Datasets:

moukaii

/

Tuberculosis_Dataset

like 16

PMC6329029_02

Male

A 10-years-old boy was diagnosed with tuberculous meningitis (TBM) and started on ATT consisting of HRZS along with prednisolone (2 mg/kg/day) in September 2012. CT brain showed calcific densities in the parietal lobe of the cerebrum. Cerebrospinal fluid (CSF) examination showed proteins of 248 mg/dL, sugar of 36.8 mg/dL, 100 white blood cells (WBCs) with 91% lymphocytes and 10 red blood cells (RBCs) per high-power field (hpf). In October 2012, he still had persistent fever. CT brain in October 2012 showed multiple tuberculomas with persistent meningeal enhancement, following which Eth and Ofx were included in the ATT, and steroids were gradually tapered. Streptomycin was discontinued after completion of 2 months of ATT. Serial MRI brain showed regression in size of granulomas. In January 2014, the patient was asymptomatic, and his MRI brain showed decrease in size and number of granulomas. His Eth and Ofx were discontinued. His ATT was stopped in March 2015. MRI still showed presence of granulomas though with reduction in size. He is subsequently lost to follow-up.

anti-tuberculous therapy, children, tubercular meningitis, tuberculoma

PMC6329029_05

Male

A 4-year-old boy presented with limping of the right lower limb in October 2011. He was already on three drugs ATT (HRZ) for the past 6 months in view of TBM (details of which are not available, as he was treated at another centre). On examination, he had right lower limb spasticity with brisk reflexes. CSF showed proteins of 130 gm/dL, WBC count of 12 cells/cumm (100% lymphocytes) and sugar of 76 mg/dL and CSF culture for TB was sent. MRI brain and spine showed tubercular granuloma in the mesial cortex of the right temporal lobe and dorsal spinal cord with associated meningitis and hydromelia. He was started category 2 ATT comprising of HRSEZ along with prednisolone (2 mg/kg/day). TB culture did not grow any organism after 6 weeks. In December 2011, streptomycin was stopped after 2 months. In January 2012, EZ were omitted, and steroids were stopped in February 2012. After serial MRIs showing decrease in size of granulomas, MRI brain and spine in March 2013 showed resolved granulomas. ATT was stopped subsequently.

anti-tuberculous therapy, children, tubercular meningitis, tuberculoma

PMC6329029_06

Female

An 8-year-old girl was referred in January 2012 for further management of her TB. In March 2011, she had convulsions and vomiting. CT brain revealed multiple tuberculomas, and Mantoux test was positive. She was started on HRSE. CSF examination was not done. In October 2011, CT brain showed increase in size of granulomas with appearance of new granulomas, and she developed drug-induced hepatitis. Her ATT was changed to Ofx and E. She was restarted on HR in December 2011 in addition to E and Ofx. On presentation to us in January 2012, she was symptomatic and ATT was shifted to HR. In April 2012, her MRI brain showed that the lesions in the left medial temporal, right temporal and right parietal lobe had resolved but the lesion in the left opercular cortex was unchanged in size and morphology. In May 2012, she was advised to discontinue HR and was started on E and Ofx in view of increase in serum glutamic pyruvic transaminase (SGPT) levels. By July 2012, she was shifted back to HR and E, and Ofx was stopped. In March 2013, her ATT was stopped after 2 years of ATT. She continued to remain asymptomatic. In May 2013, MRI brain showed decrease in size of the left opercular lesion.

anti-tuberculous therapy, children, tubercular meningitis, tuberculoma

PMC5313427_01

Female

An 80-year-old woman was admitted to our hospital because of progressive dyspnea on exertion for the previous two months. She had been treated for hypertension and dyslipidemia. She had no known history of cancer. On admission, her oxygen saturation (SpO2) was 94%, which decreased to 74% with exertion. Her body temperature was 37C, heart rate was 82 beats per minute (regular), and blood pressure was 161/77 mmHg. Physical examination of her heart and chest showed no abnormality at that time. Several submental lymph nodes were palpable as rubbery, non-tender masses, and they measured less than 2 cm in size. Arterial blood gas (ABG) on ambient air showed arterial oxygen tension (PaO2) of 64 mmHg and alveolar-arterial oxygen tension difference (AaDO2) of 43 mmHg (Table). Chest X-rays, electrocardiography (ECG), and ultrasound cardiography (UCG) showed no abnormality. Pulmonary function tests showed a decreased diffusing capacity (%DLCO; 74%). A high-resolution computed tomography (HRCT) scan showed almost no abnormalities in the lung fields and a contrast-enhanced CT scan showed no findings of pulmonary embolism. Transbronchial lung biopsy (TBLB) and bronchoalveolar lavage revealed no evidence of disease, including malignancy. As this patient showed a decreased diffusing capacity without any parenchymal lung abnormalities, we suspected that she had problems in her pulmonary circulation. We could exclude pulmonary thromboembolism by contrast-enhanced CT. These findings indicated that this patient had peripheral pulmonary vascular disease. A lung perfusion scan was performed and revealed multiple wedge-shaped subsegmental defects (Fig. 1A). From these findings, we considered PTTM to be a possible cause of her illness. Her serum tumor markers and immunological tests were normal (Table). Upper gastrointestinal endoscopy and mammography revealed no evidence of malignancy. Positron emission tomography (PET)-CT showed an abnormal uptake in her right deep neck with a maximal standardized uptake value (SUVmax) of 3.8. There were no remarkable uptakes in the lung fields. MRI of the head and neck showed a right parotid mass that had invaded the parapharyngeal space, medial pterygoid muscle, and mandibular bone. A biopsy of the submandibular lymph nodes revealed metastatic adenocarcinoma, and an immunohistochemical examination showed cytokeratin 7 (CK7) and gross cystic disease fluid protein 15 (GCDFP15) to both be positive. These findings were compatible with salivary duct carcinoma. We diagnosed her to have PTTM caused by adenocarcinoma of the parotid gland according to these radiological and pathological findings. We could not perform a biopsy directly from the parotid gland because its location was deep and difficult to approach. The patient complained of increasing exertional dyspnea, and a further decrease of SpO2 at rest was noted within a month after admission. A split of the second heart sound (S2) at the apex, a clinical sign of pulmonary hypertension, had become apparent by this time. ECG showed new-onset T-wave inversion in leads II, III, aVf, and V1-5. UCG at this time revealed tricuspid regurgitation with a pressure gradient (TRPG) of 57 mmHg, right ventricular dilatation, and flattening of the interventricular septum. These findings suggested that the patient had significant pulmonary hypertension. HRCT showed dilatation of the peripheral pulmonary arteries and a diffuse patchy distribution of ground-glass opacity (GGO) in the bilateral lung fields (Fig. 2). Enhanced CT revealed no findings of pulmonary emboli or deep vein thrombosis of the lower extremities. Based on these findings we considered the cause of pulmonary hypertension to be diffuse pulmonary embolization at the peripheral pulmonary arteries, which was compatible with the findings of PTTM. Although the diagnosis of PTTM was not pathologically definitive, we started chemotherapy with paclitaxel (PTX; 170 mg/m2)/carboplatin (CBDCA; AUC 4.5). Dyspnea and the physical signs of PAH improved gradually during the first two weeks after starting chemotherapy, and a decrease of TRPG was found after another two weeks. The defects in the lung perfusion scan also showed some improvement (Fig. 1B). Two months after the first course of chemotherapy, her symptoms deteriorated again with the increase of TRPG. We treated her with five courses of PTX/CBDCA and a course of docetaxel (DOC). Her symptoms and the findings of PAH first improved, but then deteriorated repeatedly (Fig. 3). Eleven months after her initial visit, severe dyspnea, hypoxia and pulmonary hypertension developed and she died suddenly on her way to the restroom. Autopsy findings of her lung showed multiple tumor embolisms, thrombus formation, recanalization, and intimal fibrocellular proliferation in the muscular pulmonary arteries measuring from 100 to 200 mum in diameter (Fig. 4). The diagnosis of PTTM was made pathologically. Salivary duct carcinoma with lymphovascular invasion was found in her right parotid gland and it was considered to be the primary lesion of PTTM. Her heart showed significant dilation and thickening of the right ventricle, and her other organs were congestive, which suggested that significant PAH and right-sided heart failure were the causes of death. Slight alveolar wall thickening and inflammatory cell infiltration with hyaline membrane formation was observed focally. There were almost no tumor cells in these alveoli.

PMC7748904_01

Female

A 30-year-old female with a past medical history significant for WPW and a psychiatric history of major depressive disorder, posttraumatic stress disorder, borderline personality disorder, and several suicide attempts presented to the Emergency Department (ED) with complaints of decreased energy, swollen lymph nodes, weight loss (approximately 13.5 kg), and mild abdominal pain. Subsequent interviews revealed that while waiting for the results of her evaluation, the patient overdosed on 1200 mg of trazodone, 1200 mg of quetiapine, and 900 mg of venlafaxine, as a suicide attempt. Two hours postoverdose, the patient began to exhibit a prolonged QTc interval of 486 ms which contrasted with her QTc baseline of 445 ms (Figure 1). Of note, no delta wave was appreciated in the EKG. Her PR interval was 160 ms at baseline and 146 ms 2 hrs after (Table 1). Baseline blood pressure was noted at 114/70, but 2 hours postoverdose, the patient developed hypotension of 86/45 mmHg. In addition, the patient complained of palpitations with a heart rate ranging from 83 to 97. All psychiatric medications were discontinued, and intravenous fluids were provided. Forty-eight hours after discontinuation of her medication, the patient's EKG normalized including her QTc interval (QT/QTc of 414/434) (Figure 1), and her PR interval was at 160 ms (Table 1). At this point, the patient was medically cleared and transferred to our inpatient unit. On the inpatient unit, the patient was slowly reintroduced to her psychiatric medications. On day 1, the patient was started on quetiapine 100 mg at bedtime, trazodone 100 mg at bedtime, and venlafaxine 150 mg in the morning. This was gradually raised to a maximum dose of quetiapine100 mg in am and 300 mg at bedtime. Venlafaxine was increased to 225 mg daily and trazodone remained at 100 mg at bedtime. Apart from mild sedation, the patient reported no symptoms or side effects from medications such as sensation of rapid, fluttering, or pounding heartbeats (palpitations); dizziness or lightheadedness; or shortness of breath. The patient was discharged after 11 days of inpatient psychiatric treatment. After discharge, maintenance treatment consisted of 300 mg of quetiapine, 100 mg of trazodone, and 225 mg of venlafaxine. A year later, the patient was seen in the ED for chest palpitations, pain, and dizziness. Her initial EKG was significant for heart rate of 109 beats per minute, QTc of 450 ms, and PR interval of 160 ms. Twenty-four hours later her EKG showed a QTc interval of 457 ms, PR interval of 170 ms, and heart rate of 89 bpm (Figure 1). Of note, delta waves were not appreciated on either EKG. Initially, the patient was worked up for chest pain via 3 sets of troponins, EKG, and stress test. All test results came back negative. Her symptoms resolved within 24 hours with no changes in medication, and the patient was discharged without further issues.

PMC6280227_01

Male

A 14-year-old adolescent boy was referred to our Endocrinology Department for evaluation of short stature. As no medical records were available, previous growth velocity could not be evaluated. The patient reported that he had always been short for his age throughout his childhood. His recent medical history was negative for headaches, vomiting, or vision changes. There were no reports of fatigue, cold intolerance, constipation, and skin or hair changes. Appetite was normal with no recent weight loss. There were no academic concerns. He regularly played football, with no history of traumatic or nontraumatic fractures. He took no medications. For several months, he had reported minor bilateral symmetrical crookedness on his second fingers, without any pain or local symptoms. He had been born at 36 gestational weeks, weighing 2450 g with no history of abnormal gestation, breech presentation, ischemic insult at birth, or other neonatal events. Parental heights were normal, with a target height of 177.5 cm. Parental pubertal timing was also within normal limits. Family history was negative for short stature, endocrine, or autoimmune conditions. Clinical examination revealed a dysmorphic, proportionate, and relatively short adolescent with normal vital signs. His anthropometric parameters were -2 SDs (standard deviations) for weight (37 kg) and between -2 SDs and -2.5 SDs for height (148 cm) (Belgian charts). His height was below his midparental genetic interval. His upper:lower segment ratio and arm span were normal. His hands and feet appeared short, with middle, painless tumefaction of soft tissue around the index proximal interphalangeal joints. No spinal abnormalities were noted, but a mild pectus excavatum was present. There was no thyromegaly. Testicular and pubic hair development was in Tanner stage II (testicular volume 6 ml). The most prominent dysmorphic features were a pear-shaped nose, a thin upper lip with small lower jaw, prominent ears, and markedly thin and sparse blonde hair with rarefaction of the lateral eyebrows (Figure 1). The teeth examination was difficult because he wore dental braces to correct dental irregularities. An extensive biological workup was performed. Complete blood count and serum levels of inflammatory markers, electrolytes, glucose, renal function, liver enzyme, and tissue transglutaminase antibody levels were normal. The laboratory findings showed normal thyroid and adrenal function and normal growth hormone secretion (normal levels of insulin-like growth factor and insulin-like growth factor binding protein). Additional pituitary and gonad testing revealed a normal prolactin level and pubertal testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels (Table 1). The bone age was evaluated at 12 years 6 months. A renal and cardiac ultrasound looking for other possible somatic malformations wasperformed and showed normal morphological kidneys, ureters, and urinary bladder and no cardiac abnormalities. After this first clinical, biological, and radiological evaluation, the working diagnosis was constitutional growth delay with late normal puberty, but skeletal dysplasia (dysmorphic features in the context of short stature) was considered for differential diagnosis. During the follow-up 6 months later, the initial apparent soft tissue tumefaction of his indexes had progressed to localized noninflammatory and painless deformity, causing limited difficulty in writing and typing on a keyboard. This sign was isolated, and the patient did not complain of pain or history of local trauma or infection. At this time, his clinical appearance was normal, except for the aforementioned dysmorphic traits. His growth velocity (5 cm/6 months) was normal in the context of spontaneous pubertal progress (Tanner stage III, testicular volume 8-10 ml). Clinical examination of his hands revealed isolated ulnar deviation of the second fingers and symmetrical deformity of proximal interphalangeal joints of both hands (Figure 2). He had no other painful or deformed joints. His feet look normal, but the toes are short (Figure 3). Theoretically, a differential diagnosis with inflammatory arthritis was considered, but the clinical findings (dysmorphic features, short stature, and relatively asymptomatic finger abnormalities) were more suggestive of a skeletal dysplasia. Radiographs of hands, feet, and pelvis were performed and allowed the definitive diagnosis. The plain radiograph of his wrists showed cone-shaped epiphyses of the middle phalanges of the second digit of both hands with moderate deviation of the phalangeal axis (Figures 4(a) and 4(b)). Similar cone-shaped epiphyses were found in the proximal phalanx of the great toe and up to the fourth one of both feet with shortness of all toes (Figure 5). No other radiological joint impairments (juxtaarticular osteopenia or erosions) were found. Radiographs of the pelvis and whole-body magnetic resonance imaging (looking for fine abnormalities, particularly long bone cysts not visible on plain radiographs) were normal. The bone age was retarded at 12 years 6 months (the chronological age was 14 years 6 months). Taking together the clinical and particularly the radiological findings, the correct diagnosis of trichorhinophalangeal syndrome (TRPS) was achieved. This was a delayed diagnosis, and our explanations for this include the underrecognition of the dysmorphic features (in our first examination), the underinterpretation of fingers tumefaction in the clinical context, and consecutively no hand radiological exam being conducted. Other entities associating ectodermal and skeletal phenotypes were reviewed, particularly Albright osteodystrophy, acrodysostosis, and other brachydactyly syndromes, but several features of the presentation were inconsistent with these diagnoses. Cytogenetic analysis was not performed. The family history appeared to be negative, his parents and his sister do not manifest the syndrome phenotype, and in such conditions, a sporadic case of TRPS type I was considered highly possible.

PMC4821334_01

Female

A 60-year old woman was referred to the tuberculosis (TB) out-patient clinic for Mycobacterium avium (MAC) pulmonary disease after having received 1st line antituberculosis treatment (isoniazid, rifampicin, ethambutol, pyrazinamide) for one month. The initial clinical diagnosis was pulmonary TB, based on patient's symptoms, consisting of fever, productive cough and weight loss for the last 2 months, along with compatible to tuberculosis chest x-ray and computed tomography (CT) scan. The CT scan had revealed 3 cavities and tree-in-bud appearance of the right upper lobe (Fig. 1). Acid-fast smears from sputum and bronchial lavage were negative, however cultures from the lavage revealed the presence of MAC. The patient had a decade-long history of bronchiectasis with her respiratory tract being chronically colonized with P. aeruginosa. She reported infectious exacerbations during the last 10 years, which were mostly treated with macrolides or quinolones. Due to increase in the frequency of the exacerbations to 3-4 per year in the last two years, the patient was on maintenance treatment with azithromycin 250 mg three times per week for the last six months, as suggested by her treating physician. On examination, after one month of anti-TB treatment, the patient was found to have gained weight and she reported as being afebrile for the last 2 weeks and without cough. Despite this initial response to treatment, positive culture results from one bronchial washing sample, along with the patient's symptoms and radiological findings, fullfilled ATS criteria for MAC pulmonary disease diagnosis. Her treatment was modified to rifampicin, ethambutol, azithromycin and amikacin. One month later, resistance to macrolides was detected, so azithromycin was discontinued and isoniazid and moxifloxacin were added to the regimen. The patient received treatment for 24 months (amikacin for eight months) and showed a significant clinical and radiological improvement. The patient was unable to produce sputum so microbiological follow up could not be performed. Her CT scan at the end of treatment was also significantly improved (Fig. 2). Due to the persisting presence of a cavity in the right upper lobe at the end of the treatment, the option of surgical resection was proposed but the patient refused. At present, six months after the completion of her treatment, she remains clinically stable and does not report any bronchiectasis-related infectious exacerbation.

bronchiectasis, macrolides, non-tuberculous mycobacteria

PMC9144385_01

Male

A 64-year-old Caucasian male with a past medical history of non-small cell lung cancer (NSCLC) (status post radiation therapy 5 years prior), chronic obstructive pulmonary disease, pulmonary embolism on rivaroxaban presented to the emergency department with worsening bilateral visual loss in the left field of vision for 4 weeks. On prior outpatient evaluation, there was initial concern for glaucoma but later there was suspicion of a central nervous system pathology prompting his arrival to the emergency department for further evaluation. He reported unintentional 30-pound weight loss over 2 months along with a progressive decline in short-term memory. He also reported recent falls due to subjective lower extremity weakness. He denied numbness, tingling, difficulty swallowing, slurred speech, difficulty finding words, headache, sleep disturbances, dizziness, nausea, vomiting, and bowel or bladder dysfunction. Vital signs were within the normal range. Physical examination was pertinent for left homonymous hemianopsia. Initial laboratory workup including total blood count, electrolytes, lipid panel, TSH, HbA1C, ESR, vitamin B12, and folic acid was within normal range. C-reactive protein was mildly elevated 1.45 m/dl. MRI brain showed extensive, multifocal white matter signal abnormalities with subcortical U-Fiber involvement and sparing of adjacent gray matter with white matter lesions in the right hemisphere that were T2 hyperintense, T1 hypointense which did not enhance with gadolinium administration (Fig. 1). The imaging findings were strongly suggestive of PML, but differential diagnosis included viral encephalitis and acute disseminated encephalomyelitis. The patient tested positive for Human Immunodeficiency Virus (HIV) using the 4th generation screening assay. HIV-1 viral load was 267,501 copies/ml, absolute cluster of differentiation 4 (CD4) cell count was 58/mm3 with CD4% 4%. Serology was positive with plasma JCV PCR showing < 500 copies/ ml. The autoimmune encephalitis panel was negative. Other infectious workups for syphilis, tuberculosis, gonorrhea, chlamydia, toxoplasmosis, cytomegalovirus and hepatitis were negative. Further inquiry revealed that the patient had a needle stick injury during his work in a laboratory many years ago. Antiretroviral therapy with once-daily fixed-dose Abacavir-Dolutegravir-Lamivudine was initiated along with trimethoprim-sulfamethoxazole regimen for Pneumocystis jerovecii prophylaxis. He was discharged home and lumbar puncture was performed as an outpatient. CSF analysis was positive for JCV on qualitative PCR. A definite diagnosis of PML was made at this time based on the overall clinical picture. Two months after initial admission, the patient was re-admitted for left-sided weakness, declining functional status, repeated falls, and worsening vision loss. The patient's presentation was consistent with the progression of PML supported by the progression of white matter lesions on repeat brain MRI [Fig. 2]. There was no contrast enhancement thus immune reconstitution inflammatory syndrome (IRIS) was considered less likely. Repeat Lumbar puncture showed CSF normal protein and glucose levels, 5 nucleated WBC, 119 RBCs. CSF VDRL, HSV - 1 and - 2 PCR, cryptococcus antigen testing were negative. Serum fungal antibodies for Histoplasma, Blastomyces, Aspergillus, and Toxoplasmosis were negative. CD4 cell count had improved from the prior 58-144/mm3 from the time of HIV diagnosis. Intravenous (IV) Pembrolizumab 2 g/kg was started for compassionate use with plans to repeat every 4 weeks. Even after a week, there was no improvement in left hemiparesis and patient developed left hemineglect. He also developed hospital acquired pneumonia for which was treated with piperacillin-tazobactam. Due to deteriorating neurological status, a repeated brain MRI was performed which showed further progression of PML (Fig. 3). There was now localized mass effect and edema which were concerning for PML-IRIS. Dexamethasone 8 mg every 6 h was started with only a slight improvement in left-sided strength. The patient developed Clostridioides difficile colitis and oral vancomycin was initiated. Eventually, the patient was transitioned to hospice care and passed away.

pembrolizumab, pembrolizumab for pml, pembrolizumab for pml in aids, progressive multifocal leukoencephalopathy (pml)

PMC8053466_02

Female

Her previous medical history revealed that she was diagnosed with RA at the age of 58 years old and was receiving orally 20 mg of leflunomide per day. She had been treated with methotrexate and hydroxychloroquine in the past, under which she had experienced many relapses that required oral corticosteroids. It was only when her antirheumatic therapy was switched to leflunomide that she had a long-term remission. The last time she had received oral corticosteroids was 3 years ago for a period of 6 months. Initial laboratory studies were normal, apart from a slightly elevated C-reactive protein (CRP) (CRP: 4.7 mg/dl, normal range: <0.5 mg/dl) with a normal white blood cell count (WBC: 6,9 x 103/mul) and no history of fever. In the next 48 h a single fever wave of 39 C was documented, followed by subfebrile body temperatures, and a slight deterioration of her speech and orientation. A brain MRI demonstrated a left parietal, rim-enhancing collection of fluid with diffusion restriction and dimensions of 48 mm x 25 mm x 19 mm that resembled a BA [Figure 2a-d]. Blood cultures were obtained and a CT scan of the thorax, abdomen and pelvis as well as a transesophageal echocardiogram were performed, to rule out a possible primary location. The initial antibiotic regimen included ceftriaxone, metronidazole, and vancomycin. Due to the suspected BA, dexamethasone was discontinued and a prophylactic therapy with levetiracetam 1000 mgIVq 12H was initiated, given the high risk of seizure. In the next 48 h her hemiparesis improved, as well as her laboratory infection parameters. However, her aphasia deteriorated further and she additionally developed dyscalculia. This deterioration of the neurological status was attributed to the space-occupying effect of the BA during the stage of the early capsule formation, as well as the expansion of the surrounding edema, due to the discontinuation of dexamethasone. Neurosurgery consultation led to patient's immediate surgical treatment. A left craniotomy was performed and an intraparechymal abscess was detected and evacuated. Cultures for common microbes as well as Mycobacterium tuberculosis and Nocardia were obtained intraoperatively from both the liquid and the solid part of the BA. The patient was extubated successfully and at her postoperative clinical evaluation she had a significant improvement of her neurological status. The intraoperatively obtained cultures came up negative, probably because of the early start of empirical antibiotic therapy. Histopathology revealed an aggregation of lymphocytes, macrophages, and neutrophils in a loose extracellular matrix, consistent with an abscess. No malignant cells were present. Seven days postoperatively only a slight paresis of patient's right upper extremity remained. The patient was discharged 6 weeks after her surgery and she continued receiving an oral antibiotic therapy (amoxicillin/clavulanic acid in combination with levofloxacin) for another 4 weeks. At her follow-up examination (1 month postoperative) she did not have any focal neurological deficits and she was able to resume her daily activities. The postoperative brain MRI demonstrated only the usual postoperative changes of the brain without any sign of fluid collection or gadolinium enhancement [Figure 2e]. Despite this incident, leflunomide was resumed after the termination of the antibiotic therapy, since her RA was refractory to the other antirheumatic therapies.

brain abscess, infections, leflunomide, rheumatoid arthritis

PMC9940231_01

Female

A 52-year-old female presented with esophageal dysphagia. The patients' past medical history was significant for GERD, constipation, hypertension, and arthritis. The patient had a 23 pack-year smoking history, history of alcohol abuse, and daily non-steroidal anti-inflammatory drugs (NSAIDs) use for her joint pain. A brief timeline of events follows (Table 1). On initial presentation, she had two episodes of food impaction. EGD showed severe circumferential ulceration in the distal esophagus with low-grade narrowing (Figure 1). Esophageal biopsy revealed reflux esophagitis without evidence of eosinophilic esophagitis and gastric biopsy revealed Helicobacter pylori-negative chronic gastritis. The lower esophagus was dilated from 15 to 18 mm with a controlled radial expansion (CRE) balloon. Proton-pump inhibitor (PPI) therapy was initiated, and the patient reported improvement of symptoms on routine follow-up. Sixteen months later, the patient returned with 2 months of solid food avoidance due to trouble swallowing. The patient also reported increased frequency of heartburn from once or twice weekly to every day despite adherence to daily PPI therapy. Patient reported increased severity of heartburn when she drank soda. Otherwise, patient reported normal appetite and no significant weight changes. She denied nausea, vomiting, chest pain, abdominal pain, or change in bowel habits. Physical exam revealed a healthy-appearing, obese woman in no acute distress. Family history was significant for gastritis and recurrent vomiting. The patient reported she desired relief of the food stuck in her mid-chest. Subsequent EGD revealed fine rings and diffuse yellow-white exudate (Figure 2). No esophageal stricture, ring, or hiatal hernia were seen to suspect a mechanical cause of the dysphagia (Figure 3). However, multiple openings in the esophageal mucosa were noted, suspicious for EIP (Figure 4). Random biopsies of the middle and upper esophagus also showed active esophagitis and were positive for focal Candida spp. In contrast to the H. pylori-negative gastritis at initial presentation, random gastric biopsies (Figure 5) revealed reactive gastropathy with focal H. pylori colonization. In addition, the patient underwent high-resolution esophageal manometry (HRM), which revealed strong contractions of the esophageal body with normal lower esophageal sphincter relaxation (Figure 6) with a distal contractile integral of 11,576 mm Hg s cm (normal range = <8000 mm Hg s cm). HRM findings were consistent with hypercontractile peristalsis ("Jackhammer esophagus") based on the Chicago v3.0 classification. Patient was initiated on a 14-day course of 200 mg Diflucan once daily for esophageal candidiasis. Patient was also treated for H. pylori colonization with standard quadruple therapy for 14 days, consisting of four times daily administration of bismuth subsalicylate 262 mg, metronidazole 250 mg, and tetracycline 500 mg, along with pantoprazole 40 mg twice daily. Despite adherence to therapy, patient reported symptoms of dysphagia and heartburn were not fully resolved at 1-month follow-up. Due to lack of clinical improvement, decision was made to repeat EGD to monitor for resolution of esophageal mucosal damage and undergo empiric esophageal dilation. Repeat EGD revealed normal-appearing esophageal mucosa with regular Z-line. Esophageal dilation with 16 mm Savary was successfully performed. Patient reported full resolution of her symptoms at 2-week follow-up. Patient remained asymptomatic at her most recent appointment 7 months after empiric dilation.

esophageal intramural pseudodiverticulosis, dysphagia, esophageal intramural pseudodiverticulosis

PMC7396118_01

Female

A 47-years-old female with a past history of sarcoidosis and endometriosis was referred to the gynecological consultation of Erasme University Hospital for an acute left lower abdominal painful mass at the gynecologic examination. Abdominal computed tomography (CT) examination showed a 17 cm left adnexal cystic lesion containing thin septa highly suspicious of malignancy. This tumor was surgically resected and frozen section examination suggested the diagnosis of a (mucinous tumor possibly invasive). Therefore, due to the age of the patient (without desire of fertility), a total hysterectomy with contralateral salpingo-oophorectomy and omentectomy was performed. Macroscopic examination revealed a complex multilocular 17 cm left ovarian tumor, with yellowish mucinous component and solid areas with some of them containing osseous tissue. There was no disruption on the external surface of the tumor (Figure 1). Microscopically, the tumor was heterogeneous with both benign, borderline, and invasive mucinous components (expansile and destructive patterns of invasion). Cytologically, the glands are lined by columnar cells with numerous goblet cells. Moderate to severe atypia and brisk mitotic activity were noted (Figures 2). By immunohistochemistry, as we have previously described, the tumoral cells were positive for CK7, CK20, CDX2, PAX8, P53 (diffuse (diffuse/mutated staining), SATB2 and negative for WT1, ER, PR, p16 (Figure 3). HER 2 staining was moderately positive (++) but FISH examination was negative. Immediately adjacent to the malignant glandular component, residual teratomatous bone tissue was observed (Figures 2). Endometriotric lesions were also observed at the periphery of the tumor but no Whaltard cell nest. No implant was noted in the epiplon and no tumoral cell was present in the peritoneal washing. The contralateral ovary, the rest of the gynecological examination, and the appendix were unremarkable. The tumor was staged pT1a according to the UICC 2017. No complementary treatment was applied and to date with a follow-up of 3 months the patient was disease free. After the dissection of the tumoral component, gene mutation testing has been performed by next generation sequencing (NGS), as we have previously validated, with a panel of 16 genes described in Table 1. Next generation sequencing (NGS) is a DNA sequencing technology technique that enables massive gene sequencing in parallel. Two mutations were found: R248Q (exon 7) mutation of the P53 gene and E545K (exon 9) mutation of the PIK3CA gene.

PMC10242122_01

Female

A 37-year-old woman first presented in the beginning of 2019 complaining of arthralgias, sicca symptoms, tiredness, and fatigue. Her personal history revealed that she was a non-smoker without prior allergies. She had been diagnosed with HT and vitamin D deficiency since 2012, but she was taking vitamin D irregularly. Family history suggested a strong autoimmune disease background: her mother had SLE and Sjogren's syndrome, and her grandmother had cutaneous lupus and pernicious anemia. In 2017, the patient had a cosmetic SBI. However, a seroma was found repeatedly in the right breast that required drainage on three occasions. At that point, no seroma analysis was performed. She was treated by a plastic surgeon and periodically received short corticosteroid courses and antibiotics. Prednisone therapy led to some symptoms' relief and seroma reduction, but the symptoms re-emerged after the corticosteroid therapy was discontinued. In 2018, magnetic resonance imaging (MRI) showed right breast capsulitis; a year later, breast ultrasound showed no signs of rupture and contractures ( Figure 1 ). At her first visit at our clinic in 2019, her erythrocyte sedimentation rate was 48 mm/h, complete blood count, CRP, D-dimer, and complete biochemistry (Blood urea nitrogen (BUN), creatinine, Na, K, Cl, total protein, albumin, bilirubin, aspartate transferase (AST), ALT, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), creatine kinase (CK), and lactate dehydrogenase (LDH)) were normal, as well as urine analysis. The TSH and FT4 levels were in the reference range. The 25 (OH) vitamin D level was low:22 nmol/L indicating deficiency). The physical examination was unremarkable. Immunological analysis showed a positive ANA homogenous/nucleolar pattern on the Hep2 cells substrate in the titter 1:640, positive anticardiolipin (aCL) IgG, and anti-SSA antibodies. Ophthalmological testing was normal, as were nailfold capillaroscopy and abdominal ultrasound. The unstimulated salivary flow rate was 0.2 ml/min. The diagnosis of ASIA was made based on clinical presentation (arthralgias, sicca symptoms, tiredness, and fatigue), immunological tests (+ ANA, + anti SSA antibodies, and aCL IgG), the co-occurrence of AID (HT), a family history of AID, and time correlation between SBI and clinical presentation. The removal of SBI was suggested, and vitamin D therapy was introduced. Also, salivary gland biopsy was indicated for suspected Sjogren's syndrome and genetic testing as well. However, the tests were not completed due to the COVID-19 outbreak, and the patient missed her follow-up visits. Almost 2 years since the first visit, she returned with similar symptoms, but some new ones have appeared in the meantime, such as skin and vaginal dryness and tingling in extremities. Also, hypothyroidism was diagnosed in 2020 and levothyroxine therapy was introduced. The seroma in the right breast was found once again. An ultrasound revealed right breast intracapsular rupture and contracture in 2021. The immunological analysis of seroma was positive for ANA (indirect immunofluorescence, IIF) of centromere pattern in the titer 1:640 and anticentromere (ELISA) antibodies. There were no malignant cells in seroma, and bacteriological and mycological findings were normal. Immunological testing in the serum showed + ANA on Hep-2 cell substrate (IIF) centromere pattern 1:640. Her laboratory work was normal, as well as her serum vitamin D level. In the following months, an extensive diagnostic workup was done. Keratoconjunctivitis, the unspecific nailfold capillaroscopic changes, and reduced diffusing capacity of the lungs for carbon monoxide (67%) were found. There were no abnormalities in her spirometry, chest CT, heart ultrasound, electroneuromyography, and color Doppler ultrasound of lower extremities. There was an evolution of the patient's symptoms over the years, alongside with the change of autoantibodies profile from 2012 to 2021 as shown in Figure 2 . We treated the patient with corticosteroid therapy (prednisone 20 mg daily initially with tapering) and antimalarial (hydroxychloroquine sulfate 2 x 200 mg), and vitamin D supplementation was continued. The therapy led to the reduction of most symptoms, except for the persistence of sicca symptoms. The explanation of SBI was indicated, but the patient was reluctant to accept it.

aid, asia, hashimoto thyroiditis, sbi, familial autoimmunity

PMC8435476_01

Female

A 28-year-old female was admitted to our hospital on August 17, 2017, with lymphadenomegaly on her right cervical area for approximately 2 months and repeated fever for more than 1 month, accompanied by a red rash, edema, and painful subcutaneous nodules in bilateral legs. Physical examination revealed lymphadenopathy in the right cervical bone and painful erythema nodosum in the bilateral calf. The patient had a history of pet rat bites in 2015. Laboratory tests showed that hemoglobin (9.4 g/dL) and hematocrit (28.8%) levels were decreased, while white blood cell count (16.27x109/L), neutrophils (78.6%), platelet count (418x109/L), blood C-reactive protein (138.15 mg/L) and erythrocyte sedimentation rate (88 mm/h) were elevated. HIV serology and serum cryptococcal capsular antigen tests were negative. Immunoglobulin levels and lymphocyte subsets were normal. T cell spot test (T-SPOT) was indeterminate. Culture of blood, sputum, bronchoalveolar lavage fluid (BALF), and skin lesions were all negative. Chest computed tomography (CT) displayed patchy infiltrates in the right upper lung with enlargement of hilus pulmonis and mediastinal lymph nodes (Figure 1A). Pathological examination of the cervical lymph nodes suggested granulomatous inflammation, but acid-fast staining and periodic acid-Schiff (PAS) staining were negative (Figure 2A and B). EBUS-TBNA biopsy examination showed scattered granulomatous inflammation. During the course, empirical treatments with cefoxitin (CFX), levofloxacin (LVFX), moxifloxacin (MFX), cefodizime (CDZ), clarithromycin (CLA), etimicin (ETM) and anti-tuberculosis isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E) regimen were successively administered, but no improvement was observed. By the end of October 2017, the patient developed pain in the head, right shoulder, gingiva, and knee-joint. Cerebrospinal fluid examination was normal, its smear and culture were all negative. Although bone marrow biopsy was consistent with infection and there was no evidence of hematological malignancy, the culture of bone marrow and lymph node tissue was both negative. Pathology examination of cervical lymph nodes showed suppurative necrotizing lymphadenitis, no fungus, and PAS (-). Positron emission tomography-computed tomography displayed enlargement of multiple lymph nodes of the right hilar, mediastinum, right supraclavicular and right neck, splenomegaly and increased bone metabolism in multiple places. The symptoms persisted after multiple rounds of antibiotic treatments, raising the possibility of a fungal infection. As the patient had a history of rat bites, an important natural reservoir for T. marneffei, we conducted T. marneffei qPCR and obtained a result of 1798 copies/uL. Therefore, the patient was diagnosed with disseminated T. marneffei infection, and intravenous antifungal therapy with amphotericin B liposome (AMPB) commenced on November 6, 2017. Owing to suspicion of coinfection with NTM, the patient was also treated with cefoxitin beginning on November 10, 2017. Subsequently, her body temperature dropped to normal, and symptoms of cough and sputum improved. The patient returned to the local hospital and continued treatment with itraconazole and cefoxitin. However, the lymph nodes remained enlarged. In December 2018, the patient presented with hemoptysis and recurrent intermittent fever, cough, sputum, fever, and rash. The patient presented with recurrent fever, rash and lymph node enlargement, which did not improve despite treatment with various antibiotics and anti-infective treatment for T. marneffei and M. tuberculosis. The pathological manifestations were granulomatous inflammation, but we could not rule out NTM infection because the cultures for M. tuberculosis and NTM were negative. Therefore, we performed an mNGS test, which revealed M. fortuitum in the lymph nodes. Additionally, in January 2020, qPCR analysis of a BALF sample detected T. marneffei. The patient was diagnosed with coinfection with M. fortuitum and T. marneffei and was treated with a combination of amphotericin B, voriconazole (VRC), linezolid (LZD) and ETM. Her body temperature returned to normal and respiratory symptoms improved. On March 19, 2020, chest CT showed patchy infiltrates, banded and nodular shadows, as well as pleural effusion (Figure 3A). Emission computed tomography suggested abnormal concentration of imaging agent in various parts of the bone. One month later, the therapy was adjusted to a combination regimen of VRC, LZD, MFX and CLA, which have continued to date. During follow-up in May and August 2020, the patient had no fever, the symptoms of cough and sputum had improved, and the rash had subsided. Re-examination of chest CT indicated that the enlarged hilar lymph nodes had gradually shrank (Figure 1B-E), and the lung lesions were significantly absorbed (Figure 3A-C). The patient experienced significant pain for more than 2 years between onset to the definitive diagnosis. The hospitalization and drug administration process throughout the history is summarized in Figure 4. Unfortunately, we overlooked the possibility of immunodeficiency in HIV-negative patient coinfected with M. fortuitum and T. marneffei.

mycobacterium fortuitum, talaromyces marneffei, coinfection, non-hiv

PMC4496840_01

Male

A 46-year-old man, former professional athlete, presented with a hypertensive stroke secondary to use of intravenous (IV) drugs, including heroin and cocaine. While admitted to the hospital, it was discovered that he was human immunodeficiency virus (HIV) positive. The patient's stroke resulted in hypoxic-ischemic brain damage leading to severe spasticity. He developed 4/5 bilateral lower extremity spastic diplegia as per the Ashworth scale. Weakness of his right arm and face were additionally noted. The patient's speech was dysarthric but understandable. For 7 years poststroke, the patient underwent physical therapy, botulinum toxin injections, and took oral baclofen for his increased tone without relief. The patient was wheelchair bound due to the increased tightness and loss of strength in both of his legs. He was unable to stand up or mobilize independently, and needed assistance with daily activities such as bathing and dressing. The goals of his spasticity management included improvement in mobility and gait, as well as a better range of motion. Unable to achieve these goals with pharmacological treatment, his physiatrist administered an intrathecal test dose of baclofen through a lumbar puncture. A test dosage of 75 ug of ITB was administered. The patient responded positively and underwent surgical implantation of a 40 ml SynchroMed II pump with a T10 level catheter. Postoperatively, the patient did well and was transferred back to inpatient rehabilitation after 48 hours of flat bed rest and IV cefazolin. Two weeks postoperatively, the patient developed leakage of CSF from the lumbar incision and was subsequently transferred back to the neurosurgical service. The lumbar incision was oversewn and a lumbar puncture below the level of the catheter was done. A pressure of 24 cm H2O was documented. A computed tomography scan of the head showed mild to moderate ventricular enlargement. The next day, a right frontal Codman ventriculo-pleural shunt was placed. The patient's ventricular CSF did not initially show any bacteria. However, the following day the lumbar puncture CSF grew Staphylococcus epidermidis, sensitive to oxacillin. The patient was placed on IV antibiotics to prevent infection of the newly placed pump. After finishing 8 weeks of IV antibiotics, another area of the patient's incision site opened. Subsequently, the patient received a peripherally inserted central catheter line for another round of IV antibiotics. Due to these recurrent infections, it was decided to remove the patient's right-sided pump, and replace it with a new pump and spinal catheter on the left-side of his body. Postoperatively, the patient developed an infection at the abdominal incision site of the second pump, and the device was removed. At this time, the patient developed deep vein thrombosis and sepsis, and received 45 days of IV antibiotics through long-term IV access. Although the HIV was under control and the viral load was undetectable, it was believed that the patient's recurrent infections were due to his immunocompromised status. In addition, his urinary and fecal incontinence may have contributed to recurrent lower abdominal infections, secondary to contamination from his diaper. At this time, botulinum toxin injections were re-instituted as the primary treatment for the patient's spasticity: 600 units of botulinum toxin were administered in the adductors, plantar flexors, and hamstrings every 3 months. He reported improvement of his gait 2 weeks after each injection, and experienced maximum effect of the treatment 4 weeks postinjection. The patient was able to walk with a rolling walker; however, he noted difficulty with balance while standing. The effect of the botulinum toxin lasted approximately 2.5 months before wearing off. The patient became septic with a Staphylococcus infection secondary to multiple, recurrent intramuscular botulinum toxin injections. At this point, almost all options were exhausted, and the neurosurgeon proposed a SDR. The patient was explained the risks and unknown but potential benefits of SDR. The surgery would reduce the patient's tone, but could make it difficult for him to walk postprocedure if he was currently using his tone to ambulate. The risk of numbness in lower extremities, neurogenic bladder, and CSF leak were also discussed. The patient agreed to the procedure in an attempt to eliminate or decrease the frequency of the botulinum toxin injections. The patient underwent selective dorsal rhizotomies at levels L2-S1 bilaterally. Osteoplastic laminectomies were performed from L1 to L5. The dura was retracted laterally. The L2 nerve root on the left was dissected out and confirmed electrically. The nerve root was separated out into the ventral motor and the sensory dorsal portions. Each dorsal sensory nerve was isolated using intraoperative microscopic dissection, and the rootlets were separated into thirds or quarters. Each motor nerve was stimulated, and then each sensory rootlet was stimulated. Rootlets were sectioned if stimulation of the rootlet was associated with clonus and prolonged contraction of the involved muscle groups. This was repeated for L2 through S1 bilaterally based on electrophysiological stimulation and the observed and recorded results. Approximately 50-75% of each dorsal sensory nerve on each side was sectioned. Spinal nerve root function was tested in this procedure by recording spontaneous and electrically-triggered EMG activity from iliopsoas, adductor, quadriceps, tibialis anterior, gastrocnemius, biceps femoris, and external anal sphincter muscles innervated by these roots. Portions of these roots were selectively sectioned based on triggered EMG discharge patterns. At completion of the dorsal rhizotomy, the dura was sewn closed with a 6-0 Nurolon. The lamina of L1 through L5 was put back into position and laminar fusion was done using the Synthes laminar plating system. An epidural spinal catheter was placed for pain management control. There were no intraoperative complications. Postoperatively, the patient did well and was transferred back to inpatient rehabilitation. His spasticity was significantly reduced according to the Ashworth scale. Prior to his SDR, his lower extremity spasticity was 4/5. Postoperatively after SDR, this patient's Ashworth scale is consistently 1/5 bilaterally. The patient experienced no numbness or change in bowel and bladder control postsurgically. At the present time, 3 years postsurgery, the patient attends physical therapy twice a week. The patient has no spasticity. Although he still requires assistance to ambulate, he experiences increased comfort due to the reduction of his tone and associated pain. The patient continues to present with lower extremity weakness and cannot stand without support. His muscular strength is about 3/5 in both legs proximally and 2/5 distally. This weakness resulting from the stroke is permanent and cannot be improved via a dorsal rhizotomy, as most poststroke paresis is irreversible after 6 months. His hydrocephalus is well-controlled with his shunt set at 180 mm H2O. His HIV viral load is undetectable. The patient is extremely satisfied with the outcome of his dorsal rhizotomy.

