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PMC3123906_01

Male

A 54-year-old ex-smoker presented with an abnormal chest radiograph. He was asymptomatic had a normal physical examination, and the radiograph was taken as part of a license application. CT scan revealed a well-circumscribed lesion in the right lower paratracheal region abutting the azgos vein. EBUS-TBNA was performed using the 7.5 MHz convex probe bronchoscope (BF-UC260F; Olympus Ltd, Tokyo, Japan). The lesion was identified as a round, anechoic structure and distinguished from surrounding blood vessels using color Doppler (Figure 1). A dedicated 22-gauge needle (NA-202, Olympus Ltd, Tokyo, Japan) was used to puncture and aspirate the lesion under direct visual guidance. To ensure complete drainage of the lesion, the gradual shrinkage of the cyst was observed on ultrasound while 50 milliliters of serous fluid was aspirated (Figure 1). Cytological examination of the aspirate yielded metaplastic squamous cells with negative microbiological cultures. He has remained clinically and radiologically stable on followup for 18 months.

PMC3123906_02

Male

An 18-year-old male presented with an abnormal chest radiograph that was performed before military enlistment. He was also asymptomatic and had a normal physical examination. CT scan revealed a mass in the right hilum. EBUS-TBNA was performed and ultrasound identified a round lesion with an echogenic centre and thickened, hyperechoic walls (Figure 2). Ten milliliters of purulent aspirate was drained. Cytological examination identified numerous neutrophils, occasional squamous cells and an amorphous granular background. Bacterial cultures grew Haemophilus influenza. He was treated with antibiotics and referred for surgical resection. A lobulated mass at the root of the right upper lobe with a cystic cavity was found on right thoracotomy. Histopathological examination revealed a well-defined cystic space lined by inflamed respiratory epithelium consistent with the diagnosis of an intrapulmonary bronchogenic cyst.

PMC6512394_01

Male

A 52-year-old obese (100 kg, 1.80 m) Caucasian man presented in January 2017 with multiple nodules with purulent drainage on the upper extremities persisting for more than 10 years. Several attempts of treatment with oral antibiotics had been unsuccessful. The number of nodules was increasing over the time. He had a medical history of chronic inflammatory demyelinating polyneuropathy diagnosed in 2000. Therefore, he was on immunosuppressive therapy with methylprednisolone 20 mg per day and azathioprine 200 mg per day. Additionally, he was on medication with acetylsalicylic acid after a myocardial infarction in 2010 and antihypertensives. Physical examination showed a violaceous firm nodule with purulent drainage over the proximal phalanx of the left middle finger (Figure 1A) and up to 20 reddish to violaceous firm nodules up to 4 x 2 cm in size on the right arm (Figure 1B). Additionally, there were extensive well-demarcated, erythematous macules with scaly borders on the chest. All finger- and toenails showed onychodystrophy and yellowish discoloration. Furthermore, physical examination revealed an enlarged lymph node in the left axilla. Abdominal ultrasound revealed a slight hepato- and splenomegaly. Biochemical examination showed an elevated white blood cell count (16.300 /mul) with relative lymphocytopenia, low hemoglobin (9.9 g/dl) with iron deficiency and elevated HbA1c (7.9%). Other routine laboratory tests were unremarkable. Screening for human immunodeficiency virus and tuberculosis was negative. Direct microscope examination by potassium hydroxide (KOH) preparation of scales from a lesion of the chest, of nail scrapings and of pyogenic fluid of a nodule showed each branched septate hyphae. Fungal culture of each of the above mentioned specimens revealed T. rubrum. Bacterial cultures were negative. A biopsy specimen of a nodule from the right forearm showed a dermal abscess with massive neutrophils in the center and macrophages in the border area (Figures 2A,B). The Periodic Acid Schiff (PAS) staining showed branched septate hyphae in the transition zone between granulomatous inflammation and abscess (Figure 2C). Fungal culture of the biopsy specimen also showed T. rubrum. Culture for non-tuberculous mycobacteria was negative. Furthermore, a biopsy specimen from the erythematous macula on the chest showed the histopathologic picture of tinea superficialis with branched septate hyphae in PAS staining. The patient was diagnosed as deeper dermatophytosis by T. rubrum presenting in form of multiple dermal abscesses. Treatment was started with oral itraconazole 200 mg per day and local application of ciclopirox twice a day. The patient did not show up for follow up and medication was only unsteadily taken. Four months later the patient presented again in our department with now multiple well-demarcated erythematous scaly plaques on the trunk and growing size of the abscesses on the right elbow. He had presented to an office-based doctor, where a drug eruption was assumed, why treatment with itraconazole was stopped. However clinical examination and biopsy specimen of the plaques revealed tinea superficialis. Nevertheless, a treatment change to griseofulvin 500 mg twice a day was conducted. Again, the patient took the medication only unsteadily which resulted in an improvement of the clinical outcome but no cure with nodules still present after 6 months.

trichophyton rubrum, abscess, dermatophytosis, fungal infection, immunosuppression

PMC9380727_01

Male

A 3-year-old Ethiopian boy came to the hospital with four months history of progressive dry cough and progressive worsening of shortness of breath accompanied by low grade intermittent fever. There was no history of contact with a tuberculosis patient. He had no history of weight loss, yellowish discoloration of the skin or sclera, abdominal pain and abdominal distention. He passed most of his day time playing with the dog. The patient received different kinds of po antibiotics and salbutamol puffs considering pneumonia and hyper reactive airway disease since the age 2 years and 6 months with no relief. Physical examination during admission revealed an acutely sick-looking child with a breathing rate of 60 breaths per minute, a saturation of oxygen (80% with atmosphere oxygen) and a temperature of 37.4 degrees centigrade. Chest examination showed flaring of alae nasi, subcostal and intercostal retractions, diffuse bilateral wheeze and decreased air entry on lower lung fields bilaterally. Investigations from referral showed the complete blood count, organ function test and abdominal ultrasound were non-revealing. During admission a posteroanterior chest X-ray was done, which showed bilateral lung mass with homogenous opacification of the right and left hemithorax (Figure 1). Chest ultrasound showed well-defined cystic mass lesions at the site of the mass with no septations or debris and the impression being cystic lung mass lesions. For further clarification computed tomography of chest was done and showed large bilateral thick-walled cystic lesions sizes of 9 x 7.5 x 7.6 cms in the right side and 8.3 x 7.8 x 5.4 cms in the left side, both located in the lower segments of the upper lobe. Bilateral perihilar extension and pressure effect on the diaphragm with surrounding atelectatic changes and fissural thickening with minimal interfissural fluid were found in the left side (Figure 2). With the consent from the parents, left posterolateral thoracotomy and hydatid cystic mass excision (cystectomy) were done. Intraoperatively there was a 8 x 7cms well-defined cystic mass arising from left upper lobe inter-lobe fissure attached to the left lower lobe surface. The whole cyst was removed with no spillage (Figures 3A and B). Two months later, right posterolateral thoracotomy and cystectomy were done for the right lung hydatid cyst. The whole cyst was removed with no spillage for the right hydatid cyst as well and the child recovered well post-operatively.

echinococcus granulosus, chest tomography, cyst excision, hydatidosis

PMC3068586_01

Female

A 19-year-old girl presented with swelling in the left side of the neck of 1 year duration. She also had fatigue and headache. She did not have any history of fever or night sweats. Physical examination revealed pallor, icterus, and multiple left cervical lymph nodes. These lymph nodes were firm, nontender, matted, and mobile. Systemic examination showed mild splenomegaly. Laboratory findings on admission were as follows: hemoglobin 3.5 g/dL, total WBC count 4800/mm3(52% neutrophils and 48% lymphocytes), platelet count 225,000/ mm3, MCV 97, MCH 30.5 fL, and reticulocyte 12%. Peripheral smear showed anisopoikilocytosis with macrocytosis and spherocytosis. Bone marrow examination showed erythroid hyperplasia. Biochemical tests were as follows: total bilirubin 3.7 mg/dL, direct bilirubin 2.0 mg/dL, indirect bilirubin 1.7 mg/dL, LDH - 720 U/L and haptoglobulin 20 mg/dL. Coomb's test done prior to transfusion was positive (Table 1 for hematological parameters before starting anti-tuberculosis therapy). Serum levels of urea, creatinine were within normal limits and glucose 6 phosphate dehydrogenase activity was normal. Serologic tests for antinuclear antibodies, human immunodeficiency virus, mycoplasma, hepatitis B and C virus were negative. Left cervical lymph node biopsy showed caseating granulomatous lymphadenitis [Figure 1] Mantoux test was positive (18 mm induration). Chest X-ray was normal and ultrasound of abdomen revealed splenomegaly. Patient was started on antituberculosis treatment with isoniazid (300 mg qday), rifampicin (450 mg qday), ethambutol (800 mg qday), and pyrazinamide (750 mg bid). Her symptoms of fatigue and headache started improving after 2 weeks of treatment. Hemoglobin improved to 5 gm/dL after 2 weeks of treatment and Coomb's test became negative after 2 months [Table 2]. She is on follow-up and is in excellent health.

anemia in tuberculosis, immune hemolytic anemia, tuberculous lymphadenitis

PMC5724727_01

Female

A 35 year old female, presented with right sided chest pain, associated mild abdominal pain, and partial obstructive symptoms for several years. There was no significant past personal or family history). There was no history of trauma. Clinical examination revealed that she was mildly dehydrated, tachycardic (heart rate 110 beats per minute), afebrile, normotensive, and had mild abdominal tenderness. Investigation revealed a raised white cell count of 12.35x 10gl (reference range 4-10xgL). A chest radiograph revealed radio-opacity of right basal area (Figure 1) an abdominal erect radiograph was unremarkable. The patient was admitted with a presumed diagnosis of intra-abdominal tuberculosis, the medical officer was asked to do right thoracocentesis, which yielded a small amount of blood. While the patient was awaiting a chest and abdominal computed tomography (CT), she developed a mechanical intestinal obstruction. An emergency exploratory laparotomy was performed through a midline incision. We found a right sided Bochdalek's hernia containing transvers colon, right colon, along with the appendix and terminal ilium. The worrisome finding was that of a closed-loop intestinal obstruction. Incidentally, there were three accessory liver lobes, likely constituting the right lobe of the liver. The diaphragm had to be divided slightly to enable reduction of the incarcerated contents. These contents appeared compromised, but viable. Of particular interest, there was no hernia sac. The right lower lobe of the lung appeared hypoplastic. After reduction of the hernia contents, the diaphragmatic defect was repaired in a tension-free fashion. A limited resection and primary repair of the compromised redundant transvers colon was carried out. After careful consideration, we decided to carry out an incidental appendectomy. A right-sided chest tube was placed under direct vision, before closure of the diaphragmatic defect. The patient was transferred in to intensive care unit (ICU). She made an uneventful recovery and was discharged home. She was discharged home in excellent condition, and remains well at nine month follow-up (Figure 1).

bochdalek hernia (bh), appendectomy, colon, congenital, hernia repair

PMC7248675_01

Female

A 41-year-old female consulted with 3-month history of pain in the sacroiliac region associated with arthralgias and myalgias of the lower limbs that partially improved with nonsteroidal anti-inflammatory drugs (NSAIDs). She denied cutaneous, digestive or ocular symptoms. An MRI of the sacroiliac joints showed subchondral bone marrow edema in both sacroiliac joints suggesting active sacroiliitis. A diagnosis of seronegative spondyloarthropathy with negative HLA-B27 was performed. Two months later, she started Etanercept 50 mg administered subcutaneously once weekly, showing significant clinical improvement. After the third dose of the drug, she presented dry cough without expectoration and moderate effort dyspnea. She denied orthopnea, paroxysmal nocturnal dyspnea or upper respiratory symptoms. She had no chest pain, syncope or hemoptysis and did not refer digestive, genitourinary, cutaneous or neurological symptoms. Her past medical history included two cesarean sections and a septorinoplasty. She denied previous exposure to tobacco or allergic diseases. In addition to Etanercept, she received vitamin D 2000 IU and Etoricoxib 90 mg daily. She had not traveled recently, did not have contact with animals, dust, particulate material or ill people. The respiratory symptoms progressed rapidly. Thus, the patient consulted to the emergency department (ER). On admission to the ER, she was in acceptable general conditions, without signs of respiratory distress or requirement of supplementary oxygen at rest. Her blood pressure was 118/84 mmHg, pulse 96/bpm, respiratory rate 18/bpm, and weight 64.85Kg. She had no neck masses or jugular engorgement, the heart sounds were rhythmic without murmurs, the vesicular murmur was preserved in both lung fields. On pulmonary examination basal scanty pulmonary rales "Velcro"-like were auscultated. The abdomen had no masses, the extremities had neither edema nor inflammatory signs. The Tinel's sign was negative, Phalen's sign negative. Sacroiliac pain provocation tests were positive. A high-resolution thoracic CT scan showed incipient ground-glass interstitial infiltrates of centrifugal distribution, especially involving the upper lobes. The EKG revealed a normal sinus rhythm. The transthoracic echocardiogram was normal without evidence of pulmonary hypertension. We decided to perform bronchoscopy with bronchoalveolar lavage (BAL), which showed a negative GeneXpert for Mycobacterium tuberculosis and a negative methenamine silver stain. Laboratory tests taken during admission revealed Hb 13 gr/dL, Hct 42%, leukocytes 4100/mm, neutrophils 2000/mm, lymphocytes 1400/mm, eosinophils 50/mm, platelets 325,000/mm, AST 29, ALT 23, total bilirubin 0.3, direct bilirubin 0.1, creatinine 0.6 and BUN 16. A new high-resolution thoracic CT scan was performed. This scan showed a mosaic pattern of disseminated attenuation in both lungs with foci of ground glass infiltrates (Fig. 1 A, B, C). To dismiss the possibility of an infection a new bronchoscopy with a transbronchial biopsy was also performed. In the bronchoscopy, the aspect of the airway was normal, without endobronchial lesions or bleeding (Fig. 1 D), washing cytology showed a predominance of lymphocytes in 46% without the presence of malignant cells. The methenamine silver stain was negative. The pathology report showed the presence of rounded granulomas, composed of macrophages, epithelioid cells, multinucleated giant cells, and scarce lymphoplasmacytic infiltrate. No central necrosis or microorganisms were identified. Based on the results obtained, we diagnosed acute toxicity by Etanercept presenting as granulomatous pneumonitis. Consequently, after a multidisciplinary evaluation, we decided to initiate pulses of methylprednisolone 500 mg for three days, continuing with an oral dose of prednisone 50 mg daily for twelve weeks. The dose was reduced progressively until reaching 12.5 mg daily with adequate tolerance and decrease of symptoms of cough and dyspnea. Four weeks after starting the treatment with steroids, the patient was in an excellent general condition, without respiratory symptoms. A new high-resolution thoracic CT scan showed a notable decrease in the mosaic attenuation (Fig. 2 C, D). Two months later, she was in good clinical condition and had returned to work without new relapses nor respiratory symptoms.

anti-tnf, case report, etanercept, pulmonary granulomatosis, spondyloarthropathy, tnf-α

PMC8497141_01

Female

A 33-year-old primigravida consulted the emergency department with a 40-week pregnancy and history of spontaneous rupture of membranes (SROM). The diagnosis of SROM was confirmed, and she was admitted to labor and delivery. Augmentation of labor was initiated, and approximately 2 hours after admission, fetal bradycardia was observed, and she was taken to an emergency cesarean delivery. During surgery, about 50% of placental abruption was diagnosed. No important bleeding was reported afterwards, and no surgical complications were reported. A healthy female newborn was obtained, who weighed 3.3 kgs, Apgar score was 8-9, and no neonatal complications were reported. Fourteen hours after the surgery, the patient was noted jaundiced, oliguric, and hypoglycemic (glycemia: 40 mg/dL). She was conscious and alert, and no important obstetric bleeding was evidenced at the time. Her vital signs at that moment were the following: heart rate: 120 beats per minute (BPM), peripheral capillary oxygen saturation (SpO2): 95%, respiratory rate: 16 respirations per minute (RPM), temperature 36.3 degree Celsius, and blood pressure: 74/48 mmHg. Laboratory tests evidenced important hepatic dysfunction (Total Bilirubin (TB) 7.9 mg/dL, Indirect Bilirubin (IB) 2.7 mg/dL, direct bilirubin (DB) 5.149 mg/dL, Aspartate Aminotransferase (ASAT) 170 U/L, and Alanine Aminotransferase (ALAT) 149 U/L), coagulopathy (prothrombin time (PT) 27 seconds, International Normalized Ratio (INR) 2.56, and fibrinogen 71 mg/dL), acute kidney injury (creatine 2.7 mg/dL) as well as hyperammonemia (126 mumol/L), low platelets (95 000), and leukocytosis (33 030/microliter). At this point, her hemoglobin level was 9.9 mg/dL, hematocrit 27.8%, and lactate dehydrogenase (LDH) 432 IU/L. Due to the laboratory anomalies, an abdominal ultrasound was ordered. The ultrasound revealed an echogenic liver with fatty infiltrates and mild hepatic steatosis. It is important to note that on the days prior to her hospital admission, the patient had not presented with any symptoms suggesting hepatic failure, and she had no known exposure to virus or medications that could explain the clinical alterations. At this moment, the patient was considered to have 7 Swansea criteria and was admitted to the ICU with suspicion of AFLP. In the ICU, resolution of the coagulopathy was initiated with blood products. The transfusion was guided by rotational tromboelastography (ROTEM). She required platelets (1 pool), fresh frozen plasma (1 unit), and cryoprecipitates (1 unit). The patient remained stable for the next 3 days. On postoperative day 5, the patient deteriorated importantly. She turned disoriented and encephalopathic; she was coagulopathic (prolonged PT and INR > 5) once more and persistently hypoglycemic despite an adequate diet. Other causes of hepatic failure in pregnancy and postpartum were discarded, such as viral hepatitis. At this point, the decision to start plasma exchange therapy was made, she received a total of three sessions (one daily) of PE, and recovery of her neurological status and laboratory tests was reached on postoperative day 9. Once the coagulation disorder was reversed, she was taken to a transjugular hepatic biopsy. The biopsy reported microvesicular steatosis, ballooning degeneration of hepatocytes, canalicular cholestasis, and cholangiolitis, findings suggesting AFLP considering the clinical context. On postoperative day 15, the patient was discharged home, with complete resolution of symptoms and normalization of hepatic and renal functions.

PMC6556304_01

Female

A 50-year-old Caucasian female with a history of difficult-to-control asthma since 1994 and chronic rhinitis presented to the hospital with severe jaw and ear pain in late February of 2009. She had been suffering from intermittent pain for a few months and underwent bilateral myringotomy tube placement about a month prior for recurrent otitis media with some benefit. The pain was distributed over the rami of the mandible bilaterally with radiation to her ears. She denied any fever, night sweats, weight loss, purulent nasal discharge, odynophagia, dysphagia, or shortness of breath. No significant history of travel or sick contact including contact to TB patients. The patient was a past smoker with 15 pack year history of smoking. Vital signs on admission showed a BP of 101/63 mm Hg, pulse of 105 beats/minute, temperature of 97.9 F, respiratory rate of 18 breaths/min, and SPO2 of 96% on room air. Physical examination revealed a patient in moderate distress. Bilateral tenderness was elicited while palpating the mandibular rami. The myringotomy tubes were intact without and significant drainage. The nasal mucosa appeared normal without any evidence of erythema, epistaxis, or discharge. The rest of the physical examination was unremarkable. The laboratory data are shown in Table 1. Urinalysis showed trace proteinuria and no RBC cast. Electrocardiogram and a chest X-ray were normal. She underwent a CT scan of her neck with contrast which was unremarkable except left maxillary sinus thickening. However, the apical part of the lungs showed multiple nodules bilaterally. A dedicated high-resolution CT scan of the chest revealed multiple bilateral nodules, 5-11 mm in diameter. The largest nodule was noted in the lingula that measured 11 x 9 mm. There was also evidence of pericarditis and small pericardial effusion. Given her long standing history of uncontrolled asthma, upper airway symptoms, eosinophilia, and multiple pulmonary nodules, a clinical diagnosis of EGPA was made and the patient underwent an extensive rheumatologic workup which is shown in Table 2. The patient underwent an open lung biopsy of the lingular nodule as well as a pericardial biopsy. The histopathology was consistent with necrotizing granulomatous vasculitis with extravascular eosinophilic infiltrate. The histopathology slides are shown in Figures 1 and 2. The diagnosis of EGPA was confirmed. The patient was started on high-dose prednisone and azathioprine in March 2009. She initially did well, but in August 2009 the patient was admitted to the hospital with pulmonary edema secondary to heart failure with reduced ejection fraction (HFrEF). The echocardiogram showed an EF of 25-30% with biventricular dilatation and global hypokinesis. No wall motion abnormality was identified. Cardiac catheterization was negative for coronary artery disease. No endomyocardial biopsy was performed. Given the high incidence of cardiac involvement in EGPA and a negative coronary angiogram, the myocardial dysfunction was thought to be secondary to EGPA and she was started on IV cyclophosphamide. Over the course of next 6 months, the patient completed 6 cycles of IV cyclophosphamide and started on mycophenolate. Steroid taper was continued. Her EF recovered completely, but she suffered from multiple vertebral body compression fractures and developed cushingoid appearance secondary to chronic steroid therapy. Between September 2009 and July 2011, she suffered from 2 episodes of sinusitis which was treated with short course of antibiotic. Her disease remained well controlled with normal inflammatory markers. During an office visit in July 2011, the patient was noted to have depressed nasal ridge (Figure 3). Physical examination showed nasal mucosal erythema. The patient underwent reconstruction of her nasal bridge in July 2013. Since 2011, the patient has been managed with mycophenolate without any incidence of exacerbation and is doing well currently.

PMC2929613_01

Male

A 55-year-old man, who was a former smoker and had chronic silicosis caused by 14 years of work in the granite industry, was admitted to the hospital after an episode of hemoptysis. The amount of blood expectorated was estimated at more than 200 mL. He also had a one-month history of productive cough with blood in the sputum. He had previous history of tuberculosis, with the last episode approximately two years prior, when he received isoniazid, rifampin, and pyrazinamide for two months, followed by four months of isoniazid and rifampin. He had been asymptomatic since then. On physical examination, the patient was emaciated and pale. His blood pressure was 100/70 mmHg, his pulse was 104 beats/min, and his respiratory rate was 20 breaths/min. Lung auscultation revealed rhonchi and wheezing in both lungs. No other alterations were seen in the physical examination. A blood chemistry screening was normal, including negative finding by anti-HIV. Immunodiffusion tests were negative for Aspergillus. A chest radiograph (Figure 1) and high-resolution computed tomography (HRCT) of the thorax (Figure 2) showed bilateral conglomerate masses, one with cavitation, associated with multiple small nodules, in addition to calcifications of the hilar and mediastinal lymph nodes, paracicatricial emphysema, architectural distortion, and enlargement of the central pulmonary arteries. No other parenchymal findings were suggestive of active tuberculosis. The expectorated sputum was negative for acid-fast bacilli and the patient underwent a bronchoscopy that showed evidence of active bleeding. Direct examination of the bronchoalveolar lavage was negative for tuberculosis, fungi, or malignancy. Culturing was positive for Mycobacterium tuberculosis and negative for fungi. Because of the enlarged pulmonary arteries, Doppler ecocardiography was performed, showing left ventricular diastolic function, mild tricuspid regurgitation, and pulmonary arterial hypertension with a systolic pulmonary artery pressure of 48 mmHg. The patient underwent an angiogram of the common bronchial trunk that showed marked hypervascularity and enlargement of left bronchial artery, which was selectively catheterized and subsequently embolized with polyvinyl alcohol particles (PVA). Bleeding stopped after embolization. The patient was treated for tuberculosis with isoniazid, rifampin, pyrazinamide, and ethambutol for two months, followed by seven months of isoniazid and rifampin. After the embolization and clinical treatment for tuberculosis, the patient progressed well, with improvement in his respiratory symptoms, and no rebleeding after a follow-up of two years.

