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Tuberculosis_Dataset

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PMC8342147_01

Female

A 12-year-old girl presented to hospital A with a complaint of headache for one month. The headache was of sudden onset, and it gradually increased in severity over the period of time. Headache was associated with multiple episodes of vomiting. Fever was off and on. There was no history of any skin rashes, seizure, or loss of consciousness. Neither there was history of contact with a tuberculosis patient nor had she past history of any significant illnesses. She looked ill. General examination showed heart rate 64/min, respiratory rate 30/min, temperature 37.1 C (98.7 F), and blood pressure 90/60 mm Hg. On chest examination, bilateral vesicular sounds with no added sounds were noted. Cardiovascular examination revealed normal first and second heart sounds with a pansystolic murmur. Abdomen was soft and nontender. Hepatomegaly (2 cm) was detected. No splenomegaly was detected. Glasgow comma score was 14/15. Pupils were bilateral reactive 4 mm, and the fundus showed signs of early papilledema. Examination of musculoskeletal system revealed muscle bulk was slightly decreased, tone was flaccid, and power was 4/5 in all limbs. Sensory perception was intact, tendon reflexes were grade II, and the plantar was down-going. Kernig's and Brudzinski's signs were positive. The patient was admitted with a working diagnosis of meningitis. Investigation showed hemoglobin 13.2 g/dL (11.5-14.0 g/dL), white blood cell (WBC) count 13,000/mm3 (5,000-12,000/mm3) (neutrophil 85% (40-70%), lymphocyte 10% (28-48%), monocyte 5% (2.0-10.0%), and eosinophil 0% (2.0-6.0%)), platelets 211,000/mm3 (150,000-400,000/mm3), and erythrocyte sedimentation rate 31 mm in first hour (<20 mm). Red cell indices, liver function tests, and clotting profiles were within a normal range. Random blood sugar was 105 mg/dL (70-200 mg/dL), blood urea nitrogen was 30 mg/dL (6-20 mg/dL), and serum creatinine was 0.46 mg/dL (0.6-1.1 mg/dL). Tests for human immunodeficiency virus I and II, hepatitis B surface antigen, and hepatitis C virus were negative. Ultrasound abdomen showed mild hepatomegaly, chest X-ray showed bilateral consolidation, and MRI brain showed enhancement and mild thickening of leptomeninges without basal exudates and without hydrocephalous, features suggestive of meningoencephalitis. Echocardiograph showed perimembranous ventricular septal defect (VSD) with a size of 12 mm and was partially closed by the septal leaflet of tricuspid valve and with mild tricuspid regurgitation with normal pulmonary artery pressure. Lumbar puncture was done. The opening pressure was 27 cm of H2O (7 to 20 cm of H2O). Results of routine and biochemistry investigation of CSF were RBC 3 cells (0 cells), WBC 204 cells (<5 cells) (neutrophil 5% (30-40%) and lymphocyte 95% (60-70%)), sugar 46 mg/dL (50-80 mg/dL), protein 24 mg/dL (15-45 mg/dL), and adenosine deaminase 2.1 U/L (<3.0 U/L). Gram stain, staining for acid-fast bacilli (AFB), India ink preparation, and culture were negative. CrAg test was not available in the hospital. Blood culture and urine culture results were negative. With these investigation findings, the patient was diagnosed with meningoencephalitis with VSD, and antimicrobial treatment was started. The patient was treated with injection (inj) ceftriaxone 1.5 g intravenous (iv) 12 hourly and inj vancomycin 100 mg iv 6 hourly for 7 days. During hospitalization, she had one episode of seizure, which was treated by antiepileptics. She could not maintain oxygen saturation (SpO2) with room air, and supplemental oxygen was provided. After 7 days of the antimicrobial treatments, her general condition did not improve. She was then brought to hospital B. At the time of admission to hospital B, she was at semiconscious state. She was admitted to the pediatric intensive care unit. Further laboratory investigations: leptospira immunoglobulin M, brucella immunoglobulin M, malaria antigens, and Mantoux tuberculin skin tests were done, and all came out negative. Blood culture and urine culture were negative. Sputum AFB and culture were negative. GeneXpert was not available. It was important to rule out tubercular meningitis. There was no history of contact with active tubercular patients, CSF color was clear, CSF AFB staining was negative, and CSF ADA was not raised. Therefore, we did not consider tubercular meningitis as the first differential diagnosis. CSF India ink preparation showed Cryptococcus spp. (5 to 10 muM in size) with surrounding with a capsule (Figure 1). CSF culture, Sabouraud dextrose agar media, after 48 hours showed whitish mucoid colonies (Figure 2). CrAg test in CSF by enzyme immunoassay was positive. CM was diagnosed and treated with inj lysosomal amphotericin B 100 mg in 750 ml 5% dextrose iv over 2 hours once a day and inj flucytosine 625 mg in 50 ml iv 6 hourly. The general condition of the patient did not improve despite the treatment for CM. She had one episode of seizure, which was treated with antiepileptics. She developed severe respiratory distress; she was intubated and kept on mechanical ventilation. On 9th day of admission, she died.

PMC3834984_01

Female

The 17-year-old nonsmoking female patient was admitted to the department of chest diseases with cough, sputum, fatigue, and chest pain. The case had undergone a subtotal thyroidectomy for goiter at the age of 9, and histopathologic examination of surgical material had revealed dyshormonogenetic goiter. Histopathologic examination revealed irregular nodular structures separated by fibrous bands; colloid containing follicles and papillary structures had nuclear hyperchromasia with the follicular epithelium, secondary follicules in the papillary structures, atherosclerotic changes in the thyroidal arteries, and hyperplastic thyroid tissue in one area. The nuclei were not in the feature of papillary carcinoma in the papillary areas. On physical examination, there was decrease in bilateral respiratory sounds. Laboratory parameters were as follows: Hb: 12.5 g/dL, Htc: 39.0%, WBC: 10900/muL, PLT: 303000/muL, free T3: 4.18 (2.5-3.9) pg/mL, free T4: 0.76 (0.61-1.12) ng/dL, and TSH: 3.69 (0.34-5.60) uIU/mL. The other biochemical parameters and tumor markers were also normal. Tuberculosis bacilli were not seen in sputum examination. In the chest radiography, a bilateral nodular opacity was detected (Figure 1). Thorax CT revealed multiple nodule formations that were atypically scattered along bilateral lungs (Figure 2). The neck USG displayed multiple hypoechoic and isoechoic nodules that have the greatest size of 13 x 12 mm in the thyroid gland. There were also multiple lymphadenopathies in the left cervical chain which has the greatest diameter of 13 x 11 mm. A diagnostic bronchoscopy was tried, but the patient could not tolerate it. The case underwent CT guided trucut biopsy on the left lung. The patient had respiratory insufficiency during followup due to pneumothorax on the left hemithorax. Therefore, she received a tube thoracostomy for pneumothorax treatment. The result of biopsy was consistent with thyroid papillary carcinoma (Figures 3 and 4). Then, she was referred to the Endocrinology and General Surgery Outpatient Clinic. Completion thyroidectomy, neck lymph node dissection, and radioactive iodine treatment were planned to the patient.

PMC6186351_01

Male

Abbott Freestyle Libre: this groundbreaking device allows accurate and affordable 24-hour glucose monitoring. It also makes it possible to register meals as carbohydrate portions (CP) (one CP is equal to 10 g of carbohydrate) and the insulin dosage (units) Fitbit Charge HR: this is an advanced tracking wristband that gives an automatic, continuous heart rate and activity tracking during workouts and throughout the day. It records number of steps, distance, floors climbed, and sleep time. It stays connected wirelessly and can be synchronized with a smartphone and computer to monitor trends. With this smartband the following features were recorded: steps, heart rate, and sleep. In order to explore the possibilities of the monitoring described above, a case study was carried out. For that, the following devices were used: Patients also recorded their meal intake and schedule, indicating periods of work time or playing sports. Although we listed other features (temperature, blood pressure, and perspiration), they were not monitored due to limitations in the chosen devices, and the additional devices would not have been able to be acquired easily and/or were not affordable. As this was a preliminary study, we considered the measured features with the available tools to be relevant enough to make a first evaluation of the monitoring experience. The patient studied was a healthy man, 25 years old, DM1 for 12 years, and with diabetes under control. We considered this individual to be a good example for a preliminary study. He was under continuous monitoring for 14 days. In this period, he continued with his daily routine, including work, sports, dietary habits, and insulin dosages. The monitoring was carried out in a passive way, so there was no intervention in his diabetes treatment. A physician checked his medical condition daily, with the aim of assuring the safety of the process. Data were collected every 5 minutes, although it could have been recorded with a higher frequency. At this rate, the datasheet comprises more than 24,000 measurements; the level of detail achieved is really high. However, in terms of data storage, it is easily affordable. Figure 2 shows the results from a few days and represents an example of the results that can be achieved. As can be observed, the data provides more information than a simple glucose graph, and, therefore, caregivers can better understand the phenomena that influence the patient's status. With just a glance, it is now possible to understand glycemia evolution just by looking at the relationship with physical activity, for example. Furthermore, all of the data can easily be transmitted to a smartphone or to the Cloud because of the connections of the CGM and smartbands, or other medical devices, mainly via Bluetooth. With all of these values, the possibilities that arise using machine learning techniques are boundless. It is in this context that the derived "on-board" variables are especially meaningful and have sense to be generated, that this idea encloses aggregative significance, and it is in this situation where the power of this perspective can be completely exploited.

PMC5340654_01

Male

A previously healthy 56-year-old man presented with progressive jaundice for 6 weeks and abdominal distension with swelling of feet for 4 weeks. He also had symptoms of fatigue and mild generalized itching. His past medical history was unremarkable, with no prior history of liver disease. On physical examination, he was deeply icteric, had bilateral pitting lower-limb edema, a left-sided pleural effusion, a short apical systolic murmur, and a flapping tremor. His abdominal examination revealed massive hepatosplenomegaly with moderate ascites. His clinical presentation was akin to acute-on-chronic liver failure (ACLF) with the appearance of ascites and encephalopathy within 2 weeks of presentation with jaundice. His primary physician referred the case to our center after he developed signs of liver decompensation. Hence his initial diagnostic work-up focused on identifying the underlying etiology. Complete blood count and serum electrolytes were within normal limits. Laboratory studies showed blood urea 45 mg/dL, creatinine 0.9 mg/dL, total bilirubin 22 mg/dL, serum albumin 24 g/L, international normalized ratio 3.2, alkaline phosphatase 1,496 IU/L, gamma-glutamyltransferase 136 IU/L, alanine aminotransferase 128 IU/L, and aspartate aminotransferase 170 IU/L. C-reactive protein was elevated, and immunoglobulin (Ig) levels were normal with IgG 12 g/L, IgA 3.15 g/L, and IgM 0.52 g/L. Serum protein electrophoresis and beta2 microglobulin were within normal limits, and urinalysis was negative for Bence-Jones proteinuria. Alpha-fetoprotein was within the normal range. Serologies for hepatitis were all unremarkable. Autoimmune work-up, including antinuclear, anti-smooth muscle, and anti-DNA antibodies, were negative. The 24-hour urinary protein excretion was 0.068 g/L. Abdominal ultrasonography revealed hepatosplenomegaly with no focal liver lesions and normal intra- and extrahepatic bile ducts. Computed tomography of the abdomen showed the liver measured 16.6-cm in craniocaudal span, with a subtle lobulated outline and widened interlobar fissures. The main portal vein was mildly dilated with thin collaterals, suggestive of portal hypertension. There was no evidence of retroperitoneal or mesenteric lymphadenopathy (Figure 1). Transthoracic echocardiography showed normal chambers with diastolic dysfunction, normal systolic function with ejection fraction of >60%, and no pericardial effusion. Ascitic fluid analysis showed 500 cells, 90% lymphocytes, high serum albumin ascitic gradient (2.1), low protein (2.4 g/L), and low adenosine deaminase (5.7 IU/L). Polymerase chain reaction was negative for tuberculosis and there were no malignant cells on cytology. These findings were consistent with portal hypertension. Transjugular liver biopsy was performed. Hepatic venous pressure gradient was 14 mm Hg, confirming the clinical diagnosis of portal hypertension. Liver biopsy showed near complete effacement of acinar architecture by sinusoidal and portal deposits of extracellular, pale eosinophilic, hyaline, amorphous, acellular material. Hepatocytes showed pressure atrophy and focal presence of canalicular bile. Portal tracts showed no significant inflammation with F1 fibrosis (Figure 2). The material stained positive with Congo red and displayed green birefringence when viewed under polarized light, confirming amyloid deposition. Stains for iron and copper deposition were not remarkable. Immunohistochemistry revealed that the amyloid deposits consisted largely of light chains, with lambda being stronger than kappa (Figure 3). Bone marrow aspiration showed erythroid hyperplasia with normoblastic to mild megaloblastic erythropoiesis. Plasma cells were 9%. No evidence of myeloma was seen. Serum free light chains were negative. Skeletal survey did not reveal any lytic lesions. Rectal biopsy showed maintained crypt architecture. There were focal deposits of acellular eosinophilic amorphous material in the wall of blood vessels in submucosa. These deposits also showed apple green birefringence on staining with Congo red under polarization. This confirmed extrahepatic deposition of amyloid (Figure 4). The patient's clinical condition rapidly deteriorated over the next few days, and he developed fulminant liver failure and sepsis. He could not be offered chemotherapy due to liver failure, and was deemed unfit for liver transplantation. He died within 12 days of presentation at our center.

PMC6174786_01

Male

The 57-year-old was an African male, originally from Rwanda, from where he initially immigrated to Russia. He lived in Russia for 20 years (1984-2004) before he eventually immigrated to Canada in 2004. He started to experience right shoulder pain and stiffness in 2010. There was no history of trauma to the joint and morning stiffness nor involvement of other joints. The right shoulder pain and stiffness progressed in severity over the ensuing three years and became debilitating, limiting his ability to work in construction. He had undergone multiple courses of physiotherapy and had been prescribed high doses of nonsteroidal anti-inflammatory medications without a meaningful response. For the six months prior to presentation, he had been experiencing night sweats without accompanying fever, weight loss, or respiratory symptoms. He did give a history of exposure to MTb while living in Russia as one of his workmates developed pulmonary Tb; however, our patient was not investigated at that time. Examination of the right shoulder revealed minimal swelling and that erythema and warmth were absent, but there was a decreased range of motion. Due to the worsening right shoulder pain and stiffness, a plain radiograph of the chest and shoulder was performed, revealing only an old clavicular injury and that the acromioclavicular and glenohumeral joints were intact. Neither acute nor chronic parenchymal lung, bone, or joint space abnormalities were observed. An X-ray (Figure 1) and MRI (Figure 2) of the right shoulder were therefore performed, demonstrating intra-articular effusion and erosions of articular margins, compatible with a septic joint. The erythrocyte sedimentation rate (ESR) was 68, and HIV test result was negative. Operative drainage and debridement were undertaken, and the thick purulent joint fluid subsequently yielded MTb by direct smear examination with Ziehl-Neelsen staining and nucleic acid amplification tests (NAATs), the Xpert MTB/RIF test, establishing the diagnosis of osteoarticular Tb. Antituberculosis therapy was therefore initiated with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) in addition to pyridoxine. The subsequent Tb culture revealed no resistance to the standard first-line regimen RIPE. He was treated with RIPE for 2 months followed by rifampin and isoniazid for 10 months.

PMC4317210_01

Male

A 27-year-old previously healthy African male medical intern sustained a needle-stick injury from a wide bore needle (gauge 18) to his little finger while performing a lumbar puncture on a HIV-infected patient. He sustained a small lesion that bled a little and he immediately washed it with water and soap. He was immediately started on postexposure prophylaxis Anti-Retroviral drugs (ARVs): Zidovudine, Lamivudine and Kaletra for 28 days as per the Kenya National AIDS Control Program protocol. His initial rapid HIV test (Determine) test was negative and so was a PCR done on completion of the ARVs. He had no significant past medical history. The patient source, an African Female, was WHO clinical stage 4, not on ARVs and was being investigated for meningitis died soon the lumbar puncture and her results were not followed up until several months later. Two weeks after the injury, the intern had swelling of the little finger associated with a persistent dull ache for which he sought surgical intervention. Pus was aspirated from the finger and incision and drainage were done under local anesthesia. Culture of the pus grew Staphylococcus aureus sensitive to flucloxacillin on which he was started. His little finger now had an open wound that persisted for several months despite debridement and different antibiotic regimens: levofloxacin, clindamycin, ceftriaxone, and vancomycin. The intern continued to clean and dress his wound daily. He developed painless axillary lymphadenopathy 6 weeks after the injury. For the next 6 months, there was persistent swelling of the little finger which seemed to be spreading to the hand (Fig.1). This was accompanied with low-grade fever, night sweats, and subjective weight loss. He underwent a surgical debridement 6 months after the injury and was started on levofloxacin. Intraoperatively necrotic debris was found. Radiographic examinations done during the course of illness showed no bone involvement. Serial blood counts done in the course of illness showed persistently elevated lymphocytes and a raised ESR. Liver function test and renal tests were normal. Ten months later and with no improvement of symptoms, he underwent yet another surgical debridement. Histological examination of the tissue taken revealed a chronic inflammatory process (Fig.2), granulomatous tubercles with epithelioid cells (Fig.3), giant cells of Langerhans (Fig.4), and a mononuclear infiltrate but no acid-fast bacilli (AFB) were demonstrated on Ziehl-Nelson stain. He was started on rifampicin, isoniazid, pyrazinamide, and ethambutol for duration of 2 months to be followed by a 4-month course of rifampicin and isoniazid. The intern had complete recovery by the end of the 6 months. A rapid HIV test done at the end of the anti-TB treatment was negative.

cutaneous, primary, tuberculosis

PMC6295758_01

Male

A 44-year-old, male, type 2 diabetic patient with a previous diagnosis of diabetic foot disease, was referred to our unit after sustaining a 2.5% total body surface area (TBSA) deep dermal burn to his bilateral soles after falling asleep while resting his feet against a radiator (Figures 1 and 2). He presented one day after the injury and on that day the wounds were cleaned and dressed with chlorhexidine-soaked gauze. Routine blood testing demonstrated haemoglobin glycated levels (HbA1c) of 106 mmol/mol. Other comorbidities included peripheral vascular disease with an ABPI of 1.4 (right) and 0.8 (left). The following day, NexoBrid was applied to the wounds, obtaining a satisfactory debridement (Figures 3 and 4). A spinal block was used to avoid any unexpected discomfort while enzymatic debridement took place. The area was then dressed for 2 hours with chlorhexidine-soaked gauze which was later replaced by lyophilised porcine skin (Xenoderm, Ideal Medical Solutions) and moist gauze. This patient was kept hospitalised with strict elevation of his lower extremities. At his first dressing change three days later, the clinical team noticed that a new eschar had formed, suggesting a deepening of his previously viable debrided wounds (Figure 5 and 6). Over a period of four weeks, this patient underwent three surgical debridements along with the use of topical negative pressure dressings, until a suitable wound bed was obtained. Split skin grafting was performed at that stage with good results (Figure 7), achieving wound healing in 6 weeks post injury.

enzymatic debridement, nexobrid, bromelain, burns, contact, diabetic, foot

PMC6295758_02

Male

A 56-year-old, male, diabetic type 1 patient, with a previous diagnosis of diabetic foot disease, presented to our unit after sustaining a deep dermal burn. His wounds extended on the lateral aspect of his ankle and foot, 1.5% TBSA, as the result of prolonged contact with a hot water bottle (Figure 8). The HbA1c levels for this patient were of 102 mmol/mol. The patient had a previous history of ischaemic heart disease and coronary stenting. Due to the suspicion of peripheral vessel disease, a computed tomography angiography (CTA) was organised pre-debridement, showing bilateral atherosclerotic disease on his lower extremities, but no signs of clinically significant lumen stenosis. Chlorhexidine-soaked gauze was used to prepare the wounds for enzymatic debridement, which took place three days after the injury. After a successful NexoBrid debridement, under a spinal block, the patient requested to be discharged and advice on leg elevation and modifications to his insulin regime were given. Two days later he presented with desiccated wounds and a new eschar (Figure 9). He subsequently underwent wound excision and split skin grafting. Even though it was documented at one week postoperative a 70% graft take, during the following week the lateral portion of the sole and heel declared as necrotic. Three weeks after the first surgical debridement, a second debridement and skin grafting of the resulting wound was performed, achieving a healed wound 8 weeks after the injury.

enzymatic debridement, nexobrid, bromelain, burns, contact, diabetic, foot

PMC5761908_01

Male

Patient 1 is a 68-year-old married white British male with a diagnosis of TRS. He first presented with psychosis to psychiatric services in 1965 at age 17. Over the next four decades he was treated with a number of antipsychotic agents including sulpride, aripiprazole, haloperidol and olanzapine; all were at up to maximal British National Formulary recommended doses and a minimum of 12 weeks' duration with compliance assured during inpatient episodes; he experienced a number of relapses over time. He did not achieve remission and was started on clozapine in 2002 (dose 400 mg daily). Following that, he was functional and relatively stable for 11 years, aside from some minor residual psychotic and anxiety symptoms. His medical history at this time included ischaemic heart disease (IHD), cardiomyopathy with an ejection fraction of 35%, congestive heart failure (NYHA II) and bilateral pedal oedema. In 2014, following a decline in his cardiac function, his maintenance clozapine dose was reduced from 350 mg to 300 mg daily. Unfortunately, this was followed by a severe psychotic relapse characterized by prominent thought disorder, paranoid delusions, self-neglect and increasingly aggressive and challenging behaviour. His clozapine dose was increased back to 350 mg but his mental state continued to deteriorate and due to violence and aggression he was transferred to a psychiatric intensive care unit in March 2015. In August 2016 he was admitted to the National Psychosis Unit, having been an inpatient for over 2 years. His symptoms at this time included persistent persecutory delusional beliefs, obsessive-compulsive traits, anxiety, mood lability, prominent difficulties in concentration and memory and irritability with outbursts of aggression. Psychotropic medication on admission included lurasidone 111 mg (which he had been treated with for over 1 year), sertraline 100 mg and diazepam 6 mg daily. On admission, he scored 115 on the PANSS total score and 29/30 on the Mini Mental State Exam (MMSE). An MRI brain scan was within normal limits; blood tests on admission were mostly within normal limits, except for a raised urea of 13.9 mmol/L (3.3-6.7) and an increased prolactin level of 894 mIU/L (100-410), attributed to lurasidone. The pharmacotherapeutic approaches considered included a trial of high-dose olanzapine, switching from sertraline to vortioxetine because of the added benefit in attention and cognitive flexibility, or adding either memantine or donepezil as adjuncts to aid cognition. In August 2016 it was decided to increase his lurasidone dose to 148 mg daily. Sertraline was switched to adjunct vortioxetine 10 mg, which was gradually titrated to 20 mg over the next couple of weeks. By September 2016 there was noticeable improvement in symptoms, and by December 2016 he was in remission, scoring 44 on the PANSS total score. Pregabalin 25 mg BD was prescribed as an anxiolytic after stabilization on lurasidone and vortioxetine, and benzodiazepines were down-titrated and stopped. He was successfully discharged home in January 2017. Psychotropic medication on discharge included lurasidone 148 mg, vortioxetine 20 mg and pregabalin 25 mg BD. He described his wellbeing as 9 out of 10, compared to having been 1 out of 10 at admission. The family described his change as 'miraculous, and that he had not been so well, even while being treated with clozapine'. Subsequent follow up confirmed a sustained functional and symptomatic recovery.

cognition, novel treatment, refractory schizophrenia

PMC9651021_01

Male

A 43-year-old male presented to the Makerere University Lung Institute in Kampala as a referral from a rural tertiary hospital in Uganda. He presented with a 30-year history of a productive cough, whose initial onset followed an episode of cough during a nationwide outbreak of whooping cough at 10 years of age. The cough had worsened over the past one year, had no diurnal variation, was wet and associated with copious amounts of purulent sputum, difficulty in breathing, chest pain and weight loss for 3 months. The chest pain was predominantly left-sided and non-radiating. There was no history of hemoptysis, nasal blockage, loss of sense of smell, fever, or night sweats. Patient reported no history of loud snoring, he had no episodes of gasping for air during sleep and no history of somnolence. He however reported palpitations, dyspnea, orthopnea, and body swelling involving the lower limbs and abdomen. On presentation, he had had several admissions because of worsening cough, and had unscheduled outpatient visits almost monthly for the cough in the past 30 years. He had been treated with intravenous and oral medications with minimal to no improvement. At 19 years of age, he was treated for clinically diagnosed pulmonary TB (no bacteriological confirmation), but with no improvement. He had no known allergies. He denied any history of cigarette smoking and alcohol use. He had no family history of similar illness. He was a farmer until 3 years prior to presentation when the symptoms limited his physical activity. On physical examination, he was sick-looking, severely wasted (37kgs body weight, height -160.5cm, BMI-14.4 kilogram per meters2; Figure 1A). He had proptosis grade 3 digital clubbing (Figure 1B), central and peripheral cyanosis and pretibial oedema (Figure 1C). He was afebrile (temperature 36.9 Celsius). He had no pallor, jaundice, lymphadenopathy or signs of dehydration. On respiratory system examination, he had mild respiratory distress with a respiratory rate of 32 breaths per minute (tachypneic). His SPO2 was 99% on room air. He had no chest deformities or asymmetry. The trachea was centrally placed. There was equal air entry bilaterally with bilateral widespread loud harsh breath sounds, bilateral crepitations and rhonchi. In cardiovascular examination, he had a thin volume pulse with a tachycardia of 108 beats/minute. The blood pressure was normal (92/70mmHg). The apex beat was in the 5th intercostal space, mid-clavicular line. The heart sounds I and II were heard, with a 3rd heart sound (a gallop rhythm) and a loud second heart sound in the pulmonary area (loud P2). On abdominal examination, he had mild abdominal distension, shifting dullness (indicative of moderate ascites), and a tender hepatomegaly of 8 cm below the coastal margin with a positive hepatojugular reflux. The diagnostic work up is summarized in Table 1. Serum creatinine, urea, electrolytes, liver enzymes, bilirubin were all normal. Spirometry evaluation was attempted but he had very poor respiratory effort to complement the examination. The chest X-ray showed dilated trachea and principal bronchi with diffuse reticulolinear and ring-like opacities involving mainly the mid and lower lung zones bilaterally. Figure 2 shows the chest X-ray. A sequential high resolution computed tomography (HRCT) scan was performed using a 128-slice multidetector CT scanner. The study was performed in full inspiration with a scan time of five seconds. The scan time was short enough to enable the patient hold his breath throughout the scanning period and this avoided motion artifacts. An expiratory scan would have complemented the findings; however, this was not performed. Figures 3-5show the High-resolution chest computed tomography (HRCT). In this patient, a diagnosis was made of tracheobronchomegaly (Mounier Kuhn syndrome), complicated with pulmonary hypertension, and right-sided heart failure. Differential diagnoses of cystic fibrosis and bronchiectasis were considered. The patient was initiated on oral prednisolone 20 mg (short-course), oral furosemide 40 mg, rhinathiol syrup, oral azithromycin (empirically for suspected lung infection), megestrol (for cachexia), and low-dose oral morphine (for the dyspnea), inhaled corticosteroid/long-acting beta agonist, inhaled tiotropium, and chest physiotherapy. Two months later, the patient reported improvement. The sputum volume was much less, had less exercise intolerance and had gained 3 kgs. He was also linked to the palliative care team to offer home-based palliative care in addition to the long-term therapies above. He was also scheduled for monthly reviews at the Makerere University Lung Institute. However, he passed away from home in the fourth month of follow-up from a lung infection that was managed at a peripheral rural health facility.

mks, mounier-kuhn syndrome, tracheobronchomegaly

PMC8450262_01

Male

A 52-year-old man with 40-pack year smoking history and daily alcohol consumption of 4 liters of beer was hospitalized with severe shortness of breath for one week, unproductive cough for "several months", occasional night sweats but stable body weight. On physical examination he was orthopneic with absent breath sounds and a dull percussion note were present on the left side of his chest. Vital parameters were: blood pressure 143/88 mmHg, heart rate 105/min, respiratory rate 21/min, body temperature 37.6 C, oxygen saturation 94%. Laboratory tests showed elevated inflammatory parameters and serum enzymes: C-reactive protein (CRP) 221.7 mg/l, white blood cells (WBC) 22.7 x 109/l, alkaline phosphatase (AP) 254 U/l, gamma-glutamyl transferase (yGT) 223 U/l, aspartate transaminase (ASAT) 55 U/l, alanine transaminase (ALAT) 82 U/l, lactate dehydrogenase (LDH) 285 U/l. Computed tomography (CT) of the thorax revealed a massive pleural effusion on the left with mediastinal lymphadenopathy and shift to the right side (Fig. 1 A, B). Bronchoscopy was unremarkable. Pleural tapping revealed turbid effusion fluid, a low pH of 7.15, low glucose of 1.5 mmol/l, elevated pleura/serum ratios of LDH 2.44 (normal<0.6) and of protein 0.69 (normal<0.5), all parameters suggestive of an empyema. Microscopy, however, did not show bacteriae. Especially to rule out pleural carcinomatosis, as cause of the mediastinal shift, medical thoracoscopy was performed, which besides turbid empyema fluid, revealed widespread adhesions, parietal and visceral pleural thickening, multiple septae formation, which in part were mechanically dissolved by forceps (Fig. 1 C, D, E). More than 2000 ml empyema fluid was removed, a chest tube was placed in dorsobasal position. To promote enzymatic lysis of septae and adhesions 10 mg alteplase and 5 mg dornase-alpha were instilled into the pleural cavity. The follow up chest X-ray (CXR) and CT thorax demonstrated an expanded lung and residual multiloculated pleural effusion on the left (Fig. 1 F, G). Matrix-assisted-laser-desorption-ionization-time-of-flight mass-spectrum (MALDI-TOF MS) analysis from pleural effusion fluid and septae biopsies, both retrieved during thoracoscopy, confirmed A. meyeri, susceptible to amoxicillin/clavulanic acid (AMC). Tuberculosis and malignancy were ruled out. Antibiotic treatment with intravenous AMC 2.2 g q8h were started on day 2. Because of persistent infection signs surgical minithoracotomy with empyema evacuation, complete parietal pleurectomy, decortications of the left upper and lower lobes were performed (day 6). Postsurgical respiratory insufficiency, could be successfully treated with a few days of non-invasive ventilation (NIV). Because of transient renal function impairment AMC was adjusted to 1.2 g q8h and switched to Amoxicillin (AMX) 1000 mg q8h from days 14-43. The patient gradually improved and was transferred for rehabilitation on day 19. Laboratory parameters during the following two month were unremarkable.

actinomyces meyeri, decortication, pleural empyema, thoracoscopy

PMC4014816_01

Female

A 50-year-old female presented with history of progressive quadriparesis and stiffness of neck for 2 years, dysphagia to liquid for past 3 months. She had visited several doctors without any relief for the said complaints. Magnetic resonance imaging (MRI) of cervical spine was done one year back. On the basis of clinical history and supportive MRI finding, she was previously diagnosed as a case of high cervical compressive myelopathy with cord changes due to thickening of ligamentum flavum and posterior longichudinal ligament extending from foramen magnum up to C4 vertebral level. Corticosteroid was prescribed by her previous physician. Following which her condition deteriorated rapidly.Her neck became so stiff that she was unable to move it, numbness extended to all over her body; she developed dysphagia to liquid and became bed ridden. Physical examination revealed high cervical compressive myelo-radiculopathy with lower cranial nerve palsy and rigid neck. Recent contrast MRI was suggestive of circumferentially, grossly thickened, enhancing dura extending from caudal aspect of posterior fossa up to C7 level with variable compression of cord and emerging nerve roots [Figures 1-4]. Radiological features were in favor of hypertrophic pachymeningitis (HPM). An extensive search was carried out to find out the cause of HPM. Her vital signs and other laboratory data were normal except low hemoglobin level (Hb and Hct, 9 g/dL and 32%, respectively), elevated erythrocyte sedimentation rate (ESR) (patient: 110 mm/h, normal: <25 mm/h) and positive tuberculin skin test. Serologic tests for tuberculous antibody were Immunoglobulin M (IgM) positive indicating persisting infection. The serum was negative for rheumatoid factor, antinuclear antibodies, Venereal disease research laboratory (VDRL) test, hepatitis B surface antigen (HBsAg), and antidouble-stranded DNA. Work up for sarcoidosis such as chest radiograph, serum calcium, and angiotensin converting enzyme were negative. Bone marrow examination and ultrasound scan of the abdomen, to exclude a neoplastic and chronic inflammatory process, were normal. CSF analysis after lumbar puncture revealed 80 lymphocytes/mm3, protein of 90 mg/dl, and sugar of 35 mg/dl. Microbiological evaluation of the CSF for cryptococcal antigen, VDRL, and cultures for acid fast bacilli (AFB) and fungi yielded no positive results. An increase in the adenosine deaminase level in CSF was observed. On basis of radiological, serum analysis, and CSF study, a diagnosis of tuberculous HPM was made. Screening for systemic source of tuberculosis was negative. She was discharged on antituberculosis therapy with regular follow up. At the 3-month follow-up, the patient was able to walk with a cane, neck rigidity vanished, dysphagia and limb spasticity improved. Antitubercular treatment continued for 15 months. At present, she can walk independently with some spasticity.

cranio cervical, hypertrophic pachymeningitis, tuberculous

PMC10018008_01

Unknown

The development of ETVAX may provide a valuable roadmap for development of other improved inactivated whole cell enteric vaccines, and I. Khalil, personal communication. A first-generation precursor of the current ETVAX candidate was a whole cell vaccine consisting of formalin-inactivated ETEC bacteria expressing CFA/I and CS1 to CS5, combined with cholera toxin B-subunit (CTB), which is highly homologous to the B-subunit (LTB) of LT enterotoxin produced by approximately 66% of ETEC strains. This 2-dose vaccine candidate was found to be immunogenic in children and adults in endemic areas. Furthermore, it protected adult travelers against moderate/severe diarrhea. In these studies, an anti-CTB serum IgA titer > 360 when trial participants arrived in Guatemala or Mexico was found to be associated with a reduced risk of developing moderate to severe ETEC traveler's diarrhea (TD) ( Table 1 ), suggesting that level of anti-toxoid IgA antibody may be a marker for effective vaccination in travelers. In pediatric studies, a full dose of the vaccine caused vomiting in 6-17 months old Bangladeshi children; but a quarter dose was found to be safe. The vaccine did not confer protection in 6-24 months old Egyptian children, but both vaccinated and unvaccinated children experienced mainly mild disease during the study period and the impact on moderate/severe diarrhea could not be evaluated. These data were reviewed by a WHO panel, which recommended overexpression of antigens on the cells comprising the vaccine and inclusion of an adjuvant in the formulation to help improve vaccine immunogenicity in the target age-group. ETVAX is now undergoing clinical trials as a second generation multivalent oral ETEC vaccine-containing inactivated E. coli strains over-expressing colonization factor antigens CFA/I, CS3, CS5 and CS6 (the latter was not included in the first-generation vaccine) at significantly higher levels than in naturally occurring cells. In addition, it was also noted that formalin inactivation of the CS6 expressing ETEC was detrimental to CS6 immunogenicity, and this was overcome in the second-generation formulation by phenol inactivation of the CS6 strain. The current generation vaccine is administered together with the more LT-like toxoid LCTBA. To further enhance the immunogenicity of the vaccine, it was combined with the double mutant labile toxin of ETEC (dmLT) adjuvant. When tested in Swedish adults (ISRCTN91363076), ETVAX with or without dmLT was found to be safe and to induce significant fecal SIgA responses as well as IgA antibody-secreting cell (ASC) responses against all CFs and LTB. Addition of 10 ug dmLT to the vaccine significantly enhanced ALS responses only to the CS6 component. ETVAX also induced long-lasting immunological memory in Swedish adults (; ISRCTN27096290). Subsequent results demonstrated that ETVAX induced IgA antibody responses that cross-react with CFs belonging to the same CF families, possibly expanding the coverage of the vaccine. These successful results have led to clinical evaluation of ETVAX in a large phase 1/2 trial in adults and lower age groups (5 years to 6 months) in Bangladesh. Adults: The safety of ETVAX alone or together with dmLT adjuvant was evaluated in Bangladeshi adults to provide the basis for studies in Bangladeshi children and infants [; NCT02531802]. The Bangladeshi adults received two oral doses of ETVAX with or with-out dmLT adjuvant or placebo in the initial part of a randomized, double-blind, placebo-controlled, age-descending, dose-escalation trial. This was the first clinical trial of the second generation ETVAX vaccine conducted in an ETEC endemic country. Two full doses of ETVAX, both when administered alone and with 10 ug dmLT adjuvant, were safe and well tolerated in the healthy Bangladeshi adults tested, confirming previous safety data from studies in Swedish adults. This vaccine was highly immunogenic in Bangladeshi adults, inducing intestine-derived ASC responses in all, and plasma antibody responses in a majority, of the vaccine recipients to all primary vaccine antigens (four CFs and LTB). Addition of dmLT adjuvant to the vaccine had no apparent effect on the ALS responses in the adults in this study. In contrast, in adult Swedes, 10 ug of dmLT significantly enhanced ASC responses to CS6, which is the CF present in the lowest amount in the vaccine. Both the Swedish and Bangladeshi trials demonstrated that the oral ETVAX vaccine is safe in adults and induces strong mucosal as well as systemic immune responses against key vaccine antigens. These findings have provided a base for further evaluation of this vaccine in descending age groups in children and infants. Children and infants: Healthy children in one of three age groups (24-59 months, 12-23 months, and 6-11 months) were randomly assigned with block randomization to receive either ETVAX, with or without dmLT, or placebo (; NCT02531802). ETVAX (half [5.5 x 1010 cells, 500 ug LCTBA], quarter [2.5 x 1010 cells, 250 ug LCTBA], or eighth [1.25 x 1010 cells, 125 ug LCTBA] adult dose), with or without dmLT adjuvant (2.5 mug, 5.0 mug, or 10.0 mug), or placebo were administered orally in two doses 2 weeks apart. The primary endpoint was safety and tolerability, assessed in all children who received at least one dose of vaccine. Antibody responses to vaccine antigens, defined as at least a two-times increase in antibody levels between baseline and post-immunization, were assessed as secondary endpoints. No solicited adverse events occurred that were greater than moderate in severity, and most were mild. The most common solicited event was vomiting which appeared related to dose and age. The addition of dmLT did not modify the safety profile. Mucosal IgA antibody responses in lymphocyte secretions were detected against all primary vaccine antigens (CFA/I, CS3, CS5, CS6, and the LCTBA toxoid) in most participants in the two older age groups, whereas such responses to four of the five antigens were less frequent and of lower magnitude in infants aged 6-11 months than in older children. Mucosal antibody response frequencies were consistently higher in the adjuvanted vaccine group when >= 3, 4 or 5 antigens were considered ( Table 2 ). Seventy-eight (56%) of 139 infants aged 6-11 months who were vaccinated developed mucosal responses against at least three of the vaccine antigens versus 14 (29%) of 49 of the infants given placebo. Addition of the adjuvant dmLT enhanced the magnitude, breadth, and kinetics (based on number of responders after the first dose of vaccine) of immune responses in infants. A similar positive dmLT effect was observed on the mucosal antibody response in the 12-23 month age group in this study when the antigenic breath of the responses was considered. In more in-depth immunological studies, the inclusion of dmLT in the vaccine formulation improved expression of B cell memory markers and T cell responses to key ETEC antigens as well. Subsequent findings showed that ETVAX induced mucosal and systemic immune responses against O78 LPS (present in three of the CS expressing strains in the vaccine) in all age groups and that dmLT improved intestinal immune responses among infants. These observations may have implications for more successful use of dmLT with other oral vaccines, like cholera (OCV), which have experienced difficulty in inducing protective O antigen antibody responses in children and infants under 5 years of age. Also, the enhancement of protein colonization factors and 078 LPS responses in infants and young children suggests in the case of OCV that including dmLT in the formulation may make single dose vaccine strategies more protective, thereby extending available stockpiles of this vaccine. The Swedish and Bangladeshi studies showed that ETVAX could induce strong intestine-derived and/or fecal immune responses in a majority of vaccinated adults and in different age groups, including infants, in Bangladesh. This trial assessed for the first time the safety and immunogenicity of ETVAX in young children and infants in a low and middle income country (LMIC) and was the first analysis of dmLT adjuvant with a vaccine in this population in a LMIC. Immune responses were improved in infants aged 6-11 months by administering dmLT with the vaccine. Importantly, this study showed that occasional mild to moderate vomiting can be reduced without loss of immunogenicity by reducing the dose of vaccine, even when dmLT was included in the formulation.

etec vaccine, adjuvant, immunity, oral immunization, vaccine

PMC10018008_02

Male

A double-blind, placebo-controlled, age-descending, dose-finding trial was undertaken in 40 adults, 60 children aged 10-23 months and 146 aged 6-9 months old (; PACTR201905764389804). Adults received a single full dose of ETVAX and children received 3 doses of either 1/4 or 1/8 of the vaccine. All vaccine doses also included 2.5 ug of dmLT. There were no differences in the frequency of solicited or unsolicited adverse events between vaccine recipients receiving 1/4 and 1/8 dose and no increase in frequency or severity of systemic reactogenicity with increasing number of vaccinations or decreasing age. The vaccine induced plasma IgA and IgG responses against LTB in 100% of the adults and 80-90% of the children. In children aged 6-9 months, IgA response rates against >= 4 vaccine antigens after 3 doses determined as >= 2-fold and >= 4-fold rises were significantly higher for 1/4 dose compared to placebo (65.1% vs 27.6%, p=0.004 and 32.6% vs 6.9%, p=0.01, respectively). The Zambian studies further demonstrated that ETVAX was safe, tolerable, and immunogenic in adults and children. Using 3 doses, the maximum expected number of doses to be used in children in LMICs, the 1/4 dose was again shown to be safe and induced significant IgA responses in children. Evaluation of pre-and post-vaccination plasma samples from 20 children aged 10-23 months was accomplished using a proteome microarray. Post-vaccination, reactivity to CFA/1, CS3, CS6, and LTB was stronger than baseline among the vaccinated compared to the placebo group. The CS5 protein was not included in the microarray. Three other purified non-vaccine ETEC proteins; CS4, CS14, and PCF071 had significantly higher post-vaccination responses. These data suggest that ETVAX induces cross-reactive IgG antibody responses to non-vaccine CFs CS4, CS14, and PCF071 from the class 5 fimbriae. This activity could provide some broad IgG antibody coverage beyond the core vaccine antigens (CFA/I, CS3,CS5, CS6 and LTB) themselves. Field evidence that effective immunization with ETVAX can be protective in man.

