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PMC8059450_01

Male

An 18-year-old boy presented with on and off low-grade fever for 3 months and anorexia and progressive pallor for 1 month. The fever was more in evening times as remembered by the caregivers but was not associated with chills/rigor. There were no symptoms suggestive of respiratory, cardiovascular, gastrointestinal, hepatic, or renal involvement such as cough, fast breathing, breathlessness, pain abdomen, abdominal distension, jaundice, and change in color or amount of urine output. There was no history of any drug ingestion, apart from paracetamol during these 3 months and before that. Apart from pallor, the systemic examination was otherwise normal. Hematological parameters revealed hemoglobin of 6 g/dl, normocytic and normochromic red blood cells, leukocyte count of 2640/mul, 64% lymphocytes, platelet count of 37,500/mul, and erythrocyte sedimentation rate was 22 mm in 1st h. Peripheral smear did not show any hemoparasites or any other abnormalities. Liver and kidney function tests, autoimmune profile, serum triglyceride, and ferritin levels for hemophagocytic lymphohistiocytosis (HLH), workup for viral and parasitic causes including malaria, hepatitis B and C, Epstein-Barr virus, parvovirus, and human immunodeficiency virus (HIV) were noncontributory. Workup for atypical bacterial infections such as bartonellosis and brucellosis was also negative. Serum Vitamin B12, folate, and lactate dehydrogenase levels were normal. Although Mantoux test showed an induration of 11 mm at 48 h, Chest X-ray was normal, and ultrasound abdomen showed only a few subcentimeteric mesenteric lymph nodes. Computed tomography of neck, chest, and abdomen also did not reveal any significant abnormality. On asking leading questions, the parents revealed paternal grandfather is taking ATT for sputum-positive pulmonary TB for the past 5 months. Subsequently, bone marrow (BM) examination was performed, which revealed a hypocellular marrow, no blast cells, with infiltration by epithelioid granulomas having central caseating necrosis. Stain for AFB and GeneXpert was negative, but in view of positive contact history and corroborative findings, the diagnosis of bone marrow TB was considered. Sarcoidosis was ruled out as serum angiotensin-converting enzyme level, and urine calcium creatinine ratio was normal. He showed favorable clinical response with slow improvement in hematological parameters (repeat Hb-9 g/dl, total leukocyte count - 5670/mul, platelet count - 152,000/mul) and resolution of pyrexia within 2 months after starting ATT. Currently, on follow up after 1 year of instituting ATT, the child has completed the course of ATT 6 months back, latest hematological parameters are all within normal limits.

bone marrow cells, pancytopenia, pulmonary, tuberculosis

PMC3293089_03

Transgender

Combined with the 2 patients in our series, 76 patients in China have been reported (Table 2). Among the 76 patients, 50 were men, with a male to female ratio of 1.9:1. The mean age of the 71 patients which have a clear age or mean age record was 51.0 years old (range, 10-77 years), and 88.1 percent (52/59) of the patients were older than 40 years. Most of hepatic MFH were large neoplasms, and only 13.2 percent (10/76) were smaller than 5 cm. The exact sizes of hepatic MFH were mentioned in 59 cases, including 19 cases with diameter descriptions in radiological investigations. The mean diameter was 10.3 cm (range, 2.5-23.5 cm). Among the 76 cases, 82.9 percent (63 cases) of the tumors were described as solitary lesions, while only 17.1 percent of the tumors were composed of multiple lesions. The information of tumor localization was provided in 66 cases, including 10 cases with multiple tumor nodules. Among the 10 cases, the tumor nodules of 4 cases were found in both right and left lobes and the tumor nodules of the remaining 6 cases were confined to one lobe of the liver, 3 in the left and 3 in the right lobe. Among the 56 cases with a solitary lesion, tumors were often found in the right lobe (33 cases), and less frequently in the left lobe (21 cases), and the lesions of the remaining 2 cases (3.6%) were in the middle part of the liver. For clinical manifestation of hepatic MFH, 74 cases provided details. The symptoms were usually non-specific. 58 patients (78.4%) complained of abdominal pain or discomfort of different degrees, accompanied with loss of body weight in 12 cases, obstructive jaundice in 1 case, nausea and anorexia in 8 cases, and fever in 15 cases, including 2 cases with the temperature more than 39 degree. Nearly 14.9 percent (11 cases) of the patients were asymptomatic, with the tumors found during routine physical examinations or unrelated conditions. In addition, 2 patients were admitted to hospital for obstructive jaundice and 2 patients were for fever. The last one patient was admitted for loss of body weight and the lesion was found by the radiological investigation on admission. A variety of radiological investigations were performed for the evaluation, including ultrasonography (US, 46 cases) and computed tomography (CT, 63 cases) in the vast majority of the patients, and magnetic resonance imaging (MRI) in only 16 patients. The tumors were described on cross-sectional imaging as solid, cystic or heterogeneous (solid and cystic) masses. Among the US investigations of 46 cases, 34 cases provided details. The tumors appeared hypoechoic in 10 cases, hyperechoic in 10 cases, anechoic in 2 cases, and showed a mixed pattern that may include extensive necrotic areas in 8 cases. In addition, the tumors were described as cyst-like lesions in 2 cases. Among the remaining 2 cases, the lesions of one case were not detected and the other case had a lesion in each lobe of the liver, a cyst-like lesion in the left lobe and a hypoechoic lesion in the right. We have detail CT descriptions of 49 cases. The lesions that were not detected in the US investigation were not detected either in the CT investigation. Another case had one lesion in each lobe of the liver, a hypodense mass in the left lobe and a cyst-like lesion in the right. Among the remaining 47 cases, on plain CT scanning, MFH appeared as hypodense masses with necrotic areas of differing degrees in 40 cases, cyst-like masses in 4 cases, mixed masses in 3 cases. 45 cases provided details on the enhancement scanning. The solid components or the cystic walls of 41 cases were introduced to be variably enhanced, from slightly to markedly, while the masses of the remaining 4 cases showed no enhancement. Among the 16 cases with MRI examinations, 2 cases provided no information of T1-weighted MR images. The T1-weighted MR images of the remaining 14 cases all showed low signal-intensity masses. T2-weighted MR images of all the 16 cases showed high signal-intensity solid masses. 11 cases provided details on contrast-enhanced dynamic MR images. A gradual enhancement of internal components was present in 10 cases, and no obvious enhancement was showed in only 1 case. For laboratory examinations, 5 cases provided no details. It showed that 77.8 percent (35/45) of liver function tests and 60.8 percent (31/51) of hepatitis investigations were normal in the patients. About the tumor marker, only a few of patients have slightly elevated tumor marker levels, such as serum alpha-fetoprotein (AFP, 7/68), carcinoembryonic antigen (CEA, 1/41), carbohydrate antigen 19-9 (CA19-9, 3/34). 5 cases have the description of carbohydrate antigen 125 (CA125) examinations and only 1 patient has an elevated level. Despite the technological advances, pre-operative diagnosis of hepatic MFH is still difficult, and the rate of misdiagnosis is extremely high. We had information about preoperative diagnosis for 67 patients, none of which, including one case with puncture biopsy before operation in our series, got the exact diagnosis. 48 cases were diagnosed as hepatic neoplasms, 8 cases were only diagnosed as masses of liver. In addition, 10 cases (14.9%) were even misdiagnosed as benign lesions of the liver, including hemangioma in 3 cases, hepatophyma in 5 cases, hepatic hydatid cyst in 1 case and hepatic cyst in 1 case. The remaining 1 case was only diagnosed as calculi of intrahepatic duct, and the hepatic mass was not discovered until surgery. Surgical procedure was the main treatment for hepatic MFH (Table 3). Among the 68 patients whose treatments were available, 49 cases (72.1%) had integrated resection, 4 cases (5.9%) had palliative operation (local resection), 7 cases had (10.3%) puncture biopsy, and the other 8 cases (11.8%) were found unresectable at laparotomy and underwent biopsy. In one case with integrated resection, a lesion in the lung was also detected synchronously with the one in the liver, and left pneumonectomy was performed 50 days after operation. The lesion of the lung was demonstrated as metastatic MFH and no adjunctive therapy was performed afterward. Among the remaining 48 vases with integrated resection, 3 cases received chemotherapy, 2 cases received radiation therapy, 1 case received hepatic artery and portal vein subcutaneous embedding alternate infusion chemotherapy after operation, 1 case received hepatic arterial infusion chemotherapy twice because of tumor recurrence 2 months after operation, and 1 case received lymphadenectomy and 125I radiation therapy because of lymph nodes metastasis 3 months after operation. Among the 4 cases with palliative operation, 1 case received intrahepatic dehydrated alcohol injection and hepatic arterial chemoembolization six times and regular antituberculosis treatment because misdiagnosised as intrahepatic nonspecific inflammatory granuloma, HCC or tuberculosis respectively before operation, and after operation superselective arterial chemoembolization and hepaticarteriography chemoembolization were also performed, another case received drainage fenestrated with laparoscope because misdiagnosised great cyst in the left lobe of liver before laparotomy, and received palliative operation because of intraperitoneal plant. Among the 7 cases with puncture biopsy, 1 case received percutaneous cryoablation combined with transarterial chemoembolization. Among the 8 cases with biopsy after laparotomy, 2 cases received chemotherapy. Most cases of primary hepatic MFH were the type of pleomorphic storiform MFH. One case in the Chinese literature was the type of inflammatory MFH, which has not been reported in the English literature. In the English literature, the only case that was diagnosed as giant cell MFH was also from China. For immunohistochemical investigations, only 28 cases provided details. Immunohistochemically, the tumor cells showed typically positive for Vimentin(27/27), CD68(13/13), and MAC387(2/2), and AAT(13/14), Lysozyme(11/12), ACT(10/12) showed positive in most cases. AFP(5/5), FVIII(2/2), CEA(4/4), EMA(9/9), CK8/18(7/7), Hep parl(4/4), CD10(3/3), HMB-45(7/7), Actin(5/5), Desmin(13/13) showed all negative, and CK(1/12), CD34(1/5), S-100(1/10), SMA(1/5) were expressed only in a few tumors. To our knowledge, follow-up periods ranging from one month to 10 years were mentioned for 42 patients. The 8 cases with no treatment introduction have no follow-up either. Among the 49 cases with integrated resection, a postoperative follow-up was conducted in 33 patients. 10 cases of these 33 patients had recurrence or metastasis within a year, 2 cases had recurrence or metastasis over a year, 5 cases had no recurrence or metastasis within a year, 2 cases had no recurrence or metastasis over a year, 8 cases died within a year, and the remaining 6 cases were still alive with no detail information provided (the follow-up periods of these 6 cases was 1 month, 3 months, 23 months, 26 months, 3 years and 10 years respectively). Among the 4 cases with palliative operation, 2 cases were followed-up. 1 case died of multiple organ failure 2 months after operation, and the other was lost after finding the lesion was increasing 4 month after operation. Among the 7 cases with puncture biopsy, 2 cases were followed-up, and died 1 month and half of 1 month respectively after discharge from hospital. Among the 8 cases with biopsy by operation, 5 cases were followed-up. 4 cases died 1 month, 2 month, 3 month and half of 1 year respectively after discharge from hospital, and 1 case died without the surviving time provided.

PMC7485089_01

Male

A 68-years-old male complained with xanthochromia, scleral icterus, and abdominal distension for over 20 days was admitted to our hospital in January 2018. He lost about 10 kg of body weight. Physical examination showed deep jaundice of the patient and the left supraclavicular lymph nodes were palpable. The performance status (PS) score was 3. Laboratory tests showed that total bilirubin (TB) was 707.9 umol/L, and CA19-9 level was over 12,000 U/mL, while AFP level was <20 ug/L (Table 1). Magnetic resonance imaging (MRI) found a 47 x 42 mm space-occupying lesion in Segment 4 (S4) and S5 of the liver and a mass in the common bile duct, suspicious for ICC. Subsequent positron emission tomography (PET) showed multiple distant metastases to lungs, abdominal lymph nodes, and left cervical lymph nodes. Histology of the liver lesion biopsy found numerous tubular structures of adenocarcinoma and a fibrous stoma (Figures 1A,B). Immunohistochemistry (IHC) analysis showed the following: CK(+), CK7(+), CK20(weak +), and Ki-67(3%+). The diagnosis was confirmed as stage IV ICC. The presumed survival time was only 3-5 months. According to the opinion of the ICC multi-discipline team in our hospital, the patient was not a candidate for conventional treatments including surgery and chemotherapy, considering both tumor and PS status. Then, percutaneous transhepatic cholangial drainage (PTCD) was performed to relieve the jaundice and the patient's appetite recovered and the PS score was still 3. To comprehensively investigate the immune microenvironment, the tumor tissue of the liver lesion was submitted for subsequent tests. Additional IHC analysis found a low expression level of programmed cell death ligand 1 (PD-L1) and a low frequency of CD8+ T cells (Figures 1C-F). The whole-exome sequencing (WES) data showed high levels of both MSI and TMB (16.9 mutations/Mb), which indicated the potential benefit of immunotherapy. Additionally, there were 420 indels (insertions and deletions) and 660 single nucleotide variants (SNVs), with five mutations (including MLH1, SMARCA4, BRCA2, POLE2, and ARID1A) known to be associated with sensitivity to immunotherapy while one gene (B2M) conferred resistance to immunotherapy. We further included another 36 ICC cases in the Cancer Genome Atlas (TCGA) dataset to comparatively analyze the patient's tumor immune microenvironment based on the RNA-seq data. This case was found to have a moderate level of immune infiltration under a comprehensive immune signature (Figures 2A,B). Analysis of immune cell components in the tumor microenvironment using the CIBERSORT algorithm revealed scarce CD8+ cells but a large number of M2 macrophages, which is consistent with the IHC result and indicates an immunodeficient state (Figure 2C). After all, anti-PD-1 immunotherapy (pembrolizumab, at a dose of 200 mg every month) combined with radiotherapy was considered as treatment for the patient, which was initiated in February 2018 (Figure 3A). After two cycles of immunotherapy, the patient's symptoms relieved and his PS improved. The size of the liver lesion slightly reduced to 38 x 33 mm but CA-199 was still over 12,000 U/mL (Figure 3B; Table 1). After six cycles, PS score was 1 and CA-199 was decreased to 4620.49 U/mL (Table 1). Contrast-enhanced computed tomography (CT) scans showed that the liver lesion reduced to 32 x 23 mm (Figure 3B). However, the number of lung metastases increased, which indicated a mixed response to immunotherapy (Figure 3C). Anti-PD-1 immunotherapy continued while radiotherapy was introduced to control the liver and lung lesions, with doses of 50.0 and 48.0 Gy, respectively. All visible tumors reduced in size gradually in the follow-up and the PTCD was removed 3 months later (Figure 3C). Currently, after 26 months of treatment, the patient is alive with high life quality. There aren't any symptoms and PS score is 1. The patient regained 5 kg of body weight. All tumor biomarkers including CA19-9 level are normal. The latest imaging examinations show invisible signs of the liver lesion, the metastatic lymph nodes, and the lung metastases. CR is achieved in this stage IV ICC case (Figure 3C; Table 1).

biomarkers, combination therapy, immunotherapy, intrahepatic cholangiocarcinoma, radiotherapy

PMC7186880_01

Male

A 55-year-old Chinese man was referred to our department with a history of asymptomatic thrombocytosis over 1 year's duration. Apart from pleural tuberculosis 2 years ago treated with systemic anti-tuberculous therapy, his past medical history was unremarkable. His physical examination was unremarkable. A full blood count revealed a white blood cell count of 9.2x109/L with lymphocytes count of 3.0x109/L, haemoglobin 132g/L and platelet count of 629x109/L. Peripheral blood film showed thrombocytosis and there was no significant dysplasia. His biochemistry profile revealed a slightly raised total globulin level of 41.9g/L (normal range: 20-40g/L), uric acid: 507mumol/L (normal range: 208-428 mumol/L) and lactate dehydrogenase 242U/L (normal range: 109-245U/L). His serum immunoglobulin analysis revealed an elevated immunoglobulin M (IgM) of 21.5g/L (normal range: 0.46-3.04g/L), kappa light chain of 26.8g/L and lambda light chain lambda of 5.03g/L. Serum immunofixation confirmed the presence of monoclonal IgM. Ultrasound imaging study did not reveal lymphadenopathy, hepatomegaly or splenomegaly. A bone marrow (BM) aspiration and trephine biopsy were performed. The BM aspirate morphology showed an excess of platelets and lymphoplasmacytoid lymphocytes (Figure 1A and B). The trephine reported cellularity of 55%, with increased numbers of lymphocytes and mature megakaryocytes with hyperlobated nuclei (Figure 1C). Flow cytometric immunophenotyping of his BM aspirate confirmed monoclonal B lymphocytes, which were positive for CD19, CD20 and cell membrane kappa light chain, but negative for CD5, CD10 and CD23 (Figure 2). Next-generation sequencing (NGS) with a 126-mutation panel was adopted to further investigate his gene/molecular mutation status which detected JAK2 V617F, MYD88 L265P, and ATM F1036L. BCR-ABL1 mRNA was not detected by quantitive real time-PCR. Taken together, a diagnosis of ET with concomitant WM was made. He was treated with pegylated interferon and low-dose aspirin (100mg per day). After two months of treatment, his platelet count dropped to 324x109/L and IgM level to 11.80g/L.

janus kinase 2, waldenström macroglobulinaemia, myeloid differentiation factor 88, myeloproliferative neoplasm

PMC8683236_01

Female

A 35-year-old female presented to the Emergency Department (ED) for evaluation of 3 months of worsening exertional dyspnea and bilateral lower extremity edema. The patient initially noted mild dyspnea on exertion, which gradually progressed to the point of being unable to climb a single flight of stairs without stopping to rest. The patient endorsed a nonproductive cough, pleuritic chest pain, occasional orthopnea, and an unintentional 20-pound (9.1 kg) weight loss over a one-month period. She denied any associated fevers, chills, or night sweats; had no nausea or vomiting; and had no easy bruising or bleeding. The patient denied any other recent illness and also denied any significant exposures or risk factors for tuberculosis. She had no significant past medical history including any previous cardiac pathology, thromboembolic disease, structural heart disease, indwelling catheters, or asthma. She denied any current or prior intravenous drug use (IVDU). Family and surgical history was also noncontributory. Physical exam demonstrated a nontoxic appearing patient sitting comfortably in bed. Vital signs included a temperature of 98.1 F (36.7 C) with mild tachycardia at 109 beats per minute, blood pressure of 107/64 mmHg, and respiratory rate of 20 breaths per minute. Pulmonary examination revealed lungs clear to auscultation bilaterally without adventitious sounds or retractions; however, the patient was only able to speak in 4-5-word sentences with effortless tachypnea and no accessory muscle use. Cardiac examination demonstrated mild tachycardia without murmurs, rubs, or gallops; no jugular venous distention; and no carotid bruits. Extremity examination was notable for symmetric 2+ pitting edema to the midshin of both lower extremities. Skin exam revealed no purpura, Osler nodes, Janeway lesions, splinter hemorrhages, or track marks. Abdominal exam was nontender, and neurological examination was nonfocal. Multiple laboratory studies including 2 sets of blood cultures were obtained (Table 1) and remarkable only for mild hyponatremia with a sodium of 127 mEq/L, a chloride of 90 mEq/L, and mild anemia with a hemoglobin of 8.5 g/dL. There was no leukocytosis, troponin was undetectable, and brain-natriuretic peptide was within the normal range. These laboratory findings were not suggestive of any particular pathological processes. The finding of anemia was noted, but the lack of any corresponding elevation in bilirubin made acute hemolysis less likely. The hyponatremia was felt to be consistent with the patient's hypervolemic clinical picture. The lack of leukocytosis was noted, though limited inferences can be made from this value in isolation. Overall, the laboratory results made acute decompensated congestive heart failure and bacterial pneumonia lower on the differential. A 12-lead electrocardiogram revealed sinus tachycardia with normal axis and intervals, with no acute injury pattern and no evidence of right-heart strain. A chest radiograph was obtained (Figure 1) and was interpreted by the radiologist as demonstrating "bilateral patchy atelectasis":however, the emergency physicians felt it demonstrated a pleural-based wedge-like consolidation in the right inferior lobe consistent with Hampton's Hump. The initial differential considered by the providers included pulmonary embolus, pneumonia, congestive heart failure, pulmonary hypertension, cardiomyopathy, and infectious endocarditis. At this time, a third set of blood cultures were added to the patient's workup. A limited bedside transthoracic echocardiogram (Figures 2(a) and 2(b)) in the ED revealed findings concerning for tricuspid valve vegetations as well as a slightly enlarged right ventricle without any D-sign (i.e., a D-shaped left ventricle on parasternal short-axis view, consistent with right ventricular strain causing shift of the ventricular septum). Cardiology was consulted for concern for potential IE. A CT-angiogram (CTA) of the chest was ordered to assess for pulmonary embolism and further characterize the pulmonary lesions seen on radiography, and the patient received intravenous (IV) ceftriaxone and azithromycin to cover possible community-acquired pneumonia while the CTA was pending. The CTA revealed findings consistent with multiple septic emboli and mycotic aneurysms (Figures 2(c) and 2(d)), as well as multiple segmental pulmonary arterial occlusions with associated infarcts or hemorrhage. A stat formal echocardiogram was obtained and interpreted at bedside by the cardiology fellow, confirming the presence of tricuspid vegetations as well as moderate tricuspid regurgitation, with no evidence of right ventricular strain. The patient was treated with IV vancomycin, gentamycin, and ciprofloxacin to provide coverage for possible MRSA endocarditis, due to the concern for possible undisclosed IVDU, and was admitted with consultation of Cardiothoracic Surgery and Infectious Disease (ID). The patient was maintained on IV gentamycin and vancomycin and underwent a transesophageal echocardiogram (TEE) on hospital day 2 which revealed a large 2.0 x 2.1 cm posterior leaflet tricuspid valve vegetation with severe tricuspid regurgitation. On hospital day 5, the patient admitted to a history of heroin IVDU but was not forthcoming about the date of her most recent use, and a urine toxicologic screen was negative. The patient underwent a tricuspid valve annuloplasty and reconstruction using autologous pericardial tissue by Cardiothoracic Surgery on hospital day 8. The patient's blood cultures remained negative on hospital day 9, at which time ID recommended the patient receive ceftriaxone 2 g IV daily for 6 weeks. Pathology of the valve leaflets resulted on hospital day 10 and indicated granulation tissue with focal areas of bacterial colonization without bacterial identification. The remainder of the patient's postoperative course was uncomplicated, and on hospital day 15, she was transferred in good condition to a skilled nursing facility to complete her 6-week course of IV ceftriaxone. The blood cultures remained negative, and the causative pathogen was not identified.

PMC5225336_01

Male

A 66-year-old male who was a long standing inmate in a forensic psychiatric hospital presented to the Emergency Department with a complaint of abdominal distention. The patient denied any nausea or vomiting but reported a decreased appetite which he attributed to abdominal discomfort. His last bowel movement was five days ago. The patient also endorsed dysuria. A computerized tomography (CT) scan of the abdomen and pelvis was performed prior to ED arrival and the images were brought with patient. The patient had a past medical history notable for paranoid schizophrenia, bipolar disorder, latent tuberculosis, and ascending aortic aneurysm. There was no known history of liver disease. The patient's medications included clozapine, fluphenazine, lithium, paroxetine, lorazepam, and haloperidol. He had no known drug allergies and had no recent medication changes. Complete review of systems was otherwise negative. The patient had no history of previous surgeries, did not smoke, drink, or consume illicit drugs, and had a noncontributory family history. On initial presentation to the ED his vital signs were heart rate (HR), 104; blood pressure (BP), 147/101; respiratory rate (RR), 22; pulse oximetry, 93% on room air; and temperature, 36.4 degrees Celsius. On examination of the patient, his oral mucosa was noticeably dry. His cardiac exam was unremarkable with normal S1 and S2, no murmurs, rubs, or gallops, and 2+ pulses in all four extremities and his lungs were clear to auscultation bilaterally. The patient's abdomen was firm and grossly distended and was noted to resemble a full-term pregnant patient. Dilated superficial veins were noted on the abdomen and palpation revealed mild, diffuse tenderness without rebound or guarding. The patient was awake, alert, and orientated to time, date, and environment. Labwork was notable for sodium of 115 mmol/L and a serum osmolality of 251 mOsm/kg. The potassium level was 5.2 mmol/L, chloride 80 mmol/L, bicarbonate 21 mmol/L, creatinine 1.58 mg/dL, lactic acid 1.5 mmol/L, troponin T < 0.01 ng/mL, and lithium level 1.0 mmol/L. The patient was mildly anemic with a hemoglobin of 11.5 g/dL, while his remaining complete blood count (CBC) was unremarkable with a white blood cell (WBC) count of 9.44/L and platelets of 318/L. An electrocardiogram was obtained during the ED evaluation (Figure 1) which showed a sinus tachycardia of 105 beats per minute, QRS 98s, QTc 415 ms, and peaked T waves in the precordial leads. Upon review of the CT, large dilated loops of colon were noted up to 12 cm (Figures 2 and 3). During the ED course, the acute care surgical service was consulted for further management. A rectal exam was performed by the resident physician with a plan for disimpaction immediately following. The patient was positioned on his left side. Soft stool was found on rectal exam. During the rectal examination, the nurse in the room noted that the patient was apneic and a code was called. The patient was unresponsive for less than one minute prior to the nurse noticing his status change. The patient had no new complaints prior to his arrest. Unfortunately, the patient was not on a cardiac monitor at this time. Upon immediately placing the patient on a monitor, a bradycardic rate was noted. Following a pulse check, the patient was then found to be in pulseless electrical activity. Cardiopulmonary resuscitation (CPR) was started and advanced cardiac life support (ACLS) protocol was followed including intubation. Initial bedside ultrasound showed no cardiac activity. Following multiple rounds of CPR and ACLS medications, return of spontaneous circulation (ROSC) was obtained. The patient then again went into PEA with a bradycardic rhythm but ROSC was again obtained and remained. A postarrest arterial blood gas was notable for pH 6.84, pCO2 100 mmHg, and pO2 94.5 mmHg. The patient was then admitted to Intensive Care Unit (ICU) on epinephrine, norepinephrine, and vasopressin infusions. At time of ICU admission the patient was in a normal sinus rhythm of 98. Eight days later the patient expired following confirmation of anoxic brain injury and a decision made to provide comfort care.

PMC4867071_01

Male

61-year-old patient, smoker, with a history of specific process (in 1992) and COPD, was treated with painkillers by GP in April 2015 because of headache for 2 weeks. After a week nausea and pain in the upper abdomen appeared. He experienced numbness of the fingers and balance disturbance. He was admitted to the Department of Neuroinfections with suspicion of tick-borne encephalitis, as he was bitten by tick. On admission patient complained of headache, vertigo, numbness of the fingers, and nausea. Physical examination revealed neck stiffness, positive Romberg test, positive Kernig symptom, impaired sensation in the left upper limb, hushed murmur of prolonged exhalation, and a sign after tick bite on the left popliteal area. Cerebrospinal fluid was xantochromic and clear, protein 162.5 mg/dL (15-60), albumin 145.6 mg/dL (10-30), and cytosis 44 cells/muL (0-5), with predominance of lymphocytes: 79% (40-80). Based on anamnesis, clinical picture, and CSF results lymphocytic meningitis was diagnosed. After two days of treatment (mannitol, painkillers) the patient's condition deteriorated with the appearance of balance disturbances. Head CT revealed in the parietooccipital part of the right hemisphere of the brain heterogeneous lesions, mostly marginal contrast enhancement (50 x 40 x 40 mm) with large mass effect, a vast zone of grade III edema, covering the structures of the right hemisphere and displacing the middle cerebral structures towards the left (11 mm). A similar minor (13 mm) lesion was present in the left frontal lobe with a small area of swelling and in the subtentorial area, in the left cerebellar hemisphere (16 mm). These lesions suggested metastates (Figure 1). In chest X-ray widening knobby outline of the right recess was found. Chest CT showed lesion (29 x 22 mm) in the upper lobe of the right lung. In the upper fields of both lungs there were nodulo-linear opacities with small calcifications. In segment 6 of the left lung irregular linear and patchy opacity merging with linear pleural shadings were present. There were nodular densities of 7 mm diameter in the right lung. In the mediastinum there were small lymph nodes (max. 7 mm), in the right hilum (12 x 9 mm and 11 x 6 mm). The histopathological examination allowed the final diagnosis: small-cell lung cancer. Man, aged 57, farmer, smoker, and previously healthy, referred to the GP in February 2015 due to left upper limb pain, most severe in the elbow, persistent since January. He could not deny the injury (perhaps at work on the farm). Neither swelling nor redness were found. He received Profenidum 2 x 100 mg for 1 week with slight improvement. He was referred to the Department of Neurology with the diagnosis of neuropathy of the ulnar nerve. The clinical picture suggested neuroborreliosis (radicular syndrome), as the patient was the resident of endemic area for tick-borne diseases and was exposed to tick bite. During the following days numbness of fingers of the left upper limb appeared. The straightening of the upper limb at the elbow was not feasible due to the severe pain. X-ray of elbow joints and bones of the forearm revealed osteolytic lesions. Brain CT presented cyst (28 mm x 40 mm), with inhomogeneous marginal contrast enhancement in the right occipital lobe with the vast area of hypodension in the parietooccipital region of the lobe, the area of similar nature (36 mm x 27 mm) in the right hemisphere of the cerebellum with hypodense zone of edema, metastases. Hyperdense area (11 mm x 7 mm) in the midline at the base of frontal lobes, with heterogeneous contrast enhancement suggested meningioma. Midline brain structures were displaced by 9 mm to the left side, the right lateral ventricle and the fourth ventricle were narrow, and left lateral ventricle was extended. The grooves of the right hemisphere were oppressed and had edematic characteristics. Features of intussusceptions were observed. Chest X-ray showed nodular shade in the upper right lung. On admission to the Department of Lung Diseases and Tuberculosis patient complained of pain and weakness of left upper limb. Chest CT showed enlarged lymph nodes in the mediastinum. In the top of the right lung heterogeneous mass of irregular lumpy shape with uneven margins and calcifications linked to the upper pole of the right lung cavity was observed. The distal section of the artery was caught into the upper lobe of the right lung (tumor mass). The right main bronchus was modeled by the lymph nodes. In segment 3 in the front of the right lung there was a lumpy mass with smooth contours (26 x 19 mm), and in segment 6 parahiliar nodular lesion (14 x 13 mm) there was suspicion of metastases. In the left adrenal gland metastases were stated. Bronchofiberoscopy showed no abnormalities. Chronic inflammation was diagnosed. Ultrasonography of the abdomen showed metastases in liver. After cytology examination the final diagnosis of low-differentiated cancer, probably squamous, was established.

PMC8378835_01

Male

The patient was a 55-year-old man current smoker. He underwent a left pneumonectomy with lymph node resection in 2007 for a huge tumor of the left lower lobe. The pathological examination found a typical carcinoid tumor of 8 cm long axis of the left lower lobe with minimal infiltration of the upper lobe, pulmonary and lymph node caseo-follicular tuberculosis. Hilar and mediastinal lymph node examination had shown no metastasis. A histological diagnosis of bronchial carcinoid tumor was made. No adjuvant chemotherapy was undergone. Pulmonary tuberculosis was treated using a six-months-lasting oral quadritherapy including Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol. Clinical and radiological follow-up for ten years had shown no recurrence sign. The patient presented in 2019 an intense lumbar squeezing pain progressively worsened, not relieved after using Paracetamol or Ibuprofen. Our patient noted also crural electrical discharges when he walked. On examination, there were new obvious signs detected on sight: protruding lower jaw and brow, an enlarged nose, thickened lips, coarse fingers and toes (Fig. 1). Acromegaly was recognized and we suspected a paraneoplastic mechanism. We detected on examination also, the presence of a left paravertebral swelling at the level of T 12, quite painful on palpation. A whole-body scanner was requested. It has shown a left pneumonectomy with a free right bronchial stump, diffuse dense right pulmonary nodules of different sizes. The largest nodule sits at the ventral segment of the right upper lobe and measures 13mm. We spotted multiple osseous lesions concerning the posterior arch of the 12th left rib with extension to the soft parts, the right side of the third lumbar vertebra, and into the medullary canal (Fig. 2). CT scan had shown also multiple hypodense liver nodules, the greatest of which sized 21 mm in diameter, osteocondensing lesions of the skull, which sit at the frontal bone and the left parietal bone. A biopsy of the hepatic nodule by echo-guided route was performed, concluding with a secondary localization of a typical carcinoid tumor (Fig. 3). Oral route morphine was prescribed to get sufficient spinal analgesia. Palliative chemotherapy based on Cisplatin and Etoposide was started. After having received four cycles of chemotherapy, a body CT scan compared to the first imaging findings concluded to stability of the tumor volume. There was no regression of the paraneoplastic signs after chemotherapy. The patient is alive nowadays after a follow-up of 14 months.

acromegaly, carcinoid tumor, paraneoplastic syndrome, recurrence

PMC5012831_01

Male

A 22-year-old male patient who was a farmer had a brief-history of waist pain and chest wall mass and the patient was suggested to undergo anti-tuberculosis therapy, which not subsided after a standard 4 week therapy of anti-tuberculosis. He complained of waist pain during the treatment and chest wall mass did not change, for which he was given pain killers and was advised rest. The pain disappeared after the use of pain-killer pills (500mg), but they did not gave total relief. Doctors advised two CT's scan (Computed Tomography Scan) of Chest and Spine and a MRI of Spine. CT's were clear. CT scan of chest shows the right chest wall mass with abscess formation and calcified shadow (Figure 1). CT scan of rib, not done to rule out bone destruction, was maybe abnormal and CT scan of sacroiliac joint shows obvious bone destruction and the huge abscess (Figure 2). Nevertheless, the CT features of lumbar vertebral bone destruction in L4 and L5 is the most impressive and the CT images of the patient are special and not typical, which look like a halo sign (Figure 3 (A,B)). It is very rare CT features of spinal tuberculosis infection, Moreover, CT features of spinal tuberculosis is changing after anti-tuberculosis treatment for more than 1 years later. Another CT Scan done at 15 months revealed the changes of spinal bone destruction in L4 and L5 (Figure 4 (A,B)). It may be related to the patient's own immunity and we need to search the specific reason. MRI of spine shows areas of bone destruction in T1, T4, T5, T10 and T12 vertebral bodies and it looks like a round of bone destruction (Figure 5). It is a difference compared with typical MRI findings of spinal tuberculosis and it is impressive. The patient, who was infected with tuberculosis for multiple organs, was diagnosed as spinal tuberculosis combined with sacroiliac joint tuberculosis, pulmonary tuberculosis, chest wall tuberculosis and tuberculous pleurisy and he needed surgical treatment. Surgery was undertaken when the ESR (erythrocyte sedimentation rate) decreased and after the preoperative examination without surgical contraindications and diagnosis was confirmed by pathology after the surgery. He was advised complete bed rest and was given a lumbosacral brace to be worn and spinal movements were restricted. Multi-vitamin injections were given and a high protein diet was recommended after the operation. Anti-tuberculosis treatment of the patient has been carried out so far after the surgery. Furthermore, the patient with waist pain has disappeared and the body weight increased significantly 1 year later. There was a weight gain of 8 kgs and there were no complications.

spinal tuberculosis, case report, imaging

PMC4995393_01

Male

A 26-year-old man with a history of long standing smoked hashish, inhaled ketamine and lysergic acid diethylamide use was admitted to the emergency department with 5-days of uncontrolled, large amplitude movements of left hemibody and fronto-temporal headache and photophobia in the last 12 days. On arrival, Glasgow coma scale was 8, he was afebrile; arterial pressure of 84/55 mmHg, with a normal capillary blood glucose level. Chest auscultation revealed rhonchi bilaterally. The patient had whitish lesions on the oral mucosa and on neurological examination he avoided eye contact, he had isocoric and symmetric pupils, without abnormal eye movement; fundoscopy revealed no papilledema, the speech was disorganized and he had ballistic movements of left hemibody, more severe in the upper limb. Serum analysis showed hemoglobin 9.2 g/dL, normal white blood cell count, C-reactive protein and renal function, Lactic acid dehydrogenase was 798 U/L. The electroencephalogram was not conclusive due to the lack of conditions to perform a correct test. The HIV serology and confirmatory test were positive and other serologic exams showed: HBV immune, HCV negative, Toxoplasma IgG positive, EBV IgG positive, IgM negative, CMV and HSV 1/2 IgG/IgM negative and negative tests for syphilis. The first cranial CT (computed tomography) revealed a: slight hypodensity at lower left cerebellar hemisphere, with small dots among it - calcifications/petechial hemorrhages. Based on these results, anti-toxoplasmosis therapy (pyrimethamine 75 mg/day plus clindamycin 600 mg every 6 h and folinic acid 25 mg/day) and high doses of antiepileptics and neuroleptics were initiated. Twelve hours later he was transferred to the intensive care unit. Successive brain MRI showed: lesions at lower left and right cerebellar hemisphere with adjacent parenchymal changes, one of them thalamus-mesencephalic with extension to the internal capsule, another one frontobasal, suggesting toxoplasmosis [Fig. 1, Fig. 2]. A lumbar puncture was performed and cerebrospinal fluid (CSF) analysis showed: 5000 WBCs/muL (3150 neutrophils/muL, 1100 lymphocytes/muL), protein 232 mg/dL, Glucose 28 mg/dL, ADA 12.0 IU, HIV-RNA 1188 copies/mL; India ink test was negative; Cryptococcus antigen, V.D.R.L/FTA-abs, CSF culture and polymerase chain reaction (PCR) for Toxoplasma, HSV, CMV, VZV, JC virus, EBV, Enterovirus and Mycobacterium tuberculosis were all negative. Serum HIV viral load was 1337147 copies/mL, cd4 40/mm3 and ART: tenofovir/emtricitabine 245/200 mg plus raltegravir 400 mg was initiated. Despite anti-toxoplasmosis, ART, antimicrobials and anti-epileptics, in the 24th day of hospitalization involuntary movements remained and a stereotaxic cerebellar biopsy was performed [Fig. 3]. The histologic result raised the hypothesis of Whipple's disease; however the upper endoscopy didn't show erythema and duodenum biopsy did not reveal PAS material. After one month of admission, another CSF was performed and the PCR for Tropheryma whipplei was negative and positive for M. tuberculosis with an undetermined Quantiferon test. Culture of bronchial aspirates didn't isolate M. tuberculosis, but anti-tuberculosis treatment with isoniazid 300 mg/day, rifampin 600 mg/day, pyrazinamide 1500 mg/day and ethambutol 1200 mg/day was started. The patient kept uncontrolled and refractory movements despite medical treatment, therefore stereotactic right pallidotomies were performed in the day 46 and 69 of hospitalization. During almost 12 weeks at intensive care unit, anti-epileptics were titrated, sedation reduced, while ballistic movements were progressively disappearing. The patient was referred for immunodeficiency consultation after 5 months of hospitalization and has been under anti retroviral therapy, after 12 months of anti-tuberculosis and almost one year of neurotoxoplasmosis maintenance treatment. In the last control he had cd4 count of 436/mm3 and undetectable viral load with a decrease in the left globus pallidus lesion and a right globus pallidus scar [Fig. 4], with no more choreiform movements, just a thin tremor on left hand.

hiv, hemiballismus, pallidotomy

PMC5359457_01

Female

A 32-year-old Asian woman received a successful two-antigen mismatched deceased donor renal transplant. She underwent Alemtuzumab and Methylprednisone induction. The immediate posttransplant course was uncomplicated. She was discharged with a nadir serum creatinine of 0.9 mg/dL. Immunosuppression consisted of Mycophenolic acid delayed release (MMF) 720 mg twice daily and Tacrolimus therapy (target trough 9-12 ng/mL). Three months after transplant the patient developed elevated liver enzymes associated with fever of 102 F. Initial blood cultures, CMV, parvovirus B-19 and EBV by quantitative polymerase chain reaction were negative. Computed tomographic imaging studies (CT) revealed periaortic lymphadenopathy (Figure 1). Liver biopsy revealed noncaseating granulomas and no evidence of posttransplant lymphoproliferative disorder (Figure 2(a)). Para-aortic lymph node biopsy revealed acid fast bacilli which were confirmed to be Mycobacterium tuberculosis (MTB) by nucleic acid amplification test and culture (Figure 2(b)). Review of pretransplant records revealed that the patient developed a 5 mm induration on tuberculin skin testing. Based on a history of prior administration of the BCG vaccine and a completely normal radiograph of the chest, the decision to forego Isoniazid prophylaxis against latent TB was made. Treatment was begun with Isoniazid 300 mg daily, Rifampin 450 mg daily, Ethambutol 800 mg daily, and Pyrazinamide 1000 mg daily. Her immunosuppression was reduced to maintain target Tacrolimus trough levels of 6 ng/mL and MMF was decreased to 180 mg twice daily. Resolution of symptoms occurred after initiation of therapy and reduction of immunosuppression. Five months after initiation of therapy the patient developed fever, weight loss, back pain, and weakness. CT scan demonstrated multiple lobulated peripherally enhancing fluid collections within the iliopsoas muscles as well as within the left hepatic lobe, most suggestive of abscesses (Figure 3). Empirical intravenous Ampicillin/Sulbactam was initiated at 3.1 grams every 8 hours. She underwent drainage of fluid collections, and gram stain, and cultures were obtained. Gram stain and acid fast stain of fluid revealed multiple neutrophils and no organisms. Fluid cultures revealed no growth of bacteria or MTB. The diagnosis of IRIS was established, corticosteroids were not administered, and the patient was maintained on two-drug anti-TB therapy consisting of Rifampin and Isoniazid. During the course of therapy, she was rehospitalized for fever of unknown origin. Fever, abdominal pain, and fullness slowly resolved over the course of therapy. Repeat CT imaging of the abdomen revealed resolving iliopsoas fluid collections (Figure 4). After 4 months of 4-drug regimen, the patient was continued on Rifampin and Isoniazid. The patient finished one year of antituberculosis therapy and has remained symptom-free with a functioning allograft. This patient received lymphocyte depleting induction with Alemtuzumab and her immunosuppression was reduced after the diagnosis of active TB. As IRIS may occur in the setting of treatment for TB and immune reconstitution, the time course of her illness and her total lymphocyte count are displayed (Figure 5).