intrathecal baclofen, selective dorsal rhizotomy, spastic diplegia, spastic paraparesis, spastic paraplegia, spasticity

PMC7784232_01

Male

A 58-year-old man initially had a three-month history of persistent severe headache, lethargy and decline in sexual function with no visual and neurological deficit. There were no drenching night sweats, unexplained weight loss, fever, abdominal discomfort, swelling on the neck, axilla or groin, arthralgia and joint swelling, myalgia or myositis, shortness of breath or cough. His past medical history was unremarkable with no history of autoimmune disorders or endocrinopathy. The baseline early morning serum cortisol level was low (<22 nmol/L) (N: 68-469) with a normal serum adrenocortical hormone (ACTH) level of 5.0 pg/mL (N: 0-46.0). Despite the subnormal serum luteinizing hormone (LH) 0.9 IU/L (N: 2.0-12.0) and the follicle stimulating hormone (FSH) of 1.9 IU/L (N: 1.5-14.0) at the lower limit of normal, the corresponding serum testosterone level of 1.71 nmol/L (N: 9.9-52.4) was also low. In addition, the low level of serum TSH (0.86 uIU/L) (N: 032-5.0) response was inappropriate to the low serum free thyroxine (T4) level of 9.26 pmol/L (N: 9.10-23.80). There was also a low growth hormone (GH) level of <0.15 mIU/L (N: 0.16-16.0) with normal prolactin level of 2.04 ug/L (N: 1.61-18.77) at presentation. Formal perimetry showed no visual field deficit. There was no diabetes insipidus. Anti-thyroid peroxidase (TPO) antibodies level was not raised at 20.4 IU/mL (N: 0-35). The full blood picture did not show any histiocytes. Chest X-ray also showed no mediastinal enlargement, pulmonary infiltrates or hilar lymphadenopathy in both the lung fields. However, serum angiotensin-converting enzyme was not sent as there was no suggestion of sarcoidosis from our clinical assessment. Moreover, this assay was not available in our institution, and the patient could not afford the additional cost of sending to another laboratory with the facilities. Initial magnetic resonance imaging (MRI) demonstrated a 20 mm by 14 mm by 10 mm non-homogenous mass occupying the pituitary fossa. This enlarged pituitary mass (white arrow in A) is associated with suprasellar extension (Figure 1). There is a T1 hyperintense rim around the wall of the mass, with some more amorphous hyperintensities at a dependent location within the lesion core. These T1 hyperintensities could represent either methemoglobin or proteinaceous content. Polypoidal T1 hypointensity within the sphenoid sinus anteriorly (white arrowhead in A), which enhanced post-gadolinium (not shown), is attributed to reactive inflammation. No appreciable enhancement of this mass was detected, nor was there evidence for a thickened pituitary infundibulum or hypothalamus. This initial MRI features of the enlarged pituitary, no thickening of pituitary infundibulum or hypothalamus, the negative clinical screening test for autoantibodies, sarcoidosis, tuberculosis, lymphoproliferative disorders and other granulomatous lesions suggested a macroadenoma. Correction of the hormonal deficit was the priority as our patient did not have compression of the optic nerve leading to visual field deficit. A physiological dose of hydrocortisone (10 mg am and 5 mg at noon) and oral levothyroxine of 75 mcg daily were commenced. Intramuscular testosterone 250 mg every three weeks was also initiated. His symptoms improved with the hormonal replacement therapy, which correlated with the improvement in his repeated hormonal profile. After the hormonal treatments for more than six months, the free T4 level improved to 16.72 pmol/L with only a minimal decline in the serum TSH level (0.27 uIU/L) and an improvement in serum testosterone of 49.8 nmol/L. His early morning serum cortisol level remained at <0.22 nmol/L. During this interval period, he denied any symptoms, such as syncope and severe headache, nor there was a new hormonal deficit to suggest pituitary apoplexy. An MRI of the pituitary was repeated seven months following clinical improvement with hormone replacement therapy. Despite the absence of visual field deficit, reassessment of the size of pituitary mass is important for the determination of the subsequent treatment course. This follow-up MRI showed a drastic regression of the pituitary mass (Figure 2). While the T1 hyperintense "bright spot" of the posterior pituitary is appreciated (white arrowhead in A), much of the anterior pituitary appears to be flattened against the seller floor (white arrow in A). The optic chiasm prolapsed directly and inferiorly into the sella from its normal suprasellar location (black arrow in B), possibly reflecting traction due to post-inflammatory fibrotic process. Predominantly cerebrospinal fluid-filled pituitary fossa and the resolution of the inflammatory changes within the sphenoid sinus is also noted. A third MRI six months later revealed similar features of an empty sella. Formal perimetry assessments on both follow-up assessments did not show any visual field deficit.

autoimmune hypophysitis, empty sella, hypopituitarism, older male, pituitary enlargement

PMC7154255_01

Female

All patients attained Tanner stage 5. In this group, there was one patient with breast cancer. The diagnosis was conducted on a 37-year-old patient during her twenty-fourth year of therapy. This patient had had a myeloblastic acute leukemia at age 12 and had been submitted to conventional chemotherapy and BMT with previous ablative chemotherapy (busulfan, cyclophosphamide) and TBI (12 Gy) as a conditioning regime. She had had one spontaneous menstrual cycle before the illness and, upon starting hormonal therapy, at age 13, she had an LH level of 49 mIU/mL and FSH of 42.9 mIU/mL (NV <15). The breast tumor was intraductal with positive receptors for E2 (85%), Prog (85%), ErbB+ and Ki67 (30%). She is alive and, after surgery and chemotherapy, has been disease-free for the past 4 years. This occurrence represents an incidence rate of 0.94/1,000 patient-years of exposure to treatment (Table 3). In this group, lumbar/femoral osteopenia was found in 20%/14% of patients and osteoporosis in 12%/7%. Treatment improvement was achieved in 38%/31% at lumbar and femoral points, respectively (Tables 4, 5, 6). We have not found any case of breast cancer in this patient subgroup. Regarding bone density, lumbar/femoral osteopenia was found in 22%/19% and osteoporosis in 4%/1% of patients. Treatment improvement was achieved in 50%/57% at lumbar and femoral points, respectively (Tables 4, 5, 6). One patient developed breast cancer in this subgroup. At 51 years of age, she had had a multiple myeloma and had been treated with chemotherapy. At 52 years of age, she underwent BMT with previous ablative chemotherapy (melphalan). She immediately started menopause, complaining of flushes and high gonadotropin values (LH-49.1 mIU/mL and FSH-88 mIU/mL). She was started on HRT and after 3 years, she was diagnosed with intraductal breast cancer with positive receptors E2 (100%) and ErbB+. She was submitted to surgery, radiotherapy and antiestrogen therapy and died with myeloma relapse at age 70. This patient had a family history of breast cancer (her grandmother, grandaunt and sister). This occurrence represents an incidence rate of 3.42/1,000 patients-years of exposure to treatment (Table 3). Lumbar/femoral osteopenia was found in 17%/31% and osteoporosis in 21%/7% of the patients. Treatment improvement was achieved in 64%/55% at lumbar and femoral points, respectively (Tables 4, 5, 6). During the follow-up, 6 vascular complications were observed, 4 of which were thrombosis occurring in areas treated with radiotherapy, and the remaining 2 were leg phlebitis (Table 7). Looking at the whole sample, we can see an incidence rate of 2.63 cases per 1,000 patients-years of exposure to treatment (Table 8).

breast cancer, hormonal replacement therapy, oncological survivors

PMC7524186_01

Male

The patient was a 21-year-old male plaster worker, living in one of the North-Western provinces of Iran, who presented with skin lesions on his face and upper lip that had appeared about 3 months previously. Skin lesions were prurient and some of them were prominent and hemorrhagic. The patient reported no other symptoms, such as fever, chills, fatigue, urinary and/or respiratory symptoms. Familial, allergy and drug history were negative. On physical examination vital signs were normal. On facial skin examination; lesions appeared as multiple separate hyperkeratotic nodular lesions with erythematic and prominent borders on the face and upper lip with normally appearing skin around the lesions (Figure 1). The skin demonstrated no other significant changes, and the patient had no notable local lymphadenopathy. Other examinations demonstrated no significant findings. The patient had visited multiple physicians/clinics and had been treated with multiple topical therapies, oral antibiotics, and antihistamines but the medications had no affect on the lesions. Topical corticosteroids subsided inflammation and swelling of the skin lesions. Finally, a skin biopsy, a chest x-ray and blood tests were performed. The patient's blood tests were normal but skin biopsy revealed skin tissue with multiple granuloma formation in a subepithelial area composed of epithelioid cells, with giant cell and lymphocyte around them (Figure 2). Acid-fast stain of Ziehl-Neelsen (Figure 3) and a purified protein derivative (PPD) skin test due to epidemiology of the tuberculosis helped in the final diagnosis of cutaneous tuberculosis (CTB), caused by acid-fast positive bacteria Mycobacterium tuberculosis infection. Due to the high prevalence of TB infection in North-Western Iran, no response to medications but topical corticosteroids, and normal blood tests we suspected the cutaneous manifestation of TB in spite of its rarity. Also, a 2-time rapid ELISA test for HIV infection was negative. The Ziehl-Neelsen stained histopathological assessment and positive PPD test confirmed the tuberculosis diagnosis. The patient underwent standard anti-TB regimens involving 2 months of quadruple therapy of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a further 4 months of isoniazid plus rifampin. Continued treatment resulted in lesions clearance at the end of the course of treatment and even the scars had begun to regress. At the end of the 8th month (2 months after ending the medical therapy), the patient had no cutaneous and systemic signs or symptoms and the course of treatment ended without any complications (Figure 3).

mycobacterium tuberculosis, cutaneous tuberculosis, orolabial lesions

PMC9520523_01

Male

The first case was a 65-year-old man with paroxysmal bilateral temporal headache, a 20-kg weight loss over 3 months, hoarseness, dysphagia with paroxysmal diplopia, and intermittent fever for 1 month. A neurological examination revealed dysarthria, restricted right eye abduction, and left vocal cord paralysis. Laboratory tests yielded the following results: white blood cell count, 10,010/mul; hemoglobin, 6.9 g/dl; erythrocyte sedimentation rate (ESR), 140 mm/h; C-reactive protein (CRP), 131 mg/L. Tests for infections were negative, including blood bacteria cultures, Mycobacterium tuberculosis antibodies, respiratory viral antigens, human immunodeficiency virus, and fungi antigen. Rheumatologic assays were negative (such as antinuclear antibody, cyclic-citrullinated peptide IgG antibody, rheumatoid factor, anti-cardiolipin antibody, lupus anticoagulant, and angiotensin-1 converting enzyme), except for titers of serum cytoplasmic ANCA (1:32), myeloperoxidase antibodies (MPO-ANCA) (1:100) and elevated IgG4 (411 mg/dl; normal: 8-140 mg/dl), although the total IgG level was normal. Routine urinalysis was unremarkable. Cerebrospinal fluid (CSF) showed lymphocytosis (25 cells/mm3), and three well-defined oligoclonal bands were present in both the CSF and serum. The CSF infectious disease test was negative. Chest and paranasal sinus CT found no abnormalities. Gadolinium-enhanced brain magnetic resonance imaging (MRI) revealed enhanced and thickened dura mater, predominantly in the posterior fossa (Figure 1). Intravenously administered dexamethasone (10 mg/day for 5 days) markedly relieved the patient's headache, but it recurred after the oral administration of prednisolone (28 mg/day). An additional intravenous cyclophosphamide administration (0.4 g once) achieved stable improvement. On discharge, fever and headache had disappeared, and dysarthria had significantly improved. The 6-month follow-up examination showed great clinical and radiological improvement, and intravenous cyclophosphamide administration at intervals allowed to taper prednisolone. The CRP and ESR also returned to normal levels.

anca-associated vasculitis, igg4, igg4-related disease, antineutrophil cytoplasmic antibody, hypertrophic pachymeningitis

PMC9520523_03

Female

The third patient was a 61-year-old woman admitted for weakness and stiffness in both lower limbs for about 1 year, accompanied by thoracic back pain and constipation for 8 months. The neurological examination on admission revealed paresis in the bilateral lower limbs (3 to 4/5), decreased pain and thermal sensation in the trunk and lower limbs below the T10 level, brisk bilateral knee and Achilles tendon reflexes, and bilateral extensor plantar response. The routine blood tests and inflammatory markers levels were normal. Infections assays were negative. Rheumatologic assays were negative, except for seropositivity for perinuclear ANCA (titer, 1:32), MPO-ANCA (titer, 1:100), and elevated IgG4 (441 mg/dl). Chest and paranasal sinus CT found no abnormalities. A spinal cord MRI revealed a ribbon-like thickening of the dura mater between vertebral levels T7 and T11 (which was moderately enhanced by gadolinium administration) and a compressed and flattened focal spinal cord (Figures 3A-C). Although the patient underwent emergent T7-T11 right pediculectomy and partial corpectomy for decompression and resection of the dural lesion, her neurological deficits did not improve. The CSF analysis during the operation was negative for bacteria, tuberculosis, viruses, and fungi. A broad panel of immunohistochemical markers was assayed, such as S-100, EMA, CK-P, GFAP, Vim, CD20, CD68, CD38, CD138, CD34, and Ki67. A histopathology analysis showed lymphocyte infiltration, high IgG4+ cell infiltration, and a storiform pattern of fibrosis without granulomatous changes (Figures 3D,E). We systematically searched the PubMed database for studies on humans, written in English, and published between 1976 and April 2022 using the keywords: "pachymeningitis, meningitis, dura, antineutrophil cytoplasmic antibody, myeloperoxidase, and proteinase-3." We excluded cases described in insufficient detail. Ultimately, we analyzed 10 cases, including our three cases. The patients' ages ranged from 48 to 79 years (median 61.5 +- 3.2 years), and the male/female ratio was 1:1. Table 1 summarizes the clinical, radiological, and pathological characteristics of all patients. We re-evaluated the cases according to the Comprehensive Diagnostic Criteria (CDC) for IgG4-RD. Possible IgG4-RD was defined by suggestive organ involvement associated with elevated serum IgG4 levels (>135 mg/dl). We identified probable IgG4-RD by looking for classical histopathological features (i.e., dense lymphoplasmacytic infiltration, storiform fibrosis, obliterative phlebitis, and mild-to-moderate eosinophil infiltration), IgG4/IgG positive plasma cell ratio >40% and >10 IgG4+ cells per high power field. Definitive IgG4-RD was identified by suggestive organ involvement associated with elevated serum IgG4 levels and histological features. For AAV, we used the American College of Rheumatology (ACR) 1990 criteria and the definitions from the 2012 Chapel Hill Consensus Conference and the EMA algorism for GPA, MPA, and EGPA. Due to a lack of histopathological examination, only a possible diagnosis of IgG4-RD was established in our two patients (Nos. 1, 2) according to the currently accepted criteria, although we cannot fully exclude the diagnosis of AAV in the current stage. We diagnosed four cases with definitive IgG4-RD and three with probable and possible Ig4-RD. Eight patients had anti-MPO ANCA, and two had anti-proteinase-3 (PR3) ANCA. Two cases (Nos. 7 and 10) fulfilled the CDC for IgG4-RD and the ACR and Chapel Hill criteria and the EMA algorism for AAV. One had biopsy results compatible with both GPA and IgG4-RD, and the other (No. 7) had a clinical overlap. Eight patients had documented symptom courses, and most of them had a diagnostic delay of several months before admission. In patients with intracranial dura mater involved, headache was the most common symptom, followed by cranial nerve deficits, such as hypoacusis, dysphagia, diplopia, vertigo, hypoglossal nerve palsy, and trigeminal nerve palsy. Headaches were often described as a sense of persistent local crushing with progressive exacerbation and refraction to drugs. Two patients (Nos. 4 and 5) had papilledema, most likely caused by intracranial hypertension. Patients with spinal hypertrophic pachymeningitis often experienced radicular pain and spinal cord compression symptoms (Nos. 3, 6, and 8), but rarely fever. MRI revealed focal pachymeningitis in eight cases, with the posterior fossa and occipital lobe most commonly involved, which might explain the neurological symptoms. Lymphocytosis and oligoclonal bands were commonly found in the CSF, as well as elevated blood non-specific inflammatory indicators, such as CPR and ESR. Eight patients had elevated serum IgG4 levels, while one displayed mild neutrophil-predominant leukocytosis, thrombocytosis, and normocytic anemia. The overall responses to immunosuppressants were good, with six cases attaining great clinical and radiological improvement; two cases suffered from one or two relapses, and only one patient expired from secondary infection.

anca-associated vasculitis, igg4, igg4-related disease, antineutrophil cytoplasmic antibody, hypertrophic pachymeningitis

PMC8581154_01

Male

A 34-year-old Chinese male visited his local tertiary hospital due to progressively worsening occipital headache for the past 4 days, without showing any other symptoms of fever, projectile vomiting and so on. His medical history showed that he had had cryptococcal meningitis and HIV infection for about 1 year, and he had been receiving (with good compliance) fluconazole and tenofovir-lamivudine-dolutegravir based antiretroviral therapy (ART) during the same time period. The levels of the inflammatory markers were normal (Leukocytes 5.61*109 cells/mL, C-reactive protein 7 mg/dL). His neurological signs showed no abnormal indications. Head Computed Tomography (CT) scan revealed no abnormalities. The lumber puncture was performed and the test result of CSF is shown in Table 1. It shows rising levels of OP, lymphocytes and protein in CSF. The cryptococcus capsular antigen test result of CSF was positive but the results for the gram staining and culture study were negative. The patient was diagnosed with cryptococcal meningitis and was given fluconazole (400 mg, QD) continuously and TMP-SMX (0.48, QD) for 1 week by the doctor at the local hospital. However, his headache problem was not resolved. Then he came to our institution, the Infectious Disease Department of the First Affiliated Hospital, School of Medicine, Zhejiang University, and was hospitalized. Upon arrival, the patient's body temperature was 36.7 C, pulse rate was 95 beats/min, blood pressure was 138/97 mmHg, respiratory rate was 23 breaths/min, and finger pulse SpO2 was 98%. He was suffering from headache but his neurological signs were normal. The laboratory results are as follows: white blood cell count 7.0 x 109/L, with a neutrophil ratio of 42%, hemoglobin 150 g/L, and platelet count 294 x 109/L; C-reactive protein (CRP)1.8 mg/L; CD4 count 171 cells/muL; normal blood biochemical; negative 1,3-beta-D-glucan test (G test) and galactomannan test (GM test) results (0.1 mug/L). The IgG antibodies of Epstein-Barr virus (EBV) and Human Cytomegalovirus (CMV) were positive, while the IgM antibodies and the test of the nucleic acid of EBV and CMV were negative. The test result for mycobacterium tuberculosis (MTB) was negative based on the blood test with T-SPOT, and the result for cryptococcus capsular antigen test of the blood was positive. The chest CT scan and echocardiography results were normal. The lumber puncture was performed on day 2 and the opening pressure was 285 (cm H2O). The test result of CSF is shown in Table 1. The cryptococcus capsular antigen test of CSF was positive. An India Ink microscopy on the CSF sample for cryptococcus was also performed and the result was negative. The results of the blood and CSF smears of bacteria and fungi were negative. The results of the acid-fast staining of CSF smear and GeneXpert were both negative for MTB. The test of the nucleic acid of CMV and EBV in CSF was negative. Based on the negative gram staining and culture study results of CSF provided by the local hospital and the above results, the CSF sample was sent to the laboratory for conventional tests and NGS test (using the Illumina Platform, IngeniGen. Ltd, Zhejiang, China) for pathogen-induced meningitis verification. Contrast-enhanced and diffusion-weighted MRI (3.0T) was performed on day 3, and the partial cerebellar surface enhancement was revealed (Figure 1), which matched the manifestation of cryptococcal meningitis, and no abnormal signals were detected in the cerebral parenchyma. Two days later, the NGS results showed that streptococcus suis (6 reads) and streptococcus mitis (1 reads) were found in CSF. The results of the blood and CSF culture of bacteria and fungi were still negative on day 5. So, we inquired the patient's medical history again, and he told us he had had close contact with a truck transporting pigs and had choked on water in a water park 2 weeks before his admission. Based on the test reports and his contact history, the diagnosis of streptococcus suis infection was made and intravenous Ceftriaxone (2.0, QD) was given. The patient's headache problem was resolved gradually. A second lumber puncture performed on day 12 revealed improved conditions of CSF (see Table 1), with negative gram staining and culture study results. Ceftriaxone was given to the patient for another 2 weeks and then oral moxifloxacin (0.4, QD) for 2 days. The third lumber puncture was performed on day 17, showing continuous conditional improvement of CSF. The patient was discharged in stable condition on day 21 after 1 week of receiving moxifloxacin. Three weeks later, we performed the fourth lumber puncture to confirm that the meningitis infection was cleared, but the patient's OP level was still abnormal, so fluconazole was given continuously until the OP level and cryptococcus capsular antigen test turned normal 6 months later.

hiv, cerebrospinal fluid, cryptococcus, meningitis, next-generation sequencing, streptococcus suis

PMC7338606_01

Female

The patient is a 39-year-old woman who presented 1 year ago with progressive proteinuria, renal failure, and hypertension. A biopsy was performed after development of significant renal dysfunction; serum creatinine was 3 mg/dL. The protein excretion rate was 1-2 g/24 h initially, which increased to 4-6 g/24 h with worsening renal function. The initial biopsy result at an outside institution was reported as non-diagnostic, with features of chronic autoimmune glomerulonephritis. The patient had a thorough infectious disease evaluation which was negative for hepatitis A, hepatitis B virus (HBV), and hepatitis C virus (HCV) serologies, negative for human immunodeficiency virus (HIV), negative for treponemal serologies, and with no evidence of tuberculosis, coccidiomycosis or other chronic infections. She did not have known diabetes, obesity, or malignancies. Extensive serological evaluation was negative for lupus serologies [anti-nuclear antibody negative (<1:40 titer), anti-double stranded DNA (anti dsDNA) negative (<200 international units/ml), DNAase B antibody negative (<86 Units/ml), anti-histone antibody negative 0.4 units, anti-centromere <1, ribonucleoprotein <20 units, anti-smith antibodies <20 units, Sjogren's syndrome (SSA and SSB) antibodies <20 units, rheumatoid factor negative <1, scleroderma antibodies negative at 1 AU/ml, anti-citric citrulline peptide negative at 3 units, Cardiolipin IgA, IgG, IgM was negative, and ANCA panel (c-ANCA, p-ANCA, proteinase 3 and anti-myeloperoxidase were all negative <1:20 titer). Complement titers (CH 50) were near the lower limit of normal at 43 units/mL [Reference range 42-95 Units/mL], and there was isolated depression of C3 at 67 mg/dL [Reference range 76-165 mg/dL] but with normal C4 levels at 23 mg/dL [Reference range 16-48 mg/dL]. Serum and urine electrophoretic studies and immunofixation studies did not reveal a monoclonal spike. Free light chain kappa to lambda ratio was also normal with a ratio of 1.66. On renal biopsy (Figure 1), the dominant finding by light microscopy was an MPGN pattern of injury that was predominantly chronic with segmental sclerosis, extensive global glomerulosclerosis, and parenchymal scarring. However, there was residual activity including focal cellular-to-fibrocellular crescents, karyorrhexis, and diffuse, and mild endocapillary hypercellularity. Along with prominent glomerular basement membrane double contours, there was also some suggestion of mesangiolysis and marked endothelial cell swelling raising the possibility of endothelial cell injury, although definitive morphologic features of TMA were not identified. Immunofluorescence studies showed segmental to global granular staining for IgG (2+), IgA (trace), IgM (trace), C1q (2+), C3 (3+), and kappa/lambda light chains (both trace). At least two glomeruli exhibited segmental fibrinogen staining (2-3+) in areas of capillary loop necrosis. Electron microscopy revealed amorphous electron dense deposits present in a predominantly subendothelial and mesangial distribution with occasional subepithelial and intramembranous deposits. Endothelial cell cytoplasm was swollen. There were no tubuloreticular inclusions or extra-glomerular deposits. A diagnosis of immune-complex mediated membranoproliferative glomerulonephritis was rendered. Given the negative evaluation for underlying infectious, autoimmune diseases, and neoplastic disorders, the possibility of a complement-mediated disorder was investigated. Complement profile testing did not reveal C3Nef, C4Nef, anti-factor H, or factor B antibodies. Soluble C5b-9 levels were not elevated (within the normal range of <250 ng/mL), a finding which was compatible with the patient's glomerular disease having entered a quiescent stage. No known genetic mutations or variants of uncertain significance were found at the time (Iowa complement laboratory) in the 2017 panel that was sent. The panel sent included CFH, CFI, MCP (CD46), CFB, CFHR5, THBD, C3, ADAMTS13, PLG, DGKE, MMACHC, G6PD. Multiple Ligation Probe Amplification (MLPA) was included in the testing to determine copy number variants over the complete complement Factor H related region. It should be noted that the rate of capture of genetic mutations remains only 41-60%, as not all mutations leading to complement mediated disorders are known at this point. However, C3 levels remained low at 67-75 mg/dL a year after the renal biopsy, supporting the presence of a complement-mediated disorder. The patient has remained off renal replacement therapy and is scheduled to undergo a preemptive renal transplant. Treatment with mycophenolate mofetil with the transplant may be able to prevent any complement mediated disease process recurrence; however, further therapy would depend on demonstration of recurrent glomerulonephritis in renal allograft biopsy.

c3 glomerulonephritis, alternative pathway, complement mutations, membranoproliferative glomerulonephritis, proteinuria

PMC6421267_01

Female

An 81 year-old woman was admitted to our oncology unit (Military Training Hospital Begin, Unit of Oncology, Paris, France) for the management of grade 3 diarrhea due to fluoropyrimidine-related toxicity. She suffered from an invasive ductal carcinoma of the left breast (Elston-Ellis grade 3, RH+ HER2-) diagnosed in 2007. Medical management was initially based on surgery, radiation therapy and chemotherapy (adriamycine and cyclophosphamide). Hormonal therapy (anastrozole then exemestane) was performed during the following 5 years (2008-2012), and then she entered a regular clinical and radiological follow-up program. As bone and hepatic metastases were diagnosed in 2016 and 2017, respectively, hormonal therapy (exemestane) and chemotherapy (paclitaxel) were reintroduced. In May 2018, given evidence of CNS progression with multiple cerebral metastases, capecitabine (1,500 mg twice a day) was administered. The patient presented signs of major toxicity requiring urgent hospitalization in our department 20 days after capecitabine treatment, and the main symptoms included diarrhea (grade 3) and asthenia (grade 3). She was admitted to our department for close monitoring, with intensive fluid and nutritional support. Biological investigations performed at admission revealed hematological toxicity with grade 4 neutropenia (absolute neutrophil count: 0.31 x 109/L; reference interval, 1.5-4 x 109/L) and grade 4 thrombocytopenia (platelet count: 35 x 109/L; reference interval, 150-300 x 109/L). The consequences of the severe diarrhea resulted in low blood levels of potassium (2.8 mmol/L; reference interval, 3.5-4.5 mmol/L), phosphate (0.4 mmol/L: reference interval, 0.81-1.45 mmol/L) and magnesium (0.63 mmol/L; reference interval, 0.7-1.05 mmol/L). Moreover, prothrombin time was increased (prothrombin ratio: 41 %; reference interval, >70 %) with a mild elevation of liver transaminase levels (ALT: 60 UI/L; reference interval, <33 UI/L and AST: 106; reference interval, < 32 UI/L) and a marked hypoalbuminemia (albumin level: 22.3 g/L, reference interval, 35-52 g/L). Stool cultures failed to detect bacterial pathogens, including C. difficile strains. Capecitabine treatment was suspended upon the patient's admission to our service. The clinical evolution was slowly favorable: no diarrhea was observed after 72 h, and cell blood counts were normalized in 1 month. DPD deficiency was suspected as a potential explanation for the severe toxicity following the first cycle of treatment with capecitabine. DPD phenotype assessment was performed by measurements of plasma uracil (U) and dihydrouracil (UH2) using an LC-MS/MS method. Analysis revealed a partial DPD deficiency according to the established criteria (U: 40.4 ng/mL, deficiency cut-off > 16 ng/mL and/or UH2/U ratio: 5.0, deficiency cut-off < 6). The patient signed written informed consent for genotyping and related data for scientific research. The four DPYD SNPs most commonly observed in the Indo-European population were genotyped according to the current recommendations of the Clinical Pharmacogenetics Implementation Consortium. The SNPs (c.1905+1G>A, rs3918290; c.2846A>T, rs67376798; c.1679T>G; rs55886062 and c.1236G>A, rs56038477) were genotyped using LAMP Human DPD deficiency kit (LaCAR MDx Technologies, Lieges, Belgium). None of the four variant were detected. However, an atypical profile of the melting curve relative to rs3918290 genotyping was observed (Figure 1). As the presence of an uncommon SNP was suspected, sequencing of DPYD exon 14 was performed which revealed that the patient harbored a SNP in a heterozygous state: c.1903A>G (p.Asn635Asp) (chromosome position 1:97915617, A/G). To the best of our knowledge, this is a novel variant and is not identified in any of the specific Ensembl, dbSNP, ExAC, Alfred, HGMD or LOVD databases. In order to evaluate the impact of the proximity of this variant to the intron 14 mRNA splice donor site, we used the most popular in silico tools to predict potential functional alterations involving splicing sites. SIFT (Scale-Invariant Feature Transform, http://sift.bii.a-star.edu.sg/, accessed 28 September 2018) and MutationTaster (http://www.mutationtaster.org/, accessed 28 September 2018) predictions suggested a deleterious effect for this variant, with scores of 0.002 and 23, respectively, while PolyPhen-2 prediction (http://genetics.bwh.harvard.edu/pph2/index.shtml, accessed 28 September 2018) indicated a benign effect, with a confidence score of 0.371. The PROVEAN (Protein Variation Effect Analyzer:http://provean.jcvi.org/index.php, accessed 28 September 2018) tool indicated a neutral prediction with a score of -1.770, while the Human Splicing Finder (htt://www.umd.be/HSF3/index.html, accessed 28 September 2018) tool referred to an exonic splicing enhancer (ESE) mutation "Alteration of an exonic ESE site. Potential alteration of splicing." Furthermore, the SwissModel web tools (http://swissmodel.expasy.org/, accessed 28 September 2018) indicated that the missense variant did not affect the final structure of the protein. Therefore, in order to characterize the potential pathogenic features of the identified variant, a peripheral blood sample stored in PAXgene Blood RNA Tube (Qiagen, Hilden, Germany) was sent to the Oncogenomic Research Center (University of Bari, Italy) for further molecular analysis. Total RNA was extracted from whole blood using the PAXgene Blood RNA Kit (PreAnalytiX GmbH, Hombrechtikon, Switzerland) and reverse transcribed into cDNA with an iScript cDNA Synthesis Kit (BioRad, Hercules, CA, USA). Using a pair of primers spanning exons 13 and 15 of DPYD, the cDNA was amplified and sequenced using a 3500 Genetic Analyzer (Applied Biosystems, 3500 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). Sequence analysis performed on the cDNA tract including exons 13-15 did not indicate exon 14 skipping (Figure 2). The cDNA was then used to perform real-time quantitative PCR assays using the iTaq Universal SYBR Green Supermix (BioRad) in the Step One Plus instrument (Applied Biosystems). The mRNA levels were measured using 3 replicates per sample, with the comparative threshold cycle (Ct) method using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin (ACTB) as endogenous controls, and with related values calculated by DeltaCt. As controls, equal amounts of RNA extracted from whole blood of 3 subjects, previously genotyped and identified as wild-type for variants in the DPYD gene, were used. DPYD mRNA levels in the patient carrying the variant were reduced by an average of 45% compared to those observed in healthy subjects expressing the wild-type DPYD gene. A potential limitation in this analysis is that it is difficult to normalize across patients in samples containing multiple cell types that have different expression levels of house keeping genes, but normalizing with either a structural gene and a metabolic gene gave similar results, suggesting the effective reduction of gene expression in the patient. As a subsequent analytical step, 5 pairs of primers were designed to perform sequencing of a 3296 bp cDNA segment, including the 3078 bp coding sequence of the DPYD gene (Table 1). Analysis of the results allowed the identification of the variants c.85T>C (Cys29Arg) and c.496A>G (Met166Val) recognized as the reference SNP (refSNP) Cluster Report rs1801265 and rs2297595, described with clinical significance of "Pathogenic" and "With drug-response allele" respectively (http://www.ncbi.nlm.nih.gov/snp/ accessed 28 September 2018). The re-introduction of capecitabine at lower doses (1,000 mg twice a day) was associated with recurrence of adverse effects (grade 3 diarrhea and thrombocytopenia:platelet count: 88 x 109/L) and treatment was stopped. Following this, new therapies were adopted (Palbociclib and Fulvestrant) until the patient died 3 weeks later.

capecitabine, dihydropyrimidine dehydrogenase, fluoropyrimidine, gene variation, pharmacogenomics, toxicity

PMC9061986_01

Male

In February 2021, a 53-year-old man who had a smoking and drinking history of more than twenty years was admitted to our hospital with complaints that his front chest pain had lasted for half a year without breathlessness, wheeze, or stridor. There were no abnormalities of the chest shape, and any scars or skin deposits on the chest wall. The breath sound vesicular and no additional sounds, namely, crackles and pleural friction rub occurred. In no time, chest CT detected three soft tissue masses with irregular margins and mild heterogeneous enhancement in his mediastinum, the biggest one was of 59 x 39 x 26 mm3 in the anterior mediastinum and infiltrated the sternum, and the other lesions less than 22 mm located in the upper and lower mediastinum was close to the aorta ( Figure 1A ). However, most of his laboratory tests were normal, namely, blood cell counts, blood coagulation tests with tests of prothrombin time, and liver function tests. Regarding to tumor markers, serum level of AFP was normal (0.89 ug/L, normal range, 0-20.0 ug/L) and carcinoembryonic antigen (CEA) was slightly increased (5.08 ug/L, normal range, 0-5.0 ug/L), CA125 and CA199 were also normal. No abnormality was found in the hepatitis tests, namely, hepatitis B and hepatitis C. Initially, we diagnosed a likelihood of lung cancer, invasive thymoma or lymphoma. In order to confirm the diagnosis, a percutaneous needle biopsy of the anterior mediastinal lesion was performed under CT guidance. The histopathologic examination revealed that the rows and small nests of neoplastic cells were very pleomorphic. ( Figure 1B ). By immunohistochemistry, the tumor cells stained positive for different cytokeratin antibodies (CK19, CK7, and CK20). HepPar1, focal AFP, and CD117 were also positive. Germ cell markers (CD30, OCT 3/4) along with other markers were negative, namely, CK5/6, TTF-1, NapsinA, TdT, Vimentin, P40, CD20, CD79a, CD3, CD5, Arginase-1, SALL4, P63, Syn, SATB2, CDX-2. Proliferative activity by Ki67 labeling index was high (70%). The pathologist drew a conclusion that it was consistent with the epithelial malignant tumor. Considering the hepatoid differentiation phenotype, it was necessary to distinguish the hepatoid adenocarcinoma from hepatocellular carcinoma metastasis. However, mediastinal metastases from a gastric hepatoid carcinoma or hepatocellular carcinoma were ruled out in this case soon, because no obvious gastric or liver tumors were apparent on the preoperative CT contrast-enhanced scan. HCCs are often associated with similar clinical context like cirrhosis, chronic hepatitis B or chronic hepatitis C infection. HAC of lungs have been reported with positive TTF-1 which was negative in the present case. An angiography also illustrated tumors stained and the left internal thoracic artery was expanding and supplying blood of the tumors ( Figure 1C ). The bronchial artery, the most common blood supply artery of pulmonary cancer, was normal. Taking these results together, the patient was diagnosed with HAC of mediastinum. Because of the invasion of the sternum and the close relationship to the aorta of multiple lesions, the patient was not suitable for surgical resection, and debulking was refused from the patient and his family for the risks. The lesions are relatively localized and obviously stained by the left internal thoracic artery. Therefore, a transcatheter chemoembolization of feeding artery of the tumor was performed with lipiodol-epirubicin farrago after the left internal thoracic artery had been prophylactic embolization using steel coils. Local-regional chemotherapy was applied to increase the drug concentration and reduce systemic toxicity. Transarterial infusion of palliative chemotherapy was administered with FOLFOX (oxaliplatin 85 mg/m2 on day 1; LV 200 mg/m2 on days 1 and 2; and FU 400 mg/m2 followed by 600 mg/m2 on days 1 and 2). A following FDG-PET/CT scan on 15 March 2021 revealed an enlargement of the biggest mass, which had abnormal uptake of FDG (SUVmax = 15.3). Meanwhile, PET/CT showed no lesion in the liver and stomach, except for the known mediastinal lesions. Moreover, there was an elevation of ferroprotein about 1,325.38 ug/L (normal range is 16.40-323.00 ug/L). The patient was treated with 200 mg of Sintilimab, the PD-1 inhibitor usually used in lymphoma and advanced non-small cell lung cancer. The patient received additional four cycles of regional chemotherapy with FOLFOX4 regimen by the left internal thoracic artery infusion combined with systemic anti-PD-1 therapy every three weeks. The latest CT scan on 28 July 2021 showed that the size of the biggest lesion was minimized to 29 x 26 x 19 mm3 and the other lesions disappeared ( Figure 1D ). Ferroprotein has fallen to 430.91 ug/L. No significant adverse event was found, and the patient still remains alive and continues to follow up till 12 November 2021.

arterial infusion, hepatoid adenocarcinoma, interventional radiology, mediastinal, prognosis

PMC10024043_01

Male

51-year-old male, with no significant personal history, non-smoker, no known allergies, no occupational exposures, no history of traveling six months prior to consultation, and no pet owner. He consulted with two-week asthenia, adynamia, malaise, rhinorrhea, and dyspnea (modified Medical Research Council) mMRC1, that worsened with exposure to air conditioning. Additionally, he presented with xerostomia and weight loss of 3 kg in 3 months. Physical examination showed normal vital signs, oropharynx erythema without lesions of the oral mucosa, no neck masses nor jugular engorgement, crackles at the end of inspiration in lung bases at auscultation. The rest of the physical examination was unremarkable. Chest radiograph showed basal reticular opacities, without consolidation areas. Chest CT-scan showed thickening of inter and intralobular septa, grounded glass areas predominantly in the bases with multiple consolidation areas (Fig. 1). Blood count showed leukocytosis and neutrophilia, hemoglobin of 14 g/dL, C-reactive protein of 5, normal lactate dehydrogenase (LDH), creatinine and liver tests. Sputum bacilloscopic (BK) was negative. With these findings, multilobes community acquired pneumonia was suspected, IV antibiotics were initiated, with gradual improvement, until the patient was finally discharged. One month after discharge, he consulted at the outpatient clinic due to persistent cough and worsening of dyspnea (mMRC2). Chest radiograph showed persistence of bilateral basal interstitial infiltrates, severe DLCO decrease up to 29% of predicted, non-interpretable spirometry due to non-toleration of the procedure. ANAs were found in 1:320 (speckled pattern), positive ENAs Anti Ro/SSA of 100 U/mL, Anti La/SSA of 60 U/mL, Anti-Smith (Sm) of 2.4 U/mL, Anti RNP (antinuclear ribonucleoprotein antibodies) of 2.3 U/mL (Table 1). Physical examination revealed persistence of crackles at the end of inspiration, predominantly in the bases, with adequate oxygen saturation at rest. These findings were considered secondary to an interstitial lung disease. He was admitted for a rheumatology assessment with the suspicion of pulmonary affection as the presenting feature of SS, with a European League Against Rheumatism-Sjogren's Syndrome (EULAR-SS) disease activity index (ESSDAI) score at diagnosis of 15 points. Upon admission blood workup was completed finding a normal blood, negative c-reactive protein, normal complement, negative anti cardiolipin synthase (anti-CLS), negative anti deoxyribonucleic acid (anti-DNA), negative antineutrophil cytoplasmic antibodies (ANCAs), positive ANAs, ENAs, Anti Ro and Anti La (Table 1). Bronchoscopy with transbronchial biopsies was performed along with bronchoalveolar lavage (Fig. 2). Direct microscopic examination and cultures for bacteria, fungi and mycobacteria and Gen-Expert for tuberculosis were all negative. Histological sections showed pulmonary parenchyma with altered architecture given by the presence of collagen foci and young fibroblasts that in some places protrude towards the alveolar spaces. In some alveolar septa there is lymphoplasmacytic cellularity without acute inflammation. This was considered compatible with organizing pneumonia (Fig. 3). Treatment with methylprednisolone pulses was initiated for three days along with intravenous cyclophosphamide 500 mg/m2. Improvement of symptoms such as cough and dyspnea were seen, as well as of the basal crackles. Given the clinical improvement, the patient was discharged with oral steroids and cyclophosphamide with outpatient control with pulmonology and rheumatology. Although Schirmer's test was not performed, a salivary gland biopsy was done without histological alterations. The patient fulfilled 3 points of the EULAR criteria with positive anti-SSA. Despite the above, the patient still considered to have primary SS, since all etiologies of secondary SS were ruled out.

bronchoscopy, case report, organizing pneumonia, sjögren syndrome, transbronchial biopsy

High-resolution chest CT-scan showing thickening of inter and intralobular septa associated with grounded glass opacities predominantly in lung bases. Multiple foci of multilobes consolidation areas, bronchiolectasias without evidence of honeycomb, suggestive of unspecified interstitial pneumonia.

