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Tuberculosis_Dataset

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PMC9534663_01

Female

A 42-year-old G0 female was referred to the gynecology oncology outpatient clinic for evaluation of symptoms and imaging findings concerning for ovarian cancer. She reported six months of abdominal discomfort and distension, night sweats, fever, and weight loss. Her previous gynecologic history included a ruptured ovarian cyst five years prior, but medical records were not available for review. She had no chronic medical conditions and did not take any medications. She had been born and lived in Brazil until moving to the U.S. three years prior to the current presentation. In Brazil, she had worked in a public health clinic that provided tuberculosis care; she had never been evaluated for M. tuberculosis infection or tuberculosis. On physical examination, she was generally well-appearing. The abdomen was distended but soft and nontender to palpation. External genitalia, vagina, and cervix had normal appearance; the uterus and cervix were deviated to the right on exam, and rectovaginal examination was normal. There was no thrush, peripheral lymphadenopathy, or lower extremity edema; heart and lung exams were normal. CT with contrast of the abdomen and pelvis showed a moderate volume of free fluid throughout the abdomen with diffuse nodularity throughout the omentum, enlarged right retroperitoneal lymph nodes measuring 1.4 and 1.2 cm in the short axis diameter, and a bilobed right ovarian cyst measuring 6.5 cm at maximum diameter (Figure 1(a)). A transvaginal ultrasound showed a hypoechoic lesion with low-level internal reticular echoes within the right ovary, consistent with a hemorrhagic cyst (which resolved based on follow-up ultrasound examination); an 0.8 cm hypoechoic structure in the endometrium; and cystic structures throughout the myometrium. A test for antibodies to HIV-1 and HIV-2 was nonreactive. Complete blood count and metabolic panel were normal. Blood CA-125 level was 1289 U/mL (normal <= 38.1 U/mL). Paracentesis was performed and showed rare benign mesothelial cells. Endometrial biopsy showed secretory endometrium without evidence of malignant cells. A CT-guided omental biopsy showed granulomas without evidence of neoplasm; mycobacterial and fungal stains and cultures were negative. Diagnostic laparoscopy was performed. Upon inspection, there was diffuse studding of intraperitoneal surfaces with 1-2 mm tan nodules, and the omentum was adherent to the anterior abdominal wall (Figures 1(b) and 1(c)). There was an enlarged uterus with multiple fibroids, and the ovaries were without masses. Pathology of the omental and abdominal wall biopsies showed benign fibroadipose tissue with necrotizing and nonnecrotizing granulomas but without acid fast bacilli seen on modified Ziehl-Neelsen staining; mycobacterial cultures using the Mycobacteria Growth Indicator Tube (MGIT) liquid culture system and Lowenstein-Jensen solid media were negative, and nucleic acid amplification testing was negative for Mycobacterium tuberculosis. Due to unknown cause of intraperitoneal granulomas, she was referred to an infectious disease physician and to the local health department. CT of the chest showed a 4 mm left lower lobe nodule and biapical mild pleural parenchymal scarring. A tuberculin skin test showed 10 mm induration, and a blood QuantiFERON-TB Gold Plus interferon-gamma release assay (Qiagen) was positive. Due to concern for peritoneal tuberculosis, treatment was initiated with isoniazid, rifampin, pyrazinamide, and ethambutol. Within four weeks of treatment, the CA-125 had decreased to 74 U/mL, and she had substantial clinical improvement including resolution of fevers, reduction in abdominal discomfort, increased appetite, and weight gain. At eight weeks after tuberculosis treatment initiation, her abdominal pain was entirely resolved, weight had increased from 56.6 kg at presentation to 62.1 kg, and CT abdomen and pelvis showed resolution of omental caking, ascites, and lymphadenopathy. A clinical diagnosis of tuberculosis peritonitis was made, and standard tuberculosis treatment was administered for a total of 6 months.

PMC4329683_01

Male

A 57-year-old male presented with acute epigastric pain and decreased urine output. The pain was mild-to-moderate in severity, intermittent, with occasional vomiting. There was no radiation of pain, and the patient had little relief with analgesics. The patient had decreased urine output over the past 24 h. He was a chronic smoker. There was no past history of diabetes mellitus, hypertension, or tuberculosis. There was no past surgical history. On examination, there was mild pallor. Mild tenderness was elicited in the right upper quadrant. Hemogram revealed a low platelet count (14,000/mul). There was mild elevation of liver enzymes [aspartate transaminase (AST) 87 IU/l, alanine transaminase (ALT) 95 IU/l, alkaline phosphatase 198 IU/l] and serum bilirubin (1.5 mg/dl). Renal function tests were within normal range. Abdominal USG (iU22 x MATRIX, Philips, Best, Netherlands) revealed echogenic contents within gallbladder (GB) lumen. Common bile duct (CBD) was prominent (8 mm). There was no intrahepatic biliary radical (IHBR) dilatation and the pancreas was normal. A magnetic resonance cholangiography (MAGNETOM Aera, Siemens, Erlangen, Germany) was performed that revealed mild dilatation of CBD and intrahepatic biliary radicles [Figure 1]. No filling defects were noted within the CBD. GB was normal. There was worsening of the abdominal pain over the ensuing few days associated with progressive elevation of conjugated bilirubin (7.5 mg/dl). Endoscopic retrograde cholangiography (ERCP) was performed. There was blood ooze seen at the papilla. However, cholangiogram did not reveal any filling defects. A naso-biliary drainage (NBD) tube was placed which resulted in decline of conjugated bilirubin to 4.4 mg/dl. Cholangiogram was performed through the NBD after 1 week, which revealed filling defects within the GB and CBD suggestive of blood clots. Patient continued to deteriorate with a falling hemoglobin suggesting ongoing hemobilia. A vascular cause [pseudoaneurysm or arteriovenous (AV) malformation] was suspected and computed tomography (CT) angiography (SOMATOM Definition Flash, Siemens, Erlangen, Germany) and digital subtraction angiography (Allura Xper FD 10, Best, Netherlands) was performed. The vascular causes were ruled out. Finally, an exploratory laparotomy was performed. Cholecystectomy and CBD exploration was performed. No calculus or mass was detected within the CBD. Intraoperative cholangioscopy, however, revealed unhealthy mucosa at the confluence that was biopsied. A T-tube was left in situ to achieve continuous drainage. Subsequently, there was no hemobilia. Histopathologic examination of the tissue revealed only inflammation. There was improvement in patient's condition with falling levels in serum bilirubin. However, 4 weeks later, there was mild rise in the serum bilirubin as well as alkaline phosphatase. A T-tube cholangiogram was performed. There were filling defects within the proximal CBD with no opacification of IHBR suggestive of an inflammatory stricture at or just beyond the confluence [Figure 2]. Cholangioplasty was planned through the T-tube tract under conscious sedation. A 0.035'' guidewire was passed into the left ductal system across the stricture at the confluence. After removal of the T-tube, a 7F 35 cm sheath was inserted over the wire and advanced into the biliary tree. Balloon dilatation was performed using a 10 mm diameter by 40 mm long angioplasty balloon (Advance , ATB PTA dilatation catheter; Cook Medical, Bloomington, IN, USA), inflated for 10 min. We also did cholangioplasty of the lower end of CBD as filling defects were seen in the proximal CBD on the T-tube cholangiogram suggesting distal stasis. Repeat balloon dilatation of the hilar stricture was done after 3 weeks. A temporary external drainage tube [12F percutaneous transhepatic biliary drainage catheter (PTBD catheter)] was placed with its tip just across the stricture, after each session of cholangioplasty. Cholangiography via the biliary catheter following the procedure revealed good opacification of the entire biliary tree [Figure 3]. The external biliary drainage catheter was finally removed 3 weeks after the second session of cholangioplasty. The procedure was successful, with no complications. Patient was followed with serial evaluation of serum bilirubin, alkaline phosphatase, and ultrasound examinations. At the last follow-up, i.e. 7 months after the procedure, the patient was asymptomatic.

balloon dilatation, t-tube, cholangioplasty

PMC8462861_01

Female

The patient was a 35-year-old African American female with a history of asthma and polysubstance abuse who presented to the emergency department (ED) with severe shortness of breath. She reported that the shortness of breath was progressive over several months and associated with weight loss. She denied a history of HIV infection. The patient's only known home medication was albuterol as needed for asthma. She also reported a history of smoking 10 cigarettes a day and drinking alcohol a couple of times a week. On physical examination, she was cachectic, ill-appearing and tachypneic with the use of accessory muscles for respiration. Her blood pressure was 88/55 mm Hg, temperature was 37.4 C, pulse rate was 146 beats per minute and regular, oxygen saturation of 70% on room air, and body mass index of 18.9. Lung auscultation revealed bilateral rhonchi. Heart auscultation revealed normal S1 and S2 without significant murmurs or rubs. She was placed on a non-rebreather mask with FiO2 of 100% without improvement of respiratory status and was switched to non-invasive mechanical ventilation. Her status continued to decline, and she underwent endotracheal intubation within an hour of arriving at the ED for hypoxic respiratory failure. SARS-CoV-2 testing done upon arrival in the ED was negative. She tested positive for HIV, and further evaluation revealed an initial viral load of 343,636 copies per milliliter and an absolute CD4 count of 5 cells/muL. On day 1, a chest radiograph (Figure 1(a)) revealed extensive right lung opacities, most prominent in the right middle lobe. The cardiac silhouette was slightly enlarged. A chest CT scan with intravenous contrast (Figure 2) revealed severe cavitary and partially necrotic opacities in the right upper lobe. There was also a small right pleural effusion and a moderate pericardial effusion. An echocardiogram (Figure 3) revealed a large pericardial effusion, as large as 4.16 cm, with no signs of tamponade. Initially, she was placed on vancomycin, cefepime, azithromycin, anidulafungin, trimethoprim/sulfamethoxazole (TMP/SXM) and methylprednisolone. She also required norepinephrine and vasopressin for the first 5 days for hypotension, most likely due to septic shock. On day 5, she underwent bronchoscopy for BAL after tuberculosis was ruled out with three negative sputum acid-fast bacillus smears and a negative polymerase chain reaction (PCR) test. Chest radiography on day 8 (Figure 1(b)) revealed an increase in the right-sided infiltrates and new patchy infiltrates at the left lung base. On day 13, PCR of the BAL was positive for CMV with CMV DNA of 197,000 IU/mL. Fungal culture of the BAL fluid did grow Candida albicans, which was determined to be a colonization. All other tests performed on the BAL (summarized in Table 1) were negative. Additionally, tests for Cryptococcus antigen, Histoplasma antigen, Legionella antigen, A. Galactomannan antigen and (1,3)-beta-D-glucan were negative. She was started on IV ganciclovir 250 mg twice a day for CMV pneumonia and antiretroviral therapy for HIV. Anidulafungin, methylprednisolone and all other antibiotics were discontinued except for TMP/SXM, which was continued for Pneumocystis jiroveci pneumonia (PJP) prophylaxis. She was extubated on day 13 and switched to high-flow nasal cannula. On day 17, a follow-up echocardiogram showed that she still had a large circumferential pericardial effusion that had not changed significantly in size since the day of admission. Pericardiocentesis was performed, draining 500 mL of straw-colored fluid. Pericardial fluid analysis was positive for CMV DNA using PCR and negative for adenosine deaminase. All other tests performed on the pericardial fluid (summarized in Table 1) were negative. A chest radiograph on day 22 (Figure 1(c)) showed reduced infiltrates in the right lung field, with a moderate overlying pleural effusion. Her HIV viral load had decreased to 5,522 RNA copies per milliliter. She was breathing comfortably on room air. She was discharged on oral valganciclovir 900 mg twice a day until her CD4 count improved to over 100 cells/muL, TMP/SXM for PJP prophylaxis and Biktarvy as antiretroviral therapy.

hiv, bronchoalveolar lavage, cytomegalovirus, hypoxic respiratory failure, pericardial effusion

PMC6752114_01

Male

An 8-year-old male patient presented after suffering blunt trauma to the left side of the face during a football game. On initial evaluation, the patient denied malocclusion or chin deviation. Computed tomography (CT) identified a displaced intracapsular left-sided mandibular condylar fracture (Fig 1), and conservative treatment was attempted. After 1 week, the patient developed malocclusion and chin deviation (5 mm) (Fig 2) and subsequently was started on a 3-phase protocol utilizing elastic therapy. Phase I used 6-oz 3/4-inch "fixating elastics" (class II ipsilateral to injury, class I contralaterally) (figure-of-eight configuration) (Fig 3). In phase II, 6-oz 1/4-inch "guiding elastics" were placed (class II ipsilaterally, class I contralaterally) (non-figure-of-eight configuration). In phase III, 6-oz 1/4-inch "supportive elastics" were placed (class I bilaterally) (non-figure-of-eight configuration). Each phase lasted 2 weeks, with advancement criteria including centric occlusion without chin deviation. Diet was advanced with phase of therapy from liquid to blenderized to soft. At conclusion of therapy, centric occlusion with congruency of dental and facial midlines (0-mm deviation) was achieved (Fig 4). What is the etiology of pediatric mandibular fractures? How are pediatric patients affected by condylar fractures? What are the different methods of treatment of pediatric condylar fractures? What are the benefits of closed reduction with dynamic elastic therapy?

condylar fractures, dynamic elastic therapy, guiding elastics, mandibular fractures, pediatric injuries

PMC6138103_01

Female

A 13-year-old adolescent girl was admitted to the Department of Child and Adolescent Psychiatry with complaints of lack of enjoyment of pleasurable activities, sleep disturbances, suicidal thoughts, binge eating episodes, self-induced vomiting episodes and excessive exercising, leading to significant weight loss last 1 year in association with a situation of a family conflict. The patient lived with her mother and sister. She was very distressed and unhappy because her mother forced her to talk with her father. She stated that her father had deserted them for someone else 9 years ago, she did not talk and see him until this time anymore and she found this difficult to accept him and everyday her father phoned her mother and insisted on establishing a new relationship. In this month, she began to take money from home without permission, especially after each time her father called her mother. And she started to have conflicts with her peers and siblings. She was admitted to the paediatric inpatient clinics in two different hospitals because of self-induced vomiting episodes and weight loss before admission to the Department of Child and Adolescent Psychiatry. She had no complaints of dysphagia, retrosternal pain and heartburn; physical examinations and detailed investigations including blood tests and abdominal-pelvic ultrasound and endoscopy were normal on both paediatric occasions. Paediatric gastroenterology specialist reported that this medical condition was not associated with any primary oesophageal motility disorders (achalasia, diffuse oesophageal spasm, nutcracker oesophagus, etc.) and secondary oesophageal motility disorders (diabetes mellitus, scleroderma, etc.). Following this, she was referred to a child and adolescent psychiatry outpatient clinic along with a pre-diagnosis of psychiatric disorders to be able to associate with secondary oesophageal motility disorders. At the psychiatric evaluation, she expressed no fear of getting fat but her self-esteem was strongly affected by her physical appearance, and she seemed very unhappy. She reported binge eating episodes and self-induced vomiting at least 7-8 times a day. She had lost 13 kg in the previous 6 months (weight: 41 kg, height: 162 cm, body mass index: 15.6 at admission). Laboratory evaluations including haemogram, liver function tests, total protein, vitamin B12, folic acid, T3, T4, TSH, FSH, LH, E2, prolactin levels were within normal limits. The abdominal-pelvic ultrasound and plain abdominal radiography were repeated and reported as normal. A physical examination at the paediatric clinic ruled out medical complications. Achalasia and other oesophageal motility disorders were ruled out according to physical examinations and test results. Baseline psychiatric evaluation with the Children's Depression Inventory and the Clinical Global Impression scale revealed scores of 40 and 7 (extremely ill), respectively. According to those evaluations and DSM-IV-TR criteria, the patient was diagnosed with major depressive disorder and BN, and she was started on fluoxetine 20 mg per day. Cognitive behavioural therapy focusing on body-focused cognitions was also started. Partial response to treatment was observed at the 11th week (i.e. binge or vomiting reduced to 2-3 per day and weight gain of 1.4 kg), and fluoxetine was titrated to 40 mg/day. The subject of seeing her father was closed. She stated that this made her feel good, and she registered for a painting course. While she was under follow-up in a child and adolescent psychiatry clinic, she was admitted to a paediatric gastroenterology clinic because of complaints of dysphagia with retrosternal pain, heartburn, involuntary vomiting of undigested food and weight loss. Oesophagogastrodu-odenoscopy showed retention of liquid in the oesophagus, so oesophageal manometry was quickly carried out, and the results were strongly consistent with achalasia in the patient. After a joint meeting of the paediatric gastroenterology and paediatric surgery departments, a decision to operate was made. The patient underwent surgery, and oesophagogastromyotomy and fundoplication were performed during the operation. After surgery, her vomiting decreased. And she stated that she felt better but she still experienced anxiety regarding her physical appearance and weight. She was receiving 40 mg/day fluoxetine and cognitive behavioural therapy sessions weekly, and she is still under follow-up. Her Children's Depression Inventory and the Clinical Global Impression scale scores were 25 and 2 (borderline mentally ill), respectively, during her last visit.

PMC4631868_01

Male

In early November 2014 an 18-year-old man presented to our department with fever above 40 C, headaches, night sweats, and diffuse arthralgia for the last two weeks. Suspecting a bacterial infection with an unknown focus, he had been treated with ampicillin/sulbactam in a secondary care hospital for two weeks. The patient reported having been on a one-week holiday in Turkey three months ago. At the time of admission he was doing his military service. Before military service he lived at his parents' farm, where several different animal species are kept, including cattle, chicken, and cats. The full medical examination showed no abnormalities except bilateral cervical lymphadenopathy. Laboratory investigations revealed markedly elevated C-reactive protein (CRP) of 11.41 mg/dL on day of admission. White blood count was within the normal range with 9.21 G/L. Differential blood count showed a decrease in lymphocyte count of 16%. Antimicrobial therapy was stopped and serial blood cultures, serologies for Entamoeba, Francisella tularensis, Brucella spp., and fungal, bacterial, and viral broad-spectrum PCRs were performed. All results were negative and did not provide evidence for a specific infectious pathogen. Similarly, QuantiFeron-TB test for Mycobacterium tuberculosis showed negative results and screening for autoimmune antibodies including rheumatoid factor, c-ANCA, and p-ANCA did not indicate autoimmune disease. Due to the patient's symptoms, such as fever and lymphadenopathy, and his inconclusive laboratory findings, a CT scan was performed, which showed multiple hypodense hepatic and splenic lesions; the largest is 2 cm in diameter (Figure 1). Furthermore subchondral sclerosis and erosion of the ventral thoracic spine were shown with maximal affection of the seventh vertebral body. Given the ambiguous structure of the spine, a MRI was done, confirming a ventral base plate fracture of vertebral body 7 with reduction in height of 20% and bone marrow edema (Figures 2, 3, and 4). The lesions were suggestive for an underlying infectious origin as were the hepatosplenic lesions. Due to the radiological appearance, the stagnant infection parameters with negative serologies for Francisella tularensis, Brucella spp., Entamoeba, and blood cultures for common infectious pathogens, and the patient's history of residency on a farm with cats, serologic testing for B. henselae was performed. IgM (1 : 1000) and IgG (1 : 10.000) antibodies for B. henselae were highly elevated. Consequently, according to recently published guidelines, the diagnosis of an atypical presentation of visceral cat scratch disease with bone involvement was established. Consequently, regarding a histopathological examination of a cervical lymph node, we decided not to take a biopsy, to avoid potential risks involved with this procedure, especially since diagnosis could be established with the patient's clinical presentation, history, laboratory findings, and serology. A PCR for Bartonella henselae could not be performed, as this test is not available in our hospital.

PMC5288301_01

Male

A 77-year-old Vietnamese male presented with a one-week history of hemoptysis. He had had a progressive cough for 6 months for which he was seen by his primary care physician 5 months prior to admission. Chest X-ray (CXR) done at the time revealed right middle lobe infiltrate. He was treated with antibiotics without improvement. Two months prior to admission, he started experiencing night sweats, low grade intermittent fever, fatigue, loss of appetite and 4 pound weight loss. The patient was a chronic hepatitis B carrier but was not on treatment. There was no history of chronic pulmonary disease, pulmonary tuberculosis (PTB) or contact with PTB, HIV test was negative. He was a Vietnamese prisoner of war who migrated to United States of America 21 years previously. He lived with his son and two grandchildren. There was no history of cigarette smoking. On examination, he was cachectic with a temperature 98.7 F, heart rate 81/minute and regular, respiratory rate 21/minute, blood pressure 120/82 mmHg, oxygen saturation, 95% in room air. Chest examination was remarkable for right upper lung bronchial breath sounds. The leukocyte count was 8400/muL (normal range 4800-10800/muL) with normal differentials, and hemoglobin concentration was 11.8g/dl (normal range 14-18g/dl). A comprehensive metabolic profile was within normal limits. A chest readiograph revealed extensive right upper lobe destruction and fibrotic atelectasis (Fig. 1) while a CT scan of the chest with intravenous contrast showed pulmonary parenchymal fibrosis and chronic cystic bronchiectasis of the right upper lobe with consequent superior migration of the right horizontal fissure and rightward mediastinal shift (Fig. 2). Acid fast bacilli (AFB) were detected in the expectorated sputum. The patient was treated with RIPE (Rifampicin, isoniazid, pyrazinamide and ethambutol). Although the initial amplified mycobacterium tuberculosis direct (MTD) test was negative, RIPE therapy was continued because of high clinical suspicion for PTB. Despite RIPE therapy, sputum AFB smear continued to be positive with all broth medium mycobacteria growth indicator tube (MGIT) cultures growing in 7-10 days. Subsequently, DNA PCR detected M. abscessus but did not detect Mycobacterium avium-intracellulare (MAI). RIPE therapy and airborne isolation were discontinued on day 14; and treatment with amikacin, cefoxitin and meropenem was started. MTD test was repeated and positive on day 19. RIPE therapy was restarted and airborne isolation was reinstated while continuing the treatment for M. abscessus. Five weeks later, sputum culture from day 19 grew MTB in addition to M. abscessus. Expectorated sputum samples became negative for AFB in the 5 week of admission and patient was subsequently discharged home to continue treatment for both MTB and M. abscessus. The patient's son and grandchildren were diagnosed with latent TB infection and were currently being treated.

PMC10257542_01

Male

The 15-year-old male patient had undergone auto-transplantation therapy at the University of North Carolina at Chapel Hill (UNC-CH) Adams School of Dentistry (ASOD) Graduate Periodontic Clinic. The treatment planning included a full periodontal examination, such as probing depths and plaque index. Cone beam computed tomography (Orthophos SL 3D, Dentsply Sirona, Charlotte, NC) was used to evaluate recipient sites and donor teeth for surgical planning. The periodontic resident determined the auto-transplantation procedure by selecting donor teeth #4 and #13 and transplanting the teeth at recipient sites #29 and #20, respectively (Figures 1(a), 1(b), 1(c), 1(d), and 1(e)). All auto-transplantation procedures were performed by the periodontic resident at the UNC-CH ASOD Graduate Periodontic Clinic. While one auto-transplanted tooth (donor tooth #4, recipient site #29) was successfully integrated into recipient sites, the other auto-transplanted tooth (donor tooth #13, recipient site #20) developed severe bone loss and apical periodontitis. Therefore, after 6 weeks, the patient was referred to UNC-CH ASOD Graduate Endodontic Clinic for evaluation of #20 (Figures 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), and 2(h)). Upon evaluation at UNC-CH ASOD Graduate Endodontic Clinic, the patient's chief complaint was minor pain when biting and the presence of a sinus tract on the mandibular left quadrant. His medical history was unremarkable. He had no drug allergies, medications, or cardiac/joint diseases requiring antibiotic prophylaxis. His dental history included routine dental care, low caries risk, and good oral hygiene. The extra oral exam and perioral soft tissue exam were within normal limits. His temporomandibular joint function was normal, without any deviation upon opening or discomfort upon palpation. The intraoral examination revealed normal soft tissues with neither pathology nor symptoms. Clinically, tooth #20 had no restorative or carious defects. Examination did not reveal any cracks or fractures, and discomfort upon percussion, palpation, and bite stick testing was minor. Teeth #19 and #21 were tested with EndoIce (Coltene Whaledent, Cuyahoga Falls, OH, USA) and responded within normal limits. Tooth #20 did not respond to EndoIce. The radiographic examination revealed normal PDL space around teeth #19 and #21 but widening of the PDL space, loss of lamina dura, and localized loss of marginal bone on the mesial and distal of tooth #20 (Figure 2(f)). The endodontic diagnosis for this patient was pulp necrosis with chronic apical abscess. Treatment options discussed with the patient included NSRCT or extraction. After considering the risks and benefits of both procedures, an agreement was made to proceed with NSRCT due to recent auto-transplantation. The NSRCT for this tooth started the day of the evaluation to alleviate the patient's discomfort and sinus tract. Local infiltration of 3.6 ml of 4% articaine with 3.6 ml of 1 : 100,000 epinephrine (Septocaine; Septodont, New Castle, DE, USA) was administered. Dental clamp and dental dam modifications were necessary to achieve the appropriate isolation due to the present orthodontic bracket and archwire; adjunctive endodontic isolation was performed with OraSeal (Ultradent Products, South Jordan, UT, USA). Access to cavity preparation was challenging due to multiple factors, including tooth mobility and maxillary premolar anatomy in a mandibular arch. Magnification up to 20x and illumination of 125 K (Prima, Labomed, Gurgaon, India) were used for canal identification and to reduce the possibility of missed canals. A single canal was found, and the working length was determined using an electronic apex locator (Root ZX II, Morita, Kyoto, Japan); measurement films were taken at multiple angulations to visualize canal configurations and apical termini. Debridement was accomplished using hand instrumentation with K-type and Hedstrom files (Dentsply-Sirona, Johnson City, TN, USA) to a size #80 (Figure 3(a)). Copious irrigation of 2.5% sodium hypochlorite (NaOCl) (Henry Schein, Melville, NY, USA) was used during the cleaning and shaping process, followed by a final rinse of 17% ethylenediaminetetraacetic acid (EDTA) (Henry Schein, Melville, NY, USA) to remove the smear layer. The irrigation solutions were delivered via the EndoVac Negative Pressure Irrigation system (Discus Dental, Culver City, CA, USA). The tooth was dried with medium endodontic paper points (Dentsply-Sirona, Johnson City, TN, USA) until the paper points were stiff. Calcium hydroxide (Sultan Healthcare, York, PA, USA) was mixed with 2.5% NaOCl and placed with an amalgam carrier 2 mm from the radiographic apex (Figure 3(b)). The tooth was then temporized with Teflon tape and Fuji TRIAGE (GC America, Alsip, IL, USA). The patient presented 4 weeks later for follow-up and obturation. No symptoms were observed, the chief complaint had been resolved, and mobility had decreased to class two. Administration of local anesthesia and a rubber dam placement technique was used. A nickel-titanium plugger (SybronEndo, Kerr, Brea, CA, USA) was selected to obtain an appropriate apical fit of 2 mm from the radiographic apex and working length (Figure 4(a)). After the nickel-titanium plugger placement was confirmed, the canals were dried with medium paper points (Dentsply-Sirona, Johnson City, TN, USA). Once the canal was dried thoroughly, it was obturated using EndoSequence Bioceramic Root Repair Material Fast Set Putty (Brasseler, Savannah, GA, USA) in 2 mm incremental layers. A radiograph was exposed to ensure a proper 2-4 mm apical seal (Figure 4(b)). The aim of this technique was to achieve a three-dimensional fill and create an apical plug to prevent gutta-percha extrusion. After the apical plug, backfill was performed with a Kerr Backfill unit (SybronEndo, Kerr, Orange, CA, USA) in incremental layers of gutta-percha to the cementoenamel junction (CEJ). When obturation was complete, excess gutta-percha was removed from the chamber using a heated posterior endodontic plugger (Kerr Dental, Orange, CA, USA). The tooth was restored by placing 37% ortho-phosphoric acid etch on the enamel for 30 seconds and rinsing with water. Once the tooth was dry, Optibond Solo Plus (Kerr Dental, Orange, CA, USA) was coated and scrubbed in the endodontic access for 20 seconds, air-dried, and cured for 30 seconds. Lastly, a packable composite (Filtek Supreme, 3M, Two Harbors, MN, USA) was placed in 2 mm incremental layers until access was filled and then cured for 1 minute. The composite was smoothed and polished with a football-shaped bur (Komet USA, Rock Hill, SC), and occlusion was checked with articulating paper until acceptable occlusal contact was determined. The final post-operative radiograph was exposed (Figure 5). The patient was referred to his orthodontist for continued care. The patient was recalled for an 8-month follow-up to NSRCT, and the endodontic outcome was considered favorable. The radiograph showed normal PDL, and the lamina dura had no signs of periapical pathology. The patient has remained asymptomatic after the completion of NSRCT; a radiographic exam revealed complete healing of periapical pathosis (Figure 6). The permanent restoration was intact without any evidence of leakage. All probing depths were within normal limits with normal physiological mobility.

PMC8189782_01

Male

The case is a 28-year-old Chinese male with no past medical or psychiatric history presenting with complaints of constant "static" in his entire field of vision which he subsequently described as "a subtle overlay of an out-of-signal TV screen over my entire vision." Symptoms began shortly following diagnosis with COVID-19 infection. The patient developed symptoms of COVID-19 (fever, cough, loss of sense of taste, and smell) on March 12, 2020, and was confirmed positive for COVID-19 via nasopharyngeal swab on March 20, 2020, by way of a nasopharyngeal swab tested for the coronavirus with reverse transcription-polymerase chain reaction RNA testing. He was subsequently hospitalized for 2 days and treated with IV azithromycin and hydroxychloroquine. The patient was discharged home and eventually tested negative for COVID-19 on April 11, 2020, also via nasopharyngeal swab and RNA, RT PCR. He then reported associated photophobia and palinopsia (after images). He denied prior visual symptoms prior to COVID-19 infection. He was also found to have decreased vision in the left eye by his optometrist and was referred for further evaluation. The patient presented with best-corrected visual acuity (BCVA) of 20/20 in both eyes (OU). Intraocular pressure (IOP) was 17 mmHg in the right eye (OD) and 16 mmHg in the left eye (OS). Confrontation visual field was full, extraocular motility intact, and pupils equal reactive and reactive to light. Slit lamp exam (SLE) was with clear lens OU and with rare to trace white blood cells (WBCs) in the vitreous OU, but otherwise unremarkable. The cells were only noted with complete darkness and the slit beam and patient inspection of the vitreous over several minutes. Dilated fundus exam (DFE) was without posterior vitreous detachment (PVD) and retinal tear/break/hole, and the cup to disc (c/d) ratio was 0.6 OD and 0.7 OS (shown in Figures 1(a) and 1(b)). Optical coherence tomography (OCT) of the macula showed mild macular thickening OS (shown in Figures 2(a) and 2(b)). OCT retinal nerve fiber layer (RNFL) analysis showed RNFL thickening OD > OS. Fluorescein angiography (FA) studies showed no overt signs of retinal vascular leakage, but subtle staining of retinal vessels and subtle hyperfluorescence of the disc were present. The Octopus 30-2 visual field showed diffuse suppression OU (shown in Figure 3). Given the subtle inflammatory changes on clinical exam and diagnostic imaging, he was trialed on topical bromfenac 0.075% twice daily (BID) OU. At a subsequent visit, ancillary tests confirmed retinal and optic nerve dysfunction including an electrooculogram (EOG) which showed suppression OD and borderline suppression OS with an Arden ratio of 1.41 (OD) and 1.85 (OS) (shown in Figure 4). Visual evoked potential (VEP) demonstrated mild suppression (shown in Figure 5). Handheld flash electroretinogram (ERG) showed mild to moderate delayed implicit time with reduced photopic negative response OU (shown in Figure 6). The patient underwent laboratory testing with ACE, HLA-B27, ANA, lysozyme, CRP, rheumatoid factor, HIV 1 and 2, ESR, syphilis Ab IgG, QuantiFERON Gold, mitogen, TB1 Ag, TB2 Ag, and CBC, all of which were negative for another cause of ocular inflammation or visual symptoms. Follow-up examination at one month showed decreased retinal thickness consistent with improved posterior segment inflammation but some mild persistent rare cells in the vitreous, and a final follow-up visit three months later revealed resolution of inflammatory cells, stable retinal thickness, and no change in the visual symptoms. Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast identified mild sinus disease and an incidental 1.6 cm by 1.7 cm arachnoid cyst in the left anterior temporal region. Orbits were unremarkable, and optic nerve was negative for perineural contrast enhancement (shown in Figure 7). The patient was also seen by a neuroophthalmologist who initially diagnosed the patient with presumed optic neuritis in the left eye despite negative MRI findings but, on follow-up, confirmed the diagnosis of visual snow given the absence of ocular inflammation and other pathology that could account for his symptoms. The patient did report subjective improvement in symptoms with compliance with topical bromfenac and subjective worsening without the use of the topical bromfenac. Symptoms of "static" persisted on follow-up despite resolution of vitreous cells and a normal ophthalmologic exam. Symptoms continue to date of writing, which is more than ten months since the onset of symptoms.

PMC5586773_01

Male

A 59-year-old male smoker (30 pack-years) was investigated for productive cough of 1 month. He had a past history of pulmonary tuberculosis (25 years ago; unavailable medical records) and mentioned occasional episodes of dry cough every year for the last 3 years. His family and occupational history were not significant. One month earlier, he had been diagnosed with pulmonary tuberculosis at another institution, but his sputum smear and culture were negative for acid-fast bacilli at the time of admission. His physical examination was unremarkable apart from the respiratory rate of 21/min. Laboratory studies revealed a white blood cell count of 5.54 x 109/l, platelet count of 104 x 109/l, neutrophils 72.6%, and an erythrocyte sedimentation rate of 21 mm/h. Liver and renal function tests were normal except for a high uric acid level (937.9 mumol/l). He tested negative for HIV and HBV antibodies. CT demonstrated increased density in the lateral segment of the right middle lobe, but was otherwise normal. The bronchial provocation test with methacholine was unremarkable. Bronchoscopy revealed an uneven layer of inflamed mucosa. Histopathological examination showed bronchial mucosal inflammation with squamous metaplasia but serum bone morphogenetic protein 2 was negative. An antimycobacterial combination regime (rifampicin + isoniazid + pyrizinamide + ethambutol) was initiated with a provisional diagnosis of endobronchial tuberculosis. The patient experienced relief of symptoms and was discharged, with follow-up scheduled after 1 month. At follow-up, the patient reported worsening cough and occasional blood-tinged sputum. CT revealed an increased density in the cartilage ring surrounding the trachea (fig. 1a). Bronchoscopy showed tracheal stenosis with white, hard spicules (fig. 1b, c). Histopathology confirmed the presence of cartilaginous and osseous nodules in the bronchial submucosa with a moderate degree of squamous metaplasia (fig. 1d). An interdepartmental consultation recommended a temporary discontinuation of the antimycobacterial combination regime (to verify that his airway changes were not drug-induced). Within 1 week of discontinuation, his symptoms eased and he had a better respiratory status. The patient was managed with bronchoscopic nodule removal and laser ablation. At the 4-month follow-up, radiographic findings were negative and the patient reported progressive relief in his symptoms.

PMC6039961_01

Male

A 93-year-old Japanese man who presented with gluteal and coccygeal pain was referred to our hospital. Furthermore, discharging were observed in his fistula in the posterior peri-anal region. He had neither fever nor respiratory symptoms. He had history of pulmonary TB at 25 years of age, and underwent surgery for the removal of complex anal fistula at 75 years of age at another institution. Based on clinical examination, there were two fistulous orifices between the anus and coccyx with purulent discharge (Fig. 1). He did not present with cough, fever, weight loss, and anorexia. The chest radiograph result was normal, and hematologic examination showed no abnormalities, except for a slight elevation in C-reactive protein level. Fistulography showed a complex supra-elevator track that is connected to the pre-sacral area and another track ending blindly behind the rectum. The connection between the track and the rectum or anus was not identified on fistulography (Fig. 2). A computed tomography (CT) scan of the whole body reveled a lytic destruction of the sacrum (S3-5) and coccyx, with a low-density area in front of the sacrum, suggesting fluid collection (Fig. 3A). No abnormality was found in the lungs and other vertebrae on CT scan. Colonoscopy findings showed normal colorectal mucosa and no evidence of fistula. Based on these radiological findings and the past medical history of the patient, the recurrence of complex anal fistula with osteomyelitis, or metastatic bone tumor of unknown origin, was suspected. Bacterial examination of the fistula discharge showed normal bacterial culture and was negative for acid-fast bacilli (AFB). However, real-time polymerase chain reaction (PCR) using COBAS TaqMan MTB test (Roche Molecular Systems, the USA) was used to test the cold abscess fluid, and results showed that the patient was positive for Mycobacterium tuberculosis. AFB test and PCR were negative for sputum. However, the T-SPOT.TB (Oxford Immunotec, the UK) blood test result was positive. Thus, the diagnosis of isolated sacrococcygeal TB was confirmed. The patient was treated with rifampicin, isoniazid, and ethambutol for 2 months, followed by rifampicin and isoniazid for 7 months. The patient's pain resolved, and the purulent drainage stopped within the first 2 months of treatment. Based on the physical findings, closure of the fistula was not achieved. However, the PCR test result for PCR DNA turned to be negative. A follow-up CT scan was carried out during treatment, and results showed that fluid collection in front of sacrum had disappeared (Fig. 3B).

anal fistula, case report, sacrum, spinal tuberculosis

PMC6812294_01

Male

A 68-year-old man came to the ER (emergency room) with shortness of breath over the last 3 days, wheezing, a fever and a cough with purulent sputum. He had been experiencing cough and exercise-induced fatigue for one year. Earlier, he had two episodes of pulmonary tuberculosis. Five years earlier, he was treated by primary health care for six months with standard first-line tuberculosis drugs and declared cured but 2 years later he was diagnosed with pulmonary multi-drug resistant TB (MDR-TB). He took anti-tuberculosis therapy from December 30, 2014 until September 30th, 2016 with a regimen consisting of Km-Lfx-Eto-Cs-Z-E during the intensive phase and Lfx-Eto-Cs-Z-E for the continuation phase. Sputum culture converted to negative in the second month of this therapy. He has had Diabetes Mellitus for 5 years and has been on insulin therapy. He had a previous history of smoking 4.5 packs per year but stopped smoking 5 years ago. There was no history of asthma, food or drug allergies. On physical examination, the patient was alert with respiration rate 28 cycles per minute, blood pressure 140/80 mmHg, a pulse of 100 beats per minute, axillary temperature 38.5 C. Thoracic examination showed symmetrical chest movement, sonorous percussion, bronchial sounds with rhonchi on the right side of the chest and bilateral wheezing. Laboratory results were Hemoglobin 14.6 g/dL; Leukocytes 29.130 x 109/L; Thrombocyte 215.000 x 1012/L, BUN 19 mg/dL, Creatinine 1.12 mg/dL, AST 24 U/L, ALT 17 U/L, Total Bilirubin 2.30 mg/dL, Direct Bilirubin 1.42 mg/dL, CRP 307.6 mg/dL, Sodium 132,7 mmol/l, Potassium 3.51 mmol/l, Random blood glucose 379 mg/dL. Blood gas analysis with 3L oxygen were pH 7.50, PaCO2 26.6 mmHg, PaO2 94.5 mmHg, HCO3- 21.1 mmol/l, BE -2.2 mmol/L, SaO2 98.2%, A-aDO2 71.9 mmHg, P/F ratio 337.5. A chest X-ray on day 1 of hospital admission demonstrated fibrosis and consolidation was observed in the right lung field (Fig. 1B). Sputum microscopy for acid fast bacilli staining was negative, Gram staining showed gram negative bacteria, Xpert MTB/RIF from sputum result was negative for tuberculosis. With aerobic culture of sputum, we found Acinetobacter baumanii (sensitive to Gentamycin, Amikacin, Ceftazidime, Cefoperazone-Sulbactam, Ciprofloxacin, Levofloxacin); MTB culture of sputum was negative. Total IgE serum was 242.9 IU/mL, no worm infection was found by faecal examination, differential count of sputum showed eosinophils 5%, basophils 1.1%, and neutrophils 6.6%. Spirometry was performed after pneumonia and COPD exacerbation resolved. Pre-bronchodilator spirometry results were FVC 3.66 L (107% of predicted), FEV1 2.46 L (94% of predicted), FEV1/FVC 67.2% and post-bronchodilator spirometry results were FVC 3.97 L (116% of predicted), FEV1 2.71 L (104% of predicted), FEV1/FVC 68.2%. Reversibility testing showed 10.1% (250 ml) increase on bronchodilator treatment. Patient was diagnosed with pneumonia and eosinophilic COPD exacerbation based on findings of high total IgE serum and high eosinophil count of sputum. Eosinophilic COPD has several clinical characteristics, one of them is preserved FEV1. A corresponding finding was seen in this patient (predictable FEV1 is 94%). In this case, irreversible airflow obstruction (pre-bronchodilator FEV1/FVC 67.2% and post-bronchodilator FEV1/FVC 68.2%) is related to COPD and also previous episodes of pulmonary TB. Oxygenation was given at 3 L/min, medications given were salbutamol + ipratropium bromide nebulizer solution every 6 hours, methylprednisolone 62.5 mg IV every 8 hours, continuous infusion of aminophylline 480 mg IV in 24 hours, infusion of Ceftazidime 1 g IV every 8 hours, subcutaneous short-acting insulin 10 IU 3 times before meals and long-acting insulin 14 IU at bedtime. Patient's condition improved after a week of hospitalisation. Laboratory data showed a decrease of leukocyte count (8.020 x 109/L). A follow-up chest x-ray 2 weeks later showed resolution of consolidation in the right lung field (Fig. 2).