PMC7254980_01

Female

A 10-year-old girl referred to our clinic with a six-year history of chronic watery diarrhea and unresponsiveness to a gluten free diet. She had been evaluated and treated previously for chronic diarrhea, intermittent fever, recurrent pneumonia, candida esophagitis, pancytopenia, hypoalbuminemia, hypolipidemia, vitamin B12 and folic acid deficiencies. She was diagnosed with CD, based on serologic and histopathological findings. She was placed on a strict gluten free diet for a year, but diarrhea did not improve. She has two healthy brothers. Her parents were consanguineous. On physical examination, she was cachectic; with height for age below 3 % (height SDS -5.18) and weight for age below 3 % (weight SDS -5.27). Bone age and height age of the patient were 6 years, 10 months and 5 years, 3 months, respectively. She had protuberant abdomen and clubbing. Liver and spleen were palpable at 1 cm and 4 cm below the costal margins. Laboratory tests revealed mildly increased liver transaminases. Hemoglobin was 8.32 g/dl; MCV, 85 fL; RDW, 23.4 %; white blood cell, 5570/mm3; platelet, 230,000/mm3; reticulocyte count, 1 % and ferritin, 2.8 ng/ml. Coombs test was negative. Sedimentation rate was 18 mm/h, C-reactive protein, 1.78 mg/dl. Stool examinations were normal. 25-hydroxi vitamin D level was 25.7 ng/ml. Insulin like growth factor 1 (IGF-1) was 3.5 ng/mL (Normal, 108-648 ng/mL) and insulin like growth factor binding protein (IGFBP-3), 580 ng/mL (Normal, 2690-7200 ng/mL). Stimulated IGF-1 and IGFBP-3 were 2.85 ng/mL and 720 ng/mL, respectively, both markedly reduced. Basal and stimulated growth hormone levels were compatible with growth hormone insensitivity (12.9 ng/mL and 9.79 ng/mL, respectively). Anti-tissue transglutaminase IgA was positive with a titer of 200 IU/ml. Thyroid auto-antibodies, anti-saccharomyces cerevicea antibody and pANCA were negative. Bone mineral density showed severe osteoporosis (Z score, -5). Chest X-ray showed reticular density in the parenchyma of the lung. High-resolution chest tomography showed bilateral tubular bronchiectasis. Smear staining for acid resistant bacteria and tuberculosis PCR, and culture were negative. Upper gastrointestinal endoscopic examination revealed scalloping in the duodenal mucosa. Colonoscopy showed nonspecific nodularity in the colon mucosa. Histopathological examination of duodenum revealed total villous atrophy, crypt hyperplasia and intraepithelial lymphocytosis. Biopsies of the other parts of the gastrointestinal tract demonstrated mild reflux esophagitis, chronic active gastritis and focal cryptitis in the colon. She suffered from sepsis, disseminated intravascular coagulation, severe dehydration, metabolic acidosis, severe electrolyte imbalance and renal tubulopathy. Her clinical findings were improved by antibiotherapy and intravenous fluid therapy. Oral prednisone was started with the diagnosis of refractory CD, but she was not responsive. Immunologic investigation was undertaken for primary immunodeficiency disease because of her chronic diarrhea, celiac antibody positivity, celiac-like mucosal findings, recurrent pulmonary infections with bronchiectasis, severe sepsis and severe growth retardation. Immunological evaluation revealed normal IgG, elevated IgA and slightly decreased IgM levels with normal isohemagglutinin titer, normal T, B, NK cell counts and normal activation response to PHA and anti-CD3 (Tables 1 and 2 in supplementary data). She has slightly decreased switched memory B cells. In light of the clinical and biochemical findings, initial genetic studies focused on sequencing the gene for STAT5B, which proved to be wild type. A novel homozygous frameshift mutation in the LRBA-gene c.5505delT (p.Ile1836*) was highlighted as the causal variant in whole exome sequencing analysis (Fig. 1). Sanger sequencing confirmed this variant to be homozygous in the patient and absent in the unaffected brother (Family Studies and Gene Analysis in Supplementary data). As she has HLA fully matched healthy sibling donor and multiple organ dysfunction (bronchiectasis, tubulopathy and severe colitis), a novel non-myeloablative conditioning regimen consisting of BU/Flu/ATG, was applied. She received 8 x 106 peripheral blood CD34+cells/kg from her brother. CsA (-1) and methotrexate (+1,+3, +6) was used for GvHD prophylaxis. The early post-transplantation period was uncomplicated and she was discharged at +37. She has herpes zoster at +5 mo. treated with acyclovir. She is now 1 year post-transplant, with 97 % donor chimerism. Her health improved markedly, with an increased growth velocity (15 kg/ year and 10 cm/year) following the HSCT.

PMC6387725_01

Female

The proband is a 39-year-old South Asian female of Indian origin who was diagnosed with systemic amyloidosis of unknown type when she was 16 years of age. At the time of diagnosis, she was pregnant and was experiencing gastrointestinal symptoms of abdominal bloating, dyspepsia, heartburn, and nausea. These symptoms persisted postpartum, and the patient underwent an upper endoscopy with biopsy, which was consistent with the presence of amyloid material; however, the type could not be determined. Thereafter, the patient continued to live a fairly normal life and did not seek any further medical attention until her daughter who when turned 16 started experiencing similar symptoms and underwent an upper endoscopy with biopsy results consistent with the presence of amyloid. At that time, the family sought medical attention at our institute. The proband reported that, in spite of an overall normal life, she had continued to experience dyspeptic symptoms that worsened with stress. She also reported around 12-15 episodes of hematemesis since her initial diagnosis. Additional symptoms on close questioning included easy bruisability, periorbital purpura, and ecchymosis associated with activities such as retching and vomiting. An upper endoscopy was performed at the Mayo Clinic. No morphological abnormality was seen on the endoscopy; however, Congo red stain demonstrated the presence of amyloid material in the gastroesophageal junction, stomach, and duodenum. Serum and urine protein electrophoresis were normal. Proteomic assessment with laser capture mass spectrometry (LCMS) evaluation of the congophilic material detected an amino acid sequence abnormality in the lysozyme protein (I56T). Peripheral blood genotyping confirmed I56T mutation (DNA change c.221T > C) in exon 2 of the lysozyme gene, which replacing isoleucine with threonine at position 56. I56T mutation per human genome variation society (HGVS) nomenclature is now known as I74T. Patient's renal and hepatic functions were normal, and she did not have any adenopathy. Besides iron deficiency and mildly delayed gastric emptying, no other abnormality was noted. The patient continues with yearly follow-up in our amyloidosis clinic with periodic exacerbations of dyspeptic symptoms and a few episodes of small-volume hematemesis, which have responded to high-dose acid suppressive treatment. Proband's daughter at 16 year of age started experiencing anxiety and upper abdominal pain along with dyspeptic symptoms, which lead to an upper GI tract endoscopy and biopsy confirming I56T mutant Alys via LCMS. Her most significant symptoms were indigestion, anorexia, altered bowel habits, and easy bruisability. She was also noted to have moderate iron deficiency anemia secondary to heavy menstruation. Her symptoms subsequently improved with change in dietary habits. At the time of most recent evaluation, which was a year ago, the patient has been doing relatively well with the exception of intermittent nausea and abdominal bloating.

PMC3415050_01

Male

A 52 year old male patient was referred to our institute as a massive tumor of right thigh (Figure 1) for further management. There was no history of fever or loss of appetite; however history for night sweats and weight loss and low back pain was positive. He denied any history of cough, shortness of breath, hemoptysis or history of contact with a tuberculous patient or relative. There were no other medical illnesses. Physical examination revealed normal vital signs. The right thigh was massively swollen and was non tender and was not associated with any inflammation. The patient looked ill and underweight, but there was no lymph node enlargement or clubbing. Chest and cardiovascular examination was unremarkable. Abdominal examination revealed soft, non-tender abdomen and no organomegaly. Palpation of lumbar spine revealed tenderness (Figure 1). Laboratory investigations revealed normal full blood count, liver enzymes, electrolytes, urea and creatinine. ESR was 85 and HIV serology was negative. X-rays of the chest, pelvis and thigh was normal. X-rays of the lumbar spine (Figure 2) revealed decreased disc space between L1 and L2 vertebra along with collapse of L2. Magnetic resonance imaging of thigh (Figure 3) revealed large well encapsulated abscess in the back of thigh extending upto popliteal fossa, in continuation with ilio-psoas abscess (Figure 2 and Figure 3). The abscess was aspirated under ultrasound guidance. Ziehl- Neelsen stain of the aspirate was positive for acid-fast bacilli. Culture of the aspirate revealed Mycobacterium tuberculosis resistant to isoniazid, and rifampicin, but sensitive to ethambutol, pyrazinamide, streptomycin, capreomycin, ofloxacin and amikacin. He was started on pyrazinamide, ethambutol, streptomycin, ofloxacin and amikacin. Isoniazid and rifampicin were discontinued. The abscess was then drained under ultrasound guidance and 650 ml of purulent fluid was obtained. Streptomycin was locally instilled and the drain was kept in place for seven days. A period of 18 months of therapy was completed. At the end of the treatment course, the swelling resolved completely, the patient improved clinically, gained weight and was walking normally.

tuberculosis, pseudo-tumor, thigh

PMC6131835_01

Female

Baby A was born at term by caesarean section due to fetal distress. Her birthweight was 3.1 kg, length (L) 45 cm, head circumference (HC) 36 cm. The mother was HIV positive. Baby A was abandoned at six weeks, with a bag of clothing and a tin of infant formula and her birth record. Unable to trace the mother, she was placed in care and arrived at ITL on 21 September 2006 when she was eight months old. She weighed 8.18 kg, was HIV positive, Mantoux positive and negative for syphilis. Her eczema was severe, as is commonly associated with HIV positive children. She was started on DHM immediately. She was placed on treatment for tuberculosis from October 2006 until May 2007. In June 2007, her CD4 count was 18 and she was started on ARV. She had a severe dose of chicken pox and mumps at two years of age, but other than that had no repeated infections commonly associated with HIV positive children. Her milestones were appropriate for her age. She continued to receive DHM until she was three years old. The decisions were made to continue for a longer period than normal as whenever the DHM was stopped, her eczema was exacerbated. She was a happy, confident, intelligent little girl who enjoyed good health despite her medical status and ongoing treatment. She was adopted in July 2011 aged five years (Fig. 1).

breastfeeding, case series, donor human milk, failure to thrive, fullterm infants, hiv

PMC6131835_02

Female

Baby B was born weighing 2.5 kg. His mother and grandmother had full blown AIDS and he was diagnosed with HIV at birth. He was found in his home neglected, as his mother was too ill to care for him and she signed him over for adoption. He arrived at ITL at 2.5 months, weighing just 3.1 kg. He was suffering from malnutrition, tuberculosis, respiratory distress and was HIV positive. In addition, he had scabies and severe eczema. DHM was started upon arrival. A month later, at 3.5 months, he began treatment for TB. Apart from drainage of a few skin abscesses at four months of age, his general condition improved on the DHM, as did his eczema and he thrived and attained all his milestones appropriately. He remained on the DHM until he was 14 months old. At the age of 21 months he was started on ARVs which increased his CD 4 count from 13 to 30% in a six month period and was adopted at this time.

breastfeeding, case series, donor human milk, failure to thrive, fullterm infants, hiv

PMC4564422_01

Male

We report a case of a 30-year-old man who presented electively in our clinic with a history of intermittent high grade fever and right lower quadrant non-radiating abdominal pain for 1 year + 6 months duration, for which he consulted and treated in 5 different health facilities with no favourable evolution. On review of his systems; presence of non-productive cough, intermittent night sweat, loss of appetite, nausea but neither vomiting nor altered bowel habit. His past history is remarkable for appendicectomy 10 months ago after he consulted for similar complaints. Also, there is a history of contact with relative diagnose with pulmonary Tuberculosis (TB) 2 years ago. On examination; our patient was normotensive (BP=110\70mmHg) febrile to touch (Temp=38 c), lost 10% body weight within 6 months, ill-looking, asthenic with moderately pink conjunctivae and anicteric sclera. Head and neck exam revealed palpable submental, right and left anterior and posterior superficial cervical lymph nodes and right and left axillary lymph nodes. Nodes were mobile, non-tender with the left cervical node having the largest diameter of 4cm. Presence of fine inspiratory crackles on chest examination. Abdominal examination revealed grid-iron incision mark and mild tenderness around the right lower abdominal quadrant. A working diagnosis of Mesenteric adenitis + Lymph node Tuberculosis was made. A Full Blood Count (microcytic hypochromic anaemia with Hb=11g\dl, lymphocytosis), Chest X-Ray (showed parahila nodes), normal abdominal ultrasound, lymph node biopsy and histopathology (showed granulomas with langham giant cells and central caseation). Patient was then placed on a 6 month Anti-TB regiment under Direct Observational Therapy. Two weeks after onset of treatment evolution was favourable with normal body temperature and gain of appetite. Three months later, patient gained 4kg body weight, no palpable submental and axillary lymph node; there is mark reduction in size of cervical lymph nodes. Patient is fine now, has no complaint and has resume work.

history taking, diagnosis, lymph node, physical examination, resource-limited settings

PMC7585809_01

Female

A 31-year-old previously healthy female presented with 4 days of bilateral numbness that started distally in her feet and hands simultaneously then involved her whole four extremities and the front and back of her trunk. She also lost her balance over the same period, first becoming unable to walk then unable to sit without falling to either side. She also reported difficulty reaching for objects. She denied having double vision, slurring of speech, facial numbness or droop, tremors, limb weakness, abdominal distention, sphincteric problems, or dryness of the mouth or eyes. There was no weight loss, and no joint stiffness, swelling or pain. Family history was unremarkable. She had developed a generalized skin rash that started 10 days prior to the onset of her neurological symptoms, which was diagnosed as a primary Chickenpox infection by a dermatologist who prescribed oral acyclovir. Neurological examination demonstrated normal higher mental functions and intact cranial nerves, with no nystagmus, ptosis, or limitation of eye movements. Muscle strength was 5/5 throughout. Sensory examination was remarkable for severe impairment in joint position and vibration sensation in both upper limbs to the elbows and lower limbs to the knees. Pain and temperature sensation were symmetrically impaired over both upper and lower limbs and the trunk, but the impairment was more pronounced over the anterior trunk than the back. There was no sensory level. Reflexes were absent all over. Babinski's sign was negative bilaterally. Coordination revealed impaired finger to nose and heel to shin, with significant exacerbation by eye closure. She could not maintain a sitting position due to severe truncal ataxia and demonstrated pseudo-athetoid movements in the hands. Dysautonomic signs such as blood pressure and pulse fluctuations were absent, and there was no ileus. Initial basic labs were normal. Lumbar puncture revealed CSF protein 61.1 mg/dl (reference range 15-45 mg/dl), with normal CSF white cell count (3 cells). CSF cultures and viral PCRs were negative, including HSV I and II, Mycobacterium tuberculosis (M. tb), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and enterovirus PCRs. CSF VZV PCR was unavailable. Brain MRI with and without contrast was normal. Whole spine MRI with contrast demonstrated enhancement in multiple thoracic and lumbar nerve roots (Figure 1). NCS performed on the fifth day of admission (Table 1) showed absent sensory responses in her four extremities, with normal motor responses and F-waves. Initial electromyography "EMG" using concentric needle was normal (Table 2). Serum VZV IgM was elevated (18.9). HIV screen was negative. Serum B12, folate, thyroid, zinc, vitamin E, and Creatine Kinase "CK" were within normal limits. Serum protein electrophoresis and immunofixation electrophoresis were negative. A paraneoplastic panel, including Hu, Yo, Amphiphysin, Ri, CV2, and Ma2/Ta antibodies, was negative. A comprehensive autoimmune panel was also negative. Ganglioside antibody screen also was negative. CT scan of the chest, abdomen and pelvis did not reveal any malignancy. Symptoms peaked two weeks from onset. A diagnosis of sensory GBS was made based on clinical presentation, supportive investigations, and the exclusion of alternative diagnoses. The patient received intravenous immunoglobulin "IVIG" 0.4 gm/kg daily for five days. At discharge, she had a GBS disability score of 4 (bedridden or chair bound). On follow up six weeks later she reported improvement in numbness and unsteadiness. She could stand unsupported with her eyes open but fell if they were closed and could not walk independently. On examination, her dysmetria showed improvement but was still worsened with eye closure. Improvement was noted in all sensory modalities and the pseudo-athetoid movements. Repeat NCS was similar (Table 1). EMG was remarkable for minimal denervation activity in the right anterior tibialis, gastrocnemius, and lower lumbar paraspinal muscles (Table 2). Clinical examination six months after admission demonstrated significant improvement in pinprick and temperature sensation, and proprioception impairment was limited to fingers and toes. She walked independently. Dysmetria was mild but still exacerbated with eye closure. Trace deep tendon reflexes reemerged. She had a GBS disability score of two (able to walk 10 meters or more without assistance but unable to run). Further improvement was evident at her eight-month follow up. EMG studies performed at months six and eight demonstrated persistence of minimal denervation in several upper and lower extremity muscles (Table 2).

guillain-barre syndrome, acute inflammatory polyradiculoneuropathy, intravenous immunoglobulins, neurophysiology

PMC3634207_01

Female

A 24-year-old Tanzanian woman, primigravida at the gestational age of 26 weeks, was referred from another nearby facility with a one-month history of persistent abdominal pain associated with long standing recurrent vaginal bleeding during the antenatal period. She had been admitted repeatedly at a local community hospital due to abdominal pain. She denied any history that would suggest previous pelvic inflammatory disease, intrauterine contraceptive device use or pelvic surgery. During her last admission, abruptio placenta was suspected, and the patient was unsuccessfully induced twice with oxytocin without knowing the status of the fetuses. She was subsequently transferred to our hospital for further evaluation and treatment. On arrival, physical examination revealed a conscious woman in severe pain, pale, afebrile. Her abdominal examination was notable for distended abdomen consisted with uterine fundus of 30 cm, generalized tenderness was elicited on palpation and fetal heartbeats could not be detected by fetoscope. Vaginal examination revealed a closed, uneffaced, firm and posterior cervix, and the presenting part was not found. Transabdominal ultrasound revealed live intrauterine diamniotic-dichorionic twins, estimated gestational age was 26 weeks and there were enlarged cystic placentas suggestive of retro-placental clots. Laboratory investigation revealed hemoglobin level of 7.0g/dl, the blood group A, and Rhesus positive. The diagnosis of concealed abruptio placenta with live twin pregnancy was reached, and the patient was counseled and an emergency abdominal delivery was performed. At laparotomy, the findings were: A thickened peritoneum with area of hematoma resembling a cystic mass, and a normal-sized intact uterus separate from the pregnant sac which was engulfed by thickened omentum. Both fallopian tubes and ovaries were grossly normal. Live female twins were extracted from the gestational sacs. Two placentas were seen, one attached to the ceacum and ascending colon and the other firmly adhered to the posterior aspect of the omentum, the transverse and the sigmoid colon. The placenta attached to the ceacum and ascending colon developed profuse bleeding during the delivery of the babies, requiring ligation of placental blood vessels to control bleeding. Both placentas were left in situ with their umbilical cords cut to 2cm long. Estimated blood loss was 2000ml; the patient was subsequently transfused 4 units of whole blood. The first twin weighed 700 g and the other 800g, each with Apgar score of 5 at first minutes and 6 at fifth minute. Grossly, both fetuses had no congenital abnormalities and were admitted to the neonatal intensive care unit due to prematurity [Figure 1]. Unfortunately, both babies died within the first week of life. Postoperatively, the patient was covered with broad spectrum antibiotics and admitted to the intensive care unit. Three days later she developed septicemia which was successful treated with meropenem. The patient improved and was discharged on postoperative day 14, with plan for outpatient follow-up in one month. Fourteen days after discharge, the patient was readmitted with peritonitis which necessitated repeat laparotomy and attempt to remove the placentas provoked massive hemorrhage which was controlled by intra-abdominal packing and the patient was transfused with 3 units of blood. The abdominal packs were removed after 48 hours with no active bleeding from placental site. Eight days after removing the packing, the patient developed fascial dehiscence and was taken to operating room for exploration, where both placentas were easily detached without provoking bleeding. Her postoperative recovery thereafter was unremarkable, and she was discharged to attend outpatient clinic. After three visits of 11 months, she was discharged from the clinic in a good condition.

abdominal pregnancy, advanced, live, placenta, twin gestation

PMC4512596_01

Male

A 6-year-old male presented with his mother for evaluation of painful and bleeding gingiva. The patient's mother reported that the gingival changes began seven months ago and that the onset was not associated with any identifiable inciting events, including mechanical, thermal, and chemical trauma; dietary changes; use of new dental hygiene products; or exposure to cinnamon-containing products or foodstuffs. She also denied a history of fever, malaise, and GI symptoms. The patient had seen his pediatrician two weeks prior and undergone a complete blood count (CBC) and metabolic panel, which revealed no abnormalities. A thorough dental prophylaxis had also been performed one week prior with no significant improvement in the appearance of his gingiva. The patient's medical history was significant for asthma, for which he was using mometasone furoate inhaler once daily and albuterol sulfate inhaler on an as-needed basis. His mother stated that he took special care rinsing his mouth after use of the steroid inhaler as directed by his pediatrician. His review of systems and family history were otherwise unremarkable for cardiovascular, endocrinologic, GI, genitourinary, musculoskeletal, hematologic, and neurologic disorders. Intraoral examination revealed a very subtle area of mucosal erythema involving the gingiva buccal to the right primary maxillary molar, canine, and lateral incisor (Figure 1) and a more well-defined area of erythema involving the alveolar mucosa facial to the left primary maxillary central and lateral incisors and canine (Figure 2). Also noted were multiple mucosal-colored swellings and ulcerations of the gingiva facial to the right permanent mandibular central and lateral incisors and primary canine (Figure 3). Mild tenderness was elicited on gentle palpation of the affected sites. The remainder of the oral mucosal examination was within normal limits. No bone loss was evident on radiographic examination. As requested by the referring periodontist, biopsy of the affected mandibular gingiva was performed. Microscopic examination revealed curved portions of oral mucosa surfaced by spongiotic stratified squamous epithelium with evidence of mild inflammatory cell exocytosis; beneath the epithelium, there was a proliferation of fibrous connective tissue with a patchy infiltrate of lymphocytes and plasma cells (Figure 4(a)). In isolated areas, there were well-formed, noncaseating granulomas composed of epithelioid histiocytes and lymphocytes (Figure 4(b)). Periodic Acid-Schiff (PAS), Grocott-Gomori's methenamine silver (GMS), and Acid-Fast Bacilli (AFB) stains were performed to rule out deep fungal infections and mycobacterial infections such as tuberculosis and leprosy as causes of the granulomas. All stains were negative. Examination of the biopsy under both light and polarized light microscopy did not reveal foreign body material. Hence, a diagnosis of granulomatous inflammation was rendered with a comment pertaining to possible etiologies such as Crohn's disease, orofacial granulomatosis, and sarcoidosis. The patient was provided with a prescription for a mild topical steroid rinse and instructed to rinse and spit four times daily for 14 days. He was also referred to his pediatrician for additional evaluation to rule out for Crohn's disease and other systemic conditions associated with granulomatous inflammation, including sarcoidosis. The patient returned for follow-up three weeks later and demonstrated a modest reduction in the erythema of the maxillary gingiva and swelling of the mandibular gingiva. The patient's mother also reported less pain and bleeding during brushing. The patient was again advised to pursue diagnostic evaluation for systemic causes of granulomatous inflammation. Following evaluation by his pediatrician, he was referred to a pediatric gastroenterologist for consultation. The patient subsequently underwent endoscopic examination and biopsy which showed acute inflammation of the intestinal mucosa. A diagnosis of early Crohn's disease was made. The patient was placed on mesalamine, an anti-inflammatory aminosalicylate, and azathioprine, an immunosuppressant. At one-year follow-up by phone, the patient's mother reports that he continues to respond well to his medications. She states that his oral lesions have completely resolved and that he is currently free of intraoral and GI symptoms.

PMC6010665_01

Male

A 58 year old male presented to the emergency department after he was found on the floor of his apartment. The patient was unable to provide detailed history of the events, however, he was noted to have had several episodes of loose bowel movements. He denied any change in the stool color or blood in the diarrhea. There was no associated abdominal pain, nausea, vomiting, recent antibiotics use, fever, cough, chest pain or dyspnea. He was not hospitalized within the past year, moreover, he has never traveled outside the United States. He was diagnosed with Crohn's disease 40 years ago and had multiple bowel resections in the past; he is not on steroids. Currently he is being treated with Vedolizumab for the last 8 months, in addition, he was being treated with infliximab which was stopped prior to the initiation of Vedolizumab. Physical examination showed an emaciated patient, with vital signs as follows: blood pressure 78/50, heart rate 98, respiratory rate 22 & temperature 99 F, lung exam showed crackles over the right lung, abdominal and cardiovascular exam were unremarkable. Investigations were significant for elevated WBCs count to 20.9 (Neutrophils 96.1%, lymphocytes 0.8%, monocytes 2.3%, eosinophils 0%), and chest X ray with multiple opacities in the right lung field (Fig. 1); IgE level was 205, HIV was negative. Accordingly he was admitted to intensive care unit for management of septic shock caused by pneumonia, where he was started on Vancomycin, Aztreonam, Levofloxacin and vasopressors. The clinical picture didn't improve on the following days despite being on antibiotics; sputum and blood cultures were negative. Due to lack of improvement and paucity of microbiological data, patient had a CT of the chest which showed opacification within the entirety of the right lung with air bronchograms (Fig. 2). On the 4th day of admission the patient underwent a bronchoscopy that showed normal mucosa without lesions in the upper and lower airways. Bronchoalveolar lavage was obtained and cultures were negative for bacteria, tuberculosis & fungi. Bronchial washing cytology showed acute inflammation and filariform larvae (Fig. 3) and serology was positive for Strongyloides antibodies. He was started on ivermectin and his condition improved significantly and he was discharged in good condition.

CT chest showing Opacification within the entirety of the right lung with air bronchograms suggestive of a infectious process and Bilateral pleural effusion.

PMC9074690_01

Male

A 28-year-old man was brought to a local hospital in April 2021 because of the secondarily generalized epileptic-seizure, which presented itself with a sudden loss of consciousness, staring eyes, and stiffness of the limbs and convulsions. The various symptoms lasted for several minutes and terminated before reaching the hospital, and the patient was unable to recall the onset of this seizure. The patient had only one epileptic episode. The type of seizure was considered as focal impaired awareness with motor onset seizure. For the past one week, he suffered from headache and dizziness, but his medical history was unremarkable. Magnetic Resonance Imaging (MRI) of the brain showed significant hyperintensity of the cortical and subcortical of the left frontal lobe ( Figures 1A-C ). Thereafter, lumbar puncture was performed two days later, which revealed an increased intracranial pressure (250mmH2O), high protein levels (1.28 g/L) and increased accumulation of cells (610 white blood cells/mm3), but normal glucose and chloride levels. During hospitalization, the patient occasionally suffered with fever with a temperature of around 38.5 C. He was initially diagnosed with meningoencephalitis. Therefore, he was administered empirical intravenous (IV) anti-viral (acyclovir, 500mg/d, Q8h) and antibiotic (ceftriaxone sodium, 2000mg/d) therapy, and the above symptoms were gradually alleviated. After one week, the patient developed blurred vision in the right eye, which deteriorated markedly with binocular vision loss after 10 days and continued to worsen continuously over the following month. Repeated brain MRI showed enlarged lesion involving the left frontal, orbital gyrus and bilateral optic nerve with substantial contrast enhancement ( Figures 1D-F ). Hence, he was transferred to our tertiary care center for further diagnosis. Neurological examination revealed binocular vision loss with only light perception, and lateral visual field was impaired ( Supplementary Figures 2A, B ). Muscle weakness, sensory nervous system, cerebellar functions, Babinski sign and meningeal irritation signs were observed to be in the normal range. Electroencephalograph (EEG) revealed a small amount of scattered slow waves. Repeated lumbar puncture depicted lower white blood cell count (11 cells/mm3) and protein (0.51 g/L) level. Anti-HHV-7 IgM and IgG antibodies were detected in both the serum and cerebrospinal fluid (CSF). CSF testing for HHV-7 RNA by next generation sequencing (NGS) metagenomics and polymerase chain reaction (PCR) yielded positive result. All other CSF tests for the neurotropic viruses and other bacteria displayed negative results. Upon search for anti-neural antibodies (to anti-NMDAR, anti-LGI1, anti-CASPR2, anti-AMPAR, anti-GABABR, anti-DPPX, and anti-mGLuR5), NMDAR antibodies (1:10) were found positive in the patient's CSF by cell-based assay (CBA) (Euroimmun, Lubeck, Germany) ( Figure 2A ). We also used CBA (Euroimmun, Lubeck, Germany) to detect CNS demyelinating antibodies (AQP4, MOG, GFAP), MOG antibodies were found positive in CSF (1:32) ( Figure 2B ) and the serum (1:10) ( Figure 2C ), whereas both AQP4 antibody (not shown) and GFAP antibody ( Figure 2D ) were negative. Besides, we found a weak fluorescence response in the TBA detection, which indicated that the disease was immunological in nature ( Supplementary Figures 1A, B ). The various tests conducted for the paraneoplastic antibodies, rheumatological autoantibodies, blood routine examination, biochemistry, tumor markers, thyroid profile, mycobacteria, treponema pallidum, human cytomegalovirus, and viral serological were all found to be negative ( Supplementary Table 1 ). NGS metagenomics tests, TBA tests, and CBA tests for anti-neural antibodies and CNS demyelinating antibodies also were performed at the Center for Precision Medicine, West China Hospital, Sichuan University. Study methods are provided in the Supplementary Material .

hhv-7 infections, mog antibodies and nmdar encephalitis overlapping syndrome (mnos), anti-nmdar encephalitis, case report, optic neuritis

PMC5125985_01

Male

A 63-year-old Chinese male with COPD was admitted to our hospital in October 2013. He was presented with a 20-year history of chronic productive cough and progressive dyspnea. The patient was an ex-smoker (40 pack-years), had suffered from secondary tuberculosis before 30 years, and had been taking salmeterol/fluticasone propionate (50/500 mug) twice daily for 2 years. Pulmonary function tests administered on admission revealed severe irreversible airflow obstruction after bronchodilator inhalation (forced expiratory volume in one second [FEV1]/forced vital capacity [FVC] =46.9%; FEV1 =0.89 L, 28.9% of predicted value) and severe hyperinflation (residual volume [RV] =5.03 L, 222% of predicted value, total lung capacity [TLC] =7.92 L, 131% of predicted value). Additional tests revealed the following: 6-min walking distance (6MWD), 144 m; St George respiratory questionnaire (SGRQ) score, 64; and Modified Medical Research Council (MMRC) dyspnea score, 4. Analysis of the blood gases at pH 7.40 revealed the following: PaO2, 65.7 mmHg and PaCO2, 42.1 mmHg. High-resolution chest CT (HRCT) indicated heterogeneous emphysema with a marked predominance in the bilateral upper lobes and middle lobe (Figure 1A and B). The right oblique fissure was complete, and a peripheral minor defect was found on the horizontal fissure in the coronary and sagittal views; however, we calculated the integrity of horizontal fissure to be 91.6% and 91%, respectively (Figure 1C and D). We performed a purified protein derivative test, erythrocyte sedimentation rate analysis, contrast CT, sputum smears, and cytopathology. No evidence of lung cancer or active secondary tuberculosis was present. With the patient's informed consent for BLVR, we administered 0.5 mg atropine to minimize bronchial secretion and 50 mg pethidine to reduce the cough. We performed bronchoscopy using 20 mL lidocaine as a local anesthetic and measured the CV using the Chartis system. We blocked the right upper bronchus using a balloon catheter and measured the expiratory airflow. This assessment revealed sudden stops in expiratory flow during the three breathing maneuvers that were accompanied by sharp increases in resistance, which is a common characteristic of the low-flow phenotype (Figure 1E). It was difficult to confirm whether CV was present; therefore, we measured CV in the ipsilateral lobes. Assessment of the middle lobe revealed that CV was negative or CV was positive with on/offs in expiratory flow that occurred during deeper and lower breathing maneuvers, which were signs of mini-collaterals that were open only during deeper inspirations (Figure 1F). Assessment of the right lower lobe (RLL) revealed a good signal with a gradual downward trend without CV (Figure 1G). We implanted three EBVs (Zephyr EBV 4.0; Pulmonx) in the right upper bronchus for economic reasons. One month later, the patient exhibited limited improvements in lung function, 6MWD, and volume reduction of the RUL on HRCT (Figure 1H). We speculated that this lack of improvement might have been associated with latent CV between the RUL and RML that caused a minor leak in the horizontal fissure. Therefore, we decided to block the right middle bronchus using another EBV (Zephyr EBV 5.5). Two weeks later, quantitative analysis of the HRCT images (Lung CAD1.2; Neusoft, Shenyang, People's Republic of China) revealed that the volume of the right lung had decreased from 3,838 to 2,935 mL, the RUL and RML had begun to shrink, the right diaphragm had become elevated, and the mediastinum had shifted to the right side (Figure 1I and J). The patient exhibited significant clinical improvement. The FEV1 increased to 1.52 L (+0.63 L) and the 6MWD increased to 216 m (+72 m); in addition, the RV decreased to 4.21 L (-16.3%), the TLC decreased to 7.10 L (-10.4%), the SGRQ score decreased to 41, and the MMRC dyspnea score decreased to 2. The patient reported slight chest pain after the second EBV implantation, and HRCT revealed some pleural effusion, which was localized to the minor fissure and absorbed spontaneously.

copd, chartis assessment, bronchoscopic lung volume reduction, collateral ventilation, endobronchial valves

PMC3487145_01

Female

The patient, an 86-year-old woman with Alzheimer's dementia and hypertension, was chronically taking aspirin, amlodipine, and donepizil. She was admitted after an episode of hematochezia with orthostatic hypotension and a hemoglobin of 6.8 mg/dl. Her baseline hemoglobin 12 months prior had been 12.4 mg/dl. She received intravenous fluids and a total of five units of packed red blood cells for resuscitation. The aspirin and amlodipine were stopped. Nasogastric lavage of one liter produced neither blood nor bile. Hematochezia continued and she was transferred to the intensive care unit. She was started on continuous pantoprazole intravenous drip for possible upper gastrointestinal bleeding and prepared for upper and lower endoscopy with polyethylene glycol-electrolyte solution. The upper endoscopy showed multiple small (1-3 mm) antral erosions with no evidence of bleeding, and colonoscopy showed many diverticula scattered throughout the colon, but no blood was seen in the lumen or in the diverticula. No source of bleeding was identified. Her hematocrit stabilized with transfusions and conservative management. She was hospitalized for three days. She was discharged to a nursing home with a hemoglobin of 12.8 mg/dl and aspirin was restarted the day after discharge. The patient was re-admitted three days later (day 6) with recurrent hematochezia and a hemoglobin of 10.5 mg/dl. The aspirin was stopped. Enteroscopy, performed on day 7 after the initial bleeding event, was normal to 50 cm past the pylorus with no evidence of bleeding. Colonoscopy showed multiple diverticula, none specifically bleeding, but maroon blood throughout the colon and maroon blood pooling in the cecum. The terminal ileum was not examined. Continued hematochezia led to a tagged RBC scan which showed increased tracer activity throughout the colon, specifically the ascending, transverse, and descending colon on delayed images at 6 h. The actual site of bleeding was not identified. It was felt by interventional radiologists that angiography would not localize the bleeding site as the bleeding rate was too slow. Capsule endoscopy was performed to further assess the small intestine as the patient continued to pass red blood and clots from the rectum. It showed two 2 mm angiodysplastic lesions not actively bleeding at 43 and 81 min, a small mucosal break at 89 min, and a few small submucosal hemorrhagic lesions at 120 min, all of which were not actively bleeding. There was no fresh or old blood seen in the lumen. The capsule reached the cecum at 2 h and 6 min. Eight hours after the capsule endoscopy was completed, the patient had another episode of bright red blood per rectum. A third colonoscopy was performed after thorough polyethylene glycol preparation. It showed diverticulosis throughout the colon with trace amounts of old blood, but no bleeding site could be identified. Given persistent rectal bleed without evidence of blood in the small intestine or bleeding arteriovenous malformations on capsule endoscopy, we felt that the most likely source of bleeding was colonic diverticula. Our therapeutic options were limited since she was a poor surgical candidate given her age and dementia and since she had not been bleeding briskly enough on the tagged RBC scan for angiography to be helpful. Previous case reports have shown that therapeutic barium enema can successfully stop bleeding in patients diagnosed with presumptive diverticular bleed. For this reason, our patient was taken to the radiology suite for therapeutic high-density barium enema. 1,400 g of E-Z-HD barium sulfate (98% w/w, E-Z-EM, Westbury, N.Y., USA) were dissolved in 300 ml of tap water to prepare a final volume of 800 ml of 171.5% w/v suspension in water, and a Lafayette Aircon XL 3000 disposable air contrast enema kit (Mallinckrodt Inc., St. Louis, Mo., USA) was used to instill the high-density barium by gravity into the colon. Contrast was seen to reach the cecum, and numerous diverticula were noted scattered from the sigmoid colon to the cecum. The patient was asked to change position every 5 min by rolling 90 degrees to the next of four positions over a two-hour period, and at the end of the examination none of the barium could be expelled by the patient (fig. 1). No anti-motility agent such as glucagon was given prior to or during the procedure. Immediately after the procedure, normal saline at 175 ml/h was initiated. Eighteen hours after the procedure, treatment with polyethylene glycol 17 g mixed in 8 ounces of water p.o. bid and liberal oral fluids were added in an effort to clear the intraluminal barium and minimize any risk of colonic impaction. Ambulation was encouraged and the patient complied. She continued to pass large amounts of barium per rectum for 48 h and was able to tolerate clear liquids without any nausea, vomiting, or abdominal pain. She remained free of symptoms worrisome for obstruction, and daily abdominal films were obtained. The abdominal X-ray done 48 h after treatment showed barium remained in the diverticula throughout the colon but was largely cleared from the lumen proper (fig. 2). She remained hemodynamically stable without further evidence of bleeding. Her hematocrit remained stable. She was able to tolerate a regular diet and was discharged. Follow-up in the outpatient clinic two weeks later showed her to be doing well with no recurrence of hematochezia, and her hematocrit was stable at 12.1 mg/dl on day 16 (fig. 3). Follow-up blood counts on days 60, 76 and 120 showed no drop in hemoglobin, and the patient, the assisted living center staff, and the patient's children reported no further episodes of bleeding. Aspirin has been discontinued since she was discharged from the hospital.

