patient had no subjective symptoms and did not require clinical intervention. The hemoglobin, white blood cell count, and neutrophil count were within the normal range. The above adverse reactions were considered related to anti-PD-1 antibody and PARP inhibitor drugs, rather than the new adverse reactions due to the triplet combination therapy. At baseline, the patient's CA125 level was 33.35 U/mL. After the 2nd cycle of treatment, CA125 level decreased to 4.78 U/mL, and was within the normal range on subsequent visits. Moreover, the patient underwent genetic testing and additional immunohistochemical tests during treatment of triplet combination. Genetic testing revealed BRCA1 (+), which was performed on September 22, 2021. Immunohistochemistry indicated PD-L1 (SP263), TC < 1%, CPS: 2, MLH1 (+>90%), MSH2 (+>90%), MSH6 (+>90%), and PMS2 (+>90%), which was performed on October 10, 2021. The patient is still receiving triplet combination treatment with stable vital signs, significantly improved mental status, good appetite, and weight increased by 3 kg than before. Quality of life has been greatly improved, including significantly improved physical condition and mental and psychological status compared with those before participating in the clinical trial. The patient is self-sufficient in daily living with the eastern cooperative oncology group performance status (ECOG PS) of 2.

parp inhibitors, antiangiogenic agents, immunotherapy, platinum resistance, recurrent ovarian cancer

PMC8516381_01

Female

A grossly obese 26-year-old lady with a body mass index (BMI) of 43, gravida-1, para-1 + 0, type 2 diabetes mellitus, and hypothyroidism. She came to the causality with 12 days history of severe continuous right-sided lower back pain, right side pelvic pain increased with ambulation. Her pain started in a mild way prior to her recent admission for elective cesarean section for twin babies, using spinal epidural anesthesia, got worse and began to radiate to the back of the right thigh, increased with ambulation. There was no history of trauma, fever, chills, urinary, gynecological, or other systemic symptoms. Her physical examination revealed a temperature of 37.1 C, severe tenderness over the lower back, and right side of the pelvic region with intact neurology. Her cesarean section wound in the abdomen has healed. Her lower back and pelvis were stiff with severe pain on movements, standing, or sitting. The straight leg raising test was positive (30-40 ), and the FABER Patrick's test was difficult to evaluate due to intense pain despite the strong analgesia. The lumbo-sacral spine X-ray was unremarkable, but the pelvis X-ray revealed a 12 mm widening of the symphysis pubis (Figure 1). She was hospitalized for further examinations and pain control after a clinical diagnosis of perinatal right-sided lumbo-pelvic pain (LPP). Laboratory testing found 6.85 white blood cells (WCC) G/l with 69.2% neutrophils, a 48 mm/h elevated erythrocyte sedimentation rate (ESR) (Figure 2), normal procalcitonin (0.02), and a 68.7 mg/L elevated C- reactive protein (Figure 3). The lumbar spine magnetic resonance imaging (MRI) was negative, but the pelvic MRI found minor fluid signal amplitude in the right SIJ, which was associated with myositis (Figure 4). The patient was accused of developing unilateral sacroiliac arthritis and piriformis muscle syndrome. In the context of pain modality and incremental mobilization, we started her treatment with narcotic and non-narcotic analgesics, as well as non-steroidal anti-inflammatory medicines and physiotherapy. Her pain could not be controlled, and she became worse, unable to ambulate or step in or out of bed. Neurosurgery, neurology, rheumatology, anesthesia, obstetrics, and gynecology teams were consulted, but nothing was added to the preliminary diagnosis or the treatment plan. Despite the absence of any symptoms or signs indicating an acute or chronic infection, urine and blood cultures, protein purified derivative (PPD) for tuberculosis, and serology for brucella were required on Day 8. Because it was impossible to place the patient in the prone position on the same day, CT-guided aspiration of the right SIJ was performed in the left lateral position (Figure 5), but no aspirated fluid was obtained; however, SIJ block was performed using 20 mL of 0.25% bupivacaine after which she briefly noticed some relief of her shooting pain. Although the blood culture, brucella serology, and PPD all came back negative, the urine culture revealed asymptomatic Escherichia coli bacteriuria. The patient was started on IV ceftriaxone 1 g every 12 h and gentamicin 400 mg once a day by the infectious disease (ID) team. She showed steady and progressive clinical improvement just 48 h after intravenous antibiotics (IVAB). Ceftriaxone was given for another 2 weeks, and gentamicin was given for another 10 days. Her pain score (visual analogue scale (VAS) 2 out of 10) improved significantly, as did her walking capacity, bathroom privileges, and blood parameters. Following discharge on Day 26, the patient was sent home with oral ciprofloxacin 750 mg twice daily for 6 weeks. Nevertheless, her MRI on institutional discharge showed no substantial improvement compared to the initial one. She did well with regular ambulation and normal blood parameters at 6-week, 3-month, and 6-month follow-up visits. Her 1-year follow-up MRI was uneventful (Figure 6), while she did have periodic minor right-sided LPP that did not interfere with her daily activities.

pelvic pain, infection, magnetic resonance imaging and pregnancy, sacroiliac joint

PMC7679475_01

Male

A 54-year-old man was referred to our hospital with a history of high non-progressive dysphagia to solid food, meat impaction and ~8 kg of weight loss over last ten months because low intake on account of dysphagia as his appetite was normal. He denied heartburn, acute caustic ingestion, any history of chest pain, vomiting or loss of appetite. His medical history and family history (including atopic disease) were unremarkable as well as physical examination; in particular, the patient has no anemia, koilonychia, glossitis or stomatitis. Basic biochemical tests and complete blood count were normal (white blood cell count: 9730/mm3, eosinophils: 70/mm3, hemoglobin level: 14.2 g/dl, mean corpuscular volume: 91.7 fL, serum iron level: 91 mcg/dL and ferritin level: 113 mg/L). Antigliadin and antiendomysial antibodies for celiac disease were negative. We performed a barium swallow esophagram that showed two linear, circumferential filling defects on the anterior aspect of the cervical esophagus, consisting with the diagnosis of esophageal webs (Figure 1). Likewise, upper gastrointestinal endoscopy confirmed the presence of the cervical webs at 17 cm from the incisors with the endoscope not able to pass through (Figure 2). In order to exclude any other causes of dysphagia, computed tomography was performed. This revealed no abnormality around the esophagus, such as a tumor or swollen lymph nodes, which can cause luminal stenosis. Thus, other causes of cervical esophageal webs were ruled out, including motility disorders, celiac disease, PVs syndrome, Zenker diverticulum, benign or malignant tumors or extrinsic compression of esophagus. The treatment consisted of endoscopic balloon dilation without any complications (Figure 3). We used the Boston Scientific CRE Wireguided Balloon Dilation Catheter with the size 15 - 16.5-18 mm, who was inflated to 7 atm, the pressure needed to obtain an 18 mm diameter. Only one dilation was performed with excellent clinical and endoscopic results. After this procedure the patient's dysphagia resolved immediately and the endoscope passed easily in through the esophagus showing normal esophageal, gastric and duodenal mucosa. At the first follow-up, twelve months after endoscopic ballon dilation, the patient gained weight and he had no complains. Likewise, he remained asymptomatic and did not show any recurrence for three years. A second procedure was not considered necessary by the medical personnel or the patient during the follow-up.

cervical esophagus, dysphagia, endoscopic dilation, esophageal webs

PMC10336253_01

Male

A 54-year-old man presented with a three-month history of headache during the fourth wave of the Delta variant of COVID-19 in Iran. The headache was progressively worsening and intensified during exertion or walking but improved when lying down. Additionally, for the past week, he had been experiencing speech difficulties, hypernasality, swallowing difficulties due to loss of gag reflex, and purulent otorrhea on the right side. During detailed history taking, the patient did not mention any accompanying diseases, current medication consumption, trauma, or recent COVID-19 infection, despite receiving the Sinopharm vaccine. However, he did have a history of previously treated Tuberculosis and Brucellosis several years ago. Three months ago, during initial evaluations at another medical center, sphenoid sinusitis was detected. Despite receiving maximum medical treatment with antibiotics, the patient did not respond, leading to the decision of performing endoscopic endonasal sinus surgery. However, there were no obvious mucosal changes except for discharge from the sphenoid sinus. Histopathologic examination results showed no specific findings other than inflammation. During the physical examination, the patient appeared ill but was conscious and oriented. There was no evidence of orbital involvement, and cranial nerve 7 (facial nerve) was intact. The patient presented with trismus (difficulty in opening the mouth) and unilateral deviation of the uvula to the left, indicating involvement of cranial nerves 9 (glossopharyngeal), 10 (vagus), and 12 (hypoglossal). Due to the patient's general condition, it was not possible to examine cranial nerve 11 (accessory nerve). Additionally, there was loss of sensation in the region innervated by the V2 branch of the trigeminal nerve (maxillary nerve), but no mucosal changes were observed in the palate or nasal cavity. A comprehensive work-up was conducted, taking into account the differential diagnosis. The initial laboratory data showed anemia and elevated levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fasting blood sugar (FBS) at 229 (Table 1). A brain CT scan was performed, which revealed a destructive lesion forming sequestration in the skull base. The lesion involved the clivus, occiput, greater wing, and pterygoid process of the left-sided sphenoid, indicating the presence of skull base osteomyelitis. Additionally, mucosal thickening was observed in the sphenoid sinus (Fig. 1). To further evaluate the condition, a multiplanar contrast-enhanced brain MRI was conducted. The results showed abnormal bone marrow infiltration in the clival, skull base, and pterygoid plates, with the most prominent involvement on the left side. The post-contrast enhancement was heterogeneous, suggesting skull base osteomyelitis. However, the possibility of neoplastic infiltration could not be completely ruled out. Furthermore, the right cavernous sinus, Meckel's cave, and oval foramen showed involvement, and abnormal enhancement of leptomeninges and dura was observed (Fig. 2). A cervical spine MRI study did not reveal any significant lesions. A neck MRV (Magnetic Resonance Venography) showed no evidence of thrombosis in the cervical venous system, and both jugular veins exhibited normal signal and diameter. A chest HRCT (High-Resolution Computed Tomography) scan did not show any remarkable findings. Based on the imaging findings, osteomyelitis, tuberculosis (TB), and malignancy were considered more likely in the case of the patient, while fracture was ruled out. Mucormycosis was also considered as a possible differential diagnosis based on the patient's physical examination findings and the presence of the ongoing COVID-19 pandemic, along with the imaging data. Due to the imaging findings and clinical presentation, the patient was admitted to the intensive care unit (ICU), where he gradually developed respiratory distress and required intubation. Neurosurgery and rhinology specialists consulted on the case and decided to perform skull base debridement and biopsy of the skull base lesion. During endonasal endoscopy of the sinonasal cavity, the mucosa appeared normal without typical necrosis, except for the presence of purulent discharge from the sphenoid sinuses. Using the endoscopic endonasal trans-pterygoid approach, all the necrotic bone involved in the pterygoid palates, greater and lesser wings of the sphenoid, and clivus were resected extradurally. Macroscopically, the involved bone exhibited typical necrosis characteristic of an increasing number of mucormycosis cases. Additionally, through the endoscopic endonasal access to the craniovertebral junction, the remaining necrotic bone and sequestra, including the occipital condyles, were resected extradurally. The dura appeared thick and had adjacent granulation tissue near the involved bone. No cerebrospinal fluid (CSF) leak was observed, and considering the infectious nature of the disease, no reconstruction was performed. Following the surgery, a tracheostomy was performed, and the patient's neck was stabilized using a collar. The day after the surgery, a percutaneous endoscopic gastrostomy (PEG) tube was inserted to provide nutritional support. Surprisingly, both the KOH smear and culture of the surgical tissue sample revealed the presence of aseptate hyphae, consistent with Mucormycosis. The histopathologic examination confirmed the angioinvasion by fungal hyphae, further confirming the diagnosis (Fig. 3). The patient received amphotericin B treatment for 38 days following the surgery. After spending 12 days in the ICU, the patient regained consciousness and achieved physical stability, leading to a transfer to the ward. However, he developed high blood sugar levels and was diagnosed with new-onset diabetes. Unfortunately, after 30 days, his general condition deteriorated due to uremia, due to acute renal injury (AKI), and he passed away 8 days later.

cranial nerve palsy, cranial nerves, garcin syndrome, mucormycosis, osteomyelitis