eosinophilic copd, exacerbation, multi-drug resistant tuberculosis

PMC4677762_01

Female

A 13-year-old girl was admitted on May 26, 2014, presenting with idioglossia and unprovoked smile. On admission, she was conscious but had impaired concentration, bizarre thinking, trouble with emotional expression, lack of insight, and poor sleep. She was therefore diagnosed with schizophrenia. Physical examination revealed a normal body temperature of 36.7 C, pulse rate of 78 beats/min, respiratory rate of 19 times/min, and blood pressure of 90/60 mmHg. An ambulatory electrocardiogram (ECG) examination taken at Xi'an Children's Hospital indicated negative results, and normal results were obtained from all other examinations, including blood biochemistry, prolactin levels, thyroid function, and head computed tomography. Thus, the possibility of physical illnesses was ruled out. Orally disintegrating aripiprazole tablets (Bosiqing , Kanghong Sagent [Chengdu] Pharmaceutical Co., Ltd., Chengdu, People's Republic of China, 5 mg/d) in combination with the traditional Chinese medicine, Annaowan (Harbin Dandelion Pharmaceutical Co., Ltd., Harbin, People's Republic of China) were administered to the patient for management of her psychiatric symptoms. On May 28, the patient presented with a chief complaint of lightheadedness and dizziness. In light of these symptoms, she had undergone routine auscultation and ECG follow-up. Arrhythmia with premature heart beats (approximately 20 beats/min) was observed during auscultation, and abnormal results were obtained by sequential ECG. Frequent, premature ventricular contractions (trigeminy) occurred, which did not improve after repeated auscultations. Oral metoprolol (Toprol-XL ; AstraZeneca Pharmaceutical Co. Ltd., Wuxi, People's Republic of China, 50 mg) was administered, and dynamic ECG examinations were initiated that afternoon. Since the severe arrhythmia occurred after administration of Bosiqing , we speculated that this drug induced the attack. As a result, all antipsychotic medications were stopped on May 29, and metoprolol (25 mg/d) was administered with a simultaneous venous infusion of polarized solution. The patient's symptoms then improved. To verify that the arrhythmia resulted from aripiprazole administration, we readministered Bosiqing after obtaining approval from the patient and her relatives. If the arrhythmia was relieved by aripiprazole withdrawal and reappeared after remedication, a correlation between Bosiqing use and the incidence of arrhythmia could be identified. Thus, after a 7-day withdrawal period, we readministered Bosiqing to the patient. Three days after remedication, (June 8), the patient's premature heartbeats increased with occasional trigeminy. After consultation with cardiologists, the arrhythmia was confirmed to be an adverse reaction caused by Bosiqing . We thus informed the patient's relatives of the diagnosis and replaced aripiprazole with Risperidone (Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou, Jiangsu, People's Republic of China, 4 mg/d), since it causes less cardiovascular damage. We further increased the use of metoprolol to 50 mg/d. On June 12, no premature beats were observed on auscultation, although bradycardia occurred. Later, we reduced the use of metoprolol to 25 mg/d. The patient's psychotic symptoms were well controlled, with a normal ECG; therefore, we decided to continue the new therapeutic regimen. ECG monitoring of this case is illustrated in Figure 1.

antipsychotics, aripiprazole, arrhythmia, schizophrenia

PMC6107079_02

Female

The past medical history was notable for major depressive disorder treated with trazadone and aripiprazole, asthma treated with ventolin inhaler and advair, and hypercholesterolemia treated with atorvastatin. The patient denied taking any nutritional supplements, including biotin, which can interfere with certain thyroid hormone assays. The patient had smoked half a pack of cigarettes per day for the past thirty years. Family history was remarkable for mother who had died at age 88 years and suffered with hyperthyroidism and atrial fibrillation, an identical twin sister previously diagnosed with RTH (case 2; figure 1), three adult children (ages 41, 33 and 28 years old) alive and in good health, and five grandchildren (ranging in age from 7-14 years old) who were all reportedly asymptomatic (figure 1), i.e. no hyperthyroidism, goiter or cardiac ailment. Physical examination revealed an anxious older woman with resting tremor and pressured speech. Height 63 inches, weight 159 lbs. Seated blood pressure was 122/87 mm hg, resting heart rate was 77 bpm (irregularly irregular), respirations were 14 breaths per minute (non-labored), and the patient was a febrile. After the patient stood up, walked a few steps and sat down on the examining table, her heart rate increased suddenly to 170 bpm. The skin was warm and dry. There was no proptosis or exophthalmos, and the visual fields were normal to confrontation testing. There was no jugular venous distension at 15 degrees. The thyroid was symmetrically enlarged, approximately 25 grams, and there were two palpable (1-2 cm) nodules, one in each lobe. Lung exam revealed scattered wheezes, decreased breath sounds at the right base and no rales. Cardiac examination was remarkable for rapid, irregular rate and rhythm, no s4, s3 gallop or rub was appreciated. There was no edema of the lower extremities. Neurologic exam was non-focal and deep tendon reflexes were brisk. Magnetic resonance imaging of the brain was performed and it was negative for a pituitary mass lesion. Thyroxine binding globulin (TBG) was within the normal assay range (Table 1). Antithyroid autoantibody levels: thyroid stimulating immunoglobulin (TSI), anti-thyroglobulin and anti-thyroid peroxidase (TPO) were within the normal assay ranges: TSI 97% (0-139%); Thyroglobulin Ab < 1 (0-0.9)IU/ml, Anti-TPO Ab 13 (0-34) IU/ml. An iodine-123 radioactive thyroid uptake and scan revealed an enlarged gland with two cold nodules. The four-hour radioactive iodine uptake was 23.2%, normal range (3-10%); the 24 hour uptake 67.3%, normal range (10-40%). Serum albumin and total cholesterol were both within the normal ranges, and alkaline phosphatase was elevated at 174 (39-117) U/L. A blood sample was drawn and sent out for resistance to thyroid hormone mutational analysis testing. Owing to the patients' refractory congestive heart failure requiring frequent hospitalizations, and the unexpectedly long delay in obtaining the results of thyroid hormone resistance mutational analysis, a 'modified L-T3 suppression test' (without serial I131 thyroid uptake determination) was performed to substantiate a working clinical diagnosis of resistance to thyroid hormone. Low-dose cytomel (L-T3) 25 micrograms was given once daily in the morning to evaluate suppressibility of TSH. After three weeks' L-T3 treatment, repeat thyroid function tests demonstrated a 22% decline in the free T4 level, unchanged total T3 level and a 50% decline in TSH level compared to basal levels (T+171 vs T+115 days; Table 1; Figure 2). During the treatment interval, the patient reported a reduction in her symptoms of dyspnea and dizziness and was not hospitalized. After discontinuation of L-T3, however, free T4 and TSH levels reverted to their pre-treatment levels (T+ 201 days; Table 1; Figure 2), and dizziness and dyspnea also recurred requiring the patient to be hospitalized again and treated for congestive heart failure.

atrial fibrillation, congestive heart failure, identical twins, mutation, resistance to thyroid hormone

PMC4750320_01

Female

A 15-year-old girl without any premorbid medical or surgical illness was brought to our hospital with complaints of fever and drowsiness of 2 days duration. She had a history of fever with multiple cervical lymph node enlargement 2 weeks ago, for which she was treated outside with oral levofloxacin 500 mg once daily for 1-week. On examination, the patient was drowsy. She was febrile. Bilateral cervical lymphadenopathy was present involving a posterior group of cervical lymph nodes. Neurological examination showed vertical gaze palsy with bilateral horizontal gaze-evoked nystagmus. Blepharospasm was present [Videos 1 and 2]. Convergence was impaired in both eyes. Fundus examination was normal. Slit lamp examination did not show any evidence of Kayser-Fleischer ring. No focal motor deficits were noted. Bilateral knee and ankle jerks were sluggish with bilateral extensor plantar. Bilateral cerebellar signs and gait ataxia were present. Meningeal signs were present. Laboratory investigations showed leukopenia (total leucocyte count: 3000 cells/cu.mm). Erythrocyte sedimentation rate was 20 mm/1st h. Cerebrospinal fluid (CSF) analysis showed glucose 76 mg/dl, protein 28 mg/dl, and 45 white blood cells with 100% lymphocytes. Video electroencephalogram was normal. Magnetic resonance imaging of brain plain and contrast showed altered signal intensity which was hyperintense on T2-weighted [Figure 1] and fluid-attenuated inversion recovery sequences without any postcontrast enhancement in dorsal pons and midbrain [Figure 2]. CSF tuberculosis polymerase chain reaction (PCR) and Herpes simplex PCR were negative. CSF culture was sterile. CSF adenosine deaminase was 6.9 IU/L. CSF was negative for Listeria, Epstein-Barr virus, Enterovirus, and Cryptococcus. Enzyme-linked immunosorbent assay for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus were negative. Antinuclear antibody, double-stranded DNA, and venereal disease research laboratory test were negative. Serum paraneoplastic neuronal antigen and antibody profile was negative. Mantoux test was negative. The patient was managed with intravenous ceftriaxone 2 g twice daily and intravenous dexamethasone (4 mg thrice daily) for 10 days in suspicion of brainstem encephalitis. She was managed with 0.5 mg once daily clonazepam and 1 mg twice daily trihexyphenidyl for 10 days for blepharospasm. Cervical lymph node fine-needle aspiration cytology was done which showed lymphocytes, sinus histiocytes, endocapillary buds, monocytoid cells, necrosis, karyorrhectic debris, and nodal reticulum suggestive of Kikuchi-Fujimoto disease [Figure 3]. Positron emission tomography (PET) computed tomography brain showed increased focal uptake of tracer in the left frontal lobe, anteriosuperior to anterior cingulate gyrus [Figure 4]. After 10 days of treatment, the patient improved significantly. Cervical lymph nodes resolved. Eye movements were full. Cerebellar signs and blepharospasm disappeared [Videos 3 and 4]. Gait became normal. The patient was followed up at 1-3 months without any residual neurological deficits. Magnetic resonance imaging brain done after 1 month of treatment showed complete resolution of lesions in midbrain and pons [Figure 5].

blepharospasm, kikuchi-fujimoto disease, encephalitis, neurological manifestations

PMC7519790_01

Unknown

A 25-year-old patient with no specific history consulted for dysphagia and bilateral hearing loss with rapid progression for two months associated with fever, night sweats, deep asthenia and eight kilograms weight loss. The examination found an asthenic patient with a 9/6 blood pressure, a 110/mn heart rate and a 39 C fever. Examination of the neck revealed bilateral, firm, sensitive and mobile cervical lymphadenopathies. Oral pharyngeal examination showed multiple, diffuse, non-confluent granulations along the posterior wall of the pharynx and veil, with associated purulent secretions (Figure 1). Endoscopic pharyngolaryngeal examination showed diffuse congestion of the nasal cavity mucosa with a tissue process filling the cavum. The latter had a global purulent appearance. Biopsies were performed in the cavum and oropharyngeal granulations finding an epithelioid granulomatosis suggestive of tuberculosis. The cervico-thoracic CT confirmed the cavum tissue lesion and showed excavated lesions of the two pulmonary fields (Figure 2). Search for Koch bacillus in sputum proved to be positive. A general assessment was carried out, finding no other locations of tuberculosis. The HIV serology was negative. Biology showed an inflammatory syndrome with 15700/mm3 white blood cells, 11800/mm3 neutrophils and a 190mg/l C-reactive protein (CRP). The rest of biological assessment was normal and showed no obvious immunosuppression. The diagnosis of multifocal tuberculosis was therefore made associating miliary acute tuberculous pharyngitis (Isambert disease) and pulmonary tuberculosis. An anti-tuberculous regimen was started with an excellent clinical and radiological evolution.

isambert, pharyngeal tuberculosis, miliary

chest CT scan: excavated lesions of the pulmonary apex very suggestive of tuberculosis.

PMC8055247_01

Female

A 25 year-old-female Tunisian patient born to a first degree consanguineous marriage was followed for H syndrome. There was no family history, or similar cases. Her past medical history included type 1 diabetes since the age of two years, hyperpigmentation and hypertrichosis discovered at the age of five years on the inner thighs with extension of lesions to the lower limbs, back, abdomen and arms, right-side hypoacousia, delayed puberty occurring at the age of 17 years, hepatosplenomegaly, mild anemia, bilateral camptodactyly of both fifth fingers. Transthoracic ultrasound of the chest performed at the age of 12 years showed cardiomegaly with pericardial effusion. Mutation screening in the SLC29A3 gene was performed using direct analysis of DNA sequence extracted from the samples according to standard techniques. All coding exons of the SLC29A3 gene were amplified using polymerase chain reaction (PCR). Direct sequencing of PCR products was performed with the ABI prism 3500 DNA Genetic Analyzer (Applied Biosystems, Foster City, CA, USA), using the ABI Prism Big Dye Terminator v3.1 Cycle Sequencing Ready Reaction Kit (Applied Biosystems). This molecular analysis revealed a novel homozygous frameshift mutation in exon 2 of the SLC29A3 gene: p.S15Pfs*86 (c.42delC) inducing a premature stop codon (Figure 1). Genetic analysis was also performed for the parents and both were found heterozygous for the mutation (Figure 1). At the age of 22 years, the patient was referred to our department to investigate newly diagnosed ascites. The patient reported progressive abdominal distension since one month and worsening abdominal discomfort. There was no fever, no change in bowel habits, no intestinal obstruction signs, no weight loss neither asthenia. Vital signs were stable Physical examination revealed distended abdomen with shifting dullness. There were no dilated veins, no evidence of pleural effusion or cardiac dysfunction signs nor oedema. Abdominal ultrasound showed high abundance ascites, known hepatomegaly without portal hypertension signs and 6 cm left latero-uterine mass. Analysis of the ascetic fluid showed a white blood cell count of 200/microL with 80% lymphocytes and fluid protein level of 3.1 g/dl. Gram staining, bacterial culture, Mycobacterium tuberculosis screening and cytology were negative. While investigating cardiac origin of ascites, new transthoracic ultrasound was performed showing non-compressive circumferential pericardial effusion without deep deterioration of ventricular function (59%). Upper endoscopy and colonoscopy were normal. Seric tumor markers showed high CA-125 concentration of 59 U/mL (normal value 0-35 U/mL), with normal blood levels of alpha-fetoprotein and carcinoembryonic antigen. Magnetic resonance imaging (MRI) confirmed the presence of left ovarian cystic mass of 6*3*3 cm with thin regular wall and enhanced septa after Gadolinium injection (Figure 2). As the combination of ascites with negative work-up and ovarian mass was suggestive of Meigs' syndrome, she was referred to the department of gynecology and underwent surgery. Perioperative exploration showed a benign-looking left ovarian tumor and a massive amount of ascites (3.5 L). Ovarian cystectomy was successfully performed. Histopathological examination of the resected ovarian mass revealed serous cystadenoma (Figure 3), orienting the diagnosis towards pseudo-Meigs' syndrome. After tumor removal, ascites decreased rapidly then subsequently resolved postoperatively and the patient become asymptomatic. During 3 years follow-up there was no relapse of ascites.

h syndrome, slc29a3 gene, tunisian patient, pseudo-meigs’ syndrome, rare disease

PMC6524313_02

Male

B was a 15-year-old boy referred to an inpatient unit for severe disruptive behaviors after being expelled from his school. He lived with his 10-year-old younger brother and two half-brothers (aged 20 and 30 years). The parents were separated although living together. B had commonly been exposed to severe arguing and fighting between them. Both parents were unemployed. The father had an untreated alcohol addiction and the mother had no specific past psychiatric history. The family had been followed by social services since B was 3. The patient's pregnancy was complicated by gestational diabetes and occasional maternal alcohol intake. B was born prematurely at 35 weeks of gestation. He had a delayed onset of speech (first words at 2 years) and fine motor difficulties. At entrance in first grade, he had difficulties understanding verbal instructions and performing graphomotor activities. Distractibility and emotional dysregulation were also noted. At age 6, a Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) test found a heterogeneous functioning in normal range (Verbal IQ = 100, Performance IQ = 75). At age 7, the patient was addressed to a foster care family with a full-time inclusion in an educational facility for youths with behavioral problems. Improvement in emotional control was noted. At age 13, B faced multiple adverse life events (incarceration of his half-brother, left foster care to return to family home, and change in the pedagogic team). He became physically aggressive against peers and adults with several rage outbreaks per day. Different medications were tried with no or partial improvement: tiapridum (a first generation antipsychotic) up to 15 mg/day, carbamazepine up to 200 mg/day, risperidone gradually increased to 4 mg/day. B was excluded from his educational facility following the aggression of a member of the educational staff. Since then, the patient has stayed at home all day. He was described as severely irritable with multi-daily outbursts of uncontrollable anger. He was verbally and physically aggressive against his parents in a context of frustration and tried to strangle a neighbor after a banal remark. During this period, B maintained his interests in his usual activities, for example, caring for animals or cooking. He drastically increased time on his computer following school expulsion. He mostly played Role-Playing Games and First Person Shooter Games, with violent scenarios. Daily playing sessions lasted 2-6 h, occasionally during the night. He could compulsively watch online videos during several hours, either childish cartoons or violent videos of aggression. B had daily alcohol consumption usually alone of one glass of wine or a can of beer with binge-drinking sessions almost every month (i.e., 10 g of alcohol each day or 8.75 units per week on average). He explained that alcohol was a means to "calm down." Of note, the patient was very critical of his father's addiction problem, criticizing his father's inability when drunk to care for him. He also had very occasional cannabis use (smoked one joint every 2 months). During individual interviews, B was calm. He described a feeling of hostility, persisting anger and ambivalent feelings toward adults ("worry, shame and anger at the same time"). He reported being exposed to violent conflicts at home and frequently having to take care of his drunk father. Globally, he described a situation of physical and emotional neglect at home. B expressed concern about the consequences of his behavior and his future (he wished to become a cook). He was afraid of "being always angry" after leaving the hospital or that similar problems would repeat with his young brother. Sleep and appetite were preserved. In the unit, he had few contacts with other youths. He was too clumsy to be involved in sport activities and was often rejected by the group when playing board games. He felt more comfortable with younger patients with whom he shared common interest in animals. When he felt worried, the patient sought attention from adults with provocative behaviors or threats. He could suddenly give a blow to a wall, against a window, or against a piece of furniture without any explanation. Psychomotor assessment showed evidence of a developmental coordination disorder (F82): general motor and coordination test score was at 0.1 percentile, visuomotor integration test score was very low, and he had -7 standard deviations for writing abilities ( Table 1 ). Language evaluation showed evidence of severe dyslexia (Reading disorder, F315.0) with normal to weak abilities in oral language but very deficient reading competency ( Table 2 ). The diagnosis of disruptive mood dysregulation disorder (F34.8) in an adolescent with multiple learning disabilities (developmental coordination disorder, dyslexia, dysgraphia) was set up and explained to the patient and his parents. The treatment with carbamazepine was discontinued and risperidone was decreased to 2 mg/day, a dose more typically used in youths with disruptive behaviors. A benzodiazepine, diazepam, was added for its anxiolytic effect. The patient also started a psychomotor rehabilitation in the service (weekly group relaxation and individual sessions). The need for an intensive speech therapy was explained to the parents. Collaboration with social services was of main importance in this hospitalization. He was accompanied to a juvenile court session where a placement decision was set up. During the last week of the hospitalization, he visited a new residential care facility. A major clinical improvement was observed during the hospitalization with a decrease in the behavior problems. At discharge, B no longer presented diagnostic criteria for IGD, and no specific intervention was required. Six months later, B no longer presented clinical or functional impairment. We found in this vignette a relation between disruptive behaviors and gaming misuse in line with preexisting literature in adolescents. A Spanish study showed that disruptive behavioral disorder was the most frequent diagnosis associated with IGD in a clinical sample of youths. It seems that IGD is associated with both proactive and reactive (impulsive) types of aggressive behaviors in adolescents. Wartberg et al. found that in a large community-based sample of adolescents, those who self-reported symptoms for IGD were more prone to anger control problems, antisocial behavior, and SDQ hyperactivity/inattention subscale, in multivariate analysis. The description of patient B's usual way of dealing with emotional stressors since his early childhood was strongly evocative of an anxious-resistant subtype of attachment disorder (also called ambivalent attachment). Children with an anxious-resistant subtype of attachment disorder exhibit a high level of distress on separation and tend to be ambivalent when his/her caregiver returns. In middle childhood, these children are more likely to adopt "controlling" behavior (i.e., role-reversed) on caregivers. The displays of anger or helplessness towards the caregiver on reunion have been regarded as a strategy for maintaining the availability of the caregiver by preemptively taking control of the interaction. A persistent lack of predictability of the caregiver's responses, such as found in B's family, did not allow children to develop reliable expectations about adults' behaviors. As a consequence, these children did not develop a proper sense of trust in their own ability to interpret their social world: they have, in general, more difficulties to accurately anticipate and interpret emotional cues (e.g., facial expression) and to understand their own mental state. The fact that these children are immersed in a social world unintelligible to them and have more difficulties to stay "attuned" to others' emotional state explained the difficulties to develop optimal emotional regulation strategies and the myriad of associated behavioral problems (e.g., oppositional behavior, poor tolerance to frustration, temper tantrums, impulsive aggressive behaviors, peer rejection). A low level of emotional regulation skills in childhood is a significant risk factor for behavioral addictive disorders in adolescents, including GD and Internet-related disorders. Youths with difficulties to regulate their emotions could engage in such repeated behaviors to avoid or regulate negative feelings and emotions or to prolong positive emotional states. In the Discussion, we explain how poor emotional regulation strategies could represent both shared vulnerability factors and mediators of the relation between psychopathology and gaming misuse in the patient.

internet gaming disorder, adolescents, behavioral addiction, emotional dysregulation, externalizing disorders, gaming misuse, insecure attachment, internalizing disorders

PMC5548692_01

Male

A 19-year-old man was transferred to our emergency department after the onset of convulsions and loss of consciousness in March 2016. The patient had a medical history of febrile seizures in childhood. He had not received influenza vaccination during the season. Initially, the patient's body temperature had risen to 38.5C at home, and he had presented with convulsions and loss of consciousness 7 hours following the onset of a fever. The patient did not have a cough, nasal discharge, sore throat, headache, arthralgia, or sore muscles. In the emergency room, he appeared to be a well-developed, well-nourished man. His body temperature was 39.1C, blood pressure was 139/68 mmHg, pulse was 96 beats/min, respiratory rate was 21 breaths/min, and oxygen saturation was 97% on room air. The Glasgow Coma Scale (GCS) score was 4 for eye opening (E), 4 for best verbal response (V), and 6 for best motor response (M). The physical examination was unremarkable, and his pupillary reflexes were normal. Neck rigidity and Kernig's sign were not apparent. He had a generalized convulsion lasting 1 minute in the emergency room. The nasopharyngeal swab sample was analyzed using a rapid test kit (Quick Chaser Flu A, B; Mizuho Medy, Japan) and did not indicate the presence of either influenza A or B viral antigen. An initial laboratory examination showed a white blood cell count of 4,500 /muL (62% neutrophils), C-reactive protein level of 1.46 mg/dL, blood urea nitrogen level of 8.8 mg/dL, and creatinine level of 1.06 mg/dL. The serum interleukin (IL)-6 level was 9.06 pg/mL (normal range, <2.41 pg/mL). Lumbar puncture was performed, and a cerebrospinal fluid analysis revealed a normal cell count (<1 /muL), a protein level of 27.9 mg/dL, and a glucose level of 94 mg/dL. A computed tomography (CT) scan of the brain and chest radiograph showed normal findings. The anti-influenza virus treatment peramivir was started based on the information that there had been an outbreak of influenza A and B virus infections in the area during that time. After admission, the patient's consciousness level worsened. He was somnolent with closed eyes. The GCS score was 12 (E2V4M6). Brain T2- and diffusion-weighted MRI on the same day showed multifocal high-signal lesions in the right parietal and frontal lobes, indicating acute encephalopathy (Fig. 1). On day 2 following admission, a repeated examination of a nasopharyngeal swab sample indicated the presence of influenza B virus antigen. The patient was treated with peramivir (300 mg/day) and methylprednisolone (1,000 mg/day) for 3 days. An EEG on day 5 showed diffuse slowing of the background activity consistent with encephalopathy (Fig. 2). The patient's physical condition gradually improved (Fig. 3). The serum IL-6 level was decreased to 0.673 pg/mL on day 8. The patient was discharged without any neurological impairment on day 10 and has been followed up at an outpatient clinic. An examination showed no evidence of underlying diseases or immunodeficiency. His serum levels of immunoglobulin G, A, and M were normal. Brain MRI and EEG on day 20 following the onset showed no abnormal findings. In addition, the serum antibody titers against influenza B virus, as measured using the complement fixation test, were 1:8 on admission and 1:64 on day 20. The serum antibody titer against influenza A virus was not found to be increased at admission or throughout the clinical course.

adult, encephalopathy, influenza b, methylprednisolone

PMC9452728_01

Female

In Family 1, a 29-year-old woman (Patient 1) was born to nonconsanguineous parents although her grandparents were cousins (Figure 1A). She was affected with low-grade predominantly conjugated hyperbilirubinemia for more than 6 years. This patient was tested for hyperbilirubinemia in a health physical examination in 2015. There were no other significant abnormalities in her liver function test. She received no other medical treatment then. During her pregnancy, her jaundice was markedly aggravated. She gave birth on 18 August 2018. The obstetrician used reduced glutathione (1.2 g/d, from 16 August 2018 to 20 August 2018) and ursodeoxycholic acid (500 mg/d, from 20 August 2018 to 31 August 2018) to control her jaundice. Her clinical jaundice gradually disappeared after childbirth in 2018. She took oral contraceptives from January 2021 and presented with recurrent mild jaundice again. The jaundice was in remission after she stopped taking oral contraceptives; she was never affected with pruritus. The patient had a previously free medical history. When she came to us as a medical genetic outpatient in July 2021, the physical examination revealed mild splenomegaly. The timeline with relevant data for Patient 1 is shown in Supplementary Figure S1. During the patient's pregnancy, her level of total bilirubin (TBIL) ranged from 43.1 mumol/L to 82.8 mumol/L (normal range: 3.4-17.1 mumol/L). Her direct bilirubin (DBIL) level ranged from 25.2 mumol/L to 65.1 mumol/L (normal range: 0-6 mumol/L). The ratio of DBIL/TBIL was always greater than 50%. There were no abnormalities in other liver function indexes. She was serologically negative for hepatitis A, B, C, and E viruses. There were no abnormalities in coagulation function, autoimmune liver disease-associated antibodies, immunoglobulin G, or serum ceruloplasmin testing. The abdominal ultrasound examination revealed her portal vein diameter to be about 10 mm and the portal venous maximum velocity was 18 cm/s. The thickness of her spleen was about 49 mm and its inferior margin was about 20 mm below the costal margin. A hepatic hemangioma was also detected by the ultrasound examination (Supplementary Figure S2; Table 1). The whole-exome sequencing (WES) was conducted in July 2021, revealing that Patient 1 carried both the heterozygous c.2980delA and c.1834C>T ABCC2 mutations. Her son also shared the heterozygous c.1834C>T ABCC2 mutation (Figure 1B; Table 2). Considering her symptoms, clinical examinations, and genetic testing, she was diagnosed with DJS. Intrahepatic cholestasis of pregnancy (ICP) was excluded.

abcc2, dubin–johnson syndrome, hyperbilirubinemia, multidrug resistance-associated protein 2, mutation

PMC9452728_02

Male

In Family 2, an 18-year-old male (Patient 2) presented with intermittent mild jaundice for more than 9 years. This patient showed intermittent jaundice from the age of nine, which would be aggravated by fatigue. He had a previously free medical history and no special personal and family history (Figure 2A). When he came as a medical genetic outpatient to our hospital, he presented with yellow skin and sclera. In the physical examination, his liver could be palpated at the lower margin of the ribs. Patient 2's TBIL level was 110.6 mumol/L and his DBIL level was 70.4 mumol/L, with no other abnormalities in the liver function test. There were no abnormalities in autoimmune liver disease-associated antibodies or serum hepatitis B and C virus testing. A CT scan revealed hepatomegaly. The lower margin of the liver exceeded the lower costal margin (Table 1, Supplementary Figure S2). The WES indicated that Patient 2 harbored the heterozygous c.2980delA variant inherited from his mother and the heterozygous c.4465_4473delinsGGCCCACAG mutation inherited from his father (Figure 2B; Table 2). He was also diagnosed with DJS and chose to observe his jaundice (without drug interventions). In the telephone follow-up, he still complained of intermittent jaundice. However, both patients refused the 99mTc-HIDA cholescintigraphy and liver biopsy. The candidate variants in the ABCC2 gene were validated by Sanger sequencing. The primer sequences are listed in Table A1. The methods of genetic testing are described in the supplementary materials. The family members participating in the study signed written informed consent forms. This study complied with the ethical guidelines of the Declaration of Helsinki and was approved by the ethics committee of the Second Xiangya Hospital of Central South University (2014 ethical approval No. S046).

abcc2, dubin–johnson syndrome, hyperbilirubinemia, multidrug resistance-associated protein 2, mutation

PMC9807346_01

Male

A 50-year-old patient presented with hematuria and a mass in the posterior wall of the bladder discovered with an ultrasound scan. He had already been hospitalized months earlier for an ischemic stroke treated with fondaparinux and clopidogrel for a month. Following an episode of melena, he underwent blood transfusions and performed a gastroduodenoscopy, with clinical diagnosis of erosive gastritis with a discrete eosinophilic infiltrate. The anamnesis was negative for allergies, asthma, or respiratory diseases. Physical examination revealed dark macules alongside the interdigital space of his hands. After a cystoscopy, which confirmed the ultrasound finding, he underwent an endoscopic resection of the lesion with a histological report of polypoid cystitis. Blood transfusions and hemostatic transurethral resection (TUR) surgery were performed due to incoercible hematuria and consequent anaemia. In the following, he was readmitted to the Emregency Room (ER) and underwent further blood transfusions and hemostatic TUR with new biopsy sampling. Cystoscopy showed inflammation of the mucosa and an ulcerated pseudopolypoid lesion on the bottom of the bladder (Fig. 1). The histological examination (Fig. 2) revealed a rich eosinophilic-giant cell lympho-granulocyte infiltrate with granulomatous aspects and some necrotic focus, in the absence of peripheral hypereosinophilia. The patient returned to the hospital for hematuria after about one week and underwent blood transfusions and hemostatic TUR with biopsy sampling again. The histological examination showed intense chronic inflammation with a large amount of eosinophilic granulocytes, in the absence of microorganisms. Uro-computerized tomography (CT) was performed and the results showed a diffuse thickening of bladder walls, with low capacity and small lumen, enlarged regional and para-aortic lymph nodes. Microbiological testing (Quantiferon, Mycobacterium tuberculosis in urine, and Schistosoma eggs in stool) were performed, all with negative results. As hematologists suggested, the study of coagulation factors and thromboelastogram (TEG) was performed in the suspicion of a hemostasis disease, but with a negative result.Due to gross hematuria, another hemostatic TUR and blood transfusions were performed. The biopsy samples were sent for microbial analysis for the search of parasites, fungi, and bacteria. The result was positivite for Klebsiella pneumoniae and Enterococcus faecalis on histological specimens. The infection was treated with fosfomycin (4 g/thrice a day) and vancomycin (1 g/twice a day). It was decided to avoid radical cystectomy in the young patient. Rheumatological and neurological counseling were required: the rheumatologic etiology was neglected, but antinuclear antibodies (ANA) were found with fine-speckled pattern positivity (1:320); the neurological examination revealed polyneuropathy of upper and lower limbs. After finding total IgE 11 times higher than the cut-off, therapy with Cetirizine (10 mg/die) was set and hyperbaric therapy (2 h/day for 5 days) was performed. Positive urine culture confirmed the infection on the histological finding; therefore, cortisone therapy was postponed. He was discharged with a bladder catheter, cetirizine (10 mg/day), and prednisone (30 mg/day) therapy, in order to keep the disease inactive. The macules and gross hematuria disappeared and polyneuropathy improved, but gross hematuria reappeared with new fondaparinux therapy for orthopedic injury. Triphasic contrast CT highlighted flogosis of the maxillary sinuses and low-capacity urinary bladder with thickening of the posterolateral wall and an effusion nearby the resection area (Fig. 3). Hematochemical analysis showed iron-deficiency anemia and total IgE 3 times higher than the upper limit. An urinary bladder biopsy revealed a rich eosinophilic and lympho-monocytic infiltrate without perivascular fibrinoid necrosis. Rheumatologic counseling excluded vasculitis and hematological counseling suggested to perform a bone marrow biopsy (BMB), which revealed a hypereosinophilic crisis. In addition, research for FIP1L1-PDGFR1alpha fusion gene was prescribed. Corticosteroid and antihistaminic therapy was set and hematuria resolved. If symptoms reappear, cystoscopy will be performed and second line therapy will be considered.

conservative therapy, eosinophilic cystitis, hematuria, hyperbaric therapy, hypereosinophilic syndrome

PMC5385583_01

Female

The patient is a 27-year-old, left-hand-dominant woman, previously published by Riviere et al. as LP98-085 and by Verloes et al. as B2. She has a medical history significant for BWCS with associated intellectual delay, right cochlear agenesis causing hearing impairment, and bilateral colobomata causing visual impairment. She has behavioral issues with irritability, aggression, and defiance. She has an ACTB mutation of c.34A > G. She was born at term, had a normal delivery without complications, but was hypotonic. She was delayed in gross and fine motor skills, as well as speech. She began having seizures at the age of two years. She has three seizure types. With the first type she has behavior arrest, staring, and unresponsiveness without preceding aura. These episodes last between a few seconds to a minute. She has post-ictal exhaustion and confusion. The second most frequent type of seizure involves a sudden tonic flexion of the head and neck with abduction of the arms; there is sometimes tonic extension of the lower limbs. There can be brief jerks of the upper limbs. She falls if she is standing when these seizures occur. These episodes last 5-20 s. She had clusters of up to 60 of these seizures per day. The last seizure type is generalized tonic-clonic. She has approximately one every five years with her last one in 2012. She currently takes the following antiseizure drugs, which do not completely control her seizures: clobazam 20 mg total daily, lamotrigine 350 mg total daily, perampanel 6 mg daily, phenytoin 300 mg total daily, rufinamide 1600 mg total daily, and valproate 1000 mg total daily. She had three months of seizure freedom after starting rufinamide. On physical examination she had slow and deliberate speech. She had bilateral ptosis, bilateral epicanthal folds, triangular irides, a coloboma on the right, and an elliptical left pupil. Her visual acuity was 20/200 in both eyes. She had roving eye movements. There was decreased bulk in her hand intrinsic muscles bilaterally. She had bilateral lower limb spasticity. Her muscle strength was normal. Her reflexes were brisk in the lower extremities with no clonus. Coordination testing was normal. An MRI of the brain showed bilateral cortical dysplasia with fairly symmetric thickening seen in her frontal lobes, precentral gyri, insulae, and parietal lobes (Fig. 1). She was admitted to our epilepsy monitoring unit for continuous video-EEG. Her EEGs revealed normal background activity at 9-10 Hz with well developed and normal sleep potentials. She had frequent generalized spikes, polyspikes, polyspikes-and-waves, and frequent electrographic seizures during wakefulness without apparent clinical findings (Fig. 2). Her generalized spikes, polyspikes, and polyspikes-and-waves were augmented during sleep (Fig. 2). On continuous monitoring two of her stereotyped, typical generalized tonic seizures were captured. There were also multiple electrographic generalized seizures with generalized epileptic recruiting rhythms. Some of these may have represented absence seizures. In a video-EEG of her typical seizure she can be seen to display sudden tonic bilateral abduction of her arms then elevation of her arms (Video 1).

baraitser–winter cerebrofrontofacial syndrome, dysmorphology, generalized epilepsy, video eeg

PMC5594545_01

Male

A 55-year-old Bangladeshi male with a history of type 2 diabetes mellitus and hypertension presented to the Emergency Department of Farwaniya Hospital, Kuwait in December 2015 with a left-sided neck swelling (8 cm x 6 cm) discharging pus through multiple sinuses. He was suffering from this condition for the past 2 weeks. On examination on alert, voice, pain and unresponsive (AVPU) scale, he was conscious and oriented with stable signs and without fever (oral temperature of 36.7 C). Examinations covering the respiratory, cardiovascular, gastrointestinal and respiratory systems were unremarkable. His body mass index (BMI) was 27.4 (classified as overweight and a risk factor for type 2 diabetes). Blood examination by flow cytometry (Sysmex 9000, Bornbarch, Norderstedt, Germany) showed leukocytosis (18 x 109/L, mainly neutrophils, normal range is 3.7 x 109/L)) and by oxygen rate method (Beckman Coulter DxC 800, Brea, CA, USA) hyperglycemia (random blood sugar of 20 mmol/L; normal range is 3.9-6.1 mmol/L). A diagnosis of carbuncle with hyperglycemia was made. He was given parenteral insulin on a sliding scale (1-14 units with increments of 1-2 units during a 24 h period). Incision and drainage of the carbuncle were done and pus was sent for microbiological studies. An empirical therapy with clindamycin (300 mg intravenously every 8 h) was started suspecting infection with Staphylococcus aureus which is a common cause of carbuncle. This therapy was continued for 3 days until culture and susceptibility report became available (see below). Pus was cultured on blood agar, MacConkey agar, chocolate agar and gentamicin blood agar. Blood agar and MacConkey agar were incubated aerobically, chocolate agar microaerobically and gentamicin blood agar anaerobically. Incubation was done at 37 C for 24-48 h. All plates except the gentamicin plate grew a pure culture (organism was susceptible to gentamicin, see below) which was identified as a Salmonella species using Phoenix method (Becton-Dickinson, Franklin Lakes, NJ, USA) and Vitek 2 and Vitek-MS methods (Biomerieux, Marcy l'Etoile, France). Blood, urine and stool were sent for culture. Blood culture was done using BD BACTEC system (Becton-Dickinson) and there was no growth of any organism. Urine culture was done on blood agar and cysteine-, lactose-, and electrolyte-deficient (CLED) agar. There was no bacteriuria and Salmonella species was not isolated. Stool was cultured on MacConkey agar, Campy agar and Salmonella-Shigella agar (SSA) and enriched in selenite F broth with subsequent subculture on SSA. No bacterial diarrheal pathogen including Salmonella species was isolated. In vitro susceptibility of the Salmonella isolated from carbuncle (designated as CSE76F) to antibiotics was done by Vitek II system (bioMerieux) and E test (AB Biodisk, Solna, Sweden) and interpreted by Clinical and Laboratory Standards Institute (CLSI) guidelines. It was susceptible to amikacin, amoxicillin-clavulanic acid, chloramphenicol, tetracycline, ceftazidime, ceftriaxone, cefuroxime, cephalothin, imipenem, meropenem, ciprofloxacin, gentamicin, piperacillin-tazobactam, tigecycline, and trimethoprim-sulfamethoxazole, but resistant to ampicillin and clindamycin. The antibiotic therapy was changed to ciprofloxacin (400 mg intravenously every 12 h) for 14 days at which time he recovered. This prolonged intravenous therapy was necessitated to avoid relapse because the patient was immunocompromised (due to diabetes mellitus) and the wound was large. After debridement of the wound (Fig. 1), the patient was referred to plastic surgery for skin grafting. The Salmonella organism was typed as Enteritidis species by multilocus sequence typing (MLST) and a sefA (S almonella Enteritidis fimbria)A gene-specific PCR. A draft genome sequence for isolate CSE76F was determined using the whole genome shotgun method. The sequencing library was prepared using the Nextera XT DNA sample preparation kit (Illumina, San Diego, CA) and the sequence read data were produced on the Illumina NextSeq instrument (paired end, 150 base reads). A total of 3,213,288 reads yielded 477,626,349 bases of usable sequence data after filtering to remove low quality sequence data and adapter sequences (approximately 100- fold read coverage of the genome) (Sequence Read Archive [SRA] Accession Number, SRR5198927). De novo assembly of the read data with MegaHit yielded a draft genome sequence comprising a total of 4,743,613 bases in 61 contigs (minimum contig size 500 bases). The MLST type was confirmed from the draft genome sequence (Senterica scheme, ST 11) from the genome sequence and the antimicrobial resistance gene profile of the isolate was determined using Abricate and the ResFinder database. This showed that the isolate carried a bla TEM-1b gene (encoding a class A beta-lactamase). This fits with the observed resistance of the isolate to ampicillin. The most related closed genome sequence was that from Salmonella enterica subsp. enterica serovar Enteritidis strain P125109 isolated from an outbreak of human food-poisoning (RefSeq: NC_011294) with 55 SNPs identified across 98.82% of the strain P125109 genome sequence. Aligning the CSE76F contigs to the P125109 genome sequence revealed no apparent major genomic deletions, inversions or rearrangements (Fig. 2). Analysis of the virulence gene profile was performed using Abricate with the VFDB database of virulence genes. CSE76F strain possessed three additional virulence genes-pef (p lasmid-e ncoded f imbriae with all four subunits-pefA, pefB, pefC, pefD), spv (s almonella p lasmid v irulence with all three subunits- spvA, spvB, spvC) and rck ( r esistance to c omplement k illing)-that were absent in strain P125109. Phylogenetic relationship of CSE76F strain based on single nucleotide polymorphism (SNP) with that of 60 closed genomes of S. Enteritidis strains available in GenBank (shown in Additional file 1: Table S1) was constructed using FastTree. Core SNP differences were called using Nullarbor. Strain CSE76F did not occupy a unique position, but clustered with several other strains from the United Kingdom, South Korea, Canada and the United States of America (Fig. 3).

carbuncle, s enteritidis, virulence genes, whole genome sequencing

PMC5424951_01

Female

A 75-year-old woman was admitted to our institution with a 2-week history of cough, sputum production, and fever. She had undergone right middle and right lower lobectomy for a double lung cancer 13 years earlier and recently underwent chemotherapy for tumor recurrence in the right thoracic cavity just before admission. On physical examination, the patient was thin with a body mass index of 16.9. She was febrile, with a body temperature of 37.8 C, but all other vital signs were normal. Vesicular sounds were weak on right chest auscultation. Chest X-ray and computed tomography (CT) revealed that compared with a previous study, there was a new contractive consolidation with cavity in the remaining right upper lobe (Fig. 1). Laboratory tests showed elevation of inflammatory markers: white blood cell count (WBC) 9180/muL and C-reactive protein (CRP) 9.87 mg/dL. We clinically diagnosed bacterial pneumonia; intravenous imipenem (IPM)/cilastatin (CS) was administered, but symptoms did not improve. Since fungal infection was a differential diagnosis of the CT findings, we added micafungin (MCFG). Treatment with IPM/CS and MCFG was continued for 2 weeks, but there was no improvement. On further test, 3 sputum acid-fast bacillus (AFB) smears yielded a positive result of 2+, but polymerase chain reaction for tuberculosis and Mycobacterium avium complex (MAC) were both negative. We assumed the causative organism to be NTM other than MAC, including the progressive and rapidly growing Mycobacterium abcessus. With this in mind, we continued IPM/CS at 1000 mg/day and started LVFX at 250 mg/day and CAM at 800 mg/day. Symptoms, laboratory tests, and chest X-ray and CT improved after initiation of LVFX and CAM (Fig. 2). AFB culture of all 3 sputum specimens was positive for NTM. DNA-DNA hybridization (DDH mycobacteria; Kyokuto Pharmaceuticals, Tokyo, Japan) identified M. triviale in one sputum specimen, but could not detect the specific NTM from the other two specimens. We assumed negative conversion of sputum AFB smear, and culture was noted 2 weeks after initiating pharmacotherapy with LVFX and CAM. We considered that the pathogenic bacteria do not contradict M. triviale by the result of DNA-DNA hybridization and the clinical course. We suggested additional intake of anti-tuberculosis drugs, but the patient declined and we reluctantly continued treatment with only LVFX and CAM for 12 months; IPM/CS were discontinued after symptom resolution. Twelve months after completing pharmacotherapy with LVFX and CAM, there have been no clinical manifestations of recurrence and sputum AFB smear and culture have remained negative.

mycobacterium triviale, non-tuberculous mycobacteria, respiratory infection

Chest X-ray and CT before treatment. A) Chest X-ray before admission shows volume loss on the right lung due to right middle lobe and right lower lobe lobectomy.