anemia, diverticula, diverticular hemorrhage, hematochezia, lower gastrointestinal bleeding, therapeutic barium enema

PMC4739151_01

Male

A 58-year-old male with severe developmental delay, convulsive seizure disorder since the age of three, left hemiparesis, recurrent aspiration pneumonia, and urinary retention presented for evaluation of hypothermia. Over the preceding year, he had experienced nine hypothermic episodes, with temperatures ranging from 90 F-95 F (Fig. 1). The hypothermia was usually thought to be secondary to infection. Upon presentation, his temperature was 92 F at his group home and 95 F in the office. The patient, who was noncommunicative at baseline, was hospitalized and on examination appeared awake with no distress, calmly sitting in his wheelchair. He is normally hyperactive, but his caregivers noticed he would become listless during his hypothermic episodes. His blood pressure was 138/74 mmHg, pulse was 59 beats per minute, and oxygen saturation was 96%. The patient's lungs were clear to auscultation, and his heartbeat had a normal rate and rhythm, with no murmurs. He had full visual fields, intact extraocular movements, no nystagmus, pupils equal and reactive to light, and a midline tongue. He also had a left facial droop, increased spastic tone in the left arm and leg, and intact reflexes, but sensation and strength could not be tested. Bair Hugger therapy, a forced air warming blanket, successfully raised the patient's temperature to 97 F, which was maintained after it was removed. Empiric cephalexin and ciprofloxacin were started to treat any potential infectious etiology of temperature dysregulation. However, a urinalysis and chest X-ray were both unremarkable, and cultures remained negative, so antibiotics were discontinued on hospital day two. TSH and cortisol levels were normal. Additional past medical history included hyponatremia, hypertension, cyclothymia, renal cell carcinoma, iron deficiency, thrombocytopenia, osteoporosis, and gastroesophageal reflux disease. The patient was taking phenytoin (200 mg/day), levetiracetam (3000 mg/day), and clobazam (10 mg bid) for seizures, amlodipine (10 mg/day) for hypertension, quetiapine (100 mg/day) and fluoxetine (30 mg/day) for cyclothymia, clonazepam (1 mg/day) for behavior, and aspirin (81 mg/day). He had previously taken oxcarbazepine for epilepsy but switched to clobazam because of hyponatremia. Clobazam had been started one year prior, and it was the last drug added. Because of this and the fact that clobazam had been recently linked to hypothermia, the drug was tapered from 10 to 5 mg bid over one week. During this period, the patient experienced one more hypothermic episode. Clobazam was then discontinued after this week, and since then, there have been no episodes of hypothermia for over half a year.

antiepileptic drug, benzodiazepine, clobazam, epilepsy, hypothermia

PMC9888489_01

Female

We report the case of a 19-year-old female diagnosed with Ph-negative B-cell ALL in February 2019, who presented with hyperleukocytosis (WBC count 317 x 109/L). Flow cytometry on a bone marrow (BM) aspirate showed that 93% of cells were positive for CD45, CD10, CD19 and CD22, and had an aberrant expression of CD33. FISH performed using the Cytocel probe detected a deletion at 6q21/SEC63 in 43.5% of the analysed nuclei. The BCR::ABL1-like predictor was positive and showed a CRLF2 upregulation and an IKZF1 deletion. Molecular-cytogenetic analysis, performed using the ZytoLight SPEC CRLF2 Dual Color Break Apart probe, and the LSI IGH Dual Color, Break Apart Rearrangement Probe (Vysis-Abbott) showed hybridization patterns consistent with the presence of an IGH : CRLF2 rearrangement. Targeted RNA sequencing detected no mutations or rearrangements. The patient was enrolled in the chemo-immunotherapy GIMEMA LAL2317 protocol, which exploits a risk-oriented strategy based on disease characteristics and MRD evaluation at fixed time-points, intercalating a maximum of two cycles of blinatumomab into a pediatric-like chemotherapy backbone (clinicaltrial.gov NCT03367299). Our patient, classified as very high risk, underwent three cycles of chemotherapy, obtaining a complete morphologic remission (CR) after induction. Central nervous system (CNS) prophylaxis was carried out as per protocol. MRD assessment by RQ-PCR Ig gene rearrangement remained strongly positive (>10-2) after all three chemotherapy cycles. After a single cycle of blinatumomab which induced the molecular remission (<10-5), the patient underwent an allogeneic hematopoietic stem cell transplant (HSCT) from an HLA-identical sister. Conditioning consisted of treosulfan, fludarabine and TBI 4 Gy, and the graft versus host disease (GvHD) prophylaxis included post-transplantation cyclophosphamide and sirolimus. A post-transplant aspirate documented a CR with full donor chimerism, FISH and a molecular MRD negativity. Sirolimus was discontinued six months later. The patient never developed GvHD. In January 2021, 18 months after the HSCT, a BM evaluation detected a relapse (5% blasts). The patient had also a palpable mass in her right breast, whose histology was compatible with an ALL localization. No CNS disease was detected. The patient was deemed fit for anti-CD19 CAR-T cell therapy with tisagenlecleucel. After lymphapheresis in early February, we started a bridging treatment with ponatinib 45 mg daily for 30 days on compassionate use and 1 mg/kg prednisone for 14 days. No cardiac, hepatic or hematologic toxicity was reported. In mid-February, we repeated a BM aspirate that confirmed a morphologic relapse (12% blasts). A third aspirate after a month of ponatinib showed a stable disease (8% blasts) and on physical examination a reduction of the palpable breast nodule was documented. We withdrew bridging drugs and started lymphodepletion with fludarabine-cyclophosphamide, followed by a CAR-T cell infusion on March 2021. The patient developed a grade 4 neutropenia and received three doses of tocilizumab for grade 1 cytokine release syndrome (CRS). No neurotoxicity occurred. Three months later the patient was in CR with a full donor chimerism and a MRD negativity. A breast ultrasound revealed a regression of her nodule. In June 2021, maintenance with ponatinib at a lower dose (15 mg/day) was initiated. In November 2022, 20 months after the CAR-T cell infusion the patient is in good clinical conditions and in persistent molecular CR. She still receives ponatinib maintenance with excellent tolerance, except for a 10-day discontinuation due to a transient G4 neutropenia. Figure 1 summarizes the case timeline. We longitudinally monitored the patient's CAR-T cell expansion and their subsequent persistence by flow cytometry and plotted the data over time in Figure 2A . After a marked expansion peak at day 7 after infusion (1819.6/mcl), CAR-T cell counts decreased, though persisting over time. At late time-points (day 180 and 270), the patient still had circulating anti-CD19 CAR-T cells (4.0 and 4.3/mcl, respectively). At the last available follow-up (365 days, April 2022), circulating CAR-T cells were no longer detectable. However, a concomitant B-cell aplasia is ongoing and we are monitoring it as a decisional tool for future treatment. Peak levels of inflammatory cytokines and chemokines occurred within the first week after the CAR T-cell infusion, with particularly high levels of monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein 10 kDa (IP-10), interleukin-6 (IL-6) and interferon-gamma (IFN- gamma, Figure 2B ).

car-t, philadelphia-like all, bridge therapy, maintenance therapy, ponatinib

PMC9343706_01

Female

An otherwise healthy 20-year-old woman was diagnosed with GCTB in February 2009, after an accidental fall while skiing. X-Ray examination showed an osteolytic area in the proximal tibia. The lesion was resected via curettage, and histological examination was positive for GCTB. Subsequent systemic staging highlighted a 5-cm large sacral primary ( Figure 1 , left panel), multiple bone (D9-11, L3, L5, right hemi-sacrum, and right femur) metastases and one single pulmonary metastasis in the superior lobe of the left lung. Diagnosis of GCTB was histologically confirmed on the sacral lesion. Family history was negative for cancer, and patient had no comorbidities at the time of the event. The patient was symptomatic for diffuse back and buttock pain, invalidating her normal daily activities and gradually determining an impairment in walking, which finally constrained her to the use of a wheelchair. Given the diagnosis and the disease extent, in November 2009, she was started with denosumab (120 mg subcutaneously, once per month, following the loading dose of 120 mg day 1-8-15), obtaining a reduction in tumor size and resolution of all GCTB-related symptoms ( Figure 1 , right panel). The disease response and clinical benefit were maintained for over 10 years. After 132 months of treatment (November 2019, at the age of 30), the drug was interrupted due to a fracture of the left femur diaphysis, after a minor trauma (low-energy fall while walking). The fracture carried the typical clinical and radiological features of a complete displaced AFF ( Figure 2 , left panel), which was related to denosumab. The patient was treated with open reduction and intramedullary nailing, along with calcium and vitamin D daily supplements, to accelerate fracture healing ( Figure 2 , right panel). However, bony callus fully consolidated only 13 months after the nailing. GCTB remained stable for 14 months after denosumab discontinuation, when a new CT scan showed progressive disease by RECIST, marked by the appearance of two new lesions in the right iliac wing and in L5 soma ( Figure 3 , left panel). After multidisciplinary evaluation and orthopedic assessment, denosumab was restarted at the previous dosage (120 mg per month, subcutaneously). At the first re-assessment, 3 months later, a new tumor stabilization was documented and confirmed at 1 year, with no evidence of AFF relapse or additional serious adverse events reported ( Figure 3 , right panel).

atypical femur fracture, bone tumor, denosumab, giant cell tumor of bone, sarcoma

PMC8101658_01

Female

A 50-year-old woman presented to the neurosurgery outpatient department complaining of progressively increasing headache, and diminished vision for 1 year. On physical examination, the patient was conscious and oriented. There was no pallor, icterus, cyanosis, clubbing, edema or lymphadenopathy on clinical examination. Her weight and height were 164 cm and 72 kg respectively. Her Glasgow coma score was 15 (E4V5M6). The lungs examination was clear on auscultation. The patient was hypertensive on medication. The routine laboratory workup showed hemoglobin of 10.6 g/dl (reference range [RR]; 14g/dl - 16g/dl), leukocytes 8300/mm3 (RR; 4000 - 11000/mm3), and platelets 2.2x105/mm3 (RR; 1.5x105- 4.5x105/ mm3). ESR was 40 mm in the first hour. The biochemical examination showed prolactin level of 58.00 ng/ml (RR; 2.1 - 17.7 ng/ml), luteinizing hormone <0.216mIU/ml (RR; 1.5 - 9.3 mIU/ml), follicle-stimulating hormone 3.07 mIU/ml (RR; 1.4 - 18.1 mIU/ml), serum cortisol 2.27 ng/ml (RR; 4.30 - 22.0 microg/dl), thyroid-stimulating hormone 0.2microIU/ml (RR; 0.35 - 5.5 IU/ml), T3 - 0.96 ng/dl (RR; 0.6 - 1.65 ng/ml), and T4 - 4.30 microg/dl (RR; 4.4 -11 microg/dl). The serum electrolytes were within normal limits. Her chest X-ray revealed normal lung parenchyma. There was no family or close contact history with tuberculosis. No evidence of extrapulmonary lesion that could raise the suspicion of tuberculosis was noted. The contrast-enhanced magnetic resonance imaging (MRI) scan revealed enhancing mass lesion of 1.7 x 1.4 cm arising from the sella, causing compression of optic chiasma (Figure 11B). A radiological diagnosis of pituitary macroadenoma was given, and the patient was submitted to a transsphenoidal endonasal tumor excision. The postoperative period was uneventful. The histopathology showed numerous epithelioid cell granulomas with Langhans giant cells with a mixed and variable proportion of pituitary parenchymal cells arranged in a nested and alveolar pattern (Figure 222C). Reticulin stain demonstrated reticulin fibers around the nest of viable pituitary parenchymal cells (Figure 2D). Ziehl Neelsen staining demonstrated acid-fast bacilli (Figure 3). Based on the above histomorphology, a diagnosis of Pituitary tuberculoma was given. Suspicion of pituitary adenoma was ruled out by the reticulin stain, and the demonstration of acid-fast bacilli by Ziehl Nelson stain. Treatment for tuberculosis was initiated with a 2-month combination of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by 7 months of isoniazid and rifampicin. Her headache rapidly resolved and restored normal vision. Her hormone levels returned to normal after 2 months of follow-up. The outcome was uneventful and the patient is doing well after 15 months of follow-up.

adenoma, granuloma, pituitary gland, tuberculosis

PMC4300286_01

Male

TP is a 63-year-old Caucasian male, former accountant, with younger-onset, sporadic Alzheimer's disease (AD) for 12 years. In 2001, at age 51, he began to complain of short-term memory loss, initially attributed to depression. The condition inexorably worsened and, during 2006, he had to give up his job and stop driving. By then, he was displaying characteristic features of AD dementia, including increasingly severe memory loss, poor concentration and organization, misplacing important items, inability to carry out activities of daily living, and inability to spell and read. Between 2004 and 2008 his Mini-Mental State Examination (MMSE) score declined from 23 to 12. Brain MRI on 8/18/2004 was reported normal; however, MRI on 6/16/2008 showed diffuse involutional changes of frontal and parietal lobes and moderate left-sided and severe right-sided atrophy of amygdala and hippocampus, consistent with AD. He was found to be APOE epsilon4-positive. Because of published information suggesting MCTG-induced increases in plasma ketone levels might benefit AD patients, TP was initially placed, on May 21, 2008, on 35 ml coconut oil (CO) once daily [CO contains ~15% ketogenic MCFA]. Then, over several months, MCTG was added and increased gradually to a 4:3 mixture with CO, eventually reaching 165 ml/d divided into 3-4 servings. Use of the MCTG/CO mixtures as dietary supplements was associated with rapid improvement in TP's personality, mood, and tremor. MMSE improved from 12, measured on May 9, to a high of 20, 75 days later. During the ensuing year, additional gradual improvement occurred in gait, social participation, word finding and recall of recent events. Thus, during MCFA treatment for twenty months, TP showed considerable cognitive improvement (ADAS-Cog [Alzheimer's Disease Assessment Scale-Cognitive]) rose 6 points and ADLs [Activities of Daily Living] rose 14 points), followed by stabilization. MRI findings on 4/28/2010 were no different from those on 6/16/2008. Hence, during the two-year period of MCTG/CO treatment, TP's brain remained MRI-stable. During the winter of 2010, while participating in a crossover clinical trial of the gamma-secretase inhibitor, semagacestat, TP retrogressed when shifted from placebo to drug. The deterioration, which presumably resulted from semagacestat-induced collateral damage to other proteins affecting neurocognitive function, persisted after the drug was stopped. It is now known that TP was on placebo during at least the initial twelve months of the study. He discontinued participation in the study March 1, 2010, owing to new problems appearing in the prior month, including poor wound healing, fainting, elevated CPK (non-cardiac), a respiratory infection, and outbreak of fever blisters. Also, throughout February and March 2010, he became increasingly depressed and began to experience confusion with images in the mirror and his whereabouts in the home. He began wandering, lost interest in yard and house work, and required step-by-step instruction and considerable assistance to dress and complete hygiene-related tasks. As TP's condition worsened, his wife/caregiver, a neonatology specialist, became increasingly desperate for a remedy. Searching for new treatments, she found several articles suggesting that, in certain AD patients, ketone-ester induced elevation of plasma KB to levels approximating to those obtained during a fast, might prove more effective than the lower concentrations achievable by MCTG administration. On April 29, 2010, with his full cooperation and consent, TP was started at home on orally administered KME. Throughout KME treatment, TP remained on his usual diet and also continued to take the MCTG/CO mixture, as described in 4.2. During the first two KME days, TP received 21.5g thrice daily. Thirty minutes of video taken between 2 to 3 hours following the first dose of KME demonstrate a marked improvement in mood and the ability to recite and write out the complete alphabet, which he had been unable to do for many months. The next morning he spontaneously chose clothes and dressed himself:also a new development. On third day of KME treatment, the amount administered was increased to three 28.7g servings/d. Following serving- size increase, he began to initiate and complete many other activities without prompting or assistance. These included showering, shaving, brushing teeth, finding his way around the house, choosing and ordering food from a menu, and distributing utensils from the dishwasher. These activities had not been observed for months before KME was started. Abstract thinking, insight, and a subtle sense of humor returned to his conversation. In his own assessment of his response to KME, he stated that he felt "good", had "more energy" and was "happier." He also found it "easier to do things" - which coincided with the caregiver's observations. After six to eight weeks of taking 28.7g of the KME thrice daily, he began to exhibit improvement in memory retrieval, spontaneously discussing events that occurred up to a week earlier. He was again able to perform more complex tasks, such as vacuuming, washing dishes by hand, and yard work. Plasma betaHB levels were measured occasionally to assess KME-plasma betaHB dose-response relationships (Fig. 2). Noticeable improvements in performance (conversation, interaction) were observed at higher, post-dose betaHB levels, compared to pre-dose values. Of a battery of commonly ordered blood chemistry tests done on TP before and during KME treatment, the only noteworthy changes were in certain plasma lipids. Over 20 months, total cholesterol fell from a pre-KME mean (n=2) of 244 to 163mg/dl. HDL cholesterol fell from 85 to 68mg/dl, and LDL cholesterol from 145 to 81mg/dl. The fact that relatively high plasma KB levels (6-8mM) can be maintained indefinitely when KME is ingested at 3-4h intervals may raise questions about the long-term safety of this degree of hyperketonemia. Before KME became available, the only way to obtain comparable plasma KB elevations was by prolonged fasting or strict adherence to a very-high-fat, very-low-carbohydrate KD. Because these methods have confounding metabolic side effects, such as dehydration, urate nephrolithiasis, substantial weight changes, and amenorrhea, neither can serve as a satisfactory test for the long-term safety of KME-induced hyperketonemia. Nevertheless, three severely obese inpatients who sustained mean KB levels of ~8mM while undergoing 5-6 weeks of starvation for weight loss did not exhibit adverse clinical effects attributable to the protracted hyperketonemia. In rare instances, hyperketonemia, by reducing renal uric acid clearance, can raise plasma uric acid to levels sufficient to precipitate a flare in gout-susceptible individuals. Drugs that inhibit uric acid synthesis can prevent this complication. At present, there is no evidence that, by itself, chronic hyperketonemia (at concentrations of ~8-mM) may be clinically unsafe. However, if valid safety issues arise, they should be considered in the light of a possible beneficial effect of KME on such devastating diseases as AD, and on disabling convulsions in infants and children who are refractory to antiseizure medications. Given the report by Henderson et al. indicating that that the APOE epsilon4-positive subjects in their study failed to show statistically significant improvement in their ADAS-Cog scores in response to MCTG treatment, it is noteworthy that TP, although APOE epsilon4-positive, exhibited clear cognitive and behavioral improvement while consuming equivalent or larger quantities of ketogenic, medium-chain fatty acids. The findings of Henderson et al. (which may have lacked the statistical power to detect a change in APOE epsilon4-positive subjects) do not rule out the possibility that carriers of the epsilon4 allele could show cognitive improvement if studied for longer periods of time and/or given higher doses of MCTG.

brain insulin resistance, fasting, ketogenic diet, ketone bodies, ketone monoester, medium-chain triglyceride, pyruvate dehydrogenase, β-hydroxybutyrate

PMC6864591_01

Female

a 34-year-old woman presented to the out-patient department of dermatology with a history of fever associated with chills, rigors, itchy red raised lesions all over the body, swelling of the face, headache, dizziness and tinnitus for the last four days. The rashes appeared on the face and progressed to involve trunk, upper limb and lower limb within a day. Medication history revealed that she was on isoniazid (H) (5mg/kg), rifampicin (R) (10mg/kg), pyrazinamide (Z) (25mg/kg), ethambutol (E) (15mg/kg) and streptomycin (S) (15mg/kg) for the last 35 days for pulmonary tuberculosis (Fig. 1). She also revealed a past history of pulmonary tuberculosis 19 years back, which was successfully treated with HRZE for 2 months and HR for 4 months. On clinical examination, the patient was febrile (101oF) and submandibular, axillary and inguinal lymph nodes were enlarged. Multiple maculopapular erythematous lesions were present over the face, trunk, upper and lower extremities. She had facial edema, dry lips and aphthous ulcers. Hematological investigations revealed that the total leukocyte count (TLC) was raised (15000/mul), differential leukocyte count [neutrophils (46%), eosinophils (30%), lymphocytes (18%) and monocytes (6%)] was suggestive of eosinophilia [absolute eosinophil counts (AEC), 4500/mul]. Peripheral smear showed mild anisocytosis of red blood cells. Liver function test showed raised aspartate aminotransferase (AST) (112 IU/L, normal range<31 IU/L), low total serum proteins (6g/dl, normal range=6.4-8.3g/dl) and decreased serum albumin (3.2g/dl, normal range=3.5-5.2g/dl). Serology for dengue and malaria was negative. Blood and urine culture was sterile. Fasting and postprandial blood sugar levels, lipid profile, kidney function tests and serum electrolytes were within normal range. Skin biopsy showed mild focal spongiosis with mild perivascular lymphocytes and neutrophils infiltration. Chest radiography showed hyper-inflated lung fields with bilateral hilar lymphadenopathy. Non-contrast computed tomography (CT) head was normal. A diagnosis of DRESS was made. Pulmonary medicine consultant advised the withdrawal of anti-tubercular therapy immediately and recommen-ded a follow up after the resolution of skin lesions. The dermat-ologist advised the administration of hydrocortisone 100mg intravenously 8 hourly for one day, tablet prednisolone 40mg once daily per orally for three days followed by tapering of the dose, tablet paracetamol 500mg per orally one as needed, tablet cetirizine 10mg per orally one daily, cream fusidic acid 2% for topical application, cream fluticasone 0.05% for topical application and calamine lotion for local application on the skin lesion. The patient became afebrile (98.6oF) immediately whereas skin lesions and facial edema started resolving after two days of treatment. After ten days, ethambutol (800mg) was re-introduced as it is least known to implicate DRESS. But within 12 hours, her periorbital edema and pruritus worsened. Her TLC (16900/mul) and AEC (4800/mul) raised further. Ethambutol was stopped immediately and tablet isoniazid (50mg) was started (day 1). The dose of isoniazid was increased to 300mg on the next day (day 2). On day 3, capsule rifampicin 150mg was added with a gradual increase in dose to 300mg and 450 mg on day 4 and 5 respectively. On day 6, tablet pyrazinamide 500mg once daily was introduced with a subsequent increase to twice a day. She tolerated H, R and Z well for the next ten days and her skin lesions and facial edema improved. The lower dose of ethambutol (100mg) was introduced again. Within a day, skin lesions worsened with the appearance of new urticarial lesions. Immediately ethambutol was replaced with a second line anti-tubercular drug, levofloxacin (750mg per orally once daily). Patient's symptoms improved and cutaneous lesions recovered completely after a week.

atds, drug reaction with eosinophilia, adverse drug reaction, drug-induced, ethambutol, systemic symptoms syndrome

PMC4458315_01

Male

Thoracic empyema is a disease of substantial morbidity and mortality, mainly in the developing world where tuberculosis remains a common cause. It is known to be associated with prolonged respiratory symptoms requiring longer times for drainage due to excessive fibrosis and pleural thickening. Suppurative bacterial infections are also an important cause of empyema, which if not diagnosed and treated early by antibiotics alone or with early under water seal intercostal tube, may result in to chronic empyema or even empyema thoracis necessitans requiring open drainage and decortication. Empyema necessitans is spillover of pleural space infection or pus in to soft tissue of the thoracic wall. It may burst out via weak part of the chest wall to skin and start discharging pus; otherwise it may involve surrounding structures in any direction. After Streptococcus pneumonia, Staphylococcus aureus, is the commonest cause of empyema in children, but it is not uncommon in adults either. Chronic suppurative empyema is more common and even recurrent in patients with past history of poly trauma or chest surgery. Chronic empyema treated with decortications results in rapid resolution of infection and better re-expansion of the lung as compared to only under water seal intercostal tube. We report 55 years old Saudi male with history of road traffic accident, poly trauma, chest surgery and paraplegia admitted for rehabilitation in Sultan Bin Abduaziz Humanitarian City (SBAHC), Riyadh, Saudi Arabia and diagnosed with empyema thoracis necessitans due to Staphylococcus aureus, treated initially with under water seal intercostal intubation and antibiotics but subsequently required decortication. A Saudi male 55 years of age suffered poly trauma in a road traffic accident including chest two years ago and was admitted in SBAHC for rehabilitation for having paraplegia on 16-6-2013. Three days since admission he was running fever and his chest x-ray on admission being abnormal was referred a bit late for pulmonary consultation on 19-6-2013, he was being treated by the primary team as pneumonia. He had mild cough, feeling of heaviness and discomfort on the left lateral chest without significant expectoration. He had poor oral hygiene, malodorous fetor with pyorrhea and dark brown deposits on the teeth. On systemic examination his BP was 120/70, HR = 88, RR = 19, T = 38.5, O2 Saturation = 95% at room air, Weight = 78 Kg. There were obvious old thoracostomy scars (Figure 1) performed two years ago on the left chest wall. Percussion note was dull and reduced breath sounds on the ipsilateral side. Percussion note was stony dull. There was no paradoxical, respirartion and heart rate pattern on clinical examination as well as on electrocardiogram. Echo cardiac examination was unremarkable with no out flow obstruction apart from mild left ventricular diastolic dysfunction consistant with his age. His chest x-ray (Figure 2) showed left sided thick biconvex opacity occupying left lower and middle zone. Lab works showed Hb = 12gm, RBC = 3.6, WBC = 12.6, N = 88, L = 10, M = 1, E = 1, PLT = 366, ESR = 32, BU = 6.2, SCR = 76, LDH = 40, CRP = 16, PPD = 5mm. Under the provisional diagnosis of chronic empyema patient was started on empirical injection clindamycin 600 mg iv q8hrs. Culture on blood, urine and sputum was awaited. After having CT scan chest (Figure 3) an urgent external thoracic surgical consultation was requested as our hospital is a rehabilitation facility there is no thoracic surgical specialty. The color of an old thoracostomy scar started changing dark brown to red color and in next 24-48 hours it became umblicated and yellow (Figure 4). On the 7th day of admission on 23-6-2013 while he was being examined by the thoracic surgeon he had an intractable bout of cough which lead to spontaneous rupture with pouring out of frank pus. A specimen of the pus was sent for bacterial and mycobacterial culture besides Acid Fast Bacteria (AFB) direct smear microscopy. Patient felt relieved and had no adverse events like breathlessness or pain. He was taken to the operation room and was inserted underwater intercostal tube as part of traditional thoracostomy. Patient was sent back to the unit where he felt better his temperature became less but his lung remained unexpanded with residual loculations and still residual pus on post intercostal tube (ICT) chest x-ray (Figure 5). Culture on the pus, was reported heavy growth of Staphylococcus aureus, sensitive to clindamycin so same antibiotic was continued. Pus was reported AFB negative on direct smear microscopy. Blood and urine culture were reported negative. Next day the patient was taken for decortication and was kept subsequently in the high dependency unit (HDU). He remained stable initially on ventilator for 48 hours, then on spontaneous breathing and oxygen subsequently maintaining normal range O2 saturation at room air. His lung remained well anchored and expanded with no complications, hence all three one anterior apical, and two posterior apical and basal under water seal drainage tubes along with Robert's pump application were removed one by one. Culture on pus for Mycobacteria was reported negative. Patient remained stable made good uneventful recovery and was discharged home on 16-7-2013, his last chest x-ray shown (Figure 6). There was complete re-expansion of the lung with no residual collection. He was advised OPD follow up which he failed.

empyema, staphylococcus aureus, paraplegis

(a and b) CT scan chest showing left sided chronic empyema.

PMC4458315_01

Male

Thoracic empyema is a disease of substantial morbidity and mortality, mainly in the developing world where tuberculosis remains a common cause. It is known to be associated with prolonged respiratory symptoms requiring longer times for drainage due to excessive fibrosis and pleural thickening. Suppurative bacterial infections are also an important cause of empyema, which if not diagnosed and treated early by antibiotics alone or with early under water seal intercostal tube, may result in to chronic empyema or even empyema thoracis necessitans requiring open drainage and decortication. Empyema necessitans is spillover of pleural space infection or pus in to soft tissue of the thoracic wall. It may burst out via weak part of the chest wall to skin and start discharging pus; otherwise it may involve surrounding structures in any direction. After Streptococcus pneumonia, Staphylococcus aureus, is the commonest cause of empyema in children, but it is not uncommon in adults either. Chronic suppurative empyema is more common and even recurrent in patients with past history of poly trauma or chest surgery. Chronic empyema treated with decortications results in rapid resolution of infection and better re-expansion of the lung as compared to only under water seal intercostal tube. We report 55 years old Saudi male with history of road traffic accident, poly trauma, chest surgery and paraplegia admitted for rehabilitation in Sultan Bin Abduaziz Humanitarian City (SBAHC), Riyadh, Saudi Arabia and diagnosed with empyema thoracis necessitans due to Staphylococcus aureus, treated initially with under water seal intercostal intubation and antibiotics but subsequently required decortication. A Saudi male 55 years of age suffered poly trauma in a road traffic accident including chest two years ago and was admitted in SBAHC for rehabilitation for having paraplegia on 16-6-2013. Three days since admission he was running fever and his chest x-ray on admission being abnormal was referred a bit late for pulmonary consultation on 19-6-2013, he was being treated by the primary team as pneumonia. He had mild cough, feeling of heaviness and discomfort on the left lateral chest without significant expectoration. He had poor oral hygiene, malodorous fetor with pyorrhea and dark brown deposits on the teeth. On systemic examination his BP was 120/70, HR = 88, RR = 19, T = 38.5, O2 Saturation = 95% at room air, Weight = 78 Kg. There were obvious old thoracostomy scars (Figure 1) performed two years ago on the left chest wall. Percussion note was dull and reduced breath sounds on the ipsilateral side. Percussion note was stony dull. There was no paradoxical, respirartion and heart rate pattern on clinical examination as well as on electrocardiogram. Echo cardiac examination was unremarkable with no out flow obstruction apart from mild left ventricular diastolic dysfunction consistant with his age. His chest x-ray (Figure 2) showed left sided thick biconvex opacity occupying left lower and middle zone. Lab works showed Hb = 12gm, RBC = 3.6, WBC = 12.6, N = 88, L = 10, M = 1, E = 1, PLT = 366, ESR = 32, BU = 6.2, SCR = 76, LDH = 40, CRP = 16, PPD = 5mm. Under the provisional diagnosis of chronic empyema patient was started on empirical injection clindamycin 600 mg iv q8hrs. Culture on blood, urine and sputum was awaited. After having CT scan chest (Figure 3) an urgent external thoracic surgical consultation was requested as our hospital is a rehabilitation facility there is no thoracic surgical specialty. The color of an old thoracostomy scar started changing dark brown to red color and in next 24-48 hours it became umblicated and yellow (Figure 4). On the 7th day of admission on 23-6-2013 while he was being examined by the thoracic surgeon he had an intractable bout of cough which lead to spontaneous rupture with pouring out of frank pus. A specimen of the pus was sent for bacterial and mycobacterial culture besides Acid Fast Bacteria (AFB) direct smear microscopy. Patient felt relieved and had no adverse events like breathlessness or pain. He was taken to the operation room and was inserted underwater intercostal tube as part of traditional thoracostomy. Patient was sent back to the unit where he felt better his temperature became less but his lung remained unexpanded with residual loculations and still residual pus on post intercostal tube (ICT) chest x-ray (Figure 5). Culture on the pus, was reported heavy growth of Staphylococcus aureus, sensitive to clindamycin so same antibiotic was continued. Pus was reported AFB negative on direct smear microscopy. Blood and urine culture were reported negative. Next day the patient was taken for decortication and was kept subsequently in the high dependency unit (HDU). He remained stable initially on ventilator for 48 hours, then on spontaneous breathing and oxygen subsequently maintaining normal range O2 saturation at room air. His lung remained well anchored and expanded with no complications, hence all three one anterior apical, and two posterior apical and basal under water seal drainage tubes along with Robert's pump application were removed one by one. Culture on pus for Mycobacteria was reported negative. Patient remained stable made good uneventful recovery and was discharged home on 16-7-2013, his last chest x-ray shown (Figure 6). There was complete re-expansion of the lung with no residual collection. He was advised OPD follow up which he failed.

empyema, staphylococcus aureus, paraplegis

(a and b) CT scan chest showing left sided chronic empyema.

PMC2628938_01

Male

A 20-year-old man belonging to a moderately endemic leprosy area in the Terai region of Nepal presented in our clinic as a referred patient from a teaching hospital with the history of 2 years. On clinical examination, a solitary hypopigmented, anaesthetic lesion was present on his left thigh extending to his knee. The surface of the lesion was dry and it had a length of approximately 15 cm with raised edge as shown in Figure 1. No other lesions were noted over the entire body. There was no peripheral nerve thickening. No history of contact with leprosy could be elicited. Furthermore, the rapid lateral flow test (supplied by Linda Oskam, KIT Biomedical Research, The Netherlands and Ray Cho, Yonsei University, Korea) for anti-Phenolic glycolipid-I (PGL-I) antibody of M. leprae was positive. Blood count was normal and the standard nerve function measurements by voluntary muscle testing and sensory test (VMT/ST) of the hand and feet were within normal limits. His slit skin smear and biopsy were sent for laboratory investigations. His clinical presentation was consistent with tuberculoid leprosy (TT) and paucibacillary (PB) multidrug treatment (MDT) was initiated immediately comprising 600 mg of Rifampicin once a month and 100 mg of Dapsone daily. The patient was under PB MDT for a week; however, once the slit skin smear report was obtained, this prompted the clinician to change treatment from 6 months PB to 24 months multibacillary (MB) MDT regimen comprising Rifampicin 600 mg once a month, Clofazimine 300 mg once a month followed by 50 mg daily and Dapsone 100 mg daily. Slit skin smear examination for M. leprae from the lesion revealed a Bacterial Index (BI) of 4+ (10-100 acid fast bacilli per oil immersion microscopic field on Ridley's logarithmic scale) as shown in Figure 2 while it was negative from the routine sites of the ear lobes, thigh and arm. The Morphological Index was 0%. On histopathological examination, the biopsy from the lesion revealed skin and subcutaneous tissue. There was an epidermal atrophy with mild orthokeratosis. Small aggregates of histocytes and lymphocytes were seen around vessels and skin adnexa and in and around nerves. The granuloma fraction was about 5%. Solid acid fast bacilli were seen in some of the granulomas, singly and in small clusters of 3 to 5 bacilli; the BI of the granuloma was 2+. Based on the smear results and histopathological report, the patient was classified as borderline tuberculoid (BT) in the spectrum of Ridley and Jopling's classification. Five months after commencement of MB MDT, the patient developed a Type 1 or reversal reaction. This time, there was palpable enlargement of a nerve and evidence of nerve function impairment was observed. Again, we assessed the patient for clinical, bacteriological and immunological investigations. Clinically, the patient still had the same single lesion. Bacteriologically, the routine sites were still negative and the BI of the lesion was 1+. The lateral flow for anti-PGL-I antibody was positive with lesser intensity than the test done on his first visit indicating a lower bacterial load. The standard nerve function measurements by VMT/ST were normal on both feet and hands but some weakness was observed on the left foot which concurs with enlargement of the left lateral popliteal nerve. Blood count was normal at this time and a whole blood interferon gamma (IFN-gamma) test was also performed to measure the cell mediated immune responses towards Mycobacterium tuberculosis purified protein derivative (MTB PPD), M. leprae soluble antigen devoid of lipoarabinomannan (MLSA-LAM) and M. leprae cell wall antigen (MLCwA), which were free of endotoxin and M. leprae lipoarabinomannan, supplied by Professor Patrick J. Brennan, Colorado State University, Fort Collins under NIH contract NO1-AI-25469. These were tested by QuantiFERON-CMI (Cellestis, Australia). IFN-gamma production levels were generated in response to stimulation with Cellestis mitogen but no detectable levels of IFN-gamma were obtained against these antigens in our patient. The reversal reaction was treated with 12 weeks of oral prednisolone in a tapering dose and MDT was continued unaltered during this period. Initially, the prednisolone was prescribed at a dose of 40 mg per day for a 2-week period, then decreased to 30 mg per day for 2 weeks, 20 mg per day for 2 weeks, 15 mg per day for 2 weeks, 10 mg per day for another 2-week period and finally 5 mg per day for 2 weeks.

PMC8100382_01

Female

A 33-year-old woman with Down syndrome was referred to our department for the investigation of low blood pressure. She was born, at term, to nonconsanguineous parents with no history of birth trauma, neonatal hypoglycemia, and prolonged jaundice. Her past medical history was unremarkable apart from surgery for tympanic imperforation. Her age at menarche was 12 years and she had regular periods. Her family history was notable for type 2 diabetes mellitus and arterial hypertension without any history of autoimmune diseases or congenital hypopituitarism. The patient complained of asthenia, dizziness, and palpitation with arterial hypotension for the past 4 years. Concomitant capillary glucose levels were about 0.82 and 0.85 g/L. Neither bodyweight loss nor polyuria were reported. She was not taking any drugs. On physical examination, she had a bodyweight of 64 kg, a height of 153 cm corresponding to a body mass index of 27.3 kg/m2, a blood pressure of 90/60 mmHg, and a regular pulse of 75 bpm. The skin was pale without hyperpigmentation. The hydration state and thyroid, abdominal, and neurological examinations were normal. The results of biological investigations are shown in Table 1. The thyroid function was normal and anti-thyroperoxidase antibodies were negative. The peak of the cortisol level in response to the insulin-induced hypoglycemia test was 9.4 mug/dl. The ACTH level was normal indicating corticotrope deficiency. Other pituitary hormones were normal, consisting with the diagnosis of an isolated corticotrope deficiency. Magnetic resonance imaging (MRI) scan revealed a small and homogeneous anterior pituitary gland with a partially empty sella turcica. There was no tumor and the posterior lobe bright spot was normal. The pituitary stalk was median and thin (Figure 1). Genetic analysis using high-throughput sequencing showed no mutations and no copy number variants of the TBX19 and NFKB2 genes. Pituitary antibodies were not available. Lifelong replacement therapy with an oral hydrocortisone dose of 20 mg per day was prescribed to our patient. The other pituitary hormones remained normal over the course of follow-up.