PMC9530368_01

Female

A 66-year-old Chinese woman was referred to our hospital in June 2021 due to olfactory hallucination. In 2004 the patient had been admitted to our hospital due to insomnia and nightmares. She had difficulty in initiating sleep and frequently awaked almost every night. The sleep disturbance caused her distress in daily life. She was diagnosed with insomnia disorder. Administration of 12.5 mg doxepin per night improved her sleep, and the patient reported stable mood and good social function during follow-up. However, in May 2017 she gradually manifested olfactory hallucinations, claiming that she could smell some Chinese medicines, even in wide open spaces on mountains. She did well in her job as a storekeeper and took good care of her grandson. At first, she went to the otorhinolaryngologic department, but the nasal endoscopy revealed normal structural nasal cavity or nasopharynx, axial and coronal computed tomography of the nose did not show abnormalities, so she did not get any treatment but psychiatric consultation was recommended. She was diagnosed with brief psychotic disorder after 20 days of olfactory hallucination onset in a local hospital, and she denied manic, depressive or anxious mood, denied unexpected panic attacks, denied psychotic symptoms except olfactory hallucination. The psychological tests administered by clinicians indicated a Hamilton Depression Scale (HAMD) score of 5, Hamilton Anxiety Scale (HAMA) score of 3. She received olanzapine (10 mg/night) for 2 months, followed by aripiprazole (20 mg/day) for 1 month, but her symptoms continued. When the patient was admitted to our hospital in June 2021, she reported that 6 months before, her olfactory hallucinations had worsened and that the phantom smells had changed to something like a mixture of scallion, ginger, and garlic. At the same time, she reported being unable to smell normal scents, being unable to fall asleep at night, feeling restless and fatigued, having difficulty concentrating on daily activities, and often feeling limb muscle tension and sweating. She worried a lot about her daughter's marriage, feared that some accidents would happen to her family members. She can still take care of her grandson. She denied depressed mood, unexpected panic attacks, and phobic avoidance. The patient had completed primary school and had worked as a storekeeper until her retirement. She reported having grown up in a strict family environment and having a bad relationship with her ex-husband. She brought up her daughter alone and she lives alone since her daughter got married. She had a history of tuberculosis and cholecystectomy. In 2011 she had been diagnosed with hyperlipidemia and since then she had been taking 5 mg atorvastatin every night. The patient and her family members denied any drug abuse, smoking or drinking. She had no family history of mental disorders. In light of the patient's long history of olfactory hallucination, the otorhinolaryngology department was asked to examine her, and those clinicians suggested the possibility of phantom olfactory perception. To exclude organic lesions, auxiliary examination and nasal endoscopy were performed. Endoscopy failed to reveal obvious structural auxiliary abnormalities, or abnormalities in the nasal cavity or nasopharynx (see Figure 1). Axial and coronal computed tomography of the nose showed only paranasal sinusitis (see Figure 2). And brain magnetic resonance imaging only showed a few ischemic foci in the brain parenchyma and paranasal sinusitis (see Figure 3). Chest computed tomography showed soft tissue nodules in the anterior basal segment of the lower lobe of the right lung, while both lungs showed multiple, scattered, small inflammatory nodules as well as mild chronic inflammation. Bilateral pleural thickening and adhesion, enlarged mediastinal lymph nodes, and aortic wall calcification were also observed. Thyroid color Doppler ultrasonography revealed bilateral lobular thyroid nodules suggestive of nodular goiter, while conventional color ultrasonography of the abdomen and urinary system indicated the presence of fatty liver, liver cyst, dilated common bile duct, and enlarged spleen. Electrocardiography and electroencephalography were unremarkable. Neurological examination showed no obvious abnormalities, and her apolipoprotein E genotype was E3/E3, suggesting low risk of Alzheimer's disease. In addition, no obvious abnormalities were found in routine blood or urine indices, liver or kidney function, electrolytes, blood lipids or glucose, coagulation or thyroid function, tumor markers, or glycosylated hemoglobin. Assessment of symptoms was based on a Chinese version of HAMD and HAMA administered by a psychiatrist. HAMD score of 8, HAMA score of 22. Chinese version of Childhood Trauma Questionnaire score 33 (emotional abuse score 9, physical abuse score 5, sexual abuse score 5, emotional neglect score 9, and physical neglect score 5) which indicated without childhood trauma. Mini-mental State Examination score25, and Montreal Cognitive Assessment score of 24, indicating no obvious abnormalities in cognitive function. Based on the patient's reported symptoms and the tests, the patient was diagnosed at our hospital with generalized anxiety disorder based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. After diagnosis, the patient was treated with paroxetine (20 mg/day), tandospirone (10 mg three times a day), and lorazepam (0.5 mg/night) to relieve anxiety and control sleep disorders, as well as atorvastatin calcium (5 mg/night) to control hyperlipidemia. This medication was combined with electroencephalographic biofeedback training and repetitive transcranial magnetic stimulation once a day. After 4 days of this therapy, the patient started to smell strong odor of ammonia in the restroom, especially in the afternoon. Therefore, we adjusted the medication to tandospirone (10 mg three times a day), paroxetine (40 mg/day), and lorazepam (0.25 mg/noon and 0.5 mg/night). After 6 days on the modified drug regime, the patient claimed that the odor became mild, but she still had hyposmia for normal smells, especially in the afternoon. After 10 days on the physiotherapy and modified drug regime, the patient reported feeling relaxed and sleeping well at night, with no olfactory hallucination. After a total of 20 days hospitalization, transcranial magnetic stimulation sessions were stopped. She was discharged on tandospirone at 10 mg three times a day, paroxetine at 40 mg/day, and lorazepam 0.5 mg/night. She scored 7 on the HAMD and 8 on the HAMA. A timeline of treatment is shown in Figure 4. At 3-month follow-up, she reported no olfactory hallucination, and she slept well. She scored 5 on the HAMD and 4 on the HAMA. She lived with her daughter and took good care of her grandson every day. She denied anxious and her mood was relatively easy to maintain a smooth. She also had good tolerability of the medication.

anti-anxiety treatment, anxiety disorder, case report, first-episode, olfactory hallucination

PMC8060148_01

Male

This patient is an 87 year-old man with NYHA class III heart failure with reduced left-ventricular ejection fraction (35-40%), and a history of hypertension, atrial fibrillation, and chronic kidney disease. ECF%TBW was markedly elevated (56.7%) upon study entry, and the patient was readmitted to the hospital on study day 5. After a skilled nursing facility (SNF) stay, home monitoring resumed on study day 30. His ECF%TBW remained very high (57.0%), and bumetanide dose increases between study days 30 and 49 had minimal effect on fluid volumes and weight. Metolazone was started on study day 64, and the patient responded with a reduction in ECF%TBW to 52.7% on study day 76. He then left the study briefly only to be re-enrolled after his second readmission for heart failure. When BIS measurements resumed on study day 87, his ECF%TBW had risen to 54.7%. Metolazone therapy was reinitiated, and clinical, fluid volume, and weight stability was finally achieved by study day 115. The ECF%TBW strata shown in Figure 3B are based on population data and should be interpreted in clinical context. This patient was almost exclusively >51% (fluid overloaded state); achieving normal fluid status (41.5-46.4%) is an unrealistic goal in this case. With unblinded, real-time BIS data, it's likely that his caregivers would have recognized persistent fluid overload at the time of study entry as his ECF%TBW was 56-57%, markedly elevated even for this patient. An ECF%TBW of 50% and an ECF volume of 16 liters turned out to be reasonable targets in this case; a future goal of fluid monitoring in HF would be to identify and maintain target fluid volumes more quickly than is currently possible with weight tracking alone. Given that the BIS device used in this report (Figure 1) operates while the test subject is sitting or standing without contacting metal and/or electronic objects, use in the intensive care setting is impractical. For these patients, volume status can be monitored invasively via pulmonary artery catheterization, and for whom fluid intake and loss is carefully tracked. BIS technology, however, may play a role in the following settings: (a) emergency departments (EDs) and urgent care centers; (b) risk stratifying HF patients at the time of hospital discharge based on the extent of residual congestion; (c) longitudinal management in clinic and skilled nursing facilities; and (d) assessing at-risk HF populations for health care managers and chief medical officers. Because the ED and urgent care settings rely upon rapid, quantitative measures, bioimpedance-based assessment of fluid status may help facilitate triage of patients presenting with dyspnea. BIS measurements obtained in the ED:by serving as a point of comparison:may assist in the next phase of care if admission is required. HF patients, when admitted to the hospital, usually need diuresis, but knowing when sufficient decongestion has been achieved can be challenging. Currently, physical exams, weights, and echocardiographic measures are used to assess hydration; however, despite use of these methods, 30-day readmission rates remain high. BIS-measured ECF%TBW at the time of hospital discharge may help identify patients at high-risk of readmission owing to persistent congestion. In the outpatient setting, providers currently struggle with quantifying the extent of congestion. BIS may help distinguish between patients that are managed appropriately from those who may need an adjustment to their medication regimen.. As shown in Figure 4, BIS measurements correlate strongly with ultrasound-measured inferior vena cava size which has been used in clinic to manage diuresis and identify early fluid overload. Unfortunately, ultrasound is labor-intensive, requires a skilled operator, and is not always available. As more HF patients enter alternative payment models for care, objective measures of wellness are sought. A recent study of more than 500,000 patients identified leg impedance measures as an independent risk factor for clinical deterioration; hence, BIS measurements at a population level may eventually help identify at-risk individuals. By directing resources to patients who pose the greatest risk for decline, healthcare systems can better meet the demand for high-yield care. The case study presented in this report (Figure 5) is intended to provide an example of how BIS-derived fluid volume measures may be used to aid in monitoring patients with HF. It shows that ECF%TBW and ECF volume targets can be identified for heart failure patients [point (c), above]. This case also shows that patients may be discharged from hospitalizations for decompensated HF with substantial residual congestion [point (b), above]; this occurred on three occasions for this patient on study day 1 (ECF%TBW of 56.7%), day 30 (57.0%), and day 87 (54.7%).

bioimpedance spectroscopy, case study, extracellular fluid, heart failure, total body water

PMC7881396_01

Male

An Iranian 50-year-old man attended Taleghani Gastrointestinal Clinic for recurring epigastric pain. This patients complaints included epigastric pain, heartburn and dysphagia. He suffered from these signs and symptoms from four months before the tumor detection. No weight loss was detected. Past surgical history and family history of the patient were negative too. He did not smoke or drink alcohol. He was treated several times with omeprazole, anti-acids, and baclofen. Finally, he was referred to Taleghani Hospital Clinic by food sensation. In our setting, he was evaluated by endoscopy and a submucosal mass in cardia was detected. On physical examination, his temperature was 37.1 C, heart rate was 82 beats per minute, respiratory rate was 10 breaths per minute, and blood pressure was 130/80 mm-Hg. Abdominal examination showed neither distention nor tenderness. No organomegaly or palpable mass was found. Furthermore, laboratory tests had no remarkable findings. The evaluations included endoscopy of upper and lower gastrointestinal tract at the same time. The result of colonoscopy was normal. Endoscopy of the upper GI tract showed a 19x13 mm homogenous and hypoechoic submucosal lesion, with smooth and defined border in cardia at the third layer. In addition, EUS reported a small calcification in the center of lesion. Case presentation 2

endoscopic mucosal resection, subepithelial tumor

PMC7881396_02

Female

An Iranian 40-year-old lady was referred to the gastroenterology department of Taleghani Hospital with a submucosal mass lesion. The patient described her symptoms as intermittent epigastric pain, discomfort, dyspepsia, and heartburn from more than six months before the admission. No significant weight loss was detected in our case. She revealed two caesarean sections as the past medical history and the family history of gastrointestinal malignant disorders was negative. In addition, she denied any positive history of alcohol drinking or smoking. On physical examination, her temperature was 37.6 C, heart rate was about 84 beat per minute, and blood pressure was 110/70 mm-Hg. Abdominal examination showed a soft and non-tender abdomen with no sign of organomegally or palpable mass. The rest of the physical examinations and laboratory tests were normal. The evaluations before the referral included upper and lower GI tract endoscopy and ultrasonography. Endoscopy reported a polyp-like lesion in the antrum, while the mucosa in this place was normal. In addition, EUS showed a 16.3 mm subepithelial, iso-hyperechoic lesion originating from the submucosal layer. The pillow sign of the mass was negative. The gross feature of the lesion was in favor of lipoma. Endoscopic devices and procedures A soft, straight, transport cap with an inside rim (D-201-11802, Olympus) was fitted on to the tip of a standard single channel endoscope (GIF-260, Olympus). Other devices included Needle Knife (Olympus), Hot snares, and Hemoclips (Micro-Tech Nanjing Co., Ltd.). Under sedation with intravenous propofol in standard position, endoscopy was performed. The procedures included the following steps and all of them were attended by an expert and single endoscopist (Figure 1). The submucosal lesion was detected by retroflexed maneuver. Then, after the estimation the site of the polyps. The mucosal surface was unroofed with needle knife (this part is different with other previous known methods.). The lesion was retracted with grasps, and the mass was enucleated. It was resected with standard polypectomy hot snares. After resection, the mass was sent to a pathologist. Two hemoclips for each mass were inserted on the base of the lesion (Figure 1). Follow-up assessment In both cases, second look endoscopy was performed after six hours of the resection. The outcomes were followed up by endoscopy after the two months following the procedure, to confirm the healing of the artificial ulcers and other complications. The assessment of endoscopic parameters included resection rate, early and delayed perforation rate, early and delayed bleeding rate, dehiscence rate, and recurrence rate. Histopathological examinations In both cases, the tissue specimens were fixed in formalin solution. The histological analysis included the identification of cell types, nuclear atypia, histopathological type, tumor size, and tumor invasion. In the first case, immunohistochemical study was also performed. Furthermore, the margins of resection were examined macroscopically and microscopically. Histopathological results Case 1 The specimen consisted of a polypoid creamy tissue fragment measuring 1.7x1.5x1 cm and tiny fragments of creamy soft tissue measuring 1x0.7x0.3 cm. \4The primary histopathological analysis suggested gastrointestinal stromal tumor (GIST). IHC study included Smooth Muscle Antibody (SMA), Desmin, CD117, and DOG1. Desmin and SMA were positive but CD117 and DOG1 were negative. IHC and histologic findings were in in line with leiomyoma. Case 2 The specimen consisted of adipose tissue fragment measuring 1x1x0.5 cm. Histologic findings of endoscopic biopsy confirmed lipoma. Follow up Re-endoscopy, after six hours of resection reported no early complication, in both cases. After 12 hours of the procedures, both patients were discharged. Once discharged, the patients were prescribed daily oral Proton pump inhibitors (PPI) for two months. After two months, patients were evaluated by endoscopy again. Repeated endoscopy revealed, the hemoclips were spontaneously removed and the mucosa of the antrum was normal, in both cases. No macroscopic evidence of tumor was detected. Furthermore, the resection margins of the polyp were evaluated microscopically. Microscopically, all margins were free. Delayed perforation or delayed bleeding were not detected after 2 months.

endoscopic mucosal resection, subepithelial tumor

PMC8348966_01

Male

Case 1. An 87-year-old man with a history of smoking of 45 pack-years presented with blood-tinged sputum. Chest computed tomography (CT) revealed a large mass (7 cm) in the left hilar region, which was lumped together with the left hilar lymph nodes. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed on the hilar lymph nodes, and poorly differentiated lung adenocarcinoma was confirmed by immunohistochemistry. Biomarker analysis was negative for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation, and PD-L1 was highly expressed (TPS: 90%). The clinical stage after a systemic evaluation was cT4N2M0, stage IIIB. Pembrolizumab monotherapy was initiated because the patient was not eligible for curative radiation. Although tumor progression was observed immediately before treatment, partial response (PR) was achieved after two treatment cycles, and CR was achieved after nine cycles. After 35 cycles of pembrolizumab, the patient was found to have maintained CR during treatment-free follow-up, and currently, the patient is alive 36 months after treatment initiation.

alk, anaplastic lymphoma kinase, cr, complete remission, ct, computed tomography, complete remission, ebus-tbna, endobronchial ultrasound-guided transbronchial needle aspiration, egfr, epidermal growth factor receptor, ici, immune checkpoint inhibitors, immunotherapy, lung adenocarcinoma, nlr, neutrophil-to-lymphocyte ratio, nsclc, non-small cell lung cancer, os, overall survival, pd-l1, programmed death-ligand 1, pr, partial response, pembrolizumab, rr, response rate, tps, tumor proportion score

PMC8348966_02

Male

Case 2. A 63-year-old man with a smoking history of 43 pack-years was referred to our hospital for a detailed examination of abnormal shadows on chest radiography. Chest CT revealed an irregular nodule (15 mm) in the right upper pulmonary lobe with lymphangitic carcinomatosis and multiple enlarged right hilar and mediastinal lymph nodes. EBUS-TBNA was performed for the sub-tracheal lymph nodes, and immunohistochemistry confirmed lung adenocarcinoma. Biomarker tests were negative for both EGFR mutation and ALK translocation, and PD-L1 was highly expressed (TPS: 70%). The clinical stage after a systemic evaluation was cT3N3M1c (LYM), stage IVB with cervical lymph node metastasis. Pembrolizumab monotherapy was initiated. PR was observed after two cycles, and CR was achieved after 12 cycles. After completion of 34 cycles of pembrolizumab (the patient skipped one cycle for his own convenience), the patient was found to have maintained CR during treatment-free follow-up and is currently alive 42 months after the start of treatment.

alk, anaplastic lymphoma kinase, cr, complete remission, ct, computed tomography, complete remission, ebus-tbna, endobronchial ultrasound-guided transbronchial needle aspiration, egfr, epidermal growth factor receptor, ici, immune checkpoint inhibitors, immunotherapy, lung adenocarcinoma, nlr, neutrophil-to-lymphocyte ratio, nsclc, non-small cell lung cancer, os, overall survival, pd-l1, programmed death-ligand 1, pr, partial response, pembrolizumab, rr, response rate, tps, tumor proportion score

PMC4841995_01

Female

A 74-year-old Iranian woman presented with a 10-day history of malaise, weakness, fever, chills and sweating with no weight loss. She had received oral antibiotics four days after initial symptoms but did not improve. She had travelled to Thailand about one month earlier and stayed there for three weeks. She reported swimming in the sea there. After returning, she had an 8-day travel to south of Iran, Ahwaz. Few days after coming back to Tehran, her symptoms began. She was a housewife and non-smoker and was diabetic from one year ago, hypertensive for many years and had hypothyroidism in the past eight years. She reported two Cesarean section surgeries and cholecystectomy many years ago. Her medications included glibenclamide, atenolol and levothyroxine. She had no history of blood transfusion, asthma or allergy. The patient had been admitted to another hospital first where chest X ray was performed and bilateral pleural effusion was observed; pleural tapping was performed and the result showed exudative neutrophilic pleural effusion. She had WBC count of about 2,500/mL (PMN=60%, lymph= 40%), LDH was 240 IU/l, protein and glucose were 4.2g/dL and 74 mg/dL, respectively. Simultaneous serum LDH and protein were 300 IU/L and 5g/dL, respectively. She had received intravenous antibiotics for five days due to the impression of pneumonia but did not improve. Then, she was admitted to our hospital; she was febrile and reported non-productive cough and dyspnea, malaise and sweating. Complete blood count showed only anemia (Hb =9) without any leukocytosis or leukopenia. The erythrocyte sedimentation rate was 120mm/h and C-reactive protein was 68mg/L. Biochemistry tests, electrolyte levels and thyroid function tests were normal. Tuberculin skin test was negative and angiotensin-converting enzyme level was 63mu/L (normal range is up to 65mu/L) High-resolution chest computed tomography (CT) scan was requested, which showed bilateral pleural effusion again (Figure 1). There was no evidence of pulmonary emboli in chest CT angiography scan and echocardiography. Her echocardiography showed mild pericardial effusion with possible pericardial thickness. At this time, pleural tapping indicated lymphocytic exudative pleural effusion; the WBC count was 750/mL (PMN=40%, lymph=60%). Adenosine deaminase (ADA) was normal and smear was negative for Acid-fast bacilli and other bacteria. Mycobacterium tuberculosis polymerase chain reaction was negative. Meropenem and ciprofloxacin were initiated but the patient did not improve and worsened. Paecilomyces variotii was isolated from fungal culture of pleural effusion in several plates. Colonies grew on Sabouraud dextrose agar and reached about 7-8 mm after one week. The fungus was recognized based on its colony morphology, microscopic structures and thermophilicity (Figure 2). Thus, the patient was started on Itraconazole 200mg twice daily. After 48 hours, the patient became afebrile and the symptoms improved. She was evaluated for immunodeficiency. Immunoglobulin levels were normal, rheumatologic evaluation and tumor markers were unremarkable and NBT test was 100%. We continued treatment with itraconazole for four weeks. After four weeks, the patient had good general condition without any sign or symptom, erythrocyte sedimentation rate was 70mm/h, hemoglobin was 10.8mg/dL and her new chest X ray was clear (Figure 3).

diabetic patient, paecilomyces variotii, pleural effusion

PMC4660012_01

Female

An adolescent female softball player presented with gradually worsening right anterior knee pain and knee stiffness of several months duration. She had focal tenderness in the right infrapatellar region on palpation and mild pain during knee flexion. Initial radiographs of the right knee (Figure 1) were interpreted as normal. The patient was treated with a presumed diagnosis of patellar tendinitis and instructed to undergo a brief period of rest followed by physical therapy with gradual return to normal activity. She returned 9 months later with persistent anterior right knee pain and mild knee pain with deep knee flexion. At this time, mild medial joint line tenderness was also elicited on palpation. Due to the medial joint line tenderness, a right knee MRI was performed to assess for medial meniscal pathology. A 1.6 x 1.4 cm osteochondral lesion of the medial femoral condyle was identified on MRI with mild marrow edema and cystic change at the interface between the osteochondral lesion and femoral condyle (Figure 2). There was no defect in the overlying cartilage or fluid-like signal at the interface of the osteochondral lesion and femoral condyle. The remainder of the MRI exam was normal. The patient's medial joint line pain improved, but she continued to have mild anterior knee pain. A repeated MRI of the right knee was performed 6 months after the initial MRI to assess for changes in the osteochondral lesion. MRI of the left knee was performed at the same time due to the patient complaining of vague anterior left knee pain similar to the presenting right knee pain, which raised clinical concern for an occult osteochondral lesion of the left knee. She was at chronologic age of 13 years and 3 months at the time of the bilateral knee MRI. The osteochondral lesion of the right medial femoral condyle was unchanged in appearance between the two MRI exams (Figure 3). However, in the interim, a 9 mm focal periphyseal edema (FOPE) zone developed in the anterolateral aspect of the central proximal right tibia (Figure 4). A similar appearing 13 mm FOPE zone was present in the anterior aspect of the central proximal left tibia on the left knee MRI (Figures 5 and 6). While the distribution of FOPE zone periphyseal edema was equal on the epiphyseal and metaphyseal sides of the proximal right tibia, the periphyseal edema was more exuberant on the epiphyseal side of the proximal left tibia. The remainder of the left knee MRI was normal. The proximal tibial physis was narrowed, but open, bilaterally. It was uncertain whether the patient's bilateral anterior knee pain was due to the FOPE zones or another etiology not elucidated on the MRI. However, the patient pain resolved after a several-week period of rest. She was released to continue activity as tolerated with instruction to return if pain increased. She did not return for follow-up.

PMC4660012_03

Female

An adolescent female at chronological age of 13 years and 10 months presented with acute right knee pain after hyperextending her knee while playing basketball. She felt a "pop" during the hyperextension and had been unable to bear weight after injury. On physical examination, she had lateral joint line pain without ligamentous laxity. There was limited knee range of motion, and a moderate joint effusion was present. Presenting radiographs of the right knee were normal (Figure 10). MRI of the right knee showed pivot-shift bone marrow contusion pattern in the lateral compartment and root ligament avulsion of the lateral meniscus posterior horn (Figure 11). A 5 mm FOPE zone was also present in the central portion of the distal femur physis (Figure 12). The distal femur physis was still open. She underwent 2 months of conservative management without relief in symptoms. The patient subsequently had knee arthroscopy for repair of the lateral meniscus posterior horn root ligament. The right knee pain and joint effusion resolved after surgery with return of normal range of motion by 3 months after meniscal repair. The patient has not returned for additional follow-up.

PMC6288450_01

Female

A 52-year-old Australian Indigenous women presented with 6 months history of dry cough. There were no other respiratory symptoms. She did not have any constitutional symptoms, in particular no history of fever, anorexia or unintentional weight loss. She denied any history or known contact for tuberculosis. Her past medical history included Sjogren's syndrome, initially diagnosed at the age of 42 years and had clinical manifestation of sicca syndrome, xeropthalmia and xerostomia (dry eyes and dry oral cavity). She had a family history for breast cancer, Sjogren's syndrome and Systemic Lupus Erythematosus. She had a very insignificant history of smoking as a teenager. She was not on any regular medications other than NSAID for nonspecific back pain. Physical examination was un-remarkable other than for an enlarged thyroid gland. There was no palpable lymphadenopathy, clubbing or other signs of connective tissue disease. Respiratory examination was normal, in particular there were no crackles to suggest presence of interstitial lung disease. Laboratory examination demonstrated normal white cell/differential count. Serum electrolytes and liver function testes were also normal. Her ESR was elevated at 38mm/h, anti-nuclear antibody (ANA) titre was raised with a titre of 1:1280 demonstrating a speckled and nucleolar pattern. Extractable nuclear antigen (ENA) was positive for SS-A (Ro) and SS-B (La) and other ENA such as RNP, Sm, Scl - 70 and Jo-1 including ds-DNA antibody were negative. Thyroid function test was also normal, HIV and hepatitis serology were negative. Serum immunoglobulin showed slightly elevated IgG level at 17.7 (6.5-16.0) and IgA and IgM were normal. Pulmonary function test was normal with a Forced Vital Capacity (FVC) of 3.00L (88%), Forced Expiratory Volume in 1 second (FEV1) was 2.55L (94%) with FEV1/FVC Ratio of 0.85 (107%). The Gas transfer (DLCO) was normal at 86% and the lung volumes were preserved with Total lung Capacity (TLC) at 80% predicted respectively. A CT of the chest performed demonstrated multiple pulmonary nodules bilaterally, including a solitary non-calcified multilobulated opacity in the right lower lobe (RLL) measuring 28 x 17 mm with slight speculation (Fig. 1). The CT scan also demonstrated multiple bilateral pulmonary cysts. (Fig. 1). There was no evidence of Interstitial Lung Disease (ILD) or hilar or mediastinal lymphadenopathy. Incidental retrosternal extension of the enlarged thyroid gland was noted. Ultra sound of the thyroid gland demonstrated benign cystic lesion. A high index for malignancy with multiple metastasis was considered in the differential diagnosis. Hence, she underwent a bronchoscopy, which did not demonstrate endobronchial abnormalities and washings were negative for malignant cells and acid-fast bacilli. Cultures were negative for Acid fast bacilli (AFB), bacterial or fungal elements. She underwent a PET scan which showed positive uptake in the right lower lobe lesion with an SUV of 4.2, suspicious for malignancy and included in the differential of possible inflammatory process (Fig. 2). A percutaneous CT guided biopsy of the right lower lobe lesion was attempted, which was unfortunately complicated by an iatrogenic pneumothorax, and the results were inconclusive. In order to make a definitive diagnosis she underwent a video assisted thoracotomy with a wedge excision of the RLL nodule. Surprisingly, the biopsy showed evidence of amorphous material and demonstrated apple-green birefringence under polarised light after staining with Congo-Red in keeping with pulmonary AL amyloidosis (Fig. 3, Fig. 4, Fig. 5). In-situ hybridisation with kappa and lambda stains showed preferential kappa staining (Fig. 3, Fig. 4, Fig. 5). Biopsy results also identified Immunoglobulin heavy chain, with rearrangement studies demonstrating polyclonal lymphocyte population in pulmonary infiltrate. Serum electrophoresis did not identify paraprotein with free light chains showing Kappa 29 mg/L (3-19), Lambda 26 mg/L (6-26) and K/L Ratio of 1.11 (0.25-1.65). In order to exclude systemic AL amyloid, patient underwent bone marrow biopsy and skeletal survey, which were normal. Her cough improved with symptomatic management. As localized AL amyloidosis has a very low likelihood of systemic dissemination she remains on surveillance and was not offered systemic treatment as she had interval symptom resolution.

amyloidosis, indigenous, lung nodule, pulmonary cysts, sjogren's syndrome

CT chest showing multiple cystic lesions and right lower lobe nodule.

PMC6288450_01

Female

A 52-year-old Australian Indigenous women presented with 6 months history of dry cough. There were no other respiratory symptoms. She did not have any constitutional symptoms, in particular no history of fever, anorexia or unintentional weight loss. She denied any history or known contact for tuberculosis. Her past medical history included Sjogren's syndrome, initially diagnosed at the age of 42 years and had clinical manifestation of sicca syndrome, xeropthalmia and xerostomia (dry eyes and dry oral cavity). She had a family history for breast cancer, Sjogren's syndrome and Systemic Lupus Erythematosus. She had a very insignificant history of smoking as a teenager. She was not on any regular medications other than NSAID for nonspecific back pain. Physical examination was un-remarkable other than for an enlarged thyroid gland. There was no palpable lymphadenopathy, clubbing or other signs of connective tissue disease. Respiratory examination was normal, in particular there were no crackles to suggest presence of interstitial lung disease. Laboratory examination demonstrated normal white cell/differential count. Serum electrolytes and liver function testes were also normal. Her ESR was elevated at 38mm/h, anti-nuclear antibody (ANA) titre was raised with a titre of 1:1280 demonstrating a speckled and nucleolar pattern. Extractable nuclear antigen (ENA) was positive for SS-A (Ro) and SS-B (La) and other ENA such as RNP, Sm, Scl - 70 and Jo-1 including ds-DNA antibody were negative. Thyroid function test was also normal, HIV and hepatitis serology were negative. Serum immunoglobulin showed slightly elevated IgG level at 17.7 (6.5-16.0) and IgA and IgM were normal. Pulmonary function test was normal with a Forced Vital Capacity (FVC) of 3.00L (88%), Forced Expiratory Volume in 1 second (FEV1) was 2.55L (94%) with FEV1/FVC Ratio of 0.85 (107%). The Gas transfer (DLCO) was normal at 86% and the lung volumes were preserved with Total lung Capacity (TLC) at 80% predicted respectively. A CT of the chest performed demonstrated multiple pulmonary nodules bilaterally, including a solitary non-calcified multilobulated opacity in the right lower lobe (RLL) measuring 28 x 17 mm with slight speculation (Fig. 1). The CT scan also demonstrated multiple bilateral pulmonary cysts. (Fig. 1). There was no evidence of Interstitial Lung Disease (ILD) or hilar or mediastinal lymphadenopathy. Incidental retrosternal extension of the enlarged thyroid gland was noted. Ultra sound of the thyroid gland demonstrated benign cystic lesion. A high index for malignancy with multiple metastasis was considered in the differential diagnosis. Hence, she underwent a bronchoscopy, which did not demonstrate endobronchial abnormalities and washings were negative for malignant cells and acid-fast bacilli. Cultures were negative for Acid fast bacilli (AFB), bacterial or fungal elements. She underwent a PET scan which showed positive uptake in the right lower lobe lesion with an SUV of 4.2, suspicious for malignancy and included in the differential of possible inflammatory process (Fig. 2). A percutaneous CT guided biopsy of the right lower lobe lesion was attempted, which was unfortunately complicated by an iatrogenic pneumothorax, and the results were inconclusive. In order to make a definitive diagnosis she underwent a video assisted thoracotomy with a wedge excision of the RLL nodule. Surprisingly, the biopsy showed evidence of amorphous material and demonstrated apple-green birefringence under polarised light after staining with Congo-Red in keeping with pulmonary AL amyloidosis (Fig. 3, Fig. 4, Fig. 5). In-situ hybridisation with kappa and lambda stains showed preferential kappa staining (Fig. 3, Fig. 4, Fig. 5). Biopsy results also identified Immunoglobulin heavy chain, with rearrangement studies demonstrating polyclonal lymphocyte population in pulmonary infiltrate. Serum electrophoresis did not identify paraprotein with free light chains showing Kappa 29 mg/L (3-19), Lambda 26 mg/L (6-26) and K/L Ratio of 1.11 (0.25-1.65). In order to exclude systemic AL amyloid, patient underwent bone marrow biopsy and skeletal survey, which were normal. Her cough improved with symptomatic management. As localized AL amyloidosis has a very low likelihood of systemic dissemination she remains on surveillance and was not offered systemic treatment as she had interval symptom resolution.

amyloidosis, indigenous, lung nodule, pulmonary cysts, sjogren's syndrome

PET-CT scan showing positive uptake in the right lower lobe.