PMC5424951_01

Female

A 75-year-old woman was admitted to our institution with a 2-week history of cough, sputum production, and fever. She had undergone right middle and right lower lobectomy for a double lung cancer 13 years earlier and recently underwent chemotherapy for tumor recurrence in the right thoracic cavity just before admission. On physical examination, the patient was thin with a body mass index of 16.9. She was febrile, with a body temperature of 37.8 C, but all other vital signs were normal. Vesicular sounds were weak on right chest auscultation. Chest X-ray and computed tomography (CT) revealed that compared with a previous study, there was a new contractive consolidation with cavity in the remaining right upper lobe (Fig. 1). Laboratory tests showed elevation of inflammatory markers: white blood cell count (WBC) 9180/muL and C-reactive protein (CRP) 9.87 mg/dL. We clinically diagnosed bacterial pneumonia; intravenous imipenem (IPM)/cilastatin (CS) was administered, but symptoms did not improve. Since fungal infection was a differential diagnosis of the CT findings, we added micafungin (MCFG). Treatment with IPM/CS and MCFG was continued for 2 weeks, but there was no improvement. On further test, 3 sputum acid-fast bacillus (AFB) smears yielded a positive result of 2+, but polymerase chain reaction for tuberculosis and Mycobacterium avium complex (MAC) were both negative. We assumed the causative organism to be NTM other than MAC, including the progressive and rapidly growing Mycobacterium abcessus. With this in mind, we continued IPM/CS at 1000 mg/day and started LVFX at 250 mg/day and CAM at 800 mg/day. Symptoms, laboratory tests, and chest X-ray and CT improved after initiation of LVFX and CAM (Fig. 2). AFB culture of all 3 sputum specimens was positive for NTM. DNA-DNA hybridization (DDH mycobacteria; Kyokuto Pharmaceuticals, Tokyo, Japan) identified M. triviale in one sputum specimen, but could not detect the specific NTM from the other two specimens. We assumed negative conversion of sputum AFB smear, and culture was noted 2 weeks after initiating pharmacotherapy with LVFX and CAM. We considered that the pathogenic bacteria do not contradict M. triviale by the result of DNA-DNA hybridization and the clinical course. We suggested additional intake of anti-tuberculosis drugs, but the patient declined and we reluctantly continued treatment with only LVFX and CAM for 12 months; IPM/CS were discontinued after symptom resolution. Twelve months after completing pharmacotherapy with LVFX and CAM, there have been no clinical manifestations of recurrence and sputum AFB smear and culture have remained negative.

mycobacterium triviale, non-tuberculous mycobacteria, respiratory infection

Chest X-ray and CT before treatment. B) Chest X-ray on admission shows apparent consolidation in the right lung field.

PMC5424951_01

Female

A 75-year-old woman was admitted to our institution with a 2-week history of cough, sputum production, and fever. She had undergone right middle and right lower lobectomy for a double lung cancer 13 years earlier and recently underwent chemotherapy for tumor recurrence in the right thoracic cavity just before admission. On physical examination, the patient was thin with a body mass index of 16.9. She was febrile, with a body temperature of 37.8 C, but all other vital signs were normal. Vesicular sounds were weak on right chest auscultation. Chest X-ray and computed tomography (CT) revealed that compared with a previous study, there was a new contractive consolidation with cavity in the remaining right upper lobe (Fig. 1). Laboratory tests showed elevation of inflammatory markers: white blood cell count (WBC) 9180/muL and C-reactive protein (CRP) 9.87 mg/dL. We clinically diagnosed bacterial pneumonia; intravenous imipenem (IPM)/cilastatin (CS) was administered, but symptoms did not improve. Since fungal infection was a differential diagnosis of the CT findings, we added micafungin (MCFG). Treatment with IPM/CS and MCFG was continued for 2 weeks, but there was no improvement. On further test, 3 sputum acid-fast bacillus (AFB) smears yielded a positive result of 2+, but polymerase chain reaction for tuberculosis and Mycobacterium avium complex (MAC) were both negative. We assumed the causative organism to be NTM other than MAC, including the progressive and rapidly growing Mycobacterium abcessus. With this in mind, we continued IPM/CS at 1000 mg/day and started LVFX at 250 mg/day and CAM at 800 mg/day. Symptoms, laboratory tests, and chest X-ray and CT improved after initiation of LVFX and CAM (Fig. 2). AFB culture of all 3 sputum specimens was positive for NTM. DNA-DNA hybridization (DDH mycobacteria; Kyokuto Pharmaceuticals, Tokyo, Japan) identified M. triviale in one sputum specimen, but could not detect the specific NTM from the other two specimens. We assumed negative conversion of sputum AFB smear, and culture was noted 2 weeks after initiating pharmacotherapy with LVFX and CAM. We considered that the pathogenic bacteria do not contradict M. triviale by the result of DNA-DNA hybridization and the clinical course. We suggested additional intake of anti-tuberculosis drugs, but the patient declined and we reluctantly continued treatment with only LVFX and CAM for 12 months; IPM/CS were discontinued after symptom resolution. Twelve months after completing pharmacotherapy with LVFX and CAM, there have been no clinical manifestations of recurrence and sputum AFB smear and culture have remained negative.

mycobacterium triviale, non-tuberculous mycobacteria, respiratory infection

Chest X-ray and CT before treatment. C) Chest computed tomography before admission shows volume loss on the right lung due to right middle lobe and right lower lobe lobectomy.

PMC5424951_01

Female

A 75-year-old woman was admitted to our institution with a 2-week history of cough, sputum production, and fever. She had undergone right middle and right lower lobectomy for a double lung cancer 13 years earlier and recently underwent chemotherapy for tumor recurrence in the right thoracic cavity just before admission. On physical examination, the patient was thin with a body mass index of 16.9. She was febrile, with a body temperature of 37.8 C, but all other vital signs were normal. Vesicular sounds were weak on right chest auscultation. Chest X-ray and computed tomography (CT) revealed that compared with a previous study, there was a new contractive consolidation with cavity in the remaining right upper lobe (Fig. 1). Laboratory tests showed elevation of inflammatory markers: white blood cell count (WBC) 9180/muL and C-reactive protein (CRP) 9.87 mg/dL. We clinically diagnosed bacterial pneumonia; intravenous imipenem (IPM)/cilastatin (CS) was administered, but symptoms did not improve. Since fungal infection was a differential diagnosis of the CT findings, we added micafungin (MCFG). Treatment with IPM/CS and MCFG was continued for 2 weeks, but there was no improvement. On further test, 3 sputum acid-fast bacillus (AFB) smears yielded a positive result of 2+, but polymerase chain reaction for tuberculosis and Mycobacterium avium complex (MAC) were both negative. We assumed the causative organism to be NTM other than MAC, including the progressive and rapidly growing Mycobacterium abcessus. With this in mind, we continued IPM/CS at 1000 mg/day and started LVFX at 250 mg/day and CAM at 800 mg/day. Symptoms, laboratory tests, and chest X-ray and CT improved after initiation of LVFX and CAM (Fig. 2). AFB culture of all 3 sputum specimens was positive for NTM. DNA-DNA hybridization (DDH mycobacteria; Kyokuto Pharmaceuticals, Tokyo, Japan) identified M. triviale in one sputum specimen, but could not detect the specific NTM from the other two specimens. We assumed negative conversion of sputum AFB smear, and culture was noted 2 weeks after initiating pharmacotherapy with LVFX and CAM. We considered that the pathogenic bacteria do not contradict M. triviale by the result of DNA-DNA hybridization and the clinical course. We suggested additional intake of anti-tuberculosis drugs, but the patient declined and we reluctantly continued treatment with only LVFX and CAM for 12 months; IPM/CS were discontinued after symptom resolution. Twelve months after completing pharmacotherapy with LVFX and CAM, there have been no clinical manifestations of recurrence and sputum AFB smear and culture have remained negative.

mycobacterium triviale, non-tuberculous mycobacteria, respiratory infection

Chest X-ray and CT before treatment. D) Chest computed tomography on admission shows contractive consolidation with a cavity in the right upper lobe.

PMC5424951_01

Female

A 75-year-old woman was admitted to our institution with a 2-week history of cough, sputum production, and fever. She had undergone right middle and right lower lobectomy for a double lung cancer 13 years earlier and recently underwent chemotherapy for tumor recurrence in the right thoracic cavity just before admission. On physical examination, the patient was thin with a body mass index of 16.9. She was febrile, with a body temperature of 37.8 C, but all other vital signs were normal. Vesicular sounds were weak on right chest auscultation. Chest X-ray and computed tomography (CT) revealed that compared with a previous study, there was a new contractive consolidation with cavity in the remaining right upper lobe (Fig. 1). Laboratory tests showed elevation of inflammatory markers: white blood cell count (WBC) 9180/muL and C-reactive protein (CRP) 9.87 mg/dL. We clinically diagnosed bacterial pneumonia; intravenous imipenem (IPM)/cilastatin (CS) was administered, but symptoms did not improve. Since fungal infection was a differential diagnosis of the CT findings, we added micafungin (MCFG). Treatment with IPM/CS and MCFG was continued for 2 weeks, but there was no improvement. On further test, 3 sputum acid-fast bacillus (AFB) smears yielded a positive result of 2+, but polymerase chain reaction for tuberculosis and Mycobacterium avium complex (MAC) were both negative. We assumed the causative organism to be NTM other than MAC, including the progressive and rapidly growing Mycobacterium abcessus. With this in mind, we continued IPM/CS at 1000 mg/day and started LVFX at 250 mg/day and CAM at 800 mg/day. Symptoms, laboratory tests, and chest X-ray and CT improved after initiation of LVFX and CAM (Fig. 2). AFB culture of all 3 sputum specimens was positive for NTM. DNA-DNA hybridization (DDH mycobacteria; Kyokuto Pharmaceuticals, Tokyo, Japan) identified M. triviale in one sputum specimen, but could not detect the specific NTM from the other two specimens. We assumed negative conversion of sputum AFB smear, and culture was noted 2 weeks after initiating pharmacotherapy with LVFX and CAM. We considered that the pathogenic bacteria do not contradict M. triviale by the result of DNA-DNA hybridization and the clinical course. We suggested additional intake of anti-tuberculosis drugs, but the patient declined and we reluctantly continued treatment with only LVFX and CAM for 12 months; IPM/CS were discontinued after symptom resolution. Twelve months after completing pharmacotherapy with LVFX and CAM, there have been no clinical manifestations of recurrence and sputum AFB smear and culture have remained negative.

mycobacterium triviale, non-tuberculous mycobacteria, respiratory infection

Chest X-ray and CT after treatment. A) Chest X-ray after medication shows resolution of the consolidation in the right lung field.

PMC5424951_01

Female

A 75-year-old woman was admitted to our institution with a 2-week history of cough, sputum production, and fever. She had undergone right middle and right lower lobectomy for a double lung cancer 13 years earlier and recently underwent chemotherapy for tumor recurrence in the right thoracic cavity just before admission. On physical examination, the patient was thin with a body mass index of 16.9. She was febrile, with a body temperature of 37.8 C, but all other vital signs were normal. Vesicular sounds were weak on right chest auscultation. Chest X-ray and computed tomography (CT) revealed that compared with a previous study, there was a new contractive consolidation with cavity in the remaining right upper lobe (Fig. 1). Laboratory tests showed elevation of inflammatory markers: white blood cell count (WBC) 9180/muL and C-reactive protein (CRP) 9.87 mg/dL. We clinically diagnosed bacterial pneumonia; intravenous imipenem (IPM)/cilastatin (CS) was administered, but symptoms did not improve. Since fungal infection was a differential diagnosis of the CT findings, we added micafungin (MCFG). Treatment with IPM/CS and MCFG was continued for 2 weeks, but there was no improvement. On further test, 3 sputum acid-fast bacillus (AFB) smears yielded a positive result of 2+, but polymerase chain reaction for tuberculosis and Mycobacterium avium complex (MAC) were both negative. We assumed the causative organism to be NTM other than MAC, including the progressive and rapidly growing Mycobacterium abcessus. With this in mind, we continued IPM/CS at 1000 mg/day and started LVFX at 250 mg/day and CAM at 800 mg/day. Symptoms, laboratory tests, and chest X-ray and CT improved after initiation of LVFX and CAM (Fig. 2). AFB culture of all 3 sputum specimens was positive for NTM. DNA-DNA hybridization (DDH mycobacteria; Kyokuto Pharmaceuticals, Tokyo, Japan) identified M. triviale in one sputum specimen, but could not detect the specific NTM from the other two specimens. We assumed negative conversion of sputum AFB smear, and culture was noted 2 weeks after initiating pharmacotherapy with LVFX and CAM. We considered that the pathogenic bacteria do not contradict M. triviale by the result of DNA-DNA hybridization and the clinical course. We suggested additional intake of anti-tuberculosis drugs, but the patient declined and we reluctantly continued treatment with only LVFX and CAM for 12 months; IPM/CS were discontinued after symptom resolution. Twelve months after completing pharmacotherapy with LVFX and CAM, there have been no clinical manifestations of recurrence and sputum AFB smear and culture have remained negative.

mycobacterium triviale, non-tuberculous mycobacteria, respiratory infection

Chest X-ray and CT after treatment. B) Chest computed tomography after pharmacotherapy shows resolution of the contractive consolidation in the right upper lobe.

PMC4246641_01

Male

A 45-year-old male patient presented to the Hangzhou Red Cross Hospital (Hangzhou, Zhejiang, China) with a painless swelling in the left side of the neck that had gradually increased in size over two weeks. There was no complaint of dysphagia or dyspnea. The patient did not report any history of fever, coughing or hemoptysis, but complained of weight loss of 4 kg within the prior three months. The patient had no past or family history of tuberculosis. Upon examination, a solid, non-tender, 40x30-mm ill-defined mass was present in the left lobe of the thyroid. The cervical lump moved with deglutition, and no enlargement of the regional lymph nodes was observed. The white cell count in the peripheral blood was 10.9x109/l (normal range, 3.0-9.0x109/l), the neutrophil level was 45% and the erythrocyte sedimentation rate (ESR) was 60 mm/h. A thyroid hormonal profile revealed a euthyroid status. Human immunodeficiency virus testing was negative and investigations for infectious or inflammatory conditions were unremarkable. A chest X-ray revealed no pulmonary abnormalities, but the tuberculin test (1:10,000) was strongly positive. US of the thyroid gland was performed using a real-time machine equipped with a 9-11 MHz probe (Philips, Amsterdam, Netherlands). US examination revealed a 34x27x24-mm, ovoid-shaped mass in the left lobe of the thyroid gland. The thyroid lesion was inhomogeneously hypoechoic, with ill-defined margins. An anechoic area with internal hyperechoic spots was present within the mass (Fig. 1A). Color Doppler examination revealed punctate or linear flow signals around the nodule with no intralesional vascularization (Fig. 1B). The patient's general condition worsened three days after admission. There had been an increase in the size of the swelling, associated with a 37-38 C low-grade fever. A repeat US examination demonstrated that the mass in the left lobe of the gland had increased in volume to 65x35x38 mm. The lesion partially protruded from the upper pole of the left thyroid lobe (Fig. 2A). Compression with the probe and positional changes demonstrated the presence of liquid within the mass. Blood flow signals were observed by color Doppler examination around, but not inside the lesion (Fig. 2B). A US-guided fine-needle aspiration (FNA) biopsy of the thyroid mass yielded a thick, caseous and bloody material (Fig. 2C and D). Microscopic examination revealed the presence of follicular epithelial cells in flaked or honeycombed formations on a bloody background, together with clusters of purple-stained colloid and a field of granular caseous necrosis (Fig. 2E). In order to obtain a histological diagnosis, a US-guided CNB of the adjacent solid tissue was performed with a 21-gauge cutting needle. Histopathological examination revealed that multifocal granulomatous nodules were distributed in between atrophic thyroid follicles, chronic inflammatory cell infiltration and fibrous tissue proliferation (Fig. 2F). Acid-fast staining on frozen-sections did not indicate the presence of bacteria. However, the presence of multifocal granulomatous inflammation associated with caseous necrosis was strongly suggestive of tuberculous infection. The patient was administered an oral three-drug regimen of antituberculous medication (0.3 g isoniazid, 0.6 g rifampicine and 0.2 g ciprofloxacine, once daily for a total of 3 months). Subsequent to three months of treatment, US demonstrated clinically significant shrinkage of the nodule down to 16x10x12 mm and the appearance of coarse calcifications inside the lesion. A repeat US examination was performed six months later without any marked changes in size, but with progressive loss of the definition of the nodule limits (Fig. 3). The patient remains without clinical symptoms at the time of writing.

thyroid tuberculosis, ultrasound, ultrasound-guided core-needle biopsy

PMC8841644_01

Male

A 91-year-old male was admitted to the Department of Respiratory and Critical Care Medicine, Ruijin Hospital in October 2020 because of an incidental finding of a lung mass for 20 days, increased carcinoembryonic antigen (CEA) levels, and localized emphysema in a local hospital (Figure 1). The patient first consulted at the local hospital because of cough, shortness of breath, anorexia, fever, chest pain, and other respiratory symptoms with unknown causes for more than 3 months. For further diagnosis, the patient was admitted to our hospital. He denied a smoking and drinking history, but both parents died of lung cancer. The patient had coronary heart disease (taking aspirin), hypertension (taking candesartan cilexetil), lacunar cerebral infarction, colon polyps (tubular adenoma with low-grade intraepithelial neoplasia revealed by colonoscopic polypectomy), and a history of tuberculosis 60 years ago. Positron emission tomography (PET):MRI of the chest revealed a highly metabolic mass in the upper right lobe, a highly metabolic nodule at the apex of the right lung, and small nodules in the upper right lobe with traction of the adjacent pleura, with a slightly increased metabolism (Figure 2). Furthermore, adenocarcinoma cells were found by right upper lobe lesion biopsy. After subsequent evaluation, he was diagnosed with stage T3N2M0 adenocarcinoma of the right lung. Amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR)-based single gene tests for EGFR, ALK, ROS1, BRAF, NRAS, KRAS, ERBB2, PIK3CA, and MET exon 14 skipping were all negative in the tissue biopsy. Then, rare mutations were tested by next-generation sequencing (NGS) for tissue biopsy (F1CDX; Foundation Medicine, Massachusetts, United States) and liquid biopsy (America Geneseeq Prime, Nanjing, China). An MET Y1003S mutation was detected in the tissue (Figure 3) but not in the liquid biopsy. There were no EGFR mutations, MET amplifications, or ALK/ROS1 fusion events in both testing. The patient started crizotinib 250 mg b.i.d. on December 20, 2020. Chest CT scan on January 11, 2021 showed a partial response and significant improvement of the lung lesions (right upper lung: from 55 x 43 mm to 23 x 17 mm, Figure 4). After 1 month of crizotinib treatment, the patient was admitted because of chest distress, which could be alleviated by rest. Pulmonary artery thin layer CTA revealed pulmonary embolism in the left lower lobe. He was treated with low-molecular-weight heparin subcutaneous injection 0.4 ml q 12 h for 3 days and q.d. for 4 days, and then rivaroxaban 10 mg/day. His symptoms were alleviated after the treatment. Drug-induced abnormal liver function was considered because of the increased ALT and AST. The patient was given polyene phosphatidylcholine 228 mg two tablets t.i.d. On May 21, liver function was recovered. On July 30, 2021, the right upper lung lesion was 26 mm x 9 mm, which suggested a partial response.

met y1003 mutation, case report, crizotinib, next-generation sequencing, non-small cell lung cancer

Computed tomography (CT) scan of the primary lung lesion before and after crizotinib treatment. In November 2020, the tumor size was 55 x 43 mm.

PMC8841644_01

Male

A 91-year-old male was admitted to the Department of Respiratory and Critical Care Medicine, Ruijin Hospital in October 2020 because of an incidental finding of a lung mass for 20 days, increased carcinoembryonic antigen (CEA) levels, and localized emphysema in a local hospital (Figure 1). The patient first consulted at the local hospital because of cough, shortness of breath, anorexia, fever, chest pain, and other respiratory symptoms with unknown causes for more than 3 months. For further diagnosis, the patient was admitted to our hospital. He denied a smoking and drinking history, but both parents died of lung cancer. The patient had coronary heart disease (taking aspirin), hypertension (taking candesartan cilexetil), lacunar cerebral infarction, colon polyps (tubular adenoma with low-grade intraepithelial neoplasia revealed by colonoscopic polypectomy), and a history of tuberculosis 60 years ago. Positron emission tomography (PET):MRI of the chest revealed a highly metabolic mass in the upper right lobe, a highly metabolic nodule at the apex of the right lung, and small nodules in the upper right lobe with traction of the adjacent pleura, with a slightly increased metabolism (Figure 2). Furthermore, adenocarcinoma cells were found by right upper lobe lesion biopsy. After subsequent evaluation, he was diagnosed with stage T3N2M0 adenocarcinoma of the right lung. Amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR)-based single gene tests for EGFR, ALK, ROS1, BRAF, NRAS, KRAS, ERBB2, PIK3CA, and MET exon 14 skipping were all negative in the tissue biopsy. Then, rare mutations were tested by next-generation sequencing (NGS) for tissue biopsy (F1CDX; Foundation Medicine, Massachusetts, United States) and liquid biopsy (America Geneseeq Prime, Nanjing, China). An MET Y1003S mutation was detected in the tissue (Figure 3) but not in the liquid biopsy. There were no EGFR mutations, MET amplifications, or ALK/ROS1 fusion events in both testing. The patient started crizotinib 250 mg b.i.d. on December 20, 2020. Chest CT scan on January 11, 2021 showed a partial response and significant improvement of the lung lesions (right upper lung: from 55 x 43 mm to 23 x 17 mm, Figure 4). After 1 month of crizotinib treatment, the patient was admitted because of chest distress, which could be alleviated by rest. Pulmonary artery thin layer CTA revealed pulmonary embolism in the left lower lobe. He was treated with low-molecular-weight heparin subcutaneous injection 0.4 ml q 12 h for 3 days and q.d. for 4 days, and then rivaroxaban 10 mg/day. His symptoms were alleviated after the treatment. Drug-induced abnormal liver function was considered because of the increased ALT and AST. The patient was given polyene phosphatidylcholine 228 mg two tablets t.i.d. On May 21, liver function was recovered. On July 30, 2021, the right upper lung lesion was 26 mm x 9 mm, which suggested a partial response.

met y1003 mutation, case report, crizotinib, next-generation sequencing, non-small cell lung cancer

Computed tomography (CT) scan of the primary lung lesion before and after crizotinib treatment. In January 2021, the tumor size was 26 x 17 mm.

PMC8841644_01

Male

A 91-year-old male was admitted to the Department of Respiratory and Critical Care Medicine, Ruijin Hospital in October 2020 because of an incidental finding of a lung mass for 20 days, increased carcinoembryonic antigen (CEA) levels, and localized emphysema in a local hospital (Figure 1). The patient first consulted at the local hospital because of cough, shortness of breath, anorexia, fever, chest pain, and other respiratory symptoms with unknown causes for more than 3 months. For further diagnosis, the patient was admitted to our hospital. He denied a smoking and drinking history, but both parents died of lung cancer. The patient had coronary heart disease (taking aspirin), hypertension (taking candesartan cilexetil), lacunar cerebral infarction, colon polyps (tubular adenoma with low-grade intraepithelial neoplasia revealed by colonoscopic polypectomy), and a history of tuberculosis 60 years ago. Positron emission tomography (PET):MRI of the chest revealed a highly metabolic mass in the upper right lobe, a highly metabolic nodule at the apex of the right lung, and small nodules in the upper right lobe with traction of the adjacent pleura, with a slightly increased metabolism (Figure 2). Furthermore, adenocarcinoma cells were found by right upper lobe lesion biopsy. After subsequent evaluation, he was diagnosed with stage T3N2M0 adenocarcinoma of the right lung. Amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR)-based single gene tests for EGFR, ALK, ROS1, BRAF, NRAS, KRAS, ERBB2, PIK3CA, and MET exon 14 skipping were all negative in the tissue biopsy. Then, rare mutations were tested by next-generation sequencing (NGS) for tissue biopsy (F1CDX; Foundation Medicine, Massachusetts, United States) and liquid biopsy (America Geneseeq Prime, Nanjing, China). An MET Y1003S mutation was detected in the tissue (Figure 3) but not in the liquid biopsy. There were no EGFR mutations, MET amplifications, or ALK/ROS1 fusion events in both testing. The patient started crizotinib 250 mg b.i.d. on December 20, 2020. Chest CT scan on January 11, 2021 showed a partial response and significant improvement of the lung lesions (right upper lung: from 55 x 43 mm to 23 x 17 mm, Figure 4). After 1 month of crizotinib treatment, the patient was admitted because of chest distress, which could be alleviated by rest. Pulmonary artery thin layer CTA revealed pulmonary embolism in the left lower lobe. He was treated with low-molecular-weight heparin subcutaneous injection 0.4 ml q 12 h for 3 days and q.d. for 4 days, and then rivaroxaban 10 mg/day. His symptoms were alleviated after the treatment. Drug-induced abnormal liver function was considered because of the increased ALT and AST. The patient was given polyene phosphatidylcholine 228 mg two tablets t.i.d. On May 21, liver function was recovered. On July 30, 2021, the right upper lung lesion was 26 mm x 9 mm, which suggested a partial response.

met y1003 mutation, case report, crizotinib, next-generation sequencing, non-small cell lung cancer

Computed tomography (CT) scan of the primary lung lesion before and after crizotinib treatment. In May 2021, the tumor size was 27 x 9 mm.

PMC3113210_01

Female

A 67-year-old woman with intense esophagitis (grade III of Savary) and a mild hiatal hernia underwent a laparoscopic Nissen fundoplication in February 2000. Her most important clinical symptoms were retrosternal pain, acid and food regurgitation, and heartburn. She was also dependent on proton-pump inhibitors for symptom relief. No problems or difficulties occurred during the procedure. At laparoscopy, no abnormality was found. Her immediate postoperative period was unremarkable. A hook electrocautery was used for dissecting the diaphragmatic crura and opening the retroesophageal window. Twenty days after the surgery, the patient complained of abdominal pain and distension. Physical examination revealed an increased abdominal girth, ascites, and exaggerated tympanism. Diffuse ascites was also confirmed by an ultrasound examination. A paracentesis was performed and showed a white-milky odorless fluid with a specific gravity of 1.030, sodium 135 mEq/L, potassium 3.6 mEq/L, total protein 4.4 g/L, amylase 25 U/L, triglycerides 1024 ng/dL, cholesterol 241 ng/dL, red blood cell count of 3450, and white blood cell count of 2150 (70% lymphocytes). Electrophoresis of the fluid showed that lipids were mainly in the form of chylomicrons. Gram stain and bacterial cultures were negative. A central line was placed and parenteral nutrition started. Over the next 3 weeks, the abdominal girth improved with decreased firmness and increased bowel sounds. The central line was removed on day 20 and oral fat-free diet restarted. One-month later, abdominal ultrasound demonstrated no ascites.

PMC5712115_01

Male

A 54-year-old male was diagnosed with Philadelphia (-) acute B lymphoblastic leukemia in 2015. A relapse with central nervous system involvement was demonstrated 4 months after ending Hyper CVAD chemotherapy. He received intrathecal methotrexate with FLAGIDA chemotherapy achieving a second complete remission (CR) followed by a haploidentical myeloablative transplant with cyclophosphamide and total body irradiation (TBI) using peripheral blood hematopoietic stem cell transplantation (PBSCT) from a 3/6 HLA matched sibling. GVHD prophylaxis consisted of post transplant cyclophosphamide (days +3 and +4), tacrolimus and mycophenolate mofetil. 1 week post transplantation he developed febrile neutropenia and a progressive hepatic failure. After engraftment on day 12, he developed a progressive respiratory failure and required invasive mechanical ventilation. At day 14 an evanescent rash was noticed and the skin biopsy showed grade 3 aGVHD. Chest CT Scan showed an interstitial pattern of infiltration without images suggesting fungal infection. BAL was performed an all assays were negative (bacterial cultures, CMV PCR, EBV PCR, aspergillus test, no cardial test). He was started on high doses of methylprednisolone (1.5 g total dose) followed by prednisone 2 mg/kg/day without improvement after 14 days of treatment. A diagnosis of corticoid refractory acute GVHD NIH grade 3 was established and EP was started. During the first session of apheresis, his respiratory function worsened. We started low doses of ruxolitinib (5 mg BID), and after 2 weeks of treatment all cutaneous and hepatic alterations resolved and chest CT scan showed a significant resolution of the interstitial pattern. This allowed the weaning of the 2-month mechanical ventilation. After 12 months of treatment the patient have normal lung function and no other signs of GVHD nor leukemia relapse (Fig. 1).

corticoid refractoriness, extracorporeal photopheresis, graft versus host disease, ruxolitinib

PMC5712115_06

Female

A 36-year-old woman was diagnosed with Ph (+) acute lymphoblastic leukemia in 2013. She was treated with HyperCVAD chemotherapy and dasatinib, with complete molecular remission after 4 months of treatment. She received a PBSCT from her HLA identical brother after a myeloablative conditioning (CY-TBI) and GVHD prophylaxis with methotrexate and cyclosporine. She developed aGVHD NIH grade 1 with intestinal involvement initially treated with budesonide. 24 months later she started with hyperpigmentation in thorax and severe and rapidly progressive sclerodermoid features in the legs, arms and neck, with deep panniculitis and fasciitis-like sclerotic cGVHD NIH grade 3. Skin biopsy confirmed cGVHD, and systemic corticosteroids and low-dose oral methotrexate were started, with only partial response after 2 months of therapy. There was no clinical improvement after 4 months with progression of her scleroderma with severe involvement of movement in the legs and hip rotation. There was no response to ECP 12 sessions. Ruxolitinib 10 mg QD was started and scleroderma improved significantly after 3 months allowing a normal deambulation. After 11 months of ruxolitinib, sclerodermic form persists but in lower grade and normalization of skin changes. Modified Rodnan score improved from 26 to 16 (Fig. 5).

corticoid refractoriness, extracorporeal photopheresis, graft versus host disease, ruxolitinib

PMC3118057_01

Male

A 50-year-old farmer presented to us with fever and serosanguineous discharging swelling over the dorsum of right foot. To start with the growth was small, approximately 1-2 cm in size and without any pain and discharge. Over the last 18 months, it has progressed gradually and occupied the whole of the dorsum of right foot. Past history was nothing significant, no history of trauma or injury to the foot, non-diabetic, non-hypertensive and not suffering from tuberculosis. But 3 months back at the local hospital the patient was diagnosed as having tuberculosis and treated with anti-tubercular drugs. However, there was no improvement even after 2 months of treatment, hence discontinued the treatment. Local examination revealed a grossly swollen entire dorsum of the right foot with intense erythema, numerous elevated, well-demarcated small to large nodular lesions with few discharging sinuses. Sinus openings were inflamed and mostly blocked with dried pus. The foot was grossly deformed, and it was tender. Veins of the right leg were dilated and pitting edema extended almost up to the knee. Discharge was yellowish, purulent and foul smelling without any apparent granules [Figure 1]. Pus was collected in a sterile bottle by aspirating with sterile Pasteur pipette. A piece of biopsy 4 x 6 mm was obtained from one of the nodular swellings and subjected for microbiological and histopathological examination. A thorough physical examination revealed no other abnormality except that the patient had mild fever. His hemoglobin was 10 g/dl, total leucocyte count was 11,900/mm3, polymorphonuclear leucocytes 80%, ESR 40 mm/h [Westergen's method]. HIV seronegative, LFT, RFT and electrolytes were within normal limits. There is no evidence of any other disease or abnormality. The radiological examination of antero-posterior and lateral view of right foot showed soft tissue density occupying the inter-pharyngeal and metatarsal joint space causing spreading of 2nd and 3rd inter-pharyngeal joint space and there was no bone involvement. In the laboratory, a smear was prepared from the sample and stained with Gram's stain, which revealed thin, long, branching, Gram-positive filamentous bacilli [Figure 2]. On modified Ziehl-Neilson stain (1% H2SO4 decolorizer) the filaments were weakly acid fast. Culture was done on sheep blood agar and Sabouraud's dextrose agar (SDA) with antibiotics. A small, dry, granular, wrinkled chalky white to cream colored colonies were grown after a week's incubation at 37oC. The colonies were identified as Nocardia species by culture smear and were subjected for biochemical testing for confirmation and speciation. The colonies were inoculated onto different decomposition media like urease, casein, xanthine, and hypoxanthine to see the hydrolysis of media. These differential plates were incubated at 30oC for 3 weeks. As per the morphological, cultural and biochemical characteristics the isolates was identified as N. asteroides. The histopathological examination of biopsy revealed structure of skin, sub-cutaneous tissue and sinus tract lined by granulation tissue. Few irregular lobulated light basophilic granules were present. The granules are not bordered at the periphery by the eosinophilic material; the filaments in the granules are weak acid fast giving an impression of multiple discharging sinuses of foot - Actinomycetes Mycetoma - Nocardia species. The patient showed dramatic improvement with Minocycline, Dapsone, and Amikacin in cycles of 5 weeks followed by an additional course of Ciprofloxacin. After 6 months of treatment, the lesion healed with significant scarring.

mycetoma, nocardia, subcutaneous

PMC4821339_01

Female

A 40-year-old Chinese woman presented to the hospital with cough and a history of recurrent rash on the skin of the wrist and knee that disappeared spontaneously. As the rash tended to resolve spontaneously, she did not pay attention to it. A CT scan revealed the presence of diffuse ground glass opacity. Her personal and family history did not reveal anything remarkable, and reviews of systems were otherwise unremarkable. Physical examination revealed normal vital signs, no fever, clear lung fields on both sides, and no palpable lymphadenopathy. The results of routine lab investigations, including complete blood count and biochemistry, were normal. The tumor markers that were measured included CEA, NSE, CA125, CA199, and AFP, were in the normal range. HIV testing was negative. The result of the purified protein derivative (PPD) skin test (5 IU) was negative. Blood gas analysis showed that the pH was 7.432; PaO2, 77.1 mm Hg; PaCO2, 38.8 mm Hg; AaDO2, 26.6 mm Hg. A pulmonary function test showed that the VC was 87% predicted; the FEV1/FVC was 100% of the predicted value; and the DLCO was 86% of the predicted value. Lung HRCT showed diffuse fine nodular lesions, ground glass opacity, and minor lymphadenopathy (Fig. 1a and b). Flexible bronchoscopy and transbronchial biopsy of the lung parenchyma and bronchoalveolar lavage (BAL) were performed. The endoscopic findings did not reveal any endobronchial lesions. Microbiological culture of the bronchial secretion showed no evidence of bacterium, fungus or mycobacterium growth. BAL fluid showed turbid liquid. The pathology report indicated the presence of epithelioid granulomas with no caseous necrosis. The result of the acid-fast bacillus test was negative. The pathologist could not confirm the diagnosis of intrathoracic sarcoidosis due to the small size of the tissue biopsied using the flexible bronchoscope and lack of clinicoradiologic evidence. Differential diagnoses, including tuberculosis, mold infection, tumor, and other granulomatous diseases, could not be completely excluded. Therefore, thoracoscopy was performed in order to obtain a relatively large tissue mass and histologically confirm the potential disease. Right lateral thoracoscopy was performed, along with wedge resection of the right lower lobe. Intraoperative examination of the resected tissue by the pathologist revealed the presence of epithelioid granulomas. Additional pathologic examination was performed, and numerous epithelioid cell granulomas were also found in all the resected lung fields (Fig. 2). There was no evidence of tuberculosis, mold infection, tumor, or other granulomatous diseases. Based on the histological findings, the diagnosis was pulmonary sarcoidosis. The patient was discharged 7 days after the operation. As the patient reverted back to her general state of health, 40 mg/d of prednisone was administrated orally, and it was recommended that the corticosteroid therapy be continued for 1.5 years with tapering of the dose. HRCT was performed after 6 months; the corticosteroid therapy resulted in significant ablation of the ground glass opacity in the lung (Fig. 3a and b).

ground glass opacity, hrct, sarcoidosis

PMC10267660_03

Male

A 41-year-old haemodynamically unstable diabetic male patient was referred to our hospital after having undergone multiple procedures including placement of a double-J (D-J) stent for a previous ureteric stricture and an emergent tracheal tube insertion. He presented with right-sided pleural effusion and was a known case of tuberculosis receiving modified anti-tubercular therapy, due to altered liver and kidney function. On admission, initial laboratory investigations revealed raised procalcitonin values, and a provisional diagnosis of sepsis and tubercular empyema was made. He was then moved to the ICU and catheterized for monitoring of kidney function. The patient had a fever spike on the eighth day, with urine microscopy revealing pyuria. A urine culture was sent to the laboratory and extensively drug-resistant Myroides spp. were isolated which were only sensitive to minocycline. Urine infection subsided by day 7 of minocycline administration and repeat cultures showed no further growth after cessation of treatment.

flavobacteriaceae infections, myroides, case report, catheter-related infections, multiple drug resistance

PMC7494791_01

Male

A 22-year-old Indian male who was previously healthy, presented to the emergency department (ED) at our acute care hospital with one-week history of subjective fever, cough, and weight loss. Clinical examination was generally unremarkable, including a normal temperature, but with reduced breath sounds at the right lung base. Hematological, biochemical parameters including inflammatory markers were unremarkable, including ESR of 22 mm/h, but TB QuantiFERON assay was positive. Chest radiograph (Fig. 1) revealed faint right lower zone consolidation with minimal pleural effusion. The patient was initially assessed as a possible case of community-acquired pneumonia, but clinical deterioration with nausea, vomiting, headaches, and confusion, prompted further evaluation. Brain CT scan was unremarkable while lumbar puncture and CSF analysis demonstrated significant lymphocytic pleocytosis with 300 cells with 90 % lymphocytic predominance combined with low CFS glucose at 1.7 mmol/l (normal 2.22-3.8 mmol/L), high CSF protein at 1.98gm/dl (normal 0.15-0.45gm/dl). Microscopy showed no organisms, while bacterial cultures were negative. The diagnosis of disseminated TB with TBM was supported by a positive CSF GeneXpert MTB/RIF PCR assay from sputum and CSF showing no preliminary resistance, confirmed upon culture as a fully sensitive Mycobacterium Tuberculosis. The patient was started on conventional quadruple regimen including Rifampicin, Isoniazid, Pyrazinamide and Ethambutol with adjuvant tapering doses of steroid therapy planned for 12-month duration. The patient made a significant clinical response with reversal of all symptoms up to discharge with no residual complications. One month following discharge, the patient presented to the ED with intense acute headache and vomiting. Physical examination was unremarkable with no neurological deficit. Urgent CT head revealed acute subarachnoid hemorrhage (Fig. 2). Further assessment with brain CT angiogram, Magnetic Resonant Imaging, and angiogram (MRI/MRA) confirmed left tempo-partial subarachnoid hemorrhage together with probable left middle cerebral artery infective aneurysm (Fig. 3). The patient underwent urgent craniotomy with warping of the left aneurysm, followed by embolization. Despite the grave implications, all the patient acute symptoms resolved, followed by a short period of rehabilitation to continue remaining therapy. Follow up showed no residual neurological sequelae.

aneurysm, subarachnoid hemorrhage, tb, tuberculous meningitis, vasculitis

PMC8249151_01

Male

The patient was a 24-year-old male with a past psychiatric history of schizophrenia who was seen in the outpatient clinic due to hypersexuality after starting aripiprazole. The patient had no known health problems. He had no history of head trauma, seizures, sexually transmitted disease, or significant substance abuse problems. He was first diagnosed with schizophrenia at the age of 19 years and was started on olanzapine, which he responded well to for years. The patient was living with his mother and had completed 11th grade level education. He did not have any history of developmental or intellectual difficulties. He was working part time in a fast food restaurant when he started to have the decline. He was single, never married, and had no significant other. The patient did not have very many acquaintances and led a quiet life. He has no known legal issues so far. The patient used cannabis occasionally when he was 17, but denied any use now. He did not have any problems with alcohol and or other illicit substances. He did not have any history of tobacco use. There was no known family history of mental illness. The patient was previously stable on olanzapine 20 mg/day for four years and then became noncompliant due to unclear reasons, leading to worsening of psychotic symptoms. He was switched to oral aripiprazole 15 mg/day with a plan to switch to a long-acting injectable due to possible nonadherence. During the initial oral one-week trial, the patient became increasingly unstable, with physical and verbal altercations with his mother. The patient also ran away from home and lost his job due to public masturbation at his workplace. His mother also noticed that the patient was increasingly flirtatious and inappropriate in public with females, which were behaviors he had never displayed previously. Given his worsening behaviors, the patient was admitted to the inpatient unit and was switched to intramuscular injection (IM) of aripiprazole 400 mg, assuming that he would benefit from a long-acting injectable and that he could be non-adherent with the oral medication. He became increasingly sexually aroused and was acting inappropriate in the days following. During the hospital stay, there was an instance where he had sex with a female peer and had to be placed on 1 : 1 observation, i.e., one staff was assigned to continuously observe the patient. After discharge from the hospital, the patient needed constant reminders in his group home to keep his hands out of his pants. Despite these attempts to reduce the inappropriate behavior, the patient endorsed that his sexual arousal was more than normal after starting the aripiprazole. At this point in time, the patient had received two doses of aripiprazole 400 mg IM. While on aripiprazole, he did not show any gambling urges and or other impulsivity other than the sexual preoccupations. The sexual preoccupations started within a week of starting with aripiprazole. Further aripiprazole injections were discontinued, and the patient was again prescribed olanzapine 20 mg/day given his previous good response. In the group home, the patient continued to remain occasionally agitated with outbursts and required constant redirection about appropriate sexual behaviors in public. He also continued to display sexually inappropriate behaviors towards females in a day program and was banned from attending the program until he was able to behave appropriately. Although he had reduction in the intense sexual behaviors four weeks after stopping the aripiprazole injections, he did not completely return to baseline. Given his ongoing sexually inappropriateness and possible reports of being internally stimulated, he was started on paliperidone 6 mg/day for augmentation and with plan to taper and stop olanzapine. The patient started to have fewer outbursts and was noted to be in much better mood after three to four weeks of starting the paliperidone. He was noted to be less sexually preoccupied and with reduction in inappropriate behaviors in public. When writing this report, the patient was on both olanzapine 20 mg/day and paliperidone 6 mg/day, with the goal of attaining paliperidone monotherapy, initially oral and subsequently long-acting injections. The patient continued to live in the group home to learn social skills before moving into independent housing. After 12 weeks of paliperidone use, the patient was completely free from hypersexual thoughts and behaviors.