PMC9133493_02

Female

After 3 months, the intake process was completed successfully, yielding the following diagnostic summary. An 18-year-old woman was referred to the treatment due to ongoing trauma, panic attacks, school dropout, and a difficult family situation. She had experienced multiple traumatic events (sexual and abusive) that have had a major influence on her self-image and image of others. Consequently, Michelle showed avoidant coping behavior in difficult situations, poor coping skills, and anger. She had to deal with several family issues at home and had gone through many changing family compositions (Figure 1). Michelle's symptoms were classified as PTSD and agoraphobia. A hypothesis about the coherence of Michelle's problems was formulated (Figure 2). Subsequently, a treatment plan that described treatment goals was drawn with Michelle (Table 3). As part of Youth Flexible ACT involvement, baseline and follow-up outcome measures were administered to assess overall psychological distress (OQ-45) and severity of PTSD symptoms (PSS-SR). The OQ-45 is a self-report questionnaire consisting of 45 items yielding a total score and 3 subscale scores. Items were scored on a 5-point rating scale, ranging from never (0) to almost always (4). A cut-off score of 55 on the full scale indicates clinically significant distress. The PSS self-report version consists of 17 items corresponding to the PTSS symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Items were scored according to the frequency of symptom occurrence in the past week, ranging from 0 (not at all) to 3 (5 or more times per week). The PSS-SR provides a total score and three subscores. Higher scores represent more severe symptoms. After the intake report and treatment plan had been approved, the active treatment phase could start. Multiple team members were assigned to Michelle: A head practitioner (healthcare psychologist/skilled in systemic working) coordinated the care process, became acquainted with the family system, mapped out why previous care services failed and provided EMDR therapy; A PNP provided support to help Michelle cope with problems in her everyday life and provided parent counseling sessions; A social worker (also skilled in systemic working) provided Emotion Regulation Therapy (ERT) and offered support with searching and referring to community resources, such as school or job opportunities, and with conducting parent counseling sessions, and A psychiatrist examined whether medication could be a helpful addition. Official systemic therapy was not indicated, as team members believed therapy would not be feasible for the family due to the stressful and changing home situation. Additionally, immediate treatment for trauma and anxiety symptoms was not indicated due to Michelle's limited trust in mental healthcare workers. During this first year, the team focused on initiating and sustaining contact with Michelle and her ex-stepfather. Gradually, the involved team members got to know her better, and Michelle started to speak freely. Michelle had gained more confidence in the care process. Michelle explained to the PNP that she was afraid to take a shower and go to the dentist. When showering, she experienced a lot of tension because of earlier traumatic events in the bathroom. The PNP practiced exposure therapy techniques with Michelle to become less anxious to go out alone and supported her with visits to the dentist. Additionally, they started setting up a crisis and contingency plan. Meanwhile, the social worker started with ERT, and during the year, Michelle gained more insight into her emotional self-regulation. Furthermore, Michelle started taking fluoxetine to feel calmer, less panicky, and less agitated. When necessary, she also took quetiapine to suppress her unrest. At the end of the year, Michelle managed to undertake activities by herself (go to the store, dentist, shower). She appeared calmer and indicated she would like to start trauma therapy. With the support of the social worker, Michelle set up a resume and dared to take the step to apply for work in a department store. The social worker had arranged that Michelle could start working while she continued to receive disability benefits. Michelle was hired, and the employer was very helpful and understanding of her mental health issues. The first working days went well, and Michelle was very proud. Psychiatric Nurse Practitioner provided psychoeducation to the ex-stepfather, Michelle's mother, and her therapist, explaining Michelle's problems and describing the ways in which her parents could support her. Michelle has managed to distance herself from the home situation during the year by focusing on the application process and work. However, the team members noticed that Michelle was still very dependent on her ex-stepfather. Although her situation had improved, she hardly ever left his side. Together with the social worker, Michelle took steps in administrative matters, managing her financial situation. Eye Movement Desensitization and Reprocessing therapy sessions were scheduled in the second year. The conversations with the PNP, social worker, and psychiatrist continued. Michelle gained more insights into her avoidance pattern during the sessions with the involved team members. She understood the role of avoidant coping and distrusting others in previous (unsuccessful) treatments. During the introductory talks with the EMDR therapist, Michelle pointed out that she had not yet reported sexual abuse to the police and wanted to do so. They decided first to file a report and subsequently start EMDR. However, when the EMDR sessions eventually started, she kept canceling the sessions. She mentioned that she had a lot on her mind concerning her home situation. Her half-sister was in a closed youth care institution, and Michelle was very worried about her. Furthermore, her mother lived temporarily with Michelle's ex-stepfather for her mother's safety. This caused a lot of stress in the family, eventually leading to Michelle's emotional outburst. Michelle took (small) overdoses of sleeping pills to suppress these emotions. The team members who were already involved were increasing the contact frequency. Other team members knew what was going on and, when necessary, could help immediately. After 2 weeks, when Michelle was calmer again, the situation was re-evaluated with Michelle and family members and with her mother's therapist. Together with the social worker, Michelle talked about her stress triggers, methods she could use to manage and reduce stress symptoms, and different ways she could ask for support. Michelle had had a good start at work and handled her fears. She understood that she had not gained successful and positive experiences due to anxiety and avoidance, which hurt her self-image. Now, she showed perseverance. Unfortunately, after a few months, she suffered from tension headaches and experienced a lot of stress due to family issues. Michelle couldn't handle going to work, and as a result, her temporary contract was not being renewed. Michelle, her mother, and her ex-stepfather knew that Michelle had to maintain a healthy balance between paying attention to others and doing what was good for herself. Acting on this has proven difficult. Her mother and her mothers' therapist discussed that the mother should not take responsibility for Michelle. Michelle missed an appointment with the occupational physician, for which a fee was charged. Michelle was already stressed, and then experienced even more stress as she couldn't afford this. She told the social worker she also failed to pay her healthcare insurance. Eventually, the income and work consultant of the municipality had set up a plan through which a payment arrangement was agreed. Michelle knew she should have contacted several organizations to arrange her finances but did not do so. She found it very difficult to make the necessary phone calls, and because she felt ashamed, she postponed and avoided this. The social worker discussed and addressed this recurring avoidance tendency with Michelle. During the third year, an IPS counselor (Individual Placement and Support) was deployed to help Michelle search for work. The EMDR sessions were continued, and the social worker still provided support and parent counseling sessions. Medication continued to be administered. The PNP was only deployed when necessary. The EMDR sessions, during which the social worker was closely involved by driving Michelle to and from the sessions and providing aftercare during the supportive contacts, were resumed. This agreement gave Michelle a safe feeling and helped her deal with emotions in daily practice. Michelle no longer suffered from trauma-related complaints. She had no traumatic memories, no nightmares, and she was less hyper-alert. Michelle felt less irritation and anger and dealt with her emotions more adequately. Because her level of tension decreased, she was much more daring to go out alone and less dependent on her ex-stepfather. She even got her driver's license. Michelle was introduced to the IPS counselor, and together they set up a new work plan. A basic qualification was required to retain social assistance benefits for a good starting position in the labor market. Michelle refused to take classroom education, and given her avoidance pattern, it was not expected to be successful at this time. A home study (preparation for maternity nurse) was set up to get her used to education. The IPS counselor contacted the municipality, and they paid for the home study and laptop while retaining sickness benefits. Michelle was afraid to start with the study, but it did go well after a few days. However, after a few months, Michelle had trouble following the study. She indicated that the discussed theories were too difficult to understand and gave her a feeling of failure. Initially, Michelle wished to quit her study, but after joint meetings with the social worker, Michelle, and other relatives, she managed to catch up with the study again. Michelle was much less irritated and more patient with her relatives. She was more successful in making choices for herself (going to therapy, studying) and stopped trying to take over someone else's problems. For example, when her mother moved to another house and called on her for help, Michelle could cope in a controlled and calm way. At the request of Michelle, her ex-stepfather helped her manage financial matters. During the fourth year, the spread of coronavirus caused lockdowns worldwide. In the beginning, sessions mainly took place by telephone or video calling, in the garden, or during walks. IPS, EMDR, sessions with the social worker, and medication consults were continued. Halfway through the year, a horrible event took place. Michelle's half-sister, still a minor, went missing. Luckily, her sister returned home after 2 weeks. During this period, the team care provided additional support, and a social worker, the PNP, or head psychologist visited Michelle daily. Because of the episode with her sister, new cases of abuse came to light that triggered trauma complaints. The EMDR sessions were resumed with images that were not treated before. The sessions went well. Michelle still experienced some anger but indicated she was no longer re-experiencing the symptoms. During the fourth year, Michelle showed much more control in handling her emotions. Despite the turmoil in her family, Michelle was more stable and started to cope better with the things she's gone through. She could handle setbacks more easily and react more calmly. Her medication (fluoxetine) was gradually reduced. Michelle caught up with her studies but soon indicated that it took a lot of effort for her to consistently comprehend the theory and that she wanted to stop with the study. The IPS counselor listened and indicated that a work-study program suited Michelle better. Individual internal training at an organization seemed more appropriate than classroom training or home study. Together with the IPS counselor, Michelle had visited several employers, and she applied for a learn/work trajectory at a healthcare institution. During the fourth year, Michelle developed better communication with family members and her mother and ex-stepfather did no longer involve her as much in their daily struggles. Michelle managed to maintain a healthier balance between her needs and those of others. She had more control in taking care of things for herself (i.e., reschedule an appointment, make a phone call to institutions). When Michelle's two youngest siblings came to live with her ex-stepfather, it was getting more crowded, and Michelle expressed carefully that she needed a place to live on her own. The team already had this in mind earlier but deliberately did not focus on it because they still expected resistance and avoidance at that time. The social worker helped Michelle explore other housing options. Flexible ACT care is provided as long as necessary and as briefly as possible to achieve symptomatic, functional, and personal recovery. Whether the specialized intensive mental health care can be downgraded to primary [General Practitioner (GP), primary care psychologist, social district team] or secondary office-based mental health care is continuously monitored throughout the care period and carefully considered by taking into account symptomatic remission, complex medication use, school attendance, having a job or other form of daytime activities, availability of support systems, financial situation, confidence in the recovery, and ability to accept guidance and call for help when necessary. In addition to leaving care upon recovery, clients exit Youth Flexible ACT when they reach the age limit. When clients reach the age of 23, various forms of follow-up care are considered, depending on the situation. Exits and transfers are discussed and planned carefully with the clients and their relatives and are structured and staged. The team ensures a "smooth" transfer from old to new care providers through shared contacts to guarantee continuity of care. Michelle recently turned 23; therefore, the Youth Flexible ACT team discussed with her the transition to AMHS in the coming year. Michelle and the team members agreed that intensive Flexible ACT care was no longer necessary While Michelle reported high scores on overall psychological distress (OQ-45) and on severity of PTSD symptom (PSS-SR) at the start of Flexible ACT, her distress and trauma symptoms decreased sufficiently at the end of Flexible ACT (Table 4). Michelle still experienced some anger after the EMDR sessions, but she was no longer suffering from re-experiencing symptoms. The communication with family members improved. She applied for a work-study program, felt more empowered, and made choices and arranged things for herself. The final phase (phasing out) would focus on preparing for the transition to adult- and primary care, maintaining the progress achieved, and preventing Michelle from reverting to negative behavior. Setting up a relapse prevention plan, which describes triggers, coping tools, and support group information is always an important part of this final phase. The following interventions were included in the final treatment plan of Michelle: setting up a relapse prevention plan, continuing IPS counseling, transferring medication to a general practitioner, contacting mother's therapist, contacting involved social services, and becoming acquainted with a new mental health care provider. The IPS trajectory could be continued without Flexible ACT.

flexible assertive community treatment, adolescents, early intervention, family centred, fragmented care, integrated care approach, intensive case management, mental healthcare model

PMC4246147_01

Female

A 42-year-old African American woman with a history of sickle cell trait (SCT) was admitted to the hospital for painless gross hematuria with the passage of clots for 3 weeks. She also complained of fatigue, dizziness, and general malaise. She denied abdominal pain, dysuria, or fever. She had a remote history of similar presentation 20 years ago that resulted in right-sided partial nephrectomy. It was performed in an outside hospital and medical records were not available. She reported no other significant medical history and was not taking any medications at home. Family and social history was unremarkable. On physical examination, the patient had stable vital signs with a blood pressure of 120/70 mm Hg, heart rate 90/min, and temperature of 98.4 F. She appeared comfortable but with marked pallor. Her abdomen was soft, non-tender, non-distended, and revealed no costovertebral angle tenderness. The rest of the physical examination was unremarkable. Laboratory data revealed hemoglobin of 5.7 g/dl, hematocrit 17.2%, platelets 317 K/microl, INR 0.93., and creatinine of 0.9 mg/dl. Other pertinent laboratory values showed bilirubin of 1.1, LDH of 139 U/L, and haptoglobin of 90 mg/dl. Hemoglobin electrophoresis demonstrated Hb A 74.7%, Hb A2 2.9%, Hb F 0.4%, and Hb S 22%, but it was drawn after transfusion. Urinalysis showed numerous red blood cells (RBCs), 2+ protein, and 2-5 WBC/HPF. Peripheral smear, vasculitis work up, or urine culture were not performed. Initial CT scan of abdomen and pelvis revealed hyper dense material in collecting system of right kidney extending into renal pelvis but no aneurysm or calculus was demonstrated. Later patient underwent renal angiography, which demonstrated normal arterial anatomy. She also underwent CT urography that revealed a filling defect within the pyramid of the lower pole of the right kidney representing papillary necrosis as demonstrated in Fig. 1. The patient was managed conservatively during the hospital course. She was transfused with 3 units of blood and blood counts remained stable after transfusion. In the beginning, our differential diagnosis was broad, including renal papillary necrosis, IgA nephropathy, bladder cancer, and renal medullary carcinoma. But the diagnosis was narrowed down to renal papillary necrosis after CT urography was performed. Patient was started on sodium bicarbonate infusion along with aggressive hydration and diuretics. After 3 days of treatment, her hematuria had completely resolved and she was discharged home in stable condition. SCT is a carrier state of sickle cell disease with one copy of normal beta globulin gene and one copy of sickle variant gene-producing heterozygous HbAS. SCT is estimated to have prevalence of 300 million worldwide, mostly concentrated in Africa, Middle East, and Mediterranean region. In the United States, the prevalence of SCT is around 8-10% in African American population. Although SCT is considered a benign condition with no increased mortality in individuals, it has been associated with several complications. A number of abnormalities have been reported in SCT, including renal medullary carcinoma, papillary necrosis, thromboembolic events, and hyposthenuria. Renal complications are listed in Table 1 . Our discussion will be limited to renal papillary necrosis. Renal papillary necrosis is frequently associated with sickle cell disease, but it is not uncommon in SCT as well. It has been usually associated with diabetes, analgesic nephropathy, chronic pyelonephritis, and renal tuberculosis. Renal papillary necrosis is usually precipitated by some factors such as intense exercise, dehydration, and taking NSAIDs. In our patient, none of these factors were present. To date no comparative data exist with regard to the distribution and frequency of occurrence of renal papillary necrosis among persons with SCT, hemoglobin SC, and thalassemias; however, there have been case reports on hemoglobin SC but none to date on thalassemia unless associated with a sickling hemoglobin (Sbeta+). Papillary necrosis results from obstruction of the vasa recta producing ischemia and micro infarction of medullary region of the kidneys. Polymerization of the RBCs in the vasa recta of the renal medulla is the main trigger for renal papillary necrosis. Numerous factors are involved in initiating the sickling of RBCs including hypoxia, hypertonicity, and acidosis. Once sickling starts it leads to increased blood viscosity and decreased blood flow to medulla, which ultimately results in micro infarction of vasa recta causing papillary necrosis. The extent of polymerization of RBCs depends upon the concentration of HbS. The clinical presentation varies from painless gross hematuria to acute condition with pain, fever, and obstructive urinary symptoms. Hematuria is by far the most important clinical feature. It usually manifests in the age group between 30-40 years and there seems to be no sex predominance. Any patient with SCT, who presents with hematuria, needs a thorough clinical investigation especially in young patients because renal medullary carcinoma can also presents in a similar fashion. Renal medullary carcinoma is a rare, aggressive fatal tumor, which presents in young patients with SCT. Because renal medullary cancer is very rare, there is no epidemiological data available, but according to one report in 2003, there are 55 cases of renal medullary cancer that were reported in literature.

ct urography, sickle cell trait, renal papillary necrosis

PMC4285239_01

Male

A 33-year-old international male student studying in England traveled to Japan and stayed with a friend in Tokyo during July-September 2014. In late August, an acute high fever (39.7 C), severe headache, retro-orbital pain, malaise, and loss of appetite developed. He did not have cough, sputum, or rhinorrhea. He returned to England 3 days after symptoms developed. On day 5 after symptom onset, the man noticed a scattered papular erythematous rash on the anterior chest wall. His symptoms had improved substantially. One week later, he experienced exacerbation of the same symptoms (again without cough, sputum, or rhinorrhea), which continued for a few days until he sought care 12 days after initial onset. He had no significant medical history or known allergies and had not traveled to any countries other than Japan. On examination, the man appeared ill and had a high fever (38.5 C). His lungs were clear, but his pharynx was markedly swollen and erythematous with cervical lymphadenopathy. Despite his severe symptoms, results of laboratory tests showed no or only mild elevations: normal leukocyte count and differentials (6,700 cells/mm3 [reference 4,000-11,000] with neutrophils 60% and lymphocytes 26%) and slightly elevated C-reactive protein (0.9 mg/dL [reference 0.0-1.0 mg/dL]) and erythrocyte sedimentation rate (14 mm/h [reference 1-10 mm/h]). Liver enzyme levels were elevated: lactate dehydrogenase 623 IU/L (reference 125-243 IU/L), alanine aminotransferase 78 IU/L (reference 0-55 IU/L), aspartate aminotransferase 58 IU/L (reference 5-45 IU/L), and gamma-glutamyl transpeptidase 81 IU/L (reference 12-64 IU/L), with normal total bilirubin (1.0 mg/dL [reference 0.2-1.2 mg/dL]). Mild hyponatremia (sodium 132 mmol/L [reference 135-145 mmol/L]) also was noted; otherwise the test results were unremarkable, including normal platelet count and coagulation panel. Serologic tests were positive for anti-dengue virus IgM but negative for anti-dengue virus IgG: viral RNA was not detected. The patient was hydrated with intravenous fluid and discharged with acetaminophen as needed for fever and pain. He was instructed to avoid nonsteroidal antiinflammatory drugs because of possible bleeding risk. The sore throat resolved within 1 day, and his pain and fever were well controlled with acetaminophen. This dengue outbreak in Japan started in Yoyogi Park, a public park in the Tokyo metropolitan area. From August 26, 2014, when the first case was identified, through October 30, a total 160 autochthonous dengue fever infections occurred. The patient reported here stated that the house where he stayed in Japan is a 2-minute walk from Yoyogi Park and that he was bitten multiple times by mosquitos in late August, although he did not enter the park or other implicated parks. This outbreak has several possible causes. First, Aedes albopictus mosquitoes:1 of 2 main vector mosquitoes of dengue virus:are widespread in Japan. Although the other species, A. aegypti, has not been established in Japan, it was once identified at Tokyo International Airport. Second, the worldwide dengue fever incidence has increased exponentially during the past 50 years, and the number of cases imported to Japan has increased steadily since 1999. Third, increased international travel, trade, and shipping, in addition to global warming, might have contributed to geographic expansion of the vectors. Why this dengue fever outbreak started from Yoyogi Park remains unknown. One possibility is the popularity of Yoyogi Park, which holds 100 events annually, including many international events. In July and August 2014, just before the first case was identified, Yoyogi Park hosted multiple festivals of countries in dengue-endemic regions, including Southeast Asia and South and Central America (http://www.yoyogipark.info/ad2014/). Dengue virus could have been spread from infected visitors by mosquitoes in the park. Any events that include persons from dengue-endemic regions and held where the vectors are prevalent could be the source of spread. This case highlights the possible risk for a dengue outbreak in countries to which dengue is not endemic but where the vectors are present. and thus the potential exists for travelers to become infected. Physicians need to be aware of the possibility of dengue fever in patients returning from non-tropical/subtropical countries, obtain a full travel history, and keep apprised of the latest epidemic information.