PMC4607964_02

Female

A 48-year-old Tunisian woman, presented to our consultations with a history of intermittent palpitations and exertional dyspnea of 4 months duration, progressively worsening for 2 weeks before, without any history of chest pain or syncope. She had a past history of systemic sarcoidosis diagnosed in April 2009 on the basis of the following compatible clinical and radiologic findings: systemic symptoms (such as fatigue, anorexia, and weight loss), parotid enlargement, negative tuberculin skin test, lymphopenia, hypercalciuria, increased serum ACE level, intrathoracic lymphadenopathies which were hilar (Figure 3), bilateral symmetrical, and associated with right paratracheal window lymph node involvement. Pulmonary functions tests demonstrated decreased volumes and CO diffusing capacity. Lymphocytosis in broncho-alveolar lavage was observed and a CD4+/CD8+ lymphocyte ratio was greater than 3.5. Lip biopsy of accessory salivary glands was compatible with grade 1 according to Chisholm's classification. After ruling out the other granulomatous diseases such as tuberculosis, lymphoma, crohn's disease, Wegner granulomatosis..., the diagnosis of systemic sarcoisosis was ascertained. A short-course corticosteroid therapy with antimalarial drug were initiated with a favorable evolution both clinically and radiogically. The patient was presented in November 2011 with a history of intermittent palpitations and exertionaldyspnea of 4 months duration, progressively worsening for 2 weeks before. She denied any history of hypertension, diabetes mellitus, coronary artery disease and thyroid disease. She did not smoke, consume alcohol, or illicit drugs. On physical examination, she was conscious, cooperative, and afebrile. She had a BP of 120/70 mmHg and a pulse of 160 beats/minute. There were no signs of cardiac failure; the rest of the physical examination did not reveal any abnormal findings. She was admitted to the cardiac intensive care unit. The admission ECG showed a ventricular tachycardia at 160 cycles/minute. In the light of these typical symptoms and electrocardiographic alterations in a patient having systematic sarcoidosis, the diagnosis of sarcoidosis with cardiac involvement was suspected. The echocardiography showed a FE of 50%, bright shadows consisting with infiltration in the basal and inferoseptal ventricular myocardium, and moderate mitral regurgitation. Coronary angiography revealed normal coronary arteries. The cardiac electrophysiology study showed a monomorphic ventricular tachycardia induced by isoproterenol. Laboratory tests showed no relevant alterations in myocardial necrosis biomarkers, blood cell count, renal and liver function, or electrolytes. Given the absence of primary heart disease that would explain the cardiac abnormalities and especially the previous diagnosis of systemic sarcoidosis, the final diagnosis was sarcoidosis with cardiac involvement. The patient started with a dose of 1 mg/kg/day of corticosteroid, in addition to supportive care. Over 8 months, the steroids were tapered to a dose of 10 mg/day. Anti arrhythmic drug therapy (Amiodarone) and beta blocker were initiated. Given the recurrent ventricular tachycardia with amiodarone, we proceeded to the implantation of an automated implantable cardioverter-defibrillator (ICD). Evolution was favorable.

cardiac sarcoidosis, sarcoidosis, ventricular arrhythmias

PMC8725728_01

Male

A 41-year-old man presented with a 1-day history of rapidly growing erythema and pustules on the face, trunk, and extremities. One day before, he took isoniazid, rifampicin, ethambutol, and pyrazinamide to treat pulmonary tuberculosis in lazaretto. At admission, the patient was febrile to a temperature of 40 C. He also had a 2-year history of plaque psoriasis with no history of smoking. Routine laboratory testing revealed white blood cell count of 13,890/mul (normal range, 1,214-5,110/mul) and serum levels of C-reactive protein (CRP) of 7.75 mg/dl (normal range, 0-0.2 mg/dl). Physical examination revealed widespread erythema and dried-up lakes of pus, taking up body surface area of 80%. Pustules and erythema multiforme-like lesions were diffusely spread over the upper arms and palms (Figures 1a-d). Biopsies of pustule and erythema multiforme-like lesions on the arms were performed. The result demonstrated subcorneal pustules, spongiosis as well as lymphocyte and eosinophils infiltration in the dermis (Figures 1h,i). The patient was assessed using a diagnostic score according to the EuroSCAR study. The final score was nine, which was defined as the definitive AGEP. The patient was subsequently treated with expectant treatment and topic potent steroids for 4 days, followed by no improvement. However, given the patient's femoral head necrosis, systemic glucocorticoid was not recommended. Repeated computed tomography on the chest showed multiple calcifications and thus excluded the possibility of active tuberculosis. Other infections including hepatitis B and hepatitis C were also excluded. The patient received secukinumab 300 mg after being informed of impersonal medical risks (Supplementary Figure). After the first therapy of secukinumab, all pustules faded at day 3, and erythema substantially darkened with defervescence (Figures 1e-g). The Dermatology life quality index (DLQI) decreased rapidly from 25 to 1 at week 4. There were no clinical symptoms and radiological data related to the progression of latent tuberculosis infection.

agep, biologic, drug eruption, interleukin-17a inhibition, secukinumab

PMC10267826_01

Female

An 80-year-old female, height 155 cm, weight 45 kg, was admitted to our department with chief complaint of "lower back pain and limited mobility for more than 10 days". The patient had lower restricted movement and back pain for unobvious reasons. The pain aggravated while she was turning over or waking up, but it was not relieved after conservative treatment. The patient had a history of pulmonary tuberculosis healed after regular anti-tuberculosis treatment, and had not taken medicine for a long time. Besides, the patient had no history of blood system disease or long-term anticoagulation therapy. She had a history of osteoporosis and multiple old spinal fractures. In recent years, the patient gradually appeared hunchback. Physical examination revealed slight kyphosis of the thoracolumbar spine and restricted range of motion. There was tenderness and percussion pain in the back. Both Lasegue's signs and Babinski's signs were negative. No edema was in the lower limbs and the peripheral blood supply was normal. Magnetic resonance imaging (MRI) revealed OVCFs in the 5th and 12th thoracic vertebrae and the 1st and 4th lumbar vertebrae, with multiple old vertebral fractures. Besides, radiographies illustrated compression of spinal vertebrae (Figures 1A,B). Laboratory examinations showed that white blood cell (WBC) was 8.02 x 109/L, red blood cell (RBC) 3.78 x 1012/L, hemoglobin (HB) 115 g/L, platelet (PLT) 205 x 109/L, erythrocyte sedimentation rate (ESR) 28 mm/h, C-reactive protein (CRP) 55.00 mg/L. Thromboelastography results showed that coagulation factor level, fibrinogen function, platelet function and fibrinolysis system were normal, with R value at 5.8 min, K value at 1.6 min, Angle value at 67.8 degree, MA value at 61.5 mm, LY30 value at 0%, EPL value at 0% and CI value at 0.5. These suggested that the coagulation function were normal. Bence-Jones protein qualitative test result was negative. T-SPOT (tuberculosis) test result was negative. Our initial diagnosis included 1. OVCF (T5/T12/L1/L4), 2. Old spinal fracture, and 3. A history of pulmonary tuberculosis. The patient received anti-inflammatory treatment due to the high inflammatory index before operation. There were 4 OVCF requiring surgical treatment, and they were divided into two operations. The first surgical plan including three OVCFs (T12/L1/L4) was successfully completed, and the postoperative vital signs were stable. A symptomatic treatment was conducted, including infection prevention, analgesia, local ice bag compression and so on. There was no swelling or hematoma at the surgical sites. PVP for the OVCF (T5) was performed on the 2nd day after the initial surgery before postoperative radiographies were taken (Figures 1C,D). During the operation, a mild local swelling was found at the operation site, with minor bleeding. Therefore, an local ice bag compression was applied to stop the bleeding for 30 min, and the bleeding was successfully stopped, with blood pressure at 98/60 mmHg. However, about 90 min after surgery, the patient developed shock. She fainted for a few seconds, and the blood pressure gradually dropped to 62/36 mmHg, accompanied by obvious swelling of his back. She was immediately given a rapid infusion of liquid to raise her blood pressure, and at the same time, 400 ml of blood including 2 units of red blood cells was transfused. Meanwhile, local ice bag compression was applied to stop the bleeding and detumescence. The emergency blood tests indicated that WBC was 11.26 x 109/L, RBC 2.95 x 1012/L, HB 84 g/L, PLT 262 x 109/L, CRP 11.00 mg/L, prothrombin time (PT) 12.00 s, activated partial thromboplastin time (APTT) 31.20 s, thrombin time (TT) 20.07 s, fibrin/fibrinogen degradation products (FDP) 12.67 microg/ml, potassium (K+) 3.20 mmol/L, sodium (Na+) 138 mmol/L, and chloride (Cl-) 106 mmol/L. Additionally, an emergency computed tomography (CT) scan revealed that an irregular soft tissue mass with uneven density on the left chest wall, with a subcutaneous hemorrhage amounted to approximately 1500 ml, and without evidence of bone destruction or hematoma in ribs adjacent to the 5th thoracic vertebra (Figure 2). The patient was in hemorrhagic shock. After the emergency consultation, a symptomatic treatment was given, which including 400 ml of blood transfusion (containing 2 units of red blood cells), 500 ml of glucose and sodium chloride rehydration (containing 25 g glucose and 4.5 g sodium chloride) and 30 ml of oral potassium chloride supplement (containing 3 g potassium chloride). Meanwhile, patient's vital signs were monitored by electrocardiography. After 800 ml of blood were transfused, the blood pressure increased to 110/70 mmHg. The blood tests (5 h after the first tests) showed that WBC was 7.93 x 109/L, RBC 3.19 x 1012/L, HB 93 g/L, PLT 214 x 109/L, and CRP 10.00 mg/L. On the 2nd day, besides the same volume of glucose and sodium chloride rehydration, antibiotics and analgesics, the patient was given infusion with 500 ml of multiple electrolytes rehydration (containing 2.63 g sodium chloride, 2.51 g sodium gluconate, 1.84 g sodium acetate, 0.185 g potassium chloride and 0.15 g magnesium chloride) and 100 ml of oral potassium chloride supplementation (containing 10 g potassium chloride). The 2nd day blood tests showed that WBC was 9.92 x 109/L, RBC 3.43 x 1012/L, HB 106 g/L, PLT 192 x 109/L, CRP 5.00 mg/L, K+ 3.90 mmol/L, Na+ 141 mmol/L, Cl- 105 mmol/L. The 3rd day blood tests showed that WBC was 10.57 x 109/L, RBC 3.22 x 1012/L, HB 102 g/L, PLT 212 x 109/L, CRP 4.00 mg/L, K+ 4.70 mmol/L, Na+ 141 mmol/L, Cl- 106 mmol/L. After about 2 weeks of treatment, the swelling of the patient's back obviously subsided and the ecchymosis area faded. Therefore, the treatment was effective and confirmed by CT examination on the 12th day after operation (Figure 3). An OVCF of the 3rd lumbar vertebra happened without visible reasons, on the 16th day after the 2nd surgery. PVP was performed again smoothly without any complications. Therefore, she was discharged on the next day. A follow-up of chest CT showed that there was no residual hematoma at 12th and 17th months postoperatively (Figures 4, 5). There was no recurrence during the follow-up.

case report, osteoporotic vertebral compression fracture, percutaneous vertebroplasty, shock, treatment

PMC7276235_01

Male

The patient, male and 18 years old, showed reoccurrent sweating, fever, cough and fatigue for 1 month, having a history of being in Wuhan for an exam a month ago and then returning to Jingmen 2 days later. Community authorities checked his body temperature, showing 37.8 C, and realised that the patient had reoccurrent fever and cough for more than a month, and had been to Wuhan in the past month. This attracted much attention and he was sent to an infectious disease department of a general hospital in Jingmen to be hospitalised and was isolated for suspected COVID-19. The results of physical examination were as follows: isometrical pupils sensitive to light reflection, no rigidity in the neck, body temperature of 37.8 C, heart rate of 110 beats/min, respiratory rate of 20 breaths/min and blood pressure of 110/70 kPa. Chest CT showed a few fibrous foci in the right middle lobe. Nucleic acid test of novel coronavirus was negative on admission day and on the third day. Tests of nine respiratory virus, influenza A and B virus antigens showed negative. Mycobacterium tuberculosis antibodies were negative. Thirteen items of extractable nuclear antigen antibody were negative. Ten items of toxoplasma, others, Rubella virus, Cytomegalovirus, erpes virus were negative. No abnormalities were found in blood, urine routine, liver and kidney function, myocardial enzyme spectrum, thyroid function, C reactive protein, equivalent series resistance, hepatitis B, hepatitis C, HIV antibody and treponema pallidum antibody. The patient's temperature did not improve for 5 days after admission. All blood biochemical and auxiliary examinations were normal. Chief complaints from the patient were as follows: when going to Wuhan to take an important exam a month ago, he felt more stressed than before and was always worried about failing the exam; during that time, when COVID-19 was outbreaking, he developed symptoms such as nervousness, sweating, fever, insomnia and dizziness, which made him consider himself as suffering from COVID-19. The patient's mood was low, pessimistic and negative. He reported sleeping poorly at night, sleeping for only about 3 hours a night, being restless in the ward and being nervous during the day. He often sweated after having body tension, and then the body temperature dropped; after experiencing a cold irritation, his body temperature rose again, between 37.5 C and 38 C. His family members reported that he showed a depressed mood for more than a month and had a 6-year history of depression. After ruling out any physical illnesses causing the fever, psychiatrists carefully inquired interviewed the patient and his family members and considered that (1) although the patient had been to Wuhan a month ago, he did not have any close contact with people in Wuhan. He was driven back and forth to Wuhan by his father (2) there were no clinical indicators of 'COVID-19' in all auxiliary examinations in the patient (twice nucleic acid test was negative, and no ground-glass CT was seen in the lung), and the close contacts of the patient (his parents and grandpa) did not have fever, cough and other discomforts (and the father, who stayed with him during the hospitalisation, also underwent a novel coronary pneumonia nucleic acid test, which showed negative); given that the patient had a history of depression for 6 years and was hospitalised in our hospital three times due to the reoccurrence of depression, was particularly anxious during each episode, and then sweated followed by an increased body temperature; when the symptoms of depression and anxiety improved, his body temperature returned to normal. Considering these aforementioned facts, we thought that the fever symptom was caused by repeatedly catching cold, after a sweat due to anxiety. Hence, he was immediately transferred to the psychology department because of depression and, before the exclusion of COVID-19, underwent isolation treatment from medical staff who were under secondary protection. The patient was admitted to the hospital with complaining of 'anxiety, depressed mood, slow thinking, self-blame, reoccurrent fever, cough, fatigue for 1 month, and a 6 year history of depression'. The results of psychological examination were as follows: clear consciousness; complete orientation; appropriate emotional response; passive contact; negative pessimism; slow thinking; self-blame and self-incrimination; repeated complaints of infection by 'novel coronavirus', which had encumbered his family members; depressed mood; anxiety; poverty of speech; and good insight. Laboratory examinations and blood biochemical examination showed no abnormalities. The Hamilton Depression Scale score was 26; the Emotional Self-rating Scale/Depression-Anxiety-Stress Scale 21 showed a depression score of 25, an anxiety score of 16 and a stress score of 30. After admission into the hospital, he was treated with venlafaxine sustained-release tablets (75 mg/tablet, oral administration, two times per day in the morning and midday), olanzapine tablets (2.5 mg/tablet, once a day in the midday, oral anxiolytic) and olanzapine tablets (5 mg/tablet, oral, once every night). After 3 days, the patient's night-time sleep improved significantly with 7 hours of deep sleep every night; anxiety during the day significantly improved; the symptom of sweating in the patient disappeared; and the body temperature dropped to between 36.5 C and 37 C. The patient's depressive mood significantly improved after 10 days of treatment. The patient smiled when talking and even said that he was in a good mood and was full of hope for his future life. Additionally, he displayed active thinking and showed no anxiety or low self-esteem and pessimistic mood. After being hospitalised for half a month, he was ruled out from having COVID-19 and was cured of depression and discharged from the hospital. After a week, the telephone feedback showed that the patient's mood was stable and that no discomfort such as fever and cough had occurred.

affective disorders, psychotic

PMC4107492_01

Male

A 46-year-old homosexual male presented at the emergency room on February 22, 2002 for a 5-month progressive visual impairment, headache and occurrence of right hemiparesis in the last week. He was diagnosed with HIV infection in December 1987. His past history was not significant except for varicella in July 1996. At this previous time, his CD4+ count was 650 cells/muL (24%) with a CD4+/CD8+ ratio of 0.37. In July 2000 and November 2001, the CD4+ cell counts were 420 and 330 cells/muL, respectively. No HIV-1 viral load measurements were available for these dates. Until he was admitted to our hospital, the patient had declined any antiretroviral therapy. At admission, he was afebrile and his physical examination was unremarkable except for right hemi paresis and left homonymous hemianopsia. His complete blood count (CBC), liver function tests and routine biochemistry were within normal limits. The CD4+ count was 340 cells/muL (16%) with a CD4+/CD8+ ratio of 0.20. A brain CT-Scan and a magnetic resonance imaging (MRI) revealed multifocal coalescent lesions with no mass effect and very little or no enhancement in the white matter of upper left parietal and left occipital, right temporal and frontal lobes with cerebral atrophy, suggestive of progressive multifocal leukoencephalopathy (PML) (Figure 1, panels a and b). Serologic tests for syphilis (RPR and Treponema/TP-PA), EBV-VCA IgM, toxoplasmosis (IgG and IgM) and search for cryptoccoccal antigen were negative.The patient had positive results for EBV-EBNA-1 IgG, CMV IgG, hepatitis C (anti HCV), hepatitis A, anti HBs, antiHBc. The HBs Ag was negative. He was started on AZT 300/3TC 150 mg (Combivir ) BID and lopinavir 200/ritonavir 50 mg (Kaletra ) 2 tablets BID. The HIV viral load was not performed (for technical reasons) before initiating antiretroviral therapy, but after two weeks it was 2 279 (3.36 log10) HIV-1 RNA copies/ml. Because of clinical deterioration, dexamethasone was initiated on March 15, 2002, and continued until April 8, 2002. Since no clinical improvement was apparent, i.v. cidofovir (5 mg/kg) and probenecid twice at one week intervals, then every 2 weeks were started on April 11, 2002 and continued until February 3, 2003. His immune status improved, and on June 10, 2002, the CD4+ count showed 440 (26%) with a CD4+/CD8+ ratio of 0.38, whereas the viral load decreased to 91 HIV-1 RNA copies/mL. Moreover, the patient reported a subjective improvement of his right hemiparesis. On June 26, 2002, AZT was replaced by D4T to avoid anemia due to AZT and probenecid interaction. The patient was again hospitalized on August 22, 2002 for fever (39 C), seizures and status epilepticus, necessitating admission to the Intensive Care Unit (ICU), for intubation and mechanical ventilation. Anti-convulsive therapy with phenytoin and lamotrigine was then initiated. Laboratory analysis revealed this time a CD4+ count of 380 (21%) with a CD4+/CD8+ ratio of 0.38 and a HIV viral load below the limit of detection (<50 HIV-1 RNA copies/mL). The brain lesions had not changed since the previous brain MRI. A lumbar puncture was performed on August 23, 2002. The cerebrospinal fluid (CSF) examination revealed proteins 0.53 g/L (normal 0.1-0.5), and glucose 4.3 mmol/L (normal 2.2-3.9). Tests for viral DNA of Poliomavirus JC, BK virus, CMV, PCR for herpes group viruses (HSV-1, HSV-2, VZV, CMV, EBV, and HHV-6/7-8), Mycobacterium tuberculosis, and search for cryptococcal antigen and VDRL all remained negative in CSF. Plasma CMV DNA, urine cultures, blood cultures for bacteria, Mycobacteria and fungi were negative. An ophthalmologic examination confirmed bilateral blindness of the central origin, but showed no retinitis, keratoconjonctivitis or deep corneal stromal infection. He was discharged on September 19, 2002, and was seen every two weeks at the Ambulatory Unit. On September 23, 2002 his HIV viral load was again below the limit of detection; CD4+ count was 350 cells/muL (22%) and CD4+/CD8+ ratio was 0.36. Despite an optimal control of HIV infection and continuous combination antiretroviral therapy (cART), the patient's status did not improve and he was re-admitted to the ICU for status epilepticus on April 28, 2003, intubated and mechanically ventilated. A subsequent brain MRI showed no change as compared with the previous examinations, but was still suggestive of PML. At admission, lactic acid and CK levels, as well as platelet count, remained within normal limits. AST and ALT were slightly elevated: 65 and 67 U/L respectively. While in the ICU, the patient developed multiorgan failure with rhabdomyolysis (CK 47,500), elevated liver enzymes (AST 2 557 U/L), elevated LDH (4 070 U/L) and disseminated intravascular coagulation: thrombocytopenia (12 x 109/L), diminished fibrinogen levels, increased prothrombin time (INR). Lactic acid levels rapidly increased to 17.11 mmol/L on April 29, 2003 before he expired. Rhabdomyolysis and lactic acidosis were probably the consequences of repeated muscular convulsions. Blood and urine cultures remained negative. Search for the cryptococcal antigen was again negative. Permission for post mortem examination was obtained. At macroscopy, the cerebral hemispheres were unremarkable. The circle of Willis showed a normal architecture without significant arteriosclerotic lesions. Leuko-encephalopathic lesions associated with secondary atrophy predominantly localized in the white matter were noted. These lesions were multifocal and bilateral, the largest observed in the orbito-frontal lobes. Another grey lesion measuring 0.8 x 0.6 cm, which differed from the leuko-encephalopathic lesions was noted in the right internal pallidal nucleus. The corpus callosum had secondary atrophy. Transverse sections of the brain stem showed atrophy of the right bulbar pyramid. Sagittal sections of cerebellum revealed ill-demarcated grey areas within and around dentate nuclei. At microscopic examination, cerebral microsporidiosis was documented affecting predominantly the white matter (mostly on the right side) of the orbito-frontal lobes with central, right temporo-parietal and cerebellum extension and a right internal pallidal abscess. Intracellular clusters of microsporidial spores were found, some of them with tubular extensions (Figure 1 panels c and d). In addition, a generalized severe anoxic ischemic encephalopathy was noted. Numerous microscopic foci of wallerian degeneration of the perivascular white matter, predominantly fronto-temporo-parietal, compatible with cerebral arterial ischemia were evidenced. No suggestive criteria for PML, such as oligodendrocytic inclusions (Papova type) or reactive dysmorphic gliosis were noted; the immunoreactivity for simian virus (SV) 40 was absent. Furthermore, the absence of giant multinucleated cells rendered a diagnosis of HIV encephalopathy improbable. Nonetheless, several extensively calcified small arteries as noted in HIV encephalopathy were present. No immune reactivity to anti Toxoplasma antibodies was present. The Grocott and PAS stainings were negative. The PCR for JCV on brain tissue was not performed.

cerebral lesions, hiv, microsporidiosis, progressive multifocal leukoencephalopathy

PMC5727565_01

Female

A 16-year-old female was admitted to hospital with a one-week history of gradually worsening shortness of breath. For more than two months, she described having a nonproductive cough, nocturnal fever, significant weight loss, joint pains, and fatigue. The patient had previously sought treatment from her local primary care physician for a cough and fever approximately two months prior to this presentation. At this time, a HIV test was done which was negative. No further follow-up was done until her subsequent deterioration and presentation at our hospital. On presentation the patient was tachypnoeic and tachycardic, with a respiratory rate of 40 bpm, a heart rate of 148 bpm, and a temperature of 37.8 C. Her oxygen saturation was 100% on facemask oxygen at 6 L/min with a blood pressure of 123/85 mmHg. Crepitations were heard throughout both lung fields. The remainder of the physical exam was normal with the patient noted to be alert and oriented. An urgent CXR was requested which showed multiple miliary opacities scattered throughout both lung fields (Figure 1). Laboratory results at this time were significant for microcytic anemia, leukocytosis (Hb, 7.6 g/dL, MCV, 76 fL, and WBC, 15.4 x 109/L) and a normal platelet count (332 x 109/L). Serum creatinine and electrolytes were grossly normal. A CT scan of the chest confirmed miliary opacities, with no mediastinal or hilar lymphadenopathy (Figure 1). Differential diagnoses at this time included pneumocystis pneumonia, viral/fungal pneumonia, miliary tuberculosis, and metastatic disease. Patient was reviewed by the Infectious Disease Unit and transferred to an isolation room on the medical ward. An HIV rapid test was performed, which was subsequently reported as negative [Determine and UNI-GOLD ]. Due to the lack of any historical evidence suggesting frequent infections or an immunocompromised state, no immunological tests were requested. An interferon-gamma release assay [QuantiFERON ] was also requested and the patient was empirically started on levofloxacin, fluconazole, and acyclovir. On day 2 of admission the patient deteriorated (SPO2 70% on Nonrebreather Mask set at 15 L/min), was transferred to the ICU, intubated, and placed on mechanical ventilation. Her P/F ratio at that time was 130 indicating moderate ARDS. After initial stabilization, worsening oxygenation (P/F ratio 113) prompted administration of bolus and infusion of cisatracurium. The patient was ventilated using a lung protective approach with a tidal volume of 330 ml (6 ml/kg), a PEEP of 10 cmH2O, RR of 20, and flow rate of 35 L/min. Sputum, via endotracheal tube suction catheter, was taken for testing at the regional public health lab. On a FiO2 setting ranging from 70 to 100%, the patient's oxygen saturation remained between 85% and 90%. On further questioning of the patient's parents, it was revealed that she was in contact with a relative who had a nonproductive cough of unknown but prolonged duration. There was no testing or TB confirmation done in the family. On admission day 3, patient was noted to be hypotensive with MAP's < 60 mmHg and persistently pyretic. Multiple polygeline fluid boluses were given and a noradrenaline infusion was started. As her condition continued to deteriorate, the noradrenaline dose increased to a max of 50 ug/min. Despite this the patient's hypotension persisted and she progressed to a fatal cardiac arrest early on the fourth day. Shortly after her demise, Nucleic Acid Amplification [Xpert MTB/RIF] results from her sputum became available and it was positive for Mycobacterium tuberculosis with no rifampin resistance being detected. No smear microscopy or culture was performed in this case. Previously requested QuantiFERON test was marred by postprocessing issues and a retest was suggested. On the evening before her death, a decision had been made to empirically start antituberculosis therapy; however due to its infrequent presentation in our regional hospital, no drugs were kept in stock and they had to be sourced from our local TB treatment center. Unfortunately, the patient's death preempted this.

PMC4085278_01

Male

In July 2012 a 51-year-old German male patient was diagnosed with acute myeloid leukemia with maturation. The disease proved refractory after administration of two cycles of induction chemotherapy and ASCT from a non-related donor with human leukocyte antigen-A mismatch (9/10 antigens matched) was performed as salvage therapy in December 2012. Conditioning consisted of the FLAMSA-RIC regimen (fludarabine 120 mg/m2, cytarabine 8,000 mg/m2, amsacrine 400 mg/m2, total body irradiation 4 Gy, cyclophosphamide 120 mg/kg and anti-thymocyte globulin (ATG, Fresenius, 60 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A from day -2 (target serum trough level of 180-220 mug/l) and mycophenolate mofetil from day 0 (2 g/day). Ciprofloxacin, acyclovir, voriconazole and monthly pentamidine inhalations were administered as anti-infective prophylaxis. Pre-transplant X-ray of the lungs did not show any pathologic findings and polymerase chain reactions (PCR) for CMV and EBV genomes in the peripheral blood were negative. The patient reported exposure to TB in an affected classmate decades ago but denied previous infection. BCG vaccination status was unknown. Tuberculin skin test is not routinely performed at our institution. The patient tolerated the conditioning regime well and received a non T-cell-depleted peripheral blood stem cell allograft containing 4.9 x 106 CD34+ cells/kg and 76.8 x 106 CD3+ cells/kg. From day +5 granulocyte-stimulating factor (5 mug/kg/day) was given intravenously until the absolute leukocyte count exceeded 1 x 109/l. On day +1 after transplantation the patient developed fever of up to 38.5 C and the antibiotic treatment was switched to meropenem. After detection of Staphylococcus haemolyticus in a blood culture, vancomycin was added and the fever subsequently subsided. On day +8 fever recurred and vancomycin was exchanged for linezolid. Computer tomography (CT) of the lungs revealed micronodular lesions suspicious of calcified granulomas but did not show signs of acute pulmonary infection. Subsequently, the fever ceased and engraftment of neutrophils was achieved on day +19. On day +26 fever was noted again and antibiotic treatment was re-initiated with piperacillin/tazobactam, which was exchanged for meropenem/vancomycin and then meropenem/linezolid after persistence of fever. Thoracic CT-scan showed multiple small pulmonary nodules and due to the morphology of the lesions pulmonary mycosis and extramedullary leukemia were primarily considered. On day +34 right cervical lymphadenopathy was noted and ultrasonography confirmed three enlarged, inhomogeneous and echopenic lymph nodes with a maximum size of 14x15 mm. Histological analysis of one extirpated lymph node showed complete effacement of its architecture due to multiple epithelioid cell granulomas with only occasional necrosis (Figure 1a,b). In addition, focal polymorphous lymphoid infiltrates (Figure 1c) composed of blastic activated B cells expressing CD20 and CD30 were identified, which were accompanied by plasma cells with polytypic expression of the immunoglobulin light chains. Further immunohistological investigations revealed that the activated B-blasts expressed the EBV encoded latent membrane protein-1 and the nuclear antigen EBNA2, both of which are involved in EBV-induced B cell activation and proliferation (Figure 1d) (Thorley-Lawson ). As a sign of a transition of the latent to the lytic EBV infection phase several lymphoid cells expressed the BamHI Z fragment leftward open reading frame 1 (BZLF1)-protein of the virus. Gene rearrangement analysis of the immunoglobulin heavy chains detected the presence of a monoclonal B-cell population. These findings led to the diagnosis of an EBV-associated polymorphic post-transplantation lymphoproliferative disorder combined with granulomatous lymphadenitis. Cultures remained sterile and microscopic examination revealed no acid-fast bacilli. However, PCR analysis of the lymph node revealed presence of Mycobacterium tuberculosis (M. tuberculosis) consensus sequences. Repeated thoracic CT showed mediastinal and hilar lymphadenopathy of up to 20 mm and unchanged pulmonary nodules (Figure 2a,b). Bronchoalveolar lavage was performed and PCR revealed presence of both M. tuberculosis and CMV (191,000 CMV copies/ml). Additionally, sputum samples were found positive for both microscopic and cultural detection of M. tuberculosis. Tuberculostatic therapy consisting of isoniazid, rifampicin, ethambutol and pyrazinamide was initiated. EBV and CMV replication was also detected in the peripheral blood by quantitative PCR (99,300 and 53,800 copies/ml, respectively). Intravenous ganciclovir was initiated and rituximab was administered three times (375 mg/m2/dose) with subsequent dropping of copy numbers of EBV and CMV below the detection limits. Two weeks after initiation of TB therapy the patient had completely recovered from all infectious symptoms and sputum samples turned negative for M. tuberculosis. The patient was subsequently discharged from the hospital for outpatient continuation of tuberculostatic therapy. Unfortunately, bone marrow examination on day +77 revealed fulminant relapse of the leukemia without signs of infection. Palliative cytoreduction using hydroxyurea was initiated and the patient was transferred to a hospice, where he died three weeks later. The patient's next of kin consented to the publication of this report.

allogeneic stem cell transplantation, cytomegalovirus, epstein-barr virus, post-transplant lymphoproliferative disorder, tuberculosis

PMC3699946_01

Male

A 33-year-old male patient resident of Manguinhos - Rio de Janeiro - Brazil was diagnosed 18 months ago with polymyositis and was irregularly taking methotrexate (15mg/weak) with prednisone (40 mg/day); however, he failed to attend medical follow-up visits regularly. One year ago, he was hospitalized with pulmonary tuberculosis. He was prescribed rifampicin, isoniazid and pyrazinamide and completed a six-month treatment period. Six months later, he was admitted at the Hospital with painful warm nodules of various sizes on his body in addition to gummatous lesions developed two months earlier (Figures 1,2 and 3). He presented intermittent fever which responded to metamizole. There was throbbing pain in his limbs, aggravated by movement and alleviated by resting. He also complained of muscle weakness in pectoral and pelvic girdle. At admission, he had tachypnea, tachycardia and fever. Lymphadenopathy was absent and the blood pressure was normal. The laboratory tests showed leukocytosis (21,100 leukocytes), thrombocytosis (573,000 platelets) and normocytic normochromic anemia. Lactate dehydrogenase (LDH) levels were 515 U/I and creatine phosphokinase (CPK) 282 IU/l. Chest x-ray revealed no abnormalities. During hospitalization, leukocytosis, thrombocytosis and normocytic normochromic anemia persisted, as well as increased LDH levels. Creatine phosphokinase returned to normal levels. The differential diagnosis of the nodular disease mainly considered myositis and vasculitis, methotrexate-related panniculitis, Weber-Christian disease, subcutaneous panniculitis-like T-cell lymphoma, erythema nodosum, bacterial, fungal and mycobacterial infections. At admission antibiotic therapy with oxacillin was initiated against infection by Staphylococcus. However, no specimen has confirmed the suspicion of diagnosis. These results hampered the investigation for presence of staphylococci bacteria and made the decision to maintain or not the antibiotics difficult. The patient's fever and skin rash persisted despite the therapy. On the seventh day of treatment, the antibiotic was changed to vancomycin at 500 mg qid intravenously for 14 days; no improvement occurred in the patient's clinical condition. The material collected from the lesions was studied for histopathology patterns, bacterioscopy and culture studies. Ultrasound confirmed a subcutaneous structural alteration on the posterior region of the upper third of the right leg, with 8 cm in size and without liquid. The possibility of purulent material being accumulated inside the lesion could not be discarded. Skin histopathology studies revealed acanthosis, edema of the reticular dermis, and mild infiltrate of lymphocytes with some neutrophils around vessels and skin adnexa. Panniculitis was suggested by the presence of subcutaneous necrosis of adipocytes, deposits of fibrinoid material and hyaline eosinophilic strands. Initially, aspirated secretion from the lesions was negative for acid-fast bacilli. One week later, a new sample showed acid-fast bacilli (+ + +). Rifampicin 600 mg qd, isoniazide 400 mg qd, pyrazinamide 2 g qd and ethambutol 1.2 g qd were initiated. Within a five-day treatment period the patient improved considerably, the fever disappeared and he was discharged. Culture studies revealed growth of Mycobacterium tuberculosis. Lesions were totally cured after 6 months.

PMC5821965_01

Female

A 16-year-old female was admitted to the hospital with a 7-day history of tenderness in the abdomen who was referred from another centre to us with reported ascites in ultrasonography. No chronic diseases, no alcohol use, no family history, no herbal agents, or no suspected drug use were reported. Vital signs of the patients were in the normal ranges with 36.3 body temperature, 120/70 arterial blood pressure, and 82/min heart rate. Our physical examination referred ascites in the abdominal region, and there was no other abnormal finding. Our laboratory results reported no anemia, no white blood cell elevation, and no thrombocyte abnormality. Her peripheral smear was normal with no atypical cells. No renal function or hepatic function abnormality and no electrolyte abnormality were also reported. CRP was 39 (normal range: 0-5 mg/L) and erythrocyte sedimentation level was 42 (normal range: 0-20 mm/h). Her chest X-ray was completely normal with no infiltrations or effusions. Her abdominal ultrasonography reported abdominal free liquid deposition, septations in the fluid accumulation, and multiple implants in peritoneal surfaces in hepatic diaphragmatic region and right paracolic area, in which the biggest one was 16 millimetres. Endometrium thickness was in the normal range, but in the left ovary, there was a septated cyst with dimensions of 39*27 millimetres (hemorrhagic cyst?). We suspected from ovarian pathology and performed paracentesis and sent this fluid to pathology laboratory. Pathology reported inflammatory cells which are rich in lymphocytes. There were no malignant cells in the fluid. According to the laboratory results, serum albumin ascites gradient was <1.1, and this showed us that the fluid was exudate. The patient's thyroid function tests were completely normal. Laboratory investigations showed the following values: AFP level 2.48 (normal range: 0-7 ng/mL), CEA level 0.39 (normal range: 0-3.8 ng/mL), CA15-3 level 26.15 (normal range: 0-26.4 U/mL), CA19-9 level 1.14 (normal range: 0-27 U/mL), and elevated CA125 level of 107.5 (normal range: 0-35 U/mL). Brucella markers and viral markers were negative. Although the patient had no encounter with any tuberculosis patient, we performed tuberculin skin test for differential diagnosis. As a result, it was anergic. Tuberculosis quantiferon PCR was negative, and ascites fluid direct microscopic examination revealed that there were no tuberculosis bacilli and acid-fast stain was negative. Tomography of the thoracoabdominal region revealed nasopharyngeal soft tissue with the dimensions of 20*18 millimetres, bilateral lymphadenopathies in the levels of 1a, 1b, 2, 3, 4, and 5, and right supraclavicular area in the cervical region. The nasopharyngeal biopsy revealed just lymphoid hyperplasia. Paratracheal and subcarinal lymphadenopathies were also seen, and the biggest one was 20*13 millimetres. Also, there were bilateral anterior diaphragmatic and right cardiophrenic lymphadenopathies. Abdomen tomography showed fluid accumulation and hepatic peritoneal surface nodular lesions. There were a reticular density increase in the omental area and a cyst in the left ovary with the dimensions of 23*18 millimetres. There were also lymph nodes in the mesenteric fatty tissue. Although malignancy was important for differential diagnosis, ADA (adenosine deaminase) level was 62 (normal range: 0-30 U/L). These results strongly supported tuberculosis. Then, we sent peritoneal fluid to the pathology laboratory again and no malignant cells were reported. Abdomen magnetic resonance imaging reported bilateral cysts in both the ovarian regions, bilateral expanded fallopian tubes, nodular opacities in the peritoneal region, and ascites (Figure 1). We performed trucut biopsy from nodular opacities in that peritoneal surface, and pathology laboratory reported granulomas with histiocytic cells in that specimen. We communicated with infectious diseases committee and started four-agent tuberculosis treatment (isoniazid, ethambutol, pyrazinamide, and rifampin) to the patient. After 6 months of treatment, she had good clinical response and ascites were completely absent.