PMC5224771_02

Male

Serial apneic attacks were noted during early infancy, and he developed infantile spasms by 1 year old. Abnormalities were identified on electroencephalography, and antiepileptic agents were administered. At 14-month old, he was referred to Tenshi Hospital for surgical treatment of a tumor developing in the sacrococcygeal region. At that time, serious psychomotor retardation was evident. He could not sit, turn over, or even suck milk. Distinctive dysmorphic features were evident, including prominent forehead, hypertelorism, shallow orbits, thick eyebrows, long eyelashes, depressed nasal root, upturned nostrils, low-set ears, hypospadias, right undescended testis, and overlapping fingers. Further examinations revealed atrophy of bilateral optic nerves, bilateral sensorineural deafness, broad ribs, and bilateral hydronephrosis (Fig. 1). The tumor was removed surgically at 16-month old, and histological analysis revealed malignant teratoma. DNA was extracted from peripheral lymphocytes, and the SETBP1 coding sequence was determined according to standard protocols. A heterozygous guanine-to-adenine missense mutation was found at position 2602, predicting an amino acid substitution (D868N). The patient died at 2 years and 9 months old due to generalized metastasis of malignant teratoma.

mutation, setbp1, schinzel–giedion syndrome, prenatal diagnosis

PMC5224771_03

Female

Patient 2, a female infant, was born to unrelated healthy Japanese parents. The father was 25 years old and the mother 24 years old when she was born. At 28 weeks of gestation, the mother was sent to our hospital after esophageal atresia was suspected in the fetus. Excess amniotic fluid, hydrocephalus, bilateral hydronephrosis, overlapping fingers and toes, high prominent forehead, hypertelorism, and depressed nasal root were observed in the fetus on ultrasonography (Fig. 2A-C). The female infant was delivered at 37 weeks and 4 days of gestation, weighing 3106 g and with a length of 47 cm. Soon after birth, she developed respiratory difficulty due to middle airway obstruction attributed to the posteriorly placed tongue and narrow nasal cavity. Esophageal atresia was not found on nasogastric tube examination. The patient showed a characteristic facial appearance with high prominent forehead, hypertelorism, upturned nostrils, midface hypoplasia, depressed nasal root, and micrognathia (Fig. 2D). She also had a large fontanel, malformed auricles, low-set ears, and overlapping fingers and toes (Fig. 2E). By 17 days after birth, her respiration had improved and oral milk feeding was started. Further examinations revealed mild hydrocephalus, hydronephrosis (Fig. 2F), normal heart structure, and normal external genitalia. No neoplasia was detected before she left our hospital at 30 days old. Peripheral blood was withdrawn for chromosomal and DNA examinations. GTG-banded chromosome examination revealed 46,XX. SETBP1 coding sequence analysis revealed a heterozygous guanine-to-adenine missense mutation at position 2608, predicting amino acid substitution (G870S). This research was prospectively reviewed and approved by the Committee for Genetic Testing and Counseling at Tenshi Hospital in Japan.

mutation, setbp1, schinzel–giedion syndrome, prenatal diagnosis

PMC9710505_01

Male

Participant 1 trained as an apprentice to his grandfather for 17 years, since he was 12 years old. His grandfather started bone setting in 1890 on cattle and as he found success, he began doing the same on humans. His fame grew by word-of-mouth. After learning from his grandfather, Participant 1 practiced with his father and passed the knowledge on to his own children and grandchildren. Two of his sons assisted him and another was studying to be a physiotherapist and helped in the clinic when not at school. His daughter assisted with herbal preparations. His wife apprenticed with him after their marriage. Thus, a sub-theme developed involving women TBS. Participant 1's wife was the reason he could travel to satellite facilities to see patients in remote areas, as she managed the patients in the clinic at home. His mother treated patients with jaundice using traditional medicines which she learned from her mother. Because of his family history of treating livestock, Participant 1 continued to get calls from veterinarians for bone setting of animals. Participant 2 learned the tradition from his father who was a traditional venom healer (e.g., snake bites). He also trained in various schools of the Kalari martial art of Kerala, preparing medicated oils to use for massage as part of the martial arts, as well as practicing traditional bone setting which in turn he learned from his father. His early apprenticeship included collecting herbs to prepare "Thailams", the oils used in massage. His sister, wife, and daughters practiced TBS with him, and he had many students, both male and female. Participant 3 learned this tradition from his father and grandfather. While his father treated animals, Participant 3 did not learn to treat animals. TBS was known by different names in different regions, and in this area of the state, called Sathuvachari, it is known as "Elumbu Murivu Vaidyar". Participant 4 learned the tradition from his grandfather whose occupation was agriculture and treated animals before he used the same techniques on humans. He taught TBS to all his children and grandchildren, including women. Participant 5's father was the first to establish a TBS clinic in their small village. Since then, their large family of several brothers, sisters, children, grandchildren, and in-laws practiced TBS all over the state of Andhra Pradesh. The roots of TBS in his Kshatriya warrior community were based on his ancestors hunting in forests where they collected herbs and plants for medicinal purposes, initially to use on domestic animals and later humans. Participant 6 began his apprenticeship at the age of four years from his uncle who raised him. As a young apprentice, he climbed into barrels of Arishta and Asava (fermented Ayurveda formulations) to titrate these mixtures as he was small enough to fit in the barrels. Ayurveda is a traditional source of medicine combining various products such as plants, animals, and minerals. As Participant 6 advanced in age, he collected plants and made the medical pastes and oils. His sisters also learned this art from their uncle. Two of his sisters practiced with him, while other sisters and their children had their own independent establishments. He estimated that within his family they were probably the 6th or 7th generation in this tradition and the story in his family was that the teacher of his ancestors was a guru named Putru Maharishi. Participant 1 and his family were farmers. They grew crops and had mango orchards. These crops were their main source of income. They had a TBS clinic in Puttur and conducted camps in various underserved areas around the state. Participant 2 worked as a salesman in the Middle East for several years, but now was involved full time in practicing and teaching martial arts and TBS. He had a registered martials arts academy at his home. He also had two TBS clinics. Participant 3 had no other occupation outside of TBS. Participant 4 and his family were engaged in agriculture. Participant 5 was the headmaster of a primary school. Participant 6's father passed away when he was very young, so he did manual labor to earn enough while he was an apprentice until he established an independent practice. Now, TBS was his only occupation. Participant 1 learned medical terminology from looking at x-rays or reports that patients brought into his office. He read books to learn more. He had been invited by ayurvedic universities to talk about traditional bone setting practices and received honorary certificates. He was a member of an organization known as a Traditional Vidya Sangha which is an open forum of traditional healers who get together and share knowledge of their respective fields. He was writing a book about the various techniques used in bone setting along with case studies/success stories. While he did not have a formal degree/certificate for traditional bone setting, in his 37 years of service he had never been asked for these credentials. Participant 2 completed a basic high school education, while learning Kalari, a traditional martial art and traditional bone setting from his father as his apprentice. As mentioned, he had a licensed martial arts academy which included students who learn Kalari and traditional medicine and he went through a rigorous process with the sports counsel to acquire and maintain this license. His students were expected to master Kalari first before they learned traditional bone setting practices as he believed that it set the foundation on which to learn more. They learned human anatomy, movement, and kinesiology and built the mental and physical strength required to do the procedures. He participated in the World Ayurveda Congress in New Delhi and was involved in research about medicinal plants and Kalari. He also was a member of an association of traditional bone setters who met monthly for conferences where they shared their skills, methods, and cases. He had a certificate from this association, but no other formal credentials. He was a Gurukul or disciple of Kalari. Many of his patients referred to him as "doctor" but he told them that he was simply "Vaidyar" or "Traditional Healer". Participant 3 acquired his skills from his father, and in turn imparted them to his children. His education was through the "gurukula" system where the "guru" imparted his knowledge to a "shisya" or student, and in turn the student's duty was to be a guru to the next generation. It was a sacred relationship and was how most traditional medicine practices were passed down. He learned TBS this way and had over 30 students/ apprentices whom he mentored over the years. He always was learning new things from them, as well as from other bone setters and believed that continuous learning was the only way to improve one's skills. Participant 4 learned this tradition as an apprentice and had several students including his own children. He was a member of several associations of bone setters and other traditional healers, as well as associations related to ayurvedic medicine. He served on a forestry department board and taught others about medicinal plants. He had a certificate from FRLHT endorsing his status as a traditional healer and received many awards for his service. He had been consulted by many because of his knowledge of medicinal plants. Participant 5 had a bachelor's in science and education. When he was a young college student, he would assist his father at the TBS clinic after class. It initially was a hobby to him, but he found that he had a passion for it. Participant 6 studied civil engineering for a few years but due to the death of his father he had to stop his college education. He expressed some regrets about not completing his degree. He apprenticed with his uncle from the age of 4 and began independently practicing as a TBS at age 25. He was certified in "varma" which was an Indian traditional art of vital points and "marma" which was a special massage technique. He traveled to Thailand where he participated in workshops about these techniques. At Vivekananda Kendra in Kanyakumari, which was a social and religious organization, he was a respected teacher of marma where he had taught more than 5,000 students. He had a certificate from the Red Cross Society and from FRLHT endorsing his status as a traditional healer. He was awarded an honorary doctorate for his expertise in marma. He had several apprentices, who undergo a screening process which involved teaching them how to "behave" like a vaidyar, by abstaining from alcohol and tobacco. He had both male and female students, and the bulk of the education was hands-on learning in the clinic. There was some didactic teaching for which he used ancient manuscripts written on palm leaves, as well as modern textbooks on ayurveda. He also taught them how to collect medicinal plants and to make them into preparations used for treatment. He claimed this was the "weed-out" exercise for his students as many do not want to go through the trouble of foraging for plants. He was a student of "Silambam", a weapon-based Indian martial art originating in South India and taught it to his students. He founded an organization to unite Indian folk healers including tribal healers. They participated in knowledge exchange forums periodically and formed a co-operative trust. He received several awards by the state bio-diversity board for his work. He envisioned an academy on 400 acres of land that they have acquired through this trust, where students will receive a rigorous education from age 4 to 18. After which, students may stay and teach or leave and serve their communities. About 90% of people treated by Participant 1 lived in poverty. He saw approximately 200 patients a month. Medical students have visited him for treatment, but once they finish their studies, he thought they developed "an attitude" and no longer visited him. However, there was a primary care doctor in their village who sent patients to him and his brother. His charges were between Indian Rupees (INR) 100 - 500 (based on the current exchange rate = $1.33 - $ 6.66), but if someone could not afford it, he would not only treat them for free, but also give them food and bus fare. Hence, a sub-theme of cost of treatment was developed. Participant 1 was confident that his son will continue this charitable work despite growing up and living in a more capitalistic society. Participant 2 did not provide an estimate of his patient volume but as his popularity increased by word-of-mouth advertising, he saw more patients. He made house calls and traveled considerable distances if his services were requested. His fees were in the range of INR 100 - 500, though he sometimes asked his patients to buy some of the items such as bandages and herbs, in which case he charged less. He also provided free services to patients who could not pay. Participant 3 estimated that approximately 75% of his patients lived in poverty or were lower middle class, but he also saw a few patients who were affluent. He did not have a set fee. He allowed his patients to donate what they could, but typically provided free services. He also relied on word-of-mouth advertising and had only good responses from his patients. Participant 4 saw between 5 - 15 patients a day. They were not only from his village but from many nearby towns and villages. Many of his patients came to him after they had been treated by an orthopedic surgeon, sometimes because their previous treatment was unsuccessful, and other times to supplement their treatment/recovery with herbal remedies and massage. His fees only reflected the cost of some of the raw materials in the range of INR 50 - 100 but he did not charge for his services/time. Participant 5 had the highest volume of patients of all participants in the range of 400 or more a day. He started 6 am and continued until 10 pm. He appeared to be very popular and claimed that many celebrities have visited his clinic. He had not heard a bad report from any of his patients. His fees were in the range of INR 100 - 500. However, he had an x-ray machine and charged extra for the cost of films but claimed that his prices were much lower than an allopathic facility. There were four orthopedists within a reasonable distance to his town, but people chose to go to him because of his lower cost. A large percentage of patients visited Participant 6 because they had failed treatment in other systems of medicine especially allopathic, and he was able to treat them successfully. He also gained popularity by word-of-mouth publicity. His patients honored him with gifts and considered many of his treatments to be "miracles" as many of his cases were those that modern medicine was not able to fix. He also was developing a project, funded by donations, that would enable him to provide free treatment for those who cannot afford it. Participant 1 had one clinic at his home in Puttur, as well as clinics in other locations. He also traveled to conduct bone-setting camps. He did not have an x-ray machine but many of his patients brought various imaging and radiology reports, which he sometimes used to aid in diagnosis. His approach to diagnosis was by inspection, palpation, and testing range of motion. For rib fractures, he asked the patient to breathe and inspected the chest and back. He conducted various musculoskeletal tests to test for specific joints. He diagnosed 95% of his cases by this method, although he sometimes recommended that they have an x-ray or magnetic resonance imaging for a definitive diagnosis. Aside from bone setting, he also treated kidney stone and jaundice. In general, his approach to treatment included reducing the fracture, splinting, and bandaging. He used an ointment made from several native plants, coconut oil, camphor, and other ingredients. He also gave oral herbal supplements that may have analgesic properties. For young children, he recommended only gooseberry juice. He also made a powder with ayurvedic herbs and egg-shell powder. He was not sure if this provided calcium supplementation, but it yielded good results. He made these ointments and powders on his own. Originally, these ingredients were sourced from forests, but with deforestation this has been a challenge. Some ingredients were grown on tribal lands, and others were bought at local shops. He emphasized a healthy diet as key to recovery, which included local fruits, vegetables, sesame seeds, honey, whole grains, chicken, and clarified butter. He did not recommend eating root vegetables as they seemed to increase blood glucose due to their starch content. Participant 2 had two clinics in different towns. Dislocations and fractures were the majority of cases. He believed that before he can start any treatment, gaining the trust of the patient was most important. His approach to diagnosis involved taking a thorough history. Then, he used "Darshana", which was inspection and "Sparshana" which was palpation. If a joint was dislocated, he repositioned it and wrapped it with a bandage. Fractures were reduced before dressing. He took care to make sure that the pressure point of the bandage was not over the nearby nerves. He did not have an x-ray machine at his clinic. He did not use x-rays for diagnosis as he believed that speedy first-aid and treatment will benefit the patient more than imaging. However, if the patient chose, he encouraged post-treatment x-rays. He checked "vital points" of the patients to assess their humoral status and assessed which class of medicines should work. Once the issues had been diagnosed, Participant 2 applied an oil which he made from the juice of various medicinal leaves. This juice was added to a paste of sesame oil, clarified butter, sambrani (a natural resin), and incense. Next, Participant 2 prepared an ointment with various ingredients and applied it. These medicines were custom made based on what he determined the patient needed and might include 10-12 ingredients. Next, medicinal leaves were applied before splinting and dressing. He used bamboo sticks and coconut palm stalks as splints. He also sometimes used a wood ruler to splint. They were held in place with cloth bandages, and knots were placed strategically based on the nature of the injury (Figure 2). The dressing was changed every 3-4 days. The ingredients in his preparations were sourced from forests and shops that sold folk medicine. As availability of certain ingredients have dwindled, he has altered some of his recipes. He helped patients with the traditional medicine methods of physical therapy. He advised patients to drink goats' milk, and to consume a broth made from mutton bones, especially the bone marrow and believed that the collagen helped with faster recovery. He emphasized a healthy diet and active lifestyle. For pain relief, he did not recommend allopathic over-the-counter medicines, but instead recommended a tea made with ingredients that included nuts and seeds. Some patients took acetaminophen if they could not handle the pain, however, he did not prescribe it as it is illegal for him to prescribe Western medicines. Participant 3 believed it was important to gain the trust of his patients before treating them. Inspection and palpation were also the mainstays of his approach to diagnosis. He used a soft cotton bandage to treat fractures and dislocations. If the pain was unbearable, he asked patients to consult an allopathic doctor. Massage and physiotherapy were part of his treatment. Besides TBS, Participant 4's scope of practice included treating gastrointestinal ailments, asthma, fistulas, and abnormal vaginal discharge. He ran his clinic out of his home. Diagnosis involved inspection and palpation. Range of motion and special tests further localized the injury. Treatment included oil massage, which aided in reducing the dislocation or fracture. He used bamboo sticks to splint and tied it with a cotton cloth bandage. It required a series of dressing changes. He also gave patients supplements prepared mostly from plant-based products. Some ingredients used in his remedies were bought from local markets, some were sourced from nearby forests, and some were cultivated on his own land. Participant 5 had a busy clinic in which he treated a wide range of fractures and dislocations. He began with inspection, then palpation to diagnose a problem. He had an x-ray in his clinic to aid in diagnosis. He used sandbags to stabilize a fracture if needed. He also used an oil that he concocted using herbal ingredients to massage the affected area. He then applied another herbal preparation. He believed that these help in reducing swelling and pain and have antibiotic properties. He sourced these plants from his native village, which he visited 2-3 times a year. His relatives who lived there collect these plants from the forests and dry them. Some items were bought from local shops. He used eggs in his bandage, but it was unclear as to what the exact purpose was. His treatment included physiotherapy, and he prescribed over-the-counter calcium and multi-vitamin supplements. He emphasized following a healthy diet that included whole grains and adequate protein. He was emphatic about eating no white rice. Participant 6 treated not only fractures and dislocations, but also kidney stones, liver cirrhosis, and uterus related issues. He has had clinics in several locations, but his current clinic was acquired from a grateful patient who was a retired military captain. Participant 6 had treated the captain's psoriasis, and the grateful captain converted a piece of land under a trust and gifted it to him for his clinic. His treatment was focused mainly on marma points. Marma points are specific anatomical locations in the body through which the energy of these elements is believed to flow. Marma points therapy is the practice of stimulating these spots through gentle massage therapy. Participant 6 asked the patient to lie supine and palpated these points with his fingers which helped him identify fractures, spinal problems, and other conditions. He also used gait to make a quick initial assessment, specifically when they walked into his clinic. There are specific marma points to relieve pain at particular sites, and he claimed to be able to relocate the pain site. For instance, pain from the hand could be transferred to the spinal region and from there it could be relieved. This "vayu" point in spine stimulation was his "style" and it was known colloquially as Vayukkalam, one who treats using the vayu point. He also used pulse points to aid in diagnosis. When a patient first comes to Participant 6, his primary objective was pain relief. He did not use x-rays in his diagnosis, but his patients were free to get one if they chose. Based on the injury, he used bamboo stick splints and bandages. For smaller bandages, he used stalks of a pine tree and sometimes parts of the coconut leaf. Most of the time, he used a gauze bandage. For a typical wrist dislocation, he provided pressure to a particular point at the palm and the fingers were pulled to reduce it back in place. He even used ice cream sticks as splints for some cases. He poured a generous amount of oil called kaya thirumeni, made from herbs on the skin, which aided in reducing inflammation. Some oils were ingested, along with Arishta or Asava so as to overcome the gastric uneasiness of consumption of a strong oil. His ingredients were of both plant and animal origin and he believed that all parts of plants and animals were useful. He sourced most ingredients from local markets, and from some local tribes. He also procured items from folk medicine raw drug shops as well as forests and villages. He was experimenting with growing certain plants indigenously and collaborating with a group to cultivate them. Participant 1 did not treat humoral neck fractures as it had a high risk of avascular necrosis. He also did not treat spinal cord injuries. These cases were sent to allopathic hospitals. If he had anything more than a 10% lack of confidence in a particular case, he allowed them to decide if they wanted to continue with the treatment. Patients who consumed excessive alcohol or smoke and those with diabetes, hypertension, and other chronic problems were challenging and did not heal well. He faced considerable bias from the modern medical community. He believed that if people were patient and gave natural remedies a chance, they would be surprised at the favorable results. He would like to expand the Traditional Vidya Sangha to include allopathic doctors and envisions more collaboration. He accepted that there were TBS who were untrained and gave their community a bad reputation. He had been instrumental in organizing training programs for those interested. Participant 2 regretted to say that while he has had great success, he also had a few failures. He speculated that it was perhaps a mistake he made, but sometimes cases were complicated, or patients were allergic to certain items in the herbal remedies. He also knew his limitations and did not treat cases of cardiac arrest, patients receiving cancer treatment, or immunocompromised patients. In such cases, he might administer first-aid, then referred them to an allopathic hospital. If he thought that the patient could not afford to go to a private hospital, he sent them to a government hospital. He faced several challenges as a TBS. For example, it was difficult to procure certain rare ingredients. He was saddened by the lack of support from the Indian government. They did not provide any recognition, certification programs, or support. He had treated the chief minister of his state and other traditional healers with good success, but they did not do anything to advance their cause. He believed that TBS uses a holistic approach and healing was designed for the whole mind and body. He regretted that many traditional healers simply took their skills and knowledge to their grave as there was no documentation or official system to pass on this knowledge. He believed that TBS were relevant in India, where a large portion of the population lived in poverty or did not have access to modern medical care. There was a lot of politics between folk healers, ayurvedic doctors, and modern allopathic physicians and he wished that there was more collaboration. Participant 3 remarked that cancer was a challenge, and he was interested in finding a medicine for this disease. He did not hesitate to refer a patient who required care that was beyond his expertise. The patient was the focus and pride should not cloud judgment. He found that patients have been more appreciative to him for guiding them to appropriate treatment, rather than regarding it as a failing on his part. He also echoed the thoughts of other TBS regarding government support. He did not care much about having a certificate to hang on a wall but wanted to legitimize folk medicine, so practitioners have good training and treat patients safely. Participant 4 did not treat fractures with open wounds as he believed that needed to be handled in a sterile way, including sutures and internal fixation. He also did not have the confidence or expertise to treat head injuries. These cases were referred to an allopathic hospital. He also lamented about the lack of government support. He knew of several TBS who were very poor and did not have money to produce the raw materials for treatment. He wished that government would allow TBS to grow plants and be self-supporting. Participant 5 referred complicated cases, especially multiple fractures and open wounds. He echoed the thoughts about government involvement. Participant 6 let his patients know if he found that the case was too complicated and gave them the choice to visit other practitioners/other disciplines of medicine. Some of his challenges regarded procurement of raw materials. Many species of native plants have become impossible to find because of invasive species that have been introduced. For example, a factory in their area planted easy to grow plants which have destroyed the normal flora. He also would like to collaborate with ayurvedic and allopathic practitioners and envisioned an India in which folk healers were respected and supported.

india, bone and bone tissue, orthopedics, qualitative research, traditional medicine

PMC9055255_01

Female

A 73-year-old woman was urgently admitted to the Department of Internal Medicine and Clinical Pharmacology due to shortness of breath, fever, cough, and exercise intolerance. The patient denied direct contact with SARS-CoV-2-infected person in the last 14 days. However, she was not vaccinated against COVID-19. Medical interview showed symptoms of hypertension, diabetes type 2, hyperuricemia, chronic kidney failure in stage G3a according to Kidney Disease Improving Global Outcomes (KDIGO) and paroxysmal atrial fibrillation. Due to the coexistence of comorbidities, the patient had been ordered the following: ramipril, amlodipine, acetylsalicylic acid, chlorthalidone, glimepiride, spironolactone, metformin, allopurinol, and bisoprolol. In the physical examination on admission, temperature of 36.1 C, blood pressure of 110/60 mmHg, respiratory rate of 24/min, and blood oxygen saturation of 81% were observed, and during lung auscultation, bilateral crackles, wheezing, and decreased respiratory sound in the base parts of lungs were examined. In the electrocardiography, atrial fibrillation with a ventricular rate of 100-130/min was observed. The examination revealed dyspnoea, tachypnoea, and increased work of additional respiratory muscles. Laboratory tests showed white cells count 16.89 x 103 cells/microL (reference range, 4-10 x 103 cells/microL) with neutrophilia (92.4%) and lymphopenia (5.6%), hemoglobin count 8.5 g/dL (reference range, 11.5-15 g/dL), hematocrit 27.9% (reference range, 36-46%), platelets count 332 x 103 cells/microL (130-400 x 103 cells/microL), C-reactive protein concentration 34.6 mg/L (reference range: 0-5 mg/L), procalcitonin concentration 1.02 ng/mL (reference range: <0.5 ng/mL), interleukin-6 concentration 24.3 pg/mL (reference range: <7 pg/mL), serum creatinine concentration 1.06 mg/dL (reference range: 0.51-0.95 mg/dL), GFR MDRD: 54.01 mL/min (reference range: >60 mL/min), D-dimer concentration 1,040 ng/dL (reference range: <500 ng/dL). ABG showed pH 7.31 (reference range: 7.35-7.45), pCO2 44.3 mmHg (reference range: 35-46 mmHg), pO2 53.3 mmHg (reference range: 70-100 mmHg), SpO2 83% (reference range: >96%), lactate 3.15 mmol/L (reference range: <1.8 mmol/L), base excess (BE) 4.2 mmol/L (reference range: (-2) to 3 mmol/L), and 21.9 mmol/L (reference range, 21-26 mmol/L). Electrolytes, liver enzyme concentration, coagulation, and clinical urine tests were normal. Due to reported symptoms and laboratory results, COVID-19 was suspected. In order to assess the severity of pneumonia, it was decided to perform lung HRCT. In HRCT bilateral, superimposed air space consolidations with GGO in lowers and uppers lobes, more marked on right were described. Moreover, thickening of the interlobular septa was observed. There were mediastinal hilar lymphadenopathy and bilateral pleural effusion. The lesions accounted for 48% of the lungs. These HRCT findings were described as typical for COVID-19 pneumonia with a moderately advanced British Society of Thoracic Imaging (BSTI) score (Figure 1). A nasopharyngeal swab sample for SARS-COV-2 was collected three times: two times for antigens tests and one for RT-PCR test. Both antigen tests and RT-PCR tests were negative. Microbiological and mycological blood cultures and sputum cultures were performed. Additionally, there were taken blood tests for the presence of IgM and IgG antibodies for Mycoplasma pneumoniae, Chlamydophila pneumoniae, SARS-CoV-2, Influenza A, B, and Respiratory Syncytial Virus, but they were all negative. Also, abdominal ultrasound examination and echocardiography were performed. No other outbreaks of potential infection were detected. Before the results of the laboratory tests were obtained, due to the severe clinical condition, empirical therapy was introduced using ceftriaxone, levofloxacin, low molecular weight heparin, dexamethasone, budesonide, and ipratropium bromide. Due to increasing respiratory failure despite oxygen therapy given and deteriorating results of ABG (pO2: 45.4 mmHg, SpO2: 79%) anesthesiologist's consultation was performed. Prone position and switch type of oxygen therapy to high flow oxygen delivery 60 L/min FiO2: 0.9 was recommended. Moreover, it was recommended to take a nasopharyngeal swab in the SARS-CoV-2 infection one more time, and until the result is obtained, the patient should be treated like a COVID-19-positive person. Recommended procedures improved saturation of patient to 98%; however, this next swab was also negative. Despite the suggestions of anesthesiologists, remdesivir and tocilizumab were not included in the treatment, suspecting other than viral etiology of pneumonia. In the cultures following results were obtained: blood and urine were negative, whereas in sputum Candida albicans and Candida glabrata were identified. They were sensitive to fluconazole, amphotericin B, caspofungin, and micafungin. The antifungal drug Fluconazole 200 mg daily per os was added to therapy. During further hospitalization, improvement in the general state of the patient was observed. Oxygen therapy was gradually reduced. Atrial fibrillation was converted to regular sinus rhythm with ventricular action of 65 beats per minute. On the 10th day, the shortness of breath was not observed, and the patient did not require oxygen therapy (SpO2, 94%). Auscultation of the lung revealed a reduction of crackles and wheezing; the symmetrical respiratory sound was the dominant one. Laboratory determinants of inflammation were normalized. The control chest HRCT showed full withdrawal of inflammatory changes and regression of pleural effusion (Figure 2). At the base of the lungs, fibrous-atelectasis changes were reported. The patient has been discharged from the hospital in a good general condition without any complaints and continued outpatient treatment with fluconazole.

covid-19 pneumonia, differential diagnosis, fungal pneumonia, high-resolution computed tomography

HRCT scans on hospital admission: bilateral, superimposed air space consolidations with GGO in lower and upper lobes, more marked on right are described.

PMC3703707_01

Male

A 43-year-old man was referred to the Department of Stomatology at the Heliopolis Hospital by a private dentistry complaining oral lesions. The lesions were asymptomatic and oral examination revealed ulcerative areas with granulomatous bed affecting the gingival papillae between lower central incisors, partially covered by a pseudomembranous material [Figure 1]. On physical examination, no regional and extra-regional lymphadenopathy or organomegaly was detected. His medical history includes episodes of dry cough, costal pain, and weight loss under medical investigations. The chest radiography [Figure 2a] and computed tomography scan [Figure 2b] of the thorax have revealed a diffuse infiltrate of nodular and linear/irregular coalescent opacities, distributed throughout both lungs [Figure 2]. The hypothesis of tuberculosis has been discussed at that moment in spite of negative results for acid-fast bacilli from sputum and culture. The CD4/CD8 lymphocyte count and rate were normal. Tests for human immunodeficiency virus (HIV) were negative. Among the requested serological exams, it has been found antibodies against H. capsulatum on immunodiffusion test. However, culture and histology of the specimens obtained by bronchoalveolar lavage failed to confirm the presence of fungi. Thus, the patient remained under this medical investigation without any specific treatment plain at that moment, in which the patient was evaluated by a private dentist complaining the gingival lesions described previously. We conducted the case performing an incisional biopsy of the oral lesion. Routine sections show fragments of squamous mucosa with a marked granulomatous infiltrate composed by Langhans-type multinucleated giant cells interspersed with extensive macrophagic infiltrate with variable amounts of lymphocytes and neutrophils [Figure 3a]. Staining slides with Grocott-Gomori methenamine silver, scarce oval structures with apparent single budding, measuring 3-5 mm in diameter were found suggesting histoplasmosis [Figure 3b]. A specimen was collected with a swab from the base of lesion and sent to culture. In slide culture preparations, hyaline and septated hyphae producing numerous thick-walled and tuberculated macroconidia were also consistent with histoplasmosis [Figure 3c]. The incubation of this material on Sabouraud Dextrose Agar at room temperature by 3 weeks was sufficient to reveal the typical growth pattern of H. capsulatum, which consists of white to brownish filamentous colonies on the slants [Figure 3d]. The patient was treated with Itraconazol 200 mg, given 6 times/day, reducing to two tablets per day after the 3rd day until the condition improves [Figure 4]. After 6 months of control the patient was referred again to his private dentist for periodontal and restorative treatment plain.

diagnosis, histoplasmosis, multidisciplinary communication, oral

PMC5253166_01

Female

An 8-year-and-1-month old Caucasian female presented to her pediatrician with complaints of nocturnal enuresis and hyperactivity. Child was adopted at 2 years of age along with her younger sibling due to history of parental neglect by biological parents. Adoptive parents reported hyperactivity as a major concern. Physical examination revealed her weight to be 24.8 Kg (25th percentile for age) and height to be 128.7 cm (35th percentile for age). Vitals were stable and blood pressure at presentation was 113/75 mmHg. A comprehensive neurologic exam by her pediatrician revealed fine tremors in the upper extremity. Laboratory workup was initiated and a comprehensive metabolic panel revealed sodium (Na) of 124 mEq/L. She was referred to our medical center for comprehensive evaluation. Initial exam revealed an otherwise healthy child who was alert and oriented in time, space, and person. Vitals including blood pressure were normal for age. Admission chemistry and other laboratory values are shown in Table 1. While the causes of hyponatremia can be extensive, her presentation was consistent with euvolemic hyponatremia suggestive of Syndrome of Inappropriate Antidiuretic Hormone (SIADH). Evaluation by us confirmed our impression of SIADH with serum Na of 123 mEq/L, serum osmolality of 264 mOsm/Kg (ref range 280-300), and urine osmolality of 614 mOsm/Kg (300-900). Adrenal function as assessed by early morning cortisol of 8.6 mcg/dL and thyroid function tests were normal. Magnetic resonance imaging of the brain demonstrated asymmetric T2/FLAIR hyperintense, nonenhancing enlargement of the right hypothalamus, concerning for a hypothalamic glioma (Figure 1). Other workups including ultrasound of abdomen, pelvis, chest X-ray, and a PPD (purified protein derivative) skin test to rule out tuberculosis were essentially negative. Initial management consisted of fluid restriction, furosemide (at a dose of 2 mg/Kg/day divided into three doses), and salt and potassium chloride supplementation. Though this resulted in her Na levels gradually improving to a maximum value of 130 mEq/L, the fluid restriction regimen was very difficult to follow and family expressed ongoing frustration. Given limitations for treatment options in treating children with SIADH and with Na levels trending down (range: 121-124 mEq/L), we initiated Arginine Vasopressin (AVP) V2 receptor antagonist therapy with oral tolvaptan. Current literature is lacking data on use of these agents in children. So tolvaptan therapy was started at a dose of 7.5 mg under close supervision in the inpatient setting. The dose initiated was half of the lowest approved dose in adults which is 15 mg. Initial response to therapy was dramatic in terms of correction of hyponatremia, with Na improving to low 130 mEq/L range. With initiation of tolvaptan therapy, her Na levels improved allowing us to loosen our recommendation on water intake to a maximum of 2.5 L/day. Liberalization of fluid intake with this regimen seemed to help the family initially. Gradually though, Na levels trended down because her water intake was much more than her urine output with the therapy (Table 2). Child psychology and later child psychiatry were involved to help family and child be compliant with the fluid restriction. Dose of tolvaptan had to be increased gradually to a maximum of 30 mg daily. In an effort to keep the Na levels up, water restriction to 2.5 L/day was encouraged. But even this degree of fluid restriction proved to be difficult as she developed compulsive drinking behaviors. She would sneak water from bottles in trash cans, bathtub, faucet, and even toilets. With ongoing management issues due to behavior problems and recent black box warning issued by the Food and Drug Administration (FDA) for liver failure in patients on long-term therapy, decision was made to wean tolvaptan. She was weaned off V2 antagonist therapy over a period of 6 months. While her persistent hyponatremia was concerning, the limited benefits we were observing with treatment and the potential side effects led us to make this decision. Following this, patient was briefly on oral furosemide, which was eventually discontinued as long-term furosemide is known to exacerbate chronic hyponatremia. She was also noted to develop hypertension with blood pressures ranging around 140/106 mmHg requiring input from pediatric nephrology during the course of her treatment. She was initially started on amlodipine 2.5 mg twice a day but needed the addition of enalapril maleate in 4 months due to poor control of her blood pressure. She is currently on amlodipine 2.5 mg twice a day and enalapril 10 mg twice a day. Secondary causes of hypertension were ruled out by pediatric nephrology team. While hypertension was noticed after initiation of therapy, this is not a reported side effect of V2 receptor antagonist therapy. Her hypertension continued after she was weaned of tolvaptan therapy. It is unlikely that the hypertension was caused by volume overload as her weight continued to be stable. Etiology of hypertension is unclear as preliminary workups including renal ultrasound and renal Doppler were all within normal limits. A complete neuropsychological assessment revealed IQ to be low normal. Patient had reading, attention, and auditory processing problems making school more challenging for her. She had no difficulties in doing grade level mathematics and spelling. These contributed to ongoing difficulties at school. Due to the well-known determinant effect of hyponatremia on bone health, DXA scan was done which revealed Z-score of -1.8 at AP spine and -1.1 at total body less head region. Since she never suffered from any pathological fracture, education was provided to optimize calcium and vitamin D intake. 25-Hydroxyvitamin D levels checked periodically were always in the sufficient range (>30 ng/mL). Currently, she is off all pharmacological therapy for her hyponatremia and her sodium levels range within 113-118 mEq/L. Fluid restriction is encouraged but not very strictly enforced due to fear of her developing unhealthy drinking habits. She is performing at age appropriate level in school. Regular monitoring for endocrinopathies by stimulation testing has so far been normal.