PMC4309343_01

Male

The patient was a 76-year-old man referred to our clinic with screening results suspicious for gastric cancer. His past medical history consisted of hypertension and benign prostatic hypertrophy. Physical examination and laboratory data were nonspecific except for asymptomatic macroamylasemia. Esophagogastroduodenoscopy showed a 20 mm type 0-IIc lesion in the gastric subcardia, preoperatively diagnosed as cT1, cN0, cM0, cP0, cStage IA. The patient underwent a planned total gastrectomy with D1 lymphadenectomy followed by Roux-en-Y reconstruction with no complications. The postoperative course was unremarkable, and the patient was discharged on postoperative day 10. Pathologic evaluation revealed an 8 mm moderately differentiated tubular adenocarcinoma on the anterior wall. Macroscopically, the tumor was flat and slightly depressed (type 0-IIc). Histologically, it showed an INFbeta growth pattern, and the tumor invaded the submucosa (pT1 SM). There was no evidence of lymph node (pN0) or liver (pH0) metastasis or venous (v0) or lymphatic (ly0) invasion. The proximal and distal resection margins were clear. Peritoneal cytology was also negative (pP0, CY0). The final stage was pT1N0M0, Stage IA according to the Japanese classification of gastric carcinoma staging system). Except for occasional heartburn, a sense of abdominal distension, and elevated serum amylase levels, he had no obvious signs and symptoms during postoperative follow-up. He took nifedipine (Adalat CR , Bayer Healthcare, Osaka, Japan), theophylline (Theodur , Mitsubishi Tanabe Pharma, Tokyo, Japan), etizolam (Depas , Mitsubishi Tanabe Pharma), bifidobacterium (Lac-B Granular Powder , Kowa Company Ltd., Nagoya, Japan), magnesium hydrate (Yoshida Pharmaceutical, Tokyo, Japan) and eviprostat (Eviprostat , Nippon Shinyaku, Kyoto, Japan). His basal serum vitamin B12 level was followed monthly and initially maintained within the normal range by intramuscular injections of mecobalamin (Methycobal , Eisai, Tokyo, Japan). Nine months after surgery, his serum vitamin B12 levels suddenly increased to 33,000 pg/ml, which is approximately 36-fold higher than the normal range (233-914 pg/ml). This level of hypercobalaminemia persisted for approximately one year without mecobalamin injections. The patient's diet did not contain any obvious excess sources of vitamin B12. Fortunately, he did not show any obvious symptoms or laboratory abnormalities (Table 1). He later reported that he had started drinking half a bottle of an energy drink as a supplement during this time. After he discontinued the energy drink, his serum vitamin B12 levels quickly declined to within the normal range (Figure 1). The ingredients on the energy drink label included caffeine, fructose, beta-carotene, vitamins B2, B6 and C, octacosanol, garlic, licorice, ginseng, bracket fungus, Polygonatum falcatum and chlorella extract; there was no mention of vitamin B12. Concentration analysis revealed an undetectable amount of vitamin B12 in the energy drink.

energy drink, hypercobalaminemia, supplement, total gastrectomy, transcobalamin

PMC2663463_01

Female

A 75-year-old woman was referred in acute care for mental deterioration, gait disorder, urinal incontinence, and unusual headache progressing over the six months. The family reported that the short-term memory loss gradually developed over the last two years. The daily activity was disturbed and required the presence of a caregiver. The past medical history included hypertension treated with atenolol. The medical family history was unremarkable. On admission, the patient was bedridden. Neurological examination revealed a fluctuation of vigilance. She was mute and had a bilateral grasp reflex. There was no motor or sensory deficit. General physical examination was normal. Blood pressure was 150/70 mmHg and temperature was 37 C. Complete blood count, liver enzymes and serum electrolytes were normal. The results of blood inflammatory test were as follows: erythrocyte sedimentation rate 35 mm/hour, C-reactive protein 620 mg/dL (normal < 100), fibrinogen 51 mg/dL (normal < 40). Serum protein electrophoresis and immunoelectrophoresis were normal. To rule out a diagnosis of meningitis, a lumbar puncture was performed, yielding a clear cerebral spinal fluid (CSF) with 78 erythrocytes/mL, 2 leukocytes/mL, 250 mg/dL protein (normal < 45) with 14.6% IgG in a polyclonal pattern (normal < 10), and 63 mg/dL glucose (normal < 75). Bacterial examination of the CSF did not show any germ and cultures were negative. All serum and CSF tests for infection were unremarkable, including herpes simplex virus, varicella zoster virus, human immunodeficiency virus types 1 and 2, cytomegalovirus, mycoplasma pneumoniae, Lyme disease, syphilis, mycobacterium tuberculosis, and cryptococcosis. Brain computed tomography (CT) scan showed extensive hypointensities in the white matter in both hemispheres and a mild ventricular enlargement. There was no iodine fixation. Axial brain magnetic resonance imaging (MRI) showed T2-weighted high-intensities in the periventricular white matter and was negative in T1-weighted sequences with and without gadolinium infusion. On coronal images, the left hippocampus was atrophic. Search for antinuclear antibody was negative. Because of the severely disabled clinical status and the abnormality of the CSF, an intravenous corticotherapy was initiated seven day after admission with 120 mg dexamethasone per day associated with antibiotics. Vigilance and mutism improved in few days revealing a severe dementia with complete temporo-spatial disorientation. After three weeks of corticotherapy, CSF protein concentration was 46 mg/dL and C-reactive protein was normal. Brain CT scan was unchanged. The neurological status stabilized with a severe dementia. Corticosteroids were progressively tapered over the next five weeks and the patient was transferred to a geriatric rehabilitation hospital. She died four months later of a pulmonary infection. On postmortem examination, the brain weighed 1180 g. Macroscopically, coronal brain slices showed a mild atrophy of the left hippocampus and a moderate enlargement of the lateral ventricles. The cortical band had a normal thickness. Focal small dark red infarcts were disseminated in the subcortical white matter of both hemispheres. The brainstem and cerebellum were normal. The circle of Willis was permeable. Samples of the hippocampus, entorrhinal cortex, middle frontal gyrus, superior and middle temporal gyri, inferior parietal lobule, and midbrain including the basal ganglia were fixed in 10% neutral-formalin and examined by light microscopy. On paraffin-embedded and hematoxylin-eosin-safran and congo red stained sections, lesions consisted in senile plaques, CAA, angiitis, and microinfarcts. Amyloid deposits were present in the neocortex of both cerebral lobes where they appeared as amorphous material in senile plaques. The wall of numerous vessels located in the leptomeningeal space and cortex were also infiltrated by these amyloid deposits. Inflammatory infiltrates consisting in lymphoid cells and macrophages surrounded both amyloid and non amyloid vessels in the leptomeningeal space and less frequently in the cortex (Figure 1A). There were neither multinucleated giant cells nor fibrinoid necrosis. In addition, numerous vessels including some with amyloid deposition showed severe intimal fibrosis occluding the lumen, and suggesting a post inflammatory healing process (Figure 1B). Multiple disseminated small infarcts were observed all over both hemispheres respecting the basal ganglia. They were filled with macrophages and surrounded by siderophages. Immunohistochemical study showed that amyloid deposits, present in the senile plaques and in the wall of vessels including some with an inflammatory infiltrate, were stained with betaA4 amyloid antigen (DAKO, Glostrup, Danemark) (Figure 1C, D). Tau (DAKO) immunolabeled the periphery of the majority of amyloid plaques, and defined neuritic plaques. Tau protein filamentous accumulation was present within the cells bodies of neurons indicating the presence of neurofibrillary tangles, especially in the isocortex (Figure 1E). A semiquantitative assessment of neocortical senile plaques density was estimated as superior to 17 per square millimeter in all the investigated samples of the neo-cortex. The density of neurofibrillary tangles was higher in the hippocampus and the entorrhinal cortex. In the myocardium, the wall of a coronary artery was infiltrated by lymphocytes, mononuclear cells, and giant multinucleated cells (Figure 1F). An interstitial fibrosis was present between the myocytes, likely due to hypertension. Vessel inflammatory changes were not found in the autopsy samples of lung, kidney, liver, spleen, and muscles examined by light microscopy.

alzheimer’s disease, cerebral angiopathy

PMC9905025_01

Female

Our patient is a 62-year-old post-menopausal female with past medical history of psoriatic arthritis and left breast DCIS. She is status post left lumpectomy followed by left skin-sparing mastectomy with sentinel node biopsy and reconstruction for positive margins due to multifocal low-grade DCIS, ER/PR+, HER2-. Post mastectomy margins and lymph nodes were negative for disease, however of note, the patient never started adjuvant anti-endocrine therapy. Two years later, she presented to clinic with a chief complaint of several small nodular masses along the left mastectomy scar extending from the reconstructed nipple to the lateral axillary chest wall. Ultrasound of the palpable masses showed diffuse thickening with skin edema. Over a week-long period, the nodules progressed in number and size (20-25 in total - Figure 2) prompting histologic evaluation. A core-needle biopsy was performed but was read as fibroadipose tissue and discordant to our findings on physical exam. We then proceeded with an excisional biopsy, which showed benign fatty tissue; again, discordant with our physical exam. MRI with and without contrast was performed (Figure 3) showing multiple areas of nodular enhancement with skin thickening and no evidence of lymphadenopathy. A second excisional biopsy was performed, removing more tissue from the lateral chest wall. Immunohistochemical stains of this sample showed: nodules with proliferation of solid and papillary plasmacytoid cells with amphophilic cytoplasm and focal pink cytoplasmic granules. The lesional cells were CK-5 - and diffusely ER/PR+, HER 2- (Ki67 18%) with absence of myoepithelial cells by p63 and smooth muscle myosin. Findings were most compatible with invasive solid-papillary carcinoma, grade 1. The case was submitted for expert consultation to Johns Hopkins Laboratories. In their test center, the lesional cells were found to be diffusely GATA-3 + with absence of myoepithelial cells by p63/SMMHC (multiplex stain). No lymphovascular invasion was identified via D2-40 and ERG immunostains. After presentation at multidisciplinary tumor board (MTB), she was determined to have unresectable disease due to the extent of axillary and chest wall skin involved. PET/CT showed no evidence of distant disease. The consensus recommendation was to proceed with anti-endocrine therapy with an aromatase inhibitor (AI) plus cyclin-dependent kinase (CDK 4/6) inhibitor based off the phase three PALOMA-2 trial. PALOMA-2 has shown significant benefit in the progression free survival of hormone receptor positive, HER2 negative invasive breast cancers. She was initiated on letrozole 2.5 mg daily and palbociclib 125 mg daily. Our patient is currently still undergoing neoadjuvant anti-endocrine and immunotherapy. Thus far, she has been tolerating treatment well without complication. After 6 months, she has experienced a complete clinical resolution of her nodules and an almost complete resolution of disease on restaging MRI. After discussions with out multi-disciplinary tumor board, we plan to continue current therapy for a total of 2 years with surveillance imaging. Pending adequate response to neoadjuvant therapy, we plan to proceed with definitive surgery and adjuvant radiation therapy. The extent of her disease was tattooed shortly after initiating neoadjuvant therapy in preparation for future radiation therapy.

paloma 2, papillary breast cancer, recurrent breast cancer

PMC184447_01

Male

A 45-year-old man presented to the surgical wing with swelling in the right axilla of 2 months duration. There was a past history of pulmonary tuberculosis, two years back, for which patient had taken anti tubercular treatment. On examination the thyroid, breasts, chest, abdomen, and per rectal examinations were normal. Examination of axilla revealed a tiny, indurated, non tender, pink skin nodule of about 5 mm diameter (figure 1) with multiple, firm, non tender, discrete, axillary lymph nodes measuring 1 to 4 cm. Hematological and biochemical investigations were within normal limits. Chest roentgenogram showed healed tubercular lesion in right apical area. A contrast enhanced computerized tomographic scan (CECT) of the chest and fiber optic bronchoscopy was carried out which did not reveal any significant pathology except healed fibro cavitatory lesion in the right apex. Ultrasound examination of both the breasts, and abdomen was essentially normal. Fine needle aspiration cytology (FNAC) from the axillary lymph node revealed metastatic adenocarcinoma. Excision biopsy of the lymph node and suspected primary skin lesion was performed which revealed metastatic sweat gland adenocarcinoma with solid and glandular pattern (figure 2). The tumor cells were Periodic Acid Schiff (PAS) positive, diastase sensitive and were estrogen receptor negative. A diagnosis of sweat gland adenocarcinoma, probably of eccrine origin was made. An axillary lymph node dissection along with excision of the previous scar was carried out. While raising the upper skin flap two-satellite cutaneous nodules each measuring, 2-3 mm in diameter, were found and were excised en bloc. Histological examination of the resected specimen confirmed the diagnosis of metastatic sweat gland adenocarcinoma of eccrine origin. Patient had an uneventful recovery and is disease free after two years of follow-up.

PMC3976091_01

Male

A 75-year-old patient was admitted to our department of urology for three years persisting anorexia, progressive weight loss, dehydration and indeterminate significant abdominal distension. Patient was treated for pulmonary tuberculosis, arterial hypertension and hypercholesterolemia. He had no urological symptoms. Physical examination revealed a normal blood pressure, a ballotable mass arising from beneath the costal margin, extending across the midline and into the pelvis. The abdomen was painless on palpation and percussion, the abdominal wall was tough and distended, the prostate was benign. Routine hematology, biochemistry, and serum tumor markers were within normal limits. Voluminous ascites was described on ultrasonographic examination of abdomen. An abdominal paracentesis was performed and gained about 2000 ml of roily brownish fluid without any complications. Fluid's laboratory examination concluded to transudate with negative microbiological tests and no cytological evidence of malignancy. Computed tomography of his abdomen revealed bilateral simple renal cysts with an exceptionally giant sized renal cysts measuring 35 x 32 x 22 cm on the right kidney (Figure 1). The size of the left renal cysts was 6 cm. The cysts had oval shape, good acoustic enhancement, no internal echoes, and sharply marginated smooth walls. The right giant cyst was shifting the kidney to the midline. The kidney parenchyma was preserved. Treatment consisted of continuous percutaneous catheter drainage with negative pressure on the right kidney, and simple aspiration with sclerotherapy on the left kidney; 8 liters of fluid were removed with negative cytology. The patient reported rapid weight loss of 6 kg and restoration of appetite within days; there were no major post-operative complications. Subsequent Computed tomography after six months revealed quasi-normal aspect of the cysts (Figure 2), and the patient remained asymptomatic.

PMC3893753_01

Male

A 49-year-old previously healthy male was admitted to the hospital with a history of increased dyspnea and fatigue over the course of several weeks. Other history was negative apart from a history of longstanding heartburn that was controlled with proton pump inhibitors and a history of early satiety for the last 1-2 years. There was no family history of malignancy. He was diagnosed with severe anemia (hemoglobin 52 g/L) and his peripheral smear showed schistocytes and polychromasia, as well as nucleated red blood cells (Figure 1). Serum free haptoglobin level was undetectable. Coombs' test was negative, bilirubin and LDH were elevated (73.1 mumol/L [normal < 17.1] and 917 U/L [normal < 225], resp.), and a diagnosis of MAHA was made. In order to rule out an underlying solid tumor, CT scan of the chest, abdomen, and pelvis was performed demonstrating widespread metastatic disease, with thickening of the stomach and a GE junction mass measuring about 6 x 3.2 cm (Figure 2(a)). Gastroscopy was done and confirmed a gastroesophageal junction mass, with the biopsy showing low grade adenocarcinoma.

PMC5796804_01

Female

A 4-year-8-month-old girl was referred for evaluation of hyperactivity and palpitations. She was previously healthy, with the only past history being early-onset tooth development. She reportedly had her first tooth erupt at 3 months of age, and, recently, she shed two primary teeth. Her birth history was normal, and, developmentally, she was on target for all milestones. Her family history was notable for teenage Graves' disease in her mother, treated by thyroidectomy. On physical examination, all vital signs were normal for age. Her weight was 19.4 kg (79th percentile), her height was 103.5 cm (35th percentile), and her body mass index was 18 kg/m2 (94th percentile). Her growth velocity was 5 cm/year, without any note of acceleration. Her eye exam result was normal, with no proptosis or lid lag. Her thyroid gland was palpable, with no gross enlargement or tenderness. Her heart rate and peripheral pulses were normal, and the extremities were well perfused, with no tremor or hyperreflexia. Her neurologic exam result was normal, and she was Tanner stage I. The remainder of her examination result was normal. Initial laboratory evaluations showed an elevated serum total T4 level of 22.03 mug/dL (reference range 4.5-12 mug/dL), elevated free T4 level of 3.03 ng/dL (reference range 0.58-1.64 ng/dL) (measured by direct automated immunometric assay), and a normal thyroid-stimulating hormone (TSH) concentration of 2.38 mIU/L (reference range 0.34-5.6 mIU/L). Her bone age was 5 years at a chronological age of 5 years. Repeat testing confirmed these results as well as elevated thyroperoxidase and thyroglobulin (TG) antibody titers. Thyroid-stimulating immunoglobulin and thyrotropin-binding inhibitory immunoglobulins were not detected. On subsequent follow-up, laboratory evaluations showed persistence of high serum total T4 levels with a non-suppressed TSH. A free T4 level measured using direct equilibrium dialysis coupled with tandem mass spectrometry was also elevated at 2.9 ng/dL (reference range 0.58-1.64). Specific tests to rule out antibody interference with the TSH assay produced negative results. Given these results, along with her mother's thyroid history and the advanced dental age, an evaluation was undertaken to rule out a TSH-secreting pituitary tumor or resistance to thyroid hormone (RTH). She had normal levels of the alpha subunit of TSH, and no mutations in the thyroid hormone receptor beta ( THRB ) gene were identified, ruling out a TSH-secreting pituitary tumor and RTH, respectively. Without a clear diagnosis, further testing including genetic analysis was undertaken in the patient and members of her immediate family. The study was approved by the Institutional Review Board of the University of Chicago, where the analyses were performed. After obtaining informed consents, we investigated the family members in terms of their thyroid function tests ( Figure 1 ). The normal free T4 index, calculated from the total T4 and the resin T4 uptake ratio, combined with increased T4-binding capacity not due to excess T4-binding globulin (TBG), suggested the presence of an abnormal serum T4-binding substance. Furthermore, the normal total serum T3 with high rT3 concentrations, together with similar abnormalities found in the father, was compatible with a dominantly inherited defect, likely FDH. The presence of an abnormal T4-binding albumin was confirmed by isoelectric focusing analysis. Sequencing of the ALB gene revealed the most common mutation associated with FDH, c.653G > A producing p.R218H, in both the patient (proband) and her father. In light of this finding, a free T4 level was again measured, this time using equilibrium dialysis coupled with RIA. This assay produced a normal free T4 measurement of 2.4 ng/dL (reference range 0.8-2.7), consistent with the genetic diagnosis of FDH. The symptoms of hyperactivity and palpitations were not replicated during any of the examinations and ultimately resolved spontaneously during the course of the evaluation. At follow-up 2 years later, the girl was asymptomatic, growing and developing appropriately, and euthyroid without requiring anti-thyroid therapy.