PMC6409095_02

Female

In 2017, decellularized dermis was suggested as a platform for airway mucosa engineering in tracheal transplantation. In this study, human bronchial epithelial cells and human respiratory fibroblasts were cultured onto a decellularized dermis. After three weeks, the engineered structures were implanted onto a decellularized trachea in New Zealand white rabbits. A muscle wrap had been also applied for prevascularization. The findings showed the formation of pseudo-stratified ciliated layer 24 hours after implantation [73]. Moreover, there are some successful case reports in the field of human airway transplantation with stem cell-based bioartificial grafts for structural airway diseases. The first human case of regenerative technique of tracheal tissue was done on a 78-year-old woman. In this study, the defective area of the trachea was replaced with a Marlex mesh tube covered by collagen sponge. The epithelialization was observed after two months and continued to cover all areas for two years. They did not report any complications during two years. In 2008, Macchiarini, et al, reported a 30-year-old woman who suffered from severe hypoxia and right to left ventilatory shunt. This was due to destruction of the upper respiratory tract by tuberculosis that had led to expiratory collapse, despite primary placement of Dumon stent. After removal of the stent, transplantation of tissue-engineered airway was planned. A trachea segment was received from a deceased person. All loose connective tissues of the donor's trachea were removed, decellularization protocol was done for 25 cycles and its matrix was colonized by epithelial cells, which were obtained by the culture of the recipient's nasal epithelium. Then, chondrogenic MSCs were added to the matrix. This engineered tissue was successfully implanted. Moreover, follow up was done for the next four months with full recovery. In 2012, Elliott, et al, reported a 12-year-old boy with long-segment congenital tracheal stenosis. He underwent autologous patch tracheoplasty, but due to intolerance to the patch, it was replaced with a balloon-expandable intraluminal stents in the 6th year of his life. Then again, it was removed after three years due to aortic erosion. Consequently, implantation of the tracheal homograft was planned. However, one year later, airway hemorrhage caused by aorto-tracheal fistula proposed the idea of replacing the trachea by allogenic stem cell-based tissue-engineered tracheal graft. A tracheal segment was received from a deceased body and decellularized as the scaffold. Bone marrow-derived MSCs were obtained from the patient and together with patches of autologous epithelium were added to the scaffold. Additionally, the tissue-engineered trachea was saturated by human recombinant erythropoietin and transforming growth factor beta in order to stimulate angiogenesis and chondrogenesis, respectively. A bronchoscopy was performed after one week and it showed neovascularization. Eighteen months later, a chest CT showed tracheal growth. The patient was followed up for two years with full recovery.

cell-based therapies, mustard gas, stem cell, tissue engineering, trachea

PMC10165254_01

Male

Case 1 is an 11-year male who presented with a history of progressive haemoptysis for a 1-year duration. On presentation, he was well nourished with no other symptoms. He was previously treated for 6 months for unconfirmed pulmonary tuberculosis (PTB) at the age of 8 years based only on suggestive radiology. Chest examination revealed dullness to percussion over the right upper zone anteriorly with decreased air entry over that region. Frontal and lateral chest radiographs showed a well-circumscribed opacity within the right tracheobronchial angle (Fig. 1a and b). Contrasted CT chest confirmed a well-defined, heterogeneously enhancing right paratracheal mass with foci of coarse intralesional calcification and intraluminal invasion into the right main bronchus (Fig. 1c and d). Flexible bronchoscopy showed an infiltrative mass at the entrance of the right upper lobe bronchus (Fig. 1e). This lesion was close to the carina so extensive biopsies were done around the lesion to exclude mucosal involvement. Histopathology of the biopsy showed features consistent with mucoepidermoid carcinoma. The atypical fragments of tissues showed cells with intracytoplasmic mucin on Alcian blue PAS stain. On immunohistochemistry, the cells were positive for CK7 and scattered cells showed positivity for p63.

bronchoscopy, endobronchial lesion, hemoptysis, mucoepidermoid carcinoma, radiotherapy

PMC3842215_01

Female

GV, a 29-year-old Caucasian woman suffering from panic disorder with agoraphobia, was referred to our clinic for recurrent gastroenteric panic symptoms. She had a negative family history for mental illness and had no past history of substance use/abuse. The patient's psychiatric history dated back to 8 years previously when, at the age of 21 years, she presented with somatic panic symptoms, ie, tachycardia, chest tightness, heartburn, and panic attacks. On her first outpatient visit to the gastroenterology clinic at the age of 26 years, she presented with recurrent heartburn, but tested negative for hiatal hernia, Helicobacter pylori, and esophagogastric reflux. At that time, she was also experiencing isolated panic attacks characterized by palpitations (tachycardia), chest tightness, somatopsychic depersonalization, fear of dying, anticipatory anxiety, harm avoidance, and a fear of being alone. She was not given any psychopharmacologic treatment but was treated with triple gastric therapy comprising a proton pump inhibitor (esomeprazole), antacids (alginic acid and sodium bicarbonate), and an antidopaminergic gastrointestinal prokinetic agent (clebopride). At the first outpatient visit, the patient presented primarily with somatic symptoms, including heartburn, chest tightness and pain, somatopsychic depersonalization, tachycardia, and fear of dying and anxiety in the context of asthenia and anergia. We assessed her symptomatology using the Structured Clinical Interview for Panic-Agoraphobic Spectrum lifetime version, and the score was 85 at the first visit. We initially prescribed citalopram 20 mg/day, but the patient reported sexual dysfunction (reduction/loss of libido and difficulty achieving orgasm), cognitive impairment, and fatigue. The patient reported improvement in her anxiety symptoms and panic attacks on a selective serotonin reuptake inhibitor, but not in her troublesome gastric somatic symptoms. We therefore decided to gradually reduce the dose of citalopram and introduced escitalopram 7 mg/day, but the patient continued to report loss of libido with no change in her gastric symptoms. We then prescribed duloxetine 30 mg/day, which was subsequently increased to 60 mg/day, with slow withdrawal of escitalopram. After 6 months of treatment, the patient showed complete remission of her gastric and panic-related symptoms, and all three gastric treatments were able to be discontinued.

anxiety disorder, nausea, palpitations, panic attacks, tachycardia, tachypnea, vertigo

PMC3201585_01

Female

About 1 am, a 34-year-old G8 P7 woman from a remote village in Ghana experienced a sudden onset of abdominal pains, nausea, and lightheadedness. When it didn't resolve by morning, she and her relatives began walking to the nearest road to get to the District Hospital. She had received no prenatal care and had vaginally delivered her previous seven children at home without complications with the help of a traditional birth attendant. All were alive and healthy; although she did not know her oldest child's exact age, that woman now had three children of her own. The patient had never had abdominal surgery and was otherwise healthy. Since her symptoms resolved somewhat while walking, the group stopped along the way to bathe, wash their clothes and eat. However, upon arriving at the small town, she experienced severe nausea, increased abdominal pain, and near-syncope. Her memory of subsequent events was hazy. A taxi, which her companions had to pay for in advance (she had only the government insurance provided to pregnant women, rather than the 15 Ghana Cedis ($10.70 U.S.)/year family health insurance), took her on the two-hour ride to the Kintampo Municipal (District) Hospital. She arrived at 7:10 pm. Upon arrival, an emergency department nurse found that she had a distended, diffusely tender abdomen. (The nurse had advanced emergency medicine training through Columbia University's sidHARTe Program: www.sidHARTe.org). Her vital signs were: BP, 70/40 mm/Hg; RR, 34/min; HR, 96/min; T, 34.8 C (axillary). The nurse immediately called the local surgeon who found a very pale woman with guarding and rebound tenderness. Suspecting an ectopic pregnancy, he first did an abdominal tap, which did not yield any blood. He immediately performed an abdominal ultrasound and visualized a 17-week intrauterine fetus with a heartbeat and a large amount of intraperitoneal free fluid (Figures 1). An ultrasound-guided abdominal tap yielded non-clotting blood. Laboratory studies that had been drawn on arrival showed Hgb 7.4 g/dL; Hct 27%; WBC 11.2 X 103/microL . She was prepared for emergency surgery and entered the operating room at 8:20 pm. Just before anesthesia induction, the patient suddenly said that she would not consent to the operation unless she could be assured that the pregnancy would be terminated. She said that she had enough children. Since the surgical staff couldn't assure her of that, she refused anesthesia until she was informed (with no hyperbole) that, without the operation, she would quickly die. She immediately agreed to the surgery. A transverse C-section incision was made. Immediately, a tiny umbilical cord appeared, floating in the blood-filled abdomen. The fetal head was then seen protruding from a macerated uterine fundus with the placenta attached in the right uterine cornu. (This was a "cornual pregnancy," gestation in the horn of the uterus). The now dead fetus and remaining placental tissue were quickly removed from the uterus through the gaping fundus. The fundus was then clamped and oversewn. At that point, the patient was hypotensive (80/40 mmHg) and receiving both packed erythrocytes and crystalloid. About 4L of sanguineous fluid was removed from her abdomen. After ascertaining that bleeding had ceased, the fallopian tube that had not been removed with the uterine fundus was ligated and bisected. Following surgery, the patient's condition improved with fluids and blood administration. The next day she was stable, with normal vital signs, a postoperative ileus, and pain only at the incision site. She was discharged two days later.

ghana, pregnancy, grand multiparity, nurse education, ruptured uterus, ultrasound diagnosis

PMC6925795_01

Male

A 40-year-old black male patient was referred to the nephrology service to investigate plasma creatinine elevation in the last 6 months. He reported two previous medical evaluations in emergency departments. The first occasion was due to severe abdominal and low back pain with irradiation to hypogastrium, associated with nausea and vomiting. Pancreatic enzymes were elevated and the case was conducted as pancreatitis, but the patient presented no radiological changes. In the second occasion, he had a similar clinical presentation, but with concomitant macroscopic hematuria. Ultrasonography of the urinary tract identified the presence of bilateral nephrolithiasis, microcalculi in the lower third of the right ureter with mild pelvicalyceal dilation and normal-sized kidneys with increased renal parenchymal echogenicity. There was expulsion of the ureteral stone without urological interventions. Because of the persistent elevation of plasma creatinine not justified by nephrolithiasis, the patient was referred for nephrological investigation, but it took some months until the patient got this appointment. Relevant findings in the physical examination included discolored mucosa +/4, high blood pressure (160/110 mmHg), liver 4 cm from the right costal margin, and palpable spleen and lower limb edema +/4. There were no palpable peripheral lymph nodes. The patient also reported increased urinary volume, sporadic fever and unintentional weight loss around 30 kg over the past 6 months. Past medical history included chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) and bilateral knee replacement 5 years before presentation, due to a destructive arthropathy of undetermined etiology. He denied previous systemic arterial hypertension, diabetes mellitus, or kidney disease. He was hospitalized for additional investigation. Admission laboratory tests revealed several laboratory abnormalities: persistent elevation of plasma creatinine, severe hypercalcemia, anemia, thrombocytopenia, and elevation of pancreatic enzymes and alkaline phosphatase, in addition to changes in urinalysis with nonnephrotic proteinuria, hematuria, leukocyturia, and calcium oxalate crystals (Table 1). In the initial days of hospitalization, diuresis ranged from 4 to 6 L/day. Abdominal computed tomography (CT) showed multiple retroperitoneal and iliac lymphadenopathy, enlarged liver with heterogeneous attenuation, and splenomegaly, as well as multiple nonobstructive renal micro calculi and a normal pancreas (Figure 1). In this scenario, the presence of hypercalcemia associated with a consumptive syndrome and lymphadenopathy suggested the initial hypothesis of a neoplastic condition, more likely a lymphoproliferative disease a priori. The serum parathormone (PTH) level was low, and there was hypercalciuria. Thus, we proceeded the investigation based on differential diagnoses of hypercalcemia with low levels of PTH. There was no history of vitamin D supplementation, and calcidiol level was normal. Unfortunately, we did not have PTH-related peptide (PTHrP) and 1,25(OH)2D analysis. Radiographic study of the long bones, skull, and spine did not identify lytic bone lesions. Serum protein electrophoresis identified polyclonal gamma globulin peak, and the myelogram was unchanged. Diagnostic laparoscopy was indicated for retroperitoneal lymph node biopsy; however, intraoperatively it was decided for the performance of liver biopsy since this organ had multiple white lesions (Figure 2(a)). The histopathological study showed epithelioid granulomas without caseous necrosis, with the presence of asteroid bodies, highly suggestive of sarcoidosis (Figures 2(b)-2(d)). Despite the absence of respiratory symptoms, a chest CT scan showed micronodular infiltrates with perilymphatic distribution and mediastinal and hilar lymphadenopathy (Figure 1), corroborating the hypothesis of sarcoidosis. The angiotensin-converting enzyme (ACE) level test was not available in our service. The purified protein-derived (PPD) test for the tuberculosis bacillus was nonreactive (0 mm), and the culture for acid fast bacilli and fungi from the liver biopsy was negative. Ophthalmologic, cardiac, and neurological assessment was unremarkable.

PMC5206423_01

Female

The patient was a 27-year-old woman (weight = 48 kg, height = 171 cm) admitted to a general hospital with primary diagnosis of acute abdomen because of acute epigastric pain, nausea, and vomiting. She had a history of activity-induced dyspnea and chest discomfort for 18 months. Anorexia, weight loss (approximately 10 kg), and episodes of flushing and syncope while standing were added to her symptoms at the past 3 months. In spite of a few medical visits at the past year, there was not any definitive diagnosis. Episodic epigastric pain referred to the right shoulder lasted for 15 min; nausea and vomiting were reported as the main symptoms in the last two weeks. In the physical examination, she was cachectic, acyanotic, ill, and tachypneic with respiratory distress. Her vital signs were as follows: a regular heart rate 100 beat/min, blood pressure 80/45 mmHg, axillary temperature 36.7 C, and respiratory rate 24 per minute. Respiratory sounds decreased in the lower half of the lungs. There was a muffled first heart sound with a moderate holosystolic murmur in the apex. There was not either guarding or tenderness on abdomen or abdominal organomegaly. Laboratory data were normal except for a mild increase in ESR. The chest X-ray revealed increased chest/thoracic ratio and bilateral plural effusion. A thoracic and abdominal CT scan revealed cardiomegaly with a large mass (45*32 mm) in LV and bilateral pleural effusion without any pathologic findings in the abdomen. Transthoracic echocardiography (TTE) was done as a final diagnostic modality and reported a completely occupied LV with a large nonhomogenous mass protruding into aortic valve and severely compromised ejection fraction (0.15), limited valve opening, and flow through mitral and aortic valves. Preoperative lab tests were showing the normal values for blood, renal, and hepatic function tests. She was transferred to our heart hospital for an emergency surgery. With invasive arterial blood pressure monitoring, anesthesia was induced using midazolam 10 mg, ethomidate 10 mg, fentanyl 100 mug, and cisatracurium 10 mg. Intraoperative transesophageal echocardiography (TEE) revealed severely decreased LV function; LV chamber was totally filled with a large mass (76*44 mm), compromised mitral valve opening (moderate regurgitation), and a systolic protrusion of the mass to the aorta (approximately 1.5-2 cm). On the TEE, it seemed that the mass was pedunculated, originating from the LV lateral wall (Figure 1). Using cardiopulmonary bypass (CPB) and a transmitral and aortic root approach, the huge multilobulated jelly-like mass was resected piece-by-piece. It had been attached to the apical-lateral wall. After deairing of the heart, CPB discontinued using dobutamine infusion 10 mug/kg/min with a sinus rhythm. Postbypass TEE revealed a moderate MR with severe LV systolic dysfunction (ejection fraction 0.10-0.15). Postoperative period was without any complication, and almost all the complaints were resolved rapidly. Renal, hepatic, and routine blood tests were within normal limits postoperatively. A blood sample was prepared and sent to a referral regional lab in order to measure the serum IL-6 concentration, in the second postoperative day. The patient left the ICU and hospital on the third and seventh postoperative days, respectively, in a good clinical condition. TTE on the third postoperative day showed a moderate eccentric mitral regurgitation (MR) with LVEF of 0.30. Pathologic examination confirmed myxoma diagnosis. Three months later, TTE showed a normal heart (LVEF 0.45) with only mild MR. Lab report presented the postoperative serum IL-6 concentration (assayed by Bender MedSystem, Austria) as a normal value (2.98 pg/mL).

PMC6363242_01

Male

A 72-year-old male with a long standing history of chronic lymphocytic leukemia (CLL) presented with upper respiratory symptoms including mild productive cough and dyspnea. An outpatient chest CT showed innumerable bilateral ill-defined solid pulmonary nodules in a peribronchovascular distribution, which were new from a prior scan 6 months earlier (Figure 1). Many of the lesions had a peripheral ground-glass halo. Nonenlarged mediastinal and bilateral axillary lymph nodes were suspected to be related to the patient's history of CLL. The pulmonary nodules were not a typical manifestation of CLL and other etiologies were considered such as atypical pulmonary infection, sarcoidosis, Kaposi sarcoma, and metastasis, even though patient had no other known malignancy. He was treated with antibiotics and steroids for his symptoms; however there was progressive clinical decline over several weeks and thus the patient was admitted for further work-up. At the time of admission, vital signs showed exertional hypoxia, mild tachycardia in the low 100's, and a fever up to 102.4, which raised the concern for an infection and septic emboli. However, there were no significant pulmonary findings on exam. Skin examination revealed erythematous/purple skin papules on both lower extremities which broadened the differential to also include autoimmune and vascular etiologies. Aside from normocytic anemia (Hb 11.6 mg/dL), initial laboratory evaluation with CBC and BMP showed no significant abnormalities. IgG levels were low. Blood and sputum cultures were negative. QuantiFERON was negative for tuberculosis. Serologies for aspergillus, blastomycosis, coccidioides, cryptococcus, histoplasma, HIV, and toxoplasma were negative. Bronchoalveolar lavage was negative for acid-fast bacilli, fungal organisms, and pneumocystis. Immunologic evaluation was negative for ANCA, proteinase 3, and myeloperoxidase antibodies. This excluded granulomatosis with polyangiitis as a differential diagnosis. Bronchoalveolar lavage was negative for cytology. Punch biopsy of one of the skin lesions demonstrated poorly circumscribed granulomas surrounding blood vessels and skin appendages, mild lymphocytic infiltration with no features to suggest cutaneous lymphoma, and no evidence of leukocytoclastic vasculitis. Stains for fungal and acid-fast bacilli were negative. Left upper and lower lobe wedge biopsies of the nodules were taken through video-assisted thoracoscopic surgery (VATS) as the diagnosis was still unclear. The biopsies revealed EBV-positive DLBCL with features of LG grade 3 (Figure 2). The features that favor LG over DLBCL include a background that consisted predominantly of inflammatory cells with a minority of large B-cells and vascular invasion. In addition, lung involvement and EBV positivity are not exclusive to LG, but are almost always present in LG. Flow cytometry did not detect the large B-cells which are sometimes too fragile to survive flow cytometric processing, but did detect rare, small monoclonal B-cells with a CLL/small lymphocytic lymphoma (SLL) phenotype. The flow cytometric findings are compatible with the morphology as no significant CLL/SLL population could be identified with CD5 and CD23 immunostaining (Figure 3). In this case, the source of rare CLL cells is likely peripheral blood, either physiologically through the inflammatory response or contamination during resection. Features of secondary organizing pneumonia were also present. The patient underwent PET-CT 4 weeks following the initial chest CT (Figure 4). This showed significant progression and confluence of bilateral peribronchovascular lung opacities. The lung opacities had diffuse FDG uptake with a maximum SUV of 22.3. The PET/CT also demonstrated intense uptake in the cutaneous lesions of the lower extremities. Bone marrow biopsy was consistent with hypercellular marrow with 20-30% marrow involvement by CLL/SLL cells. The patient was started on R-CHOP chemotherapy with Neupogen support. IVIG was also given for hypogammaglobulinemia.

PMC3284021_01

Male

A 24 year old male patient, a basketball professional player, suffered a traumatic crown fracture of the upper right central incisor (11), with the fracture line being located in the middle third of the tooth. The patient reported promptly to the clnician with the fractured fragment. The tooth involved showed no evidence of pulpal exposure or of periodontal lesions consequent to the dental injury. Our operative protocol, preliminarily to any restorative step, started with a clinical examination in order to evaluate the traumatic injury, and the condition and the margins of the fragment. The fractured tooth was evaluated by trans-illumination in order to rule out the presence of enamel fissures. In the radiographic assessment, there was no fracture of the root or the alveolar bone [Figure 1]. The fractured portion was disinfected with 0.2% chlorhexidine, and stored in physiologic solution (Ogna Sodiomu Clorum 0.9 % ) to maintain the hydration. Tooth vitality test was performed by giving thermal stimulus to the tooth (cold) and it responded as vital. The first step of the operative procedure, after administration of local anaesthesia, was the isolation of the operating field with a rubber dam. Prior to the reattachment procedure, the fractured tooth was cleansed and polished; and, the fractured portion was "tried-in" to check for any presence of disruptions or defects between the remaining tooth structure and the fragment. To facilitate its handling, the fragment was fixed on its vestibular aspect to a holder with an adhesive tip (Pic-n-stic, Pulpdent Corp.) We decided to proceed with the attachment of the fractured fragment with no additional tooth preparation as there was no loss of dental hard tissues and the edges matched without any disruptions. The fragment was treated with an "etch and rinse" technique using 37% phosphoric acid (The acid time application was related to the different tooth surface. It was 30 seconds for enamel, 1s seconds for dentine), followed by a separate application of priming and bonding agents (Scotchbond MP, 3M ESPE), and the fragment was kept away from light or heat sources until the reattachment phase. The fractured tooth was etched and treated with the same adhesive system (Scotchbond MP, 3M ESPE). The fragment was thus placed in its proper position on the tooth paying attention to the perfect fit between the two parts and only after this point was the bonding agent photopolymerized. The polymerization was carried out on both the vestibular and lingual aspects using a 60 seconds for each surface light-emitting diode (LED) light-curing unit (Elipar Freelight 2, 3M Espe). The restored tooth was then finished and polished using silicon points immediately after the fragment reattachment (HiLuster Plus Identoflex, KerrHawe). Patient was then recalled for a follow up control at 6 and 12 months. All the clinical evaluation demonstrated a good maintaining of the previous treatment with good aesthetics and function. 25 months later the patient injured the same tooth during a sport activity and sustained a small enamel fracture at the incisal margin of the fragment reattached [Figure 2]. The other maxillary central incisor (21) was involved by a small enamel lesion too caused by the same traumatic event. At this time vitality test by giving thermal stimulus to the tooth (cold) was performed again and the tooth was still vital. The clinicians observed the stability of the fragment. Therefore, a direct restoration of both of the fractured teeth was performed using Scotchbond MP (3M Espe) and composite resin (Filtek Supreme, 3M Espe). Patient was recalled for follow up control at 3 months and no function, clinical or aesthetic problems were recorded. However, 4 months later a new trauma caused the detachment of the fragment. After clinical evaluation the treatment plan of choice was the same one used on the occasion of the first fracture [Figure 3]. After 3 years (5.5 years from the first injury) a follow-up control was performed. Aesthetics and pulp vitality were confirmed clinically. A radiographic control showed no evidence of periapical pathology [Figure 4].

adhesive technique, crown fracture, dental trauma, reattachment, tooth fragment

PMC9282706_01

Male

In April 2015, a 42-year-old married male visited the outpatient clinic suffering from high-grade fever and a large painful ulcer around the anus for the past 3 weeks. Medical history revealed that he was seropositive and diagnosed with HIV in 1997. His history also confirmed high-risk behavior involving anal sexual intercourse with another man. Treatment was deferred repeatedly for antiretroviral treatment (ART) in 1997 and 2005 as his absolute CD4 counts were >400 cells/mm3. For the past 3 months, (2015), he was experiencing low-grade fever with rising temperature in the evening often associated with chills. He suffered from loss of appetite and had lost 15 kg weight in the past 4 months. He has no history of headache, vomiting, cough, breathlessness, and diarrhea. Clinical Examination revealed oral candidiasis, a large ulcer measuring 8" X 2" around the anus that was painful and bled on touch as shown in Figure 1. There was no lymphadenopathy. Systemic examination was normal. As the ulcer was painful and bled on touch, a skin biopsy and Tzanck Smear test were recommended. Four days later, on his 2nd visit, as per NACO, his HIV-1 status was confirmed by HIV-enzyme-linked immunosorbent assay. His CD4 count (Absolute count and Percentage) was 10 cells/mm3, CD4-<4%, and plasma viral load was 43,803 copies/ml. Genotypic drug resistance (DR) testing for HIV-1 was done to rule out (r/o) transmitted DR (TDR) or primary DR. Hemogram, blood sugar level, renal and liver function tests, urine tests were otherwise normal except thrombocytosis. For investigating fever, the following tests were done which were all negative: Malaria antigen test for Plasmodium vivax and Plasmodium falciparum, Dengue NS1, IgM, IgG, HBsAg, hepatitis C virus, venereal diseases research laboratory/Treponema pallidum Hemagglutination, and Herpes IgM, IgG. Blood culture for aerobic and anaerobic organisms showed no growth. All the tests related to fever were insignificant. Koch's infection was also ruled out. He tested IgG positive for toxoplasmosis. He received chemoprophylaxis for opportunistic infections, (Co-trimoxazole, INH, and Azithromycin) and ART regimen of Tenofovir disoproxil fumarate (TDF) + Emtricitabine (FTC) + Efavirenz (EFA) (TDF + FTC + EFV) fixed-dose combination while awaiting the results of DR, and skin biopsy. There was no improvement in his symptoms despite treatment for over 3 weeks. Thereafter, he was admitted to the hospital with high-grade fever and large painful perianal ulcer. He received intravenous antibiotics along with ongoing medications. His perianal biopsy report was suggestive of superficial aphthous ulcer. Tzanck smear test was done suspecting herpetic infection but was negative. 18F-fluoro-2-deoxy-D-glucose positron emission tomography computed tomography (18FDG-PET) scan was done which did not show any abnormal uptake suggestive of malignancy. Thus, tuberculosis and malignancy were ruled out by the TB specialist and oncologist. The dermatologist treated the ulcer as a giant herpetic ulcer with valaciclovir 1 g thrice a day for 2 days, thereafter 500 mg thrice a day while continuing the chemoprophylaxis. While on valaciclovir, the ulcer size reduced in size and developed scarring and pigmentary changes. While this treatment was ongoing, the ART DR report showed he was resistant to Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-NRTIs (NNRTIs) while being susceptible to protease inhibitors and integrase strand transfer inhibitors. Before switching the patients' regimen, CD4 and viral load tests were repeated which showed that his CD4 absolute count was 10 cells/mm3 and CD4- below 4% and plasma viral load was 52,935 copies/ml. The regimen selected post DR test report and counseling was Lopinavir/ritonavir (LPV/r) + Lamivudine (3TC) + Raltegravir (RAL). The patient was afebrile and asymptomatic. The skin lesion healed and he was discharged within 15 days while maintaining the ART regimen. Five days later, while on the new ART regimen, the patient complained of giddiness and loss of balance. The patient was managed conservatively with oral betahistine (Vertin) by an Otorhinolaryngologist. Subsequently, within few days, the symptoms worsened with him developing headache, vomiting, and blurring of vision. Neurological evaluation revealed tendency to fall on either side during tandem walking, bilateral finger nose ataxia, and Romberg's sign was present. Magnetic Resonance Imaging brain suggested acute demyelination with a differential diagnosis of lymphoma. FDG-PET scan was repeated after a gap of 40 days from the previous scan. It showed a single space-occupying lesion in the vermis of cerebellar area with no other abnormality as shown in Figure 2. Stereotactic biopsy suggested lymphoma- Non-Hodgkin's diffuse large B-cell lymphoma. Immunohistochemistry showed positive expression for CD20 and negative expression for CD-10. Cultures of CSF and tissue did not reveal any aerobic or anaerobic infection. Fungal culture, TB-MGIT, and identification of MAC and Gene Xpert for MTB were negative. EBV was present. The patient was eventually diagnosed with PCNSL through a process of elimination. The patient was started on chemotherapy but did not improve. Despite being on ART for 3 months and taking chemotherapy/radiotherapy, his CD4 counts did not rise although, his viral load was undetectable. The patient ultimately died in the 4th month of his treatment.

antiretroviral, human immunodeficiency virus and malignancy, human immunodeficiency virus diagnostic dilemma, non-hodgkins lymphoma, primary central nervous system lymphomas

PMC9193965_01

Female

A 46-year-old female patient had a history of elevated alkaline phosphatase (AKP) for 4 years. She had occasional thirst, with no abdominal pain, abdominal distension, acid reflux, heartburn, constipation, dyspepsia, or nocturia. The history of renal insufficiency was denied. The patient had regular physical examination every year and found that his AKP level increased progressively. Osteoporosis was found by physical examination two years ago with no bone pain or fracture history. The patient's menstruation is still regular, and there is no obvious history of dysmenorrhea. Blood test results one month before operation showed that AKP was 294 U/L (normal range 30-100 U/L), PTH 981.20 pg/mL (normal range 15-65 pg/mL), calcium 2.93 mmol/L (normal range 2.00-2.60 mmol/L), phosphorus 0.64 mmol/L, Vitamin D 6.97 ng/mL (normal range >=30 ng/mL). Right forearm bone mineral density detection showed BMD 0.391, Z score -5.33, and t score -5.44. Computed tomography scan showed posterior superior mediastinal was occupied with a cystic solid tumor whose maximum cross-section size was about 3.3 x 1.9 cm (Figure 1A-1D). No special signs were found by neck ultrasound. The patient underwent 99mTechnetium sestamibi scanning, indicating a mass with increased uptake of imaging agent in the posterior mediastinum (Figure 1E-1F). The patient had daily subcutaneous injection of a total amount of 100-300 IU per day of salmon calcitonin preoperatively due to hypercalcemia and underwent single-port thoracoscopic resection of the mediastinal tumor. The tumor was carefully removed by ultrasonic scalpel. The volume of the tumor was about 6.0 x 4.2 x 1.0 cm at pathological examination. Postoperative pathology confirmed parathyroid adenoma (Figure 2). The PTH and blood calcium levels decreased instantly after the operation. The PTH level on the first day after the operation was 93.96 pg/mL, and on the second day after the operation was 7.29 pg/mL. However, on the fourth day after the operation, the PTH level raised to 65.61 pg/mL (normal range 15-65 pg/mL) and continued to rise to 159.2 pg/mL one month after the operation. Serum calcium concentration was still within the normal level and no specific symptoms were shown. Meanwhile, the vitamin D level was found lower than the normal level in the first month after surgery. So the patient was supplemented with vitamin D 800 IU per day. The PTH level continues to decrease, whereas vitamin D levels continue to rise ever since exogenous vitamin D was supplemented. One year after the operation, serum PTH, calcium, and vitamin D levels returned to normal (Figure 3). The timeline of clinical interventions for this patient was shown in Figure 4.

ectopic parathyroid adenoma, posterior superior mediastinum, primary hyperparathyroidism, thoracic surgery, vitamin d deficiency

PMC4904552_01

Male

A 19-year-old man was referred for further management given a history of recurrent pneumothoraces and a recent CT of the thorax which revealed multiple bilateral pulmonary cysts. His past medical history included a surgically resected osteochondroma from the medial aspect of his right tibia a year ago, a remote appendectomy, and a childhood diagnosis of asthma. He did not take any medications regularly. He smoked half a pack of cigarettes a day for the last six years and also smoked seven marijuana joints per day. He denied consuming alcohol or any other illicit drugs. He worked in the family restaurant and both of his parents smoked tobacco. Other than chest pain and dyspnea experienced at the time he was diagnosed with pneumothoraces, he denied any symptoms. He did describe drinking about 15 liters of water a day due to a dry mouth. He denied any bone pain, skin rashes, or abdominal pain. Review of systems was unremarkable. Prior to referral, he had presented to hospital with a spontaneous right-sided pneumothorax on two occasions and bilateral pneumothoraces on one occasion. The third time he was treated surgically and a video-assisted thoracoscopic bullectomy with apical pleurectomy of the right lung was performed. He was found to have asymptomatic recurrence of a right-sided pneumothorax when seen in follow-up and was treated successfully with chemical pleurodesis in the form of bleomycin. On examination, he was afebrile, blood pressure was 115/75, heart rate was 88 beats/min, and respiratory rate was 16 breaths/min. Weight was 93.5 kg and height 183 cm, resulting in a BMI of 27.9. The cardiovascular examination was normal except for a loud P2. The respiratory examination revealed normal breaths sounds bilaterally. The remainder of the examination was unremarkable. Pulmonary function tests revealed airflow obstruction with an FEV1/FVC ratio of 43% (normal >= 70%), an FEV1 of 2.14 L (44% of predicted), and a FVC of 4.95 L (86% of predicted). There was no evidence of restriction and the diffusion capacity for carbon monoxide (DLCO) was decreased at 60%. His spirometry did demonstrate significant reversibility postbronchodilator. A CT of the thorax performed prior to referral showed bilateral thin-walled pulmonary cysts of variable sizes and irregular shapes (see the following list). There were a few ill-defined centrilobular nodules and no consolidation, pleural effusions, or lymph node enlargement (Figures 1(a), 1(b), and 1(c)). Langerhans cell histiocytosis Lymphoid interstitial pneumonia Neurofibromatosis Birt-Hogg-Dube syndrome Pneumatoceles (due to prior Pneumocystis carinii pneumonia) Tuberous sclerosis Lymphangioleiomyomatosis The following are the differential diagnoses of cystic lung disease: The patient's clinical presentation and investigations were consistent with the diagnosis of pulmonary Langerhans cell histiocytosis (PLCH) and possibly concurrent asthma. In fact, a previous bullectomy specimen showed histological features consistent with PLCH (Figures 2(a) and 2(b)). Given his history of polydipsia, he underwent a brain MRI which showed focal nodular thickening with enhancement of the infundibulum with otherwise normal size of the pituitary gland; findings were found to be consistent with posterior pituitary involvement (Figures 3(a) and 3(b)). Subsequent bloodwork showed a high-normal plasma sodium concentration of 142 mmol/L and a urine osmolality of 91 mmol/k, less than the plasma osmolality of 294 mmol/k. He did not have evidence of any other endocrinopathy on bloodwork. An echocardiogram did not show evidence of pulmonary hypertension. Given his history of a bone tumor resection, we obtained pathology results from the treating hospital which confirmed that the tumor was in fact an osteochondroma and not consistent with Langerhans cell histiocytosis. He was treated with an inhaled corticosteroid and long-acting bronchodilator combination puffer. With desmopressin, his water intake reduced dramatically to 1-2 L/day. He presented again a year later with bilateral spontaneous pneumothoraces (left larger than right) and was treated with left-sided pleurodesis in the form of doxycycline. After a couple of relapses, he quit smoking after using varenicline and has remained smoke-free for 12 months at last follow-up. His latest FEV1 is 2.98 L (58% of predicted) with an FEV1/FVC ratio of 64%.

PMC5735078_02

Female

A recent experience at CHOP illustrates well the importance of integrated genomic workup for AML. An 11-year-old patient with cytogenetically normal AML (CN-AML) was referred for further genetic testing for risk stratification. The Comprehensive Hematological Cancer Panel identified a FLT3 internal tandem duplication (FLT3 ITD) (Figure 1C) along with two other somatic variants, IDH2 p.R140Q and GATA2 p.W10*. FLT3 ITD is often missed by NGS-based assays due to the size of the duplications. However, we have designed our panel and bioinformatics analysis pipeline to enable the detection of this mutation. The FLT3 variant changes the patient's prognosis from intermediate (based on CN-AML) to poor. Moreover, recent clinical trials suggest adding FLT3 inhibitor to frontline chemotherapy in FLT3-mutated AML confers a survival benefit. The FLT3 ITD present in this patient qualifies her for clinical trials investigating FLT3 ITD targeted therapies. Juvenile myelomonocytic leukemia (JMML) is a rare type of leukemia found mainly in children less than 2 years of age. The prognosis of JMML is poor, and without treatment it is most often fatal within 5 years of life. Hematopoietic stem cell transplant is currently the only curative approach for JMML. Since both the clinical presentation and the morphologic features of JMML can resemble reactive processes, molecular studies are usually required for diagnosis. Most individuals with JMML have mutations in the RAS pathway, particularly PTPN11, KRAS, NRAS, CBL, or NF1. Some mutations in the RAS-MAPK pathway genes can occur in the germline and these patients are at risk for JMML-like myeloproliferations. JMML patients without RAS mutations may have mutations in ASXL1, SETBP1, RUNX1, JAK3, and SH2B3, all of which have also been observed as secondary mutations in RAS-mediated JMML. In the 2016 WHO classification, the RAS-pathway mutations are among the diagnostic criteria for JMML.

diagnosis, genomic profiling, pediatric leukemia, prognosis, therapy

PMC7334767_01

Female

A 22-year-old woman, resident of Acapulco, Mexico, presented to our unit with a two-month clinical picture of headache, incoherent language, aggressive behavior, inappropriate conducts of disinhibition, and visual-auditory hallucinations. The previous day, the patient had gradually developed a diminished state of awareness. Her medical history was unremarkable. She had two uncomplicated previous pregnancies. Her mother denied any animal contact, recent traveling, ingestion of drugs, or exposure to toxics. She referred a lack of water and food intake in the previous days. On physical examination, her blood pressure was normal, and she was tachycardic with a weak pulse, dry mucous membranes, and prolonged capillary refill time. In the neurological sphere, she was disoriented and presented retrograde amnesia, impairment in judgment, and loss of abstract thinking. Her chest X-ray and head computed tomography (CT) were normal. Laboratory results revealed severe hypernatremia (Na 180 mEq/L) and acute kidney injury (AKI) (measured creatinine 2 mg/dl-baseline creatinine 0.6 mg/dl). Serum electrolytes, liver tests, blood count, urinalysis, and toxicologic screen were normal. Her spot urinary electrolytes showed a urinary sodium of 20 mEq/L, with a fractional excretion of sodium (FeNa) of 0.5% suggesting hypovolemia. Her calculated water deficit was of 7.5 liters. However, her calculated electrolyte-free water excretion was of 805 ml within a 24-hour urinary volume of 1,000 ml, a value that was inappropriately elevated. We initiated treatment with enteral administration of free water and hypotonic intravenous solutions for restitution of intravascular volume. During her hospital stay, the patient presented a partial clinical response, with optimization of volemia and resolution of (AKI). A new electrolyte profile showed persistence of hypernatremia (Na 157 mEq/L) and mild hypokalemia (K 3.2 mEq/L). She had a urinary sodium level of 8 mEq/L, with a calculated urine osmolarity of 85 mEq/L, in the context of a 24-hour urinary volume of 4 liters and electrolyte-free water excretion of 3.3 liters. The documented aqueous polyuria and hypernatremia suggested diabetes insipidus. The water deprivation test, that is normally the next step in the diagnosis, was contraindicated, so we ordered a brain magnetic resonance imaging (MRI), which showed a pituitary stalk lesion with chiasmatic and hypothalamic extension (Figure 1(a)). Treatment with desmopressin was initiated, with progressive normalization of her sodium level, urinary volume, and volemia status (Table 1) (Figure 2). The hormonal profile was compatible with panhypopituitarism, so we initiated treatment with thyroid and glucocorticoid hormones. The cerebrospinal fluid (CSF) analysis showed an elevated protein level of 75 mg/dl, normal glucose, a cell count of zero, and negative Gram and India ink stains. An electroencephalogram documented diffuse cerebral dysfunction without the epileptiform activity. Her blood, urine, CSF, and bone marrow cultures were all negative. A CSF polymerase chain reaction (PCR) for the detection of viral agents and Mycobacterium tuberculosis was negative. The determination of anti-N-methyl-D-aspartate (NMDA) receptor antibodies in CSF was positive. Diverse imaging studies such as thoraco-abdominopelvic CT, endovaginal ultrasound, and whole-body scintigraphy showed no significant abnormalities. Considering the characteristic clinical behavior of the patient, we decided to order a stereotactic biopsy of the pituitary mass. The pathology report revealed noncaseating granulomatous inflammation and gliosis (Figures 1(b)-1(d)). The periodic acid Schiff stain (PAS), Ziehl-Neelsen stain, and Grocott stain of the tissue were all negative. Immunohistochemical markers CD1a and langerin to rule out Langerhans cell histiocytosis were negative. Serological tests for Epstein-Barr, hepatitis B, hepatitis C, cytomegalovirus, toxoplasma, and Brucella spp were all negative. A PCR for the detection of Rickettsia spp, Ehrlichia spp, Anaplasma spp, and Borrelia burgdorferi were also negative. A nested PCR in biopsy tissue for the detection of Mycobacterium tuberculosis was also negative. The angiotensin converting enzyme serum level was in the normal range. Based on the pathology findings and the 2018 consensus diagnostic criteria, we concluded the final diagnosis of isolated neurosarcoidosis. She received treatment with prednisone and showed significant improvement of the neuropsychiatric symptoms. The patient was discharged from our unit to continue ambulatory treatment; however, she was lost at the follow-up.