etec vaccine, adjuvant, immunity, oral immunization, vaccine

PMC10018008_03

Unknown

A randomized, double-blinded, placebo-controlled phase 2b trial of ETVAX supplemented with 10 ug of dmLT was conducted among 729 Finnish volunteers (18-65 years old) randomized to receive two doses of either ETVAX or placebo two weeks apart (; EudraCT2016-002690-35; NCT03729219). Although the data for this trial are being prepared for initial publication elsewhere, it can be said that the safety, immunogenicity and efficacy data are encouraging for moving on to Phase 3 planning for travelers and further studies among infants and young children in low to low-middle income countries (LMICs) that will lead to Phase 3 testing for both indications. The Benin Phase 2B study was a critical step in the development of the ETVAX vaccine since it was a very stringent test of its impact on ETEC TD since the burden of co-pathogens in the field proved exceptionally high and ETEC was found in 75% of all severe diarrhea cases. These data for protection are consistent with those reported for the first generation inactivated ETEC vaccine. As described above, ETVAX has been shown to be safe and induce strong intestinal-mucosal IgA antibody responses to CF antigens and LTB when tested among adult Swedish volunteers, healthy Bangladeshi adults and children, and in healthy Zambian children. An ongoing trial in The Gambia is a randomized, double-blind, placebo controlled (1:1) trial to measure the safety, immunogenicity, and protective efficacy of three ETVAX doses given as 1/4 of an adult dose plus 2.5 ug of dmLT. Vaccine is given on days 1, 15, and 90 to healthy Gambian children aged 6 to 18 months (; PACTR20201081021852). As of 17 November 2022, 4936 children have been enrolled and received at least one vaccine dose and 88% of these children received all three doses. Although safety data is blinded to group assignment, the investigational product appears safe. Active surveillance using home visits for solicited adverse events (i.e., diarrhea, vomiting, fever, acute allergic reactions) within seven days of any vaccine or placebo dose in a cohort of 350 children detected 89 events, only two events (1 vomiting, 1 fever) were severe and considered product related. Among all other children (n = 4115), there were 348 adverse events during dosing; three were severe (1 pneumonia, 1 measles, 1 bronchiolitis) and none were product related. For 32 serious adverse events, none were found product related. To 31 October 2022, 360 moderate to severe diarrhea cases have been detected and 94 (26%) were ETEC positive by multiplex PCR. Stool specimens are under testing for ETEC phenotypes and co-pathogens. To date the only licensed inactivated whole cell vaccines against enteric diseases are against cholera, and most depend upon delivery of acid-resistant polysaccharide antigens. The presentation for these vaccines not requiring a buffer involves a cell suspension in a plastic tube that can be dispensed directly into the recipient's mouth. A more complex presentation may be necessary to exploit the potential of whole cell vaccines containing adjuvants and conserved protein antigens. This need has been studied extensively with ETVAX so that the number of vaccine components and their presentation for administration can be simplified (N. Carlin, personal communication). The presentations now being considered for traveler and LMIC pediatric use of ETVAX will consist of a spray dried sachet (dmLT [10 ug] + antacid buffer + LCTBA) and a liquid bottle of 10 ml of bacterial cells For adults the sachet may be reconstituted in the bacterial suspension of cells in a glass containing 150 ml of water prior to consumption. For children in LMICs, the sachet contents are anticipated to be mixed directly with the bacterial suspension for administration. The two-component, self-contained formulation is a significant advance. The need for no extraneous water overcomes a delivery issue that has been problematic for widespread use of some oral inactivated whole cell vaccines (i.e.Dukorall). At this point, ETVAX has a practical formulation designed to minimize user error. Future work may be able to further reduce the footprint of this vaccine for refrigeration. Although ETVAX promises to be an effective vaccine with broad protection against ETEC, the value proposition for this vaccine could be greatly increased by using it as a platform to immunize against other pathogens; I. Khalil, personal communication). For example, recombinant protective antigens against other mucosal pathogens could be cloned into one or more of the strains now comprising ETVAX. Alternatively, other whole cell vaccines alone or themselves expressing heterologous antigens could be co-formulated with ETVAX. These could include the cross-protective inactivated Shigella whole cell vaccine or the Hikojima or Euvichol cholera vaccines. An advantage of a practical means of oral vaccine delivery compared to parenteral injections is that the other whole cell vaccines would not need to be mixed before administration to be acceptable. Instead, after administering the ETVAX with buffer and adjuvant, a second simpler plastic vial containing just the additional whole cell antigens in PBS could be used for further oral immunization, possibly benefitting from the buffer and adjuvant in ETVAX.

etec vaccine, adjuvant, immunity, oral immunization, vaccine

PMC5506868_01

Male

A 37-year-old man presented to the Emergency Department with a two-week course of asthenia, weight loss, night sweats, dyspnea, left pleuritic chest pain, and cough with putrid sputum. The patient was HIV-positive for about 7 years (risk factor: intravenous drug use) and had started antiretroviral therapy but with poor therapeutic compliance. His medical history also included a hepatitis C and B virus co-infection, lymph node tuberculosis 10 years before (completed 12 months of treatment), and a left lobar pneumonia 4 years earlier, complicated by empyema (he underwent left lower lobectomy and had a persistent bronchopleural fistula). On physical examination, he was cachectic with caseous-purulent drainage and exteriorization of air with cough effort from an orifice in the antero-lateral left chest wall (Fig. 1a and b). Acid-fast bacilli were identified in this drainage. Initial exams included hemogram (normocytic and normochromic anemia - hemoglobin 10.0 g/dl [13.0-18.0 g/dl]; lymphocytes in the lower limit of normal - 1.03 x 103/mul [1.0-4.8 x 103/mul]; and thrombocytopenia - 123 x 103/mul [150-440 x 103/mul]), electrolytes (normal values), hepatic enzymes (elevated aspartate aminotransferase - 80 U/L [4-33 U/L]), serum albumin (hypoalbuminemia - 1.8 g/dl [3.4-4.8 g/dl]), and coagulation tests (normal values). His HIV viral load had increased from <20 copies/mL to 107409 copies/mL and his CD4+ count had decreased from 591 cell/mul to 241 cell/muL. The chest radiograph showed bilateral infiltrates (Fig. 2) also evident on the chest computed tomography (CT) scan showing several bilateral cavitary lesions (Fig. 3) and a pleurocutaneous fistula extending from left pleural cavity to left anterolateral chest wall (Fig. 4). He was admitted to the Infectious Diseases Unit with the diagnosis of fistulized pulmonary tuberculosis, confirmed by visualization of acid-fast bacilli, positive polymerase chain reaction and cultures for Mycobacterium tuberculosis in the sputum. Was identified resistance to isoniazid and streptomycin on the culture sensitivity tests. The patient started on antituberculous therapy with rifampin, pyrazinamide and ethambutol and improved symptomatically with a favorable outcome. The discharge from the cutaneous site stopped after 7 days.

bronchopleural fistula, hiv, pleurocutaneous fistula, pulmonary tuberculosis

Axial CT chest showing subcutaneous emphysema in a fistulous path (arrow) corresponding to the pleurocutaneous fistula extending from left pleural cavity to left anterolateral chest wall.

PMC9869367_01

Female

A 13-year-old girl was admitted to the hospital because of dizziness for 3 days and syncope twice. She experienced syncope first during school recess, which lasted for approximately 10 min, accompanied by salivation and urinary incontinence. She was immediately sent to the emergency department of a local hospital. During hospitalization, she suffered syncope for a second time, and she was then transported to our hospital by ambulance. After admission, physical examination revealed that the child was conscious with a normal heart rate but an irregular heartbeat. Echocardiography showed normal left ventricular systolic function and a normal cardiac structure. Multiple bedside electrocardiograms (ECGs) showed frequent multisource premature ventricular contractions. Holter ECG showed frequent multisource premature ventricular contractions (43,729 beats/day, with some occurring in pairs and some occurring in doublet or triplet patterns) with the R-ON-T phenomenon and Tdp (Figure 1A). The QTc ranged from 410 to 468 ms. For treatment, the patient was administered an intravenous infusion of magnesium sulfate (0.5-1.0 mg/kg h) and potassium to maintain serum potassium concentration at 4.5-5 mmol/L. She received oral propranolol tablets (0.5 mg/kg) every 8 h. After 1 week of treatment, the child recovered and did not experience palpitations or dizziness in the hospital. An ECG showed that the premature ventricular contractions were significantly reduced and that no ventricular tachycardia (VT) occurred, and the QTc was 416 ms (Figure 1B). Occasionally, a biphasic T wave was observed in Lead V2 in this patient in sinus rhythm. Second-generation gene sequencing was performed after receiving approval by the Medical Ethics Committee and parental informed consent. As a result, a heterozygous mutation, namely, c.11714T > C (p.M3905T), in the AKAP9 gene of the patient was detected, which was inherited from her mother (Figure 2), whose ECG was normal without QT prolongation and no history of syncope. This variant has not been previously described in the literature and has also not been previously reported in the Human Gene Mutation Database (HGMD). No other possible causative mutations were found, and no history of related genetic diseases was detected in the family. After 9 months, the child suffered from syncope and convulsions again during housework. She was transferred to our hospital after cardiopulmonary resuscitation for 2 h. The ECG showed frequent multisource VT with Tdp (Figure 1C). Temporary subclavian pacing was given to the patient, and vasoactive drugs were used to maintain circulatory stability. Oral propranolol tablets were adjusted to 1 mg/kg every 8 h, and the patient received intravenous potassium and magnesium supplementation. The Holter ECG showed that the incidence of ventricular arrhythmia was 19,924 beats in 24 h with no occurrence of Tdp. Considering that the child had syncope after drug treatment, she was implanted with an implantable cardioverter defibrillator (ICD) under general anesthesia after 7 days of stabilization (Figure 3). Her parents were informed that she needed activity restriction and exercise reduction. Two weeks after discharge from the hospital, the patient developed obvious palpitations, fatigue, dizziness, and a sense of electric shock at night. Because she experienced several suspicious electric shock events, she was readmitted to our hospital. The bedside program control of the ICD confirmed that the child had multiple VT at home, and electrical cardioversion terminated the tachycardia after antitachycardia pacing (ATP) failed. In order to alleviate her anxiety, the ATP function was turned off, the VT judgment threshold was adjusted from 180 beats/min to 200 beats/min, and the energy of the first electric shock was lowered from 30 to 20 J. To reduce the incidence of ventricular arrhythmias, the patient was prescribed oral propafenone tablets (3 mg/kg) every 8 h. A repeated Holter ECG showed that the frequency of ventricular arrhythmias (3,387 beats/day) was significantly lower than before and that the ventricular pacing function was normal. The morphology of the T wave was normal in the lateral precordial leads. No malignant arrhythmia and electric shock events occurred during the 1-, 3-, and 6-month follow-ups. The child returned to school with restricted activities, and her parents were satisfied with the treatment provided.

akap9 gene, case report, implantable cardioverter defibrillator (icd), long qt syndrome (lqts), torsades de pointes (tdp)

PMC10413191_01

Male

Case 2: A 30 year old male presented to our institute with history of fever, night sweats, and productive cough since 1 year. It was associated with weight loss. After thorough clinical, radiological examination, positive sputum and culture for TB mycobacteria, patient was finally diagnosed with tuberculosis. Patient was treated with anti-tubercular drugs for 6 months. After 2 months of completion of treatment, the patient developed excessive coughing along with massive haemoptysis (roughly 300 ml/hr) for 2 days. Subsequently the patient was brought to the emergency room with a GCS ( Glasgow coma scale )of 10 of 15. His vitals were stabilized and patient was further evaluated by laboratory and radiological examinations. Mild decrease in haemoglobin level was documented. However other blood parameters were within the normal limits. A chest radiograph revealed a cavitating lesion involving the upper zone of the left lung. The patient underwent a CT pulmonary angiogram, which demonstrated an irregular shaped cavity measuring ~ 7 x 3.5 x 6.5cm in apico-posterior segment of left upper lobe (wall thickness~ 12mm). Non-enhancing dependant content was seen within the cavity. Extensive areas of fibrobronchiectasis were noted in adjoining lung parenchyma in left upper lobe. Few centrilobular nodules were seen in left lower lobe with surrounding ground glass opacity. No active extravasation of contrast was seen. Multiple focally dilated sub-segmental division of left upper lobe pulmonary artery which were seen coursing along the periphery of the cavitary lesion representing Rasmussen aneurysm. Bronchial arteries were normally visualized (Fig. 1, Fig. 5, Fig. 6, Fig. 7). Patient was then transferred to the interventional radiology department for further management of the aneurysm. The patient was taken to DSA for embolization of the pulmonary artery to halt the source of bleed. The right common femoral vein approach was used in combination with a pigtail catheter and guidewire access, into the pulmonary trunk and subsequently to the left pulmonary artery. Selective angiogram revealed multiple focally dilated pulmonary artery. The patient underwent glue embolization of the aneurysms and remained stable without further haemoptysis.

complications, embolization, infectious disease, pulmonary tuberculosis, rasmussen aneurysm

PMC10413191_02

Male

Case 3: A 28 year old male patient who was treated for pulmonary tuberculosis two years back, complained of recurrent mild haemoptysis which aggravated in the last 10 days. He also complained of cough with evening rise of temperature for 20 days. On physical examination, patient was conscious and alert with maintain vitals with no cyanosis, clubbing, icterus or pedal oedema. Laboratory investigations were within normal. Computed tomography demonstrated fibrotic opacities with varicose bronchiectatic changes in entire left upper lobe with volume loss and ipsilateral mediastinal shift. A thick walled cavity measuring ~35 x 20mm was noted in left upper lobe with soft tissue density within. Few patchy fibrotic opacities were also noted in apical segment of right upper lobe. On angiography a small aneurysmal dilatation of segmental branch of left pulmonary artery was noted, coursing along the cavity. Multiple other tortuous dilated vessels were also seen surrounding the cavity. Sputum and culture for TB mycobacteria were positive. He was treated successfully with antitubercular drugs for six months. He had no further episodes of haemoptysis (Fig. 1, Fig. 8, Fig. 9, Fig. 10).

complications, embolization, infectious disease, pulmonary tuberculosis, rasmussen aneurysm

PMC7687405_01

Male

RR is a 17-year-old previously healthy Hispanic male who presented to a community emergency room with a 1- week history of progressive worsening of shortness of breath, abdominal pain, diarrhea, and ageusia. Past medical history revealed a 3-months history of dry cough and 9 pounds unintentional weight loss for which he had not sought medical care. Pertinent positives include smoking cigarettes for two years and vaping nicotine and Delta-9-tetrahydrocannabinol for one year. Pertinent negatives include traveling outside of the country, or exposure to known contacts with COVID-19 or tuberculosis. Initial workup included testing for SARS CoV-2, which was undetected by real time-polymerase chain reaction (RT-PCR) from the nasopharynx. He was transferred to our hospital for further evaluation of respiratory distress where repeat SARS CoV-2 by RT-PCR was then detected. Additional laboratory studies revealed a white blood cell count (WBC) of 27,500 mm 3 with 84% neutrophils, 2% bands, and 10.1% lymphocytes. C- reactive protein (C-RP) and procalcitonin were elevated to 33 mg/dl and 3.14 ng/ml, respectively. Urine toxicology screen was positive for Delta-9-tetrahydrocannabinol metabolites. The initial chest radiograph demonstrated patchy bilateral opacities without focal consolidation (See Fig. 1 ). A diagnosis of e-cigarette, or vaping, product-associated lung injury (EVALI) was also suspected in addition to COVID-19 given his history of vaping in the previous 90 days, respiratory symptoms alongside characteristic radiographic findings, consistent with the Centers for Disease Control and Prevention (CDC) definition. A chest computed tomography (CT) revealed patchy ground-glass pulmonary opacities and scattered opacities throughout both lungs, primarily in a perihilar and peripheral distribution (See Fig. 2 ). The patient was admitted to the COVID-19 special isolation unit. Given the presence of oxyhemoglobin desaturation to 88%, the patient was placed on 1.5 L per minute (lpm) of oxygen via nasal cannula during admission with resolution of hypoxemia. Shortly after admission, the pulmonology team was consulted. With growing evidence that patients with COVID -19 with moderate to severe illness may have a favorable response to dexamethasone in association with evidence that patients with EVALI may benefit from glucocorticoid use, pulmonology recommended to start the patient on oral dexamethasone 6 mg daily. He demonstrated an excellent response to glucocorticoids with resolution of respiratory symptoms and was weaned to room air and discharged home on the second day of admission. One day after hospital discharge, the patient returned to the emergency room with worsening chest pain and shortness of breath. Vital signs revealed a temperature of 38.5 C, respiratory rate of 39 and an oxyhemoglobin saturation of 91%, and the lung exam revealed clear breath sounds. Due to hypoxemia and tachypnea, he was admitted to the intensive care unit and started on 15 L of heated high flow nasal cannula (HHFNC) and supplemental oxygen (0.45 fraction of inspired oxygen). The infectious disease team was consulted and recommended a 5-day course of remdesivir and dexamethasone was continued for a total of 10 days. The patient was weaned to room air on the third day of admission. On day 4 of admission, repeat C-reactive protein level had decreased to 22.9 mg/dl, and repeat chest radiograph on day 7 showed improvement of patchy opacities. He could subsequently be discharged to home with follow up to his primary care provider and the pulmonary clinic.

covid-19, dexamethasone, evali, remdesivir, vaping

Chest computed tomography with findings of patchy ground-glass pulmonary opacities and scattered opacities throughout both lungs, primarily in a perihilar and peripheral distribution.

PMC2943094_01

Male

A 69-year-old man presented at our hospital with a 5-month history of a rapidly enlarging mass in the right thigh. His past history was pulmonary tuberculosis treated with thoracoplasty and hepatitis C. Physical examination revealed the presence of a large irregular mass with multiple ulcers and necrotic tissues, measuring approximately 10 x 10 cm in the lateral side of the proximal thigh (Figure 1). Admission laboratory data showed high levels of LDH, GOT, GPT, and ALP, which are 643, 80, 39, and 441, respectively. Typical tumor markers were within normal limits. A roentgenogram of the right proximal thigh showed no apparent expansion to the femur. Chest roentgenogram and computed tomography showed no apparent metastatic lesion and no focus of pulmonary tuberculosis. MR images demonstrated relatively a well defined and heterogeneous mass, which was attached to the fascia lata and expanded across the skin layer (Figures 2(a), 2(b)). The signal intensity of the mass was isointense to the adjacent skeletal muscles on T1-weighted images and inhomogeneous hyperintense on T2-weighted images. The mass was relatively well defined and enhanced with Gd-DTPA on STIR sequences (Figure 2(c)). However, partial infiltrating expansions to subcutaneous tissues of the mass made its margins unclear. Despite the mass contacted with the compression to the tensor fascia lata muscle, the gluteus maximus muscle, and the gluteus medius muscle, no apparent signal intensity changes of muscles were seen. Thallium-201 scintigrams showed a robust accumulation accorded for the mass in both of early and delayed phases (Figure 3). No other abnormal accumulation was detected. Based on clinical findings and imaging characteristics, the tumor was diagnosed as a primary soft tissue tumor and an incisional biopsy was performed. Histopathology of the permanent sections showed the nodular or sheets-like proliferation pattern of small round cells with a high nuclear/cytoplasmic ratio in the background of sparse extracellular collagen (Figure 4). Immunohistochemistry of the sections demonstrated that the staining of BCL2, MIC2, CD56, O-13, neuron specific enolase (NSE), and synaptophysin were positive. They were negative for HMB-45, S-100, broad cytokeratin (AE1/AE3 and MNF116), CD45, CD79a, CD3, and CD20. In addition, the RT-PCR showed the presence of EWS/FLI-1 fusion transcript from tumor specimens. Together with the results of several examinations, we diagnosed this tumor as EES. Considering patient's age, hepatic dysfunction, and patient's disagreement with chemotherapy, we precluded the choice of the neoadjuvant chemotherapy. To define surgical margins especially at subcutaneous tissues and to increase tumor resectability, we determined to treat the patient with pre-operative low-dose RT and additional administration of sanazole before surgery. As a result of the total dose irradiation of 30 Gy in 15 fractions with sanazole (0.6 g/m2 x 10 days), the tumor volume was reduced to approximately 40% of the pre-treatment condition (Figure 5). On thallium-201 scintigrams, the accumulation of the tumor markedly decreased in both of early and delayed phases. Subsequently, we could perform the surgical resection with subtotal resection of the tensor fascia lata muscle, the gluteus maximus muscle, the gluteus medius muscle, and adjacent soft tissues to obtain wide surgical margins (Figure 6(a)). The huge surgical defect in the lateral thigh was repaired with a musculocutaneous flap of rectus abdominis (Figure 6(b)). There was no major complication in the perioperative period. Histological examination of the resected tissue demonstrated clear surgical margins. Because the tumor cells completely showed necrotic appearances and there were no viable tumor cells in the tumor specimen, we diagnosed the necrosis ratio as 100% (Figure 7). Based on the histological findings, we could confirm a high efficacy of pre-operative low-dose RT with sanazole in the present case. The patient underwent follow-up without any local recurrence or distant metastasis, and presented without any postoperative functional disturbance for 24 months after surgery.

PMC6556212_01

Male

A 27-year-old Thai male with AIDS from Saraburi Province presented with acute abdominal pain that had lasted for 4 days. He originated from Mukdahan Province, in Northeastern Thailand, but had moved to Saraburi Province which is situated in the southern part of Northeastern Thailand, 200 km from Bangkok. He denied other travel histories outside these areas during the past year. He was diagnosed with AIDS 2 months before at another hospital, which recorded an initial CD4 count of 91 cells/mm3 (unknown percentage and HIV viral load) and no complete immune status evaluation was performed. At the time, he presented with respiratory distress which was later identified as pneumocystis pneumonia and presumptive smear-negative pulmonary tuberculosis. He was given a 3-week course of trimethoprim/sulfamethoxazole, and anti-tuberculosis treatment consisting of isoniazid, rifampicin, pyrazinamide, and ethambutol during hospitalization. Anti-retroviral therapy (ART) comprising tenofovir disoproxil fumarate, emtricitabine, and efavirenz was introduced 2 weeks later when he was an outpatient. The anti-tuberculosis regimen was adjusted to isoniazid, rifampicin, ethambutol, and levofloxacin after 4 days, and a chest radiograph demonstrated complete resolution of prior pulmonary opacities after 50 days of treatment. He reported 100% adherence to both anti-tuberculosis treatment and ART and no other new medications had been added to the regimen. The CD4 count 8 weeks before this admission was 91 cells/mm3 (unknown percentage). At this admission, he presented with abdominal pain mainly in the left upper quadrant that he described as a dull ache, without radiation. The pain was not related to eating food, physical activity, or position. He reported no other associated gastrointestinal complaints such as diarrhea or nausea. Two days later, he developed a high-grade fever without chills, with the highest temperature of 38.9 C. Abdominal pain persisted and partially responded to acetaminophen. In response to this, he attended the emergency department where a physical examination revealed a blood pressure of 120/75 mmHg, a heart rate of 110 beats/min, a temperature of 38.7 C, and a respiration rate of 20 breaths/min. His abdomen was soft, normal bowel sounds were heard, but tenderness on palpation in the left upper quadrant was evident. The spleen could not be palpated. The remaining physical examination was unremarkable including a negative complete skin examination, with no cutaneous lesions on his face, trunk, or extremities, and a neurological examination within normal limits. Initial laboratory investigations revealed hemoglobin levels of 9.8 g/dL, a white blood cell count of 14,000 cells/mm3, and a platelet count of 225,000 cells/mm3 on a complete blood count. Serum galactomannan (GM) levels by Platelia enzyme-linked immunosorbent assay (ELISA) (BioRad) were 6.84. The CD4 count on admission was 272 cells/mm3 (19%). A fungal blood culture obtained on hospital day 1 grew white to tan-colored, velvety and flat colonies with red soluble pigment (Figure 1) on day 9. Direct microscopic examination of the colonies with lactophenol cotton blue staining demonstrated septate hyphae and smooth conidia aloft phialides directly borne on metulae (Figure 2). A bone marrow culture grew similar colonies to the blood specimen (Figure 3) on day 12 after the procedure. Contrast-enhanced computed tomography of the abdomen revealed a small hypodense lesion with a thin enhancing rim at the spleen and extensive intra-abdominal lymphadenopathy (Figure 4). At the time, the patient was not able to provide sputum sample for culture and due to the high-risk procedure, intra-abdominal lymph node biopsy for culture and histologic analysis was not performed. Because of a concern of disseminated fungal infection on admission, empirical intravenous amphotericin B deoxycholate was given at a dose of 1.5 mg/kg/day for 7 days. This was switched to liposomal amphotericin B at 3.2 mg/kg/day in response to acute kidney injury for a total of 21 days. Before discharge, a loading dose of itraconazole was initiated at 600 mg/day for 3 days, then 400 mg/day for the maintenance phase. Of note, plasma itraconazole levels drawn on day 4 were 0.13 mcg/mL, with the highest value throughout the treatment course of 0.21 mcg/mL. The patient continued to improve clinically and was discharged from the hospital after 29 days. Repeat imaging was initially planned at 6 months but was deferred at the patient's request. Serum GM levels 9 months after therapy had declined to 0.11, and he remained asymptomatic at the 12-month follow-up.

aids, cutaneous involvement, disseminated fungal infection, talaromycosis

PMC9253414_01

Male

A 67-year-old male patient was admitted to the hospital with new onset fever, chest pain and dyspnea for 7 days and previous diagnose of right lung squamous cell carcinoma. His previous medical history was notable for right lung squamous cell carcinoma stage IV (T3N3M1) complicated with mediastinal lymph nodes and liver metastasis 1 year before. Cardiac and pulmonary function was normal at that time. Four cycles of chemotherapy with paclitaxel-cisplatin regimen was initiated but afterwards stopped due to 2019 coronavirus outbreak. Ten months thereafter, he was admitted to the hospital because of right massive pleural effusion. Twice bacterial culture of pleural effusion displayed Prevotella nigrescens, indicating right lung squamous cell carcinoma complicated with empyema. With subsequent treatment of meropenem as the anti-bacterial agent, his symptoms were relieved and his temperature was normal. As a result, chemotherapy was discontinued and replaced with PD-L1 immune checkpoint inhibitor, durvalumab monotherapy for four cycles (500 mg intravenous drip). And he presented with the symptom of fever, chest pain and dyspnea 7 days after last cycle of durvalumab. Moreover, the previous medical, family, and psychosocial history as well as genetic information showed nothing special. Physical and laboratory examination was done for the patients upon this admission. The highest temperature was 39.4 C. His blood pressure was 121/69 mmHg. Chest computed tomography (CT) examination indicated right bronchial obstruction, obstructive pneumonia and right pleural effusion (Figure 1A). Echocardiography revealed ventricle size within normal range (left ventricle end diastolic dimension 46 mm), increased atrium size (left atrium dimension LA 36 mm) and markedly decrease cardiac ejection fraction (left ventricular ejection fraction 41%), tracing 2 mm pericardial effusion (Figure 1B). The electrocardiogram showed sinus tachycardia, low voltage of limb leads, T wave inversion in anterior waves and V1-V3 QS type (Figure 1C). Markers of myocardial injury were elevated: Natriuretic peptide BNP 18 942 ng/L; Troponin T 0.066 ng/L; Troponin I 200.83 ng/L; Creatine kinase (CK) and Creatine kinase isoenzyme (CKMB) normal. Moreover, inflammatory indicators were significantly elevated. Erythrocyte sedimentation rate (ESR) was markedly increased with the level of 101 mm/h, and C-reactive protein (CRP) 268.2 mg/L. Interleukin-6 was 44.93 pg/mL. Judging by the decreased cardiac function and elevated myocardial injury markers at this admission, the patient was diagnosed of acute immune-associated myocarditis and right lung squamous cell carcinoma complicated with empyema. Treatments included methylprednisolone to suppress inflammation (40 mg, once per day, iv), meropenem to control infection (1.0 g, q8h, iv.drip) and symptomatic and supportive treatments. Seven days after admission, the patient's symptoms were relieved. Myocardial injury and inflammation markers were significantly decreased: Natriuretic peptide BNP was down to 2,298 ng/L; Troponin T, Troponin I, CK and CKMB normal; ESR 41 mm/h; CRP 29.8 mg/L; and Interleukin-6 normal. The electrocardiogram showed normal sinus rate and V2-V5 T wave inversion (Figure 1C). Echocardiography revealed ventricle size within normal range (left ventricle end diastolic dimension 48 mm), increased atrium size (left atrium dimension LA 30 mm) and markedly recovered cardiac ejection fraction (left ventricular ejection fraction 66%). The patient was discharged with prescription of continuing oral methylprednisolone (20 mg, once per day, po) and anti-bacterial therapy of faroenem to control infection (150 mg, q8h, po). No further heart failure exacerbations have occurred to date.

pd-l1 inhibitor, durvalumab, empyema, lung squamous cell carcinoma, myocarditis

PMC4700156_01

Male

A 46-year-old male presented in 2002 to an outside institution with five to six years of right hip pain radiating down the lateral thigh. Initial imaging is unavailable but by report radiographs showed a large mass involving the ischial tuberosity and portions of the adjacent inferior and superior rami of the right pelvis. He subsequently transferred care to our institution. Biopsies performed at the outside institution were reviewed and confirmed giant cell tumor of bone. He subsequently underwent partial internal hemipelvectomy in November 2002. Histopathologic analysis showed GCT (Figure 1). Postoperatively, the patient was started on alendronate (dose unknown). Follow-up MRI in February 2003 showed an enhancing, high T2 signal, 2 cm soft tissue mass within the right adductor musculature, adjacent to the former location of the ischial tuberosity, suspicious of recurrence. CT imaging in August 2003 showed a mass within the surgical bed, within the obturator externus and pectineus muscles, and abutting the root of the penis. CT guided biopsy confirmed recurrent benign GCT. Reexcision of the mass was performed in September 2003. The pathology specimen showed a 4 cm mass embedded within excised soft tissue. Giant cell tumor was present at multiple resection margins. Postoperatively, the patient did well, with intermittent complaints of pain. Follow-up MRI eight months after surgery showed an enhancing multilobulated mass at the margins of the original hemipelvectomy surgical bed, the largest mass measuring up to 2.7 cm. Edema and abnormal enhancement were noted within the obturator externus, obturator internus, and quadratus femoris muscles. Another 1.5 cm nodule was noted in the proximal adductor brevis muscle. He was subsequently followed up with approximately yearly MRI studies. The recurrent tumor showed progressive, interval growth, reaching a measurement of 3.2 x 3.6 cm in December 2005 (Figure 2), 9.2 x 3.4 cm in January 2008, and 11.0 x 8.9 cm in January 2012, at which time there was possible invasion into the right corpus cavernosum. The patient was started on denosumab (120 mg subcutaneous monthly) in July 2012. Imaging over the next 2 years showed stable disease, with possible slight decrease in size of the tumor. In November 2014, the patient developed osteonecrosis of the left mandible after tooth extraction, and denosumab was held for two doses. Denosumab was restarted in late December 2014 after presenting to clinic with severe right groin pain radiating inferiorly. Follow-up CT scan in February 2015 showed enlargement of the pelvic mass to 13.6 x 13.0 cm with extension into the ischioanal fossa and subsequent mass effect on the rectum, prostate, bladder base, and base of penis (Figures 3 and 4). The imaging findings were highly suggestive of sarcomatous transformation of the GCT. Multiple nodules were also now noted throughout the lungs. No additional potential primary tumor that could account for the lung nodules was identified on imaging, and metastases from a malignant GCT were suspected. Denosumab was discontinued. CT guided biopsy of a right lower lobe nodule showed a high grade spindle cell sarcoma with nuclear atypia and low mitotic rate (up to 4 mitoses per high power field) (Figure 5). By immunohistochemistry, the tumor stained for smooth muscle actin (SMA) and p63, with focal S-100 protein staining. Subsequent CT guided biopsy of the pelvic mass revealed a high grade sarcoma with discohesive round to epithelioid cells that expressed SATB2 and weak SMA and lacked p63 (Figure 6). The morphology and IHC staining results were consistent with transformation to osteosarcoma. Subsequent CT scan showed interval increase in size of the pelvic mass, an increase in the number and size of lung nodules, pulmonary lymphadenopathy, and a hepatic lesion suspicious of additional metastasis. The patient was started on doxorubicin and ifosfamide. CT scan showed slightly decreased primary tumor but an increased number of pulmonary nodules, two liver lesions, inguinal lymphadenopathy, and a probable 3.7 cm metastasis to the penis. He was then started on docetaxel and gemcitabine. He transferred care from our institution shortly thereafter.

PMC4700156_02

Male

A 49-year-old male presented in July 2007 with a six-month history of left knee pain and swelling. Radiographs from an outside institution showed a cystic lesion in the left femur condyle with sclerotic borders and expansion of surrounding bone. GCT was strongly suspected and the patient underwent curettage with PMMA packing in August 2007. Histologic evaluation confirmed giant cell tumor of bone (Figure 7). The patient was followed postoperatively with radiographs of the knee. One month after surgery, a rim of lucency around the cement packing was noted (Figure 8). There was interval increase in the lucency until February 2009, when MRI showed an 8.15 x 3.9 x 1.8 cm area of marrow infiltration corresponding to the lucency, consistent with recurrence. There was minimal interval increase in size on MRI through November 2013, during which time the patient experienced some intermittent left knee pain, when an additional 2 x 1 cm mass was identified, along with mild periostitis along the lateral distal femur (Figure 9). The patient was offered, and declined, both denosumab and surgery at that time. With continued knee pain and weakness, however, he opted for denosumab treatment in January 2014. He initially did well, denying pain except with running or other significant impact activities. But, by July 2014, he reported two months of significantly increasing knee pain and swelling. Radiographs showed continued increase in size of the lucency, measuring up to 5.0 cm, with periosteal reaction suggestive of impending pathologic fracture (Figure 10). Because of the intolerable pain, the patient opted for surgery. Due to the tumor's proximity to the bone cortex and articular surface, curettage was not possible and arthroplasty was scheduled. The patient underwent wide resection with endoprosthetic reconstruction in August 2014. The pathology specimen consisted of a 15 cm length of distal femur with minimal attached soft tissue and muscle and with an up to 4.0 cm ill-defined heterogeneous mass proximal to the PMMA (Figure 11). Histologic examination showed that the mass was comprised of pleomorphic osteoblastic cells in a fibrosarcomatous arrangement with bone, osteoid, and focal cartilage formation (Figure 12). Mitoses averaged 18 per high powered field. By immunohistochemistry, the tumor cells stained with SATB2, p53, and p63. Multiple soft tissue margins were positive. The findings were consistent with a high grade osteosarcoma arising from giant cell tumor. Cytogenetic analysis of tumor tissue revealed a complex karyotype that included loss of chromosome 17, a recurrent finding in osteosarcoma. The patient was given four cycles of doxorubicin and cisplatin in September 2014 but developed skeletal metastases. He was then started on high dose methotrexate. He initially had stable disease but again progressed after several months, with development of pleural and additional skeletal metastases. He was then placed on gemcitabine and docetaxel but died soon after.

PMC3968897_01

Female

A 62-year-old right-handed French Caucasian woman was diagnosed in October 2007 for an ASS and treated by corticosteroids (methylprednisolone 40 mg/week and prednisolone 20 mg/day) and mycophenolate mofetil (3 g/day). In March 2010 white blood cell count showed profound lymphopenia (486/mm 3, normal range 1,500 to 4,000/mm 3, Figure 1). Because the ASS was controlled, methylprednisolone was stopped and prednisolone was progressively tapered to 7.5 mg/day. In May 2010 she presented progressive cognitive impairment, followed by a brisk worsening in July 2010 with dizziness and falls. At admission on July 8 th 2010 neurological examination revealed mental slowness, attention and memory troubles, and paresis of the left lower limb. Brain axial T2-WI MRI revealed confluent subcortical white matter hyperintensities of the right frontal and parietal region ( Figure 2A). Axial T1-WI MRI displayed hypointensities with multiple foci of gadolinium enhancement ( Figure 2B). Prednisolone and mycophenolate mofetil were stopped. The differential diagnoses were viral encephalitis, tuberculosis, cerebral lymphoma, paraneoplastic disorder and CNS involvement of a connective tissue disorder. General examination did not demonstrate any activity of the ASS. Blood cell count showed 750 lymphocytes/mm 3 ( Figure 1). Cerebrospinal fluid (CSF) examination on day 2 was normal, and in-house PCR ( Herpesviridae, enterovirus, JCV, BK virus, Toxoplasma gondii and Mycobacterium tuberculosis), and serologies (HIV, Borrelia and syphilis), were negative, as well as direct staining and cultures for bacteria and fungi. Blood immunophenotyping showed 673 CD4 + T cells/mm 3 (normal range 500-1,500), 82 CD8 + T cells/mm 3 (normal range 250-950) and 37 CD19 + B cells/mm 3 (normal range 100-600) ( Figure 1). The level of anti-Jo1 antibodies previously detected (Nov 2009, 7.4 AI (normal range 0-0.9) was decreasing (5.9 AI) and a screening for anti-neutrophil cytoplasmic and onconeuronal antibodies was negative. A computed tomography scan showed steady lung interstitial infiltrates, and no evidence for sarcoidosis, tuberculosis or cancer. A stereotactic brain biopsy of the right parietal lobe was performed on July 16 th 2010. Neuropathological examination showed demyelinated lesions with axonal loss and a severe inflammatory reaction with a vasculitic component and endothelial damage ( Figure 2D-E). Perivascular and parenchymal inflammatory infiltrates showed a pronounced CD3 + T cell infiltrate ( Figure 2F) composed mostly by CD4 + T cells, in association with a few CD68 + macrophages/microglial cells and CD138 + plasma cells. Anti-Simian virus 40 (SV40) immunohistochemistry (cross-reacting with the JCV) was positive, and a second aliquot of the CSF taken on day 2, sent to Dr. Major's laboratory at the NIH, was positive for JCV by Real-time TaqMan PCR at a low level (23 copies/ml) , both firmly establishing the diagnosis of PML. A diagnosis of simultaneous PML-IRIS with vasculitis was made. As in the meantime her neurological status had stabilized, the patient did not receive corticosteroids. When followed up in November 2010, mental slowness and paresis of the left lower limb had completely recovered, and repeated MRI showed improvement of previous lesions. In parallel, blood immunophenotyping showed partial normalization ( Figure 1). However, concomitantly she presented with a severe flare of the ASS, with myositis, polyarthritis and active interstitial pneumonitis. A one-week course of oral corticosteroids was initiated together with monthly intravenous polyclonal immunoglobulin therapy (IVIg). By December 2012 the ASS was considered under control with IVIg alone. The patient was fully independent without any neurological abnormalities, while MRI showed sequellar lesions ( Figure 2C).

PMC8803630_01

Male

A 42-year-old asymptomatic male patient received thoracic CT scans on a routine health examination at a local hospital in February 2021 with an incidental finding of a 1.5 x 1.2 cm endobronchial nodule of the right bronchus intermedius and a 5.1 x 3.1 cm patchy lesion centrally located at the left upper lobe (Figure 1). The patient underwent fiberoptic bronchoscopy, which showed a neoplasm with an unsmooth surface at the opening of the right bronchus intermedius with normal distant bronchial tree. Transbronchial biopsy of the neoplasm was suggestive of low-grade mucinous epidermoid carcinoma. The patient further underwent PET/CT scans, which revealed weak FDG uptake in the endobronchial nodule and high uptake in the left upper lobe lesion. To discern the nature of the left upper lobe lesion, the patient underwent a CT-guided percutaneous lung biopsy. Pathological examination revealed a chronic granulomatous inflammatory disease, suggesting the diagnosis of tuberculosis. Due to the specific location of the endobronchial tumor, the patient was recommended by the treating physician at the local hospital to receive bronchoscopic cryoablation over surgical resection. Because of concerns that the tumor might recur with bronchoscopic therapy, the patient was referred to our department for seeking surgical resection. The results of preoperative routine blood biochemistry were normal. Pulmonary function test showed mild obstructive ventilation dysfunction, with FEV1 being 2.38L and FEV1%PRED being 76%. Considering the patient's 30-year history of bronchial asthma (manifested as wheezing sounds in both lungs) and the fact that lung parenchymal resection might lead to decreased quality of life, the patient underwent a single-port thoracoscopic tumor resection, reconstruction of the secondary carina and systemic lymph node dissection (including stations 2, 4, 7, 9, 10, 11, 12) in March 2021 (Figure 2). The patient was placed in a left lateral decubitus position. After the intubation of the double-lumen tube, single lung ventilation of the contralateral lung was performed under general anesthesia. The utility incision was a 3-cm incision at the 4th intercostal space along the anterior axillary line. After the careful dissection of the right main bronchus, the right upper bronchus and the right bronchus intermedius, the tumor at the opening of the right bronchus intermedius was resected (see Supplementary Video 1). The stumps were trimmed and sent for intraoperative frozen section, which showed no residual cancer at any bronchial stumps. Then, the anastomosis procedure was initiated. First, the lateral walls of the right upper bronchus and the right bronchus intermedius were sutured continuously to join up with a 3-0 Prolene (one thread with two needles). Second, two another 3-0 Prolene (both sutured with one stitch in the bronchi nearby) were tied with the two ends of the first 3-0 Prolene into a knot outside of the bronchi, respectively. Subsequently, a circumferential and continuous suture of the right main bronchus with the right upper bronchus and the right bronchus intermedius was performed via these two 3-0 Prolene and a knot was tied outside of the bronchi. Last, the anterior wall of secondary carina was reinforced with interrupted sutures using a 3-0 Monocryl (Y316, one thread with one needle) and the anterior mediastinal fatty tissue was freed to cover the anastomosis with another 3-0 Monocryl. There were no air leakage from the anastomotic area after puffing of the lungs with the addition of warm saline to the chest cavity. The operation lasted 200 mins totally. Postoperative pathology showed solid adenoid arrangement of tumor cells and focal invasion of bronchial cartilage, consistent with a well-differentiated mucinous epidermoid carcinoma. No lymph node metastasis was observed. The patient recovered well after surgery and was discharged on postoperative day 3. He receive anti-tuberculosis treatment for 9 months postoperatively and did not complain of any specific discomfort at the 9-month postoperative follow-up, with no local recurrence observed.

parenchymal sparing procedure, secondary carinal reconstruction, tracheobronchial mucoepidermoid carcinoma, uniportal, video-assisted thoracoscopic surgery

Uniportal VATS secondary carinal resection and reconstruction for tracheobronchial mucoepidermoid carcinoma. Contrast-enhanced CT of the chest showed a 1.5 x 1.2 cm endobronchial nodule of the right bronchus intermedius (see arrow,.