PMC10129352_01

Female

A 79-year-old woman was referred from another hospital for full-thickness RP measuring 4 cm in length (Figure 1a). She had a habit of straining hard during defecation and had a history of seizures, stroke, subarachnoid hemorrhage, and spondylosis. Considering the patient's age, comorbidities, and preferences, we decided to perform the GMT procedure. The surgery was performed under general anesthesia in the lithotomy position 13 weeks after the first visit due constraints brought about by the coronavirus disease 2019 (COVID-19) pandemic. Intraoperative evaluation revealed that the RP had worsened to >10 cm in length (Figure 1b). The GMT procedure was performed as previously reported, and CV-0 suture (W. L. Gore and Associates, Inc., Elkton, MD) was used as material for the Thiersch procedure. The patient did not develop serious postoperative complications, such as bleeding, perforation, or pelvic abscess. However, 3 weeks after surgery, RP recurred due to loosening of the Thiersch suture. Therefore, an additional CV-0 suture was placed under local anesthesia 5 weeks after the first surgery. Unfortunately, the ligature has also loosened 1 week after reinsertion of the CV-0 suture, and RP recurred. Thus, laparoscopy-assisted suture rectopexy was planned as a third surgery. Nevertheless, due to the outbreak of a new variant of COVID-19, surgery was performed 17 weeks after the initial GMT procedure. Figure 2a-d show a laparoscopic view during rectal mobilization:with marked edema and rough and membranous adhesions noted in the retrorectal space:between the fascia propria of the rectum and the pre-hypogastric fascia, especially above the upper layer of the rectosacral fascia. In contrast, no adhesions were noted on the serosal side of the rectum. The postoperative course was deemed favorable, and the patient is currently under follow-up. An abdominal-pelvic CT was performed 13 weeks after the initial GMT procedure to assess the perirectal fat tissue using the SYNAPSE VINCENT software (Fujifilm Co., Tokyo, Japan). The CT attenuation values around the rectum were analyzed by drawing an elliptical region of interest and compared with those recorded in the abdominal subcutaneous fat (Figure 3a, 3b). The CT attenuation values were found to be higher in the mesorectum versus the subcutaneous fat, especially in the posterior area of the mesorectum (P < 0.05) (Figure 4a, 4b). Such an increase in CT attenuation value was not observed except around the rectum where the GMT procedure was performed.

gant-miwa-thiersch procedure, mesorectum, rectal prolapse, rectopexy, retrorectal space

PMC8051228_01

Female

A 45-year-old female patient who presented with a vulvar ulcer for one year without other symptoms. She was HIV infected with CD4+ of 291 cells/muL on highly active retroviral treatment. She was previously treated for pulmonary tuberculosis for six months. She had no other co-morbidities or family history of malignancy. On examination, she had good performance score. The abdomen was soft with right inguinal lymphadenopathy. Per vaginal examination revealed an ulcerated nodule on the right labia majora extending from the right labia minora into the right lower 2/3 of the vagina. This lesion was close to the anal sphincter, but did not involve the pelvic bone. It was draining foul smelling dark discharge. She did not have pigmented lesion/nevus on any part of the body. A biopsy of the ulcer showed malignant melanoma. The patient was counselled about the disease and the prognosis thereof. She was further investigated for extent of the disease and possible metastasis. The chest X-ray (CXR) was unremarkable (Figure 1A). The Magnetic Resonance Imaging (MRI) revealed a vulvovaginal tumour which pushed the uterus superiorly. It did not show bladder or rectal involvement (Figure 1C). Computed Tomography (CT) showed pelvic lymph nodes metastasis (Figure 1D). The full blood count showed hemoglobin of 9.2 g/dl while the rest of the blood investigation was unremarkable. She was offered pelvic exenteration but declined. A hemivulvectomy and vaginectomy with inguinofemoral and pelvic lymphadenectomy was performed. An ulcerated, multinodular and rubbery tumour measuring 90x50x25mm was received (Figure 2A, Figure 2B) with pelvic and inguinal lymph nodes for histopathological assessment. Microscopy showed a malignant nodular melanoma evidenced by an ulcerated tumour arranged in a nodular pattern without epithelial component (Figure 2C, Figure 2D). The tumour cells had pleomorphic and vesicular nuclei with prominent inclusion-like nucleoli. Intracytoplasmic melanin pigment was not seen (Figure 2E). The tumour corresponded to Clark level V and Breslow stage V. There was no brisk intratumoural lymphocytic infiltrate. The mitotic count was 15 per square millimeter. The tumour cells were immunoreactive for melanin A (Figure 2F), HMB45 and S-100 protein. Molecular studies confirmed a BRAF pV600E mutation. The tumour was present at the vaginal resection margin and 1mm from the closest soft tissue excision margins. Only 3 of the 17 inguinofemoral lymph nodes showed metastatic diseases. Post-surgically, she presented with recto-vaginal fistula after 23 days. A diverting colostomy was performed and discharged to home. She came back after a month to the gynaecology clinic with shortness of breath, weakness and pain of the lower limbs. Per vaginal examination revealed bleeding and non-healing operation side and a well colostomy. Although the biopsy was not done at this stage, a clinical diagnosis of local recurrence was made. A CXR at this point showed upper lobes nodules and left pleural effusion in keeping with lung metastasis (Figure 1B). She was referred to radiation oncology where she received palliation radiotherapy of 8 Grays and one fraction of radiation. She was discharged from oncology due to poor treatment response. She was eventually discharged home for palliation care and has since been lost to follow-up clinic.

hiv, case report, malignant, metastasis, nodular melanoma

PMC4913425_01

Female

To elucidate the pathogenesis of V. vulnificus in South Korea, a clinical strain, V. vulnificus FORC_017, was isolated from a 63-year-old woman with the symptom of a hemorrhagic rash after consuming a raw dotted gizzard shad on Jeju Island. The genome was completely sequenced and analyzed using various bioinformatics tools. In addition, comparative genome analysis of the FORC_017 strain and other clinical isolates was performed. The results of this study would provide genomic insights into the main factors associated with food-borne outbreaks and pathogenesis, and is probably useful for further control of this highly virulent pathogen in seafood.

genome sequencing, hemolysin, hybrid assembly, pathogenesis, secretion system, vibrio vulnificus, virulence factor

PMC7344129_01

Female

A seven year old girl was referred to our hospital with abdominal pain and nausea, which started two weeks ago, and she also described mild pruritus in the last week. There was slight jaundice, epigastric tenderness, and hepatomegaly on physical examination. Laboratory investigations revealed hypertransaminasemia and marked elevation in alkaline phosphatase and gamma-glutamyl transpeptidase, while total bilirubin, direct bilirubin, lipase and pancreatic amylase were slightly increased. Acute-phase reactants such as white blood cell count, platelet count, C-reactive protein, and erythrocyte sedimentation rate were markedly elevated, which were compatible with a systemic inflammation. Viral hepatitis serology was negative. The patients had hypergammaglobulinemia (serum IgG 2 710 mg/dL, upper limit of normal for age <1 682 mg/dL), and a significant elevation in serum IgG4 level (143 mg/dL, N: 1.0-108.7 mg/dL) was observed. Antinuclear antibody (ANA) and perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) were positive by indirect immunofluorescence test, whereas liver kidney microsome type 1 antibody (anti-LKM-1), anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA) were negative. Magnetic resonance imaging (MRI) of the abdomen revealed hepatomegaly with a heterogeneous parenchyma of the liver and a diffuse enlargement of the pancreas, surrounded by a capsule-like rim, and it was compatible with autoimmune pancreatitis (Fig. 1). Further radiologic investigation with magnetic resonance cholangiopancreatography (MRCP) confirmed a narrowing at the bifurcation of the common hepatic duct and mild dilatation of intrahepatic bile ducts (Fig. 1). The histopathologic examination of liver biopsy showed lymphoplasmacytic inflammation around the portal bile ducts with periportal fibrosis and mild bridging necrosis (Fig. 2). Furthermore, immunostaining of the liver biopsy revealed intense IgG, but only scarce IgG4 (+) plasma cells (8 plasma cells/high-power field). The patient was given ursodeoxycholic acid 15 mg/kg/day treatment. During follow-up, the patient reported bilateral orbital edema around the upper orbital rim and the eyelid with no pain or erythema. Orbital MRI demonstrated enlarged lacrimal glands with contrast enhancement (Fig. 1). On the second month of admission, the patient developed bloody diarrhea and underwent an ileo-colonoscopy. All colonic segments were erythematous and scattered exudative lesions were more pronounced in the distal colon. A histopathologic examination of the colonic biopsies demonstrated lymphoplasmacytic inflammation in lamina propria, cryptitis, destruction of crypts, and vasculitis. Hence, both the endoscopic and the pathologic findings were consistent with IBD, favoring ulcerative colitis. Upper GI tract endoscopy revealed erosions in the duodenum, and histopathology confirmed duodenitis with patchy lymphoplasmacytic inflammation and focally enhanced gastritis. The patient was investigated for tuberculosis and missing vaccines were completed before commencing long-term immunosuppressive therapy. Later on, treatment with intravenous methylprednisolone 1.5 mg/kg/day, oral mesalazine 60 mg/kg/day was initiated. Methylprednisolone was gradually tapered to 4 mg/day over 10 weeks. Her signs and symptoms improved dramatically, and follow-up imaging of the abdomen at the second week of treatment demonstrated complete resolution of pancreatic enlargement (Fig. 3). The initial peak of total IgG (3 350 mg/dL) and IgG4 (177 mg/dL) levels improved to 1790 mg/dL and 77 mg/dL, respectively 2 weeks later. At the 3rd month of treatment, serum ESR and CRP levels improved and returned to normal. The patient has been asymptomatic while using 4 mg/day methylprednisolone treatment, and laboratory examinations have been normal during the last 12 months of follow-up. A written informed consent of the patient is obtained.

autoimmune pancreatitis, child, immunoglobulin g4-related disease

PMC4976604_01

Female

Our patient was a 76-year-old woman from a nursing home. She had a previous left nephrectomy in 2003 for chronic pylelonephritis. Her recent medical history has been complicated by obstruction of her post nephrectomy single kidney of unknown cause. The obstruction was managed with a nephrostomy tube insertion. Her nephrostomy fell out on several occasions and had again on this occasion. She presented to the community hospital with urosepsis. She had multiple comorbidities including dementia, heart disease, chronic kidney disease, gastroesophageal reflux, osteoporosis and hypertension. She was treated with intravenous (IV) antibiotics and was referred for a fresh nephrostomy tube insertion. The procedure was complicated. The first attempt failed with the catheter seen "outside the collecting system". The catheter was removed. The second attempt was technically challenging because of the blood filling the collecting system with reduced visualization on ultrasound. They proceeded with nephrostomy tube placement and at the end of the procedure, contrast injected through the catheter demonstrated filling of the inferior vena cava (IVC). A non contrast computed tomography (CT) confirmed the pigtail formed in the IVC. It also showed a sheared wire fragment curled in the kidney (Fig. 1). At this time, a second nephrostomy was placed appropriately in the collecting system and after stabilizing the patient, they transferred her immediately to our institute. The patient was first seen by the vascular team but the surgeons were reluctant to operate because of the comorbid conditions of the patient. They consulted Interventional Radiology. It was not clear to us based on the non contrast CT and before knowing what transpired if the tube was inserted directly into the IVC past the kidney or if it was the renal vein that was traversed and the tip was advanced into IVC via the vein. On examination, the pulse rate was 102/min and the blood pressure was 124/66 mmHg. She was getting 2 L of oxygen through nasal prongs and her peripheral oxygen saturation was 98%. Her abdomen was soft and not tender. She had two nephrostomy tubes with bags attached, one of them was draining bloody urine whereas the other just had small amounts of blood with clot. An indwelling bladder catheter drained very small amount of clotted blood. The patient's white blood cell count was 36.8 x 109/L. Her potassium is slightly elevated at 5.3 mmol/L and creatinine 269 mumol/L, with normal coagulation parameters and hemoglobin of 90 g/L. Four units of cross-matched packed red cells were placed on standby. The patient was immediately taken to interventional radiology department. Vascular Surgeon was also present at the time of the procedure in case there was any significant bleeding, which there was not and she did remain stable afterwards. A substitute informed consent from the patient's son was obtained. Controlled removal of the misplaced nephrostomy catheter utilizing percutaneous intravenous balloon tamponade technique was performed according to the following procedure. The right common femoral vein was punctured using ultrasound. A 5-French pigtail angiographic catheter was inserted and an IVC venogram was subsequently performed. This showed the aberrant pigtail catheter was likely within the IVC through the right renal vein (Fig. 2a). A large compliant (Coda) balloon was placed in the peri-renal IVC (Fig. 2b). Via a left-sided common femoral vein puncture, a 7-French renal double curve sheath was inserted and the right renal vein accessed with a Cobra (C2) catheter through which a renal vein venogram was performed. It delineated the branch was most likely traversed by the aberrant nephrostomy based on where the nephrostomy traversed. A 6 x 20 mm balloon was placed across this area (Fig. 2b). Once these balloons were satisfactorily positioned, we rolled the patient upright anterior oblique in order to access the aberrantly placed nephrostomy tube. We used the second nephrostomy tube which is in the right position as a monitor and opened this up so we could see what was draining. Under fluoroscopic guidance, a wire through the aberrant nephrostomy was advanced and the wire went up the IVC. We then proceeded to inflate the IVC balloon as well as the renal vein balloon and then the nephrostomy tube was successfully retracted out over the wire. A large gush of blood then came into the appropriately positioned nephrostomy tube so this was subsequently clamped. A 5-French long sheath was advanced over the wire and a venogram of the IVC performed. This was pulled back slowly and I was able to elucidate a renogram confirming good position of my balloon. The sheath was retracted back slowly. We waited at least 10 min before deflating the coda balloon once it was determined that her blood pressure was stable throughout as well as her heart rate. The IVC Coda balloon was then exchanged out for a pigtail and did an IVC venogram which showed no evidence of extravasation from the IVC (Fig. 2c). At that point the renal vein balloon was finally deflated and repeated the venogram and again no evidence of extravasation was seen. This balloon was removed and then gradually removed the long sheath and wire. Her infection was clearing and her white count continued to decrease while in hospital. She remained afebrile on oral antibiotics. She maintained her baseline kidney function with no further gross hematuria. She was tolerating a regular diet and appeared to be at her baseline. She was discharged home uneventfully. The plan was to try to retrieve the aberrant guidewire via the nephrostomy tube tract in a couple weeks as an outpatient procedure. But unfortunately the patient died four weeks later due to congestive heart failure secondary to coronary artery disease. Percutaneous nephrostomy catheter placement is one of the most commonly performed procedure for acute or chronic upper urinary tract obstruction. Intravenous misplacement of nephrostomy catheters into the inferior vena cava (IVC) is extremely rare complication. In the literature, most of these complications were seen following percutaneous nephrolithotomy (PCNL) or nephrostomy tube exchange. The majority of these cases were treated with controlled removal in the operating room (OR) under general anesthesia in one or two steps. Surgical retraction procedures such as open pyelotomy and exploratory laparotomy have been reported. Intravenous misplacement of nephrostomy catheters is usually seen on the left side according to the literature. The pre-existing chronic infection like in our case is a risk factor for intravenous catheter migration. Patients with solitary kidney are more prone to have this rare complication. Poor visualization of the renal calyces owing to bleeding in the kidney may contribute to misplacement of the tube into the vascular system. Mazzucchi and his colleagues reported two cases of intravenous misplacement of nephrostomy catheters following PCNL. Their first case was a misplacement into the left renal vein and removed under general anesthesia in the operating room. Their second case was inadvertent placement of the nephrostomy catheter into the IVC. This catheter was repositioned in the collecting system in OR and removed 48 h later. Kotb et al. reported a percutaneous silicon catheter insertion into the inferior vena cava, following percutaneous nephrostomy exchange in the outpatient clinic. They treated this complication with open surgical pyelotomy. Chen and his colleagues reported three cases of intravenous misplacement of nephrostomy catheter following PCNL. Two of these nephrostomy catheters were placed inadvertently into the IVC and were removed under US monitoring. The third case was misplaced into the renal vein following PCNL and was removed under US monitoring with the surgical team on standby. They recommended that once intravenous misplacement is detected, the tube should be closed immediately. Then, the closed tube should be pulled back and repositioned immediately at the site of entry into renal vein under CT, ultrasound or fluoroscopic monitoring, if its tip is located in the renal vein trunk, IVC or even the atrium. The closed nephrostomy tube can be removed in the operating room under CT, US or fluoroscopic guidance. They recommended one step removal if the misplaced catheter tip is in the renal vein adjacent to the sinus after seven days. Li and his colleagues did a literature review on management of intravenous migration of urologic catheter. They added two cases of intravenous misplacement of nephrostomy catheters to the literature as well. The first one was a misplaced nephrostomy catheter following PCNL which was removed using US guidance in the OR under general anesthesia. The second case was complete intravenous migration of double J ureteric stent into the IVC which was removed from the IVC through the femoral vein. There is another case report of misplaced nephrostomy catheter in left renal vein mentioned by Tarhan et al. The nephrostomy catheter was removed by open surgery under general anesthesia by the vascular surgeon in the operation room according to their report. Dias-Filho et al. reported inadvertent renal vein catheterization and migration of the nephrostomy catheter to the right atrium during nephrostomy catheter change treated with fluoroscopically monitored removal. Wang et al. mentioned a rare case of both arterial and venous injury as well as intravenous nephrostomy catheter misplacement of the kidney at the same time following PCNL. He reported intravenous misplacement of nephrostomy catheter and subsequent pseudaneurysm formation. The nephrostomy tube was withdrawn in stages with the surgical team on standby. The pseudoaneurym was treated with percutaneous embolization successfully. In our case, balloon tamponade was very effective and minimally invasive procedure to control the bleeding from the injured renal vein and IVC. Our procedure was performed in the interventional radiology suite under conscious sedation. We were able to remove the misplaced nephrostomy catheter in one step at the same day. Alternating the patient's position between prone and supine position during the procedure was the main challenge of using endovascular balloon tamponade for removal of the misplaced nephrostomy catheter.

complication, computed tomography, inferior vena cava, nephrostomy catheter, venogram

PMC7423344_01

Female

The patient was a 64-year-old female. She was admitted because of fever and cough for 1 week. She had suffered from hypertension for more than ten years. She had been diagnosed with SLE 10 months previously because after developing a rash, which was mainly distributed in the skin, neck and both upper limbs. Meanwhile, laboratory tests showed positive results for anti-DS-DNA and anti-SSA antibody spectra. She was further diagnosed with membranous lupus nephritis based on pathological findings of renal puncture 7 months ago prior to admission. Her medications included methylprednisolone 24 mg once daily, cyclosporine 50 mg twice daily and hydroxychloroquine 0.2g twice daily, amlodipine 5mg once daily, febuxostat 40 mg once daily combined with a sodium bicarbonate tablet 0.5g three times a day, warfarin tablets 2.5mg once daily, torasemide 10mg once daily, potassium chloride 0.5 g once-daily. After treatment at a local hospital, the rash subsided. However, the urine protein of the patient remained positive, with an elevated erythrocyte sedimentation rate and hypoproteinaemia, and the patient therefore remained on immunosuppressive therapy. A physical examination revealed a weak state. Her temperature was 36.4 C on admission (maximum temperature 38.5 C), her heart rate was 85 beats/min, her respiratory rate was 18/min, and her blood pressure was 140/76 mmHg. No obvious dry or wet rales were noted in either lung by auscultation. Laboratory data showed a white blood cell count of 6360/mm3, with 92.6% polymorphonuclear cells, 4.9% lymphocytes, and 2.1% monocytes. Platelets (34*109/L) were significantly decreased. Serum complement C3 (0.69g/L) and serum albumin (23.5 g/L) were reduced. Ur Prot/UrCreat (6.51g/g) was significantly elevated. The result of anti-DS-DNA result was negative, but anti-SSA antibody spectra were weakly positive (1:32). CD3+ (348*106/L), CD4+ (168*106/L) and CD8+ (180*106/L) lymphocyte subsets had a significantly decreased. In addition, the patient tested negative for human immunodeficiency virus (HIV). The chest CT showed pneumonia in both lungs (Figure 1A). The patient was diagnosed with pneumonia, and received treatment with sulfamethoxazole and cefuroxime. The patient's body temperature fluctuated between 36 C and 38 C during hospitalization, and her pulmonary infection did not improve. It is necessary to exclude pulmonary tuberculosis and pneumocystis jiroveci pneumonia (PJP). Sputum for gram stain, culture and acid-fast smear was obtained. Culture of the sputum generated abundant normal oropharyngeal flora and Candida tropicalis. In addition, blood cultures were negative. The patient remained febrile, with a temperature as high as 39.1 C. A repeat chest CT also showed further infection in both lungs compared with that at admission (Figure 1B). A bronchoscopy with BAL was performed. Purulent secretions were observed and a sample was taken from the left upper lung. A large amount of mould was also isolated in large amounts from the BAL fluid. BAL fluid stained with Gram, fluorescence and hexamine silver stains showed the presence of somewhat dichotomously branching septate fungal hyphae (Figure 2A-C). The GM results in the BAL and serum were 1.85 mug/L and 0.89 mug/L, respectively. According to the latest guidelines for invasive fungi, the GM results indicated the presence of fungal infection. Sulfamethoxazole and cefuroxime were discontinued and a new regimen of micafungin (150mg/d) and ganciclovir was initiated. The patient began to defervesce but the repeat chest CT also showed further infection in both lungs (Figure 1C). The patient died 10 days later. No autopsy was performed. The purulent secretions were cultured on Sabouraud dextrose agar (SDA) (Emmon's modification) and on SDA with chloramphenicol at 28 C.The fungus grew at 28 C on SDA and on SDA with chloramphenicol. No growth was observed on Mycosel agar. Fungal morphology stained with Medan lactate showed a branching mycelium. Conidial terrier grew from the side ends of hyphae and formed a short broom at the top. The stem of the bottle was in the shape of a bottle. The conidia were spherical or elliptic (3-6 mum in diameter) (Figure 2D). The organism had white-coloured villiform and produced a slight yellow pigment on the reverse side, showing that had the most pronounced growth at 5 days on potato dextrose agar (Figure 2E). Notably, the organism developed a purple pigment on the reverse side after 14 days of growth on potato dextrose agar (Figure 2F). Attempts to identify the fungus were unsuccessful by morphology and the MALDI-TOF-MS system. The isolate was identified by sequencing using primers (ITS1: 5'-TCCGTAGGTGAACCTGCGG-3'; ITS4: 5'-TCCTCCGCTTATTGATATGC-3'). The mould was later identified as P. janthinellum by its DNA sequence. Antibiotic susceptibility testing was performed using a microdilution technique (CLSI M38-A2) (Clinical and Laboratory Standards Institute, 2008). Antibiotic susceptibility profiles showed that this strain had higher minimum inhibitory concentrations (MIC) values in response to many antifungal drugs (Table 1).

bal fluid, penicillium janthinellum, sle

The chest CT showed nodules and patches in the upper lobe of the left lung on admission.

PMC4746846_01

Male

A 53-year-old asthmatic male with a previous history of carcinoma of tongue subjected to left hemiglossectomy with suprahyoidal neck dissection 10 years back, was presented with right cervical lymphadenopathy and fever. He was normotensive and euglycemic. He denied of any weight loss, night sweats, and cough. Sputum examination was negative for acid-fast bacilli (Mycobacterium tuberculosis). C-reactive protein was negative and ultrasonography of neck had showed multiple bilateral cervical lymphadenopathy. Suspecting it to be metastatic disease, a whole body F-18 FDG PET/CT was performed which showed metabolically active cervical, mediastinal, abdominal, pelvic, left inguinal and femoral lymph nodes [Figure 1]. Diffuse low-grade uptake noted in the region of soft palate, base of tongue, and valleculae was considered to be physiological. The pattern of increased FDG uptake is not typical for squamous carcinoma for head and neck metastasis and so it raised the possibility of lymphoma. FNAC showed the Ziehl-Neelsen staining to be strongly positive for acid-fast bacilli [Figure 2]. Tuberculin skin test was positive (15 mm induration after 48 h). The patient was started on first line antitubercular medication. Six months later after the initiation of therapy, a follow-up whole body F18-FDG PET/CT scan showed a significant resolution of previously FDG avid lymph nodes but for residual hypermetabolism at right cervical level I, right paratracheal and right axillary lymph nodes [Figure 3]. The maximum standardized uptake value (SUVmax) of different lymph nodes before and after therapy is depicted in Table 1.

18fluorine-fluoro-d-glucose, lymphoma, tuberculosis

PMC3937271_01

Female

A 65 year old female presented to our hospital with complaints of breathlessness on exertion and right sided pleuritic chest pain lasting for one year. There was also a history of off-and-on low grade fever and dry cough but no hemoptysis. She also had significant loss of appetite and weight loss of around 10 kg in the past one year. Her symptoms had increased in severity in the past three months. Ten months earlier she noticed a nodular swelling in the right upper quadrant of her breast followed by involvement of the left upper quadrant. Swelling was painless, non-tender, and mobile. This was followed by the appearance of cutaneous nodules in the inguinal region. In the course of time, the breast lesions turned hard and the overlying skin ulcerated. On examination of the breast, a serosanguinous type discharge was present at the ulcer site. The patient was a non-smoker and non-diabetic. There was no history of tuberculosis or any other illness in her past. However, the patient's daughter died of endometrial cancer at the age of 42 years. There was no other history of malignancy in the family. On examination, the patient's general condition was poor. General physical examination, cyanosis, clubbing, lymphadenopathy, or edema. Local examination of the breast revealed bilateral enlarged breasts along with ulcerating lesion over the right and left upper quadrants with serosanguinous discharge and underlying mass 3 x 3 cm in size. Mass was fixed to the overlying skin and was non-tender on palpation. There was no axillary lymphadenopathy. There was another 2 x 2 cm painless non-tender nodule present in the midline below the umbilicus in the right inguinal region fixed to the skin and the surrounding skin was puckered. Chest examination revealed decreased air entry with few crepitations present on the right side. Cardiovascular system and abdominal examination revealed no abnormality. Complete blood counts revealed: hemoglobin - 8.4 gm%, total leukocyte count -19280 cells/cumm, differential leukocyte count - polymorphs 92%; lymphocytes 6%; monocytes 1%; eosinophils 1%, and platelets - 3.77 lakhs per cumm. Ertyhrocyte Sedimentation Ratio (ESR) was high at 113 mm in the 1st hour. Kidney function tests and liver function tests were within the normal limit. Chest X-ray was suggestive of a well defined consolidation of the right lower lobe with pleural effusion. The patient was carrying an extrahospitalary PET-CT scan, which revealed a soft tissue density mass with increased Fluorodeoxy Glucose (FDG) uptake and central necrosis involving the lower lobe of the right lung, 4.6 x 2.8 cm in size, abutting the oblique fissure. Contiguous thickening with mild FDG uptake was seen extending along the oblique fissure to the periphery. An irregular pleural based consolidation with interspersed air bronchogram showing mild peripheral uptake and central necrosis was seen in the right lower lobe adjacent to the mass lesion. A few irregular infiltrates were also seen in the adjacent lung parenchyma with mild right sided pleural effusion. Induced sputum for acid fast bacilli tested negative. Fine needle aspiration cytology from the breast lesion showed clusters of malignant cells with the morphology not very clear. Further marker for breast cancer, the CA-15-3 level was normal at 30.08 [normal range: 0-35]. Pleural fluid analysis was done, which showed 80 cells, P60 L40, sugar - 7 mg%, proteins - 3.6 gm%, and Adenosine Deaminase (ADA) - 34. Cytology revealed atypical cells with squamous differentiation in the necrotic background. Later an excisional biopsy of the breast lesion showed moderately differentiated squamous cell carcinoma, likely metastatic in origin (Fig. 1). A decision regarding CT guided lung biopsy was made and it revealed moderately differentiated squamous cell carcinoma of the lung (Fig. 2). Ultrasonography of the abdomen revealed an enlarged liver 17.5 cm in size, two hypoechoic lesions of 1 x 1 cm noted in segment III of the left lobe of the liver, another 2 cm hypoechoic lesion noted in segment VI, and two 1 cm hypoechoic lesions in segment VII. Ultrasound of the thyroid gland showed that there is evidence of multiple heterogenous hypoechoic nodules in the right lobe of the thyroid with one of them showing peripheral calcification, the largest measuring 1.7 cm in size, with peripheral vascularity. An excisional biopsy of the inguinal nodular lesion was also done and it was suggestive of moderately differentiated squamous cell carcinoma. The patient was started on conservative treatment including oxygen inhalation via mask, injectable antibiotics, and general care of nutrition. A decision regarding her transfer to the oncology department was made but the patient's condition was deteriorating. Finally, owing to severe respiratory distress and cardio-respiratory collapse, she succumbed to her illness.

breast lump, metastasis, squamous cell carcinoma of lung

PMC6246101_01

Female

A 6-month-old female infant (6000 g; 3rd percentile) with an unremarkable medical history was transferred to our pediatric ward because of postprandial vomiting for 5 days. On clinical examination, she was subfebrile (38 C) and had a distended but soft abdomen. No mass was palpable. Abdominal ultrasound suggested the possibility of intussusception. As an enema to reduce intussusception was no therapeutic option at our center, the abdomen was surgically explored. On laparotomy, blood-stained but clear ascites was found as well as intestinal adhesions. Moreover, we saw diffuse granulations, mesenteric lymphadenopathy, and ischemia of the terminal ileum ( Figs. 1 and 2 ). Peritoneal cultures were harvested, appendectomy was performed, and the intestinal lymph nodes were biopsied. Postoperatively, tuberculin intradermal reaction (IDRt) was positive at 9 mm and cultures grew tuberculous contagium. The Anti-TB treatment administered was: rifampicin, isoniazid, pyrazinamide, ethambutol (RHZE) for 2 months, then RH the following 4 months. This regimen was applied before receiving the biopsy results which showed tuberculoid follicular lesions ( Figs. 3 and 4 ). The patient was declared cured after this treatment. She had no abdominal symptoms after 2 years of follow-up.

acute abdomen, infant, laparotomy, peritoneal tuberculosis

PMC6246101_02

Male

An 8-month-old (7000 g; 3rd percentile) boy from Mauritania with no particular pathological history was transferred from a health center near the Senegal-Mauritanian border for the management of peritonitis. The clinical picture had evolved for 15 days, with the appearance of abdominal bloating associated with vomiting and cessation of bowel movements. On clinical examination, he had a temperature of 38 C, and was tachycardic at 148 beats per minute. He showed nutritional edema and flank dullness. His abdomen was distended and had peritonitis on palpation. Therefore, the boy was taken to the operating room. Surgical exploration revealed clear ascites associated with small intestinal granulations and adhesions. We performed adhesiolysis, biopsies, and drainage of the peritoneal cavity. Postoperatively, GeneXpert tests were performed on the peritoneal fluid and the IDRt was negative. Anatomopathological examination of the operative specimens revealed the presence of caseous necrosis compatible with peritoneal TB. The medical treatment and the evolution were identical to Case 1.

acute abdomen, infant, laparotomy, peritoneal tuberculosis

PMC6202747_01

Male

The patient is a 17-year-old male born at term following a pregnancy complicated by maternal alcohol and substance abuse. Development was delayed: he walked at age 18 months, requiring braces for support, and his first words were at age 4 years. Medical history includes strabismus status post surgery at age 1 year, hypothyroidism, asthma, gastroesophageal reflux disease, kidney dysfunction, ischemic stroke, and epilepsy well controlled on valproic acid. The patient had an episode of dystonia associated with anti-psychotic treatment (haloperidol, aripiprazole) for bipolar disorder and aggression at age 9. Limited medical record documentation exists regarding the history of ischemic stroke. Magnetic resonance imaging (MRI) of the brain at ages 9 and 12 were normal. Family history is positive for bipolar disorder in his mother. Paternal family history is unknown. The patient has three healthy maternal half-siblings; ancestry is Caucasian. He first presented to our institution at age 15 years 6 months for management of his seizures. The patient had a wide-based gait, balance impairment, and dysarthria. He demonstrated developmental skills at the 3- to 5-year level. At 2 months after his initial evaluation, he had the abrupt onset of severe choreo-athetotic movements affecting his face, arms, and trunk (see Supplemental Video). These movements dramatically affected his gait and resulted in use of a wheelchair. His speech, behavior, and short-term memory worsened as well. There was no acute preceding event or change of medication (benztropine 1 mg twice daily, valproic acid 500 mg twice daily, dextroamphetamine 5 mg once daily, diphenhydramine 50 mg every 6 h as needed, levothyroxine 31.25 mcg once daily, fluoxetine 20 mg once daily). Shortly thereafter, the patient was admitted twice to a psychiatric hospital because of anger issues and aggression, but did not require change of medication. He had another seizure after his 16th birthday and a third brain MRI was normal. Over the next several months, his condition worsened due to the involuntary movements and he was no longer able to feed or bathe himself. Gastrostomy (G) tube feeding was required for caloric support. His hyperkinetic movements failed to respond to benztropine 1 mg BID and valproic acid 500 mg BID. Evaluation in a Pediatric Movement Disorders clinic at age 16 years and 4 months showed continuous choreo-athetotic movements of his face, trunk, and extremities. A trial with tetrabenazine (TBZ) 12.5 mg BID was initiated, which markedly improved his involuntary movements within 2 weeks. At his most recent follow-up visit (age 17 years), he was able to walk, feed himself, and use the bathroom independently. He continued to have antecollis and difficulties with gait, balance, and dysarthria, but was close to his baseline presentation. Additional neurodiagnostic testing included a normal (fourth) brain MRI, single-nucleotide polymorphism (SNP) chromosomal array, Fragile X DNA testing, and mitochondrial DNA sequencing and deletion/duplication testing. A fasting lumbar puncture revealed a slightly low cerebrospinal fluid (CSF) glucose of 48 mg/dL (normal range 50-75); however, plasma-to-CSF glucose ratio (0.56) was not suggestive of GLUT1 deficiency. CSF lactate, pyridoxal phosphate, neurotransmitter metabolites, tetrahydrobiopterin, neopterin, 5-methyltetrahydrofolate, and succinyladenosine were all normal. CSF amino acids did not identify any abnormalities consistent with a metabolic disorder. Plasma amino acids showed elevated alanine and glycine, but were normal on repeat testing. Lactate, pyruvate, and urine organic acids were normal. In light of extensive negative work-up, whole exome sequencing was performed using the methods previously described. Results identified a heterozygous missense variant, c.737T>C (p.L246P) in the EEF1A2 gene (NM_001958.3). Targeted testing of the patient's maternal grandmother was negative; biological parental samples were not available to confirm a de novo occurrence in the patient.

epilepsy, autism, chorea, genetics, treatment

PMC9524480_01

Male

A 13-year-old boy was admitted to our hospital due to an intermittent fever for 12 days. Prior to this, the patient was perfectly healthy. It was confirmed by the patient and his relatives, that he had recently been in contact with a kitten but not with pigeons, sheep, or other animals. Prior to fever onset, the patient experienced some shivers and then went on to develop headaches during the fever episodes, a poor appetite, and weight loss. He had been given various antimicrobial drugs before being admitted to our hospital, but none of them proved effective. The boy's temperature gradually rose to 40.2 C, and the feverish episodes became more frequent; thus, the patient's relatives asked for him to be admitted to our hospital. According to the admission records, the patient initially had a temperature of 38.2 C, with the fever occurring once a day. The patient experienced no other discomfort such as a cough, vomiting, diarrhea, rash, arthralgia, headache, or convulsion. Laboratory examination (performed in a local hospital) showed that the patient's complete blood count and the immune function were normal. However, they did detect an increase in the serum C-reactive protein (CRP) levels to 54.08mg/L (normal 0-5 mg/L) and in the erythrocyte sedimentation rate (ESR) to 23 mm/h (normal 0-20 mm/h). Chest computed tomography (a CT scan) showed the presence of small nodules on the upper lobe of the right lung and on the lower lobes of both lungs, with a maximum diameter of about 4 mm. An ultrasound detected splenomegaly; the spleen was about 126 mm long and 40 mm thick. Etiological examination revealed no abnormalities, including mycoplasma, respiratory syncytial virus, Epstein-Barr virus, or Coxsackie virus. A lumbar puncture was performed, but no abnormality was detected in the patient's cerebrospinal fluid. At admission, the physical examination identified no positive signs. Although the ultrasound performed at the local hospital showed an enlarged spleen, it was not palpable at the left costal margin. The laboratory investigations on the first day of admission showed a significant increase in serum CRP (94.73 mg/L), and an ESR of 78 mm/h. The procalcitonin concentration was 0.285 ng/mL (normal 0-0.02 ng/mL). Other laboratory tests, including complete blood count, blood biochemical examination, coagulation test, and thyroid function, were all within the normal range. All other laboratory test results also came back negative; these included HIV infection, tuberculosis, other viral infections (e.g., cytomegalovirus, herpes simplex virus, hepatitis virus, influenza virus, among others), galactomannan test, connective tissue disease antibody test, tumor markers, two sets of blood cultures for the detection of aerobic and anaerobic bacteria, and bone marrow cytology and culture tests. Furthermore, echocardiography, a chest CT scan, and cranial magnetic resonance imaging (MRI) failed to detect noticeable abnormalities. During the initial phase of treatment, the patient received empiric antimicrobial drugs such as latamoxef sodium, rifamycin, and penciclovir for four days. However, the fever persisted and the CRP levels and ESR rose to 107.58 mg/L and 98 mm/h, respectively. On the fifth day after admission, metagenomic next-generation sequencing (mNGS) was performed on the patient's peripheral blood, using an Illumina Next 550 sequencer with a single-end 75 base pair sequencing strategy. A total of 19,446,948 reads were generated within 24 h. After quality control, 19,186,121 were aligned with the human reference genome (HG38) and 260,404 reads were used for downstream analysis. Finally, four B. henselae-specific sequences were detected. Since neither our hospital nor the Henan Center for Disease Control could perform serological antibody tests or polymerase chain reaction (PCR) for B. henselae, we carried out another blood culture but this time extended the culture period to six weeks. The patient's treatment plan was adjusted, and the following antibiotics were administered: azithromycin (500 mg on the first day and 250 mg on the second to fifth days) together with rifampin (20 mg/kg/d, given in two doses), followed by doxycycline (200 mg/d, given in two doses) with rifampin. The fever gradually subsided and the shivering and headaches eventually disappeared. The patient's CRP levels also decreased and his temperature returned to normal on the 17th day after admission. The patient was feeling well enough to be discharged on the 19th day. He continued to take doxycycline and rifampin orally for the entirety of the one-month-long course. When the patient returned to our hospital for a follow-up reexamination, he was in good health. No abnormalities were detected in his blood after the following tests were performed: complete blood count, CRP, ESR, procalcitonin concentration, blood biochemical examination, and mNGS. We were therefore able to discontinue the patient's treatment. The patient's follow-up prolonged blood culture remained negative for B. henselae.

bartonella henselae, cat-scratch disease, diagnosis, infection, mngs

PMC9935969_01

Male

A 34-year-old male transferred from an outside hospital presented to the emergency department with dyspnea, mild fever, and myalgia. Pulse oximetry showed an O2 saturation of 85% at room air, which increased to 95% with the application of 4 L/min O2 by nasal cannula. On the initial chest radiograph, diffuse ill-defined haziness with multifocal Kerley B lines was observed in both lungs, especially in both lower lobes. Bilateral pleural effusion was also seen (Fig. 1A). On the chest CT, multiple patchy consolidations with a lower lobe predominance and peripheral distribution were demonstrated in both lungs. In addition, ill-defined ground-glass opacities and diffuse interlobular septal thickening were seen in both lungs, especially in the basal segments. Small amount of pericardial effusion and bilateral pleural effusion was present as well (Fig. 1B). Initial lab results revealed elevated erythrocyte sedimentation rate (26 mm/hr), C-reactive protein (20.570 mg/dL) levels, and leukocytosis (21.59 x 103/uL), while the eosinophil ratio (1.7%) was within normal limits. Our first impression from the imaging and lab findings were viral pneumonia, coronavirus disease 2019 (COVID-19) pneumonia, or interstitial pneumonia such as scrub typhus. Cryptogenic organizing pneumonia and AEP were also possible differential diagnoses. Follow-up peripheral blood eosinophil levels, apprehended four days later, were elevated (9.7%). Additional bronchoscopy showed no endobronchial lesion, however, bronchoalveolar lavage (BAL) fluids revealed increased eosinophil ratio (79%) levels, suggesting the possibility of eosinophil related lung disease. Additional culture and infectious lab results were negative for infectious causes, such as COVID-19, tuberculosis, scrub typhus, and other infectious pathogens. With a careful and more thorough history, the patient revealed to be a 14 pack-year smoker and used vaping e-cigarettes. Other than vaping 5 cc of nicotine a day, he denied usage of different substances such as THC. With the initiation of steroid treatment and cessation of vaping, the patient's diffuse ill-defined bilateral haziness decreased on follow-up chest radiographs (Fig. 1C). After three months of steroid treatment and then tapering, the patient did not show signs nor symptoms of relapse. By the proposed diagnostic criteria, we were able to make a final diagnosis of only-nicotine vaping EVALI manifested as AEP. This study was approved by the Institutional Review Board of our institution and the requirement for informed consent was waived (IRB No. 2021AS0375).

e-cigarette vapor, electronic cigarette, eosinophilic pneumonia, lung injury, vaping

PMC9520153_01

Female

A 26-year-old female presented with symptoms of awareness of heartbeat, easy fatigue, and exertional dyspnea since childhood, with worsening of symptoms for the past 6 months. She was diagnosed with type 1 diabetes mellitus 1 year before presentation. Her gynecological history revealed she had one successful vaginal delivery and 3 spontaneous abortions. On examination, she was tachypneic with oxygen saturation of 77% on room air, an irregular pulse rate of 85 beats per minute, and a normal blood pressure of 113/77 mmHg. She had distended neck veins with positive hepatojugular reflux. There were multiple pulsations visible over the third intercostal space right of the sternal border and the sixth intercostal space left of the sternal border with parasternal heave. Systolic and diastolic murmurs were heard all over the chest. She had epigastric distension with palpable, tender mass of around 8 cm extending below the left subcostal margin. On her electrocardiogram, she had atrial fibrillation (Figure 1). A transthoracic echocardiogram showed a common atrium with a large atrial septal defect (Figure 2). She had severe mitral and tricuspid regurgitation with moderate aortic regurgitation, and an elevated right ventricular systolic pressure of 168 mmHg. The chest computed tomography (CT) showed the cardiac apex directed toward the left, with both cardiac atria having the morphology of the left atrium. There is a large atrial septal defect resulting in a common atrium (Figures 3 and 4). The left and right ventricles are in a normal position with a possible atrioventricular canal defect. The left superior vena cava drains via the coronary sinus, and the inferior vena cava, residing near the midline, drains into the common cardiac atrium. The common ostium of the left pulmonary vein drains into the posterior cardiac atrium (Figure 5), while the right superior and inferior pulmonary veins drain into the anterior cardiac atrium. The aortic arch is toward the right (Figure 6). The origin of the left main coronary artery is visible and arises from the left coronary cusp. The right coronary artery is not visible. There are 2 vessel arches; the first vessel is a dominant right common carotid and the second is a right subclavian artery that produces a dominant right vertebral artery (Figure 7). The left common carotid and left subclavian arteries do not arise from the arch and are supplied via a small tortuous vessel arising from the proximal descending aorta at the level of T4-T5, which courses superiorly across the midline. As a result, the left common carotid, subclavian, and vertebral arteries are diminutive. The trachea is midline, and both the lungs are bilobed with a hyperarterial location of the airways relative to the pulmonary arteries. The abdominal CT showed the liver is midline (Figure 8), and there are clustered foci of splenic tissue in the right upper quadrant consistent with polysplenia (Figure 9). The stomach resides underneath the right hemidiaphragm. All of the small bowel loops reside in the left abdomen and colon on the right, consistent with bowel malrotation. Highly vascular adrenal glands are observed to the right and left of the abdominal aorta, which appears fused (Figure 8). Duplicated inferior vena cava with hemiazygos continuation. As a result, a diagnosis of heterotaxy syndrome with left isomerism was made. She was kept on sildenafil 25 mg once daily, spironolactone 25 mg once daily, digoxin 0.25 mg once daily, furosemide 40 mg once daily, and basal insulin. Additionally, bisoprolol 5 mg once daily was added later on follow-up, and continuous counseling was done over her medication use, lifestyle changes, and regular follow-up. The option of surgery was brought up, but due to the risk of complications, the patient opted out of the surgery.

congenital heart disease, diabetes mellitus, fused adrenal glands, imaging, polysplenia, pulmonary arterial hypertension

PMC9315306_01

Male

Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a nonconsanguineous family-1. He had typical PCD symptoms, such as chronic cough and sputum production, dyspnea, hemoptysis, sinusitis, etc. In addition, he complained of abnormalities in his sense of smell and hearing. However, his fertility was unknown because he was not married. He denied any history of asthma, tuberculosis, measles pneumonia, or drowning. No relevant family history was reported. High-resolution CT (HRCT) showed sinusitis, bronchiectasis, and situs inversus. Upright radiograph revealed scoliosis with a Cobb's angle of 14 (Figure 1). Furthermore, the semen routine test showed that the percentage of motile sperm was 0. Proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-2. She had chronic cough and sputum, dyspnea, and sinusitis. She also had abnormalities in the sense of smell and hearing. In addition, she suffered from infertility. HRCT findings were similar to P1, and upright radiograph revealed scoliosis with a Cobb's angle of 11 (Figure1). The HRCT also indicated an immature uterus. Her forced expiratory volume in 1 second (FEV1)%prediction, forced vital capacity (FVC)%prediction, FEV1/FVC, and nasal NO were 36%, 50%, 60%, and 8.4 nL/min, respectively (Supplementary Tables S1-S3; Figure1). We used the patient's peripheral blood to extract DNA for Whole exome sequencing (WES). After WES, 12.02 and 6.8 GB data were used for subsequent analysis. The percentages of bases with a coverage depth of more than 10x were 99.6% and 98.1%, respectively. Two variants, DNAAF4 (NM_130810.4): c.988C > T (p.Arg330Trp) in P1 and a novel variant DNAAF4 (NM_130810.4): c.733C > T (p.Arg245Ter) in P2, were identified. We classified the pathogenicity of the two variants according to ACMG. The results showed the variant in P1 was consistent with PM2+PM3+PP3+PP5 (likely pathogenic), and the variant in P2 met the criteria PVS1+PM2+PP5 (pathogenic). These two disease-causing variants were validated by Sanger sequencing (Supplementary Table S2; Figure2). High-speed microscopy showed complete static of sperm flagella and a few residual beating of respiratory cilia in P1 and complete static of the respiratory cilia in P2 compared with normal control (Supplementary Videos S1-S3). Immunofluorescence showed the deficiency of DNAH5 and DNALI1, which labelled ODA and IDA, respectively, in the respiratory cilia of both probands. In addition, the DNALI1 and DNAI1 which respectively labelled the ODA and IDA in the sperm flagellum of P1 were also absent. TEM revealed the absence of ODA and IDA of P2 respiratory cilia. HE staining showed irregular flagella, short, absent, coiled, and bent, indicating asthenoteratozoospermia (Figure3).

dnaaf4, asthenoteratozoospermia, bronchiectasis, primary ciliary dyskinesia, scoliosis, situs inversus

PMC5133214_01

Male

A male patient, aged 13, was hospitalized in February mainly due to aggravated kinesalgia of left knee for 1 year and 9 months, which was accompanied by left lower limb lameness for two months. The pain was present when the patient was active and was relieved after rest. Fever, night sweats, nausea, vomiting, night pain and other symptoms were not concurrent. The symptoms were worsened due to strenuous exercise 2 months ago. X-ray and MRI examinations of left knee performed in other hospital revealed no abnormalities; CT and MRI examinations of bilateral hip joints revealed abnormalities. CT images showed that bilateral acetabular articular surfaces were rough with increased densities; cortical bone fractures and small free bone fragments were observed; the left femoral head was irregular with rough edges and unclear bone trabeculae; the right femoral head was basically normal. MRI examinations of bilateral hip joints showed that bilateral hip joints were in asymmetry; a small amount of hydrops were present in the left hip joint cavity; the joint space was widened, the acetabulum became shallow; the femoral head was slightly shifted upward, the femoral head and acetabular articular surface were rough and irregular; areas with abnormal signal intensity were observed in local sclerotins; T1W1 scan showed uneven and slightly lower signal intensities; T2W1 and STIR scans showed heterogeneous signal hyperintensity; the peripheral soft tissues were swollen with irregular heterogeneous signal intensity. The right hip joint space was present, the superior margin of the acetabular articular surface was rough; abnormal intensities were not observed in the right femoral head or in the upper segment of the femur and acetabulum. The imaging findings were as follows: (1) Right hip joint dysplasia; (2) Left hip joint abnormalities. Infectious disease, preferably the joint tuberculosis was considered. Aseptic necrosis of the femoral head was not excluded. The physical examinations on admission showed that the left lower limb lameness was present, tenderness of bilateral hips and inguinal region was absent, left patrick sign was positive, external rotation of left hip was obviously limited. The circumferences of the left and right knees at 15 cm above the patellas were 38 and 41 cm respectively. The distance from the anterior superior iliac spine to the medial malleolus was 82 cm for the left side, and 83 cm for the right side. Bilateral lower limbs had muscle strengths of Class V, symmetrical sensations, normal physiological reflections and negative pathological signs (-). After admission, the pelvic X-ray examinations showed that the left femoral epiphysis was irregular with bone defect areas on both outer and inner margins; the local bone density was increased, local bone defects were also observed on the outer margin of the femoral neck without obvious periosteal reactions. The left acetabulum was inhomogeneous in density and had multiple saccular low-density shadows. The space of the left hip joint was uneven with local stricture; peripheral spindle-shaped soft tissue density shadows were observed. The right acetabulum was thickened and whitened, and multiple mottled shadows with low signal densities were observed. The right hip joint space was not narrow. Other parts of bilateral hip joints had no obvious bone abnormalities. The findings also indicated high possibility of hip joint tuberculosis. The imaging data are shown in Figs. 1, 2, 3, 4.

arthritis, coxarthrosis, subclinical hemophilia

PMC9126715_01

Male

A 39-year-old man who was a carpenter complained of right hindfoot pain after he fell from a stepladder during work. At the first visit to our hospital, he could not walk due to his right hindfoot pain. Physical examination revealed swelling, ecchymosis, and tenderness at the posterior aspect of his ankle. Plain radiographs of the right ankle showed no abnormal findings in anteroposterior and lateral views (Figure 1). Noncontrast computed tomography (CT) demonstrated a fracture line from the lateral side of the posterior lateral process to the medial side of the talus body. In addition, the fracture line extended to the posterior ankle and subtalar joints, and the bone fragment was slightly displaced (Figure 2). Based on the physical examination and radiological findings, the diagnosis of the talar body fracture was made. Because of the displaced bone fragments from the fracture, surgical treatment was applied for this case. The surgery was performed under general anesthesia in the prone position. A thigh air tourniquet and a fluoroscopy were used. Based on the hindfoot endoscopic technique reported by van Dijk et al., posterolateral and posteromedial portals were created. The posterolateral portal was used as a viewing portal, and the posteromedial portal was used as a working portal for the motorized shaver and guide wires. First, the posterior aspect of the talus was observed using a 4.0-mm-diameter 30 arthroscope. Soft tissues around the talus including synovium, adipose tissue, and coagulation clot were removed with a 4.0-mm-diameter motorized shaver, and the fragment was easily reduced using a guidewire sleeve and fixed with two 0.8 mm guidewires. A lateral view of the ankle joint was visualized by a fluoroscopy in the prone position, and we confirmed the guidewires in an adequate position and the alignment after the reduction of the bone fragment. Through the guidewires, the fragment was fixed with two cannulated double-threaded screws (Double Thread Screw Japan Mini, Meira, Nagoya, Japan) (Figure 3). The wound was sutured, and the surgery was concluded (Figure 4). Postoperatively, a nonweightbearing short leg splint was applied for 2 weeks, and when the splint was removed, active and passive ranges of motion exercises of the ankle were initiated. Partial weightbearing was allowed at 6 weeks postoperatively, and full weightbearing at 10 weeks postoperatively. The patient was permitted to return to work after confirming consolidation of the fracture site on CT at 14 weeks after the operation (Figure 5). At 2 years after surgery, he was able to work as a carpenter without any complications nor symptoms, and the AOFAS score was 97.