PMC7132002_01

Male

A 10-day-old male neonate with birth bodyweight of 3700 g, firstborn of non-relative parents in which the pregnancy was induced by intrauterine insemination (IUI) and the baby was born by cesarian section (C/S) with a gestational age of 40 weeks and good Apgar score was referred to the pediatric emergency department of Motahari hospital of Urmia. According to the mother's statements, the chief complaints were shortness of breath, rapid breathing, and vomiting. Also, the patient had a history of NICU admission on 2nd day after birth because of dehydration and poor feeding for 1st day. The patient could not take enough oral feeding for the last 2 days and vomiting was progressive. On physical examinations, the anthropometric measures were normal, the patient was non-dysmorphic and chest X-ray showed mild to moderate cardiomegaly with bilateral perihilar infiltrates. Vital signs were as follows; PR: 162/min, RR: 62/min, BT: 36.5 C, and oxygen saturation of 94% (room air). Mucous membranes were dry but skin turgor and fontanels were normal. The chest shape was normal and symmetric with subcostal retraction and tachypnea. Cardiac auscultation revealed a grade II/VI continuous murmur. Peripheral pulses were palpable. On abdominal examination, the liver span was increased on palpitation and generalized edema was obvious. Primitive neonatal reflexes such as Moro, sucking, and rooting were normal. The urgent ABG evaluation revealed PH of 7.14, PaCO2 of 29 mmHg, HCO3 of 9 mEq/L, and PaO2 of 43 mmHg. Serum electrolytes, BUN, creatinine, serum albumin, and blood sugar were in normal ranges. Primary complete blood count (CBC) and coagulation tests were normal except for the platelet count and INR. The patient had thrombocytopenia (platelet count of 95x103/mm3) and an INR of 1.19. Due to severe pulmonary distress, the patient was intubated and admitted to NICU. After stabilizing the vital signs and hydration, a pediatric cardiology consultation was done. Echocardiography demonstrated no visible RPA, PDA with right to left flow, mild supravalvular aortic stenosis, mild aortic insufficiency, a severe reversal flow in aortic arch, secundum type ASD, dilated right atrium, right ventricle, and main pulmonary artery, severe tricuspid regurgitation and severe pulmonary hypertension, moderate mitral regurgitation and pulmonary insufficiency, dilated inferior vena cava, mild bilateral pleural effusion, and severe ascites. Due to the findings, close cardiological follow up and CT-angiography was performed. Multi-slice computed tomography of the heart and major vasculature with special reconstructed views (dynamic and delayed images with contrast medium) revealed; anomalous arising of RPA from ascending aorta (hemitruncus), PDA 3.5 mm in size, stretched PFO (6 mm), atelectasis and congestion in both lungs with pleural effusion (Figure 1). Serious efforts to perform cardiac surgery in addition to medical therapy such as inotropes and diuretics began. However, pediatric cardiac surgery was not available in the health care center or nearby cities. So, the patient was maintained on medical therapy and supportive care until cardiac surgery was a possibility. Gradually, the patient's respiratory distress increased and liver function tests were more impaired and eventually cardiopulmonary arrest occurred on the 24th day of admission in the NICU. Immediate CPR was begun by cardiac massage, intravenous epinephrine, and positive pressure ventilation. After 30 mins the patient had no vital response and CPR was stopped. The last blood tests revealed metabolic and respiratory acidosis. The last blood test values were in Table 1.

hemitruncus arteriosus, cardiac anomaly, patent ductus arteriosus, pulmonary artery, thrombocytopenia

PMC6350603_01

Female

A 20-year-old right-hand-dominant and otherwise healthy female student presented with protrusion of the left upper back and left periscapular pain that occurred after sport activities. Ten months previously, the patient had been seated in the left rear passenger seat in a car that was hit in the left side by another car. Further details such as the posture and the arm position of the patient at the time of the accident were uncertain. At the time of the car accident, the patient visited an orthopedic clinic where a surgeon diagnosed left shoulder contusion without any abnormal radiographic findings. The left arm was kept in a sling for 2 months, as left arm elevation caused severe pain in the upper back. After sling removal, the patient returned to basketball, which generated continuous dull pain around the left scapula. She presented at our clinic because her mother had noticed the deformity of her back. The patient had no relevant family or medical history. There was no neurological deficit in the left shoulder and arm. The left scapula was slightly higher than the contralateral scapula and exhibited atypical medial winging with the arm at the side. The distance between the spinal process and medial scapular border was shorter on the left side than the right side at the inferior angle level, but these distances were almost the same at the scapular spine level (Figure 1(a)). Contraction of the scapular stabilizing muscles was good. There was a palpable bony protuberance without tenderness on the ventral side of the ISA. The limitations of the active ranges of motion of the left shoulder compared with the right shoulder were 25 for total elevation, 15 for external rotation, and none for internal rotation and horizontal adduction; however, there were no limitations of the passive ranges of motion. The winged scapula became prominent at 0-45 of active flexion, while it disappeared when the patient flexed the left arm while consciously attempting to depress the scapula (Figure 1(b)). The winged scapula did not emerge when the patient pushed on a wall at chest level. Radiographs showed a small bony fragment in the ventral side of the ISA, with a narrow space between the fragment and the scapular body (Figure 2). Computed tomography revealed a bony protrusion extending from the medial scapular border to the bony fragment, with a narrow gap between the protrusion and the fragment (Figures 3(a)-3(c)). The patient was instructed to avoid elevating the left arm for 2 months and then performed reinforcement exercises of the SA such as the scapular push-up and the bear hug using an elastic band for 2 months. At examination 4 months later, the periscapular pain and the winging of the scapula with the arm at the side and in active flexion had resolved. The push-on-the-wall test at waist level was negative, and the range of motion of the left arm was the same as the unaffected side, except for a 15 limitation in external rotation. Although the radiographic findings were the same as at the first visit, computed tomography demonstrated bony union (Figures 4(a) and 4(b)). The patient was permitted to use the left arm without restrictions. At the time of the final follow-up 10 years of postinjury, the patient reported that there was an occasional painless click and a sporadic floating feeling of the scapula with initial active flexion of the arm. However, there was no pain or any disturbance to the patient's activities of daily life and work as a physical therapist. The patient's colleague confirmed the disappearance of the winged scapula associated with shoulder movement. The DASH score was 0, and the Constant score ratio compared with the right shoulder was 100%.

PMC10332921_01

Male

A nine-year-old boy presented to the Department of Pediatric and Preventive Dentistry with a chief complaint of dental fractures. The patient had an Ellis III fracture in the maxillary left central incisor (tooth #21) and an Ellis II fracture in the maxillary right central incisor (tooth #11) due to a traumatic injury sustained while playing football (Figure 2). The parents promptly brought the child to the department, approximately six hours after the incident occurred. The patient did not experience any spontaneous pain at the time of presentation. During the intraoral examination, pulp exposure was observed in the maxillary left central incisor (tooth #21) with mild pain upon percussion. No periodontal pockets were detected, and the affected teeth showed class I mobility. Pulp vitality testing revealed a positive response to cold stimulation. The extent of pulp exposure in tooth #21 was measured to be approximately 2-3 mm. The radiographic examination did not reveal any root fractures or periradicular radiolucency in the regions of teeth #11 and #21, but it did confirm an enamel-dentin fracture in the maxillary right central incisor (tooth #11; Figure 3). According to Cvek's classification, both incisors were determined to be at stage 3 of root development; with two-thirds of root length present (Figures 1 and 3). Oral prophylaxis was performed, and the sandwich technique followed by composite buildup was carried out for tooth #11 (Figure 4). For tooth #21, the treatment plan involved a partial pulpotomy procedure, which was explained to the patient and parents. Local anesthesia (LA) was administered through the infiltration of 2% lidocaine HCl with 1 : 100,000 epinephrine (LA). Using a sterile high-speed diamond bur and water irrigation to prevent thermal damage, approximately 2-3 mm of visibly inflamed pulp and adjacent dentin were removed from tooth #21. The access cavity was then rinsed with normal saline, and the coronal pulp tissue was removed until adequate hemostasis was achieved. A moistened sterile cotton pellet was placed over the remaining pulp for 5 minutes. White MTA powder (ProRoot MTA, DENTSPLY, Tulsa, OK, USA) mixed with distilled water was applied to the exposed pulp without pressure. A moistened cotton pellet was gently placed over the MTA to facilitate its setting. After 10 minutes, the MTA was covered with glass ionomer restorative cement (GC Gold Label II, GC Fuji II Tokyo, Japan), and the patient was discharged (Figures 4 and 5). During the two-week follow-up, the patient remained asymptomatic, with no pain, periodontal pockets, mobility, or sensitivity upon cold testing. The glass ionomer restoration was partially replaced with a direct bonded composite restoration (Figure 6). Clinical and radiographic evaluations were performed at one month, three months, six months, and one-year post-treatment, with no symptoms observed. Radiographs showed increased root lengths, accelerated apical closure, complete root growth, increased thickness of the root wall, and the formation of a calcified bridge above the vital pulp (Figure 7). The periodontal ligament space appeared normal in thickness, and the continuity of the lamina dura was observed. No radiolucent lesions were detected during the six-month follow-up or in subsequent examinations conducted over one to two years (Figure 8).

PMC9078855_01

Male

A 36-year-old African man presented to the emergency department (ED) with a large right-sided facial mass causing massive facial disfigurement. The patient's right ear was displaced superiorly while his mouth was deviated to the left (Figure 1(a)). The foul-smelling tumorous tissue appeared necrotic with purulent and bloody excretions. The mass had been growing over the past eight years, and the patient had undergone multiple resections in Africa, including a right parotidectomy prior presentation at our ED. In addition, the patient had a fever as high as 38.5 C without other systemic symptoms. Contrast-enhanced computed tomography (CT) of the head and neck showed an exophytic and lobulated mass (dimensions, 28.0 x 9.5 x 23.5 cm) centred at the right preauricular region. It appeared as a moderately hypoattenuated lesion with moderate contrast enhancement without calcifications. In addition, a mass effect was shown on the surrounding tissues with bone scalloping of the right posterior mandibular ramus, the external auditive canal, and the mastoid, all of which are indicative of a slow-growing process. CT angiography showed multiple branches of the external carotid artery circumferentially encased by tumoral tissue. The right upper lobe showed findings compatible with an active open tuberculosis (TB), which most likely was causing the fever in this patient. On magnetic resonance imaging (MRI), the tumour appeared hypointense on T1-weighted imaging and moderately hyperintense on T2-weighted imaging and showed marked homogeneous contrast enhancement with peripheral zones of necrosis (Figures 2(a)-2(c)). The adjacent right masseter muscle, medial and lateral pterygoid muscles, and the perioral muscles were not separately visible due to deep muscular invasion. In addition, there was anteroinferior displacement of the submandibular gland and the prestyloid and poststyloid parapharyngeal space without clear signs of invasion. Positron emission tomography with CT showed F-18 fluorodeoxyglucose accumulation in the right facial tumour and in the right upper lobe (due to TB). However, there were no signs of metastasis. Based on the imaging findings and the location of the tumour, we posed a differential diagnosis consisting of chronic tuberculous lymphadenitis, plexiform neurofibroma, liposarcoma, DFSP, and giant pleomorphic adenoma. Histopathological examination showed an unencapsulated but well-defined nodule consisting of monomorphic spindle cells in a storiform pattern. Immunohistochemistry for CD34 was strongly positive. These findings revealed the diagnosis of DFSP. Given the tumour's massive size and proximity to important structures, the patient underwent a debulking excisional surgery, a mass of 2.8 kg tumorous tissue was removed in total (Figure 3). The tumour debulking included the excision of the right ear and was restored by means of a transposition flap of the masseter muscle to cover the buccal communication (Figure 1(b)). A second reconstruction using a split-thickness skin graft from the right thigh was used to cover the remaining defect after two weeks of granulation of the original wound bed (Figure 1(c)). The resected specimen showed diffuse tumoral involvement of the peripheral and deep margins on histopathology. Therefore, curative adjuvant radiation therapy was performed on the resection site after complete healing of the skin graft.

PMC7424535_01

Female

A 64-year-old female presented to the Dermatology Outpatient Department, BPKIHS, with complaints of a nonhealing ulcer over dorsum of the left hand for one year. There was no any history of diabetes, hypertension, and tuberculosis and no any history of trauma over the site. The lesion started as a small papule which over time increased in size and got ulcerated. On examination, there is crusted plaque with oozing pus mixed with blood with granulation tissue at the base of size 3 x 3 cm (Figure 1). An incisional biopsy of the lesion was sent for histological examination which showed epidermis lined by keratinized stratified squamous epithelium with parakeratosis, plasma crusting and focal neutrophilic infiltration, and pseudocarcinomatous hyperplasia. Dermis revealed suppurative to early plasma cell granulomas, along with eosinophils, macrophages, multinucleated giant cells, and focal abscess formation (Figure 2). Crescent-shaped organisms with a pointed anterior end and rounded posterior end were seen in the dermis with morphological resemblance to tachyzoites of Toxoplasma gondii which were positive for Periodic Acid Schiff (PAS) but negative for Silver Methenamine (SM) (Figures 3(a) and 3(b)).

PMC3056360_01

Male

A 30-year-old patient of Asian decent was transferred to our institution following recurrent bouts of hemoptysis in which approximately 250-300 ml of blood was expectorated over a span of <3 h. Four years ago, he had been treated for pulmonary tuberculosis. Two earlier episodes, 6 and 4 years earlier, were conservatively managed with antibiotics. He gave a history of necrotizing pneumonia in infancy. No fever or elevated white count was present upon arrival to indicate septicemia. A contrast-enhanced CT scan of the chest revealed consolidation and bronchiectasis involving the lateral segment of the right middle lobe and a larger surrounding zone of hazy airspace opacities [Figure 1] probably representing hemorrhage. A hypertrophied right internal mammary artery (IMA) was noted supplying a complex vascular malformation in the right middle lobe [Figure 2] via large pleural and phrenic collaterals draining into the right pulmonary artery. We decided to undertake angiographic evaluation and embolization of this malformation. A pigtail oblique thoracic aortogram showed an asymmetrically enlarged right IMA with otherwise normal brachiocephalic arterial and aortic anatomy. More selective injection of the right IMA demonstrated a high-flow plexiform fistulous communication between the right internal mammary and the pulmonary arteries via a plexiform vascular malformation in the right middle lobe [Figure 3A]. Multiple feeders arising from the distal half of the right IMA supplied the malformation. A right bronchial angiogram and contralateral pulmonary and bronchial artery angiograms did not reveal any significant contributors to the malformation. The high-flow rate and large caliber of many of the fistulous communications within the malformation made particulate embolization seem inadvisable. The liquid embolic agent, Onyx, was decided upon as an effective and efficient means of achieving both distal penetration into the malformation and a relatively rapid occlusion of the long segment of the IMA which was supplying the malformation. An Echelon-14 microcatheter (MTI, Irvine, CA, USA) was advanced coaxially through the existing 5-French diagnostic catheter. The microcatheter was positioned just below the lowest contributory side branch of the IMA and several fibered microcoils, ranging in diameter from 3 mm to 5 mm, were deployed to prevent distal escape of Onyx into the epigastric arteries. After priming of the microcatheter with dimethyl sulfoxide (DMSO) to fill the catheter dead space, Onyx-34 was slowly injected under fluoroscopy over approximately 20 min using a volume sufficient to occlude the distal half of the IMA and the contributory side branches. Due to the viscosity of the selected Onyx, the degree of distal penetration into the malformation was less than what we had anticipated or hoped for. Nevertheless, satisfactory occlusion of the IMA was achieved [Figure 3B, C] without opacification of any arterial feeders from the ipsilateral bronchial artery and contralateral intercostal artery, as demonstrated on the postembolization angiogram. We considered empiric embolization of the right bronchial artery as well, but then decided to await the results of the present embolization before undertaking any further interventions. On follow-up, the patient has been symptom free for 21/2 years.

ethylene vinyl alcohol copolymer, hemoptysis, liquid embolic agent

CT scan of the chest at two contiguous levels shows areas of bronchiectasis surrounded by air space opacities (arrow in A) representing hemorrhage within the consolidated right middle lobe, extending to the pleural surface (arrow in B).

PMC7253637_01

Female

A 14-year-old girl presented to the Department of Gynecology of the First Affiliated Hospital of Xi'an Jiaotong University with no obvious cause of persistent and severe lower abdominal pain that began 8 h prior. After receiving 450 mL of plasma at another hospital, she was referred to our facility since her test results suggested that her fibrinogen was only 0.10 g/L. She developed spontaneous epistaxis bleeding 7 days after she was born. At 2 years of age, CFD was diagnosed. She had a history of spontaneous auditory canal bleeding at 7 years of age. Her menarche took place at the age of 13, every menstrual period she needed to use more than 40 sanitary pads, accompanied by fatigue, rapid heartbeat, and unable to attend physical education classes or daily physical exercise, showing that she may have hypermenorrhea. She even had two hospitalizations due to hemorrhagic anemia caused by menorrhagia 9 and 3 months prior. But no medical treatment was performed afterwards. Upon presentation at our hospital, she was in the middle of her menstrual cycle. Her abdominal pain was accompanied by nausea, vomiting, dizziness, and palpitation. Besides, she denied the history of smoking. After admission to the Department of Gynecology, we had a detailed physical examination. She was 155 cm and weighed 50 kg. Her vital signs exhibited blood pressure of 107/74 mmHg, a heart rate of 105 beats/min, a respiration rate of 23 breaths/min, and the body temperature of 36.5 C. General examination revealed marked pallor, but the mind was clear and no bleeding spots on skin. Abdominal examination revealed a soft abdomen without tenderness or rebound pain, but the mobile voiceless was positive. No obvious abnormalities were found in other physical examinations. Since the girl and her parents firmly asserted a history of asexual life, we didn't perform a gynecological examination. Then the patient underwent transabdominal ultrasound demonstrating that a visible 3.1 cm x 2.4 cm cystic mass next to her right ovary. The mass boundary was clear and the morphology was regular. No obvious blood flow signal was observed. The fluid dark area in front of her uterus was approximately 8.3 cm x 8.0 cm, and the fluid dark area of her uterus rectal lacuna was 5.5 cm x 2.8 cm, where sparse spot reflection was visible. The right iliac fossa level was 3.9 cm, and that of the left iliac fossa was 2.0 cm. There was no abnormality in the appendix. The patient's coagulation function examination revealed signs of difficult coagulation. Her prothrombin time was 23.30 s (normal: 11-14 s), prothrombin activity was 37% (normal: 84-128%), international standard ratio was 2.07 (normal: 0.94-1.3), activated partial thromboplastin time was 43.8 s (normal: 28-43.5 s), thrombin time was 33.3 s (normal: 14.0-21.0 s), fibrinogen was 0.30 g/L (normal: 2-4 g/L). Her hemoglobin was 71 g/L. When the girl was admitted to our hospital due to abdominal pain, we considered it may be ruptured corpus luteum, ruptured follicles, ectopic pregnancy, torsion of the ovarian cyst or appendicitis. Since the girl was too young, and deny the history of sex life resolutely, we ruled out the possibility of ectopic pregnancy. Her abdominal pain was not metastatic, and there were no signs of peritoneal irritation. Ultrasound showed the appendix was normal, so appendicitis can also be ruled out. Ultrasound images confirmed the presence of hemoperitoneum, so the possibility of torsion of ovarian cyst pedicles was also low, thus the initial judgment was ruptured corpus luteum or ruptured follicles. The complete diagnosis of the girl included: hemoperitoneum (ruptured corpus luteum? ruptured follicles?), CFD, abnormal uterine bleeding-coagulation (AUB-C), and hemorrhagic anemia (moderate). Considering the patient's vital signs were stable, based to the advice of a Department of Hematology consultation, we utilized conservative treatment including rehydration support, aminocaproic acid hemostatic treatment, 2 units of red blood cell suspension, 200 mL of frozen plasma, and 6 g of fibrinogen. After 3 days of hospitalization, her fibrinogen reached 0.50 g/L. We then placed a LNG-IUS (52 mg/piece) under intravenous anesthesia. Diagnostic curettage was performed simultaneously. The pathological results suggested that it was the proliferative phase of the uterus (Figure 1), it also clarified that this hemoperitoneum was caused by ruptured follicles rather than the corpus luteum. The patient received COC (30 mug ethinylestradiol with desogestrel, 30 DSG) on the day of surgery, and then one tablet at approximately the same time every day for 63 consecutive days. When her anemia was corrected, COC administration was changed to 21 days of continuous medication as usual.

aub, cfd, coc, lng-ius, hemoperitoneum, hypermenorrhea

PMC6699275_01

Female

A 7-month-old ex-30-week preterm female infant presented to the emergency department of our hospital with a two-month history of worsening intermittent vomiting and failure to thrive despite nutritional optimization and trial of different infant formulas. Past medical history was notable for prolonged NICU stay mainly due to delays in oral feeding. She had no pulmonary, cardiac, or intestinal complications of prematurity. She did not require any surgical procedure or hospital admission following NICU discharge at around 6 weeks of age. History is also negative for recent fevers or recurrent infections. On presentation, she was in no acute distress and had normal vital signs. Weight and height were both below the first percentile. Physical examination was significant for the presence of hepatosplenomegaly. Laboratory workup was notable for elevated transaminases and significant hypercalcemia (4.47 mmol/L; Normal Range: 2.12-2.74mmol/L). Baseline phosphorus level was normal and the parathyroid hormone level was appropriately suppressed as seen in Table 1. She was admitted to hospital for management and further workup. Aggressive intravascular fluid resuscitation with normal saline only partially improved serum calcium levels. Furosemide and calcitonin were used in succession, but they also failed to have a noticeable impact on serum calcium levels. Two doses of pamidronate, 0.5 mg/kg each two days apart, were eventually successful in restoring normal calcium levels. She also switched to low calcium infant formula, Calcilo- XD. An extensive workup for viral and fungal etiologies was negative, as was the evaluation for metabolic, genetic, and oncologic causes of hypercalcemia. The skeletal survey did not show any lytic lesions; CT scan of the chest, abdomen, and pelvis was negative for the presence of lymphadenopathy or pulmonary lesions. Hepatosplenomegaly was confirmed with a CT scan; however, the underlying pathology was not revealed until a liver biopsy was performed for persistently elevated liver enzymes and massive hepatomegaly. Liver biopsy showed lobular histiocytic infiltrate with well-formed granulomas, hemophagocytosis, and increased portal/periportal and pericellular fibrosis with bridging indicating chronicity, with no further evidence to indicate an underlying etiology of the granulomas. She was discharged home after 3 weeks of hospitalization once adequate weight gain and normal and stable calcium levels were achieved. Liver enzymes were improved but remained elevated. She had required readmission after one month for the recurrence of vomiting and poor weight. She had no fevers. Workup on this admission showed leukopenia and return of hypercalcemia (Table 1). Chronic granulomatous disease, immunodeficiency, tuberculosis, and hemophagocytic lymphohistiocytosis (HLH) were considered in the differential; however, screening was negative. HLH genotyping showed only a single allele mutation on UNC13 gene, but this variant did not explain her findings. Despite the lack of a standard definition of infantile sarcoidosis, this disease was considered due to elevated levels of angiotensin-converting enzyme (ACE) at 108 U/L (18-90). In the light of negative results for a possible underlying immunodeficiency and malignancy, she was placed on prednisolone 1 mg/kg/day for hypercalcemia. She remained afebrile and was discharged home in stable condition with prednisolone. After 5 weeks of prednisolone treatment, she presented with daily emesis and low-grade fevers. Complete blood count showed pancytopenia, peripheral smear showed fungal elements. She was admitted to the intensive care unit for disseminated fungal infection. Urine Histoplasma antigen was found to be positive. Systemic antifungal treatment was started. Of note, serum calcium and liver enzyme levels were normal during the third admission (Table 1). Because of disseminated fungal infection, prednisolone was discontinued and a hydrocortisone taper was initiated. She had an excellent response to antifungal treatment. Hepatosplenomegaly resolved and all other serum markers have improved. She remained on systemic antifungal treatment for 9 months. She made full-recovery and caught up with growth and development.