PMC10476221_01

Female

A 23-year-old female presented with features of small bowel obstruction. She complained of vomiting for the past 3 days, failure to pass stools for 5 days and abdominal distension. She was diagnosed with HIV four years earlier, and had a CD4 count of 294 x 10 cells/microL with an undetectable viral load at presentation. Her cART comprised daily fixed combination of tenofovir, emtricitabine and efavirenz for the past four years. She reported no fever, weight loss or night sweats. On physical examination, she had an elevated blood pressure of 156/106 mmHg and a tachycardia of 150 beats per minute; however, she was apyrexial with a normal respiratory rate. Her abdomen was markedly distended, firm and generally tender. She had involuntary guarding and rebound tenderness. Digital rectal examination revealed an empty rectum. Per vaginal examination and assessment of other systems were unremarkable. The patient's biochemistry results are shown in Table 1. Patient's elevated white cell count (WCC) and inflammatory marker C-reactive protein (CRP) as well as neutrophilia indicated a systemic infection. Haemoglobin level was also abnormally low at 4.7 g/dL. All other parameters, including renal and liver function tests as well as arterial blood gas analysis (ABG), were normal. Air fluid levels were demonstrable on erect abdominal X-rays (see Figure 1). Computed tomography (CT) scan showed target signs with small bowel wall thickening and dilation. Intra-abdominal fluid collection was also evident (see Figure 2). The following differential diagnoses were considered: Abdominal tuberculosis, lymphomas, small bowel neuroendocrine tumours, gastrointestinal stromal tumours (GIST) and sarcomas. The radiological findings suggested intussusception, complicated by small bowel obstruction. After fluid resuscitation, the patient was prepared for an exploratory laparotomy. Intraoperative findings included a reducible intussusception at the ileo-caecal juncture and another at the mid-jejunum, which needed a wedge resection and a jejunostomy (see Figure 3). Bilateral ovarian tumours were observed, with the left larger than the right. Multiple intramural granulomatous masses, measuring approximately 1.5 cm x 1.5 cm, were disseminated over the entire small bowel. Some granulomas in the small bowel had broken down to release pus. The small bowel looked oedematous and had areas of haematoma. Jejunal intussusception and left ovary specimens were sent for histological analysis. A high-grade large B-cell NHL was found in the two specimens. The patient fully recovered from the bowel obstruction and gained full functional health while awaiting chemotherapy.

anaemia, bowel obstruction, granuloma, immunosuppression, intestinal lymphoma, intussusception, lead point, non-hodgkin’s lymphoma (nhl)

PMC7191395_01

Male

A 37-year-old man presents to the Emergency Department with abdominal pain exacerbation of 3 hours of evolution associated diarrhea with melena. The patient had a documented medical history of intermittent abdominal pain and diarrhea over the 6 months prior to the current admission. Upon admission, the patient presented febrile and in anasarca, with major edema in lower limbs. Initial blood work showed moderate microcytic anemia (Hb 10.3 g/dl, Hct. 23.7%, and MCV 75 fL), severe hypoalbuminemia (1.7 g/dL), inversion of albumin/globulin ratio, and CBC did not show signs of infection. The patient was started on protein replenishment with human albumin which resolved partially the edema. An exhaustive workout was performed to identify the underlying cause of the edema and low protein levels. Liver disease was ruled out due to normal liver profile (total bilirubin 0.21 mg/dL, indirect bilirubin 0.11 mg/dL, direct bilirubin 0.10 mg/dL, AST 9 IU/L, and ALT 8 IU/L) and the negative liver ultrasound. Nephrotic syndrome was also ruled out as a possible diagnosis. Due to the persistence of abdominal pain, structural damage or tumor processes were investigated; however, abdominal CT only showed edema in the small intestine wall suggesting chronic enteropathy. Although the patient was considered initially immunocompetent, there was a significant drop in complement C3 0.5 g/L (negative <0.8 g/L) and C4 0.03 g/L (negative <0.10 g/L). Further laboratory testing showed hypogammaglobulinemia (22 mg/dL IgA (normal 22-149 mg/dL), 150 mg/dL IgG (normal 615-1530 mg/dL), 20 mg/dL IgM (normal 31-272 mg/dL)), and 20 mL/24 hrs alpha-1 antitrypsin clearance. An upper digestive endoscopy was performed showing a whitish lace pattern and erythematous walls in the second portion of the duodenum. In addition, a colonoscopy showed hemorrhoidal packages, multiple ulcerated lesions in sigma, and elevated, pseudopolypoid, infiltrative lesions in cecum and ileocecal valve. Since our patient lived in a tuberculosis endemic area and that the lesions simulated intestinal tuberculosis, empirical antituberculosis therapy (isoniazid 75 mg, rifampicin 150 mg, ethambutol 275 mg, and pyrazinamide 400 mg) was started until biopsy results came back. Multiple cryptococci were found in samples taken from the cecum, sigma, and ileocecal valve using the techniques of immunohistochemistry CD68, Grocott stain, PAS stain, and Alcian blue stain (Figure 1). In addition, the presence of intestinal lymphangiectasia was confirmed with D240 staining (Figure 2). After receiving the pathology report, antituberculosis therapy was suspended and a regimen consisting of fluconazole 800 mg/day IV for 2 weeks, and octreotide 1 ml subcutaneously every 8 hours was initiated. Due to the severity of the presentation octreotide was started along with dietary treatment. Octreotide and oral fluconazole 600 mg were maintained for 90 days after discharge with favorable symptomatic evolution, additionally, following laboratory controls shown that albumin levels went back to normal.

PMC7569535_01

Male

A 57-year-old man was hospitalized in our service in 2017 to explore a mMRC grade 2 dyspnoea in the context of interstitial pneumonia on his chest X-ray. His main medical history was emphysema of upper lobes diagnosed 5 years earlier, his follow-up consisted of a medical consultation with CT scan and pulmonary function test every 6 months (his last spirometry found a FEV1/VC ratio of 73% and a DLCO of 71%); he also presented a ventricular tachycardia which required the installation of a cardiac defibrillator. We did not find any significant family medical history. This patient was living in a healthy house, but, reported multiple exposures. In his past work as a plumber, he was exposed to asbestos then he worked in a foundry with possible exposition to alloys of copper, bronze, iron, aluminium and zirconium compounds. He also described domestic exposures (hens of which he cleaned the excrement for 5 years) and during his current hobbies (welding, grinding); finally, he had a smoking history of 30 pack-years, stopping 10 years ago. His daily medications were amiodarone, bisoprolol and esomeprazole. On examination, we found finger clubbing and dry crackles at the lung bases at auscultation; the remainder of the clinical examination was without particularity, we did not find in particular any extra thoracic sign or symptom such as arthralgia, myalgia or a dry eye or dry mouth syndrome. High-resolution computed tomography (HRCT) showed ground glass opacities surrounding cystic lesions or emphysematous destruction; these anomalies predominated in posterior territories (Fig. 1a, 1b, 1c). The antinuclear antibodies (ANA) were at 1/200, speckled type and nonspecific; the rest of the autoimmune evaluation was without particularity. The search for bird fancier's precipitin was negative especially for hens' excrements. Bronchoalveolar lavage (BAL) found a macrophagic alveolitis (presence of 180 elements/mm3 including 80% macrophages, 5% lymphocytes, 10% neutrophils and 4.5% polynuclear cells eosinophils) with multinucleated giant cells. The bacteriological and mycobacteriological cultures were sterile. An accessory salivary gland biopsy showed no arguments for Sjogren's syndrome and the Schirmer's test was negative. Pulmonary function tests were the following: FVC 2.72L or 73% of the predict values, FEV1/VC ratio of 77%, DLCO at 27% of predict values. During a 6 -minute walk test, the patient travelled a distance of 434m with an 83% O2 desaturation. After a Multidisciplinary Discussion, it was decided to perform a surgical lung biopsy using video-assisted thoracoscopic surgery. The left lower lobe biopsy led us to find outbreaks of desquamative interstitial pneumonitis with "plump" macrophages associated with emphysema lesions and with numerous giant-epithelioid granulomas without necrosis, sites of dusting. We did not find foamy macrophage that could evoke an amiodarone impregnation (Fig. 2). Therefore, our conclusion was a Desquamative Interstitial Pneumonia associated with pulmonary granulomatosis. We studied the mineral particles on the lung biopsy with the following method: the anatomopathological slides were analysed with an electronic scanning microscope (JEOL JSM-6010LV) coupled to a spectrometer EDX (EDS detector Oxford Aztec-DDI X MAXN 50), each mineral particle has a specific spectre. This analysis revealed abnormally high rates of zirconium compounds (5.2% versus 0.0%), aluminium compounds (4.4% versus 0.05%), aluminium oxide (2.0% versus 0.2%) and steel (14.0% versus 0.6%) in our patient compared to a reference population from the Forensic Institute of Lyon (Fig. 3) . The diagnosis then retained in our patient is a Desquamative Interstitial Pneumonia associated with granulomas secondary to an exposure to metals: Aluminium, Zirconium compound and Steel. Systemic corticosteroid therapy at a dose of 0.75 mg/kg was introduced for 3 months followed by a progressive decrease over 1 year. The one-year evaluation showed (i) a clinical improvement: a reduction in dyspnoea to MRC grade 1 and an improvement of 80 meters over the distance covered in the 6-minute walk test; (ii) a functional improvement: the FVC was about 4.15L, i.e. 107% of predict values (gain of 34%) and the DLCO was 44% (gain of 17%); and (iii) a radiological improvement: the HRCT showed a marked improvement with the disappearance of the areas of ground glass opacities, however, there remained emphysematous zones that may correspond to its emphysematous medical history (fig. 1d).

aluminium lung, interstitial lung disease, metal analysis, zirconium lung, desquamative interstitial pneumonia

PMC5667532_01

Male

A 58-year old male patient was referred to our department due to normocytic anemia and leucopenia in May 2008. His anamnesis included mild diabetes type II and solitary congenital kidney with normal renal function, and he was on no medication. A complete blood count performed a year ago was showing hemoglobin (Hb) 121 g/L and average leukocyte count (WBC) and platelet counts. The patient was in relatively good condition complaining only of mild fatigue, and the physical examination was unremarkable. Haemoglobin was 74 g/L, platelets 165 x 109/L, MCV 83 fl, WBC 2.98 x 109/L and the absolute neutrophil count (ANC) 1.4 x 109/L, while biochemistry, including LDH, was normal. The rest laboratory workup revealed erythropoietin serum level of 19.6 IU/L (normal range 3.3-24.4 IU/L), ferritin levels 418 ng/dl and B12 levels 1166 pg/ml. The blood film showed dimorphic red cells, and hypogranular neutrophils with ringed nuclei (Figure 1a) and the bone marrow aspirate was consistent with refractory anaemia with multilineage dysplasia, and 40% ringed sideroblasts (RCMD-RS). Blast count was 1%. Bone marrow biopsy also revealed a hypercellular marrow with trilineage dysplasia and grade I reticulin fibrosis by Gomori's silver stain. Cytogenetic studies were performed in bone marrow by using conventional G-banding analysis and showed 12/20 metaphases carrying the 46, XY, i(17q)(q10) and 8/20 residual normal metaphases. By using PCR we found mutations in SETBP1, U2AF1 and KIT genes, whereas no mutations were found in SF3B1, JAK2, MPL, CALR, IDH1, IDH2, DNMT3A, SRSF2 and ASXL1 and no chimeric transcripts of BCR/ABL were detected. The patient was transfused and started on recombinant erythropoietin (EPO) at 40.000 IU/week. Two months after, Hb was 87 g/l, and we doubled the EPO dose at 80.000IU/week. He remained untransfused for 7 months when his Hb rose at 112 g/L, and although EPO was reduced to 40.000 IU/week, after 3 months the Hb levels reached 140 g/L, and EPO was discontinued. He did not receive further EPO for 12 months, being asymptomatic with normal Hb levels, whereas due to a synchronous rise in WBC and platelet counts we performed JAK2V617F mutation analysis with negative results. However, 24 months after diagnosis the patient developed splenomegaly 5cm below left costal margin and low-grade fever peaking in the afternoon. His Hb dropped at 84 g/L, his platelet count at 103 x 109/L and the WBC rose to 21.7 x 109/L. Peripheral blood smear showed 9% blasts, and immunophenotypic analysis by 4-color flow cytometry demonstrated a CD45low population with typical myeloblast phenotype, positive for CD34, CD117, CD33, HLA-DR and CD13, and negative for CD15, CD19, CD10, CD56, CD7 and CD61 (Figure 1b). The aspirate was unsuccessful (dry tap) and the bone marrow biopsy showed a hypercellular marrow with myeloid and megakaryocytic hyperplasia, decreased erythropoiesis, 9% blasts, and reticulin fibrosis grade 2-3, whereas low-grade collagen fibrosis was also present. A new cytogenetic study was pursued and, unexpectedly, revealed a regular 46, XY[30] karyotype and normal FISH findings (Supplemental Figure S1), whereas his mutational profile remained unchanged. The patient received 5 courses of subcutaneous azacytidine at 75 mg/m2 for seven days on 28-day cycles, but his splenomegaly progressed, and along with the ongoing fever he developed night sweats and weight loss. We administered induction chemotherapy with cytarabine (Ara-C) 100g/m2/d iv d1-7 and idarubicin 12 mg/m2/d iv d1-3, but the patient succumbed to sepsis after 23 days. The course of the patient's CBC is shown in Figure 1c.

isochromosome, mds, spliceosome

PMC6719466_01

Male

This is a 21-year-old Caucasian male with a history of recurrent episodes of generalized joint pains (polyarthralgia) over a 2-year period before the current presentation. These recurred multiple times and resolved spontaneously with no specific rheumatologic diagnosis (he was HLA B27 negative). The only pertinent findings of note on physical examination were diffuse cervical lymphadenopathy, inflamed tonsils and splenomegaly. The patient had been experiencing polyarthritis for the previous 2 years. These arthralgias and arthritis recurred multiple times, however would resolve spontaneously without any treatment. No specific diagnosis made under Rheumatology Care. Due to increased dysphagia and potential airway compromise, he underwent a tonsillectomy at the beginning of August 2015. At the same time, he was also noted to have diffuse lymphadenopathy as well as splenomegaly. Computed tomography (CT) scan showed bilateral tonsillar hypertrophy which was dealt with surgically. For anaemia, he had upper and lower gastrointestinal scopes which showed no lesions, a subsequent capsule endoscopy showed ulceration in terminal ileum. This was followed by a double balloon push enteroscopy for tissue diagnosis. He lives with his parents and played competitive Ice Hockey. He was a non-smoker, occasional alcohol user and not a recreational drug user. He worked mainly at construction sites. Escitalopram 20 mg daily May and June 2014, Pregabalin 50 mg three times daily from July to December 2014, Duloxetine 30 mg daily from December 2014 to June 2015. Patient underwent tonsillectomy for dysphagia and potential airway compromise in the community before his referral to nephrology service. The tonsillar tissue did not show any evidence of lymphoproliferative disorder on histopathology. Further workup showed a positive cANCA with PR3 positivity (a titre of 881 MFU (Normal < 120 MFU)). Chest x-ray showed vague pulmonary infiltrates, and the patient tested negative for tuberculosis (Figure 1). CT chest showed pulmonary parenchymal findings in keeping with an infectious process (Figure 1). He had evidence of significant anaemia and underwent an endoscopy for gastrointestinal symptoms and anaemia (Haemoglobin 63 g/L (Normal 135-175 g/L)) that showed only ulceration in terminal ileum. The biopsy of the intestinal tissue did not show any evidence of vasculitis. The kidney function was normal at presentation and remained stable (within the normal range) throughout the follow-up period (Figure 2). At 2 months of follow-up, he was noted to have new onset of microscopic haematuria and low-grade proteinuria. Urinalysis showed 1+ haemoglobin and trace protein, and urine protein: creatinine ratio of 36.9 mg/mmol (Normal < 13 mg/mmol) (Figure 2). Urine Microscopy for sediment showed dysmorphic red blood cells. A urinalysis completed 3 months prior to presentation was completely bland (we could not trace any urinalysis after this till Nephrology was consulted). Relevant serology results were all negative except for the ANCA PR3 positivity. The serology workup completed was as follows, and were all negative or within a normal range: Antinuclear antibody (ANA) Rheumatoid factor <10 (20 KU/L) Anti-cyclic citrullinated peptide (anti-CCP) < 8 (0-16 U/ml) Anti-double stranded DNA (anti-dsDNA) 14(<120 MFU) Extractable nuclear antigens (ENA) Hepatitis B surface antigen (HBsAG) Hepatitis B surface antibody (HBsAb) 4.98 IU/L Hepatitis C antibody Parvovirus IgM Serum complements [C3 1.1.(0.80-2.1 g/L) and C4 0.38(0 > 15-0.50 g/L)] IgG 12.6 (6.94-16.18 g/L) IgA 2.51 (0.70-4 g/L) IgM 0.87 (0.60-3.00 g/L) Immunoglobulins: Based on the previous features of a systemic illness and new findings on urinalysis and urine microscopy, the patient underwent a kidney biopsy, and the tissue was analysed and reported by our pathology service (Figure 3). The diagnosis was in keeping with ANCA-associated vasculitis (focal proliferative and necrotizing glomerulonephritis). In summary, there were 11 glomeruli present in representative sections, and two contained segmental proliferative foci. The remaining glomeruli showed no conspicuous changes on light microscopy. In the plastic embedded material prepared for electron microscopy, the light microscopy revealed seven additional glomeruli of which one showed segmental sclerosis and another showed segmental proliferative focus with crescentic formation. There was mild interstitial edema and patchy mild interstitial fibrosis and tubular atrophy without significant interstitial inflammation. In consultation with our pathologists, the lesion was classified as focal based on Berden's classification. We did evaluate the case using the Birmingham Vasculitis Score (BVAS), and overall score was eight.

anti-neutrophil cytoplasmic antibody–associated glomerulonephritis, asymptomatic urinary abnormalities, normal renal function, young adult

PMC7278298_01

Female

A 33-year-old Caribbean Black woman with no prior medical history presented to the emergency department with a 1-week history of fever, dyspnea, and generalized weakness. There was no reported history of night sweats. The patient experienced a 5-month duration of unintentional weight loss of approximately 20 pounds. The patient is a medical doctor; however, there was no exposure to patients with tuberculosis. The family history was significant for first-degree relatives with Hodgkin's lymphoma and cholangiocarcinoma. The patient was tachycardic at 130 beats per minute, tachypneic at 24 breaths per minute, saturating 92% on high flow nasal cannula. There was decreased air entry at the lower base of the left lung. A chest radiograph revealed complete opacification of the left lung zone ("white-out") and a mediastinal mass. A 12-lead electrocardiogram demonstrated marked sinus tachycardia with secondary ST-T changes suggestive of "demand-ischemia." An arterial blood gas sample was consistent with mixed respiratory and metabolic acidosis. The initial tentative diagnosis was suspected type 1 respiratory failure, likely multifactorial from the large pleural effusion in addition to suspected pulmonary embolism. A subsequent computed tomography "pulmonary embolism protocol" scan confirmed an anterior mediastinal mass (6.9 cm x 3.2 cm x 2.6 cm) with an associated large-sized left pleural effusion with perihilar lymphadenopathy and metastatic nodules. It also revealed a large right atrial thrombus (3.8 cm x 2.5 cm x 3.2 cm) without overt pulmonary emboli (see Figures 1 and 2). She was subsequently transferred to the intensive care unit, where she was stabilized and initiated upon therapeutic enoxaparin, low-dose aspirin, statin, ivabradine, and beta-blockade based on her high-risk Khorana score of 3. Her routine blood investigations were reflective of dehydration (see Table 1). She also had 350 mL of serosanguinous fluid aspirated from her left lung via thoracentesis. Blood, urine, and pleural fluid cultures returned without bacterial growth. During her ensuing 2-week hospitalization, histopathology revealed features suggestive of thymic carcinoma. Neoadjuvant therapy comprising cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC) was commenced. Surgical resection of the mass was performed where it was discovered that the tumor had metastasized to the left lung. Subsequent biopsies confirmed this diagnosis, and the neoplasia was staged as pT4 Nx M1. A transesophageal echocardiogram and cardiac MRI (magnetic resonance imaging) confirmed the presence of the right atrial thrombus (see Figures 1 and 2) with a preserved ejection fraction and no McConnell's sign. She was discharged on most of her inpatient regimen and also transitioned from enoxaparin to oral rivaroxaban at 15 mg twice daily for 3 weeks, thereafter at 20 mg daily for 3 months based on her intermediate-risk HAS-BLED score of 2. During this period, she underwent six cycles of gemcitabine and capecitabine chemotherapy, and a subsequent computed tomography scan 3 months later revealed near-complete right atrial thrombus dissolution (1.1 cm x 2.1 cm x 0.9 cm) (see Figure 3). She has a scheduled serial scan in 3 months with interim outpatient cardiology follow-up appointments.

thymic carcinoma, direct oral anticoagulation, rivaroxaban, thrombus, thymoma

PMC6451813_01

Male

The patient was a 46-year-old Hispanic male who presented with a six-month history of productive cough and pleuritic chest pain associated with intermittent episodes of fevers and chills. Approximately three months into his symptoms, the patient began to experience dysphagia and subsequent decreased appetite. His dysphagia progressed from solids to liquids. He denied having trouble breathing. The patient reported an unintentional 40-pound weight loss over the three-month period following the onset of his dysphagia. His vital signs were within normal limits, and the patient appeared his stated age. The physical exam was remarkable for cachexia. Initial lab work was unremarkable. Initial chest X-ray revealed a prominent right upper lobe cavitary lesion (Figure 1). Further workup was obtained with a CT chest, which showed "tree-in-bud" opacities in bilateral lung fields, along with "thick walled" cysts of the right upper lobe (Figure 2). This was reported to be suggestive of TB versus fungal infection. Additionally, the imaging revealed mediastinal lymphadenopathy. Sputum acid-fast bacilli (AFBs) were collected, and the patient started treatment with rifampin, isoniazid, pyrazinamide, and ethambutol (commonly referred to as RIPE therapy), prior to sputum acid-fast bacilli cultures returning positive. To determine the etiology of the dysphagia, the patient underwent a swallow evaluation which revealed combined oral and pharyngeal dysphagia. Follow-up studies with an esophagogastroduodenoscopy (Figure 3) and bronchoscopy (Figure 4) revealed bronchoesophageal fistulas, which were presumed to be a result of MTB infection. Given his inability to tolerate oral nutrition, a percutaneous endoscopic gastrostomy (PEG) tube was placed for nutritional purposes. Once he was able to tolerate PEG tube feeds, he was discharged home on RIPE therapy and given a follow-up appointment in an infectious disease clinic. At a three-month follow-up appointment on RIPE therapy, the patient was able to tolerate oral nutrition. He was reevaluated with a bronchoscopy (Figure 5), which showed interval healing of the bronchoesophageal fistulas. Since the patient was tolerating a regular diet, the PEG tube was scheduled to be removed three months after it was placed. The patient followed up at nine months in the clinic. At that time, he reported no symptoms. He completed a nine-month course of RIPE therapy with no further complications.

PMC4602323_02

Male

The Childhood Autism Rating Scale, Second Edition (CARS-2), was administered as part of a routine evaluation of the child's severity prior to a change that is his academic placement. Prior to PEA, CARS-2 scoring placed the child at 43.5 total (82nd percentile) with a verbal communication subscale of 3 out 4. A speech assessment was performed including a mean length of utterance (MLU) measurement. MLU is based on the linguistic concept of morphemes as the smallest component of speech. Speech therapists use MLU as a routine assessment and, in this case, MLU was obtained prior to a change in school placement. MLU was observed to be 3.0 prior to PEA and this corresponded to an age equivalent of approximately 34-35 months (just under a 3-year-old level of speech). After the practitioner reviewed the medical literature and the therapeutic rationale with his parents, they treated the child with Normast 600 mg tablets (Epitech Group Srl, Milano, Italy). Normast is available without prescription in Italy and Spain and is classified as "Food for Special Medical Purposes" by the Health Authorities of European Union member states according to standards set forth under European Commission Directive 1999/21/EC. Initially, 1/2 tablet (300 mg) was given orally with water twice daily on an empty stomach to this boy (a child capable of swallowing tablets). After a week with no observable negative effects, the dose was increased to 1 (600 mg) tablet twice daily. Subject 1's parents returned for assessment after one month of oral supplementation with PEA. They reported "remarkable" changes in his behavior and his expressive language. Specifically, they noted he was spontaneously joining a conversation and commenting on various things happening in the home. The parents also reported the schoolteacher and speech therapist inquired about what had changed and noted similar positive changes at school. Equally noteworthy was the significant reduction in tantrums, outburst, self-talking, and stereotypies. Further, nose-picking, asthmatic cough, allergy stigmata (dark circles under eyes and nasal itching), nasal edema, and both skin eczema and urticaria diminished clinically after a month of PEA administration. No adverse effects were noted. Following these comments, we readministered the CARS-2 test and noted a total score of 32 (representing the 28th percentile) whereas the starting score was 43.5 (net change 11.5 points and 54 percentiles less). The subscale for expressive language changed to 2 out 4 and represented significant and noticeable changes. Due to these observations, we suggested repeating the MLU assessment for further definition of the degree of language changes. Reassessment of MLU also changed significantly to 5.4 (approximately 58 month's age-equivalency). This represented a 2-year age gain in expressive language in only one month of supplementation with PEA. Total serum IgE testing after PEA was introduced remained essentially unchanged at 567 IU/mL (nl < 200). Serum vitamin D-OH25 levels rose to 46 ng/mL after PEA was started (possibly due to better absorption). CD57+ natural killer (CD57+ NK) cell counts increased after PEA to 52 cells/muL (nl = 60-300 cells/muL), with a total white count remaining similar at 5.6 x 103/muL. Noticeably the percentage of lymphocytes reduced to 44%, and the other cell indices were also in the normal range.

PMC3238472_01

Unknown

A 45-year old Caucasian women was diagnosed with tuberculous spondylitis and paraspinal abscess. M.tuberculosis could be isolated from intraoperativ biopsy; resistance testing revealed a completely sensitive strain. On July 2, treatment was started with rifampicin (RIF) 600 mg/day, Isoniazid (INH) 300 mg/day, Pyrazinamid (PZA) 1500 mg/day and Ethambutol (ETB) 1200 mg/day. After results of the resistance test where available, Ethambutol was stopped. Liver enzymes where elevated at one occasion but fell into normal range spontaneously. After two month of combination therapy RIF/INH/PZA, PZA was stopped according to international guidelines. Four month after begin of treatment, liver enzymes rose again, and INH was replaced by moxifloxacin. Liver enzymes fell to normal level, but the disturbed liver enzymes where later interpreted as alcohol induced. December 12, progression of the paraspinal abscess was diagnosed, and the treatment was stopped for allowing new biopsies. On January 5, 2010, the patient was re-operated but mycobacteria couldn't be cultured in this second biopsy. Antimycobacterial treatment was reinstalled January 7. Because of possible non-compliance, we started again with a four drug combination for one month, followed by INH/RIF/PZA. The patient then did not come to the visits until April 12. At that time the patient complaint about shortness of breath NYHA 2. Haemoglobin level had fallen to 47 gram/L with a mean cell volume of 96 fl and a mean cell haemoglobin concentration of 334 g/L. PZA was stopped, but the other treatment was not changed. Two packs of red blood cells where transfused the day after. One week later, haemoglobin level had risen only to 51 gram/L. Bone marrow aspiration and biopsy was performed on April 20 (under Isoniazid-treatment). Isoniazid was substituted by moxifloxacin, rifampicin was not changed. Again two packs of red cell where transfused. Haemoglobin level rose to 89 gram/L, and reticulocyte production index rose from 0.48 to 2.9 one week after cessation of Isoniazid. No further transfusions where needed, and one week later, haemoglobin level was at 100 gram/L (Figure 1). Folic acid, Cobalamine and Ferritin values where in normal range, Parvovirus B19 PCR was negative. Bone marrow was not typical for PRCA, as it showed an enhanced, dysplastic erythropoiesis with 30% ringsideroblasts (Figures 2 and 3). No rearrangement of the MLL gene could be observed by fluorescent in situ hybridisation (FISH). Erythrocyte count in peripheral blood was 1.5 G/L. Erythropoietin level was high, 1171 IU/L (normal range 12-23) and erythropoietin antibodies negative. Under treatment with rifampicin/moxifloxacin, haemoglobin levels returned to normal level and remained stable.

isoniazid, sideroblastic anaemia, tuberculosis

PMC6942731_01

Female

A 13-year-old right-handed girl presented to our outpatient clinic with motion pain and apprehension of her right elbow. The symptoms included intense pain with apprehension at the elbow when the forearm was supinated, which had been present since playing basketball 1 week earlier. On the other hand, asymptomatic stiff prominence at the anterolateral aspect of her right elbow had been recognized for 3 years. The painless phenomenon had been present when the forearm was supinated and absent when the forearm was in neutral to pronated positions. A physical examination revealed anterior dislocation of the RH when the forearm was supinated to an angle of approximately 30 or more, regardless of the elbow position (flex-extension). There were no deficits in the ranges of motion (ROMs) of the elbow and forearm. No general joint laxity was found. Plain radiographs (Figures 1(a) and 1(b)) and computed tomography (Figures 2(a) and 2(b)) performed at our clinic revealed isolated RH dislocation without deformity at the radius or ulna. Notably, the RH was anteriorly dislocated with the forearm in supination; whereas, complete reduction of the RH to the intact position could be obtained in neutral to pronated forearm positions. Magnetic resonance arthrography revealed the absence of the annular ligament (Figures 3(a)-3(c)). Surgical treatment was performed under a diagnosis of recurrent RH dislocation due to insufficiency of the lateral collateral ligament complex. With tourniquet control, a 6 cm skin incision was created at the lateral elbow. Through Kocher's approach, the absence of the annular ligament in contrast to the continuity of the lateral ulnar collateral ligament (LUCL) was identified. The proximal region of the LUCL corresponding to part of the radial collateral ligament (RCL) was found to be relatively thin and fragile. The RH was easily dislocated with the forearm in supination; however, in neutral to pronated positions, the RH was reduced with suppression by tension of the supinator muscle. We performed surgical treatment with a focus on the reconstruction of the annular ligament (Figures 4(a)-4(c)). We also aimed to facilitate the RCL because of potential weakness against varus stress. We harvested the plantaris tendon (width, 3 mm; length, 20 mm) from the ipsilateral leg. We decided to harvest the tendon because the palmaris longus tendon had been found to be of insufficient width and length for grafting according to preoperative sonographic examination. Moreover, we used 1.3 mm SutureTape (Arthrex, Naples, FL, USA) to increase the initial strength of the reconstructed regions, according to the concept of internal brace augmentation. A bony tunnel was created with a 3.5 mm cannulated drill at the radial aspect of the proximal ulna, and the loop of a number 2 FiberWire (Arthrex) was advanced through the tunnel. Then, the graft complex composed of the autograft tendon and the SutureTape were shuttled through the loop. After completing double-bundled reconstruction of the annular ligament, the graft complex was fixed to the tunnel using an interference screw (3 x 13.5 mm SwiveLock, Arthrex). The end of the graft complex was advanced proximally and fixed to the lateral condyle using a soft anchor (FiberTak, Arthrex) that had been placed at the region where the RCL attached. Postoperatively, the patient was immobilized with a long-arm spica orthosis for 2 weeks and performed ROM exercises that were taught by a therapist. Daily activities were encouraged after the removal of the orthosis. However, the patient was instructed to avoid excessive exercise that supinated the forearm and to avoid returning to sports until 6 weeks and 3 months after surgery, respectively. At a 12-month follow-up examination, the patient had no pain or elbow limitation (Figures 5(a)-5(d)). The patient successfully returned to sports. Plain radiographs and magnetic resonance imaging (Figures 6(a)-6(d)) showed that the reconstructed annular ligament could support the position of the RH.

PMC5421091_01

Female

A 36-year-old, morbidly obese primigravida presented at our emergency room at 17 + 0 weeks of gestational age complaining of abdominal pain. At clinical examination, the uterus appeared to be of higher volume compared to the gestational age, the abdomen was painful but treatable, and the obstetrical examination was normal. The patient was then referred to US Unit of our Department for further evaluation. The sonographic assessment revealed the presence of three subserous uterine myomas located on anterior wall (maximum diameter: 13.2 cm), the right wall (maximum diameter: 12.6 cm), and the left wall (maximum diameter: 11.7 cm) of the uterus, respectively. All myomas were vacuolated inside as for suspected necrosis. The scan also showed other multiple myomas less than 3 cm in size. Vital signs were monitored (blood pressure 140/90 mmHg, maternal heart rate 124 bmp, SO2 94%, apyretic). Amniotic fluid was normal and fetal well-being was preserved. Thus, the patient was admitted to the High-Risk-Pregnancy Unit. When collecting the medical history, the first trimester ultrasound scan, performed at 11 weeks' gestation, revealed the presence of the same lesions with a size of 10.8 cm, 10.2 cm, and 6.14 cm, respectively. Laboratory studies demonstrated rising inflammatory markers (C-reactive protein: 354 mg/L; WBC: 16.92 x 103 muL). Due to the persistence of the symptoms, despite of two days of analgesic, antispastic, and antibiotic therapy, after multidisciplinary discussion, and a thorough counseling to inform the parents of the surgical and postoperative risks connected with uterine surgery during the gestation, the patient underwent surgery. Laparotomy approach by longitudinal skin incision, considering the volume and the position of the myomas, was performed under general anesthesia. Three huge bulky subserous pedunculated myomas were evidenced, the largest located at the uterine fundus, with a maximum diameter of 15 cm and a torsion of its pedicle (Figure 1). Furthermore, intra-abdominal adhesions were found within peritoneal cavity. Blunt dissection was undertaken to free the omentum and look for the appendix, which was normal. The three large myomas evidenced by ultrasound were removed and sent for pathologic examination. A pelvic drainage was left and removed 24 hours postoperatively. Pathology showed widespread phenomena of necrosis, especially in the myoma with torsion of its pedicle. During the following nine days, the patient received antibiotics, low molecular heparin, and progesterone, and fetal heartbeat was checked daily. Considering the improvement in clinical condition, the patient was discharged with an indication to treatment with progesterone and low molecular heparin. Three weeks later, at 21 weeks' gestation, the patient was admitted again due to abdominal pain. Obstetrical evaluation revealed cervical effacement and the transvaginal ultrasound scan showed a reduction of cervical length (18 mm), funneling, and sludge. An ultrasound scan was performed showing good fetal variables. Consequently, the therapy with progesterone was increased. The patient had a positive vaginal culture for Staphylococcus haemolyticus, urine culture was negative, and C-reactive protein resulted to be positive. Therefore, antibiotic therapy with macrolides was given, according to antibiogram result. A cervical cerclage was proposed to the patient, but she refused to undergo the procedure. Hospitalization lasted for seven days; then the woman was discharged due to an improvement of her clinical condition. The patient underwent obstetric evaluation every two weeks until she presented in labor and delivered vaginally at 38 + 1 weeks' gestation a healthy female newborn of 2940 g, appropriate for gestational age according to national growth curves. Apgar score was 9/10 at 1' and 5' respectively. To identify potentially eligible studies, we searched PubMed, Scopus, and Cochrane Library (all from inception to 16 March 2017). No language restrictions were initially applied. We used a combination of key words and text words represented by "myomectomy," "myoma," and "pregnancy." Two reviewers (Annachiara Basso and Mariana Rita Catalano) independently screened the titles and abstracts of records retrieved through database searches. Both reviewers recommended studies for the full-text review. The screen of full-text articles recommended by at least one reviewer was done independently by the same two reviewers and assessed for inclusion in the systematic review. Disagreements between reviewers were resolved by consensus. For all full-text manuscripts, reference lists were analyzed in order to find additional eligible studies.

PMC9166903_02

Female

A 64-year-old female patient with a history of cervical cancer was admitted in our clinic for odynophagia, anorexia and weight loss, all due to a nodular, ulcerated, infiltrating mass on the left side margin of the tongue, extending inferiorly towards the ventral surface (Figure 2). The lesion was described as a tumor, and a biopsy was taken. Chest X-ray showed bilateral diffuse micronodular and nodular opacities, and an infectious substrate was suspected. Pneumology consult raised a suspicion of secondary pulmonary tuberculosis. A surgical consult for intense abdominal pain with muscular defense established a diagnosis of acute abdomen with generalized peritonitis. An emergency segmental enterectomy of the jejune was performed. Macroscopic inspection revealed a semi-circumferential and transverse ulcer. Histopathological examination of both lingual biopsy and jejune resection specimen showed numerous caseous and non-caseous epithelioid and giant cells granulomas (Figure 3). Acid-fast bacilli were identified using Ziehl-Neelsen stain (Figure 4), and the diagnosis of lingual and jejunal tuberculosis was established. Unfortunately, the patient's postoperative evolution was severe, and she died within 10 days from being admitted in the intensive care unit, from acute circulatory and respiratory insufficiency.

case report, extra nodal, head and neck, nasopharynx, oral tuberculosis, tuberculosis

PMC9166903_03

Female

A 71-year-old female patient was referred to our clinic from a Psychiatric Hospital (where she was institutionalized for several years) for the diagnosis and treatment of a round, mobile, elastic, submandibular tumor of around 5 cm, which has been slowly growing in the last year (Figure 5). The fact that she had no close relatives and a scarce medical record, made it impossible to establish a history or opportunity of TB contact. However, the fact that she came from a psychiatric institution may be considered circumstantial evidence in this direction. The evaluation protocol included a complete ENT, chest X-ray and complete blood work, all of these showing minimal changes. The mass was excised under general anesthesia, and an additional smaller one (about 1 cm) was found intraoperatively, beneath it. Both masses had suppuration, being filled with a creamy yellow puss. The histopathological examination revealed lymph nodes with modified architecture, with frequent granulomas of various shapes and sizes, necrosis, giant multinuclear cells, areas of ulceration and granulation (Figure 6). The patient followed an uneventful post-operative course and was referred to the Infectious Disease Department for further diagnosis and treatment. The final diagnosis of primary tuberculous adenotonsilitis was set by special cultures and AFB staining of the sputum, and the classic WHO Category-3 regimen was employed. Follow-ups at 3, 6 and 12 months revealed no sign of recurrence or residual disease.

case report, extra nodal, head and neck, nasopharynx, oral tuberculosis, tuberculosis

PMC9166903_04

Male

A 74-year-old male patient was referred to our clinic from the same Psychiatric Hospital as Case 3, which led us to the conclusion that a TB exposure is present in that institution. He presented with a 5 to 6 cm round, mobile, elastic, supraclavicular tumor on the left side that has been slowly growing for the last year. A complete medical history and TB exposure history was also impossible to obtain. The evaluation protocol included a complete ENT, chest X-ray and blood work showing minimal changes. The mass was excised under general anesthesia and sent for histopathological examination. It also had suppuration and was filled with creamy yellow puss. The histopathological examination revealed similar results as Case 3, with intensely modified lymph nodes by the presence of frequent granulomas of various shapes and sizes, necrosis, giant multinuclear cells, areas of ulceration and granulation. The post-operative course was in this case rather laborious due to the precarious healing of the wound (Figure 7) which had to be re-stitched several times until it completely healed. After complete recovery, the patient was referred to the Infectious Disease Department for further diagnosis and treatment. The final diagnosis of primary tuberculous adenotonsillitis was set by special cultures and AFB staining of the sputum and the classic WHO Category-3 regimen was employed. Follow-ups at 3, 6 and 12 months revealed no sign of recurrence or residual disease. Case 1, 3 and 4 did not receive the positive diagnosis of tuberculosis in our surgical clinic, but after they were sent to the infectious diseases clinic. Thus being said, the four cases of extra-pulmonary tuberculosis had minimal, non-specific changes in regards to the laboratory and imaging studies, having had modified erythrocyte sedimentation rates (elevated ranges of approximately 3 to 4 times the normal values) and elevated fibrinogen values (above the normal range), revealing the active inflammatory state of the patients. At the same time, the X-rays of patients 1, 3 and 4 had minimal changes, with accentuated interstitial pattern, while in case 2, the X-rays revealed a more complex reticular pattern with micronodules and a condensing area located peripherally, in the right medial lung lobe. In case 2, at first the patient refused the surgical intervention on her abdomen (due to intense, diffuse pain both spontaneous and when palpating, with muscle defence and right pneumoperitoneum), having accepted only the biopsy from the tongue pseudo-tumor. A diagnosis of perforated bowel (or perforated stomach) accompanied by acute peritonitis was established and due to worsening of symptoms, the patient consented to being operated, with the aforementioned final development.

case report, extra nodal, head and neck, nasopharynx, oral tuberculosis, tuberculosis

PMC8450265_01

Male

A 23-year-old healthy Caucasian male presented to the emergency department (ED) with acute intermittent, severe substernal chest pain radiating to both forearms. He had experienced two similar episodes during the prior week which were of lesser severity and had resolved spontaneously. The day of admission, his symptoms returned with increasing severity, prompting presentation to the ED. The patient's past medical history included generalized anxiety disorder and seasonal allergies. He denied any personal or family history of cardiac disease. He worked as a landscaper and denied recent illnesses or sick contacts. He consumed alcohol infrequently, chewed tobacco, and did not smoke or use illicit drugs. He had recently returned from a three-day camping trip to Pigeon Forge, Tennessee one day prior to the first episode. He denied any history of international travel or Tuberculosis risk factors. Animal exposures included a pet dog and chickens. Sublingual nitroglycerin administered en route to the ED improved his pain with complete resolution of symptoms by one hour. Vital signs were temperature 98.5 F, pulse 68, blood pressure 128/75, and SpO2 98% and physical examination was without pertinent findings. Initial differential included acute coronary syndrome, stress-induced cardiomyopathy, myocarditis, pericarditis, and pulmonary embolism. Initial electrocardiogram (ECG) revealed only subtle lateral ST elevations (Fig. 1). Laboratory work-up revealed an elevated serum troponin of 8.51 ng/mL with peak of 12.8 ng/mL (normal< 0.30 ng/mL), mildly elevated transaminases of aspartate aminotransferase and alanine aminotransferase at 108 and 91, respectively, with otherwise unremarkable complete blood count, basic metabolic panel, erythrocyte sedimentation rate, C-reactive protein, D-dimer, urine drug screen, and chest x-ray. COVID-19 real-time reverse-transcription polymerase chain reaction (PCR) was negative. Urgent coronary angiography showed normal coronary artery anatomy with no acute obstruction. Left ventriculogram showed no wall motion abnormality or changes suggestive of stress cardiomyopathy. Transthoracic echocardiography was normal with left ventricular ejection fraction 60-65% and no structural heart disease or pericardial effusion. Cardiac magnetic resonance imaging (cMRI) showed evidence of biventricular myocarditis and failure, with LVEF of 45% and RVEF of 41% (Fig. 2). Comprehensive infectious work-up (Table 1) subsequently revealed elevated Toxoplasma gondii IgM and IgG titers (IgM > 160 AU/mL, IgG 36.7 IU/mL). The patient was initiated on a planned four-week course of pyrimethamine, sulfadiazine and leucovorin plus guideline-directed medical therapy for ventricular systolic dysfunction. He had ophthalmologic evaluation which ruled out ocular involvement. HIV testing, which had been performed and was negative during the initial work-up, was repeated to rule out the possibility of false negative result and was again negative. As myocardial biopsy was ultimately deferred given clinical improvement with antibiotics, serial toxoplasma serologies were followed to support diagnosis (Table 1): at 5 days, IgM was> 160 AU/mL and IgG 97.6 IU/mL, and at 5 weeks, IgM was> 160 AU/mL and IgG 117 IU/mL. During follow-up evaluation with cardiology and infectious disease, he only complained of occasional intermittent fatigue with otherwise complete return to baseline without limitation in activity level. Eighteen days into the planned four-week antimicrobial course, he developed significant gastrointestinal intolerance and antimicrobial therapy was stopped. It was not restarted given his symptomatic improvement and return to clinical baseline. Repeat echocardiography performed five weeks after discharge showed normal cardiac function. The patient was instructed to have repeat cardiac MRI in 6 months to ensure sustained resolution of myocarditis.

cardiac magnetic resonance imaging, immunocompetent, myocarditis, toxoplasmosis

PMC3461289_01

Male

A 82-year-old man was admitted to our hospital with a 7-day history of fever of unknown origin. He had a history of colonic diverticulitis but no other infective hotbeds were found. Gastrointestinal investigations were inconclusive. A virtual colonoscopy was asked in order to discover a possible cause of fever as patient could not perform the optical one because he had a very low FE and he was having oral anti-coagulant therapy. In order to obtain a suitable bowel cleaning, patient was asked to follow a low dross content diet during the three days before the examination; the morning of the CTC, patient was asked to drink about 200 mL of dimeglumine diatrizoate (Gastrografin, Bayer-Schering) in order to tag both feces and fluid remains. A previous basal CT scan was obtained in order to exclude the presence of radiological sings of an active diverticulitis which is a contraindication to CTC because at risk for colonic perforation. CTC, performed after gently colonic room air distension, showed the presence of many diverticula spread on the whole colon, especially at the level of sigma, without any lumen stenosis, any evidence of masses or polyps. As extracolonic findings, it was reported the appearance of gas in mesenteric vein (Figures 1(a) and 1(b)) and within the portal venous system, involving both hepatic lobes (Figure 2). There was no evidence of pneumatosis intestinalis or colonic perforation or free fluid in the abdomen. Then, a CT scan without enema was required after 24 hours in absence of worsened patient conditions. During the night patient only complained for slight abdominal pain but his conditions remained stable. The CT scan performed after 24 hours revealed the disappearance of gas in mesenteric vein and portal venous system (Figure 3).