PMC8803630_01

Male

A 42-year-old asymptomatic male patient received thoracic CT scans on a routine health examination at a local hospital in February 2021 with an incidental finding of a 1.5 x 1.2 cm endobronchial nodule of the right bronchus intermedius and a 5.1 x 3.1 cm patchy lesion centrally located at the left upper lobe (Figure 1). The patient underwent fiberoptic bronchoscopy, which showed a neoplasm with an unsmooth surface at the opening of the right bronchus intermedius with normal distant bronchial tree. Transbronchial biopsy of the neoplasm was suggestive of low-grade mucinous epidermoid carcinoma. The patient further underwent PET/CT scans, which revealed weak FDG uptake in the endobronchial nodule and high uptake in the left upper lobe lesion. To discern the nature of the left upper lobe lesion, the patient underwent a CT-guided percutaneous lung biopsy. Pathological examination revealed a chronic granulomatous inflammatory disease, suggesting the diagnosis of tuberculosis. Due to the specific location of the endobronchial tumor, the patient was recommended by the treating physician at the local hospital to receive bronchoscopic cryoablation over surgical resection. Because of concerns that the tumor might recur with bronchoscopic therapy, the patient was referred to our department for seeking surgical resection. The results of preoperative routine blood biochemistry were normal. Pulmonary function test showed mild obstructive ventilation dysfunction, with FEV1 being 2.38L and FEV1%PRED being 76%. Considering the patient's 30-year history of bronchial asthma (manifested as wheezing sounds in both lungs) and the fact that lung parenchymal resection might lead to decreased quality of life, the patient underwent a single-port thoracoscopic tumor resection, reconstruction of the secondary carina and systemic lymph node dissection (including stations 2, 4, 7, 9, 10, 11, 12) in March 2021 (Figure 2). The patient was placed in a left lateral decubitus position. After the intubation of the double-lumen tube, single lung ventilation of the contralateral lung was performed under general anesthesia. The utility incision was a 3-cm incision at the 4th intercostal space along the anterior axillary line. After the careful dissection of the right main bronchus, the right upper bronchus and the right bronchus intermedius, the tumor at the opening of the right bronchus intermedius was resected (see Supplementary Video 1). The stumps were trimmed and sent for intraoperative frozen section, which showed no residual cancer at any bronchial stumps. Then, the anastomosis procedure was initiated. First, the lateral walls of the right upper bronchus and the right bronchus intermedius were sutured continuously to join up with a 3-0 Prolene (one thread with two needles). Second, two another 3-0 Prolene (both sutured with one stitch in the bronchi nearby) were tied with the two ends of the first 3-0 Prolene into a knot outside of the bronchi, respectively. Subsequently, a circumferential and continuous suture of the right main bronchus with the right upper bronchus and the right bronchus intermedius was performed via these two 3-0 Prolene and a knot was tied outside of the bronchi. Last, the anterior wall of secondary carina was reinforced with interrupted sutures using a 3-0 Monocryl (Y316, one thread with one needle) and the anterior mediastinal fatty tissue was freed to cover the anastomosis with another 3-0 Monocryl. There were no air leakage from the anastomotic area after puffing of the lungs with the addition of warm saline to the chest cavity. The operation lasted 200 mins totally. Postoperative pathology showed solid adenoid arrangement of tumor cells and focal invasion of bronchial cartilage, consistent with a well-differentiated mucinous epidermoid carcinoma. No lymph node metastasis was observed. The patient recovered well after surgery and was discharged on postoperative day 3. He receive anti-tuberculosis treatment for 9 months postoperatively and did not complain of any specific discomfort at the 9-month postoperative follow-up, with no local recurrence observed.

parenchymal sparing procedure, secondary carinal reconstruction, tracheobronchial mucoepidermoid carcinoma, uniportal, video-assisted thoracoscopic surgery

Uniportal VATS secondary carinal resection and reconstruction for tracheobronchial mucoepidermoid carcinoma. (E) Contrast-enhanced CT of the chest at the 6-month postoperative follow-up showed resolution of tuberculosis lesion in the left upper lobe.

PMC8803630_01

Male

A 42-year-old asymptomatic male patient received thoracic CT scans on a routine health examination at a local hospital in February 2021 with an incidental finding of a 1.5 x 1.2 cm endobronchial nodule of the right bronchus intermedius and a 5.1 x 3.1 cm patchy lesion centrally located at the left upper lobe (Figure 1). The patient underwent fiberoptic bronchoscopy, which showed a neoplasm with an unsmooth surface at the opening of the right bronchus intermedius with normal distant bronchial tree. Transbronchial biopsy of the neoplasm was suggestive of low-grade mucinous epidermoid carcinoma. The patient further underwent PET/CT scans, which revealed weak FDG uptake in the endobronchial nodule and high uptake in the left upper lobe lesion. To discern the nature of the left upper lobe lesion, the patient underwent a CT-guided percutaneous lung biopsy. Pathological examination revealed a chronic granulomatous inflammatory disease, suggesting the diagnosis of tuberculosis. Due to the specific location of the endobronchial tumor, the patient was recommended by the treating physician at the local hospital to receive bronchoscopic cryoablation over surgical resection. Because of concerns that the tumor might recur with bronchoscopic therapy, the patient was referred to our department for seeking surgical resection. The results of preoperative routine blood biochemistry were normal. Pulmonary function test showed mild obstructive ventilation dysfunction, with FEV1 being 2.38L and FEV1%PRED being 76%. Considering the patient's 30-year history of bronchial asthma (manifested as wheezing sounds in both lungs) and the fact that lung parenchymal resection might lead to decreased quality of life, the patient underwent a single-port thoracoscopic tumor resection, reconstruction of the secondary carina and systemic lymph node dissection (including stations 2, 4, 7, 9, 10, 11, 12) in March 2021 (Figure 2). The patient was placed in a left lateral decubitus position. After the intubation of the double-lumen tube, single lung ventilation of the contralateral lung was performed under general anesthesia. The utility incision was a 3-cm incision at the 4th intercostal space along the anterior axillary line. After the careful dissection of the right main bronchus, the right upper bronchus and the right bronchus intermedius, the tumor at the opening of the right bronchus intermedius was resected (see Supplementary Video 1). The stumps were trimmed and sent for intraoperative frozen section, which showed no residual cancer at any bronchial stumps. Then, the anastomosis procedure was initiated. First, the lateral walls of the right upper bronchus and the right bronchus intermedius were sutured continuously to join up with a 3-0 Prolene (one thread with two needles). Second, two another 3-0 Prolene (both sutured with one stitch in the bronchi nearby) were tied with the two ends of the first 3-0 Prolene into a knot outside of the bronchi, respectively. Subsequently, a circumferential and continuous suture of the right main bronchus with the right upper bronchus and the right bronchus intermedius was performed via these two 3-0 Prolene and a knot was tied outside of the bronchi. Last, the anterior wall of secondary carina was reinforced with interrupted sutures using a 3-0 Monocryl (Y316, one thread with one needle) and the anterior mediastinal fatty tissue was freed to cover the anastomosis with another 3-0 Monocryl. There were no air leakage from the anastomotic area after puffing of the lungs with the addition of warm saline to the chest cavity. The operation lasted 200 mins totally. Postoperative pathology showed solid adenoid arrangement of tumor cells and focal invasion of bronchial cartilage, consistent with a well-differentiated mucinous epidermoid carcinoma. No lymph node metastasis was observed. The patient recovered well after surgery and was discharged on postoperative day 3. He receive anti-tuberculosis treatment for 9 months postoperatively and did not complain of any specific discomfort at the 9-month postoperative follow-up, with no local recurrence observed.

parenchymal sparing procedure, secondary carinal reconstruction, tracheobronchial mucoepidermoid carcinoma, uniportal, video-assisted thoracoscopic surgery

Uniportal VATS secondary carinal resection and reconstruction for tracheobronchial mucoepidermoid carcinoma. (F) CT bronchography at the 6-month postoperative follow-up showed no bronchial stenosis of the right lung.

PMC7560630_01

Male

A 15-year-old male presented to the Pediatric Cardiology Department in January 2019 with dyspnea at rest accompanied by chest pain. Medical interview revealed that the patient was suffering from mild abdominal pain, headache and asthenia in last few days. Medical and family history was unremarkable, he was diagnosed with allergic rhinitis and scoliosis. He has never been chronically treated. Physical examination revealed a young Caucasian who was in an obvious acute distress. Vital signs at presentation were blood pressure 110/82 mmHg, heart rate 100/min, respiratory rate 24/min, temperature 36.6 C, oxygen saturation 99% without oxygen support, height 179 cm, weight 52 kg. Pertinent objective findings were muffled heart sounds, distention of the jugular veins, ascites with hepatomegaly and right lower quadrant tenderness on palpation with no guarding or rebound tenderness. Laboratory results showed white blood cells (WBC) 4,870/uL, hemoglobin 14 g/dL, hematocrit 44.7%, platelets 152.000/uL, glucose 124 mg/dl, international normalized ratio 1.3; C-reactive protein <5 mg/l, Troponin T 8.8 ng/l. Electrocardiogram revealed sinus tachycardia, small amplitude of QRS complex, ST elevation and depression of PQ segment in many canals. Echocardiography was performed, 40 mm pericardial fluid was depicted. Patient was diagnosed with heart tamponade. An emergency pericardiocentesis was performed, what is more, drainage tubes were inserted into the pericardial cavity. The samples of blood and purulent fluid were collected for microbiological tests. No germs developed in the bacterial examination of the pericardial fluid. Broad-spectered antibiotics were applied with colchicine, non-steroidal anti-inflammatory drugs and corticosteroids. Contrast-enhanced computed tomogram revealed pericardiac and bilateral pleural effusions, moreover an appendix with appendicolith (Fig. 1). After evaluation by a general surgeon, the appendectomy was postponed until the etiology of pericarditis would be clarified. Although, the patient was consulted by many specialists, none of them was able to disclose the ground of the patient's disease. Many laboratory tests were conducted. Not only contagious diseases were excluded, but also lymphoma, cystic fibrosis, connective tissue disorders, immune deficiency, hypothyroidism, coeliac disease. The patient's plasma level of antibodies was negative for numerous pathogens (aerobic and anaerobic bacteria, Mycoplasma tuberculosis, Toxoplasma gondii, Ebstein-Barr virus, Cytomegalovirus, hepatic viruses, Chlamydia trachomatis, yersinia enterocolica, Candida etc). Moreover, heart magnetic resonance imaging was performed and, based on the results, the patient was diagnosed with restrictive pericarditis (Fig. 1). After one month of hospitalization the inflammatory parameters increased (WBC 22.210/ul, C-reactive protein 14.1 mg/l, procalcitonin 0.18 ng/mL) additionally the hemodynamic parameters worsened. The patient subsequently underwent partial pericardectomy through anterolateral left thoracotomy performed by the an experienced professor of pediatric cardiac surgery. The clinical postoperative evolution was favorable, with normal echocardiographic aspect. The drainage tubes were extirpated. From the patient's point of view that period of hospitalization was the most stressful. He demanded some psychologists' help in aim to return to normal activity. 5 days after the patient had been discharged, he was readmitted to the Emergency Department, because of acute abdominal pain. Physical examination revealed right lower quadrant tenderness on palpation without vomiting, nausea or fever. The abdominal ultrasonography revealed prominent appendix with an appendicolith up to 25 mm consistent with probable acute appendicitis. In addition, echocardiography was performed and reported recurrence of pericardial effusion. After evaluation by a surgeon, the patient subsequently underwent laparoscopic appendectomy. The clinical postoperative evolution was favorable moreover the effusive fluid absorbed completely. The patient was discharged 4 days after the operation with signs of normal wound healing and continues to do well 1 year postsurgery. He does his regular check-ups in a medical clinic.

appendicitis, case report, heart tamponade, pericardectomy, pericardial effusion, pericarditis

PMC6667483_01

Male

A 48-year-old Northern African man affected by Crohn's disease, protein-energy malnutrition and lymphopenia presented with fever, cough and respiratory failure in March 2018. He had received therapy with infliximab in December 2017. He received the last dose one month before the development of symptoms. His baseline Mantoux tested negative. At admission, a high resolution computed tomography (HRCT) showed bilateral pleural effusion, large parenchymal consolidation on the upper-right lobe, bilateral nodular consolidations, multiple mediastinic lymphadenopathies. We performed bronchoalveolar lavage (BAL) that showed positivity for M. tuberculosis PCR (XPert MTB/RIF ). QuantiFERON -TB Gold Plus test resulted indeterminate. We than started antitubercular therapy with rifampicin 600 mg, isoniazid 300 mg, ethambutol 1200 mg and pyrazinamide 1500 mg plus pyridoxine 300 mg 3 times per week. He was also on treatment with dexamethasone 8 mg twice daily and on total parenteral nutrition due to the poor clinical condition. At admission he had WBC 2,300/uL, lymphocytes 440/uL, CD4 + 250/uL, hemoglobin 9.9 g/dL, C-reactive protein (CRP) 2.68 mg/dL (upper normal value 0.5). He reported penicillin allergy. The ECG on admission showed sinus rhythm with a QTc interval of 390 ms. Three days later, he developed atrial fibrillation that was successfully cardioverted with amiodarone. He remained apyretic for the following 7 days and the steroid dosage was slowly tapered to 4 mg of dexamethasone per day. Over the next two days he developed fever with chills and progressive worsening of dyspnea. All the blood cultures resulted negative. Five days later, he developed respiratory failure, and another HRCT showed worsening of the pleural effusion and of the parenchymal lesions, with the appearance of new areas of consolidation. CRP was 12.7 mg/dL. Empiric therapy with linezolid and meropenem was added. In addition, we performed a second bronchoscopy and a thoracentesis. The Gene XPert MTB/RIF test resulted negative both on BAL fluid (BALF) and on pleural fluid. BALF culture resulted positive for extended-spectrum beta-lactamase producer (ESBL) Klebsiella pneumonia and methicillin-resistant Staphylococcus aureus (MRSA). Moreover, galactomannan determination on BALF resulted strongly positive and, therefore, liposomal amphotericin B (L-AmB) therapy was started at 3 mg/kg/day. Despite a slight improvement during the first days of antimicrobial therapy, ten days after the BAL he developed again respiratory failure (PaO2/FiO2 ratio: 129). We performed another HRCT that showed worsening of the bilateral pleural effusion that required left chest drainage tube placement. Oxygen therapy and dexamethasone (8 mg I.V. BID) were reintroduced. After that, he became apyretic and CRP levels declined (from 13.9 mg/dL to 1.4 mg/dL during the next ten days). Antibiotics were interrupted after 21 days. In the meantime, steroidal therapy was progressively tapered. He stopped ethambutol and pyrazinamide after 8 weeks of treatment and he continued with TB maintenance therapy; chest drainage tube was removed after 27 days. During L-AmB therapy hypokalemia occurred, with daily need for potassium supplementation. After 8 weeks of antifungal therapy, L-AmB was interrupted, rifampin was substituted with moxifloxacin 400 mg per day and isavuconazole was started at 200 mg every 8 h for the first 48 h, followed by 200 mg daily, along with daily ECG monitoring. No significant alterations in sinus rhythm and QTc interval were seen during therapy with isavuconazole compared to baseline ECG on admission. After the withdrawal of L-AmB, potassium levels returned normal. He was discharged after 83 days of hospitalization in good clinical conditions on maintenance therapy with isavuconazole 200 mg daily, moxifloxacin 400 mg daily and isoniazid 300 mg daily. After discharge, no alteration in sinus rhythm and QTc interval was noticed at weekly follow-up. On follow-up chest HRCTs performed one and three months later, pulmonary lesions and pleural effusion were significantly reduced. He received a total of 24 weeks of antitubercular and antifungal therapy.

infliximab, invasive pulmonary aspergillosis, isavuconazole, tuberculosis

PMC4316402_01

Male

The following information is from an extensive pre-session questionnaire Simon was asked to complete before his first meeting with me: Simon is 43 years old man, married with two adult children; he is a middle-level manager at a supermarket chain, normally a competent and well-organized man. Four months ago he was in a car accident: he was driving home from work in the late afternoon at 75 mph on an Interstate highway when a tractor trailer went out of control just ahead of him, colliding with several other cars. He was convinced that he was going to die; but after sideswiping a couple of cars he ended up in the breakdown lane. Apart from a few minor bruises he reported being unhurt; his air-bag went off and he was wearing his seat belt. He was, however, taken to a local emergency room for an examination. On arriving home that evening, he felt very shaken and teary, but pushed away the impulse to cry and told himself that he should "pull himself together." The next morning he woke up feeling depressed and anxious, and was unable to organize himself to rent a car and get to work. He became angry with himself. The following day he managed to rent a car and as he began driving to work, he had a panic attack before getting onto the Interstate. He was able to get to work by the back roads, but found himself unable to concentrate at work. Over the following 4 months he continued to feel "not himself"; he alternated periods of depression and anxiety with bouts of extreme irritability and outbursts of anger, all of which had a negative impact on his work and his marriage. He describes having chronically cold hands and feet, a pounding heart, a knot in his stomach and a fuzzy feeling in his head. Also he notes that whenever he is outside, he has a tendency to be hyper-focused on passing traffic to the point of being distracted from what he is doing. After 2 months, at his wife's urging, he went to see a therapist, but got extremely angry at what he described as the therapist's implication that it was "all in his head." He says that he knows he should not be reacting this way, that it is not rational, that after all "nothing really happened to him," but feels completely powerless to change how he feels. Through a friend he heard about Somatic Experiencing, and on being assured it was "not talk therapy," he decided to give it a try. When discussing the autonomic nervous system (ANS), pioneering researcher and Nobel prize winner in physiology and medicine, Hess as well as early researcher Gellhorn used the terms "ergotropic" (energy seeking) and "trophotropic" (nutrition seeking) to point out that the two principal branches of the ANS cannot be isolated from the somatic and central nervous systems and the neuroendocrine system. The ergotropic system includes activation of the sympathetic nervous system as well as the motor and premotor system (increased muscle tension and preparedness to act), the endocrine system (increased secretions of a number of stress hormones), and the central nervous system (increased sensory alertness), in a coordinated preparation for strong energy expenditure ("fight or flight"). In contrast, the trophotropic system involves these same systems in a preparation for rest, feeding and recuperation. This recognition of an integrated response of the whole nervous system, especially the integration of the autonomic and somatic systems, is central to our thesis. Unlike conventional psychotherapy which focuses largely on verbal cognitive processes, the focus of SE is on the functioning of the deeper, regulatory, levels of the nervous system, in particular the autonomic nervous system (ANS); the emotional motor system (EMS) (Holstege et al.,); the reticular arousal systems (RAS) (Krout et al.,; Strominger et al.,); and the limbic system (LS) (Heimer and Van Hoesen,); these four subcortical structures form what we term the core response network; see Figure 1. There is extensive evidence that these four networks interact strongly (Gellhorn,; Weinberg and Hunt,; Hamm et al.,; Critchley,; Thompson,; Coombes et al.,; Hajcak et al.,; Sze et al.,; Kim et al.,; Herbert and Pollatos,; Price et al.,; Norman et al.,). The ANS can intensify or calm the activity of the viscera, alter blood circulation, trigger hormonal and endocrine activity, change muscle tone, increase or decrease cognitive arousal, and contribute to emotional experience (Norman et al.,). The LS, including amygdala, hippocampus, and septal regions, is central to fear- and pleasure-based experience and to the recall of emotional significance (Heimer and Van Hoesen,). This network has strong bi-directional links to the ANS (Uylings et al.,), and the RAS (Strominger et al.,), and triggers emotion-specific movement and posture via the EMS (De Gelder,). The RAS involves multiple networks which trigger arousal through several different pathways. It controls alertness and orientation in different contexts, and interfaces strongly with LS, ANS and EMS (Krout et al.,; Berntson and Cacioppo,). The EMS involves multiple subcortical motor centers [striatum, red nucleus, periaqueductal gray (PAG)] which are involved in emotion-specific movements and postures which can occur outside voluntary cortical control. It is primarily extra-pyramidal. It is strongly influenced by ANS, LS and RAS, and provides important kinesthetic and proprioceptive feedback to them (Holstege et al.,; Holstege,). The CRN responds very quickly to arousing or threatening stimuli, with little input from higher cortical evaluative processes (Porges' "neuroception" Porges,). This view is very similar to Panksepp's concept of the core self (Panksepp,): a network of largely subcortical structures, centered on the PAG, which are responsible for primal affective experiences and their concomitant motor response organization. We also note the similarity to Damasio's concept of the "proto-self" (Damasio,) and Schore's "implicit self" (Schore,). SE views this core system as the primary target for the treatment of stress and trauma. We suggest that SE works by restoring optimal function to this network by way of the interoceptive (insula/anterior cingulate) and premotor cortices (Critchley et al.,; Craig,). Although words are used in the process of SE therapy, they are used to point to and elicit non-verbal experiences of internal bodily sensation (interoception), sense of position and orientation (proprioception), sensations of movement (kinesthesis), and spatial sense. These are mediated respectively by the insular and anterior cingulate gyrus (Critchley et al.,), the premotor cortex (Desmurget and Sirigu,), the parietal cortex (Bartolomeo,; Briscoe,), as well as by the orbitofrontal cortex (Roy et al.,). All these areas have very rich and direct communication with the subcortical networks mentioned above, and SE views them as the basis for voluntary intervention on the dysregulated subcortical networks; see Figure 2. Since its first use in physiology, the word "stress" has been subject to multiple definitions and interpretations and the word is often used imprecisely. Hans Selye acknowledged his poor command of English as responsible for a use at odds with that of physics, where "stress" refers to the force acting on an object and "strain" to the resulting distortion; Selye used the word to refer to the response of the organism, and the word "stressor" came to be used for the impacting situation (Rosch,). Stressors may broadly be divided into biological, where the stressor has an unambiguous physical and physiological effect on the organism; and psycho-social, where the effect of the stressor is determined by the interpretation the organism makes of the external situation (Everly and Lating,). Using the same word "stress" to describe the organism's response to these very different categories of events is justified by Walter Cannon's concept of the "stress response" (Cannon,), a supposedly unitary response of the organism to any stressor regardless of its nature. This early approach led to several difficulties, which have been pointed out by many authors (Levine,; Lupien et al.,; Berntson and Cacioppo,; McEwen and Wingfield,; McVicar,): first, although certain psycho-social situations may be referred to as "stressors," the event can only be so defined in relation to the response of a specific organism, rendering the definition meaningless (it no longer makes sense to assert that a certain situation "is a stressor" in any absolute or generalized sense). Second, the division into physical and psycho-social stressors neglects the fact that the general state of the organism influences its response to every kind of event, not merely psycho-social events (Vosselman et al.,). Some individuals have conclusively demonstrated voluntary (Kox,) and teachable (Kox et al.,) control over functions usually believed to be purely "physiological," such as sympathetic thermogenesis and inflammatory immune responses. The division into physiological and psycho-social is a legacy of the now outmoded Cartesian mind-body separation. Third, current research demonstrates that even the response of the autonomic nervous system to simple physical stressors (pain, temperature, thirst...) is extremely nuanced and individually variable (Saper,), and cannot be summed up as unitary "stress response." In an effort to resolve these issues, attempts were made to define "good stress" and "bad stress" (Selye,), adding awkward and unwieldy concepts to the mix (Levine,). Although current views of stress emphasize the role of cognitive appraisal of the stress-inducing situation, recent writers (Porges,; Cohen,) have pointed out that emotionally charged and sudden situations are responded to very rapidly at a sub-cortical level, involving the amygdalar complex and the hippocampus, and not initially engaging the complex associative cortex with its capacity for reasoned decision. In fact much psychological research (Bargh and Chartrand,; Chaiken and Trope,; Cohen,) demonstrates that even apparently rational thought processes are strongly influenced by emotional states. Conscious thought and unconscious emotional processes influence each other reciprocally, it is not a one-way street. Emotional processes equally influence the physical state at the pre-motor level; reciprocally, the state of the body frames the emotional response. Since the 1920s, ideas about the functioning of the ANS have evolved from a simple homeostatic linear reciprocal system (Cannon,; Selye,), through concepts of homeodynamics and allostasis (McEwen and Wingfield,; Berntson and Cacioppo,) to the current framework of an allodynamic system, capable of very complex self-regulatory behavior involving feed-back and feed-forward loops and integration with rostral brain centers (Berntson and Cacioppo,). Predating many of these developments, Levine, in his 1977 Ph.D. thesis (Levine,), suggests that the ANS (and related subcortical structures) form a complex dynamical system (CDS) (Abraham et al.,). He acknowledges Gellhorn's seminal discovery that, although under normal circumstances the sympathetic and parasympathetic (or ergotropic and trophotropic) systems maintain a reciprocal relationship and return to baseline after disturbance (see Figure 3) following even moderately intense disturbance they can become "tuned" (Gellhorn,), chronically biased in one direction, and can fail to return to baseline; see Figure 4. In Gellhorn's experiments, rats subjected to stressful stimuli below a certain threshold demonstrated temporary elevation in sympathetic activation and diminished parasympathetic tone, followed by a spontaneous return to baseline levels; however if the stimulus exceeded a certain level of intensity or duration, the ANS did not return to baseline and the rats remained in a chronic state of elevated sympathetic and depressed parasympathetic activity (Gellhorn,). Under extreme and inescapable stress, the ANS may start to respond in paradoxical ways, and even manifest simultaneous extreme activation of both sympathetic and parasympathetic branches (Gellhorn,). Working with anesthetized cats, Gellhorn clamped the trachea, inducing suffocation. There was an initial extreme rise in sympathetic arousal, followed by an even greater co-activation of the parasympathetic system. This phenomenon has been verified by other researchers (Paton et al.,), and is believed to underlie the well-recognized phenomenon of "tonic immobility" (Nijenhuis et al.,; Marx et al.,), which is known to occur in both animals and humans under conditions of extreme stress. Gellhorn's animal experiments clearly demonstrate this unexpected behavior of the ANS (Gellhorn,), and Levine clarifies the clinical implications of this phenomenon (Levine,). Levine demonstrates the use of the mathematics of catastrophe theory (Thom,) to explicate and predict the behavior of the ANS under extreme conditions, and relates this model to clinical approaches to treating PTSD and related conditions. "Stress," in the sense of an undesirable state, is defined by Levine as the inability of the complex dynamical system of the ANS to recover to normal functionality (Levine,). This is distinct from the current concept of allostatic load in describing stress. Allostatic load refers to the complex neurological and endocrine changes ("wear and tear") that result from having to make continual adaptations to environmental challenges (McEwen and Wingfield,), but leave the exact nature of the stress response itself still undefined. The "wear and tear" is the effect of the stressed condition, and it may lead to circular patterns of perpetuated disruption of normal functioning (Juster et al.,). However Levine's approach suggests that to be "stuck" in a "stressed-out" or traumatized state is for the CRN to be stuck in a dysfunctional dynamic mode which is, in principle, fully reversible, and is not determined by the external situation (Levine,). This suggests that (again, in principle) someone whose CRN is fully functional will not accumulate allostatic load in response to challenging environmental circumstances and will thus manifest extraordinary resilience. As with "stress," the term "trauma" is used in different ways in different contexts. In SE, a traumatic event is defined as an event that causes a long-term dysregulation in the autonomic and core extrapyramidal nervous system (Levine,). The implication of this is that trauma is in the nervous system and body, and not in the event; an event that is very traumatic to one person may not be traumatic to another, as people differ very widely in their ability to handle various kinds of challenging situations due to different genetic makeup, early environmental challenges, and specific trauma and attachment histories. This view implies a continuum of stress conditions; a chronic but mild elevation of sympathetic response at one end, and chronic extreme activation of both sympathetic and parasympathetic (or more exactly, ergotropic and trophotropic) systems at the other. At precisely what point the stress should be regarded as "traumatic" is less important than the understanding of the nature of the dysregulation of the nervous system; however, the phenomenon (demonstrated in cats by Gellhorn,) of extreme co-activation of sympathetic and parasympathetic systems under life-threatening conditions offers a compelling model for the freeze, collapse, and dissociation often observed in PTSD (Nijenhuis et al.,; Halvorsen,); see Figure 5. The medical term in common use, post-traumatic stress disorder (PTSD), implies pathology; however SE, (which was developed several years before the definition of PTSD in the DSM III) views the trauma response as part of a natural, non-pathological process that has been interrupted, and therefore prefers the term post-traumatic stress syndrome (PTSS) (Levine,). The criteria laid out in DSM IV and V for the diagnosis of PTSD have been challenged by several authors (Shin and Handwerger,; Bovin and Marx,; Scaglione and Lockwood,) and impose limitations not relevant to the theory of SE; most importantly, the DSM V requires exposure to a situation which is threatening to life or body, and limits the range of peri-traumatic emotion acceptable for this diagnosis. Recent authors have pointed to the diversity of various kinds of trauma, suggesting that a unitary diagnosis of PTSD should be replaced by a spectrum of trauma-related disorders (Bovin and Marx,). The theories of SE might provide a framework for such future classification.

autonomic nervous system, core response network, interoception, meditation, premotor system, somatic experiencing, stress, trauma

PMC4501538_01

Female

A 15-year-old non-smoking Japanese female was admitted to our hospital because of the symptoms of productive cough and dyspnea on exertion, which appeared 6 months before admission. She had been diagnosed with alopecia universalis as a 1-year-old, and was hospitalized for 1-2 weeks for recurrent lower respiratory tract infections at the ages of 1, 4, and 10 years old. At 12 years old, she was treated for chronic sinusitis by antibiotics and some mucolytic agents. The physical examination on admission revealed a body temperature of 36.6 C, blood pressure of 99/56 mmHg, and regular pulse of 87 beats/min. The skin was normal apart from the absence of hair, and lung auscultation revealed coarse crackles in the right chest. The results of the laboratory data, an arterial blood gas analysis on room air and a pulmonary function test on admission showed a white blood cell count of 8800/muL; hemoglobin, 9.7 g/dL; cold agglutinin x 64; pH, 7.43; PaCO2, 42 Torr; PaO2, 96 Torr; vital capacity (VC), 2.18 L; %vital capacity (%VC), 75.2%; forced expiratory volume in one second (FEV1.0), 1.51 L; and forced expiratory volume % in one second (FEV1.0%), 67.9%. Reversibility of airway obstruction was not noted in the patient. A chest X-ray revealed cystic changes with an air-fluid level localized in the right lower lung field (Fig. 1A). The chest CT scan on admission showed complex cystic lesions with an air-fluid level in the right lower lobe, and diffuse centrilobular nodules in the whole lobe of the lung (Fig. 2A). On flexible bronchoscopy examination, sputum and bronchoalveolar lavage fluid (BALF) cultures revealed methicillin-sensitive Staphylococcus aureus (S. aureus) which was sensitive to clarithromycin (the minimal inhibitory concentration is < 2.0 mug/mL). The differential cell counts of BALF obtained from the medial segmental bronchus and the CD 4/8 ratio were as follows: total cell count, 3.77 x 105/mL; alveolar macrophages, 2.46 x 105 (65.3%); neutrophils, 0.58 x 105 (15.4%); lymphocytes 0.73 x 105 (19.3%); and CD 4/8 ratio, 1.8. The pathologic examination of transbronchial lung biopsy (TBLB) specimens obtained from the lateral segmental bronchus demonstrated noncaseating granuloma in the alveolar spaces and neutrophil infiltration (Fig. 1B). No acid-fast bacilli were detected by Ziehl-Neelsen staining of TBLB specimens and culture of BALF. An electron microscopic examination of the biopsy specimens obtained from the bronchial mucosa showed deficiency of the inner dynein arm in the cilia (Fig. 1C). Left nasal polyps were detected by CT scan. Based on these findings, we diagnosed the patient with PCD. Treatment with clarithromycin (400 mg/day) was commenced 2 weeks after admission and was continued for 6 months. As a result of the treatment, there was improvement in the patient's symptoms of productive cough and dyspnea on exertion, and in pulmonary function (VC, 2.59 L; %VC, 87.2%; FEV1.0, 2.15 L; and FEV1.0%, 80.1%). In addition, the 6-month chest CT scan revealed that the diffuse nodular shadows and the fluid in cystic lesions were diminished (Fig. 2B), whereas CT angiography demonstrated an aberrant systemic artery arising from the celiac trunk and supplying the cystic mass lesions with systemic blood flow (Fig. 2C). The cystic lesions were located in the normal lobe and lacked their own pleural covering. These results indicated that this patient, diagnosed with PCD, was also affected by ILS. A right lower lobectomy and closure of the anomalous systemic artery was performed by video-assisted thoracic surgery. The aberrant artery arising from the celiac trunk, and penetrating the right lower lobe, was detected in the right pulmonary ligament. After isolation and cutting of the aberrant artery, a right lower lobectomy was performed. The diagnosis of ILS with PCD was based on the macroscopic and microscopic appearance of specimens obtained from the patient's resected lung that showed multiple cystic lesions without pleural covering and an aberrant artery penetrating the right lower lobe (Fig. 3A,B). At present, 3 months after the surgery, the patient is free from respiratory symptoms such as dyspnea and cough.

alopecia, bronchopulmonary sequestration, cilia, macrolide

PMC6240939_01

Male

A 37-year-old man was admitted to hospital for several months of headache, hoarseness and dysphagia; a month of right-sided deafness and nasal bleeding; and a week of dysarthria. He had experienced sinusitis for 1 year before admission and had been treated with antibiotics. He was successfully treated with glucocorticoids (GC) for sudden right-sided hearing loss 9 months before admission. His body weight had decreased by 10 kg over the previous month. A week before admission, he developed a right steppage gait and numbness in the right L5 distribution. On admission, body temperature was 37.7 C and the rest of his vital signs were normal. Neurological examination showed a bilateral mixed hearing loss, a right curtain sign, weakness of the right trapezius, rightward tongue deviation, and paralysis of the right peroneal nerve. Initial blood tests showed a slightly elevated erythrocyte sedimentation rate (29 mm/h) and C-reactive protein (CRP) levels (1.06 mg/dL), and white blood cell count was slightly increased (8.9 x 109/L). His renal and liver function was normal (eGFR 118 ml/minute/1.73 m2) and the urine test was also normal (proteinuria, hematuria, urinary cast were negative). Anti-nuclear antibody, rheumatoid factor, angiotensin converting enzyme, myeloperoxidase-anti-neutrophil cytoplasmic antibody and soluble interleukin-2 receptor were normal, but proteinase 3-anti-neutrophil cytoplasmic antibody was increased (16.9 IU/mL). Cerebrospinal fluid was normal. A gadolinium-enhanced MRI scan of the head showed an enhancing infiltrative lesion in the right retropharynx encasing the carotid sheath (Fig. 1a), which seemed to cause the paralysis of IX, X, XI and XII nerves. Lumber spine MRI showed no evidence of lumbar disk herniation and nerve conduction study showed the paralysis of the right peroneal nerve. Chest computed tomography showed a 23 mm nodule in the left upper lobe. A CT-guided needle biopsy of the lung lesion and biopsy of the nasal mucosa were performed but showed only infiltration of inflammatory cells and no evidence of malignancy, vasculitis or granuloma. Culture of the lung specimen showed no evidence of infection and the interferon-gamma release assay for Mycobacterium tuberculosis was negative. We diagnosed GPA based on the American College of Rheumatology classification criteria for Wegener's granulomatosis (WG) and classification of WG by the Watts algorism. The patient was treated with prednisone (PSL) 1 mg/kg daily and IVCY 1000 mg every 3 weeks (Fig. 2). His fever, headache, and swallowing function improved rapidly, and peripheral neuropathy also improved, but hoarseness persisted. His Birmingham Vasculitis Activity Score 2008 version 3 score improved from 14 to 4, and he was discharged on IVCY and a tapering dose of PSL 45 mg/day. Three months later, while receiving oral GC and IVCY, he was readmitted for recurrence of headache and right-sided hearing loss. On MRI, the lesion encasing the right carotid sheath has not reduced (Fig. 1b). CRP levels remained slightly increased (1.04 mg/dL). He was treated with RTX 600 mg/week for 4 weeks and GC for re-induction therapy. His headache improved rapidly and hearing ability improved slowly. He was still on GC 1 year after RTX administration, with persistent hoarseness as his only symptom. To investigate immune status, we tracked peripheral T and B cell counts after RTX administration (Fig. 3). According to the peripheral T and B cell counts, whereas CY treatment with GC reduced the number of peripheral CD4+ and CD8+ T cells and B cells, RTX selectively reduced the number of peripheral B cells slowly over time. B cells tended to decrease 2 weeks after RTX treatment, with the reduction lasting 8 months.

b-lymphocytes, cranial neuropathies, drug resistance, granulomatosis with polyangiitis, rituximab

PMC9289150_01

Female

A 17-year-old (y/o) woman presented with progressive pain in her bilateral hips. The patient was a wheelchair user and was previously diagnosed with developmental dysplasia of the hip (DDH), seeking hip replacement surgery. Additionally, she had shallow acetabuli and flattened femoral heads (Figure 2). Radiology noticed spondyloepiphyseal dysplasia, suggestive of a genetic cause. The urinary sample was collected for the GAG level test, and a blood sample was collected for genotyping via whole-exome sequencing (WES). WES discovered compound heterozygous variants of GALNS (NM_000512.5). Together with clinical manifestations, radiographic and laboratory tests, MPS IVA was diagnosed. The patient received bilateral total hip arthroplasties (THAs) sequentially and regained mobility. The patient is now under supportive therapy elsewhere. Femoral heads were preserved after surgeries. In this case, we will review the epiphyseal parameters via micro-CT (muCT) and histology analysis in the MPS IVA femoral heads with the patient/guardian's consent. We studied a 17 y/o woman with a complaint of progressive walking pain in bilateral hips which gradually disabled her from any motion of lower extremities since the clinical manifestation debuted at her age of 8. At admittance, the patient was 145 cm tall with normal intelligence. Whole-body skeletal radiographs were obtained and found mild dysostosis multiplex (Figures 1, 2). Extremity deformities involve small irregular carpal bones, the ulnar deviation of the distal portion of the radius, mild genu valgum, ankle valgus, and 4th metatarsal shortening (Figures 1, 2). Cervical stenosis was excluded by MRI (Figures 2C,D). WES was performed due to the radiographic findings of systemic skeletal anomalies which suggested a genetic cause. Targeted capture high-throughput WES revealed two heterozygous variants, Exon 11 (NM_000512.5:c.1156C>T) and Exon 12 (NM_000512.5:c.1288C>G) of the GALNS gene, respectively, in this patient (Figure 3A). To confirm the phase of variants, WES was performed on the patient's parents and maternal grandmother who are free of the clinical phenotype. Parental testing confirmed that variants are in trans (Figure 3A). Sanger sequencing confirmed the occurrence of the compound heterozygous GALNS variants in the patient. The first morning void urine was collected from the patient, mother, and maternal grandmother. The urinary excretion of GAG (uGAG) was measured by the Dimethylmethylene Blue (DMMB) method and was normalized with urinary creatinine. The uGAG content was significantly higher in the patient's urine when normalized to urine creatinine, while the patient's family members exhibited normal levels (Figure 3B). Bilateral femoral heads were preserved after THAs for muCT analysis (Figures 4A-F). Percentage bone volume (BV/TV, P = 0.005) and trabecular thickness (Tb.Th, P < 0.001) were significantly lower in the non-weight-bearing area (NWBA) when compared to the weight-bearing area (WBA), while the trabecular number and separation were indistinguishable (Figures 4G-J). Sections of the articular surface from both WBA and NWBA of the preserved femoral heads were stained with hematoxylin & eosin (H&E), Safranin O/Fast green, or Masson to evaluate the morphological change of cartilage and subchondral bone in the femoral heads of MPS IVA patient. In the WBA of the femoral head, the articular cartilage was abnormally thick and divided into two layers (Figures 4K-M). The superficial layer exhibited fibrous change, while the chondrocytes in the middle zone appeared to be hypertrophic. The disorganized chondrocytes were accompanied by clusters formation. In the deeper layer, the subchondral bone was filled with metaplastic tissue composed of irregular fibrous-like structure with no mature chondrocytes seen. Both layers of WBA were strongly stained by Safranin-O, indicating GAG accumulation (Figures 4L,O). In the NWBA, the thickness of the articular chondrocytes appeared near-normal and chondrocytes cluster formation was found throughout the cartilage layer, while the subchondral bone in the NWBA was discontinuous (Figures 4N-P).

galns, morquio a syndrome, wes, compound heterozygous variants, femoral head, micro-ct

PMC6975012_01

Female

A 25-years-old female patient reported to our unit with pain in the right lower back tooth region for 1 month. Pain was sudden in onset, throbbing in nature, and continuous in character. There was no history of fever, swelling, or paraesthesia associated with the pain. On intraoral examination, pain seemed to be because of irreversible pulpitis with respect to 46. There was no sinus opening or tooth mobility present with respect to the same tooth. Electric pulp vitality test was negative. Medical history was noncontributory. IOPA was obtained and periapical radiolucency of 4 cm x 4 cm in size was seen with respect to the same tooth. Thereafter, an orthopantamogram (OPG) was recommended. The OPG revealed well-defined multilocular lesions [Figure 1], around 4 cm x 4 cm in size associated with respect to the right mandibular first and third molars and a well-defined unilocular radioluceny of about 12 cm x 5 cm size, extending from the mandibular canine to the third molar on the left side of the mandible. Another well-defined unilocular lesion of 10 cm x 10 cm in size was present with respect to the mandibular anterior region. There was no associated resorption of roots or pathological displacement of tooth. A cone-beam computed tomography image was acquired to establish the position of the inferior alveolar neurovascular bundle and to determine the status of bone [Figure 2]. The findings revealed no buccal and lingual expansion of bone. The inferior alveolar canal was severely displaced downward. On the basis of radiological and clinical findings, our differential diagnosis of the individual lesions consisted of SBC (traumatic bone cyst [TBC]), keratocystic odontogenic tumor (KCOT), and central giant-cell granuloma. Multiple KCOTs are seen in basal cell nevus syndrome. However, on clinical examination, no evidence was found for the same. We subsequently proceeded with the diagnosis of multiple TBC. Aspiration was negative and an incisional biopsy specimen was obtained from the periapical region of the right second molar under local anesthesia. No tissue lining was obtained, so a second incisional biopsy was performed on the opposite side with respect to the left mandibular molars. Very scant tissue was obtained, which was sent for histopathological examination, which showed a thin band of vascular fibrous connective tissue with scant liquid content without any evidence of epithelial lining. These features were suggestive of a TBC. Under general anesthesia, enucleation and curettage of the lesion were done, followed by bone graft placement. The lesion was approached by buccal crevicular incision. Full-thickness mucoperiosteal flap was raised. Surgical exploration revealed empty cavities with scarce amounts of tissue [Figures 3a and b]. A diagnosis of multiple SBC was surgically confirmed. Thorough curettage of the internal walls of the cavities was carried out and bleeding was induced. The cavity was packed with chips of Perioglas allogenic bone graft and closure was done using 3-0 vicryl sutures [Figure 4]. Histopathological examination of the excised specimen confirmed the diagnosis. Postoperatively, the patient had mild diffuse swelling for 3-4 days, which subsided eventually. The patient has been followed up for 9 months and is asymptomatic with no positive findings of pain, swelling, and paraesthesia. Follow-up panoramic radiograph showed satisfactory bone healing without any evidence of enlargement of lesion and recurrence.

mandible, multiple lesions, traumatic bone cyst

PMC6875249_01

Female

We report the case of a 44-year-old multiparous woman, without previous medical history, having a positive family history for breast cancer in her paternal aunt. She presented elsewhere for a one-month history of cough and abdominal distention, followed by episodes of fever at 39 C. Abdominal ultrasound was done, showing large ascites and a right ovarian mass. An abdominopelvic MRI was done showing a hyperintense, heterogeneous mass of the right ovary, measuring 20 x 17 mm, with restriction of diffusion, in favor of a malignant process. Tumor markers showed an elevated CA 125 level of 543 and normal CA 19-9 level of 13.2. Serum C-reactive protein (CRP) was 53. A diagnostic abdominal tap was done with cytology examination showing no malignant cells in the peritoneal fluid. A PET/CT scan was also done revealing peritoneal thickening and diffuse peritoneal fixation with hypermetabolism at the right ovary (SUV = 6.7) of 2 cm, as well as bilateral pleural fluid that was not hypermetabolic. The patient was admitted at our department for further investigations. New work-up with total body CT scan was done showing moderate enhanced ascites associated with mesenteric fat streaking with millimetric nodules suggestive of peritoneal carcinomatosis (Figure 1). Abdominal tap was repeated revealing only inflammatory reaction and serous fluid without evidence of malignant cells and with negative culture. An ultrasound-guided Tru-cut biopsy of the peritoneum was performed and revealed only inflammatory changes without malignant cells. Right pleural fluid was aspirated and sent for cytology and culture. Analysis showed no evidence of bacteria, infection, or malignant cells. Ultimately, a laparoscopic exploration was done with multiple biopsies taken from peritoneal nodules. Histological result showed a necrotizing, epithelioid, and gigantocellular granulomatous reaction, with Ziehl staining showing exceptional acido-alcohol resistant bacilli compatible with Koch bacilli (Figure 2). Subsequently, pulmonary sampling was done and samples were analyzed for Mycobacterium tuberculosis by polymerase chain reaction (PCR), with a negative result showing no sign of pulmonary infection. The patient was started on quadritherapy (rifampicin, isoniazid, ethambutol, and pyrazinamide) for 2 months with significant improvement in her clinical picture and weight gain of 4 kg and will continue for an additional 6 months of biotherapy with rifampicin and isoniazid. Follow-up imaging with abdominal MRI was done showing no ascites or masses in the abdomen.