PMC10331026_01

Female

A 38-year-old woman with advanced HIV disease (antiretroviral treatment experienced with treatment interruption) presented to Khayelitsha District Hospital with multiple cutaneous abscesses and associated constitutional symptoms of loss of appetite, loss of weight and night sweats. She reported a 3-month history of subcutaneous swellings with overlying hyperpigmentation affecting the arms, legs and buttocks, which subsequently formed spontaneous sinuses with drainage of purulent discharge. The patient had a history of three previous episodes of drug-sensitive TB and had completed anti-TB treatment on all occasions (Table 1). She had recently been admitted to the surgical department where she was diagnosed with lower limb cellulitis complicated by soft tissue collections. During that admission, an incision and drainage procedure was performed, and the patient received an oral course of amoxicillin and clavulanic acid. Routine microscopy, culture and sensitivity of the pus did not identify any bacterial pathogen; however, a specific mycobacterial culture was not requested. On admission to the internal medicine department, the patient had a tachycardia and a documented fever. She was cachectic with pallor and generalised lymphadenopathy. She had multiple skin lesions with a widespread distribution, affecting predominantly the lower limbs, perianal area, hands and face. The lower limb and perianal lesions involved subcutaneous collections with overlying hyperpigmented patches and central fluctuance. Certain of these collections had ulcerated with draining sinuses (Figure 1). Her facial lesions were hyperpigmented papules and plaques predominantly affecting the nasal area and associated with crusting suggestive of lupus vulgaris (Figure 2). Initial blood results showed acute kidney impairment, normocytic anaemia and an elevated C-reactive protein (Table 2).

hiv, south africa, tb, cutaneous tuberculosis, human immunodeficiency virus, tuberculosis

PMC3335636_01

Female

A 38-year-old woman with an eating disorder and depression became light-headed and fell, spilling boiling water from a kettle on herself at home. She was treated for 3 days at a local medical clinic and was then referred to the Plastic and Aesthetic Surgery Department, Kitasato University Hospital, 4 days postburn. The patient sustained partial and full thickness burns over 5% of her total body surface area: the left buttock (Figure 1(a)) and the right posterior thigh and calf (Figure 1(b)). The patient was 158 cm tall with a body weight of 33 kg; thus, her BMI (body mass index) was 14. Examination of other body systems revealed that they were normal. Laboratory data results were within normal limits except hemoglobin 9.9 g/dL, total protein 6.2 g/dL, and albumin 3.0 g/dL in her blood serum. Surgical treatment and alimentation with hospitalization was planned, but consent could not be obtained. We, therefore, chose to treat her at our outpatient clinic. Consent for hospitalization was obtained 24 days postburn, and the patient was admitted. But the patient strongly desired to leave the hospital as soon as possible, so she was discharged on postburn-day 39. Burn wound infection occurred on around day 20, but the infection was controlled with silver sulfadiazine and povidone-iodine gel. On day 53, she experienced dyspnea and lower-limb edema and returned to the hospital, whereupon, pleural effusion was observed on the chest X-ray (Figure 2). Laboratory data results were: hemoglobin 7.9 g/dL, total protein 4.8 g/dL, and albumin 2.7 g/dL. The pleural effusion was treated with a colloid solution and a diuretic agent with hospitalization (Figure 3). The operation for the burn wound was performed using a sequential excision and split-thickness skin graft from the right buttock on postburn-day 76 and lasted 2 hours. The burn covered 5% of the patient's body surface area. But because of the skin graft on the left buttock and posterior right thigh, the patient required bed rest and splinting her right leg for 7 days; afterwards, the skin graft stabilized. The burn wounds were successfully covered with skin grafts and treated with petroleum jelly. Rehabilitation was given for 1 week thereafter, and the patient was discharged on postburn-day 95. By postoperative-month 8, the patient was satisfied with the burn wound scars, skin grafts, and donor sites (Figure 4).

PMC5769267_01

Female

A 64-year-old woman complaining of left shoulder pain with resulting impairment in daily activities underwent radiography and computed tomography. The imaging examinations revealed an expanding lytic lesion of the left clavicle along with multiple osteolytic lesions in other regions, including the skull, right scapula, humeri, ribs, cervical and thoracic vertebra, right ilium and femora. On tumor staging studies, there was no evidence of pulmonary metastasis or other primary tumors. The patient became increasingly bed-confined due to multifocal bone pain. An iliac bone tumor biopsy revealed atypical spindle cell proliferation with active mitosis (>20/10 high-power fields) and partial necrosis. Osteoclast-like giant cells were occasionally observed (Fig. 1). Immunohistochemical analyses revealed expression of alpha-smooth muscle actin (smooth muscle-specific actin), h-caldesmon and vimentin (Fig. 1). These observations confirmed the diagnosis of bone leiomyosarcoma. Denosumab (120 mg/day) was administered subcutaneously for 4 weeks, in addition to daily supplementation with calcium and vitamin D. Furthermore, the right scapula, cervical and thoracic vertebrae, left clavicle, femora and right humerus were subjected to standard radiation therapy as palliative care. The patient did not undergo adjuvant chemotherapy or surgery. After 10 weeks of denosumab administration, the pain symptoms resolved and the patient recovered from the bedridden status. There were no reported denosumab-related side effects. The first follow-up computed tomography examination, performed 2 months post-denosumab treatment, revealed that all tumor growth had stabilized. Osteosclerotic changes were observed in multiple osteolytic lesions following denosumab and radiation combination therapy and denosumab therapy alone (Figs. 2 and 3). However, after 14 months of denosumab administration, a new lumbar vertebral metastasis was detected. At 56 months since denosumab administration, the patient had developed multiple metastases that had led to multiple organ failure, and finally succumbed to gastrointentinal bleeding. RANKL gene expression was evaluated in a biopsy of the iliac bone metastasis in the present case, and in surgically resected samples from giant cell tumors of bone (GCTB, n=6), aneurysmal bone cysts (ABC, n=2), fibrous dysplasia (FD, n=6) and bone metastases from breast cancer (BC; n=3). Total RNA was prepared from iliac bone biopsies using ISOGEN reagent (Nippon Gene; Tokyo, Japan) according to the manufacturer's recommendations. cDNA synthesis was performed using the PrimeScript RT reagent kit (TaKaRa Bio; Tokyo, Japan). Quantitative polymerase chain reaction analysis was performed using SYBR Premix Ex Taq II in a Thermal Cycler Dice Real-Time System TP800 (TaKaRa Bio; Otsu, Japan). RANKL was selected as the target gene (forward primer: 5'-GCCTTTCAAGGAGCTGTGCAA-3', reverse primer: 5'-ATCTAACCATGAGCCATCCACCAT-3') and GAPDH was selected as the reference gene (forward primer: 5'-GCACCGTCAAGGCTGAGAAC-3', reverse primer: 5'-TGGTGAAGACGCCAGTGGA-3'). A standard curve was generated using the SaOS2 osteosarcoma cell line, and was used to calculate gene copy numbers. RPMI8226, a myeloma cell line, was used as the calibrator. The target gene expression level was calculated as the ratio of the copy number of the target gene to that of the reference gene. Finally, the relative level of expression was calculated as [copy number of the target gene (RANKL)/copy number of the reference gene (GAPDH)]/copy number of the target gene (RANKL) in the RPMI8226 cell line. In the present case, RANKL gene expression was 747-fold higher compared with that of the calibrator. The results for the other tumor types are shown in Table I. The median fold changes for RANKL relative expression levels were 994-, 1,030-, 616- and 69-fold for GCTB, ABC, FD and bone metastasis from BC, respectively (Fig. 4). All the procedures were conducted following international and national regulations, in accordance with the Declaration of Helsinki. Informed consent was obtained from all subjects for participation in the study, the use of their tissue and publication of the data.

bone tumor, denosumab, leiomyosarcoma, osteoclast-like giant cells

PMC8282161_01

Female

A 69-year-old female presented to our clinic with a longstanding history of symptomatic right shoulder rotator cuff tear arthropathy. She exhausted non-operative management including activity modification, oral anti-inflammatories, physiotherapy and multiple corticosteroid injections (Figure 1). Her physical exam demonstrated significantly limited pre-operative active range of motion: 40 degrees of forward elevation, 20 degrees of abduction, 0 degrees of external rotation (with arm adducted to the side) and internal rotation to the buttock. X-ray and CT scan imaging studies demonstrated superior migration of the humeral head, an acromiohumeral interval <6 mm and acetabularization of the acromion, consistent with grade 3 Hamada rotator cuff tear arthropathy. Due to persistent pain and dysfunction negatively impacting on her quality of life, it was recommended that her most reliable surgical option would be a RTSA. After a thorough discussion regarding the risk and benefits, she elected to move forward with the procedure. In October 2013, a RTSA procedure was completed (Biomet Comprehensive Reverse Shoulder prosthesis (Biomet Inc, Warsaw, Indiana, USA) with a 6-mm mini cemented stem, 28-mm glenoid baseplate, 36-mm standard glenosphere (Versa-Dial between position B and C providing a 2 mm inferior offset) and a standard 44-mm humeral tray with a 36-mm polyethylene humeral cup was implanted (Figure 2). The procedure was uncomplicated. She was provided a routine rehabilitation protocol that consisted of an abduction sling and non-weightbearing in the right upper extremity for 6 weeks followed by active physiotherapy treatment to increase range of motion and gradual strengthening. She did not return for additional assessments after the 6-week clinical and radiographic check as she lived a significant distance from our hospital. Thus, her preference was to follow-up on an as needed basis and objective measures of motion and strength subsequently were not available. However, she stated she did well during this time returning to all her normal activities of daily living of self-care and house-hold tasks both at and above shoulder level maintaining independent function. In November 2018, she sustained a mechanical fall onto her right shoulder. Repeat radiographs demonstrated an isolated mid-to-distal one-third clavicle shaft fracture without any evidence of prosthetic loosening or change in position of her RTSA implants (Figure 3). Her initial physical exam demonstrated no significant clinical deformity consisting of an ipsilateral shoulder droop, significant clavicular shortening, or an anterior rotational deformity with shoulder ptosis and/or scapular winging. Radiographically, the clavicle fracture had minimal shortening of <1cm and mild angulation. Therefore, non-operative treatment was recommended and a sling was applied for comfort with therapy to be initiated after 2 weeks to maintain motion. On serial reassessments, the fracture failed to demonstrate healing on standard clinical and radiographic examinations and she subsequently developed a chronic symptomatic non-union of her right clavicle fracture (Figure 4). She had no history of bone metabolic abnormalities. At 6 months post-injury, she continued to have pain localized to the right clavicle, motion at the fracture site, as well as significantly reduced active range of motion. Her forward elevation was 60 degrees, abduction was 50 degrees, external rotation was 0 degrees, and internal rotation was limited to the greater trochanter. X-rays revealed an oligotrophic non-union of the clavicle fracture. The scapula had a notable increase in superior tilt, as demonstrated with increasing upward rotation angle with scapular measurements taken according to Endo et al. and shoulder AP radiographs (Figure 5), in addition to scapular notching and exposure of the inferior base plate screw compared to her initial postoperative imaging (Figure 6). While the glenoid base plate was still noted to be stable on CT imaging, given the potential of further notching and impingement leading to progressive glenoid loosening and persistent symptoms, the decision was made to proceed with operative fixation of her clavicle fracture. In May 2019, the patient underwent open reduction and internal fixation of her clavicle fracture. Her pseudoarthrosis was excised and a 3.5-mm precontoured clavicular lateral locking plate (DePuy Synthes, West Chester, PA) was used to anatomically reduce and stabilize the clavicle fracture with local autograft. Her surgery was uncomplicated. At her 4 month post-operative follow-up, her fracture had healed, both clinically and radiographically (Figure 7). There was no further progression of her superior scapular tilt or scapular notching (Figure 8). Her active range of motion improved, such that she was able to forward elevate and abduct to 100 degrees, externally rotate to 20 degrees and internally rotate to the sacrum.

clavicle fracture, reverse shoulder arthroplasty, scapular notching, shoulder biomechanics

PMC9356588_01

Male

Patient A; This is a 40-year-old male patient who came with a non-productive cough for one month and a three-month history of unquantified but significant weight loss. He also had a history of losing his appetite. On initial presentation, he appeared to be chronically ill, and all of his vital signs were within normal limits. The man weighed 52 kilograms and stood 1.74 meters tall, with a BMI of 17.2 kilograms per square meter, indicating that he was underweight. The lymphoglandular system revealed 3 by 4 cm enlarged masses that were mobile, had no overlying skin color change, and were tender in the cervical areas bilaterally, as well as 2 by 3 cm enlarged masses that were soft in consistency, mobile, had no overlying skin color change, and were non-tender on the submental areas. Other findings in the abdomen were a palpable mass in the right upper quadrant, about 5 cm below the right costal border, indicating hepatomegaly, and a soft mass along the line of spleen expansion, suggesting splenomegaly. He was then probed for a possible TB diagnosis, despite the fact that all of the standard TB diagnostic tests were negative. However, as shown below, the abdominal ultrasonography and FNAC (fine needle aspiration cytology) both supported the tuberculosis diagnosis. Abdominal ultrasonography revealed calcified and hypoechoic micronodules in the liver and spleen, as well as numerous enlarged centrally necrotic intra-abdominal lymphadenopathies, indicating disseminated tuberculosis (likely resolving). A FNAC biopsy revealed bilateral cervical and submental lymphadenopathies, with a tuberculous abscess as the most likely diagnosis. He was then tested for retrovirus infection and was found to be positive. The CD4 cell count was 14 cells per millimeter squared. He was offered urine LAM for tuberculosis diagnosis, and the result was positive for TB LAM. He began antiTB treatment, and on the tenth day of treatment, he was started on highly active antiretroviral therapy (HAART) with Tenofovir+Lamivudine+Dolutegravir (TLD) as per the recommendation. He is now on his 7th month and is apparently healthy, and taking his medication regularly. His weight also increased to 63 kilograms, with a BMI of 20.8, which is normal. The viral load was done 2 weeks back, and it was 800 copies, which is below the threshold for viral transmission (greater than 1000 copies).

diagnosis of tuberculosis, human immuno deficiency virus, urine lipoarabinomannan

PMC9356588_02

Male

Patient B: The patient, a 27-year-old man, was just diagnosed with HIV/AIDS (3 months ago) after being tested for HIV serostatus following notification that his wife had tested positive for the virus at a nearby clinic. He has no complaints about anything else. All of the physical evidences were unremarkable. Except for the CD4 count, which was determined to be 77cells/mm3, all baseline examinations, including tuberculosis investigations using a sputum gene expert, were non-revealing, and he subsequently tested for TB LAM, which yielded a positive result. He was subsequently started on anti-TB as recommended, and after a month, he was started on HAART withTenofovir+Lamivudine+Dolutegravir (TLD). He is using his medications without any problems so far, and the viral load will be sent on his six month of HAART initiation.

diagnosis of tuberculosis, human immuno deficiency virus, urine lipoarabinomannan

PMC5966696_01

Male

The patient in this case was an otherwise healthy 6-year-old male who presented to the emergency room with a right elbow deformity from an injury sustained while playing football. He reported being tackled and falling back, leading to a direct impact onto his flexed right elbow. Examination demonstrated his right arm to be neurovascularly intact despite having a closed gross deformity at the elbow joint. X-ray evaluation revealed an anteromedial elbow dislocation with fracture of the radial head (Figure 1). Two attempts were made at closed reduction in the emergency room under ketamine sedation with no appreciable reduction or improvement in alignment. Given the lack of success with closed reduction, the decision was made to take the patient to the operating room urgently for closed versus open reduction and possible fixation. Once under general anesthesia and with muscle relaxation employed, another closed reduction maneuver was attempted again with no success (Figure 2). A direct posterior approach to the elbow was then performed with exposure carried around to the subcutaneous border of the ulna. It was noted that the olecranon apophysis remained in its anatomic position despite the ulna being anteriorly dislocated. Interestingly, the proximal ulna was found to be buttonholed through the anterior joint capsule, thus preventing reduction of the joint. The radial head was also noted to have an angulated Salter-Harris II fracture which was realigned with direct pressure application. No epicondylar fracture was noted with direct inspection. Once the entrapped proximal ulna was freed from the anterior capsule, it was easily reduced into its anatomic position (Figure 3). Braided suture was used to reattach the olecranon apophysis to the proximal ulna through two drill holes in a figure of eight fashion. Final clinical exam and fluoroscopy images through a full range of motion revealed stable reduction of both the elbow joint and olecranon apophysis. The patient was splinted for approximately four weeks followed by progression of gentle passive and active elbow range of motion. At his most recent 7-month follow-up, the patient was doing very well with 0o-135o of elbow extension and flexion and 75o each of forearm pronation and supination. Radiographs revealed well aligned and healed fractures with maintained physes (Figure 4).

PMC3292825_01

Female

A 47-year-old right-handed housewife noted a soft swelling on the volar aspect of her left distal forearm 3 years ago. She was diagnosed with a ganglion, and local resection surgery was performed twice at another hospital. Similar methods were used to perform both operations, which involved intralesional resections of the cyst with 1-cm skin incisions of the volar aspect of the forearm without following the stalk of the cyst. However, 1 year after the last surgery, the swelling reappeared and was associated with numbness and pain in the radial volar aspect of the hand, thumb, index finger, and middle finger. She came to our hospital and a physical examination revealed decreased sensitivity of the left median nerve area associated with a positive Tinel's sign on the volar aspect of the distal forearm. The patient had no evidence of polyneuropathy, vasculitis, tuberculosis, hypertrophic tenosynovitis, sarcoidosis, gout, or other systemic disorders. She did not give history of previous trauma except for the surgeries at the other hospital, and her wrist joint showed no signs of carpometacarpal arthrosis or instability. The nerve conduction velocity (44.2 m/s) and terminal latency (5.94 ms) of the left median nerve were prolonged and delayed respectively, compared with those of the contralateral nerve (58.0 m/s, 4.12 ms). A radiograph of her left forearm showed no space-occupying lesions around the median nerve and carpal tunnel, and significant osteoarthritic changes of the carpal bones were not observed. Magnetic resonance imaging revealed that the multi-cystic lesion originated from the Scaphotrapezial joint and had expanded beyond the wrist (Figure 1). We decided to perform surgery. Exploration of the left median nerve showed that it was compressed by a large ovoid cystic lesion at the distal forearm near the proximal end of the carpal tunnel (Figure 2). We resected the cystic lesion, following the stalk of the cyst to the Scaphotrapezial joint with elongation of the incision, and released the carpal tunnel simultaneously. Nerve compression was observed only around the cyst in the distal forearm and not in the carpal tunnel. Her symptoms had disappeared 1 week after surgery, and pathological examination of the resected cystic lesion showed an appearance consistent with a ganglion. On the basis of these findings, we diagnosed median nerve neuropathy in the forearm due to recurrence of anterior wrist ganglion originated from the Scaphotrapezial joint. Complications or recurrent symptoms were absent 13 months after surgery.

PMC5609782_02

Female

She developed slowly during childhood and was shorter compared to her peers of the same age. She had significant academic difficulties, did not finish primary education, and never had a job. She did not experience the onset of menstruation after puberty. She married when she was 32 years old, but never had children. Because of amenorrhea and short stature, she gradually became depressed and self-blamed, had no self-confidence, and believed she was useless. She isolated herself at home and hesitated to meet others. She had poor appetite and sleep and tried to suicide. Because of these problems and symptoms, she was admitted to the mental health center in 1991. She was diagnosed with depression and secondary hypopituitarism and treated with doxepin, which did significantly improve her symptoms. In November 1992, the patient was admitted to the center again for depressive mood and suspicion of others. She suspected that her home had been stolen by one of her sisters-in-law and showed lack of impulse control and loss of temper. She was diagnosed with depression and depression-induced psychotic disorder. After perphenazine (16 mg/day) and doxepin (100 mg/day) treatments, her symptoms improved, and she was discharged from the center. At home, she kept up with taking her medication. In 1995, after the discontinuation of the medication, she was admitted to the center a third time for excessive talking, hyperactivity, buying things for others without reason, and excessive praying. At home, she had difficulty controlling herself and would have outbursts with shouting and crying and other disruptive behavior. She was diagnosed with affective disorder with manic episodes, pulmonary tuberculosis, which was shown in a chest X-ray, and hypopituitarism. Her symptoms improved after treatment with antituberculosis drugs and clozapine, after which, she was discharged from the center. The patient was hospitalized in both 2001 and 2004, for the same manic episodes including excessive talking, hyperactivity, rash spending, and difficulty controlling herself. In 2005, the patient became depressed and stupefied, slow in her movements, lazy, and maintained erratic hours. During hospitalization, a karyotypic analysis was performed and the karyotype of 45, X/46, X, i(Xq) was identified which led to the diagnosis of TS. An endocrinologist initiated estrogen and progestin replacement therapy, and sodium valproate (1.0 g/day) was also prescribed. The patient's mood stabilized, and she was discharged from the center; however, she did not continue the estrogen and progestin replacement therapy. Menses was present during the second cycle of treatment. In 2009, the patient was hospitalized again for a manic episode. During hospitalization, her fasting blood sugar was found to be high, leading to a diagnosis of diabetes mellitus for which metformin was prescribed, in addition to sodium valproate for the manic symptoms. It was concluded that the previous diagnosis of hypopituitarism was incorrect as there was no laboratory evidence to support this diagnosis. Unfortunately, the misdiagnosis had not been corrected until 2005 when a karyotype of 45, X/46, X, i(Xq) was identified. It is likely that the psychiatric practitioner was not knowledgeable regarding TS and hypopituitarism.

turner’s syndrome, bipolar disorder, comorbidity, karyotype

PMC10132894_01

Female

Among the eight HCWs who were vaccinated with the BNT162b2 mRNA COVID-19 vaccine, one HCW was diagnosed with RA and was taking MTX. The HCW with RA (patient with RA) was a 60-year-old Japanese male who had been diagnosed with seropositive RA since 2010. The remaining seven HCWs were aged 40-58 years (median 49 years), and there were three females and four males. Details of the characteristics of the participants in this study are presented in Table 1. Obesity and comorbidities were observed in older HCWs. Although age and smoking have been reported as risk factors for lower antibody titers after COVID-19 vaccination, no clear association was observed between antibody titers and age or smoking, possibly owing to the small number of participants (Table 1, Supplementary Table S1). The patient with RA was in remission after MTX (8 mg/week) and bucillamine (200 mg/day) treatment. MTX was withdrawn for 1 week after each vaccination according to the American College of Rheumatology (ACR) guidance. All participants received a primary vaccination of two doses (30 mug each) in April and May 2021 (3-week interval) and a booster vaccination (single dose, 30 mug) in January 2022. Anti-S antibody titers were measured at 10 days, 7 months, and 8 months (1-month postbooster) after the second vaccination. In the patient with RA and in a poor responder HCW whose anti-S antibody titers at 10 days did not reach the upper detection limit, anti-S antibody titers were also measured at 4 months. The upper detection limit of the anti-S antibody titer was set to 999 U/mL at 10 days and 4 months and 9,999 U/mL afterward. The anti-S antibody titers of seven HCWs indicated at 10 days were beyond the upper limit of the assay in six (good responders) of seven HCWs and 909 U/mL in one (poor responder) (Figure 1). In the patient with RA, the titer was significantly lower (196 U/mL). At 4 months, the titer of the patient with RA increased to 373 U/mL (1.9-fold increase), which was higher than that of the low-responder HCW (264 U/mL) and similar to the median titer of 380 U/mL in the other HCWs at 7 months (Supplementary Table S1). One-month postbooster, the titer of the patient with RA was 8,437 U/mL, while four HCWs had titers above the upper limit. The titers for the other two HCWs were 6,415 U/mL and 6,817 U/mL, while data were unavailable for one HCW.

PMC5356393_01

Male

A 62-year-old male patient presented with the chief complaints of swelling on the left side of face and neck region for 2 months, which was of sudden onset. Swelling started as a discomfort on the left side of the neck followed by the appearance of swelling, which gradually increased in size and associated pain for 1 month. Had multiple medical consultations and multiple courses of antibiotics and a course of antifilarial over the past 1 month, with no reduction in symptoms. There were no other associated signs or symptoms. He was under medication for hypothyroidism and diabetes mellitus. History of filariasis 10 years back followed by 3-4 episodes of lymphadenitis and had antifilarial therapy during these episodes. He was a cigarette smoker for 20 years, smoking two cigarettes per day which he quit 3 years back. Extraoral examination revealed facial asymmetry of the left side. Multiple lymph nodes were palpable, including left submandibular and level II cervical lymph node with the largest one measuring approximately 4 cm x 5 cm in size. Lymph nodes were non-tender, firm in consistency, mobile, and some were matted together. Skin over the lymph nodes appeared normal without any signs of inflammation or infection. Patient consent was obtained for taking photograph and using it for study and publication purposes [Figure 1a and b]. Intraoral examination revealed poor oral hygiene with the presence of local factors and signs of periodontitis. On hard tissue examination, tooth number 36 had a crown with tenderness on vertical percussion. Thus by history and clinical examination, a differential diagnosis of cervical lymphadenopathy due to locoregional infection, filariasis, tuberculosis, NHL was given. Patient advised to discontinue all antibiotics and antifilarial drugs. Panoramic radiograph revealed generalized horizontal bone loss and endodontically treated 36 with crown and periapical bone density [Figure 2a]. Posterior-anterior chest radiograph was noncontributory [Figure 2b]. All hematological investigations were within the normal limit except for lactate dehydrogenase (307.8 U/L, normal range 0-248 U/L). Blood smear was negative for filarial microbes, and Mantoux test was negative. Computed tomography (CT) of the neck with contrast showed multiple discrete and conglomerate lymph nodes in left level Ib, II, III, and V. Largest node measured 3.5 cm x 4.4 cm [Figure 2c]. The nodes did not show any enhancement/necrosis and were pushing the submandibular gland to one side. However, the gland appeared normal and was separated from the nodal mass [Figure 2d]. The adjacent bones did not show any erosion/lytic change. The right side also showed level Ib, II, and V nodes, but they were discrete and showed no evidence of necrosis or any other mass lesion [Figure 2e]. A tru-cut nodal biopsy taken from cervical lymph node, microscopic features were suggestive of lymphoproliferative disorder. Immunohistochemistry (IHC) was performed to categories the lesion; cells were positive for leukocyte common antigen, CD20, some for CD30 and Epstein-Barr virus latent membrane protein-1 (EBV-LMP-1) and were negative for CD3, CD10, cyclin D1, B-cell lymphoma-6 (BCL-6), CD23, anaplastic lymphoma kinase-1 and terminal deoxynucleotidyl transferase. IHC confirmed NHL, that is, suggestive of EBV-positive diffuse large B-cell lymphoma (DLBL) of elderly. Bone aspiration from pelvic bone ruled out the bone marrow involvement. Fluoro-2-deoxyD-glucose (FDG) positron emission tomography/CT (PET/CT), showed extensive FDG avid supra and infra-diaphragmatic lymph nodal lesions indicating metabolically active NHL. Focal FDG avid within spleen were present [Figure 3a]. Thus, according to Ann Arbor staging of primary lymphoma, he had Stage III S. A final diagnosis of NHL of DLBL was made based on the clinical presentations and investigations. The patient received six cycles of standard R-CHOP chemotherapy regimen which included rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 50 mg/m2. On the 1st day of each cycle, the patient received rituximab, doxorubicin, vincristine, and cyclophosphamide and a 5-day course of prednisolone. At the end of the 21 days, patient started with second cycle of the R-CHOP chemotherapy, he completed six cycles of chemotherapy regimen. Whole-body PET/CT was done after six cycles of chemotherapy to assess the response to treatment, which showed complete metabolic and near complete anatomical resolution of supra/infra-diaphragmatic lymph nodes and splenic deposits [Figure 3b]. No new FDG avid lymph nodal/extranodal lymphomatous deposits were evident. Thus, a Deauville Score I was made suggesting an overall good response to chemotherapy and indicating no need of further chemotherapy at that level.

lymphadenopathy, lymphoma, non-hodgkin's lymphoma, positron emission tomography/computed tomography