PMC6010662_01

Female

In April 2007, a 56 year-old female visited our clinic with history of productive cough with whitish sputum, mild shortness of breath on exertion and low-grade fever especially in the evening for several months. She denied hemoptysis, anorexia, weight loss, other chronic respiratory symptoms and history of tuberculosis close exposure. Her previous medical illness was unremarkable. Additionally, she never smoked nor used alcohol and illicit drugs. On examination, there were no abnormalities on physical findings, including no fever, normal breath sounds and no lymphadenopathies. Chest radiography showed reticulonodular and patchy opacities at the right middle lung (RML) field and minimal bilateral apical pleural thickening (Fig. 1 left). One of the sputum specimens for acid fast bacilli (AFB) smear was positive but Polymerase Chain Reaction (PCR) for M. tuberculosis was negative (Seegene, Korea, Republic of). In Thailand, the negative predictive value of the PCR for M. tuberculosis in smear positive specimens was 97%. However, concerning of her persistent symptoms and risk of spreading tuberculosis infection, we decided to start the anti-tuberculous regimen of daily isoniazid 300 mg, rifampin 450 mg, pyrazinamide 1500 mg and ethambutol 800 mg during the waiting time for a result of mycobacterium culture. The treatment was justified according to the local guideline. At the 2-month follow-up visit, her symptoms were significantly improved, and chest radiography showed interval decrease in the size of the opacities. Nevertheless, the sputum culture showed nontuberculous mycobacterial growth. The working diagnosis was changed to pulmonary NTM disease with partial response to the anti-tuberculous medication. Thus, high-performance liquid chromatography (HPLC) for specific mycobacterial identification and in vitro drug susceptibility test were subsequently performed. Besides, we sent a repeated sputum specimen for mycobacterium culture. In addition, we planned to alter the therapeutic regimen after receiving the drug susceptibility result. Four months after the treatment, the definite species of the mycobacterium was unable to be identified due to inconclusive results of HPLC. The drug sensitivities showed susceptibility to rifampin but resistance to isoniazid, ethambutol, streptomycin, amikacin, ciprofloxacin, clarithromycin, imipenem and tetracycline. As a consequence of uncertain diagnosis and the knowledge of the discordance between in vitro drug susceptibility and therapeutic response of NTM infection, clarithromycin 1000 mg daily and levofloxacin 500 mg daily were added, and pyrazinamide was discontinued. However, 1 month later, levofloxacin and ethambutol were withdrawn due to tendinitis and toxic optic neuropathy. Thus, she took only isoniazid, rifampin and clarithromycin. Subsequently, her respiratory and constitutional symptoms disappeared in the 5th month of the latest regimen, and M. asiaticum was certainly identified during this period. The treatment was planned for total of 18 months, which was completed eventually. The timeline of the anti-mycobacterial treatment was shown in Fig. 2. In addition, all sequential sputum cultures for mycobacterium became negative and chest radiography after treatment completion showed residual bronchiectasis in the RML field (Fig. 1 right). Interestingly, she had regular follow-up visits for 10 years without relapse of this infection.

mycobacterium asiaticum, ntm infection, pulmonary infection

PMC8273166_01

Male

In 2018, a 67-year-old Chinese man was admitted to our hospital with dryness of mouth for 6 years and elevated serum creatinine for 2 years. Six years ago, he felt dryness of mouth. Enlargement of salivary gland were discovered, and resection of bilateral submandibular gland was performed. The pathologic examination revealed severe chronic inflammation. Two years ago, the patient felt fatigue. The serum creatinine was 164 mumol/L (corresponding to estimated glomerular filtration rate of 40.2 ml/min/1.73 m2 as calculated by the CKD-EPI equation) with benign urinary analysis. Half a year later, his serum creatinine elevated to 175 mumol/L (corresponding to estimated glomerular filtration rate of 37.5 ml/min/1.73 m2 as calculated by the CKD-EPI equation). Positive antinuclear antibody (ANA) with titer of 1:3,200 was discovered. Oral methyprednisolone was prescribed as 32 mg per day and tapered quickly because of deteriorating dry mouth. After that, his serum creatinine suddenly elevated to 517 mumol/L within 3 months. And he had intermittent facial rash when exposed to the sun. The patient had tuberculous pleurisy 50 years ago and fully recovered. Family history was of no significance. On admission, physical examination revealed blood pressure of 125/70 mmHg, temperature of 36.3 C, pulse of 75 beats/min, and respiratory rate of 15/min. His tongue was dry, and dental caries could be found. Laboratory data were as follows. Urinary analysis showed proteinuria+, glucose+ with normal blood glucose. Urine sediment analysis revealed red blood cell 0-2 cells per high power field (HPF) with white blood cell 0-1/HPF. Urinary protein excretion was 1.00 g/24 h (urine volume 2,700 ml). The urinary alpha 1 microglobulin was 343 mg/L (normal range: 0.00-12.00 mg/L) and N-Acetyl-D-Glucosaminidase 22 IU/L (normal range: 0-21 IU/L). Urine osmotic pressure was 314 mOsm/kg with normal blood osmotic pressure. Urine protein electrophoresis showed 58.90% of small molecule protein, 32.9% of albumin, and 8.20% of large molecule protein. Blood routine test showed mild anemia (hemoglobin 95 g/L). Blood chemistry tests showed increased levels of blood urea nitrogen and serum creatinine (16.91 mmol/L and 456.00 mumol/L, respectively). Serological studies revealed a high titer of ANA (1:10,000) and an increased level of anti-dsDNA antibody (>800 IU/ml) with negative ENA. Decreased serum levels of C3 (0.240 g/L) and C4 (<0.017 g/L) were detected. Total IgG was elevated to 33.80 g/L, and IgG subtypes were IgG1 19.8 g/L, IgG2 3.84 g/L, IgG3 2.24 g/L, and IgG4 2.43 g/L. Coombs test was positive. Tear break-up time (BUT) indicated dryness of eye (<10 s). Labial gland biopsy did not indicate the diagnosis of Sjogren's Syndrome. Submandibular gland pathology revealed severe chronic inflammation of the left submandibular gland. Immunochemistry staining of immunoglobulin showed IgG3 positive. Percutaneous renal biopsy was performed. Light microscopy examination showed that 3/14 glomeruli were globally sclerosed and 6/14 glomeruli showed ischemic sclerosis. Other glomeruli showed minor shrinkage of glomerular capillary wall, but no significant glomerular change. Tubular epithelial cells exhibited focal vacuolization and eosinophilic granules in the cytoplasm and focal loss of brush border. There were profound interstitial infiltration with lymphocytes, plasma cells, and a few eosinophils. "Storiform" fibrosis with tubular atrophy can be seen in the tubulointerstitium (Figures 1A-C). Immunofluorescence microscopy revealed one out of seven glomeruli with crescent and granular mesangial staining for IgG and C3, and granular staining for IgG, kappa, lambda, IgG1, IgG2, IgG3, IgG4, and C1q along TBM and interstitium and linear staining for lambda also along TBM (Figure 1D). Electron microscopy revealed one glomerulus with numerous electronic dense deposits along tubular basement membrane with focal mesangial deposits (Figure 1E). Immunohistochemistry revealed that IgG1-positive plasma cells were 35-45/HPF, IgG2-positive plasma cells 40-50/HPF, IgG3-positive plasma cells 90-100/HPF, and IgG4-positive plasma cells 10-15/HP (Figures 1F-I). Taken together with the diagnosis of SLE, these findings indicated the renal lesion as predominant acute and chronic tubulointerstitial nephritis with dominant IgG3 positive plasma cell infiltration. Oral prednisone 30 mg was prescribed immediately. Hydroxychloroquine 0.2 g and mycophenolate mofetil 1.0 g were given later. The serum creatinine was gradually reduced from 456 mumol/L to 210 mumol/L. The urinary protein was reduced to 0.17 g/24 h in 8 months. The patient was stable for the last 31 months during follow-up.

igg3, lupus nephritis, predominant interstitial nephritis, storiform pattern, systemic lupus erythematosus

PMC5290082_02

Male

The patient had been a professional basketball player from 18 to 25 years old and practiced competitive weightlifting until 30 years old. He admitted having taken a few cycles of oral and injectable steroids during the weightlifting competitive practice time. Currently, he is a bouncer and a recreational weightlifting practitioner. The patient assured not having taken steroids or any other supplements for the last three years. He reported no previous injuries to his knees and denied chronic knee pain. At the time of the trauma, the patient body type was athletic, weighing 120 kg and was 192 cm tall. The X-rays showed cephalic patellar migration and small calcification avulsions of the inferior poles of both patellae. An isolated undisplaced spiral fracture of the left fibular neck was also identified (Fig. 1). Ultrasound confirmed total bilateral rupture of the patellar tendons. Intraoperatively we found both tendons torn in their substance near the inferior patellar poles, with some segments avulsed from the patellar insertion. Lateral and medial retinacula were disrupted bilaterally. An end-to-end primary Kessler-type tendon repair reinforced with intraosseous sutures was performed in both knees. We temporarily protected it with cerclage wiring, followed by immobilization with a leg cylinder cast. We chose a nonabsorbable monofilament loop suture that allowed a proper tendon suture tension, by its second passage through the middle of the loop (Fig. 2). The tension within stitches was carefully adjusted to avoid shortening of infrapatellar length, according to the patellae position. The ruptured retinacula were repaired with Vicryl sutures. The strength of the repair was tested by careful flexion of both knees (Fig. 3). Cerclage wiring was applied in a figure-of-eight tension band running around the superior pole of the patellae, passing in front of the tendon, fixed with a transverse screw through the tibia tubercle and tied at average 60 of knee flexion (Fig. 4). The postoperative course was uneventful and radiographic control was satisfactory (Fig. 5). The cast immobilization was removed at the third postoperative day and the patient began ambulation with crutches using extension knee braces and full weight-bearing allowed as tolerated. At the 2rd postoperative week he began periodic removal of knee braces and a daily rehabilitation program, initially consisting in isometric muscle strengthening and knee flexion exercises restricted to 60 , complemented with peripatellar soft tissue massage. At the 4th week the patient could walk without crutches, had no pain and attained 40 of maximum bilateral active knee flexion. At the 6th week he had 60 of flexion and the knee braces were discontinued. At the 8th postoperative week, the cerclage wire was removed and the patient continued the daily physiotherapy program with progression to full knee flexion allowed and emphasis on muscle strengthening exercises. Stationary bicycle was introduced at the 9th week. Eleven weeks after surgery, the patient presented 100 maximum bilateral knee flexion and returned to work. On examination 5 months after surgery, the patient presented a satisfactory range of motion of both knees (135 flexion, 0 extension) good quadriceps strength and no signs of muscular atrophies or extensor lag (fig. 6). He denied any sense of instability or swelling, and therefore he returned to recreational sportive activities. He reported feeling that his knees were as strong as they were prior to the lesions and he was able to run, squat, and hop in place without difficulty.

patellar ligament, rehabilitation, rupture, spontaneous, steroids, tendon injuries

PMC8282150_01

Female

The participant in Case 1, a 79-year-old woman with mild symptoms of dementia (Mini-Mental State Examination [MMSE] = 22), lived with her husband in a single-story condominium. She reported that she used to walk a lot for recreation but does not as much anymore, but her husband loves to ride his bike around the neighborhood. She reported not participating in any regular exercise the month prior to the program. She was still able to care for herself and assisted her husband with shopping, cooking, and cleaning activities as his physical health was not the best. She was very social and loved to visit with family in the area. The participant depicted in Case 2, a 75-year-old male with severe symptoms of dementia (MMSE = 11), lived with his wife in a single-story home with a basement and required constant assistance for all of his basic activities of daily living (ADLs) due to his cognitive status. He enjoyed watching sports and working on puzzles with his wife. His wife reported some occasional wandering behavior and difficulties attending to tasks. She was still able to take him with her on shopping trips and out to restaurants. He attended a day program for IWDs a few times per week and participated in approximately 20 min/week of regular exercise in the month prior to the study. The participant in Case 3, a 63-year-old male with moderate symptoms of dementia (MMSE = 17), lived in the community with his wife in a single-story home. He was still very active in the community and had a newborn grandson who lived nearby. He reported working out approximately 120 min/week at the local senior center including weight training. He still golfed with his friends, tended to the garden at home, and traveled to see his family in other states. A physical assessment was completed for each participant prior to initiation of the moderate-intensity exercise intervention including comfortable and fast gait speed via the 8-foot walk test, lower extremity via 30-s chair stand test, and balance via the modified Berg Balance Scale (m-BBS). In addition, each participant completed the Geriatric Depression Scale (Short Form) to examine depressive symptoms and the Trail Making Test:Part B (TMT-B) to assess executive function. Finally, each participant completed a 16-item self-report tool to assess their perceived difficulty with both instrumental and personal ADLs. Baseline performance is summarized in Table 1. Overall, at baseline, these participants demonstrated minimal to no deficits in strength and balance; however, all had comfortable and fast gait speeds that were well below published normative data for age and gender. At baseline, none of the participants revealed depressive symptoms above the recommended cut-off of 5 points. Two (cases 2 and 3) participants were unable to complete the TMT-B due to their cognitive limitations while case 1 completed the TMT-B in 2 min and 37 s indicating no significant deficits in her executive function at baseline. All participants had different perceptions of their overall health, ranging from 0 being "poor" to 3 being "excellent," while all perceived minimal to no difficulty with their ADLs. The intervention was a moderate-intensity home-based functional exercise program consisting of strength and balance exercises. The functional strength and balance program was delivered individually in the participants' home by a board-certified geriatric physical therapist twice weekly for 12 weeks. Each session was composed of 4 elements: (1) Review, which examined results from previous sessions and identified of barriers to exercise completion reported by caregiver or IWD; (2) Education, which initially outlined the purpose of the intervention and provided subsequent education to improve adherence; (3) Planning allowed the utilization of available implementation strategies, based on the Strength-Based Approach Judge et al., to overcome barriers reported by the IWD or caregiver; and (4) Activity, which delivered a tailored functional strength and balance program based on the participant's functional status. The development of the intervention protocol was guided by principles from exercise science and the Strength-Based Approach Judge et al., allowing for a structured, standardized intervention protocol that is flexible to the needs of the individual participant each session. In the larger study, the intervention was found to be highly acceptable and feasible by the participants and the exercise practitioners via adherence, tolerance, and individual session evaluations highlighting engagement, fidelity to the protocol, confidence, and enjoyment. This was consistent from the beginning of the intervention throughout the 12 weeks. Initial starting exercises were determined by placing participants in a Physical Function Group based on initial walking performance as developed by Littbrand et al. (see Table 2). All 3 participants were placed in Physical Function Group 1 throughout the intervention, which indicated they could "walk without any physical support or supervision." The therapist and participant chose initial starting exercises based on this initial performance. Due to the high-level baseline of each participant, the exercise categories included higher level functional exercises (Categories A and B) to challenge the participant. Category A included static and dynamic balance exercises in combination with lower-limb strength exercises, such as step-ups, sit to stand, forward or side lunges. Category B included dynamic balance exercises while walking, such as stepping over obstacles, tandem walk, tossing ball in air while walking. To account for needs of this special population, strategies from the Strength-Based Approach were included in the protocol design to enhance the implementation of the intervention (Table 3). A few examples of these strategies within these 3 cases included using an external memory aid (dots on floor) to assist with foot placement during a lunge exercise; always giving the individual a choice of 2 exercises to allow them to choose a more preferred activity (eg, "would you rather do step-ups or sit to stand this time?"); cuing using one- to two-step commands such as "Charlie, get down on the floor. Okay, get back up."; and modeling each exercise prior to completion. Many of these strategies were integrated into the protocol (eg, modeling and giving 2 choices) while others were used as needed to overcome barriers by the participants (eg, targets on ground during lunges). Over the first 2 weeks of the program, a 15RM (repetition maximum) was targeted to allow acclimation to exercises and act as a build-up process. This intensity is representative of 50% of an individual's 1RM. Target intensity of strength exercises following this initial phase ranged from 8RM to 12RM, representing 60% to 80% of a 1RM; therefore, as more repetitions were completed, the exercise intensity was increased appropriately. Once the participant was able to complete more than 12 repetitions of a particular strengthening exercise, the intensity was increased either by addition of a weighted vest, weighted belt, or medicine ball, or increased by progression of activity (eg, progress to floor to stand tasks). For example, in Case 1, she began at the initial session with a body-weight forward lunge completing 15RM then, over time, was able to complete at 20RM in subsequent sessions; therefore, she held a medicine ball for completion of 15RM, which required continued progression to 10-pound weight vest. Once she was able to complete the appropriate repetitions, this was progressed to a body-weight walking lunge in the hallway. She eventually increased to completing the walking lunge with a 20-pound weight vest. Intensity of balance exercises was altered by variation of base of support or increased compliance of surface to continue to challenge the participant's postural stability. For example, lateral hopping was initiated on a firm surface, then progressed to a compliant surface once the participant did not report a challenge. A representation of the exercise sessions for the 3 case studies is outlined in Table 4. All 3 cases demonstrated a progression of strength and balance activities throughout the sessions as indicated by either completing more challenging exercises (eg, lunge to walking lunge; progression to floor to stand exercises; addition of dual-task component) or increased difficulty of same exercise (eg, addition of medicine ball or weighted vest; progression from firm to compliant surface). All of these progressions were completed without significant concern of injury due to the systematic progression using the multiple RM method of measuring intensity in the strength exercises. It is noteworthy that cognitive status did not hinder participation in the moderate-intensity program since the program was developed with the needs of IWDs in mind. For example, Case 2 who had severe cognitive impairment (MMSE = 11) was able to successfully complete moderate-intensity strengthening and balance activities including weighted floor to stand exercises (with 15-pound weight vest), weighted sit to stand exercises (up to a 25-pound weight vest), plyometric jumping (with 14-pound weight belt), hopping, and tandem walking. This success was likely due to conceptual frameworks that guided the development and implementation of the exercise program. Specifically, the principles of exercise science that guided the incremental increases in dosage ensuring that participants met the minimum requirements to promote beneficial adaptations. In addition, the use of functional exercises was critical in the success of the program, which allowed participants to challenge the entire neuromuscular system relying on procedural memory, which aligns with tenets from the Strength-Based Approach.

balance, cognitive impairment, physical activity, strength

PMC2913787_01

Male

A 58-year-old Caucasian male was referred to the otolaryngology outpatient clinic from the oncology department with a complaint of a right-upper neck mass which had been growing for one year. The mass was painless and had rapidly increased in size during the preceding 3 months. The patient reported no loss of weight and had no other masses. He denied swallowing or breathing difficulties. There was no history of exposure to tuberculosis. He was a farmer and life-long nonsmoker. On physical examination, he was a well-nourished man with a palpable, freely mobile nontender right level II lymph node measuring 3 cm x 3 cm. Oropharyngeal examination showed a moderately enlarged right tonsil. The rest of the physical examination was unremarkable. Rigid direct laryngoscopy showed a normal laryngopharynx and hypopharynx. Due to a possible vascular relation to the mass, an MRI of the neck was done, showing a sharply defined ovoid 3 x 3 x 4.5 cm nonspecific soft tissue mass with heterogeneous enhancement, likely a lymph node, with a mass-like bulge in the right tonsillar fossa suspicious for a primary tumour (Figure 1). This supported the clinical diagnosis of a tonsillar primary lesion with a regional nodal deposit. Two previous fine-needle aspirates (FNAs) of the neck mass had already been undertaken by the oncologists, but these were inconclusive. The aspirates were heavily blood stained and showed small tissue fragments composed of small lymphoid cells admixed with histiocytes. The sparse material suggested an inflammatory/reactive process, and flow cytometry was nondiagnostic. Therefore an excision biopsy with frozen sections was recommended for definitive diagnosis. If this revealed a squamous cell carcinoma, the operation would proceed to a selective neck dissection. The patient consented to the procedure and underwent a right tonsillectomy and excision of the enlarged lymph node. Frozen sections suggested a plasmacytoma and therefore a neck dissection was not carried out. Histologies of both the tonsillar mass and the lymph node were similar, showing effacement of normal architecture and extensive infiltration with diffuse sheets of neoplastic cells possessing plasmacytoid morphology with eccentric nuclei exhibiting "clock-faced" nuclear chromatin pattern that typically represent plasma cells. Binucleate and multinucleate forms were also present (Figure 2). The tonsillar lesion was fairly circumscribed and the epithelium was not infiltrated (Figure 3). Further immunohistochemical analysis on the specimens showed CD138 plasma cell marker positivity (Figure 4), while CD20 and CD3 were negative, with kappa light chain restriction. This profile was in keeping with plasmacytoma. Serum protein electrophoresis showed the presence of monoclonal IgG kappa with normal levels of residual immunoglobulins. Skeletal survey, bone marrow biopsy, serum-free light chain, and urine analysis for Bence-Jones protein showed normal results. Six months after surgery the patient remained well. Repeat immunoglobulin assay at the 3-month postoperative review showed that the monoclonal IgG had returned to normal levels, with normal light chains and no evidence of multiple myeloma on bone marrow biopsy and no lytic lesions on skeletal survey. Repeat investigations at the 6-month mark remained negative.

PMC5841111_01

Female

A 28-month-old girl was referred to our clinic because of a persistent cough, wheeze, and increased work of breathing for the preceding three months. Despite oral antibiotics and high doses of inhaled corticosteroids prescribed by her primary physician, cough and wheeze were persistent. Parents denied any history of witnessed foreign body aspiration, and there were no feeding-related symptoms. The patient was born at term with an uneventful postnatal course. Her history was significant for episodes of cough and intermittent wheeze that begun at one year of age; these episodes were usually treated with bronchodilators and inhaled steroids. There was no history of atopy in the family. Initial physical examination revealed normal growth parameters, a respiratory rate of 40 breaths/minute, and no retractions. Oxygen saturation ranged from 94 to 95% on room air, and she was afebrile. Lung auscultation revealed decreased air exchange in the left lung; the rest of her physical examination was normal. A chest X-ray was performed for abnormal breath sounds and showed hyperlucency of the left lung (Figure 1). A barium swallow study was normal with no apparent external indentation or displacement of the esophagus and no evidence for GERD. Blood work, including routine hematology and biochemistry tests, was within normal limits. Results of virology PCR for CMV, EBV, and adenovirus were negative. Acid-fast bacilli smear, culture, and TB PCR were negative. On flexible bronchoscopy examination of her lower airways, no foreign body was seen, but significant external nonpulsatile compression over the left main bronchus was noticed; the rest of the airway anatomy was normal. This finding prompted us to undertake a detailed evaluation. Thoracic computed tomography (CT) scan and angiogram showed a soft tissue mass in the middle mediastinum, compressing the carina and proximal part of the right and left main bronchi, more pronounced on the left main bronchus (Figure 2). This mass was further delineated by magnetic resonance imaging of the thorax with contrast which revealed a lobulated cystic mass lesion (Figure 3). These findings were in favor of the diagnosis of a bronchogenic cyst in the middle mediastinum. Therefore, the patient underwent thoracotomy and surgical removal of a cystic mass which was found during surgery to be adjacent to the posterior trachea and left main bronchus. Pathological examination of the mass showed a cystic lesion lined by the ciliated columnar epithelium surrounded by a fibromuscular wall containing the cartilage and nests of bronchial submucosal glands, confirming the probable diagnosis of a bronchogenic cyst. There was no evidence of malignancy. The postoperative course was uneventful. The patient had been free of any respiratory symptoms and signs, including a cough and wheezing in the subsequent follow-up visits.

PMC4227368_01

Female

A 43-year-old female with a medical history of nonsteroid dependent asthma presented to an outside hospital complaining of one-month frequent bloody diarrhea, body aches, loss of appetite, and 15 kg weight loss. Upon admission she was febrile (39 C); however the rest of the physical examination was reportedly benign. Laboratory findings were remarkable for leukocytosis (18.2 k/mm3; reference value: 4.5-11) and hypokalemia (2.6 meq/L; reference value: 3.3-5.3); the hemoglobin level was within normal range (13.9 g/dL; reference value: 12-16 g/dL). Although the initial workup for infectious etiologies was nondiagnostic, she was empirically treated with piperacillin-tazobactam. Two days later, she was transferred to our hospital for a higher level of care. Upon arrival, she was febrile (39.3 C) and tachycardic (125 bpm); moreover, she was found to have polyarthritis, involving the distal joints of her upper extremities. Significant laboratory findings included a low hemoglobin level (8.9 g/dL; reference value: 12-16), hypoalbuminemia (1.2 g/dL; reference value: 3.5-5), elevated C-reactive protein (40.3 mg/L; reference value: <3), and elevated erythrocyte sedimentation rate (104 mm/hr; reference value: <20). Repeated blood cultures in our facility were negative for bacteremia; however antibiotic therapy with piperacillin-tazobactam was continued as the computed tomography scan of the abdomen and pelvis showed evidence of colitis. Studies for infectious colitis were negative. On day three of admission, a peripherally inserted central catheter (PICC) was placed for total parenteral nutrition. One day later, the patient underwent colonoscopy which showed diffuse mucosal inflammation with numerous deep, clean-based ulcers from the rectum to the distal ascending colon. The differential diagnosis included cytomegalovirus (CMV) colitis versus IBD. Empiric ganciclovir was started; however it was discontinued once CMV colitis was ruled out by serology, quantitative polymerase chain reaction, and immunohistochemistry studies. Histopathology revealed subacute colitis, small crypt abscesses, fragments of granulation tissue, and neutrophilic exudate. An extensive rheumatologic workup for her seronegative polyarthritis led to the diagnosis of enteropathic arthritis. On day eight of hospitalization, once the serology for human immunodeficiency virus was confirmed as negative, intravenous methylprednisolone and oral mesalamine were initiated. On the same day, an episode of massive rectal bleeding was reported by the patient. The hemoglobin decreased from 7.8 to 6.7 g/dL and the patient was transferred to the intensive care unit and transfused with packed red blood cells. Two sets of blood cultures obtained at that time showed growth of gram-negative rods in aerobic bottles only. The methylprednisolone was held due to sepsis and the PICC was removed and sent for culture, which was negative. The microorganism was identified as L. adecarboxylata, using the fully automated Vitek 2 Compact 60 system (bioMerieux, Inc. Hazelwood, MO). The microorganism showed a pan-sensitive antimicrobial profile (Table 1), so the antibiotic regimen was changed to intravenous ceftriaxone and repeated blood cultures were negative. Therapy with methylprednisolone was resumed, achieving resolution of her bloody diarrhea and partial improvement of her polyarthritis. In light of the aforementioned clinical and paraclinical findings, the patient was diagnosed with ulcerative colitis with severe disease activity (ulcerative colitis disease activity index of 11), responsive to steroids and mesalamine. After a negative workup for latent tuberculosis and completion of the antibiotic course, treatment with infliximab was initiated which resulted in a complete recovery of the polyarthritis and normalization of the inflammatory markers. She was subsequently discharged to an acute rehabilitation facility with a gradual taper of oral prednisone and infliximab infusions every eight weeks.

PMC9977547_01

Male

A 76-year-old Japanese man visited a nephrologist with complaints of edema and dyspnea. He had first been diagnosed with nephrotic syndrome at 38 years old. Nephrotic syndrome had recurred at 57 and 63 years old. With the previous recurrence at 63 years old, he underwent renal biopsy and was diagnosed with MN (Ehrenreich-Churg stage II) with granular deposition of IgG, IgA, and IgM along the capillary wall. After the biopsy, he was treated with oral prednisolone (PSL) at 25 mg/day. Ten days later, the PSL dose was increased to 40 mg/day because urinary protein levels remained elevated. Urinary protein gradually decreased, and the patient achieved remission 3 months later. PSL was tapered and discontinued after 2 years of maintenance treatment. Although immunoglobulin (Ig) levels were not available, the ratio of albumin to globulin was 1.29 (total protein, 7.1 g/dL; albumin, 4.0 g/dL), suggesting that no hyperglobulinemia was present after remission at 65 years old. During follow-up, edema of the lower extremity and pericardial effusion gradually developed, and he was referred to a cardiologist. Laboratory workup then revealed a recurrence of nephrotic syndrome, and he again consulted a nephrologist. Initially, body temperature was normal with no obvious abnormalities in other vital signs. On physical examination, the patient showed pitting edema of the lower extremities and lymphadenopathy bilaterally in the axillary and inguinal regions. Laboratory data showed massive proteinuria (4.4 g/day) and hypoalbuminemia (1.4 g/day) (Table 1), suggesting nephrotic syndrome without hematuria. Notable findings were newly developed polyclonal gammopathies (IgG, 3,468 mg/dL; IgA, 534 mg/dL; and IgM, 284 mg/dL). Anemia and systemic inflammation were indicated from: hemoglobin, 9.8 g/dL; C-reactive protein, 0.63 mg/dL; and IL-6, 22.1 pg/mL (Reference; <7 pg/mL). Computed tomography (CT) showed multiple lymphadenopathies in the mediastinum, inguinal, and axillary regions. Blood culture, tuberculosis tests, tumor markers, and protein electrophoresis of sera and urine, and autoantibodies all yielded negative results. Figure 1 indicates the clinical course of this case. Before administration of PSL to treat nephrotic syndrome, an inguinal lymph node biopsy was performed for a definitive diagnosis. Light microscopy revealed diffuse interfollicular infiltration of plasma cells. Immunohistochemistry revealed CD20-positive lymphocytes in the follicular region and significant CD138-positive plasma cells in the interfollicular region (Figure 2). As hyaline vascular proliferation was not evident, this case presents the plasma cell type of MCD rather than the hyaline-vascular type. Furthermore, additional staining to diagnose malignant lymphoma yielded negative results, and the lack of monoclonality indicated no evidence of deviation in the light chain limitation. Based on polyclonal gammopathy, the pathology of lymphadenopathy, and elevated IL-6, we diagnosed MCD with renal involvement. Nephrotic syndrome promptly responded to PSL, and proteinuria improved and reached 0.2 g/day by day 14, along with decreases in disease markers of MCD such as IgG, IgA, C-reactive protein, serum IL-6, and plasma vascular endothelial growth factor (VEGF). At the same time, leg edema, and pericardial effusion gradually improved. During the tapering of PSL, proteinuria was transiently elevated, and we performed a renal biopsy to evaluate the activity of renal involvement and the differential diagnosis of primary or secondary MN. The renal specimen contained 12 glomeruli, with global sclerosis in three. No infiltration of inflammatory cells or mesangial cellular proliferation, crescents, or adhesions were noted (Figure 3(a)). Glomerular capillaries were diffusely and globally thickened and periodic acid methenamine silver staining showed spikes and bubbling in basement membranes (Figure 3(b)). Electron microscopy revealed subepithelial and intramembrane deposits of homogenous size estimated as Ehrenreich-Churg stage II late to III, partially with stage IV, and mild subendothelial enlargement (Figure 3(c)). Immunofluorescent investigations showed marked granular deposition of IgG, IgA, and IgM along the glomerular basement membrane, but no staining for complement (Figure 3(d)). We further assessed IgG subclass and revealed positive staining for IgG4, while faintly stained in IgG1 and negatively stained in IgG2 and IgG3 (Figure 3(e)). Regarding antigen-specific antibody staining, deposition of phospholipase A2 receptor (PLA2R) was positive in this case, while any other representative antigen-specific antibodies were not stained (thrombospondin type-1domain-containing 7A, neural epidermal growth factor-like 1 and exostosin-1) (Figure 3(f)). Finally, he was diagnosed with recurrence of primary MN of Ehrenreich-Churg stage II to III coincident with MCD. At discharge after 6 weeks of hospitalization, we performed a CT to confirm the effect of the lymph node reduction in size throughout the body. The periaortic and lung hilar lymph nodes were reduced in size (Figure 4), as were the lymph nodes in the bilateral axillary and inguinal regions. This case of proteinuria was successfully controlled for 6 months with corticosteroid monotherapy, and proteinuria was kept below 0.5 g/day. However, during the process of tapering PSL to 15 mg/day, the serum IgG titer (bottom; 1,275 mg/dL) began to increase, and at a PSL dose of 7.5 mg/day, urinary protein increased from 0.5 g to 1.9 g, CRP changed from negative to positive (0.33 mg/dL), and polyclonal gammopathy (IgG 2,161 mg/dL, IgA 471 mg/dL, and IgM 445 mg/dL) appeared. The patient was referred to another hospital for induction of anti-IL-6 therapy (Figure 5). Combination therapy with PSL and tocilizumab has successfully decreased concentration of IgG, C-reactive protein, and proteinuria, again.

PMC9381722_01

Male

An 11-year-old male presented to clinic with a large anterior bony prominence just distal to the tibial tubercle of his right knee. The patient was athletic and recently began experiencing pain over his proximal tibia with physical activity. Approximately 4 years prior, the patient presented to another orthopedic surgeon with concern about the bony prominence. He was diagnosed with severe OSD and an MRI demonstrated chronic osteochondrosis distal to the tibial tubercle with an overlying bursa. The patient was treated conservatively at that time without resolution of the prominence. On physical examination, the prominence was not tender to palpation. Full and painless range of motion was observed for the hip, knee, ankle, and toes, and sensorimotor function was intact distally throughout the lower extremity. X-ray demonstrated a possible osteochondroma of the proximal right tibia (Figure 1A and B). MRI confirmed the diagnosis and revealed that the patellar tendon partially inserted on the osteochondroma as well as the tibial tubercle (Figure 2A and B). Given that the mass appeared to be growing in size and the patient was progressively symptomatic, it was decided that surgical excision would be the most appropriate treatment (Figure 3). A total resection of the mass was performed using an anteromedial approach. An incision spanning 3 inches was made. Local soft tissue from the proximal tibia was dissected. A dissection was also performed on the portion of the patellar tendon that was attached to the anterior tibial mass. The mass was demarcated using a combination of anatomic parameters and C-arm fluoroscopy while taking care not to violate the physis. The mass was resected with a combination of osteotomes and a rongeur. Bleeding was mitigated with bone wax and cautery. The distal insertion of the patellar tendon was then reattached to the bone of the tibia with a suture and anchor technique. The repair was evaluated with motion of the patella, which was found to be excellent and stable. Patellar height was found to be equivalent compared to the contralateral side. Wound irrigation and closure were followed by a sterile dressing and a brace that was locked in extension. Dimensions of the resected mass were 5.0 cm x 4.0 cm x 2.0 cm (Figure 4A). Pathology confirmed that the mass was a benign osteochondromatous proliferation, with irregular architecture and immature cartilage giving rise to disorganized woven bone (Figure 4B and C). Additional areas of reparative changes were suggestive of fracture callus. These histopathology findings were distinct from those expected in OSD, although OSD also presents with changes in fibrocartilaginous tissue. Postoperatively, the patient was instructed to abstain from athletics for 8 to 10 weeks. At his 2-week postoperative visit, the patient was observed to be compliant with non-weightbearing and mobilizing with a wheelchair. Range of motion in the knee brace was increased, and the patient was permitted to toe-touch. Given that the patient had difficulty adjusting to crutches, physical therapy was prescribed to increase weight-bearing capacity. At the 5-week follow-up, the patient had intact straight leg raise and was able to bear weight as tolerated in the brace. Range of motion in the knee brace was subsequently increased from 0 to 90 . At the 8-week follow-up, knee range of motion was 0 to 120 without discomfort. Bracing was discontinued given that the patient was observed to bear weight as tolerated and the radiographs showed no concern for fracture (Figure 5A and B). The patient was instructed that he may resume some sports activities (eg, shooting baskets) but should avoid competitive or gym activities until fully cleared. At the 16-week follow-up, range of motion further increased to 130 without discomfort, and the patient was instructed to resume activities. At the 19-month follow up, patient had full resumption of athletic activities and experienced minimal pain. Radiographs demonstrated progressively healing tissue in surgical site evident by remodeling in the area of the lesion inferior to the tibial tubercle (Figure 6A-C). Clinical examination showed fully healing of the incision without any recurrence of the anterior mass (Figure 7). The patient's PEDI-IKDC score at approximately 19-month post-operatively was 94.6.

pediatric, orthopedic, osteochondroma

PMC3841921_01

Male

A 16-year-old male presented with right-sided numbness, dysphagia, and right peripheral vision loss after working out during football practice. In the emergency room (ER) his right-sided visual field defect persisted, with anomia and alexia. He stated that he had experienced intermittent episodes and discreet events over the past year including weakness, numbness, and vision loss. He had a computerized tomography scan of the head, which revealed areas of hypodensity in the left temporoparietal region suggestive of stroke. This finding was confirmed by magnetic resonance imaging, which revealed multiple strokes of different ages. Specifically, he had an acute stroke in the left temporoparietal region, along with subacute strokes in the right thalamus, spanning the corpus callosum and left cerebellum. The patient was then admitted to the pediatric intensive care unit (PICU) for observation and further workup. A cerebral angiogram revealed a focal dissection of the distal right VA with a small nonocclusive thrombus proximal to the dissection. The only suspicious event from the patient's history was a wrestling incident in the locker rooms a few days before the onset of stroke. He was followed by neurology and hematology/oncology, and had workups to rule out vasculitis, metabolic, hypercoagulable, and cardiac embolic sources, all of which were negative. Anticoagulation with enoxaparin was then initiated, and the patient was discharged home with instructions to avoid weight lifting and contact sports. Approximately 3 months after his initial presentation and completing his 3-month course of anticoagulation with therapeutic enoxaparin, the patient experienced new transient neurological symptoms of headache, blurred vision, and confusion. Incidentally, he began weightlifting a week prior to the onset of his new symptoms. Magnetic resonance imaging of the brain revealed a subacute stroke in the left medial cerebellum, and a new area of encephalomalacia, suspicious for a stroke, in the parietal region near the vertex that occurred after his initial hospitalization. The patient was then admitted for further evaluation. A dynamic cerebral angiogram was performed and revealed that the patient had a Bow Hunter's type phenomenon, with dynamic occlusion of the right VA in the chin up position looking to the left [Figure 1]. A dynamic computerized tomography angiogram performed with the patient's head in rotated position showed a near complete occlusion of the V3 segment of the right VA resulting from an anomalous spur emanating from his right occipital condyle that pinched off his VA between the C1 ring and this condylar spur [Figure 2]. This was determined to be the etiology of the dissection. Therefore, the patient was managed by neck immobilization via a cervical collar, and we initiated aspirin 81 mg and coumadin with an INR goal of 2-3. At this time, the plan was to allow the dissection flap to heal and then bring the patient back for elective surgical decompression of the condylar spur. However, 2 weeks after the treatment modality of immobilization and pharmacotherapy, the patient presented with a transient ischemic attack. He reported right hemibody numbness and tingling. His INR at that point was subtherapeutic, first at 1.8 then at 1.6. A magnetic resonance imaging and magnetic resonance angiography of the head and neck revealed persistent narrowing of the V3 segment of the VA to 50%, with new strokes noted in the occipital lobe, right cerebellum, and a thrombus in the left P2-3 segment of the left posterior cerebral artery. Since the patient had further thrombotic episodes due to the dissection, he was admitted and placed on 325 mg aspirin, clopidrogrel (300 mg load followed by 75 mg daily), and a heparin infusion. After a thorough discussion of all treatment options, including stenting of the artery, surgery to drill off the spur, or continued medical therapy, the decision was made to proceed with coil embolization/sacrifice of the right VA so as to prevent further thromboembolic events as well as to avoid the future need for surgical decompression of the anomalous occipital condyle process. The right VA was sacrificed with coil embolization and trapping of a 4 mm thrombus over the dissected segment [Figure 3]. The patient tolerated the procedure without complication and was subsequently discharged home. During his initial postoperative clinic visit, one week status-post right VA sacrifice, his cervical collar was discontinued. During his 5 week postoperative clinic visit, he reported no further episodes of seizures, paresthesias, headache, or neck pain. He was doing well on aspirin 81 mg with a plan to continue antiplatelet therapy indefinitely Three months status-post right VA sacrifice, the patient had a baseline right homonymous hemianopsia and a mild nystagmus, especially with right lateral gaze, but was otherwise doing well and denied any symptoms. He had increased his level of activity and started weightlifting but was not cleared for contact sports.

bow hunter's syndrome, coil embolization, endovascular surgery, stroke, vertebral artery

PMC7334807_01

Female

In September 2019, a 46-year-old female was hospitalized at First Affiliated Hospital of Chongqing Medical University due to "recurrent fever for one month, up to 38.9 C accompanied by chills and sweating", but otherwise no complaints. She was treated with meroxicillin sulbactam sodium + ribavirin locally and her temperature back to normal. However, 1 week after treatment, the patient's temperature increased again, with the highest value of 39 C. After admission to our hospital, besides high body temperature, through laboratorial inspection, she had leucopenia and low neutrophils, slightly elevated hypersensitive C - reactive protein, procalcitonin and other inflammatory parameters (Table 1). Blood culture was positive for Gram-negative bacillus biochemically identified as Brucella melitensis (Fig. 1). Simultaneously, serum agglutination test was positive. The patient was treated with intravenous aminoglycoside etimicin 300 mg (once a day for 14 days) plus minocycline 100 mg (first dosage 200 mg, then once every 12 h) in combination. Her temperature rapidly returned and maintained to normal and she was discharged and continued to take minocycline for 6 months without any recurrent signs during the follow-ups. Interestingly, the woman did not have any history of exposure to farm animals, drinking raw milk, and blood transfusion. She reported, however, that her husband, a lorry driver, had an intermittent low-grade fever prior to her illness. Her husband had ever been to Lanzhou, Gansu Province (a brucellosis outbreak occurred from vaccine factory's pollution due to failed disinfectants just during that period) and had a short stay in a farm unloading goods. The husband also presented with mild redness of the urethral orifice and complained of testicular pain. Subsequently, his blood culture also grew Brucella melitensis and the serum agglutination test was positive as well. He was treated with the same strategy and recovered.

brucella, couples, sexual transmission

PMC6912930_01

Female

A 16 years old female was referred from district hospital. Her main complaints were abdominal pain and enlargement for the last 2 months. The suspicion of malignant ovarian cyst was established from referring obstetrician based on abdominal ultrasound. Defecation and micturition pattern were normal. Her menstrual cycle was normal, with 28-30 days' cycle and 4-5 days of menstrual period in each cycle. There was no history of fever, vaginal discharge, chronic illness, chronic cough, and significant weight loss. There was no obvious contact with person with tuberculosis or those in tuberculosis therapy. A thorough physical examination revealed slightly distended abdomen, with palpable cystic mass up to 2 cm above pubic symphysis. From bimanual palpation, uterus was palpable within normal size, with palpable cystic mass in left adnexa. Abdominal ultrasound showed a cystic mass in left adnexa, measured 43 x 37 mm, with solid parts and irregular border, along with peritoneal free fluid. Abdominal computed tomography (CT) scan further showed a complex left ovarian cyst with ascites, suggesting malignant appearance. CT also founded right renal pelviectasis, hepatosplenomegaly, and bilateral inguinal lymphadenopathy. Laboratory workup for tumor biomarker was performed, with result supporting the suspicion of malignancy process (CA-125: 886 U/mL). Exploratory laparotomy was performed to found the fragile, solid mass which filled most of abdominal cavity and adhered to the pelvic wall, a condition commonly known as 'frozen pelvis', causing further exploration without making massive tissue destruction was impossible. Operator decision was to close the abdomen after collecting some tissue for histopathology workup. Histopathology report came out a week later, revealing a granulomatous inflammation related to tuberculosis process (Fig. 1). The diagnosis of abdominal tuberculosis was subsequently established.

abdominal tuberculosis, diagnosis, laparotomy, ovarian mass

PMC6912930_02

Female

A 16 years old female was referred from a private local hospital with suspected ovarian malignancy. She reported painful abdominal enlargement since the last year along with nausea and vomiting and marked weight loss. No history of fever, chronic cough, nor contact with tuberculosis-positive persons. Previous ultrasound examination showed ovarian mass with malignant appearance. She appeared cachexic, with body mass index only 15.8 kg/m2. Abdominal palpation revealed a lower abdominal mass originating from pelvic cavity up to umbilical level. Abdominal ultrasound showed large multilocular abdominal mass filling the pelvic cavity. No ascites fluid was found. Unfortunately, abdominal CT scan was not performed for this patient. Tumor marker was checked and CA-125 was found high (481 U/ml). She was diagnosed with suspected ovarian malignancy and laparotomy was planned. During surgery, parietal peritoneum was found thick and easily bleed. After it was opened, massive adhesion of abdominal organ was found and further exploration was considered impossible without damaging surrounding organs. Surgery was completed after collecting peritoneal tissue to be sent to pathology laboratory. Histopathological result showed granulomatous inflammation specific for tuberculous infection. The patient then was sent to internal department to receive extrapulmonary tuberculosis drug regimen.

abdominal tuberculosis, diagnosis, laparotomy, ovarian mass

PMC6885805_01

Female

A 21-year-old NCAA Division 1 Lacrosse player presented to the training room with right anterior thigh pain of 4-5 weeks duration. Onset was gradual, occurring in the spring lacrosse season and starting during training and practice. She did not report any new activity or specific mechanism of injury leading to the pain. She had no history of surgery or major injury to the region. She had previously been seen by the athletic trainer at the onset of pain, described initially as a soreness in her anterior thigh of gradual onset at practice, and started on conservative management for a presumed quadriceps strain. This initial management consisted of modified activities at practice, rehabilitation therapy in the training room, NSAIDS, ice, cupping, and needling. Despite some initial improvement with these treatments, symptoms increased with gradual return to lacrosse. The pain was now throbbing, worse after games, occurring at night, waking her up from sleep, and exacerbated when her leg would hang over the edge of the chair. On exam, she had full active and passive range of motion and strength of the hip as well as the knee. She had tenderness over the right anterior mid-proximal thigh, extending over and area of approximately 10 cm. The tenderness was worse medially than laterally with no palpable defect in the muscle, and she had a positive fulcrum and hop test. Her neurovascular exam was intact. An X-ray of the femur did not reveal any abnormalities. An MRI was ordered to rule out a stress fracture and to evaluate the quadriceps muscle further. The MRI showed an acute complete disruption of the inner bipennate muscular component of the right rectus femoris from the more superficial unipennate muscular component with retraction of the inner component, consistent with an acute degloving injury. No abnormality was noted in the osseous structure. These findings are highlighted in Figures 1 and 2. Given these findings of a closed degloving injury of the rectus femoris, the decision was made to discontinue all lacrosse activities and start a period of rest. After 2 weeks of rest with only a gentle range of motion exercises, her pain had improved. She progressed through therapy conservatively as the lacrosse season had just ended, starting with isometrics, and then progressing as tolerated to dynamic exercises followed by lacrosse-specific drills and exercise. By six weeks (42 days), she felt great and was cleared for full activity in therapy/progression to sport with estimated return to full competition at eight weeks (56 days) had it not been the offseason. The patient was able to participate in all offseason activities and had no setbacks or recurrence of symptoms the following season, returning fully to the level of play prior to injury.