PMC10166214_01

Female

A 56-year-old female with past medical history of heart failure with preserved ejection fraction, obesity treated with Roux-en-Y gastric bypass surgery, type 2 diabetes mellitus, recent COVID-19 related massive pulmonary embolism (PE) 2 months prior, presented with chief complaints of dyspnea on exertion. Dyspnea prevented her from doing activities of anything more than minimal exertion (NYHA class 2). She also noted generalized weakness, and bilateral lower extremity edema for one month. In addition, she complained of sharp nonradiating retrosternal chest pain that worsened with inspiration. Her home cardiac medications included twice daily furosemide and rivaroxaban, with which she reported compliance. She denied orthopnea, paroxysmal nocturnal dyspnea, and cough. This was her third admission in a month for similar complaints. The initial onset of her symptoms was one month after her recent massive PE that had occurred two months prior to the current hospitalization, in the setting of COVID-19 infection. She had required systemic thrombolysis after multiple failed attempts at catheter-directed thrombolysis due to difficulty engaging the pulmonary artery. Despite multiple hospitalizations and aggressive diuresis, she had had progressive worsening of her dyspnea. Her vitals at presentation were blood pressure 90/67 mm Hg, heart rate 108 beats per minute, temperature 99 F, respiratory rate 20 breaths/minute, and oxygen saturation of 96% on room air. Physical examination was suggestive of right-sided heart failure with elevated jugular venous pressure, 3+ bilateral lower extremity pitting edema and clear lungs. Her BMI was 30 kg/m2. Cardiac auscultation revealed normal S1 and S2 with no rubs, murmurs, or gallops. Her initial labs (Table 1) were significant for mild transaminitis and an elevated brain natriuretic peptide. Her creatinine was also elevated at 1.57 mg/dL (baseline 0.81-1.00 mg/dL). Electrocardiogram (EKG) showed normal sinus rhythm at 98 beats per minute and nonspecific ST-T wave changes in inferior and lateral leads, which were similar to her prior EKGs. Initial Computed Tomography (CT) scan of the chest with contrast obtained in the emergency department showed interval resolution of pulmonary embolism but revealed bilateral pleural effusions and trace pericardial effusion. She was admitted with a diagnosis of acute on chronic heart failure with preserved ejection fraction and intravenous diuresis was initiated. A transthoracic echocardiogram (TTE) was performed which was technically a very difficult study due to patient's body habitus but revealed a low-normal left ventricular ejection fraction (LVEF) of 50% and no regional wall motion abnormalities. Patient did not respond to diuretic therapy and developed hypotension requiring midodrine. Cardiology was consulted who reviewed the TTE images more closely and noticed respirophasic abnormal septal motion concerning for constrictive physiology. The patient underwent right and left heart catheterization, which showed a mean right atrial pressure of 19.5 mm Hg with a prominent y descent. The right ventricular pressure was 35/19 mm Hg. The pulmonary artery pressure was 30/19 mm Hg with a mean of 24 mm Hg. The mean wedge pressure was 20 mm Hg and the left ventricular end-diastolic pressure was 24 mm Hg. In addition, there was an equilibration of diastolic pressures across all cardiac chambers, square root sign (dip and plateau pattern of right ventricular and left ventricular diastolic tracing), and discordant respiratory variation (Fig. 1). These hemodynamic findings were all consistent with CP. Cardiac catheterization also showed a low cardiac index of 1.09 based on thermal dilution and 1.6 based on Fick's principle. Thus, she was transferred to the cardiovascular intensive care unit for intravenous inotropes and vasopressors. Patient underwent a transesophageal echocardiogram (TEE) and a coronary angiogram in anticipation of a pericardiectomy procedure. The TEE (Fig. 2) showed an LVEF of 55% with respirophasic abnormal septal motion, bi-atrial dilation, significant respiratory variation of the mitral and tricuspid valve inflow, and increased echodensity of the pericardium with no pericardial effusion, all of which again pointed towards constrictive physiology. Coronary angiogram did not reveal any obstructive coronary artery disease. To establish the cause of her CP, we obtained more history and reviewed her chart in greater detail. She denied any cardiac surgery, prior chest irradiation, travel to tuberculosis endemic areas, any symptoms concerning for autoimmune disease, or use of any medications associated with a risk for developing CP. There were also no concerns for malignancy as she did not have any suggestive symptoms and was up to date on her cancer screenings. However, she was found to have a moderate pericardial effusion on a CT scan of her chest one month after systemic thrombolysis for her massive PE, which was noted to be only trace on CT scan at this admission (Fig. 3). We hypothesized that she developed a hemorrhagic pericardial effusion from the systemic thrombolysis versus the multiple failed attempts at catheter-directed thrombolysis for her massive pulmonary embolism, which led to constrictive pericarditis. A gadolinium enhanced Cardiac Magnetic Resonance Imaging (CMRI, Fig. 4) was performed to rule out restrictive cardiomyopathy that showed mild diffuse thickening of up to 4 mm and subtle enhancement of the pericardium with a positive septal bounce. This confirmed CP as the diagnosis. She underwent pericardiectomy which resulted in significant improvement of her symptoms, hemodynamics, kidney function and liver enzymes. Her pericardial biopsy revealed marked fibrosis, mild acute and chronic inflammation with hemosiderinladen macrophages, and no malignancy (Figs. 3 & 5). This confirmed our suspicion of hemorrhagic pericardial effusion being the etiology of her constrictive pericarditis. The patient was weaned off of all blood pressure support measures and was subsequently discharged to cardiac rehab.

atraumatic hemopericardium, catheter-directed thrombolysis, constrictive pericarditis, massive pulmonary embolism, systemic thrombolysis

PMC5457767_01

Male

A 13-year-old male athlete presented to the emergency department with an injured left tibia. The patient reported a left knee forced hyperflexion during a football match, which caused the injury. The described mechanism of injury was violent contraction of the quadriceps muscle against a fixed tibia. The left knee was held in 100 of flexion with complete inability to extend the knee or bear weight. On examination, there was obvious swelling over the proximal tibia and on palpation there was tenderness on the anterolateral part of the proximal end of the tibia. No neurovascular impairment was identified. The patient was able to actively move his ankle, as well as his toes, and both posterior tibialis artery and dorsalis pedis artery were palpable. From the plain radiographs, a displaced flexion type Salter-Harris type II fracture of the proximal tibia epiphysis was identified (Figure 1). Few hours after admission, the patient was led to the theatre and, under general anesthesia, a closed reduction of the fracture was performed by extending the knee and putting strong pressure over the tibial tubercle. Reduction was confirmed using image intensifier (Figure 2) and stability of the fracture was verified, as there was no displacement at 80 of knee flexion. After reduction, the dorsalis pedis artery and the posterior tibial artery were palpable. Since there was no displacement with that degree of flexion, percutaneous pinning of the fracture was not performed and only a circumferential cast with the knee in full extension was applied. Patient was hospitalized in the Orthopaedic Department under close observation of limb neurovascular status. On the same night after reduction, the patient developed severe pain, which subsided after splitting the cast. The next few days, the patient developed severe swelling over the anterior tibia compartment, but there were no clinical signs of compartment syndrome. Posterior tibialis remained easily palpable, whereas the dorsalis pedis became weak but easily identifiable with the Doppler ultrasound scan. Fracture remained in a satisfactory position one week after reduction (Figure 3) and a full femur-tibia-ankle cast in 5 of knee flexion was applied. 2 weeks after injury, radiographs of the fracture were still satisfactory. 6 weeks after injury, fracture position was satisfactory with radiographic evidence of healing (Figure 4) and the cast was removed, encouraging active range of motion of the knee. At the same time, the anterior tibialis artery was easily palpable and a triplex ultrasound scan of the lower limb was normal. 8 weeks after injury, the patient achieved full range of motion, and full weight bearing was allowed. MRI scan was performed at this point; as occasionally, these fractures are associated with ligamentous injuries around the knee. MRI scan was normal regarding the cruciate and the collateral ligaments as well as the menisci. Patient's follow-up will continue with serial radiographs at 4 months, 8 months, and 12 months in order to detect early signs of growth arrest or angular deformity and genu recurvatum.

PMC8608663_01

Male

A 55-year-old gentleman with a history of diabetes mellitus, systemic hypertension, hypercholesterolemia, and hyperuricemia was admitted to our Medical Intensive Care Unit (MICU)with a 10-day history of shortness of breath, fever, and productive cough. On admission he was found to have a positive COVID-19 PCR with a cycle threshold (CT) value of 21. The patient was not vaccinated against COVID-19 at the time of this hospital admission. He received treatment according to the local COVID-19 protocol. His respiratory failure was managed with oxygen supplementation via Non-re- breathing Mask, then he was shifted to high flow nasal cannula (HFNC) alternating with Continuous Positive Airway Pressure (CPAP). Pulmonary embolism was ruled out with a CT pulmonary Angiogram. As the respiratory functions deteriorated, the patient was Intubated on Day 11. On Day 20; the patient was extubated to be re-intubated again emergently for worsening respiratory failure on day 23. He was finally extubated on day 26. On day 27, the patient developed a prolonged generalized tonic-clonic seizure which lasted for about 10 min aborted with IV midazolam. A subsequent CT head was nonrevealing. Subsequently as the seizure was prolonged (status epilepticus), the patient was loaded and kept on maintenance Levetiracetam. On day 30, he developed 3 discrete episodes of seizures (each lasting approximately 2 min and responding to iv boluses of midazolam). Lacosamide was added for seizure control. The patient's level of consciousness was not improving so he was re-intubated. His respiratory status improved, as reflected by ventilatory setting of 0.4 FIo2 and a PEEP of 5. He was kept off sedation on ventilator, but his level of consciousness did not improve. On day 34 again he developed 2 episodes of complex partial seizure that responded to IV midazolam boluses. EEG was done to rule out non convulsive status epilepticus and it showed generalized slowing suggestive of severe encephalopathy. MRI head (Fig. 1) was done and showed, scattered sporadic high cerebral mainly left sided cortical gyriform pattern with DWI bright signal with ADC map iso signal and FLAIR mild to moderate bright signal seen mainly at left high frontoparietal gyri as well as left cingulate gyrus possibly of post ictal versus early ischemic changes with no established infarction. Multiple punctate micro bleeds showing SWI dark signal are noted within the body and splenium of corpus callosum as well as left parietal subcortical regions likely of COVID-19 related micro thrombotic or hypoxic sequelae. Postcontrast, bilateral cerebral pachymeningeal dural enhancement with no nodularity is seen. Cranial and neck MRA was unremarkable. Subsequently, lumbar puncture (LP) and cerebrospinal fluid (CSF) analysis was done on day 35 after the MRI result. CSF analysis revealed a colorless CSF with a white blood count (WBC) of 3/microl, Red blood cells (RBC) of 2425/microl, and protein was> 6 gm/L, glucose was 5.44 mmol/L. Gram stain and culture of the CSF were negative. As was the Mycobacterium tuberculosis PCR, AFB Smear and TB culture and other viral panel including EBV and Adenovirus PCRs. CMV CSF PCR showed; 103,614 copies of the virus DNA (Test method: Altona Diagnostics Real-Time PCR assay for quantitative detection of Cytomegalovirus on ABI 7500 analyser). Subsequently, Ganciclovir treatment was started. One month later a repeat CSF analysis showed absence of CMV DNA. Other investigations including Hepatitis B, Hepatitis C, HIV and Quantiferon TB tests were negative. Connective tissue screen with antinuclear antibodies (ANA) was also negative. Tracheostomy was done on day 48, in view of persistent low GCS and prolonged intubation. The patient's ICU course was complicated by Candida Auris and Candida Albicans sepsis and secondary bacterial infection with Pseudomonas Aeruginosa and Klebsiella Pnemoniae of the sputum requiring antifungal and antimicrobial treatment respectively. Eventually the GCS improved to 15 and the patient was weaned off the ventilator and transferred to the medical ward on day 66. On day 95 he was transferred to the rehabilitation unit with persistent limb weakness. Our patient received Dexamethasone 8 mg IV Daily D1 to D10 and Methylprednisolone 40 mg BID IV from D19 to D27.

cmv, covid 19, case report, ganciclovir, immunosuppression, meningoencephalitis, opportunistic infections, steroids

PMC9880206_01

Female

A 59-year-old woman developed sudden but constant rhinorrhea with yellow mucus or occasional blood in January 2020. She denied any family history or mental illness. A month later, she developed hyposmia in addition to the symptoms above. She was evaluated at a local hospital and the brain magnetic resonance imaging (MRI) showed a mass located in the nose and protruded into the skull. This result was confirmed by a rhinoscopy. A grayish-white, infiltrative neoplasm, centered in the inferior meatus and common nasal meatus, was found. To further diagnose the disease, the patient underwent endoscopic nasal tumor resection, open sinus surgery, skull base repair following endoscopy, and radiofrequency ablation at the local hospital in April 2020. The surgical procedure was successful, and the postoperative pathology confirmed ONB with 90% Ki-67 ( Figure 1 ). The patient received radiotherapy with a total dose of 59.36Gy/28F from April to June 2020. She was also treated with 1 cycle of etoposide (200mg, day1-3) and cisplatin (40mg, day1-2) in April 2020. Unfortunately, the treatment was unsuccessful, and the patient's symptoms remained unimproved. In July 2020, two weeks before she was admitted to our hospital, her symptoms progressed with a developed and worsening weakness in both lower legs. When the patient was transferred to our hospital in July 2020, she complained that her rhinorrhea was not getting any better compared to 6 months ago, and the weakness in both legs was worsening. On admission, physical examination revealed reduced mental clarity and a lack of speech fluency. She also had impaired orientation, comprehension, calculation, and memory. Cranial nerve testing showed that the pupillary light reflex was dull and that the shoulder shrug was bilaterally eliminated. The grading of power was 2-3 in the right lower limb, 2 in the left lower limb, and 5 in both upper limbs. She also had hypotonia and hyperesthesia, but no abnormalities in proprioceptive sensation. To better evaluate her condition, we performed a series of baseline tests. The MRI revealed abnormal signals in the front lobe, nasal cavity, cervical spinal cord, upper thoracic spinal cord, and lumbar spinal cord ( Figure 2B ). CSF, which nourishes the brain tissue and carries away the metabolites, can relatively reflect the tumor condition in the brain. Correspondingly, the CSF test showing the presence of tumor cells (7%) confirmed the progression of the LM ( Figure 3A ). Based on the patient's symptoms, physical examination, MRI, and pathology, we concluded that the patient had ONB with Kadish stage D. Kadish D is the most advanced grade, according to the Kadish classification. As previous chemotherapy had been unsatisfactory, we sought to apply a more individualized treatment. We performed a next-generation sequencing (NGS) and the result showed a nonsense mutation in the APC gene, a tumor suppressor gene involved in the regulation of cell proliferation, migration, adhesion, and chromosomal stability ( Table 1 ). APC mutation can accelerate the cell cycle, and further promote tumorigenesis and metastasis. Considering that there were no obvious immunotherapeutic target genes detected, we chose to use the broad-spectrum chemotherapeutic agent, MTX, with a novelty way of intrathecal injection. Based on these findings, the patient received two cycles of intrathecal MTX injection (10mg, day1, 4, 6) and the intravenous ICE regimen (isocyclophosphamide 1.5g day1-3, etoposide 100mg day1-3, cisplatin 30mg day1-3) since July 2020 ( Figure 2A ). After the first cycle and to reduce the damage and discomfort of each intrathecal injection through a lumbar puncture, we performed Ommaya reservoir implantation in her right frontal brain. The intrathecal injection was performed through the Ommaya reservoir thereafter. The patient was regularly followed up with monthly complete blood count, T and B natural killer cells (TBNK) panel, comprehensive metabolic panel (CMP), and advanced MRI scan. Due to the severe side effects of isocyclophosphamide, we changed the treatment to intrathecal MTX injection (10mg, day1, 4, 7) and intravenous EC regimen (etoposide 100 mg, day1-4, and carboplatin 100 mg, day1-4) for a total of 3 cycles during October to December 2020. Strikingly, we had a thrilling result of achieving a partial response (PR) and there was an improvement in her physical examination. She became capable of conversing fluently with her healthcare team. She had normal orientation, comprehension, and calculation, with a mildly decreased memory. The grading of power in both upper limbs remained 5. The grading of power was 4 in the right lower limb and 3-4 in the left lower limb. In October 2020, her brain and spine lesions shrunk by >= 30% ( Figure 2C ), and in December 2020, her CSF test showed no tumor cells ( Figure 3B ). The proportion of T cells and T helper cells with killing functions increased. The proportion of the Ts cells, which suppress T cells, decreased, further indicating that the treatment had a good regulatory effect on the T cell population( Figure 3C ). However, after the third cycle of intrathecal MTX injection and intravenous EC chemotherapy, the patient relapsed on February 2021. She rapidly developed drowsiness and a lack of conversation fluency. Her orientation and comprehension remained normal. However, her calculating capacity and memory were impaired. Her grading of power in the lower limbs decreased, with 2-3 in right lower limb and 3 in the left lower limb. The grading of power of both upper limbs was 5. The MRI showed that the intracranial lesion increased by over 20%, along with cerebral edema ( Figure 2D ). There was also an increase in the percentage of tumor cells in the CSF ( Figure 3B ). When combining the above results with the patient's symptoms and physical examination, we concluded that she had progressive disease (PD). Although craniospinal irradiation was recommended by our hospital department of radiotherapy, the patient and her family were concerned about the risk of organ damage and bone marrow suppression, and therefore, decided to pursue chemotherapy as a treatment option. To eliminate the brain edema and better prolong the patient's survival, bevacizumab was added for four cycles from February to May 2021. During this period, there was no significant difference in her physical examination. Thus, based on these results and the MRI findings ( Figure 2E ), we determined that she reached stable disease (SD). Bevacizumab was stopped in June 2021. Unfortunately, these approaches failed to further prolong her lifespan. After adjusting to intrathecal MTX injection and intravenous IC regimen with bevacizumab for one cycle, and intrathecal injection of cytarabine (Ara-C) and intravenous IC regimen for another cycle, she passed away in November 2021.

case report, intrathecal administration, leptomeningeal carcinomatosis, olfactory neuroblastoma, ommaya reservoir

PMC5964554_01

Female

In December 2013, a 64-year-old African female was referred to the rheumatology clinic at our hospital with suspected RA. She reported painful hands and knees associated with early morning stiffness of two to three hours for the duration of one year. On further questioning, she reported that she had been diagnosed with pulmonary tuberculosis (TB) on the basis of positive sputum testing eight months prior to the time. The Gene Xpert test on her sputum had detected Mycobacterium tuberculosis complex, which was sensitive to rifampicin. She had subsequently been started on antituberculosis (TB) chemotherapy, which included rifampicin, isoniazid, ethambutol, and pyrazinamide. However, she had taken the treatment for only three months reportedly due to intolerance of the chemotherapy. Rheumatological examination at that visit revealed a clinical picture suggestive of RA. She had seven swollen joints all of which were metacarpophalangeal joints and seven tender joints including the wrists, knees, and metacarpophalangeal joints. Her patient global assessment was seven, and physician global assessment was four. This indicated high disease activity with a calculated clinical disease activity index (CDAI) of 25. Her chest radiograph showed features suggestive of active tuberculosis in the right upper lobe. Periarticular osteoporosis suggestive of an early inflammatory arthritis was identified on plain radiographs of hands and feet. There were no erosions or joint space narrowing identified on the latter. Blood investigations revealed positive serological tests for RA, with a rheumatoid factor (RF) of 69 international units per millilitre (normal value < 15) and an anti-citrullinated peptide antibody (ACPA) of 53 units per millilitre (normal value < 20). Inflammatory markers were also elevated which could be either due to active arthritis or as a result of active pulmonary tuberculosis. On the basis of chronic symmetrical polyarthritis involving predominantly small joints, plain radiographs suggestive of an early inflammatory arthritis, and supportive serological features, we diagnosed her arthritic condition as RA. Recognizing that she had not completed her anti-TB chemotherapy and she still had clinicoradiological features suggestive of active pulmonary TB, the original anti-TB chemotherapy was restarted and she was referred to the local clinic to continue the treatment for six months. As for RA, we decided not to initiate methotrexate until anti-TB chemotherapy was completed. We opted instead for a combination therapy of chloroquine and low-dose prednisone for the arthritis. In the follow-up clinic, a month later, we added sulfasalazine as her disease activity was persistently high. She subsequently defaulted the RA treatment. She however continued going to the local TB clinic to complete anti-TB chemotherapy. When she finally returned to the rheumatology clinic after completion of six months of anti-TB therapy, we found that she had no residual symptoms and signs of RA without any specific therapy for at least 4 months. We felt that a complete resolution of arthritis would be very unlikely under anti-TB chemotherapy without adequate DMARD therapy if the patient had rheumatoid arthritis. This led to a retrospective diagnosis of PD, which is a condition known to completely resolve without joint damage on anti-TB chemotherapy. In the subsequent 2-year follow-up without any form of pharmacological treatment, there was no relapse of the arthritis despite the serological tests for RA remaining positive, and she was discharged from the clinic. However, she presented again in January 2017 with a painful right foot, and she had been limping for a few months due to the pain. Clinical examination revealed swelling of the second and third metatarsophalangeal joints and tenderness of all of the right metatarsophalangeal joints. Repeated plain radiographs of the hands and feet revealed periarticular osteoporosis without erosions or joint space narrowing. Musculoskeletal ultrasound revealed active synovitis with increased Doppler signal in the right second and third metatarsophalangeal joints (Figure 1). No erosions were detected in the hand joints on ultrasound examination either. Serum RF was 166 international unit per millilitre, and serum ACPA was 100 units per millilitre. Serum C-reactive protein was mildly elevated at 17 milligrams per litre. She had no features to suggest reactivation of TB or reinfection with TB at this time. RA was diagnosed, and she was then started on oral methotrexate, folate, and low-dose prednisone leading to improvement of her symptoms. Written informed consent was obtained from the patient to allow publication of her clinical diagnosis and management.

PMC9301103_01

Male

The patient, a 33-year-old man, was hospitalized with complaints of headache, fever, unresponsiveness, irritability, and neck pain. The patient was reported to have lost 35 kg during the last 2 years (Figure 1). Twenty days before admission, the patient experienced persistent acute headaches, primarily in the front of the ear, temporal and posterior occipital part of the right side, without any distinct cause. These headaches were mainly characterized by unbearable distending pain, occasionally accompanied by dull, tingling, throbbing pain, which led to prolonged insomnia. Moreover, the patient experienced loss of appetite, but without nausea, vomiting, fever, diplopia, limb movement disorder, chest tightness, or shortness of breath. Eighteen days before admission, the patient sought medical help to manage the headaches. At that time, brain computed tomography (CT) scans were normal and the patient was given analgesic drugs, including rotundine (60 mg, orally three times per day), which relieved the headaches for 4 h and partly ameliorated the insomnia. Gradually, the degree of the headaches reduced, only occurring three to four times a day for approximately 4 h. However, 3 days before admission, the patient developed a low-grade fever when a headache occurred, accompanied by irritability and neck pain. Brain MRI was normal, but chest CT images revealed that the upper lobe of both lungs had lesions secondary to tuberculosis, and the left pleura was thickened and had encapsulated effusion (Figures 2A,B). The patient had no history of chronic disease, smoked for 20 years (10 cigarettes per day), occasionally drank a small amount of alcohol, and denied to have a family history of genetic disease. At admission, the patient was irritable and unresponsive, and upon examination, verbal reduction (unable to express full sentences), mild loss of comprehension, decreased calculation ability, and poor spatial learning and memory were confirmed. The eyeballs were in place on both sides, and horizontal nystagmus to the right was observed. The patient also showed signs of meningeal irritation, with nuchal rigidity (neck flexion angle of approximately 5 ), positive bilateral Kernig's sign, and negative Brucella's sign. According to the Clinical Assessment Scale in AIE (CASE), modified Rankin scale (mRS), Glasgow coma scale, mini-mental state examination (MMSE), and the Montreal Cognitive Assessment Test (MoCA) the patient scored 6, 3, 13 (E3M4V6), 9, and 8, respectively. Laboratory tests showed that the erythrocyte sedimentation rate was 56 mm/h, and serum blood cell counts and C reactive protein levels were within normal range. Lumbar puncture showed an increased opening pressure, and cerebrospinal fluid (CSF) analysis revealed elevated white blood cell (WBC) count and protein levels (Table 1). Based on these findings, the initial clinical diagnosis of possible viral meningoencephalitis was achieved. The patient was treated empirically with intravenous acyclovir 10 mg/kg three times per day. However, his health status continued to gradually worsen, with the highest body temperature reaching 39 C, with confusion, occasional nonsense, and partial third cranial nerve palsy, on day 3 (Figure 1). The CASE and mRS scores were 13 and 4. Furthermore, CSF and serum analyses revealed the presence of anti-NMDAR antibody IgG, determined by cell-based assay (CBA) and tissue-based assay (TBA). The result of tuberculin-purified protein derivative (PPD) skin test was positive (++), and that of the T-SPOT.TB assay was positive. CSF was positive for the MTB complex DNA assay; however, the modified acid-fast staining and metagenomic next-generation sequencing (mNGS) result was negative. Moreover, MRI showed nodules and ring enhancement in the right lateral ventricle, left temporal and left cerebellar hemisphere, abnormal signal foci were observed in the right temporal lobe and basal ganglia, as well as enhancement of the pia mater of the right frontotemporal area (Figures 2C,D). Furthermore, the patient was negative for anti-MBP, anti-AQP4, anti-MOG, anti-GFAP, and anti-GQ1b IgGs, and neuron antibodies in serum and CSF. Tumor markers, blood cultures, and autoantibodies associated with other autoimmune diseases were also negative. Moreover, color Doppler ultrasound of lymphatic, reproductive, urinary, and digestive systems, and of the heart were all normal. The lungs were also normal as per bronchoscopy analysis. Diagnosis of tuberculosis meningoencephalitis combined with anti-NMDAR encephalitis was achieved, and a standard antituberculosis regimen (rifampicin 0.45 g/day, ethambutol 0.75 g/day, isoniazid 0.6 g/day, and pyrazinamide 1.5 g/day) and intravenous 1,000 mg/d glucocorticoid pulse therapy (halved every 3 days, and switched to oral after 12 days) was initiated. Thereafter, the consciousness status of the patient and irritability gradually improved, and the head and neck pain was substantially ameliorated. On day 8, despite the health improvements noticed, the comprehension, calculation ability, spatial learning, and memory impairments remained unchanged, and depression manifestations appeared. The pain symptoms disappeared, but neck resistance increased to 15 C. On day 13, a lumbar puncture was performed with intrathecal isoniazid (0.1 g) and dexamethasone (5 mg). CSF analysis revealed evident improvements (Table 1), and the comprehension, mood, verbal reduction, and partial oculomotor nerve palsy showed some improvements. The neck flexion angle of 25 remained. The CASE and mRS scores were 6 and 3. The patient was discharged with an oral standard antituberculosis regimen combined with prednisone (60 mg/day) for 2 weeks, which was tapered to 50 mg/day until the following medical examination. After 1 month of follow-up, the patient had gained 8 kg without any discomfort. Physical examination showed only right ptosis and diplopia. Moreover, the CASE, MMSE, MoCA, and mRS scores were 3, 29, 27, and 1, respectively. The CSF anti-NMDAR antibody titer remained unchanged. Noteworthily, the serum anti-NMDAR antibody titer, and protein and WBC of CSF were significantly reduced (Table 1). Brain MRI revealed significant shrinkage of the primary nodules. Nevertheless, the lesion in the right basal ganglia was larger than before, new lesions appeared in the right pontine and right-sided temporal lobe, and the right frontotemporal leptomeninges showed more evident enhancement than before (Figures 2E,F). The patient continued to receive the antituberculosis treatment regimen along with regular tapered prednisone. Additional evaluations revealed that the patient was still experiencing mild visual acuity decline in the right eye but without impact on his daily life, and the ptosis and memory disorders disappeared without further complaints. Physical examination remarkably improved after 3 months of discharge. The CASE and mRS scores were 2 and 1. The lesions on the CT chest and brain MRI (Figure 2G) showed evident improvements.

mycobacterium tuberculosis, anti-nmdar antibody, autoimmune encephalitis, case report, tuberculosis meningoencephalitis

PMC3322782_01

Female

An 18-year-old woman from Jazan (southwest of Saudi Arabia) had a 3-day history of confusion, fever, and blurred vision at the time an RVF outbreak was peaking in Jazan. Philadelphia-chromosome-positive chronic myeloid leukemia (CML) had been diagnosed in her several months before (leukocyte count 108 x 109/L). She responded well to hydroxyurea, and she had been in stable-phase CML for a few months. At the time of her visit, her temperature was 39.2 C, blood pressure 110/70 mm Hg, pulse 120 beats/min, respiratory rate 22/min. She had no lymphadenopathy, pallor, or jaundice. Results of her head, neck, and throat examinations were normal. Her chest was clear, and her abdomen was soft and nontender. Her spleen was 3 cm below the left costal margin. She was conscious and oriented. No meningeal signs could be elicited. Pupils were equally reactive to light with normal extraocular movements. Extremities had normal tone, power, sensation, and reflexes. Plantar reflex was flexor bilaterally. She had ataxic gait and bilateral retinal hemorrhages. She was unable to count fingers. Hemoglobin was 100 g/L, leukocyte count 5.1 x 109/L, and platelets 373 x 109/L. Renal and liver function tests were normal. Contrast-enhanced computed tomography (CT) scan of the brain was normal. Urine analysis and malaria smear were negative. CSF was clear. CSF glucose was 3.9 mmol/L (serum 5.8), protein 455 mg/L. CSF leukocyte count was 323 x 106/L, 58% lymphocytes, and 38% polynuclearleukocytes. Tests for hepatitis B surface antigen, antibodies to hepatitis C virus, HIV, cytomegalovirus antigenemia, rheumatoid factor, and antinuclear antibodies were negative. Cultures from blood, CSF, and urine were negative for bacteria. CSF viral culture was negative. Polymerase chain reaction for herpes simplex virus and enterovirus from CSF was negative. Tests for serum anti-RVF virus immunoglobulin M were positive. No other tests for RVFV were performed. Bone marrow on admission day was consistent with CML in remission. Prednisone was started on admission for 7 days. On hospital day 5, the patient was noted to be agitated, confused, and unresponsive to commands. She was transferred to the intensive care unit after her level of consciousness decreased; she was moving all four limbs but did not respond to verbal commands or painful stimuli. Pupils were 5 mm equal bilaterally with a sluggish reaction to light. Corneal reflexes were reactive bilaterally. Gag reflex was present, and tone was increased in all four limbs with brisk reflexes and extensor planter responses. The next day, her condition deteriorated, and she became unresponsive to painful stimuli. Repeated CT scan of the brain showed no pathologic changes. Electroencephalogram showed generalized continuous rhythmic sharp and spike wave activity consistent with nonconvulsive status epilepticus. Magnetic resonance imaging (MRI) of the brain showed bilateral frontoparietal high signal intensity on T2-weighted images and evidence of subtle right posterior thalamic hyperintensity with no corresponding abnormalities in T1-weighted images. The axial diffusion MRI images were more elaborative, showing multiple bilateral asymmetrical cortical hyperintense areas consistent with an ischemic or inflammatory process. Phenytoin was started. The next day, the patient was able to open her eyes and responded to painful stimuli, corneal reflexes were present bilaterally, oculocephalic reflex was present, and planters were flexors bilaterally. Repeat CSF studies on day 30 showed glucose of 3.8 mmol/L, protein 431 mg/L, leukocyte count of 12 x 106/L, and 68% polynuclearleukocytes. Repeat CT scan of the brain showed new bilateral temporo-occipital hypodensity more on the left side and a probable right middle cerebellar and left thalamic internal capsule infarct. There was no intracranial hemorrhage or hydrocephalus. She was discharged home awake, blind, quadreparetic, and incontinent, on anticonvulsants. After 1 year, her neurologic condition had not changed. Encephalitis and retinitis are severe complications of RVF, developing 1 or 2 weeks into the course of diseases. By that time, RVFV antigen assay is negative. Our patient met the definition of an RVF case during the outbreak. In one outbreak in Mauritania, 4.9% of observed infections had encephalitis, although the true frequency of encephalitis in RVF may be overestimated because infection can go unrecognized. The literature contains limited clinical description of this syndrome. Detailed neuroimaging findings, including MRI and flow studies, have not been previously reported. These findings, along with the patient's clinical signs and symptoms, suggest cerebral vasculitis; however, no angiogram was performed, and markers of vasculitis were negative. A more likely cause would be direct viral parenchymal invasion. The pathogenesis of RVF encephalitis in humans is not clear. Animal studies indicate that active viral replication and necrotizing encephalitis with diffuse perivascular infiltrates of lymphocytes and macrophages occur in cerebral parenchyma. Postmortem histopathologic examination of brains of fatally infected rhesus monkeys have shown a mild, nonsuppurative, multifocal, perivascular encephalitis in the cerebral cortex, primarily of lymphoplasmacytic cells and nodular aggregates of neutrophils in association with mild necrotic changes of neurons. In one patient who died of meningoencephalitis in South Africa, brain pathologic findings showed perivascular cuffing and round-cell infiltration. In humans, we are not aware of positive RVFV cultures from CSF, blood, or brain during encephalitis. We have no reason to suspect CML to influence disease manifestations in this patient. CML was in stable phase for several months and should not have affected immune response of the patient towards RVFV.

PMC9873443_01

Male

The patient is a 40-year-old Haitian man who presented with progressive right-sided weakness, dysesthesias, and headaches. He denies any symptoms of dizziness, vision changes, nausea, vomiting, or neck stiffness. His neurological exam showed upper motor neuron pattern weakness (4 out of 5) in the right upper and lower extremities, increased sensitivity to temperature in his right upper and lower extremities, and gait abnormalities in his right lower extremity. All reflexes were intact and no cranial nerve abnormalities were detected. Computed tomography (CT) scan of the head without contrast showed widespread cystic lesions in the cerebral region of the brain. MRI brain showed numerous bilateral intraparenchymal cystic enhancing lesions, some of which demonstrated internal hemorrhagic components (Figure 1). The largest cystic lesion was in the left paramedian frontoparietal lobe measuring 5.0 x 3.4 x 4.0 cm. It also demonstrated a significant mass effect leading to distortion of the body of the corpus callosum and the body of the left lateral ventricle. Another lesion was found in the left caudate nucleus head region measuring 2.1 x 3.0 x 1.6 cm. A left basal ganglia lesion posterior to the left caudate nucleus lesion had a prominent rim of hemorrhagic products. The septum pellucidum was shifted approximately 5 mm to the right at the level of the frontal horns of the lateral ventricles. On the right, one of the lesions was centered in the white matter of the right superior frontal gyrus measuring 1.8 x 1.5 x 1.6 cm. CT chest and abdomen did not show any primary or metastatic masses. Syphilis serology was nonreactive, and the Quantiferon test was reactive. The patient had no history of latent tuberculosis (LTBI) therapy. Cerebrospinal fluid (CSF) analysis showed a cell count of 10 WBC per mm3, protein 69 g/L, and glucose 70 mmol/L. CSF cytology was significant for atypical cells, raising concern for malignancy. Other infectious workup including venereal disease research laboratory (VDRL), routine blood cultures, acid-fast bacillus (AFB), and serum Cryptococcus antigen was negative. Human immune deficiency (HIV) virus, galactomannan, Fungitell, and toxoplasmosis serology were negative. The patient experienced worsening right lower extremity weakness three days after his admission. His hemiparesis had progressed to a full right lower extremity paralysis. CT head without contrast demonstrated hyperdense material layered within a cystic structure, likely representing blood products. The fundoscopic examination did not report evidence of retinal or subretinal parasites. The patient was started on dexamethasone 4 mg every 6 hours for vasogenic edema, which slightly improved his right-sided hemiparesis and lower extremity paralysis. Despite cysticercosis antibodies being tested negative, the patient was also initiated on albendazole, praziquantel, and levetiracetam for the empiric treatment of neurocysticercosis and seizure prophylaxis. Due to high suspicion of brain tuberculoma, the patient was treated for latent tuberculosis. On day eighteen, the patient had a right-sided open resection craniotomy with biopsy and left-sided stereotactic cyst drainage. The pathology of the specimen showed high-grade, nonlymphoid neoplasm favoring glioblastoma with undifferentiated small cell components (Figure 2) with O-methylguanine-DNA-methyltransferase (MGMT) promoter methylated. Next-generation sequencing with glioma panel detected mutation in PTEN and APC with wild-type IDH1 and wild-type IDH2. The patient was deemed unfit for surgery and was initially offered enrollment in clinical trial at Memorial Sloan Kettering Cancer Center; however, he was not interested. The patient ultimately elected to be treated with the standard of care of concurrent chemotherapy with radiotherapy followed by adjuvant chemotherapy with temozolomide based on the Stupp trial. His treatment was modified to a shorter course of radiotherapy with concurrent temozolomide followed by adjuvant chemotherapy based on the study by Perry et al.. The patient received a total dose of 40.05 Gy, given in 15 daily fractions over three weeks, along with concurrent temozolomide (75 mg/m2) for twenty-one days. Interval CT of the head without contrast 10 days after initial treatment showed decreased size of the brain lesions. The patient did not receive adjuvant temozolomide (150-200 mg/m2) for five consecutive days of a twenty-eight-day cycle for up to 12 cycles as he decided to return to Haiti.

PMC6394360_01

Female

An 84-year-old Japanese woman was admitted with the history of fever (axillary temperature: 38.5 C) and dyspnea. As the patient presented leukocyturia, a urinary tract infection was the working diagnosis. Her past medical history included the diagnosis of diabetes mellitus, and myelodysplastic syndrome (MDS), refractory anemia with excess of blasts in transformation (RAEB-t) diagnosed 5 months ago, and humeral and pelvic fractures that occurred 5 and 4 months ago, respectively. She had been started on cyclosporine (100 mg/day) in addition to receiving blood transfusions after the diagnosis of MDS. The initial laboratory work-up is shown in Table 1. Despite the intravenous treatment with cefmetazole (2 g/day) for 7 days, the fever did not subside. She was found to have some hepatic nodules, up to 15 mm. On the thoracic computed tomography, bilateral pleural effusion and mediastinal lymphadenopathy were detected. Also, the polymerase chain reaction (PCR) of her sputum was positive for Mycobacterium tuberculosis, and the diagnosis of tuberculosis (TB) was made. Anti-tuberculous therapy was not started because she suddenly died soon after the diagnosis was made on the 14th hospital day. Immediate antemortem (about 1 hour before death), she was able to talk and eat as usual. However, she developed sinus tachycardia at a rate of 140 beats per minute, followed by ventricular fibrillation, and collapsed. Cardiopulmonary resuscitation was not performed in accordance with the patient's and family's wishes. An autopsy was carried out 90 minutes after death.

autopsy, bone marrow, death, sudden, embolism, fat, necrosis, tuberculosis

PMC5457921_02

Female

The patient was a 72-year-old woman with a history of surgery for pulmonary tuberculosis at 19 years of age. She had no history of allergies, smoking, or drinking consumption. Her height was 154 cm, weight 44 kg, and BMI 18.5 kg/m2. Her HCV genotype was 1b, and she had not previously received treatment for HCV infection. She was found to have compensated cirrhosis: 23.3 kPa on Fibroscan testing, a Child-Pugh score of class A5, and a HCV RNA level of 6.8 log IU/mL. She had no comorbidities and had been taking only an oral ursodeoxycholic acid agent. Her laboratory test results were as follows: albumin 3.7 g/dL, total bilirubin 0.37 mg/dL, AST 60 IU/L, ALT 44 IU/L, ALP 578 IU/L, LDH 260 IU/L, total cholesterol 132 mg/dL, triglyceride 68 mg/dL, and blood glucose 101 mg/dL (Table 1). The hepatitis B virus test result was negative. The ECG QTc ratio was 430 mm, and there was no evidence of premature ventricular contractions (VPcs). SOF (400 mg) and LDV (90 mg) were administered. Two days later, ECG monitoring showed VT, although the patient remained asymptomatic. The VT resolved spontaneously. However, 5 days later, ECG monitoring detected a similar episode of VT. LDV/SOF was discontinued after consultation with a cardiologist. The patient had no specific symptoms during the VT episodes. Her cardiac function was assessed using a standard ECG, echocardiogram, Holter monitoring, and heart rate monitoring; the results were unremarkable. She was discharged from the hospital 20 days after admission (Fig. 2).