PMC7783198_01

Female

As it is summarized in Figure 1, after the approval of the ethical committee (RIF.CE: 4520) a 39-year-old with disease onset in 2005 with visual acuity disturbance and diagnosis of RRMS on July 2008, regularly followed in MS Center S. Andrea Hospital, University of Rome Sapienza. She started Natalizumab treatment, stopped after 30 infusions due to de-risking strategy in JCV positivity. After pregnancy on 2011, neurologist opted for treatment with Dimethyl fumarate, stopped after 8 months because persistence of disease activity, so patient was shifted to Fingolimod with partial response and worsening in EDSS score. Considering the young age, Alemtuzumab was started in 2016, with second cycle in February 2017. Unfortunately, patient showed an additional clinical progression, with a stable worsening of 1.5 point in the EDSS at 12 months despite the treatment, configuring a secondary-progressive form of disease. She not experienced relapses at least 1 month before the start of the protocol, the EDSS evaluation was 4.5 at baseline evaluation and she received the authorization to practice Adapted Physical Activity from Sport Medicine Physician at the City University; she was not engaged in physical activity exercise during the 6 months before the beginning of the protocol. All baseline characteristics are reported in Table 1. The primary outcome of the study was to evaluate the effect of a combined training on expression levels of total adiponectin and its oligomerization state. Before (T0), after 4 months of concurrent training (see following) (T1) and 6 months after the end of the protocol (T2) the patient underwent to a functional and psychological (QoL) evaluation as well as a blood sample collection. The second aim was to identify the adiponectin expression and its oligomerization state in a healthy female group and in un untrained MS patient group. Baseline demographic and clinical characteristics of the subject are presented in Table 1. Ten sex- and age- matched healthy controls (all females, mean age 41 +- 2) were enrolled in the study. Ten sex- and age- matched secondary progressive MS patients (all females, mean age 40 +- 3) were recruited. The study was approved by local Ethical Committee, all patients gave their informed consent to participate in the study. The assessment of body composition (fat mass percentage (FAT %), and free fat mass (FFM %) was obtained using the digital bioelectrical impedance device (Handy 3000; DS Medica, Milan, Italy), with a frequency of 50 and 100 kHz. Body mass index (BMI) was also determined. In order to make the measurement reproducible, the patient has to be fasting for 4 h, no physical activity for 12 h, no alcohol, and diuretics (unless prescribed) for 48 h, well hydrated (water only). The 6-min walking test (6MWT) was used to assess endurance and functional capacity; the Handgrip test was performed to measure the muscular strength through the handgrip dynamometer (Jamar Plus ; Patterson Medical Ltd.) for each arm; and the Timed Up and Go Test (TUG) to evaluate the muscular function and mobility. The National Institute of Clinical Evidence (NICE) guidelines also advocate the use the TUG test for assessment of gait and balance in the prevention of falls. The Multiple Sclerosis Quality of Life-54 (MSQOL-54), which investigate physical functions, limitations related to the physical and emotional sphere, perception about health, social, cognitive and sexual functions, and general QoL. The MSQOL-54 summary scores are the physical health composite summary and the mental health composite summary. The Fatigue Severity Scale (FSS) it is designed to differentiate fatigue from clinical depression in these patients and to explore severity of fatigue symptoms. The PHQ-9 Questionnaire used as a screening tool for major depressive disorder. A total of 24 h before training and follow final training session, a venous blood sample (10 ml) was collected after a 10-h overnight fast between 7:30 a.m. and 9:00 a.m. Total serum adiponectin of healthy controls, MS patients, and the MS case undergone a physical activity training was measured by ELISA-test using house-produced polyclonal antibodies as previously described. Each serum sample was tested three times in triplicate. Serum proteins were isolated from healthy controls, MS patients, and the MS case undergone a physical activity training as previously described by. For the immunoblot analysis, an equal amount of proteins (10 mug) was resolved in SDS-polyacrylamide (BIO-RAD) gels (10%) and transferred onto nitrocellulose membranes (Amersham). Thereafter, membranes were incubated with adiponectin antibodies (Novus Biologicals, Littleton, CO, United States) appropriately diluted in Tween Tris-buffered saline (TTBS). Proteins were revealed by the enhanced chemiluminescence (ECL) with Kodak BioMax Light film, (GE Healthcare Bio-Sciences Pittsburgh, PA, United States), digitalized with a scanner (1200 dpi) and analyzed by densitometry with ImageJ Software1. All samples were tested twice in duplicate. After 6 months, during which the patient was not enrolled into a structured physical activity protocol, the same evaluations were performed to verify the long-term effect of the concurrent training, and the IPAQ questionnaire was administered in order to assess the total level of physical activity during the follow up. Adapted concurrent training and 1-RM assessment: The patient was enrolled in a structured concurrent training, which last 4 months (34 sessions, twice a week, 50 min per session). The single session of this protocol was divided in four phases: warm-up, resistance training, endurance training, and cool down. The first phase of warm up consisted in 3 min of stationary bike without slope and resistance and 2 min of dynamic warm up for the upper body. In the second phase the patient was involved in strength exercises, where the loads of the upper and lower limbs were set at 50% of 1-RM of the patient, using six types of strength machines (Technogym equipment): Leg Press, Leg Extension, Leg Curl, Vertical Traction, Row Pull, and Abdominal Crunches. After a period of familiarization, the maximal strength was assessed by one repetition maximum (1-RM) test using Brzycki equation. The same equipment used for the 1-RM assessment were used for the resistance training that lasted 25 min and consist in eight repetitions for two sets, with 1 min of rest between the sets. The third phase consisted in aerobic training including 10 min of stationary bike at moderate intensity, 65% heart rate reserve (HRR) evaluated using the Karvonen formula: Exercise HR = % of target intensity (HRmax - HRrest) + HRrest. The last phase consisted in 10 min of cool down involved static stretching for all major muscle trained: shoulders and upper limbs, trunk and lower body, both in sit and in stand position. As shown in the Elisa-test (see Figure 2A), we analyzed total serum adiponectin in healthy controls, MS patients, and baseline (T0), post physical activity intervention (T1) and at follow-up (T2) in the MS case patient, in which, we found a decrease of serum adiponectin levels [9.05 mug/ml (T0) vs. 7.78 mug/ml (T1)] before and after physical activity intervention. Interestingly, at the follow-up (T2), adiponectin levels remained stable (7.44 mug/ml) indicating that the effects of the training last for at least 6 months. As control, we confirmed that higher levels of serum adiponectin were found in untrained MS patient compared to healthy controls (9.25 vs. 8.13 mug/ml, respectively, p < 0.05). Furthermore, as shown in the Western blots (Figures 2B,C), we analyzed the distribution of serum Acrp30 in healthy controls, MS patients, and baseline (T0), post physical activity intervention (T1) and at follow-up (T2) in the MS case patient. Three bands corresponding to HMW (>=250 kDa), MMW (180 kDa), and LMW (70 kDa) oligomers were evident in MS patient (Figure 2B). The densitometric evaluation of oligomeric distribution showed that the expression of HMW, MMW, and LMW oligomers are higher in MS patients compared to healthy controls (p < 0.05). When we analyzed adiponectin oligomeric profile in the MS case undergone physical activity, we found that all oligomers are lower in the MS patient after physical activity intervention compared to baseline. In particular, a more evident decrease in HMW oligomers, the most biologically active oligomers, was found (Figure 2C). The adiponectin oligomerization state at the follow-up (T2), do not substantially change for all oligomers (Figure 2). As shown in Table 2, all functional parameters improved after 4 months of concurrent aerobic and resistance training. The patient reported a decreased BMI (-0.9%), more in deep the impedance analysis showed an increase of FFM (+0.8%) and a decrease of FAT (-2.6%) suggesting a positive modification of body composition. The tests related to walking ability and autonomy showed an improvement at T1 (10mwt = -4.3%; 6mwt = 6.7%), as well as the strength (Handgrip Sx = 8.9%; Handgrip Sx = +23%) and flexibility (TR Dx = +37%; TR Sx = 106.1%) analysis, confirming the functional improvements on these patients due to an adapted exercise. The TUG test performance reported a slight decrease after the protocol (+1.6%), instead the Berg Balance score did not reveal changes over the time, probably due to the good starting point of the patient. After 6 months, from the end of the protocol, most of the evaluated parameters decrease returning to the basal level. As shown in Table 2, BMI increase at T2 compare to T1 and T0 (T1/T2 = +2.8%; T0/T2 = 1.8%), the body composition analysis revealed that FFM decrease (T1/T2 = -2.0%; T0/T2 = -1.2%), and FAT increase (T1/T2 = +13.2%; T0/T2 = +9.4%). The tests related to walking ability and autonomy reported a worsening in these parameters after 6 months (T2), compared to T1 and T0 (TUG T0/T2 = +1%; 10mwt T1/T2 = +4.5%; 10mwt T0/T2 = 0%). An exception was reported by the TUG analysis between T1 and T2 (-0.6%) and the 6mwt that did not showed changes at T2, both comparing to the data collected at T0 and T1. The IPAQ at T2 revealed a LOW level meaning that the volunteer did not reach the criteria for either moderate or high levels of physical activity. The EDDS evaluation showed a decrease after training (EDDS T0/T1 = -11.1%) that remain the same after 6 months of follow up, suggesting the general positive effect of this protocol on the disease severity and on patient functionality. The psychological parameters (Table 2) reported an increase in QoL, both in physical (45MSQOL P T0/T1 = +5.3%) and mental (45MSQOL M T0/T1 = +11.2%) Score after the concurrent training, the patient experienced a general well-being after the protocol, she also revealed a decrease in Fatigue perception (FFS T0/T1 = -5.4%) and Depressive status (PHQ T0/T1 = -40%) at T1. According to the results Fatigue and Depression have decreased further after 6 months (FFS T1/T2 = -5.7; PHQ = -16.7) and the scores did not return to the baseline level over the time (FFS T0/T2 = -12%; PHQ T0/T2 = -100%), suggesting that the effect of these training could be a long term effect. The QoL, instead, decreased after 6 months compare to T1 (45MSQOL P T1/T2 = -4.3%; 45MSQOL M T1/T2 = -12.5%) and almost return to the baseline level (45MSQOL P T0/T2 = +0.6%; 45MSQOL M T0/T2 = -2.8%).

edss, hmw oligomers, adiponectin, multiple sclerosis, training

PMC6358573_01

Female

A 56-year-old woman presented to the emergency department after a motor vehicle accident. She had no complaint except generalized musculoskeletal pain. No visible bleeding was noted, and dedicated computed tomographic (CT) imaging of the chest/abdomen/pelvis was negative for any evidence of blood loss or fracture. She reported occasional melena alternating with hematochezia in the last 4 years. She had been transfused with packed red blood cells (PRBC) for symptomatic anemia 4 years prior to presentation. Esophagoduodenoscopy (EGD) and colonoscopy done at that time were both normal. She had another normal EGD and colonoscopy 1 year prior and declined further workup for the source of her intermittent GI bleeding. Her past medical history was notable for a mesh repair of an abdominal wall hernia 10 years prior and chronic atrial fibrillation, which was treated with the anticoagulant warfarin. On admission the patient appeared comfortable. Her vital signs were within normal limits, and the physical examination was normal except for mild bruising in the distribution of a seatbelt across her chest and abdomen. Her vital signs were within normal limits. Her labs were notable for low hemoglobin (5.4 g/dL) and subtherapeutic international normalized ratio (1.7). She received 2 units of PRBC at the time of admission. EGD and colonoscopy performed upon admission were both normal. On the third day of admission, she had a large bloody bowel movement and became hemodynamically unstable. Repeat EGD was normal. She continued having bloody bowel movements with ongoing anemia and required transfusion of 5 additional units of PRBC. CT angiography of the abdomen revealed a paramedian ventral mesh located inferiorly on the right lower abdomen, and no evidence of contrast extravasation (Figure 1). A tagged red blood cell study suggested an active bleed in the right upper quadrant likely originating from the proximal small bowel (Figure 2). Selected angiography of the celiac and superior mesenteric artery failed to demonstrate any active bleeding. Due to persistent low hemoglobin, hemodynamic instability, and massive transfusion requirements (a total of 14 units of PRBC), surgical exploration was performed. Exploratory laparotomy findings showed a synthetic abdominal mesh protruding into the mid portion of the ileum, extensive surrounding adhesions, and serosal tears. We resected 30 cm of the involved small bowel and performed primary anastomosis. Pathological findings were notable for dense mesh invading the bowel wall, blood in the ileum, and hyperemic mucosa with multiple areas suggestive of perforation. Postoperatively, anticoagulation was resumed, and she had no further episodes of melena or hematochezia. She was discharged 2 weeks later with a stable hemoglobin (8.3 g/dL).

PMC4714489_01

Female

A 27-year old female presented with clinical and biochemical thyrotoxicosis (TSH - 0.01 muIU/mL (ref. range: 0.27-4.2 muIU/mL); free thyroxine (FT4) - 1.58 ng/dL (ref. range 0.98-1.63 ng/dL); free triiodothyronine (FT3) - 4.56 pg/mL (ref. range 2.6-4.4 pg/mL). Clinical examination revealed tachycardia about 100 beats/min and no obvious goitre. Autoimmune profile was suggestive of Graves' disease [anti-TSH-receptor antibodies (aTSHR) - 16.69 IU/L (ref. 0-1.75), anti-thyroid peroxidase antibodies (aTPO) - 1780 IU/mL (ref.: 0-34 IU/mL)]. The patient had a history of Hodgkin's lymphoma, diagnosed and treated with chemo- and radiotherapy (including the neck) at the age of 18. At the age of 20 she developed severe hypothyroidism (TSH > 100 muIU/ml), though with high titres of both aTPO (150 IU/mL) and aTSHR (37.56 IU/mL) antibodies. Thyroid function tests normalised after treatment with L-thyroxine (100 mug o.d.). At the age of 26 she became "anxious" and experienced "heart palpitations". She was found to have suppressed TSH, that remained suppressed even when the dose of L-thyroxine was reduced and then discontinued. After further four months she was found to have raised FT3 (see above). Thyroid scintigraphy revealed a normal and homogenous iodine uptake (41 %). The patient responded very well to treatment with low dose thiamazole (10 mg od, later 5 mg o.d.) that was discontinued after about 12 months. About a year later (while 16-week pregnant) she was off medication and had mild subclinical thyrotoxicosis (TSH - 0.035 muIU/mL, FT4 - 1.04 ng/dL, FT3 - 3.09 pg/mL) and raised aTSHR antibodies, albeit at lower titre than before (7.87 IU/L). According to the literature data thyroid dysfunction is one of the most common abnormalities seen after radiotherapy for Hodgkin's disease that includes the neck. Primary hypothyroidism, the most common radiation-induced thyroid dysfunction, appears in 20-30 % patients who had therapeutic radiotherapy administered to the neck region, and this usually occurs within the first 5 years after therapy (peak 2-3 years after treatment). Irradiation of the thyroid may also increase the risk of Graves' disease (relative risk 7.2-20.4), or Graves' ophthalmopathy, thyroiditis, benign adenomas and thyroid cancer. The aetiology of radiation-induced thyroid dysfunction includes vascular damage, parenchymal cell damage and auto-immune reactions. There are reports, that after neck irradiation Graves' disease may develop in patients previously receiving thyroxine, and indeed 33 % of the patients with Graves' hyperthyroidism had received thyroxine before its onset. Therefore thyroid hormone-replacement therapy in patients with hypothyroidism after irradiation of the neck does not eliminate risk of other thyroid abnormalities at a later date. According to some authors, thyroiditis observed in Hodgkin's disease may be the result of immune regulation disorders in Hodgkin's disease. Furthermore, a possibility of a change from hypo- to hyperthyroidism typical for Graves' disease is has been known for some time, and was also confirmed in more recent publications. Takeda et al. demonstrated, by measuring changes in cyclic AMP, that thyroid stimulating and thyroid blocking antibodies may coexist within the same patient and their relative activities may change over the course of the disease. Our case illustrates that after neck irradiation, severe hypothyroidism can be followed by thyrotoxicosis. It should be noted that in our patient, both during hypo and hyperthyroidism, aTSHR were elevated. There are two types of aTSHR: thyroid stimulating antibodies (TSAb) and TSH-stimulation blocking antibodies (TBAb). TBAb block TSH-stimulation of the thyroid and cause hypothyroidism. On the other hand, TSAb stimulate the thyroid and result in Graves' hyperthyroidism. In our opinion, in this case there was a gradual switch from TBAb into TSAb. In some patients, TSAb and hyperthyroidism develop unexpectedly after hypothyroidism that is caused by TBAb. Fan et al. described a case with documented cycles of hypothyroidism alternating with hyperthyroidism. Also, as mentioned above, some hypothyroid patients after irradiation of the neck, while treated for the Hodgkin's disease, developed hyperthyroidism. A number of mechanisms may be involved in switching from TBAb to TSAb. Significantly, thyroxine treatment in some patients is associated with increase TSAb that - in extreme cases - might lead to development of hyperthyroidism in hypothyroid patients, though whether this was a case in our patient is speculative as neck irradiation per se is considered to be capable of influencing changes in patients' immune status.

graves’ disease, neck irradiation, thyroid antibodies, thyrotoxicosis

PMC6198597_01

Female

A 50-year-old female with 17 years of psychiatric illness, episodic in nature, presented with the current episode for the past 8 months, with acute onset and no apparent stressor. On inquiry, her family reported that the illness began with increased talkativeness in the initial 10-14 days, when she would do her household works with more vigor (including getting up in the middle of the night to wash utensils and preparing food) accompanied by a decreased need for sleep. She started going to market without informing the family members and buying a lot of unwanted grocery. She had anger outbursts and abusive behavior when confronted. After around 2 weeks of onset, she was brought to the outpatient department (OPD) and started on tablet lithium (600 mg/day) and tablet quetiapine (up to 200 mg/day) along with lorazepam 2 mg/day. The family members noted over the next few days that the patient's speech output was markedly reduced. She would keep staring in one direction for long and not participate in any household chores. Her medications were continued for 1 month but she deteriorated. She would occasionally say she is missing some distant dead relatives or talk about her parents who expired around 10 years ago. Subsequently, her appetite and self-care deteriorated as well. She would frequently void urine on bed and had to be assisted by her daughter for changing clothes. Dose of lithium and quetiapine had been increased to 900 mg/day and 350 mg/day, respectively. She was thereafter admitted in August 2014 to the psychiatry ward in view of difficulty in management and a thorough reassessment. In the past, she had the first episode of postpartum manic episode in the year 1996-1997 at the age of 33 followed by two more episodes (mania and depression) in the years 2002 and 2005-06 respectively. She apparently maintained well for subsequent 5 years till when she had three episodes in quick succession (possible mania followed by 2 weeks' depression, followed by treatment-emergent mania) in the year 2011-2012. The compliance to medications and follow-ups had been highly irregular throughout. Her next episode in 2013 was characterized by running away, disorganized behavior, mutism, and crying spells, after which the treating psychiatrist revised to nonaffective psychosis and started on tablet haloperidol. She again dropped out of treatment after improvement, till she presented in the year 2014 with an episode of persecutory ideas, suspiciousness, anger outbursts, and irritable behavior, which was soon managed again with haloperidol. Thereafter, she came back after an interval of 1 year in the year 2015 with the current episode, for which she was admitted. Her physical examination was unremarkable except mild pallor and low body mass index (BMI) (19 kg/m2), and low hemoglobin, with normal thyroid function tests, kidney function tests, liver function tests, folic acid, and Vitamin B12 levels. After admission, the patient was observed to have mutism, reduced activity, occasional crying lasting 30-40 min few times in a day, and would stay awake during the night. With no response to quetiapine in the current episode over the past few months, it was cross tapered with olanzapine, with gradual optimization of dose. Lorazepam was increased to 6 mg/day in divided dosages for catatonic features. The patient showed some improvement over a period of the next 3-4 weeks in terms of her interaction and biological functions, but progress soon plateaued. As the patient started interacting, it was found that she would often call her daughter as her younger sister and misidentify other family members and her doctor. She was unable to identify the place she was in, in spite of repeatedly reorienting her. She would go to the toilet and, at times, was found to be drinking water from the toilet pot. She would not give any explanation for these behaviors. Her sleep-wake cycle was reversed. On three occasions in the ward, she took off her clothes with no regard for surroundings (later on careful questioning, the husband reported that she had expressed to have intercourse with her husband in the ward that time). She would greet the members of the ward, sometimes clinging on to them, but could not be engaged in meaningful conversation. Serial mental status examinations showed disorientation to time/person/place, restricted affect, and no thought or perceptual abnormality. This continued persistently for the next 7-10 days. Medicine, gynecology, and neurology consultations were sought and investigations were ordered to look for the cause of disorientation. Serum electrolytes, creatine phosphokinase levels, magnetic resonance imaging brain, and electroencephalogram came out to be within normal limits. Ultrasound sonography abdomen and pelvis showed incidental finding of a benign ovarian mass (tubo-ovarian abscess). Repeated attempts to perform Mini-Mental status examination on a daily basis yielded a score of 9-11 consistently. There was minimal improvement in her symptoms despite continuing medicines and regular re-orientation cues by family members and ward team. A re-workup was done after which her diagnosis was revised to bipolar disorder not otherwise specified (mania) with delirium ("delirious mania") in the 6th week of admission. Lithium was restarted in the 6th week itself after discussion with the family members (serum lithium levels: 0.85 mEq/L). The patient improved within the next 2 weeks. She would now recognize her daughter and her doctor, was able to identify the place she was in, oral intake improved, she gained weight (BMI: 21 kg/m2), and self-care improved markedly. She was discharged in November 2014 on lithium 900 mg, olanzapine 20 mg, and lorazepam 6 mg/day. She had resumed with her household activities, with euthymic mood, normal biological functions, and no residual symptoms. She was seen on regular follow-ups in the OPD till the next 8 months till July 2015.

bipolar disorder, catatonia, delirious mania

PMC8641443_01

Female

A 25-year-old woman was admitted for intermittent hematochezia. A digital rectal examination revealed a polyp 20 mm above the pectinate line. A full clinical investigation revealed no tumors elsewhere. A liquid-based cytology test combined with a human HPV-DNA test was performed to exclude cervical disease. The patient underwent a transanal resection, and the sessile rectal polyp (25 mm) was removed. Histologically, a poorly differentiated submucosal tumor with relatively clear boundaries was discovered beneath the non-neoplastic rectal mucosa. The submucosal tumor showed a lymphoepithelioma-like growth pattern (Figure 1). The tumor was composed of sheets of large tumor cells with oval or round vesicular nuclei and prominent nucleoli, and had a syncytial cytoplasmic appearance. The intratumoral stroma was densely infiltrated with lymphocytes and plasma cells. The tumor invaded the submucosa to a depth of 11 mm, and the deep and radial margins were clear. Immunohistochemically, the tumor cells were positive for pan-CK, P63, P40, and CK5/6 (Figure 2A), and negative for SATB2, Villin, CDX2, and CK20 (Figure 2B). Diffuse block-type immunoreactivity (diffuse nuclear and cytoplasmic staining) of p16 was shown (Figure 2C). Therefore, a diagnosis of poorly differentiated squamous carcinoma with lymphoepithelioma-like morphology was made. Since LELCs have been previously reported to be closely related to EBV infection, in situ hybridization for EBV-encoded small RNA (EBER) was performed. The tumor cells were negative for EBER, while strongly positive staining was observed in the external positive control (Figure 2D). Linear array HPV genotyping (Yaneng Bio, Shenzhen, China) was performed for the detection of 23 HPV types, namely, 17 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51-53, 56, 58, 59, 66, 68, 73, and 82) and 6 low-risk HPV types (6, 11, 42, 43, 81, and 83). High-risk HPV-16 was detected in this case. Therefore, this was a case of HPV-associated LELC of the anal canal. Given that there was a strong local immune infiltration in the tumor microenvironment, immunostaining was performed for DNA mismatch repair (MMR) proteins, PD-L1, and CD8. The tumor showed intact nuclear staining of four MMR proteins (MLH1, PMS2, MSH2, and MSH6). Normal colonic mucosa (adjacent to the carcinoma) and lymphocytes served as positive internal controls. The immunostaining intensity of PD-L1 was evaluated by the combined positive score (CPS), and a strong immunoreaction was observed with a CPS > 70 (Figure 2E). We also analyzed the presence of intratumoral CD8+ T cells and found that abundant tumor-infiltrating lymphocytes (TILs) were CD8-positive (Figure 2F). The patient subsequently underwent further endoscopic evaluation and mapping biopsies. Neither endoscopic nor microscopic examination revealed any abnormalities. Thereafter, the patient received three cycles of chemotherapy (paclitaxel + Cisplatin + capecitabine) combined with concurrent radiotherapy. The patient continued to be asymptomatic with no signs of recurrence or metastasis 8 months post-operation.

anal canal, case report, human papillomavirus, immune microenvironment, lymphoepithelioma-like carcinoma

PMC6174834_01

Male

A 25-year-old Indian male without any significant past medical history presented to a hospital in the United States with progressively worsening systemic symptoms over the course of three months. Symptoms included fatigue, night sweats, and fever, as well as a non-productive cough. He reported unintentional weight loss of 30 pounds over three months, as well as ten days of worsening low back pain that radiated to his thighs. Notably, the patient had immigrated to the United States from India two-and-a-half years prior to this admission and had briefly visited India one year prior. He had no history of tuberculosis, and he denied any known exposures to tuberculosis. In the emergency department, he was febrile to 103.1 F and tachycardic to 160 beats per minute. However, he was normotensive and breathing comfortably on room air with an oxygen saturation of 97%. On general examination, he appeared thin but was awake and alert in no acute distress. On pulmonary examination, he was found to have decreased breath sounds and dullness to percussion over the right middle and lower lung fields, as well as mild clubbing of the digits. The remainder of the physical examination was unremarkable. He received a chest x-ray and subsequent CT angiogram of the chest, which demonstrated a large right loculated pleural effusion, right upper lobe density, right-sided compressive atelectasis, multiple bilateral subcentimeter nodules, and a 1.5 cm right hepatic lesion (Fig. 1). To evaluate his reported back pain, an MRI of the lumbar spine was ordered, and the results showed multiple poorly defined bony lesions consistent with metastatic disease in the vertebral bodies (Fig. 2A). In an attempt to identify the primary source of the metastases, an ultrasound of the testes was then performed, which demonstrated bilateral masses suspicious for additional metastases, though primary testicular malignancy could not be excluded by imaging alone. Follow-up serum alpha fetoprotein (AFP) and beta-hCG levels were within normal limits. Initial hematologic studies revealed a mild normocytic anemia, leukocytosis, and mild thrombocytosis. A metabolic panel revealed hyponatremia (127 mmol/dL) and elevated alkaline phosphatase (201 IU/L), and hypoalbuminemia. Thoracentesis was performed upon admission, which showed a lymphocyte-predominant exudative effusion. No acid fast bacteria were isolated from the pleural fluid, and an adenosine deaminase (ADA) level was normal. The patient subsequently underwent bronchoscopy, and the culture was negative for acid fast bacilli after six weeks. However, transbronchial biopsy demonstrated necrotizing granulomas in the lung and fibrous tissue. Stains for mycobacteria and fungi were negative. This was followed by pleural biopsy, which was also negative for mycobacterial culture but demonstrated focal granulomatous inflammation. Interferon gamma release assay (QuantiFERON Gold) and tuberculin skin test were both positive. The patient was started on antibiotic therapy of rifampin, isoniazid, pyrazinamide, and ethambutol. After a week of treatment, the patient continued spiking fevers, we proceeded to ruling out central nervous system involvement. An MRI of the brain was done and demonstrated calcanerium abscesses, infiltration of the bone marrow, and thickening of the dura (Fig. 2B). Given these findings, a bone marrow biopsy and lumbar puncture were performed, which were both normal with once again negative acid fast bacilli staining and culture. The patient continued with standard antituberculous therapy and gradually improved. After his fevers resolved and mental status normalized, the patient was discharged.

disseminated tuberculosis, extra-pulmonary tuberculosis, skeletal tuberculosis, testicular tuberculosis

PMC6875408_01

Male

The patient was a 27-year-old man who sprained his right thumb while playing softball, resulting in tenderness and swelling around the interphalangeal (IP) joint. He was a software engineer, and his dominant hand was the right hand. Physical examination revealed complete loss of active extension and also that passive extension and active flexion of the IP joint were full. The IP joint was stable against radial and ulnar stress. The images of plain radiography and computed tomography showed an avulsion fracture of one-third to half of its articular surface at the base of the distal phalanx (Figure 1). Using the hook plate technique, open reduction was performed under general anesthesia 19 days after the injury (Figure 2). An incision was made along the crease on the dorsal side of the IP joint. The fracture was reduced and fixed using a hook plate adapted from a 1.5 mm micro module (KLS Martin, Germany, Figure 3(a)). One of the holes was cut, and one-third of its circumference was removed. The ends of the crescent arc were bent approximately 100 by pliers to form two sharp pointed hooks (Figure 3(b)). Two small longitudinal incisions were made at the EPL. The hook plate was slid under the nail matrix, the hooks were inserted through the slips, and the bone fragment was gripped. The screw was inserted into the plate hole to add compression to the fragment. The articular congruency and stability of the fragment in the direction of passive flexion were checked, and the wound was closed. The splint was maintained for 1 week before motion of the IP joint was allowed, and the patient returned to work 1 day after surgery. Bone union was achieved and the plate was removed 3 months after the procedure (Figure 4). At the last follow-up of 6 months after surgery, the active range of motion at the IP joint was 80 degrees of flexion and 8 degrees of extension. The range of motion on the contralateral side was 85 degrees of flexion and 10 degrees of extension (Figures 5(a) and 5(b)). The patient had a transverse line nail deformity (Figure 6) that gradually improved. According to Crawford's evaluation criteria, the result was excellent. The patient experienced no injury-related difficulties both at work and while playing softball.