PMC9393113_01

Male

A 51-year-old male patient was admitted to our hospital with persistent fever for >20 days and blurred vision in his left eye. He had a history of untreated diabetes. The patient was aware of abdominal distention, but did not attend the hospital until he developed a fever of 39.5 C. At the community hospital, he was diagnosed with pneumonia, uncertain intestinal obstruction, uncertain vitreous hemorrhage, and diabetes, and was treated with empirical antibiotics. When his condition became critical, he was transferred to the local tertiary hospital for further treatment. Laboratory tests revealed a white blood cell count of 11.94 x 109/L (normal range = 4-9.5 x 109/L), a neutrophil count of 10.95 x 109/L (normal range = 2-6.5 x 109/L), serum albumin of 25.6 g/L (normal range = 40-55 g/L), serum creatinine of 123 mumol/L (normal range = 35-97 mumol/L), and random blood glucose of 22.4 mmol/L. Inflammatory markers were also measured, with results showing C-reactive protein exceeding 200 mg/L and procalcitonin of 29.82 mug/L. A computed tomographic scan showed multiple nodules in both lungs and intrahepatic cystic lesion with air accumulation (Figure 1), but imaging detected no intestinal obstruction. The clinician considered the patient's infection to be fatal, although the pathogen had not yet been identified. Meropenem was used for antimicrobial chemotherapy after blood was taken for bacterial culture. Treatment measures such as albumin infusion and nutritional support were implemented simultaneously. However, the effect of treatment was poor. The patient's body temperature continued to rise to 40.4 C, which was attributed to the accumulation of pus in the liver abscess. Under the guidance of color ultrasound, the liver abscess was drained with percutaneous puncture, and 350 mL of brown pus was collected for bacterial culture. After the operation, the patient's body temperature dropped rapidly and his inflammatory indicators gradually decreased. However, sight in his left eye was still blurry. After consultation with an ophthalmologist, he was diagnosed with endogenous endophthalmitis (EE) (Figure 2A and C) and an emergency vitreous injection was performed. The pus in the vitreous cavity was also aspirated for bacteriological culture. Five days after admission, the bacterial culture of the collected pus samples yielded Klebsiella pneumoniae. In vitro antimicrobial sensitivity tests showed that both strains were sensitive to all the drugs recommended by the Clinical & Laboratory Standards Institute (CLSI). Viscous strings from the colonies were both >5 mm in length, indicating positive string tests (Figure 3). A multilocus sequence typing (MLST) analysis of the isolated strains was performed with PCR amplification, as previously described. Seven housekeeping genes (gapA, infB, mdh, pgi, phoE, rpoB, and tonB) were amplified and sequenced. The multiple sequence information was compared with the MLST database and the strains were identified as belonging to ST25. The associated virulence genes and capsule serotypes were also determined, as previously described. The strains were positive for virulence genes iucA, rmpA2, rmpA, aerobactin, and entB. The serotype of the capsule was K2. Therefore, we diagnosed the patient with invasive syndrome secondary to ST25-K2 HvKp infection, with multiple infected lesions in the liver, lung, and eye. Two weeks after admission, the patient had lost all vision in his left eye, accompanied by a very prominent headache and very high intraocular pressure. The ophthalmologist was consulted again and identified secondary glaucoma (Figure 2B). After a comprehensive evaluation and communication with the patient, he finally underwent left eye enucleation. The patient recovered and was discharged from the hospital on day 42 after admission. There was no recurrence of the disease at the 6-month follow-up.

endogenous endophthalmitis, hypervirulent klebsiella pneumoniae, liver abscess, sequence type 25, serotype k2

PMC6218752_01

Male

A 68-year-old male with past medical history significant of end-stage renal disease on hemodialysis, hypertension, hyperlipidemia, diabetes mellitus type 2, cirrhosis, hepatitis C, chronic obstructive pulmonary disease, and benign prostate hyperplasia presented to the emergency department with a 2-week progressive dyspnea. In addition, the patient complained of generalized weakness, subjective fevers, and abdominal pain in the right upper quadrant. The initial blood tests showed a normal complete blood count, no renal function abnormalities, and no electrolyte abnormalities and aspartate transaminase (AST) of 19 IU/L, alanine transaminase (ALT) of 5 UI/L, albumin of 2.9 g/dL, total bilirubin of 1.4 mg/dL, and prothrombin time of 15.6 seconds. Hepatitis B surface antigen and human immunodeficiency virus (HIV) 1 and 2 antibodies were negative. CXR was obtained and revealed a large left pleural effusion. Diagnostic thoracentesis revealed an exudative pleural fluid per Light's criteria and negative cytology. Ascites was noted on physical exam, and the patient underwent a diagnostic paracentesis that revealed a serum ascites albumin gradient of <1.1, polymorphonuclear cell count <250/mm3, and negative culture. Repeat paracentesis was performed to rule out malignancy or tuberculosis as the cause of ascites. No malignant cells were found, adenosine deaminase (ADA) activity was 3.4 IU/L, and Ziehl-Neelsen stain, Lowenstein-Jensen cultures, and polymerase chain reaction (PCR) amplification were negative for mycobacteria. Decision for abdominal computed tomography was made, which revealed peritoneal carcinomatosis with multiple subcentimeter lesions in the liver, spleen, and adrenal glands. Interventional radiology was consulted, and an omental biopsy was obtained which showed necrotizing granulomatous inflammation with rare acid-fast bacilli (AFB). Repeat biopsy was done for tissue culture, and this was positive for Mycobacterium tuberculosis complex. He was started on treatment with rifampin, isoniazid, pyrazinamide, and ethambutol immediately after biopsy, based on very low resistance rates of M. tuberculosis complex in our area. This patient's mycobacterial isolate was sent to the local Department of Health laboratory, to confirm antimicrobial susceptibility. The patient's AFB sputum cultures have remained negative. The patient's systemic symptoms improved days after treatment was started.

PMC9909052_01

Female

This is a 30-year-old gravida 3 para 2 patient from western Ethiopia whose gestational age from reliable last normal menstrual period (LNMP) was 39 weeks plus 4 days presented to Wollega University Referral Hospital (WURH) for elective cesarean delivery. Here, previous two deliveries were by cesarean section. The interval between the first and the second pregnancy and between the second and the third pregnancy (current pregnancy) was 17 and 4 months, respectively. During the current pregnancy, she had five antenatal care (ANC) contacts during which time she was supplemented with iron and folic acid. She was also given two doses of tetanus toxoid. She had a history of hyperemesis gravidarum in all pregnancies. Her past obstetric history showed unremarkable maternal complications. Her postoperative conditions during previous deliveries were smooth. Postpartum ultrasound examination showed no isthmocele. But she had early neonatal death in her second delivery. This made her get pregnant only after 4 months of delivery. She has no history of trauma to her abdomen. Her past medical and surgical history is unremarkable. On examination, she was healthy-looking. Her vital signs were blood pressure (BP) = 110/70 mmHg, pulse rate (PR) = 80 beats per minute, respiratory rate (RR) = 18 breaths per minute, and temperature of 37.5 C. She had pink conjunctivae. Lymph glandular system, chest, and cardiovascular system were normal. On abdominal examination, there was a transverse suprapubic healed scar, 38 weeks-sized uterus, longitudinal lie, cephalic presentation, no uterine contraction, on the area of tenderness, and fetal heartbeat (FHB) = 142 beats per minute. Pelvic examination showed an unfavorable Bishop score. On the integumentary system, she had no palmar pallor. On neurologic examination, she was oriented to time, person, and place. She had normal reflexes and no neurologic deficits. Ultrasound examination was done by radiologist four times during the current pregnancy (in first trimester, second trimester, early third trimester, and at admission). However, the uterine defect was not detected during these examinations. Uterine wall thickness was also not measured. The last ultrasound examination showed aggregate gestational age of 39 weeks plus 3 days, cephalic presentation, reassuring biophysical profile, fundal placenta, and adequate amniotic fluid. On laboratory investigation, urinalysis, complete blood count, and serum blood glucose level were normal. Serology for syphilis, hepatitis, and human immunodeficiency virus was non-reactive (Table 1). With the final diagnosis of full-term pregnancy and previous two cesarean scars, the patient was prepared for a cesarean section. Intraoperatively, there was a transverse lower uterine segment defect including more than two-thirds of its length through which fetal parts were visible and moving. The defect was only covered by a fetal membrane (Figure 2). After rupturing the fetal membrane, a female alive neonate weighing 3200 g and placenta was delivered. The edge of the defect was trimmed and sutured in two layers with chromic catgut. The abdomen was closed in layers. The patient was transferred to the recovery room with stable vital signs. The patient was counseled for family planning, and she preferred Implanon. On the sixth postoperative day, the patient and new born were discharged in good condition.

case report, cesarean scar, pregnancy, scar dehiscence, western ethiopia

PMC7305531_01

Male

An 11-year-old boy was admitted to the pediatric respiratory department of the Shandong Provincial Hospital due to 2-day history of intermittent mild hemoptysis. Six days earlier, the child had a fever with the highest temperature of 38.0 C. He had no other symptoms, and no examination was performed or treatment was given. Three days before the admission, the child was accidentally injured in the abdomen by the elbow of a classmate while playing. The resulting pain subsided soon, and no special treatment was given. The next day, the boy began coughing up bright red or dark red blood, 2-4 times a day, with a 30-40 mL of blood loss over 24 hours. He did not experience heart palpitations, nosebleed, skin bleeding, coma, hematuria, bloody stool, weight loss, or other symptoms. The boy had been full-term at birth, healthy, and without a history of tuberculosis or measles. At the time of admission, the patient was not febrile and had a respiratory rate of 30 breaths/min, heart rate of 92 beats/min, blood pressure of 107/80 mmHg, and oxygen saturation of 99% in ambient air. The weight was 35 kg. The breath sound of the right lung was slightly lower, and the results of other physical examinations were unremarkable. The complete blood count showed white blood cells 10.18 x 109/L, hemoglobin 141 g/L, and platelets 324 x 109/L, and the C-reactive protein (CRP) level was less than 0.2 mg/L. The coagulation function was normal. The chest radiograph documented right lower pneumonia (Figure 1). After the admission, the boy was treated by ceftriaxone, vitamin K1, and etamsylate and was told to remain in bed and avoid strenuous activity. On the night of admission, hemoptysis occurred more than 10 times, with 20-30 ml of blood each time. The events were accompanied by obvious chest tightness and pain. Physical examination revealed body temperature 36.8 C, heart rate 120 beats/min, respiratory rate 35 breaths/min, blood pressure 118/92 mmHg, oxygen saturation of 98% in ambient air, and low breathing sounds in the right lung. According to the result of chest radiography and the reduction in the right lung breath sound, the possibility of right lung hemorrhage was considered. The vital signs of the boy were stable, and no signs of respiratory failure were present. Therefore, the patient was subjected to the administration of oxygen via a nasal catheter, ECG monitoring, infusion of hemocoagulase, and continuous administration of pituitrin. He was placed in a right lateral position to protect the airway. Auxiliary examination indicated normal blood count (white blood cells 10.22 x 109/L, hemoglobin 134 g/L, platelets 337 x 109/L). Normal values were obtained in liver function tests, biochemical tests, myocardial enzyme test, urine test, antistreptolysin O test, autoantibodies, immunoglobulin, complement, prothrombin time, activated partial thromboplastin time, and erythrocyte sedimentation rate. The tests for pathogens including bacteria, mycoplasma, tuberculosis, and fungi were all negative. Cardiac ultrasound was normal. Acute CT angiography (CTA) showed that bronchial artery 1 originated from the thoracic aorta to the left at the level of the upper margin of T5 and entered the right hilum above the bifurcation of the trachea. Bronchial artery 2 arose from the right side of the thoracic aorta at T6 and passed up to the right and then down to the right hilum with a 2 mm widening of the primary and middle tube diameters (Figure 2). Bronchial artery 3 originated from the left side of the thoracic aorta under T6 and was divided into two branches going, respectively, to the right and left, without an evident expansion of the lumen. The pulmonary CTA did not identify significant abnormalities. The chest CTA also showed intra-alveolar hemorrhage, partial bronchial stenosis on the right side, atelectasis in the middle lobe, and partial consolidation in the lower lobe. The interventional therapy department physicians concluded that the massive hemoptysis might be caused by bronchial artery dilatation, and bronchial arteriography was recommended to obtain a definite diagnosis, with bronchial artery embolization (BAE) if necessary. Bronchial arteriography was performed 4 hours after the discontinuation of pituitrin. The imaging demonstrated that the right lower bronchial artery had the same origin as the left bronchial artery, and the vascular lumen was dilated. The right lower lung branches were disorganized, with a small amount of light staining in the parenchymal phase (Figure 3). The distal end of the right inferior bronchial artery was embolized by microspheres combined with a metal coil, this occlusion was confirmed by a repeated bronchial arteriography. Aortic angiography visualized an ectopic bronchial artery originating from the right renal artery and entering the right lower lung, with tortuous and disordered peripheral vessels, and the pulmonary artery branch was apparent in the arterial phase (Figure 4). In consideration of the presence of a bronchial-pulmonary artery fistula, embolization was performed at the distal end of the vessel (Figure 5), and the subsequent revealed that the artery was occluded at the distal end. On this basis, it was concluded that bronchial artery 3 and the ectopic bronchial arteries originating from the kidney were the vessels responsible for the bleeding, and not the slightly dilated bronchial artery 2. No incidence of hemoptysis occurred after BAE, but the child continued to have paroxysmal chest tightness and chest pain. Subsequent chest X-ray documented atelectasis in the right lung (Figure 6). To avoid rebleeding, bronchoscopy was performed 2 days after the BAE. A large number of blood clots were found in the right main bronchial lumen, the right upper lobe bronchial lumen, and the right middle bronchial lumen. The thrombus was removed using forceps, bronchoscopic brush, and freezing. After the bronchoscopy, the child did not experience chest tightness or other discomforts and occasionally coughed up a small amount of brown blood clot. The chest radiograph did not reveal any evidence of atelectasis on the second day of bronchoscopy (Figure 7). Bronchoscopy performed again 5 days later did not detect hemorrhagic points or bloody sputum suppository. Given the circumstances preceding the admission, the experienced trauma is considered to be the cause of bleeding from the malformed bronchial artery. The child was hospitalized for 10 days. No incidence of hemoptysis occurred during one and a half years of follow-up, and no abnormality was found in the chest radiograph.

PMC9763264_01

Male

A 50-year-old male presented with a progressive cognitive decline, expressive aphasia, and personality changes. Brain MRI revealed a non-enhancing small region of increased T2-weighted signal in the right frontal lobe; a follow-up MRI 25 weeks later revealed an avidly enhancing mass exhibiting significant mass effect. He was eventually submitted for craniotomy and gross-total resection of the enhancing lesion. Integrated diagnosis was consistent with glioblastoma, WHO grade 4, IDH-wt, and MGMT hypermethylated. At four-weeks post-surgery, there was improvement in cognitive performance although personality changes persisted. He was treated with pLDR as part of a prospective phase II study (NCT04747145) to a total dose of 60 Gray (Gy) in 30 fractions with concurrent TMZ, which he tolerated with anticipated side effects. This was followed by adjuvant TMZ and TTF. The patient completed a total of four cycles of TMZ and TTF before MRI of the brain, obtained at 20 weeks post-pLDR, which raised concerns for tumor progression. Increased nodular enhancement around the resection cavity ( Figure 1A ) was observed in the setting of the patient experiencing neurocognitive decline. FTB maps revealed predominantly treatment effect with 70.3% non-tumor, 22.9% tumor admixture, and 6.8% tumor tissue ( Figures 1B, D ). At 23 weeks post-pLDR, the patient was submitted for redo-craniotomy in the absence of FTB-guidance. Near-total resection of the enhancing lesion was later confirmed by postoperative MRI ( Figure 1C ). Microscopy of the five tissue specimens revealed a combination of necrosis, hyalinized and necrotic blood vessels, chronic inflammation, foamy macrophages, mineralization, and reactive gliosis, consistent with treatment effect. Therefore, the patient resumed adjuvant treatment with TMZ and TTF. Of note, compliance with TTF averaged 90% of "ON" time throughout the treatment period. At four weeks post-redo surgery, the patient remained clinically stable.

mri, fractional tumor burden (ftb), glioblastoma, pseudoprogression, pulsed low-dose-rate radiotherapy (pldr), relative cerebral blood volume (rcbv), treatment effect, tumor progression

PMC9763264_02

Male

A 56-year-old male presented with a history of seizure and expressive aphasia. Brain MRI revealed a left parietal mass with surrounding vasogenic edema and mass effect. Craniotomy and gross-total resection were performed, and integrated diagnosis was consistent with glioblastoma WHO grade 4, IDH-wt, and MGMT unmethylated. The patient was treated with pLDR as a part of a prospective phase II study (NCT04747145) to a total dose of 60 Gy in 30 fractions with concurrent TMZ followed by adjuvant TMZ and TTF. At one week post-pLDR, there was clinical decline with MRI demonstrating significant vasogenic edema for which a bevacizumab infusion was provided every two weeks at 10 mg/kg. It was discontinued after two infusions due to a poor response and continued clinical decline. At five weeks post-pLDR, MRI demonstrated an increase in the left parietal peripherally enhancing lesion size ( Figure 2A ). FTB maps revealed predominantly treatment effect within the contrast enhancement surrounding the resection cavity with 84.0% non-tumor, 9.6% tumor admixture, and 6.4% tumor ( Figures 2B, D ). At eight weeks post-pLDR, redo-craniotomy was performed in the absence of FTB-guidance. Reduced vasogenic edema and regions of enhancement around the resection cavity were later confirmed by MRI performed four weeks post-surgery ( Figure 2C ). Three tissue specimens were evaluated, two of which showed necrosis and hyalinized vessels, consistent with treatment effect, while the last sample revealed hypercellular high-grade glioma. The patient continued adjuvant treatment with TMZ and TTF. At nine weeks post-redo surgery, the patient's neurological symptoms included fatigue, right hemiparesis, and global aphasia. At 10 weeks post-redo surgery, he was restarted on bevacizumab at 10 mg/kg every 2 weeks, completing two infusions. Ultimately, he experienced a traumatic fall complicated by intraparenchymal hemorrhage and was transitioned to hospice.

mri, fractional tumor burden (ftb), glioblastoma, pseudoprogression, pulsed low-dose-rate radiotherapy (pldr), relative cerebral blood volume (rcbv), treatment effect, tumor progression

PMC9763264_03

Male

A 55-year-old male presented with a seizure, visual impairment and personality changes. Brain MRI revealed an enhancing left occipital mass surrounded by diffuse FLAIR hyperintensity signal. Craniotomy and gross-total resection were performed and integrated diagnosis was consistent with glioblastoma WHO grade 4, IDH-wt, and MGMT unmethylated. Following surgery, his symptoms included right hemiparesis, global aphasia, and a right homonymous hemianopsia. The patient was enrolled in a prospective phase II study (NCT04747145) to be treated with pLDR to a total dose of 60 Gy in 30 fractions with concurrent TMZ followed by adjuvant TMZ and TTF. Near completion of pLDR (fraction 24) and 8 weeks post-surgery, he was admitted for worsening symptoms of gait dysfunction, nausea and vomiting, and dysphagia. MRI revealed increased enhancement around the resection cavity with increased mass effect and left ventricular trapping ( Figure 3A ). FTB maps revealed predominantly treatment effect within the contrast enhancement surrounding the resection cavity with 64.6% non-tumor, 19.1% tumor admixture, and 16.4% tumor ( Figures 3B, D ). Radiation was withheld and redo-craniotomy was performed in the absence of FTB-guidance. Five tissue specimens revealed necrotic tissue and sparse reactive brain tissue, consistent with treatment effect. Neurologically, the patient improved in memory and speech with residual comprehensive aphasia and right visual field defect. Bevacizumab was subsequently started at 10 mg/kg every 2 weeks. The patient continued adjuvant treatment with bevacizumab, TMZ, and TTF. Of note, compliance with TTF averaged 75-90% of "ON" time throughout the treatment period. At one week post-surgery, brain MRI demonstrated retraction of the resection cavity and decreased peripheral enhancement along the surgical margins ( Figure 3C ). At 29 weeks post-redo surgery, the patient was transitioned to hospice, experienced respiratory failure caused by aspiration from worsening dysphagia and expired.

mri, fractional tumor burden (ftb), glioblastoma, pseudoprogression, pulsed low-dose-rate radiotherapy (pldr), relative cerebral blood volume (rcbv), treatment effect, tumor progression

PMC9763264_04

Male

A 60-year-old male presented with progressive left hemiparesis and memory decline. Brain MRI revealed an enhancing mass within the right frontal lobe that was resected. Integrated diagnosis was consistent with glioblastoma WHO grade 4, IDH-wt, and MGMT unmethylated. There was significant postoperative improvement in symptoms. The patient was treated with pLDR as a part of a prospective phase II study (NCT04747145) to a total dose of 60 Gy in 30 fractions with concurrent TMZ followed by adjuvant TMZ. Adjuvant TTF were declined. Follow-up brain MRI studies demonstrated progressively increasing enhancement around the resection cavity. At 13 weeks post-pLDR, FTB maps revealed 47.9% non-tumor, 19.2% tumor admixture, and 32.9% tumor within the contrast-enhancing tissue. Seven weeks later, brain MRI demonstrated increased enhancement, particularly at the superomedial resection cavity margin ( Figure 4A ). FTB maps were again obtained with increasing proportions of vascular tumor tissue suggesting progression: 42.9% non-tumor, 13.5% tumor admixture, and 43.6% tumor ( Figures 4B, D ). At 30 weeks post-pLDR, redo-craniotomy was performed in the absence of FTB-guidance. Significant debulking was later confirmed by MRI ( Figure 4C ). Two tissue specimens revealed moderately cellular atypical glial proliferation, supportive of active tumor. At three weeks post-redo surgery, the patient progressed with gait dysfunction, dysphagia, expressive aphasia, and left facial droop.

mri, fractional tumor burden (ftb), glioblastoma, pseudoprogression, pulsed low-dose-rate radiotherapy (pldr), relative cerebral blood volume (rcbv), treatment effect, tumor progression

PMC9932026_01

Female

We present a case of a 53-year-old Caucasian female patient. When she was 42 years old, falls and loss of balance occurred. Furthermore, at the age of 48, progressive, involuntary, uncoordinated movements of the upper limbs and head, tongue stereotypes (licking and extending movements), speech problems (dysarthria), memory deterioration, and hearing loss occurred. Since childhood, she has shown skin and conjunctiva hypersensitivity to the sun. She underwent splenectomy due to spherocytosis at the age of 18 and cholecystectomy at the age of 20. Before the age of 40, she was diagnosed with premature ovarian failure. In vitro fertilization was performed with a donor oocyte. She gave birth to a female baby. There was no family history of genetic diseases and consanguineous parents. She pursued philological education. Initially, she had been working as a teacher of the Russian language and then in a library. Currently, she is living on a pension. The neurological examination revealed chorea syndrome, cerebellar ataxia, dysarthria, and bilateral hearing loss. She has numerous pigmented lesions on her brown-colored skin (Figure 1). Brain MRI demonstrated massive cortico-subcortical atrophy (Figures 2, 3 ). The consulting otolaryngologist diagnosed bilateral sensory hearing impairment. The electroneurographic examination did not reveal any signs of peripheral polyneuropathy. Laboratory tests showed the presence of macrocytic anemia, significant vitamin B12 deficiency, and high levels of homocysteine. The consulting hematologist recommended supplementation with vitamin B12, iron, and folic acid. Endoscopic examination showed atrophic gastropathy. At the age of 48, a neuropsychological examination was performed which revealed cognitive-behavioral disorders with a predominance of subcortical symptomatology. Additionally, a slowdown in the pace of work, periodic drops in the tension of free attention, difficulties in organizing complex visual materials, and deficits in learning and memory, mainly of an executive nature, were described. The neuropsychological examination performed at the age of 53 revealed dysfunctions in the executive domain in the field of attention (maintenance, selectivity, and divisibility), working memory, organizing, and planning activities (mainly activities on visual materials). There was variability in the severity of dysfunction in the cognitive and non-cognitive spheres. The clinical details are presented in Table 1. The genetic diagnostics was performed which excluded spinocerebellar ataxia types 1, 2, 3, 6, and 17, Huntington's disease, and FMR1 premutation. Exome sequencing using the next-generation sequencing (NGS; SureSelectXT Human All Exome v7 (Agilent)) method was performed in further genetic diagnostics as previously described. Two variants in the ERCC4 gene, namely, missense c.2395C > T and a novel non-sense c.1349G > A, in the configuration of the heterozygote, were identified (Table 2). The presence of the c.1349G > A variant of the ERCC4 gene was found in a heterozygous state in the proband's mother but excluded in the father, while the presence of the c.2395C > T variant of the ERCC4 gene was found in a heterozygous state in the proband's father but excluded in the mother. It is consistent with in trans variant transmission in the autosomal recessive mode of inheritance. Moreover, in the proband, a heterozygous non-sense variant in the SPTB gene (hg38 chr14:064786837-C>T; NM_001355436.2:c.3128G>A (p.Trp1043Ter), rs1594775390) was identified (Figure 4). The c.3128G > A variant has 0 frequency in the gnomAD v3.1.2 database and was described in the ClinVar database as "pathogenic" and classified as "pathogenic" according to ACMG classification (total score 11, PVS1 very strong, PP5 moderate, and PM2 supporting). Variants in the SPTB gene, including the c.3128G > A variant identified in our patient, are associated with spherocytosis type 2, 8, and 9. The parents showed no clinical or laboratory signs of spherocytosis. So far, a rare phenotype of progressive spinocerebellar ataxia, chorea, cognitive impairment, and hearing loss with a history of skin photosensitivity has been described in single patients with ERCC4 gene variants.

ercc4, ner (nucleotide excision repair), ataxia, brain atrophy, chorea, gene variant

PMC9762491_02

Male

Patient 2 (P2) was a 44-year-old man who underwent OLT for acute-on-chronic liver failure (ACLF). The patient had chronic hepatitis B for several years and received irregular treatment. During the transplant operation, the patient suffered severe post-reperfusion syndrome (PRS) due to hyperkalemia, that is, cardiac arrest after reperfusion. After cardiopulmonary resuscitation, the heartbeat and circulation returned to normal levels. Nevertheless, the initial recovery from transplantation was excellent, and there were no early operation-related complications. Intraoperative immune induction and postoperative baseline immunosuppression were the same as those in Patient 1. One week after transplantation, the patient exhibited a consciousness disorder, mainly manifested as unclear content of consciousness, loss of orientation, calculation ability, and logical ability. The vital signs were stable, except for a slight fever, with a maximum temperature of 38.0 C. Brain magnetic resonance imaging (MRI) revealed two abnormal signals in the left temporal lobe and right frontal lobe, and the possibility of infection was considered (Figure 2A). CSF routine, biochemistry, and culture also showed no abnormalities, but NGS confirmed an invasive Aspergillus infection in the CSF. Based on these guidelines, voriconazole was selected as the antifungal therapy. Meanwhile, the dosage of tacrolimus was adjusted to maintain the concentration below 8 ng/ml. After three weeks of antifungal treatment, the patient's neurological symptoms slightly improved, but re-examination of brain MRI showed that the lesion was larger than before (Figure 2B). A second NGS of the CSF showed Candida, but no Aspergillus. After multidisciplinary consultation and discussion, a biopsy was performed to confirm the pathology; however, the patient and his family refused to do so. Considering the antifungal effect of sirolimus, immunosuppression was adjusted to sirolimus monotherapy for maintenance therapy. Meanwhile, fluconazole was added for antifungal therapy and the plasma concentration was maintained between 4.5 mg/mL and 5.5 mg/mL. After 2 weeks of combined treatment, re-examination of brain MRI showed that the lesions did not increase significantly, and the neurological symptoms were significantly improved. During the following three weeks, antifungal therapy was maintained, and re-examination of the brain MRI showed that the infected lesions were smaller than before (Figure 2C). Immunosuppression was gradually restored by tacrolimus combined with sirolimus. After comprehensive treatment, the patient recovered well and was discharged three months after liver transplantation.

hhv-6 encephalitis, immunosuppressant, intracranial infections, opportunistic infections, orthotopic liver transplantation

PMC6843078_04

Male

A 29 year old man from Somalia was transferred to our out-patient clinic from the Department of Infectious Diseases after hyperglycemia and ketosis had unexpectedly been found during a negative tuberculosis work up. His family history was positive in that his mother and two uncles had T2D-like diabetes. His medications consisted of human insulin isophane 16 + 10 U (thus a daily insulin dose of 26 U [0.42 U/kg b.w.]). Upon his first visit at our out-patient clinic, physical examination showed a BMI of 21.1 kg/m2 and was otherwise unremarkable. He had a B-HbA1c of 82 mmol/mol (9.9%) and fS-LDL-cholesterol concentration 3.4 mmol/l. He was negative for autoantibodies against GAD-65 and IA-2 and his C-peptide concentration rose from 0.483 to 1.17 nmol/l upon meal stimulation, indicative of non-autoimmune non-insulinopenic diabetes. All insulin therapy was discontinued and replaced with sitagliptin (100 mg q.d.) and atorvastatin (40 mg q.d.). Upon revisiting the diabetes nurse 6 months later, his fP-glucose was usually around 5 mmol/l, prandial P-glucose usually below 7 mmol/l, B-HbA1c 44 mmol/mol (6.3%) and fS-LDL-cholesterol was 1.8 mmol/l. The patient was referred to a primary care health center.

flatbush diabetes, glp-1–glucagon-like peptide-1, sglt 2 inhibitor, atypical diabetes, ketosis

PMC4643339_01

Female

An 80-year-old white woman was referred to the Department of Surgery for a symptomatic thyroid nodule (Fig. 1). The nodule had been diagnosed four years earlier by US, which revealed a solid and well defined heterogeneous formation in the right hemithyroid, measuring 33 x 21 mm, containing an area of cystic degeneration. The patient was asymptomatic at that time, with a euthyroid status. FNAB guided by US of the thyroid nodule was performed and the cytological examination was inconclusive. Given the age of the patient, comorbidities and her asymptomatic status, surveillance was decided. Her medical history included hypertension, dyslipidemia, obesity, paroxysmal atrial fibrillation, pulmonary tuberculosis, chronic thrombocytopenia and RCC nine years ago, treated by a radical nephrectomy. The tumor removed was 5 cm in size; it was located in the upper pole of the right kidney and a clear cell carcinoma was reported, of Fuhrman nuclear grade 2. The patient's postoperative course and subsequent recovery were uneventful. Neither postoperative chemotherapy nor interferon was proposed. During follow-up, a computed tomography (CT) scan revealed a 20 mm vascularized nodule in the middle portion of the pancreas body (Fig. 2). A subsequent magnetic resonance imaging (MRI) identified a solid nodule in the transition between the pancreatic body and tail, measuring 20 x 13 mm, with an enhancement pattern suggestive of a neuroendocrine origin (Fig. 3). An octreotide scintigraphy was performed identifying a focus of anomalous hyper-expression of somatostatin receptors, with increased uptake in the pancreas and the right lobe of the thyroid. In order to rule out von Hippel-Lindau syndrome a cerebral MRI was done, as well as ophthalmologic evaluation, which were normal. In 2012 the patient remained euthyroid but the appearance of symptoms, such as cervical pain and hoarseness, led to a new FNAB guided by US that once again was inconclusive. Cervical examination revealed a nodule in the right lobe of the thyroid, measuring about 3 x 3 cm. Due to the symptoms, a hemithyroidectomy and isthmectomy was performed. The resection was carried out without difficulty after identifying superior and inferior right parathyroid glands and the right laryngeal recurrent nerve (Fig. 4). The postoperative course was uneventful. After 11 months, the patient was doing well and had not developed any additional metastasis. The follow-up CT-scan showed an increase in the size of the nodule in the body of the pancreas previously identified, and a new one in the head of the pancreas with similar characteristics. After the multidisciplinary team discussion no further investigation or treatment was proposed due to patient's age and comorbidities.

renal cell carcinoma, thyroid metastasis

PMC4900026_01

Male

A 42-year-old man with a prior history of anabolic steroid use presented to his primary physician one day after falling on both elbows while playing football. On physical examination, he had mild tenderness and a palpable defect over the olecranons bilaterally. He had full strength on extension; however, he complained of weakness and pain in both arms. Initially, three view radiographs of both elbows showed a 1-cm ossific fragment in the posterior soft tissue located approximately 4 cm proximal to the posterior aspect of the olecranon. The margins of the fractured fragments were not corticated and thus appeared to be acute. Soft-tissue swelling was also appreciated on the posterior aspect of both arms. These findings indicated bilateral enthesophyte fracture with proximal retraction, suggestive of bilateral partial or complete avulsion/tear of the triceps tendon (Fig. 1). Subsequent fat-saturated proton-density-weighted MRI of the right (Fig. 2) and left (Fig. 3) elbow revealed bilateral full-thickness tears of the triceps tendons, with extensive edema within the myotendinous portions and surrounding hemorrhage. The patient underwent bilateral open triceps tendon repair without complication 15 days after sustaining injury.

mri, magnetic resonance imaging

PMC8355942_01

Male

A 21-year-old Afghan man presented to the emergency department with a 7-day history of fever, chills, hemoptysis and hematuria. He denied any recent exposure to any patient with COVID-19. He had no significant history of rheumatologic disorders or any other diseases. The patient had tachypnea and tachycardia on admission. He demonstrated normal blood pressure. Oxygen saturation was measured 86% in room air by pulse oximetry which reached 96% using the 60% venture mask. On examination, his lungs displayed bilateral coarse crackles. Electrocardiography findings were normal. At the time of hospital admission, laboratory tests showed HGB: 14.7 gr/dl; WBC: 11.61x103/mm3; PLT: 162x103/mm3; D-dimer: 900 ng/ml; CRP: 12 mg/dl; ESR: 60. In arterial blood gas analysis, pH: 7.35, pCO2: 50.7 and HCO3: 27.3 were noted. Urine analysis was notable for protein: 1+; WBC: 12-14; RBC: 20-25 and blood: 2+. Other laboratory parameters were in normal ranges. No bacterial growth was seen in blood and urine culture. Respiratory mucus smear and culture were also negative for Mycobacterium tuberculosis and bacterial infection. Due to his respiratory signs, a spiral computed tomography (CT) scan of lungs was performed which revealed evidences of bilateral ground glass opacity and multifocal consolidation distributed along the subpleural regions suggesting for COVID-19 (Figure 1 A-C). Reverse transcriptase polymerase chain reaction test for COVID- 19 was performed to confirm the diagnosis which showed positive result. During hospitalization, hemoptysis and dyspnea worsened and the patient deteriorated. Since hemoptysis was uncontrolled and tachypnea was worsened, the patient underwent endotracheal intubation on the second day of hospitalization. Active airway bleeding was noticed during intubation. Due to his concurrent hemoptysis and hematuria, the patient was suspected to have vasculitis. Therefore, rheumatologic tests including ANA, Anti ds-DNA, C ANCA, P ANCA, anti CCP, RF, SSA-RO and SSA-LA were performed for the patient. All the performed rheumatologic tests were negative. On the third day of hospitalization, laboratory examinations were notable for HGB: 13.7 gr/dl; WBC: 0.8x103/mm3(lymphocyte count was undetectable); PLT= 84x103/mm3; BUN=52 mg/dl; Cr=2.66 mg/dl, lactate dehydrogenase (LDH) =774 U/l and aspartate aminotransferase (AST)=50 U/l. Venous blood gas analyses showed a pH of 7.12; a PCO2 of 53.6 and a HCO3 of 17.2. Despite supportive, anti-viral and antibiotic therapy, the patient died due to respiratory failure and multi-organ damage on the third day of hospitalization.

covid-19, corona virus, hematuria, hemoptysis, sars-cov-2

PMC6000718_01

Female

A 31-year-old woman in the 15th week of gestation suddenly lost consciousness and was transferred to our institution. She was in a deep coma with her left pupil dilated and right hemiplegia. Computed tomographic scans showed an intracerebral hemorrhage in the left basal ganglia extending to the temporal lobe and a small, enhanced mass above the APS [Figure 1a]. An endoscopic hematoma evacuation was promptly performed [Figure 1b]. She recovered consciousness and motor function soon after the operation. The fetal growth and development was also satisfactory. Angiograms showed a nidus, fed by the AChAs, the LSAs, and perforators from the A1 segment of the anterior cerebral artery, which drained into the basal vein of Rosenthal (BVR), the deep middle cerebral vein, and the anterior communicating vein. The maximum diameter of the nidus was 25 mm with an SM grade of 3 [Figure 1c and d]. Curative surgery was indicated because both she and her husband wanted her pregnancy to be continued to full term. A bolus injection of rocuronium bromide (0.9 mg/kg) and propofol (2 mg/kg) was given before tracheal intubation. She received a continuous infusion of propofol (3-5 mg/kg/h) thereafter. An obstetrician monitored the fetal heartbeats. We performed an orbitozygomatic craniotomy and a partial temporal lobectomy to obtain a wide surgical field. A grid strip with 16 electrodes (Unique Medical, Tokyo, Japan) was inserted into the subdural space to facilitate electrical stimulation to the motor cortex (Neuropack X1, Nihon Koden, Tokyo, Japan). The filters were at 20 Hz and 3 kHz (low- and high-band passes, respectively). We confirmed the muscle action potentials from the contralateral thenar muscles. Intraoperatively, the motor cortex was stimulated at 2 mA above the threshold level. A monopolar anodal electrical stimulus with five pulses was applied. The frequency of the train pulse was 500 Hz, and the duration of each single pulse was 200 ms. The internal carotid artery, the A1 segment of the anterior cerebral artery, and the M1 segment of the middle cerebral artery were all well exposed after widely opening the Sylvian fissure. More than 10 perforating arteries were found to feed the nidus in the APS adjacent to the M1 segment. There were four AChAs feeding the nidus, and the distal two were cut because the test occlusion for 5 min did not induce a depression of the motor evoked potential (MEP) [Figure 2a]. The proximal two AChAs were preserved because the amplitude decreased 1 min after clamping [Figure 2b]. A few A1 perforators were also cut after the test occlusion. The LSAs were clamped, one at a time, proximally to distally, with Sugita microclips (Mizuho Ika, Tokyo, Japan) and the MEP was measured at 1 and 5 min after the occlusion. The LSAs were cut when the amplitude was not decreased [Figure 2c]. An LSA branching from the most distal part of the M1 segment was preserved because the amplitude decreased 5 min after clamping [Figure 2d], even though there was no MEP depression at 1 min. The preserved LSA was revealed passing through the nidus [Figure 3a]. The nidus was lifted from the APS after all the arteries supplying the nidus were cut [Figure 3b]. We confirmed that the nidus was not stained by indocyanine green (ICG), and that there was a reflux of the ICG in the BVR [Figure 3c]. The nidus was finally removed after dividing the main drainer. The MEP was maintained at the time of dural closure [Figure 2e]. The fetal heart rate was maintained in the normal range (<80 bpm) throughout the procedure. A postoperative magnetic resonance image revealed small infarcts in the nonfunctional areas, which did not produce any additional symptoms. Pre [Figure 4a] and postoperative [Figure 4b] angiograms showing the AVM had completely disappeared, and two AChAs and one LSA were preserved. The patient successfully delivered a term neonate by cesarean section 122 days after the operation. She could take care of her baby herself, and the child developed normally. The mother, however, suffered dysgraphia due to initial intracerebral hemorrhage that remained 1 year after the onset.

anterior perforated substance, arteriovenous malformation, motor evoked potential, pregnancy

PMC5540464_01

Female

A 40-year-old woman with trisomy 21 developed an acute eruption on the hands, legs, and face 57 days after her second pancreas transplant for type 1 diabetes. Initial pancreas transplant was 12 years prior, complicated by antibody-mediated rejection. Patient received her second pancreas from a deceased male donor. She had induction with thymoglobulin and oral corticosteroids. Three units of irradiated blood were given in the operating room. The patient had stable white blood cell counts following transplantation with no evidence of leukopenia. Two weeks prior to her eruption, she had elevated liver enzymes, which resolved after discontinuation of isoniazid, prescribed for latent tuberculosis, and fluconazole. On physical examination, there were scaly pink plaques in the periocular area, dorsum of the hands, and the lower legs. In addition, she had punctate firm hemorrhagic papules of the fingertips and palms (Figure 1). The patient also had mild cervical adenopathy. Two skin biopsies were performed on the different morphologies on the hands. Immunosuppression was not reduced or altered following the onset of the rash. Histopathologic evaluation of both specimens revealed scattered apoptotic keratinocytes within the epidermis, with vacuolization at the dermal-epidermal junction. There was a dense superficial to middermal lymphocytic infiltrate, with some scattered eosinophils (Figure 2). Additional finding of hemorrhage was seen in specimen from the fingertip. Findings were consistent with lichenoid tissue reaction and thus raised concern for lichenoid GVHD (grade 2) versus lichenoid drug eruption. Fluorescence in situ hybridization (FISH) testing for chromosomes X and Y found the lymphocytes as XY, while the surrounding normal tissue was XX, indicating that the inflammatory infiltrate was primarily of male (donor) origin, confirming the diagnosis of GVHD. Chimerism analysis on the peripheral blood showed 0% donor DNA. Patient was diagnosed with cutaneous GVHD and was treated with topical corticosteroids. The rash and cervical adenopathy promptly resolved. Investigation for other organ involvement was done with routine laboratory analysis, as well as EGD and colonoscopy. No other organ involvement was identified, and she remained stable with no progression of her disease.