PMC5633293_01

Male

In 2016, a 53-year-old man for the first time was admitted in Phramongkutklao Hospital. He had suffered from progressive visual loss and redness for 2 months in the left eye without any photophobia, ocular pain, or discharge. His right eye was not affected. The visual acuity was 20/20 in the right eye and hand movement in the left eye. The examination of the left eye showed generalized ciliary injection with whitish scleral nodule at inferotemporal area. Anterior segment examination revealed anterior chamber cell 3+, seclusio pupillae. Fundus examination showed vitreous haze with unclear retinal details. Intraocular pressure was 18 in both the eyes. The right eye was normal when examined. Ocular ultrasonography showed hypohyperechogenicity, membrane-like lesion in intravitreous cavity without retinal detachment, fluid collection, or any mass. Nodular scleritis and chronic panuveitis in the left eye was the initial diagnosis. Scleral exploration, phacoemulsification with intraocular lens implantation, and diagnostic vitrectomy left eye were performed. In intraoperative, we found scleral necrosis with small abscess (Figure 1A and B) at inferotemporal area. The fundus showed dense yellowish turbid vitritis (Figure 2), retinal and perivascular infiltration, retinal edema, and shallow subretinal fluid at inferior retina. A vitreous sample was sent to the laboratory to perform polymerase chain reaction (PCR) for tuberculosis, herpesvirus family, gram stain, potassium hydroxide (KOH), culture for bacteria and fungus, and cytology for malignancy. The left eye was treated as infectious scleritis and endophthalmitis by using intravenous cefazolin and amikacin for 2 weeks followed by oral augmentin, topical cefazolin, and amikacin which were later changed to vancomycin and ceftazidime, 3 times of sclera debridement, and intravitreous vancomycin and ceftazidime injection. After the treatment for 2 weeks, the findings on his left eye showed no improvement. The investigations included scleral and vitreous gram stain, KOH, culture for bacteria, fungus, mycobacteria, PCR for herpes 7 types, and tuberculosis which were all negative. The pathology of scleral biopsy presented necrobiotic xanthogranulomatous inflammation of sclera with severe acute and chronic inflammation and mycobacteria and fungus were also negative. He was diagnosed with necrobiotic xanthogranulomatous scleritis with panuveitis in the left eye. Then, topical 1% prednisolone acetate eye drop 4 times a day and oral prednisolone 1 mg/kg/day were prescribed. The clinical injection and sclera necrosis, was much improved that included the decrease of anterior chamber cells from 3+ to 1+ after the administration of steroids; however, the visual acuity was still hand motion. After that, steroids were slowly tapered. After 5 months, the patient was admitted to internal medicine service for prolonged fever. He had low-grade fever without chills for 6 weeks. No source of infection was identified after thorough evaluation including blood culture, urine culture, bone marrow aspiration, echocardiogram, and chest film. He was treated with ceftriaxone and doxycycline for 7 days with no improvement and was later switched to meropenem for 7 days without resolution of fever. During this admission, he developed bilateral foot drop and numbness in both hands. This time of admission, besides fever, foot drop and numbness, he complained of transient visual loss duration of 1 minute 5-6 times a day in his right eye. Physical examination found high blood pressure 150/100 mmHg and body temperature of 39 C. The visual acuity was 20/70 in the right eye and light projection in the left eye. The right eye presented dot and blot hemorrhage at posterior pole of fundus. The left eye was not injected and showed quiet anterior chamber with occlusio pupillae. He had no rash or cervical lymphadenopathy. Heart, lung, and abdominal examinations were normal. Neurological examination confirmed weakness of ankle flexion, bilaterally and numbness in both hands. It consisted with pathology in common peroneal nerve and median nerve, respectively which were consistent with multiple mononeuropathy. Initial work-up found hemoglobin of 8.3 mg/dL, white blood cell count of 11,400 cell/mL, platelet of 107,000/mL, erythrocyte sedimentation rate (ESR) 31 mm/h, creatinine 1.0 mg/dL, blood urea nitrogen 1.3 mg/dL, aspartate aminotransferase 17 IU/L, alanine aminotransferase 20 IU/L, total bilirubin 0.5 mg/dL, direct bilirubin 0.2 mg/dL, TG 78 mg/dL, cholesterol 194 mg/dL, high-density lipoprotein 86 mg/dl, and low-density lipoproteins 114 mg/dL. Peripheral blood smear revealed normochromic microcytic red blood cells, normal morphology of WBC, and platelet. Both direct and indirect Coombs tests were negative. Urine analyses found no proteinuria, red blood cell 3-5 cell/HPF, white blood cell 0-1 cell/HPF, and no red blood cast. Serum protein electrophoresis showed polyclonal gammopathy with albumin 36.5%, alpha1 8.2%, alpha2 14.9%, beta1 6.1%, beta2 5.2%, gamma 29.1%. Infectious work-up were negative including HIV, hepatitis B virus, hepatitis C virus, Quantiferon TB gold test, treponema pallidum hemagglutination, and venereal disease research laboratory test. Immunologic studies found positive antinuclear antibody 1:80 speckle pattern. Anti-ds-DNA and antiextractable nuclear antibody was negative. Anti-neutrophilic cytoplasmic antibody (ANCA) found cytoplasmic pattern and later confirmed that anti-proteinase 3 (PR3) positive 3+, IgG4 was 4.60 g/L. Chest X-ray was normal. Nerve conduction study and electromyography found asymmetrical axonal sensory motor polyneuropathy. Left sural nerve biopsy confirmed mild medium-sized vasculitis. This patient was diagnosed with granulomatosis with polyangiitis based on granuloma found in scleral tissue, vasculitis seen in sural nerve biopsy and serologies (C-ANCA and anti-PR3 antibody). This patient was treated with high-dose dexamethasone and later switched to prednisolone (1 mg/kg/day) and intravenous cyclophosphamide monthly as well as antihypertensive drugs. He responded well to treatment, ankles flexion improved and numbness of both hands was reduced. Regarding the transient visual loss, the computed tomography angiography was done and no filling defect was reported. The amaurosis fugax was diagnosed and suspected from vasculitis. He did not develop recurrent transient visual loss. At the final visit, the visual acuity was 20/20 in the right eye and no light perception in the left eye. Both eyes were not injected and quite anterior chamber. The left eye presented early phthisis bulbi. This case report was approved by the Institutional Review Board, Royal Thai Army Medical Department. Written informed consent was obtained from the patient to have the case details and for any accompanying images published. Multiple scleral biopsies were performed, and the findings revealed erosive scleral mucosa with submucosal infiltration by sheets of mononucleated foamy histiocytes (xanthoma cells), accompanied by variable degree of fibrosis with necrobiosis of collagen (Figures 3 and 4). Variable numbers of dispersed hemosiderin-laden macrophages, neutrophils, lymphocytes, plasma cells, and erythrocytes without Touton giant cells, or cholesterol clefts were scattered among these xanthoma cells. These infiltrating xanthoma cells often have small, round nuclei, and abundant clear or vacuolated cytoplasm (Figure 5). Some of these histiocytes show hemophagocytic activity (Figure 6). Despite the absence of Touton giant cells and cholesterol clefts, the findings previously confirmed were favorable of necrobiotic xanthogranulomatous inflammation of the sclera. Left sural nerve biopsy confirmed small- and medium-sized vasculitis by lymphocytic and neutrophilic infiltrate in wall of subcutaneous vessels (Figure 7).

gca, autoimmune, ocular inflammation, pathology, scleritis, uveitis, xanthoma cells

PMC4646441_01

Unknown

The bronchial dilations also called bronchiectasis are permanent and irreversible increase in the bronchial tubes. They can be extended or localized especially in pulmonary tuberculosis sequelae. This affection is serious, because it is at the origin of an embarrassing obstructive pulmonary disease, leading to social discomfort and preferentially in Cote d'Ivoire, it affects young subjects between 30 and 40 years old and former tuberculous. The place of surgery is still debated. Mr Coulibaly is 30 years old, hospitalized in the Thoracic Surgery Department of BouakeTeaching Hospital for pulmonary tuberculosis sequelae type symptomatic left lower bronchiectasis lobe and well localized (A). After a satisfactory preoperative evaluation, we performed a left lower lobectomy on this patient. Transection in the third world of the bronchial lower lobe resected reveals multiple tubular dilations with thickened wall containing purulent secretions (B). The specimen was sent to the pathology laboratory for confirmation of tuberculosis sequelae.

bronchietasis, lobarbronchiectasis, tuberculosis sequelae

PMC9941408_05

Male

A 29-year-old male soldier presented to the orthopedic clinic complaining of left ankle pain that started one year prior while he was playing football. He had a height of 158 cm and a BMI of 33.3. He is a current smoker and had a medical history of hypertension and pericarditis. On clinical assessment, he was found to have moderate ankle pain and ankle joint locking and giving way. He was started on a trial of conservative treatment, which consisted of serial casting for six weeks, NSAIDs for analgesia, and physiotherapy for exercises to strengthen and stretch the injured ankle for six months, but his symptoms showed no improvement. Consequently, an MRI was ordered, which showed no ligament or tendon injuries. However, degenerative subchondral cystic changes were found in the distal tibia and talar dome. As his pain and instability symptoms persisted, surgery was booked for left lateral ankle ligament repair. Intraoperatively, there was evidence of laxity in both the ATFL and CFL, so the reconstruction of the CFL and ATFL was performed by the modified Brostrom technique. After the surgery, a cast was applied below the knee for the left lower limb, and the patient was referred for physiotherapy. Postoperative assessment in the next one year showed that the patient's ankle pain and instability had resolved (Figures 1A, 1B). Case 6

ankle instability, anterior talofibular, calcaneo-fibular, normal mri, posterior talofibular ligament

PMC10202400_01

Male

A 7-year-old male child, with a known case of nephrotic syndrome under treatment, presented to paediatrics emergency in September 2019 with features of shock with abdominal swelling. The child also had a history of fever, multiple episodes of loose watery stools and vomiting (three-four episodes per day), along with dull abdominal pain prior to shock. He was admitted in paediatric intensive care unit and managed with antibiotics and inotropes. Spontaneous bacterial peritonitis with sepsis was the diagnosis, although the aerobic culture of peritoneal fluid was negative. Blood and urine cultures were also sterile. The child had nephrotic syndrome since the age of 1.5 years and was on prednisolone and steroid-resistant since December 2015. A renal biopsy was performed in January 2016 and reported minimal change disease. The patient was then started on tacrolimus 1 mg twice daily orally. The first relapse after taking tacrolimus was reported in April 2017 followed by two more relapses in 2017. The dose of tacrolimus was increased to 1.2 mg in July 2017. After that, multiple episodes of relapse were seen. Up to January 2019 the patient was on 10 mg prednisolone once daily orally along with tacrolimus. In February 2019, the dose of tacrolimus was increased to 2 mg twice daily along with prednisolone 30 mg per day (1.5 mg kg-1). During the course of treatment the child had developed steroid-induced posterior subcapsular cataract and grade II hypertension. For hypertension he was on antihypertensive medication. He also suffered from pulmonary tuberculosis in 2018, for which he completed treatment. Further, there was a history of failure to gain weight and height proportionate to age. On general examination, oedema was observed with rashes on the face and left knee. A stool sample was received in the microbiology laboratory and direct microscopy using 0.9 % saline and 1 % Lugol's iodine wet mount preparations revealed trophozoites and cysts of Giardia intestinalis, shown in Fig. 1. Modified Ziehl-Neelsen staining was performed for the identification of coccidian parasites and microsporidia and was negative. Chromotrope staining was also performed to see microsporidia and was also negative. However, on chromotrope staining, lightly stained cysts and trophozoites of G. intestinalis were seen, as shown in Fig. 2. Stool culture was negative for enteric pathogen. Metronidazole 100 mg three times daily orally was prescribed for 10 days. After completion of the therapy with metronidazole for 10 days, cysts and trophozoites of G. intestinalis were still detected in stool samples on multiple occasions (four occasions up to the first week of February 2020), along with persistence of clinical symptoms intermittently. The child was on and off metronidazole therapy for 4 months at the same dose. In the first week of February nitazoxanide 200 mg (twice daily orally) was added to the therapy for 7 days. The last stool sample received on last week of February 2020 was negative for Giardia cysts and trophozoite. The child also had a past history of passing loose stool on and off with increased frequency and bloating since for the previous 1.5 years, but no significant findings had been reported in stool samples previously.

giardia intestinalis, corticosteroid, nephrotic syndrome, nitroimidazole

PMC8315862_01

Female

A 28-year-old female patient suffered from postprandial lower chest pain and heartburn for more than one year. Her past medical history and family history were unremarkable. She lost 4 kilograms and did not experience dysphagia or regurgitation. Three months before her visit to our hospital, the pain had become more severe. The upper gastrointestinal endoscopy (UGIE) performed at another hospital showed a lower esophageal ulcer, which was located just above the gastroesophageal junction, hiatal hernia, and antral-predominant gastritis (Figures 1(a) and 1(b)). The H. pylori antibody test was positive, and the histological result of esophageal ulcer was benign. The patient received H. pylori eradication therapy followed by a regimen of proton pump inhibitor (PPI) at a standard dose in combination with antacid for more than 8 weeks. However, her pain did not resolve and she sought for medical consultation in our hospital. We managed the patient as a case of refractory GERD. At first, the patient was treated with rabeprazole 20 mg bid in combination with alginate-antacid at bedtime for 2 weeks. The pain improved but was still intolerable and badly affected her sleep quality. The regimen was switched to rabeprazole 20 mg bid in combination with amitriptyline 12.5 mg at bedtime, which resulted in a complete clinical response and was continued for 10 weeks. The dose of rabeprazole was then tapered to 20 mg qd aiming to stop completely before UGIE was performed to document the efficacy of treatment. However, the pain recurred badly after about a week. The patient requested us return to double-dose rabeprazole, which again relieved the pain. The second UGIE performed when the patient was still on PPI showed that the lower esophageal ulcer had completely healed (Figures 1(c) and 1(d)). There was a protrusion at the cardia, which was only identified when air was minimum insufflated, suspected of a submucosal lesion. Endoscopic ultrasound (EUS) and CT scan were performed which surprisingly showed a giant submucosal tumor at the fourth layer of the lower esophagus and the cardia (Figures 2 and 3). EUS-FNA was performed, and the histological examination confirmed that this lesion was a leiomyoma (Figure 2). The patient was performed laparoscopic transhiatal surgery to enucleate the esophageal leiomyoma. In addition, hiatal hernia was repaired with laparoscopic Nissen fundoplication (Figure 4). As the tumor is too large, it was cut into pieces to facilitate its removal. The solid straightened tumor was approximately 8 cm x 3 cm in size (Figure 4). The patient made an uneventful postoperative recovery. During the first two weeks, she had experienced dysphagia and regurgitation, which have resolved completely. Four months after her surgery, UGIE was performed again which showed good results of fundoplication surgery (Figures 1(e) and 1(f)). The patient sometimes had epigastric pain which could be completely controlled with intermittent rabeprazole therapy at a standard dose.