PMC4033585_01

Female

Miss EJ, a 28 year old, single was received in our emergency unit for pelvic pain at 9 weeks and 5 days of pregnancy. The pain started five days prior to consultation and was associated with dark and light vaginal bleeding. She first consulted in a health center where she received antispasmodics without success. She was then referred to our emergency unit for better management. In past history, the patient had her first menses at 13 and the first sexual intercourse at 19. Her menstrual cycle is regular lasting 30 days and she bleeds for 5 days. She has no history of sexually transmitted infection. As contraception, she has always used male condom and practiced interrupted coitus . Her first pregnancy resulted in a normal vaginal delivery at term. The ongoing pregnancy was the second and was at 9 weeks and 5 days. She is a dizygotic twin. She was successfully treated for pulmonary tuberculosis four years ago. On admission she had a good general condition and the vital parameters were normal. Gynecological examination revealed an enlarged uterus consistent with a 10 weeks pregnancy, a painful left adnexal mass of 10 centimeters of diameters and cervical motion tenderness. There was no vaginal bleeding. We suspected an ectopic pregnancy associated to uterine fibroids. Differential diagnoses were a complicated ovarian cyst in pregnancy and pelvic inflammatory disease in pregnancy. One hour after admission, while being in the imaging unit for emergency pelvic ultrasonography, she felt a sudden, intense and cramp-like pelvic pain associated with vomiting. The pain then diffused progressively to the whole abdomen. The findings of the ultrasonography were: an evolving singleton intrauterine pregnancy of 7 weeks and 6 days, a gestational sac in the right uterine adnexae containing a non living embryo of 8 weeks and 2 days and 300 milliliters of hemoperitoneum. On reevaluation, vital parameters remained normal. On abdominal palpation, we noted a slight pelvic tenderness. On vaginal digital exploration the cervix was long and closed, and adnexae were tender and difficult to palpate. The pouch of Douglas was painful and bulging. Culdocentesis brought back 4 milliliters of non clotting blood. We concluded that the extra-uterine pregnancy was ruptured. After an intramuscular injection of 500 milligrammes of long acting progesterone, we carried out an emergency laparotomy. We found a left tubal ruptured pregnancy, a homolateral corpus luteum, a globular and soft uterus consistent with a pregnancy of 9 weeks, 1,300 milliliters of hemoperitoneum and left adnexae embedded in type B adhesions (Figure 1, Figure 2). We did a total left salpingectomy. Postoperative course was uneventful and the patient was discharged five days after surgery. Every week she received an intramuscular dose of 500 milligrammes of long acting progesterone till the eighteenth gestational week. The course of the pregnancy was normal and our patient gave birth at term to a live girl weighing 3.1 kilogrammes.

cameroon, ectopic, hemoperitoneum, heterotopic, pregnancy

PMC5585647_01

Female

Patient was 31-year-old female and 15 weeks into her second pregnancy, when she commenced her antenatal care. Her Body Mass Index (BMI) at booking was only 15.53 kg/m2, with a booking weight of 36 kg. She had been experiencing intermittent, dull, right-sided abdominal pain that was associated with diarrhea, for 3 months and in this span of time, her weight had decreased markedly by 20 kg. Her primary healthcare provider at the district maternal and child health clinic subsequently treated her for acute gastroenteritis twice in the following weeks, but she experienced no improvement in her symptoms. At 29 weeks and 6 days of gestation, she was admitted to a district hospital, complaining of acute right-sided abdominal pain that radiated to the right lumbar region. She also complained of dyspnoea and near-syncopal episodes, as well as a reduced effort tolerance the preceding week. She had been compliant to her oral hematinics therapy and denied any history of dysuria, haematuria, haematemesis, or haematochezia. A recent peripheral blood film revealed normochromic, normocytic anaemia, and serum ferritin was normal. On physical examination, she appeared pale and she was febrile. On palpation, her fundal height corresponded to 30 weeks of gestation. Tenderness and guarding were elicited at the right lumbar region. However, she did not exhibit any signs of preterm contraction and renal punch was negative. Transabdominal scan revealed a singleton fetus, with parameters corresponding to her gestation. She had hemoglobin of 7.4 g/dl and a white cell count of 15.87 x 109. Broad-spectrum antibiotic was commenced. She was also transfused with 1 pint of packed cells and she was referred to both the obstetrics and surgical teams of a tertiary hospital. An urgent ultrasound abdomen was arranged, which revealed a heterogeneous collection in the subhepatic region and multiple enlarged mesenteric lymph nodes. A diagnosis of likely perforated appendicitis was made and she underwent an emergency laparotomy. The intraoperative finding was that of a perforated caecal tumour. The tumour was firm and hard with irregular margins and surface. There was evidence of multiple enlarged mesenteric lymph nodes. A right hemicolectomy was performed. Appendix was normal. She received 3 pints of packed cells transfusion and 4 units of fresh frozen plasma. Postoperatively, she was transferred to the Intensive Care Unit (ICU), where she recovered well and was transferred to the general ward after 2 days. 7 days after surgery, she developed spontaneous preterm contractions and delivered a baby boy of 1.2 kg, at 31 weeks of gestation with Apgar score of 7 in one minutes and 9 in five minutes. The baby was given Bacillus Calmette-Guerin (BCG) vaccination immediately after delivery as routine procedure. The histopathological examination showed caecal tuberculosis. She was referred to the Infectious Disease (ID) team and started on anti-TB medication. She denied any pulmonary TB contact. Her pulmonary TB work-up including chest X-ray, sputum acid fast bacilli (AFB), and Mantoux test was negative. Screening tests for HIV were negative. She developed surgical wound breakdown at 14 days postoperatively and secondary suturing was performed. Her baby was initially admitted to the Neonatal Intensive Care Unit (NICU) for extreme prematurity but was subsequently discharged well with good catch-up growth and a negative Tuberculin skin text/Mantoux test. At a subsequent follow-up upon completion of 6 months of anti-TB medications, she had put back most of her weight and her baby was assessed to have achieved age-appropriate developmental milestones.

PMC6304558_01

Female

A 35-year-old gravida 6, para 5 mother who is 38-week pregnant from last normal menstrual period has presented to Tercha General Hospital (a rural hospital in Southern Ethiopia). The patient is referred from a health center 60 kms far from this hospital for suspected "big baby" in labor. The patient was an illiterate housewife. In terms of past obstetrics history, all previous deliveries occurred at home vaginally with live birth with no major complication. During the index pregnancy, she had antenatal care visits at a nearby health center without ultrasound examination. She reports that the current pregnancy is heavier than previous ones and associated with significant discomfort than her previous pregnancy experiences. Otherwise, she has no self or family history of twinning in the past. Examination shows a stable gravida with normal vital signs. Abdominal examination shows big for date uterus with two cephalic poles in the lower abdomen and positive fetal heartbeat. Standard ultrasound examination confirmed twin pregnancy with both in cephalic presentation and adequate amniotic fluid; single placenta with no visible dividing membrane; fetal heartbeat is visible at two sites and is in a normal range. Upon pelvic examination, the cervix is 8cm dilated with left occiput-anterior position at a station 0. Fetal membrane is ruptured with clear liquor passing. With diagnosis of twin pregnancy (both cephalic presenting), in active phase of first stage of labor patient is admitted to labor ward and management of labor started in the standard way. In the next few hours labor progressed well and the first baby is crowning. Duty midwives are attending the delivery. Subsequently, with maternal effort the head and upper extremities of the first baby are delivered and the remaining part of the fetus is delivered by 'gentle' traction by the midwives. But after delivery of the whole body, baby 1 remained 'attached' to the mothers' perineum, though the baby is crying vigorously (Figure 1). The midwives started to shout for help and senior obstetrician arrived. On reevaluation, we noticed the same and we found that the anterior abdomen of baby 1 from xiphisternum to the site of umbilical cord insertion is continuous into the uterine cavity. This led to sudden and unexpected consideration of the possibility of conjoined twins. Bedside ultrasound showed alive remaining fetus with fetal heart rate of 76 and in a transverse lie with the head in the right iliac fossa and fetal dorsum anterior. Initial attempt to access the extremities and aid delivery of the remaining fetus vaginally is not possible due to failure to reach the extremities for intrauterine manipulation. Emergency laparotomy is decided. Emergency laparotomy under general anesthesia with midline subumbilical abdominal incision and lower uterine segment vertical hysterotomy is performed. We corrected the lie of the born baby such that it is parallel to that of the unborn baby; with deep vaginal examination along with the caudal end of the attachment and managed to manipulate the lower extremities of the intrauterine fetus to vagina and after grasping those with the right hand vaginally, we brought it to the perineum. Then there is careful manipulation to bring those extremities posterior to the born baby with a second assistant holding and manipulating the born baby away from the area of manipulation. Progressive delivery of the second baby of the conjoined pairs is affected by total breech extraction with minimal difficulty. Both newborns were depressed at completion of the procedure and recovered after aggressive resuscitation for 10 minutes (Figure 2). Both are male and their combined weight is 5800 gm. Ultrasound examination of the twins shows shared liver with no other organs shared. Latter the second baby passed away after 1 hour of stay at the NICU. The second baby died after 20 hours of stay, during transportation to higher center for possible emergency separation. The mother was discharged to home on her sixth post-op day after counseling.

PMC9443577_01

Male

Male 51-year-old patient without systemic or otological disease, complained of tinnitus of pulsatile nature on the left, synchronous with heartbeat, which had started 9 months before and hindered his professional performance (administrative assistant) and resulted in marked anxiety. The patient had taken antidepressants, anxiolitic and vasoactive drugs prescribed by the neurology, without any response. ENT physical examination presented normal otoscopy and the patient had past history of septoplasty two years before the onset of tinnitus. Neurological examination had no significant findings. Pure tone audiometry - mild decrease in high frequencies (3000Hz 30 dB; 4000Hz 35 dB; 6000Hz 40 dB) bilaterally. Brainstem evoked potential did not evidence any abnormalities. Nuclear Magnetic Resonance of the head, with gadolinium- isolated focus of reduced signal in T1 and elevated in T2, not impregnated by the contrast medium in the left frontal radial crown, suggestive of cerebral lacuna. Basilar artery was elongated and tortuous, describing anterior-lateral loop on the left under the pons. Head angioresonance - brain images in T2 showed hyperintense focus on left radial crown, which may correspond to small area of gliosis or lacuna infarction. Tortuous vertebral-basilar transition towards the pontine-cerebellum angle cistern on the left (Figure 2). We conducted the following complementary tests: In both neuroimaging studies the other head and vascular structures were normal. After excluding the hypothesis of surgical treatment, we prescribed clonazepam 2mg/day associated with propranolol 20mg TID, which made tinnitus more tolerable to the patient.

PMC3960811_01

Male

A 23-year-old man presented with diffuse swelling in the left half of the neck and the left half of the chest of 4 weeks' duration and gradual onset of breathlessness of 1 week duration. He also complained of early satiety and unquantified weight loss. He was a farmer by occupation, did not smoke or drink alcohol and did not have any significant past medical history. On examination, he was afebrile and normotensive, with respiratory rate of 26 breaths/min and a pulse rate of 98 beats/min. His neck swelling was a diffuse lymphedema, extending to the upper chest, up to the mammary area. The jugular venous pressure was not elevated and there was no erythema, tenderness or elevation of local temperature over the swelling. The respiratory system examination revealed findings consistent with left pleural effusion. The rest of the physical examination was unremarkable. Investigations showed a hemoglobin count of 13.7 g/dL, leukocyte count of 8000 cells/cm3 with 78% neutrophils and a platelet count of 2.1 x 105/L. His liver function tests showed a total protein of 5.5 gms/dL, albumin of 2.7 gm/dL, normal transaminases and alkaline phosphatase of 1848 U/L. His serum creatinine was 0.8 mg/dL and lactic acid dehydrogenase (LDH) was 203 U/L (normal 140-280 U/L). Chest radiography showed a large left-sided pleural effusion. Diagnostic pleurocentesis revealed milky white pleural fluid, with a cell count of 708/cm3 and differential count of 98% lymphocytes and 2% neutrophils. The fluid was consistent with an exudative effusion (by Light's criteria), with protein of 3.4 gm/dL, albumin of 2.4 gm/dL and LDH of 172 U/L. The other pleural fluid characteristics were glucose of 90 mg/dL, adenosine deaminase (ADA) of 5.8 U/L, amylase of 18 U/L, triglycerides of 274 mg/dL and cholesterol of 104 mg/dL. The pleural fluid analysis was suggestive of chylothorax. Cytology was negative for malignant cells in the pleural fluid and the gram stain revealed no microorganisms. An appropriate low-fat diet for chylothorax was initiated, with most fats in the form of medium-chain triglycerides. He was also started on octreotide to reduce chyle formation. Intercostal tube (ICD) insertion and drainage was performed to relieve his grade IV breathlessness. Three hundred milliliters to 400 mL of fluid was drained per day during the first 6 days of hospitalization. A search for the cause of chylothorax was undertaken. The patient denied any history of recent trauma or abdominothoracic surgery. There was no history of any febrile illness suggestive of tuberculosis. A computed tomogram (CT scan) of the chest showed moderate lymphangitis in the left lung, left-sided pleural effusion, minimal right-sided pleural effusion and minimal ascites [Figure 1]. A CT scan of the neck region revealed multiple enlarged left submandibular, posterior triangle and supraclavicular lymph nodes, the largest measuring 2.2 cm x 1.3 cm [Figure 2]. The left internal jugular vein was narrowed by 80% as compared with the right jugular vein. This, along with the lymphangitis, was concluded as the cause of chylothorax. Ultrasound-guided fine needle aspiration of the neck lymph node was suggestive of adenocarcinoma [Figure 3]. As part of the work-up for malignancy, his carcinoembryonic antigen was elevated with a level of 11.91 ng/mL (normal 0.2-3.8). Upper gastrointestinal endoscopy showed an ulcerated growth with everted margins measuring 2 cm x 2 cm in the posterior part of the stomach [Figure 4]. Biopsy of the ulcer confirmed it to be signet ring cell adenocarcinoma [Figure 5]. A diagnosis of gastric adenocarcinoma with metastasis to neck nodes was made. The chylous drain reduced to 100 mL/day after the first week. He was offered chemotherapy, which he wished to receive in his home town. The patient was discharged home at his request after ICD removal. On further telephonic follow-up, it was revealed that the patient expired 4 months after diagnosis after receiving alternative medicines.

chylothorax, gastric adenocarcinoma, lymphedema

PMC9935826_01

Female

A 68-years-old woman presented with weakness and numbness of all four limbs. The patient consented to participate in this case report. She could slide her legs sideways but was unable to lift them. She was able to move both arms with better movement in the left arm. However, she had difficulty clenching and grasping objects using her hands and fingers. The patient was right-handed. She was able to turn over in bed and sat reclining with the caregiver's assistance. All of her daily activities were performed with assistance, and she could not sit without support. She also could not feel the urge to urinate and defecate, and had incontinence. She felt pain in the middle back, which radiated to her legs, with a numerical rating scale (NRS) of 7. The pain was sharp and was accompanied by a burning sensation unrelated to any activity. The patient was administered gabapentin 300 mg daily for the last two weeks, and the NRS score was reduced to 5. The patient also experienced localized pain in her right shoulder and buttocks, with an NRS of 5, respectively. In addition, she complained of bilateral knee pain with an NRS score of 3. The patient often refused to be seated in a reclined position and preferred to lie prone all day. She slept a lot during the day and had difficulty sleeping at night. She also experienced malaise, epigastric discomfort, nausea, episodic vomiting, and a yellowish appearance on the sclera and skin in the previous week. She lost her appetite, which resulted in decreased food and drink intake, although she had no difficulty swallowing liquids or solid foods. The presumptive diagnosis was spondylitis tuberculosis. She had consumed anti-tuberculosis drugs for two months. Magnetic resonance imaging (MRI) revealed destruction of the vertebral bodies at the level of the 5th and 6th cervical area, with paravertebral and longus colli muscle abscesses (Figure 1). Subsequently, she underwent debridement and spinal stabilization surgery. The spine stabilization procedure was anterior cervical corpectomy decompression and fusion (ACDF). Her body mass index (BMI) was 14.98 kg/m2 (categorized as underweight). Her vital signs were uneventful, and communication was good. Both the sclera and skin were icteric. No palpable enlargement of the liver or spleen was observed. She also had a pressure injury at the sacrum measuring 2 x 1 cm, grade II. This patient had a limited range of movement (ROM) in the neck and upper extremities. She also had limited flexion in all parts of the metacarpal joints. Neurological examination revealed that she had SCI with an Asia Impairment Score (AIS) grade C and neurological level (NL) at the 5th cervical area (SCI AIS C NL C5). The patient wishes to return to her role as a grandmother and perform activities in a sitting position. We found that this patient was categorized as malnourished, with a score of 4, as assessed using the validated Mini Nutritional Assessment (MNA) tools. She also had a mid-upper arm circumference of 17 cm, categorized as low circumference. She had mild cognitive impairment (MCI) with a score of 22 as measured using Montreal Cognitive Assessment Indonesian version (MOCA-INA). This patient also had suggestive sarcopenia with a score of 18 on the SARC-Calf score. We could not perform a bioelectrical impedance analysis (BIA) to confirm the diagnosis of sarcopenia because the patient could not stand properly on her own. We also tried using a hand dynamometer to measure the strength of the hand grip, but the patient was unable to press the handle maximally due to the stiffness of the metacarpophalangeal (MCP) joints in both hands. In addition, she was considered inactive according to the International Physical Activity Questionnaire (IPAQ). She was also regarded as dependent, with a score of 21/100 on Spinal Cord Independence Measurement (SCIM) with poor QOL. This patient had probable depression based on the Geriatric Depression Scale (GDS). Her caregiver has a caregiver burden, scoring 44, based on the Zarit Burden Scale (ZBS). She received pain management therapy during hospitalization. We used extracorporeal shock wave therapy (ESWT) and infrared radiation (IRR) to manage the right shoulder pain due to tendonitis, with an NRS score of five. Both were assigned to the insertion of the rotator cuff muscle area. ESWT was performed once a week, and IRR was performed twice a week. Laser therapy has been used to treat buttock pain caused by piriformis syndrome. It was administered to the piriformis muscle twice a week. All therapy modalities will be administered for one month and will be evaluated monthly. Our patient performed the 3-month outpatient PRM program after the initial assessment with flexibility and strengthening exercises for the extremities (Figure 2), as well as activity of daily living (ADL) adjustment training (for eating, grooming, and upper dressing). Additionally, she received psychological support from a psychologist. The short-term goals of our PRM intervention were increasing body weight, reducing shoulder pain, ensuring appropriate sleep time, independent ADL for eating, grooming, and upper body dressing, partial dependency on bed mobilization, partial dependency on transfer, managing depression, and no SCI complications. The long-term goals for the patient include managing tuberculosis, increasing the QOL, and reversing the sarcopenia condition.

activity of daily living, elderly, physical medicine and rehabilitation, quality of life, spinal cord injury

PMC4626642_01

Male

A 32-year-old man was admitted to The Alfred Hospital, Melbourne, Australia in December 2010 following a high-speed motorcycle accident with an initial Glasgow coma score (GCS) of 14. In addition to a TBI, he sustained C4 to C7 ligamentous damage, multiple fractures of the pelvis, ribs, sternum and facial bones, and significant soft-tissue trauma. By day 2 of admission, his GCS had normalised. Despite a mild TBI and the absence of structural damage on CT and MRI brain imaging, he developed post-traumatic amnesia and subjective long-term cognitive deficits preventing him from returning to work. Formal neuropsychiatric evaluation and functional imaging was not performed, so there was no objective evidence of permanent brain damage. The GCS was introduced as a method for determining the severity of brain dysfunction 6 h after head trauma and cannot predict long-term cognitive function, so it likely underestimated the impact of this injury on our patient's long-term cognitive function. On day 3 of his admission, he developed hyponatremia consistent with SIADH: serum sodium 117 mmol/l (reference range: 135-143), serum osmolality 247 mmol/kg (280-300), urine sodium 112 mmol/l (>30) and urine osmolality 920 mmol/kg. He was symptomatic with nausea, but cognition remained intact with a GCS of 15. He was clinically euvolemic with a urine output of 100 ml/h and an overall minor positive net external fluid balance (total daily fluid input 2600 ml, total daily fluid output 2450 ml). His thyroid function was normal: fT4 15.5 pmol/l (9.1-19.6), TSH 2.29 mU/l (0.3-5), and repeated cortisol levels were robust: day 4 admission 0820 h cortisol 357 nmol/l (100-540), day 6 admission 0910 h cortisol 583 nmol/l. An MRI pituitary was also performed, which was normal. An insulin tolerance test was not performed as repeated cortisol levels were considered sufficient especially a value >550 nmol/l. Furthermore, it might be unsafe to perform in a head-injured patient at least in the acute setting. He was not taking any medications at the time of presentation and denied a history of illicit drug use. Temporary 1.5 l fluid restriction normalized sodium levels. Following discharge to a rehabilitation unit he experienced recurrence of moderate hyponatremia, again consistent with SIADH, requiring long-term fluid restriction. Over the subsequent 3 years, he was advised to adhere to 1.2 l fluid restriction, which only maintained serum sodium levels of 128-130 mmol/l. Adherence was difficult, resulting in nine hospital admissions due to worsening hyponatremia with symptoms including nausea and malaise. On each occasion biochemistry remained consistent with SIADH and serum sodium improved with tight fluid restriction as low as 500 ml daily. Psychogenic polydipsia is an important consideration in those presenting with recurrent euvolaemic hyponatraemia, but the fluid restriction required in this case to achieve normonatraemia was severe and inconsistent with a diagnosis of psychogenic polydipsia. There was no evidence of hypopituitarism, malignancy, intercurrent pulmonary disease or nervous system disorders during this time, and pain was well controlled on paracetamol and buprenorphine. The etiology of his chronic SIADH was considered to be most likely secondary to prior TBI. He was most recently admitted in September 2014, presenting with several hours of nausea, malaise and anorexia in the context of not adhering to his fluid restriction. He was clinically euvolaemic. Biochemistry was consistent with SIADH: serum sodium 119 mmol/l, serum osmolality 253 mmol/kg, urine sodium 119 mmol/l, urine osmolality 764 mmol/kg, TSH 0.55 mU/l (0.3-5), fT4 12.6 pmol/l (9.1-19.6), cortisol at 0600 h 347 nmol/l (100-540). Serum sodium improved with a daily 500 ml fluid restriction. Please refer to the preceding case description.