PMC3919864_01

Male

In November 2010, a 23-year-old male was referred to the Hematology Clinic of the Second Xiangya Hospital (Changsha, China) with a fever and dry cough for one week. The patient's blood routine (BR) showed a white blood cell count of 76.8x109/l, hemoglobin count of 6.6 g/dl, red blood cell count of 1.87x1012/l and platelet count of 31x109/l, with 87.80% neutrophils. Subsequently, the patient was admitted to the Department of Hematology (The Second Xiangya Hospital, Central South University, Changsha) for further evaluation. The patient had no history of tuberculosis in the family. On admission, the patient had a body temperature of 39.0 C. No abnormality was identified on physical examination. In the peripheral blood work, lactic dehydrogenase (LDH) was high at 937.5 mu/l (upper limit of normal, 245.0 mu/l) and bone marrow aspiration revealed 77% myeloblasts. Peroxidase staining was positive and immunophenotype examination revealed that these cells had originated from myeloblastic cell lines. In addition, AML1/ETO fusion gene expression was positive. X-ray chest radiograph showed enlargement of the left hilar, laminar shadow and marginal infiltration in the right lower lung lobe. Therefore, the diagnosis of AML-M2a was determined and the induction chemotherapy was initiated, with empiric antibiotics. However, although the BR and bone marrow aspiration indicated that the patient had achieved remission 14 days following the first cycle of chemotherapy, the patient continued to complain of repeated irregular fever and occasional frothy sputum, which did not respond to the broad-spectrum antibiotic and antimycotic treatments. During that time, sputum acid-fast smear was negative three times, and blood and sputum cultures for bacteria and fungi were sterile five times. One month following the completion of the induction chemotherapy, the patient was administered the second cycle of chemotherapy. In order to identify the origin of the fever, bone marrow aspiration was performed again, which presented the morphology of myeloblasts to be roughly normal, accounting for 3%, with occasional hemophagocytosis. Computed tomography (CT) of the brain, abdomen and pelvis showed splenomegaly; chest CT identified multiple enlarged lymph nodes in the bilateral supraclavicular fossa, mediastinum and left hilus and a number of lymph nodes that had become confluent masses, with a maximum size of 3x4 cm (Fig. 1). In addition, the blood C-reactive protein levels were 81.70 mg/l (upper limit of normal, 8.00 mg/l), ferritin levels were 2,098.27 ng/ml (upper limit of normal, 274.66 ng/ml), LDH levels were 382.5 mu/l and fibrinogen levels were 522 mg/dl (upper limit of normal, 400 mg/dl). The immunological examination for infections of bacteria, viruses and parasites suggested PPD-antibody (Ab) IgG (+), MycoDot (+), Widal reaction (-) and galactomannan (GM) test (-), and cardiac color ultrasound revealed marginal pericardial effusion. The patient exhibited 8 mm of induration in response to the PPD skin test. The patient was administered a diagnostic treatment, including isoniazid, rifampicin, pyrazinamide and fluoroquinolones. One week later, due to poor liver function, the rifampicin was terminated and the patient was discharged with prescriptions for isoniazid and pyrazinamide only, in January, 2011. One month later, the patient was referred to our department again for the second consolidation chemotherapy with no complaints of fever and cough. However, several peanut-sized lymph nodes were palpated in the right supraclavicular fossa and subclavicular area, without tenderness. CT revealed enlarged lymph nodes in the bilateral supraclavicular fossa, mediastinum and left hilus. Some of the nodes had merged into masses, the maximum diameter of which was 3 cm. The air tube and bronchus were marginally compressed and bilateral pleural thickening was observed. The patient then underwent surgical excision of the supraclavicular fossa lymph node. The histology of the specimen showed caseous necrosis, epithelioid cell nodules and multinuclear giant cells (Fig. 2A). However, the acid fast bacilli (AFB) staining of this specimen was negative. Due to the liver dysfunction (high levels of transaminase and total bilirubin), only two antituberculosis drugs (isoniazid and ethambutol) and the second consolidation chemotherapy were administered simultaneously. The surgical incision healed well and the patient was discharged with prescriptions for these two antituberculosis drugs and liver protective drugs. During the ensuing two months, the patient frequently had a cough with no fever and the biopsy incision became infected, covered by a yellow-green pyogenic moss. BR, bone marrow aspiration and AML1-ETO fusion gene showed that the patient had achieved complete remission. In addition, chest CT revealed a few massive dot shadows in the left upper lobe, with obscured edges and evidently enlarged lymph nodes of the mediastinum and left hilus, with the neighboring bronchus compressed and narrowed. Due to the fact that the tuberculosis had been poorly controlled and lung deterioration was radiographically observed, chemotherapy was interrupted. The patient received three antituberculosis drugs (isoniazid, rifapentin and ethambutol). Two months following the initiation of the three antituberculosis drug treatments, the patient continued to occasionally present with a mild fever during the afternoon; however, the patient's temperature returned to normal levels without special treatment. In addition, the dry cough continued and a yellow-green purulent ulcer continued to exist in the biopsy incision, the size of which was 1.0x0.5 cm. The patient exhibited 22 mm of induration in response to the PPD skin test and GM test (-), PPD-IgG Ab (+) and MycoDot (+). Chest CT showed a nodular shadow in the dorsal segment of right lower lung, with rough edges, thickening bilateral bronchovascular bundles and multiple enlarged lymph nodes in the mediastinum. CT-guided percutaneous needle lung biopsy (PNLB) and fiberoptic bronchoscopy (FB) were performed. PNLB was performed several times, but all attempts failed to reach the nodule, as shown by CT. The results of FB revealed that red granulomatous materials existed at the opening of the left main bronchus, where the submucosa was swollen and congested. In addition, the opening of the left lingular bronchus exhibited red granulomatous elements, without obstruction of the lumen. However, red granulomatous materials and white necrotic elements obstructed the opening when the biopsy was performed. These observations were consistent with the diagnosis of bronchial tuberculosis (lesions of the left main bronchus, left lingular lobe and left lower lobe) and scrofula (ruptured lumens). The pathology of the specimen showed abundant coagulative necrosis, epithelioid nodules and a few Langhans giant cells (Fig. 2B). The AFB staining of the biopsy specimen and lavage fluid were negative. However, considering the patient's poor liver function and adverse reaction of liver damage by rifapentine, isoniazide and ethambutol, plus strong liver protective drugs were administered. Simultaneously, the fifth cycle of chemotherapy was initiated. During hospitalization, the patient's cough improved. To date, the patient's condition has remained stable and the AML is in remission. The patient was monitored for one year, without tuberculosis and leukemia relapse. The patient provided written informed consent.

leukemia, lymphadenopathy, tuberculosis

PMC3275470_01

Female

While driving a van and wearing a seatbelt, a 19-year-old Caucasian woman, was involved in a head-on vehicle collision (speed about 40 km/hour), followed by a rear-end hit from another vehicle. When rescue services arrived at the scene, the patient was found sitting in her car with her head immobilized in a left rotation. She was transferred onto a spinal board. The application of a stiff neck collar was not possible as her head was fixed in the rotated position. After admittance to a regional hospital, the physician in charge tried to reposition her head but she reported painful paresthesia in the left arm. She was transferred to our spine and trauma center. Upon admittance, the woman complained about strong, immobilizing pain in the upper cervical spine with torticollis to the left side. A computed tomography (CT) scan revealed an atlantoaxial rotation of 46 to the left without any signs of osseous lesions (Figure 1). The neck was then reduced by cautious rotation under traction with the cervical spine in flexion thus avoiding harm by potential posttraumatic disc lesions. During this process, the patient was awake and did not report any new paresthetic sensations during the procedure. There were no clinical signs of neurological sequelae before or after reduction. However, a fluoroscopic control still showed signs of atlantoaxial pathology (Figure 2) and magnetic resonance imaging (MRI) of the cervical spine was done (Figure 3). It showed the integrity of the transverse and the alar ligaments and a traumatic discus protrusion on level C5/6 (Figure 4). After three days of immobilization and analgesic therapy, a CT (with maximum bilateral head rotation) showed no persisting atlantoaxial fixation (Figure 5). Subsequently, she was discharged three days after admittance and immobilized in a soft collar for six weeks. At a follow-up examination six weeks after the trauma, the pain and paresthesia in the left arm had receded completely and the patient had a full range of motion. A follow-up MRI of the cervical spine showed only slight persistent atlantoaxial rotational displacement of C1/2.

PMC10348358_01

Male

A 66-year-old man presented with episodic limb weakness beginning at 2 years of age, sometimes in both lower extremities and sometimes in both the upper and lower limbs. Prolonged walking was often the predisposing factor, with seizure frequency occurring once or twice a month. With age, he appeared to have permanent muscle weakness, manifested by difficulty in running, squatting, standing up, and lifting the upper limbs. During this period, he visited many hospitals to check his creatine kinase (CK) levels, which ranged from approximately 600-1,000 U/L. Muscle biopsies of his calf, shoulder, and back were performed at the ages of 13, 20, and 26 at two hospitals. The examination results showed no abnormalities, leading to a suspicion of muscular dystrophy as a possible cause. He underwent genetic testing at the age of 26, but the diagnosis was still inconclusive. Twenty-five years ago, an electrophysiologic concentric needle examination of the iliopsoas muscle, the gluteus maximus, and the lumbar paraspinal muscles indicated the presence of myopathy in the patient. There was a suspicion of limb-type muscle malnutrition, but treatment with coenzyme Q10 was found to be ineffective. It is worth noting that he had all his teeth extracted due to difficulties during intubation during vocal cord polyp surgery and was found quadriplegic after general anesthesia 10 years ago. The doctor conducted a cervical spine magnetic resonance imaging (MRI) on the patient, but the results showed no abnormalities. The patient complained of limb weakness, which progressively worsened in the morning before admission. He fell to the ground, could not stand up, and was brought to the emergency department of our hospital. Physical examination of the patient's proximal part of the extremities presented amyotrophy (Medical Research Council Grade 4) and decreased tendon reflexes, and negative bilateral pathological signs. The electrocardiogram of our patient showed a U-wave inversion (Figure 1), and the 24-h dynamic electrocardiogram showed 245 premature ventricular contractions (PVCs) in a total of 91,847 heartbeats. The EMG examination revealed narrow and irregular waves during the needle examination, with no pronouncement of the fibrillation. A long-term exercise test indicated a significant decrease in the compound muscle action potential (CMAP) amplitude of the right little finger abductor muscle, measuring 74.4% lower than the baseline and a 66% reduction in the area (Figure 2). The blood test results showed a potassium level of 2.9 mmol/L (normal value: 3.5-5.5 mmol/L). Additionally, the CK (creatine kinase) level was measured at 1,600 U/L, lactic acid level at 2.8, and lactate dehydrogenase (LDH) at 224 U/L. We considered the possibility of ATS given the patient's characteristic physical features, including short stature, small hands and feet, clinodactyly of the fifth toe, hypoplastic mandible, and low-set ears (Figure 3). An electrocardiogram revealed slightly inverted U waves. Further genetic analysis using the sequencing system (Amplicon Gene, Inc.) identified a heterozygous c.220A > G mutation in the exon 2 region of chromosome 17 of the KCNJ2 gene. This mutation resulted in the substitution of alanine with threonine at amino acid 74 (p.T74A) (Figure 1), which was reported to be a pathogenic mutation for ATS. Our patient had special physical characteristics. Based on the positive results of the long-term exercise test, muscle symptoms, and the genetic testing outcome, it was determined that he was not affected by the myopathic condition but rather ATS.

andersen-tawil syndrome, kcnj2, anesthetic considerations, long-term exercise test, malignant hyperthermia

PMC5926216_01

Male

The patient is a 57-year-old man with past medical history significant for epilepsy and left hemiplegia secondary to right-sided traumatic brain injury (TBI) 28 years prior to presentation. He presented with a 3-week history of depression, anxiety, and active suicidal ideation resulting in psychiatric admission to an outside hospital. He had three prior craniotomies for right subdural hematoma (SDH), one at the time of his TBI, one 8 years prior to presentation, and one 5 years prior to presentation. On follow-up imaging 3 years after his last craniotomy, he underwent head CT showing a small subacute SDH, which was managed nonoperatively [Figure 1]. He has no significant prior psychiatric history. His home medications include baclofen 20 mg, keppra 1000 mg BID, memantine 10 mg BID, gabapentin 600 mg TID, duloxetine 600 mg QD, quetiapine 50 mg PRN (for sleep), and simvastatin 40 mg. After a multiday admission at the outside hospital for depression with suicidal ideation, he underwent noncontrast MRI because of his prior history of craniotomy, revealing a 1.4 x 2.3 x 3.6 cm right-sided crescent-shaped collection consistent with subacute SDH [Figure 2]. There was no significant restricted diffusion on diffusion weighted image (DWI). The patient was at his neurologic baseline on presentation upon transfer to our hospital, and he was afebrile with a normal white count. The patient was brought to the operating room for evacuation of the presumed subacute SDH 21 h after admission to our hospital. During the craniotomy he was found to instead have an EDA. The craniotomy bone appeared infected and it was discarded. Epidural drain was left, and he was started on vancomycin, ceftriaxone, and metronidazole until tissue cultures grew ampicillin-sensitive enterococcus, at which point he was transitioned to 6 weeks of ampicillin-sulbactam. After surgery, the patient demonstrated elevated white blood cell count until day 3 of admission and elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) for the duration of admission. Outside of one elevated temperature of 99.5 F in the morning of the procedure, there were no preoperative signs of infection. The patient continued to function at his neurological baseline, and suicidal ideations and behavioral problems resolved by postoperative day 5. He was started on valproate 500 mg BID after surgery for seizure prophylaxis. He was discharged to a rehabilitation facility 13 days after admission. Cranioplasty with a PEEK implant was performed 6 months after this surgery. Three months after cranioplasty he was doing well, without evidence of infection on repeat MRI, and at his neurological baseline without any psychiatric problems.

depression, epidural abscess, subdural empyema, suicidal ideations

PMC7399251_01

Male

A 64 year old Caucasian man presented to the Emergency Room in 2016 with approximately 2 months of generalized malaise, weight loss (7 kg), anorexia and vesperal temperatures of around 37.5 C. He also noticed epigastric abdominal pain, liquid stools (once a day, without blood or mucous) and night sweats in the two previous weeks. He denied increased ganglia, increased abdominal volume, vomits or respiratory symptoms. The patient was born in Angola (Sub-saharan Africa), but was living in Portugal since 1975 and denied any trip abroad since then. His past medical history was not remarkable. On clinical presentation, he was underweight and febrile (temperature of 38.1 C). Skin was colored and hydrated. Cardiopulmonary auscultation was normal. Abdominal palpation was slightly painful in the epigastric region. Hepatosplenomegaly or peripheric adenopathy were not found. The fundoscopy was normal. No additional clinical findings were noticed. The laboratory study revealed mild thrombocytopenia and slightly elevated C-Reactive Protein. The HIV screening was positive with ELISA and Western blot for infection with HIV-1. The patient was unaware of this condition. Immunologically the patient presented with CD4 + T-cel count of 64.8/uL (6,4 %) and HIV-1 viral load of 61,249 copies/mL. The abdominal ultrasound revealed multiple ganglia in the emergence of the celiac trunk (the largest one with approximately 20 mm). The CT scan confirmed the presence of this multiple adenopathy, sometimes necrotic and coalescent, diffusely distributed in the mesenterium, the largest with 2 cm in diameter (Fig. 1). There were also multiple adenopathy around the mesenteric vessels and around the aorta and inferior vena cava, predominantly in the emergence of the renal vessels and in the retrocural region. As imagiological findings suggested lymphoproliferative disease, a bone marrow aspiration was performed. It failed to detect abnormal lymphoid populations, showing a normal ratio of the myeloid/erythroid lineage and the molecular study using RT-PCR for nontuberculous mycobacteria (NTM) and Mycobacterium tuberculosis (MTB) was negative. Bone marrow mycobacterial culture was ensued yielding the growth of Mycobacterium genavense six weeks later. The patient was also submitted to laparoscopic mesenteric ganglia biopsy. Molecular biological analysis using RT-PCR was positive for NTM and negative for MTB; mycobacterial cultures were negative. The histopathological examination showed an alteration of the ganglia architecture, filled with histiocytes and numerous Ziehl-Neelsen+, PAS- microorganisms (Fig. 2), which was compatible with an atypical mycobacteriosis. Upper endoscopy revealed focal hyperemia and loss of the vascular appearance in the duodenum; the stomach antrum was atrophic with reduction of the vascular supply. Histopathological examination of the duodenum mucosa showed infiltration by histiocytes (CD68+, S100-, PAS-), filled with numerous mycobacteria (Ziehl Neelsen and FITE+) (Fig. 3). The diagnosis of a disseminated mycobacteriosis by Mycobacterium genavense was then confirmed. As the HLAB5701 was not present and the HIV drug resistance test was negative, antiretroviral therapy was initiated with a single tablet regimen containing abacavir, lamivudine and dolutegravir with good tolerance and adherence. Due to severe immunosuppression trimethoprim/sulfamethoxazole prophylaxis was also initiated. Antimycobacterial treatment was started empirically with rifabutin, ethambutol and clarithromycin. After 4 months under the antimycobacterial treatment, the patient, although clinically stable and with no signs of immune reconstitution inflammatory syndrome (CD4 + T-cel count of 94/uL and HIV viral load of 0 copies/mL), showed imagiological deterioration of the adenopathy, with presence of the "sandwich sign" (Fig. 4), meaning the mesenteric ganglia compressing the superior mesenteric vein. After 6 months of treatment, we had access to the drug susceptibility testing, which showed resistance to all first and second lines antibacillary drugs (ethambutol, linezolide, amikacin, rifampicin, rifabutin, ofloxacin, olarithromycin, Isoniazid, ciprofloxacin). At the time, the patient was kept under the antymicobacterial treatment described before as the drug susceptibility testing is not clearly validated for this microorganism. After 9 months of treatment, the patient still complained about abdominal pain and presented with CD4 + T cel count of 204/uL and indetectable HIV viral load. Another abdominal CT scan was performed, presenting similar findings as the ones previously described and thrombosis of the inferior mesenteric vena (Fig. 5). To exclude the presence of another HIV-associated infection or lymphoproliferative disease, a second mesenteric ganglia biopsy was performed, which revealed persistence of the atypical mycobacteriosis on the histopathological examination. Bone marrow aspiration was also repeated. Both products were negative for culture and RT-PCR of NTB and MTB. Because of the imagiological deterioration and antibacterial resistance pattern, it was considered the possibility of non-response and treatment was revised at that time for amikacin, rifampicin, moxifloxacin and clarithromycin and enoxaparin. Due to drug interactions, dolutegravir was changed to efavirenz with good tolerance. The patient was kept under this antimycobacterial treatment for 3 months, but due to intolerance to the amikacin (local injection site pain), this drug was discontinued. After more than 3 years, the patient is currently alive, clinically stable, with no imagiological deterioration, although he is still on antimycobacterial treatment with rifampicin, moxifloxacin and clarithromycin.

hiv infection, mycobacterium genavense, opportunistic infections

PMC6286767_01

Female

A 19-year-old woman was referred and admitted to our hospital because of a progressive fever and persistent cough. The patient was a university student who lived with her parents, brother, and grandmother. Her medical history was uninformative regarding risk factors; the patient had no smoking history. She had not received influenza vaccination during the season. Six days prior to admission, she experienced fever and visited a clinic. There had been an outbreak of influenza A and B virus infections in the area during that time. Aside from this, she had no episodes of exposure to pathogens causing acute fever. The nasopharyngeal swab sample was analyzed using a rapid test kit and did not indicate the presence of either type A or B influenza virus antigen. Repeated examination of a nasopharyngeal swab sample on the following day did not indicate any influenza virus antigen. Clarithromycin was administered based on a diagnosis of acute upper respiratory infection. As there was no clinical improvement in spite of five days of treatment, the patient was referred to our hospital. At admission, a physical examination indicated that the patient was a well-developed and well-nourished woman. Her body temperature was 39.6 C, blood pressure was 108/65 mm Hg, pulse was 106 beats/min, respiratory rate was 24 breaths/min, and room air percutaneous oxygen saturation (SpO2) was 95%. The physical examination was unremarkable, and her respiratory sound was normal. An initial laboratory examination showed a white blood cell count of 5,200/microL (70% neutrophils), C-reactive protein level of 18.58 mg/dL, and procalcitonin level of 0.63 ng/mL (normal range <0.5 ng/mL). A nasopharyngeal swab sample analyzed using a rapid test kit (Quick Chaser Flu A, B; Mizuho Medy Co., Saga, Japan) indicated the presence of influenza B virus antigen. Stained sputum smears revealed Gram-positive cocci and Gram-negative rods. No pathogenic bacteria were cultured form repeated blood or sputum cultures. Chest radiography and CT scan (Figure 1) showed dense consolidation in the left upper lobe, indicating the presence of lobar pneumonia. The patient was diagnosed with influenza B virus infection accompanied by community-acquired pneumonia. The patient was treated with peramivir (600 mg/day) and sulbactam/ampicillin (SBT/ABPC; 12 g/day). Following admission, the patient's fever persisted, and her respiratory condition worsened. The course of the patient's illness is shown in Figure 2. On day 3 after admission, her body temperature was 40.0 C, and a laboratory examination showed no improvement. Therefore, ciprofloxacin (CPFX; 600 mg/day) was added. On day 5, the high fever persisted, and the room air SpO2 was 88%. A chest CT scan revealed extension of the consolidation areas with air bronchogram in the left upper lobe and opacities in the right lung (Figure 3). On day 6, the SBT/ABPC and CPFX treatment was changed to meropenem (MEPM; 3 g/day) and levofloxacin (LVFX; 500 mg/day). On day 8, the patient's physical condition gradually improved, and the SpO2 recovered to >95% without oxygen administration. The sputum sample analyzed using a loop-mediated isothermal amplification assay (Mitsubishi Chemical Medience Co., Tokyo, Japan) revealed the presence of M. pneumoniae-specific DNA. There was no outbreak of M. pneumoniae infection in the area at the time. On day 13, the patient became afebrile and was discharged. The serum antibody titer against M. pneumoniae was 1 : 160 on admission and 1 : 10,240 on day 18 using the particle agglutination method and 1 : 32 on admission and 1 : 1024 on day 18 using the complement fixation test. In addition, the serum antibody titer against influenza B virus, measured using the complement fixation test, was <4 on admission and 1 : 128 on day 18. The serum antibody titer against influenza A virus did not increase throughout the clinical course.

PMC3524082_01

Male

A 37-year-old man presented with right eyelid ptosis, which disappeared when the patient opened his mouth and reappeared when he closed his mouth. Synkinetic activation of the left orbicularis oculi muscle when attempting to voluntarily open the right eyelid was also present. Symptoms had been present since birth. The subject's family history revealed that both his father and two paternal uncles were affected by the same disorder. The neurological examination disclosed no further abnormality while the ophthalmological examination revealed eterophory at distance and vertical strabismus. Electromyography (EMG) recordings from the facial muscles were normal, as were the brainstem auditory evoked potentials. The control group for the neuroradiological examinations comprised 29 age- and sex-matched healthy subjects (41+-5.6 years). Twenty out of the 29 healthy volunteers were also involved in the neurophysiological investigations (age: 37+-5.0 years). Both the MGJWS patient and the healthy subjects gave their written informed consent to the experimental procedures, which were approved by the Ethics Committee of University of Rome "Sapienza" and conducted in accordance with the Declaration of Helsinki. The kinematics of the eyelid and jaw movement was recorded using a 3D optoelectronic motion system (SMART motion system, BTS, Milan, Italy). The displacement of the reflective marker taped on the centre of the lower margin of the upper eyelid and on the mental prominence of the jaw in three-dimensional space was reconstructed off-line by a dedicated software (SMART Analyzer, BTS, Milan, Italy). Onset, offset, duration, peak velocity and amplitude were automatically computed for each downward and upward eyelid and jaw movement. Differences between the onset of eyelid and jaw movement were calculated. The Paired-sample T test was used to compare the onset of the upper eyelid and jaw movements during jaw opening and closing. Pearson's correlation coefficient was used to analyse movement duration of eyelid and jaw opening and closing movements. The blink reflex, the masseter inhibitory reflex and the blink reflex recovery cycle were performed according to previously described techniques. The blink reflex recovery cycle was studied by delivering paired electrical shocks to the supraorbital nerve at interstimulus intervals (ISI) of 250 and 500 ms. The R2 recovery index was also calculated. All the subjects underwent an MR imaging examination on a 3T scanner system (Intera Achieva, Philips Medical Systems, Best, The Netherlands). Diffusion-weighted images were corrected for head motion and eddy current distortions using FDT (FMRIB's Diffusion Toolbox 2.0), after which brain tissue was segmented using BET. Tensor fitting employed a constrained non-linear least squares procedure (CAMINO), followed by Fractional Anisotropy (FA) map estimation. Voxelwise statistical analysis of the data was carried out using Tract-Based Spatial Statistics (TBSS). TBSS projects all the subjects' FA data onto a mean FA tract skeleton, before applying voxelwise cross-subject statistics. The latter included full correction for multiple comparisons over space using permutation-based non-parametric inference (50,000 permutations). P-values were calculated and corrected for multiple comparisons using the "2D" parameter settings with threshold-free cluster enhancement.

PMC9931384_01

Female

A 20-year-old female from the Gondia district's Magardoh hamlet visited the Acharya Vinoba Bhave Rural Hospital (AVBRH), Sawangi (Meghe), Wardha, India with the chief complaints of diffused low back pain that had been plaguing her for the last two years and had crept up on her slowly at first. Additionally, the patient also reported a loss of sensation in the front and back of the distal lower limb. The patient gave a negative history of any other comorbidities. The patient had already been referred to a few private hospitals where she underwent a few investigations which revealed the presence of an abscess in the pre- and paravertebral space of the lower spine. After magnetic resonance imaging (MRI) and biopsy were carried out, the patient was diagnosed with TB of the spine L4-L5 and L5-S1. The patient was prescribed anti-TB medications and physiotherapy. On observation The patient was seen in a supine position with upper limbs by the side and lower limbs extended. An abscess was seen on the lower spine region. On palpation Grade 3 tenderness (patient winces and withdraws the affected part) was present on the lower lumbar region of the back. On examination range of motion (ROM) and manual muscle testing were taken (Tables 1 and 2). Sensory examination The assessment was done using American Spinal Injury Association (ASIA) impairment scale. All the motor functions were intact. There was a sensory deficit in the L5 and S1 segments with both pinprick and light touch impaired. Loss of sensation over the lateral and posterior calf and dorsum of the foot was noted. Intervention The main goal of physical therapy is to minimize the symptoms. The primary goal is to improve respiratory function, relieve back pain, increase muscle strength, increase ROM, improve sensory function, improve quality of life and prevent secondary complications. Before initiating the treatment, it is essential to educate the patient about her condition, its complications, the prognosis, and the benefits physical therapy will have in easing her symptoms, relieving pain, and early recovery. Strengthening exercises included isometrics initially, followed by resistive exercises first by manual resistance later using weights and mechanical resistance with 10-20 repetitions. Low back pain was managed with the application of transcutaneous electrical nerve stimulation (TENS) and moist heat. ROM exercises (both active and passive) up to full range were given to improve mobility. Mobility exercises for the trunk were given with proper assistance. Breathing exercises included pursed lip breathing and thoracic expansion exercises with five and ten repetitions respectively twice a day. Sensory re-education was done once a day. Postural correction techniques were taught. Aerobic exercise training was started in the fourth week using a static cycle and treadmill (Table 3).

low-back pain (lbp), physical medicine and rehabilitation, physiotherapy intervention, pott's disease-tuberculous spondylitis, sensory re-education, spinal tuberculosis

PMC4020313_01

Female

The patient checked in the sector of Cardiovascular Rehabilitation in the Study Centre in Physiotherapy and Rehabilitation of Faculdade de Ciencias e Tecnologia - UNESP, in Presidente Prudente, Brazil, following medical recommendation, in September 2011. She was 36 years old, white, primigravida, diagnosed with SCAD ten days postpartum, neither showing previous cardiopathy nor history of drug use, no problems during prenatal, and she was subjected to a cesarean delivery in April 2010. Ten days after delivery, the patient had a sudden illness and was sent to Intensive Care Unit, where she suffered an Acute Myocardial Infarction (AMI). A Diagnostic Cardiac Catheterization was performed followed by a Therapeutic Cardiac Catheterization, on which an "STENT" implant was placed in the anterior descending coronary artery. One month after the AMI the patient was subjected to another Diagnostic Cardiac Catheterization and obstruction of 90% "intra-STENT" was found; the diagonal artery (DA) totally obstructed in the middle third and the circumflex artery (CxA) showing a target lesion of 80% in the middle third. In November 2010 the patient was subjected to a Cardiac Resonance, and borderline left ventricular function equal to 52% was found due to a hypokinesia of the basal anterior and lateral walls of the left ventricle. An Angiotomography showed the presence of significant single-vessel luminal reduction; there was in CxA the presence of dissection of the distal left main coronary artery and DA proximal; the presence of pervious "STENT" and no luminal reduction in DA were also found. In December 2010 the patient submitted to coronary artery bypass surgery (CABG) with the placement of a mammary artery bypass and coronary artery bypass. In January 2011 the Angiotomography was re-done and the venous graft was occluded in its emergency of anterior face of the ascending aorta. In July 2011 an exam stress/rest Myocardial was performed in which a persistent hipoperfusion in the anterolateral wall of the left ventricle was observed, with discreet component of transience associated in the basal area beyond a low degree depressed contractile function of the left ventricle. A Holter was done, in which dominant sinus rhythm, absence of arrhythmias and heartbeat rate varied from 48 to 110 beats per minute (bpm), with an average of 70 bpm. The Ecocardiogram found mild mitral regurgitation and ejection fraction of 63%. In the clinical examination, in September 2011, she reported great limitation in performing daily life activities, tiredness, dizziness when lowering and standing up, the right upper limb was weak if compared to the left and she described a discomfort under the right breast triggered by effort, which would get better at rest and worse if the triggering activity would not stop. She took 125 mg of Atenolol, 100 mg of acetylsalicylic acid and 10 mg of atorvastatin per day.

aerobic exercises, cardiac rehabilitation, spontaneous coronary artery dissection

PMC9897702_01

Male

A 17-year-old male with a remote past medical history of three prior right patellar dislocations presented to our emergency department (ED) with a first-time locked left lateral patellar dislocation after pivoting on his left foot during a football game. He underwent a failed attempt at a reduction at the time of the injury by the on-field attending orthopedic physician. The patient was transported to the ED in an ambulance due to the inability to transport him off the field because of his high BMI (body mass index). En route to the ED, he was given nebulized ketamine and temporarily splinted in situ by emergency medical services. In the ED, the splint was removed, radiographs were obtained, and the patient underwent two further failed closed reduction attempts by the ED physician after being given IV fentanyl and nebulized ketamine. At this time, orthopedics was consulted for further management. On examination, the patient had an immobile left knee fixed at 10 degrees of flexion, was neurovascularly intact with no other injuries, and had a patella that remained rigidly fixed in a dislocated position with gentle manipulation. His height and weight were 165 cm and 140.6 kg, respectively (a BMI of 51.6). Radiographs demonstrated a laterally displaced left patellar dislocation (Figures 1, 2). At this time, a modified sunrise view of the left patella and a sunrise view of the right patella (for comparison) were obtained. Careful evaluation of the sunrise views demonstrated a medial avulsion fracture of the patella with hinging of the patella on the lateral trochlear ridge via an acute impacted medial patellar defect (Figures 3-5). The patient was then consciously sedated with IV ketamine to assure adequate relaxation of the musculature and a further closed reduction attempt in the ED. Under conscious sedation, the patella remained rigidly fixed against the initial anteromedial relocation force with the knee fully extended. This maneuver would have normally reduced a typical patella dislocation but was unsuccessful. Therefore, this novel technique was employed: with the application of a firm superolateral force with the knee extended, the patella readily unlocked, and a subsequent superomedial force reduced the injury. Subsequent post-reduction exam under sedation was improved and displayed a ligamentously stable knee that had regained full mobility; although it displayed lateral tilt, it was found to track within the trochlea with knee flexion under sedation and was confirmed on the intra-sedation sunrise view with mini-c-arm fluoroscopy (Figure 6). The patient was placed in a hinged knee brace locked in extension. Subsequent post-reduction treatment included computed tomography (patient or guardian declined acute MRI for soft tissue evaluation, due to ER wait times), which confirmed reduction, the lack of unrecognized fractures or intra-articular osseous bodies, the lack of previously unrecognized soft tissue injury, and better characterized the previously appreciated medial avulsion fracture and impaction defect of the patella (Figure 7). Based on patient and family preference, no other acute treatments were conducted, and he was discharged to follow-up in the clinic for further treatment; clinic follow-up had not occurred at the time of manuscript submission, and therefore concomitant acute soft tissue injuries are currently not known.

atraumatic, irreducible, irreducible closed reduction, locked patella dislocation, patella dislocation, patella fracture

PMC7323278_01

Female

A 24-year-old woman of Malay ethnicity presented to the thalassemia unit with a month history of prolonged fever, headache, and painful enlarged neck lymph nodes. She is known to have Hb H CS thalassemia, in which, she is on 3-monthly blood transfusion. She is on iron chelation subcutaneous deferoxamine 500 mg thrice weekly. She has a family history of Hb H disease. There is no history of parental consanguinity. She is a nonsmoker, a teetotaler, and works as a bank clerk. Physical examination revealed a pale and jaundiced female with persistent pyrexia of 38 C. She was not septic looking and did not reveal any skin rash. She had bilateral palpable tender cervical lymphadenopathies with the largest measuring 4 x 4 cm. They were rubbery on palpation with no obvious nodal discharge or overlying skin colour changes. She had hepatosplenomegaly. Other systems were unremarkable. The complete blood count revealed hypochromic microcytic anaemia, leucopenia, and a normal platelet count. She had hyperferritinemia of 3500 ng/mL. The other laboratory parameters are as tabulated in Table 1. Peripheral blood film (Figure 1) portrayed features consistent with hemoglobinopathy associated with chronic hemolysis. Capillary electrophoresis (Figure 2) showed Hb A of 69.1%, Hb A2 of 0.4%, Hb F of 0%, Hb H of 26.6%, Hb Barts of 1.5% and Hb CS of 2.4%. The agarose alkaline and acid gel electrophoresis (Figure 3A and B) revealed a faster-move band (Hb H band). The DNA analysis of alpha-globin gene showed heterozygosity for alpha zero thalassemia South East Asian (SEA) deletion with termination codon mutation (TAA-CAA) which was consistent with Hb H-Constant Spring thalassemia. The DNA analysis for Beta globin gene did not reveal any mutations. Blood, fungal, and tuberculosis cultures were sterile. A complete autoimmune panel was negative. An abdominal ultrasonogram and transthoracic echocardiogram did not reveal any microabscesses or vegetations. Magnetic resonance imaging (MRI) T2* of the cardiac and liver showed moderate liver iron overload and normal myocardial iron load. A whole body computed tomography (CT) imaging showed diffuse cervical, axillary, and abdominal lymphadenopathies with the largest lymph node measuring 4 x 4 cm. A decision was made to perform a cervical lymph node biopsy. It showed paracortical expansion by histiocytes, small lymphocytes, and tingible body macrophages. The histiocytes had pale and crescentic nuclei. Extensive apoptosis with large areas of necrosis were present. There were no neutrophils, granulomas, or multinucleated giant cells seen. Immunohistochemical studies showed histiocytes positive for CD68 and myeloperoxidase (MPO). Most small lymphocytes were CD8+ T-lymphocytes. Periodic acid Schiff (PAS), Grocott's methenamine silver (GMS), and Ziehl-Nielsen stains were negative for fungal bodies and acid-fast bacilli. On the basis of these findings, a diagnosis of KFD was made. She was treated with oral prednisolone 1 mg/kg daily for a month followed by a gradual taper of 10 mg 2 weekly based on response. She responded clinically with complete resolution of symptoms. A repeat end-of-treatment whole body CT imaging showed complete resolution of lymphadenopathies. Currently, she is on a 3-monthly follow up at the thalassemia clinic.