PMC7171626_01

Female

A 33-year-old woman, originally from Pakistan, immigrated to the United Kingdom in 2014. She was a nonsmoker and presented at 37 weeks of pregnancy in the Emergency Department with persistent back pain, paraesthesiae of the left L5 dermatome, and numbness in the S1-2 dermatomes. Examination revealed bilateral suprasacral masses with no signs of contusion or trauma. Motor examination showed MRC 4/5 hip flexion (L2), 4/5 knee extension (L3), 2/5 ankle (L4), EHL dorsiflexion (L5), and absent ankle reflexes (S1, 2). Neurological examination of the cranial nerves, bilateral upper limbs, and right lower limb was unremarkable. PR revealed normal voluntary anal contraction and perianal sensation, with normal bladder and bowel functions. Chest examination was clear, with equal air entry and normal respiratory rate, and no cervical, axillary lymphadenopathy. She was discharged but returned again at 40 weeks gestation with intractable back pain, left L5 sciatica, and left foot drop. Further history revealed no other constitutional symptoms except weight loss which had been notable over the period of one year. Obstetric examination of the foetus showed small for gestational age (SGA) and symphysis fundal height measuring 33 weeks of gestational age in 40 weeks of pregnancy. Due to a high level of suspicion for TB, a CXR was requested after clinical examination. It showed mild bronchial thickening and minimal linear scarring in the left lung base but no definitive focal consolidation, Ghon's focus, or lymphadenopathy (Figure 1). A CT scan of the pelvis and the spine was obtained showing spinopelvic dissociation with osseous destruction extending into S1 and S2 (Figure 2). MRI showed extensive oedema of the posterior paraspinal muscles bilaterally from L4 to S2 levels and diffuse marrow oedema of the sacrum. A large collection in the right posterior paraspinal muscles tracked inferiorly and anteriorly through a large bony defect in the right half of the sacrum (Figure 3) which extends anteriorly into the pelvic sidewall just posterior to the iliopsoas muscle. The collection appears hypointense on T1, hyperintense on T2, and STIR with multiple internal septae and a thick wall suggestive of an abscess, measuring 4.8 x 1.6 cm in axial dimensions and 11.1 cm superoinferiorly. A similar small collection was seen on the left side coursing through a linear defect in the left half of the sacrum. It measured 3.5 x 0.5 cm in axial dimensions, which courses into the greater sciatic notch causing mass effect on the lumbosacral plexus. A few more tiny loculations are also seen medially in the right iliacus muscle and marrow oedema in the pedicles of the L5 vertebra. Vertebral discs were spared (good discs); however, there were disc bulges from the L2-3 to L5-S1 levels. The L3-4 and L4-5 disc bulges contact the traversing L4 and L5 nerve roots bilaterally. Dehydration signals change in the L2-3 and L4-5 discs. The cord returns to normal signal intensity. This was followed by paraspinal abscess US-guided drainage, which showed mixed echogenicity collection with multiple locules seen in the right sacroiliac joint space. A bone biopsy was performed. Bone and soft tissue samples obtained were sent to microbiology for microscopy, culture, and sensitivity (MCS), TB, and prolonged cultures. Microbiology sample revealed that acid-fast bacilli were not detected, and TB culture bottles revealed no growth after 42 days. PCR TB was done, and the molecular amplification test was negative for Mycobacterium tuberculosis complex. A sample from the placenta detected two small granulomata within the chorionic villi. These samples were taken after delivery but notably after the TB treatment was initiated.

PMC9068340_01

Male

A 57-year-old man, with a 20 pack-year smoking history, was diagnosed at the age of 10 with a possible miliary tuberculosis due to an interstitial lung pattern on a chest X-ray. He received specific tuberculosis treatment, without radiological improvement. A lung biopsy was performed in which alveoli with macrophages loaded with vacuoles were observed. Later on, he was diagnosed with hepatosplenomegaly. At the age of 47, he required a splenectomy due to spontaneous splenic rupture. A liver and a skin biopsies were performed, suggesting a deposition disease. The skin biopsy also revealed very low levels of sphingomyelinase in cutaneous fibroblast culture (6.5%), establishing the diagnosis of type B NPD. The patient had been referred from a tertiary hospital from a different administrative area. But the skin and lung biopsies, on which the diagnosis was based, had been done at another hospital from the one that referred him from another different area. For all these reasons and due to the speed of progression of the disease, it was not possible to access these samples before the transplant. He is the father of two children. The only information we have in our hospital is that their children are carriers of SMPD1 gene mutation, but they have not developed any symptoms compatible with the disease, and they are healthy. In the same way, they are being followed in another hospital, and we do not have access to further information. He had extensive pulmonary involvement at chest computed tomography (CT) with a diffuse interstitial disease and a radiological pattern of "crazy paving" in the lower and middle lung fields (Figure 1). His pretransplant pulmonary function tests demonstrated preserved lung volumes (FEV1: 2960 ml (95%), FVC: 4190 ml (106%), and FEV1/FVC: 70.70) and a significantly reduced adjusted DLCO (DLCO: 24% and DLCO/VA: 31%), his blood gas at room air showed hypoxemia (PaO2: 62 mmHg, PaCO2: 39 mmHg, and HCO3: 24 mmol/L), and he covered 498 meters in the 6-minute walking test, but with a desaturation up to 77% using oxygen at 3 liters/minute. He had hepatomegaly without cirrhosis, but no neurological or visual alterations. He was at functional class 4 of modified Medical Research Council (m-MRC) scale with rapidly worsening dyspnea in the last 6 months; hence, in the absence of serious extrapulmonary organ dysfunction, he was accepted as a candidate for lung transplantation. On December 2019, the patient received a bilateral lung transplant, with no relevant surgical incidents. He was extubated 36 hours after the transplant. A right phrenic nerve paresis was observed, which did not require ventilatory support, and he did not have evidence of primary graft dysfunction. He was discharged from the intensive care unit to the hospital ward 4 days after the surgery. At the time of awakening, the patient reported visual disturbances without clear diplopia or blurred vision. A cranial CT scan, performed 4 days after transplant, revealed "cortico-subcortical hypodense foci in posterior cortical border territories compatible with acute infarcts. Other hypodense foci were noticed in the anterior border of centrum semiovale that could correspond to acute infarcts, although difficult to assess due to its small size." He was examined by ophthalmology, without ocular structural alterations, or motor deficits in the oculomotor muscles. The patient was also examined by neurology, without any clear pathological finding. The evaluation was completed with an electroretinogram and a visual evoked potential study, which were normal. It was concluded that the findings were related to acute ischemic lesions. On day 24th posttransplantation, he began with sudden dyspnea, tachypnea, desaturation, central cyanosis, and plegia in the left arm with a muscular strength 0/5. An urgent chest angio-CT scan was performed in which pneumothorax and pulmonary embolism were not seen. A cranial angio-CT was also made, without any evidence of acute ischemic or embolic lesions. Later on, he began with a focal seizure with myoclonus in the left arm and then a generalized seizure, which was resolved with the administration of 10 mg of diazepam. The patient started antiepileptic treatment with levetiracetam, and the neurological symptoms subsided. A cranial magnetic resonance imaging, performed on the 28th day posttransplantation, revealed the same lesions with some hemorrhagic transformation. All of these findings were interpreted as watershed cerebral infarctions, probably secondary to hypotension during surgery. Induction immunosuppression with basiliximab was administered (20 mg 2 hours before unclamping the first pulmonary artery and other 20 mg 96 hours after the first dose) followed by immunosuppression with tacrolimus (based on serum levels, with a target level of 12-15 mcgs/L for the first months), mycophenolate mofetil (1000 mg every 12 hours), and corticosteroids (initially in pulses of methylprednisolone, followed by 1 mg/kg/day of prednisone for the first few weeks, with a subsequent descending regimen), but with the first radiological alterations in the central nervous system and the suspicion of a posterior reversible leukoencephalopathy syndrome (PRES), a change in immunosuppression was made to cyclosporine (based on serum levels, with a target level of 350-450 mcgs/L for the first months). Although the alterations in the central nervous system were finally classified as ischemic, the same immunosuppression scheme was maintained due to a satisfactory respiratory evolution. In the transbronchial biopsy, performed 3 weeks after the surgery, an acute cellular rejection grade A1 of the Working Formulation (WF) of International Society of Heart and Lung Transplantation (ISHLT) was diagnosed. It was decided not to treat with high doses of corticosteroids in the context of neurological complications and the frailty of the patient, and because he was respiratory asymptomatic without clinical or radiological signs of rejection. According to our protocol, grade A2 of the WF of ISHLT rejections or higher is always treated, but grade A1 rejections without symptoms or signs of rejection during the first month are not treated with high doses of corticosteroids due to the lack of evidence of their benefit effect. Histopathologic findings in the explant lungs revealed a morphological pattern of unclassifiable interstitial pneumonia with foamy histiocytes suggestive of NPD (Figures 2-4). It was also found an incidental microscopic acinar adenocarcinoma pT1a, pN0 UICC Stage IA1 in the right lung, without any involvement in the 26 lymph nodes analyzed. Due to its microscopic size, without lymph node involvement, with a very early stage, no changes in immunosuppressive treatment were considered necessary. He did not have any infectious complication, and he was discharged from the hospital 31 days after the surgery. During follow-up visits, there was a progressive improvement in pulmonary function tests, reaching their maximum FEV1 values 11 months after the transplant without related complications. There was no evidence of pulmonary involvement in the CT scans of the chest, and he maintained m-MRC functional class 0. Electrophysiological evaluation of the phrenic nerve was repeated 15 months after the transplant, and it was normal. He remained with visual disturbances which improved a little after undergoing cataract surgery, but until this day, these disturbances have not been resolved, but without motor disturbances. The patient has been receiving levetiracetam without further seizures. He has not had abnormal liver function measured by fibroscan with 4.9 kPa, performed one-year posttransplant. 23 months posttrasplantation, the patient maintains a good quality of life, without having any relevant complications.

PMC5446869_01

Female

23-year-old Filipino lady, previously healthy, presented to the emergency department with vertigo and imbalance in walking of six days prior to admission; her symptoms were also associated with blurring of vision, diplopia, and headache, in addition to numbness in the lower limbs initially that resolved at the time of presentation. The patient denied history of fever, sweating, or weight loss and history of orogenital ulcers or arthralgia. There was no personal or family history of thrombotic events and she was nonalcoholic. On examination, patient was conscious, oriented, and alert, with apparent right sided and upward jerky nystagmus, but normal range of motion of both eyes, normal pupillary reflexes, and fundoscopy; patient was found to have loss of coordination in the four limbs manifested by abnormal finger nose test and dysdiadokinesia, with abnormal heal shin test, that was more marked on the left side; otherwise motor, tone, touch, and position sensation were all intact. MRI of the brain and spinal cord showed evidence of multiple foci of faint bright signal intensity involving the posterior pons and left brachium pontis (Figure 1), with superior extension extending to cerebral subcortical and deep white matter, bilateral thalami, and basal ganglia (Figure 2), and inferior extension along the spinal cord at multiple levels (Figure 3), with small punctate enhancement that aligned along fine curvilinear enhancing structures; given the typical features, the possibility of CLLIPPERS was raised by the radiologist. Cerebrospinal fluid study (CSF) showed lymphocytic pleocytosis (WBC: 12, lymphocyte 98%) with normal protein and glucose, and viral serology for HSV1, HSV2, CMV, EBV, VZV, mumps, adenovirus, enterovirus, and parechovirus were negative. CSF Gram stain and culture were negative. CSF TB PCR and VDRL were nonreactive. Complete blood count and peripheral smear were normal; HIV and Quantiferon TB were also negative. CSF oligoclonal band was negative, in addition to normal visual evoked potential; both made multiple sclerosis unlikely. Antinuclear antibodies were found to be positive (1 : 320, nucleolar in pattern) but anti-double stranded antibodies and anti-cardiolipin antibodies were negative; accordingly the probability of having autoimmune disease without any suggestive symptoms was rather low. Our patient showed some spontaneous improvement; however, following the institution of steroids with a 60 mg of prednisolone she responded dramatically and started to walk with improvement of balance, nystagmus resolved, and coordination improved significantly. After 2 weeks of prednisolone as outpatient, she returned back to normal functioning, free of any symptom, with completely normal neurological exam.

PMC2492175_01

Female

To our knowledge, we present the first case of necrotizing pneumonia following incision of a Bartholin's abscess. In October 2006, a 23-year-old woman with no systemic signs of infection had a surgical incision of a Bartholin's abscess (3 x 5 x 3 cm) without the installation of a drainage. The patient was discharged without antimicrobial therapy. The abscess fluid was submitted for culture. 24 hours later, the woman developed fever and her state of health worsened continuously, so she was admitted to a local hospital 4 days after surgery. Community-acquired pneumonia was diagnosed and a macrolide was administered. One day later, the patient became critically ill and was transferred to our tertiary care hospital and immediately admitted to the intensive care unit. She presented with an influenza-like illness with severe muscle pain in all extremities, spiking fever up to 40 C, dry cough but no sore throat. She showed ortho- and tachypnoea with a respiratory rate of 30 breaths/minute, oxygen saturation was 96% with the supply of 31/minute of oxygen but no need for intubation. Her blood pressure was 100/60 mmHg and her heart rate 140/minute. Physical examination revealed crackles in the inferior and middle parts of both lungs, a diffuse tenderness of the abdomen, and severe pain in the muscles. Auscultation of the heart was unremarkable. Vaginal examination revealed a postoperative wound without any signs of infection. She denied ever having used illicit drugs. Admission laboratory data revealed an elevated leukocyte count of 13.6 x 109/L, a very low platelet count of 24 x 109/L, elevated inflammatory markers including a C-reactive protein of 399 mg/L (reference range (RR) < 5 mg/L) and a procalcitonin level of 34 ng/L (RR < 0.1 ng/L), and an elevated creatinine of 1.27 mg/dl. Her hemoglobin was only slightly reduced with 11.5 g/dl. As the patient did not present during the influenza season and first occurence of the influenza-like symptoms was parallel with the positive blood cultures, testing was not performed. Testing for HIV was negative and fasting glucose was normal. As the patient had no increased rate of infections in the past, we did not test for complement of IgG deficiency. Multiple blood cultures and swabs of the postoperative wound and the vagina were obtained and sumitted for culture. A computed tomography scan (CT) of the chest showed diffuse bilateral alveolar infiltrates and nodular opacities with cavity forming consistent with necrotising pneumonia (Figure 1). Transthoracal echocardiography on the day after admission showed no abnormal findings, in particular no vegetations suggestive of infective endocarditis. Community-onset pneumonia and severe sepsis with coagulopathy was diagnosed. Empirical intravenous antibiotic therapy with piperacillin/tazobactam and levofloxacin was started immediately. On day 2, the initial abscess fluid yielded S. aureus fully susceptible to antistaphylococcal agents with the exception of penicillin and tetracyclin. Therefore, piperacillin/tazobactam was changed to high-dose intravenous flucloxacillin 4 g tid and levofloxacin was discontinued. On day 3, blood cultures and both wound and vaginal swab taken on admission also grew S. aureus. On day 4, rifampicin 600 mg Rifampicin 600 mg (once daily) was added as blood cultures continued to be positive and the patient still suffered from high fever and severe dyspnoea. CT scans of the chest and abdomen showed newly emerged extensive bilateral pleural effusions. In addition, multiple abscesses had evolved in the pectoralis, supraspinatus, and gluteus muscle. A reevaluation of the heart valves by transesophagal echocardiography revealed no abnormalities. On day 6, polymerase chain reaction (PCR) amplification of the lukS-lukF genes was performed as described previously and confirmed the presence of the PVL gene in all available S. aureus isolates. Subsequently, clindamyin 600 mg tid was added on day 7. With this treatment, blood cultures became negative on day 8. On day 11, bilateral pleural drainage tubes had to be inserted as effusions increased. Cultures of the pleural fluid showed no growth. All S. aureus isolates from the abscess, the postoperative wound and multiple blood cultures had identical susceptibility profiles. Minimal inhibitory concentrations (MICs) were <0.25 mg/l for oxacillin, <0.25 mg/l for clindamycin, and <0.5 mg/l for rifampicin. Pulsed-field gel electrophoresis (PFGE) of SmaI digests of genomic DNA from all available S. aureus isolates showed identical patterns (data not shown). The patient recovered very slowly with a 3 weeks stay at the intensive care unit with maximal supportive care. Respiratory support and vasopressors had not been necessary. Subsequently, the patient stayed for another 8 weeks on a regular ward until recovery. Antibiotics were continued for a total treatment duration of 5 weeks for rifampicin and clindamycin and of 8 weeks for flucloxacillin. Swabs of persons in close contact to the patient were taken but were negative for PVL-producing S. aureus. S. aureus is a major cause of respiratory, skin, bone, joint, and endovascular infections. Mostly these infections occur in persons with known risk factors such as cardiovascular disease, malignancy, or diabetes mellitus. S. aureus is responsible for at least 10% of cases of nosocomial pneumonia but only for 2% of community-acquired pneumonia. Our patient was a young immunocompetent woman with no apparent risk factors who sustained severe community-onset necrotizing pneumonia, multiple abscesses, and extensive pleural effusions. These clinical features are characteristic for invasive infections with S. aureus exhibiting the putative virulence factor PVL. The true incidence of PVL-associated pneumonia is unknown, since the number of cases published is likely to be an underestimate. Besides its occurence in methicillin-sensitive S. aureus (MSSA), PVL is more often identified in community-acquired methicillin-resistant S. aureus (MRSA). PVL is a very virulent toxin expressed by S. aureus, which was first characterized in 1932. Less than 5% of all S. aureus strains harbor PVL genes. PVL is a pore-forming toxin destroying the membrane of the host defence cells and erythrocytes. Lina et al. screened S. aureus isolates to correlate toxin production with disease manifestation. They found a definite association between the occurrence of PVL genes and furunculosis and community-onset pneumonia. Gillet et al. compared the clinical features of PVL-positive pneumonia with PVL-negative pneumonia and found significant differences. PVL-positive patients were younger without risk factors for infection. They presented more often with haemoptysis, high fever, tachycardia, tachypnoea and developed diffuse bilateral infiltrates and pleural effusion. The mortality rate was significantly higher with 75% in PVL-positive compared to 47% in PVL-negative infections. Other case series confirm the characteristics and severeness of the PVL-positive infections. The symptoms of our patient fitted very well into this disease. Since PVL-positive S. aureus strains may spread between persons in close contact to the index patient, swabs should be taken to prevent further spreading. In a report from Germany, control of a furunculosis outbreak involving PVL-positive MSSA in a rural village was achieved by stringent decolonization of carriers, but established public health recommendations do not exist. For the therapy of necrotizing pneumonia caused by PVL-positive S. aureus no specific guidelines have been published. Combination therapy is widely used empirically in life-threatening infections. Bactericidal antibiotics such as beta-lactam antibiotics are preferrd over bacteriostatic agents. For pneumonia, good penetration into the tissue has also to be considered. We added levofloxacin empirically to piperacillin/tazobactam to treat potential atypical bacteria. As soon as cultures became positive for S. aureus the antibiotic regimen was changed from piperacillin/tazobactam to high-dose flucloxacillin, as this is the antibiotic of choice for beta-lactamase-positive S. aureus. As blood cultures remained continuously positive and the patient's condition worsened, rifampicin, another very potent antistaphylococcal antibiotic, was added. The efficacy of rifampicin as an adjunctive drug in patients with life-threatening infections remains controversial. As soon as the S. aureus isolates turned out to be PVL-positive, clindamycin was added. Several authors recommend the addition of clindamycin to the treatment of toxin-producing grampositive bacteria as it targets the bacterial ribosomes thereby potentially blocking the toxin production. New in vitro data showed an augmentation of PVL toxin production by beta-lactam antibiotics, but no in vivo data have supported these observations so far. Other in vitro data showed that the addition of rifampicin or clindamycin to oxacillin inhibits PVL production. PVL-positive MRSA infection requires treatment with vancomycin as the first-line agent. In severe S. aureus infections intravenous antibiotic therapy should be given for at least 4 weeks after the last blood culture positive for S. aureus . Although PVL plays a key role in the pathogenesis of necrotising pneumonia and Labandeira-Rey et al. could show in a mouse model that the PVL toxin alone might be sufficient to cause pneumonia, it is not likely to be the only virulence determinant responsible for this syndrome. The outcome of patients with necrotizing pneumonia may be poor in many cases even if appropriate antibiotics are administered. In addition, intensive supportive care is crucial for improving the outcome in these severe infections. In our patient, necrotizing pneumonia developed shortly after incision of a Bartholin's abscess. Infection of the Bartholin's gland is the most common infectious vulvar disease and develops in approximately 2% of all women. Surgical intervention is considered the primary treatment, and controversy on the benefit of antibiotics exists. Complication rates are very low, but cases of severe infections have been reported. S. aureus appears to be only very rarely involved in these cases. Clinical complications have included septic shock, toxic-like-syndrome, necrotizing fasciitis, myocarditis, and gangrene but pneumonia has not been reported. Bartholin's abscesses mostly contain a mixed flora of aerobic and predominantly anaerobic bacteria. The most frequently isolated aerobe is Escherichia coli, while S. aureus is only rarely detected. PVL-positive S. aureus infection should early be included in the differential diagnosis when young immunocompetent persons develop necrotizing pneumonia. Various minor infections:such as Bartholin's abscess:can precede this life threatening syndrome. Antibiotic treatment with bactericidal antistaphylococcal agents is recommended, and invasive surgical procedures may become necessary.

PMC4895071_01

Male

A 35-year-old man presented with a four-year history of right hip pain and disability exacerbated by physical activity and weightbearing. The patient denied any prior trauma. He did not have any fever, chill, night sweat or weight loss. Right hip radiographs showed an expansile and septated lesion affecting the right acetabulum. Pelvic CT confirmed the large and aggressively appearing acetabular lesion with diffuse trabecular destruction. The tumor had cortical bone expansion with multiples foci of osseous erosion and disruption (Figure 1A, Figure 1B, Figure 1C, arrows). The tumor measured 8 x 5 x 12 cm extending from the inferior ilium to the ischium without definite adjacent soft tissue invasion. MRI showed a large lesion of the left iliac bone involving the acetabulum and ischium (Fig. 2, arrows). The mass was isointense to muscles on T1-weighted images and hyperintense on T2-weighted sequences. Cortical breaches were detected at the medial aspect of the acetabulum and iliac bone. There was no hip joint mass or effusion. Since CT and MRI showed features of an aggressive tumor, bone scan was obtained for search of potential metastasis. The whole body technetium-99m MDP scintigraphy showed increased radiotracer uptake of the right acetabulum and right ischium (Fig. 3, arrows) but did not detect any additional osseous lesion. An initial CT-guided bone biopsy showed rare fragments of reactive woven bone, several irregular aggregates of spindle cells with round to oval shaped nuclei, bland-appearing chromatin patterns and no apparent mitotic figures. The spindle cells were in a fibromyxoid matrix with presence of scattered thin-walled blood vessels and rare giant cells. There was no histologic evidence of plasmacytoma or giant cell tumor. This CT-guided biopsy was not diagnostic but favored a low-grade neoplasm. A subsequent surgical open biopsy reached the diagnosis of iliac bone hemangioma. Due to the large size of the tumor, a conservative approach was observed. Close follow-up for two years showed continuously increasing pain requiring radiation therapy. Additional two-year posttherapeutic monitoring witnessed clinical improvement with stability of the iliac hemangioma on cross-sectional imaging.

ct, computed tomography, mri, magnetic resonance imaging

PMC10149197_01

Male

In April 2022, a 62-year-old man was admitted to the Department of Infectious Diseases at the University Clinical Centre in Pristina due to a high fever that had been initially intermittent and later on had become persistent for two weeks prior to hospitalization. The patient had been seen by several physicians, including a family physician, gastroenterologist, pulmonologist, and urologist, but the cause of the high fever could not be identified. On admission, the patient had a fever of 38.5 C and slightly enlarged spleen. Blood tests were performed and showed the following results: erythrocyte sedimentation rate (ESR) = 5 mm/h, leukocytes = 4.0 x 109/L, erythrocytes = 4.02 x 1012/L, hemoglobin = 11.5 g/dL, platelets = 123 x 103/mm3, hematocrit = 31.3 %, C-reactive protein (CRP) = 54.9 mg/dL, procalcitonin (PCT) = 0.35 ng/mL (< 0.25), serum albumin = 44.1 g/L (34-54), direct bilirubin = 2.85 micromol/L (< 5.1), total bilirubin = 9.4 micromol/L (< 20.5), aspartate aminotransferase (AST) = 25 UI/L (8-33), alanine aminotransferase (ALT) = 43 UI/L (4-36), gamma-glutamyl transferase (GGT) = 153 UI/L (5-40), lactate dehydrogenase (LDH) = 288 U/L (105-333), D-dimer = 16 (0.5), PT = 10.5 s (11-15), INR = 0.98 (< 1.1), PTT = 30 s (24-39), TT = 16 s, anti CCP = 7.0 U/mL (< 500), C3 = 100 mg/dL (80-178), C4 = 19 mg/dL (12-42), IL 6 = 13.9 pg/mL (< 5.90), CK-MB = 35 ng/mL (< 25), AFP = 13.24 IU/mL < 40), CEA = 2.06 ng/mL (< 10), Anti ENA = negative, ANA = negative, ANCA = negative, Anti DSDNA = 4.58 IU/mL (< 30), PSA = 1.50 ng/dL (< 4.1), Fr PSA = 0.123 ng/dL (< 0.87), FrT3 = 4.6 pg/mL (1.5-6.0), T4 = 11.61 microg/dL(4.5-12.5), TSH = 2.29 mIU/mL (0.4-4.5). Several serologic tests were also performed, including Leptospira IgM/IgG, Lyme Borreliosis IgM/IgG, Wright, Widal,TORCH, HBsAg and Anti HCV. All results were negative except for Toxoplasma IgG and Rubella IgG, which were positive. The patient also underwent additional examinations, including lumbar puncture, bone marrow aspiration, urine culture, blood culture, smear of peripheral blood, QuantiFERON TB gold test, echocardiography, bone scintigraphy, and CT scans of the brain, head, chest, abdomen, and pelvis. However, except of QuantiFERON TB gold test which was positive, and splenomegaly (170 mm) on CT scan of the abdomen, none of other tests revealed any other pathological findings. Due to the positive result of the QuantiFERON TB gold test and the lack of any other identifiable cause for the patient's fever, treatment with four antituberculous drugs was started. However, this treatment had to be interrupted after several weeks due to severe toxic hepatitis. During the patient's two-month stay at the hospital, laboratory tests demonstrated a progressive multilineage cytopenia and increased values of inflammation markers, despite several courses of different antibiotics used as single agents or in combination (ceftriaxone, gentamycin, vancomycin, meropenem, azithromycin, and levofloxacin) (Table 1). The patient was subsequently discharged from the department at the end of June 2022 and referred for further treatment abroad with a diagnosis of fever of unknown origin (FUO). The patient was admitted to the LIV Hospital Vadi Haematology Department in Istanbul, Turkey, on June 26, 2022, where examinations revealed splenomegaly and pancytopenia. Abdominal MRI showed an abscess in the left psoas muscle with dimensions of 68 x 45 mm, which expanded the muscle. The material provided by the abscess biopsy revealed MRSA, which was eventually drained. After six days on antibiotics (Tigecycline), the patient became afebrile, and acute phase inflammatory reactants regressed to normal levels. The antibiotic was given for three weeks, but the patient's pancytopenia persisted throughout the follow-up period, until July 19, 2022. The biopsy material from the bone marrow taken in Kosovo was reexamined in the Istanbul hospital, and the findings were interpreted as bone marrow findings secondary to infection, medications, and immune system-mediated pathologies. 18-FDG-PET (18-fluorodeoxyglucose positron emission tomography) showed a prominent spleen with involvement of the liver and bone marrow. A diagnostic splenectomy was recommended, but the patient declined the procedure. In January 2023, six months after hospitalization in Istanbul, the patient was hospitalized for the third time, this time at the University Clinical Centre in Pristina, Haematology Department, due to fever, chills, weight loss, and night sweats. Repeated tests showed persistent anemia/pancytopenia, and peripheral blood smear examination was again without pathological changes. Abdominal and pelvic scan revealed an enlarged spleen and liver. Repeated puncture of the bone marrow was performed, and light microscopic examination of a Giemsa-stained bone marrow specimen finally revealed the presence of amastigotes of Leishmania infantum within the macrophages (Fig. 1). The microscopic findings were corroborated by a positive serological test for Leishmania IgG = 2.783 (IgG cut-off 0.481). As a result, the patient was referred to the Department for Infectious Diseases of the University Clinical Centre in Pristina for further assessment and management. Treatment with liposomal amphotericin B (LAMB) 1.5 mg/kg/day for 14 days was administered to the patient. Following the treatment, the patient's fever subsided, and their overall health condition improved. The laboratory results obtained three weeks after the treatment indicate a significant improvement (Table 1).

kosovo, misdiagnosis, visceral leishmaniasis

PMC4782539_01

Female

A 37-years-old female patient presented with complaints of pain in the left arm since three months followed by weakness a month later. The patient had dull boring pain around the left shoulder which radiated on lateral aspect of left arm. The pain progressed over 15 days to involve lateral forearm as well as the thumb and the index finger. This pain did not interfere in her daily activities and would respond partly to analgesics. After about a month, she noticed acute onset weakness in raising her left arm above the shoulder. The weakness progressed over a day to involve the entire left limb and she was unable to flex her elbow or grip objects. The patient also had decreased perception of hot and cold as well as texture of clothes. The patient had noticed that her left shoulder appeared thinner than the right and had history of occasional fasciculations in that region. There was no history of weakness or sensory loss in lower limbs or bladder bowel complaints. The patient had no history of fever, cough with expectoration or hemoptysis, trauma, weight loss, diabetes mellitus or hypertension. The patient did not complain of arthralgia, arthritis, rash or oral ulcers. She denied recent vaccination or unsafe sexual practices. With these above complaints, she consulted neurologist and was subjected to nerve conduction studies and electromyography and was diagnosed to have idiopathic left upper trunk brachial plexopathy. The patient was started on oral steroids, pain subsided transiently and the weakness did not respond to treatment. After about a month's therapy, she started noticing similar complaints in the right arm and at that time she was referred to our center for further evaluation and management. When the patient was presented in our outpatient department, she had developed painful weakness in both upper limbs (left > right) along with paraesthesia in both arms. On examination, she was conscious, oriented and had normal higher mental functions. Cranial nerve examination was normal. Wasting was noted around the left shoulder girdle and left arm. The patient had hypotonia in both upper limbs. The power was grade 2 at shoulder joint, grade 3 at elbow joint, grade 4 at wrist extension and grade 5 at wrist flexion in the right upper limb as per Medical Research Council (MRC) grade. On the left side, power was MRC grade 2/5 at shoulder joint, 2/5 at elbow joint, 3/5 at wrist extension, 4/5 at wrist flexion and hand grip weakness was noted. The patient had normal power in both lower limbs. Deep tendon jerks in bilateral biceps, triceps, supinator were absent, ankle and knee jerk were normally elicitable. Bilateral plantar reflexes were flexor and abdominal reflex were present in all 4 quadrants. Sensory examination revealed about 30% loss in pin prick sensation in left arm in C5-C7 dermatome. Joint position and vibration sensation were impaired in the upper as well as lower limbs. The patient had positive Romberg's sign. There were no cerebellar signs, thickened nerves, stigma of tuberculosis or syphilis. No lymphadenopathy or spine abnormality was noted. Complete hemogram, fasting blood sugar, renal and liver function tests were within normal range. Erythrocyte sedimentation rate was 24 mm at the end of one hour by Westergren method. C-reactive protein and anti- nuclear antibodies were negative. Anti-neutrophilic antibody (cANCA and pANCA), extractable nuclear antigens (ENA), serum were negative and cerebrospinal fluid (CSF) angiotensin converting enzyme (ACE) level was within normal limits. Microscopy of CSF revealed 10 cells, all of which were lymphocytes. CSF biochemistry showed protein 48 mg/dl and CSF sugar 67 mg/dl (corresponding blood sugar: 98 mg/dl). CSF for oligoclonal bands was positive. The CSF virology assessment for HSV PCR and IgM antibodies against herpes simplex, cytomegalovirus, Japanese encephalitis, varicella zoster virus, dengue and Epstein Barr virus was negative. Enzyme linked immunoassay (ELISA) for human immunodeficiency virus I and II was negative. Hepatitis B surface antigen (HBsAg) and anti- HCV antibody were also negative. Polymerase chain reaction for M. tuberculosis was negative. Cancer antigen 125 (CA-125) level was 45.39 U/ml (normal value below 35 U/ml). Onconeural antibodies could not be performed. The repeat nerve conduction studies revealed left sided pan-plexopathy and right upper trunk plexopathy. Electromyography was suggestive of denervation and showed fibrillation, fasciculations and large amplitude motor unit action potentials. Magnetic resonance imaging (MRI) of cervical spine showed mild swelling of the cord along with hyperintense signals within the spinal cord on T2 weighted images. In addition, hyperintensities of multiple radicles were noted bilaterally on T2 fat suppression images [Figure 1]. Incidentally, MRI revealed an ill defined, heterogeneously enhancing lesion (4 x 3 x 3 cm3) in the left upper lung [Figure 1]. Computed tomography (CT) thorax showed well defined heterogeneously enhancing soft tissue attenuation lesion with speculated margin in apico posterior segment of left upper lobe [Figure 2]. Rest of the lung parenchyma was normal and no significant mediastinal lymphadenopathy was noted. CT guided fine needle aspiration cytology revealed malignant epithelial cells lying in clusters in a hemorrhagic background [Figure 3]. The patient received intravenous methylprednisolone 1 gm/day for 5 days followed by oral prednisolone 1 mg/kg/day for one month. After the confirmation of the lung malignancy on follow up imaging, she was referred to oncology and was advised chemotherapy followed by radiotherapy. MRI cervical spine [Figure 2] done after one month of steroid therapy showed disappearance of the cord hyperintensity but the mass lesion had increased significantly in the size (6 x 4 x 6 cm3). The arm pain had responded but weakness persisted. The patient is currently receiving chemotherapy and radiotherapy.

myelo-radiculoplexopathy, non small cell carcinoma, onco-antibodies, paraneoplastic neurological syndromes, person in the barrel syndrome

(d) STIR coronal view shows resolution of signal changes in the nerve roots. Figures e and f shows contrast enhancing rounded opacity in the apex of left lung on computed tomography of chest.

PMC6030028_01

Male

We report the case of a 15-year-old boy who experienced frequent myoclonic seizures and ataxia for 3 years. He had normal neuropsychiatric development before the initial onset of seizures at the age of 12 years. He presented with generalized and focal myoclonic seizures. Progressive ataxia and psychomotor and speech regression developed 6 months later. The myoclonic seizures were refractory to multiple antiepileptic drugs (AEDs) including clobazam, sodium valproate, levetiracetam, and phenobarbital in full dosage. Furthermore, he had dysarthria and poor feeding, which necessitated nasogastric tube feeding. He was completely bedridden for several months. When he was admitted to our hospital at the age of 15 years and 9 months, he had nearly continuous focal facial myoclonus, which subsequently spread to the extremities. The facial myoclonus lasted for 15-20 s and occurred more than 100 times per day. His electroencephalogram (EEG) (Fig. 1) revealed focal spikes arising from bilateral centrotemporal regions, followed by ictal myoclonic seizures with generalized muscle contraction activities lasting 15-20 s observed on the EEG. Because progressive myoclonic epilepsy was suspected, extensive workups were performed. The plasma amino acid test, tandem mass spectrometry, and muscle biopsy revealed nonspecific changes. Magnetic resonance images (Fig. 2) of the patient's brain showed mild brain atrophy. Apocrine skin biopsy did not show the presence of Lafora bodies. Genetic testing for EPM2A, EPM2B, and CSTB revealed negative results. However, abnormal somatosensory-evoked potentials with giant cortical waves were found. Cherry-red spots on bilateral maculae on the eye grounds were observed. Therefore, we performed genetic testing under the suspicion of sialidosis. Direct sequence analysis of PCR-amplified DNA of this patient had identified the presence of compound heterozygous mutations in NEU1. One of the mutations was a common missense mutation c.544A > G, causing the amino acid substitution Ser182Gly. The other one was a nonsense mutation c.619C > T, which yielded a termination codon, thus producing a truncated protein (Fig. 3). The diagnosis of PMEs with sialidosis type I was thus made. After admission, the patient had a partial myoclonic status, which was resistant to many antiseizure medications and also did not respond to a ketogenic diet. The patient's condition was complicated by aspiration pneumonia and generalized tonic-clonic (GTC) seizures. Eventually, he was started on perampanel therapy at 4 mg/day, with rapid titration to 8 mg/day. He showed a positive response. The number of seizure episodes significantly reduced after 3 days' of treatment with 8 mg/day of perampanel. Complete remission of the myoclonus and GTCs was achieved after titration to 10 mg/day for 3 days. The patient's clinical condition also improved. He could speak a few sentences, and feed himself with assistance. After 2 months, he could walk several steps with device. During 20-month follow-up, complete remissions of the myoclonic seizures and GTCs sustained under combination therapy with topiramate, sodium valproate, levetiracetam, clobazam, and perampanel, with total weaning of phenobarbital. He is currently receiving a perampanel dose of 10 mg/day. His neurological and cognitive functions remained stable. He has returned to school and moves with a wheelchair. His recent intelligence quotient (IQ) was 52. No previous IQ data were available for this patient before the disease onset.

neu1 gene, perampanel, progressive myoclonic epilepsy, sialidosis

PMC9281255_01

Female

Our patient was a 58-year-old Caucasian woman, who was referred to the Emergency Department because of dyspnoea. Her past medical history was significant for psoriatic arthritis, treated with adalimumab (tumour necrosis factor blocker) and methotrexate. She presented with a tachycardia of 124 beats/minute and blood pressure of 126/62 mmHg. Respiratory rate was 30 breaths/min and SpO2 89% at room air. The arterial blood sample at 4L/min supplemental oxygen showed a pH of 7.54 (ref 7.35-7.45), pCO2 25 mmHg (ref 35-45), pO2 78 mmHg (ref 75-100), and lactate of 3.44 mmol/L (ref 0.5-2.2). Laboratory tests showed elevated C-reactive protein (CRP) of 150 mg/L (ref 0-5), lactate dehydrogenase of 1327 U/L (ref < 248), and a considerably elevated ferritin of 25,476 mcg/L (ref 22-204). Thrombocytes were 70 x 109/L (ref 150-400 x 109/L), whereas haemoglobin and leukocytes were within the normal range. The patient had slightly elevated alanine aminotransferase (ALAT) of 93 U/L (ref 0-34), aspartate transaminase (ASAT) of 410 U/L (ref 0-31), and gamma-glutamyltransferase of 63 U/L (ref 0-35). Chest X-ray showed patchy, bilateral infiltrates. Thoracic computed tomography (CT) scan showed bilateral, coalescent ground-glass opacities and pulmonary embolisms. An abdominal ultrasound showed no signs of cholecystitis, cholelithiasis, or hepatosplenomegaly. On admission, the clinical presentation was not clear-cut. The initial working diagnosis was community-acquired pneumonia with concurrent pulmonary embolisms. Antibacterial treatment was started with cefuroxime, ciprofloxacin, metronidazole, and gentamicin to cover for infection of unknown origin. Low molecular weight heparin was started at a therapeutic dose. The thrombocytopenia was devoted to sepsis and disseminated intravascular coagulation. The elevated ferritin was attributed to an underlying infection, though rare causes such as HLH were also examined. On admission, our patient met only two non-specific HLH-2004 diagnostic criteria (Table 1). Nevertheless, soluble IL-2 receptor (sIL-2r) test was initiated. Serological testing showed a prior infection with Epstein-Barr virus, cytomegalovirus, and herpes simplex virus (HSV), and no signs of human immunodeficiency virus, hepatitis B, and C virus and Mycoplasma pneumoniae. SARS-CoV-2 polymerase chain reaction (PCR) on nasopharyngeal specimens was negative twice. Anti-SARS-CoV-2 antibodies turned positive, with no known previous clinical course of COVID-19 or vaccination. A urine legionella antigen test was negative. A broncho alveolar lavage (BAL) was performed: Influenza virus A and B, respiratory syncytial virus, Pneumocystis jirovecii, Mycobacterium tuberculosis, and SARS-CoV-2 PCR were all negative. Aspergillus fumigatus and mycobacterial cultures were also negative. No acid-fast bacilli were identified by direct microscopy. A HSV type 2 PCR was positive with a cycle treshold of 37.5 and therefore considered clinically irrelevant. Four days after admission, the patient was transferred to the intensive care unit (ICU) because of respiratory failure which prompted mechanical ventilation and prone positioning. Dexamethasone 6 mg daily for 10 days was started for treatment of acute respiratory distress syndrome following SARS-CoV-2 pneumonitis. All antibiotics were discontinued after cultures came in negative. Two days later, our patient developed a progressive thrombocytopenia accompanied by gastro-intestinal bleeding and anaemia. During ICU admission, serum sIL-2r turned out to be elevated. A bone marrow biopsy was performed and the smear showed hypocellular bone marrow with hemophagocytosis (Fig. 1). At that moment, our patient fulfilled six HLH criteria (Table 1). Under the diagnosis of HLH, our patient was started on etoposide 100 mg weekly, dexamethasone 10 mg/m2 daily for 2 weeks, and intravenous immunoglobulins 1 g/kg daily for 2 days. At that point, there was no clear underlying aetiology for the HLH. Infectious diseases (post-SARS-CoV-2, HSV type 2) and medication (adalimumab) were considered. No signs of malignancy or lymphadenopathy were seen on imaging. Bone marrow biopsy did not show signs of lymphoproliferative disease. A cutaneous T cell lymphoma was excluded after biopsies of two erythematosquamous plaques. The initial HLH treatment did not lead to improvement: respiratory failure persisted and our patient developed a pancytopenia. Three days after HLH treatment initiation, anakinra (interleukin-1 receptor antagonist) 5 mg/kg daily was added. At that moment, we noticed a decrease in ferritin levels down to 7249 mcg/L. However, despite increasing anakinra doses, respiratory failure and cytopenia worsened. Etoposide was discontinued and acyclovir (10 mg three times daily) was added to cover a HSV pneumonitis. Serial chest X-rays and thoracic CT scans showed extensive bilateral consolidations and ground-glass nodules which were repeatedly progressive. One week after start of HLH treatment, our patient developed fever with further respiratory deterioration. Despite lung protective ventilation with high FiO2 levels up to 100%, serial arterial blood gas analyses showed a progressive hypoxia (pO2 57-88 mmHg). After the initial drop in ferritin levels, there was an evident increase up to 9899 mcg/L. Anakinra was replaced by the anti-IL-6 receptor monoclonal antibody tocilizumab (8 mg/kg) and piperacillin/tazobactam (4 g/500 mg four times daily) and hydrocortisone (50 mg four times daily) were started. Despite aggressive supportive care, our patient showed no improvement and succumbed to the illness after 18 days in our ICU. Autopsy was performed and confirmed striking hemophagocytosis in bone marrow. More surprisingly, it revealed a miliary pneumonia involving all pulmonary lobes (Fig. 2) with Ziehl-Neelsen staining showing acid-fast bacilli. In fact, epithelioid cell granulomatosis of all organs was found. Mycobacterium tuberculosis PCR was positive in paraffin-embedded lung tissue. In conclusion, our patient died as a result of HLH with underlying miliary tuberculosis.

case report, hemophagocytic lymphohistiocytosis, intensive care units, tuberculosis

PMC3647711_01

Female

A 44-year-old woman was admitted to our clinic with a 2-month history of fatigue, cough, dyspnea and fever with hemoptysis. There was not familiarity for lung tumor or tuberculosis. On pathological examination, the spleen was 3 cm palpable below the left costal margin on the mid axillary line. The physical examination of other organs was normal. The results of laboratory tests showed hemoglobin level of 12, 2 g/dl, hematocrit 37,5%, white blood cell count 10,200/mm3, platelet count 1,014,000/mm3. The peripheral blood smear demonstrated normochromic normocytic red blood cells, an increased platelet number, a normal differential leucocyte count with 70% neutrophil, 2% eosinophil and 28% lymphocyte. The laboratory parameters were as follows: Iron (Fe): 49 ug/dl, transferrin: 210 ug/dl, Fe saturation: 16%, UIBC: 252 ug/dl, TIBC: 301 ug/dl, VitB12: 228 pg/ml, and ferritin: 88 ng/ml. Urine analysis revealed normal findings. Sedimentation rate was 18 mm/h; C-reactive protein was 5 ng/ml. A pulmonary nodule (3,5 cm) was detected in the upper right lobe on the chest X-ray. Then, thoracic CT was planned. Thoracic CT revealed a solid peripheral subpleural nodule in the right upper lung lobe apical segment with diameter of 37 mm. Nodule has homogeneous pattern showing umbilication in lobule contour-good bordered medial part (Figure 1). Abdominal CT scan, performed to exclude metastatic renal cell carcinoma, showed only mild splenomegaly. The nodule looked like benign pattern on CT scan and total excision was performed for curative and diagnostic treatment. Microscopically, the tumor was composed of nests of rounded or oval cells with distinct cell borders, optically clear cytoplasm and small nuclei. By immunohistochemistry, tumor cells were positive for HMB-45, NSE and focal S100 antigen. The immunohistochemical staining for synaptophysin was negative. And, it was diagnosed as clear "sugar" cell tumor. Malignant features of Clear "Sugar" Cell Tumor were excluded by imaging investigations before and after surgical tumor treatment. However, considering that thrombocytosis continued after the surgical removal of the clear cell tumor in the third month in absence of infections, bone marrow biopsy was performed. The cellularity was 70% and the myeloid/erythroid series ratio was 4. Megakaryocytic series was hyperplasic. There were no atypical cells. Iron stores were normal. Normal karyotype was provided by GTL banding (G banding). JAK V617F heterozygote mutation was detected by polymerase chain reaction (PCR). Essential thrombocythemia was diagnosed according to the World Health Organization (WHO) criteria. Being the platelet count over 1,000,000/mm3 in the 3rd month after the surgical intervention, the patient was started on therapy with oncocarbide. At present she is at 18th month of the follow-up in good condition with a normal abdominal and thoracic CT.