PMC9234165_01

Female

A 52-year-old female was admitted to the hospital due to recurrent cough, expectoration, and shortness of breath for more than 10 years. In her hometown, she frequently presented to the hospital with lung infections and was treated with antibiotics. She received a pulmonary function test in September 2021 in Shanghai, which indicated obstructive ventilatory dysfunction because FEV1/FVC was less than 70%. Consequently, she was diagnosed with chronic obstructive pulmonary disease (COPD). She was treated with long-acting beta2-receptor agonist (LABA) + long-acting cholinergic receptor antagonist (LAMA) (Olexin) inhalation for about 2 months. Two days prior to the current admission, she was presented with increased cough and yellow sputum. She had no fever, chills, fatigue, night sweats, progressive emaciation, chest pain, or other symptoms. She had a history of spontaneous pneumothorax because of ruptured bullae of the lung. However, she could not provide the X-ray and a detailed history of the previous therapies. Although clear that she had situs inversus, she was treated as a common pulmonary disease. She denied any history of PCD in any of her parents or risk factors such as inbreeding. She has a son and a daughter, both of them are healthy with no apparent signs of lung disease. There is no other person with similar symptoms in her family. On a physical examination, her blood pressure was 140/90 mmHg, pulse rate of 107 beats/min, respiratory rate of 15 times/min, and oxygen saturation of 98% at room air. On cardiovascular examination, heartbeats were audible on the right side of the chest. There were not any coarse crackles in both lungs. An initial investigation revealed a white cell count of 3,290/muL and a C reactive protein level of less than 1 mg/L. The arterial blood gas analysis showed her PO2 level was 111 mmHg when she received an oxygen flow rate of 3 L/min. There were not significant abnormal findings in liver and kidney functions, electrolytes, ESR, procalcitonin, peripheral blood lymphocyte subsets, markers of autoimmunity, and antinuclear antibody. In sputum smear, Gram-positive cocci, suspected to be Streptococcus was identified. The bronchial alveolar lavage fluid (BALF) was obtained to perform metagenomic sequencing and Nocardia gelsenkircheni was identified. Chest X-ray (posteroanterior view) showed a cardiac shadow on the right side (Figure 1). Many tree-in-buds on both sides of lung lobes were found in Chest computed tomography (CT) (Figure 2). Abdominal CT confirmed complete situs inversus totalis (Figure 3). Otitis media tympanitis with effusion was found by an otolaryngologic examination (Figure 4). Fiberoptic bronchoscopy showed total bronchial inversion and bronchial mucosal inflammations in both lungs (Figure 5). Given the history of repeated respiratory infections and situs inversus, combined with the physical examinations, she was suspected to have PCD. Following the European Respiratory Society (ERS) guidelines for the diagnosis of PCD, we intended to evaluate nasal nitric oxide (nNO) levels and perform a high-speed video analysis (HSVA). Unfortunately, we were unable to conduct those tests because of our technical limitations. We then performed genetic testing of her peripheral blood to confirm the diagnosis, according to the diagnostic criteria of the Chinese Expert Consensus on the Diagnosis and Treatment of Primary Ciliary Dyskinesia. We performed whole-exome sequencing to detect the presence of any mutation(s). Two milliliters of peripheral venous blood preserved in an ethylenediamine tetraacetic acid (EDTA) coated tube was sent to the Shenzhen BGI Medical Test Laboratory. The sequencing was performed by capture high-throughput chip technology. Sanger sequencing was used to verify the mutations. The results showed that two suspected pathogenic mutations were located on chromosome 17; CHR17:11513858-11513859 and CHR17:11593470 (Figure 6), and detected in DNAH9 gene associated with PCD type 40, which was partially related to the phenotype of the subjects with PCD. One of the mutations, DNAH9 (NM_001372.3, c.760_761delTT, p.Phe254Leufs*6) is a frame-shift mutation caused by the deletion of two nucleotide TT at nucleotide positions 760-761 of the coding sequence of the gene, resulting in the phenylalanine codon at position 254 being changed to leucine, and a stop codon at position 260. The c.760_761delTT mutation is mentioned in ClinVar. Another mutation, DNAH9 (NM_001372.3C, c.4331G > A, chr17:11593470) is a nonsense mutation caused by the substitution of nucleotide A with G, resulting in the leucine codon at position Trp being changed to a stop codon. We could not get blood samples of her parents or children for the gene analysis, but they had no clinical manifestation of PCD. This study was approved by Shanghai Ethical Review Board (2022-047). Ampicillin tazobactam was administered to treat the infection, ambroxol hydrochloride was administered to reduce sputum, albuterol, and acetylcysteine were inhaled to dilate the airways and promote sputum excretion. After treatment, the symptoms were relieved, and she was discharged. The patient was then prescribed fordostine to eliminate phlegm and urmetrium bromide and verranterol for inhalation therapy.

dnah9, pcd, gene mutation, kartagener syndrome, situs inversus

PMC7235927_01

Male

A 31-year-old man, was admitted to the outpatient clinic with major complaints of reddish skin transformation, warmth, and swelling of the right knee that progressively occurred since 2013; there was also intermittent pain that has been experienced since the symptoms emerged. The pain characteristically was exacerbated after strenuous activities without respiratory manifestations were found. Losing appetite and weight for 3 kg in one month has been suffered, and no symptoms of night-sweats and chills are experienced. Contact history with TB patients was not found, but a traumatic injury occurred in September 2012. The patient had a motorcycle accident, injuring the same leg. The history of medication was analgesics and oral antibiotics, including cephalosporin. There were no allergic indications, including food and drugs. There was no history of malignancy or genetic abnormality in his family background. In 2013, this patient was admitted to another hospital and had been diagnosed with acute infections with malignancy as a differential diagnosis. The patient was suggested to undergo further diagnostic examinations. However, he preferred to undergone alternative treatments such as massage and herbal medicines. The patient and his parents still thought that his condition was not dangerous to get surgery. After several years of these treatments, no improvement of symptoms and clinical conditions were reported. The swelling of the leg became more severe, with the increased frequency of pain exacerbated after 5 years of alternative medicine approach. Physical examinations have reported the presence of swelling, reddish, and warm through palpation of the right knee with impaired proper motions. The affected extremity could not be flexed under 110 C, and extended -30 with no abnormality was found based on physical examinations of the spine, hip, and left knee. Meanwhile, chest radiograph demonstrated infiltration in both upper lobe lungs. From the sequence radiograph examinations, it showed the progression of knee destruction. In 2013, there was only a narrowing of the joint gap (Fig. 1a). Still, after being ignored for 3 years, it has progressed to the bone destruction, which was indicated by the presence of a lytic lesion in both fibula and tibia (Fig. 1b). Finally, another modality which has favorable of soft tissue infiltration, Magnetic Resonance Imaging (MRI) was used later. It showed the well-defined iso-hyperintense mass and free fluid collection that lead to right tuberculous knee arthritis with posterior abscess and synovitis infection (Fig. 2). Based on blood examination, no abnormality of complete blood count and thrombosis parameters were found. The patient was performed synovectomy in June 2018 by an orthopedist. Spinal anesthesia was performed before debridement and arthrotomy, followed by total synovectomy. The medial incision of the right patella revealed the synovial mass without any attachment to the adjacent structure (Fig. 3a). Later, histopathology revealed the epitheloid proliferation, granuloma, necrotic, lymphocyte infiltration, and localized fibrosis, suspecting a chronic specific inflammation, which included tuberculosis mass (Fig. 3b). Then, the patient was diagnosed with knee tuberculosis. Patient was prescribed with isoniazid (10 mg/kg/day), pyrazinamide (30 mg/kg/day), rifampicin (15 mg/kg/day), ethambutol (15 mg/kg/day), and streptomycin (25 mg/kg/day) daily for 2 months followed the synovectomy procedure. Treatment was then continued for 9 months with isoniazid (10 mg/kg/day) and rifampicin (15 mg/kg/day). Clinical improvement was observed after eight months of treatments; it was clinically proven that the improvements on flexed and extended ability to 130 and -10 . The side effect of treatments did not really affect the patient's condition. After 1 year, the patient has shown no clinical symptoms with the exception of limited flexibility movement (maximal flexed ability 160 ), and there was an improvement of radiologic examinations. After a year, follow-up x-ray examinations on the chest showed scanty fibrotic in the upper pulmonary lobe. MRI was performed, and it showed the more prominent of the lytic lesion compared with the previous MRI without secondary infection (Fig. 4). The patient was suggested to attend physical rehabilitation to ameliorate his joint movement without arthroplasty procedure scheduled. This time, he has been work as before he suffered the disease without any serious limitation. Clinical and radiological followed up might be considered to detect the long term complication, including secondary osteoarthritis.

knee, rare case, surgery, tuberculosis

PMC3206111_01

Male

The patient was a 29-year-old male from Tehran, with a history of multiple hospitalizations for lung infection who presented to the pulmonary clinic with a complaint of chronic productive cough which had worsened in the previous year. He had been hospitalized two to three times for his respiratory condition and once in childhood when he was 10 or 11 years old. The hospitalizations helped him a little, but his sputum production had gradually increased. Since his last hospitalization, which had been 2 years earlier, he had had persistent sputum production with expectoration two or three times an hour. The patient also complained of shortness of breath and wheezing. He denied fever, chills, hemoptysis, or exposure to tuberculosis. He had had measles in childhood. He denied any other past medical history or surgery. He was up to date on his vaccinations, was not on any medications, and denied any drug allergies. He was a nonsmoker and did not use drugs or drink alcohol. He was married and worked in an office. He reported having kept a canary at home for the previous year. He denied any medical illnesses in his family, including lung disease. On physical examination, he was in no acute distress, with a blood pressure of 110/70 mmHg, a pulse rate of 72 beats per minute, a respiratory rate of 20 per minute, and an oral temperature of 37 C. He was alert and orientated. He had no lymphadenopathy or sinus tenderness. Heart sounds S1 and S2 were heard, with no murmurs, rubs, or gallops. On pulmonary examination, breath sounds were hyperresonant on the left side. The abdomen was soft and nontender with no organomegaly. Neurology examination was normal. There was mild clubbing of his nails, but no cyanosis or edema. Chest x-ray showed extensive pulmonary cysts on the left side, with mediastinal shift to the left. Computed tomography scan of the thorax without contrast showed a normal heart, mediastinum, and pleura, with shift to the left side and hyperaeration of the right lung. There were multiple medium-sized, thick-walled cystic lesions, some containing fluid, in the left lung (mostly in the upper lobe), with volume loss in favor of bronchiectasis. The right lung had normal parenchyma and bronchovascular markings. Laboratory investigations showed a white cell count of 10 x 103 cells/muL and an erythrocyte sedimentation rate of 17 mm/hour. In view of illness since childhood, investigations were undertaken to exclude congenital causes of bronchiectasis. The patient was referred for a sweat chloride test and measurement of immunoglobulin levels. Body plethysmography was ordered with culture of sputum for bacteria, fungi, and mycobacteria. Three consecutive sputum smears for acid-fast bacilli were negative. The etiology of bronchiectasis was most likely measles in childhood. The patient's symptoms responded to ciprofloxacin and an albuterol metered dose inhaler.

bronchiectasis, cystic lung disease

PMC3206111_02

Unknown

Electronic medical records from Masih Daneshvari Hospital, a tertiary referral center, were searched to identify all cases of bronchiectasis and associated conditions from January 2007 until July 2008. In total, 291 cases of bronchiectasis were identified, age range 5-83 years, with 24 cases being younger than 18 years. Fifty cases of old tuberculosis were found, as well as 22 cases of cystic fibrosis, 21 of congenital immune deficiency, and five cases of Kartagener's syndrome. The age range for patients with primary ciliary dyskinesia was 9-25 years and that for immune deficiency was 2-43 years. The charts of the last ten patients admitted with a final diagnosis of bronchiectasis were reviewed. Three were presumed to be due to old tuberculosis. One had a tuberculin skin test of 8 mm. All three were sputum-negative for acid- fast bacilli and polymerase chain reaction. One patient was on antituberculous medication. A 17-year-old patient with Job syndrome was identified. One child aged 5 years presented with foreign body (chicken bone) aspiration.

bronchiectasis, cystic lung disease

PMC6279882_01

Female

The patient was a 13-year-old Caucasian female that presented to the hospital with complaints of fever, nasal congestion, and worsening cough over four weeks. This was her second admission within a one-month period. On her previous hospitalization, she had presented to the emergency department with ketoacidosis, was diagnosed with type 1 diabetes mellitus, and started on insulin therapy. An outpatient chest CT had demonstrated pneumonia. Laboratory workup via serology studies immediately prior to admission included Aspergillus, Blastomyces, Coccidiodes, Histoplasma, Mycoplasma, Chlamydia, and tuberculosis, which were all negative. She was consequently placed on four separate courses of antimicrobials including cefdinir, azithromycin, clindamycin, and levofloxacin. However, she developed a brown, purulent sputum and her respiratory function progressively declined. On admission, the patient was febrile at 38.3 C, heart rate was 148 beats per minute, respiratory rate was 36 breaths per minute, blood pressure was 138/99 mmHg, and O2 saturation was 94% on room air. Physical examination revealed decreased breath sounds in right lower lobe and scattered rhonchi. Initial laboratory investigations demonstrated total WBC count 15.2 x cells per liter (81.3% neutrophil), hemoglobin 10.8 g/dL, ESR 76 mm, and CRP 312 mg/L Chest radiography indicated right lower lobe homogenous opacity suggesting consolidation, and chest CT demonstrated right middle and lower lobe pneumonia. Blood cultures were drawn, and she was empirically started on ceftriaxone and vancomycin. Overnight, the patient had increased oxygen requirement and was transferred to the pediatric intensive care unit. Infectious disease recommended sputum culture, screenings for pneumococcus and legionellosis, and change antimicrobial regimen to linezolid and meropenem. Further laboratory investigations for potential source of infection including Legionella, Pneumococcus, chlamydia, mycoplasma, and atypical mycobacteria were negative. The patient was initially improving. However, by hospital day 7, she began to experience low-grade fever. Pediatric pulmonology was consulted due to persistent tachypnea and accessory muscle use. The patient was recommended budesonide and racemic epinephrine. For the next two days, the patient and her family reported improvement. However, after four days, the patient's respiratory function declined again, bronchoscopy and bronchoalveolar lavage were performed. During the bronchoscopy, only the larynx was visualized before the patient desaturated, suffered a cardiopulmonary arrest and required immediate resuscitative efforts including CPR, epinephrine, endotracheal intubation, central line placement, and vasopressor support. The patient was subsequently placed on high-flow oscillating ventilator, and the respiratory arrest was believed to be caused by increased secretions and mucus plugging within the airways. Infectious disease changed from meropenem to cefepime once she was stabilized, and subsequently added voriconazole due to prolonged broad-spectrum coverage. While the patient stabilized over the next four days before re-attempting another bronchoscopy, all previous cultures of blood, sputum, and urine continued to remain negative for any suspected pathogens. A second bronchoscopy was performed successfully. During the procedure, a large foreign mass was removed from the patient's trachea (Fig. 1). Direct visualization revealed severe tracheitis, fibrosis of the left mainstem bronchus, and lavage was performed in the right lower lobe. Initial pathology report from the foreign body suggested possible mucormycosis, and she was placed on liposomal amphotericin B. CT of the chest demonstrated bilateral infiltrates involving right upper, middle, and lower lobes, as well as the left lower lobe with a left-side pleural effusion. On hospital day 20, the throat culture confirmed the diagnosis of mucormycosis, and both cefepime and linezolid were discontinued. Repeat chest CT revealed dilatation of the trachea and right mainstem bronchus, and an occluded left mainstem bronchus was noted. The final tracheal biopsy showed the presence of broad, non-septate hyphae in both fibroconnective tissues and cartilage, indicating invasive disease. In spite of clinical improvement of respiratory symptoms, complemented by serial chest radiography, the patient was transferred on hospital day 40 to a tertiary medical center for surgical debridement.

complications of diabetes mellitus, diabetes mellitus, invasive fungal infections, mucormycosis

PMC6026718_01

Male

A 25 years-old previously healthy male shipyard technician was repairing a 1200 V alternating current electrical generator when it exploded. His right hand was touching the circuit box at the time of blast, but he denied prolonged contact or being flung. He sustained 16% total body surface area (TBSA) burns to his face as well as both arms and hands (Fig. 1). Fluid resuscitation was commenced, and he underwent debridement of his upper limb burns (including escharotomy of his right forearm) and application of biosynthetic Biobrane dressings (UDL Laboratories, Rockford, IL) to his face (Fig. 2A). Immediately after surgery, he complained of worsening, severe right hand pain, and an emergent fasciotomy was done for presumptive compartment syndrome (Fig. 2B). He also developed AKI with hyperkalaemia, a rising creatine kinase and myoglobinuria. Haemodialysis was initiated as his urine output failed to improve despite aggressive fluid boluses, mannitol diuresis and urinary alkalinisation. His AKI resolved after two weeks along with correction of his metabolic abnormalities and renal replacement therapy (RRT) was withdrawn. Serial debridement was performed until his upper limb wounds were clean and the full demarcation of the depth and extent of his injuries had become apparent. Autologous split-thickness skin-grafting was performed; the dorsum of his right hand ultimately required coverage with a groin flap (Fig. 3). He was discharged after 4 months and returned to work after a year of intensive rehabilitation.

acute kidney injury, compartment syndrome, electrical burns, reconstructive surgery, renal replacement therapy, rhabdomyolysis

PMC8637330_01

Female

On October 7, 2020, a 56-year-old woman admitted to our hospital due to right upper abdominal pain of 3 days duration. Abdominal computed tomography (CT) revealed space-occupying lesions at the bottom of the gallbladder, and space-occupying lesions in the hilar bile duct with intrahepatic bile duct dilatation, indicating malignant lesions. Multiple enlarged lymph nodes were mainly detected in the hepatic hilar and retroperitoneum. The levels of tumor markers were as follows: carcinoembryonic antigen (CEA), 34.1 mug/L, and carbohydrate antigen CA199, 7527 U/ml. Due to jaundice, the patient planned to undergo cholecystojejunostomy and R1 resection. The patient underwent exploratory laparotomy under general anesthesia on October 12, 2020. However, the patient had extensive lymph node metastasis and was not suitable for operation, then the patient underwent percutaneous transhepatic cholangial drainage (PTCD). The postoperative pathology showed that the tumor adjacent to the gallbladder was poorly differentiated adenocarcinoma with intrahepatic metastasis, classified as clinical stage T3N2M0 according to the tumor-node-metastasis (TNM) staging of the American Joint Committee on Cancer (AJCC) ( Figure 1 ). Next-generation sequencing (NGS) revealed that these mutations were STK11, RB1, CTNNA3, KEAP1, RBM10, and TCF7L2; moreover, PD-L1 positivity was observed. The patient refused chemotherapy, therefore, considering the high positive score, Combined Proportion Score (CPS 98) and Tumor Proportion Score (TPS 90%), sintilimab was given 200 mg every 3 weeks for eight cycles from November 2, 2020, and no adverse reactions were observed. Two weeks after the first administration, the level of tumor markers decreased: CEA, 16.6 mug/L, and CA199, 1,270 U/ml ( Figure 2 ). The patient reexamined after three cycles of treatment. CT showed that the size of tumor and lymph node significantly reduced ( Figure 3 ). Moreover, the patient's jaundice subsided and PTCD was removed. Meanwhile, CEA and CA199 decreased significantly to 3.83 mug/L and 114 U/ml, respectively ( Figure 2 ). However, on March 11, 2021, CT indicated disease progression after six cycles of sintilimab treatment, accompanied by elevation of CA199 to 173 U/ml and CEA to 6.35 mug/L. The combination therapy consisting of sintilimab and Tegafur (chemotherapeutic drug) administered 3 days later. After eight treatment cycles, the patient's CA199 level increased to 222 U/ml on April 13, 2021. One week later, CT revealed local liver metastasis, and the levels of CEA and CA 199 were 14.5 mug/L and 333 U/ml, respectively. Considering the progress of the disease, the entire liver metastasis and gallbladder were removed, and the lymph node dissection in the first porta hepatis was performed ( Figure 4A ). Postoperative pathology showed a poorly differentiated malignant tumor of the gallbladder, consistent with mixed neuroendocrine-nonneuroendocrine tumors (poorly differentiated adenocarcinoma accounted for 60%, small cell neuroendocrine carcinoma accounted for about 40%) ( Figure 4B ). Considering the difference from the first pathological diagnosis, the second NGS (liver metastasis, small cell neuroendocrine carcinoma) revealed that the mutations were PIK3CA, CDKN2A, CDKN2B, TP53, RB1, CCNE1, CEBPA, CTNNA3, GRM3, KEAP1, PBX1, PRKDC, RASA1, RBM10, and TBX3. Furthermore, PD-L1 positivity was also observed (CPS 10; TPS 8%). Different pathological diagnosis showed different mutation profiles. At present, the patient has been in a stable state with better life quality and is still in continuous sintilimab and chemotherapy.

minens, a pd-1 inhibitor, case report, gallbladder, sintilimab

PMC6334315_01

Male

We report a case of a 41-year-old male, immunocompetent, with no other comorbidities who went to the hospital to investigate unintentional weight loss in the last three months and to investigate a hard and palpable mass in the left supraclavicular region. He underwent series of laboratory tests and several imaging tests, such as blood cells count, T-cells immunophenotypes, analysis of B and NK-cells, and expression of interferon gamma receptor searching for immunodeficiencies:all in the normal range: neutrophils 5,72 mil/mm3 (reference titles 4,00 -11,00 mil/mm3), lymphocytes 3,69 mil/mm3 (reference titles 1,60 - 7,00 mil/mm3), monocytes 0,55 mil/mm3 (reference titles and eosinophils 0,07 mil/mm3 (reference titles 0,05 - 0,50 mil/mm3); inflammatories parameters like C-reactive protein 151,1 mg/L (reference titles < 5,0 mg/L) were elevated; and inflammatories parameters like DHL 191 mg/L (reference titles 135-225 mg/L) were normal. Cryptococcal capsular antigen dosages were made in the blood and spinal fluid, giving positive results (reagents) with a titre of 1:32. Viral serologies like HIV, hepatitis, and HTLV were all negative; acid-alcohol resistant bacillus (BAAR) spur was negative. He also performed same imaging studies such as chest X-ray (Figure 1), chest computed tomography (Figures 2, 3, and 4), and ultrasonography (Figure 5), which demonstrate mediastinal and left supraclavicular masses, interpreted as lymph node conglomerates of unknown etiology. Therefore the main diagnostics hypothesis was lymphoproliferative or granulomatous infectious diseases, especially tuberculosis. He underwent a fine needle aspiration (Figure 5) of the left supraclavicular mass. Histopathology (Figures 6 and 7) showed a granulomatous inflammation with fungal identification, and immunohistochemistry was positive for Grocott-methenamine silver nitrate and mucicarmine (Figures 6 and 7). The final diagnostic was Cryptococcus neoformans var. gattii. Ziehl-Neelsen coloration was negative (Figures 6 and 7). He was first treated clinically, with intravenous antifungal therapy for almost 60 days (6 days of fluconazol being replaced with 57 days of flucytosine and 59 days of B-amphotericin lipidic complex), but he did not improve, with remaining pulmonary symptoms. Therefore, a multidisciplinary team decided for surgical resection. The lesion was almost entirely resected (Figures 8 and 9). Histopathology and cultures confirmed the lesion as cryptococcoma. The patient was being followed clinically and radiologically (Figure 9) and had no symptoms or complications so far.

PMC6051112_01

Male

A 76-year-old male was referred to the emergency department in May 2016 for significant unintentional weight loss of approximately 57 kg and associated chronic nonbloody watery diarrheal illness in the preceding 18 months. Medical history was notable for prostate cancer curatively treated in 2012, gout, a remote transient ischemic attack, osteoarthritis, and bilateral cataracts. In the months prior to presentation to Gastroenterology, an extensive medical workup performed as an outpatient was negative for prostate cancer recurrence, new malignancy, autoimmunity, or an identifiable malabsorption syndrome including celiac disease and pancreatic insufficiency. The patient also noticed onycholysis in both his hands and feet (Figure 1), followed by hyperpigmentation of his hands (Figure 2), soles of his feet and legs, and abdomen. In addition to the nonbloody diarrhea, the patient reported a severe change in taste, early satiety, chronic heartburn, and nonspecific abdominal pain. He denied a history of fever, cough, night sweats, or abdominal pain. There was no family history of gastrointestinal malignancy or similar disorder. Physical examination demonstrated profound cachexia with a weight of 50.9 kg and a BMI 16.5. Generalized sarcopenia was noted. The abdomen was scaphoid and nontender with no hepatosplenomegaly. Nonscarring alopecia was seen on the scalp, dystrophic nail changes were identified in both the hands (Figure 1) and feet, skin hyperpigmentation was noted primarily involving the palms (Figure 2), dorsal aspects of fingers, face, and limbs, as well as sexual pattern hair loss of the abdomen, groin, and axillary hair. No cervical, inguinal, or axillary lymphadenopathy was identified. The rest of the physical exam was unremarkable. Complete blood count was notable for a mild normocytic anemia (hemoglobin 119 g/L (reference range, 130-175 g/L) and mild eosinophilia of 0.82 g/L (reference range, 0-0.35 g/L)). Serum albumin was low at 28 g/L (reference range, 35.0-55.0 g/L). Serum electrolytes platelet count, white count, renal, liver enzyme and function tests, lipase and total protein, serum immunoglobulins, CRP, and TSH were normal. PSA was undetectable. Autoantibodies, including antinuclear antibody, antineutrophil cytoplasmic antibody, and rheumatoid factor (RF) were undetectable as were serologic tests for HIV, hepatitis, syphilis, and Lyme disease. Serum protein electrophoresis exhibited a modest elevation in kappa free light chains (23.0 g/L) but a normal kappa/lambda ratio was not consistent with a monoclonal gammopathy. There were no extended nutrient deficiencies with lead, copper, zinc, B12, or iron. Fecal elastase, stool culture, C. difficile, ova and parasites, and fecal leukocytes were negative. Stool for occult blood was positive. Abdominal computed tomography (CT) demonstrated extensive gastric and duodenal mucosal fold thickening (Figure 3). Upper endoscopy demonstrated florid gastric and duodenal polyposis, with thickening of gastric folds and "carpet-like" semipedunculated gastric and duodenal polyps ranging from 5 mm to 20 mm (Figures 4(a) and 4(b)). Histologically, the duodenal polyps showed edematous mucosa with variably dilated and branching glands, foci of gastric foveolar metaplasia, and blunted or absent intestinal villi. The inflammatory cell content of the lamina propria was mildly increased with prominent eosinophils. Where native intestinal-type surface epithelium remained, it showed a mild increase of intraepithelial lymphocytes and an occasional intraepithelial eosinophil. There was no subepithelial collagen deposition. The gastric polyps were also a characteristic of Cronkhite-Canada syndrome. The foveolar glands were elongated, irregular, and focally dilated. The lamina propria was widely expanded by edema with an infiltrate of eosinophils and mononuclear cells (Figures 5(a) and 5(b)). Helicobacter organisms were not identified in gastric or duodenal specimens. The involvement of the duodenum and gastric antrum in this process ruled out Menetrier's disease which is typically confined to the gastric body. Based on these clinical, endoscopic, and histopathologic features, a diagnosis of Cronkhite-Canada Syndrome was made. Due to near complete inability to take in enteral intake from severe early satiety and subjective global assessment of severe malnutrition, TPN was initiated in conjunction with a short course of methylprednisolone, followed by a tapering prednisone regimen starting at 50 mg per day. Azathioprine was also initiated at 75 mg daily. A jejunostomy tube was placed under radiological guidance to provide enteral nutrition, and a high protein formula was used for caloric requirements, as the patient was unable to take in more than a few tablespoons at a time. Approximately six weeks after discharge, during the course of continued outpatient evaluation, the patient exhibited a worsening of his diarrheal illness accompanied by fever and progressive abdominal pain. Stool testing was positive for C difficile, and oral vancomycin was initiated with satisfactory clinical response. After several clinical relapses on vancomycin taper, the patient was advised by infectious diseases to continue suppressive vancomycin 125 mg PO daily. Several months into steroid taper, the patient developed polyuria, polydipsia, and hyperglycemia which had not been present at higher steroid doses. Insulin was initiated with reversion to normoglycemia. Despite adequate enteral caloric intake and immunosuppression, the patient continued to experience progressive weight loss, failure to thrive, and ongoing diarrhea (C. difficile toxin-negative). Based on a successful recent case report, off-label infliximab was employed. Typical induction and maintenance infusions of infliximab were initiated with a regimen of 5 mg/kg at weeks 0, 2, and 6 followed by maintenance regimen of 5 mg/kg every 8 weeks thereafter. Remicade level was within the accepted range at week 14. Azathioprine was initiated with infliximab, at the beginning of therapy to prevent antibody formation to the anti-TNF. The patient did not have an immediate initial response, and due to nausea, azathioprine was discontinued after 3 months. Azathioprine metabolites showed a 6-thioguanine of 106 pmol/8 x 108 RBC in the nontherapeutic range (230-400) and an undetectable 6-methyl mercaptopurine, appropriate for combination therapy with infliximab. Therefore, azathioprine was discontinued. At 4 months from induction, the patient began to have nail regrowth, improvements in taste, and a modest improvement in diarrhea and weight. Eight months following induction therapy with infliximab, bowel hygiene was significantly improved with approximately two formed movements daily. The patient was able to resume eating and drinking, and weight had increased by 10 kg. The patient also noted an improved sense of taste. Physical examination showed hair regrowth on the scalp, abdomen, and axillary and pubic regions in addition with improved proximal nail bed health. Hyperpigmentation was globally improved (Figure 2(b)). Laboratory values were within normal range. Repeat upper endoscopy 9 months after initiation of anti-TNF showed notable improvement in gastric distention; however, there was persistent polyposis and no obvious pathological improvement in inflammatory cell infiltrate.

PMC3167963_01

Male

A 46-year-old male smoker presented with a history of dry cough and moderate-grade pyrexia, responding to antipyretic since 3 months. History regarding other system involvement did not suggest any other abnormality. There were no other systemic symptoms. Examination revealed decreased breath sounds at the right lung base. There was no lymphadenopathy or organomegaly. With these symptoms, the patient was provisionally diagnosed as a case of tuberculosis and started on the anti-tubercular therapy. He did not show any improvement and was referred for further management. The blood investigations were within normal range and imaging [Figure 1] of the thorax showed a mass lesion in the upper lobe of the right lung and abdominal scans were within normal range. Fine needle aspiration biopsy from the lesion showed atypical cells suggestive of malignancy. For further confirmation, Immunohistochemical (IHC) markers were performed on cell block, which suggested LCA positive, CK (cytokeratin) negative, other markers were inconclusive. The cytogenetics from the lesion suggested t (2 : 5) though Anaplastic Lymphoma Kinase (ALK) was negative. Staging evaluation suggested that it was extranodal lymphoma stage I B E (bone marrow examination showed no involvement). The primary anaplastic large cell lymphoma of lung was the final diagnosis made and patient was started on combinational chemotherapy consisting of cyclophosphamide, adriamycin, vincristine and prednisolone. After six cycles of chemotherapy, the patient is in complete remission.

primary pulmonary lymphoma, immuno histo chemistry, treatment

CT scan showing right upper lobe mass.