PMC9427312_01

Unknown

A patient (man, 87 years old) visited our hospital with suffocation for 3 days on August 31, 2019. This patient had a history of hypertension treated with valsartan amlodipine compound, with blood pressure 150/70 mmHg and 60 heartbeats per minute in peacetime. In addition, this patient had a history of lower extremity varicose veins without any therapy. We did some laboratory tests and examinations for this patient immediately after admission to the hospital. Whole blood count analysis revealed a white blood cell count of 9.1 x 109/l (reference range 3.5-9.5 x 109/l), haemoglobin level of 134 g/l (reference range 115-150 g/l), hematocrit level of 37.3% (reference range 40-50%), and a platelet count of 154 x 109/l (reference range 125-350 x 109/l). The results of NT-proBNP and creatine were 10671 pg/ml (reference range 0-1800 pg/ml) and 125.7 mumol/l (reference range 20-98 mumol/l), respectively. The level of troponin was normal. Further examination showed that autoantibodies were normal. The blood pressure was 120/80 mmHg, with 80 heartbeats per minute when admitted to the hospital. No thrombus was found in the lower extremity venous ultrasound examination. And pulmonary artery computed tomography angiography (CTA) showed bilateral pulmonary embolism (Figures 1(a) and 1(b)). Electrocardiogram showed right bundle branch block, and echocardiogram showed larger right ventricular transverse diameter (43 mm), decreased left ventricular end diastolic anteroposterior diameter (43 mm), and higher pulmonary artery pressure (89 mmHg). According to the clinical manifestations, blood pressure (20% lower than basal blood pressure), CTA, NT-proBNP, and echocardiogram, this patient was diagnosed with submassive pulmonary embolism. Pulmonary angiography was done on August 31, 2019, and the result confirmed pulmonary embolism. In addition, percutaneous mechanical pulmonary thrombectomy was done using the Angiojet system. The injection pattern by urokinase (urokinase 25 wiu + sodium chloride injection 50 ml) was used. And the main left pulmonary artery was treated with the Angiojet system for 20 s, and the main right pulmonary artery was treated with the Angiojet system for 15 s (Figure 2). However, this treatment was finished because of bradyarrhythmia, and bradyarrhythmia disappeared after catheter withdrawal. And we placed the catheter in the inferior vena cava; intravascular thrombolysis by urokinase (100 wiu/day, 1 day) was done after being back in the ward. And low molecular weight heparin was used in hospitalization, and rivaroxaban was used after discharge. In addition, whole blood count analysis revealed a white blood cell count of 11.5 x 109/l (reference range 3.5-9.5 x 109/l), haemoglobin level of 140 g/l (reference range 115-150 g/l), hematocrit level of 41% (reference range 40-50%), and a platelet count of 161 x 109/l (reference range 125-350 x 109/l) on September 1. The results of NT-proBNP and creatine were 801 pg/ml (reference range 0-1800 pg/ml) and 110 mumol/l (reference range 20-98 mumol/l) on September 9, respectively. And echocardiogram showed decreased right ventricular transverse diameter (42 mm), normal left ventricular end diastolic anteroposterior diameter (52 mm), and higher pulmonary artery pressure (72 mmHg) on September 11.

PMC9427312_02

Female

Another patient (man, 67 years old) visited our hospital with chest tightness after activity for 1 day on September 10, 2019. This patient had a history of left lower limb trauma 2 months ago without history of hypertension, diabetes mellitus, and smoking. We did some laboratory tests and examinations for this patient immediately after admission to the hospital. Whole blood count analysis revealed a white blood cell count of 7.0 x 109/l (reference range 3.5-9.5 x 109/l), haemoglobin level of 138 g/l (reference range 115-150 g/l), hematocrit level of 39.1% (reference range 40-50%), and a platelet count of 103 x 109/l (reference range 125-350 x 109/l). The results of NT-proBNP and creatine were 5305 pg/ml (reference range 0-1800 pg/ml) and 76.1 mumol/l (reference range 20-98 mumol/l), respectively. The level of troponin was normal. Further examination showed that autoantibodies were normal. The blood pressure was 110/70 mmHg, with 107 heartbeats per minute when admitted to the hospital. An old thrombus was found in the left lower extremity venous ultrasound examination. And pulmonary artery computed tomography angiography (CTA) showed bilateral pulmonary embolism (Figures 3(a) and 3(b)). Electrocardiogram showed SIQIIITIII sign, and echocardiogram showed larger right ventricular transverse diameter (46 mm), decreased left ventricular end diastolic anteroposterior diameter (34 mm), and higher pulmonary artery pressure (44 mmHg). According to the clinical manifestations, CTA, NT-proBNP, and echocardiogram, this patient was diagnosed with submassive pulmonary embolism. Pulmonary angiography was done on September 10, 2019, and the result confirmed pulmonary embolism. In addition, percutaneous mechanical pulmonary thrombectomy was done using the Angiojet system (Figure 4). The injection pattern by urokinase (urokinase 25 wiu + sodium chloride injection 50 ml) was used. And the main left pulmonary artery was treated by the Angiojet system for 20 s, and the main right pulmonary artery was treated by the Angiojet system for 20 s. Thrombus aspiration was performed in both pulmonary arteries using a catheter by 50 ml syringe, and a massive thrombus was extracted (Figures 5(a) and 5(b)). And we placed the catheter in the inferior vena cava. Intravascular thrombolysis by urokinase (100 wiu/day, 1 day) was done after being back in the ward. And low molecular weight heparin was used in hospitalization, and rivaroxaban was used after discharge. In addition, whole blood count analysis revealed a white blood cell count of 6.6 x 109/l (reference range 3.5-9.5 x 109/l), haemoglobin level of 134 g/l (reference range 115-150 g/l), hematocrit level of 37.8% (reference range 40-50%), and a platelet count of 74 x 109/l (reference range 125-350 x 109/l) on September 11. And the level of platelet count was 125 x 109/l (reference range 125-350 x 109/l) on September 12. The results of NT-proBNP and creatine were 1391 pg/ml (reference range 0-1800 pg/ml) and 54.1 mumol/l (reference range 20-98 mumol/l) on September 12 and 22, respectively. And echocardiogram showed decreased right ventricular transverse diameter (29 mm), normal left ventricular end diastolic anteroposterior diameter (51 mm), and normal pulmonary artery pressure (26 mmHg) on September 26. The clinical characteristics of these two patients are shown in Table 1. In addition, pulmonary artery computed tomography angiography showed pulmonary embolism disappearance in the second patient after 3 months (Figure 6). The patient was supine, and the conventional bilateral inguinal region skin was disinfected by sterile drapes. 1% lidocaine anesthesia was done in the right femoral vein puncture point, the right femoral vein puncture, implanted with a 5 f sheath pipe. By going through the sheath pipe, the pigtail catheter was placed at the level of L5 by an ultrasmooth guide wire. The patency of inferior vena cava and bilateral renal vein open position were confirmed by angiography. The tail catheter and sheath tube were removed, and the ultrasmooth guide wire was retained. The special long sheath for the filter was replaced using an ultrasmooth guide wire, and the inferior vena cava filter (DENALI) was implanted in the lower segment of the renal vein and the vertical segment of the inferior vena cava. The long sheath of the filter was replaced by a soft sheath tube with a hard guide wire, and the sheath tube was placed near the heart position of the inferior vena cava. Guided by the sheath tube and ultrasmooth guide wire, the pigtail catheter was placed in the main pulmonary artery, and pulmonary angiography was performed to confirm pulmonary embolism. The stiff guide wire through the pigtail catheter at the main left pulmonary artery was placed, the pigtail catheter was removed, and the sheath catheter was placed through the guide wire at the main pulmonary artery. The Angiojet system was placed in the main pulmonary artery through the sheath tube, and the injection device was used for thrombolysis treatment. And then, the Angiojet system was removed, and the catheter was placed into the main pulmonary artery through a sheath tube, with a 50 ml syringe at the end of the catheter for thrombus aspiration. Finally, the pigtail catheter was placed through the sheath at the main pulmonary artery for reexamination. The sheath was withdrawn to the inferior vena cava L5 level under the support from the thread. And we placed the catheter in the inferior vena cava. Intravascular thrombolysis by urokinase (100 wiu/day, 1 day) was done after being back in the ward. After 24 hours, the catheter and sheath tube were pulled out, and local pressure was applied for 10 minutes. Then, the bandages were bandaged. The bandage was removed, and the patient could move out of bed after 24 hours.

PMC9745554_01

Male

A 37-year-old man was reviewed in the respiratory clinic for 20-year history of chronic productive cough. He reported daily cupful sputum production and a susceptibility to respiratory tract infection since he was a teenager. He experienced dyspnoea and dizziness on exertion. There was no history of chest pain, haemoptysis or syncope. He was born prematurely and had a stillborn twin sibling. His medical history included Crohn's colitis well-controlled with infliximab infusions for the past 5 years and latent tuberculosis for which he had completed treatment. On examination, his right chest size was smaller than the left, with reduced respiratory excursion. Chest auscultation demonstrated reduced breath sounds and course crackles on the right side. The left side examined normally. He had dual heart sounds with no murmurs. Plain film chest radiograph showed contracted right hemithorax, raised right hemidiaphragm, and right lower lobe bronchial wall thickening. Left lung was hypertrophied and had normal lung fields. A contrast CT chest identified unilateral absence of pulmonary artery (UAPA), hypoplastic right lung, compensatory left lung hypertrophy and right lung bronchiectasis. The pulmonary trunk appeared to be of normal diameter. Review of imaging identified a non-contrast CT chest performed 4 years which suggested right pulmonary agenesis, but no referral was initiated. A transthoracic echocardiogram showed normal cardiac function, no congenital anomalies and no pulmonary hypertension. Lung function test was of mild restrictive pattern, with TLC of 5.6 L (76%), normal FEV1/FVC ratio, without bronchodilator response. He also had normal gas exchange. He was provided with counselling, and chest physiotherapy for education on sputum clearance strategies. Lung protection strategies including annual flu vaccinations, early antibiotic therapy for exacerbations and avoidance of sick contacts were advised. CT surveillance was planned in 24 months.

congenital, haemoptysis, isolated unilateral absence of pulmonary artery, symptoms, treatment

PMC140039_01

Male

A 33 year old male was admitted to our hospital presenting with six-month history of intermittent right epigastric vague pain, and having lost 5 kg in weight over a 2-month period. According to the patient's history, he had had no coughing, fever, jaundice, diarrhea, hematemesis and melena. He had never received a BCG vaccine, but there was no prior history of tuberculosis, or any family history. One month ago, an abdominal computed tomography (CT) performed at another affiliated hospital of our University showed a pancreatic cystic mass, and diagnosed as pancreatic cystadenocarcinoma. On admission, the physical examination revealed no abnormalities. Initial laboratory values revealed a WBC count of 7.54 x 109/L (85.4% neutrophils, 9% lymphocytes, and 4.9% monocytes), Hb 8.7 g/L, ALT 96 U/L (normal 5-45 U/L), AST 161 U/L (normal 5-45 U/L), GGT 705 U/L (normal 4-50 U/L), and ALP 593 U/L (normal 42-128 U/L), Albumin 37.6 g/L and Globulin 34 g/L, Bilirubin, serum CEA, and amylase in serum and urine were all within normal limits; oral glucose tolerance test was normal, the detection of HBV, HCV and HIV were all negative. A chest X-ray film and hypotonic duodenography showed normal. Abdominal ultrasound (US) examination revealed an irregular hypoechoic lesion of 6.6 cm x 4.4 cm in the head of pancreas, and with a calcification at the edge of the mass, and without dilation of bile duct system and pancreatic duct (Fig 1); color Doppler flow imaging did not demonstrate blood stream in the mass. The above-mentioned contrast enhanced CT scan showed a inhomogeneous cystic mass in the head and uncinate process of the pancreas with peripheral rim enhancement, the body and tail of pancreas were normal; the head of pancreas, spleen were enlarged, and mild dilation of main pancreatic duct was also demonstrated (Fig 2). It was clinically suspected as pancreatic cystadenocarcinoma. Two attempts of US-guided percutaneous fine needle aspiration (FNA) failed due to tough tissue not permitting the needle to penetrate. An exploratory laparotomy revealed 300 ml yellow ascite in abdominal cavity, lymphadenopathies around the hepatoduodenal ligament, and a few miliary nodules on pevic visceral peritoneum; omentum, liver and gall bladder were normal, serosal layer of the porta hepatis and the enlarged head of pancreas were edema without nodules. The head of pancreas was elastic hard to palpate. Incisional biopsy of the mass yielded a caseous material, and the wall of abscess cavity was about 1.2 cm in thickness. The cavity, mainly locating at pancreatic head, uncus and peri-pancreas, was separated by fibrotic septa and approximately contained 60 ml milk-like pus. The abscess wall revealed diffuse adipocyte vacuoles together with fibrocytes and lymphocytes suggestive of chronic inflammation on frozen section, but acid-fast stain was positive. After lavaging cavity, applying streptomycin 2.0 g in it, and placing a peripancreatic pigtail drainage, the laparotomy ended. Postoperative recovery was uneventful. Histopathology still confirmed chronic inflammation, without typical changes of tuberculous granuloma such as Langhan's giant cells or epithelioid histiocytes. Patient was started on 3-drug antitubercular regime and at follow up thereafter, patient was asymptomatic. The pancreas demonstrated normal in the CT scan after 7-month duration of antituberculous therapy, but the size of enlarged spleen remained invariable (Fig. 3). One year later, further examinations were performed for the patient to learn whether he has the potential risk of variceal bleeding. Moderate stenosis, not occlusion of splenic vein was confirmed by Doppler ultrasound; no esophageal or fundus varices was also found by gastroscopy.

PMC7305365_01

Male

A 30-year-old man from Southeast Asia presented with right lower abdominal pain, fatigue, and slight fever lasting for a week. As a past medical history, pulmonary tuberculosis was treated with the combined use of 4 kinds of anti-tuberculous drugs (isoniazide, rifampicin, ethambutol, and pyrazinamide) for half a year when he was 3-years old. There were no respiratory symptoms when he was admitted to our hospital. High score of CRP (13 mg/dl) and CA125 (486 U/mL) was pointed out by blood test, and ascites fluid was found by abdominal ultrasound. Chest-abdominal CT scan revealed no sign of pulmonary tuberculosis, but massive ascites and panniculitis with peritoneal nodules and the thickening of the omentumn (Fig. 1). The possibility of tuberculosis peritonitis and malignancy could not rule out, and we performed a diagnostic laparoscopy three days after admission to the TB ward. Before the operation, in the aspect of infection control and prevention, we carried out the direct smear examination three times, which were all negative and prepared N95 masks, Goggles, and Negative pressure room during the operation following the standard precaution for pulmonary tuberculosis. With the patient in a supine position, we used three ports (Fig. 2A 12 mm for scope, 12 mm for Harmonic and 5 mm) and rolled the port position on the left side of hilum because adhesion around the hilum was expected. Intraperitoneal findings were very characteristic; 1. Ascites with slightly cloudy at the both paracolic sulcus and rectovesical pouch, 2. Numerous white nodules (a few millimeters) at the abdominal wall, 3. Thicken omentum with white nodules on the surface (Fig. 2B, C). During the operation, we performed biopsy from peritoneum and omentum for rapid histological evaluation and pathological diagnosis (Fig. 2D). In addition, the culture and PCR using peritoneum, omentum, and the ascitic fluid were carried out. PCR with peritoneum and omentum found out to be negative 7 days after operation. Acid-fast bacilli (AFB) culture with peritoneum and omentum tested positive of Mycobacterium tuberculosis 25 days after operation. But Langhans giant cell and caseating granuloma with necrosis was confirmed by the rapid pathological examination from the peritoneum (Fig. 3), and the score of adenosine deaminase (ADA) resulted in a high score (136.7 U/L) during the operation. Hence, we could start the anti-TB drugs on the next day of operation. No drain was placed due to the less invasive, and the postoperative course was uneventful. He discharged 6 days after surgery. Treatment with anti-TB drugs continued 6month, and after that, the patient is currently under observation.

diagnostic laparoscopy, laparoscopic features, minimal invasion, perioperative infection control, tuberculous peritonitis (tbp)

PMC3000162_01

Female

The patient with the index case of SARS in Singapore was a previously healthy 23-year-old woman of Chinese ethnicity who had stayed on the 9th floor of a hotel during a vacation to Hong Kong, February 20-25, 2003. A physician from southern China who stayed on the same floor of the hotel during this period is believed to have been the source of infection for this index patient and the index patients of outbreaks in Vietnam and Canada. Fever and headache developed in the patient on February 25 and a dry cough on February 28. She was admitted to Tan Tock Seng Hospital, Singapore, on March 1. On admission she had oral temperature of 37.6 C and was lethargic. The chest was clear to auscultation. The remainder of her physical examination was normal. The total leukocyte count (2.7 x 109/L), lymphocyte count (0.9 x 109/L), and platelet count (102 x 109/L) were reduced below normal laboratory ranges. Electrolytes and liver biochemistry results were normal. The chest x-ray showed patchy consolidation of both upper and lower lobes of her right lung (Figure1a). Blood cultures were sterile, and tests for urinary Legionella antigen, particle agglutination test for Mycoplasma pneumoniae antibodies, and complement fixation test for Chlamydia antibodies were negative. Immunofluorescence performed on nasopharyngeal aspirates for viral antigens of influenza virus A and B, parainfluenza virus, respiratory syncytial virus, and adenovirus was negative. Intravenous levofloxacin, 500 mg once a day, was administered, but the patient's temperature continued to spike up to 40 C, and the cough persisted. On day 5 of hospitalization, she became breathless and required supplemental oxygen. Sequential chest x-rays showed progressive, extensive involvement of the right lung, with new infiltrates appearing on the left (Figure 1c). Liver enzymes became elevated, with an ALT of 200 U/L (7-36 U/L) and AST of 208 U/L (15-33 U/L); serum lactate dehydrogenase (LDH) levels rose to 1518 U/L (200-500 U/L). Intravenous vancomycin (1 g twice a day) and oral oseltamivir (75 mg twice a day) were added to the regimen. Nine days after admission, the patient began to improve clinically, the laboratory abnormalities returned towards normal, and the chest x-ray abnormalities stabilized and resolved. The patient has remained well. Electron microscopy of the nasopharyngeal aspirates swab taken on day 7 of hospitalization showed viral particles of <100 nm with widely spaced, club-shaped surface projections characteristic of coronaviruses. When the index patient was seen in early March, the clinical features and highly infectious nature of SARS were not known. For the first 6 days of hospitalization, the patient was in a general ward, without barrier infection control measures. One of eight physicians who attended her became infected, as did 9 of approximately 30 nursing staff. SARS also developed in 1 of 12 patients in adjacent beds during her hospitalization and 9 of approximately 30 family members and friends who visited her during this time. Nineteen of these 20 patients were admitted to our hospital for treatment and isolation (1 was treated outside Singapore), and we recorded prospectively the clinical features of their illnesses with a standardized data collection form. In addition to demographic data, this form elicited information on occupation, date(s) of exposure to suspected cases, travel history after February 20, dates of onset of various symptoms, results of blood tests, and chest radiographic findings. The demographic profiles of the index and 19 contact cases are shown (Table 1). An epidemic curve of the index and contact cases is shown in Figure 2. Because most healthcare staff in our hospital are women, a high proportion of the case-patients (75%) were female. The median age of patients was 28 years. All were previously healthy, except one who had diabetes mellitus and end-stage renal failure and one who had a history of childhood asthma. One patient was a smoker. For seven patients who only had one exposure to the index patient, the median incubation period was 4 days (estimated range 2-8 days). For those with multiple exposures (13 patients), median incubation period was either 7 days (range 4-12 days, calculated from day 1 of exposure), or 5 days (range 3-9 days, calculated from midpoint of exposure period). The median period from onset of symptoms to admission was 6 days (range 0-9 days)

PMC8515295_01

Male

A 60-year-old Japanese man with a history of arteriosclerosis obliterans visited our hospital. He had a history of smoking until a month before the visit (40 pack-years) and no history of environmental exposure. About a year prior to the visit, he became aware of dyspnea on exertion, which gradually increased. Approximately six months leading up to his visit, Raynaud's phenomenon appeared in his left index finger from time to time. His family doctor observed an abnormal shadow on the patient's chest radiographs and referred him to our hospital for further examination. On the patient's first visit to our hospital, his vital signs were as follows: heart rate, 72 bpm; blood pressure, 134/93 mmHg; and body temperature, 35.9 C. His percutaneous arterial blood oxygen saturation was 96% on room air, and his respiratory rate was 14 breaths/min. Chest examination revealed fine crackles in both lower lung fields. No skin rash, joint pain and swelling, muscle weakness, or other physical findings suggestive of connective tissue disease were observed. Laboratory testing on admission revealed a white blood cell count of 6300/muL, a hemoglobin concentration of 15.0 g/dL, and a platelet count of 21.6 x 103/muL. The patient had a C-reactive protein concentration of 0.50 mg/dL and a lactate dehydrogenase concentration of 351 IU/L. His Krebs von den Lungen-6 concentration was 526 U/mL, and that of his surfactant protein-D was 166 ng/mL. Antinuclear antibodies were detected at a titer of 1:320 (with a cytoplasmic pattern), although no antibodies specific for connective tissue disease or markers of vasculitis were detected. High-resolution computed tomography (HRCT) of the patient's chest revealed patchy, bilateral ground-glass opacities and reticular abnormalities in the upper to lower lobes. In addition, there were cystic spaces in the ground-glass opacities (Fig. 1). Pulmonary function tests demonstrated neither restrictive impairment nor airway obstruction; however, a reduced diffusing capacity of the lung for carbon monoxide (DLCO) was observed (59% of the predicted capacity). Bronchoalveolar lavage fluid from the right middle lobe (B5) revealed a total cell count of 5 x 105 cells/mL (82% macrophages, 7% lymphocytes, 6% neutrophils, and 5% eosinophils). TBLC was performed on S8a and S8b of the right lung. The biopsy specimens were 5.5 x 2.5 mm (S8a) and 4.4 x 3.0 mm (S8b) in size. Histologically, alveolar macrophages with abundant eosinophilic cytoplasm uniformly fill the air spaces. The alveolar and interlobular septa were infiltrated with inflammatory cells (Fig. 2). The fibrosis was mild, and the alveolar architecture was relatively well maintained. The lesion was compatible with a histological diagnosis of DIP. Despite three continuous months of cessation of smoking, the patient's dyspnea on exertion worsened, and his DLCO deteriorated to 45% of the predicted capacity. Subsequently, we started immunosuppressive treatment with prednisolone (30 mg/day; 0.5 mg/kg/day), with gradual tapering of the dose, which led to an improvement in pulmonary symptoms. Moreover, HRCT performed 3 months later confirmed this improvement, and the patient's DLCO had improved to 75% of the predicted capacity, and no adverse or unexpected events had occurred.

desquamative interstitial pneumonia, multidisciplinary discussion, transbronchial lung cryobiopsy

PMC8387082_01

Male

A 38-year-old male presented to the emergency department with worsening chronic right lumbar pain associated with legs and scrotum edema. He also had itchy and erythematous cutaneous lesions on the abdominal wall over the last 8 months, with no remission despite numerous therapeutic attempts, and complained of diffuse mild to moderate abdominal pain. He denied weight loss, fever, or night sweats. He was a smoker, and his past medical history included unilateral (right) polycystic kidney disease with functional renal exclusion and a left vicariant kidney (he was waiting for a right nephrectomy) and pulmonary tuberculosis in 2003. He frequently used diclofenac, paracetamol, caffeine, and carisoprodol for his chronic lumbar pain. On admission, he had a good general appearance, no signs of respiratory distress, no alterations in skin color. His heart rate was 95 bpm, blood pressure 166 x 104 mmHg, and room air oximetry were 96%. There were eczematous desquamating skin lesions on his thighs and legs. There were no enlarged lymph nodes. Chest auscultation revealed decreased breath sounds and dullness to percussion at the right lung base. On abdominal palpation, the liver was enlarged, palpable up to 5 cm below the costal margin and was slightly tender. His legs had 2+ symmetrical pitting edema extending from his feet to just above his knees. Laboratory workup revealed mild anemia (Hb 10.8 g/dl), normal white blood cell, and platelet count. The hepatic enzymes, bilirubin, creatine kinase, lactate dehydrogenase, uric acid, and electrolytes were within the normal range. However, the creatinine was 1.47 g/dL (RR: 0.70 - 1.20 g/dL) and the creatinine clearance estimated by the CKD-EPI equation was 69 mL/min/1.73m2. C-reactive protein (32 mg/L; RR: < 3 mg/L) and erythrocyte sedimentation rate (46 mm/1h) were increased. HIV, HCV, syphilis, and Hepatitis B virus serologies yielded negative results. The rheumatoid factor and antinuclear antibodies were negative, and the complement was normal. Urinalysis revealed 1+ of protein and 150 x 103 red blood cells/mm3. Abdominal computed tomography (CT) showed a large, contrast-enhanced mass (10 x 8 x 4cm) involving the abdominal infrarenal aorta and the iliac arteries and compressing the inferior vena cava with dilated iliac veins and the left ureter (Figure 1A), raising the hypothesis of the lymphoproliferative disease. The liver had normal size but had a heterogeneous attenuation. The chest CT showed a diffuse pleural thickening in the right hemithorax with a small loculated pleural effusion, and enlarged mediastinal and peri-esophageal lymph nodes. The patient was admitted with the working diagnosis of a lymphoproliferative disease for a confirmatory diagnostic workup. A double J ureteral stent was placed in the left ureter. A CT-guided biopsy of the right pleural thickening was performed, which lacked a precise diagnosis. The patient was submitted to a laparoscopic-guided biopsy of the peri-aortic mass. This biopsy showed a fibro-connective tissue exhibiting fibrosis, obliterating phlebitis, and moderate mixed inflammatory infiltrates with few eosinophils, histocytes, and small lymphocytes and frequent plasma cells (Figures 2 and 3). The immunohistochemical examination (Table 2) showed an increased number of IgG4 positive plasma cells. The IgG4/IgG ratio of 30% and approximately 80 IgG4 positive-plasma cells per high-power field (HPF) in areas of more density. This examination, together with the morphological and clinical findings, is highly suggestive of IgG4-RD. The patient was started on 1.0 mg/kg/day of prednisone for 2 weeks and then tapered for 0.6 mg/kg/day for two months, and to 20 mg/day for 3 months, afterward. The outcome was favorable and he gradually recovered his previous health status. The abdominal and lumbar pain ceased in about 3 weeks after starting treatment, his hemoglobin level returned to normal and his inflammatory markers decreased. Five months after initiation of corticotherapy, a new abdominal CT scan was done (Figure 1B), and the initial contrast-enhanced mass had almost disappeared, but it showed an inferior vena cava thrombosis extending to bilateral external iliac veins. He was started on warfarin. The double J ureteral stent was removed, and the patient remains asymptomatic with a good urine output with no renal function impairment. At the closure of this manuscript, he was asymptomatic and taking only 5 mg/day of prednisone.

immunoglobulin g, immunoglobulin g4-related disease, lymph node excision

PMC6604474_01

Male

A 63-year-old Caucasian man with a history of benign prostatic hyperplasia with urinary obstruction, distant history of motor vehicle accident status-post multiple fractures and emergency splenectomy, psoriatic arthritis (PsA), and diffuse idiopathic skeletal hyperostosis diagnosed more than 10 years ago presented with fever and weakness. His psoriatic arthritis had been initially controlled with nonsteroidal anti-inflammatory agents; however, eventually he required short courses of prednisone and methotrexate (MTX). Adalimumab was added to methotrexate when the patient was not improving. He had a sustained response to this therapy for almost 2 years. While on this combination therapy, he developed worsening joint pain, fever, left lower extremity weakness, severe myalgia in proximal thigh muscles, lower and upper extremity arthralgia, unsteady gait, and acute urinary retention. He had fever for 1 week prior to hospital admission. Physical examination upon admission was pertinent for tender bilateral, submandibular lymphadenopathy, and left lower extremity weakness (4/5 strength on the left hip flexor and 5/5 strength on the right) without meningismus, nuchal rigidity, wide-based gait without foot drop, up going toes (positive Babinski), decreased perianal sensation, and tender bilateral thighs. He needed Foley catheterization for urinary retention for four days after failing a voiding trial. 18 days prior to this hospitalization, he temporarily stopped adalimumab and methotrexate due to an active ear infection but restarted it one week prior to hospital presentation. Other medications included atenolol, Ativan, folic acid, sumatriptan, and tamsulosin. Family history was notable for a daughter with ulcerative colitis (UC) and bile duct cancer, a son with glioblastoma, a brother with UC, and three sisters having lupus with sicca syndrome, celiac disease, and seronegative rheumatoid arthritis. He had a 25-pack year smoking history. Investigations done during the index hospitalization included brain MRI which showed T2-FLAIR hyperintense lesions in the juxtacortical, deep and periventricular white matter of the bilateral cerebral hemispheres, and infratentorial lesions in the right middle cerebellar peduncle, some with a ring-like appearance without enhancement (Figure 1). A CT scan of the chest/abdomen/pelvis demonstrated diffuse interstitial lung diease with linear opacities at the bases and numerous small nodules measuring 2-4 mm (some in clusters and some were subpleural). There were also few tree-in-bud, mediastinal, hilar, and subcarinal adenopathy with the largest measuring 1.7 cm. A 1.7 cm x 1.3 cm hypodense lesion was seen in the liver (Figure 2). MRI abdomen noted a 2.3 cm liver lesion consistent with hemangioma, 1.8 cm cyst, and a 1.3 cm ovoid lesion (Figure 3). Cerebrospinal fluid (CSF) showed cell count 101/mm3 (85% lymphocytes), total protein 55 mg/dl, glucose 59 mg/dl, no oligoclonal bands, JC virus polymerase chain reaction (PCR) < 500 copies, negative CSF cultures for bacteria, mycobacteria, herpes simplex virus (HSV), Epstein-Barr virus, varicella zoster virus PCR, human herpes virus-6 PCR, enterovirus, cryptococcal antigen, equivocal Lyme IgG/IgM antibody (Ab), negative Lyme western blot, galactomannan, and nonreactive venereal disease research laboratory. Blood work revealed elevated erythrocyte sedimentation rate 65 mm/hr, elevated C-reactive protein 76.2 mg/L, high normal aldolase 7.2 U/L, and normal liver function tests. Serological evaluation for infection was remarkable for equivocal Lyme ELISA but negative Lyme western blot, negative blood and gonococcal cultures, negative interferon-gamma release assay for tuberculosis, negative Babesia, malaria antigen, anaplasma, chlamydia/gonorrhea nucleic acid, negative hepatitis B core Ab, surface antigen, and hepatitis C viral Ab, nonreactive HIV, negative HSV IgM by immunofluorescence assay, cytomegalovirus (CMV) viral load, and CMV Ab. Serological evaluation for inflammatory disease was remarkable for high-titer antinuclear antibodies 1 : 640, positive scleroderma-70 Ab 41.27, high normal complement C3 level 157, positive antismooth muscle Ab- 1 : 40, normal complement C4 level 30, negative dsDNA, normal serum angiotensin converting enzyme levels, rheumatoid factor <30, negative SS-A/SS-B, and neuromyelitis optica antibodies. At this point, Neurology thought this was a rare case of drug-induced cerebral demyelination secondary to adalimumab. He was started on ceftriaxone for possible Lyme myelitis on admission and acyclovir for possible HSV encephalitis. These medications were stopped because CSF and serum Lyme along with HSV PCR returned negative. His fever, left lower extremity weakness, gait instability, and urinary retention improved during his admission such that upon discharge; he had a normal neurologic exam and was voiding normally. He did not receive corticosteroids. He was discharged with plans to follow the central nervous system (CNS) and pulmonary and hepatic lesions as an outpatient. Subjective muscle weakness and gait instability took several weeks to completely resolve. He returned to work full-time. Due to concerns raised for abnormal liver lesions, a PET-CT done after hospital discharge demonstrated a 3 cm hypermetabolic liver mass concerning for neoplasm such as hepatocellular carcinoma, sarcoid nodule, or other granulomatous lesion and a resolution of the previously noted 1.7 cm subpleural nodule (Figure 4). A subsequent liver biopsy showed septal inflammation with associated portal and lobular hepatitis which was not clearly diagnostic for a specific condition but concerning for drug-induced liver injury as anti-TNF-alpha agents have been associated with this. A surveillance CT abdomen/pelvis 3 months after the initial one showed a resolving right hepatic hematoma but new numerous subcentimeter hypodense lesions throughout both hepatic lobes and numerous subcentimeter pulmonary nodules throughout both lungs (Figure 5). Concern for drug-related sarcoidosis or atypical mycobacterial infection was raised due to the multisystem involvement and drug exposure given reports in the literature. A repeat PET-CT 6 months after the initial one demonstrated decreased size of the innumerable liver lesions with no new or enlarging hepatic lesions but continued numerous pulmonary nodules. He then underwent bronchoscopy followed by video-assisted thoracoscopic surgery (VATS) wedge resection, which revealed multiple caseating granulomas (Figures 6(a) and 6(b)). Cultures from the bronchoalveolar lavage (BAL) fluid yielded rare Staphylococcus capitis thought to be from oral flora. BAL culture remained negative for fungi, Legionella, anaerobes, and acid-fast bacilli after two months. Acid-fast bacilli and silver stain performed on tissue sections from the wedge resection were negative for organisms.