PMC7544191_01

Unknown

Musculoskeletal injuries are the most common injuries in recreational, amateur, and professional sports. Approximately 64% of injuries in recreational sports are musculoskeletal related injuries. Approximately 2 million injuries, 500,000 doctor visits, and 30,000 hepatization in high school students are associated with sports injuries. The National Institute of Arthritis and Musculoskeletal and Skin Diseases has reported that 2.6 million children under 19 years old get treated for musculoskeletal injuries in emergency departments. Hootman et al. reported that more than 50% of sports injuries in college students are in lower extremities with additional injuries reported in upper extremities and back/neck. Historical data of American college football players show an increased number of upper shoulder and arm surgeries. Professional sports data is relatively discreet. Ekstrand et al. has reported that average soccer players sustained 2 injuries per season, leading to missing 37 days in a season. Furthermore, 92% of all muscle injuries are associated with lower limb: hamstring (37%), adductors (23%), quadriceps (19%), and calf muscles (13%). A recent study by Humprey et al. reported professional tennis players to sustain most of their injuries at muscles (24%), tendon (23.4%), and soft tissue bruising (6.5%). Detailed studies have shown that the overuse of musculoskeletal anatomy further adds to injuries and probabilities of the future of reinjuries. The musculoskeletal healing process involves activation of the cascade of cellular and molecular pathways. The initial response to the injury is the activation of inflammatory cytokines. Acute inflammation is an essential part of the healing process, but chronic inflammation leads to the delayed healing process as well as further damage to the tissue; thus, it is necessary to remove inflammatory cytokines and initiate the regeneration of new tissue. Currently, to restrain the level of inflammation and enhance tissue healing, athletic trainers most commonly use rest, ice compression, and elevation (RICE) method. RICE reduces the inflow of the inflammatory factors, along with reducing the blood flow to the injury site. RICE has limited efficacy in reducing inflammation and improving the rate of tissue regeneration over the healing process. Still, there is a need for add-on therapies to expedite the healing process and tissue regeneration. Post-injury, the most important concern for an athlete is when to "return to play"? This is a hard question to answer considering the multifactorial factors such as the site of injury, damage sustained, athletes' age, and the number of revised injuries along with other potential health concerns. Doctors and athletic trainers are advised to have a conservative approach, but at the same time, it important to minimize the athlete's off-field time. Thus, it is important to come with more advance, innovative, and non-invasive therapies to accelerate tissue healing. Ultrasound therapy provides a mechanotransducive localized stimulus to the injury site resulting in increased blood flow, oxygenation, exchange of nutrition, and accelerated tissue healing resulting in inhibition of inflammation. Multiple studies have shown tissue regenerative properties of ultrasound. Ultrasound increases the rate of bone healing by decreasing initial infiltration of cytokines increasing, angiogenesis, chondrogenesis, and bone remodeling. Studies have concluded the application of ultrasound increases the rate of tendon-bone interface healing in preclinical models. Walsh et al. has shown similar trends in anterior cruciate ligament reconstruction. Ultrasound is a non-invasive therapy with significant data supporting its regenerative efficacy in preclinical studies. The effectiveness of ultrasound is dependent on multiple factors such as duty cycle, intensity, duration, frequency, and energy. While ultrasound therapy has been around for a long time, its transformation to clinical practice has been limited due to the optimization of ultrasound parameters. Low-intensity continuous ultrasound (LICUS) has shown the potential to accelerate the tissue regeneration process significantly. Sustained Acoustic Medicine (SAM) uses LICUS to expedite the healing process and have shown encouraging results in clinical studies. SAM has been approved for pain management by Food and Drug Management (FDA). Langer et al., in a clinical study (n=30) has shown that after use application of SAM (3MHz, 0.132W/cm2, 18720 Joules) for 4 hours reduced pain by 15% compared to 7% in the placebo group in Trapezium muscle spasm. They also showed 52% (p<0.05) improvement in the visual analog score (VAS) in rotator cuff pain, 40% (p<0.03) pain reduction in osteoarthrosis patients (N=47), and 4.28 point VAS (p<0.001) decrease in tendon pain relief and recovery (N=25) after 6 weeks of treatment. Lewis et al. has reported an up to 1point increase in Global Rating of Change (GROC) score and a 25% reduction in VAS reduction after 10 days of SAM treatment in chronic myofascial pain. The objective of this study is to evaluate the effects of SAM in sports-related injuries as an adjuvant therapy to athletes when conservative treatment fails.

acute pain, athletic training, chronic pain, clinical trial, continuous ultrasound, long-duration ultrasound, low-intensity ultrasound, musculoskeletal healing, musculoskeletal injury

PMC9791352_01

Male

A 26-year-old gentleman with a history of epilepsy on Levetiracetam and a remote history of a gunshot wound to his abdomen was transferred to our hospital for acute liver failure after a two-day stay at an outside facility. The patient noted sore throat, productive cough, periumbilical abdominal pain, watery diarrhea, nausea, and vomiting, subjective fevers along with progressive jaundice for seven days before presentation at the outside hospital. The patient indicated that he took acetaminophen (three tablets of acetaminophen 500 mg at different times) for his abdominal pain. He was incarcerated twelve days before admission for one week at a local county jail. His illness began three days after his release. His COVID-19 test was negative while in jail. The patient history was negative for new medications, ingestions, exposures, IV drug use, smoking, sick contacts, travel, animals, water or hiking activity, tuberculosis and hepatitis. The patient reported using marijuana daily and drank half a pint of brandy once weekly. He reported being sexually active with one female partner with frequent condom use. The patient lived in Arkansas, where he had grown up, with no recent travel. The patient had a blood pressure of 140/74 mmHg on arrival to the outside hospital with a heart rate of 106 BPM, respiratory rate of 22 breaths/min, and oxygen saturation of 98 % on room air. Physical examination was remarkable for scleral icterus. The patient had a crusted lesion on his right lateral oral commissure. His left eye showed a small subconjunctival hemorrhage. He had no evidence of oropharyngeal exudate. Chest examination showed regular rate and rhythm, no murmurs, rubs, or gallops, and lungs that were clear to auscultation bilaterally with distant breath sounds. An abdominal exam revealed mild diffuse abdominal tenderness, but he did not demonstrate any stigmata of chronic liver disease. Laboratory workup showed leukocytosis, anemia, hyponatremia, cholestatic liver injury, acute kidney injury (Table 1), and a negative respiratory pathogen panel. Arterial blood gas revealed primary anion gap metabolic acidosis. Chest X-ray demonstrated patchy interstitial and alveolar opacities throughout the right and left lung that was concerning for multifocal pneumonia. Computed tomography (CT) scan of the chest, abdomen, and pelvis showed bilateral lung parenchymal ground glass consolidative lesions with central cavitation; no abnormalities were noted in the abdomen (Fig. 1). A panel of tests including an autoimmune workup (C3, C4, ANCA), blood cultures, Histoplasma and Blastomyces urine antigens, Cryptococcus antigen, 1,3 Beta D-Glucan, TB-PCR from sputum samples, Leptospira PCR, and Lyme serologies were sent. Serologies for Francisella tularensis, Ehrlichia chaffeensis (in addition to PCR) and Rickettsia rickettsii were also sent. Transthoracic echocardiography showed reduced left ventricular function with global hypokinesis and no valve lesions, although the views were limited. The patient received vancomycin, cefepime, and metronidazole and due to fulminant liver failure, was transferred to our tertiary care facility as noted. His course was complicated by hypothermia, shock, and encephalopathy. He also developed acute renal failure requiring continuous renal replacement therapy and respiratory failure requiring mechanical ventilation. Bronchoscopy with bronchoalveolar lavage (BAL) was performed, which revealed a neutrophilic predominance with negative GMS and AFB stains and negative cytology. The patient's right lip exudate was swabbed and returned positive for HSV 1 through NAAT testing. Complete etiological workup for other causes of encephalopathy (Brain CT scan), acute liver injury workup including Anti-LKM, Mitochondrial Antibody IgG, Smooth muscle Antibody IgG, A1AT levels, Salicylates, acetaminophen levels, ethanol levels, ceruloplasmin, HIV, Hepatitis Screen, EBV PCR, CMV PCR, and urine drug screen were sent and were all negative. Ammonia level was elevated. Hemophagocytic lymphohistiocytosis (patient had high ferritin reaching > 40,000 ng/mL) workup was ordered and was negative. Amylase and Lipase were also negative. Thirteen hours after collection of blood cultures, one out of two blood cultures sets was positive with a Gram stain showing gram-positive cocci and gram-positive bacilli. At 23 h after collection, four out of four blood culture bottles were positive. The Gram-positive Bacilli were elongated and tapered on one end. BAL cultures were subsequently positive as well. Using Matrix-assisted laser desorption ionization-time of flight Mass spectrometry (MALDI-TOF) for identification, Arcanobacterium haemolyticum was identified in both Blood and BAL cultures. The patient's antimicrobial therapy was narrowed from Vancomycin and Cefepime to Ampicillin-Sulbactam. Due to concern for an oropharyngeal source of Arcanobacterium septicemia, a CT scan of the neck was obtained, which showed a 1.4 cm right palatine tonsillar abscess (Fig. 2), prominence of nasopharyngeal adenoids, cervical lymphadenopathy in the bilateral anterior and posterior triangles, mediastinal fat stranding, and sinusitis; furthermore, the visualized portion of the lungs demonstrated the development of multiple abscesses and loculated pleural effusions. The internal jugular veins did not show a thrombus or occlusion. Otolaryngology assessed the patient and deemed the abscess too small for drainage. A dedicated CT chest was performed, which showed bilateral pleural fluid collections concerning for empyema, requiring multiple pigtail catheters to be placed. Chest tubes returned bloody purulent drainage, and eventually, the patient required surgical thoracotomy with evacuation of the hemothorax and pulmonary decortication. Other infectious and autoimmune workup remained negative. He had a Trans-esophageal echocardiogram which didn't show any oscillating echo-densities. There was, however, mild tricuspid, mitral and pulmonary valve regurgitation. There was mention of a tiny, delayed right to left shunt with the Bubble study that was suggestive of a pulmonary AVM. A percutaneous tracheostomy was performed, and the patient slowly improved. The previously mentioned infectious workup was all negative. The patient's multi-organ failure and septicemia were determined to be due to Arcanobacterium haemolyticum infection likely originating from initial pharyngitis. This pathogen was repeatedly isolated from cultures from various body culture sites while the other infectious workup remained negative. Susceptibilities were obtained from the outside hospital, and the organism was penicillin-sensitive. The patient completed an antibiotics therapy course for six weeks with Ampicillin-Sulbactam covering five weeks of that duration. This was associated with clinical improvement. Chest and tracheostomy tubes were removed, and he no longer required renal replacement therapy. He was discharged home after an inpatient stay of over a month. The patient had recovered fully at his two-month post-discharge follow-up.

arcanobacterium haemolyticum, cavitary pneumonia, complicated bacteremia, lemierre's syndrome, peritonsillar abscess

PMC10365095_01

Male

A 74-year-old man presented to our hospital with nausea and vomiting for 2 weeks, without any history of gastrointestinal disorders. He had a history of alcoholism for over 20 years. An enlarged liver was palpable from the right hypochondrium without obvious jaundice or anemia. Contrast-enhanced computed tomography (CT) scans revealed a mass located in the right lobe of the liver (Figure 1A), measuring approximately 19.3 x 14.6 x 13.2 cm, with enhancement in the arterial phase and rapid washout in the portal phase, suggesting a diagnosis of primary liver cancer. No evidence of significant macrovascular invasion or intra- or extrahepatic metastases was observed on the CT scan. The patient was negative for both hepatitis B surface antigen and hepatitis C virus antibody. Des-gamma-carboxy prothrombin (DCP) was markedly elevated, whereas alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen 199 (CA 199) were normal. The Child-Pugh score was 5. To obtain definite histological evidence of the tumor and assess the extent of liver cirrhosis, a biopsy was performed. Finally, the patient was diagnosed as HCC with mild liver cirrhosis and staged as BCLC-A in the Barcelona Clinic Liver Cancer (BCLC) staging system. The etiology of HCC was chronic alcoholic hepatitis. The ratio of FLR to standard liver volume (SLV) after anatomical right hemi-hepatectomy was 51.47% (Figure 1B), which was well-tolerated for hepatectomy (>40%). However, the middle hepatic vein ran almost along the edge of the lesion (Figure 1A). If a right hemi-hepatectomy were to be performed, it would be hard to ensure an adequate surgical margin. A narrow surgical margin has been proved to be an unfavorable prognostic factor. By contrast, an extended right hemi-hepatectomy would probably result in insufficient FLR (Figure 1C, FLR/SLV = 25.78%, far <40%), with a high risk of PHLF. Nevertheless, the patient wished to undergo surgical treatment. After discussion among the multidisciplinary team (MDT), a combination of PVE and multimodality therapies, comprising HAIC, Lenvatinib, and Sintilimab, was considered the optimal choice in the circumstances. HAIC with the mFOLFOX regimen (oxaliplatin, 85 mg/m2 intra-arterial infusion; leucovorin, 400 mg/m2 intra-arterial infusion; and fluorouracil, 400 mg/m2 bolus infusion and 2,400 mg/m2 continuous infusion) was performed initially. The infusion microcatheter was selectively placed into the common hepatic artery, which was the main feeding artery to the tumor (Figure 2A). After 3 days of HAIC, biological glue was utilized to embolize the right branch of the portal vein (Figures 2B,C), resulting in a brief increase in alanine transaminase (ALT) to 338.6 U/L, aspartate aminotransferase (AST) to 632. U/L, and total bilirubin (TBIL) to 32.4 umol/L. Liver function normalized with medication within 3 days, and Lenvatinib (8 mg per day) plus Sintilimab (200 mg per 3 weeks) were administered subsequently, causing no significant adverse events. After 5 weeks of multimodality therapy, follow-up CT scans showed remarkable regression of the tumor with complete disappearance of intratumoral enhancement on the artery phase (Figure 3A) and increased distance between the tumor and the middle hepatic vein (Figure 3B). The FLR/SLV reached 67.74% (Figure 3C), and the Child-Pugh score was 5, which met the requirements of the surgery. One week later, laparoscopic right hemi-hepatectomy was successfully performed with a >1-cm surgical margin. The gross of the resected specimen showed obvious hemorrhage and necrosis of the tumor (Figures 4A,B). Postoperative pathology revealed an encapsulated tumor with massive hyalinization, necrosis, lymphocyte, and granulocyte infiltration, and no viable tumor cells (Figure 4C). The patient was discharged at the 7th day after the operation without any complications. He was advised to stop drinking and follow up regularly. At the 3-month follow-up, no significant evidence of recurrence on imaging or laboratory tests was observed. The timeline of clinical events is shown in Figure 5.

case report, hepatic artery infusion chemotherapy, hepatocellular carcinoma, portal vein embolization (pve), programmed cell death-1 inhibitor, tyrosine kinase inhibitor (tki)

PMC9643805_01

Unknown

Clinical presentation: a 66-year-old patient with a history of pulmonary tuberculosis treated in 1997, declared cured, and high blood pressure present three months ago persistent neck pain with tingling and heaviness in both upper limbs. At the neurological examination, the muscular testing was normal and no sensory deficit. The American Spinal Injury Association (ASIA) score was graduated E. Diagnosis assessment: cervical spine computed tomography (CT) showed a lytic process centered on C4 with posterior wall recession and anterior epiduritis (Figure 1). Spinal cord magnetic resonance imaging (MRI) showed a cervical lytic lesion centered on the vertebral body of C4 with spinal cord compression and epiduritis without signs of spinal cord injury (Figure 2). Management: the patient underwent corpectomy of C3 and C4 with iliac graft and anterior cervical plate (Figure 3). Then a reinforced neck brace was applied 2 weeks after the surgery to enable consolidation. The anatomopathological examination revealed a Pott disease. The patient was put on antituberculosis chemotherapy treatment for 12 months: 2 months of Rifampicin - Isoniazid - Pyrazinamid - Ethambutol (RHZE) followed by 10 months of Rifampicin-Isoniazid (RH). Outcomes: at discharge, 2 weeks after surgery, the patient presented the same neurological state as at admission. Follow up: the patient was seen in outpatient three months later. No complaint was noted, and neurological examination was normal. Declaration of patient consent: the authors certify that they have obtained all appropriate patient consent.

tuberculosis, case report, management, spinal

PMC4732248_01

Female

A 52-year-old female with a background history of hypertension was referred to our center by a physician at a private clinic for a large right frontal swelling. According to the patient, she first noticed the swelling 2 years back, and it was initially the size of a marble (1 cm). The swelling gradually increased in size. It would occasionally cause itchiness on the overlying skin, and caused some discomfort as it grew bigger, but otherwise the swelling was painless. She denied experiencing a change of color or temperature over the swelling, and she denied ulceration and/or discharge from the swelling. The patient did not have any headaches, blurring of vision, nausea, and seizure. As the swelling had never caused her any problems, she only agreed for further workup after her physician coaxed her during her follow-up for hypertension. On examination, there was an obvious single lump involving most of the right side of the patient's forehead, measuring 8 cm x 8 cm. The skin overlying it was slightly stretched, but otherwise normal. We could not see any sinuses, ulcerations, nodules, or even sinuses. It had the same temperature as the rest of her face. The swelling had diffuse borders and was firm-to-hard to the touch. It was not compressible or indentable, and was nontender. The swelling was not attached to the skin, but it was not mobile; it was most likely attached to the bone. Neurological examination did not yield any abnormality. Our initial impression was a dermoid cyst, a lipoma, or an osteoma. In view of her age, we were also considering a malignant bony tumor. The patient was admitted for further workup. Blood investigations did not show any abnormality, with normal full blood count, renal function test, and serum calcium. The erythrocyte sedimentation rate (ESR) was not raised, at 15 mm in the 1st h. Plain and contrasted computed tomography (CT) imaging was done, revealing that the swelling was a lytic bone lesion, with a punched-out appearance of the affected bone. On the outer surface of the cranium, the lesion extended beyond the bony defect and sloped off at the edges. The purely extra-axial lesion was isodense with brain tissue, and only the inner surface took up contrast, likely due to the involvement of the dura [Figure 1]. From the CT imaging, our impression was a right frontal intraosseous meningioma. We counseled the patient for surgery, with the aim for cytoreduction and histological diagnosis. We designed a question mark flap to encompass the right fronto-temporo-parietal regions, and as one of our differential diagnoses was an intraosseous meningioma, we also dissected the patient's neck in a curvilinear manner at the level of C4/C5 to expose the internal and external right carotid arteries in the event that we needed a proximal control for hemorrhage. We had initially planned to raise the scalp as two layers, and to harvest the pericranium in the event that we needed to do a fascia duraplasty. However, the pericranium had eroded. The lesion was noted to be smooth and had a firm consistency, with a well-demarcated margin along the punched-out bone edge. We could not see any vessels feeding into the swelling. A craniotomy was made 1.5 cm away from the margin, but the dura, tightly adherent to the inner cranial surface, was circumferentially torn during bone cutting. There was not much bleeding during the craniectomy. We noted a single pedicle under the inner surface of the bone: The enlarged right middle meningeal artery (MMA). After ligation using sutures, the MMA was severed, and the lesion, along with a rim of bone, was excised en bloc. The brain surface was indented, but otherwise the arachnoid layer was intact, and we did not see any abnormality on the brain surface. The dura defect was closed using an artificial tissue dura, and we proceeded with primary closure of the scalp [Figure 2]. The lesion was cut in half, and we noted that under the firm, fibrous capsule, the lesion was whitish and soft-to-firm inconsistency. In view of the scalp tissue and dura involvement, we suspected a calvarial metastatic tumor. The patient recovered well-postoperatively. She did not have any neurological deficit, and she did not develop any seizures. We planned for a full workup for a primary source; however, the histopathological report came back as extensive areas of caseous necrosis surrounded by a collection of epithelioid histiocytes, lymphocytes, and several Langerhans-type giant cells forming granulomas. Ziehl-Nielsen stain for acid-fast bacilli was negative. The granuloma was also seen within the bone. The histopathological diagnosis was a caseating granulomatous inflammation, highly suggestive of tuberculosis. The patient was then subjected to anti-tuberculosis treatment, planned to complete a 1 year therapy. She was also planned for a titanium mesh cranioplasty during subsequent follow-ups. The patient was well at the time of writing, and contact screening for tuberculosis was negative.