In CT parenchyma window in right lung upper lobe apical segment, a solid peripheral subpleural situated nodule which is 37 mm in diameter and has a homogeneous formation showing umbilication in lobule with a contour-good bordered medial part.

PMC4410589_01

Female

Patient 1, a 26-year-old woman, had experienced a low-grade fever and abdominal pain for 1 month prior to admission. Macrohematuria also appeared 10 days before admission. She had no recent abdominal trauma. On admission, her body temperature was 37.5 C. No significant physical findings were observed in her chest and abdomen. Bilateral knocking dullness at a cost-vertebral angle was shown. The other examination was not significant, including skin lesions, lymphadenopathy, neurological findings and gynecological investigation. Urinalysis showed 0.2 g/day of protein and microscopic hematuria of 50-100 of RBCs/HPF with RBC deformity and RBC casts. A complete blood count in the peripheral blood revealed a white blood cell count of 10,800/mul. The laboratory data were as follows: serum urea nitrogen 13 mg/dl, and sCr 1.15 mg/dl. A chest X-ray did not show any abnormal findings. Meanwhile, an abdominal ultrasonography revealed bilateral hydronephrosis. An MRI study revealed bilateral hydronephrosis with focal stenosis of the right ureter at the pelvic-ureteral junction (fig. 1). Radiologists excluded retroperitoneal fibrosis, a tumor invasion and infection around the ureters, or prominent pelvic lesions. Retrograde pyelography and intravenous pyelography revealed a complete obstruction of the right ureter and an advanced constriction of the left ureter. Bacteriological examinations, including Mycobacterium tuberculosis in blood and urine, were negative. On the 9th hospital day, a stent graft was inserted in each ureter, leading to a complete improvement of the hydronephrosis. Nevertheless, the patient experienced a progressive renal dysfunction and deterioration in macrohematuria. Her sCr increased to 3.4 mg/dl, and her anti-GBM antibody count was 69 EU (normal value <10 EU) on the 21st hospital day. An open renal biopsy of the left kidney on the 25th hospital day revealed the presence of anti-GBM GN. Renal biopsy specimens revealed over 90% of glomeruli presenting with exuberant circumferential cellular crescents and the compression of the underlying tuft (fig. 2a). Immunofluorescent findings revealed intense and diffuse linear deposits of IgG and C3 (data not shown) along with GBM (fig. 2b). Her sCr and anti-GBM antibodies had worsened to 3.80 mg/dl and 112 EU, respectively, by the 26th hospital day. A plasma exchange and steroid pulse therapy followed by oral steroid treatment were administered, starting on the 28th hospital day. The patient's sCr and anti-GBM antibodies had decreased to 2.2 mg/dl and 28 EU by the 42nd hospital day. By the 80th hospital day, her anti-GBM antibodies had returned to normal, with a titer of <10 EU, and her sCr level had decreased to 1.7 mg/dl. The stenotic lesion of the right ureter was biopsied to investigate the cause of hydronephrosis. However, we were not able to determine the cause of her hydronephrosis.

anti-glomerular basement membrane antibody, anti-glomerular basement membrane glomerulonephritis, ureteral obstruction

PMC3593498_01

Male

A 25-year-old male from Guntur District of Andhra Pradesh presented to the Tuberculosis and Chest department of NRI General Hospital, Chinakakani with complaints of productive cough, chest pain, hemoptysis, and dyspnoea for the last four months. There was history of occasional fever but no weight loss. Physical examination revealed bilateral rhonchi on auscultation. Blood picture showed leucocytosis with eosinophilic preponderance. Routine examination of blood and urine disclosed normal findings and the sputum was repeatedly negative for acid-fast bacilli. Computed tomography (CT) scan impression was a 6x6.9x5.9 cm hypodense lesion in the posterior segment of the lower lobe of the right lung with minimal adjacent loculated effusion-probably lung abscess [Figure 1]. Ultrasound guided aspiration was done and fluid analysis revealed viable scoleces [Figure 2]. A large unilocular hydatid cyst was removed from the right lung through a right thoracotomy. Oral albendazole 400 mg b.i.d. was given for 5 days preoperatively and 4 weeks post operatively.

hemoptysis, hydatid cyst, lung

CT scan impression showing 6x6.9x5.9 cm hypodense lesion in the posterior segment of the lower lobe of the right lung.

PMC9634947_02

Female

A 29-year-old female patient was diagnosed with HIV infection in June 2017 and commenced on TDF/3TC/EFV. Her baseline CD4 count and VL are unknown. Three years later, she was switched to ABC/3TC/ATZ/r following virological failure. Four weeks after treatment switch, she developed pulmonary tuberculosis and in error was given rifampicin with ATZ/r for two months. For treatment optimisation reasons, the ART regimen was switched to ABC/3TC/DTG, but DTG was dosed at 50 mg daily with rifampicin for four months instead of twice daily according to current guidelines. The VL at switch to ABC/3TC/DTG is unknown. The clinical response to treatment was poor and she was referred to Newlands Clinic. A VL taken after seven months on ABC/3TC/DTG was 6540 copies/mL, despite adherence counselling. A genotypic resistance test taken 10 months after initiation of DTG showed extensive NRTI DRMs and one major InSTI DRM (see Table 1 for mutations and sensitivity analysis). This patient admitted to inconsistent adherence both to tuberculosis treatment and ART.

hiv, hiv drug resistance, antiretroviral treatment, dolutegravir, integrase strand inhibitor

PMC7242862_01

Female

A 27-year-old female was admitted to a local hospital with community-acquired pneumonia. She tested positive for human immunodeficiency virus (HIV) and had a baseline CD4 count of 0 cells/muL. Investigations for tuberculosis were negative. At the time of her discharge, she was started on a fixed-dose combination of antiretroviral therapy (ART) which comprised tenofovir, emtricitabine and efavirenz. Four weeks after initiating ART she began experiencing dysphagia, which was initially only to solids. Empiric fluconazole therapy prescribed by her local clinic did little to alleviate her symptoms which progressively worsened over the ensuing 6 months before presenting to our institution. She described no other symptoms. She did not have diarrhea. She reported no loss of visual acuity. On examination, she was wasted. She had no palpable lymphadenopathy, nor did she have hepatomegaly or splenomegaly. Fundoscopy revealed no evidence of retinitis. Initial haematological investigations revealed a mild normocytic anemia with a haemoglobin 10.9 g/dL. Tests for renal and liver function were normal. After 6 months of ART, the patient's CD4 count was then 106 cells/muL and she was virologically suppressed with an undetectable viral load. A barium swallow (Fig. 1A) revealed marked narrowing at the distal esophagus. A gastroscopy was performed which confirmed the presence of a distal esophageal stricture. The stricture was biopsied, and the tissue samples sent for histological examination. Haematoxylin and eosin (H&E) sections were entirely representative of granulation tissue surfaced in areas by fibrinopurulent material, consistent with ulceration. No intact mucosa was identified. The inflamed granulation tissue comprised neovascularisation and reactive fibroblasts amidst a mixed inflammatory cell infiltrate of lymphocytes, neutrophils and eosinophils. Within the granulation tissue, isolated foci of larger, atypical cells displaying nucleomegaly were identified (Fig. 1B). Futher investigation included Ziehl-Neelsen (ZN) and Alcian blue - Periodic acid-Schiff (AB-PAS) histochemical stains, as well as CMV immunohistochemistry. CMV immunohistochemical stains highlighted the presence of multiple foci of cells showing strong, nuclear staining, confirming the presence of CMV infection (Fig. 1C). ZN and AB-PAS stains showed no acid-fast bacilli nor fungal elements, respectively. The patient was commenced on ganciclovir 5 mg/kg intravenously twice a day for 14 days and underwent esophageal dilatation with good result. She was discharged home shortly thereafter being able to tolerate solid foods with no symptoms of dysphagia.

cytomegalovirus, esophageal stricture, immune reconstitution inflammatory syndrome

PMC6356048_01

Male

An abnormal chest x-ray finding in a 79-year-old man during a health checkup program in X-6 led him to consult a nearby physician. Suspected of having lung cancer, the patient presented to our department on October 28, X-6. He was confirmed to have a history of pulmonary tuberculosis, disc herniation, and chronic obstructive pulmonary disease (COPD) but no particular family history. He reported having smoked 20 cigarettes a day between the ages of 20 and 72 years and having had 1 cup of distilled spirits a day. A bronchoscopic examination performed on November 2 led to the diagnosis of EGFR mutation-negative SCC cT2aN0M1b stage IV (M1, bone metastasis) in this patient. Thus, he underwent 4 courses of first-line chemotherapy with CBDCA and S-1 from January 17, X-5 onwards, followed by an additional course of treatment with S-1, after which he was diagnosed with progressive disease (PD) with enlargement of the primary lesion. All bone metastases were shown to have disappeared on PET, which led to the patient being down-staged as cT2N0M0 stage IIA. Preferring not to be operated on for his cancer, the patient chose to undergo radical radiotherapy with 50-Gy (five fractions at 10-Gy) between January 22 and February 4, X-4 but was diagnosed with PD on CT in September the same year with enlargement of the primary lesion. Subsequently, he underwent 5 courses of chemotherapy with docetaxel from October 1 onwards, 4 courses of chemotherapy with carboplatin plus paclitaxel from February 18 onwards, and 19 courses of chemotherapy with gemcitabine from January 13, X-2 onwards. Finally, diagnosed with PD again, he was started on nivolumab as a fifth-line treatment from August 23, X-1 onwards, which elicited PR in this patient thus leading to the regimen being continued up to 20 courses (final administration, May 2, X). A blood sample was drawn from him on May 9, X, which revealed his serum sodium level to be 134 mmol/L. The patient began to complain of nausea, appetite loss, and difficulty walking from around May 13, X and further complained of worsening nausea on May 15, X and was symptomatically treated with drip infusions and oral agents. However, he had persistent nausea, difficulty eating, and abdominal bloating until he was found to have difficulty walking, dyspnea, and oliguria on May 18 and was immediately admitted on the same day. At admission, he had clear consciousness with clear breath sounds (body temperature, 34.9 C; blood pressure, 114/58 mmHg; pulse rate, 83/minute; breathing rate, 20 times/minute; and SpO2 at room temperature, 98%), with no signs of jaundice or anemia in bulbar conjunctiva, cardiac murmur, or abdominal bloating or tenderness, and with no neurological findings suggestive of paralysis. Hematological findings at admission are summarized in Table 1. Chest roentgenogram findings at admission (Fig. 1a) included a tumor mass shadow in the upper lung field, left costophrenic (CP) angle blunting, and a central venous access port device planted in the left subclavian vein. Plain chest-abdominal CT findings (Fig. 1b) included a 50-mm tumor mass shadow in the left superior lobe, left pleural effusion, and absence of gut distention or niveau formation. After admission, the patient was being observed while being treated with drip infusions, with no clues available as to the cause of nausea and appetite loss in this patient. However, on the third day of admission, he was found to have a decline in blood pressure, when adrenal failure was suspected and hydrocortisone was administered at a daily dose of 500 mg, which led to an increase in blood pressure as well as improvements in activities of daily living (ADL) and appetite in this patient. On the fifth day of admission, ACTH and cortisone levels were confirmed to have decreased based on a blood sample drawn before hydrocortisone administration, which led to the diagnosis of adrenal failure in this patient. With attention given to monitoring his symptoms and serum sodium levels, hydrocortisone was gradually down-titrated to be maintained at 15 mg/day. Subsequently, an array of endocrinological investigations were conducted to identify the organ responsible for adrenal failure as well as to assess hormone secretory status in this patient (Table 2). The insulin hypoglycemia test, GH-releasing peptide 2 (GHRP-2) test, and corticotrophin-releasing hormone (CRH) test elicited a poor ACTH/cortisol response, while the thyrotropin-releasing hormone (TRH) test and luteinizing hormone-releasing hormone (LHRH) test elicited an intact TRH/LHRH response, in this patient, which led to the diagnosis of isolated ACTH deficiency, with the pituitary determined as the responsible organ. Again, based on the pituitary MRI (Fig. 2) finding suggestive of no pituitary enlargement and the fact that this ACTH deficiency developed during nivolumab therapy, the condition was finally diagnosed as nivolumab-induced isolated ACTH deficiency. Hydrocortisone administration led to an improvement in PS and the patient was discharged on the 22nd day of admission. Subsequently, the patient was restarted on nivolumab therapy from September, X, and is currently receiving the 44th course of nivolumab therapy, which continued to elicit PR from the patient, with no evidence of recurrent adrenal failure.

anti-pd-1-antibody, ctla-4, cytotoxic t-lymphocyte-associated antigen 4, icis, immune checkpoint inhibitors, immune checkpoint inhibitors, isolated acth deficiency, lung cancer, nivolumab, pd-1, programmed death 1, pd-l1, programmed cell death ligand-1, pd-l2, programmed cell death ligand-2, iraes, immune-related adverse events

PMC5523564_01

Female

A 57-year-old female presented with sudden onset of loss of taste and tongue deviation to the left on protrusion. She had slurring of speech but no limb weakness, no syncopal attack, no headache, no vomiting, and no history of seizure. Underlying medical problems revealed that she suffered from hypertension, psoriasis, and right knee osteoarthritis. She was first seen by the neurosurgery team as the computed tomography (CT) scan showed right posterior frontal-subcortical intraparenchymal bleed with multifocal infarcts. A magnetic resonance imaging (MRI) was also performed and there was an incidental finding of right masticator space lesion following the course of the right mandibular nerve. The patient was then referred to us for further management. On examination, her face was symmetrical. She had slurred speech, tongue deviation to the left but no paresthesia of her tongue or right labiomental region. There was no buccal or lingual bony expansion at the right mandible. However, thick fibrous mucosa was palpable lingually. The panoramic radiograph showed enlarged well-defined radiolucency zone of the right mandibular canal measuring 8.6 mm compared to the left side which measures 2.3 mm. There was also loss of cortication of the mandibular canal [Figure 1]. Cone-beam CT (CBCT) confirmed the above radiological findings with intact, uninterrupted cortication of the mandibular canal only at the superior border [Figure 2]. The MRI scan showed well-defined T1-hypointense and T2-hyperintense lesion at the right masticator space invaginating into the right mandibular canal measuring 2.6 cm x 1.7 cm x 3.4 cm (AP x W x L) [Figure 3]. It had minimal central enhancement seen postcontrast. No evidence of intracranial perineural spread. Impression of the lesion radiographically was either schwannoma or neuroma. The patient declined incisional biopsy to establish the diagnosis of the lesion as she was asymptomatic and unwilling to take the risk of paresthesia postbiopsy.

clinical characteristics, imaging characteristics, mandibular canal

PMC9300819_01

Male

A 42-year-old Brazilian man was admitted to the hospital due to wasting syndrome, fever of unknown origin (FUO), hyporexia, asthenia, and night sweats. The patient reported worsening of his condition during the last month to the point of becoming bedridden. He also reported edema up to his knees, skin peeling, and severe, bilateral lower extremity weakness. One year before admission, the patient started presenting pain in his lower limbs that worsened during physical activities. Five months later, he started complaining of paresthesia and burning sensations from his knees to his feet. He reported no chronic conditions or significant past medical history and denied the use of any medications, drugs, alcohol, or tobacco. The family reported that his mother and brother were diagnosed with leprosy one year before the patient's presentation. The physical exam revealed weight loss of approximately 25 kg (55.11 lbs.) in five months, hepatosplenomegaly and lymphadenopathy confirmed with ultrasound, hypoesthesia to touch, and painful stimuli. Additional physical findings included the presence of bilaterally thickened neural trunks, inability to fully flex the fingers, and dactylitis. During the neurological exam, normal reflexes, motor coordination, and cranial nerve reactions were observed. The visual inspection yielded diffuse skin infiltration all over the body (especially on the face, hands, feet, and ears) and the presence of small lepromas on the posterior thighs and legs. The laboratory exams revealed microcytic and hypochromic anemia ( Table 1 ) and a normal pattern for serum protein electrophoresis (SPEP). Testing for HIV, T-Spot.TB, syphilis (VDRL), and hepatitis B and C were negative. The cerebral spinal fluid (CSF) analysis was normal ( Table 2 ). The chest computed tomography (CT) was normal, and the abdomen CT revealed hepatosplenomegaly. Electroneuromyography showed an asymmetrical sensory and motor axonal neuropathy with focal slowing of conduction velocity and severe impairment of ulnar nerves in the elbow segment and tibial nerves in the ankle. Ultrasonography of peripheral nerves displayed echographic findings suggestive of hypertrophic neuropathy of the ulnar, median, left peroneal, and tibial nerves (more evident at pre-tunnel levels) in addition to signs of intraneural hyperemia in the left ulnar nerve at the pre-tunnel level and mild thickening of the right peroneal nerve. A bone marrow biopsy (Figures 1, 2 ) revealed the presence of M. leprae forming globi. The ELISA anti-phenolic glycolipid I (PGL-I) IgM antibodies and M. leprae DNA were positive, with index 2.38 (normal values: <1 - negative). The slit skin smear Bacilloscopy Index (BI) mean was 4.16 ( Table 3 ). To detect M. leprae DNA, were used a real-time quantitative polymerase chain reaction (qPCR) primer/probe assay, described elsewhere, to target the M. leprae species-specific genomic element of dispersed repeats (RLEP) (ABI 7300 realtime PCR system; Applied Biosystems). The slit skin smear DNA M. leprae qPCR was positive Ct = 19 (normal values <= 35) with 3.8x108 copies/mL. The skin biopsy showed whole bacilli with BI equal to 6.0 and Ct = 21 (normal values <= 35) with 2.1x109 copies/gram. The diagnosis of lepromatous leprosy was made. The treatment was started with a supervised monthly dose of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg), and an unsupervised daily dose of ofloxacin (400 mg) and minocycline (100 mg). This treatment was chosen to avoid the use of dapsone, due to the possibility of drug-induced anemia worsening the patient's condition. During the first months of treatment, the patient gained weight, his nutritional status improved, and he was able to perform independent activities of daily living again. He has been followed up monthly by a multi-professional team at our outpatient clinic with good adherence to the proposed treatment.

bone marrow, case report, fever of unknown origin, lepromatous leprosy, neuropathy

PMC9526550_01

Male

On 21 November 2018, an 11-year-old preadolescent boy presented to our hospital with a productive cough, fever, and weight loss for four weeks. 1.5 months before the current illness, the patient was admitted to a local hospital with left neck lymphadenitis and underwent surgical drainage. The bacterial culture of the drained pus grew MRSA and received ten days of vancomycin and clindamycin. He was sent home in good condition. Symptoms started two weeks after discharge with a daily high-grade fever and productive cough. He had lost around 5 kg since his illness began with a poor appetite. There was no history of contact with tuberculous-infected patients. His older sister died six years ago due to severe pneumonia, and there was no clear underlying diagnosis. Parents are second-degree consanguineous with no family history of inherited lung disease. On admission, he was dyspneic and febrile with an oral temperature of 39 C. His blood pressure was 110/60 mmHg, his heart rate was 120/min, his oxygen saturation was 85% on room air, and his respiratory rate was 20/min. Physical examination revealed left neck enlarged lymph nodes with healed scars (Figure 1). The chest revealed bilateral diminished air entry with bilateral coarse crackles. Peripheral blood leukocyte count was 28.260/muL with 84% neutrophil, 11% lymphocyte, and 4.4% monocyte; hemoglobin and platelet counts were 9.5 mg/dL and 550 x 109 per liter. The erythrocyte sedimentation rate was 150 mm/h. All the results of biochemical tests were normal. A chest CT scan showed bilateral diffuse air space disease (Figure 2). A direct smear of sputum for acid-fast bacilli and tuberculous mycobacteria PCR was negative. Upon admission (21 November 2018), the patient was started on broad-spectrum antibiotics linezolid, gentamycin, and meropenem. After five days of therapy, the fever continued with worsening chest X ray findings. So, the infectious team decided to start antituberculosis treatment empirically, given the rapid deterioration in his condition, which was later discontinued after getting the negative PCR and AFB smear results. On 29 November 2018, the demonstration of yeast in a smear made from sputum and the appearance of pseudohyphae and budding yeast cells (Figure 3(a)) dictated the need for fungal culture. Fungal cultures were performed on Sabouraud dextrose agar (SDA) and blood agar plates. Inoculated plates were incubated at 30 C and 37 C, respectively. Plates were examined daily for microbial growth. Initial identification of the grown organism was carried out using routine growth and colonial morphology criteria -confirmation of identification of Candida spp. by the VITEK 2 system. The VITEK 2 automated system was used to confirm the identities of Candida species following protocols described by the manufacturer (bioMerieux Inc., Durham, NC 27712, USA). Candida tropicalis were isolated from a sputum specimen's culture (Figures 3(b) and 3(c)), which raised the possibility of invasive mycosis due to underlying primary immunodeficiency. Amphotericin was added at 1 mg/kg/day for two weeks, and he also received IV methylprednisolone (1 mg/kg/day twice daily for seven days), which was later tapered over two weeks. The patient improved and was weaned off oxygen with no fever. On 15 December 2018, he was referred to higher centers for further workup. The bronchoscopy was done at the higher center, which showed diffuse bronchitis with necrotic involving mainstem bronchi (Figure 2). The patient's immune system was assessed. The ranges of the immunoglobulins (Ig) were normal, which include IgG 10.4 g/l (reference 7-16 g/l), IgA 2.81 g/l (reference 0.7-4 g/l), IgM 0.675 g/l (reference 0.4-2.3 g/l), and IgE 26.3 IU/ml (reference less than 200 IU/ml). The total protein level was 8.1 g/dl (reference 6.6-8.3 g/dl) and the albumin level was 2.4 g/dl (reference 3.5-5.2 g/dl). The oxidative burst measurement with flow cytometry using the dihydrorhodamine 123 assays was performed and confirmed the diagnosis of CGD through the comparison between control (reference range 98-100%) and the patient results (0.3%). The patient was started on daily prophylaxis withTrimethoprim-sulfamethoxazole (5 mg/kg/d, based upon the Trimethoprim) and itraconazole (5 mg/kg/day). The patient was then sent for HLA-identical bone marrow transplantation (BMT).

PMC3662898_01

Male

Sport history. This participant played football in high school and in the CFL for 6 years. He had many concussions. Clinical findings. When the patient was 55-years old, his sister noted that he had difficulty with short-term memory and that he was less able to formulate arguments. He subsequently developed visuospatial impairments and was reported to get lost in familiar environments. He developed apathy and agitation, and became very depressed. His loss of judgment led to bankruptcy and at the age of 66, he became a ward of the state. He developed language deficits and exhibited word substitution, and was incoherent at times. He became depressed and had paranoid delusions. His past medical history was unremarkable except for recurrent phlebitis. The patient developed lung cancer and died of its complications at age 67. Family history. His paternal grandfather had vascular dementia. Neuropathological findings. Neuropathological examination revealed a brain weight of 1400 g with mild atrophy of the frontal and temporal lobes (Figure 1). There were findings consistent with widespread metastatic disease from a lung carcinoma and severe vascular atherosclerotic disease with recent multifocal brain infarctions. There was also thinning of the olfactory tracts and hypothalamus. Coronal sections of the brain showed an enlarged ventricular system, corpus callosum atrophy, and cavum septi pellucidi. Pigmentation of the SN appeared within normal limits (Figure 1). Microscopically, there was mild to moderate neuronal loss and gliosis in CA1, subiculum, entorhinal cortex, amygdala, mammillary bodies, and medial thalamic nuclei. There was granulovacuolar degeneration noted in the CA1 and subiculum area with pronounced subpial gliosis in the trans-entorhinal cortex. Immunohistochemically, there was widespread tau-positive neurofibrillary and astrocytic tangles in multiple layers (superficial > deep) of the cortex, especially in the depths of sulci (Figure 2). There were some inclusions noted in the gyral crowns. These inclusions were consistently found in all cortical areas with a predilection for the medial temporal, hippocampus, and amygdala areas. NFTs were also noted in thalamus, peri-ventricular hypothalamic areas extending into the mamillary bodies, the nucleus basalis of Meynert and clustering around blood vessels. Beta-amyloid staining revealed amyloid plaques. TDP-43 and alpha-synuclein staining were unremarkable. Neuropathological diagnosis. Overall, neuropathological findings and the distribution of tauopathy were compatible with changes seen in CTE. Although there were multiple infarcts noted, they appeared to be relatively recent infarcts and could not fully account for the participant's longer-term dementia. Sport history. This patient played in the CFL for 8 years. He had many concussions. Clinical findings. At age 64, he began to show behavioral changes, including anger, poor judgment, and irritability. Over the next few years his memory worsened and he began to get lost. He then began having hallucinations of strangers in his home and also developed some misidentification for others and himself. He seemed to no longer recognize himself as he would attack mirrors when he walked in front of them. He developed delusions that people were stealing from him and had episodes of aggression and agitation, as well as impaired motor function. The patient died at age 74. Family history. His mother had late onset AD and his father had late onset dementia. Neuropathological findings. His brain was atrophic with a weight of 1300 g after fixation with moderate ventricular enlargement (Figure 1). SN showed normal pigmentation. Microscopic examination revealed numerous NFTs in neurons of the deep cortical layers (Figure 2). These were concentrated to the trans-entorhinal cortex, hippocampus, and isocortex with significant extension into the primary visual cortex. There was also significant presence of tangles in nucleus basalis of Meynert, amygdala, substantia nigra, and in the Edinger-Westphal nucleus. Supplementing the tangles were numerous dense-core, beta-amyloid positive plaques. No evident TDP-43 or alpha-synuclein staining was seen. Neuropathological diagnosis. Overall, findings were consistent with severe AD (Braak Stage VI/VI) without any pathological evidence of CTE. Sport history. He began playing football in high school and played seven years in the CFL. He suffered multiple concussions. Clinical findings. At age 48, his wife noted that he was becoming withdrawn and then he gradually changed from a confident, assertive, energetic person to an anxious, insecure, and more lethargic person. At age 50, he noted his handwriting had become messier, and also complained of some cramping and numbness in his feet and decreased ability for playing baseball. He also began exhibiting memory deficits, which became progressively worse over the subsequent years. A few years later, his wife noted his speech was slurred and hypophonic and the slowing of his movements became more apparent. He did not have a tremor. At age 54, his wife became concerned about his judgment based on poor business decisions. He became obsessive about bladder incontinence and went to the bathroom multiple times a day, yet seemed incongruously unperturbed when accidents did happen. By age 55, he was having repeated episodes of loss of bladder control. He had vivid dreams that he was convinced were real, but no REM sleep behavior disorder. His judgment continued to deteriorate, and he became less attentive to hygiene. He had delusions and hallucinations, but these stopped with discontinuation of Sinemet therapy. He eventually had episodes of agitation and developed great difficulty ambulating. He had prosopagnosia at age 58. At that time, he began showing difficulty recalling the names of his children. His past medical history was unremarkable. The patient died at age 63. Family history. No family history of a neurodegenerative disease. Neuropathological findings. Neuropathological examination showed a brain of normal weight (1450 g) with mild diffuse cortical atrophy. Ventricles were mildly dilated (Figure 1). On microscopic examination, there was diffuse Lewy body disease with Lewy bodies and Lewy neuritis in the cerebral cortex, olfactory bulbs, indusium griseum, SN and limbic system, including the CA2-4 subdivisions of the hippocampus (Figure 2). There was extensive neuronal loss in the SN pars compacta, locus ceruleus, dorsal nucleus of CN X and nucleus basalis of Meynert. There was very limited tau labeling in the hippocampus, the amygdala, and peri-amygdala cortex. There was, however, widespread distribution of diffuse amyloid plaques. TDP-43 staining in this case was unremarkable. Neuropathological diagnosis. Overall, this case showed typical changes of long-term progressive PD. While the tau-deposits in the hippocampal area were age-appropriate Alzheimer-type changes (Braak Stage II/VI), there was no evidence of AD. There was also no pathological evidence consistent with CTE.

chronic traumatic encephalopathy, dementia, neurodegenerative disease, professional athletes, repetitive brain injury

PMC9073109_01

Female

A female child, three years old, 16 kg, had complaints of vomiting, weakness, and convulsion-like tremor at the right angle of the mouth a week before the admission. After a week in hospital care, the patient was discharged. A week later, the patient's head tilted to the right while talking, and the patient was less active than before. Therefore, the patient was admitted to the hospital again to be evaluated with brain magnetic resonance imaging (MRI) and brain tissue biopsy. The patient was diagnosed with tuberculoma based on first brain MRI, brain tissue biopsy and got regimens of anti-tuberculosis therapy. A week after the patient got the anti-tuberculosis therapy, the patient's condition worsened. The patient was consulted to the pediatric neurologist with general weakness, altered consciousness, and hand tremor. The patient was admitted with fever (39 C), Glasgow Coma Scale (GCS) was 7 (E2V2M3); pupils were asymmetric with slow response to the light, tetraparesis (the motoric strength were 1 of 5), increasing physiological reflexes; positive Babinsky with clonus, spastic, and hand tremorShe had high transaminases enzyme without proof of cytomegalovirus (CMV), HSV-1, HSV-2 syphilis, and tuberculosis infection. First brain MRI (two weeks before admission) (Figure 1), showed hypointense lesion and hyperintense spots in T1W1, which became hyperintense dominance on T2W1 with perifocal edema. The size of the lesion is 7,8 x 8,1 x 7,9 cm in the corpus callosum and frontal lobe bilateral (with right dominance). The lesion adheres to the falx cerebri and bilateral lateral ventricle with compression to the anterior horn of the bilateral lateral ventricle. Another smaller lesion with the same characteristics was found in the left parietal lobe that adheres to the falx cerebri with multiple nodules. These nodules are hyperintense after contrast introduction and located in the left frontal, bilateral parietal, and left temporal lobes. This condition suggests glioblastoma with a differential diagnosis of necrotizing toxoplasma encephalitis. The brain tissue biopsy showed a gemicytocytic cell adjacent to the edematous loose neutrophil stromal. A few parts of the tissue consisted of extensive necrotic tissue, which forms caseous necrosis with lymphocyte, macrophage, and epithelioid-like cell infiltration. The conclusion was a chronic inflammation in brain tuberculosis. The biopsy specimen was sent for a second opinion. The result showed a necrotic mass and inflammatory cells, suggesting an inflammatory process without malignancy or tuberculosis. The patient was still treated with anti-tuberculosis, corticosteroid, anti-convulsant, antipyretic, 20% mannitol for high intracranial pressure management. On the 3rd day of the hospitalization, the GCS was improved (E4V2M3). The second brain MRI was done (Figure 2). The lesions found in the subcortical and juxtacortical of the bilateral fronto-temporo-parietal, right occipital, bilateral parieto-occipital lobes, and bilateral head of the caudate nucleus, in the part of the putamen and the bilateral of globus pallidus without mass effect. This lesion was followed by an early subacute of hemorrhage component in the lesion of bilateral head of caudate nucleus with cortical laminar necrosis at the frontal and bilateral of parietal lobes. Spinal MRI was normal. Several viral (adenovirus, coronavirus 229E, coronavirus HKU1, coronavirus NL63, coronavirus OC43, SARS-CoV-2, Human Metapneumovirus, Human Rhinovirus/Enterovirus, Influenza A and B, Parainfluenza 1 to 4, Respiratory Syncytial Virus) and bacterial infection (Bordatella parapertussis, Bordatella pertussis, Chlamydia pneumoniae, and Mycoplasma pneumoniae) were excluded by real time-polymerase chain reaction (RT-PCR) examination. The results of cerebrospinal fluid (CSF) examination are clear fluid, 100% mononuclear cells, leukocyte 2 cells/mm3, protein 3 mg/dL, glucose 59 mg/dL, negative Nonne test, positive Pandy test, negative of tuberculosis (Gene Xpert and fast acid bacilli examination) and negative of bacterial culture. The second MRI showed hemorrhage and necrosis, which were inappropriate with the resolution of tuberculoma; then, the diagnosis ANEC was considered. The anti-tuberculosis therapy was stopped after two weeks. The intravenous (IV) acyclovir was started with consideration of HSV infection as an etiology of ANEC. The patient had 300 mg (dosis perkgBB berapa) of intravenous acyclovir three times a day for 21 days, 375 mg of methylprednisolone IV once a day for five days, and immunoglobulin IV 0,4 gram/kg BW/day for five days. On the second week of hospitalization, patient's GCS was improved to 11 (E4V2M3), motor strength was increased to 3 of 5. The third brain MRI was done (Figure 3), which showed an extension of the lesion in the subcortical and juxtacortical of the bilateral fronto-temporo-parietal, right occipital, bilateral parieto-occipital lobes, the trunk of the corpus callosum, bilateral head of the caudate nucleus, part of the putamen and bilateral of the globus pallidus. These lesions were followed by the relatively stable early subacute of the hemorrhage component at the lesion, located at the bilateral head of the caudate nucleus, part of the putamen, and bilateral globus pallidus. There was also the addition of cortical laminar necrosis in the frontal and bilateral parietal lobes. On the third week of hospitalization, the clinical condition remained. Examination of serum showed the negativity of anti-Histoplasma, aspergillus, autoimmune panel for encephalitis, and Ab MOG. The patient showed improvement with GCS 13 (E4V4M5) and slight tetraparesis after five months of discharge.

anec, acute necrotizing encephalopathy of childhood, encephalopathy

PMC6310376_01

Male

Fostering youth-staff relationships has shown to be an important aspect of the positive program experience. The fact that program staff and volunteers are often community members from the local community in which the CSC program operates is unique and may enhance connections as youth have the opportunity to connect with their neighbors and fellow community members. Additionally, some of the volunteers are alumni of the VoSNL program (i.e., community ambassadors), providing an opportunity to give back to their community and act as a leader and role model to younger youth. Further, these volunteer alumni tend to be close in age to the youth participants (e.g., 14-16 years old). The close age gap provides opportunities for volunteers to share their knowledge regarding the program, academics, and future careers aspirations with the youth (e.g., how to become a community ambassador, what courses to take in high school), while establishing a relatable connection with the youth participants. Having junior leaders of similar age to youth has been identified as a successful element of program delivery in other youth programs (Shaikh,). Further, research indicates that youth greatly benefit from access to caring non-familial adults which has been identified in general youth programs (Eccles & Gootman,; Roth & Brooks-Gunn,), and specifically STEM programs (Cutucache et al.,). Future outcome evaluations will assess whether the community context program delivery approach and the community ambassador program enhance the achievement of VoSNL outcomes in participating youth. Evaluation of the CSC program through program leader and volunteer feedback revealed three challenges related to program implementation. While many of the program successes reinforced existing best practices within literature, the summary of challenges revealed predominantly novel insights in the potential complexity of program delivery within a community context. These challenges included: (a) navigating community-based issues, (b) conducting outreach and promotion, and (c) accommodating a wide age range of youth. Delivering programming directly within communities requires collaboration with key stakeholders, including local social housing providers, post-secondary institutions, and community groups in each community. These stakeholders offered support for CSC programming, including access to space, outreach, and logistics support. In order to ensure maximum accessibility to target youth, CSCs were delivered in residential community spaces (i.e., recreation rooms of buildings and townhouse complexes) and, in some cases, neighboring schools and/or community centers. This program-delivery strategy, however, was identified as a challenge on a few occasions throughout program implementation. The findings revealed that compromising situations that occurred in the community during programming months may have inhibited youth involvement in CSC. When certain situations arose, such as imminent violence in the community, the CSC program was impacted as sessions were canceled to ensure the safety of the participants and volunteers. Moreover, any issues that occurred within the building (i.e., maintenance or repairs) directly affected the program. A number of program session cancelations occurred due to these issues, resulting in missed programming for participants and reduced exposure to the content. One leader reflected on the impact on participant attendance: "We've been running low on student attendance ever since the construction cancellation" (PP-L-2016). I've seen the impact of our [program] over the year but [the space] is physically limiting and I was worried for a while that if we had any more registrations I might not be able to accommodate the kids that came in. (PP-L-2016) In addition to community situations, limited resources within the community locations were also an identified challenge to program success. Engaging in STEM-based workshops can often require access to specific resources and amenities that are built within the program space, such as internet/technology, a kitchen with running water, and teaching aids (e.g., whiteboards). In some communities, there was an absence of these resources in the space provided by community partners as a result of the infrastructure built within the program space itself. As a result of the limited resources available in some of the space provided, the capacity of the location, the delivery of curriculum content, and, in some cases, the development of certain modules was inhibited. One leader discussed: Many times, our materials had been used or stolen by other clubs at the location. Specifically, for the year end event we had materials, such as yeast and hydrogen peroxide stolen, specifically bought for the event. It has been an ongoing issue throughout the year (e.g., markers, construction paper, science materials). (PP-L-2016) Another leader reflected: "Access to water (hot and cold) was an on-going issue throughout the year" (PP-L-2016). Additionally, many of the CSC program spaces were shared with various community groups, which was challenging when coordinating program timing and the security of experiment equipment. A program leader commented on the ongoing issue of equipment security: Outreach, promotion, and scheduling conflicts have been a documented issue for service providers within low-income communities (Schnirer et al.,). Conventionally, program outreach and promotion for CSCs has been conducted through posting flyers in community spaces, engaging directly with parents and youth after school, and door-to-door promotion, all of which are proven effective strategies to engage low-income families (Schnirer et al.,). Substantial effort was required to engage new populations of young students to join the program, as many youth are initially hesitant to join STEM-based programs. The additional outreach effort required for STEM youth programming is in contrast to other conventional extra-curricular activities for youth, such as music- or sports-based programs because of the natural popularity, sense of engagement, and motivation to engage in this activities (Guevremont, Findlay, & Kohen,). Additionally, in a few communities where the CSC program was implemented, there were several out-of-school programs to choose from. A program staff reflected on the impact of these activities: "With the weather warming up, it is difficult to compete against other activities. Many students did not come because of soccer practice and some students who did come, left early for swimming practice" (WF-L-2016). A similar sentiment was echoed at another club: "A couple students had mentioned conflict with timing of Visions of Science due to basketball and soccer practice" (WF-L-2016). This has been identified in other youth program literature as a challenge to reach and engagement (Bean, Kendellen, Halsall, & Forneris,). This finding helped reinforce to program staff that offering the program solely once per week was sufficient.