dna analysis, hb h-constant spring, kikuchi-fujimoto disease, thalassemia

PMC8044765_01

Female

A 24-year-old pregnant female (G1P0) presented to the maternity ward of the local hospital, 12 weeks pregnant with a 14-day history of a mild headache and high fever for 2 days. After two generalized tonic-clonic seizure episodes, the female was transferred to our hospital. She had a 4-year history of hypothyroidism with irregular medication. The patient had no history of nasosinusitis, head trauma, or surgery. On admission, her vital signs revealed a temperature of 39.4 C, a blood pressure of 89/55 mmHg, a pulse of 120 beats/min, and a respiratory rate of 22 breaths/min. Physical examination revealed a lethargic patient with a Glasgow coma scale (GCS) score of 15/15. She had a normal physical examination except for nuchal rigidity and a positive Kernig's sign. Blood tests showed that her leukocyte count was 22.7 x 109/L (neutrophil 85.4%), sedimentation rate (ESR) 105 mm/H, C-reactive protein (CRP) 99.1 mg/L, and procalcitonin (PCT) 0.5 ng/ml. Lumbar puncture showed that her cerebrospinal fluid (CSF) pressure was 330 mmH2O, leukocyte count 540 x 106/L (neutrophil 80.0%), protein 1.57 g/L, glucose 1.16 mmol/L, and chloride 117.1 mmol/L ( Figure 1 ). The patient was diagnosed with bacterial meningitis, and treated immediately with empirical antibiotic therapy with meropenem (2.0 q8h intravenous drip) and vancomycin (1.0 q8h intravenous drip). Levetiracetam (1.0) was administered twice daily for antiepileptic treatment. Brain magnetic resonance imaging (MRI) revealed diffuse hyperintensities on fluid attenuated inversion recovery (FLAIR) imaging, accompanying by meningeal enhancement on a T1 contrast image ( Figure 2A ). Brain magnetic resonance angiography (MRA) imaging exhibited normal findings. Head CT and MRI showed no bone destructions and fistulas. Later, blood and CSF culture indicated staphylococcus aureus, which was sensitive to vancomycin and linezolid. The results were consistent with the analysis of metagenomics next-generation sequencing (mNGS). Thereafter, temperature was gradually decreased. There was no recurrence of seizures. Repeated blood and CSF results were significantly improved. Serum and CSF antibodies were negative for all antibodies against nerve cell-surface antigens and intracellular antigens. Autoantibodies and mycoplasma pneumoniae antibody were also negative. The T-SPOT.TB test was normal. There were no cardiac valve destructions and vegetations on the echocardiography exam. A Doppler ultrasound suggested fetal growth restriction. The patient selected to abort the pregnancy because the fetus had growth restriction and had undergone medical interventions, including medications and imaging examinations, that had the potential to result in the teratogenic effect for the fetus. After 20 days of antibiotic therapy, the patient underwent a successful medication abortion. However, she developed weakness of the right limb, and fever again. She deteriorated with a fluctuating mental condition (GCS ranging from 10 to 12 of 15). Although brain MRA imaging were still normal, brain MRI revealed lesions were enlarged and meningeal enhancement was even more obvious ( Figure 2B ). Repeated multiple blood and CSF culture were negative for any bacteria. Linezolid (0.6 g bid intravenous drip) was used to as a substitute to vancomycin. Unfortunately, the patient continued to deteriorate. She lapsed into a coma with a GCS 8 of 15. The repeated MRI was confirmed the progressive condition ( Figure 2C ). Antibodies related to autoimmune encephalitis were still negative in the serum and CSF. Therefore, CNS-IRIS was considered. The patient received high-dose intravenous methylprednisolone (20 mg/d/kg body weight, 5 days) followed by oral corticosteroids. The neurologic abnormalities gradually improved, and follow-up MRI showed marked improvement ( Figure 2D ). She was discharged from hospital three months after her admission. Although weakness of the right limb continued, she was able to walk unaided.

staphylococcus aureus, bacterial meningitis, case report, immune reconstitution inflammatory syndrome, pregnancy

PMC3617540_01

Male

A 29-year-old male was referred to Infectious Disease Clinic of Hamadan Sina Hospital in summer 2008 with acute onset of fever, headache, malaise, sweating and low back pain. On examination, the patient was conscious and his temperature was 39 C. There were no obvious systemic findings such as organomegaly on physical examination. Laboratory test findings were: white blood cell (WBC) count of 13350 (Neutrophil: 85%), erythrocyte sedimentation rate (ESR) 48m/h, CRP+, RF-, ANA-, Wright's agglutination titer of 1/1280. Results of serologic testing for syphilis, hepatitis, tuberculosis and AIDS were negative. Outcomes of a lumbar puncture were normal. Blood levels, for sugar, sodium and potassium were normal. Blood cultures were negative and electrocardiogram and chest-X-ray (CXR) were normal. The patient was diagnosed with brucellosis, and treated with rifampin 600 mg/day and doxycycline 100 mg/twice daily. After a week, the patient was referred for an Ophthalmology consult with complaints of ocular pain and redness and visual complaints. On ophthalmic examination, visual acuity in both eyes was 20/25. There was diffuse conjunctival injection bilaterally which was more prominent in the right eye. The conjunctional injection was a mixture of ciliary injection, episcleritis and conjunctivitis but more severe in the ciliary area. Neither eye had signs of intraocular inflammation. Pupillary light reflexes were sluggish bilaterally but no afferent pupillary defect was present. The patient was orthophoric without any muscle involvement and there was no diplopia. On funduscopy, there was bilateral optic disc swelling along with retinal hyperemia (optic disc hyperemia and vascular tortuosity) and diffuse intraretinal hemorrhage [Figure 1]. Intraocular pressure (IOP) was 26 mmHg in the right eye and 24 mmHg in the left eye. The patient was hospitalized with a probable diagnosis of ocular brucellosis and was treated with co-trimoxazole adult two tablets, three times a day (tid), rifampin 600 mg/day doxycycline 100 mg/BID and prednisolone 1 mg/kg for 2 months. Computed tomography and magnetic resonance imaging studies of the brain and optic nerve were requested. Both studies were unremarkable. A brief visual field limitation was reported on perimetry. Fever and headache diminished within 48 hours of the treatment however, ophthalmic complaints lingered. One week after treatment, visual acuity improved to 20/20. Conjunctival hyperemia had decreased but previous funduscopic findings remained unchanged. IOP was 19 mmHg OD and 16 mmHg OS using timolol. Four weeks after treatment, there were no visual complaints. Optic disc swelling and hyperemia had decreased and IOP bilaterally was within normal limits. Thirteen months after treatment, the funduscopic examination was normal [Figure 2].

bilateral optic disc swelling, brucellosis, ocular brucellosis

PMC10344674_01

Female

A 67-year-old woman with a BMI of 31.8 kg m2 presented to our outpatient clinic with productive refractory cough (worse on exertion), wheezing, and shortness of breath. Her past medical history was significant for asthma, gastroesophageal reflux disease, obstructive sleep apnea on CPAP, and recurrent pulmonary infections. Dynamic computed tomography suggested severe expiratory collapse of the trachea, mainstem bronchi, and bronchus intermedius. Complementary findings with dynamic bronchoscopy showed collapsibility of 70% at the cricoid, 90% at mid trachea, 80% at distal trachea, 90% at right mainstem bronchus, 100% at bronchus intermedius, and 90% at left mainstem bronchus. These findings are consistent with severe ECAC in the subtype of EDAC, as portrayed in Fig. 1. Subsequently, a stent trial was attempted to assess surgical candidacy; however, it was not feasible due to complex anatomy consisting of a short epiglottis and anterior larynx. Given the persistence of symptoms and quality of life impairment, an alternate method for surgical candidacy evaluation was pursued before committing the patient to TBP. We opted for pneumatic stenting of the airways during exercise. We had the patient perform submaximal treadmill exercise (1.6 mph, 16% gradient) while CPAP was applied at 0 cmH2O (control), 9 cm H2O, and 11 cmH2O; each CPAP level was applied for 3 min (Fig. 2). At rest, the patient rated her 'exertion' (RPE) as 9 on the Borg 6-20 scale. Following the first 3 minutes of exercise at 0 cmH2O, the patient's RPE increased to 13. The exercise was also associated with worsening of the patient's cough. When applied at 9 cmH2O, the use of CPAP was associated with a decrease in RPE back to the baseline value and complete resolution of the patient's cough was achieved. Further titration of CPAP to 11 cmH2O was associated with a slight increase in RPE, but this could also reflect the duration of exercise and upward drift in heart rate rather than the lack of efficacy of the CPAP itself (Table 1). Overall, the patient and our team noticed a significant reduction in cough and shortness of breath when CPAP was applied, which led to the multidisciplinary joint decision to undergo surgical tracheal stabilization. TBP was performed without complications and resulted in an improvement of respiratory symptoms. Following this multidisciplinary management, the patient reported no recurrence of symptoms at a one-year follow-up.

airway collapse, continuous positive airway pressure, excessive dynamic airway collapse, expiratory central airway collapse, tracheobronchomalacia, tracheomalacia

PMC7447035_01

Unknown

In this study, the average age of the patients was 67+-12 years old; most of them had at least one underlying disease such as hypertension, diabetes, cardiovascular or cerebrovascular diseases. This is agreed with the previous report that the older patient with COVID-19 tends to become more severe, in particular for the patients with underlying diseases. Fever and dry cough were the main symptoms after the onset of SARS-CoV-2 infection, which is similar to the symptoms of SARS or MERS. For the laboratory, the significant increase in leukocytes, neutrophils and neutrophil-to-lymphocyte ratio suggested the severity of pulmonary inflammatory responses and impairment of the immune system in patients infected with SARS-CoV-2. The infection-related biomarkers including SF markedly elevated in the serum as well as Inflammatory cytokines including IL-6, and TNF-alpha, indicating that inflammation storm may also occur and aggravate in patients died from COVID-19 during the disease. Chest CT imaging plays an important role in the diagnosis and dynamic evaluation of COVID-19. Typical imaging features of multiple ground-glass opacities and/or consolidations in patients with COVID-19 pneumonia have been detailedly described in previous reports. Even though the pathogenesis of SARS-CoV-2 infection is not fully understood, diffuse alveolar injury and progressive respiratory failure caused by SARS-CoV-2 is the leading cause of death in severe patients with COVID-19. From the current study, we found GGO and GGO with consolidation were the most predominant imaging features in patients who died from COVID-19, which is correlated with the pathological findings of COVID-19 that severe inflammatory exudation in intra-alveolar spaces and hyaline membrane formation. The severity score of lung involvement in patients who died from COVID-19 was also significantly greater than that in patients with mild to moderate COVID-19 (12.97+-5.87 vs. 7+-4). What is more, the mild-moderate correlation between chest CT severity scores and systemic inflammation activation was also preliminarily demonstrated in this study. Therefore, the imaging features and dynamic changes could provide the most direct evidence for assessing the severity of the disease and the prognosis. The results of this study also demonstrated that the proportions of consolidation and severity scores were significantly increased on the follow-up chest CT scans as compared with the initial CT scans (14.53 +- 5.76 vs. 6.60 +- 5.65) in patients died from COVID-19. More white lungs (severe lung involvement) were observed in the late stage of the disease (57% vs. 32% for 0-7 days and >14 days before the death). In addition, considering the correlations between chest CT scores (lung involvement) and inflammatory parameters of laboratory tests, the increase of the proportions of consolidation and the extent of GGO (higher CT scores) would suggest secondary bacterial infection occurred in the late stage of SARS-CoV-2 infection, which may be responsible for the rapid deterioration and acute respiratory distress in severe patients with COVID-19. Empirically administration of antibacterial drugs was thus recommended by some clinical experts. Therefore, rapidly increased consolidation and high severity scores based on chest CT images may predict the patient's poor prognosis. The outbreak of COVID-19 has had a strong impact worldwide. Almost all countries have suffered huge losses in health, society and economy. Our results may be potential risk factors to identify patients with poor prognosis, help clinicians to provide earlier interventions for these patients, and improve their survival rate. There were some limitations in this present study. First, there was no control group included in this study. Thus, it is hard to evaluate the exact value of chest CT imaging in identifying the risk factors of poor prognosis as compared with the other clinical and/or laboratory parameters. A case-control study needs to be done shortly. Second, because many patients were transferred from the other hospitals, their early chest CT images were not available for us. In addition, some patients did not have follow-up chest CT scans due to critically ill conditions. As lung biopsy was lacked, the relationship between imaging features and histopathological findings needs to be investigated. Therefore, other potential causes of underlying disease were not estimated. Therefore, the information of dynamic changes of CT features and severity scores is limited.

PMC5078677_01

Male

A 46-year-old man was transferred to our emergency room for facial and upper trunk swelling and dyspnea with chest discomfort that had begun 1 month earlier. He was a 30-pack-year current smoker. On physical examination, neck vein engorgement was observed, with distended veins and edema on the upper trunk and both arms. Chest radiograph showed consolidation in the right paratracheal area that suggestive of central malignancy (Fig. 1). We performed chest computed tomography (CT) with contrast enhancement to rule out SVC syndrome. The CT revealed a soft-tissue mass in the right paratracheal area that has invaded into the SVC and extended to the right atrium with bilateral pleural effusions (Fig. 2A-C). Positron emission tomography (PET)-CT with 18F-fluorodeoxyglucose (FDG) showed increased FDG uptake, with a maximum standardized uptake value (SUVmax) of 10.6 in the SVC (Fig. 2D). It was not available to obtain tissue from the primary lesion in the right upper lung using CT-guided percutaneous core needle aspiration (PCNA). In the bronchoscopy, there was no endobronchial lesion. Therefore, we decided to perform EBUS-TBNA to obtain tissue from the intravascular mass in SVC. EBUS-TBNA was performed using an ultrasound bronchoscope with a linear scanning transducer. Under ultrasound visualization, the SVC was tightly packed by the mass and blood stream was not detected around the tumor. The tumor was punctured using a 22-gauge needle under real-time visualization (Fig. 3A). During the procedure, there was no serious bleeding or other complication. Cytopathology confirmed poorly differentiated adenocarcinoma, with TTF-1-positive immunohistochemistry (Fig. 3B). There were no epidermal growth factor receptor (EGFR) gene mutations or KRAS gene mutations. He received 4 cycles of gemcitabine-carboplatin chemotherapy for the treatment of lung cancer. Two months after the chemotherapy, chest CT showed that the tumor size was decreased and his symptoms were relieved as well (Fig. 4).

ebus-tbna, intravascular tumor biopsy, superior vena cava syndrome

Chest computed tomography (CT) scan shows 38 mm primary lung mass invading the right mediastinum (arrow) (A).

PMC5078677_01

Male

A 46-year-old man was transferred to our emergency room for facial and upper trunk swelling and dyspnea with chest discomfort that had begun 1 month earlier. He was a 30-pack-year current smoker. On physical examination, neck vein engorgement was observed, with distended veins and edema on the upper trunk and both arms. Chest radiograph showed consolidation in the right paratracheal area that suggestive of central malignancy (Fig. 1). We performed chest computed tomography (CT) with contrast enhancement to rule out SVC syndrome. The CT revealed a soft-tissue mass in the right paratracheal area that has invaded into the SVC and extended to the right atrium with bilateral pleural effusions (Fig. 2A-C). Positron emission tomography (PET)-CT with 18F-fluorodeoxyglucose (FDG) showed increased FDG uptake, with a maximum standardized uptake value (SUVmax) of 10.6 in the SVC (Fig. 2D). It was not available to obtain tissue from the primary lesion in the right upper lung using CT-guided percutaneous core needle aspiration (PCNA). In the bronchoscopy, there was no endobronchial lesion. Therefore, we decided to perform EBUS-TBNA to obtain tissue from the intravascular mass in SVC. EBUS-TBNA was performed using an ultrasound bronchoscope with a linear scanning transducer. Under ultrasound visualization, the SVC was tightly packed by the mass and blood stream was not detected around the tumor. The tumor was punctured using a 22-gauge needle under real-time visualization (Fig. 3A). During the procedure, there was no serious bleeding or other complication. Cytopathology confirmed poorly differentiated adenocarcinoma, with TTF-1-positive immunohistochemistry (Fig. 3B). There were no epidermal growth factor receptor (EGFR) gene mutations or KRAS gene mutations. He received 4 cycles of gemcitabine-carboplatin chemotherapy for the treatment of lung cancer. Two months after the chemotherapy, chest CT showed that the tumor size was decreased and his symptoms were relieved as well (Fig. 4).

ebus-tbna, intravascular tumor biopsy, superior vena cava syndrome

Initial lung mass in chest CT scan.

PMC5078677_01

Male

A 46-year-old man was transferred to our emergency room for facial and upper trunk swelling and dyspnea with chest discomfort that had begun 1 month earlier. He was a 30-pack-year current smoker. On physical examination, neck vein engorgement was observed, with distended veins and edema on the upper trunk and both arms. Chest radiograph showed consolidation in the right paratracheal area that suggestive of central malignancy (Fig. 1). We performed chest computed tomography (CT) with contrast enhancement to rule out SVC syndrome. The CT revealed a soft-tissue mass in the right paratracheal area that has invaded into the SVC and extended to the right atrium with bilateral pleural effusions (Fig. 2A-C). Positron emission tomography (PET)-CT with 18F-fluorodeoxyglucose (FDG) showed increased FDG uptake, with a maximum standardized uptake value (SUVmax) of 10.6 in the SVC (Fig. 2D). It was not available to obtain tissue from the primary lesion in the right upper lung using CT-guided percutaneous core needle aspiration (PCNA). In the bronchoscopy, there was no endobronchial lesion. Therefore, we decided to perform EBUS-TBNA to obtain tissue from the intravascular mass in SVC. EBUS-TBNA was performed using an ultrasound bronchoscope with a linear scanning transducer. Under ultrasound visualization, the SVC was tightly packed by the mass and blood stream was not detected around the tumor. The tumor was punctured using a 22-gauge needle under real-time visualization (Fig. 3A). During the procedure, there was no serious bleeding or other complication. Cytopathology confirmed poorly differentiated adenocarcinoma, with TTF-1-positive immunohistochemistry (Fig. 3B). There were no epidermal growth factor receptor (EGFR) gene mutations or KRAS gene mutations. He received 4 cycles of gemcitabine-carboplatin chemotherapy for the treatment of lung cancer. Two months after the chemotherapy, chest CT showed that the tumor size was decreased and his symptoms were relieved as well (Fig. 4).

ebus-tbna, intravascular tumor biopsy, superior vena cava syndrome

, and follow up chest CT shows interval decrease in size of the primary lung cancer.

PMC5256675_03

Female

Her brother, 4 years and 7 months older, was diagnosed with CF after her diagnosis. He was born at term without complications and had a past history of frequent vomiting and poor weight gain since his first months of life. He was hospitalized for dehydration at 3 months of age and for enterorrhagia by Meckel's diverticulum at 6 months of age. At 2 years of age, recurrent upper respiratory tract infections started. Despite a voracious appetite, his difficulty in weight gain worsened. In the first consultation at the CF reference centre, at 5 years and 10 months of age, his parents reported that he had frequent coughing. On physical examination, he exhibited pallor, with a weight of 15.7 kg (2nd percentile for age), height of 109 cm (11th percentile for age), BMI of 13.3 kg/m2 (3rd percentile for age), and z scores of -1.22, -1.94 and -1.81, respectively. From the first consultation, P. aeruginosa and S. aureus respiratory chronic colonization were detected and, from the following month, also A. xylosoxidans. Attempts to eradicate P. aeruginosa also failed. Regarding sporadic colonization, the boy had two positive cultures for Haemophilus. Until 18 years of age, he had 3 exacerbations of CF treated with hospitalization for 14 days each during the 7th and 8th years and another hospitalization for viral encephalitis at age 11. In the last year, at 17 years and 6 months old, liver disease was detected, and at 18 years of age he was admitted twice: once for vasculitis and another for exacerbation of CF. However, their mother claimed that she could not understand the greater debilitation of her daughter's health compared with her son's, despite the daughter's better compliance with the treatment regimen. The comparisons of lung function (forced expiratory volume in 1 s - FEV1), BMI and Bhalla CT score in two siblings were done at the same age and are presented in Fig. 1. Although both siblings exhibited some improvement in their absolute BMI during follow-up at the reference centre, the female's values were significantly lower than the male's (Mann-Whitney test, p < 0.0001; interquartile Range (IQR) - male: 2.5 kg/m2, female: 1.1 kg/m2). To measure lung structural damage, 2 radiologists who were blinded to any other information reviewed the CT scans separately. They assigned modified Bhalla scores for each CT scan and reassigned the scores 1 month later. The median of the final Bhalla scores was obtained for each available CT scan. The female had lower Bhalla scores than her brother: 18.7 (1 year and 6 months), 9 (7 year and 2 months), 6.7 (10 years and 11 months) and 6.5 (13 years and 6 months). His scores were 16.5 (5 years and 10 months), 12.2 (9 years and 7 months) and 10.2 (14 years). Their bacteriological backgrounds were studied between 3.3 and 6.5 years of age for the female and 7.7 and 9.9 years of age for her brother. Species identification was performed by conventional methods, and genotype analysis was performed by multi-locus sequence typing (MLST) of 7 housekeeping genes (nusA, rpoB, eno, gltB, lepA, nuoL, nrdA), as previously described. Allelic profiles and ST were analysed according to the PubMLST Website (http://pubmlst.org/achromobacter/). All isolates were A. xylosoxidans and belonged to the same sequence type (ST 201). This is a new ST previously identified in Brazilian CF patients by our group and added to the PubMLST Website. The determination of minimal inhibitory concentrations (MIC) of antibiotics [ceftazidime (CAZ), ciprofloxacin (CIP), imipenem (IMP) and thimethoprim-sulfamethoxazole (TMP-SXT)] was performed using E-test strips (AB Biodisk, Solna, Sweden). The breakpoints used were those recommended by CLSI for non-Enterobacteriaceae. The isolates were considered resistant when MIC >=32 mug/mL for CAZ; MIC >=4 mug/mL for CIP; MIC >=16 mug/mL for IMP and MIC >=4/76 mug/mL for TMP-SXT. The majority of isolates (58.3%) were susceptible to all antibiotics tested (95%CI: 36.5-80.1%). All isolates were susceptible to IMP and CAZ (Fig. 2). The swimming and swarming motility abilities were determined as described by Rashid et al.. The results are presented as the median diameters obtained in 3 independent assays performed in triplicate (Fig. 2). There were no differences in swimming phenotype between the isolates (unpaired t-test, p = 0.07; 95%CI - male: 38.1-58.2 mm, female: 27.2-45.4 mm), but the swarming phenotype was significantly higher for the A. xylosoxidans isolates recovered from the male (Mann-Whitney test, p = 0.004; IQR - male: 23 mm, female: 20 mm). Biofilm formation on abiotic plastic surfaces was determined as described by Tendolkar et al.. Then, the A. xylosoxidans isolates were divided into different biofilm-producer classes: N, no biofilm producer; W, weak biofilm producer; M, moderate biofilm producer; and S, strong biofilm producer, as described by Stepanovic et al.. All isolates produced biofilms, and the majority were strong producers, but no significant difference in the amount of biofilm formation was detected when isolates from both patients were compared. Data were analysed with Graph Pad Prism software, version 5.0. The specific tests used are described in the text. Significance was accepted at the p < 0.05 level.

achromobacter spp, achromobacter xylosoxidans, cystic fibrosis

PMC5577401_01

Male

A 45-year-old male presented with focal onset seizures with dyscognitive symptoms and focal to bilateral convulsions during his first visit to our institution in August 2013. Diagnosed with epilepsy at the age of 6 years, he had been on several antiseizure agents for more than 20 years, with levetiracetam, rufinamide, valproic acid, and clonazepam as his recent medications. Despite his medical management, he experienced seizures occurring in clusters, with a maximum of up to 25 per day. His semiology included motionless staring followed by body shaking lasting for 30 s without any preceding aura. The postictal period lasted for hours during which he remained groggy and had mood changes. His baseline mental functioning included intellectual disability, non-verbal status with limited sign language skills, stable mood with no behavioral outbursts, obsession for American football and normal sleep-wake cycle. He received 24-hour care from well-educated and engaged parents, with reliable adherence to medication. His past medical history also included hypothyroidism, pulmonary valve anomaly, deafness, Hodgkin lymphoma, bladder carcinoma with urostomy, and right kidney transplant. The patient's most recent EEG (electroencephalogram) (performed in October 2010 while the patient was on antiseizure medications) was within normal limits. We found no significant, pertinent abnormal findings on physical examination during his first visit. His follow-up laboratory values were within normal limits, including the anti-seizure drug levels (levetricetam 39.9 mcg/ml) and TSH (2.2 mIU/L). His brain magnetic resonance imaging was abnormal, showing mild to moderate age-advanced cerebral and cerebellar atrophy, most likely to be an insult from hypoxic-ischemic encephalopathy at birth. During the patient's follow-up period after his initial visit, he failed adjustments of levetiracetam (increased to 1500 mg BID). Hence, we decided to proceed with VNS implantation for his drug-resistant epilepsy. VNS device implantation (Model Demipulse 103, Liva Nova, Houston, TX) was performed on October 21, 2013. The electrodes were placed over the left vagus nerve following standard procedure. Two weeks later, stimulation was initiated with the following parameters: amplitude of 0.25 mA, frequency of 30 Hz, and pulse width of 500 mus with a stimulation period of 30 s followed by a 5-minute off-time. The patient's baseline height, weight, and basal metabolic index were 4 ft. 6 in, 47.6 kg, and 25.3 kg/m2, respectively. The weight measured was 22% greater than the ideal body weight (39 kg). On follow-up, the patient's parents reported improvement in seizure frequency with only 4 episodes occurring during the 3-month period and improved quality of life with no side effects from VNS such as a change in his voice or neck pain. Follow-up repeat EEG was also normal. Hence, VNS was continued with medication adjustments, including a decrease in the dose of levetiracetam to 1000 mg BID and initiation of ezogabine at 100 mg TID, after ophthalmology screening for pigment retinopathy. In addition, he was continued on his previous regimen of rufinamide, valproic acid, and clonazepam. At his follow-up visit in December 2013, the patient had complaints of throat irritation and poor oral intake. His weight was 45.8 kg, and he was advised to take Cepacol lozenges twice daily for the next 3 months. In March 2014, his weight was 41.7 kg. Because of his significant weight loss, we adjusted the stimulation parameters to a reduced setting as shown in Fig. 1. During the next 6 months, the patient's appetite remained suppressed, and VNS was eventually discontinued in August 2014. Anti-seizure drug levels were within acceptable limits (levetricetam: 73.8 mcg/ml; valporic acid: 43.1 mcg/ml). However, during his visit in December 2014, the patient reported 4 seizures, so VNS was restarted in January 2015. By October 2015, the patient's seizure frequency improved, and stimulation parameters were increased. However, this time the patient's weight and appetite improved, and he gained a total of 3.6 kg. By April 2016 his body weight exceeded his baseline weight at the time of implantation of the VNS device. Furthermore, his seizure burden continued to improve. He remained seizure free from April 2016 till his recent visit in January 2017. No changes to his antiseizure medications were made from November 2013 till January 2017.

PMC5559658_01

Male

A 64-year-old man admitted to our hospital reported watery diarrhea for the last 13 months. He had up to 8 bowel movements per day, worsening in the month prior to admission, resulting in 15 to 20 movements per day without response to antidiarrheals. He did not report steatorrhea or blood, mucus, or pus in the stool. He did not suffer from asthenia, anorexia, fever, or vomiting. He did, however, report a 20-kg weight loss during the past year. Arthralgia, dyspnea, or abdominal pain were not present. A right jugular paraganglioma was diagnosed more than 30 years ago, and its extension affected several vital structures (Figure 1). He was not on any medication and had no other medical conditions. Physical examination revealed normal vital signs, with pale skin and mucus. The right side of the face was deformed by a prominent, tight, hypervascular cervical tumor, with peripheral facial palsy. Abdominal examination showed normal bowel sounds without tenderness, distension, or masses. Laboratory studies showed anemia (9.4 g/dL), thrombocytosis (724,000 platelets/microL), elevated erythrocyte sedimentation rate (120 mm), and hypoalbuminemia (2.7 g/dL). Alkaline phosphatase and gamma glutamyltransferase were slightly altered at 141 U/L and 100 U/L, respectively. 24-Hour urine collection showed 1.2 g/d proteinuria, with normal creatinine (1.16 mg/dL). Chest x-ray was normal. Stool specimen culture (including parasite analysis) was negative, and celiac disease antibody tests (anti-tissue transglutaminase antibody) and an intestinal biopsy were unrevealing. Thyroid hormone tests, vasoactive intestinal polypeptide (VIP), and 5-hydroxyindoleacetic acid (5-HIAA) urine tests also returned normal results. Serum electrophoresis and 24-hour urine immunofixation electrophoresis did not show a monoclonal spike. Immunoglobulin G and M levels were normal; however, immunoglobulin A levels were almost twice the upper limit (843 mg/dL). Tests for hepatitis B antigens and anti-hepatitis C antibodies were negative. Rheumatoid factor, anti-nuclear antibody, anti-smooth muscle antibody, anti-mitochondrial antibody, and QuantiFERON TB tests were also negative. A computed tomography (CT) scan showed mucosal enhancement and local hyperemia in the descending and sigmoid colon without abdominal masses or thickenings. Corresponding with the CT findings, a colonoscopy revealed an unspecific inflamed and friable mucosa. A histologic assessment of the affected colon biopsies showed extracellular eosinophilic deposits in the submucosa and vessel walls, with apple green birefringence with Congo red stain, indicative of amyloidosis (Figure 2). An immunohistochemical stain was positive to AA-type amyloid (Figure 3).

PMC6560971_01

Female

Observation 1: this was a 44-year-old woman, followed by iron deficiency anemia under iron supplementation, who developed an isolated swelling of the right parotid region, evolving for 5 months. Clinical examination: The patient was in good general condition, apyretic. The tumefaction was pretragal and measured 3cm of long axis, firm, well limited, mobile and painless, associated with multiple, hard and fixed homolateral jugulodigastric adenopathies. The controlateral parotid was with no particularities. There was no chewing discomfort, no trismus or endobuccal pus exit, no peripheral facial paralysis, and the upper aerodigestive tract was free. At Parotid MRI (Figure 1), the lesions straddled between the superficial and deep lobe of the right parotid, oval 20/15mm. It shows a nodule with low intensity T1 signal, and increased T2 signal, enhanced after Gadolinium administration, with presence of multiple homolateral, right jugulodigastric adenopathies. Its characteristics were suspicious of malignancy. The rest of the biological evaluation was normal. Chest x-rays showed no evidence of a possible chest location.The diagnosis of parotid cancer has been strongly suspected. To obtain histological evidence, we decided to perform a partial exofacial parotidectomy with dissection and preservation of the facial nerve (Figure 2). Anatomopathological examination of the resected mass (Figure 3) concluded a primary parotid and cervical lymph node tuberculosis. This was confirmed by definitive histological examination. The patient was put on anti-bacillary treatment (2RHZ/4RH) for six months, with significant improvement 6 months after the end of treatment.

parotid, parotidectomy, tuberculosis

PMC6560971_02

Female

Observation 2: a 45-year-old woman, with no notable pathological history, consulted in our facility for a left sub-angulo-mandibular mass evolving for approximately 4 months. There were slight inflammatory signs nearby, particularly a slight redness with pain and fever at 38 C without weight loss, chewing discomfort, trismus, or pus exit at salivary orifices. The young woman was in good general condition and had a swelling of the left parotid area, firm, painless, measuring about 4 cm in long axis, and fixed. There was no limitation of the mouth opening or peripheral facial paralysis. Examination of the oral cavity and the opening of the stenon canal did not reveal any inflammation or pus output. Examination of the cervical lymph node areas was normal. The rest of the ENT and general examination was without any particularity. A cervical ultrasound was done to show a tumor lesion, measuring 29 x 28 x 14 mm, of mixed echostructure with central liquid predominance at the lower pole of the left parotid. Parotid MRI showed a lesional process in the deep compartment of the left parotid gland, with low intensity T1 signal, and in the other hand, high intensity signal in diffusion sequence with peripheral enhancement, measuring 30 x 29 x 15 mm. The right parotid and submandibular glands, in addition to the thyroid are without signal or morphological abnormalities. This was in favor of a left parotid abscess (Figure 4). The rest of the biological test, as well as the chest x-ray, were normal. The patient was operated benefiting conservative parotidectomy of the facial nerve. Histopathological study of the cyst wall found epithelial-gigantocellular granuloma with caseous necrosis. The culture of the puncture fluid on Lowenstein-Jensen medium revealed an acid-resistant bacillus, which allowed us to confirm the diagnosis of primary tuberculosis of the parotid gland. The young woman received a medical treatment of antituberculosis drugs combining an initial phase of 2 months based on rifampicin, isoniazid, ethambutol, pyrazinamide, followed by a consolidation phase of 4 months combining Rifampicin and Isoniazid. The evolution was favourable within 9 months after the end of the treatment.

parotid, parotidectomy, tuberculosis

PMC9280093_01

Unknown

A 22-year-old primigravida was referred for fetal echocardiography at 24 weeks' gestation given suspicion of fetal tachyarrhythmia on screening. The four-chamber view showed moderate pericardial effusion, hyperechoic endocardium, papillary muscles, and both atrioventricular valve annuli [Figure 1a and b]. The heart was otherwise structurally normal. There was ventricular diastolic dysfunction as evident in the left ventricle inflow-outflow Doppler (presystolic flow in ascending aorta) [Figure 2a and b] with no atrioventricular valve regurgitation. Left ventricle inflow-outflow Doppler showed periods of fetal sinus bradycardia [Figure 3] alternating with frequent conducted atrial ectopics triggering episodic atrial tachyarrhythmia. Left brachiocephalic vein-aorta Doppler showed the beginning and termination of the tachyarrhythmia. It was a 1:1 long VA tachyarrhythmia (VA interval 600 ms, AV interval 267 ms) triggered by an atrial ectopic, and spontaneous termination of the tachyarrhythmia followed by an atrial ectopic and bradycardia [Figure 4]. Hence, a diagnosis of TBS was made. There was no evidence of atrioventricular block. Maternal serum SSA and SSB antibody levels were elevated 145 U (normal <20) and 181 U (normal <20), respectively. There was no family history of sinus node dysfunction. Transplacental therapy with oral dexamethasone at a dose of 4 mg/day was given initially for 7 days. Reassessment after 1 week showed absent pericardial effusion and improved ventricular diastolic function [Figure 5]. However, fetal bradycardia, conducted atrial ectopics, and episodic atrial tachycardia persisted. Hence, oral dexamethasone dose was increased to 8 mg/day. Reassessment after a week showed no further improvement.

atrial arrhythmia, autoimmune associated tachy-bradycardia syndrome, fetus

PMC9353032_01

Male

A 16-year-old male student from Jieyang City, Guangdong Province was admitted to Foshan Fourth People's Hospital on 11 November 2020. The patient had an intermittent cough without obvious inducement 6 months ago, mainly dry cough, no fever, chest pain, or other adverse symptoms. He was previously healthy, with no history of bird feces or soil contact. On 19 October 2020, the chest CT examination was conducted at the local hospital, which revealed chest shadow and suspected tuberculosis. Then, he came to our hospital for treatment. There were no obvious abnormalities on physical examination after admission. The blood assay showed a white cell count of 7.20 x 109/L, neutrophils of 51.9% (3.73 x 109/L), and C-reactive protein of 9 mg/L. T-lymphocyte spot test (T-SPOT) and pure protein derivative (PPD) skin test (13 x 14 mm) were positive. In terms of bacteriology, sputum acid-fast staining was negative on 13, 14, and 15 November 2020. On 13 November 2020, a chest plain scan and enhanced CT showed left lower lobe and right pulmonary cavities lesions (Figure 1a), which suggested possible pyogenic inflammation, fungal infection, or secondary tuberculosis. The patient was given the diagnostic anti-infective treatment of cefotaxime sodium sulbactam 2.25 g twice a day. After 10 days of regular treatment, the chest CT scan showed little change compared with pre-treatment (Figure 1b). There were no significant abnormalities in the basic immunosuppressive status assessment (immunoglobulin level, T lymphocyte subsets, HIV detection, etc.). On 17 November 2020, a bronchoscopic examination showed that the bronchial mucosa of each lobe and subsegment on both sides was congestive and edematous (Figure 2). Microscopic examination of bronchial lavage fluid (BALF) showed a medium amount of squamous epithelium, bronchial columnar epithelial cells, and a small number of neutrophils, but no cancer cells. Microscopic examination of tracheoscopic brush film revealed a medium amount of columnar epithelial cells and no cancer cells. These results excluded etiologies other than infection. The etiological examination using BALF revealed that GeneXpert (-): MTB-DNA: negative, rpoB: negative. G test revealed <37.50 pg/ml. No acid-fast bacilli, bacteria, spores, or hyphae were found. Examination and diagnosis: bronchitis changes. The second tracheoscopy on 20 November 2020, indicated bilateral bronchitis. BALF GeneXpert was negative. The BALF was then sent for PACEseq mNGS (Hugobiotech, Beijing, China) on a Nextseq 550 platform (Illumina). On 21 November 2020, the mNGS result came back and showed one specific read of C. neoformans (Figure 3a). On 23 November 2020, CrAg-LFA (titer 1:80) and fungal culture (creamy mucoid colonies with relatively smooth edges on Sabouraud Dextrose Agar medium, initially colorless and which appeared lavender with time after staining using CHRMagaar color plate) revealed as positive, confirming the mNGS detection (Figure 3b). The patient was diagnosed with PC. The drug susceptibility results on 26 November 2020, suggested that this strain was sensitive to voriconazole (MIC <= 0.13), itraconazole (MIC < 0.25), fluconazole (MIC <= 4), and amphotericin B (MIC < 0.5), among which voriconazole had the lowest MIC (Table 1). Therefore, the patient was given oral voriconazole of 400 mg QD on 28 November 2020 for seven months. On 29 June 2021, a chest CT was performed and showed a progressive decrease in lesions of the patient (Figure 1c). The whole treatment process was shown in Figure 4.

cryptococcus neoformans, cryptococcosis, diagnosis, immune competent patients, metagenomic next-generation sequencing

PMC3649609_01

Male

A 44-year-old man presented with gross painful hematuria and frequency. He did not have lithuria, hematospermia or previous urinary tract instrumentation. He had received antitubercular therapy 20 years back for pulmonary tuberculosis and again 1 year before presentation to us. His urine examination and serum biochemistry were normal. Intravenous urogram showed multiple radio-opaque densities in right hemipelvis, normal left kidney and nonvisualized right kidney [Figure 1]. Micturating cystourethrogram revealed calcific densities in right pelvis and grade 1 right vesicoureteral reflux. A diagnosis of right renal agenesis with seminal vesical calculi was made and confirmed with magnetic resonance imaging (MRI) of the pelvis [Figure 2]. He was planned for endoscopic removal of seminal vesical calculi. On cystoscopy, a small stone was seen at the right vesicoureteral junction. Retrograde ureterography revealed that the right ureter was blind ending and dye was seen filling a diverticulum at the lower end of ureter [Figures 2c, and d]. Endoscopic incision of the diverticulum orifice was made. It was full with multiple, tiny, smooth-surfaced calculi which were removed endoscopically.