PMC6677927_01

Male

A 63-year-old man presented with dyspnea and stridor on effort that gradually progressed over 6 months. The patient had a drug history of anti-tuberculosis medication, including isoniazid, rifampicin, and ethambutol for pulmonary tuberculosis that he developed 32 years ago. However, he never felt restricted in his everyday life, until he recently became aware of stridor during deep breathing. Subsequently, he developed stridor at rest and severe dyspnea on effort. Thus, he visited a local hospital. Although bronchoscopy revealed tracheal scar stenosis, the sputum smear for acid-fast bacilli was negative. He was admitted to our hospital for further treatment. On admission, physical examination revealed a pulse rate of 113 beats/min, blood pressure of 132/74 mm Hg, and oxygen saturation of 97% on room air. The flow-volume curve was consistent with fixed airway obstruction with a functional vital capacity (FVC) of 2.77 L and 1-second forced expiratory volume (FEV1) of 1.18 L (FEV1/FVC: 42.7%). Chest computed tomography (CT) examination including three-dimensional reconstructions revealed thickening of the tracheal lumen and deformation of the tracheal cartilage from the annular cartilage to the middle trachea (length, 52 mm; luminal diameter, 4 mm) and severe stenosis in the orifice of the left main bronchus (Fig. 1a-d). Thus, we diagnosed him with airway stenosis probably resulting from EBTB, based on the case history and imaging findings. We believe that the latent symptoms associated with airway stenosis became apparent owing to a decrease in pulmonary function with age. Since reconstruction of the airway was considered difficult due to the site of the operation and range of the defect, we decided to perform balloon dilatation combined with laser cauterization under bronchoscopy. Moreover, the patient did not wish to undergo invasive procedures. We intended to place a stent under a rigid endoscope, if expansion was obtained. Under general anesthesia, bronchoscopy using a laryngeal mask revealed severe subglottic scar stenosis (Fig. 2) through which the bronchoscope (BF type-260, Olympus Corporation, Tokyo, Japan) with an external diameter of 4.9 mm could not pass. The stenosis was Grade III according to the Myers-Cotton subglottic stenosis grading scale. Under X-ray fluoroscopic imaging, a guide wire was placed transbronchoscopically through the stenotic portion. Subsequently, the bronchoscope was withdrawn leaving behind the guide wire. CRE Pulmonary Balloon Dilatation Catheter (Boston Scientific Corporation, Marlborough, MA, USA; Fig. 3a and b) was introduced over the wire and placed in the tracheal stenosis area. The balloon was inflated with a diluted contrast solution for 10 seconds repeatedly, gradually increasing the expansion pressures. Based on CT findings, the balloon diameter that did not exceed the airway diameter at maximum expansion was selected. After the first expansion at a pressure of 3 atm, which was performed thrice (balloon diameter: 12 mm), the bronchoscope could pass through the stenosis. After maximum cauterization of the scar site with the laser (Fig. 3c and d), balloon dilatation was performed at an expansion pressure of 4.5 atm (balloon diameter: 13.5 mm) followed by 8 atm (balloon diameter: 15 mm) thrice each, with simultaneous observation of the lumen with the bronchoscope (Fig. 2). Although the degree of tracheal stenosis improved to Grade II after balloon dilatation, placement of the Dumon stent under a rigid endoscope was impossible due to residual stenosis that did not allow sufficient expansion of the silicon stent. In this course of treatment, only the balloon dilatation was performed in the left main bronchus at an expansion pressure of 3 atm (balloon diameter: 12 mm); however, notable improvement was not observed as the stenosis grading scale remained unchanged. Subsequently, intubation with a 7-mm tracheal tube, management with a mechanical ventilator overnight, and extubation the next day were performed. He was discharged because his symptoms were alleviated; however, the stridor and dyspnea on effort gradually worsened during the follow-up period. A chest CT scan showed restenosis of the trachea (Fig. 4a and b). Consequently, we decided to perform balloon dilatation with laser cauterization after 3 months of the initial treatment. The CRE Pulmonary Balloon Dilatation Catheter (Boston Scientific Corporation, Marlborough, MA, USA) with a maximal expanded diameter of 18 mm at an expansion pressure of 7 atm was selected for this round of treatment. The balloon dilatation was performed with excision and incision of the fibrocicatrization by laser cauterization in a more aggressive manner than that during the initial treatment. Tracheal stenosis improved from Grade III to I. We also performed balloon dilatation with laser cauterization for the left main bronchus during this round of treatment; however, approximately 70% of the stenosis remained. The perioperative management after the treatment was performed in the same way as that in the initial treatment. His symptoms disappeared quickly and he was discharged from our hospital. Even after 22 months of the treatment, he was free from symptoms and good patency of the trachea was maintained, as revealed by the chest CT examination (Fig. 4c).

balloon dilatation, endobronchial tuberculosis, tracheal stenosis

PMC6677788_01

Female

A 72-yr old female visited a local hospital complaining of left lower abdominal discomfort and constipation. An abdominal computed tomography (CT) confirmed a retroperitoneal tumor and the patient was referred to our hospital for further examination. Magnetic resonance imaging (MRI) of the abdomen showed a solid mass measuring 13 cm in diameter on the left side of the pelvis and a liposarcoma containing a well-differentiated component was diagnosed (Fig. 1A). A high-resolution computed tomography (HRCT) of the abdomen revealed that the tumor was suspected to invade the left ureter and descending colon (Fig. 1B). Moreover, HRCT of the chest detected two ground-glass opacities (GGO) in the apical segment (S1) and posterior segment (S2) of the right upper lobe of the lung and was considered to be early stage lung cancer (Fig. 2A). Treatment was carried out by retroperitoneal liposarcoma and retroperitoneal tumor resection after ureteral stent placement by urologists. Intraoperative findings showed that the tumor displaced the descending colon which was therefore partially resected. The tumor size was 13 x 8 x 7.5 cm and postoperative pathological findings indicated DDLPS with invasion to the sigmoid colon (Fig. 1C, D). Four months after the retroperitoneal liposarcoma resection, a right upper lobectomy for suspected lung cancer was performed via video-assisted thoracoscopic surgery (VATS) (Fig. 2B). After lung cancer surgery, the patient was followed-up as an outpatient. Twenty months after the initial surgery, a HRCT of the chest detected a tumor with maximum diameter of 22 mm in the left lower lobe of the lung (Fig. 3A). Because the tumor was located in the peripheral lung, CT-guided fine needle biopsy was performed rather than transbronchial bronchial lung biopsy (TBLB). Pathological findings indicated pulmonary metastasis from dedifferentiated liposarcoma and the tumor tended to grow rapidly. The result of a respiratory function test on the patient showed that her current respiratory function was not sufficient to allow a left lower lobectomy, therefore, in order to preserve the superior segment of the lower lobe (S6), a left basal segmentectomy (S8+S9+S10) was conducted (Fig. 3B). Pathological findings showted DDLPS with invasion to the sigmoid colon (Fig. 3C). The postoperative course was uneventful and she was discharged on the 16th day after the operation. There is no sign of recurrence of the tumor seven months after discharge. She is undergoing outpatient rehabilitation, and she is able to live an independent life without home oxygen therapy.

limited resection, pulmonary metastasis, retroperitoneal liposarcoma

PMC6805429_06

Female

In an assessment at 18 years, she was noted to need substantial help with self-care activities and could not understand or follow instructions. Her interactions and behaviors were immature, characterized as a 4-year-old level by her school evaluations. She had short stature and obesity (weight 88.2 kg, > 98th centile; height 153.0 cm, 6th centile; BMI 37.7 kg/m2, 98th centile) with macrocephaly (head circumference 58 cm; > 98th centile) (Table 1). She had a history of continuously gorging or binge eating to the point of vomiting, requiring her parents to restrict her food intake. She was mildly dysmorphic, with sparse lateral eyebrows, telecanthus, left preauricular pit, prominent cupid bow configuration of the upper lip, and slack facial expression. She had numerous self-inflicted, skin-picking lesions on her arms, in various stages of healing, and one hyperplastic keloidal scar elsewhere. Her speech was fluent but very simple, with sound substitution errors very typical of a young child. There was periodic echolalia, in addition to outbursts of out-of-context speech, without regard to interrupting other speakers. Negative genetic testing included Prader-Willi/Angelman syndrome methylation and MLPA, fragile X, and CNV analysis via SNP microarray. However, areas of homozygosity were identified across multiple chromosomes, with an overall percentage of autosomal/genomic homozygosity of 2.5%. No candidate recessive genes were identified within the homozygous regions. As no specific disease could be suspected on the basis of the clinical presentation, family trio sequencing of GeneDx's Autism/ID Xpanded Panel with 2308 genes was performed, using oral rinse samples from her and both parents. This patient was identified through GeneMatcher. All data generated or analyzed during this study are included in this article. The primer sequences for Sanger sequencing, Real-time PCR, and RT-PCR will be provided upon request. All study participants have given written informed consent, and the genetic study has been approved by the Augusta University Institutional Review Board. All participating families agreed to publish the clinical description and photos.

at hook domain, autism spectrum disorder (asd), bhc80, intellectual disability (id), intrinsically disordered region (idr), kdm1a, neurodevelopmental disorders, phf21a, potocki-shaffer syndrome (pss)

PMC5842720_01

Male

An overweight 62-year-old male with hypertension and hyperlipidemia presented with a hemoglobin level of 20.4 g/dL, hematocrit of 0.59, normal white cell and platelet counts, and a mild eosinophilia (Table 1). The patient had no clinical signs of PV, normal spleen size, normal oxygen saturation, no endogenous erythrocyte colony formation, no evidence of abnormal hemoglobin, and no family history of a hematological abnormality. The patient was managed with intermittent venesection alone for nine years with no evidence of the JAK2 p.V617F mutations by allele-specific PCR or the JAK2 exon 12 mutations by high-resolution melt curve analysis, excluding a diagnosis of PV. At 149 months after diagnosis, thrombocytopenia (75 x 109/L) and increasing eosinophilia (1.9 x 109/L) were noted with a low serum erythropoietin (EPO) level of 0.6 IU/L (normal range 2.6-18.5 IU/L). At 154 months after diagnosis, the patient had temporoparietal stroke. Worsening pancytopenia at 157 months prompted bone marrow biopsy which demonstrated 4% myeloblasts (Table 1). Subsequent bone marrow investigations showed progressively increasing myeloblast cell numbers by both morphological and immunophenotypic evaluation with reduced dysplastic megakaryocytes, dyserythropoiesis with basophilic stippling, and binuclear red cell forms, all consistent with MDS progressing to AML (Figure 1). The karyotype at 159 months was normal. The patient was not fit for intensive treatment and was given best supportive care with EPO, intermittent red cell transfusions, and low-dose steroids but died of infection at 161 months. A targeted NGS approach panel was retrospectively employed to detect mutations possibly contributing to the erythrocytosis and subsequent development of MDS/AML in archival peripheral blood or bone marrow DNA samples from 41, 149, and 161 months. Amplicon libraries covering thirty commonly mutated genes implicated in myeloid malignancies, either covering the entire coding region (CALR, CEBPA, ETV6, EZH2, RUNX1, SH2B3, TET2, TP53, and ZRSR2) or mutational hotspots (ABL1, ASXL1, BRAF, CBL, CSF3R, DNMT3A, FLT3, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, SETBP1, SF3B1, SRSF2, and U2AF1), were generated. Sequencing was performed with Ion AmpliSeq methodology (Thermo Fisher Scientific, Paisley, UK). Calling of somatic mutations was achieved using an algorithm that excluded synonymous mutations, variants located within intronic or untranslated regions, and those present at a variant allele frequency (VAF) of <5%. A minimum target depth of coverage for variant calls was set at 500x as previously described. The nonsynonymous SH2B3 exon 2, single-nucleotide polymorphism (SNP) W262R (c.784T>C, NP_005466.1, rs3184504) was present at all three time points analyzed at VAFs of approximately 50% (Table 1). No mutations were detected in MPL exon 10 or CALR exon 9. A single CBL L380P mutation (c.1139T>C, NP_005179.2) was detected in the bone marrow sample at 161 months. Reinterrogation of sequencing data revealed this CBL mutation to be present a year previously at a VAF of 3.6% (Table 1).

PMC2647167_01

Unknown

A 40-year-old seaman presented with malaise, fever, dyspnea and a 10 kg weight loss (15% of body weight over a period of the months). High-resolution computed tomography (CT) images demonstrated diffuse ground glass opacities (GGO) in both lungs. A transbronchial lung biopsy (TBLB) was performed but was complicated by the presence of pneumothorax (Fig. 1A). However, as the size of the biopsy sample was inadequate, PCNB was performed immediately after the TBLB. Under CT guidance with the patient in the supine position, a chest radiologist with 18 months of experience performed percutaneous aspiration with the use of a 22-gauge 15-cm Chiba biopsy needle (InterV; Angiotech, Gainesville, FL). A CT scan showed that the needle was placed into the right lung lesion. The procedure was successful at the first attempt. Just after aspiration, the patient complained of dyspnea and subsequently a tonic-clonic type seizure developed with anisocoric pupil dilation. Brain CT imaging was performed with application of an oxygen mask and showed abnormal air densities in the sulci of both the parietal and occipital lobes (Fig. 1B). Unfortunately, hyperbaric oxygen therapy (HBOT) was not available at that time. The PCNB specimen showed the presence of Pneumocystis carinii organisms, and serum testing was positive for antibodies against human immunodeficiency virus (HIV) and the CD4 cell count was less than 50 cells/mm3. Accordingly, the final diagnosis was acquired immunodeficiency syndrome (AIDS) with Pneumocystis carinii pneumonia. Transthoracic echocardiography (TTE) performed two days later failed to reveal any structural abnormalities that could cause the right-to-left shunt. Despite supportive management and antibiotics, the patient died of pneumonia and sepsis without any improvement in mental status.

High-resolution CT scan demonstrates diffuse ground glass attenuations in both lungs, and small amount of right pneumothorax due to previous transbronchial lung biopsy (A).

PMC2647167_03

Male

A 67-year-old man was referred for the evaluation of a lung lesion. The patient complained of a productive cough of three weeks duration and a chest CT scan showed the presence of multiple nodules with GGO in both lung fields. As fiber optic bronchoscopy with a TBLB was not diagnostic, a chest radiologist with two years of experience performed a CT-guided PCNB with the use of an 18-gauge ACN biopsy needle (Angiotech) in a patient placed in the supine position. However, the mental status of the patient deteriorated rapidly just after the biopsy, which was followed by convulsions and left side hemiparesis. A careful review of chest CT scans obtained during the procedure revealed the presence of air fluid level in the descending aorta (Fig. 3). Brain CT scans and MRI were checked, but no abnormality was evident. According to the temporal relationship between the neurological signs and the biopsy procedure, we made a presumptive diagnosis of a cerebral air embolism. Ninety hours after the event, the patient underwent HBOT (100% oxygen, 2.2 atmospheres for 60 minutes). The mental status improved after HBOT and one day later the patient underwent one additional HBOT session. A TTE was normal. The patient was discharged without any neurological sequelae.

PMC3292808_01

Male

A previously healthy 62-year-old Caucasian man was admitted to our hospital for acute respiratory failure. Our patient developed a fever of up to 40 C seven days earlier and a non-productive cough three days later. He had not received any antimicrobial treatment prior to his hospitalization, the diagnosis of his primary care physician being influenza (A/H1N1v), given the ongoing outbreak. His medical history was remarkable for possible viral pericarditis without any consequence in 2007 and a gastric ulcer 30 years earlier. He had no drinking habits. He did not smoke cigarettes. He had not travelled abroad recently. He did not have any bird or pet. On hospital admission, our patient was in acute respiratory distress. His respiratory rate was 40 breaths/minute, his temperature 38.3 C, his pulse 98 beats/minute and his blood pressure 114/60 mmHg. Auscultation revealed crackles over his whole left lung and over his right lower lung field. A computed tomography scan showed diffuse alveolar type infiltrates in his two lung fields with air bronchograms (Figure 1). Arterial blood gas analysis (under 100% oxygen through a non-rebreathing mask) showed pH 7.54, a partial pressure of carbon dioxide (PaCO2) 44 mmHg, partial pressure of oxygen (PaO2) 38 mmHg and an arterial blood oxygen saturation of 84%. His white blood cell count was 5780 cells/muL (86% neutrophils) and the erythrocyte sedimentation rate was 92 mm/h. Laboratory values showed serum creatinine at 1.7 mg/dL, potassium at 2.8 mEq/L, creatine phosphokinase at 644 IU/L, liver test alterations (alanine transaminase at 87 IU/L), lactate dehydrogenase elevation (1708 IU/L) and D-Dimers at 7420 ng/mL, activated partial thromboplastin time of 72 seconds, normal international normalized ratio and blood platelets at 166.000/muL. His urine output was 0.4 mL/kg/h over six hours. An electrocardiogram showed a sinus tachycardia with a complete right bundle branch block. Serum samples obtained every week as from the day of admission showed a clear-cut seroconversion for C. pneumoniae antibodies (the course of the antibody titers shown in Table 1). Paired serum samples and antigens against the most common microorganisms, including atypical bacteria and common viruses such as A/H1N1v, were negative. Blood, sputum and urine tests for bacterial cultures obtained during the first day of hospitalization were negative. Our patient was treated by amoxycillin-clavulanic acid, moxifloxacin and oseltamivir. His respiratory status necessitated endotracheal intubation and mechanical ventilation. Severe arterial hypotension prompted norepinephrine infusion and the insertion of a pulmonary artery catheter. The initial hemodynamic pattern was typical for sepsis (hemodynamic values are shown in Table 2). Metabolic data showed a mixed venous saturation of 56%. Despite maximal ventilatory support (high positive end expiratory pressure, an inspired oxygen fraction (FiO2) of 1.0, nitric oxide inhalation of 20 ppm, neuromuscular blocking agents and prone positioning), our patient remained severely hypoxemic (PaO2/FiO2 = 38) which led us to initiate ECMO treatment. Venovenous ECMO (a Sorin Revolution centrifugal pump, a Sorin ECCO oxygenator and a Sorin Satcrit console from Sorin Group, Milano, Italy) was put in place on the fifth day of hospitalization, with a left femoral 22-Fr drainage cannula and a right femoral 23-Fr return cannula, inducing a drastic improvement of our patient's oxygenation parameters (PaO2 = 120 mmHg). The mixed venous oxygen saturation (SVO2) increased from 56% to 86%. Continuous veno-venous hemodiafiltration (CVVHDF) renal replacement therapy was also initiated on day three because of acute renal failure. There were no severe complications of the ECMO treatment except for hemorrhagic suffusion of the two femoral catheter insertion points, requiring a blood transfusion. ECMO and CVVHDF were withdrawn on day 12. Our patient was extubated on day 18 and discharged from our Intensive Care Unit on day 20. He went home a month later. He is now in good physical condition and has returned to work and to a normal social life.

PMC7315081_01

Female

In 2010, a 53-year-old female patient was consulted to the gastroenterology clinic with complaints of fatigue and abdominal pain. Biochemical analysis revealed elevated blood levels of alanine aminotransferase (41 U/L), aspartate aminotransferase (108 U/L), alkaline phosphatase (ALP; 649 U/L), gamma-glutamyltransferase (GGT; 361 U/L) and a negative autoimmune panel. Ultrasound examination revealed hepatomegaly, and thoracic computed tomography results indicated that the lymph nodes in the mediastinum, paratracheal, and precarinal regions were 2x1 cm in size. Tru-Cut biopsy (Becton Dickenson and Co., Franklin Lakes, NJ, USA) of the liver was performed with the initial diagnoses of tuberculosis, lymphoma, and sarcoidosis. The histopathological evaluation indicated noncaseating granulomatous inflammation in the parenchyma consistent with grade 3 macrovesicular steatosis and foci of intralobular non-necrotising granulomatous inflammation (Figs. 1-3). Ziehl-Neelsen staining results were unremarkable. As the angiotensin-converting enzyme level was 5 times higher than the upper limit of normal (250 U/L; normal: 8-52 U/L), the case was evaluated as sarcoidosis with hepatic involvement, and the patient was sent to a center with a sarcoidosis polyclinic. Treatment and follow-up continue.

granulomatous, hepatic, sarcoidosis

PMC280706_01

Male

A 66-year-old Caucasian male was admitted due to chest pain, aggravated dyspnea, and productive cough. His symptoms started 15 days earlier and gradually progressed. He was a current smoker (30 pack/years) and his previous medical history included alcohol use, arterial hypertension, and chronic obstructive pulmonary disease (COPD). He had no history of congestive heart failure or dysphagia. On admission the patient was pale, with dilated jugular veins, abdominal respiration with tachypnea (30 breaths/min), tachycardia (150 beats/min), and pulsus paradoxus (20 mmHg), while his blood pressure was with in normal range (100/60 mmHg). At auscultation, heart sounds were reduced and gallop rhythm was present; no murmurs or pericardial rub were audible. The chest examination revealed bilateral expiratory wheezing, that was attributed to the coexisting COPD. The abdomen was distended and the liver was palpable approximately 1 cm subcostally. The admission ECG showed sinus tachycardia with reduction of the amplitude of the QRS complexes and ST-segment depression in leads V4 to V6 (<1 mm). Chest X-ray demonstrated an enlarged cardiac silhouette, a small left lung lesion accompanied by a moderate pleural effusion on the left hemithorax and a minor one on the right, and elevation of the right dome of the diaphragm due to a calcified hepatic lesion (Figure 1). Arterial blood gas measurement revealed acute on chronic respiratory acidosis. Echocardiography revealed a significant pericardial effusion with compression of the right heart chambers. Due to his critical condition, an emergency pericardiocentesis was performed at the time of the admission. A quantity of 1100 cc of exudative bilious stained fluid was drained and his condition improved rapidly. Pericardial fluid showed total protein to be 2.2 g/dL, total bilirubin 4.7 mg/dL, indirect bilirubin 4.5 mg/dL and LDH 209 U/L, with absence of hemoglobin. Chest CT-scan revealed a central mass of the left lung that was not prominent on the chest X-ray, a second smaller mass located in the left interlobar fissure, segmental atelectasis of the left upper lobe, a moderate pleural effusion on the left hemithorax and a small one on the right, a residual pericardial effusion, and a typical 9-cm hydatid cyst with calcified wall, located sub-diaphragmatically on the right lobe of the liver, in close contact with the diaphragm and the pericardial cavity (Figure 2). A chest tube was inserted in the left hemithorax and 500 cc of sanguineous exudative fluid were consequently drained. In the complete blood count, white blood cells were 26,800/mm3 with marked neutrophilia (91.8%), whereas serum biochemistry values included glucose 234 mg/dL (normal range 70-110 mg/dL), total bilirubin 2.3 mg/dL (0-1 mg/dL), direct bilirubin 1.3 mg/dL, LDH 189 U/L (range 89-221 U/L), ALT 84 U/L (range 5-49 U/L), gamma-GT 96 U/L (range 0-53 U/L), CK 311 U/L (range 26-174 U/L) and CK-MB 33 U/L (range 0-24 U/L). The titer of anti-echinococcal antibodies was negative (Elisa, bioMerieux , titer of negative control <1:100). Culture of fluid from the left pleural and the pericardial effusion for common pathogens and Mycobacterium tuberculosis were negative. However, the cytology of the pericardial effusion was positive for non-small cell lung cancer (NSCLC), whereas the left pleural effusion was suspected for malignancy. Total bilirubin levels of the pericardial fluid were within normal range (0.5 mg/dL) after the third post-drainage day. Furthermore, no bilirubin was detected in the pleural fluid drained. The chest tube was removed six days later after a successful slurry talk pleurodesis. A proper percutaneous subxiphoid pericardiotomy under local anaesthesia was performed one day later. Numerous local infiltrations on the pericardium and the myocardium were observed. Initially, drainage of 500-600 cc of fluid per day was observed, but with a diminishing trend. Pericardiodesis with bleomycin was performed and the pericardial drain was removed on the 10th post-pericardiotomy day. Histological examination of biopsies obtained from the resected pericardium revealed a metastatic poorly differentiated lung adenocarcinoma. The patient was subsequently submitted to chemotherapy, but died 6 weeks later. During the follow-up no recurrent effusion was detected, clinically or radiologically. Unfortunately, the severe clinical condition of our patient did not allow us to investigate further the mechanism of pericardio-biliary communication. Postmortem examination was also not carried out.

PMC7377931_01

Male

A 74-year-old man (body height, 148 cm; body weight, 42 kg) presented with symptoms of the common cold for a few days and was transferred to our hospital due to worsening dyspnea. On arrival, his initial vital signs were as follows: Glasgow Coma Scale score, 6 (E1V1M4); respiratory rate, 18 breaths/min; percutaneous oxygen saturation, 94% under assisted ventilation with bag valve mask; heart rate, 84 b.p.m.; and blood pressure, 169/70 mmHg. He had weak breathing, and his oxygen saturation fell sharply when assisted ventilation was stopped. Results of arterial blood gas analysis revealed severe hypercapnia and respiratory acidosis (Table 1). Based on the clinical presentation, we planned to intubate the patient for mechanical ventilation. However, tracheal intubation was extremely difficult because of severe cervical-thoracic kyphosis resulting from vertebral tuberculosis. First, we administered fentanyl i.v. and tried to intubate him by video laryngoscopy; although the glottis was easily visualized, we made one attempt at intubation with an endotracheal tube (ETT) with an internal diameter (ID) of 8.0 mm (outer diameter [OD] 10.9 mm), which was unsuccessful because the abnormal curvature of the trachea prevented tube advancement. Next, we attempted to intubate by bronchoscopy with a diameter of 5.9 mm but failed to advance the bronchoscope beyond the abnormal curve. Finally, we managed to intubate with an ETT with an ID of 5.0 mm (OD 6.9 mm). However, this provided inadequate ventilation; percutaneous oxygen saturation decreased to 70% and did not improve. Supraglottic airway devices were not used because the patient's neck was short and the range of neck motion was limited. After the multiple failed attempts at ventilation by ETT, we judged that it was necessary to undertake a surgical tracheostomy to secure his airway. However, simple cricothyrotomy was not expected to resolve the issue of severe tracheal deformity (Fig. 1A). Additionally, surgical tracheostomy for severe tracheal deformity required time, but the patient lacked the oxygen capacity needed to maintain saturations while the procedure was carried out. Therefore, we decided to use venovenous ECMO for surgical tracheostomy. We chose the femoral-femoral configuration of venovenous ECMO because of the patient's short neck and limited neck motion. A 22 French gauge (Fr) drainage cannula (NSH heparin-coating cannula; Senko Medical Instrument Mfg., Tokyo, Japan) was placed percutaneously in the right atrium and the superior vena cava through the right femoral vein, and a 20 Fr return cannula (NSH heparin-coating cannula) was placed percutaneously in the inferior vena cava through the left femoral vein. Venovenous ECMO increased his percutaneous oxygen saturation to 90%, allowing a tracheostomy to be placed beyond the severe abnormal curve. We inserted the flexible spiral type of tube with an ID of 8.0 mm (GB Adjustfit Tracheostomy Tube; Fuji Systems, Tokyo, Japan). After tracheostomy, the patient was admitted to intensive care. A computed tomography scan after admission confirmed the presence of a severe tracheal deformity that was curved at a sharp angle (Fig. 1E,F). Lung rest ventilation was instituted for the duration of intensive care admission. Based on the history of events and examination findings, we diagnosed the cause of the respiratory failure to be pneumonia and initiated a course of antibiotics. The patient's oxygenation gradually improved (Fig. 2), allowing ECMO to be withdrawn on day 8. Hypercapnic respiratory failure persisted due to the chest deformity, but intensive rehabilitation made it possible to wean him off the ventilator during the daytime. He was transferred to another hospital for continued rehabilitation on day 46 and had no neurological deficits.

difficult airway, extracorporeal membrane oxygenation, tracheal deformity, vertebral tuberculosis

PMC3952427_01

Female

A 45-year-old woman presented to the surgery outpatient department with complaints of difficulty in swallowing, predominantly solid food, for the past 6 months. She had lost about 7 kg weight in the last 3 months due to difficulty in food intake since the patient was mostly on liquid diet. She had no history of chronic heartburn, smoking, fever, or altered bowel habits. Routine blood investigations were within normal limits. She was advised barium swallow and subsequently was advised contrast-enhanced computed tomography (CECT) thorax. Barium swallow showed smooth external indentation on the esophagus, predominantly from right side and from posterior aspect with slight hold up of contrast [Figure 1]. There was no evidence of stricture or mucosal irregularity. CECT thorax confirmed the barium findings and the diagnosis [Figure 2]. What is the CT finding and final diagnosis? What are the various types of this condition? Axial CECT thorax showed right-sided aortic arch with four vessels originating from aortic arch. There was an aberrant left subclavian artery going posterior to the esophagus forming a vascular ring around esophagus causing extrinsic compression [Figure 2]. Based on the imaging findings, a diagnosis of right-sided aortic arch with an aberrant left subclavian artery was made. A clinical diagnosis of dysphagia lusoria was suggested on the basis of combined clinical and imaging findings. Right-sided aortic arch is a common aortic arch anomaly and occurs in 0.05% of the population. It is commonly divided into three types based on the branching pattern: A right aortic arch with an aberrant left subclavian artery (Type 1), a right aortic arch with mirror image branching (Type 2), and a right aortic arch with isolation of the left subclavian artery (Type 3). Of this right aortic arch with an aberrant left subclavian artery as seen in our case is the most common type. This anomaly rarely produces symptoms and is usually detected incidentally. However, in some cases tracheal or esophageal compression due to the aberrant artery may be seen. Dysphagia lusoria is the term used to collectively describe all the aortic arch anomalies, which compress the esophagus and cause dysphagia. In symptomatic cases, barium swallow studies will show a smooth impression in the posterior wall of the upper thoracic esophagus due to the aberrant vessel as is seen in the present case. However, in asymptomatic cases the barium swallow may be normal. On CT or magnetic resonance scans, the diagnosis can be easily confirmed. The aortic arch is seen on the right side and the descending aorta may be seen either in midline or to the right. Four arteries are seen to arise from the aortic arch, first branch being the left carotid artery followed by the right carotid, right subclavian, and an aberrant left subclavian arteries in that order. The aberrant left subclavian artery passes posterior to the esophagus. In some cases, the aberrant left subclavian artery can arise from a diverticulum known as the kommerrel diverticulum. CT may demonstrate the "four artery sign," which shows two ventral carotid arteries and two dorsal subclavian arteries evenly spaced around the trachea. Treatment depends on the severity of dysphagia. If the symptoms are mild as in our case, dietary modification is usually adequate. However in severe cases, surgery and ligation of the vessel may have to be performed.

PMC10276616_01

Male

A 52-year-old man ingested "Tusanqi powder" at a dose of 5 g one to two times daily because of an injury sustained from a fall. Eight days later, he developed fatigue, abdominal distension, and abdominal pain. His coagulation indices were as follows: PT: 19.0 s, prothrombin activity (PTA): 42%, and international normalized ratio (INR): 1.87. On biochemical testing, his results were as follows: estimated value of the glomerular filtration rate: 98.47 mL/min/1.73 m2, TBIL: 108.9 micromol/L, direct bilirubin (DBIL): 65.4 micromol/L, ALB: 26.0 g/L, globulin: 33.4 g/L, ALT: 645 U/L, AST: 477 U/L, ALP: 148 U/L, and GGT: 251 U/L. The CT scan showed that the density of the liver parenchyma was unevenly reduced. The liver parenchyma in the arterial and venous phases showed a characteristic "map-like" appearance and uneven enhancement, and the hepatic veins were thin and unclear. Enlarged lymph nodes in the porta hepatis were observed. A liver biopsy was performed on the 10th day of the disease. Early pathological changes were observed in the specimen of the patient who underwent liver biopsy during the acute stage. Hepatocytes exhibited hemorrhagic necrosis and were fused into sheets. As hepatocytes separated, numerous red blood cells infiltrated the perisinusoidal space, and the perisinusoidal space expanded and compressed the hepatic sinus. The sinus cavity and perisinusoidal space fused and became indistinguishable, and the hepatic sinusoid appeared dilated and congested. Hemorrhagic necrosis was observed on HE staining (Figure 2). After the diagnosis of HSOS was established, treatment with low-molecular-weight heparin combined with warfarin was initiated; however, the condition of the patient continued to deteriorate. Complications, such as hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding, occurred, and the patient died on the 30th day of the disease.

tusanqi, drug-induced liver injury, hepatic sinusoidal obstruction syndrome, pyrrolizidine alkaloid

PMC10276616_02

Male

A 49-year-old man ingested 3 g of "Tusanqi powder" three times daily for 2 months. Subsequently, the patient developed fatigue, abdominal distension, and abdominal pain. The laboratory findings were as follows: TBIL: 34.6 micromol/L, DBIL: 18.73 micromol/L, ALB: 34.2 g/L, ALT: 446 U/L, AST: 543 U/L, ALP: 116.0 U/L, GGT: 103 U/L, PT: 14.0 s, PTA: 77.8%, and INR: 1.13. CT showed diffuse hepatomegaly and unevenly reduced density of the liver parenchyma. The liver parenchyma during the arterial and venous phases showed a characteristic "map-like" appearance and uneven enhancement. The hepatic veins were unclear, and ascites were present. After admission, the patient was diagnosed with HSOS and treated with low-molecular-weight heparin and warfarin. After 1 month of treatment, the patient's clinical symptoms disappeared and biochemical indices and imaging findings returned to normal. Warfarin was administered orally and monitored weekly to achieve an INR between 2.0 and 2.5. Three months after the patient was treated, a liver biopsy revealed that most liver tissues did not exhibit obvious inflammation and necrosis. Only a few areas still showed congestion in the hepatic sinus, with patchy and band-like inflammation and necrosis. Fibrotic embolism was observed in the central vein, and perisinusoidal fibrosis was also noted (Figure 3c and d).

tusanqi, drug-induced liver injury, hepatic sinusoidal obstruction syndrome, pyrrolizidine alkaloid

PMC10276616_03

Female

A 52-year-old woman intermittently ingested 3 g of "Tusanqi powder" one to two times a day. Fatigue, abdominal distension, and abdominal pain occurred after 15 days of using the drug. Her blood coagulation indices were as follows: PT: 15.0 s, PTA: 83%, and INR: 1.07. Biochemical test results were as follows: TBIL: 45.9 micromol/L, DBIL: 30.4 micromol/L, ALB: 31.0 g/L, ALT: 1142 U/L, AST: 1076 U/L, ALP: 118 U/L, and GGT: 296 U/L. Liver ultrasonography showed diffuse enlargement, liver parenchyma echogenicity with increased coarse density, uneven distribution, and visible "patch-like" areas of reduced echogenicity along the hepatic veins. A small amount of peritoneal effusion was also present. A CT scan showed an uneven reduction in liver parenchyma density, a characteristic "map-like" appearance of the liver parenchyma during the arterial and venous phases with uneven enhancement, and thin and unclear hepatic veins. Enlarged lymph nodes in the porta hepatis were also observed. After HSOS was diagnosed, treatment with low-molecular-weight heparin was initiated. After 30 days of treatment, the symptoms of the patient improved, and her biochemical indices and CT findings were close to normal (Figure 4a and b). The patient was readmitted for abnormal liver function in the 8th month of the disease and underwent a liver biopsy. Pathological features included mild inflammation in the central area, obvious dilatation of the hepatic sinus, mild fibrosis around the sinus, fibrosis deposition in the sinus, and an embolism in the central vein. Anticoagulant therapy with rivaroxaban tablets was then initiated for the patient (Figure 4c and d).

tusanqi, drug-induced liver injury, hepatic sinusoidal obstruction syndrome, pyrrolizidine alkaloid

PMC10064166_01

Female

A 12-year-old female neutered domestic shorthair cat was referred to our institution with slowly progressive bilateral forelimb lameness and a decreased range of motion (ROM) in extension of both carpal joints. No history of trauma, nor surgical intervention was reported. Clinical signs started 10 months prior to referral, consisting of right forelimb lameness that evolved, into carpal hyperflexion with a lack of carpal extension. Medical treatments were instigated by the referring veterinarian, including the use of steroidal (methylprednisolone 0.5 mg/kg q24h PO [Moderin; Zoetis]) and non-steroidal anti-inflammatory drugs (meloxicam 0.05 mg/kg q24h PO [Metacam; Boehringer Ingelheim]), but both were unsuccessful. Six months after signs were noted on the right forelimb, similar clinical signs were noted on the left forelimb. Physical examination was unremarkable, except for the presence of generalised moderate muscle atrophy of both forelimbs detected on palpation. Neurological examination was unremarkable. The cat was reluctant to move, and a carpal flexural deformity (CFD) with a certain degree of distal valgus deviation, which was more pronounced on the left side, was noted (Figure 1). A subtle permanent flexion of the digits II-V was observed, which was more pronounced on the right forelimb. A firm, non-painful induration of the flexor retinaculum was palpated, secondary to the tension of the tendons at this level, compromising carpal ROM in extension. The hyperflexion and valgus deviation were irreducible, and an increased tension of the flexor muscles, in particular the flexor carpi ulnaris muscle (FCUM) at its insertion onto the accessory bone, could be palpated. No other abnormalities were palpated at the level of the flexor muscles bellies. Blood urea nitrogen, creatinine, creatine kinase and total thyroxine values were within the reference intervals. Orthogonal radiographs of both forelimbs demonstrated a valgus deviation of the distal extremities (Figure 2). Ultrasound of the musculature and corresponding tendons of both forelimbs was performed, but no abnormalities were identified. Owing to the severity of the clinical signs and the cat's discomfort, surgery consisting of a selective tenectomy of the contracted flexor muscles was proposed.The cat was premedicated with methadone (0.2 mg/kg IV [Comfortan; Dechra]), and induced with midazolam (0.3 mg/kg IV [Dormazolam; Dechra]) and alfaxalone (Alfaxan; Jurox Animal Health) to effect. Anaesthesia was maintained with 1-2% isoflurane in 100% oxygen, alongside a continuous rate infusion of fentanyl (5-12 microg/kg/h IV [Fentadon; Dechra]). The patient received lactated Ringer's solution (10 ml/kg/h IV) intraoperatively. Cefazoline (20 mg/kg IV [Cefazoline; Sandoz]) was administered every 90 mins. The patient was positioned in dorsal recumbency with the palmar surface of both forelimbs toward the surgeon. On the left forelimb, a palmarolateral skin incision of 4 cm was made, proximal to the antebrachiocarpal joint, followed by blunt dissection to expose the flexor muscle tendons. The tendons of the FCUM, flexor carpi radialis muscle (FCRM) and superficial digital flexor muscles (SDFMs) were isolated, and resection of a 5 mm long segment of these tendons was performed using a #11 scalpel blade. The tenectomies were performed in following order: first the FCUM, then the FCRM and finally the SDFM. A progressive resolution of the carpal hyperflexion was noted during the tenectomies. On the right forelimb, a tenectomy of the FCUM tendon was performed via a curvilinear skin incision starting palmaromedial to palmarolateral and proximal to the right antebrachiocarpal joint (Figure 3). Small skin incisions were made at the palmar surface of the second phalanx of the third and fourth digits of the right forelimb, allowing for selective tenectomy of the tendon branches of the deep digital flexor muscle (DDFM) of these digits (Figure 4). The tendon branches of the remaining digits were left intact, as these are not the major weightbearing digits, and we did not want to be too invasive. Muscular and tendinous biopsies of all sectioned tendons and associated muscles were taken intraoperatively. The subcutaneous tissues were closed using a simple continuous pattern with a 4-0 poliglecaprone 25 suture (Monocryl; Ethicon). The skin was apposed with an interrupted suture pattern with 4-0 polyamide (Ethilon II; Ethicon). A bandage with the carpal joints at the maximal angle of extension was placed during the first 12 h postoperatively, and treatment with meloxicam (0.1 mg/kg q24h IV [Acticam; Ecuphar]) was initiated. Postoperative recovery was uneventful. Twelve hours postoperatively, a certain degree of hyperflexion of the carpal joints and a moderate bilateral forelimb lameness persisted (Figure 5). The cat was discharged 24 h postoperatively with meloxicam (0.05 mg/kg q24h PO for 5 days [Metacam; Boehringer Ingelheim]). Histopathology of the sectioned tendons revealed minimal leukocytic infiltration, compatible with peripheral chronic inflammation; however, an ischaemic aetiology could not be excluded. Histopathology of the muscles showed minimal signs of atrophy. One month postoperatively, the cat was still moderately lame on the left forelimb with a partial palmigrade stance and a slight retraction of the second and fifth digits. An improvement in locomotion quality was noted by the owner. Two months postoperatively, the cat presented with recurrence of clinical signs on the left forelimb, characterised by hyperflexion of the carpus and digits two, three and four, and valgus deviation. The region of the flexor retinaculum was again indurated due to tendons in tension. No abnormalities were observed on the right forelimb. A selective tenectomy was repeated on the left forelimb. The same anaesthetic protocol and surgical approach, as mentioned above, were used. Fibrous tissue connecting both ends of the tendon was present at the previous tenectomy sites. More tenectomies were performed over a length of 10 mm of the tendons of the FCUM, FCRM and SDFM proximally to the antebrachiocarpal joint. Also, the tendon branches of the DDFM of the second, third and fourth digits were sectioned. Twenty-four hours postoperatively, the lameness had improved slightly. The cat was discharged with meloxicam (0.05 mg/kg q24h for 7 days [Metacam; Boehringer Ingelheim]). Follow-up after the second intervention occurred by phone contact. One month after the second intervention, the cat was free of lameness and had no CFD of the forelimbs. The Last follow-up was performed 6 months postoperatively. The cat was doing well, although it was showing a slight lameness on the left forelimb. The owner declined any follow-up consultation.