community, evaluation, stem, science, youth

PMC6310376_02

Female

The CSCs target youth ages 8 to 14 years old. In some clubs, this age difference poses a challenge to effective teamwork and facilitation. Two volunteer facilitators reported issues related to content delivery and suggested potential solutions: "There was a significant range in age groups that made it more difficult for some kids to collaborate" (PP-V-2016) and "Given the age differences of the students, there were some tasks that some really young students could not do...the club would have been more effective in student learning if this group were split into two groups" (PP-V-2016). The recommendation to separate a large group into smaller groups to optimize program delivery and outcomes has been outlined in other community-based youth programming literature (Bean, Forneris, & Halsall,). Moreover, the engagement of older youth with the workshop material was a challenge as one facilitator noted: "I feel some of the older students are slowly becoming disinterested in participating possibly because of how long they've been attending or because they're no longer being challenged by the content" (PP-V-2016). [There is a need for] programmatic ways to involve or engage those older students as leaders or as volunteers helping with coordination of the club could be a possible solution. Moreover, as these youth progress into high school and so on, (recognizing the limits of VoSNL) are there any resources, opportunities, programs, community partners etc. we can connect them with to further their interest so as not to leave them hanging? (PP-V-2016) An unforeseen age-related challenge that emerged in the CSCs was the need to actively engage youth past the cutoff age as one facilitator mentioned: One approach VoSNL implemented to engage those youth is through opportunities to become community ambassadors and volunteers in the program in which they have aged out of. Similar strategies have been utilized in other youth programming contexts, such as summer camps and youth sport programs (e.g., Bean & Forneris,; Kendellen, Bean, Camire, & Forneris,). Integrating such an opportunity into the program can help with program sustainability, as well as provide opportunities for mentoring and leadership. This paper represents an important step in responding to calls for increased evaluation in youth programs (Roth & Brooks-Gunn,) and represents a summary of one of the first process evaluations conducted of a community-based STEM program for youth in a Canadian context. The CSC program provides consistent, hands-on STEM-learning opportunities for youth living in low-income housing during out-of-school time. This program is offered directly within social housing communities in order to increase accessibility. The purpose of this report was to provide a detailed description of the program and a summary of the process evaluation findings. Ongoing evaluation and reflection facilitated the identification of specific program successes, challenges, and lessons learned that emerged from CSC program delivery. This report addresses gaps in the literature concerning the implementation and evaluation of a STEM-based out-of-school program for youth from low-income communities in a Canadian context and the need for more process evaluations within out-of-school STEM programming. Continuous improvements to the program processes and delivery will enhance the quality of programming and achievement of intended outcomes. As noted above, youth benefit from fostering relationships with caring non-familial adults (Cutucache et al.,; Eccles & Gootman,). In support of strengthening this area of success, explicit workshop activities and facilitation techniques related to social-emotional learning will be implemented. A STEM-based example of such activities is Actua Canada's debrief and reflection exercises (Actua Canada,). Another ongoing improvement which VoSNL identified was surrounding their evaluation plan. Research has shown that program evaluation provides opportunities for reflection on past and future programming, helps programmers to better understand and improve service delivery, and showcases effectiveness of a program to key stakeholders and the community (Fitzpatrick, Sanders, & Worthen,). Further, when community organizations partner with research partners, there is the benefit of not only bridging the gap between research and practice (Ferguson,; Yuan et al.,), but also allowing for a collaborative learning environment that capitalizes on both partners' expertise (MacPherson & Hall,). As such, since the evaluation outlined in the report, VoSNL approached Youth Research and Evaluation eXchange (YouthREX)1, housed out of a major university within the Toronto area, with the collaborative goal of building evaluation capacity and developing a more comprehensive evaluation plan to assess both process and outcome indicators. Together, VoSNL and YouthREX have worked to create a logic model to provide a visual representation of VoSNL's CSC program. Additionally, the organizations collaboratively created an evaluation plan with the goals of better understanding the program experience of youth attending VoSNL, examining potential program outcomes, and identifying strategies for continuous improvement. YouthREX supported VoSNL in developing measurement tools that best meet the intended processes and outcomes of the CSC program. Although VoSNL had existing evaluation protocols in place, programmers saw value in attaining evaluation support from YouthREX to build capacity and expand existing evaluation practices. Moving forward, a mixed-methods approach will be used to assess both processes and outcome indicators, which will enhance data triangulation and strengthen results (Creswell & Plano Clark,). Ultimately, the collaboration between VoSNL and YouthREX has enhanced VoSNL's evaluation capacity and culture while producing evaluation tools (e.g., pre- and post-program surveys) that will be used for long-term program evaluation and improvement. The evaluation plan and tools are in the midst of being piloted within VoSNL programming. Although there are several processes of CSC program delivery that have been identified as successful, there remain challenges related to navigating community-based issues, conducting outreach and promotion, and accommodating a wide age range. As previously mentioned, the majority of the community-based issues outlined are external to the program. Considering the nature of the issues, it is imperative to remain committed to the communities served, despite these challenges. Further, as an organization, it is important to recognize and address challenges within program implementation to enhance achievement of intended outcomes and program sustainability (Bean, Kendellen et al.,). Therefore, constant communication with stakeholders, collaborators, and community members is integral in mitigating the detrimental impacts of these issues and improving future program delivery (Strengthening Nonprofits,.). Currently, program stakeholders are working together to adapt programming to address the identified challenges and better meet program participants' needs. Moreover, the development of workshops to cater to possible resource-related limitations underscores the notion that STEM learning can be adaptable across a range of environments. Additional long-term solutions include working with external partners to introduce necessary resources to community spaces as well as with housing providers to improve infrastructure. In the area of outreach and promotion, future strategies are focused on developing partnerships with other community-based groups. For example, in the summer of 2016, VoSNL partnered with a local community-run sport program to offer STEM-based workshops within their existing basketball camp. Moving forward, similar year-round opportunities and methods will be used to promote the CSCs and engage participants in STEM learning. Based on the identified successes, VoSNL's CSCs have expanded and moved towards a sustainable program. Through establishing partnerships between housing providers and community groups, the program has scaled from six communities in 2011 to 18 communities across three different regions within South-Eastern Ontario by 2016. This expansion has demonstrated that the model is viable and scalable across different low-income communities with each presenting its own unique challenges and opportunities. Registration intake data collected from 2013 to present indicates that an average 50% of participants are returning to their CSCs each year (VoSNL,). In many cases, youth participants are the strongest advocates who recommend the program to their peers: "I was recommended by [youth participant]; it's really fun and I didn't know it was going to be like this and she told me I should try it out" (personal communication 23 September 2016) and "I would recommend [CSC] to people who don't understand science as well. If you don't understand and you ask a volunteer to help you, they will stay by your side throughout the experiment and help you understand it the whole way" (personal communication 23 September 2016). As such, although this research provides insights on STEM programming from an adult perspective, which has been done in other STEM-related research (e.g., Krishnamurthi et al.,), future research is needed to understand program processes from the perspective of youth, as their voice is critical in program evaluation (Powers & Tiffany,). This yearly retention has also facilitated the engagement of participants beyond the projected eighth grade cutoff, where youth would typically age out of the program. Many of these alumni participants opted to continue their involvement by engaging as volunteer facilitators in the CSCs in their respective communities and are now identified as community ambassadors. This level of sustained participation further underscores the need and value of consistent programming for youth across communities. Moreover, this level of continued engagement from past participants into a leadership position aids in program sustainability as not only is it cost-effective for a charitable organization to have a large volunteer pool to help facilitate programming, but this also allows for that sense of relatedness discussed previously because of the close age gap between youth and program staff. Further, this addition to programming provides an opportunity for those volunteers to develop leadership skills and contribute to their community by giving back to a program they were involved in, which is the ultimate goal of youth development (Bowers et al.,; Lerner et al.,). Lastly, accommodating the wide age range in the CSCs has posed a challenge for program facilitators. Therefore, the plan is to develop more age-targeted module modifications and facilitation training which should help mitigate these issues. Moreover, in engaging youth beyond the age cutoff, a new structured out-of-school program for youth ages 14 to 18 will be launched in summer 2017. Although improvements can be made to best meet the needs of all stakeholders and overcome challenges to ensure program sustainability, findings from this evaluation have aided in the improvement of delivering VoSNL CSC programming. Further, results from this descriptive report may also act as a catalyst for expanding the program to more participants and communities. This report can provide a strong framework for other programmers interested in implementing a community-based STEM program for youth and can assist in the replication of similar models in other cities and enhance STEM learning amongst youth. Finally, although this report outlines important processes, future research is needed to assess the outcomes and impacts of community-based STEM programming on youth within a Canadian context.

community, evaluation, stem, science, youth

PMC4833828_01

Male

A 41-year-old Moroccan male, who had been living in Spain for 7 years, was admitted to the rapid diagnosis unit of Internal Medicine of the Complejo Asistencial Universitario de Leon, Spain with a 6 month history of abdominal pain, weight loss (10 kg in two months), fatigue and diarrhea. The patient had no relevant past medical history. He lived in an urban area, working as an electrician, and had no reported animal contact and denied ingesting unpasteurized dairy products. A depressible, soft and painless abdomen was revealed on examination with diffuse discomfort on palpation and no signs of guarding. Laboratory tests showed a normal white blood cell count and a normocytic anemia. A HIV antibody test was negative. Mantoux test (17 mm) and interferon gamma release assays were both positive. Chest X-ray and chest CT scan were normal and an abdominal CT scan showed mild ascites with small bilateral inguinal lymphadenopathy. An intense plastic peritonitis was encountered at laparoscopy affecting all abdominal spaces with soft rubbery adhesions that virtually blocked all initial access to the abdominal cavity. Countless amount of nodules were seen on the omentum and both the parietal and the visceral peritoneum and mainly on Glisson's sheath and digestive tube serosal surfaces (Fig. 1). A small amount of fluid was observed around liver and spleen. Careful adhesiolysis was needed for exposure and to obtain fluid samples. Various biopsies were taken from the omental and peritoneal nodules. All specimens were sent for microbiology, cytology and pathological examinations. Histopathology showed non-necrotizing granuloma. Acid fast stains of the tissue were negative. There was no evidence of malignancy. No acid fast bacilli (AFB) were seen on stain of the peritoneal fluid. The fluid PCR and culture were also negative for mycobacteria. Mycobacterial DNA was identified in the biopsy by PCR (Xpert MTB/Rif PCR, Cepheid AB, Solna, Sweden). Mycobacterial growth was detected with Bactec MGIT 960 system, (Becton Dickinson, Oxford, UK) on Day 26 of the peritoneal biopsy. Immunochromatographic test for MTC (TB Ag MPT 64 rapid, Standard diagnostics, INC, Republic of Korea) classified this isolate within the M. tuberculosis complex. Identification and susceptibility testing were performed as described at the National de Mycobacterium laboratory, Instituto Carlos III, Majadahonda, Madrid, Spain as M. caprae being fully sensitive to isoniazid, streptomycin, ethambutol, rifampin and pyrazinamide. The M. caprae isolate corresponded to spoligotype SIT646 in the international SITVIT database and SB0416 in the Mycobacterium bovis spoligotype database (http://www.Mbovis.org). It was performed Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain as previous described. Treatment for tuberculous peritonitis was initiated after the laparoscopy with a 4-drug regimen of including isoniazid, rifampin, pyrazinamide and ethambutol. Two months after starting antituberculous treatment, the patient reported improvement of symptoms. The patient completed 2 months of four-drug therapy without complications and an additional 7 months of isoniazid and rifampin. He is asymptomatic.

mycobacterium caprae, peritoneal tuberculosis, spoligotype sb0416

PMC7676982_01

Male

An 83-year-old man with a history of gangrenous cholecystitis requiring cholecystectomy, partial gastrectomy, and Roux-en-Y gastrojejunostomy presented to an outside hospital with severe sepsis and recurrent unstable monomorphic ventricular tachycardia (requiring synchronized cardioversion) secondary to non-ST segment elevation myocardial infarction (NSTEMI). On examination, he was febrile (102.4 F) and hypotensive (systolic blood pressure of 85 mmHg), with generalized abdominal pain, nausea, and vomiting. Labs were notable for troponin, 1.31 ng/mL; total bilirubin, 4.0 mg/dL; aspartate aminotransferase (AST), 157 U/L; and alanine aminotransferase (ALT), 122 U/L. He was intubated and started on vasopressors. The following day, he was taken emergently to the cardiac catheterization lab during which a drug-eluting stent was placed for a coronary occlusion, and the patient was started on dual antiplatelet therapy. Following stabilization of the patient, a magnetic resonance cholangiopancreatography (MRCP) was obtained due to concerns for cholangitis, which demonstrated two large obstructing stones in the common bile duct (larger stone measuring 25 mm in diameter). He was formally diagnosed with severe acute cholangitis, grade 3, according to the Tokyo Guidelines. He then underwent two unsuccessful ERCPs at an outside hospital (due to an inaccessible major papilla in the setting of SAGA) complicated by an additional cardiac arrest requiring life vest placement. On arrival to Wake Forest, he was noted to be febrile (102 F) and hemodynamically stable. After discussion with the patient and family regarding therapeutic options for choledocholithiasis and cholangitis including PTBD or EUS-HG, the patient elected to proceed with EUS-HG due to less morbidity and patient preference to avoid percutaneous drains. Given the patient's recent NSTEMI, cardiology was consulted and recommended holding dual antiplatelet therapy for no more than 3 days prior to the procedure to minimize the risk of stent thrombosis with immediate resolution 6 hours after procedure. Upper GI endoscopy revealed a gastric pouch with a patent Roux-en-Y gastrojejunostomy anastomosis (Figure 1). EUS was then performed using a linear echoendoscope (GF-UCT140-AL5; Olympus Medical Systems, Tokyo, Japan) connected to an ultrasound processor (Aloka Prosound Alpha 10; Hitachi, Tokyo, Japan). With the scope positioned in the gastric pouch, a dilated segment 3 branch was identified in the left lobe of the liver (Figure 2). The biliary radicle was punctured with a 19-gauge fine needle aspiration (FNA) needle (EchoTip Ultra HD, Cook Medical, Winston-Salem, NC). Following aspiration of the bile, contrast was injected through the needle for cholangiography. Cholangiogram showed diffuse intrahepatic ductal dilation and a dilated common bile duct measuring 18 mm in diameter with two large filling defects consistent with stones (Figure 3). A 0.025 inch in diameter and 450 cm in length straight tip VisiGlide 2 guidewire (Olympus, Tokyo, Japan) was then advanced through the needle into the biliary tree and past the major papilla into the duodenum. The hepaticogastrostomy tract was subsequently dilated using a 4 mm x 4 cm Hurricane biliary dilation balloon (Boston Scientific, Marlborough, MA, USA) (Figure 4). An 8 mm x 80 mm GORE VIABIL biliary stent (W. L. Gore Associates, Flagstaff, AZ) was placed in the left hepatic duct with the distal end in the gastric pouch. The metal stent was anchored by a plastic double pigtail stent (7 Fr x 18 cm) with the distal end of the plastic stent placed past the major papilla and the proximal end placed in the stomach (Figure 5). This procedure permitted decompression of the biliary tract while allowing the patient to recover from his acute infection. The patient returned for ERCP 3 months after resolution of cholangitis and improvement of his cardiac function. Dual antiplatelet therapy was not held before procedure. Following removable of the plastic stent with a snare from the gastric pouch, the biliary tree was accessed via the left hepaticogastrostomy using a sphincterotome preloaded with a 0.025 inch x 450 cm VisiGlide 2 guidewire. Successful balloon sphincteroplasty was performed using a CRE (controlled radial expansion) wire-guided balloon (Boston Scientific, Marlborough, MA), and the diameter was gradually increased to 15 mm (Figure 6). Cholangioscopy was then performed using a SpyScope DS (Boston Scientific, Marlborough, MA) with visualization of two large stones in the common bile duct which were fragmented using EHL (Figure 7). The biliary tree was then swept with a 15 mm stone extraction balloon (Cook Medical, Winston-Salem, NC) with antegrade advancement of stone fragments past the ampulla into the duodenum with subsequent duct clearance (Figure 8). The patient was followed up in clinic 4 weeks later, and repeat LFTs were normal.

PMC3043439_01

Female

A 25-year-old woman, gravida I, in the 24th week of gestation was admitted to the emergency room due to severe right lower quadrant (RLQ) abdominal pain coinciding with nausea and vomiting. She was afebrile (36.7 C) and had urinary frequency without dysuria. The patient had no uterine contractions, vaginal bleeding, or any bowel symptoms. Stool passage was normal before the episode. The uterine height was difficult to measure due to the patient's obesity (body weight 90 Kg). Tenderness with mild rebounding pain was found on palpation of the RLQ area of the abdomen. Deep palpation on this side provoked muscle guarding. The vaginal examination showed normal cervical status. Abdominal sonography was consistent with a 24-week pregnancy without placenta or uterine abnormalities. The fetus was normal and within a 50% growth curve. No bowel dilatation or ascites were seen. The left adnexa were normal, and a right ovarian cyst measuring 6 cm in diameter was detected. The white blood cell count was slightly elevated (12 900/mm3) and showed a shift to left phenomenon (segment 85%). C-reactive protein and an ionogram were within normal limits. Urine analysis revealed bacteriuria but with a negative culture. Because adnexal torsion and appendicitis could not be diagnosed with any certainty, it was initially decided to treat the patient with supportive care. However, 24 hours later, the pain had increased. Laparoscopic exploration with possible corrective surgery was recommended. The patient was well informed of the risks of surgery, the possible need for laparotomy, and the risk of preterm labor postoperatively. While under general endotracheal anesthesia, the patient was placed in the Trendelenburg position, and the operating table was left tilted. A Foley catheter was inserted preoperatively to enable continuous monitoring of urine output during the operation. The Veress needle with a 2-mm cannula was inserted between the xiphoid process and uterine fundus under sonographic guidance to avoid uterine injury (Figure 1). Pneumoperitoneum was created by insufflation with carbon dioxide (CO2) at a maximum intraabdominal pressure of 12 mm Hg. A 1.98-mm fiberoptic microlaparoscope (US Imagyn Laguna Niquel, California) with an attached camera was inserted through the cannula to visualize the intraabdominal organs. Laparoscopy revealed a right ovarian cyst measuring 6 cm without torsion (Figure 2), and a slightly edematous appendix. Periappendicitis coincidental to the right ovarian tumor was diagnosed. Two 5-mm trocars were introduced under visual control, one at the left upper quadrant, and the other at the opposite site. Then the 1.98-mm microlaparoscope was replaced by a 5-mm minilaparoscope followed by wedge resection of the right ovarian cyst and appendectomy with 2 Endoloop sutures (US Ethicon, Cincinnati, Ohio). An Endobag (US Ethicon, Cincinnati, Ohio) was used to contain the appendix and ovarian cyst before removal. Monitoring of the fetal heartbeat with transvaginal sonography was carried out during the entire procedure. The operation took approximately 70 minutes and was tolerated well by the patient. Pathologic examination of the excised specimen revealed a simple serous cyst and infiltration of inflammatory cells on the serous layer of the appendix. After the operation, the patient received Cefamezine 1 gram every 8 hours for 3 doses. Uterine contractions were noted on postoperative day 2. Tocolysis with ritodrine were administered parenterally, and the doses were adjusted depending on the severity of uterine contractility. Ritodrine was stopped on postoperative day 14, and the patient was discharged on the fifteenth postoperative day. At 41 weeks of gestation, an apparently healthy female baby was born via Cesarean delivery due to induction failure. The weight of the newborn was 3300 grams, and Apgar scores were 9 and 10 at 1 and 5 minutes. The postpartum period was uneventful.

PMC5890373_01

Female

A 21-year-old female underwent a routine septorhinoplasty for aesthetic and airway improvement. After envelope elevation in the sub-SMAS plane and total septal exposure through sub-perichondrial route, she underwent deviated bony and cartilaginous septal resection and caudal septal relocation, saving a sufficient L-strut. Osteotomy was internal low to low and external transverse bilaterally. Midvault reconstruction using bilateral spreader grafts was performed. Tip refinement was done by routine sutures and columellar strut graft was inserted. No tip graft was used. Overall, a routine septorhinoplasty was executed (Figure 3 and 4). There was not any problem during postoperative period, but 4 months later, she gradually developed paroxysms of headaches followed by abundant right sided rhinorrhea. Periods of headache were felt once weekly, localized in the nasal root and right retro-ocular area and lasted about 30-45 minutes. Bilateral conjunctival injection (worse in the right side), was an accompanying symptom. All symptoms and signs aggravated gradually, eventually interfering with normal life. At first, a list of differential diagnoses including infection, delayed retro-ocular hematoma or pseudoaneurysm, cavernous sinus thrombosis, different types of headaches and neuralgias, and intracranial pathology was arranged. Multiple studies including CT cysternography, dacrocystography, brain MRI, ophthalmologic evaluation and intraocular pressure monitoring were accomplished and all were normal. There was no problem in the routine hematologic and blood chemistry tests. Rhinorrhea liquid was examined clinically and pathologically to rule out CSF leakage that was negative. It was quite clear and non-purulent (Figure 5 and 6). After failure to diagnose the original cause of symptoms and signs, the patient was referred to a neurologist. Motor and cranial nerve examinations were normal, with no finding in favor of central or peripheral demyelinating disorders. MRI showed no intracranial pathology. Cluster headache, trigeminal neuralgia and temporal arteritis were all ruled out. Ophthalmologic, optometric, perimetric and lacrimal system examinations were normal. There was no past medical history, except depression and anxiety, appropriately treated by sertraline, clomipramine and propranolol. The principal distressing problem of the patient was abundant and uncontrollable runny nose. She was pain free between headache attacks, but rhinorrhea was the persistent symptom and sustained during daily activities. It was very annoying and did not respond to any kind of medical therapy including H1 blockers and local or systemic decongestants. A comprehensive review of the literature was planned. There were few papers or textbooks explaining these symptoms. Among rare complications after rhinoplasty, we encountered the Charlin`s syndrome! Literature content regarding this rare syndrome was extremely scarce. The first session of nerve block with a local anesthetic in the area around the nasal bones, confirmed the diagnosis (Figure 7). To treat the patient, authors decided to re-operate and explore surgically, however, the patient refused a revision surgery. So, phenol solution was used to ablate the irritating nerve ending. Symptoms and signs were alleviated but remained after two sessions of injection. Phenol was injected to the area around the nasal bones. During the third session, phenol was injected to the area beneath the nasal bones, bilaterally. Just after 2-3 weeks, patient`s pain was eradicated but rhinorrhea persisted and it took several months to stop completely.

charlin’s syndrome, complication, septorhinoplasty

PMC6757500_01

Female

A 17-year-old woman with no significant past medical or surgical history presented to the emergency department (ED) as a level 2 trauma activation. The patient was a restrained backseat driver's side passenger in a car traveling approximately 45 mph when a delivery truck ran a red light hitting the driver's side. The front seat air bags did deploy. She denied loss of consciousness and was ambulatory at the scene. Emergency medical service (EMS) reported approximately 6 in of intrusion into the driver's side door. Her only complaint on arrival was generalized body aches and abdominal pain. Her last menstrual period was 2 weeks prior to arrival. Vitals on arrival to the ED are as follows: 97.2 F, blood pressure of 108/62 mm Hg, heart rate of 90 beats/min, respiratory rate of 19 breaths/min, and 100% pulse oximetry on room air. Her physical examination was notable for a horizontal abrasion across the abdomen below the level of the umbilicus consistent with a positive seatbelt sign. Multiple other abrasions were noted at the anterior left knee, anterior left shin, and left shoulder. Her remaining physical examination was unremarkable. A focused assessment with sonography for trauma (FAST) was negative. A subsequent computed tomography (CT) abdomen/pelvis with intravenous contrast only per trauma protocol (performed approximately 2 h from the time of the crash) demonstrated a contusion to the lower anterior abdominal wall with no other findings (Figure 1). Her laboratory evaluation was unremarkable, including lactic acid. Given the large contusion to the lower anterior abdominal wall and risk of delayed intra-abdominal injury, even with normal vitals and negative imaging, she was admitted to the trauma service for observation. Approximately 12 h later she developed worsening abdominal pain, and by 14 h, she had abdominal distention with the absence of flatus/bowel movements. Repeat vitals at 14 h are as follows: 99.2 F, blood pressure of 102/56 mm Hg, heart rate of 96 beats/min, respiratory rate of 21 breaths/min, and 100% pulse oximetry on room air. A repeat abdominal examination was notable for percussive tenderness to the bilateral lower quadrants. A repeat CT abdomen/pelvis with intravenous and oral contrast was performed showing new free fluid favoring extravasation of contrast and concern for perforation. There are a few punctate droplets of air seen within the peritoneal cavity (Figure 2). There is also some enhancement of the peritoneal wall suggesting peritonitis. The patient was taken to the operating room (OR), where she underwent an exploratory laparotomy, small bowel resection for a full-thickness perforation in the ileum, lysis of adhesions, and placement of JP drain x2. Her remaining hospital stay was uncomplicated, and she continued to improve clinically and was discharged on day 7.

emergency medicine, surgery, trauma

PMC4856939_01

Male

A 68-year-old male patient was admitted to our hospital with chief complaints of recurrent pain in right hypochondrium, loss of appetite, and dyspepsia for the past 1 month. No fever, weight loss, or night sweating was reported. The patient denied any history of tuberculosis or hepatitis. There was no history of jaundice. The general and abdominal examinations revealed nothing significant. Laboratory investigations were normal. No abnormality was found at chest X-ray. At abdominal ultrasound, a gallbladder mass was observed, and the gallbladder was distended with multiple gallstones with associated cholecystitis. Preoperative ESR was 30 mm/h. Contrast-enhanced CT scan revealed a 5 mm thick gallbladder wall, and the interface between liver and gallbladder was not obvious, possibly indicating that gallbladder lesions had infiltrated into the liver parenchyma (Figure 1). Therefore, a diagnosis of gallbladder carcinoma was considered, and the patient underwent a subcostal laparotomy. Intraoperation, we found that the gallbladder size was around 9 cm x 5 cm x 4 cm, and there was edema in gallbladder wall. A stone was incarcerated at the neck, and gallbladder was filled with pus. The gallbladder was resected and sent for intraoperative frozen-section examination, and report indicated that no sign of malignancy was found. The definitive histopathological examination (HPE) of gallbladder reported gallbladder tuberculosis (Figure 2). Microscopical view shows epithelioid granuloma along with typical Langhans giant cells. The Mantoux tuberculin skin test was positive, and no other findings suggestive of tubercular infection were found. Therefore, the patient received antitubercular therapy for 6 months. The patient has been gradually relieved of all symptoms since cholecystectomy and was well at 6-month follow-up.

PMC9796185_01

Female

On September 7, 2022, an 18-year-old woman sought care at the outpatient clinic of Foch Hospital for symptoms such as fever, myalgia, and multiple eruptions on her vulva that began 7 days earlier (Figure). She reported a headache began on September 2, 2022, followed by feverish episodes on September 2 that stopped on September 7. The first eruptions appeared on September 2 on the gluteal area and then spread. Rashes on her hands and wrists appeared on September 7. At examination, the patient showed no odynophagia, coughing, or sputum. A gynecological examination showed ulceronecrotic lesions around the vulva and intravaginally. The cutaneous lesions were infracentimetric pustules located on the torso, fingers, and palms of the hands and above the intergluteal groove. We observed bilateral laterocervical and inguinal lymphadenopathies, but no axillary lymphadenopathy or anal lesions were evident. Tests for chlamydia and gonococcus on pharyngeal and self-collected anal swabs were negative, and no previous sexually transmitted infections were reported for the patient or her boyfriend. Tests for HIV, syphilis, herpes, toxoplasmosis, rubella, and hepatitis (A, B, and C) were all negative for both persons. A real-time reverse transcription PCR, designed at the French National Reference Center of Orthopoxvirus, was performed on a pharyngeal swab sample from the patient on September 7 and tested positive for MPXV on September 8. The patient had been in a relationship for 9 months with her boyfriend and had only had vaginal and oral intercourse with him; the most recent intercourse was 8 days before her first symptoms. On August 25, 2022, after a vacation in the southwest of France, her boyfriend began experiencing fever, pimples on his penis, and swollen inguinal glands. His rashes disappeared on September 1. We have no additional information for him. The main transmission hypothesis for MPXV in this case is oral and vaginal sex with the patient's boyfriend. She was not hospitalized but placed in confinement in her home. On October 12, the patient was seen at Foch Hospital for follow up, at which time the rashes were beginning to disappear (Appendix). Most current MPXV outbreaks in Europe have involved young men who have sex with men who attend festivals and other public events. Conversely, data regarding MPXV cases in women are sparse; only a few cases have been reported in the literature. To date, only a small proportion of infections have been reported in women; only 1.2% of total cases in Europe have been reported in women. Our patient had a regular sexual partner who had MPXV symptoms, thus reinforcing that sexual transmission might play a predominant role in the outbreak. Pharyngitis and rectal symptoms are being increasingly described as occurring after traditional skin lesions in MPXV infections, although these symptoms were not evident in our patient. The most reported clinical symptoms are painful perianal and genital lesions, together with fever, lymphadenopathy, headache, and malaise. Classic cases of MPXV included a febrile prodrome followed by generalized rash, although the ongoing outbreak has been characterized mainly by painless anogenital lesions, often without a prodrome. However, because of observed variability in clinical manifestations, the spread of the current MPXV outbreak might be underestimated. To date, only 10 cases in pregnancy have been reported worldwide, predominantly in Brazil and the United States. Those cases were mainly reported by local media, and none were severe. However, studies in pregnant women remain limited. A transplacental transmission to the fetus might be responsible for congenital MPXV, although no cases of fetal malformations or death have been reported. Nevertheless, cases of vertical transmission with clinical signs of MPXV infection, such as cutaneous maculopapular lesions on the head, trunk, and extremities and hydrops, have been reported. A neonate born from an infected mother in the United States received prophylactic vaccinia immunoglobin and did not develop MPXV disease. Of note, the ACAM2000 vaccine (Sanofi, https://www.sanofi.com) is contraindicated during pregnancy because it is a vaccinia virus (live virus); other vaccines, such as third-generation vaccines (LC16m8 or JYNNEOS [Bavarian Nordic, https://www.bavarian-nordic.com]), are preferred in pregnant women. It is imperative that health professionals become familiar with all aspects of this disease affecting women.

france, monkeypox, genital, outbreak, prevention, sexually transmitted infections, vaccine, viruses, women

PMC5214735_01

Female

A 42-year-old woman presented with recurrent acid regurgitation and heartburn. On initial upper endoscopy, multiple mucosal breaks were seen in the lower esophagus, but no abnormalities were observed in the stomach (Fig. 1). The patient took proton pump inhibitors for consistent reflux symptoms and reflux esophagitis. On follow-up endoscopy 4 years later, confluence of mucosal breaks and stenosis were seen at the lower esophagus and multiple polyps were found throughout the body of the stomach, which were diagnosed as fundic gland polyps by endoscopic biopsies. She continued maintenance therapy of proton pump inhibitors twice daily. Follow-up endoscopy at 2 years later showed more numerous and enlarged fundic gland polyps compared to the previous endoscopy (Fig. 2). Fundic gland polyps are benign, multiple, sessile, localized lumps, usually detected in the gastric body and fundus. Cystic dilatation of pits which is located in the deep mucous neck cell is one of characteristics of fundic gland polyps and they are usually observed with chief cells and parietal cells lining those microcysts. In the past, it is reported that fundic gland polyps are mainly associated with hereditary diseases. Recently, fundic gland polyps have become increasingly detected in patients who are treated with long-term proton pump inhibitor therapy. Generally, the risk for occurrence of fundic gland polyps increases after 12 months of proton pump inhibitor use. When chronic acid suppression therapy is applied, substantial physiological changes such as increased circulating gastrin and chromogranin A occur and these hormonal changes stimulate fundic gland proliferation.

PMC3959040_01

Male

A 28-year-old male presented to the emergency room (ER) with pain and redness in the right eye over the last 5 days. He was otherwise healthy and gave a past history of appendicectomy. His ocular history revealed laser refractive surgery procedure in both eyes 6 months prior to his presentation in another institution in Jordan. His history also revealed prior recent admission to a local hospital where he was found to have a high intraocular pressure of 50 mmHg which was managed by antiglaucoma medications: Latanoprost (Xalatan by Allergan) drops. He also received fortified antibiotics and topical steroids. No exact details of his treatment were available at the time of his presentation to our ER facility. He presented with vision of hand motion in the affected eye and intraocular pressure of 18 mmHg. His slit lamp examination of the right eye revealed severe conjunctival congestion with ciliary injection, opaque hazy cornea, and deep anterior chamber (AC) with 3 mm of dark pigmented hypopyon. There was no localized corneal infiltrate, but ring deep corneal dense haze was noticed possibly representing the edges of a previous laser-assisted in situ keratomileusis (LASIK) flap [Figure 1a and b]. There was no further view of the posterior cavity. The left eye examination was within normal limits. The patient was admitted as a case of uveitis. His initial B-scan showed very mild vitreous opacity and no RC layer thickening, therefore was not considered to be typical of endophthalmitis [Figure 1c]. However, he was continued on fortified antibiotic drops (vancomycin 25 mg/ml and ceftazidime 50 mg/ml every 3 h around the clock, OD) and topical steroids: Prednisolone (Predforte by Allergan) drops four times/day, OD. His differential diagnosis included post-refractive herpetic keratouveitis and masquerade syndrome. He was started on valtrex 500 mg twice daily, orally, in addition to the moxifloxacin 400 mg orally once daily. He was also kept on antiglaucoma medication: Combination of dorzolamide and timolol (Xolomol by Jamjoom Pharma) drops twice daily, OD. His repeated B scans over 4 days following admission revealed increasingly dense organized vitreous opacities and significant retina and choroid (RC) layer thickening suggestive of early endophthalmitis [Figure 1d] for which AC washout, vitreous tap and intravitreal antibiotics were given in the form of vancomycin 1 mg/0.1 ml, ceftazidime 2.25 mg/0.1 ml, and cefuroxime 1 mg/0.1 ml. Meanwhile his systemic investigations were within normal limits. His human immunodeficiency virus (HIV) testing, urine, and blood cultures were negative. His chest X-ray was clear. The smears prepared from his AC washout showed necrotic debris insterspersed with both extra- and intracellular melanin granules. Moderate number of polymorphonuclear leukocytes were also present [Figure 2a]. The Grocott's methenamine silver (GMS), gram, and acid-fast stains were all negative. No malignant cells were seen to suggest a masquerade syndrome. The AC aqueous was sent for polymerase chain reaction (PCR) to rule out infectious etiology including herpetic infection, cytomegalovirus, varicella zoster, tuberculosis, and Chlamydia which were all negative. The aqueous fluid culture proved bacterial growth identified as Listeria monocytogenes in the blood agar plate [Figure 2b] and brain heart infusion (BHI) broth. The organism was sensitive to gentamicin and penicillin G. The culture of the vitreous fluid showed few gram positive bacilli which were not further identified. Valtrex and moxifloxacin were stopped and the patient was given intravenous penicillin G 15 million units every 6 h (following a negative skin test) for 2 weeks and then shifted to oral augmentin 1 g twice daily for another 2 weeks. The patient subsequently developed cataract for which he underwent phacoemulsification with posterior chamber intraocular lens (PC-IOL) implantation 4 weeks after his admission [Figure 2c]. Another AC fluid was sent for culture at the time of his cataract procedure which was negative. His last examination 1 month following surgery showed vision of 2/200 in the right eye which improves with pinhole to 20/160 and intraocular pressure (IOP) 12 mmHg controlled on a single antiglaucoma medication (Xolamol drops). The slit lamp examination showed corneal + 2 edema and haze, total peripheral anterior synechia with shallow AC, stable IOL, and hazy fundus view [Figure 2d].

endophthalmitis, laser-assisted in situ keratomileusis, listeria, pigmented hypopyon

PMC6878774_01

Female

A 64-year-old woman with a history of refractory acute myeloid leukemia (AML), hypertension, and left ear deafness was admitted for allogeneic bone marrow transplant and subsequently died of intracerebral hemorrhage secondary to mucormycosis 13 days after receiving her stem cells. This patient was originally diagnosed with AML 8 months prior to HSCT because of fatigue and pancytopenia on lab work. Peripheral smear at the time showed 43% blasts, and a subsequent bone marrow biopsy showed 60-70% myeloblasts consistent with a diagnosis of AML. Genetic studies done of the bone marrow showed deletions of 16q and 5q, and FLT3 was negative. She was started on induction treatment with 7 + 3 cytarabine/idarubicin which was complicated by neutropenic fever and AML retinopathy. Neutropenic fever occurred on day 2 of induction treatment admission for which she was given piperacillin/tazobactam until she became afebrile on day 13 of admission. Fevers recurred on day 15 of admission for which cefepime and metronidazole were started. CT scan of her chest was done on day 16, showing a new right lower lobe opacity concerning for pneumonia along with 9 nodules in both the lungs, all less than 6 mm. Treatment dose voriconazole was added for fungal coverage. On day 19, she was broadened to meropenem and anidulafungin due to recurrent fevers. A repeat CT scan of her chest including her sinuses was done showing resolution of her previous consolidation with no evidence of significant sinus disease and no change in her lung nodules. She became afebrile on day 4 on meropenem and anidulafungin but was continued on these antibiotics until day 47 of admission awaiting her absolute neutrophil count (ANC) to reach 500. She was then switched to oral ciprofloxacin, amoxicillin/clavulanic acid, and voriconazole. She completed a total of 7 days of oral antibiotics and then was put on prophylactic voriconazole and acyclovir until HSCT. After induction, she suffered from prolonged neutropenia and never reached an ANC above 1,130 in the time between the first induction and her death (about 7 months in total). Her treatment after 7 + 3 consisted of cladribine, mitoxantrone, decitabine, and venetoclax with venetoclax finally achieving remission. At the time of transplant, her disease status was in complete remission with incomplete hematologic recovery (CRi) due to sustained cytopenia. On the last office visit prior to being admitted for HSCT, she was noted to have no symptoms and felt overall well. In terms of further imaging after initial diagnosis, she had a repeat CT scan 7 days prior to HSCT as part of her pretransplant workup to monitor the nodules previously seen. This scan showed stable nodules, all of which did not change in size or appearance. No consolidation or new findings were seen. The patient was admitted and started on trimethoprim-sulfamethoxazole, fluconazole (switched to voriconazole one day prior to HSCT), and valacyclovir prophylaxis. She then started receiving a myeloablative conditioning (MAC) regimen with total body irradiation (TBI) (total dose 12 Gray (Gy) divided into 6 fractions). Two days following TBI completion, she received her donor leukocyte infusion (DLI), followed by cyclophosphamide and mesna 3 days after DLI. She then received her CD34+ stem cells 6 days following DLI infusion. She had her first recorded fever of 101.0 on day (-5) of her transplant, one day following DLI infusion. From this day until the date of death, she was noted to have daily fevers, as high as 104.0. Blood cultures were drawn daily, all of which showed no growth. Sputum cultures were not obtained due to lack of productive cough, and urine cultures showed no growth. She was initially started on cefepime for neutropenic fever which was eventually broadened to meropenem then to piperacillin-tazobactam and vancomycin. She was also switched from prophylactic voriconazole to treatment dose voriconazole 2 days prior to death. Switching to amphotericin B or brain imaging was not considered upon first fevers due to lack of consideration for mucormycosis. Twelve days after receiving her stem cells, she started complaining of severe right shoulder pain; a chest X-ray was obtained which showed a right upper lobe consolidation. CT scan of the chest was done which showed ground glass consolidation with interlobular septal thickening and mucoid impaction. The day after the shoulder pain started, the patient became increasingly fatigue and more lethargic but was answering questions appropriately. Later that afternoon, she was noted by the nursing staff to be completely unresponsive. The patient was emergently intubated and taken for a noncontrast CT scan of the head which showed extensive cerebellar edema with peripheral hemorrhage in the cerebellar folia and petrosal surface of the cerebellum with upward herniation. There was also marked compression of the brainstem and effacement of the fourth ventricle with lucency of the brainstem compatible with ischemia (Figure 1) and associated upward herniation of the cerebellum (Figure 2). Additionally, there was a 7 mm focus of high density in the right frontal lobe and 4 mm focus of hyperdensity in the left frontoparietal junction. About 6 hours after this event, the patient was made comfort care and died shortly thereafter. On autopsy of the brain, it was noted the patient had duret hemorrhage in the pons, cerebellar intraparenchymal hemorrhages and associated subarachnoid hemorrhage with cerebellar edema, right frontal lobe hemorrhagic infarct with angioinvasive fungi, and a small left thalamic hemorrhage. On fungal stain of the right frontal lobe, it was noted she had Mucor spp. as can be seen in Figure 3. No polymerase chain reaction (PCR) or fluorescent in situ hybridization (FISH) testing was done due to identifiable appearance on microscopic examination. No fungi were found in the brainstem as can be seen in the cross-sectional imaging of the pons in Figure 4. Acid-fast bacilli (AFB) stains were negative. Her gross exam of her right lung showed a firm dark-red mass on the right upper lung lobe, measuring 9.5 x 8.0 x 6.8 cm, and the cut surfaces of this mass reveals a well circumscribed, homogenous, round, dark-red fleshy mass resembling a hemorrhagic infarction. On microscopic examination, extensive hemorrhagic areas, pulmonary edema, and small pulmonary infarct areas around some vessels occluded with thrombi were found. Aerobic and anaerobic cultures showed very light growth of vancomycin-resistant Enterococcus and very light growth of Serratia marcescens. Fungal cultures showed light growth of Mucor spp. AFB stains were negative. Fungal staining showed large, nonseptate hyphae with 90 degree angle branching and nonparallel walls consistent with Mucor spp. Again, no PCR or FISH testing was done due to identifiable appearance on microscopic examination. Examination of the sinuses showed no significant disease. The sequence of events most likely leading to her death was concluded to be frontal lobe fungal invasion causing edema and hemorrhage leading to cerebellar tonsillar herniation, brainstem hemorrhage, and ultimately death.

PMC10311226_01

Female

Patient information: a 37-year-old lady presented with complaints of painless gross hematuria and dysuria for one month. In past, she had undergone augmentation ileocystoplasty at 12 years of age for a thimble bladder and left simple nephrectomy for pyonephrosis due to genitourinary tuberculosis. One year back she underwent a cystoscopy at an outside center for similar complaints that showed a tumor lesion measuring 1 x 1 cm and located at the bladder dome. The tumor was completely ablated endoscopically. There was no histopathology or urine cytology report available from that event. The patient did not have any associated chronic medical illness, or history of any substance abuse, or addiction. There was no family history of similar complaints. Clinical findings: the patient s vital signs and abdominal exam were normal. Diagnostic assessment: her blood investigations revealed hemoglobin of 12.4 g/dl and serum creatinine of 2.5 mg/dl. Liver function tests and serum electrolytes were in the normal range. Non-contrast computed tomography of the kidney, ureter, and bladder region (NCCT-KUB) revealed mild hydronephrosis and complete mild hydroureter of the right side. The urinary bladder was distended and showed a lobulated contour. There was an irregular, lobulated, enhancing soft tissue lesion along the anterior vesical wall in the transposed ileal segment measuring 2.1 x 4.7 x 4.8 cm with mild peri vesical fat stranding. There was no evidence of any enlarged lymph nodes on NCCT-KUB (Figure 1). Urine cytology was suspicious for malignant cells. Therapeutic intervention: she underwent transurethral resection of bladder tumour (TURBT) under general anesthesia. On cystoscopy, there was a solid proliferative growth along the anterior vesical wall in the transposed ileal segment measuring 2 x 5 x 5 cm with evidence of neovascularization. The right ureteric orifice was not visible. The biopsy report was suggestive of adenocarcinoma of the ileum. The patient subsequently underwent anterior pelvic exenteration (open radical cystectomy and hysterectomy), and right-end ureterostomy (Figure 2). A decision for ureterostomy was taken considering her serum creatinine of 2.5 mg/dl and dilated thick-walled right ureter. The cut margin of the ureter was negative on the frozen section. Follow-up and outcomes: the post-operative course was uneventful. The patient was discharged on post-operative day seven. The final histopathology report was suggestive of moderately differentiated adenocarcinoma, purely intestinal type. There was no urothelial differentiation. Adjacent mucosa showed intestinal metaplasia. Tumour infiltrated the deep muscle layer. All 16 lymph nodes examined were free of tumors. The right ureteric margin was also free of tumour (final stage - pT3N0M0). Flourine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) at 3 months postoperatively showed no evidence of abnormal uptake or suspicious metabolic active disease. At 6 months follow-up, the patient was asymptomatic with a serum creatinine of 2.2 mg/dl. A medical oncologist s opinion was taken. The patient did not receive any adjuvant treatment in view of the absence of lymph nodal involvement and the absence of any metabolic active disease on FDG PET/CT. Patient perspective: during her hospitalization and after treatment, the patient was satisfied with the care she received. Informed consent: written informed consent was obtained from the patient for participation in our study.

augmentation cystoplasty, adenocarcinoma, case report