calvarial tuberculosis, cranium, mimic, skull

PMC6122482_01

Female

The patient was a 68-year-old woman who underwent laparoscopic cholecystectomy for chronic cholecystitis with gallbladder stones and suffered intraoperative bile duct injury requiring diversion of the common bile duct (Strasberg E2) about 6 years ago at another hospital. Conversion to open laparotomy and choledochoduodenostomy (C-D) were performed at that time. Two-weeks later, she was found to have leakage of the C-D anastomosis and underwent re-operation with C-J. Subsequently, a biliary-cutaneous fistula persisted for two years and eventually healed with conservative treatment. Three years after healing of the fistula, the patient presented to our hospital with back pain and high fever. On examination, there was tenderness in the right subcostal region without muscle guarding. Laboratory tests showed that the white blood cell count was 13,350/ul, C-reactive protein was 9.0 mg/dl, total bilirubin was 5.0 mg/dl, direct bilirubin was 3.1 mg/dl, aspartate aminotransferase was 166 U/l, alanine aminotransferase was 133 U/l, alkaline phosphatase was 881 U/I, and gamma-glutamyltransferase was 196 U/l. Abdominal computed tomography (CT) revealed dilation of intrahepatic bile ducts in the lower left lobe and posterior right lobe, with bile duct stones and/or debris also being visible (Fig. 1A, B). Abdominal ultrasonography (US) also showed that the right hepatic duct was filled with debris (Fig. 1C). Accordingly, percutaneous transhepatic biliary drainage (PTBD) was performed. Cholangiography via the PTBD tube showed a hilar hepatic duct stricture (Fig. 2A, long white arrow) and stones in the left intrahepatic bile duct. It also revealed a fistula between the reconstructed jejunal limb and the duodenum (Fig. 2 A, B, red arrow). Duodenal endoscopy directly revealed the fistula communicating with the reconstructed jejunal limb (Fig. 2C). Balloon dilatation of the hilar hepatic duct stricture was tried twice via the PTBD tube, resulting in failure to sufficiently alleviate the stricture. Subsequently, surgical exploration was performed. The cause of the bile duct stones and recurrent cholangitis was considered to be the patient's jejunal-duodenal fistula combined with biliary stasis due to the C-J stricture. Hepatic ductoplasty was performed along with H-J and diversion of the jejunal-duodenal fistula. A diagram of the procedure is shown in Fig. 3. First, the previous biliary-enteric anastomosis was resected and the anterior wall of the stenotic shortened hepatic duct was longitudinally incised near the liver parenchyma. Intraoperative cholangioscopy was performed to remove the bile duct stones. Cleavage of stones and washout of the remnant stones and sludge with normal saline were also done. Hepatic ductoplasty was carried out according to the method described previously. Briefly, the anteriorly incised hepatic duct was everted toward the liver parenchyma to make a wide stoma (Fig. 3A). In addition, stricture-plasty of the left intra-hepatic duct orifice was performed to relieve biliary stasis, as shown in Fig. 3B. Subsequently, H-J was performed by monolayer knob hand-sewing via the ante-colic route. Postoperative cholangiography apparently showed wide and broad H-J anastomosis in Fig. 3C. The patient had no further reflux cholangitis or hepatolithiasis when reviewed at one year after surgery.

bile duct stricture, case report, choledochojejunostomy, hepatic ductoplasty, hepatolithiasis, reflux cholangitis

PMC6584983_01

Male

A 47-year-old man was referred to our hospital with a 3-month history of abdominal distension, intermittent abdominal pain and nausea. Despite weight loss of 4 kg, the patient had no symptom of fever, chronic cough or night sweats. He had no history of abdominal surgery, liver cirrhosis or chronic hepatitis virus infection, but suffered from tuberculous pleurisy about 20 years ago. Physical examination revealed gross abdominal distension without tender and ascites of unknown aetiology. Laboratory blood analyses including serum tumor markers, erythrocyte sedimentationrate (ESR), adenosine deaminase activity (ADA) and anti-tuberculosis antibody (TB-Ab) were all within normal limits, and tuberculin skin test was negative. The results of antibody testing for HIV were negative. Chest radiograph did not demonstrate features suggestive of pulmonary tuberculosis. Plain upright abdominal X-ray showed some air in the colon without presence of air fluid levels in the loops or free gas under the diaphragm (Fig. 1a). Contrast-enhanced computed tomogram (CT) of the abdomen (Fig. 1b, c) revealed dilatation of the duodenum loops (*) and congregated small gut loops (black arrowhead) trapped in the massive ascites surrounded by a membrane (white arrowhead). Gastroscopy revealed no signs of malignancy. A peritoneal tap was performed twice and yielded blood stained ascitic fluid but no malignant cells or acid-fast bacilli. The ascities was exudates in nature and ascities ADA was within normal ranges. The patient refused laparoscopy examination and was discharged without a definitive diagnosis and further treatment. Two months later, the patient was presented to our hospital again with persistent symptoms. Despite abdominal distension, nausea and vomiting, he also complained of increasing fatigue, emaciation, and 10-kg weight loss for the recent two months. Laboratory blood analyses revealed that serum ADA was 21 U/L (normal range 4-18 U/L), ESR was 28 mm/h (normal range 0-15 mm/h), but TB-Ab was negative. Ascitic fluid obtained by paracentesis was still negative for bacteria, acid-fast bacilli and malignant cells, but ascities ADA was significantly elevated (41 U/L). Serum CA-125 was also significantly elevated (97.39 U/ml, normal range < 35 U/L). In addition, despite the presence of well-encapsulated fluid collection and central accumulation of the small intestine (Fig. 2a), CT scan also revealed smudged appearance of the greater omentum (Fig. 2b,*), as well as multiple small nodules and sheetlike lesions on the parietal peritoneum (Fig. 2. s, arrowhead), which the radiologists considered to be peritoneal carcinomatosis (PC). Mesenteric lymphadenopathy was not observed on CT scan. The presumptive diagnosis was PC or tuberculous peritonitis in our patient, however, other differential diagnosis, such as peritoneal mesothelioma, could not be completely ruled out. Diagnostic laparoscopy was performed in our patient, and the entire small bowel was found to be encapsulated in a dense, white, fibrous, cocoon-like membrane filled with a large amount of brownish ascites (Fig. 2d). Multitudinous miliary nodules or tubercles were seen on the parietal peritoneum and greater omentum. Biopsy of the nodules and plaques revealed caseous granulomatous inflammation and the specimen were stained positive for acid-fast bacilli. Histopathology of the cocoon wall revealed fibrocollagenic tissue with granulomatous inflammation, and culture of the biopsied specimen grew Mycobacterium tuberculosis 3 weeks later. A diagnosis of tuberculous abdominal cocoon was made. Complete excision of the thick membrane and lysis of adhesions were tried but failed due to the extreme difficulty in separating the fibrotic tissue from the abdominal wall and small bowel. Since there were no perforated, ischemic or dilated bowel loops, the operation was completed after obtaining samples for diagnostic biopsy. After operation, the patient had recurrent episodes of partial bowel obstruction that was resolved with conservative management. The patient was given rifampicin, isoniazid, ethambutol, and pyrazinamide for 2 months, followed by rifampicin and isoniazid for 4 months. By the end of the 2 month of anti-tuberculous therapy, serum ADA, ESR and CA 125 levels have returned to normal. Though a repeat CT scan of the abdomen and pelvis continued to show the small bowel wall thickening and membrane covering the small bowels (Fig. 3a, arrowhead), and gastrografin meal follow through study revealed adherent small bowel loops with delayed transit time (Fig. 3b), however, the ascites has greatly diminished and the patient was functioning normally. No further surgical intervention was planned for him, and he was followed up symptom-free for 6 years.

abdominal cocoon, intestinal obstruction, tuberculosis

PMC5050374_01

Male

A 66-year-old male business manager with past medical history of hypertension, diabetes mellitus, and intermittent sinusitis was transferred to our tertiary care center for progressive encephalopathy and concern for nonconvulsive status epilepticus. Three weeks prior to admission, he was prescribed a 10-day course of levofloxacin for presumed sinusitis. As cough and postnasal drip did not improve, he was treated with two courses of methylprednisolone in addition to levofloxacin and subsequently clarithromycin. Two days prior to presentation, he developed headaches and sinus pressure and complained about "feeling off," epigastric pain, and dry heaving. The night prior to presentation, he awoke frequently throughout the night with progressive confusion. The patient did not have fever, chills, or sweats. His family reported a history of anxiety, panic attacks, claustrophobia, and anger outbursts, with the last notable outburst having occurred about 6 months earlier. Of note, coworkers found a collection of various over-the-counter vitamins and nutritional supplements at the patient's desk. Given increasing confusion and agitation, the patient was taken to another hospital where he became progressively more obtunded, requiring intubation for airway protection. He was empirically started on vancomycin, ceftriaxone, and acyclovir for concern of infectious meningoencephalitis. CSF analysis revealed elevated total protein at 53 mg/dL, glucose of 160 mg/dL (serum glucose: 240 mg/dL), no pleocytosis (1 WBC/mm3), negative CSF VDRL, negative West nile virus IgM and IgG, negative cryptococcal antigen, and negative fungal and bacterial cultures. Due to development of teeth grinding and concern for subclinical seizure activity, a routine electroencephalogram (EEG) was performed that revealed no seizure activity, however findings consistent with global cerebral dysfunction. He was started on phenytoin and subsequently on levetiracetam. An MRI of the brain showed chronic mild periventricular white matter hyperintensities but no acute findings. He was transferred to our tertiary care center on hospital day 3 for concern of nonconvulsive status epilepticus. On examination, he was intubated and mechanically ventilated, with no abnormal general physical findings. On neurological examination, he was comatose, with intact brainstem reflexes and extensor posturing in all extremities to central stimulation. Initial laboratory work was notable for normal liver function panel, serum ammonia 120 mug/dL (reference range 65-107 mug/dL), and negative hepatitis panel, as well as respiratory alkalosis. Repeat CSF analysis showed 3 WBC/mm3 (76% neutrophils), 1 RBC/mm3, lactic acid 2.6 meq/L, total protein 28.5 mg/dL, and negative herpes simplex virus PCR as well as negative enterovirus panel, and acyclovir was discontinued. Treatment with lactulose was begun, but serum ammonia rapidly rose to 494 mug/dL within a few hours of arrival to our hospital. Rifaximin and L-carnitine were added, and emergent hemodialysis was initiated. An MRI of the brain on day of transfer showed extensive areas of restricted diffusion with associated FLAIR hyperintensity involving bilateral temporal lobes and bilateral insular, bilateral frontal, and parietal regions in cortical and subcortical areas and diffuse mild effacement of the cerebral sulci (Figure 1), without enhancing lesions. Continuous electroencephalogram (cEEG) for a duration of 96 hours showed continuous, irregular, generalized low voltage slowing (Figure 2); however, intermittently observed facial and lip twitching did not have an electrographic correlate on cEEG. The MRI findings of symmetric grey matter involvement in the abovementioned areas, and in absence of hypoxic-ischemic insult and seizure activity, were deemed most consistent with hyperammonemic encephalopathy. The patient underwent continuous venous hemofiltration for two consecutive days followed by regular hemodialysis for two days, with sustained correction of ammonia to levels between 29 and 67 mug/dL after day 3. Liver function panel and coagulation parameters remained within normal limits. Due to poor neurological examination and concern for elevated intracranial pressure (ICP), an ICP monitor was placed, revealing three occurrences of ICP elevation to 28-30 mmHg, which were treated effectively with mannitol boluses. The patient's nutrition was modified to a low protein, high glucose formula to avoid catabolism of endogenous protein. Two days after normalization of ammonia levels, the patient opened his eyes and started to follow commands and move his extremities, and the ICP monitor was discontinued. He was extubated on hospital day 10, at which time he was alert and conversant, without focal motor deficits, yet remained confused. A computed tomography of the abdomen with venogram did not reveal a portosystemic shunt. An amino acid panel to evaluate inborn errors of metabolism, specifically urea-cycle disorders, was sent (see Table 1). Urine orotic acid excretion was significantly elevated (>900 mmol/mol creatinine; reference range: <2), strongly indicative of a biochemical diagnosis of ornithine transcarbamylase (OTC) deficiency. Genetic testing revealed a pathogenic variant, c.118 C > T, which has been described to cause a mild form of OTC deficiency. In our patient, OTC deficiency was likely unmasked due to a combination of factors: treatment with antibiotics, intake of multiple vitamin supplements, which included red yeast rice, treatment with steroids, and potential interactions of red yeast rice with antibiotics and other herbal supplements. The patient was maintained on low protein diet and discharged to rehabilitation on hospital day 20 and to home 6 days later, with persistent mild cognitive impairment especially in fluency and memory. A repeat MRI of the brain was obtained 3 weeks after the initial MRI and showed interval decrease in diffusion restriction and FLAIR hyperintensities and resolution of the diffuse mild effacement of the cerebral sulci. He continued to improve clinically and returned to work full time 10 weeks after his initial presentation. At a 3-month follow-up visit, he had returned to his premorbid baseline functional status. At a 6-month follow-up visit, he continued to do well with maintenance of low normal ammonia levels through low protein diet. Main sources of ammonia are colon (through bacterial metabolism of proteins and urea) and small intestine (through bacterial degradation of glutamine). In a healthy human, the main metabolic route is uptake of ammonia by periportal hepatocytes followed by urea synthesis via the urea cycle. Ammonia that escapes this pathway is converted to glutamine in perivenous hepatocytes. Hepatic transformation of ammonia into urea and subsequent excretion of urea via colon or kidneys prevent entrance of ammonia into the systemic circulation. If the hepatic metabolic capacity is exceeded, or if ammonia bypasses the liver by shunting of blood, circulating ammonia levels increase and elimination of ammonia is shifted to kidneys, brain, and skeletal muscle. Ammonia that reaches the brain can be metabolized by forming glutamine from glutamate, mostly in astrocytes with subsequent transfer of glutamine to neurons, and deamination of glutamine resulting in formation of the neurotransmitter glutamate. Muscle adds to the detoxification process by ammonia uptake and synthesis of glutamine. Ammonia excretion through the kidneys, usually accounting for excretion of 30% of ammonia, can be upregulated to 70%. Ammonia penetrates the blood-brain barrier through either passive diffusion or mediated transport. While the exact pathogenesis of neurotoxicity is still elusive, ammonia is believed to play a major role by affecting neuronal function as well as creation of brain edema, each of which can contribute to the development of encephalopathy. Ammonia directly affects neuronal electric activity by inhibiting the generation of both excitatory and inhibitory postsynaptic potentials. Increased cerebral uptake of neutral amino acids, resulting from increased amino acid transport in setting of hyperammonemia, can disturb synthesis of the neurotransmitters dopamine, norepinephrine, and serotonin. Enhanced ammonia metabolism in astrocytes leads to an increase in their production of reactive nitrogen or oxygen species and increased intracellular osmolarity, eventually resulting in brain edema. Furthermore, elevated extracellular glutamate levels, a result of ammonia-induced glutamate release and impaired glutamate clearance, may cause overstimulation of N-methyl-D-aspartate (NMDA) receptors. NMDA receptor activation then triggers nitric oxide synthetase which leads to increased synthesis of the vasodilator nitric oxide. Subsequent resultant intracerebral vasodilatation may contribute to the increase in intracranial pressure. Additionally, astrocyte swelling triggers inflammatory cascades, apoptosis, and metabolic pathways that lead to elevated lactate, cerebral edema, and loss of cerebral autoregulation. The differential diagnosis of hyperammonemia that is not associated with severe liver disease largely falls into one of two categories: increased ammonia production or decreased ammonia elimination. Increased ammonia production has been observed in hematooncological disorders, organ transplantation, infections, or states of increased catabolism or protein load. The exact mechanism for hyperammonemia in patients with hematooncological disorders is unknown. Myeloma cells have been shown to produce excess ammonia due to increased amino acid metabolism, and plasma cell infiltration of the liver can lead to a portosystemic shunt. In leukemia patients, occurrence of idiopathic hyperammonemia has been described hours to days after initiation of intensive chemotherapy, often followed by progression to coma and death. Similarly, severe hyperammonemia with frequent lethal course has been described in patients with hematological malignancies treated with bone marrow transplantation. Hyperammonemia has also been described in rare cases after heart-lung or lung transplantation. Pathogenesis of hyperammonemia in these situations is believed to be multifactorial involving increased protein catabolism, parenteral nutrition, gastrointestinal hemorrhage, sepsis or mucositis, and transient acquired enzyme reductions affecting urea synthesis, as well as drug effects from chemotherapy agents. Infections with urea-producing bacteria (Proteus mirabilis, Escherichia coli, Klebsiella species, Providencia rettgeri, Morganella morganii, and diphtheroids) can lead to noncirrhotic hyperammonemic encephalopathy, mostly reported in children with congenital urinary tract abnormalities and urinary stasis. However, cases have been reported in adults with urinary retention and neurogenic bladder, or even in absence of urinary tract abnormalities. Ammonia production in the setting of urinary tract infection alkalinizes the urine with subsequent increase of the fraction of ammonium ions. The ammonium ion is less permeable than neutral ammonia and cannot diffuse back into urine and hence escapes detoxification in the liver by uptake into the systemic circulation via venous drainage from the bladder. Furthermore, systemic mycobacterium or mycoplasma infections in organ recipients as well as herpes simplex virus infection in neonates have been described to lead to hyperammonemia. Increased ammonia production also occurs during increased muscle catabolism, such as with seizures, starvation, or trauma. However, symptomatic hyperammonemia usually only occurs in patients with underlying urea-cycle disorders. Similarly, total parenteral nutrition (TPN), which contains a high protein load, has been reported to unmask a long-term asymptomatic urea-cycle disorder or occur with TPN containing only essential amino acids with subsequently impaired ammonia detoxification due to absence of ornithine. Inborn errors of metabolism (IEMs) that can cause hyperammonemia include urea-cycle disorders, organic acidurias, carnitine deficiency from defects in fatty acid oxidation, dibasic aminoaciduria, and defects in pyruvate metabolism. While most IEMs present during the neonatal period or early childhood, some, especially urea-cycle disorders, can present in adults. Every enzyme in the urea cycle, carbamoyl phosphate synthetase (CPS), ornithine transcarbamylase, argininosuccinate synthetase (ASS), argininosuccinic acid lyase, and arginase, can be affected by an inherited deficiency. OTC deficiency, which is inherited in an X-linked recessive manner, is the most common one, with an estimated prevalence of 1 : 14.000. Late presentations and phenotypic variance are widely known for OTC deficiency. Mild OTC deficiency can remain largely asymptomatic until an inciting event unmasks the deficiency and leads to symptomatic hyperammonemia. CPS deficiency, N-acetyl glutamine synthetase, and type II citrullinemia also can be present in adulthood. Precipitating factors for clinical manifestation of these deficiencies include infections, TPN, gastrointestinal hemorrhage, or valproate intake. Ammonia elimination can be significantly decreased in presence of a portosystemic shunt. Congenital portosystemic shunts are a rare cause of noncirrhotic hyperammonemia, and shunt volume determines time of manifestation, with increased prevalence in patients above the age of 60. An acquired form of noncirrhotic portosystemic shunt that can lead to hyperammonemic encephalopathy is portal vein thrombosis. Ureterosigmoidostomy is another anatomic situation that can lead to hyperammonemia, due to increased ammonia formation by bacterial degradation after urine excretion directly into the sigmoid colon. While this can occur in liver-healthy individuals, for example, due to coprostasis or infection with urea-splitting bacteria, most cases occur in the setting of hepatic failure. Drug-induced hyperammonemia can result from interference with the urea cycle or enhancement of renal release of ammonia into the systemic circulation. Valproic acid is the most well known, but others include carbamazepine, sulfadiazine, ribavirin, salicylates, and glycine. The exact pathogenesis of hyperammonemia due to valproic acid is unclear, but it has been suggested that the mechanism is through inhibition of glutamate uptake by astrocytes. The reported prevalence of valproic acid induced hyperammonemia is as high as 35-45% and seems to be higher in patients with carnitine deficiency or with congenital urea-cycle enzymatic defects. Symptoms can present as early as 2 weeks into therapy or as late as several years later. Patients can be asymptomatic with mildly elevated liver enzymes or present with cognitive dysfunction, coma, or severe hepatotoxicity. Serum valproic acid levels can be normal and do not correlate with the level of hyperammonemia or symptoms. Furthermore, ammonia levels do not correlate with the severity of encephalopathy. Symptoms can range from mild, such as irritability, headache, and vomiting, to severe with encephalopathy, seizures, ataxia, and coma. Depending on the underlying etiology, the symptoms can fluctuate and episodically occur, often precipitated by increased protein intake, drugs, or infections. Psychiatric manifestations, such as manic episodes or psychosis, may be seen in chronic manifestations of late-onset presentations of inborn errors of metabolism. Seizures, cerebral edema, and herniation are manifestations of acute hyperammonemia and usually occur with ammonia levels exceeding 200 mumol/L. The difference between acute and chronic hyperammonemia is believed to lie in the effect of glutamine on the brain. In patients with acute liver failure, a strong association of arterial ammonia levels higher than 200 mug/dL with cerebral herniation has been shown.