PMC3644770_01

Male

A 40-year-old male presented with complaints of decreased vision in the right eye of 4 months duration. There was pain in the right eye at onset and the visual loss progressed to complete loss of vision within 6 weeks of onset of symptoms. There was no history of seizures or focal limb weakness. There were no systemic features like fever, loss of appetite, or weight. Previous treatment history for the visual loss included a short course of oral steroids; no improvement was noted with the same. He presented to us nearly 4 months after onset of visual symptoms and nearly 10 weeks after manifesting complete visual loss. On examination, there was no light perception in the right eye. Relative afferent pupillary defect and optic disc pallor were noted. Magnetic resonance imaging (MRI) brain and orbit at this time (16 weeks after onset of symptoms) revealed a homogenously enhancing, diffusely thickened optic nerve [Figure 1a] with nodular enhancing lesions in the right parietal and frontal lobes. [Figures 2a1 and a2]. Human immunodeficiency virus enzyme-linked immunosorbent assay (HIV ELISA) was negative. Cerebrospinal fluid (CSF) analysis including cultures was noncontributory. There was no significant lymphadenopathy. Chest X-ray and abdomen ultrasonography were noncontributary. As there was still significant enhancement of the optic nerve, possibility of an infiltrative optic neuropathy due to an infectious (tuberculosis, cysticercosis) or inflammatory condition (sarcoidosis) was considered most likely. Infiltrations from lymphomatosis, gliomatosis, and other compressive optic neuropathies were considered less likely especially considering the brain lesions. At this stage, he was asymptomatic for the brain lesions and had already completely lost his vision in the right eye. Initiation of empiric antituberculous therapy was strongly contemplated. However, considering the risk of missing other diagnosis in which different treatment will be required, it was decided to go ahead with a biopsy for definitive diagnosis. The options included an optic nerve biopsy versus brain biopsy. While awaiting the biopsy in the ward, mild impairment of dexterity of the left hand was noted. Antituberculous therapy (ATT) (isoniazid, rifampicin, pyrazinamide, and ethambutol) with dexamethasone was started after a repeat imaging. A repeat MRI brain revealed conglomerate ring enhancing lesions in right frontal and parietal lobes with perilesional edema, mass effect, and midline shift. [Figure 2b] There was also a 30 x 21 mm ring enhancing lesion in the right optic nerve [Figure 1b] with associated thickening. Biopsy from the right parietal lesion revealed necrotizing granulomatous inflammation with numerous acid fast bacilli. Pansensitive mycobacterium tuberculosis was grown on culture. ATT with steroids was continued. Decompression of optic nerve lesion was not done as he already had complete loss of vision with optic atrophy. The mild weakness of the left hand improved completely. Repeat imaging at 2 months follow up revealed subtle increase in the size of the right optic nerve necrotic rim enhancing lesion [Figure 1c]. There was remarkable increase in the size, number, and perilesional edema of the brain lesions as well consistent with paradoxical worsening. [Figure 2c] The dosage of steroids was hiked up and ATT was continued. Repeat MRI at 18 months showed significant resolution of the intracranial lesions. [Figure 2d] The optic nerve lesion persisted, though there was a decrease in the size and degree of enhancement [Figure 1d]. Hence, ATT was continued.

antituberculous therapy, granuloma, magnetic resonance imaging, optic nerve, tuberculoma

PMC9212082_01

Female

A 23-year-old woman died during an egg donation procedure at a fertility clinic, with a cardiac arrest as the clinical cause of death. She had been married for seven years and has a four-year-old daughter born via normal childbirth. Her menarche happened at the age of 13, and her cycles were regular, occurring every 28 to 30 days. There was no history of abortion/pregnancy loss, diabetes, hypertension, asthma, allergy/drug allergy, thyroid disorder, epilepsy, tuberculosis and cardiac disorders, tobacco, alcohol, and illicit drug use. Family history was unremarkable. Her weight was 58 kg, her height was 148 cm (BMI-26.5), her blood pressure was 120/80 mmHg, and her pulse rate was 80 beats per minute when she was admitted for the egg donation. Her heart and breath sounds were normal. Laboratory results revealed hemoglobin level 12.0 g/dL (RR:12-15 g/dL), random blood sugar 81mg/dL (RR: 70-140mg/dL), SGPT 16 U/L(RR:6-55 U/L), serum creatinine 0.74 mg/dL(RR:0.57-1.11mg/dL), prolactin 8.37 ng/ml(RR:5.18-26.53ng/ml), TSH 1.45 mU/L (RR: 0.35-5.50 mU/L), and antimullerian hormone 4.69ng/ml(RR:1.66-9.49 ng/ml). Lipid profiles were normal. Serum serology for HIV, HBsAg, HCV, VDRL, and Rubella IgM was non-reactive. Serum IgG test for rubella showed an adequate immune response. A baseline transvaginal ultrasonography showed normal uterus and ovaries without any features of polycystic ovaries. There was not any risk factor for coronary artery disease. The clinical history, physical examination, and test results indicated that the patient was a healthy young woman. After taking her informed consent, an antagonist ovarian stimulation protocol was scheduled. She received oral contraceptives during her menstruation. From the 6th to 8th day of the menstrual cycle, recombinant FSH (rFSH 300 IU s/c, daily) was given. From the 9th to 14th day of the menstrual cycle, HMG 300 IU IM was given every day, and on the 15th day of her menstrual cycle, a dose of HMG 75 IU IM was administered. On the 11th day of the menstrual cycle, she began taking a GnRH antagonist (0.25 IU) and continued until the 15th day of the menstrual cycle. Serum E2 and P4 levels were measured on the 15th day of the menstrual cycle and determined to be 2048 pg/ml and 0.89 ng/ml, respectively. On the same day, ultrasonography showed five follicles in the right ovary with a 17-18 mm diameter and five follicles in the left ovary with 17-19 mm. Triggering was done on the same day (the 15th day of the menstrual cycle) at 10.30pm with decapeptyl 0.2mg s/c (GnRH agonist). Oocyte aspiration through transvaginal ultrasound was planned. On the morning of the 17th day of the menstrual cycle, a pre-anesthetic check-up revealed no risk factors. Her blood pressure was 120/80 mm Hg. Her pulse rate was 86 beats per minute. Her arterial oxygen saturation was 100%. She was given 1L of Ringer's lactate I.V., followed by 500 ml I.V. slowly as maintenance. Pyrolate and fentanyl were given as premedication. Injection midazolam 1mg was given intravenously. Injection Dynapar 75mg I.V was given slowly. Propofol 120 mg intravenously was used to induce anesthesia, then maintained with sevoflurane. At the start of anesthesia, her blood pressure was 110/68 mmHg, her heart rate was 97/minute, and her SPO2 was 100%. An ECG showed normal sinus rhythm. An ultrasound-guided aspiration of follicles started in the right ovary after confirming no vasculature in between. According to anaesthetic information, after the ovum was picked up from the right ovary, the patient had hypotension (blood pressure decreased from 110/68 mmHg to 70/40 mmHg), bradycardia (heart rate dropped from 97 to 50 per minute), arterial oxygen saturation (SAO2) dropped from 100 to 80%, and the ECG showed bradyarrhythmia. The procedure was immediately abandoned. On auscultation, the heartbeat could not be heard. Air entry was normal. Per vagina examination lacked to detect bleeding. A trans-vaginal ultrasound also showed no intrapelvic or intrabdominal bleeding. Cardiopulmonary resuscitation (CPR) was started. The patient was intubated with a 7.0 mm cuffed endotracheal tube. Position-conformed breaths were given at a rate of 10-12 per minute. Pharmacologic support, including atropine and adrenaline, was given. One 200J DC shock was given. However, her ECG rhythm remained asystole throughout. Unfortunately, she could not be saved, and an autopsy was performed because she died suddenly and unexpectedly.

death, sudden, oocyte donation, ovarian hyperstimulation syndrome, pulmonary edema

PMC4922280_01

Male

A 43-year-old male, working as a sand blaster for the past 13 years, presented with fever, cough, breathlessness, and right-sided pleuritic type of chest pain of a duration of 2 months. He had been evaluated in another hospital where he was diagnosed as sputum-negative pulmonary tuberculosis based on contrast-enhanced computerized tomogram (CECT) chest and bronchoscopy findings. The computerized tomogram (CT) done 3 months prior to presentation showed nonspecific patchy parenchymal opacities [Figure 1a]. He was started on antitubercular treatment (ATT). But his symptoms worsened and repeat CECT of the chest done a month later revealed features suggestive of nonresolving pneumonia. There were larger and newer parenchymal opacities, predominantly in the lung bases. His breathlessness had worsened since 2 days and on admission his saturation (SpO2) was 70% on room air and 90% with 5 L oxygen through Hudson's mask. On examination, he was emaciated and had bilateral end-expiratory crepitations. His erythrocyte sedimentation rate (ESR) was 86 mm/h with leukocytosis. His two sputum samples were negative for acid-fast bacilli (AFB) on Ziehl-Neelsen (ZN) stain. High-resolution CT (HRCT) of the chest showed bilateral middle and lower lobe ground-glass opacities with left lower lobe consolidation [Figure 1b and c]. CT-guided biopsy of the left lower lobe lesion was performed [Figure 1d] to rule out the possibility of malignancy and histopathological examination showed features of interstitial pneumonia with fibrosis. The papanicolaou (PAP) stain on bronchial lavage revealed benign squamous cells, pigment-laden macrophages, and extensive acute inflammatory cell infiltrate [Figure 2a and b]. The lavage fluid was positive for AFB as demonstrable by ZN stain. Detection of numerous birefringent silica particles under polarizing microscope in the bronchial lavage [Figure 2c and d], otherwise not appreciable on PAP stain, clinched the primary diagnosis of silicosis with associated tuberculosis. Initiation of ATT was done as per the patient's body weight. However, his hypoxia persisted and he was discharged on domiciliary oxygen. Repeat chest radiograph at end of 1 month did not show any radiological improvement. His respiratory failure persisted and he was continued on the domiciliary oxygen.

bronchoalveolar lavage fluid, silica, silicosis, tuberculosis

PMC5917516_01

Male

A 65-year-old male patient reported with a chief complaint of ulcer in the right lower back tooth region of 31/2 months duration and gave a history of difficulty in mouth opening and swallowing. He had a history of bidi smoking 12/day for a period of 50 years and also gave the history of tuberculosis which was treated last year. Intraorally, an ulceroproliferative growth was present in the right posterior mandibular region distal to molar which was nontender, well defined with irregular surface showing white projection [Figure 1a]. On examination, right submandibular lymph node was palpable. On radiographic examination, orthopantomograph (OPG) showed slight erosion of the underlying bone in the right posterior mandibular region [Figure 2a]. On the basis of clinical and radiographic features, a provisional diagnosis of tuberculous ulcer was given. An incisional biopsy was done and sent for histopathological examination, which showed top to bottom features of dysplasia such as altered nuclear-cytoplasmic ratio, pleomorphism, hyperchromatism and few aberrant mitotic figures in the overlying epithelium without any invasion into the underlying stroma. Hence, the diagnosis of carcinoma in situ was given [Figure 3]. Then, the complete excision of the lesion was done, and hematoxylin and eosin-stained sections revealed overlying parakeratinized dysplastic stratified squamous epithelium invading the underlying connective tissue. The underlying connective tissue stroma comprised of numerous nests, cords and gland-like lobules of closely packed pleomorphic, hyperchromatic basaloid cells with nuclear palisading. The periphery of the neoplastic nests is surrounded by a fibrous stroma with prominent areas of comedo necrosis [Figure 4]. Few islands showed squamous cells surrounded by basaloid cells. Keratin pearls, increased and abnormal mitotic figures within squamous islands were evident [Figure 5]. The mixed composition of basaloid and squamous cells was striking. Surrounding stroma showed chronic inflammatory cells and blood vessels. Based on histopathological report, the diagnosis of BSCC of retromolar area was given.

carcinoma, comparative, head and neck neoplasms, histology, squamous cell of head and neck

PMC7269532_01

Male

A 43-year-old man presented to our clinic due to headache persisting for the previous 15 days, and with fever, vomiting, and altered consciousness for two days. At physical examination, the patient was somnolent, and signs of meningeal irritation were positive. Cerebrospinal fluid (CSF) analysis revealed microprotein: 138 mg/dL, chloride: 120 mmol/L, and glucose: 32 mg/dL (simultaneous blood sugar: 128 mg/dL). The headache persisted on the seventh day of anti-microbial therapy. Magnetic resonance imaging (MRI) revealed a millimeter-scale cerebellar lesion (Figure 1). PCR for Mycobacterium tuberculosis and Quantiferon tests of CSF were positive. The patient was commenced on isoniazid, 300 mg/day, rifampicin 600 mg/day, ethambutol 2 g/day and pyrazinamide 2 g/day. CSF culture testing over the first month of treatment was reported as M. tuberculosis, susceptible to anti-tuberculous drugs. In the second month of treatment, the patient was reexamined, complaining of severe headache. MRI of the brain revealed an increased number of lesions and basilar occlusion (Figure 2). Moxifloxacin and anti-edematous therapy were added to four-drug anti-tuberculous therapy. The symptoms resolved in the third month of five-drug anti-tuberculous therapy, and treatment was maintained with two-drug anti-tuberculous therapy. Improvement was recorded by MRI in the fifth month of treatment (Figure 3). Central nervous system tuberculosis is a rare form of tuberculosis in immunocompetent individuals. It can lead to excessive tuberculosis protein release in association with basilar obliteration, particularly in tuberculous meningitis, in patients receiving anti-tuberculous therapy. This protein can lead to tuberculoma expansion, or to identification of previously unseen tuberculomas .

PMC2821765_01

Female

A 79-year-old woman who had total gastrectomy, with R-Y for gastric cancer, was admitted for the treatment of bile duct stones. Although we tried SBE-assisted ERCP (XSIF-Q260Y; Olympus Medical Systems, Tokyo, Japan), an enteroscope could not be advanced to sharply angulated R-Y limb. Three days later, we performed rendezvous technique-assisted SBE using carbon dioxide during the procedure. At first, a guidewire was passed antegradely through the major papilla after the needle puncture using a percutaneous transhepatic biliary drainage (PTBD) technique. A hydrophilic guidewire (Radifocus, Terumo, Tokyo, Japan) with an ERCP catheter was antegradely advanced beyond the Roux limb (Figures 1(a) and 1(b)). Then the enteroscope was inserted to the Roux limb after a guidewire was found and firmly grasped by a snare forceps, it was pulled out of the body through the working channel of the enteroscope resulting that the enteroscope could advance to the papilla (Figure 2(a)). Cholangiogram revealed bile duct stones (Figure 2(b)). After papillary dilation using a 15-mm large-balloon (CRE Esophageal/Pyloric, length 5 cm, Boston Scientific Japan, Tokyo, Japan) without sphincterotomy because the major papilla was not well positioned for the sphincterotomy, an enteroscope as a direct cholangioscope was advanced into the bile duct. Direct endoscopic imaging revealed bile duct stones (Figure 3(a)). Bile duct stones were removed using a basket catheter and retrieval balloon. Finally, complete removal of bile duct stones was confirmed by direct endoscopic imaging (Figure 3(b)). Then, a guidewire was pulled out through the working channel. There was no procedure-related complication.

PMC10420095_01

Female

In Uganda, cervical cancer is the most common cause of both cancer-related incidence (54.8 per 100,000) and cancer-related deaths (40.5 per 100,000). Eighty percent of patients present late with advanced stage (often terminal) disease. Late patient presentations are attributed to low levels of knowledge among health care providers and the public about cervical cancer and prevention strategies and minimal access to available (and free) public screening services. The 2010 National Strategic Plan for Cervical Cancer Prevention and Control prioritized 3 areas. The first 2 of these include an emphasis on health education and awareness-raising: Human Papillomavirus (HPV) vaccination of 10-14-year-old girls Low-cost screening using Visual Inspection with Acetic Acid (VIA) Treatment of early dysplasia (cervical intraepithelial neoplasia) using cryotherapy While HPV vaccination has become the primary preventive intervention in high income settings, Uganda's HPV vaccination program, targeting girls aged 10-14 in primary schools, has achieved only about 20% uptake. Progress has been substantially impacted by the immediate and long-term effects of extended school closures during the COVID-19 pandemic and subsequent Ebola outbreaks. For the foreseeable future, this implies continued emphasis on screen-and-treat programs working in parallel with HPV vaccination. A key goal of Priorities 2 and 3 was to have 80% of eligible women screened and treated for precancerous lesions. Despite these intentions, Uganda's national screening program faces considerable implementation gaps. In practice, screening in Uganda is erratic and absent in many regions. Unfortunately, there is very limited (or no) public funding for such programs which suffer from acute donor-dependency. Uptake of screening services that do exist are negatively impacted by limited access to facilities, compounded by the costs associated with services, travel, and wait times. There is also a shortage of trained screening providers. This explains the low lifetime screening rate of between 4.8 and 30%, and the continued prevalence of advanced disease and mortality. Cervical screening guidelines in Uganda are based on a 'see-and-treat' approach targeting women aged 25 to 49 years. VIA is the main screening procedure used. In theory, women diagnosed with positive mild-moderate precancerous lesions (diagnosed through VIA) should then be treated, in the community, using cryotherapy. In practice, even Non-Governmental Organizations (NGOs) that constitute the private 'not-for-profit', sector levy significant charges for such treatment. National Guidelines (until recently) stipulated that women who test positive for Human Immunodeficiency Virus (HIV) should be screened annually while HIV-negative women should undergo cervical screening every 3 years. Midwives and nurses are the primary providers of cervical cancer screening as well as treatment. Knowledge for Change (K4C) is a UK and Ugandan registered NGO focused on health systems change.1 At the time of the commencement of the Knowledge for Change (K4C) screen-and-treat service in Fort Portal (Uganda), the city had no public facility offering free cervical screening services. This paper presents a Community Case Study documenting a complex intervention (defined through a series of action-research cycles) drawing out the potential for scale-out of see-and-treat cervical cancer prevention in Low- and Middle-Income Countries (LMICs).

cervical cancer, frugal innovation, geographic information systems, prevention, results based finance, task-shifting

PMC4290067_01

Female

A 50-year-old female, known case of multinodular goiter, presented with chest discomfort, hemoptysis, and dyspnea to emergency. Electrocardiogram showed left bundle branch block. Hemoglobin was 8.8 g/dl. Chest X-ray showed multiple soft tissue opacities in both lung fields. Two-dimensional transthoracic echocardiography with color Doppler showed a mass of approximately 5.6 cm x 2.2 cm, attached to the right atrium [Figure 1] with mild pericardial effusion and global hypokinesia of left ventricle. The findings on echocardiography were of the opinion for primary cardiac myxoma. High-resolution computed tomography thorax showed multiple discrete soft tissue attenuated nodular lesions in peripheral lung fields with few irregular thick walled cavitatory lesions. The sputum and tuberculosis quantiferon test were negative for acid fast bacilli. Her serum thyroid stimulating hormone was 0.3 mIU/L. Ultrasound (USG) guided fine needle aspiration cytology (FNAC) from solid component of thyroid swelling was suggestive of colloid goiter. The patient was subjected to FDG PET-CT whole body study for work up. PET-CT showed a well-defined heterogeneously enhancing hypodense mass in the right atrium with intense FDG uptake (SUVma x 19.2) along with pericardial infiltration and minimal pericardial effusion [Figure 2]. A non-FDG avid thrombus was seen in right superior pulmonary vein extending up to left atrium [Figure 3]. Multiple FDG avid parenchymal and subpleural nodules were seen in both lungs (SUVma x 3.0-12.5). The mediastinal and right hilar nodes were enlarged with increased FDG uptake (SUVma x 3.3-9.2). Liver showed multiple hypodense lesions in both lobes (SUVma x 4.0-12.2). Hypermetabolic ill-defined hypodense lesions were seen in head, uncinate process and body of pancreas (SUVma x 9.7). A well-defined heterogeneously enhancing lesion was seen in inter-polar region of the right kidney (SUVma x 3.6). Hypermetabolic enlarged peripancreatic (SUVma x 9.5) and aortocaval (SUVma x 10.5) nodes were also seen. A peripherally enhancing hypodense lesion measuring 1.5 cm x 1.4 cm with minimal perilesional edema and no significant FDG uptake was seen in left frontal cortex [Figure 4]. A lobulated mass with solid and cystic areas, calcification, and septations was seen in the right lobe of thyroid with hypermetabolic solid component (SUVma x 14.2) extending up to suprasternal region. The imaging diagnosis was an aggressive right atrial angiosarcoma with neuroparenchymal, pulmonary, hepatic, pancreatic, renal and nodal metastases as the USG guided FNAC of thyroid swelling was suggestive of colloid goiter. After explaining the nature of the disease and poor prognosis, patient did not give consent for biopsy. Palliative chemotherapy with ifosfamide (7500 mg/m2, every 3 weeks) was instituted. Unfortunately, patient passed away after treatment with three cycles of chemotherapy.

atrial angiosarcoma, fluoro-deoxyglucose positron emission tomography suvmax

18F-fluoro-deoxyglucose (FDG) contrast enhanced positron emission tomography-computed tomography (PET-CT) images. coronal CT and corresponding fused PET-CT sectional images showing non-FDG avid thrombus in right superior pulmonary vein extending upto the left atrium (arrow).

PMC6120292_01

Female

Only a few cases in the literature reported an association of TA with SNHL. Hearing loss is often progressive, although it can be stable or fluctuating; is usually bilateral and asymmetric; develops over several weeks to months; and mainly involves high frequencies. SNHL may also present as a SSNHL. A good response to corticosteroid therapy has been reported for SNHL in TA, although it may also persist despite therapy. Recently, Ralli et al. described a case of a 36-year-old woman with TA who had two episodes of SSNHL involving one ear at a time with an 11-month delay between each episode of treatment with hyperbaric oxygen therapy associated to corticosteroids, with significant improvements in both ears. Relapsing polychondritis (RP) is a rare connective tissue disorder affecting organs containing collagen, such as the eye, cartilage tissue, and skin. The diagnosis is based on clinical features and no specific test for this disease is available; thus, definitive diagnosis takes a long time, and often, the prognosis is poor. Recurrent bouts of inflammation may lead to a permanent destruction of involved structures such as cartilage of the ears, nose, larynx, tracheobronchial tree, and cardiovascular system. McAdam et al. proposed diagnostic criteria for RP when three or more of the six clinical features are present: recurrent chondritis of both auricles; nonerosive, seronegative inflammatory polyarthritis; chondritis of the nasal cartilages; ocular inflammation (conjunctivitis, keratitis, scleritis, and uveitis); respiratory tract chondritis affecting laryngeal and tracheal cartilages; and cochlear and/or vestibular dysfunction (SNHL, tinnitus, and vertigo). Auricular chondritis is a quite specific sign of RP. It is present in 20% of patients at the onset of the disease and in 90% during the course of the disease. One or both ears can be affected. The ear concha is swollen, red, or less often purplish, hot, and painful even at the slightest contact. The ear lobe, which does not contain the cartilage, is spared. Audiovestibular impairment is reported in 40-54% of all patients with RP. These changes can represent the initial symptoms heralding the outbreak of the disease or appear after the onset of other symptoms. Typical manifestations can be bilateral or unilateral, are usually of sudden onset, and appear as perceptive deafness or tinnitus combined with or without vertigo and nausea. CHL can be a result of a serous otitis following chondritis of the eustachian tube. Further, the SNHL in RP patients has been suggested to be the result of inflammation of the internal auditory artery or its cochlear branch or due to autoantibodies against the cochlea and vestibular organ. This could explain the near-complete hearing recovery in patients after treatment with corticosteroids. Wegener's granulomatosis (WG) is an autoimmune disease of unknown aetiology characterized by necrotizing granulomatous inflammation of the respiratory tract, necrotizing glomerulonephritis, and systemic vasculitis that affects predominantly small vessels. Although the pulmonary, nasal, and renal manifestations of WG are well described, hearing symptoms are less appreciated. Studies available in the literature report a prevalence of audiovestibular symptoms in 8% to 65% of patients with WG, mainly auditory symptoms with SNHL or CHL in cases of WG involving the middle ear. Audiometric patterns of WG have been described as typically flat, although sometimes additional high frequency losses may coexist and differential diagnosis with noise exposure or age-related hearing loss may be difficult. Hearing impairment may also present as SSNHL; Bakthavachalam et al. identified that hearing loss was present in 56% of patients suffering from WG and SSNHL was the most common form, occurring in 47% of cases. Hearing loss may also be a presenting symptom of WG. SNHL in WG is believed to be largely irreversible, therefore potentially adding to the patient's cumulative disability. SNHL evaluation and monitoring are therefore recommended for appropriate patient management and could suggest a worsening of disease that may address to a specific treatment like cyclophosphamide rather than either methotrexate or azathioprine. Susac's syndrome (SS) is a rare immune disease characterized by encephalopathy, branch retinal artery occlusion, and SNHL. SS has a higher prevalence in females, with a male: female ratio of 1 : 3.5. The pathophysiology of SS is not entirely clear. Antiendothelial cell antibodies (AECAs) in SS have been recently documented. Potential targeted antigens suggested in studies focusing on AECAs include cytoskeletal proteins (beta-actin, alpha-tubulin, and vimentin), glycolytic enzymes (glucose-3-phosphate-dehydrogenase and alpha-enolase), and the prolyl-4-hydroxylase beta subunit, a member of the disulfide isomerase family. Clinical manifestations of SS are thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina, and inner ear that lead to a characteristic clinical trial of central nervous system (CNS) dysfunction. At clinical onset, the most common manifestations are CNS symptoms, observed in two-thirds of patients, followed by visual symptoms and hearing disturbances. Unfortunately, only a small number of patients (around 13%) show the characteristic symptoms of SS at disease onset; thus, definitive diagnosis is often delayed. Hearing loss can be a dramatic and severely debilitating feature of SS; it may be mild and insidious or may be fluctuating, mimicking Meniere's disease. A loss of low or middle frequencies is typical, suggesting a vulnerability of the cochlear apex to microinfarction; loss of high frequencies can also occur. Hearing loss often occurs overnight and may affect both ears. Dorr et al. refer to this clinical behaviour as the "bang-bang hearing loss". Severe hearing loss is often accompanied by vertigo and a roaring tinnitus; the occlusion of cochlear and vestibular arterioles may be the cause of these symptoms. In these patients that often develop severe/profound SNHL and can no longer benefit from hearing aid amplification, cochlear implantation is a valid therapeutic option. Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease characterized by xerostomia and xerophthalmia due to lymphocyte infiltration of both salivary and lacrimal glands. It may also occur as a systemic disease involving the kidneys, lungs, liver, vessels, and lymph nodes. pSS mainly affects women in the fourth-fifth decade of life, and presenting symptoms are often oral and ocular. In this context, autoantibodies to cardiolipin and M3 muscarinic receptors (mAchRs) in the serum of pSS patients are suspected to play a pathogenic role in the onset of progressive hearing loss and neurological complications.

PMC10335757_01

Female

This case report has been written according to Preferred Reporting Items for Case Reports in Endodontics (PRICE) 2020 guidelines. The PRICE 2020 flowchart was shown in Figure 1. Informed consent has been obtained from the patient for publication as a case report of the process of treatment for this ECR lesion. An overview of the treatment timeline is presented in Table 1. A 43-year-old non-smoking female was referred to our university hospital clinic by a private dental clinic for the management of an extensive ECR lesion. The patient complained of discomfort in the maxillary right lateral incisor and reported a history of a fall that happened 10 years ago. However, the patient had not paid particular attention at the time, as the patient was asymptomatic immediately after the trauma, and there was a lack of superficial damage. During the assessment of the initial trauma (10 years ago) at a private clinic, the affected tooth had undergone caries removal in the proximal and distal aspects of the tooth. Several years later, the patient was diagnosed with ECR at a private dental clinic. The discomfort at the affected tooth gradually increased, and the radiographic translucency of the ECR lesion became larger. At the time of presentation, the patient was not on any medications and had no relevant general medical or family history. Furthermore, common causes of ECR, such as history of orthodontic treatment, parafunctional habit, or abnormal occlusal pattern, were not detected. Overall, oral hygiene was good, and plaque levels were well controlled. Bruxism or occlusal interference was not apparent. There was no pathological tooth mobility of either the affected or its adjacent teeth. No tenderness was noted on palpation, and slight pain was reported on vertical percussion. Pulp sensibility tests demonstrated a negative response to thermal stimulation (cold test; Pulper, GC, Tokyo, Japan) or the electrical pulp test (Digitest II, MORITA, Kyoto, Japan) in comparison with the responses to the adjacent teeth. The periodontal probing depth was less than 3 mm on the buccal side, but 4 mm deep, with bleeding and slight pus exudate from the distal aspect of the palatal surface. Root caries as a differential diagnosis were ruled out because no infected dentine was detected. An intraoral radiograph (Figure 2(a)) revealed a large ECR lesion extending from the distal to the proximal side; however, no obvious radiolucency was evident at the root apex. No radiographic signs of swelling or sinus tract were observed at the right maxillary incisor. CBCT was performed to further explore the extent of the ECR (Figure 2). Horizontal and sagittal CBCT images showed that the ECR lesion had reached the pulp tissue in up to one-third to one-half of the root in the axial direction, and horizontally, the hard tissue defect extended by approximately 180 mainly on the palatal side. It was accordingly diagnosed as a Class III according to Heithersay's classification and Class 2Bp lesion according to Patel's classification (Figure 2(b)). After diagnosis and classification, a treatment plan (including options) was discussed with the patient. The patient was specifically informed that due to the extent of ECR, it would be difficult to perform root canal treatment (RCT) without accompanying periodontal surgery, which would also include debridement and restoration of the destructed hard tissue. Owing to the patient's desire to retain the tooth after explanation, consent was obtained for intentional replantation after RCT. Extraction of the tooth followed by placement of a conventional bridge, adhesive bridge, or dental implant (immediate or delayed) was discussed as a potential alternative to intentional replantation. 'Ideal' rubber dam isolation clamping the tooth in question was not possible due to a lack of coronal tooth substance so a split dam technique was all that could be used if RCT and intentional replantation were selected. After presenting the advantages and disadvantages of each treatment method to the patient, the placement of an adhesive bridge after tooth extraction was considered only if intentional replantation was unsuccessful. Based on the clinical examination, ECR treatment was carried out under magnification using a DOM (M320-D, Leica Microsystems, Wetzlar, Germany). Due to the nature and extent of the ECR lesion, as discussed previously the split dam isolation technique was performed under local anaesthesia, and the palatal gingival tissue adjacent to the ECR was removed using an electronic scalpel under dry conditions to facilitate coagulation. Thereafter, RCT was initiated using a diamond bur with a water-cooled high-speed handpiece. The root canal was narrowed due to ECR and required careful negotiation to access the root canal system. Apical patency was maintained with an H-file #10 (Dentsply Sirona, Ballaigues, Switzerland), and root canal length was measured electrically using an apex locator (Root ZX3, MORITA). Subsequently, a glide path was established, and the root canal was enlarged using a nickel-titanium (NiTi) file system (HyFlex EDM, Coltene, France) with an Endomotor (TriAuto ZX2, MORITA), which was capable of simultaneously measuring the electrical root canal length. The working length was further confirmed on a periapical radiograph image by placing a gutta-percha cone (Figure 3(a)). The root canal was profusely irrigated with 2.5% sodium hypochlorite (Neo Cleaner, NC, Neo Dental Chemical Products Co., Ltd., Tokyo, Japan) and 3% ethylenediaminetetraacetic acid solution (Smear Clean, Nishika, Yamaguchi, Japan) delivered using a 27-G root canal irrigation syringe (Neo Dental Chemical Products Co., Ltd.) with simultaneous agitation using a NiTi instrument (X-p Endo finisher, FKG Dentaire, La Chaux-de-Fonds, Switzerland). The root canal was then dried with sterile paper points. A calcium hydroxide dressing (Calcipex II, Nishika) was placed. The first-visit treatment was completed by carefully placing a temporary restoration of glass ionomer cement (GlassIonomer FX ULTARA, Shofu, Kyoto, Japan) up to the root canal orifice to avoid coronal leakage from the palatal side. At the second RCT visit, the tenderness on percussion had significantly subsided. The glass ionomer cement and calcium hydroxide dressing was removed after isolation using a split dam rubber dam technique, and the root canal was re-irrigated and dried. Then, the root canal was filled with a methacrylate resin sealer (MetaSEAL soft paste, Sun Medical Co. Ltd., Shiga, Japan) and a single-matched taper gutta-percha cone (Figure 3(b)). As the tooth was asymptomatic after RCT, an orthodontic hook device was placed for extrusion before intentional replantation (Figures 4(a), 4(b), and 4(c)). A video illustrating these processes is provided as video information (refer to https://doi.org/10.6084/m9.figshare.20787508.v1). After administering local anaesthesia, the temporary sealing material was removed, and the gingival tissue on the palatal side of the ECR was kept dry by removal and coagulation using an electrical scalpel. A 0.7-mm in diameter cobalt-chromium (Co-Cr) hook device was affixed in the root canal using carboxylate cement (HY-BOND Carbo Cement, Shofu), and then a custom-made wire was bridged to the adjacent teeth and fixed with 4-methacryloxyethyl trimellitate anhydride/methyl methacrylate tributylborane (4META-MMA/TBB) resin (Superbond, Sun Medical Co. Ltd., Shiga, Japan). One orthodontic thread was used to tie the wires to provide a sustained extrusion force. Follow-up procedures involved changing the orthodontic threads once per week for three weeks. The orthodontic device used to extrude the tooth was removed under local anaesthesia before intentional replantation. Intentional replantation was performed by one operator and two assistants in an operating room under magnification (Figures 4(d), 4(e), 4(f), 4(g), 4(h), and 4(i), refer to videos https://doi.org/10.6084/m9.figshare.20787613.v1). The mobility of the tooth increased after device removal, and gentle extraction was performed using forceps (Claw, YDM, Tokyo, Japan). Next, the crown was rotated 180 to confirm that it fits into the extraction socket. This permitted the ECR lesion observed under magnification, and a dye detection solution (usually used for caries detection, Caries detector, Kuraray Noritake Dental Inc., Tokyo, Japan) was utilised to identify the extent of the ECR. The lesion was then meticulously curetted to ensure that no resorptive tissue remained. A resin-based composite restoration was placed and cured using blue light irradiation (Pen cure 2000, MORITA) before the tooth morphology was adjusted. Finally, the tooth was replanted in the extraction socket. A sterile saline solution was used to minimise dryness and contamination of the dentine debris, except during ECR removal and morphological modification of composite restorations using a high-speed handpiece. The crown was sutured to the gingiva to promote initial wound healing and stability and fixed to the adjacent tooth with composite resin for reinforcement. The extraoral work time for the intentional replantation procedure was approximately six minutes. These treatments were performed by an endodontist with >10 years of experience. Follow-up appointments were scheduled at various time points (Figures 5(a), 5(b), 5(c), 5(d), and 5(e)). After one week, the sutures and resin cement were removed. Three months after intentional replantation, a provisional restoration was fabricated. RCT was performed with the split dam isolation due to the risk of periodontal exudate contaminating the canal. The tooth was observed for a prolonged period after obturation, with no subsequent symptoms or abnormal findings evident clinically or radiographically. After determining that additional root canal retreatment was not necessary based on a 6-month follow-up, a composite resin crown (Kuraray Noritake Dental Inc.) was constructed using computer-aided design/computer-aided manufacturing as the final step in the restoration process. There were no clinical symptoms during this period, and radiographs showed no detrimental effect of intentional replantation. Furthermore, no clinical symptoms or abnormal findings were observed 18 months after intentional replantation. These results demonstrate the success of ECR treatment with RCT and intentional replantation (Figure 6).

PMC8075353_01

Female

A 73-year-old Chinese female patient was admitted to our hospital in November 2019, complaining of upper abdominal pain for over 2 months. Physical examination presented mild right upper quadrant tenderness. The patient had a history of left radical mastectomy because of early-stage breast cancer 27 years ago, without postoperative treatment. And there was no special family history. Abdominal enhanced computed tomography (CT) showed gallstones and a thickened wall of gallbladder fundus, with enlargement of lymph nodes around the main portal vein. Thoracic CT suggested no obvious abnormality. After routine preoperative examinations, radical cholecystectomy and regional lymphadenectomy were performed on November 15, 2019. Postoperative pathological diagnosis confirmed moderately differentiated adenocarcinoma from the gallbladder (Figure 1), invading the whole layer, involving peripheral fibrofatty tissue and liver parenchyma, with immunohistochemistry (IHC) staining of CK7 (+), CK19 (+), MOC-31 (small partly +), CEA (+), SATB-2 (-), CDX-2 (small partly +) and MIB-1 (+, about 20%). Incisal edges of the distal common bile duct and right hepatic artery were detected for residue cancer cells. The liver incisal edge was negative. Two lymph nodes involving the para-right hepatic artery and posterior pancreatic head lymph nodes were found to be metastatic. The postoperative stage was pT4N1M0, stage IVA. After discussion with her family, the patient refused postoperative chemotherapy. About two months after surgery, routine postoperative CT imaging on January 10, 2020 revealed peritoneal nodules and enlarged lymph nodes in the ligamentum hepatogastricum and mesentery regions, which indicated metastases. The patient refused chemotherapy again and accepted the suggestion of a gene test. Next-generation sequencing (NGS) of the operative specimen and plasma were performed and showed germline mutation (c.1352_1364del, p. S451Lfs*20) in BRCA1 and somatic mutation in TP53 (exon7 p. E258G) and MUTYH (exon13 p. E420*) genes (3D Medicines Shanghai, China). Tissue-based tumor mutational burden (TMB) was 6.15. Microsatellite status was stable (MSS) and the IHC result of programmed death-ligand 1 (PD-L1) was negative. No meaningful mutations were found in other genes, including the mismatch repair gene (MMR), ERBB2, IDH1/2 and FGFR1/2. It is worth mentioning that the patient's family members also received gene sequencing using blood samples. As she had no siblings and her parents were dead, her only daughter and daughter's son received gene sequencing. The results showed that her daughter has the same germline mutation of BRCA1, while her grandson harbors no germline mutation. Given that BRCA1 mutation was proven to be a predictor of the Olaparib effect, we prescribed Olaparib 300mg every 12 hours as a first-line treatment on January 20, 2020. Unfortunately, grade 4 anemia occurred after taking Olaparib for about 1 month and was treated with a blood transfusion. The Olaparib dose was then decreased to 150mg every 12 hours and no severe adverse reaction was found. About three months after Olaparib administration, a CT scan revealed significant shrinkage of the peritoneal nodules (Figure 2), with the largest diameter decreasing from 1.58 cm to 0.98 cm, which indicated a partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. After taking Olaparib for 6 months, on July 31, 2020 an abdominal CT scan showed a new lesion in the remnant liver and enlarged peritoneal nodules, which meant progressed disease (PD). Considering the dosage of Olaparib was not enough, we suggested to the patient that the Olaparib dosage be reinstated at 300mg every 12 hours. But after careful discussion with her family, our patient decided to stop anti-tumor treatment and obtained a progression-free survival (PFS) of about 6 months. At the most recent follow-up, on March 8, 2021, she was alive and receiving the best supportive care at the local hospital.

brca1 mutation, olaparib, gallbladder cancer

PMC6258366_01

Female

A 72-year-old Japanese female was admitted to Tsukuba University Hospital (Tsukuba, Japan) in September 2015 with aggravation of consolidation in the lingular segment. She had never smoked; however, she had a 36-year history of bronchiectasis in the lower right lobe and lingular segment with several episodes of hemosputum. She also received clopidogrel to maintain a stent inserted for cerebral aneurysm. She had pet cats and slept with them for almost 30 years. Physical examination at admission was unremarkable. Laboratory findings, including white blood cell count and C-reactive protein levels, were normal. T-SPOT.TB test for tuberculosis and serum anti-Mycobacterium avium complex antibody level was negative. Chest computed tomography (CT) revealed worsened bronchodilation, bronchial wall thickness, centrilobular nodules, and air-space consolidation in the lower right lobe and lingula (Fig. 1A). Bronchoscopy was performed to confirm the pathogen identity. A large amount of purulent sputum was observed in the lingular segments (Fig. 2A). Cultures of wash specimens from the right B8a and lingular segments revealed gram-negative rods (Fig. 2B), which using Vitek 2 testing, were identified as P. canis with a 91% identification probability. In addition, culturing using MacConkey agar was negative for bacterial growth; isolated bacteria could not dissolve maltose and mannitol, but could dissolve ornithine. These results were consistent with those obtained for P. canis. Because P. canis quite rarely causes pneumonia, we performed 16S ribosomal RNA (rRNA) sequencing for confirming the diagnosis; the isolates were identified as P. multocida subsp. septica with a 99.9% probability (Fig. 2C). Based on these results, P. multocida pneumonia was finally diagnosed. While waiting for the rRNA sequencing analysis results, the patient suffered worsened hemoptysis and was readmitted to our hospital in October (Fig. 1B). Intravenous ampicillin/sulbactam (9.0 g/day) was administered for one week, followed by oral amoxicillin-clavulanic acid (750 mg/day) for another 30 days. After antibiotic therapy, the lower right lobe and lingular shadows were extremely improved (Fig. 1C). She was discharged on day 25 without any complications. Before discharge, we instructed her to strictly wash her hands after contact with her cats; we also instructed her to keep the cats away from her bed. We followed-up with her two years after her discharge, during which she had no symptoms of hemosputum related to pasteurellosis. Written informed consent was obtained from the patient for publication of the case details and associated images.

hemoptysis, pasteurella canis, pasteurella multocida, pasteurellosis

PMC3610710_01

Unknown

The CHIRPP database (1990-2009) was searched for individuals 5-19 years old who presented with a brain injury ("minor closed head injury", "concussion", "intracranial injury") while participating in ice hockey (hockey), soccer, American football (football), basketball, baseball, or rugby. Ringette and lacrosse were excluded because of the paucity of players and brain injuries. The extracted variables included age, sex, year, team sport, treatment (admitted/non-admitted), context (informal versus organized), a narrative description of the injury mechanism, and postal code. Sport context was categorized by organized and informal sport. Informal sport was defined as sport that was not regulated by third-party individuals including referees, coaches, or teachers. In contrast, organized sport was defined as sport in a setting in which formal regulation by a referee, coach, or teacher was present. Postal codes were used to determine community type (rural versus urban). Specific mechanisms of injury codes were developed by two research assistants (e.g.; "checked into boards from behind" or "hit by pitch while batting"). The specific mechanism of injury was then coded for the first 200 cases for each sport independently by the two research assistants using the developed coding list based on the narrative descriptions provided for each case. After establishing inter-coder agreement, the two research assistants applied the resulting codes to the remaining cases. Once coding was complete, proportions of injuries attributable to the specific mechanistic codes were determined. These specific mechanistic codes were also categorized into one of five categories: 'struck by player', 'struck by object' (in the environment i.e., net, post), 'struck by sport implement' (i.e., ball, stick), 'struck (playing) surface', and 'other'. A descriptive analysis was conducted where normally distributed continuous variables were presented as means and standard deviations and dichotomous and polychotomous variables presented as proportions with associated 95% confidence intervals. A chi-square test was performed to determine if there was an association between community type and sport context. Results were stratified by sport, sex, age group (5-9, 10-14, and 15-19 years), and helmet use. Helmet use data was analyzed for ice hockey, football, and baseball. Inter-coder reliability was evaluated by calculating chance-corrected Cohen's Kappa values.