bilateral contracture, carpal flexural deformity, flexor muscles, outcome, selective tenectomy

PMC6441746_01

Male

A 23-year-old man presented in March of 2014 to a community hospital in Maryland with four days of fever, chills, severe malaise, and myalgias, which he reportedly attributed to overexertion on a recent five-day ski trip to Vermont. Chest x-ray was unremarkable (Fig. 1a). He was given a diagnosis of viral upper respiratory infection and dehydration, and discharged from the Emergency Department in haste, as he needed to 'catch a flight to Hawaii' per hospital documentation. However, he returned later that day with severe dyspnea. Vital signs included maximum temperature to 102.7 Fahrenheit, heart rate 131 beats per minute, respiratory rate 48 breaths per minute, blood pressure 94/40, and arterial oxygen saturation was 55% on 100% oxygen via nasal cannula. He was emergently endotracheally intubated and copious bloody secretions from the endotracheal tube were noted. Other abnormalities included mild elevation of transaminases and total bilirubin, acute kidney injury (serum creatinine 2.3 mg/dL with protein and blood on urinalysis), rhabdomyolysis (creatinine kinase 2811 U/L), abnormal coagulation profile (prothrombin time 16.9 s, partial thromboplastin time 29 s, international normalized ratio 1.4), leukocytosis (18.3 K/l), anemia (hemoglobin 7.0 g/dL), and thrombocytopenia (96 K/ mul). CXR showed development of interstitial opacities (Fig. 1b). Vancomycin, ceftriaxone, azithromycin, and oseltamivir were initiated empirically at the community hospital, to cover for usual bacterial pathogens associated with community-acquired pneumonia including methicillin-resistant Staphylococcus aureus (MRSA), and influenza. Within 12 h of intubation, the patient had decompensated further and had evidence of acute respiratory distress syndrome (ARDS) with Pa02/Fi02 of 62, bilateral infiltrates on chest x-ray, and no evidence of left atrial hypertension. The patient was transported by helicopter to a tertiary hospital critical care resuscitation unit, and immediately initiated on veno-venous ECMO and ventilated with a protective lung strategy. Bronchoscopy revealed severe erythema and inflammation of mucosa with increasing blood secretions returned with each bronchoalveolar lavage. Additionally he required vasopressors for severe acidosis and hypotension, and was initiated on continuous renal replacement therapy for oliguric renal failure. Twelve units of packed-red blood cells were infused in the first 24 h to maintain hemoglobin levels above 7.0 g/dL. Infectious Diseases service and several other consult services were immediately notified of his arrival. On physical examination, the patient was critically ill appearing, sedated and ventilated with ECMO cannulas, endotracheal tube, and other support structures in place, but appeared to be a previously healthy well-nourished and well-developed young man. Crackles were heard in all lung fields. Rash, jaundice, and conjunctival injection were absent. A thorough investigation into the patient's medical, social, and travel history revealed that he was on a scheduled break from active military service for the United States Navy; he serves on a submarine stationed in Pearl Harbor, Hawaii (HI). Past medical history was notable only for Bells palsy as a child due to Lyme disease, and he had received recommended childhood vaccinations. He had flown to Maryland from HI, and then driven to Vermont with a friend to ski and they had skied 'hard' for five days. They stayed in a cabin, which according to the friend was clean and otherwise unremarkable. Contact with medical personnel and military officials from his unit provided an accurate travel history for the antecedent 6 months of military service, which cannot be detailed here. However, we were able to confirm that he had not traveled recently to the Middle East or any areas with endemic malaria. Based on areas traveled, mild liver involvement, and the short list of infectious causes of DAH in immunocompetent patients, leptospirosis and dengue fever were suspected. Influenza remained a possibility also as the presentation occurred during influenza season, though all military members on the ship had received annual influenza vaccination. Tick-borne illnesses, while unlikely causes of DAH, were also considered based on travel to Vermont (though seasonality was not consistent). S. aureus pneumonia also was a possibility, made less likely by the presence of viral prodrome unless it had occurred as a complication of influenza. Family history was unknown as the patient had been adopted from Romania at birth, and there were no known sick contacts or disease outbreaks on his submarine. The patient was empirically started on high dose intravenous steroids for possible vasculitis; extensive evaluation for rheumatologic disease excluded granulomatosis with polyangitis (Wegener's syndrome), anti-glomerular basement membrane disease (formerly 'Goodpastures' syndrome), systemic lupus erythematosus, antiphospholipid antibody syndrome, systemic sclerosis, and mixed connective tissue disease. Lung biopsy was not pursued due to high risk of bleeding while on ECMO. Based on epidemiologic risk factors, clinical presentation, and severity of illness, empiric antibiotic therapy with vancomycin, ceftriaxone, azithromycin, doxycycline, and oseltamivir was chosen to cover for community acquired pneumonia (including typical and atypical pathogens and MRSA), leptospirosis, tick-borne infections, and influenza. Prior to confirmation of full recent travel history, contact, droplet, and airborne isolation was instituted due to concern for MERS-CoV (Middle East respiratory syndrome coronavirus). Testing for acute and chronic HIV, hepatitis B, and hepatitis C was negative. No respiratory viruses were identified by PCR from nasal swab or bronchoalveolar lavage (BAL). Cultures of blood and BAL specimens for bacterial and fungal pathogens were also negative. Other negative tests included: thick and thin blood smears for malaria, Legionella and Streptococcus pneumoniae urinary antigens, serum CMV PCR, Lyme IgM, and IgG, IgM, and PCR for Ehrlichia chaffeensis and Anaplasma phagocytophilum. Mycoplasma IgG was positive, but IgM and PCR were not. Hantavirus IgG was also positive with negative IgM. Two days into the patient's admission to the tertiary hospital, his family recalled an important clue - they showed the medical team a digital photograph of the patient covered in mud that he had sent approximately two weeks prior to illness onset [Fig. 2]. He had participated in the "Warrior Dash" in Hawaii. The event consists of fourteen outdoor obstacles, several of which involved full body exposure to mud or fresh water. Consistent with clinical suspicion, IgM for Leptospira was positive. The Centers for Disease Control and Prevention and Hawaii Department of Health (HI DOH) Disease Investigation Branch were made aware, and they provided confirmatory testing. A four-fold increase in IgM titers from acute to convalescent phase, as well as PCR positive for Leptospira interrogans serovars Icterohaemorrhagiae and Mankarao, further bolstered the diagnosis. The dominant serovar in HI is icterohaemorrhagiae; therefore transmission likely did occur while the patient was in HI, during participation in the 'Warrior Dash' two weeks prior to symptom onset. The presence of serovar mankarao is consistent either with co-infection or with cross reactivity on testing. Per HI DOH, there were no other known cases occurring in association with this event. By the patient's sixth day on ECMO he had a significant radiographic and clinical improvement with no further evidence of DAH. He was decannulated from ECMO and endotracheally extubated the following morning. Total time on ECMO was 126 h. Two days later he was discharged from the intensive care unit and he left the hospital shortly after. At follow up one month later, patient reported being weak compared to his baseline (could 'only' perform 20 push-ups). Following a three to five month process of medical clearance, the patient was able to return to active duty for the US Navy (Fig. 3). He notes that on hikes in HI he routinely warns people he encounters of the risk of leptospirosis.

diffuse alveolar hemorrhage, extra-corporeal membrane oxygenation, leptospira interrogans, leptospirosis, leptospirosis pulmonary hemorrhage syndrome, mud-run

PMC9585379_01

Female

A 54-year-old female patient was admitted to the hospital for 14 days, complaining of fever, headache, nausea, and vomiting. The temperature at the time of admission was 38.5 C. History taking revealed that the patient had undergone a lumbar puncture some days ago in a hospital. The lumbar pressure was 120 mmH2O, white blood cell count was 281x106/L, the cerebrospinal fluid protein was 1139 mg/L, cerebrospinal fluid glucose 2.50 mmol/L, and cerebrospinal fluid chloride was 117.8 mmol/L ( Table 1 ). The lady tested positive for serum tuberculosis infection T cell, and a diagnosis of tuberculous meningitis was made. The patient experienced intermittent limb twitching daily to the present admission, accompanied by loss of consciousness. In addition, the patient confessed to having a history of "diabetes" for about half a month. Physical examination was conducted upon admission. The patient had a positive result for the neck resistance test, and the head MRI showed lacunar infarction in the left basal ganglia. A Chest CT scan revealed multiple nodules in both lungs ( Figure 1 ). Organ function tests relating to the liver and kidney returned typical results. The sodium and chloride ion levels were 124.4mmol/L and 92.2mmol/L, respectively. Both HIV antibody and syphilis monitoring tests were negative. A diagnosis of tuberculous meningitis was made, and the patient was given antituberculosis drug therapy comprising isoniazid, rifampicin, and pyrazinamide. Re-examining the lumbar puncture on the second day of admission showed a lumbar pressure of 150 mmH2O, white blood cell count was 44x106/L, the cerebrospinal fluid protein was 636 mg/L, cerebrospinal fluid glucose was 5.84 mmol/L, and cerebrospinal fluid chloride was 111.8 mmol/L ( Table 1 ). Cerebrospinal fluid cytology was suggestive of mixed cell response. No abnormalities were seen regarding cryptococcal capsular antigen and acid-fast staining tests, cerebrospinal fluid mNGS (metagenomics next generation sequencing), culture and Gene Xpert MTB/RIF. Similarly, there were no pathogenic microorganisms found in the cerebrospinal fluid. The EEG results showed slowed brain wave frequencies during the awake period, and moderately slow waves (3-5 Hz) appeared intermittently in each lead. After instituting anti-tuberculosis treatment, the clinical symptoms improved rapidly; the headache resolved, but nausea and vomiting occasionally occurred ( Figure 2 ). One week after admission, the lumbar puncture was repeated, giving the following results: lumbar pressure was 75 mmH2O, white blood cell count was 42x106/L, cerebrospinal fluid protein was 651 mg/L, cerebrospinal fluid glucose was 6.30 mmol/L, and cerebrospinal fluid chloride was 110.9 mmol/L ( Table 1 ). Re-examination of the cerebrospinal fluid mNGS found no pathogenic microorganisms. Two weeks after admission, the patient had no headache and was discharged from the hospital on oral antituberculosis drugs. However, one week after being discharged from the hospital, the patient was re-admitted to the hospital, complaining of persistent nausea and vomiting. A re-examination of the lumbar puncture showed that the pressure was 100 mmH2O, the number of white blood cells was 23x106/L, cerebrospinal fluid protein 504 mg/L, and cerebrospinal fluid chloride was 108.1mmol/L. Blood sodium and chloride ions was 128.5 mmol/L and 90.9 mmol/L, respectively ( Table 1 ). A re-examination of the head MRI showed no typical APS imaging features ( Figure 3 ). The serum AQP4 antibody test (Cytometric Bead Array method) was 1:100, while the fundus examination, visual examination, evoked potential, and spinal cord magnetic resonance was negative. Besides, anti-MOG, anti-GFAP, anti-NMDA, anti-IgG4 antibodies, and autoantibodies were all negative, leading to a definite diagnosis of NMOSD. At the same time, antituberculosis drugs were discontinued. After instituting pulse therapy using 1000 mg of methylprednisolone, nausea and vomiting reduced rapidly. Six days later, the patient was discharged on oral treatment with prednisone. Three months later, the patient's clinical symptoms did not recur. In addition, five months later, the patient developed blurred vision in one eye during the follow-up. VEP showed prolonged P100 latency and decreased P100 amplitude. The visual field test indicated a superior and temporal visual field defect, AQP4-Ab testing was reviewed, which titer was 1:10. Lumbar pressure 90 mmH2O, white blood cell count was 1x107/L, cerebrospinal fluid protein was 312 mg/L, cerebrospinal fluid glucose 6.10 mmol/L, and cerebrospinal fluid chloride was 124.7mmol/L. Therefore, the possibility of optic neuritis was clinically considered, and mycophenolate mofetil was given. The patient's vision recovered rapidly in a short time after the treatment.

aquaporin, area postrema syndrome, autoimmune inflammatory demyelinating disease, central nervous system, neuromyelitis optica spectrum disease

PMC7204857_01

Male

The patient was a 94-year-old male with a past medical history of hypertension, hyperlipidemia, iron deficiency anemia, chronic obstructive pulmonary disease, coronary artery disease status post four-vessel bypass, and tuberculosis status post right-sided total pneumonectomy. He presented to the emergency department with a 3-week history of dull/achy, nonradiating, mid-retrosternal chest pains which worsened with swallowing of solids associated with a 5-pound weight loss. On the morning of admission the patient ate a large meal and felt as though the food was lodged in his esophagus. This led to two episodes of nonbilious, nonbloody vomitus and recurrence of the chest pain. Upon admission, vitals revealed a temperature of 36.72 C, a pulse of 79 beats/min, a blood pressure of 157/69 mm Hg, a respiratory rate of 20/breaths/min, and an oxygen saturation of 93% on 2 L/min nasal cannula. Labs were remarkable for decreased hemoglobin of 10.1 g/dL, with a hematocrit of 29.4%, a mean corpuscular volume of 97.7, and a red blood cell distribution of 13.2%. Arterial blood gas was significant for PCO2 of 53.9 mm Hg, troponins were <0.05 ng/mL, and electrocardiography revealed normal sinus rhythm. A computed tomography scan of the chest did not reveal external compression of the esophagus, and thus an urgent esophagogastroduodenoscopy (EGD) was done to rule out food impaction. EGD revealed sloughing of esophageal mucosa with blueish discoloration of submucosal layer, dilated esophagus with decreased contraction, and erosive areas of ulceration (Fig. 1). Biopsies were taken in multiple regions of the esophagus. Pathological analysis demonstrated vacuolar degeneration at the midlevel of the epithelium with overlying hyperkeratosis and parakeratosis, with noted black/brown pigment present at the level of the split in the epithelium (Fig. 2). The patient was started on a full liquid diet and on this regimen reported resolution of odynophagia and chest pain. However, soon afterward, he developed acute on chronic hypoxic respiratory failure secondary to aspiration pneumonia as new left lower lung opacity was noted on chest X-ray. At this point the patient was made NPO, started on broad-spectrum antibiotics, placed on bilevel positive airway pressure, and admitted to the intensive care unit. He responded to treatment and was eventually weaned to nasal cannula. EGD was then repeated and showed a significant improvement in the esophageal mucosa and resolution of strictures and ulcerations (Fig. 3). At this point, the patient underwent a swallow evaluation and a modified barium swallow study, which were both negative. Following these results, he was placed on a soft diet which he tolerated well and was discharged home with gastrointestinal follow-up.

esophagitis dissecans superficialis, esophagogastroduodenoscopy, ferrous sulfate, pill esophagitis

PMC6526601_01

Unknown

A questionnaire was sent to healthy plasma donors in the Bama longevity area, and the number of long-lived immediate family members (>= 85 years old) within three generations in the donors were investigated. A donor with at least three long-lived immediate family members was defined as the offspring of longevous family, and donors without an immediate family member >= 85 years old within three generations were offsprings of non-longevity families. In total, 33 offsprings of longevous families were recruited as case studies (Longevous group). And also 33 ABO-, age- and gender-matched offsprings of non-longevity families were recruited as controls (Normal group). The inclusion criteria of the participators were recruited as previously described and apheresis plasma of the participators was used in this study. Briefly, all participators were over 18 years of age, healthy and unrelated. People who had prior history of thrombus or hemorrhage, usage of oral anticoagulation therapy, hepatic disease, HIV infection, pregnancy, diabetes, cardiopathy, hypertension, renal insufficiency, respiratory diseases and others were excluded from this study. Pooled plasma samples were generated by combining equal volumes of each 11 individual plasma samples from each group. The basic information of the volunteers was shown in Table 1. This study was approved by the Ethics Committee of the Institute of Blood Transfusion (No. 201716). In accordance with the Declaration of Helsinki, all participants gave informed consent prior to their entering the study. The high abundance proteins that account for approximately 80% of the total plasma protein concentration were removed from the pooled plasma samples, using a ProteoMiner Protein Enrichment Introductory Large-Capacity Kit (Bio-Rad, Richmond, USA) according to the manufacturer's instructions. After being reduced with 5 mM DL-dithiothreitol for 30 min at 56 C and alkylated with 11 mM iodoacetamide for 15 min in darkness at room temperature, the protein sample were digested with trypsin at a trypsin/protein mass ratio of 1:50 overnight in the first stage and 1:100 for 4 h in the second stage. Approximately 100 microg protein for each sample was digested with trypsin for the following experiments. Tryptic peptides were desalted by Strata X C18 SPE column (Phenomenex, CA, USA) and labeled with a 6-plex TMT kit (Thermo Fisher Scientific, CA, USA) according to manufacturer's instructions. The 6 labeled samples then fractionated by high pH reverse-phase HPLC using 300Extend C18 column (5 microm particle size, 4.6 mm ID, 250 mm length, Agilent, CA, USA). Peptides were eluted with a gradient of acetonitrile (8% to 32%) in 10 mM ammonium bicarbonate (pH 9.0) over 60 min. At last, 60 fractions were collected, and they were combined into 18 fractions and dried by vacuum centrifuging. Samples were measured using LC-MS instrumentation consisting of an EASYnLC 1000 ultra-high-pressure system coupled via a nano-electrospray ion source to a Q Exactive Plus (Thermo Fisher Scientific). Purified peptides were separated on a reversed-phase analytical column (150 mm length, 75 mum ID). For each LC-MS/MS analysis, the electrospray voltage applied was 2.0 kV. Intact peptides were detected in the orbitrap at a resolution of 70,000, and ion fragments were detected in the orbitrap at a resolution of 17,500. In the MS survey scan, a data-dependent mode with an automatic alteration (1 MS scan followed by 20 MS/MS scans) was used for the top 20 precursor ions above a threshold ion count of 5 x 104 with 30 s dynamic exclusion. Automatic gain control was used to prevent overfilling of the orbitrap; 5 x 104 ions were accumulated for generation of MS/MS spectra. For MS scans, the m/z scan range was 350 to 1800, and the fixed first mass was set as 100 m/z. MS/MS data was analyzed by MaxQuant software with integrated Andromeda search engine (Version 1.5.2.8). The mass tolerance for precursor ions was set as 20 ppm in First search and 5 ppm in Main search, and that for fragment ions was set as 0.02 Da. False discovery rate (FDR) was adjusted to < 1% and minimum score for peptides was set > 40. Only unique peptides were used for protein quantification. And for protein quantification method, TMT 6-plex was selected in Mascot. FDR was adjusted to < 1% at protein, peptide and peptide spectrum match (PSM) level. Gene Ontology (GO) annotation (the biological process, cellular component and molecular function) of the differentially expressed proteins were derived from the UniProt-GOA database (http://www.ebi.ac.uk/GOA/). PSORT/PSORT II and SubLoc (http://www.bioinfo.tsinghua.edu.cn/SubLoc/) were used to predict subcellular localization of all identified DEPs. A p value < 0.05 was used as the threshold to determine the significant enrichments of GO annotation. The HuProt V3.1 microarray (CDI Laboratories, Inc. Mayaguez, USA) composed of about 17,000 recombinant human proteins was used in this study. All of the recombinant human proteins were generated by the Saccharomyces cerevisiae expression system and carried an N-terminal glutathione S-transferase (GST) tag. Each protein was spotted in duplicate. The microarray was firstly blocked with blocking buffer (5% BSA in 0.1 mol/l TBS-T, pH = 7.5) at room temperature for 1.5 h. Then it was washed with with TBS-T and then Milli-Q water for 10 min respectively. The six pooled plasma samples of two groups were diluted 1: 2000 in 0.01 mol/l Tris-Buffered saline containing 0.1% (v/v) Tween 20 detergent (TBS-T, pH = 7.5) with 5% BSA. Five ml of diluted plasma were added and incubated with microarray under a glass coverslip at room temperature for 1 h. After rinsing with TBS-T and then Milli-Q water, Cy3-conjugated anti-human IgG diluted 1:2000 in TBS-T was added to the washed microarray and incubated in darkness at room temperature for 1 h. The microarray was then washed again as described above. After drying by centrifugation (ChipMate PMC-082, Tomy, Japan), microarray was subjected for scanning with the Axon GenePix 4000B microarray scanner (Molecular Devices, CA, USA) using an excitation wavelength of 523 nm and an emission filter specifically for cy3 fluorescent dye. The optical signal was detected by a photomultipliers tube (PMT). Human proteome microarray data analysis GenePix Pro 6.0 software (Molecular Devices, CA, USA) was used to obtain microarray signal intensity. The foreground median intensity (F median) and background median intensity (B median) for each spot on the microarray images were acquired. To quantify the signal intensity for each spot, we calculated the signal intensity for each spot, which was defined as the foreground median intensity divided by its local background median intensity (F median/B median). The intra-array signal intensity normalization and positive hits identification were taken as described in the previous reports. Briefly, the signal intensities of the spots within a protein microarray were normalized by setting the median intensity of that microarray equal to 1. To identify autoantibodies that bind to a protein on microarray (positive hits), an intensity cutoff value needed to be assigned for each microarray. We used I to denote the normalized intensity of a spot (control spots omitted) on the protein microarray. And Meani denote the average of I (control spots omitted) on a protein microarray. The standard deviation (SD) away from the mean of the signal intensities for all the spots in a microarray was calculated. A cutoff was defined as Meani + 6SD, and spots producing a signal intensity greater than the cutoff were identified as "positive hits." Moreover, each protein was printed in duplicate on a microarray, proteins and controls were considered as a positive feature only when both of their duplicate spots were simultaneously judged as a positive hit. T-test was chosen to assess the differential significance for each protein between the two groups based on signal value. The Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8 were used for the functional category analyzation of the identified autoantigens, subcellular localization prediction and GO annotation of the different autoantigens between groups. The datasets supporting the conclusions of this article are included within the article and its additional files. This study was approved by the Ethics Committee of the Institute of Blood Transfusion (No.201716). In accordance with the Declaration of Helsinki, all participants gave informed consent prior to their entering the study. All authors read and approved the final manuscript.

autoantibody profiles, bama longevity area, human proteome microarray, plasma proteomics, tandem mass tag

PMC4555582_01

Female

From November 1998 to August 2012, a total of 465 primary ACL reconstructions were performed by the senior author (W.N.L.) using autologous hamstring tendons. Drilling of the femoral tunnel was performed via the transtibial portal, and femoral graft fixation was achieved with corticocancellous cross-pin fixation. During this 14-year time period, 2 graft failures (0.4% failure rate) were noted. The first failure occurred in a 19-year-old college football player who at the 6-month postoperative visit had significant quadriceps atrophy. Despite not being cleared to resume sporting activities, the patient went on to play basketball and retore his graft. The second failure occurred in a 32-year-old woman who reinjured her knee in a skiing accident 5 years after her initial procedure. Of note, the patient was completely asymptomatic and had no residual instability prior to the accident. Furthermore, none of the patients without graft failure had subjective or objective findings of rotational instability after transtibial reconstruction. There were no cases of medial-sided pin prominence or iliotibial band friction syndrome secondary to cross-pin use. From September 2012 to October 2013, there were 69 primary ACL reconstructions performed by the senior author (W.N.L.) using an accessory anteromedial portal for the preparation of the femoral tunnel along with cortical suspensory femoral fixation. During this 13-month time period, 7 graft failures (10.1% failure rate) were noted (Table 1). These occurred in 5 male and 2 female patients, with a mean age of 18.8 years. All patients were highly competitive high school or college athletes and sustained their initial injuries while participating in their sport. They all underwent physical therapy prior to reconstruction to regain range of motion and quadriceps strength, and underwent surgery at an average of 4 weeks after injury. All 7 patients underwent uncomplicated ACL reconstruction with at the least a size 8 mm-diameter quadrupled hamstring autograft, and none of them had concomitant meniscal or chondral injuries. In addition, there was no compromise of the posterior wall in any cases. The standard postoperative physical therapy protocol, as previously described, was used to guide rehabilitation, and patients were cleared to return to competition at an average of 8.4 months postoperatively. Of the 7 cases, 6 sustained a retear of the graft within 2 weeks of being cleared for full competition, at an average of 8.8 days. The final patient retore the graft 10 months after being cleared to return to sport. In all 7 cases, graft failure occurred while the patient was competing in their respective sport. Furthermore, in each of the cases, graft failure occurred in the central portion of the graft, corresponding to a midsubstance tear.

anterior cruciate ligament, anteromedial, cross-pin fixation, graft failure, suspensory fixation, transtibial

PMC7204770_01

Male

A 75-year-old Caucasian builder with a known case of ulcerative colitis presented to the Southmead Hospital Emergency Department with a history of pyrexia associated with urinary symptoms. Three weeks prior to presentation, he had developed coryza, rigors and aching shoulders associated with pyrexia. He was seen by his GP who initially treated him for a suspected community-acquired pneumonia with amoxicillin. Seven days prior to admission, he returned to his GP with an ongoing history of intermittent pyrexia. He was treated for a urinary tract infection with a course of trimethoprim for 5 days. Despite this, he continued to deteriorate and developed progressively reduced mobility and muscle weakness. He was again treated with another course of antibiotics by his GP; however, he had deteriorated so much at this point that he was "unable to hold anything down," and it was then when he decided to go to hospital as he started vomiting. On admission, he was short of breath accompanied by wheezing. There was no cough or hemoptysis. There was no change in bowel habit, no history of foreign travel, weight loss, night sweats nor any recent history of unusual food substances. Interestingly, he mentioned that he had had occasional bouts of lower abdominal pain, which was "normal" for him. He had a past medical history of asthma, hypertension, non-ST elevation myocardial infarction, benign prostatic hypertrophy and ulcerative colitis. He lived with his wife in a house with stairs. He experienced one fall recently associated with a temperature spike. He was an ex-smoker (8-10 cigarettes per day for 55 years) and was an active builder. On physical examination, he was pyrexial with a temperature of 37.1 C and normotensive with a blood pressure of 107/62 mm Hg. Pulse was 62 bpm, and respiratory rate was 25 breaths per minute saturating at 99% SpO2. Cardiovascular examination revealed normal heart sounds accompanied by a soft systolic murmur. Upper airway wheeze was heard but not on auscultation as the lungs were otherwise clear. Abdomen was soft and non-tender with a small reducible umbilical hernia. Bowel sounds were present and normal. He was grossly moving his 4 limbs with ease. Investigations on admission revealed a white blood cell count of 14.54 x 109/L, haemoglobin of 80 g/L, mean corpuscular volume of 79.6 fL, mean corpuscular haemoglobin of 25.6 pg, neutrophils of 12.49 x 109/L, C-reactive protein of 203 mg/L and estimated glomerular filtration rate of 52 mL/min. Interestingly, his liver function tests demonstrated a bilirubin of 11 mumol/L, alkaline phosphatase of 195 U/L, alanine transaminase of 36 U/L and albumin of 26 g/L. His chest X-ray revealed a suspicious 8-mm nodule within the left apex, no focal consolidation and clear pleural spaces with right apical pleural thickening (Fig. 1). Urinalysis was negative and electrocardiogram showed normal sinus rhythm. Venous blood gas was unremarkable. At first, the patient was presumed to have an infection from unknown origin accompanied with anaemia either secondary to iron deficiency anaemia or due to an underlying malignancy. The patient was commenced on empiric intravenous co-trimoxazole and gentamicin. Blood and urine cultures were sent to the laboratory prior to this. In view of the findings of abnormal urinary symptoms and the findings on the chest X-ray, an ultrasound of the urinary tract along with a computed tomography (CT) scan of the chest, abdomen and pelvis were obtained. An echocardiogram was performed to rule out infective endocarditis. In the meantime, the patient was transferred to the Geriatric Ward. Despite all efforts, the patient continued to deteriorate with progressively worsening nausea and was no longer able to tolerate his oral medication. He began to develop new symptoms, including right-sided neck pain and intermittent rigors. CT scan of the chest, abdomen and pelvis was performed and showed 3 main findings: a right apical nodule, a small colonic lesion (being suspected malignancy or diverticulitis) and an irregular mass in the liver (Fig. 2a, b). Therefore, the differential diagnosis at the time was a liver abscess and colon carcinoma with metastatic deposits to the lung and liver. There was no evidence of intrahepatic or extrahepatic biliary dilatation. After discussion of these findings with the patient, he then openly admitted that he had a history of tuberculosis in his right lung as a child and was isolated at the age of 5 years for 9 months in Swansea. He recalled being told by medical personnel there that he had developed scarring ever since the treatment in his right lung. This would explain the appearance of the right apical nodule (Fig. 1). In view of the CT scan findings, an ultrasound of the liver was arranged, and if that would reveal a liver abscess, then an ultrasound-guided liver drain would be performed. Intravenous metronidazole was added to the antibiotic therapy regimen, more blood cultures were taken, and a colonoscopy was also arranged. The patient deteriorated so much that he began to lose the ability to mobilise without aid due to his progressive muscular weakness. He now complained of right upper quadrant pain accompanied by pain in his right shoulder with worsening nausea. After discussion with the microbiology team, S. intermedius was isolated as the main pathogen in his blood cultures, which was sensitive to teicoplanin. A liver ultrasound confirmed a large mixed echogenicity lesion at the superior aspect of the liver abutting the diaphragm measuring approximately 6.7 x 6 cm. Therefore, an ultrasound-guided drain was inserted in the cavity. Narrow-spectrum antibiotics, such as intravenous teicoplanin, metronidazole and gentamicin, were started. The patient expressed immediate relief following the drain insertion. Surprisingly, he was then able to tolerate food and was able to walk around the hospital freely for the first time. His colonoscopy revealed evidence of inflamed colon and areas of diverticulosis with no evidence of malignancy (Fig. 3). The diagnosis was most likely a liver abscess secondary to sigmoid diverticulitis caused by S. milleri group bacteria. The second differential diagnosis was an abscess as a complication of a resolving bout of ulcerative colitis in view of this patient's history. Otherwise, his neutrophilia began to improve significantly along with his liver function tests. A repeat CT scan of the abdomen was performed, which demonstrated significant improvement in the size of the liver abscess. The patient was discharged home to complete a 4-week course of oral antibiotics. A subsequent CT scan taken several months after discharge showed resolution of his abscess.

abscess, diverticulitis, infection, streptococcus

PMC7670051_01

Female

A 52-year-old woman underwent laparoscopic total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and dissection of pelvic and para-aortic lymph nodes in June, 2018. Pathological findings confirmed the diagnosis of stage IIIA serous papillary adenocarcinoma mixed with endometrioid carcinoma with squamous differentiation (~70% for serous carcinoma component and 30% for endometroid carcinoma component, respectively) (Figure 1A), with tumor metastasis to both fallopian tubes. Immunohistochemistry analysis showed loss of MSH2 (Figure 1B) and MSH6 (Figure 1C) protein expression in the EEC component. She received 6 cycles of paclitaxel and carboplatin as adjuvant therapy with complete response. Postoperative routine follow-up examination in May, 2019 showed that serum CA125 was elevated (71.66 U/ml), but CT examination did not reveal any abnormalities. The level of serum CA125 increased to 100.90 U/ml after 1 month, and ultrasound examination also showed enlarged paraaortic lymph node of 2.5 cm in diameter, suggesting tumor recurrence. Rechallenge of paclitaxel and carboplatin for one cycle failed with continued increase of CA125 to 120.1 U/ml. Subsequently, the patient switched to oxaliplatin combined with pegylated liposomal doxorubicin for one cycle with primary progression. Evaluation after the chemotherapy on August 1, 2019 showed serum CA125 level increased to 231.6 U/ml. CT scan suggested an enlarged left para-aortic lymph node (37*30 mm) (Supplementary Figures 1A,E). The patient came to our hospital for second opinion. To seek for potential targeted therapies and immunotherapies, paired tumor-normal next-generation sequencing of 1,021 cancer-related genes was performed using tumor tissue and peripheral blood. Of great interest, two heterozygous germline mutations in BRCA1 (NM_007294.3 c.3348_3351delAGTT p.V1117Rfs*11) and MSH2 (large deletion of exons 4-16) were identified (Figures 2B-D). Besides, a total of 72 somatic mutations were detected, including putative or known functional mutations in PTEN, ARID1A, TP53, FBXW7, and KRAS (Supplementary Table 1). In addition, genetic testing results showed that microsatellites were highly unstable, and tumor mutation burden was extremely high (51.84 muts/Mb). To access the cancer risk for the family members of the patient, Sanger sequencing and RT-PCR were performed to confirm the presence of germline BRCA1 and MSH2 mutations in her family members, although she has no family history of cancer. Her younger sister (I-4) and daughter (II-2) carry the BRCA1 and MSH2 mutations, respectively. Unfortunately, her son harbors both the BRCA1 and MSH2 mutations (Figures 2A, Supplementary Figures 2, 3). The patient was then treated with 200 mg intravenous tislelizumab every 3 weeks from September 4, 2019. Partial remission was achieved at 9 weeks after treatment with the shrinkage of an enlarged left para-aortic lymph node (Supplementary Figures 1B,F). In addition, the normalization of serum CA125 (12.28 U/ml) was observed after 2 months of treatment. CT scan at 15 weeks after treatment demonstrated continuous shrinkage of the enlarged lymph node (Supplementary Figures 1C,G). She has been on treatment for 4 months, and discontinued the treatment for 2 months due to the impact of COVID-19 outbreak. Fortunately, the CT scan did not reveal progression as a result of drug interruption (Supplementary Figures 1D,H). She continued the treatment and is still in follow-up. During the treatment, she experienced grade 1 treatment-related elevation of alanine transaminase (ALT) and aspartate transaminase (AST), which was relieved after symptomatic treatment.

double germline mutations, mixed serous-endometrioid endometrial carcinoma, next-generation sequencing, tislelizumab, tumor heterogeneity

PMC5080501_01

Male

A 22-year-old male patient complained about a history of painless recurrent swelling of both knees for 17 years. He was susceptible to upper respiratory tract infections since 3 years old. He was diagnosed as having aseptic synovitis at 5 years old and treated with prednisolone for 3 months. However, the joint swelling progressively aggravated. Six years ago, he received arthroscopic synovectomy with complete resolution of the clinical symptoms. The pathology of synovial biopsy showed chronic hyperplasia synovitis with fatty infiltration. Four years ago, the symptom of joint swelling relapsed. The painless swelling of both knees was persistent, without deformity of joints. He then came to our hospital for further diagnosis and treatment. The physical examination revealed that both knees were swelling without tenderness. Fluctuation and patellar tap test was positive. The magnetic resonance imaging (MRI) of the knees showed massive effusion associated with multiple frond like synovial thickening of high signal intensity in sagittal T1 weighted image especially in the suprapatellar region (Figure 1). Fat suppressed proton density images (Figure 1) revealed complete suppression of signal intensity of villous projections in suprapatellar region. Synovial biopsy guided by the ultrasound was performed and the histopathologic examination revealed a fibroadipose synovial membrane with small vascular proliferation and a small amount of lymphocytes and mononuclear cells infiltration (Figure 2). The diagnosis of LA was made according to the features of MRI and synovial pathology. The laboratory tests including autoantibodies, HIV, HBsAg, HCV-Ab, and syphilis antibody were normal. Cytologic and biochemical examinations of synovial fluid were normal. Synovial fluid culture showed no growth of pathogen. The lymphocyte culture and interferon determination and synovial fluid analysis for acid-fast bacilli were negative which excluded the tuberculosis infection. There were no history or clinical and pathological findings which were suggestive of infectious arthritis. However, the ESR was 90 mm/h (0-15 mm/h) and CRP was 1.3 mg/dL (0-0.8 mg/dL). The blood routine showed neutropenia and immunoglobulin test revealed deficiency of IgG (0.34 g/L, normal range 6.94-16.18 g/L) and IgA (0.07 g/L, normal range 0.7-3.8 g/L) with high level of IgM (23 g/L, normal range 0.6-2.3 g/L). Bone marrow examination was normal. He was suspected to have hyperimmunoglobulin M syndrome (HIGM). Gene test was performed to confirm the type of HIGM. It revealed a deletion of cytidylic acid residue in exon 5 region at position 520 (c.520delC) which led to a shift in the encoding of the reading frame from position 174 (p.Gln174fs). Premature termination occurred in 190 amino acids (numbering according to Hollenbaugh et al.; Figure 3(a)). The patient's mother carried the same mutation (Figure 3(b)). Therefore, the diagnosis of X-linked HIMG was made. Informed consent for sequence analysis was obtained from the patient and his mother. Interestingly, splenic hemangioma (5.8*5.0 cm) was found by the contrast abdominal CT scan. He had no symptoms. There was no surgical indication of the vascular tumor. We suggested he follow up closely with regular ultrasound examination once a year. The patients received synovectomy operation and were given regular IVIG therapy with 15 g * 3 days (total dose of 600 mg/kg, 75 kg) every month. No relapse of LA or infection occurred during one-year follow-up period.

PMC5662812_01

Female

A 48-year-old female presented with a leucoerythroblastic blood film, anemia (hemoglobin 10.9 g/dL), thrombocytopenia (72 x 109/L), normal white cell count, and no splenomegaly. An initial bone marrow (BM) aspirate was hypocellular with increased fibrosis suspected as the underlying cause. The JAK2 V617F and CALR exon nine insertion or deletion mutations were not detected but cytogenetic analysis revealed a karyotype of 46,XX,t(9;22)(q42;q11) in 16 metaphases, trisomy 8 in a further two Ph+ metaphases, and tetrasomy 8 in one further Ph+ metaphase. RT-qPCR analysis with standardized primers and probes did not detect BCR-ABL1 transcripts but further analysis with a qualitative PCR approach detected a single abnormal band which Sanger sequencing demonstrated to be a fusion of BCR exon 6 to ABL1 exon a2 (Figure 1). No mutations were detected in the ABL1 kinase domain. Immunophenotyping of the peripheral blood (PB) demonstrated 12% myeloblasts that were positive for CD7, CD13, CD33, CD34, CD117, and HLADR and negative for CD3, CD4, CD8, CD11c, CD14, CD15, CD19, and CD64. A repeat BM aspirate was hypercellular with 18% myeloblasts morphologically. The corresponding trephine biopsy was hypercellular and had prominent grade three fibrosis with CD34+ blasts accounting for approximately 40% of the total cellularity, consistent with a diagnosis of blast crisis CML with marrow fibrosis. In order to quantitate e6a2 BCR-ABL1 transcripts, a BCR exon 6 forward primer was used with reverse primer ENR561 and probe ENP541. A standard curve was established by tenfold dilutions of patient presentation PB cDNA (slope -3.538, r2 0.996). Control ABL1 transcripts were detected as previously described. At diagnosis the patients' PB BCR-ABL1/ABL1 transcript level was 78.6%. An NGS approach was employed to detect additional mutations cooperating with the e6a2 BCR-ABL1 fusion in driving blast crisis in this patient. Amplicon libraries covering 30 commonly mutated genes implicated in myeloid malignancies either covering the entire coding region (CALR, CEBPA, ETV6, EZH2, RUNX1, SH2B3, TET2, TP53, and ZRSR2) or mutational hotspots (ABL1, ASXL1, BRAF, CBL, CSF3R, DNMT3A, FLT3, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, SETBP1, SF3B1, SRSF2, and U2AF1) were generated using 20 ng BM genomic DNA and sequencing performed using Ion AmpliSeq methodology (Thermo Fisher Scientific, Paisley, UK). Calling of somatic mutations was achieved using an algorithm that excluded synonymous mutations, variants located within intronic or untranslated regions, and those present at a variant allele frequency (VAF) of <5%. A minimum target depth of coverage for variant calls was set at 500x as previously described. A single ASXL1 p.E1102D mutation (c.3306G > T; reference sequence NM_015338.5) was detected with a variant allele frequency of 45.5%. The patient received one cycle of daunorubicin and cytarabine (DA 3 + 10) with imatinib 400mg daily which was escalated to 600 mg daily achieving hematological and morphological remission and resulting in a PB BCR-ABL1/ABL1 transcript level of 0.06%. She was subsequently treated with a second cycle of chemotherapy (DA 3 + 8) which was complicated by septicemia. Prior to ASCT the PB BCR-ABL1/ABL transcript level was 0.03% (Figure 2). Her imatinib was stopped prior to busulfan and cyclophosphamide conditioning for ASCT from a matched sibling donor that was complicated by mucositis and a coagulase-negative staphylococcus infection during her inpatient stay. After discharge she developed grade four skin graft versus host disease (GVHD) and was treated with high dose steroids subsequently developing CMV reactivation and steroid induced diabetes. Antiviral treatment with valganciclovir caused a pancytopenia requiring treatment with granulocyte colony-stimulating factor. BCR-ABL1 transcripts were not detected by RT-qPCR at day 38 after ASCT with full donor chimerism achieved (100% at day 43 post-ASCT). The patient remains off TKI and generally well at last follow-up. The CMV reactivation has resolved and she continues on steroid taper for GVHD. Continued close RT-qPCR monitoring is planned.

PMC9884389_01

Male

An 82-year-old man presented with a three-day history of abdominal distention and nausea. His family had a history of tuberculosis, and his past surgical history included strangulated small bowel obstruction 35 days prior. Then, he underwent release surgery without bowel resection (Figure 1). Abdominal ultrasound sonography revealed ascites around the small intestine in the encapsulated area. Abdominal computed tomography further showed a mass of jejunum in the encapsulated area with ascites and calcified nodules (Figure 2). We aspirated ascites comprising serous blood. Cytology, culture, including Mycobacterium tuberculosis, and other ascites laboratory data did not indicate malignancy or tuberculosis. A blood test did not confirm tuberculosis nor other malignancy; interferon-gamma release assays, CA125, and other tumor markers were unremarkable. Then, serum albumin and C-reactive protein were 2.5 g/dL and 6.4mg/dL, respectively. The nasogastric tube did not improve the ileus, and he underwent surgery. The small intestine was enveloped in dense fibrous tissue with calcified nodules and became a contiguous mass like sclerosing encapsulating peritonitis (SEP), also known as an abdominal cocoon (Figure 3). This section, which lacked peristalsis without signs of obstruction, was resected. Histopathological evaluation of the capsule, nodules, and resected bowel did not reveal an apparent cause of abdominal cocoon; chronic dense fibrous tissue without caseous granuloma. Thus, we diagnosed an idiopathic abdominal cocoon. While tuberculosis peritonitis was most likely, we did not confirm the cause of the abdominal cocoon.

abdominal cocoon, resection, sclerosing encapsulating peritonitis, small bowel resection, small-bowel obstruction, tuberculosis peritonitis