PMC2918835_01

Female

A 33-year-old Caucasian, nulligravida patient initially presented with pleural effusion, ascites, and a left adnexal mass in August 2007. Her CA-125 level was 230 U/ml but clinically, she was asymptomatic. The patient underwent a diagnostic laparoscopy, which revealed several, diffuse peritoneal nodules. Initially, a presumptive diagnosis of small, bilateral hydrosalpinges was made. The ovaries were diffusely embedded within the disease process. Approximately 70 ml of straw-colored fluid was identified in the pelvis and left upper quadrant. The ascites was aspirated and submitted for cytologic examination. Moreover, sections of the right lower quadrant abdominal wall were biopsied to rule out malignancy (fig. 1). The differential diagnosis included tuberculosis, sarcoidosis or an unusual infection. Final pathologic evaluation revealed sarcoidosis. The patient was referred to pulmonary medicine and started on corticosteroid therapy, whereupon her condition improved dramatically. During the patient's follow-up examination in May 2009, a 9-cm pelvic mass was detected (fig. 2), although she remained asymptomatic. Her CA-125 was 128 U/ml. A diagnostic laparoscopy was performed to determine if the cystic structure could be removed laparoscopically, particularly since recurrent sarcoidosis was the presumed etiology. A variety of options were explained preoperatively, but the family's preference was conservative (i.e., fertility retention) management. However, due to the magnitude of disease, the prospect of a hysterectomy was also comprehensively discussed. The mass was cystic, containing a light brown-colored fluid. Culture and sensitivity testing was obtained. Consequently, a hysterectomy with bilateral salpingo-oophorectomy was again considered, but after an intraoperative discussion was held with the patient's family, we continued with conservative management. The mass was excised with the exception of an approximately 3.5 cm x 3.5 cm plaque, which could not be removed without excising the ovaries. Frozen section revealed endometriosis, granulomatous inflammation and focal necrosis, with no evidence of malignancy (fig. 3). The findings were consistent with sarcoidosis. Currently, the patient is doing well with 5 months of follow-up and is followed by the departments of gynecologic oncology and pulmonary medicine.

PMC6052921_01

Female

A 67-year-old woman diagnosed with primary hyperparathyroidism and a medical history of fatty liver was hospital-ized in February 2017 to undergo a parathyroidectomy for a well-defined flat single parathyroid adenoma in the left lobe that measured 15 mm. There was no family history of hypercalcemia. Although she had been infected with the influenza A virus 3 weeks prior and suffered from an URTI several days before, vital signs and physical findings were not remarkable on the day of admission. Initial blood test results revealed features of hyperparathyroidism, a high concentration of C-reactive protein (CRP), anemia, and liver function disorder, including the following measurements: white blood cell (WBC) count 6.3x109/L, hemoglobin 94 g/L, platelets 374x109/L, albumin 31 g/L, CRP 68.5 mg/L, aspartate aminotransferase 29 U/L, alanine aminotransferase 69 U/L, alkaline phosphatase 1015 U/L, -glutamyl transferase 197 U/L, creatine kinase 15 U/L, amylase 53 U/L, creatinine 47.7 micromol/L, blood urea nitrogen 4.7 mmol/L, sodium (Na) 143 mmol/L, potassium (K) 4.0 mmol/L, chlorine (Cl) 108 mmol/L, calcium (Ca) 3.02 mmol/L, phosphorus (P) 0.94 mmol/L, intact parathyroid hormone 16.2 pmol/L, parathyroid hormone-related protein <1.1 pmol/L, and 1,25-(OH)2 vitamin D 242.4 pmol/L. For surgery, the approach was started with a 4 cm lateral incision. Bleeding totaled 3 mL and the procedure was performed without any complications, after which hypercalcemia showed remission. However, a moderate fever developed 2 days after surgery (Figure 1), though there were no other symptoms such as fatigue, pain, or physical findings including surgery scar redness, joint swelling, or eruption. Body temperature never exceeded 38 C and the greatest fluctuation was within 1 C. Computed tomography (CT) scanning performed just prior to surgery revealed no remarkable findings, such as tuberculosis or abscess. Although the operation was a relatively minor procedure, the fever was considered to be the result of the healing process and the patient continued to be followed. When given acetaminophen as rescue, the fever declined, though emerged again and rose to 38 C on postoperative day 6 (Figure 1). Furthermore, blood test results showed that a moderately high concentration of CRP (79.8 mg/L) remained, though there was no increase in WBC (Table 1). For symptomatic treatment, daily administrations of acetaminophen were started, which controlled the fever. To investigate further, screening for collagen disease including vasculitis was performed, including erythrocyte sedimentation rate (ESR), rheumatoid factor, anti-cyclic citrullinated peptide antibody, antinuclear antibody, serum complement titer, antineutrophil cytoplasmic antibody, and serum ferritin. Thereafter, the patient was discharged on postoperative day 10 and asked to return on an outpatient basis. Surprisingly, pain in both shoulders and morning stiffness lasting for >1 hour suddenly appeared 3 days after discharge. The pain was too severe to sit up, and thus, the patient returned to our hospital. Our examination found no evidence of eruption, peripheral pitting edema, or tumor in a temporal artery. Furthermore, a screening blood test for collagen disease performed before discharge was negative (data not shown), except for ESR (113 mm/h), though an elevated concentration of CRP (112.4 mg/L) and high level of ESR (101 mm/h) were noted (Table 1). A CT scan did not reveal any inflammatory findings including vasculitis. Based on the symptoms and blood test results, though without joint sonography findings, the patient had >4 points in the American College of Rheumatology and European League Against Rheumatism classification criteria and disease activity as assessed by PMR activity score was >17 points. Therefore, we made a diagnosis of PMR and low-dose prednisolone was started, after which the symptoms rapidly improved and inflammation was reduced within a few days (Table 1). Body temperature, which had been under control with acetaminophen, remained controlled after switching to prednisolone. After 1 year of treatment, the dose of prednisolone was successfully reduced in February 2018. Written informed consent was obtained from the patient to use anonymized information from their medical records and the CT scan and laboratory test results. The patient granted permission for the publication of all anonymized information.

fever of unknown origin, immoderate immune activation, influenza a viral infection, parathyroidectomy, polymyalgia rheumatica, single parathyroid adenoma

PMC9556986_01

Female

A 44-year-old woman presented with persistent neck and back pain for over one year. On initial admission one year ago, Magnetic resonance imaging (MRI) suggested destruction of the thoracic vertebrae (T11 and T12) (Figures 1A,B), and computed tomography (CT) scans revealed destruction of the right 12th rib (Figure 2). Radiology consult suggested the findings resembled spinal tuberculosis. The patient underwent surgical removal of focal necrosis in the thoracic spine and thoracolumbar vertebroplasty. Though biopsy of the necrotic tissue did not reveal Mycobacterium tuberculosis, the patient received empirical antituberculosis therapy in the setting of her disease manifestations and no history of Bacillus Calmette-Guerin (BCG) vaccine. During follow-up, an abscess developed adjacent to the back wound and the patient underwent an open debridement of abscess six months after the surgery. The wound of the debridement healed, but repetitive neck and back pain struck the patients once again one month before the current admission, accompanied by numbness of bilateral upper limbs and neck immobility. Physical examination revealed a 20 cm healed surgical wound in her back. Tenderness and percussion pain were noted in the interspinous and spinous process of each cervical cone. Muscle tone was found in the bilateral trapezius, rhomboid and sternocleidomastoid muscles. MRI showed multiple cystic masses in the craniocervical junction region and effusion around the lumbar vertebrae (Figure 1C). Nothing special was noted in the abdominal contrast enhanced CT of the patient (Supplementary Figure S1). Blood tests suggested mildly elevated white blood cells with normal eosinophil count. Fecal examination suggested mildly positive occult blood. Multiple attempts were made to detect tuberculosis and other pathogens through both puncture of the effusion and cerebrospinal fluid, through culture and histopathological examination, but the results were all negative. Though spinal tuberculosis was the initial leading diagnosis in the case of this patient, the negative results from multiple biopsies led us question our assumptions and conduct further testing. Therefore, we adopted mNGS to further screen for potential pathogens in this case, and the results revealed high reads count and coverage rate for Echinococcus multilocularis, which was further verified by PCR and Sanger sequencing. To investigate the underlying reason of abscess formation, a DNBseq mNGS detection of the punctured effusion was performed. The detailed protocol is established as follows. First, 7.2 mul lysozyme was added into 0.6 ml effusion sample for wall-breaking reaction. Then we added the above solution to a 1.5 ml microcentrifuge tube with 250 mul 0.5 mm glass beads and placed into the FastPrep-24 5G bead beating grinder and lysis system for vigorous agitation. Next, we separated 0.3 ml sample into a new 1.5 ml microcentrifuge tube and used the TIANamp Micro DNA Kit (DP316, TIANGEN BIOTECH) to extract DNA. DNA libraries were constructed through DNA-fragmentation, end-repair, adapter-ligation and PCR amplification. Agilent 2,100 was used for quality control of the DNA libraries. Quality qualified libraries were pooled, DNA Nanoball was made and sequenced by MGISEQ-2000 platform. High-quality sequencing data were generated by removing low-quality reads, followed by computational subtraction of human host sequences mapped to the human reference genome (hg19) using Burrows-Wheeler Alignment. The remaining data were classified by simultaneously aligning to the Pathogens metagenomics Database, consisting of bacteria, fungi, viruses and parasites. The classification reference databases were downloaded from NCBI (ftp://ftp.ncbi.nlm.nih.gov/genomes/). The total number of reads detected was 176,712,306, of which 73,044 aligned to microorganisms. Among them, the detected reads from the specimen mapped well with the Echinococcus multilocularis genome (Figure 3A). As for the constitution, Echinococcus multilocularis was identified as the most predominant pathogen taking up to 99.74% (3,938 reads) of the total sequence reads (Figure 3B). To verify the mNGS result, we performed Sanger sequencing on the extracted sample DNA. According to the mNGS result, we designed a pair of PCR primers (EfF: 5'-GATTCCTTCTTTAGTTTTGTTGTTGATTAG-3' and EfR: 5'-CGAACTAAAAACTCTAGAAACACCTGCT-3') to specifically amplify the COX1 gene of Echinococcus multilocularis (GenBankTM accession number: AB813188). The sequencing results are consistent with the sequence alignment of the tapeworm cox1 gene, which further confirmed the mNGS results (Figure 4). After diagnosis of vertebral AE, the antituberculosis therapy was ceased and a continuous Benzimidazole treatment with Albendazole 400 mg twice per day was imitated immediately. The local symptom of the patient improved and was waiting for the next period of follow-up. No adverse events were noted one month after the Benzimidazole therapy. Our case was reported based on the CARE reporting standard (Supplementary Table S1). The whole timeline of the patients was displayed in Supplementary Figure S2.

alveolar echinococcosis, case report, diagnosis, next-generation sequencing, tuberculosis