PMC8164866_01

Male

A 61-year-old Japanese man presented with bilateral scrotal swelling noted two weeks ago. The patient had a five-year history of hypertension and DM. His current medications included amlodipine (10 mg/day), azilsartan (20 mg/day), bisoprolol (5 mg/day), linagliptin (5 mg/day), and empagliflozin (10 mg/day). His DM has been poorly controlled, and his glycated hemoglobin (HbA1c) level remained within 7-8% during the treatment period. He had no family history of TB. He was a social drinker and a non-smoker. Two years before presenting to our service, the patient was admitted to the hospital for investigation and treatment of newly developed dyspnea and fatigability. During that hospital stay, pleuritis, pericarditis, and peritonitis were identified (Figure 1A and B). However, despite extensive investigations, including repeated AFB smear, AFB culture, and Mtb polymerase chain reaction (PCR) using sputum, blood, urine, and pleural, pericardial, and peritoneal effusions, failed to determine the etiology. However, TB was strongly suspected due to a positive interferon-gamma release assay; lymphocyte-predominant pleural, pericardial, and peritoneal effusions with high adenosine deaminase levels; pleural membrane pathology, which demonstrated epithelioid cell granuloma with Langhans giant cells and caseous necrosis. Although Mtb was not isolated, TB chemotherapy was administered due to the high likelihood of having TB and his serious illness. The patient underwent two months of intensive phase treatment comprising INH, RIF, PZA, and EMB with supervision. This was followed by seven months of the continuation phase with INH and RIF. After the treatment regimen, marked clinical and radiographic improvements were observed (Figure 1C and D). Four months after completing chemotherapy, while the patient was asymptomatic, a low-intensity area in the prostate was incidentally found on follow-up computed tomography. Magnetic resonance imaging confirmed a prostate mass (Figure 2). Biopsy of the prostate did not confirm a malignancy, but it revealed epithelioid cell granuloma with Langhans giant cells and caseous necrosis. However, the AFB smear and culture from the prostate biopsy and urine were negative. The patient remained under careful monitoring and without changes in his status until the scrotal swelling was noted. Figure 3 summarizes the patient's clinical course timeline, including clinical events, chemotherapy, diabetes medications, and HbA1c level. Physical examination revealed the following: body mass index, 32.9 (height 170 cm, weight 95 kg); body temperature, 37.5 C; and blood pressure, 119/79 mmHg with a regular pulse at 107 beats/min. His scrotum was bilaterally enlarged with mild tenderness and pus discharge from a scrotal fistula. Scrotal ultrasonography revealed diffusely enlarged bilateral epididymis with a heterogeneous and hypoechogenic texture (Figure 4A and B). On magnetic resonance imaging, the mass lesion showed slightly higher and lower signal intensities relative to testicular parenchyma on T1-weighted and T2-weighted images, respectively (Figure 4C and D). The results of blood and urine examination are shown in Table 1. The glycated hemoglobin was 7.5%, which suggested that the DM was poorly controlled and complicated by stage 2 nephropathy. The estimated glomerular filtration rate was decreased relative to a baseline value of approximately 50 mL/min/1.73m2. There was a mild elevation of C-reactive protein, but neither pyuria nor hematuria was observed. The urine was sterile. The AFB smear, AFB culture, and Mtb PCR of the urine and pus discharge from the scrotal fistula were negative. Bilateral epididymectomy was then performed, and pathological examination demonstrated epithelioid cell granuloma with Langhans giant cell and caseous necrosis. Although the AFB smear was negative, the tissue tested positive for Mtb PCR. AFB culture test confirmed Mtb, and the isolated strain was resistant to INF, RIF, and EB. Table 2 summarizes the results of TB investigation. Finally, a diagnosis of multi-drug resistant (MDR) TB epididymitis was made. The patient was transferred to the TB specialized hospital for further evaluation and treatment, and then chemotherapy comprising levofloxacin, ethionamide, cycloserine, para-aminosalicylic acid, and pyrazinamide was initiated.

chemotherapy, diabetes mellitus, epididymitis, tuberculosis

PMC4300580_01

Male

A 39-year-old male patient presented with fever, left flank pain, nocturia, and daytime frequency. He was on intensive phase of antitubercular therapy for pulmonary tuberculosis. The left flank was tender on examination. Urine microscopy showed pyuria and hematuria. The serum creatinine was 1.82 mg%. Ultrasound showed a bulky left kidney with moderate hydroureteronephrosis. A left percutaneous nephrostomy was placed. He became afebrile and serum creatinine normalized after 48 h. The nephrostogram obtained subsequently showed central pooling of contrast in the excavated area [Figure 1, white arrow] in the region of interpole papilla giving "egg-in-a-cup" appearance characteristic of papillary necrosis [Figure 1].

egg in cup, nephrostogram, papillary necrosis

PMC3844251_01

Male

A 38-year-old male was seen at his local clinic with a 6-month history of loss of weight (approximately 10 kg) and progressive loss of appetite. A rapid HIV test was performed and was positive. Additional blood tests confirmed a CD4 cell count of 2 cells/muL and a positive CrAg LFA. Targeted screening of patients with CD4 cell counts of less than 100 cells/muL for cryptococcal antigenemia was recently introduced into selected laboratories in South Africa as part of the National Strategic Plan on HIV, STIs, and TB. After a positive serum CrAg LFA test, the patient was referred to our hospital for a lumbar puncture to exclude CM. He reported no headache, neck stiffness, fever, visual impairment, or night sweats. Although he had a productive cough approximately 3 weeks ago, it had resolved with antibiotics prescribed by his local clinic. On examination, temporal wasting and generalized lymphadenopathy were present. Neurological examination revealed no neck stiffness, focal neurologic deficit, papilledema, or cranial nerve involvement. No cutaneous lesions or pulmonary signs were present. The remainder of the systemic examination was normal. Laboratory blood tests showed a normocytic anaemia with haemoglobin of 11.8 g/dL. The cerebrospinal fluid (CSF) on admission was clear in appearance, and further analysis revealed lymphocytes of 1 cells/muL, neutrophils of 0 cells/muL, protein of 0.48 g/dL (normal: 0.15-0.45 g/dL), and glucose of 3.2 mmol/L (normal: 2.8-4.4 mmol/L). CSF Gram's stain, CrAg latex antigen (LA), and India ink were all negative. Xpert MTB/Rif assay of early morning sputum samples was negative for tuberculosis. A chest radiograph showed no abnormalities. A diagnosis of disseminated cryptococcosis was made. Antifungal therapy was started with high dose fluconazole of 800 mg daily according to the South African screen-and-treat algorithm for ART-naive patients with a positive CrAg and negative lumbar puncture. Cotrimoxazole was also given as prophylaxis to prevent pneumonia from Pneumocystis jiroveci. The patient was discharged from hospital a day after his admission. At the 2-week follow-up visit, the fluconazole dose was reduced to 400 mg daily and ART:with tenofovir, emtricitibine, and efavirenz:was initiated. At the 2-month visit, the fluconazole dose was further reduced to a maintenance dose of 200 mg daily. So far he is doing well and reports no symptoms of meningitis.

PMC3844251_02

Female

A 37-year-old female presented to the emergency department with a 1-week history of progressive neck stiffness, severe headache, fever, and loss of weight. She reported no other neurological symptoms. She had no medical history of TB but was diagnosed with HIV two years ago. At a visit to her local clinic about 3 weeks before this admission, laboratory tests showed a CD4 cell count of 76 cells/muL. She was subsequently started on antiretroviral therapy:with tenofovir, emtricitabine, and efavirenz. Targeted screening for cryptococcal antigenemia was not yet offered by her clinic. The physical examination revealed tachycardia, pyrexia, conjunctival pallor, and generalized lymphadenopathy. Neck stiffness was present, but no confusion, focal neurologic deficit, papilledema, or cranial nerve involvement was evident on neurological examination. No pulmonary or dermatological changes were noted. The remainder of the systemic examination was otherwise normal. The initial CSF opening pressure was raised (28 cm H20). CSF was clear in appearance, and further analysis revealed lymphocytes of 34 cells/muL, neutrophils of 5 cells/muL, protein of 1.83 g/dL (normal: 0.15-0.45 g/dL), and glucose of 1.9 mmol/L (normal: 2.8-4.4 mmol/L). Gram's stain of the CSF was negative. The cryptococcal latex antigen test (CLAT) and India ink were, however, positive. CSF CrAg titres are not routinely performed in South Africa, as antifungal treatment is standardised and fungal burden at the time of diagnosis is invariably high. Other laboratory tests showed a positive peripheral blood CrAg LFA and a normocytic anaemia (haemoglobin: 9.2 g/L). Chest radiography was normal. A diagnosis was made of cryptococcal meningitis with raised intracranial pressure and unmasking HIV-associated IRIS. ART was continued in the ward, and antifungal therapy was started with amphotericin B (1 mg/kg/day IV) and high dose fluconazole of 800 mg daily. Fluconazole is used in South Africa, as flucytosine is presently unavailable. Intravenous antimicrobial therapy with ceftriaxone was also started. To avoid nephrotoxicity and electrolyte abnormalities, she was prehydrated and given potassium and magnesium supplements. No nephrotoxicity or worsening of anaemia was noted during admission. Therapeutic lumbar puncture was performed three times a week to relieve symptoms of raised intracranial pressure, and paracetamol was given for further analgesia. Corticosteroids were also added to the regimen. By hospital day 14, her symptoms had improved greatly. Intravenous amphotericin was stopped and the dose of fluconazole was changed to 400 mg daily. She was discharged from hospital 3 weeks after admission. At her 2-month follow-up visit, she was maintained on fluconazole of 200 mg daily as secondary prophylaxis. She is currently well and reports no recurrence of her symptoms.

PMC7212466_02

Male

In April 2014, Mr. WF (now aged 73) was admitted to the Department of Neurology of Marburg University because of dizziness. After the physical causes excluded, and because Mr. WF complained of imperative and commentating voices of two witches, who:as he thought:were responsible for the dizziness, a second psychiatric in-patient admission took place. At the admission to the Department of Psychiatry and Psychotherapy of Marburg University, he experienced AVH, paranoid delusions, and perceived the control by witchcraft. In his physical examination, we saw a right-dominated tremor of the hands. Comprehensive technical examinations (including blood tests, structural MRI, cerebrospinal fluid diagnostics, FP-CIT, and 18F-FDG-brain-PET) depicted a moderate subcortical arteriosclerotic encephalopathy, which might be the cause of the vascular parkinsonism. Considering moderately elevated tau protein levels in the CSF, a mesial temporal reduced 18F-FDG utilization [NIA-AA Biomarker profile A-T+N+ ], as well as the impaired short-term verbal and figurative memory, attention, and psychomotor speed, without incapacity for independence in everyday activities, we suggested a minor non-Alzheimer neurocognitive disorder, besides the VLOSLP. For the neurocognitive assessment, the standardized Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-test battery was applied; scores are listed in the Supplemental Material , Tables S1 and S2 . A monotherapy with olanzapine (up to 20 mg/d) led to a remission of perception of control by witchcraft and dizziness. However, the AVH remitted only partially. Since no complete remission could also be achieved during the 12 weeks of further treatment, Mr. WF was re-admitted to our in-patient unit for an add-on inhibitory TBS trial (July 2014). After the first five sessions, the patient reported a significant reduction of the AVH; after ten sessions, a stable remission was achieved. After the discharge, Mr. WF resigned the out-patient psychiatric treatment and chose to discontinue his antipsychotic medication in November 2014, mostly due to the absence of any subjective complaints. In January 2015, he was again admitted to a neurologic hospital because of dizziness. Due to low body rigidity and tremor, a treatment trial with levodopa was initiated by colleagues. This medication was well tolerated but did not lead to any significant clinical effects. In June 2015, Mr. WF reported a sudden re-occurrence of AVH and paranoid delusions (evaluated by a face-to-face interview using simple YES/NO questioning, see Supplementary Material Box S1 ); thus, a psychiatric re-admission was again required. Since no remission could be achieved after dopamine-agonistic medication and an 123I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane) (FIT-CT)/single photon emission computed tomography (SPECT) revealed the non-altered density of dopamine transporter, levodopa was tapered out. Next, TBS monotherapy was carried out in July 2015, however, without significant improvement (evaluated by targeted questioning). Later, we prescribed clozapine (up to 150 mg/d, July 2015), however, failing to reduce the AVH sufficiently (evaluated by targeted questioning), and leading to a psychomotor retardation and further cognitive decline. Thus, clozapine was then tapered out. In August 2015, olanzapine was prescribed again due to prior positive experience with it during the first psychotic episode. The olanzapine monotherapy (4 weeks, 15 mg /d) led again to a merely partial response (evaluated by targeted questioning). Considering the positive experience during the previous in-patient treatment, the TBS augmentation (September 2015) was then repeated and led to a complete remission of AVH (evaluated by targeted questioning) as during the last episode. Later, the remission remained stable in combination with the maintenance medication olanzapine (5 mg/d). An overview of the full treatment course can be seen in the Supplementary Material . All essential milestones related to the diagnoses and interventions are presented there as a timeline.

auditory processing, auditory verbal hallucination, brain stimulation, elderly, functional mri, theta-burst stimulation, very-late-onset schizophrenia-like psychosis

PMC5173504_01

Male

A 42-year-old man presented with intermittent hemoptysis. Chest computed tomography (CT) showed pulmonary embolism and thickening of the pulmonary artery walls (Fig. 1a). DVT was not noted on lower extremity CT but was confirmed by lower extremity ultrasound. The laboratory findings were as follows: white blood cells (WBC) 8,500 /muL with no eosinophilia, hemoglobin (Hb) 10.3 g/dL, C-reactive protein (CRP) 8.7 mg/dL, negative anti-nuclear antibodies, negative anti-cardiolipin IgG antibody, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) <0.5 IU/mL, proteinase 3 (PR3)-ANCA <0.5 IU/mL, and D-dimer 2.4 mug/mL. Pulmonary thromboembolism was diagnosed, and anti-coagulant therapy was started. During follow-up, the patient continued to have bloody sputum, CRP remained elevated at 3 to 6 mg/dL, and gradual expansion of the pulmonary arteries was noted on chest X-ray (Fig. 2). Five months after starting anti-coagulant therapy, he was readmitted for massive hemoptysis. On arrival, his oxygen saturation was 76% breathing ambient air and 94% on 10 L/min of oxygen. The findings on his physical examination were normal, including lung sounds and lower extremity evaluation. Chest X-ray showed consolidation in the right lower lung field (Fig. 3, left). The laboratory findings were as follows: WBC 13,000 /muL, Hb 8.4 g/dL, CRP 6.3 mg/dL, erythrocyte sedimentation rate (ESR) 107 mm/hr, and D-dimer 7.9 mug/mL. Chest CT showed prominent aneurysms and thickening of the pulmonary artery walls (Fig. 1b) with consolidation predominantly located in the right middle lobe, findings which were all suggestive of hemorrhage. The results of echocardiography were normal with an estimated right ventricular systolic pressure of 27 mmHg, and right heart catheterization was not performed due to the risk associated with the procedure. Anti-coagulant therapy was immediately discontinued. Further examinations revealed that the patient had had recurrent oral ulcers since his early 30s and a history of uveitis two years prior and erythema nodosum one year prior. The uveitis and erythema nodosum had been successfully treated with topical steroids. The patient was diagnosed with Behcet's disease. Human leukocyte antigen testing was positive for B51, and findings from an interferon gamma release assay for tuberculosis and serologic tests for syphilis were negative. Intravenous methylprednisolone (1 g/day) for 3 days was followed by oral prednisone 50 mg/day (1 mg/kg/day), which was subsequently tapered. Intravenous cyclophosphamide at a dose of 750 mg (15 mg/kg) was also given every 3 weeks for a total of 6 cycles, followed by oral azathioprine. Within two weeks, hemoptysis disappeared, his CRP values normalized, and his ESR decreased to 15 mm/hr. The pulmonary artery aneurysm and thrombosis gradually resolved, and nearly returned to normal state at the end of cyclophosphamide pulse therapy, which was five months after starting treatment (Figure 1c and d, 3).

PMC5772064_01

Female

A 91-year-old woman presented to our center complaining of nonbloody diarrhea for 6 months and an associated 10-kg weight loss. Her initial lab results suggested hypochromic microcytic anemia. Upper endoscopy showed a fistula between the second portion of duodenum and the right colon (Figure 1). Through the fistula tract, a solid viscera with a nodular mucosa was visible in the lumen of the right colon (Figure 2). Abdominal computed tomography revealed a mass between the right colon, the second portion of duodenum, and the right kidney; this allowed the passage of oral contrast between these structures, confirming that the solid viscera seen on endoscopy was in fact the right kidney (Figure 3). Histology of the biopsied viscera confirmed a poorly differentiated renal carcinoma. Given the stage of her disease, age, and comorbidities, the patient was referred for palliative management; 2 months later, the patient died. Duodenocolic fistulas are classified into primary and secondary groups; primary fistulas can be due to infectious etiology, Crohn's disease, peptic ulcer disease, or active malignancies without any prior surgeries. Secondary fistulas can develop as a complication after a major gastrointestinal surgery. Colorenal and duodenal-renal fistulas, however, are uncommon. These occur primarily in patients who have undergone procedures such as percutaneous nephrolithotomy or cryoablation for renal cell carcinoma; less frequently, they occur with chronic kidney infection or tuberculosis. The only previously reported case of a secondary duodeno-colo-renal fistula was described in Taiwan, in a patient with renal squamous cell carcinoma in association with nephrolithiasis who underwent nephrolithotomy. Ours is the first case of a primary duodeno-colo-renal fistula originating from an advanced renal tumor. Fistula management is guided by the patient's disease stage, nutritional status, and comorbidities. In a localized disease, management options range from nephrectomy, right hemicolectomy with a pancreaticoduodenectomy, or segmental duodenectomy. In more advanced cases, an extensive bowel resection or palliative options like tube jejunostomy/loop ileostomy can be offered. Palliative management was offered for our patient due to her age, comorbidities, and the advanced state of her disease.

PMC9217622_01

Female

A 60-year-old woman with relapsing multiple sclerosis presented from her long-term care facility with altered mental status, fatigue, anorexia, and jaundice. She had been started on teriflunomide therapy (14 mg daily) nine months prior, at which point liver tests (LTs) were normal. On arrival, she was afebrile, tachycardic, and normotensive, without an oxygen requirement. Labs were significant for aspartate transaminase (AST) of 1,499 U/L, alanine aminotransferase (ALT) of 777 U/L, alkaline phosphatase (AP) of 478 U/L, and total bilirubin (Tbil) of 2.5 mg/dL, without significant abnormalities on complete blood count or chemistry panel. The INR was 1.20. Lactate and lipase were normal, acetaminophen level was <2 ug/ml, and COVID-19 and influenza A and B were negative. Initial CT and abdominal ultrasound showed nonspecific hepatic echogenicity, patent hepatic vessels, and no abnormalities in the biliary system. Teriflunomide was discontinued immediately upon admission given the black box warning for hepatotoxicity, and she was admitted for workup. Hepatitis and herpes serologies were negative. Antinuclear antibody, liver-kidney microsomal antibody, immunoglobulin G levels, alpha-1 antitrypsin, serum protein electrophoresis, and iron levels were normal. Rheumatologic workup was notable for a positive smooth muscle antibody with a titer of 1 : 40, which was thought to be clinically insignificant. Ferritin was significantly elevated at 28,754 ng/ml; however, MRI with iron quantification showed no evidence of iron overload. Hemochromatosis gene testing revealed heterozygosity for the H63D mutation, a genotype that has not been clearly associated with symptoms of hereditary hemochromatosis. In combination with the MRI and other lab results, this was not thought to be clinically significant. Over the course of admission, AST and ALT trended down, but AP, Tbil, and INR continued to rise. ERCP with EUS and liver biopsy were performed on hospital day 5. Biopsy was most consistent with drug-induced injury, with a minor component of steatohepatitis. Teriflunomide was the suspected culprit drug, and the patient was treated with cholestyramine 4 grams every 6 hours for accelerated elimination starting on hospital day 7. LTs dropped consistently across all lab markers by hospital day 10 (Table 1). Teriflunomide was discontinued indefinitely at the time of discharge back to her long-term care facility. At one month follow-up, LTs were markedly improved (Table 1).

PMC3278599_01

Female

Mycobacterium caprae, a recently defined member of the Mycobacterium tuberculosis complex, causes tuberculosis among animals and, to a limited extent, in humans in several European countries. While in the ten year period until 2009, there was only one human tuberculosis case with Mycobacterium caprae documented in Austria (in 2008), in 2010 three such cases were registered for this mandatorily reportable disease. Already in fall 2008, the western provinces Tyrol and Vorarlberg had begun to test all cattle for tuberculosis, after documenting occurrence of Mycobacterium caprae in some herds of one of nine Tyrolean districts. More than 100 cows from 75 farms had to be culled. Cattle were supposed to have become infected after grazing on alpine pastures contaminated by diseased deer. In the affected district, the county of Reutte, neighbouring the province of Vorarlberg, more than 10% of the red deer (Cervus elaphus) population was found to be infected with Mycobacterium caprae. Overstocking and winter feeding (with "unnatural" crowding of deer at few feeding places) was considered the cause. In 2010, public authorities ordered decimation of half of approx. 1100 red deer in the affected county. The sudden emergence of three human Mycobacterium caprae infections in 2010 raised the question as to whether there was an epidemiological link between animal and human illness. Figure 2 depicts the geographic origin of the Mycobacterium caprae infections in cattle, deer (unpublished AGES data) and humans documented in 2010. MIRU genotyping was performed on these animal and human Mycobacterium caprae isolates. MIRU patterns from deer and cattle isolates were indistinguishable from each other, but clearly different from the three patterns of the human isolates. The molecular genetic analysis did not reflect patterns indicative of spread of Mycobacterium caprae from the veterinary outbreak in western Austria to the human cases in eastern Austria. MIRU-VNTR results were substantiated by epidemiological findings: patient A, a 13 year old girl of Turkish ancestry living in Vienna probably became infected when visiting her grandparents in rural Turkey during summer breaks. Patient B, a 85-year-old lady from Lower Austria, probably got infected by her late husband, who had the cattle of his farm culled due to bovine tuberculosis in the early 1960s. Patient C, a 70-year-old patient from Upper Austria probably got infected around 1965, when the cattle of his farm had to be culled by public order because of tuberculosis. Molecular typing was not only able to exclude a connection between the recent re-emergence of tuberculosis in cattle and deer with the occurrence of human Mycobacterium caprae cases but even to disprove the existence of a human outbreak. Ten years ago, a single-endonuclease, amplified fragment length polymorphism analysis method by which the patterns are resolved by standard agarose electrophoresis, was adopted as an international standard by the European Working Group for Legionella Infections (EWGLI), especially for cases of travel-associated legionellosis. However, while this method allowed relatively reliable screening of isolates within a single laboratory, inter-laboratory comparison of the results still posed a significant hurdle. Therefore, EWGLI developed a sequence-based typing (SBT) scheme for clinical and environmental isolates of Legionella pneumophila, which is presently widely used in Europe in the investigation of outbreaks of legionellosis caused by Legionella pneumophila. The advantages of using a multilocus sequence typing approach with nonselective housekeeping genes has been well documented for various microorganisms. Using the so-called SBT protocol, the SBT database (provided by EWGLI in conjunction with the London based Health Protection Agency and the European Centre for Disease Prevention and Control in Stockholm under http://www.hpa-bioinformatics.org.uk/legionella/legionella_sbt/php/sbt_homepage.php) allows assignment of the seven ordered alleles, flaA, pilE, asd, mip, mompS, proA, and neuA as described by Gaia et al. and Ratzow et al., and representation as one of presently 1032 sequence types (ST). ST 81 for instance has the allelic profile, i.e. the ordered string of allele numbers separated by commas, 2,10,3,28,9,4,9.

dna fingerprinting, multilocus sequence typing, pulsed-field gel electrophoresis, sequence-based typing

PMC3278599_02

Female

The following example on Legionella pneumophila underlines the considerable potential of this molecular typing method to elucidate connections between an environmental source, in this case a hospital drinking water system, and a case of human illness. At the end of July 2010, the Austrian reference centre for legionella learned about a case of legionella pneumonia in a 70 year old female patient, who had died on July 26. Onset of symptoms had occurred on July 22, admission to hospital C on July 24. A urinary antigen test performed on day 2 of hospitalization was positive for Legionella pneumophila. The patient, who also suffered from neoplasm bronchi with brain metastases, had previously been hospitalized in hospital A for chemotherapy from July 6 to 16, and after spending four days at her private home (from July 16 to 20) - in hospital B for gamma-knife intervention (July 20 to 21). In order to identify the environmental source of infection, efforts were made to obtain a patient isolate for comparison with possible future environmental isolates. A blood culture drawn on July 25 (with a negative result reported by the laboratory of hospital C) was the sole specimen available (autopsy was denied due to religious constraints). Two blood culture bottles were sent to the national reference laboratory and volumes of 0.1 and 0.5 mL were directly plated onto buffered charcoal yeast extract agar with and without glycine, vancomycin, polymycin B and cycloheximide supplementation (Oxoid, Cambridge, UK). After incubating for five days, approximately ten colony forming units (CFU) per ml blood culture medium were gained: Legionella pneumophila serogroup (sg) 1 (ST 81) and Legionella pneumophila sg 3 (ST 93). Double infection is a rare, but not unusual phenomenon, be it in salmonellosis, in tuberculosis or in legionellosis. For the health administrators in charge, an available isolate usually initiates an attempt to identify the source of the patient's infection in order to prevent further fatalities. Legionella is often found in warm and cold water systems of buildings; without proof of clonal identity, the mere demonstration of Legionella pneumophila in a water system cannot be regarded as proof of causal relation with illness. Within the incubation period of 2 to 10 days, the patient had stayed in two hospitals and in her own apartment. The testing of water samples, drawn from the patient's room in hospitals A and B and at her home, demonstrated legionella contamination in all three facilities. Water samples (cold and hot water, mixed) obtained on July 29 from the room occupied by the patient during her stay in hospital A yielded 1 CFU Legionella pneumophila sg 1 (ST 81)/100 mL from the sample "hand washbasin tap" and 7 CFU Legionella pneumophila sg 3 (ST 93)/100 mL from the sample "shower". Water samples (again cold and hot water, mixed) obtained on July 29 from the room occupied by the patient during her stay in hospital B yielded 1 CFU Legionella pneumophila sg 1 (ST 442)/100 mL from the sample "shower". Water samples obtained on August 4 from the patient's home yielded 1-220 CFU Legionella pneumophila sg 10/100 mL. Sequence based typing revealed that hospital A was the causative reservoir. The financial resources necessary to sanitize this contaminated drinking water system would not have been allocated without microbiological proof of a causal connection with human illness.

dna fingerprinting, multilocus sequence typing, pulsed-field gel electrophoresis, sequence-based typing

PMC8077663_01

Female

We are reporting a 32-year-old woman known to have diabetes mellitus who presented to the emergency department initially with a 2-week history of abdominal distention and increased abdominal girth associated with shortness of breath. She denied any nausea, vomiting, abdominal pain, loss of appetite, early satiety or unintentional weight loss, hematemesis, melena, or hematochezia. The patient denied any past surgical history. She was born and raised in the USA and never traveled outside the USA. Her social history was significant for active tobacco and marijuana smoking. She had no known allergies. Her initial vitals were blood pressure of 131/79 mm Hg, a pulse of 83 bpm, respiratory rate of 18, and temperature of 98.6 F. On examination, the abdomen was soft and distended with positive shifting dullness. Bowel sounds were normal. Computed tomography (CT) scan of the abdomen and pelvis with contrast showed a large amount of ascites with normal hepatic architecture. Ultrasound of the pelvis showed large-volume ascites and normal appearing ovaries and uterus. The patient underwent paracentesis showing a low SAAG value (of 1 and repeat 0.6) with high protein (6.4 and repeat 7), neutrophilic predominance initially (total WBCs 6,760 with 95% neutrophils), then lymphocytic predominance (total WBCs 3,840 with 64% lymphocytes); cytology of ascitic fluid was negative for any malignant cells. Of note, she was found to have an adenosine deaminase (ADA) level of 113 in ascitic fluid; upon repeat testing, the level was 100.6. Acid-fast staining, MTB PCR, and mycobacterium cultures were negative in ascitic fluid. Ascitic fluid amylase level was 46 U/L, TAG level was 22 mg/dL, and LDH level was 554 U/L. HIV testing, HCV testing, HAV IgM, and auto-immune workup, including ANA, ANCA vasculitis antibodies, anti-smooth muscle antibodies, and liver kidney microsomal antibodies, were also negative. Serum pro-BNP was 40 pg/mL, lipase 37 U/L, ceruloplasmin level 38 mg/dL, alpha-1-antitrypsin level 144 mg/dL, ESR 100 mm/h, and CRP was 85 mg/L. Her serum immunofixation showed a dense polyclonal pattern suggestive of chronic inflammation. Urine testing for Chlamydia trachomatis and Neisseria gonorrhoeae was negative. CT of the chest and CT of the abdomen and pelvis with contrast material were negative for any malignant focus. She underwent exploratory abdominal laparoscopy, which revealed fibrinous exudate on the peritoneal surface, and had a biopsy of the peritoneum. The pathology report from the peritoneal biopsy showed granulomatous inflammation with no malignancy (Fig. 1). PAP smear showed atypical squamous cells of undetermined significance. Endometrial biopsy was also negative for any malignancy. Transvaginal ultrasound showed normal ovaries. She also had EGD and colonoscopy to rule out gastrointestinal malignancy and in view of the unknown origin of ascites. EGD and colonoscopy both were unremarkable, and biopsy reports were negative for any malignancy. The patient was lost to follow-up, and treatment was not initiated.

abdominal pain, adenosine deaminase, ascites, liver

PMC9909080_01

Male

A 72-year-old male patient, who previously worked as a teacher and cacao farmer, with a previous history of hypertension and ischemic stroke, in addition, the patient had been receiving treatment with botulinic toxin, as a measure to improve facial symmetry, reducing hyperkinesis, and facial imbalance due to the diagnosis of Bell's palsy. This treatment was provided by a private neurologist from another hospital, we were not provided with previous computed tomography (CT) and magnetic resonance imaging (MRI) studies. The patient presented at the emergency department to the hospital with and 10-day history of fever, respiratory symptoms, productive cough, occasional chest pain, and dyspnea with hypoxemia (SO2 85%). He has previously received 2 doses of COVID-19 vaccine, and real-time polymerase chain reaction (RT-PCR) for SARS-CoV-2 was negative. Owing to severe dyspnea and persistent hypoxemia despite administration of oxygen, the patient required orotracheal intubation and mechanical ventilation. Laboratory results upon admission were as follow: white blood cells 11.420/microL (normal value [NV]: 4.000-11.000/microL), neutrophils 94% (NV: 40%-60%), lymphocytes 22.4% (NV: 20%-40%), C-reactive protein (CRP) 38 mg/dL (NV: 0-5 mg/dL), procalcitonin 0.23 (NV: 0.25-0.50 mg/dL), ferritin 118 ng/mL (NV: 12-300 ng/mL), and D-dimer 450 ng/mL (NV: < 500 ng/mL). Chest computed tomography (CT) scan showed bilateral consolidation with left predominance (Figure 1). A diagnosis of severe CAP was made, and empirical antibiotic therapy with cefepime and levofloxacin was started. On hospital day 2, once the patient was hemodynamically stable, fiberoptic bronchoscopy was performed, wherein thick whitish mucous secretions obstructing the bronchial lumen were observed (Figure 2). The BAL sample was sent to the molecular biology laboratory, and no microorganisms were detected through a FilmArray respiratory panel and MALDI-TOF Biotyper mass spectrometry. In addition, the BAL samples were negative for Ziehl Neelsen (ZN) stain, GeneXpert MTB/RIF (Xpert), and Lowenstein-Jensen culture for tuberculosis. On hospital day 4, sedation and ventilator weaning were started; however, atelectasis of the left lung was noted (Figure 3). On hospital day 5, a second fiberoptic bronchoscopy was performed, which yielded similar findings of a thick mucus plug obstructing the bronchial lumen of the right and left pulmonary segments and scattered whitish plaques on the bronchial mucosa. Bronchoalveolar lavage was performed once again, and the samples were sent for bacteriological and fungal study. The following results were obtained: Galactomannan Aspergillus test 0.18 pg/mL (negative), mamanocandidas for Candida 166 pg/mL (positive), and KOH smear with fungal structures compatible with yeasts. In addition, MALDI-TOF Biotyper mass spectrometry identified C tropicalis (Figure 4). Treatment was started with echinocandins, specifically caspofungin 75 mg as an initial dose and then 50 mg daily. Pulmonary biopsy at the level of the carina was taken, and the sample was sent for histopathological study. By hospital day 7, due to prolonged intubation and failure to wean from the ventilator, surgical tracheostomy was scheduled. The lung biopsy report revealed the following: surface epithelium had areas of reactive hyperplasia without atypia; the chorion had variable degrees of edema and a discrete quantity of scattered lymphoplasmacytic inflammatory cells, alternating with occasional neutrophils. Few conserved bronchial glands and undamaged paired smooth muscle lamina were also identified. After 10 days of treatment with caspofungin, ventilatory weaning was finally achieved, without presenting with a new episode of pulmonary atelectasis. By day 14, the patient was decannulated from the tracheostomy. Oral antifungal treatment with voriconazole was continued, and he was discharged from the ICU in good clinical condition. One month after discharge, a high-resolution CT scan of the chest was performed revealing scarce cylindrical bronchiectasis (Figure 5).

candida tropicalis, filmarray respiratory panel, maldi-tof biotyper, bronchoalveolar lavage, pneumonia

PMC5473645_01

Male

A 51-year-old healthy male presented a sudden episode, witnessed by his wife, of diffuse jerky movements during sleep which ceased in a few minutes, rendering the patient confuse, with amnesia of the episode, and evidence of tongue biting. Transferred to the Emergency Department, he had 3 additional, convulsive episodes that were treated with benzodiazepines. He had sustained fever for 3 days prior to admission. A nasopharyngeal swab test using isothermal nucleic acid amplification technology (Alere i Influenza A & B) confirmed influenza A infection. This episode coincided with an inflenza outbreak. General and neurological examinations were normal. Complete blood counts and blood chemistries were within the normal range. He had no history of prior seizures, febrile seizures, head trauma, stroke, or family history of seizures. EEG, CSF and neuroimaging findings are described on Table 1. He was discharged on therapy with phenytoin and levetiracetam, both withdrawn after one month. He became afebrile in a week and seizures have not recurred in 18 months.

encephalitis, encephalopathy, influenza virus, seizures

PMC5473645_02

Male

A 50-year-old healthy male was brought to the Emergency Department because of a tonic-clonic seizure of about 1-2 minutes, witnessed by his wife, with subsequent confusion for 15 minutes. He had had fever and expectoration for two days before the convulsive event and was being treated with amoxicillin. Examination revealed a tongue bite and was otherwise normal. A nasopharyngeal swab test (Alere i Influenza A & B) confirmed influenza A infection, consistent with an ongoing influenza outbreak. EEG, CSF and neuroimaging findings are described on Table 1. Complete blood counts and blood chemistries were within the normal range except for an increased serum C reactive protein value of 32.9 mg/L (normal < 5 mg/L). He was discharged the following day without antiseizure antiepileptic medication and seizures have not recurred in 18 months. There was no history of prior seizures, febrile seizures, head trauma, stroke, or family history of seizures.

encephalitis, encephalopathy, influenza virus, seizures

PMC5473645_03

Female

A 19-year-old female in prior good health was brought to the Emergency Department because of a tonic-clonic seizure of about 2-3 minutes followed by confusion for 15 minutes. A throat swab test confirmed influenza B infection, also consistent with an ongoing influenza outbreak. Physical exam was normal. Results of EEG, CSF and neuroimaging are described in Table 1. Complete blood counts and blood chemistries were within the normal range except for an increased serum C reactive protein value of 17.4 mg/L (normal < 5 mg/L). She was discharged without medication and seizures did not recur in 18 months. She denied prior seizures, febrile seizures, head trauma, stroke, or family history of seizures.

encephalitis, encephalopathy, influenza virus, seizures

PMC3917524_01

Female

A 31-year-old primigravida woman (22 weeks' pregnant) presented at our Maternity Department complaining of abdominal pain, nausea and vomiting. These symptoms appeared 6 months ago. Initially, they were attributed to pregnancy, but they progressively became more severe during subsequent weeks. A clinical examination revealed a cachectic conscious anicteric woman with mild fever (38 C). The cardiovascular and pleuropulmonary examination were normal. Her abdomen was distended, deep tenderness was elicited in both iliac fossae, and a fluid thrill with shifting dullness confirmed the presence of intraperitoneal free fluid. An abdominal ultrasound confirmed the pregnancy and showed intra-abdominal fluid, mainly in her lower abdomen and a thickened peritoneum (Figure 1). No ovarian mass was identified on ultrasound. A laboratory investigation showed mild normochromic and normocytic anemia (hemoglobin level 10g/dL) and high C-reactive protein without leucocytosis. Her liver function was normal. Serology of viral hepatitis (B and C) and human immunodeficiency virus (HIV) were negative. Of tumor markers, only cancer antigen 125 (CA-125) was found to be high (500U/mL). Ascitic fluid was exudative with a white cell count of 860/mm3 (lymphocyte dominant: 480/mm3). Her serum-ascites albumin gradient was calculated to be 0.9. Ziehl-Neelsen stain which was investigated in three samples of sputum and in ascitic fluid was negative. The result of a tuberculin skin test was positive. The chest X-ray picture showed no active lesion or old lesion compatible with pulmonary tuberculosis. A diagnostic laparoscopy showed multiple extensive yellow-white nodules on her peritoneal surface with miliary deposits on the intestine (Figure 2), and the biopsy demonstrated caseous necrotic granuloma (Figure 3). She was prescribed antituberculous chemotherapy with rifampicin, isoniazid, and pyrazinamide for 2 months and 4 months of rifampicin-isoniazid. She was given pyridoxine supplementation (25mg/day). After 4 days her general condition improved significantly and her pregnancy continued without any problem. At term a spontaneous vaginal delivery occurred of a live healthy male neonate weighing 3100g. Treatment was well tolerated during pregnancy and after delivery we saw no adverse effects of antituberculosis therapy in either the mother or the neonate.

PMC3938368_01

Male

A 28-year-old male from Santarem, Para, Brazil, with a history of leisure activities in a rural area, tractor driver, a known carrier of the HIV virus since 2010, however without previous follow-up, contacted us for the first time at Fundacao de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil, for investigation of left knee chronic monoarthritis associated with tegumentary lesions. He had been using zidovudine, lamivudine, lopinavir/ritonavir for three weeks, this being the first antiretroviral regimen used. He had never used prophylactic trimethoprim-sulfamethoxazole. He denied being a smoker or alcohol user. He reported that the left knee arthritis appeared after local trauma identified five months before, preceding the tegumentary lesions that appeared two months after the fact. During the clinic exam, polymorphism of skin lesions was noted with pustules of follicular distribution, papules with central necrosis, erythematous-infiltrated plaques covered with pustules and ulcerated plaques, located on the face, trunk, abdomen and limbs, associated with left knee arthritis (Figures 1, 2 and 3A). Oral and genital mucosa were spared. Lymphadenopathy and hepatosplenomegaly were not observed. Blood cultures for aerobes, mycobacteria, fungi and leukocyte cream were negative. VDRL resulted non-reagent. The Leishmaniasis screening exam was negative. The analysis of synovial fluid suggested infectious arthritis. Left knee x-ray showed reduction of joint space and osteolytic patellar lesion (Figure 3B). Patient underwent surgical cleansing of joint, biopsy of synovial membrane and skin. Both exams identified round cells, birefringent, with multiple buddings compatible with P. brasiliensis (Figure 4). Culture of synovial tissue confirmed the finding. Complementary propedeutics suggested pulmonary involvement and the Xpert/MTB RIF sputum test was negative. At the time of diagnosis T CD4+ count was 44 cells/mm3 . Patient was treated with Amphotericin B deoxycholate 50mg/day (cumulative dose of 650mg) but despite the therapy, his clinical condition worsened, progressing to death on the 20th day of hospitalization. Necropsy revealed involvement of lungs, liver, spleen, kidneys, adrenals and bone marrow, in addition to the previously described sites (Figure 5).

PMC2700429_01

Male

A 30-year-old primigravida, diagnosed as a case of Macleod syndrome for the past 12 years, was supervised in our antenatal clinic. She had received antitubercular drugs for pulmonary tuberculosis at 8 years of age; and later on, intercostal chest tube drainage for empyema thoracis at her native place. She had recurrent episodes of fever, breathlessness and cough when she had presented in the Department of Pulmonary Medicine at our institute. Chest X-ray revealed old lesions of pulmonary Koch's with cicatrisation collapse. Computed tomographic scan showed decreased attenuation of right lung and basal segment of left lung, diminished right hilar vessels and bronchiectasis, consistent with the Swyer-James syndrome. She had regular follow-up in our clinic. General physical examination showed tracheal deviation to right side. Chest auscultation revealed diffuse crepitations in right lung fields. Spirometry revealed moderate obstruction with FEV1 (forced expiratory volume in one second) IOL, FEV1 / FVC (forced vital capacity) 69%. Maternal and fetal surveillance was uneventful. She was normotensive till 34 weeks of gestation, when she developed severe preeclampsia and features of imminent eclampsia, for which labor was induced with oxytocin. Intrapartum arterial blood gas monitoring on room air showed PO2 77 mmHg, PCO2 28 mmHg, pH of 7.40, O2 saturation 97.5%. She developed non-reassuring fetal heart rate patterns, and a live-born male baby weighing 1,830 g with normal Apgar score was delivered by emergency cesarean section under spinal anesthesia. Broad-spectrum antibiotics were given for surgical intervention, as well as pulmonary infection prophylaxis. Intraoperative and postoperative period was uneventful, and both the mother and the child were discharged in a satisfactory condition.

bronchiectasis, swyer-james syndrome, hyperlucent lung

PMC6720662_01

Male

A 66-year-old man reported to the appointment with complaints related to impaired aesthetics. The intraoral clinical examination revealed the presence of worn maxillary and mandibular dentition, with dentinal craters and sharp edges on the enamel of remaining teeth (Figures 1-4). Upon extraoral examination, the patient showed bilateral hypertrophy of the masticatory muscles. The radiographic examination revealed the absence of tooth number 20. Teeth number 9 and 19 had previous endodontic treatment and direct composite restorations (Figure 5). Both posterior maxillary and mandibular dentition displayed worn occlusal/incisal surfaces. No anterior or canine guidance for eccentric jaw movements was present. The magnitude of occlusal vertical dimension loss was achieved using the interocclusal rest space with the jaw in rest position that was found to be around 6 mm, greater than the normal value (2 to 4 mm). The treatment options were explained and a conservative treatment modality was adopted, which included the preparation of maxillary and mandibular canines and first molars for monolithic zirconia crowns in order to obtain four-point occlusal stability on the increased vertical dimension, that would allow to rehabilitate the anterior teeth with porcelain veneers and the remaining posterior teeth with ceramic overlays with facial coverage. In order to improve aesthetics, these monolithic zirconia crowns were veneered with porcelain in nonfunctional facial areas. A dental implant was proposed on the region of tooth number 20, but the patient decided to place a fixed bridge. An informed consent was obtained from the patient. After facial and smile analysis, the photographic sequences were obtained and intraoral impressions were taken with irreversible hydrocolloid (Orthoprint, Zhermack). The digital planning using a digital smile design was complemented with a diagnostic wax-up that was produced on study casts and a direct mock-up with bis-acrylic composite (Protemp Plus, 3M ESPE). All changes needed were done on the mock-up, and a silicone guide was obtained. Following this, the canines and first molars of both arches were prepared for full crowns. A medium grit diamond bur with rounded edge was used to ensure a minimum axial wall thickness for zirconia of about 1.0 mm to 1.5 mm. At gingival margin, a continuous circumferential chamfer with at least 0.5 mm reduction was made. A minimum of 1.5 to 2 mm incisal/occlusal reduction was ensured, approximately. The vertical and horizontal preparations were performed in order to obtain an angle of approximately 6 to 10 degrees between them. All edges and angles were rounded. The anterior maxillary and mandibular teeth were minimally prepared for veneers, ensuring a minimum restoration thickness on the cervical and labial area of about 0.5 mm and 0.7 mm on the incisal edge. All other teeth were only softened from the sharp edges of the enamel. Then, the retraction cords were applied (double retraction cord technique, #000 and #0 Ultrapak, Ultradent) and elastomeric single step impressions were made with putty and low consistency polyvinylsiloxane impression materials (Affinis, Coltene) to obtain the definitive casts. Maxillomandibular records (facebow) with the increased occlusal vertical dimension were obtained, and the master casts were mounted on a semiadjustable articulator. After tooth preparations, provisionals on the anterior teeth and first molars were placed and cemented with noneugenol temporary dental cement (TempBond NE, Kerr). Digital technologies were then included in the workflow with the laboratory scanning of the master casts and CAD/CAM manufacturing software, along with computer-controlled machinery (Zirkonzahn). The casts and the wax-up were scanned into the computer-aided design software in order to produce the monolithic zirconia crowns for the canines and first molar crowns. Facial cutbacks for feldspathic ceramic were made digitally in order to improve aesthetics on these crowns. These crowns were designed in such a way so that the incisal edges of the canines were included and the veneering porcelain was applied only onto nonfunctional labial/buccal areas. The monolithic zirconia frameworks were milled using CAD/CAM software according to the manufacturer's specifications (Prettau Zirkon, Zirkonzahn). Following framework proof and occlusal adjustments of canines and first molar upper and lower crowns, ceramic was applied on the facial surfaces of the monolithic zirconia frameworks (IPS e.max Ceram, Ivoclar Vivadent) and the feldspathic veneers for the anterior maxillary and mandibular teeth were produced (IPS e.max Press, Ivoclar Vivadent). The canine and first molar monolithic zirconia crowns were cemented according to the manufacturer's instructions. The crowns were pretreated with aluminum oxide sandblasting (110 mum; 3.5 bar), steam blasted, and dried with compressed air. After the application of the bonder, the excesses were removed by compressed air and the crowns were allowed to dry for 60 seconds. The dual-cured resin cement (RelyX Unicem, 3M ESPE) was applied, and the crowns were finally inserted. After an initial polymerization of 2 seconds of light cure, all the excesses were removed and a glycerin gel was applied before the final polymerization of 120 seconds. The anterior upper and lower porcelain veneers were cemented with resin cement (RelyX Veneer Cement, 3M ESPE). Immediately after cementation (Figures 6 and 7), a digital scan of remaining teeth of booth arches and a bite registration was obtained with an intraoral scanner (Trios, 3Shape) (Figure 8). Posterior facial and occlusal lithium disilicate glass-ceramic restorations were that obtained via CAD/CAM (IPS e.max CAD for Cerec and inLab, Ivoclar Vivadent) (Figure 9) and cemented on the same day with composite (Figure 10). Minor occlusal adjustments were made intraorally and polished with polishing burs. Canine guidance and anterior guidance were also verified for eccentric jaw movements with posterior disclusion. A panoramic radiograph was obtained after cementation (Figures 11-13), and oral hygiene instructions were given to the patient such as an acrylic occlusal mouthguard for nocturnal use. The patient expressed his complete satisfaction with the aesthetics and function value of the final restorations. After 4 years, no complications were found with respect to fracture or cracking of any restoration (Figures 14 and 15).