blind ureter, calculi, renal agenesis, ureteral diverticulum

PMC5061085_01

Male

CF, a 26-years-old man of North African origin, was hospitalized for persistent cough on July 2003. Chest x-ray showed at this moment bilateral hilar adenopathy and tenuous infiltration of the upper right lobe. HRTC showed multiple irregular parenchymal opacities of alveolar interstitial type at the upper lobes and bilateral hilar enlargement. Diagnosis of pulmonary TB was made after bronchoscopy on July 2003, for positivity of M. tuberculosis DNA and RNA in bronchoalveolar lavage fluid. Culture of sputum and BAL fluid were negative. Tuberculin skin test was negative. Anti TB therapy was started on July and continued for six months until January 2004. HIV infection had been diagnosed just one month before this hospitalization, on June 2003, with a CD4+ count of 371/mmc (19.6%), HIVRNA 139,000 cp/ml (wild type) and HCV coinfection (HCV type 1a). Antiretroviral therapy with (azt + 3tc) + nvp was also started on June 2003. During the first year he attained a good viro-immunological response, but later he became less compliant, and on November 2004 he was lost to follow up. On April 2006 he was readmitted at day service during a period of jail detention: CD4+ were 374/mmc (26%), HIV viremia was 3055 cp/ml and HCV RNA titre was 3,097,802 cp/ml. ART therapy was switched to tdf + 3tc + lpv/r. Chest x-ray showed pulmonary apical bilateral infiltrates without pleural effusion, but the patient was lost to follow up for a second time before doing further investigations. After two years, on March 2008, he was conducted to the service for consultation: he was in good conditions, but since 2007 he was developing chronic cutaneous maculopapular lesions at the right arm. Adherence to ART therapy was suboptimal and he was highly viremic, with 166,469 cp/ml of HIVRNA on July 2008. Therapy was modified to (tdf + ftc) + lpv/r. During the following year he developed multiple symmetric lymphadenopathies (neck, axillae and groin). Chest x-ray showed: bilateral fibronodular apical-subclavian lesions with hilar enlargement and prominence of the left second cardiac arch. CT-scan revealed mediastinal and intra-abdominal periaortic severe adenopathy (4 cm diameter). Biopsy of the forearm cutaneous lesions showed granulomatous infiltration of sarcoid type without caseous necrosis. BAAR or fungi were not detected by specific stains of the tissue. He was hospitalized in another institution for dyspeptic symptoms on October 2009. Total body CT-scan showed enlarged intra-abdominal lymph nodes (max 2.5 cm in diameter), hilar bilateral adenopathy (3 cm in diam.) and apical pulmonary fibrosis with reticulonodular infiltrates of lymphatic origin (galaxy sign). Biopsy of an axillary lymph node showed foci of chronic granulomatous epithelioid inflammation with giant multinucleated cells. No mycobacteria spp, fungi or other parasites were demonstrated by molecular or histological techniques. Bronchoscopy was also performed with BAL and the research of malignant cells and mycobacteria spp was negative (MTB and atypical mycobacteria) by PCR and culture. He was dismissed on November 2009 with the diagnosis of: "Chronic granulomatous lymphadenitis, Chronic Active Hepatitis HCV-related, Duodenitis in patient with HIV infection C3, Opioid addiction undergoing pharmacological therapy". Afterwards he continued ART therapy with better adherence, but after few months he presented general malaise, weight loss, persistent nausea and anorexia with emesis, increasing groin adenopathy and was newly hospitalized for the clinical suspect of lymphoma. Node biopsy showed: "Chronic granulomatous non necrotising epithelioid gigantocellular lymphadenitis with confluent foci as observed in sarcoidosis". PCR for M. tuberculosis DNA and for atypical mycobacteria from node sections was negative. Culture for M tuberculosis and other mycobacteria was also negative. IGRA test (Quantiferon-TB test) was negative. Functional respiratory tests were also performed: Walking test was normal, Spirometry showed moderate-severe obstructive disease, with reduction of CO diffusion. Salivary glands echography showed parenchymal disomogeneity with ectasic ducta. Eye examination was normal. Steroid therapy was started on July 2010 with prednisone at the dose of 1 mg/kg/die: after one month lymph nodes were considerably reduced; the patient was gaining weight; he had neither fever nor constitutional symptoms. He continued ART therapy with (azt + 3tc) + lpv/r. Corticosteroid therapy was continued for 6 months (including one month of voluntary auto-suspension), but on March 2011 AST/ALT values were increased (446/315 mU/ml). Liver biopsy was decided, but the patient was definitely lost to follow up for personal reasons.

diagnostic flowchart, hiv infection, sarcoidosis

PMC6467460_01

Female

Social desirability of people has been researched in various contexts. Characteristics that have been attributed to people with socially desirable qualities include willingness to help others, keeping the interest of others in mind while embarking on any task, being a good listener, willingness to admit a mistake and being embedded in the larger social matrix. Each vignette was rated to be on a person deemed to be 'socially desirable' or 'socially neutral' by the entire study team, including the psycho-oncologists and oncology clinicians, e.g. being an elderly man who is active and looks after his grandchildren, a young man who is a footballer, a lady who was previously fit and recently struggling with her household chores, a middle-aged lady with breast cancer who is feeling better in between chemotherapy sessions were all deemed to be socially desirable. Examples of 'socially neutral' vignettes were 'a 67-year-old man with lung cancer who is breathless', 'a 77-year-old retired teacher who spends his time in reading and takes a driver to drive him to the market' etc. No one was deemed to be socially undesirable but only rated as socially desirable or neutral. This is in keeping with the professional non-judgmental attitude that clinicians ought to take in ideal circumstances. A consensus rating on social desirability was made by the two psycho-oncologists and all the oncologists who were part of the study team. Each of them rated the vignettes as socially desirable or neutral and any discordance in the ratings was resolved in the second round of feedback and discussions. A comprehensive list of all doctors and nurses working in the clinical departments of the hospital who came into direct patient contact was obtained from the department of human resources. Potential participants were approached individually by the researchers. Following a sequential design, a proportion of the respondents who participated in the quantitative part of the study were purposively chosen for qualitative in-depth interviews. The clinicians working in the hospital were approached for being included in the study. They were interviewed in private, in their own offices at a time suitable to them. Clinicians were requested to rate the vignettes on the ECOG PS. In order to avoid the rare problem of being unsure of any of the items of ECOG rating scale during the data collection, we had the ECOG rating scale (vide Appendix I) with scoring criteria in front of the participant while he/she rated each vignette. This ensured that the participants could fully concentrate on the rating of the vignette rather than feel they were being evaluated on their knowledge of the ECOG rating scale as this was not the purpose of the study. On completion of the ECOG rating, some clinicians were interviewed in-depth. They were interviewed in a relaxed environment. Clinicians who specialised in various clinical specialties of oncology were invited to participate. Participants were interviewed in their own offices as per their convenience. Respondents were asked about their decision-making processes and how they usually processed the information regarding a patient's health, disease and daily life in order to come up with the ECOG PS rating in a busy clinic. The qualitative part of the study adhered to the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines for research. All qualitative interviews were recorded and transcribed verbatim. The interviewers were trained in the techniques of qualitative in-depth interviewing by a senior researcher of the team. All doctors and nurses who had been employed in the hospital and were in direct patient contact were eligible to participate in the study. All clinicians in the study hospital who offered treatment to patients were familiar with ECOG rating and used it routinely. We specifically included only those clinicians who were involved in face-to-face decision-making for patients with cancer. Non-clinical specialties such as laboratory-based disciplines like biochemistry, histopathology and others that were not involved directly in making decisions for treatment based on ECOG rating and were therefore not included in the study. A predesigned set of 12 clinical case vignettes of variable complexity was designed by senior oncologists who were part of the study team. Participants were required to rate each of the cases on the ECOG scale. The case scenarios were presented with the standard ECOG scale which is a categorical scale (0, 1, 2, 3, and so on). Usually, it is easy to identify a PS ECOG grade '0', as well as a grade '4'. The difficulty appears to be differentiating between grades 1, 2 or 3. The sample case vignettes were designed to study results of ECOG assessment in patients in all PS grades but more specifically within the grades 1, 2 and 3. Socio-demographic variables were collected using a socio-demographic sheet given to all participants. Interviewers started with a predetermined set of interview items related to decision-making in oncology and the use of the ECOG scale. The interviewer also probed clinicians about decision-making, the algorithms they used and the thought process they engage in while planning and discussing oncology treatments among peers, colleagues and with patients. Qualitative data analysis and data collection went on concurrently in order to incorporate newly emerging themes from earlier interviews until data saturation was achieved. Quantitative analysis comprised of calculation of agreement indices for the entire population and for subsets of the population. Graphical exploration of the agreement was performed using heatmaps. Prespecified subsets for which agreement was calculated included age group, gender, profession type and years of experience in the field of oncology. Additionally, the questionnaire also included a question about the participant's opinion on the ECOG rating being perceived as a subjective or objective measure. We calculated agreement metrics for this question as well. As multiple raters were involved, a model-based kappa was calculated using the methodology proposed by Nelson et al. A kappa of 1 is interpreted as perfect agreement and 0 being absolute disagreement between raters. In order to circumvent the problems of Cohen's kappa value being influenced by small number values that are different from the other values specially with symmetrical data (kappa paradox), Gwet proposed first-order agreement coefficient or the AC1 statistic, which adjusts for the fact that multiple raters may agree on a rating by chance and addresses the kappa paradox. To describe in brief, this method uses a generalised linear mixed model to calculate the observed agreement between raters while minimising the impact of a chance agreement. Unlike Cohen's kappa and other variations, this method is not affected by prevalence rates. Furthermore, measure of association was also calculated using the same model-based approach. The function for calculation of the model based kappa was provided by Nelson et al. In order to investigate the effect of patient-related factors on the ECOG PS rating, a cumulative link mixed model (CLMM) was constructed for the data. All the patients described in the vignettes were a priori assigned to having socially desirable characteristics (vignettes 1, 2, 6 & 7) or neutral characteristics (rest of the vignettes). To give an example:'a grandmother who played with her grandchildren' was deemed to have socially desirable characteristics by the researchers and 'a politician who has lost his voice' was deemed to be neutral or not specifically having any socially desirable quality in the description in the vignette. Three characteristics of the patient, namely, age of the patient in the vignette, gender of the patient and the perceived social desirability of the patient were fitted into the CLMM. In the same way, CLMM allowed us to explore the effect of individual raters on the PS rating and to explore the way groups of raters tend to rate the PS. Dot plot of the effect of the rater characteristics on the PS rating was also calculated using CLMM faceted as per rater categories. Dots are coloured as per the job role, for example, consultant, trainee doctor or nursing staff. Maximum likelihood estimates of the coefficients were calculated using adaptive Gauss-Hermite quadrature method using 10 quadrature nodes. The exponents of the coefficients allowed us to get the odds ratio of rating being rated for the aforementioned vignettes. The second part of the analysis focused on the agreement with the gold standard ratings. In this analysis, the proportion of raters who gave the correct rating was the endpoint. Given that ECOG PS is an example of ordinal rating scale, no efforts were made to calculate the distance of disagreement. We also explored if the proportion of agreement with the golden rating varied as per the rater characteristics using the variables mentioned above. Qualitative data analysis went side by side with data collection as is recommended for qualitative research. Qualitative data analysis followed the principles of thematic analysis as suggested by Braun and Clarke. The various steps we used included becoming familiar with the data, generating initial codes, searching for themes or charting data, review of themes and synthesis, generating basic and organising themes and finally, arriving at global themes which defines the data. According to experts, thematic analysis is a method of identifying, analysing and reporting patterns or themes within qualitative data and is able to provide a rich description of the data. They also suggest that one of the advantages of this approach is its flexibility and that thematic analysis should be seen as a foundational method for qualitative analysis.

ecog, decision making, heuristics, oncology

PMC9035951_01

Female

A 60-year-old Japanese female with a history of depression and tuberculosis was referred to our hospital due to a lung nodule in the right lower lobe on computed tomography (CT) upon medical examination. She quit smoking 10 years ago with an 8 pack-year history and no family history of cancer. Imaging examinations revealed pleural dissemination and mediastinal lymph node adenopathy (cT4N2M1a Stage IVA). Endobronchial ultrasound-guided transbronchial needle aspiration of the mediastinal lymph nodes revealed adenocarcinoma. Molecular diagnostics of the tumor sample revealed ROS1 gene rearrangement without EGFR or anaplastic lymphoma kinase gene alteration. Based on the presence of ROS1 gene rearrangement, oral crizotinib treatment was started. Crizotinib achieved a partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 and maintained its effectiveness with minimal adverse events. However, CT 12 months after crizotinib initiation revealed a mass in the upper pole of the right kidney protruding toward perirenal fat (shown in Fig. 1a). Contrast-enhanced CT showed a polycystic mass with enhanced edges and septa. Considering that only a small lesion was detected 4 months prior but not at the time of crizotinib initiation, partial nephrectomy was performed by the Department of Urology to diagnose the mass. Pathology revealed xanthogranulomatous inflammation characterized by infiltration of lipid-laden macrophages and other inflammatory cells, fibrosis with hyalinization, and vasculation without malignancy or microbes (shown in Fig. 2a, b), which was consistent with CARCs. The day after surgery, crizotinib was restarted. Twenty-two days after restarting crizotinib, the patient developed fever. Laboratory data revealed elevated C-reactive protein, with subsequent CT showing abscess-like inflammation in the abdominal wall near the surgical wound and around right kidney (shown in Fig. 1b). Considering that antibiotic administration (cefaclor) had no effect, crizotinib was stopped and surgical cleaning was performed. No bacteria were detected from the culture of either the swab from the wound before starting antibiotics or the specimen from surgical cleaning, suggesting that these disseminated aseptic lesions were similar to CARCs, although pathological evaluation was not performed in the second surgery. Given the improved laboratory findings after the second surgery, crizotinib was started again. However, the patient developed fever again, prompting crizotinib to be abandoned. After crizotinib was stopped, C-reactive protein and fever improved spontaneously. CT upon crizotinib cessation showed only a well-controlled primary tumor without any other obvious lesions, including those in the brain. On day 25 after discontinuation, however, she was referred to the emergency department with a convulsive seizure and right hemiparesis. Enhanced magnetic resonance imaging revealed multiple brain metastases with edema which were not detected from the CT images obtained 26 days before admission (Fig. 3a, b). Thus, the rapid disease progression after crizotinib discontinuation in the current case was considered to be a "disease flare." Anticonvulsive agent (levetiracetam), dexamethasone, concentrated glycerin administration, and whole-brain irradiation (30 Gy/10 fraction) was started. Given that dexamethasone promoted no improvement in right hemiparesis, another ROS1 tyrosine kinase inhibitor with high central nervous system (CNS) penetration, entrectinib, was started on day 10 after admission. Hemiparesis improved, with subsequent magnetic resonance imaging on day 14 of entrectinib administration, showing a remarkable regression of the brain metastases with surrounding brain edema (shown in Fig. 3c). As of 3 months after entrectinib treatment, the disease remained well controlled without recurrence of brain lesions.

adverse effects, lung cancer, metastasis, non-small cell lung cancer, recurrence, tyrosine-kinase inhibitor

PMC2718141_03

Male

A 43-year-old man presented with left lower abdominal pain which had lasted for one month. He had a history of renal tuberculosis and a left ureteral stone. Physical examination was unremarkable. US showed a mass, about 2 cm in size and slightly hyperechoic to renal cortex, in the lower pole of the left kidney. It had poor margin. Unehanced CT scan showed a lobulated mass with higher attenuation than the renal parenchyma; after the intravenous administration of contrast material, the mass did not show significant enhancement (Fig. 3A). Renal cell carcinoma was diagnosed, and the patient was referred for left nephrectomy. Pathologic analysis of the specimen showed a hemorrhagic lesion in the corticome-dullary junction of the lower pole (Fig. 3B). Microscopical-ly, the hemorrhagic area was seen to composed of capillary-sized vessels, and there was no evidence of malignancy.

PMC7485476_01

Male

A 36-years-old man was diagnosed with Philadelphia positive B-cell acute lymphoblastic leukemia (ALL) with no central nervous system (CNS) involvement in early March 2019. He was treated with daily dasatinib, weekly vincristine, and dexamethasone twice weekly. He was then treated with methotrexate and Ara-c and achieved complete molecular remission by polymerase chain reaction (PCR). Subsequently, he underwent allogeneic peripheral blood matched sibling HCT with cyclophosphamide (Cy) and total body irradiation (TBI) myeloablative conditioning (MAC) in July 2019. The course was complicated by grade II, steroid-responsive, acute gut graft versus host disease (GVHD), and cytomegalovirus (CMV) reactivation. He remains in complete molecular remission, and cyclosporine (CSA) was discontinued in March 2020 (day 237 post HCT). He is currently on prophylactic acyclovir and Bactrim. Early June 2020, he developed low grade fever of 37.9 Celsius (C) and fatigue. He tested positive for SARS-Cov2 infection by real - time Polymerase Chain Reaction (RT-PCR) on June 11, 2020 (day 323 post HCT). He did not have any further fever after June 12. He only received as needed acetaminophen. Repeat nasal SARS-Cov2 PCR on August 20, 2020, was negative, and his SARS-Cov2 total antibody test was reactive.

acute lymphoblastic leukemia, bone marrow transplant, covid-19, coronavirus, hematopoietic cell transplant, lymphoma, multiple myeloma, sars-cov-2, stem cell transplant

PMC7485476_02

Male

A 29-years-old man was diagnosed with Philadelphia negative pre B ALL with no CNS involvement in August 2017. He was treated with a pediatric-inspired protocol and achieved remission; however, he had isolated CNS relapse while on maintenance therapy. He received salvage chemotherapy with fludarabine and Ara-C, and upon remission, he was consolidated with matched sibling allo-HCT using MAC with Cy/TBI; GVHD prophylaxis consisted of methotrexate and CSA. His course was complicated by grade II, steroid-responsive acute gut and skin GVHD as well as CMV colitis. Day 170 post HCT (June 5, 2020) while he was on tapering tacrolimus, he developed fever, cough, headache, runny nose followed by loss of taste and smell. He tested positive by PCR for SARS-Cov2 infection. Chest x-ray showed small faint ground-glass opacity in the left lower lung zone. Tacrolimus was stopped, and he was treated with ceftriaxone, hydroxychloroquine(HCQ), and azithromycin. He improved after 7days and was discharged. Repeat nasal SARS-Cov2 PCRs on July 8, 2020, were negative, and his SARS-Cov2 total antibody test was reactive on July 25, 2020. Unfortunately, on August 7, 2020, he was diagnosed with relapsed ALL, and currently, he is receiving blinatumomab salvage.

acute lymphoblastic leukemia, bone marrow transplant, covid-19, coronavirus, hematopoietic cell transplant, lymphoma, multiple myeloma, sars-cov-2, stem cell transplant

PMC7485476_03

Male

A 60-years-old man was diagnosed with IgG kappa multiple myeloma (MM) in 2002. He received induction therapy followed by autologous HCT with melphalan MAC in August 2002. He relapsed 15 months after auto-HCT. He received another induction followed by allo-HCT in 2004 after achieving deep remission. His conditioning was reduced intensity with fludarabine/TBI. In 2013 he had a biochemical relapse, so he was re-induced with bortezomib based therapy followed by donor lymphocyte infusion (DLI). He had another relapse in December 2019 and has been on dexamethasone 32 mg weekly since then. In May 2020, he developed fever and body aches after contact with a confirmed case of COVID-19, and he tested positive by PCR for SARS-Cov2 infection. He was admitted and treated symptomatically only and then discharged three days after admission after symptom-improvement. Repeat nasal SARS-Cov2 PCR on August 15, 2020, was negative, and his SARS-Cov2 total antibody test was reactive on August 16, 2020.

acute lymphoblastic leukemia, bone marrow transplant, covid-19, coronavirus, hematopoietic cell transplant, lymphoma, multiple myeloma, sars-cov-2, stem cell transplant

PMC7485476_05

Male

A 58-year-old man known to have morbid obesity, dyslipidemia, hypothyroidism, and a remote history of pleural Tuberculosis (TB) was diagnosed with IgG kappa multiple myeloma in July 2015. He received induction with bortezomib, lenalidomide, and dexamethasone followed by auto-HCT with melphalan MAC conditioning after achieving a very good partial response (VGPR). He was maintained on lenalidomide with dexamethasone, but he relapsed in December 2017 and was treated with carfilzomib, lenalidomide, and dexamethasone. In late May 2020, while on therapy, he developed a sore throat, fever, and runny nose. He tested positive by PCR for SARS-Cov2 infection. He recovered well after seven days of initial symptoms. Repeat nasal SARS-Cov2 PCR on August 20, 2020, was negative, and his SARS-Cov2 total antibody test was reactive.

acute lymphoblastic leukemia, bone marrow transplant, covid-19, coronavirus, hematopoietic cell transplant, lymphoma, multiple myeloma, sars-cov-2, stem cell transplant

PMC7485476_07

Male

A 21-year-old man was diagnosed with T-cell lymphoid blast crisis with underlying chronic myeloid leukemia (CML) in May 2019. He was treated with a pediatric chemotherapy regimen plus tyrosine kinase inhibitor (TKI) and achieved major molecular remission after induction. He underwent haploidentical HCT in June 2020 with fludarabine/TBI MAC conditioning along with rabbit antithymocyte globulin (ATG) and post-transplant cyclophosphamide with CSA and Mycophenolate Mofetil (MMF) for GVHD prophylaxis. On day zero of transplant, his donor (father) tested positive for SARS-Cov2 by PCR. The collection was postponed for one day in an attempt to find another donor; in the meantime, the donor was given HCQ and azithromycin. All his other family members tested positive for SARS-Cov2 by PCR, and the decision was made to proceed with the initial donor apheresis. SARS-Cov2-PCR was negative on the apheresis product. The patient's SARS-Cov2-PCR was negative before admission and on day +1 after transplant. On day +5 post-HCT, the patient's SARS-Cov2-PCR from nasopharyngeal swab came back positive, but the patient was asymptomatic. He was treated with azithromycin and HCQ, and on day +10 post-HCT, one dose of tocilizumab was given secondary to elevated inflammatory markers (ferritin and interleukin 6). Platelet engrafted on day+9, while neutrophils engrafted on day+23. On day +12 post-HCT, SARS-Cov2-PCR from nasopharyngeal swab was repeated and was positive. On day +14, the post-HCT patient developed culture-negative neutropenic fever with further elevation in the inflammatory markers; the second dose of tocilizumab was given, and he was started on meropenem, but he was still asymptomatic besides fever, and specifically, he did not develop respiratory symptoms. On day+18, CT chest showed left lung ground-glass opacities. He then developed hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). He was treated with dexamethasone and Intravenous immune globulin (IVIG) for four days, and ruxolitinib was added due to a continuous rise in ferritin. After the addition of ruxolitinib, his inflammatory markers and liver enzymes decreased figure (1 and 2). Currently, he fully recovered and is asymptomatic; however, his repeat nasal SARS-Cov2 PCR on August 5, 2020, was definite, and his SARS-Cov2 total antibody test was non-reactive.

acute lymphoblastic leukemia, bone marrow transplant, covid-19, coronavirus, hematopoietic cell transplant, lymphoma, multiple myeloma, sars-cov-2, stem cell transplant

PMC7485476_08

Female

A 17-year-old female patient was diagnosed with Philadelphia positive B cell ALL in August 2018. She received dasatinib, vincristine, rituximab and dexamethasone induction and achieved deep molecular remission followed by haploidentical-HCT from her brother donor using fludarabine/TBI MAC conditioning in April 2019. Her course was complicated by falling chimerism and eventually autologous recovery with donor chimerism reaching zero on day 90 post-HCT. Her immunosuppression was stopped, and she was started on maintenance dasatinib. In July 2020, she tested positive for SARS-Cov2 by PCR after contact with a positive case. She is currently asymptomatic and continuing on dasatinib and acyclovir. Repeat nasal SARS-Cov2 PCR on August 20, 2020, was negative, but the SARS-Cov2 total antibody test was not done.

acute lymphoblastic leukemia, bone marrow transplant, covid-19, coronavirus, hematopoietic cell transplant, lymphoma, multiple myeloma, sars-cov-2, stem cell transplant

PMC6814345_02

Female

We report the case of Mrs. D. F., 32 years old, living in rural areas, with a history of tuberculosis exposition (tuberculosis infection in stepfather), gravida 2 para 2, admitted to the obstetric emergency department for delivery of a full-term monitored pregnancy. The patient also reported weakness in her lower limbs gradually evolving for 2 months, confining her in wheelchair after 1 month of evolution. These symptoms had been neglected by the attending physician, who recommended the patient to consult for these symptoms after childbirth. The clinical examination on admission found a conscious patient, with stable haemodynamic and respiratory status, with T12 cord compression syndrome and a low back pain, without signs of radiculalgia. The gynaecological examination confirmed the labor progress. Given the neurological condition of the patient, being already in labor, and considering the unknown status of her spinal cord, a caesarean section was made under general anaesthesia without incident, allowing the extraction of a healthy newborn. The patient underwent a day after delivery a lumbar MRI which showed an well defined ovoid epidural mass extending from T9 to T10 with a lobulated contour realising a <<wafting silk>> sign (Figure 1), compressing and flattening the dorsal spine without infiltrating it, and widening the left foraminal region and eroding the body of the vertebrae with a dumbbell-shaped morphology in transverse images (Figure 2), compressing the nerve root. The mass showed isointense signal in T1-weighted images and hyperintense signal in T2-weighted images, with intense contrast enhancement. The patient underwent surgery the next day. She was positioned in ventral decubitus. The neurosurgical exploration revealed a reddish vascular mass, bleeding on contact, measuring 30x24x13 mm, which was completely removed piece by piece after laminectomy, with good haemostasis achieved with Surgicel cellulose hemostats and bipolar coagulation. Histopathological examination of the mass confirmed its vascular origin, with many small cavernous vessels and thick hyalinised walls, without malignant cells (Figure 3). The post-operative outcome was uneventful. She started motor rehabilitation 3 days after the surgery. The patient was able to walk after 2 weeks. She achieved complete recovery after 1 month of follow-up.

epidural neoplasms, central nervous system cavernous haemangioma, pregnancy, vascular surgical procedures

PMC10012991_01

Male

Case 1- A 54-year-old male patient with a history of tuberculosis 29 years ago presented with dysphagia. In his endoscopic examination, an ulcerated lesion was detected in the esophagus between 30 cm and 35 cm from the incisors. The histopathological examination result was reported as a well-differentiated squamous cell carcinoma (Figure 1a-f). Computed tomography (CT) of the thorax detected a diffuse lesion of malignant appearance extending to the paraesophageal and subcarinal fatty tissue in the middle part of the esophagus approximately 5 cm in the segment, reaching up to 15 mm in thickness; alveolar densities and calcific nodules with chronic sequelae bilaterally in the lung parenchyma due to previous tuberculosis; and a 20x25 mm malignant nodular lesion with irregular borders in the anterior of the lower lobe of the right lung (Figure 1a, b). In addition, fluorodeoxyglucose positron emission tomography (FDG-PET) imaging showed a hypermetabolic focus in the right supraclavicular area (maximum standardized uptake value [SUVmax]: 3.98); a hypermetabolic mass lesion in the esophagus starting from the carina level and continuing as a concentric wall thickening in a 55 mm segment on the coronal axis (SUVmax: 11.20); diffuse, calcific, FDG-negative tuberculous sequela lesions bilaterally in the lung parenchyma and mediastinum; a hypermetabolic parenchymal nodular lesion with lobulated contours in the anterobasal segment of the lower lobe of the right lung showing heterogeneous metabolic activity (late SUVmax: 9.99) (Figure 1c, d). There was no metastasis evident in the cranial magnetic resonance imaging (MRI). It was decided to perform supraclavicular lymphadenopathy (LAP) biopsy and transthoracic aspiration biopsy (TTAB) from the lung mass, as agreed in the Multidisciplinary Tumor Council (MTC). The supraclavicular lymph node biopsy was negative for malignancy, but an adenosquamous cell carcinoma was revealed in the TTAB of the mass in right lower lobe. The histopathological examination was reported as revealed an adenosquamous cell carcinoma (Figure 1e). Based on these results, the esophageal tumor T3N?M0 was staged as a lung tumor T3N0M0 and neoadjuvant chemoradiotherapy (CRT) were initiated for the esophageal tumor. A total of 50.4 Gy was administered at 1.8 Gy/Fx during 28 Fx sessions with external intensity-modulated radiation therapy (IMRT) and concurrent and weekly, paclitaxel and carboplatin/AUC2 were administered at 50 mg/m2. Post-treatment control FDG-PET showed that metabolic activity completely disappeared in the esophageal lesion followed at the carina level (complete metabolic response to treatment). However, an increase in the size and metabolic activity of the mass in the right lower lobe"s superior segment was detected. The patient"s case was discussed again by the MTC regarding the re-staging results after neoadjuvant CRT. Based on the diagnosis of synchronous lung and esophageal tumors, a collective decision was made for curative resection for both tumors. In exploration, a lesion of approximately 5x4 cm mass was detected in the anterobasal segment of the lower lobe of the right lung. Frozen sections were studied after sampling the lymph nodes station of 2, 4, 9, and 7. The result was reported as tumor-negative. Based on these results, it was decided to perform a right lower lobectomy initially. Right lower lobectomy and mediastinal LND were, then, performed. Following these procedures, the esophagus was suspended and the surrounding tissues were freed. In the second stage, the abdomen was entered with a median incision over the umbilicus in the supine position. The stomach was skeletonized and tubed and a conduit was prepared. The esophagus was explored on the left side of the neck and the conduit was pulled into the neck. The posterior wall of the stomach and esophagus anastomosis was performed with a 45-mm Endo GIA (Medtronic Inc., MN, USA), while the anterior wall was anastomosed manually. After the methylene blue test on the sixth postoperative day, oral nutrition was started. Due to chylous drainage from the chest tube, a special diet for chylothorax was initiated. On Day 5 of follow-up, re-exploration was decided, as the amount of drainage from chest drain reached 1000 mL/day. Thoracic duct was reattached through the diaphragmatic hiatus. The patient was discharged on Day 16 of follow-up. The patient, who did not have any additional problems at the first month of follow-up, was consulted to the oncology outpatient clinic.

esophageal cancer, lung cancer, multidisciplinary approach, synchronous

PET-CT showing a diffuse malignant lesion in the middle part of the esophagus, and ,20 mm x25 mm malignant nodular lesion in lower lobe of the right lung, adenosquamous carcinoma,.

PMC10012991_01

Male

Case 1- A 54-year-old male patient with a history of tuberculosis 29 years ago presented with dysphagia. In his endoscopic examination, an ulcerated lesion was detected in the esophagus between 30 cm and 35 cm from the incisors. The histopathological examination result was reported as a well-differentiated squamous cell carcinoma (Figure 1a-f). Computed tomography (CT) of the thorax detected a diffuse lesion of malignant appearance extending to the paraesophageal and subcarinal fatty tissue in the middle part of the esophagus approximately 5 cm in the segment, reaching up to 15 mm in thickness; alveolar densities and calcific nodules with chronic sequelae bilaterally in the lung parenchyma due to previous tuberculosis; and a 20x25 mm malignant nodular lesion with irregular borders in the anterior of the lower lobe of the right lung (Figure 1a, b). In addition, fluorodeoxyglucose positron emission tomography (FDG-PET) imaging showed a hypermetabolic focus in the right supraclavicular area (maximum standardized uptake value [SUVmax]: 3.98); a hypermetabolic mass lesion in the esophagus starting from the carina level and continuing as a concentric wall thickening in a 55 mm segment on the coronal axis (SUVmax: 11.20); diffuse, calcific, FDG-negative tuberculous sequela lesions bilaterally in the lung parenchyma and mediastinum; a hypermetabolic parenchymal nodular lesion with lobulated contours in the anterobasal segment of the lower lobe of the right lung showing heterogeneous metabolic activity (late SUVmax: 9.99) (Figure 1c, d). There was no metastasis evident in the cranial magnetic resonance imaging (MRI). It was decided to perform supraclavicular lymphadenopathy (LAP) biopsy and transthoracic aspiration biopsy (TTAB) from the lung mass, as agreed in the Multidisciplinary Tumor Council (MTC). The supraclavicular lymph node biopsy was negative for malignancy, but an adenosquamous cell carcinoma was revealed in the TTAB of the mass in right lower lobe. The histopathological examination was reported as revealed an adenosquamous cell carcinoma (Figure 1e). Based on these results, the esophageal tumor T3N?M0 was staged as a lung tumor T3N0M0 and neoadjuvant chemoradiotherapy (CRT) were initiated for the esophageal tumor. A total of 50.4 Gy was administered at 1.8 Gy/Fx during 28 Fx sessions with external intensity-modulated radiation therapy (IMRT) and concurrent and weekly, paclitaxel and carboplatin/AUC2 were administered at 50 mg/m2. Post-treatment control FDG-PET showed that metabolic activity completely disappeared in the esophageal lesion followed at the carina level (complete metabolic response to treatment). However, an increase in the size and metabolic activity of the mass in the right lower lobe"s superior segment was detected. The patient"s case was discussed again by the MTC regarding the re-staging results after neoadjuvant CRT. Based on the diagnosis of synchronous lung and esophageal tumors, a collective decision was made for curative resection for both tumors. In exploration, a lesion of approximately 5x4 cm mass was detected in the anterobasal segment of the lower lobe of the right lung. Frozen sections were studied after sampling the lymph nodes station of 2, 4, 9, and 7. The result was reported as tumor-negative. Based on these results, it was decided to perform a right lower lobectomy initially. Right lower lobectomy and mediastinal LND were, then, performed. Following these procedures, the esophagus was suspended and the surrounding tissues were freed. In the second stage, the abdomen was entered with a median incision over the umbilicus in the supine position. The stomach was skeletonized and tubed and a conduit was prepared. The esophagus was explored on the left side of the neck and the conduit was pulled into the neck. The posterior wall of the stomach and esophagus anastomosis was performed with a 45-mm Endo GIA (Medtronic Inc., MN, USA), while the anterior wall was anastomosed manually. After the methylene blue test on the sixth postoperative day, oral nutrition was started. Due to chylous drainage from the chest tube, a special diet for chylothorax was initiated. On Day 5 of follow-up, re-exploration was decided, as the amount of drainage from chest drain reached 1000 mL/day. Thoracic duct was reattached through the diaphragmatic hiatus. The patient was discharged on Day 16 of follow-up. The patient, who did not have any additional problems at the first month of follow-up, was consulted to the oncology outpatient clinic.

esophageal cancer, lung cancer, multidisciplinary approach, synchronous

PET-CT showing a diffuse malignant lesion in the middle part of the esophagus, and ,20 mm x25 mm malignant nodular lesion in lower lobe of the right lung, adenosquamous carcinoma,.

PMC4357143_01

Male

A 76-year-old man presented with a 7-year history of dyspnea on exertion. He had received intermittent medical treatment that only relieved his symptoms. The patient had smoke for 25 pack-years and quit at the age of 66. According to his medical history, there was no evidence of tuberculosis. Table 1 presents the patient's occupational history. He reported 10 years of occupational exposure to fumes from a heat-treatment procedure and silica dust. He had worked at a wheel manufacturing company from Feb 7, 1965 to Mar 7, 1975. The working process at the factory is summarized as follows. Lumps of scrap metal were poured into a smelting furnace, melted, and then transported to a mold to be solidified. The solid mold was then sent to the heat treatment procedure area. The patient's main duty was to transport the casting by hoisting it or using a crane to move it to the heating furnace, and then control the temperature. All of these processes including those at the smelting furnace were all performed in an area covering about 997.73 m2. Bunker-C oil was the fuel source for the heating furnace. The patient stated he had inhaled a large volume of smoke from the soot produced when controlling the temperature or turning the ignition on. There were no local ventilation systems, respiratory protectors, or partitions to isolate the shaking out and finishing processes; therefore, exposure to crystallized silica from adjacent areas is likely. The patient typically worked two shifts each week and had a few days off monthly. In addition to working at the wheel manufacturing company, he also worked for 5 years as a laborer on construction sites. After he stopped working on construction sites, he installed boilers and worked general manual labor for approximately 25 years. Since 2003, he has been working as janitor in an apartment complex. On May 21, 2012, a chest X-ray and CT scan revealed an evidence of hyperinflation with emphysematous changes in both upper lobes; he was diagnosed with emphysema. A month later (Figures 1, 2), a pulmonary function test was done that included a post-bronchodilator forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and FEV1/FVC% that were 2.20 L (67% of the predicted value), 1.12 L (52% of the predicted value), and 51%, respectively, which all indicate moderate COPD.

copd, fuel oils, occupational exposure, silica

PMC6850247_01

Male

A 73-year-old male with history of multiple myeloma (in remission for 3 years after thalidomide and dexamethasone treatment) and chronic cough, presented to the Emergency Department with 3 days of left elbow swelling, which was diagnosed as olecranon bursitis based on clinical presentation and X-ray (Fig. 1). There was no history of elbow trauma. His bursitis improved with a steroid injection but recurred 2 months later and was treated with a repeat steroid injection. Unfortunately, his bursitis recurred again 2 months later, and bursa aspirate yielded a white blood cell (WBC) count of 45,708 with 98% neutrophils, suspicious for septic bursitis. Bacterial cultures were negative, and he had not been on antibiotics previously. He received a 14-day course of cephalexin. Because the elbow was still edematous after 8 days of cephalexin, he underwent elbow debridement, which revealed purulent fluid with erythematous grayish-brown tissue. Histology showed acutely inflamed synovium consistent with infection. 2 out of 3 samples were smear-positive for acid-fast bacilli. All 3 operative mycobacterial cultures and the initial aspiration grew MAC. On review of systems, he mentioned a chronic productive cough. The patient smoked a pipe for 10 years but quit 65 years ago. He had no formal diagnosis of COPD. Sputum cultures grew MAC. A chest X-ray showed basal atelectasis and multiple bilateral calcified pleural plaques, consistent with prior asbestos exposure (Fig. 2). There was no significant change compared to a chest X-ray done 3 years prior to presentation, and tuberculosis skin testing was negative. Other exposures included gardening, hot-tub use, and a pet dog. The MAC isolate was susceptible to rifabutin, ethambutol, and clarithromycin; intermediate to rifampin, streptomycin, and moxifloxacin; and resistant to ciprofloxacin, kanamycin, cycloserine, ethionamide, and amikacin. His initial treatment regimen included clarithromycin 500 mg PO BID, ethambutol 1600 mg PO daily, and rifabutin 300 mg once daily. The rifabutin was discontinued 3 weeks into therapy due to neutropenia and transaminitis. His bursitis resolved after a 12-month course of ethambutol and clarithromycin. Repeat sputum cultures were not obtained after completion of therapy. One year later, his multiple myeloma recurred, and he was started on lenalidomide and dexamethasone. Around this time, he was also diagnosed with seronegative rheumatoid arthritis (RA) and initiated methotrexate. 3 years after completing his MAC treatment, he underwent an elective right total knee arthroplasty (TKA) for degenerative joint disease. This procedure was performed at an outside facility with presumed peri-operative prophylaxis. One year later, he developed right TKA pain, instability, and swelling. X-ray showed a well-seated right TKA with a large effusion (Fig. 3). C-reactive protein (CRP) was elevated at 13.5 mg/L (reference range < 8 mg/L), and erythrocyte sedimentation rate (ESR) was elevated at 65 mm/h. Synovial fluid aspiration yielded 4524 total nucleated cells; 57% neutrophils, and 39% monocytes. The synovial fluid aspirate grew MAC. He underwent TKA resection with placement of a vancomycin/tobramycin impregnated spacer. Histology was negative for acute inflammation or granulomas. All 4 surgical tissue samples grew MAC. His multiple myeloma chemotherapy and methotrexate for RA were held. His TKA MAC isolate was still susceptible to ethambutol and clarithromycin. Although it was previously susceptible to rifabutin, it now demonstrated intermediate susceptibility. He was initially started on clarithromycin, ethambutol and rifabutin, but due to recurrent transaminitis and neutropenia, he was continued on dual therapy with ethambutol and clarithromycin for 6 months prior to consideration for reimplantation. Pre-reimplantation CRP was normal at 4.8 mg/L, and ESR was 49 mm/h. Although still on therapy, the right knee synovial fluid was aspirated prior to reimplantation and found to be negative for mycobacterial growth. Six weeks later, he underwent reimplantation. All 4 surgical tissue samples from reimplantation remained negative for MAC. One of 4 cultures grew coagulase-negative staphylococci, which was considered a contaminant. Pathology was negative for acute inflammation. He continued ethambutol and clarithromycin for another 6 months, to complete a total of 12 months. Then, he was placed on chronic suppression with azithromycin 1200 mg orally once a week. Fifteen months later, he successfully underwent an elective contralateral TKA, again for degenerative joint disease. His multiple myeloma went into remission, precluding further chemotherapy. His methotrexate for RA was switched to hydroxychloroquine. He continues to do well at 7 years of follow-up after the 2-stage exchange of his MAC-infected right TKA.