PMC8633896_01

Male

A 34-year-old retired football player started to practice football in 2001 and now worked in a gym as a personal trainer. In March 2004, the patient immediately felt pain in his right knee, and his right leg was unable to take off after a quick long jump without warming up enough. There was no swelling of the knee joint at the time of the injury. The patient felt his legs were soft, unable to exert force, and felt deep in the restricted position but he could continue to train. In December 2004, an MRI examination was diagnosed with an osteochondral contusion of the lateral femoral condyle. Sodium hyaluronate was injected in 2006. On the advice of doctors, he retired in April 2006. From 2006 to 2013, the patient mainly sold sports equipment and worked as a part-time model. During the past few years, the patient did not treat with relevant functional rehabilitation and was limited to physical activities of daily life. He has been a fitness instructor since 2013, the patient has been continuously undergoing acupuncture, physiotherapy and small needle knife treatment, but the knee joint pain still exists after the treatment, and at the same time, the knee joint pain worsens after each training session. The patient complained that there was no obvious pain in the right knee in daily life, but the knee joint would be uncomfortable when it was cold. The right knee has obvious downhill pain, deep pain, blurred pain, unable to take off normally and participating in strenuous exercises of the lower limbs, fearing to be injured again, dare not do high-intensity and difficult movements in daily life and training. On April 24, 2019, a Physical and Rehabilitation Medicine (PRM) physician performed physical examinations (Figure 1), and a PRM physician experienced in musculoskeletal ultrasound diagnostic used Samsung HM70A model 5 18 Hz frequency probe to examine the patient's painful knee joint. The results showed that active range of motion (AROM) of the right hip joint: flexion-extension-abduction-adduction-external rotation-internal rotation were 110 -12 -33 -18 -40 -35 ; left side hip joint AROM flexion-extension-abduction-adduction-external rotation-internal rotation were 115 -9 -25 -20 -36 -35 . Both sides hip joint extension and abduction were insufficient; Right and left knee flexion were 115 and 121 ; right and left ankle dorsiflexion-plantar flexion were 15 -35 and 9 -30 , which indicated the left ankle AROM of the dorsiflexion joint was insufficient. The flexion and extension of the knee joints of both lower extremities were tested on grade 5 with normal muscle strength. The patient had no other medical or family history. The musculoskeletal ultrasound examination showed that the continuity of the patellar cortex was interrupted. An echoless area (about 0.57*0.35) was visible on the deep surface of the patellar tendon (Figure 2). The inner cartilage was slightly thinner than the outer side. The diagnosis was fluid accumulation in the deep subpatellar sac and old patella fracture. The patient signed informed consent and corrective training instructions to allow the use of his personal information for this case report and promise to follow the direction of exercise intervention. The patient himself was unwilling to undergo surgical treatment and only accepted conservative treatment. The patient was approved by the ethics committee of Physical Education of Southwest University School (approval no. SWU-20180304-C1).

disability, exercise intervention, kinesiophobia, patella fracture, retired athlete

PMC3562614_01

Male

A 55-year-old male presented to us with history of pain right hip and limp for the past 12 years, with inability to walk for the past 10 days following a low energy trauma. The patient had past history of road traffic accident 15 years ago when he sustained injury to his right hemipelvis and was treated with upper tibial pin traction for 6 weeks. He was ambulant and pain free later. Past medical records were not available. He developed dull ache in his right hip and limp 3 years later. Pain was deep seated, aggravated on activities, and partially relieved with analgesics. The patient was able to walk unaided and perform activities of daily living and squat in Indian toilet. He sustained a low energy trauma while riding bicycle 10 days back, falling on his right hip. He experienced sharp pain with inability to weight bear on his right leg with restriction of right hip movements. The patient is a chronic alcoholic, taking about 300 mL/week over the past 30 years. CAGE questionnaire revealed 3 positive responses out of 4, indicating significant alcohol dependence. He is a nonsmoker. He has no history of hypertension, diabetes, tuberculosis, asthma, or chronic drug intake. Examination revealed a moderately built patient with stable vital parameters. Right side ASIS was elevated. Anterior joint tenderness and crepitus were present in right hip. He had fixed flexion deformity of 20 degrees, and all other movements of right hip were painful and restricted. 1 cm of supratrochanteric shortening was present. Investigations revealed normal blood parameters. Plain X-ray pelvis with both hips revealed old vertical shear injury to right sacroiliac joint evidenced by cephalic migration of right hemipelvis; this is the result of previous trauma. The right hip showed superior articular surface irregularity with collapse of right femoral head. Fracture head of femur was found extending from superior to inferior articular surface (Figure 1). The left hip was found to be normal. CT pelvis with both hips with 3D reconstruction confirmed the fracture line in head of femur (Figure 2). A diagnosis of fracture head of femur right hip with underlying osteonecrosis was made based on history and imaging findings. Uncemented total hip replacement was planned due to gross destruction of femur head and acetabular degenerative changes. Intraoperatively, a deformed and fractured femoral head was found and was delivered out of acetabulum and sent for histopathological examination (Figure 3). Reconstruction was done with 52 mm Duraloc shell, polyethylene liner, and 11 size CORAIL femur stem (DePuy Johnson and Johnson) (Figure 4). Histopathology of resected specimen revealed necrotic bone with reparative fibroblastic proliferation:consistent with osteonecrosis (Figure 5).

PMC4081443_01

Male

AB is a 12-year-old boy with esophageal eosinophilia (72 eosinophils in the distal and 35 in the proximal esophageal sample) identified at the time of an upper endoscopy that was performed to assess for abdominal pain. The endoscopic report and images demonstrated esophageal furrowing, friability and distal ulcerations. Because of this finding, he was treated with fluticasone 220 ug 2 puffs swallowed twice a day. He experienced no relief of his symptoms. Upon referral, his history was notable for daily heartburn and regurgitation. pH impedance monitoring of the esophagus documented an elevated reflux index of 16.3 % and >75% symptom correlation. Treatment with omeprazole 20 mg QD brought symptom relief. Over the last few years, a number of studies demonstrated 2 key points regarding esophageal eosinophilia. The first is that this histological finding is associated with a number of different clinical conditions including, and not limited to EoE. Dense esophageal eosinophilia, characterized by >15 eos / HPF can be observed in gastroesophageal reflux disease (GERD), as in this patient, and other conditions. In addition, a new sub-group of patients, who present with esophageal symptoms and have a normal pH impedance probe monitoring of the esophagus, has dense esophageal eosinophilia and both symptoms and tissue findings resolve with proton pump inhibitor (PPI) treatment. This group of patients has been described as having proton pump inhibitor responsive esophageal eosinophilila [--]. Whether they represent a variant of GERD or EoE is not certain. This clinical finding brings us to the second key group of studies that have demonstrated an alternative mechanism that PPIs may impact the GI tract. Whereas the traditional target for PPIs is the proton pump, new data has identified the role of PPIs in inhibiting cytokine responses from esophageal epithelia. In these studies, investigators demonstrate that concentrations of PPIs used for acid inhibition are able to impact the expression and release of cytokines such as IL-8 and eotaxin-3, two cytokines thought to participate in GERD and EoE respectively [--]. Taken together, these studies emphasize the importance of interpreting the histological findings in clinical context of which the biopsies were taken. Friability and ulceration are unusual features of EoE and since GERD is much more common than EoE, an alternative approach would be to treat the patient, regardless of the level of eosinophilia, with a PPI first. Future studies in these areas will need to determine if alternative biomarkers may be able to separate out different causes of esophageal eosinophilia so that appropriate treatments can be initiated early.

PMC7247764_01

Male

A 55-year-old man sought outpatient treatment with a 6-year history of progressive dyspnea, which had worsened over the prior 4 months. A CT scan showed scattered small centrilobular nodules that were a few millimeters away from the pleural surface and fissures and did not touch them (Figure 1). The patient had multiple, small interstitial nodules on CT. A nodular pattern refers to multiple, round pulmonary soft-tissue density opacities smaller than 3 cm. Small nodules (or micronodules) are those that are less than 1 cm in diameter. On the basis of their distribution in the lung parenchyma, they can be classified as perilymphatic, centrilobular, or random. A perilymphatic pattern is characterized by small nodules located predominantly along the peribronchovascular interstitium, interlobular septa, and subpleural regions (which contain the pulmonary lymphatics). This pattern of distribution is frequently found in sarcoidosis, silicosis, and lymphangitic carcinomatosis. A centrilobular distribution is characterized by nodules that are a few millimeters away from the pleural surface and fissures but do not touch them. Hypersensitivity pneumonitis, silicosis, and bronchiolitis are examples of diseases in which this pattern may occur. A random pattern is characterized by small nodules that are randomly distributed in the secondary lobule and uniformly scattered throughout the lungs. Nodular diseases that disseminate through the body via the bloodstream, such as metastases and miliary granulomatous diseases (especially tuberculosis and histoplasmosis), have a random pattern of distribution. In the case described here, the nodules had a typical centrilobular distribution, sparing the pleural surfaces. This pattern is primarily seen in silicosis, hypersensitivity pneumonitis, and some forms of bronchiolitis. In most cases, the nodules found in hypersensitivity pneumonitis and bronchiolitis exhibit ground-glass attenuation. In suspected hypersensitivity pneumonitis, a history of exposure to certain antigens usually helps establish a diagnosis. In bronchiolitis, the nodules are frequently associated with a tree-in-bud pattern, which represents centrilobular branching opacities, most pronounced in the lung periphery, resembling the budding of certain plants. In suspected silicosis, it is essential to take a complete occupational history. An occupational history of silica exposure, associated with a consistent imaging pattern, is sufficient to establish a diagnosis of silicosis, there being no need for histopathological confirmation. Our patient worked as a sandblaster at a shipyard, which allowed us to establish a final diagnosis of silicosis.

PMC6560963_01

Female

Case 1: a 38-year old female patient, diagnosed with HIV infection in 2008, presented with complaints of intermittent high grade fever associated with chills and rigor for one month to a local hospital. This was associated with loss of appetite and generalized weakness. She was transfused two units of packed RBC. She was receiving an antiretroviral regimen consisting of tenofovir, lamivudine and efavirenz. Her CD4 count was 85/mul and the viral load was 56, 670 copies/mul. With a diagnosis of virological failure, she was shifted to an atazanavir/ritonavir based regimen. She was referred to us with persistent fever. On examination, she was febrile with a pulse rate of 120/min and a respiratory rate of 25/min. She had icterus and her jugular venous pressure was elevated. Chest examination revealed decreased bilateral breath sounds and bi-basal crepitations. On abdominal examination hepatosplenomegaly was present. The baseline laboratory evaluation revealed pancytopenia and hyperbilirubinemia (Hemoglobin- 5.9 gm/dl, total leucocyte count- 1500/cu.mm, platelet count- 18,000/cu.mm and bilirubin- 3.3gm/dl). Peripheral smear showed dimorphic hypochromic anemia with a corrected reticulocyte count of 1%. Vitamin B12 and folic acid levels were normal. Lactate dehydrogenase (LDH) levels were elevated (1154 U/l). Blood culture was sterile for bacteria, fungi and non-tubercular mycobacteria. Contrast enhanced computed tomography (CECT) scan of chest and abdomen revealed hepatosplenomegaly (liver-16.8 cm, spleen-13.4cm) and multiple enlarged non-necrotic lymph nodes in mesentery, para-aortic and inguinal region. A whole body Fluorodeoxy glucose positron emission tomography (FDGPET) scan revealed hypermetabolic bilateral supraclavicular, internal mammary lymph nodes and abdominal lymph nodes. There was avid uptake in liver, spleen and bone marrow also. The biopsy from supraclavicular lymph node showed reactive hyperplasia. Staining for acid fast bacilli, GeneXpert and Mycobacterial growth indicator tube (MGIT) culture for Mycobacterium tuberculosis were negative. A bone marrow biopsy was done which showed 60-70% cellularity. It was negative for geneXpert and Cytomegalovirus (CMV) polymerase chain reaction (PCR) assay. Also, pp65 antigen detection test in blood for CMV and rk39-antibody test for visceral leishmaniasis was negative. With a presumptive diagnosis of tuberculosis, modified anti-tubercular therapy (ATT) (levofloxacin, ethambutol and amikacin) was started as the patient had elevated bilirubin level. There was no response even after one month of ATT. Introduction of rifampicin and isoniazid was attempted but the bilirubin levels rose to 9.5g/dl. Clarithromycin was empirically added to cover for Mycobacterium avium complex (MAC) infection. On further investigations, she was found to have a triglyceride levels of 435 mg/dl, fibrinogen levels of 500 mg/dl, ferritin levels of >2000 ng/ml and decreased NK cell activity. With a diagnosis of Haemophagocytic lymphohistiocytosis (HLH), dexamethasone at a dose of 16 mg per day was started. The fever and pancytopenia improved in a week's time (Hemoglobin- 7.4gm/dl, total leucocyte count- 5300/cu.mm, platelet count- 50,000/cu.mm). The patient was doing well but she started getting dyspneic fifteen days after the initiation of steroids. Chest X-ray revealed consolidation in the right middle lobe. With a diagnosis of hospital acquired pneumonia, she was started on cefoperazone sulbactam, but she succumbed to her illness after two days.

malignancy, hospital acquired pneumonia, steroids

PMC6560963_02

Male

Case 2: a 46-year old male patient on tenofovir, lamivudine and efavirenz, presented with intermittent low grade fever for the last four months. This was associated with night sweats, loss of appetite and loss of weight of around five kilograms. He also complained of decrease in urine output and generalized swelling of the body. On general examination, he was febrile and was found to have enlarged right axillary lymph node (1cm x 1cm). On systemic examination, he had ascites and a palpable spleen (8 cm below the left costal margin). Fundus examination was normal. On laboratory investigations, he was found to have pancytopenia, deranged liver function and kidney function tests (Hemoglobin- 7.4g/dl, total leucocyte count-1200/mcl, platelet count-20000/mcl, aspartate transaminase/alanine transaminase-209/117 U/l and urea/creatinine- 78/1.7 mg/dl). His baseline CD4 was 221/mul and the most recent CD4 was 158/mul. Non contrast computed tomography of abdomen revealed multiple enlarged retroperitoneal lymph nodes with the largest measuring 47 x 22 mm. Lymph node biopsy could not be performed due to deranged coagulation parameters. Blood and urine cultures were sterile. Peripheral smear showed normocytic normochromic anemia. Vitamin B12 levels were normal but the folate levels were low (2.2ng/ml). Serum LDH levels were elevated (834 IU/l). Immunochromatography for rk39 antibody was negative. Ascitic fluid analysis revealed a protein of 1.9 g/dl, albumin of 0.9 g/dl, total leucocyte counts of 380/mcl (Lymphocytes 90%, Neutrophils 10%), serum-ascitic albumin gradient of 1.1g/dl and adenosine deaminase levels of 40 IU/l. Ascitic fluid cultures were sterile. With a presumptive diagnosis of disseminated tuberculosis, he was started on ATT. His ferritin levels were elevated (>2000 ng/ml) and triglyceride levels were also high (324 mg/dl). A presumptive diagnosis of HLH was made. A lymph node biopsy was performed after correction of coagulation abnormalities to identify the primary pathology. However, he succumbed to his illness before the results of biopsy were available. The biopsy was suggestive of Hodgkin's lymphoma.

malignancy, hospital acquired pneumonia, steroids

PMC3518955_01

Female

In May 2010 a 30-years-old African female patient with preexisting compensated renal failure was brought to the attention of the Infectious Disease Department for high fever, headache, abdominal pain, renal failure (serum blood urea nitrogen 35 mg/dl, creatinine 9.5 mg/dl), severe anemia (Hb 5 mg/dl), metabolic acidosis (arterial blood gas analysis: ph: 7.33; pCO2: 28 mmHg; HCO3-(c): 14,8 mmol/L), and high blood pressure 180/100. She was diagnosed with advanced HIV infection (CD4 count, 29/mul, HIV-1-RNA viral load >than 750 000 copies/ml) and disseminated tuberculosis (TB). (Quantiferon test was positive, and this result was confirmed by the study of the sputum which was positive for the presence of alcohol acid resistant bacilli.) Total body CT spotted the presence of an abdominal abscess, supposedly TBC related. The ophthalmological examination showed a normal fundus and a visual acuity of 20/20. Antihypertensive therapy (Ramipril cp 5 mg 1 cp/day), three times a week, dialysis through groin venous access, and antituberculosis therapy (rifampicin cp 600 mg, 1 cp/day, isoniazid cp 200 mg, 1 cp + 1/2 cp/day, pyrazinamide cp 500 m, 3 cp/day, ethambutol cp 1000 mg, 1 cp 3/week, after dialysis and cotrimoxazole) were started. Calcium therapy was also administered occasionally after dialysis for a moderate hypocalcaemia (7.4 mg/dl, normal range 8.5-10.1 mg/dl). In September she started antiretroviral therapy (ART): Lopinavir/Ritonavir cp 200/50 mg (2cp x 2/day) and raltegravir (Isentress) cp 400 mg (1 cp x 2/day). At this time her blood pressure was 130/80 mmHg. After two weeks from the beginning of ART, she complained about severe asthenia, functional inability of her lower limbs, and severe loss of her sight. Her visual acuity at this time was limited to light perception in both eyes, pupils were equal, the pupillary reflex was torpid, and fundus examination showed a normal optic head and normal vascularization. Visual-evoked potential showed an increased latency and a decreased voltage. The other cranial nerves were observed to be intact. Lumbar puncture, executed at this time, showed no evidence of active central nervous system inflammation/infection. A new magnetic resonance imaging (MRI) (Figure 1(a)) of the brain revealed an abnormal T2 hyperintensity within both cerebellar and parietooccipital and frontal lobes. The classic features of neuroimages, combined with clinical presentation of decreased vision and headache, confirmed the diagnosis of PRES. The patient underwent supportive therapy. She had a clinical improvement within a few days; new imaging (Figure 1(b)) showed bilateral white matter lesions with decreasing size, and her visual acuity returned to 20/20 in both eyes. The patient was discharged without neurological deficits 10 days later. After three months of followup, the patient is doing well, HI-viral load is suppressed, CD4 count has increased to 180/mul, and kidney function has improved substantially.