PMC6100716_02

Female

Since early in life, she was prescribed a pediatric EAI (EpiPen Jr ; 0.15 mg) in case of an allergic emergency. The first use of her prescribed EAI for MS was at age 6, and she has had 2 subsequent allergic emergencies requiring the use of her EAI as of the date of this report (Table 2). At 6 years old, her height was 117 cm, weight was 17.7 kg, BMI was 12.9, and her STBD was 10.7 mm by ultrasound of the right mid-anterolateral thigh. At 7 years old, around her second event requiring the EpiPen Jr , her height was 122 cm, weight was 25 kg, and her STBD was not recorded. After this event, and during her observation period in the hospital, MS complained of pain immediately in her right thigh at the injection site. X-ray and ultrasound results were negative. It is believed that MS suffered an unintentional bone injection with her EAI based on clinical presentation following the allergic emergency. At 9 years old, her height was 141 cm, weight was 30 kg, and her STBD was 12.1 mm. In 2017, MS was evaluated again for pain and discomfort in her right thigh. The indication for the EpiPen Jr is for children between 15 and 30 kg and this device has a needle length of 12.7 mm. MS and her parents were made aware that use of her prescribed EAI could cause an unintentional injection to the bone using the standard injection technique with compression. It was suggested that, prior to injection, the vastus lateralis muscle be squeezed as to avoid full compression while using her EAI because of the high risk of unintentional bone injection. This case of possible bone injection was reported to Health Canada.

anaphylaxis, bone injection, children, epinephrine auto-injector, needle length, skin-to-bone distance

PMC8521337_01

Male

A 54-year-old man was admitted to our hospital because of sclera and skin yellowing and abdominal pain. The patient has no history of smoking and drinks alcohol occasionally. He has no history of infectious diseases such as hepatitis, tuberculosis, and malaria and has no history of hypertension. Furthermore, his mother and aunt had a history of ovarian cancer. Examination after admission showed a significant increase in serum biomarkers, including carbohydrate antigen CA199 and carbohydrate antigen CEA. The abdominal computerized tomography (CT) showed enlargement of the head of the pancreas with double-duct disease ( Figure 1 ). Pathological examination demonstrated a ductal adenocarcinoma of the pancreas. Pancreaticoduodenectomy (Whipple technology) was performed, and albumin-bound paclitaxel 125 mg/m2 qw3/4 combined gemcitabine 1,000 mg/m2 qw3/4 x 6 cycles were given as postoperative adjuvant therapy. Considering the possibility of precision treatment, the surgical specimen was submitted to NGS panel analysis, which cover the whole exon regions of 539 cancer-related genes. The qualified DNA libraries were sequenced on Illumina NovaSeq6000 platform (Illumina, San Diego, CA, USA) and generate 150-bp paired-end reads. Base calls from Illumina NovaSeq6000 were conducted to FASTQ files. BWA-MEM (v.0.7.17) algorithm was then performed to align to the reference genome (hg19 GRCh37 of UCSC). SNVs/InDels were called and annotated via VarDict (v.1.5.7) and InterVar, then the variants were filtered against the common SNPs in public database including 1,000 Genome Project and Exome Aggregation Consortium (ExAC) Browser28 (v.0.3). Fusions were analyzed by factera (v1.4.4). The NGS results suggested that KRAS wild type. Beyond that, a somatic novel KANK1-ALK and UPP2 intergenic NTRK3 fusion were identified in this patient. The mutation profile revealed that these two fusions retained ALK/NTRK3 kinase domain ( Figure 2 ). Fusions of KANK1-ALK and UPP2-NTRK3 with a frequency of 9.87% and 4.01% were detected in this patient respectively. It is worth mentioning that KANK1-ALK and UPP2-NTRK3 fusions have not been reported in any other solid tumor. What is more, both FISH and immunohistochemistry (IHC) results showed the KANK-ALK fusion could generate active protein. However, the UPP2 intergenic NTRK3 fusion showed the negative result in FISH and IHC ( Figure 3 ), probably because complex rearrangements with intergenic breakpoints made transcription outcomes difficult to predict and confound detection. Interestingly, a BRAC1 p.Q12 germline pathogenetic mutation was also identified in this patient, which provided this patient with more potential options in druggable therapy.

kank1-alk, pdac, upp2-ntrk3, next-generation sequencing, pathogenetic brca1 mutation

PMC5032851_01

Male

A 50-year-old, homeless male presented to the Department of General Surgery with complaints of multiple discharging sinuses along the penis for 1 month. He also gave a history of gradually increasing swelling of the penis for 1 year and a purulent discharge per urethra for the last 6 months. At physical examination, there was an ulceroproliferative growth of the penis (Figure 1). The penis and the glans penis were tender, edematous and indurated. However, both the testes and the epididymis were normal. The vas deferens was normal on palpation. The prostate was normal on rectal examination. Preliminary laboratory investigations revealed high sedimentation, C-reactive protein (CRP) and leukocytosis. He was referred to our Radio-Diagnosis Department for Retrograde Urethrography - Voiding Cystourethrography (RGU-VCUG) evaluation. RGU was performed through the distorted external urethral meatus which was first identified by asking the patient to micturate to observe the main stream of urine. RGU revealed multiple (around 15 to 20), contrast-filled, narrow, irregular, fistulous tracts (urethrocutaneous fistulas) arising from both the dorsal and ventral aspects of the pendulous (penile) part of the anterior urethra (Figure 2). This distal segment of the pendulous part of the anterior urethra also showed significant distortion and irregular, beaded narrowing. The proximal segment of the pendulous part of the anterior urethra showed smooth and regular dilation. The bulbous part of the anterior urethra as well as the prostatic and the membranous parts of the posterior urethra showed adequate filling of contrast and a regular outline with no evidence of communicating sinus/fistulous tracts. The VCUG showed a markedly-contracted and small-capacity urinary bladder with a thickened, irregular and edematous wall. There were multiple nodular densities in the bladder lumen suggestive of hypertrophied trabeculae along its anterior, posterior and lateral walls, representative of a 'thimble bladder' (Figure 3). There was no evidence of reflux into the ureters during micturition. Chest radiograph (posteroanterior view) ruled out presence of pulmonary Koch's (both active as well as old, healed pulmonary Koch's). Scrotal ultrasound revealed normal testes and epididymis. Renal ultrasound showed no calyceal or papillary abnormality/hydronephrosis. Intravenous urography showed no evidence of renal or ureteric tuberculosis. Mantoux test was strongly positive while pathological examination of discharge per urethra revealed caseating granulomas. Gram stain and culture examinations for gonorrhea were negative while schistosomiasis was ruled out on the basis of microbiological studies of stool and urine samples. Pseudoepitheliomatous, Keratotic and Micaceous Balanitis (PKMB) was excluded as the patient had not undergone prior circumcision and also because histopathological examination after an incisional biopsy revealed no evidence of acanthosis, papillomatosis, elongated rete ridges or cellular atypia. Balanitis Xerotica Obliterans (BXO) was ruled out on the basis of a normal Tzanck smear test. The patient was administered anti-tubercular treatment (Isoniazid 300 mg, Rifampicin 600 mg, Pyrazinamide 1500 mg, and Ethambutol 800 mg per day). The patient started to show signs of improvement by 6 weeks. There was partial obliteration of the sinus and fistulous tracts. Since the patient's symptoms regressed, he was discharged and is being currently followed up as an out-patient. At the end of this treatment regimen, a repeat RGU-VCUG will be performed and decision regarding urethroplasty and further management will be planned depending upon the presence of any remaining fistulas or strictures involving the urethra.

cutaneous fistula, tuberculosis, male genital, urethral stricture

PMC5213811_01

Female

A 44-year-old female outpatient of German origin, who had been suffering from long-term schizophrenia (length of illness: 16 years) and (subjective) sleep disorders, was the subject of this study. The patient was diagnosed by experienced psychiatrists and was found to be suffering from paranoid schizophrenia, F20.0 according to the International Classification of Diseases-10, and schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders-V. The patient had normal intelligence (IQ = 88, as measured with the MWTB test), and she had finished "Hauptschule" education, which is secondary school in Germany. The patient was on medication during the whole study. She used amisulpride (200 mg in the morning), olanzapine (5 mg at night), and pramipexole (0.70 mg in the evening). The patient was suffering from severe recurrent psychosis involving repetitive delusions. During psychotic episodes, she would have the feeling that another person, that is, the devil, was residing in her. Moreover, she was suffering from severe sleep disorders, including insomnia, frequent awakenings, and nightmares. She was also suffering from social dysfunctioning and restlessness and had had the feeling of being different within, as well as outside, the body; sometimes, she exhibited catatonic behavior. During psychosis, she would have the disturbing impression that things, such as doors and her own hands, had changed and become larger. Moreover, she claimed to feel the soul of her best friend. She was also suffering from severe anxiety with mood changes from disturbed laughing to extensive crying. Sometimes, she would feel as if someone had pushed away her feet when she was seated, and, sometimes, she would see different people present in the bodies of her friends. Finally, she would have the feeling of being observed all the time. Approval was received from the local ethics committee (Arztekammer Nordrhein, number 2008331) for this clinical case study; moreover, the study is part of a larger project that has officially been registered under number NTR3132 at the Dutch Trial Register. The following study protocol was used: (1) a psychological assessment was conducted using the Pittsburgh Sleep Quality Index (PSQI) in order to measure subjective quality of sleep, the digit span forward and backward in order to measure simple working memory performance, the letter-number sequencing task in order to measure complex working memory performance, and the Positive and Negative Syndrome Scale (PANSS) filled in by her psychiatrist in order to monitor the positive and the negative symptoms. Her psychiatrist had had more than 20 years of psychiatric experience in the LVR-Klinik Bedburg-Hau and had been trained in using the PANSS. Moreover, the psychiatrist was not involved in and/or informed about our research project. In addition, the patient wore an actiwatch (Type: Actiwatch Spectrum Plus, http://www.actigraphy.com/devices/actiwatch/actiwatch-plus.html) for 14 days, 24 hours a day, in advance of the clinical nonpharmacological intervention in order to collect data on the following seven sleep parameters: "sleep efficiency," "sleep latency," "absolute actual sleep time," "absolute actual wake time," "relative actual sleep time," "relative actual wake time," and "assumed sleep" (meaning the difference between the end of sleep and the start of sleep). (2) Then, after careful diagnosis by a licensed Oriental medical practitioner with more than five years of clinical experience, the patient received individualized manual acupuncture in accordance with traditional Chinese medicine principles. Single-use stainless-steel needles (Type: AcuPro C, Wujiang City Cloud & Dragon Medical Device Co., Ltd., China) were used. The patient was treated weekly in the clinic for twelve consecutive acupuncture treatments, and each acupuncture treatment lasted about 60 minutes (for a detailed overview of the exact acupuncture points and frequency that were used during the 12 weekly acupuncture treatments, we refer the reader to Figure 1). For each separate acupuncture needle used in the treatment, the needle was inserted and deqi was achieved. The needle was then left in place for one hour, after which it was taken out. (3) After the 12 weeks of treatment, a second psychological assessment was completed using the same psychological tests that had been used in the first psychological assessment. Moreover, again, she put on and wore an actiwatch for 14 days, 24 hours a day. (4) Finally, three months after having finished the acupuncture treatment, a third psychological assessment was completed using the same psychological tests as in the first and the second psychological assessments in order to investigate possible long-lasting treatment effects. As can be seen in Table 1, the psychological assessment results show no differences in the PANSS positive and the PANSS negative subscale scores before acupuncture, immediately after the acupuncture treatment period, and three months after the acupuncture treatment period, with all scores remaining stable at 7. The PANSS psychopathology score was observed to have decreased from 38 before acupuncture to 30 immediately after the acupuncture treatment period but to have increased to 33 at follow-up, three months after having finished acupuncture treatment. The PANSS total score was observed to have decreased from 52 before acupuncture to 44 immediately after the acupuncture treatment period but to have increased to 47 at follow-up. The PSQI total results showed a decrease from 9 before acupuncture to 3 immediately after the acupuncture treatment period, but, after three months, an increase to 10 was noted. In the literature, three empirically derived factors have been proposed, for example, sleep efficiency, perceived sleep quality, and daily disturbances, that according to the authors should be favored over the single factor PSQI total score. However, further research is ongoing and we therefore decided to report all seven components instead of the three, in order to give all necessary information. As can be seen in Table 1, the factor PSQI subjective sleep quality decreased from 1 before acupuncture to 0 after acupuncture, and it then increased to 3. The factor PSQI sleep latency first decreases from 3 to 1 and then increases back to 2 at follow-up. The factor PSQI sleep time increases from 0 to 1 in score (indicating a more problematic sleep time) after acupuncture but then decreases again. The factor PSQI sleep efficiency does not change between T1 and T2 but increases to 3 at follow-up. The factor PSQI sleep disorders decreases after acupuncture and then stays that way. The factor PSQI sleep medication decreases after the first measurement and does not change again after that. The factor PSQI daytime sleepiness remains at zero until it increases to 1 at follow-up. The factor PSQI subjective time to fall asleep in minutes decreases markedly after T1 in which the patient estimated that it took approximately 60 minutes to fall asleep each day. After acupuncture, she fell asleep after only thirty minutes and this further improved to 4.5 minutes at follow-up. The factor PSQI subjective sleep duration in hours consisted of the total sleep time that the patient filled in on the form, and it decreased dramatically after acupuncture and stayed approximately the same at follow-up. The digit span results showed an increase from 7 before acupuncture to 10 immediately after the acupuncture treatment period and remained stable at 10 three months after having finished the acupuncture treatment. Finally, the letter-number sequencing results showed an increase from 2 before acupuncture to 6 immediately after acupuncture treatment and remained relatively stable and even slightly increased up to 7, three months after having finished the acupuncture treatment. Moreover, as can be seen in Table 2, the actiwatch results before acupuncture treatment versus those after acupuncture treatment showed a statistically significant decrease in the scores for "sleep latency" (t = -3.25, p = 0.006). Moreover, a certain trend towards significance was found for the sleep parameters "sleep efficiency" (t = 1.89, p = 0.08) and "absolute actual wake time" (t = -1.89, p = 0.08). More specifically, "sleep efficiency" increased from 80.31% to 85.64% while "absolute actual wake time" went down from 107.30 minutes to 73.38 minutes after acupuncture treatment. Finally, no statistically significant change or trend towards significance was found for "absolute actual sleep time" (t = -1.09, p = 0.30), "relative actual sleep" (t = 1.58, p = 0.14), "relative actual wake" (t = -1.58, p = 0.14), and "assumed sleep" (t = -1.70, p = 0.11) (all raw actiwatch data for our patient are presented in Supplementary Table 3 in Supplementary Material available online at http://dx.doi.org/10.1155/2016/6745618).

PMC9685114_01

Male

A 31-year-old South Asian man with no significant medical history presented to the emergency department with a 1-week duration of worsening dyspnea. He did not report any angina, orthopnea, paroxysmal nocturnal dyspnea, or syncope. His social history revealed that he vaped large quantities of cannabis daily (half of a cartridge:1.5 mg, 95% tetrahydrocannabinol) or the prior 2 months without tobacco, alcohol, or illicit drug use. He did not have any recent travel history, nor did he have any pets. He did not display any antecedent viral symptoms and denied any sick contacts. On admission to the emergency department, his vital signs included a blood pressure of 115/82 mmHg, a pulse of 88 beats per minute, and regular pulse oximetry of 98% on ambient air. On physical examination, he appeared comfortable without cardiopulmonary distress, with a mildly distended jugular venous pressure of 9 cm of water, and normal heart sounds without a pericardial friction rub on auscultation. He had no crackles upon auscultation of the lung fields, and no peripheral edema was noted. His electrocardiogram revealed sinus rhythm, a rate of 83 beats per minute with small voltage complexes, and nonspecific ST-T changes such as T-wave inversions in leads V5-V6, II, III, and (aVF) (Figure 1). The chest radiograph did not indicate any acute cardiopulmonary disease. Pertinent diagnostic laboratory investigations revealed a normal troponin I 0.05 ng/mL (normal range: 0.0-0.08 ng/mL) and NT-pro-brain natriuretic peptide 105 pg/mL (normal range < 125 pg/mL). His complete blood count, renal, hepatic, and thyroid function tests were normal. A glycosylated hemoglobin and lipid panel were also normal. A 2-dimensional transthoracic echocardiogram (2D-TTE) revealed a moderate circumferential pericardial effusion ("anterior" dimension of 13 mm, "posterior" dimension of 8 mm) with no impending tamponade physiology and preserved left ventricular function (Figure 2). He was admitted to the cardiology ward and was administered high-dose aspirin (325 mg every 8 hours), colchicine (0.5 mg every 12 hours), and pantoprazole (40 mg every 12 hours). No oral or intravenous glucocorticoids were administered. Diagnostic pericardiocentesis was not performed as there was no evident tamponade physiology, and it was not deemed in the patient's risk-benefit favor. During his ensuing 1-week hospitalization, he remained hemodynamically stable, and a repeat 2D-TTE indicated a significant interval improvement in the pericardial effusion (Figure 2). No pericardiocentesis or advanced thoracic imaging was performed. Further detailed work-up included a negative interferon-gamma release assay (QuantiFERON-TB Gold Plus), hepatitis panel, HIV, enzyme-linked immunosorbent assay (ELISA), RNA, polymerase chain reaction (PCR), and respiratory pathogen panel (BioFire) tests. Inflammatory markers (erythrocyte sedimentation rate and high-sensitivity C-reactive protein) were normal. A comprehensive rheumatologic and immunologic panel was unremarkable. Coronavirus 2019 PCR and rapid antigen tests were negative, in addition to blood cultures and urinalysis. He was extensively counseled with respect to the possibility of his cannabis vaping being implicated in the etiology of the pericardial effusion and subsequently discharged for routine outpatient follow-up with a surveillance 2D-TTE.

cannabis, pericardial effusion, vaping

PMC4496156_01

Male

A previously healthy 16-year-old male presented by ambulance from a referring institution for evaluation of cold exposure/frostbite to both hands. By report the patient had been found by police wandering in the middle of the road with his coat open, his head uncovered, and his hands ungloved. The patient's feet were protected with insulated snow boots. Heavy moisture and snow to the anterior surface of the patient's clothing raised concern that he had been unconscious and lain in the snow for a period of time. The police described him as "significantly intoxicated," and he purportedly admitted to alcohol and marijuana use on the evening of injury. The ambient air temperature on the night of admission ranged between -10.5 to -12.8 degrees Celsius with wind chill factors of -14 to -19 degrees Celsius. The patient was transported home by the police and released into the custody of his parents. Upon arriving home his father described the patient's hands as "cold and red" and re-warming of the hands by soaking them in warmed water was attempted. The temperature of the water used in home therapy and the duration of warm water immersion was not reported. After home warming, the patient's fingers were noted to swell significantly, with associated darkening of the skin. At this point the patient was transported by private vehicle to an emergency department (ED) for evaluation. While at the referring facility he had a peripheral intravenous line inserted, and he was given an intravenous dose of cefazolin and divided doses of morphine sulfate and hydromorphone for analgesia. Laboratory studies revealed an ethanol level of 0.19 g/dL, white blood cell count of 27.5 k/mm3, hematocrit 50.3%, international normalized ratio (INR) 1.0, and a random glucose level of 113 mg/dL. After brief evaluation and initial treatment, the patient was transferred by ambulance to tertiary care for plastic surgery evaluation. The time of ground transport was 2 hours. The patient arrived to the tertiary center ED 4 hours after being found by police. Initial exam revealed a well-nourished, well-developed, 77-kilogram teenage boy who was lethargic but easily aroused and oriented x3. Vital signs included blood pressure 93/54 mm/Hg, respiratory rate 18 per minute, pulse 105 beats per minute, temperature 36.6 degrees Celsius, and pulse oximetry 97% on room air. Primary and secondary surveys of this patient were non-contributory except for the examination of his extremities. Bilaterally, his hands and fingers demonstrated dorsal abrasions, discoloration, and hemorrhagic blisters. The right hand demonstrated mottling and discoloration of the ring and small fingers distal to the proximal interphalangeal (PIP) joint and of the long finger tip. The ring finger had small hemorrhagic blisters on the dorsal surface. The right long finger had small dorsal abrasions. The right index finger and thumb demonstrated no significant abnormalities on examination. The left hand was more seriously injured, with all digits affected. The left index, long, ring, and small fingers were mottled and cool, with evidence of hemorrhagic blisters along the dorsal surface. The tip of the left thumb was similarly affected (Figure 1). Doppler pulses to the left index and long finger were not present distal to the PIP joint. Abrasions and pain were noted to the patient's knees bilaterally. Examination of both lower extremities demonstrated no neurovascular compromise and full range of motion. Plain films of the patient's bilateral knees and hands did not reveal fractures or acute injury. A Breathalyzer test taken 1 hour after arrival was 0.083. A 1 L bolus of normal saline was infused, and both hands were placed in 40 degrees Celsius warm water baths for 20 minutes. Tetanus prophylaxis was provided, an additional dose of cefazolin was infused, and morphine in divided doses was provided for analgesia. Computerized tomography of the head/cervical spine was performed to identify occult traumatic injury or intracranial hemorrhage. These studies were negative for intracranial hemorrhage, skull fracture, or cervical spine injury. No other interventions were performed in the ED, and the patient was taken emergently to interventional radiology for bilateral upper extremity angiography and evaluation for intra-arterial infusion of thrombolytic therapy. After informed consent and provision of conscious sedation, bilateral femoral artery sheaths were placed. Initial arteriography revealed standard anatomy of the aortic arch and patency of the bilateral subclavian, axillary, and brachial arteries. Selective angiography of the forearm and hand vessels bilaterally was performed. The radial, anterior interosseus, and posterior interosseus arteries were patent bilaterally. The right ulnar artery was also patent. Hand and finger arteriography demonstrated several areas of impaired arterial microcirculation. On the right hand initial arteriography revealed impaired distal microcirculation to the thumb, a focal radial digital artery occlusion to the index finger, with diminished tip circulation, diminished tip circulation to the long finger, distal occlusion of both digital arteries of the ring finger with absent tip microcirculation, and near total occlusion of arterial blood supply to the small finger. Initial arteriography of the left hand demonstrated ulnar artery spasm and occlusion of the ulnar artery, severe spasm of both digital arteries to the thumb with diminished micro-circulation, occlusion of the digital artery with minimal circulation to the index finger, no microcirculation to the long finger, and occlusion of the ulnar digital arteries with diminished microcirculation to the ring and small finger (Figure 2). After initial angiographic exam, 3000 units of heparin were infused into the femoral sheaths, followed by intra-arterial infusion of 50 mcg of nitroglycerine bilaterally via catheters placed in the brachial arteries. Continuous infusions of tissue plasminogen activator (tPA) 0.25 mg and 500 units of heparin per hour were provided to each brachial catheter and femoral sheath, respectively. tPA infusion was begun within 8 hours of the patient being found by police. The patient subsequently was admitted to the intensive care unit for continued wound care and evaluation. Approximately 8 hours after initiation of tPA therapy, a repeat angiography was performed through the existing arterial catheters that revealed improved circulation in the right hand but continued impairment to the distal micro-circulation of the left hand. The right-sided brachial catheter was removed, but the left remained in place for continued tPA therapy. Twelve hours later a third angiographic exam of the left hand demonstrated improved distal circulation in all digits except for the ring finger. Left-sided tPA infusion was discontinued after this study, and the left brachial catheter and both femoral sheaths were removed. Once hemostasis was obtained at the femoral puncture sites, heparin infusion was re-initiated and continued for an additional 72 hours. Wound care consisted of daily cleansing and topical silver sulfadiazine dressings to the open areas of both hands. Nutritional support and occupational/physical therapy were also started on hospital day 1. Once the patient was able to perform physical therapy exercises and dressing changes independently, he was discharged home on hospital day 6. Before discharge social workers also completed a brief intervention to address his alcohol and illicit drug use. Outpatient support for substance abuse counseling was offered to the patient and family at this time. The patient was monitored with weekly outpatient clinic visits to assess wound healing and bilateral hand function. The patient eventually required split thickness skin grafts to the left ring and small finger (total graft size 12.5 cm3). After skin grafts the patient healed without complication and has retained full function and sensation to both hands. Perfusion images before and after tPA administration are demonstrated in Figure 2. A pictorial progress of the patient's wounds is provided in Figure 3.

PMC9888012_01

Male

Case description: The patient is a 51-year-old Caucasian man diagnosed with herpetic encephalitis at 10 years of age and a left cerebellar stroke in 2006, with demyelinating disease type submissive-recurrent MS since 2007. His last outbreak occurred in November 2020 after receiving seven months of outpatient rehabilitation. Patients with multiple sclerosis who were previously treated in the rehabilitation service in the past years were invited to participate in a clinical trial to research the effectiveness of ultrasound-guided percutaneous neuromodulation. This patient was recruited in January 2022 and he didn t receive any other treatments since November 2020. He had a left hemiparesis, with a muscular strength of 3 points in the Daniels-5-point scale in the left finger flexor muscles, with hypoesthesia in the 4th and 5th left hand finger, as well as dystonia in some postures. Intervention: A single application of ultrasound-guided PN was performed. DN needles (APS, 0.30x40 with guide), an electro stimulator (Globus Genesy SII) and an imaging ultrasound device (Logiq e, GE) were used (Figure 1). The median nerve was stimulated between the two fascicles of the pronator teres muscle (Figure 2), using 10 trains of 10 seconds of electrostimulation and 10 seconds of pause between them, with a frequency of 10 Hz and an impulse width of 240 micros, as established by the protocol of Valera-Garrido et al The procedure was performed at the University Hospital of the Canary Islands after being approved by the Ethical Committee (code NEUROECO-2020) and after having signed the informed consent. This clinical trial was registered with reference NCT05053984 at www.clinicaltrials.gov. Informed consent was obtained from the patient to publish the case report. Assessment: The grip strength was measured with a dynamometer (KERN MAP 130K1, Figure 3) whereas the hand function was measured with the nine hold peg test (9HPT) (Figure 4). Three measurements were taken, choosing the highest value in the case of the grip force and the lowest one for hand function. Measurements were taken at baseline, immediately after, 24 hours and four days after the intervention.

dry needling, multiple sclerosis, percutaneous neuromodulation, physiotherapy

PMC7402956_01

Male

A 68-year-old-man was a former smoker of 1 pack of cigarettes per day for 27 years and had a history of type II diabetes. In early November 2017, dry cough occurred and worsened gradually. He visited his primary care doctor and underwent chest computed tomography (CT), which revealed some abnormalities. His serum tests also showed elevated levels of C-reactive protein (CRP). He was prescribed levofloxacin, but his symptoms persisted. Thereafter, he was referred to our hospital for further examinations and treatments in mid-December, 2017. There were no abnormalities on physical findings. A serum test showed no abnormalities except for the elevated level of CRP (0.9 mg/dL) (Table 1). Chest radiography showed mild heart enlargement and enhancement in pulmonary vascular shadow (Fig. 1). High-resolution computed tomography (HRCT) of the chest showed bronchial vascular bundle thickening, centrilobular nodules, and interlobular septal thickening on both sides. Uneven ground-glass opacity was present mainly on the right side; in addition, there was pleural effusion on both sides as well as pericardial effusion (Fig. 2). No abnormalities were noted on an electrocardiogram. Echocardiography showed a normal ejection fraction (66%) and mild elevation of the tricuspid regurgitation pressure gradient (TRPG; 36 mmHg). Based on these results, we did not strongly assume the possibility of the exacerbation of chronic heart failure. For a further inspection, we conducted a TBLB of the right upper lobe, where HRCT showed centrilobular nodules and interlobular septal thickening more strongly. In a pathological image of the TBLB specimen, phloem-like or clumping adenocarcinoma cells were noted in the thick interstitial vessels and vessels of the alveolar wall but not in the lymphatic vessels (Fig. 3). Because a tumor embolism consisting of fibrin and tumor cells was noted, a pathologist in our hospital confirmed the diagnosis of PTTM. Immunostaining showed carbohydrate antigen 19-9(+), Mac5-AC(+), D2-40(-), and thyroid transcription factor-1(-) (Fig. 4). Based on these results, we suspected that the primary tumor might be a gastric or pancreatobiliary cancer. While we planned further inspections, he was referred to the emergency room of our hospital because of worsening dyspnea in early January 2018. HRCT showed increased pleural effusion and worse interlobular separation wall thickening on both sides than had been noted in the HRCT findings acquired previously (Fig. 5). Emergency hospitalization was implemented, and chest drain placement was conducted. Once hospitalized, he underwent upper gastrointestinal endoscopy for scrutiny. Ulcerative lesions were noted in the posterior wall of the stomach (Fig. 6). The biopsy result indicated moderately to poorly differentiated adenocarcinoma and signet-ring cell carcinoma, which was in agreement with the finding of adenocarcinoma cells on the TBLB (Fig. 7). Contrast-enhanced CT was performed to rule out pulmonary thromboembolism, but no thrombi were observed in the pulmonary artery (Fig. 8). Since the D-dimer level was also in the normal range, pulmonary thromboembolism was considered negative. Therefore, a definitive diagnosis of PTTM due to gastric cancer was made. In late January, 2018, S-1 (120 mg/m2) and oxaliplatin (100 mg/m2) were administered to eradicate the gastric cancer. However, the gastric cancer worsened, so the regimen of chemotherapy was changed to S-1 (80 mg/m2), docetaxel (50 mg/m2), and oxaliplatin (100 mg/m2). After starting S-1, docetaxel, and oxaliplatin, his dyspnea disappeared gradually. This was because his pulmonary hypertension had improved, and the TRPG measured by echocardiography actually decreased from 36 mmHg to 23 mmHg. However, after four courses of S-1, docetaxel, and oxaliplatin, the progression of gastric cancer was confirmed, and his dyspnea worsened again. Echocardiography showed that the TRPG had increased from 23 to 41 mmHg. In late May, 2018, nab-paclitaxel (PTX) (100 mg/m2) and ramucirumab (8 mg/kg) were initiated. There were no marked changes in dyspnea during the administration of nab-PTX and ramucirumab, and the TRPG decreased from 41 to 35 mmHg. We were able to stop the worsening of dyspnea and improve the pulmonary hypertension a little, but the development of gastric cancer was confirmed after two courses. Therefore, irinotecan (70 mg/m2) was initiated in mid-July, 2018. Soon after initiating irinotecan, his dyspnea worsened. Steroids and narcotics were prescribed to alleviate his symptoms. At the end of July 2018, his performance status was 4 owing to fatigue, anorexia, and dyspnea, so we decided to discontinue the chemotherapy and provide best supportive care. In late August, 2018, he passed away.

angiogenesis inhibitor, gastric cancer, pulmonary tumor thrombotic microangiopathy, transbronchial lung biopsy

High-resolution chest tomography at the initial visit. (a) The mediastinal window showed a small amount of pleural and pericardial fluid retention.

PMC7402956_01

Male

A 68-year-old-man was a former smoker of 1 pack of cigarettes per day for 27 years and had a history of type II diabetes. In early November 2017, dry cough occurred and worsened gradually. He visited his primary care doctor and underwent chest computed tomography (CT), which revealed some abnormalities. His serum tests also showed elevated levels of C-reactive protein (CRP). He was prescribed levofloxacin, but his symptoms persisted. Thereafter, he was referred to our hospital for further examinations and treatments in mid-December, 2017. There were no abnormalities on physical findings. A serum test showed no abnormalities except for the elevated level of CRP (0.9 mg/dL) (Table 1). Chest radiography showed mild heart enlargement and enhancement in pulmonary vascular shadow (Fig. 1). High-resolution computed tomography (HRCT) of the chest showed bronchial vascular bundle thickening, centrilobular nodules, and interlobular septal thickening on both sides. Uneven ground-glass opacity was present mainly on the right side; in addition, there was pleural effusion on both sides as well as pericardial effusion (Fig. 2). No abnormalities were noted on an electrocardiogram. Echocardiography showed a normal ejection fraction (66%) and mild elevation of the tricuspid regurgitation pressure gradient (TRPG; 36 mmHg). Based on these results, we did not strongly assume the possibility of the exacerbation of chronic heart failure. For a further inspection, we conducted a TBLB of the right upper lobe, where HRCT showed centrilobular nodules and interlobular septal thickening more strongly. In a pathological image of the TBLB specimen, phloem-like or clumping adenocarcinoma cells were noted in the thick interstitial vessels and vessels of the alveolar wall but not in the lymphatic vessels (Fig. 3). Because a tumor embolism consisting of fibrin and tumor cells was noted, a pathologist in our hospital confirmed the diagnosis of PTTM. Immunostaining showed carbohydrate antigen 19-9(+), Mac5-AC(+), D2-40(-), and thyroid transcription factor-1(-) (Fig. 4). Based on these results, we suspected that the primary tumor might be a gastric or pancreatobiliary cancer. While we planned further inspections, he was referred to the emergency room of our hospital because of worsening dyspnea in early January 2018. HRCT showed increased pleural effusion and worse interlobular separation wall thickening on both sides than had been noted in the HRCT findings acquired previously (Fig. 5). Emergency hospitalization was implemented, and chest drain placement was conducted. Once hospitalized, he underwent upper gastrointestinal endoscopy for scrutiny. Ulcerative lesions were noted in the posterior wall of the stomach (Fig. 6). The biopsy result indicated moderately to poorly differentiated adenocarcinoma and signet-ring cell carcinoma, which was in agreement with the finding of adenocarcinoma cells on the TBLB (Fig. 7). Contrast-enhanced CT was performed to rule out pulmonary thromboembolism, but no thrombi were observed in the pulmonary artery (Fig. 8). Since the D-dimer level was also in the normal range, pulmonary thromboembolism was considered negative. Therefore, a definitive diagnosis of PTTM due to gastric cancer was made. In late January, 2018, S-1 (120 mg/m2) and oxaliplatin (100 mg/m2) were administered to eradicate the gastric cancer. However, the gastric cancer worsened, so the regimen of chemotherapy was changed to S-1 (80 mg/m2), docetaxel (50 mg/m2), and oxaliplatin (100 mg/m2). After starting S-1, docetaxel, and oxaliplatin, his dyspnea disappeared gradually. This was because his pulmonary hypertension had improved, and the TRPG measured by echocardiography actually decreased from 36 mmHg to 23 mmHg. However, after four courses of S-1, docetaxel, and oxaliplatin, the progression of gastric cancer was confirmed, and his dyspnea worsened again. Echocardiography showed that the TRPG had increased from 23 to 41 mmHg. In late May, 2018, nab-paclitaxel (PTX) (100 mg/m2) and ramucirumab (8 mg/kg) were initiated. There were no marked changes in dyspnea during the administration of nab-PTX and ramucirumab, and the TRPG decreased from 41 to 35 mmHg. We were able to stop the worsening of dyspnea and improve the pulmonary hypertension a little, but the development of gastric cancer was confirmed after two courses. Therefore, irinotecan (70 mg/m2) was initiated in mid-July, 2018. Soon after initiating irinotecan, his dyspnea worsened. Steroids and narcotics were prescribed to alleviate his symptoms. At the end of July 2018, his performance status was 4 owing to fatigue, anorexia, and dyspnea, so we decided to discontinue the chemotherapy and provide best supportive care. In late August, 2018, he passed away.

angiogenesis inhibitor, gastric cancer, pulmonary tumor thrombotic microangiopathy, transbronchial lung biopsy

High-resolution chest tomography at the initial visit. The lung window showed bronchial vascular bundle thickening, centrilobular nodules, and interlobular septal thickening on both sides.

PMC6788199_01

Male

The clinical case of an inmate is described, which included highly complex features both for the nursing staff and the medical unit, who presents a thoracic window or thoracostomy window carried out in April 2016. It is a descriptive study of the progress of the wound from when he entered Murcia I Prison (from 11 October 2016 to January 2018), using nursing methodology with the NANDA, NIC, NOC (N-N-N) language. The corresponding authorisation and the patient's informed consent were requested from the General Directorate of Prison Healthcare to carry out the research work. The case consisted of a 43 year old male, carrier of a thoracostomy window in the thoracic wall after pneumothorax and complex symptoms of tuberculosis, with empyema and persistent leakage. He was treated in Alicante Hospital, while he was interned in Villena Prison, where the thoracic window was opened to clean and drain the pleural cavity, and to assist in the process of filling and healing it. After entry in Murcia I Prison, the patient's symptoms were monitored in the Thoracic Surgery Service of the Virgen de la Arrixaca University Hospital (HUVA) and in the Internal Medicine Service of Murcia. Surgical closure of the cavity was considered to be impossible due to the major risk of severe infection.

PMC8424969_01

Female

A 56-year-old woman was readmitted to the hospital with abnormal liver function tests, persisting for the last 18 months. Her hepatic markers were as follows, tested 18 months ago: alanine aminotransferase (ALT) 113 U/L, aspartate aminotransferase (AST) 104 U/L, alkaline phosphatase (ALP) 124 U/L, and glutamate aminotransferase (GGT) 78 U/L. This was attributed to a positive HAV-IgM (ELISA, OD value of attributed absorbance >=2.1, determined to be positive). She was diagnosed with acute hepatitis A and hospitalized in isolation for treatment. Abnormal symptoms, such as fever, fatigue, abdominal pain, or yellow urine, were not observed. She was treated with glutathione 0.9 g and glycyrrhetinic acid 150 mg/day for 45 days. The liver function recovered, and the markers were as follows: ALT 56 U/L, AST 43 U/L, ALP 109 U/L, and GGT 65 U/L. However, HAV-IgM was still positive. During this time, anti-nuclear antibodies (ANA) 47 U/L (normal <10 U/L) were also detected. Tests for antimitochondrial antibodies (AMAs) and anti-liver kidney microsomal (LKM) antibodies, and anti-smooth muscle antibodies (SMAs) were negative. The immunoglobulin G (IgG) level was 18.3 g/L (normal range 6.2-16.1 g/L) and the IgM level was 2.71 g/L (normal range 0.98-2.04 g/L). Following discharge, regular monthly reexamination showed abnormal liver function with repeated fluctuations (Figure 1). The patient developed fatigue, decreased appetite, and yellow urine for 15 days, thus indicating recrudescence. Liver function tests showed abnormal results [total bilirubin (TBIL) 43 mol/L, ALT 452 U/L, AST 254 U/L, ALP 175 U/L, GGT95 U/L]. Further testing revealed the ANA level of 102 U/L, IgG 26.3 g/L, IgM 2.71 g/L, and IgA 5.32 g/L (normal range: 0.76-3.9 g/L). The analysis of a liver biopsy specimen revealed histological changes consistent with typical autoimmune hepatitis. There was moderate to severe interfacial inflammation, numerous lympho-plasma cell infiltrates, lymphocytic penetration, and rosette-like hepatocytes (Figure 2). HAV-IgM was positive. To rule out the possibility of HAV infection, a reverse transcription-polymerase chain reaction (RT-PCR) was conducted to detect HAV RNA in the serum. The analysis of the current samples, as well as those from a year ago, was found to be negative. Clinical diagnosis of AIH was made with a false-positive HAV-IgM. Methylprednisolone 32 mg/day was administered, which was tapered to 20 mg/day after 1 month. The liver function tests, done daily, returned to normal after 2 months, following which, methylprednisolone was further tapered to 8 mg/day as a maintenance treatment. On reexamination, the patient was negative for HAV-IgM and HAV RNA. The tests for Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus, and adenovirus were negative. There was also no drug-induced liver injury or history of alcohol addiction.

false-positive, hepatitis a, immunoglobulin m

PMC9556964_01

Female

A 22-year-old Asian woman developed marked changes in behavior and personality following the delivery of her first baby (Figure 1). She gave birth in the 33rd-34th week of gestation due to premature rupture of the membrane (PROM). The baby weighted 2,000 g with body length of 43 cm and APGAR score of 6 and 8 for 1 and 5 min, respectively. The patient ignored the doctor's and family's questions after the delivery. She was known to be irritable due to the emergency cesarean section. She felt sleepy; however, she could not fall asleep. Her breastmilk production was very low which made her even more irritated. She also looked confused and kept babblings meaninglessly to herself. She admitted that she heard the ghost's voices which could not be heard by others. Three months before admission, her sister posted her pregnant belly on social media without her permission, which induced conflict between the two. She shut herself for 2 months in her room and refused to eat, therefore she lost some weight. Three weeks before admission, the patient sometimes was seen crying without any specific reasons. She felt sad, fatigued, and lethargic. She also had a conflict with her husband because he ignored her request on getting health insurance. Set aside, she also got mad at her mother for no apparent reason. In addition, she experienced frequent intermittent headaches associated with mild fever which had been felt for 3 weeks before admission. The patient had been brought to the nearest health care facility for several times to check her complaint of headache. The doctor found that she experienced anemia and low blood pressure which is common in a pregnant woman. The patient then was prescribed analgesics and vitamins. There was no history of mental illness in the patient and her family. There was no known head trauma. Patient's family believe those symptoms related to her pregnancy. At the time of admission, after having a cesarean section due to PROM, she had fever (temperature: 38.7 C) with other physical examinations showed no abnormal findings. Patient was treated with cefazolin, ketoprofen, pethidine, and ketorolac regarding to her condition. Two days after admission, patient experienced loss of consciousness which was suspected due to electrolyte imbalance by physician in Emergency Department at the time of admission. Thus, she was followed up by internist. However, there was no abnormality in either electrolyte or metabolic process. Biochemical investigations were done several times since the patient's admission. After patient lost her consciousness, 2 days after admission, the hemoglobin level was 8.2 g/dl (reference range: 12.3-15.3 g/dl), platelet count was 308 x 109/L (reference range: 150-400 x 109/L), and white blood cells count was 11 x 109/L (reference range: 4-11 x 109/L). Other laboratory results including calcium, glucose, blood urea nitrogen, and creatinine were normal. She then turned into hypoactive with a negative attitude. The rapport was inadequate. She remained silent while being asked by physicians. Due to her behavioral changes, she was consulted to Psychiatric Department. According to her complaint, she was diagnosed with depressive disorder with peripartum onset. Depressive disorder was diagnosed because the patient had depressed mood most of the day; diminished interest or pleasure in all, or almost all, activities most of the day; significant weight loss; fatigue or loss of energy; feelings of worthlessness in the last 3 months. The patient was treated with olanzapine 5 mg per day. The next day, the patient screamed uncontrollably and became hysteric. Due to her condition, lorazepam 0.5 mg per day was added into her therapy regimen. Later, she developed auditory hallucination of hearing ghost's voices which no one else can hear. Five days after admission, she was then consulted to a neurologist for further assessment of her headache. From the assessment of the neurologist, the Glasgow Coma Scale (GCS) was 14 with a positive meningeal sign. Cranial nerve (CN) examinations revealed paresthesia on the right side of her face. Motoric examination revealed tetra paresthesia with positive pathological reflexes. She was suspected with tuberculous meningitis grade I and suggested to undergo thorax X-ray examination, computed tomography (CT) scan with and without contrast, and lumbar puncture. The following day, a non-enhanced CT scan of her head revealed hypodense lesions at right subcortical occipital lobe, left parietooccipital lobe, and right cerebellum accompanied by hydrocephalus. Those lesions could be an infarct due to embolization with differential diagnosis of posterior reversible encephalopathy syndrome (PRES) and tuberculoma. In an enhanced CT, we found an overlie meningeal enhancement at sulci cortical right occipital lobe, bilateral sulcus cortical temporal lobes, tentorium cerebelli, ambient cisternae, basalis cisternae, bilateral Sylvia fissures, anterior and posterior interhemispheric fissure with hydrocephalus communicans, which suggested an additional diagnosis of meningitis (Figure 2). She also underwent several other imaging to support the diagnosis of possible underlying disease. An abdominal ultrasound scan revealed hepatosplenomegaly and multiple paraaortic lymphadenopathies, which added additional suspected diagnosis of tuberculous peritonitis. A chest X-ray was performed and suggested active pulmonary tuberculosis and cardiomegaly with lung oedema. Based on the latest result that day, psychiatric diagnosis was revised to peripartum depression and neurocognitive disorders due to brain dysfunction due to tuberculous meningitis and patient was treated with clozapine 5 mg and lorazepam 0.5 mg. Also, neurologist updated the diagnosis into to tuberculous meningitis grade II with arteritis and suspected arachnoiditis, intracranial space occupying lesion due to tuberculoma. Patient was soon treated with rifampicin, isoniazid, pyrazinamide, ethambutol, dexamethasone, vit B6, omeprazole, and paracetamol. Seven days post cesarean section, the patient suddenly complained of pain throughout her body. She developed shortness of breath with a respiratory rate up to 28 x/m, fever (temperature: 38.9 C), low blood pressure 90/70 mmHg, and decreased oxygen saturation (SpO2 80%). The patient then stopped breathing. Twenty minutes after being resuscitated, the patient did not show any response and was declared dead with suspected pulmonary embolism as cause of death. However, confirmation was not possible because a thorough postmortem study was not performed. Lumbar puncture was scheduled to be done on the patient after an enhanced CT scan result was obtained. However, patient died before the test was held. We also did the acid-fast bacilli (AFB) test; however, the patient passed away before the result came out.

depression, intracranial tuberculoma, meningitis tuberculosis, neuroimaging, postpartum depression

PMC10073471_01

Female

A 37-year-old woman presented with worsening intermittent chest pain and dyspnea for 1 year and was admitted to our hospital. Interestingly, although the dyspnea was exertion-dependent, her chest pain heavily depended on the postural position as it worsened in the supine position but was alleviated by lying prone or sitting up and leaning forward. The patient had moderate anemia due to adenomyosis. She had no history of chest trauma, infective endocarditis, syphilis, tuberculosis, hypertension, diabetes, dyslipidemia, aortic aneurysm, or connective tissue disease. Her vital signs were as follows: body temperature 36.5 C, blood pressure 130/70 mmHg, pulse 75 beats/min, respiratory rate 20 breaths/min, and oxygen saturation 96% (indoor air). A physical examination revealed lip cyanosis (Figure 1A) and a diastolic murmur at the left third intercostal space was present. Respiratory and abdominal examinations revealed no abnormal findings. Written informed consent for publication was obtained from the patient. A hematological evaluation showed a hemoglobin level of 73 g/L (microcytic hypochromic anemia), a white blood cell count of 4.59 x 109/L, and a platelet count of 143 x 109/L. Other laboratory data, including myocardial enzyme levels, NT pro-brain natriuretic peptide levels, coagulation function, and hepatic and renal function were normal. Electrocardiography showed sinus rhythm, obvious ST-segment elevation in the aVR, and depression in the II, III, aVF, and V3-V6 leads when she lay flat and had angina pectoris attacks (Figure 1B). However, when she sat up for a few minutes, her symptoms and ST segment abnormalities disappeared (Figure 1C). Echocardiography revealed large unruptured aneurysms in both the left (47 mm x 43 mm) and non-coronary (44 mm x 35 mm) sinuses (Figure 2A), along with an enlarged left ventricle (58 mm, Figure 2B), a dilated aortic root (52 mm, Figure 2C), a ventricular septal membranous aneurysm (19 mm x 16 mm, Figure 2D), severe aortic regurgitation (Figure 2E), right ventricular high pressure (pressure gradient 54 mmHg, Figure 2F), and decreased left ventricular systolic function (ejection fraction 51%). Coronary angiography showed ~90% pulsating stenosis of the left main coronary artery (LM) and ~80% pulsating stenosis of the proximal left circumflex artery (LCX), presumably caused by pulsation of the dilated left SVA under blood pressure (Supplementary Video S1). The aortic root was severely distorted when we attempted to intubate the coronary arteries. Non-obstructive atherosclerosis was observed in the right coronary artery (RCA). Cardiac computed tomography angiography (CCTA) clearly showed a large unruptured left SVA (Figure 3A), which was anatomically close to the LM (Figure 3B) and proximal LCX (Figure 3C), causing severe narrowing of the vessel lumens. The dilated left SVA upwardly squeezed the pulmonary trunk (Figure 3D) and accelerated the maximum pulmonary blood flow to 3.7 m/s. The dilated non-coronary SVA adjoined the right atrium without a crevasse (Figure 3A). The right coronary sinus was normal, and the RCA blood flow was smooth. The sagittal plane view showed dual unruptured left/non-coronary SVAs (Figure 3E). Three-dimensional reconstruction images showed the LM and LCX running along the epicardium of the left SVA, with severe narrowing of the LCX (Figure 3F). To rule out other etiologies, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibody, antidouble stranded DNA antibody, anti-neutrophil cytoplasmic antibody, lupus anticoagulant, T-spot, and syphilis serology tests were performed, but all were negative. Genetic testing revealed c.1781 C > G nonsense mutations in the FLNA gene. According to the American College of Medical Genetics and Genomics (ACMG) standard, FLNA c.1781 C > G was determined as a "likely pathogenic mutation" since it satisfied the criteria of both PVS1 (pathogenic very strong) and PM2 (pathogenic moderate). On admission, we administered nitroglycerin, an oxygen mask, and metachysis to alleviate her symptoms. Three days later, the patient underwent surgical intervention, including aneurysm patch closure, coronary artery reconstruction, and aortic valve and aortic root replacement. Operative findings confirmed a dual unruptured Valsalva aneurysm of the left coronary and non-coronary sinuses (Figure 4). The right coronary sinus was normal. The modified Bentall procedure was performed using a 26 mm biological composite graft and a mechanical aortic valve (Carbomedics Inc., Austin, TX, United States). The LM artery was then re-implanted into the newly formed left coronary sinus. Unfortunately, the patient experienced cardiac arrest during the operation, and, despite receiving an emergency thoracotomy, the heart was unable to recover after surgery and she died.

flna gene mutation, case report, postural angina pectoris, pulmonary hypertension, sinus of valsalva aneurysm

PMC4117091_01

Female

A 24 year old female, an engineering graduate, previously working in a private firm was admitted to Advanced Trauma Centre of Postgraduate Institute of Medical education and Research, Chandigarh following a road traffic accident. She presented with a history of loss of consciousness and vomiting. Her Glassgow Coma Scale score was 8 (E2 V2 M4), classified as severe TBI. She was diagnosed to have left parieto-occipital EDH and left temporal pole EDH. She had to undergo two surgical procedures: i) left parieto-occipital craniotomy, posterior fossa craniotomy and evacuation of EDH and ii) left temporal craniotomy and evacuation of EDH. She had no past history of any medical or psychiatric illness. She had no associated physical or neurological deficits. At the time of discharge her Glassgow Outcome score was 4 indicating a good outcome. She was referred for neuropsychological assessment and rehabilitation at 11/2 months post injury with complaints of forgetfulness, inattention, difficulty naming objects, inability to read, increased irritability and anxiety. With the consent of the patient and family a detailed assessment was carried out at 11/2 months (pre-intervention) and 9 months (post-intervention) using following tools: PGI Battery of Brain Dysfunction: It is a measure of cognitive impairment consisting of following subtests: Verbal Adult Intelligence Scale Revised Bhatia's Short Battery of Performance Tests of Intelligence PGI Memory Scale Nahor and Benson Test: a measure of perceptuo-motor functions Bender Visuo-Motor Gestalt Test: a measure of perceptuo-motor functions Selected tests from NIMHANS Neuropsychological Battery Digit Symbol Substitution Test : a measure of information processing speed Digit Vigilance Test : a measure of sustained attention Controlled Oral Word Association Test : a measure of phonemic fluency Animal Names Test : a measure of category fluency Dysfunctional Analysis Questionnaire: measures dysfunction in the area of social, vocational, personal, familial and cognitive functioning.

brain injury, cognitive remediation, neuropsychological impairment, rehabilitation

PMC4604639_01

Female

A 24-year-old woman with no remarkable previous medical history had a 7-month history of coughing and blood-stained sputum. She also presented with a visual disturbance in the right eye occurring over 1-month. She visited a local ophthalmologist and was referred to an ophthalmologist at our hospital. Detailed examinations revealed no ophthalmological abnormality. Brain MRI showed multiple intracranial lesions and she was referred to us. On examination, she was awake and alert with no disorientation except for visual deficits rated as counting fingers in the right eye, whereas the left visual acuity was 30/50. There were no other focal neurological deficits. A brain CT scan revealed multiple 5-15 mm high-density nodules with perifocal edema in the bilateral cerebrum and cerebellum [Figure 1a]. The sulci appeared obscured, indicating the increased intracranial pressure. Emergency cerebral angiography ruled out vascular diseases such as sinus thrombosis. However, on angiography, the intracranial perfusion time of the contrast medium was prolonged, suggesting mild intracranial hypertension. MRI demonstrated that the signal of nodules was hypointense to isointense on T1-weighted images [Figure 1b] and hypointense on T2-weighted [Figure 1c]. Susceptibility-weighted images [Figure 1d] showed numerous low-intensity spots, indicating old hemorrhages. These lesions were accompanied by significant peritumoral edema. Postcontrast studies revealed little enhancement in most lesions, but a weak enhancement in some nodules [Figure 1e]. Under the suspicion of multiple brain metastasis from malignancies in other organs, chest CT scan was performed, which revealed multiple small nodules with bleeding in the lung [Figure 2a]. An abdominal CT scan showed a similar-sized mass without intralesional hemorrhage in the liver [Figure 2b]. The hepatic lesions were enhanced homogeneously [Figure 2c]. These findings were not typical of primary lung and hepatic cancers. Serum tumor markers including carbohydrate antigen 19-9, squamous cell carcinoma, and Sialyl LewisX were also negative. Sputum and bronchial lavage fluid cytology were class 1. Based on the MRIs and CT scans indicative of multiple hemorrhagic brain tumors, intracranial metastasis of melanoma, or choriocarcinoma were also included in the differential diagnoses. However, detailed dermatological inspection denied the presence of abnormal skin lesions. In addition, 5-S-cysteinyldopa, a serum tumor marker for melanoma, was negative. Gynecological examinations also excluded the possibility of any pelvic tumors. In addition, thallium scintigraphy indicated no abnormal uptake in any part of the body. The systemic and multiorgan nature of the disease led us to suspect other conditions such as metabolic, hematological, and infectious diseases. However, laboratory tests showed only mild anemia. The possibility of systemic amyloidosis was ruled out from the results of serum protein fractions and urinalysis. To eliminate the possibility of tuberculous lesions, bacterial cultures from the sputum and bronchial lavage fluid, acid-fast bacteria staining, Mycobacterium tuberculosis polymerase chain reaction, and interferon-gamma release assay were conducted; however, these examinations did not indicate tuberculosis. During the course of these examinations, the patient's condition significantly progressed. Her bilateral visual acuity rapidly declined for 3 days after admission. She also had frequent general clonic seizures. The steroid, osmotic diuretics, carbamazepine, and levetiracetam were administered to control her seizures. Although her seizures were controlled over the following 3 days, her bilateral visual acuity had further declined to light perception. Because of the necessity of determining pathological diagnosis, a biopsy of the right frontal brain lesion was performed 14 days after admission. Increased intracranial pressure was observed intraoperatively. The lesion with slight enhancement on MRIs in the right frontal lobe was removed using a navigation guide. The tumor was moderately hemorrhagic, presenting a reddish-brown color [Figure 3]. The consistency of the tumor was elastic and hard. Histopathological examination showed a diffuse cellular proliferation upon hematoxylin and eosin stain. Fine vascular channels, hemorrhage, and hemosiderosis were observed in the tissue [Figure 4a]. Cells contained a round and slightly coarse nucleus and a large volume of clear cytoplasm including large and small balloon-like lesions and erythrocytes [Figure 4b]. Immunohistochemical staining showed positivity for vimentin and CD31 of the cell membrane and cytoplasms [Figure 4c] and mild positivity for CD34 of the cytoplasm. Tumor cells were all negative for S-100, neurofilament, glial fibrillary acidic protein, IbaI, CD1a, CK AE1/3, epithelial membrane antigen, leukocyte common antigen, CD68, and alpha-smooth muscle actin. Mitotic nuclei were rare, and the MIB-1 labeling index was <3% in the tumor cells [Figure 4d]. Based on these histopathological findings and the multiplicity of lesions in the brain, lung, and liver, we finally determined the diagnosis as EHE. The patient's conditions were stable for 3 months after biopsy. After a discussion about the treatment strategy with the patient and her family, we opted for conservative therapy comprising only rehabilitation on the basis of the low proliferation rate indicated by the histopathological findings. However, after 3 months, the patient gradually developed moderate disturbance of consciousness, headache, and vomiting. MRIs demonstrated aggravation of peritumoral edema without apparent enlargement of each nodule [Figure 5a]. The bilateral ambient cisterns had narrowed, suggesting increased intracranial pressure [Figure 5b]. Steroid pulse therapy with osmotic diuretics improved her consciousness for 2 weeks, and she became able to eat. Palliative whole-brain radiation was initiated, but she did not respond to the treatment and developed diabetes insipidus requiring administration of desmopressin. Her consciousness continued to deteriorate. When she became comatose, her family hoped the termination of radiation and the provision of the best supportive care. She died after 4 months of hospitalization. The autopsy revealed the cause of death as brainstem necrosis, possibly induced by brain herniation. In addition to the multiple intracranial, pulmonary, and hepatic lesions confirmed on diagnostic imaging, multiple white nodules were observed, including two in the spleen, two in the left kidney, one in the right kidney, and one in the third lumbar vertebra. All were confirmed as EHE.

epithelioid hemangioendothelioma, hemorrhagic brain tumor, liver tumor, multiple intracranial mass, pulmonary tumor

(a) Chest computed tomography scan showed multiple nodules with hemorrhage in the lung.

PMC5982475_02

Female

However, despite this resolution, the girl was referred for neuropsychological evaluation at the age of 7 years after her family and school noticed significant difficulties with attention, task initiation, and explosive temper outbursts. She was exhibiting variations across the day and on a day-to-day basis with respect to her ability to engage in tasks; she had complained to her parents that she could "not do things as her brain was asleep." The parents also reported that typical reward-based behavioral incentives were not successful in modifying behavior.

dopa, dystonia, neuropsychological

PMC3103874_01

Female

Our patient was 25 years old when she migrated to our country from China. Her medical and childhood history was scant although both the patient and her mother insist these were uneventful and that she had been an average student in school. The patient presented to our hospital at the age of 28 years old for seizures and altered behaviour. She was described by her husband to be responding slowly when spoken to. These episodes were interspersed by verbal and physical aggression, violent outbursts, or hypersomnolence (sleeping for >24 hours) with urinary incontinence. Computed tomography (CT) and magnetic resonance imaging (MRI) of the head were normal. Electroencephalography performed during episodes of hypersomnolence was compatible with global moderate diffuse encephalopathy. Arterial ammonia (195 mmol/L) and lactate (4.5 mmol/L) levels were markedly elevated. However, other liver tests and imaging were not suggestive of liver cirrhosis and excluded the presence of any portosystemic shunt. CT imaging revealed an atrophic pancreas. Tests for hepatitis B, hepatitis C, HIV, Wilson disease, systemic autoimmune disease, and syphilis were negative. In view of her significant behavioural change and elevated ammonia levels, she was screened for inborn errors of metabolism. Citrulline levels in the blood (939 umol/L) and urine (19.6 umol/mmol) were elevated 15-fold and 5-fold, respectively. There was corresponding elevated plasma arginine and threonine : serine ratios. She was commenced on L-arginine 1 g QDS and high-dose lactulose therapy which reduced the frequency of her violent outbursts and reduced the hypersomnolent episodes to once per fortnight. However, these episodes became increasingly difficult to control despite L-arginine replacement. By 2009, she was encephalopathic/hypersomnolent as often as 3 to 4 times per week. The frequency and nature of these episodes also made drug compliance difficult and affected her daily activities. Orthotopic liver transplantation (LT) from a deceased donor was performed in January 2010. The explanted liver was slightly enlarged measuring 21 x 16 x 7.5 cm and weighed 1.036 kg. The gross cut sections appeared pale brown, and the liver emitted a peculiar sweetish odour (Figure 1). Histology showed regenerative changes with alternating atrophied and hyperplastic liver plates. Mild lobular inflammation with ballooning change in the hepatocytes was demonstrated. No significant steatosis or fibrosis was seen (Figure 2). Immunosuppression consisted of prednisolone, tacrolimus, and mycophenolate mofetil. She has recovered well after LT, without further episodes of encephalopathy/hypersomnolence despite a normal protein diet. Arterial ammonia levels (23 umol/L) normalised less than 2 weeks after LT. As her sensorium and ammonia levels had returned to normal and she was able to function in the mental capacity of a normal healthy person, citrulline levels and excretion were not measured again after transplant. She is currently on tailing doses of dual immunosuppression (tacrolimus and mycophenolate mofetil). She continues to remain well more than 1 year after LT and has since returned to work.

PMC7272571_01

Female

A 43-year-old woman with a past medical history of ileal and colonic CD for 9 years was referred to the Pituitary Center for a sellar mass. Written informed consent was obtained from the patient to report the details of her case. She had been experiencing intermittent debilitating headaches associated with photophobia, diplopia and subjective loss of peripheral vision for 9 months. During one of these episodes, she presented to an outside emergency room where MRI of the brain reportedly showed a pituitary macroadenoma. She was also seen by an ophthalmologist, and underwent formal visual field testing which was normal. Review of systems was positive for worsening fatigue, nausea and secondary amenorrhea for 5 months. She denied symptoms of polyuria or polydipsia. Her CD was considered to be in remission off of medications, but she had been on mesalamine 1 year prior, and corticosteroids were last prescribed 2 years ago. She had no family history of endocrinopathies or pituitary tumors. Her physical examination was notable for a sallow complexion, but was otherwise unremarkable. Hormonal testing revealed secondary hypothyroidism with a low TSH of 0.271 (0.45-4.5 muIU/mL) and low free T4 of 0.57 (0.82-1.77 ng/dL), secondary adrenal insufficiency with a low cortisol of 1.5 mug/mL with an inappropriately normal ACTH of 8 (6-58 pg/mL), and mildly elevated prolactin of 62.2 (4.8-23.3 ng/mL). There was no symptomatic or laboratory evidence of diabetes insipidus (DI) and her urine osmolality was 651 mOsm/kg concurrent with a serum sodium of 141 mEq/L. MRI brain revealed a 12 mm anterior-posterior x 12 mm craniocaudal x 19 mm transverse sellar lesion abutting the optic chiasm. It was reported as a pituitary adenoma, but infundibular thickening was visible upon closer examination (Figure 1A). The presumed posterior pituitary "bright spot" was visible on the MRI T1 pre-contrast sagittal view (Figure 1A, left panel). The patient was initiated on levothyroxine and hydrocortisone replacement. She underwent endoscopic transsphenoidal biopsy and partial resection of the pituitary lesion, with the surgical cavity visible on the post-operative MRI (Figure 1B). The first five surgical specimens contained adenohypophysis with lymphocytic infiltrates (anti-CD45 positive) and multiple foci of epithelioid histiocytes with focal multinucleation (anti-CD68 positive) as shown in Figure 2. The sixth specimen was a dural biopsy showing fibroconnective tissue consistent with dura, with mild chronic inflammation. Pathology was consistent with a diagnosis of GrHy (Figure 2). Special stains for fungi, acid-fast organisms and bacterial organisms were negative. Further evaluation for secondary causes of GrHy, apart from CD, including tuberculosis (TB), syphilis, vasculitis and sarcoidosis was negative (Table 1). Additionally, there was no clinical or histological suspicion for dendritic cell disorders such as Langerhans cell histiocytosis or Erdheim-Chester disease. A timeline of therapeutic interventions after surgery is depicted in Figure 3. The patient was prescribed high dose oral prednisone, starting at 60 mg daily for 2 weeks, and tapering over 8 more weeks to 5 mg. However, she continued to have a worsening clinical course, including the development of new-onset disruptive polyuria and polydipsia with a serum sodium 142 mEq/L concurrent with a urine Osmolality 320 mOsm/kg, treated successfully with demopressin 0.1 mg daily. MRI revealed relapse of her mass lesion on MRI (Figure 1C). In conjunction with her specialists in Rheumatology and Gastroenterology, a personalized medicine approach was proposed using an anti-tumor necrosis factor (TNF)-alpha inhibitor because of the efficacy of these agents in CD. Initially, she was started on infliximab. Within 3 months of therapy, she experienced a marked improvement in symptoms and resolution of the mass on MRI (Figure 1D). Azathioprine was added 3 months after infliximab, as per advice from Rheumatology, to reduce the risk for development of neutralizing human anti-chimeric antibodies against the infliximab, as they decrease its efficacy. While she has persistent central hypothyroidism and adrenal insufficiency, the symptoms of DI resolved within 4 months of initiation of immunosuppressive therapy, and she does not require desmopressin. She had temporary resumption of regular menstrual cycles as well. However, 6 months later her cycles were again interrupted due to recurrence of mild hyperprolactinemia to 33.2 ng/mL, which was thought to be due to infiltration of the stalk. She was started on low-dose cabergoline 0.25 mg weekly, with resolution of amenorrhea and hyperprolactinemia. Her course has been complicated by development of plaque psoriasis which could be due to her predisposition to autoimmunity, but can also be seen paradoxically as a side effect of infliximab. She was switched to a fully humanized anti-TNF-alpha inhibitor adalimumab at 18 months post-operatively, and azathioprine was continued (Figure 3). Subsequent MRI at nearly one and a half years after initiation of immunosuppressive therapy, including 2 months on adalimumab, revealed sustained resolution of the pituitary lesion (Figure 1E).

crohn's disease, adalimumab, anti-tnf-alpha, case report, granulomatous hypophysitis, inflammatory bowel disease, infliximab, pituitary

PMC8349034_01

Female

A 66-year-old Japanese woman presented to Kameda Medical Center, a tertiary care and teaching hospital with 925 inpatients beds, due to dyspnea that had started the previous month. She had a past medical history of hypertension, diabetes mellitus, and dyslipidemia. She had no history of smoking or alcohol abuse, and she had no familial history of connective tissue or hematological diseases. She had not come into contact with any animals, including birds. Chest radiography, performed at our hospital four years previously, had revealed no abnormalities. Upon physical examination, her blood pressure was 136/58 mmHg, and her heart rate was 83 beats/min. Her oxygen saturation level was 90% (room air), her respiratory rate was 20 breaths/min, her body temperature was 36.7 C, and her body mass index was 34. Her mucous membranes were moist, and her nasopharynx and oropharynx had no ulcerations or exudates. Cardiac examination revealed normocardia, with prominent P2 sounds and a regular rhythm without murmurs. Tachypnea was noted. Inspiratory crackles were present in both lungs. No wheezing or rhonchi were present. No clubbing, cyanosis, or edema of the arms, hands, legs, or feet was noted. The abdominal, musculoskeletal, neurologic, and cutaneous examinations were normal. Arterial blood gas quantification showed type 1 respiratory failure (Table 1). Chest radiography revealed diffuse reticular and ground-glass opacities (GGO) in both lungs. Chest computed tomography (CT) demonstrated a bilateral mosaic attenuation pattern, with enlarged pulmonary arteries and patchy GGOs with consolidation (Fig. 1 A). There was no evidence of pulmonary embolism detected via contrast-enhanced CT performed on the following day. The patient began treatment with a new medication (sitagliptin) for diabetes mellitus two months before presentation; therefore, we initially suspected a drug-induced lung disease, hypersensitivity pneumonia, or nonspecific interstitial pneumonia. On the next day of hospitalization, we stopped all of her medications and advised antigen avoidance. On the 7th day of hospitalization, bronchoalveolar lavage (BAL) was performed. BAL revealed increased numbers of inflammatory cells (Table 1), although the other findings were not specific and the BAL fluid cultures and cytology were negative. Her respiratory failure did not improve with the cessation of medications and antigens; therefore, we initiated the administration of prednisolone (40 mg/day: 0.5 mg/kg ideal body weight) on day 8. However, even after the start of steroid therapy, her respiratory status and CT findings did not improve; in fact, they continued to worsen, despite the subsequent administration of pulse steroid therapy (methylprednisolone: 1000 mg) with tacrolimus treatment (Fig. 1 B). Transthoracic echocardiography on day 10 revealed pulmonary hypertension, with findings that included a transtricuspid pressure gradient of 45 mmHg, flattening of the interventricular septum, right atrial enlargement (57 mm x 45 mm), estimated mean pulmonary artery pressure (PAP) of 27 mmHg, mild tricuspid and pulmonary regurgitation, and preserved ejection fraction of 67%. Therefore, we suspected PTTM and subsequently performed endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB), pulmonary perfusion scintigraphy, positron emission tomography-computed tomography (PET-CT), and right heart catheterization to confirm pulmonary hypertension, identify the primary tumor, and diagnose PTTM. The EBUS-TBLB revealed no malignant cells; however, arteriole stenosis with fibrous intimal thickening was observed (Fig. 3 A-B). Pulmonary perfusion scintigraphy revealed multiple small peripheral perfusion defects in both lungs (Fig. 2 A). PET-CT showed fluorodeoxyglucose (FDG) accumulation in the lungs, with consolidation, as well as in the uterine cervix (Fig. 2 C-D). Right heart catheterization indicated pulmonary hypertension (mean PAP: 28 mmHg) without elevated pulmonary artery wedge pressure (PAWP: 9 mmHg). Cytologic smears of pulmonary wedge arterial blood exhibited only a single atypical cell, characterized by a large, grooved nucleus containing coarsely granular chromatin, dense, round cytoplasm, and high nuclear/cytoplasmic ratio; these findings were compatible with the characteristics of squamous cell carcinoma (Fig. 3 C). Based on these findings, we suspected that the uterine cervical cancer caused PTTM. We consulted a gynecologist, and uterine cervical cancer was finally diagnosed on the 45th day of hospitalization. Chemotherapy was initiated immediately after diagnosis (1st course: carboplatin [AUC5] + paclitaxel [175 mg/m2], 2nd course onwards: carboplatin [AUC5] + paclitaxel [175 mg/m2] + bevacizumab [15 mg/kg]) under strict informed consent requirements. The patient was discharged on the 60th day of hospitalization. After initiation of chemotherapy, the patient's respiratory status and radiological findings (assessed by chest CT and pulmonary perfusion scintigraphy) improved concomitantly with a reduction in the size of the tumor (Fig. 1 B-C, Fig. 2 A-B). She received chemotherapy every three weeks for a total of 18 weeks (six total courses). Although chemotherapy had to be discontinued due to grade 1 epistaxis, no serious side effects were noted. After six courses of chemotherapy, the patient achieved complete remission from uterine cervical cancer. The patient is still alive and is followed up at our hospital regularly. She has recovered well from respiratory failure, and her condition has improved, even six months after the end of treatment. Currently, the patient only requires oxygen administration upon exertion, at a flow rate of 1 L/min.

bal, bronchoalveolar lavage, bevacizumab, ct, computed tomography, case report, ebus-tblb, endobronchial ultrasound-guided transbronchial lung biopsy, fdg, fluorodeoxyglucose (18f), ggo, ground glass opacity, pap, pulmonary arterial pressure, pawp, pulmonary arterial wedge pressure, pdgf, platelet-derived growth factor, pet–ct, positron emission tomography–computed tomography, pttm, pulmonary tumor thrombotic microangiopathy, pulmonary hypertension, pulmonary tumor thrombotic microangiopathy, vegf, vascular endothelial growth factor, vascular endothelial growth factor

PET-CT findings used to diagnose uterine cervical cancer (C-D). PET-CT revealing FDG accumulation with consolidation in both lungs.

PMC6068073_01

Male

A 47-year-old man presented as an activated trauma to a community based trauma center following a motor vehicle collision. He was the restrained passenger in a vehicle that struck a pole at an estimated 40-50 mph. Initially his complaint was abdominal pain with subsequent inability to urinate. The patient also noted some chest wall discomfort secondary to the seatbelt. Upon arrival he was hemodynamically stable, however physical exam revealed generalized tenderness to the sternum and suprapubic regions. Gross hematuria was noted upon insertion of a urinary catheter. Subsequent computerized tomography scans identified a small non-displaced sternal fracture, as well as an intraperitoneal bladder rupture and right lumbar hernia in the area of Petit's triangle, with complete avulsion of the abdominal wall musculature from the iliac crest. (Fig. 1) No other internal injuries were identified. The patient underwent same day laparotomy with cystorrhaphy by the urology team. The traumatic lumbar hernia repair was discussed by the general and plastic surgery teams, and immediate repair was deferred due to the bladder injury as well as the fact it was generally asymptomatic. The remainder of the trauma admission was uneventful. Over the following six months the patient began having increasing pain at the hernia site. After re-evaluation by general and plastic surgery departments, decision was made for surgical repair (Fig. 2a and b). Operative technique began with dissection being carried out directly over the hernia. A preperitoneal plane was developed after the hernia sac was freed from all subcutaneous attachments, dissecting all layers of the abdominal wall away from the peritoneum in order to place a polypropelene mesh. (Fig. 3) A 6 x 6 cm defect was measured, and a 12 x 12 cm mesh was circumferentially sewn into place utilizing the abdominal wall musculature at the superior, medial and lateral aspects. The mesh was then anchored to the periosteum of the iliac crest in the caudal portion. Muscle flaps were created utilizing the external and internal oblique muscles to allow for coverage without undo tension. Predrilled holes along the iliac crest were formed and Mitek QUICKANCHOR suture anchors, preloaded with double arm braided polyethylene/polyester composite sutures were used to secure the oblique musculature to the iliac crest, allowing precise and accurate approximation of the muscle back into its anatomic location (Fig. 3). A drain was placed within the dissected pocket and layered closure of the subcutaneous soft tissue layers and skin was performed. Post operatively the patient has continued to progress well with no recurrence or gross limitations on follow up evaluations (Fig. 4).

bone anchor hernia repair, lumbar hernia, lumbar hernia case report, pre-peritoneal lumbar hernia repair, traumatic lumbar hernia

PMC9108331_01

Female

On September 2, 2021, a 50-year-old woman presented with left upper abdominal pain for 1 day. Physical examination showed that the left upper abdomen was slightly distended, abdominal breathing movement was present, the left upper abdomen had tenderness without rebound pain, the liver and spleen were untouched under the ribs, Murphy's sign was negative, and no abnormal mass was palpable. Laboratory examination showed that the white blood cell count was 21.54 x 109/L (normal range: 4-10 x 109/L), the percentage of neutrophils was 86.9%, hemoglobin level was 114.0 g/L (normal range: 120-160 g/L), C-reactive protein level was 60.82 mg/L (normal range: 0.5-10 mg/L), total protein level was 55.45 g/L, albumin level was 29.25 g/L, D-dimer level was 3.806 mg/L, and procalcitonin level was 0.28 ng/ml (normal range: 0-0.05 ng/ml). CT of the upper abdomen showed a small amount of fluid effusion in the bilateral pleural cavity, splenomegaly with a low-density shadow in the splenic space, and a flake-like high-density shadow of the lateral margin of the left kidney, which was considered calcification. Two days later, a nuclear MRI of the upper abdomen showed splenomegaly with a mass below the spleen. The spleen occupied a space of approximately 8.4 cm x 5.7 mm x 6.3 cm, with clear boundaries. A slightly low signal was observed in T1-weighted imaging (T1WI) and a slightly high signal in T2-weighted imaging (T2WI), and the signals were uneven ( Figures 1A-E ). Small cystic degeneration or cystic spaces were observed in the mass, which showed a longer T2WI signal. The lesion showed progressive enhancement on the enhanced scan, and the enhancement range increased on the delayed scan. A spindle-shaped abnormal signal was observed above the lesion and below the splenic capsule, with smooth margins and visible separation shadows. Mixed signals and fluid-fluid levels were seen in the chamber; low, nodular T1 signal and low T2 signal were observed in association with the lesion below. The size of the mass was approximately 3.3 cm x 3.6 cm, and it compressed the adjacent left kidney. The possibility of splenic hemangioma was considered, with calcification below the lesion and splenic subcapsular hematoma formation (absorption phase) ( Figures 1F-H ). An uneven flake-like hyperintensity was observed, which was considered to be bilateral soft tissue exudation and edema of the ribs and waist. No obvious abnormalities were observed in the liver, gallbladder, or pancreas. The arc-shaped liquid signal was considered to define a small amount of fluid effusion in the left pleural cavity. After adequate examination, we combined the results with the patient's medical history, and splenic hemangioma with ruptured bleeding was strongly considered. Digital subtraction angiography (DSA), splenic arteriography, and embolization were performed 4 days after the onset of symptoms, with the consent of the patient's family ( Figure 2 ). A super-selective catheter and gelatin sponge particles were selected for embolization, and the operation was successful. Postoperatively, anti-inflammatory, nutritional, blood transfusion, anti-infection, and other treatments were administered. After the operation, the patient experienced pain in the left upper abdomen and paroxysmal aggravation, which could not be relieved after symptomatic treatment. The hemoglobin level was 106.0 g/L. CT showed a bulk-like mixed density shadow in the spleen with poorly defined margins, a maximum cross-sectional size of approximately 9.2 cm x 6.1 cm, and hemorrhage ( Figure 3C ). A flake-like high-density shadow was seen in the lower margin of the spleen, which was considered to be a change after embolization ( Figures 3D, F ). The gallbladder shrunk and the wall thickened, which was considered chronic cholecystitis. Moreover, a spindle-shaped, slightly high-density shadow with a rough margin under the left renal capsule was observed, which was considered to be a small subcapsular hematoma of the left kidney ( Figure 3E ). Bilateral pleural thickening and arc-shaped liquid density shadows were considered to be bilateral pleural effusions ( Figures 3A, B ). Based on the above description, and considering the high possibility of active bleeding, laparotomy and splenectomy were performed under emergency general anesthesia. The surgery was successful, and the patient's general condition was good postoperatively, without obvious discomfort. Intraoperative abdominal exploration showed the following: approximately 300 ml of blood accumulated in the abdominal cavity; the spleen was closely adherent to the periphery; the splenic hilum and the tail of the pancreas formed a mass and were adherent; and the lower pole of the spleen was enlarged, bleeding, and adherent to the splenic flexure of the colon, with no other abnormalities observed. Splenectomy was performed, in which the splenic flexure of the colon was fully freed from the lower pole of the spleen, and a hard mass could be palpated between the lower pole of the spleen and the left renal capsule. After dissection and ligation of the short gastric vessels, the splenic hilum was carefully separated, and the splenic artery and vein were successively dissected and doubly ligated proximally. The splenic hilum was dissected, and the spleen and the hard masses were removed. The splenectomy specimen showed a spleen size of 13 cm x 8 cm x 4 cm. Bleeding was observed on the excision of the spleen. Another free mass of 5 cm x 4 cm x 3 cm with partial calcification was observed, as well as a free clot of 18 cm x 10 cm x 4 cm with partial graying that showed a splenic soft tissue tumor ( Figures 4A-C ). Under low magnification, the tumor cells grew in diffuse sheets with a slightly woven arrangement in some areas, scattered multinucleated giant cells, and small focal necrosis ( Figure 4A ). Under medium magnification, scattered osteoblast-like multinucleated giant cells were observed among tumor cells ( Figure 4B ). Under high magnification, the tumor cells were cytoplasm-rich and round/oval in shape, with many nuclear schizophrenic images and pink-stained bone-like stroma formation (tumor osteogenesis), which was lace- or grid-like, with calcium salt deposits (purple-blue) in some areas ( Figure 4C ). Immunohistochemical staining showed that the tumor cell membrane was positive for beta-catenin, while the expression of SMA and CD99 was negative. Positive cytoplasmic CD68 expression was observed in osteoclast-like giant cells. BCL-2 expression was positive, and the proliferation index of Ki-67 was 50%. SATB-2 and P16 showed diffuse positive expression in the tumor nucleus. MDM-2 was positive in some tumor cells. The remaining indicators, CD31, CD34, F8, s-100, and desmin, were negatively expressed ( Figures 4D-L ). No abnormal radioactivity was found in the patient after the operation, as observed using a bone scan with 99mTc-MDP, further ruling out the occurrence of other bone tumors. Accordingly, the patient was diagnosed with primary ESOS. The patient was not treated with chemotherapy or targeted therapy for 12 months after the surgery. Multiple metastases in the lung, liver, and abdominal cavity were found at the 12-month postoperative reexamination. The patient died 13 months after the operation after being treated with lenvatinib-targeted therapy in another hospital, which was ineffective.

calcification, extraskeletal osteosarcoma, osteosarcoma, soft tissue tumor, spleen

PMC8305623_01

Male

A 15-year-old male with a history of familial hypertrophic cardiomyopathy (HCM) presented to discuss participation in exercise and competitive sports. He was diagnosed with HCM at age 2 and subsequent echocardiograms showed marked septal hypertrophy and a resting left ventricular outflow tract (LVOT) gradient of 36 mm Hg. He was started on beta-blockade therapy and has remained on monotherapy since. At age 9 years, cardiac magnetic resonance imaging showed a septal wall thickness of 32 mm with late gadolinium enhancement. His resting LVOT gradients have been stable over the years in the moderate range, and he has remained asymptomatic. An implantable cardioverter-defibrillator (ICD) was inserted due to his hypertrophy burden and a family history of sudden cardiac death. The patient participated in gym class but not in competitive sports in middle school. In high school, he joined the golf team but has not participated in gym class because of uncertainty around the intensity of exercise that would be considered "safe." He engages in low to moderate-intensity recreational activity, including weightlifting, jogging, skiing, and pick-up basketball games. He does not have any physical limitations or symptoms with exercise. He has no other medical history. His examination was notable for a 3/6 grade systolic ejection murmur that increases with squat-to-stand. The patient's paternal uncle died suddenly in his 50's while jogging. The patient's father has a primary prevention ICD, but it has never fired. The patient's 2 siblings each have primary prevention subcutaneous ICDs. Genetic testing identified a pathogenic variant in the MYH7 gene that was also present in his father and 2 siblings. Electrocardiogram showed left ventricular hypertrophy with repolarization abnormalities (Figure 1). Transthoracic echocardiography showed left atrial dilation, interventricular septum measuring 30 mm, systolic anterior motion of the mitral valve with peak gradient of 48 mm Hg at rest, and moderate to severe mitral regurgitation with an ejection fraction of 70% (Videos 1, 2, 3, and 4).

hcm, hypertrophic cardiomyopathy, icd, implantable cardioverter-defibrillator, lvot, left ventricular outflow tract, sam, systolic anterior motion, echocardiography, exercise, hypertrophic cardiomyopathy, shared decision making, sports cardiology, sudden cardiac death