PMC3959349_01

Female

A 77-year-old female presented to the hospital with difficulty swallowing for one week. She reported severe retrosternal pain immediately after swallowing food. The patient denied any weight loss or heartburn. Eight weeks prior to presentation, she developed painful skin blisters on her extremities and trunk. Medications included aspirin and amlodipine. Physical examination revealed generalized pruritic eruption of the skin. The patient underwent esophagogastroduodenoscopy (EGD), which revealed severe diffuse esophagitis with nodular surface (Fig. 1). Separation of the superficial epithelial surface from underlying tissue was noted at various locations (Fig. 2). The stomach and duodenum were normal. Biopsies of the esophagus showed fragments of necrosis with marked acute inflammation, without evidence of fungal or viral infection, dysplasia or malignancy. Biopsies of the skin lesions revealed sub-epidermal vesicles with neutrophil predominance. Direct immunofluorescence microscopy revealed intense linear deposition of immunoglobulin G (IgG) along the dermo-epidermal junction. Indirect immunofluorescence study with saline-split skin and patient's serum showed IgG directed against the dermal side only. The diagnosis of epidermolysis bullosa aquisita (EBA) was made and the patient was treated with intravenous steroids and discharged on high dose cyclosporine and proton pump inhibitors. She reported complete resolution of dysphagia at a short-term follow-up. EBA is an extremely rare autoimmune disorder with the prevalence of 1 case per 5 million people. Esophageal mucosal involvement in EBA is rare and it can be appreciated on EGD and histology as separation of the superficial epithelial layer and may result in ulcers, fibrosis, and stenosis.

PMC9807477_01

Female

A 67-year-old woman presented with weight loss, generalized neuropathic pain, disseminated hemangiomas of the skin (Fig. 1a), and enlarged mediastinal lymph nodes. Histology revealed the typical morphology of the hyaline vascular type of CD with hyperplastic lymphoid follicles in combination with a plasmacytoma. By multiplex PCR of the immunoglobulin heavy chain and light chain gene, monoclonal rearrangement was demonstrated, identifying CD and plasmacytoma as two distinct histological entities. Plasma cell variant of CD was excluded (Fig. 1d-f). In bone marrow biopsy, only polyclonal plasma cells and no cytogenetic aberrations were found (Fig. 1b). Despite symptoms of sensory polyneuropathy, electrophysiological studies did not demonstrate any abnormalities at initial presentation (Fig. 1g-h). VEGF serum levels were increased with > 1000 pg/ml (normal range < 445 pg/ml). HIV and HHV-8 were not detectable. There was no evidence of amyloidosis. Because of the multicentric presentation of CD, systemic therapy with one course of prednisone, vincristine, and cyclophosphamide followed by the anti-interleukin-6 antibody siltuximab was commenced. After 13 months of treatment, VEGF levels had decreased to 300 pg/ml; however, the patient experienced multiple cerebral thromboembolic events with ischemic lesions and thrombosis of the left sigmoid sinus. Treatment was changed to immunochemotherapy with 6 courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). During the 6th treatment course, lambda light chains increased noticeably. Restaging with lymphadenectomy proved complete remission of CD and persistence of plasmacytoma. Bone marrow biopsy showed progression into multiple myeloma IgA lambda with an increase of plasma cells up to 39% on average (Fig. 1c). Electrophysiological studies revealed a decrease in nerve conduction velocity and elongation of F-wave latencies (Fig. 1g-h). The initial intention to irradiate the mediastinal plasmacytoma was changed to systemic therapy with daratumumab, melphalan, and prednisone (Dara-MP). Due to the progressive peripheral neuropathy, bortezomib was not applied. The patient experienced an allergic reaction to daratumumab according to common toxicity criteria (CTC) grade 3, and therapy was continued with MP followed by lenalidomide and irradiation of osteolytic lesions on progression. Molecular analysis using next-generation sequencing (NGS, FoundationOne Heme, Penzberg, Germany) of the lymph node biopsy at initial presentation and of the bone marrow on progression into multiple myeloma revealed several genetic alterations. Mutation in Deltex (DTX1) was exclusively found in lymph node, whereas mutation in guanine nucleotide-binding protein subunit alpha (GNAS) was only detected in the bone marrow. Identical alterations of EP300, JARID2, PC, PD-L2, and SETBP1 were identified in both biopsies (Fig. 1i). This case report demonstrates the variable association between Castleman disease and plasma cell dyscrasias as a dynamic process. At initial presentation, Castleman disease and plasmacytoma could be identified as two distinct disease entities in lymph node biopsy, and the patient presented with symptoms of sensory neuropathy with no changes on electrophysiological exam. At the time of progression of the monoclonal plasma cell disorder, electrophysiological exam demonstrated sensory and motor polyneuropathy with a decrease in motor conduction velocity and elongation of F-wave latencies. Reviewing retrospectively the evolution of the case, it is likely that the POEMS syndrome was associated to the minimal systemic clonal plasma cell population from disease onset seen at the time of presentation of the solitary plasmacytoma with minimal bone marrow involvement. Whether a more plasma cell-directed therapy at initial presentation would have modified the course of the neurologic disorder can only be speculated on. It has to be noted however that, at the time of initial presentation, due to the systemic symptoms such as weight loss and the significantly enlarged mediastinal lymph nodes, CD was the disease requiring immediate attention and treatment. Several molecular abnormalities have been described in CD, multiple myeloma, and POEMS syndrome. Butzmann et al. identified molecular abnormalities in UCD predominantly in mitogen-activating protein kinase (MAPK) and interleukin signaling pathways, whereas in MCD, mostly genes affecting chromatin organization and methylation were mutated. MM is more complex, with molecular abnormalities present at the genetic as well as at the epigenetic level. Interestingly, the molecular analysis in our patient showed the presence of clonal evolution starting from a common progenitor. Five of the seven mutations identified were present both in the lymph node and in the bone marrow, suggesting a common founding clone, followed by branching evolution. This hypothesis is supported by the variant allele frequency (VAF) of the different mutations (Fig. 1i), indicating the presence of EP300, JARID2, PC, PD-L2, and SETBP1 at a clonal level and of GNAS and DTX1 at a subclonal level. Two of the five mutated genes are involved in epigenetic regulation (EP300 and JARID2), strengthening the importance of epigenetic changes in the development of B-cell malignancies. EP300 has been found to be mutated both in MM and in POEMS syndrome, while JARID2, although not formally identified as a recurrent mutated gene in MM, locates next to known susceptibility loci for MM and acts as a cofactor of the epigenetic regulator polycomb repressive complex 2 (PRC2). PRC2 has a major impact in the oncogenic transformation and progression of MM, mainly via overexpression and modulation of EZH2. Two additional mutations in the founding clone (PC and SETPB1) can be linked to neurodegeneration, thus providing a rational for the development of neuropathy in our patient. PC is involved in the synthesis of the neurotransmitter glutamate, and it is intriguing to speculate that alteration in the synthesis of glutamate might have led to or contributed to the peripheral neuropathy, while SETPB1 causes neurodegeneration in Schinzel-Giedion syndrome via p53 inhibition. Different groups have reported that genetic alterations in plasma cells can be linked to the development of neuropathy in myeloma patients, showing a deregulation of genes involved in neurogenesis in the plasma cells of patients developing peripheral neuropathy. The exact mechanism by which alterations in the plasma cells can cause neurodegeneration is still unclear. The ubiquitin ligase DTX1 regulates the Notch pathway which is involved in major regulatory pathways including differentiation and lymphocyte lineage commitment. Interestingly, DTX1 mutation developed only in the lymph node, and mutations of this gene have been identified in patients with diffuse large B-cell lymphoma or follicular lymphoma. GNAS activates protein kinase A (PKA) signaling increasing proliferation and has been reported to be amplified in several cancers. GNAS mutations have been detected in newly diagnosed MM. Whether the occurrence of GNAS mutation was responsible of MM progression remains speculative. In conclusion we identify for the first time the presence of mutations associated with neurological toxicity and neurodegeneration in the malignant clone of a patient with CD, MM, and POEMS. Whether these features are common to POEMS patients and might contribute to the development of neuropathy needs to be addressed in appropriately designed sequencing studies with a higher number of patients.

PMC10250589_01

Female

A 51-year-old woman, who had no family history of neuropsychiatric diseases, began noticing gait disturbance at the age of 45 years and upper limb weakness at the age of 46 years. These symptoms gradually worsened. Her personality showed a mild change. She developed depression associated with obsessive behavior and difficulty understanding everyday speech at the age of 49 years. She began using a wheelchair for transport at the age of 50 years. Finally, she was admitted to a psychiatric hospital because she was easily distracted and behaved violently throughout the day. Her past medical history revealed a transient ischemic attack at the age of 41 years. Neurological examination at the age of 46 years showed that the patient had mild muscular weakness of the four limbs with left distal dominance. Amyotrophy was unremarkable. Her hand grip was 18 kg in the right hand and 11 kg in the left hand. She showed hyperreflexia and spasticity in all four extremities with left dominance, and her jaw reflex was increased. Furthermore, her Babinski reflexes were positive bilaterally, and her gait was spastic. There were no abnormalities in the cranial nerves. Sensory, autonomic, and cerebellar functions were normal. Nerve conduction studies revealed that F-wave occurrences were reduced in the median nerve bilaterally (right: 56%, left: 25%; normal values: 70% <). Amplitudes of compound muscle action potentials, motor conduction velocities, amplitudes of sensory nerve action potentials, and sensory conduction velocities were normal in all nerves tested (i.e., the bilateral median, ulnar, tibial, and sural nerves). Neurogenic changes were detected in the biceps brachii muscle, the first interossei dorsalis muscle, the thoracic paraspinal muscle, the quadriceps femoris muscle, and the tibialis anterior muscle using needle electromyography. Upon neurological examination at the age of 50 years, the patient showed attention disturbances, transcortical sensory aphasia, and a positive snout reflex. Hyperreflexia, spasticity, and weakness in all four extremities had worsened, and bilateral ankle contracture was observed. She was unable to maintain a standing position. Her hand grip was 16 kg in the right hand and 6 kg in the left hand. There were no abnormalities in the cranial nerves or sensory, autonomic, and cerebellar functions. Her Mini-Mental State Examination score was 16/30, Frontal Assessment Battery score was 5/18, Alzheimer's Disease Assessment Scale was 29.3/70, and Raven's Colored Progressive Matrices was 32/36. The cerebrospinal fluid examination was negative, as were the test results for oligoclonal bands and immunoglobulin G indices at the ages of 41, 46, 48, and 50 years. Furthermore, the levels of serum creatine kinase and alkaline phosphatase were normal throughout her clinical course. Longitudinal brain MRI revealed progressive brain atrophy with temporal dominance (Figure 1A), non-progressive cerebellar atrophy (Figure 1A), and some non-specific white matter intensities (data not shown). Brain N-isopropyl-p-[123I] iodoamphetamine single photon emission computed tomography (SPECT) at the age of 50 years showed hypoperfusion in the bilateral temporal lobe with left dominance and the cerebellar hemispheres (Figure 1B). Neither the cervical MRI acquired at the age of 41 years nor the whole spinal MRI acquired at the age of 46 years showed abnormalities. Preliminary genetic analyses confirmed the absence of repeat expansions in 11 genes known to be associated with cerebellar atrophy: ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATXN8, ATXN10, PPP2R2B, TBP, NOP56, and ATN1. Her clinical or electrophysiological findings showed upper and lower motor neuron signs which met clinically probable ALS of the Awaji criteria (Table 1). Also, she did not exhibit any clinical or laboratory findings suggestive of myopathy or PDB throughout her clinical course.

vcp, amyotrophic lateral sclerosis 14 (als14), cerebellar atrophy, frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (ftdals6), missense variant

PMC7739816_01

Male

Master athletes are defined as athletes >40 years old who maintain a high level of physical fitness despite the physiological effects of aging, allowing them to compete in sporting competitions (Reaburn and Dascombe,). Participation of master athletes is steadily increasing, especially in endurance events such as marathons (Jokl et al.,), and triathlons (Bernard et al.,), with male master triathletes accounting for 48% of male finishers in Ironman triathlons during 2007-2010 (Stiefel et al.,). Master athletes strive to maintain performances they achieved at younger ages, even though athletic performance inevitably declines with aging (Lepers et al.,; Lepers and Stapley,; Louis et al.,). Regular physical activity throughout life can mitigate the age-related decline in muscle mass, muscle function, and cardiorespiratory capacity (Mian et al.,; Louis et al.,; Bieuzen et al.,). However, chronic high-level exercise as practiced by endurance master athletes may have adverse health implications including osteoarthritis (OA). OA is defined as the breakdown of joint cartilage and subsequently underlying bone as a result of joint inflammation (Friery,). Intense training programs, increased biomechanical load (Radin et al.,), and repetitive high impact activities such as long-distance running as well as family history, are among the main factors responsible for OA (Friery,). Although the precise relationship between training load and the risk of OA is not well-defined, many observational studies have reported an increased risk of knee and hip OA in former elite athletes (Lefevre-Colau et al.,). Team sports such as basketball, football, and hockey, that require many direction changes, present the highest risk of developing knee and hip OA (Lefevre-Colau et al.,). In endurance sports, the risk is lower but athletes still have a 1.73 increased chance of being admitted into hospital with severe OA, generally affecting lower limb joints (Kujala et al.,) at an average age of 59.7 years (Kettunen et al.,). The burden of OA is mainly caused by chronic pain, impaired function, and reduced quality of life (Cai et al.,). The standard course of treatment for severe OA of the hip is a total arthroplasty which replaces the entire joint (Meira and Zeni,) or resurfacing arthroplasty which replaces the surfaces of the hip joint affected by OA (Oxblom et al.,). Resurfacing arthroplasty has become the preferred treatment for athletes because it preserves more bone. Whatever the technique used, the surgery is often preceded and followed by a period of reduced activity and even immobilization of lower limbs due to pain sensations about the joint. In general, the treated lower extremity is immobilized after a hip arthroscopy for 6-8 weeks (Stalzer et al.,; Wahoff and Ryan,). Such situation inevitably leads to a decrease in muscle mass, a possible reduction in bone mass, an increase in fat tissue, accompanied with metabolic, and functional alterations such as a loss in muscle strength (Houston et al.,; Suetta et al.,). The time period of ceased training also elicits reversibility of training adaptions that take considerably longer to re-establish than the time period of detraining (Houston et al.,). Furthermore, with the additional effect of aging, this may potentially result in the requirement of a longer reconditioning time period than that of younger athletes (Hvid et al.,). During immobilization and reconditioning, dietary intake also plays an important role and can support physiological adaptation for a quicker rehabilitation. Specifically, adapting energy intake to the changes in energy expenditure while maintaining a high protein intake can limit the decline in muscle mass (Louis et al.,). Little is known on the time-course of reconditioning and return to competition of young endurance athletes following surgery, and even less is known about deconditioning and reconditioning of master athletes. With this in mind, we present the retraining and nutritional strategy that allowed an endurance master triathlete to return to competition 32 weeks following a hip arthroplasty. Training load, energy intake, body composition, and aerobic capacity were recorded at regular intervals during the period. Specifically we were interested in the changes in lean mass and bone mineral content that endured the combined effects of reduced physical activity and aging.

aging, body composition, energy availability, macronutrients, osteoarthritis, performance, triathlon

PMC7283492_01

Female

A 28-year-old Caucasian female with bipolar I disorder diagnosed 4 years before, was hospitalized in an inpatient psychiatry clinic due to treatment-resistant depressive episode with extensive suicidal thoughts. Mental status has been deteriorating for 4 months before admission. During her illness, the patient was hospitalized five times due to depressive episodes and had two manic episodes without hospitalization. The patient had been treated with ketamine twice, first during previous hospitalization (IV) and second time during described stay (oral). One year before she was hospitalized in the same facility due to severe treatment resistant depressive episode and despite treatment modifications she did not achieve remission, thus she was offered ketamine treatment. A dosage of 0.5mg/kg ketamine hydrochloride intravenous infusion over a period of 40 min was given two times per week for a period of 4 weeks (eight times in total) as add-on treatment to standard of care. After the ketamine administration period, an intermittent mood improvement lasting 1 week has been observed (six points reduction in MADRS score):no manic symptoms appeared. Further pharmacological modifications were made:after 6-month hospitalization patient achieved partial remission and was discharged on lamotrigine 400 mg/day, lithium carbonate 750 mg/day, clozapine 100 mg/day, and topiramate 400 mg/day. On admission the patient presented decreased mood, decreased energy, suicidal thoughts, feeling of constant inner tension, difficulties concentrating, withdrawal from social interactions, sleeping difficulties. Somatic causes were excluded after physical examination, neurological examination, and laboratory tests (blood morphology, electrolytes, kidney and liver profile, TSH, FT4, CRP, B12, folate levels, urine test, toxicology) which turned out normal. During the time since her previous hospitalization, the treatment has been modified in the outpatient care:clozapine has been discontinued, the dose of topiramate has been reduced to 100 mg/day, bupropion 300 mg/day, and chlorprothixene 60 mg/day have been added. Lithium serum level was 0,87 mmol/L on dose of 1,000 mg/day. In the EEG record slow basic activity and slow waves in the front-temporo-parietal region on the left side were described; the MRI scan did not reveal any pathological changes. The pharmacological changes listed above did not cause any improvement; for this reason the patient was qualified for readministration of ketamine, this time in oral form. The dose of ketamine administered orally was 2.5 mg/kg. During the first 10 min half of the dosage was administered and in the next 30 min the remaining part was sipped. Ketamine was administered twice weekly during 4 weeks. After 2nd week of ketamine administration the daily dose of lithium was reduced due to its increased serum level (1.42 mmol/L) to 750mg/day which resulted in 0.74 mmol/L serum concentration. During the third week of oral ketamine administration period, manic symptoms were observed. The patient presented increased sex drive, elevated psychomotor activity, racing thoughts, irritability, problems falling asleep and total sleep reduction. She spent a significant amount of money on online shopping, cleaned her locker several times, and became talkative. The symptoms were present for 2 days; after that time depressive symptoms returned with additional appetite increase. Thus decision for continuation of ketamine treatment was made. One day after the last dose of ketamine, the patient presented manic symptoms again. She had intermittent periods of elevated mood, her energy was constantly increased, she presented maladaptive affect regulation, decreased need for sleep, increased sex drive, she became talkative, dressed inappropriately, had increased appetite. The patient demonstrated psychomotor agitation with accompanying suicidal thoughts, lasting for 1 week. Depressive symptoms were still present, but manic symptoms clearly dominated. No psychotic symptoms were present. Drug screen was negative. One week after finishing ketamine administration lithium dose was increased again up to 1,000 mg/day reaching serum level 1.11 mmol/L. The symptoms resolved after a period of 16 days. During first three doses of ketamine administration patient presented sedation, dizziness, and some dissociative symptoms. The symptoms were of moderate intense and resolved during next 40 min after the last sip of oral ketamine. No other significant adverse events were observed. Treatment timeline is presented in Figure 1. Both protocols, intravenous and oral, included recording of basic life parameters such as heart rate, arterial pressure, oxygen saturation level, respiratory rate and body temperature measured every 15 min. In both protocols psychometric assessment included: Montgomery Asberg Depression Rating Scale structured interview (MADRS-Sigma) and Young Mania Rating Scale (YMRS) completed before IV and oral administrations and after 3rd, 5th, and 7th dose as well as 1 week after finishing the treatment. The oral route of administration is probably the least costly and most acceptable way to administer ketamine in patients with depression. The existing literature on oral ketamine suggests that oral doses should range from 2-3 mg/kg. It is approximately the dose of 0.5 mg/kg IV multiplied by the oral bioavailability correction factor which is 4-5. This factor is a result of high first-pass metabolism. It is also the dose most commonly used in the oral ketamine study by Hartberg. Nevertheless it is worth noticing that off-label use of oral ketamine is based on very limited research and no dose-ranging study has been published so far. Additionally antidepressive effect and possible adverse effects of norketamine:the main metabolite of ketamine administered orally are presently unknown although no serious adverse events have been reported so far. The case report is a part of the naturalistic ketamine trial, approved by the bioethical regulatory of the institution, NKBBN/172/2017; 172-674/2019, NCT04226963. The patient was informed about potential risks and limitations as well as reasonable expectations of ketamine treatment for depression and consent for treatment and gave an informed consent for the participation in the trial. The previously mentioned cases are presented according to guidelines for disguising case material. The MADRS and YMRS scores and concomitant medications are summarized in Table 1.

affective switch, bipolar i depression, ketamine, oral and subanaesthetic, treatment resistance

PMC9873340_01

Female

A 48-year-old female was a never-smoker and had a history of pulmonary tuberculosis cured by medication. The pulmonary nodule was found on chest X-ray, and NSCLC (adenocarcinoma) with brain and bone metastases was diagnosed in further evaluation in January 2017. She underwent gamma-knife surgery (GKS) for metastatic brain lesion and radiotherapy for pelvic and spinal bone metastases, followed by gefitinib because EGFR L858R mutation was identified. After 15 months, disease progression was noted, and pemetrexed plus cisplatin were administered as second-line therapy because there was no T790M mutation upon repeat biopsy. However, in August 2020, the patient complained of a headache, and spinal tap revealed increased intracranial pressure (IICP) and was positive for craniospinal fluid (CSF) cytology. To control IICP, a ventricle-peritoneal (VP) shunt was inserted. Given the newly developed LM and progression of extracranial disease, 80 mg of osimertinib once daily was started for LM; and bevacizumab, docetaxel, and carboplatin were administered for extracranial disease. Since then, the patient has continued combination therapy for 9.6 months without progression of LM or extracranial disease. The patient complained of general weakness of grade 1 without other adverse events. However, eventually, the patient died of pneumonia progressive to septic shock in January 2021. The brain magnetic resonance images (MRI) before and after osimertinib administration are presented in Fig. 1A.

egfr mutant nsclc, leptomeningeal metastasis, osimertinib, systemic chemotherapy

PMC9873340_04

Female

A 38-year-old, never-smoker female had been treated for pulmonary tuberculosis for 3 months but had not improved. By bronchoscopic biopsy, NSCLC was diagnosed, and multiple bone metastases were detected in the imaging workup. As an EGFR L868R mutation was confirmed by biopsy specimen, gefitinib was started in November 2018. Six months later, the disease had progressed, and the repeat biopsy was performed by endobronchial ultrasound-guided transbronchial needle aspiration, and an EGFR T790M mutation was not detected. The metastatic brain lesion was also identified in brain MRI and treated with GKS. Next, the patient was treated with a combination of atezolizumab, bevacizumab, paclitaxel, and carboplatin followed by atezolizumab and bevacizumab maintenance. However, in December 2019, the patient complained of nausea, vomiting, and headache, and LM was diagnosed with brain MRI and CSF cytology. Thus, osimertinib 80 mg once daily combined with pemetrexed were started. With osimertinib and systemic chemotherapy, the patient complained of myalgia and abdominal pain. However, the adverse events were well controlled with supportive care. Unfortunately, the extracranial disease was refractory, leading to additional regimen changes (docetaxel followed by gemcitabine and carboplatin). LM was uncontrolled, so additional WBRT and VP shunt insertion were necessary. Nevertheless, she died of extracranial disease progression in May 2021. Images of the chest CT and brain MRI before and after osimertinib administration are presented in Fig. 1D. Patient characteristics and prior treatments are described in Table 1. In four reviewed cases, median follow-up duration was 37.7 months (range, 18.1 to 54.6 months) from the date of initial diagnosis of NSCLC and 12.0 months (range, 7.1 to 17.3 months) from the date of LM progression. The median time from initial diagnosis of NSCLC to LM progression was 25.5 months (range, 5.1 to 43.6 months), and the median treatment duration of osimertinib was 9.7 months (range, 6.0 to 16.8 months). On 30 August 2021, only one patient (case 2) was alive and had been ongoing treatment with osimertinib for more than 6 months combined with systemic chemotherapy. The other three patients died of LM progression. Mean OS was 49.2 (95% CI, 41.8 to 56.7) from initial NSCLC diagnosis and 14.7 months (95% CI, 10.4 to 19.0) from LM progression. Median OS from initial NSCLC diagnosis was 43.8 months (95% CI, not reached), and median OS from LM progression was not reached. There was no >= 3 grade adverse event noted in the four cases, and there was one case of dose reduction due to grade 2 diarrhea (case 2). The most common adverse event was abdominal pain, which was noted in two patients (cases 3 and 4) but was well controlled with conservative care.

egfr mutant nsclc, leptomeningeal metastasis, osimertinib, systemic chemotherapy

PMC9217064_01

Male

Monkeypox virus (MPXV) is a double-stranded DNA zoonotic virus with a 197-kb genome, member of the Orthopoxvirus (OPV) genus and Poxviridae family, which also includes smallpox virus that causes smallpox . MPXV was first identified in a 9-month-old boy in 1970 in the Democratic Republic of Congo. Since then, several outbreaks of monkeypox have been reported in the African continent, where 1,408 suspected cases and 66 deaths were reported in 2022 alone . MPXV is currently classified into two lineages, the West and Central African clades, although a novel classification into clades 1, 2 and 3 has recently been proposed . The MPXV Clade 3 includes most human outbreaks from 2017, 2018 and 2022, and can be further divided into lineages A, A.1, A.1.1, and B.1 . In early May 2022, cases of MPXV were detected in the UK and Portugal, most of them with no known travel history to endemic countries. As of June 9, 2022, 1,240 cases have been confirmed in 33 countries on all continents , most of them in European countries and the United States . Available epidemiological and contact tracing data revealed that most cases are associated with men who have sex with men (MSM) . The first two MPXV cases from South America were reported from Argentina on May 27, 2022 . Both reported cases traveled to Spain 2 and 9 days prior to case notification, and the two MPXV partial genomes (942 bp) were made available as the first monkeypox sequences from Latin America. As of June, 8, 2022, Brazil had 8 suspected monkeypox infections in the States of Santa Catarina, Ceara, Mato Grosso do Sul, Rio Grande do Sul, Rondonia and Sao Paulo .

PMC6195924_01

Male

In February 2014, an 11-year-old male presented with a history of recurrent respiratory tract infections and suspected tuberculosis following a case within his family. On physical examination, he appeared to be in good health. Chest auscultation did not reveal any specific pathological heart or lung sounds. Abdominal objectivity was negative. His parents did not refer any other relevant medical history about him. Tuberculin skin tests resulted positive and a chest X-ray showed a dishomogeneous parenchymal consolidation in the left lower lobe (Figure 1a,b). Suspecting active tuberculosis, a preliminary CT scan of the thorax was performed showing a heterogeneous consolidation with some cystic masses containing mixed fluid and air in the left lower lobe posterior segment, not in communication with the respiratory tract, and a probable expression of a dysplastic parenchymal area (Figures 2 and 3). These findings were suggestive of pulmonary sequestration, including a differential diagnosis of congenital pulmonary airway malformation, because of the presence of a cystic component within the consolidation. The injection of contrast medium showed an artery arising from the descending thoracic aorta that divided into two 1.2 cm after its exit, with both branches extending to the dysplastic area; therefore, a diagnosis of intralobar sequestration with associated aspects of bronchial atresia was made; superinfection and trapping of contiguous parenchyma coexisted. Just below the emergence of the previously anomalous vessel, another artery was detected that crossed the midline to achieve a healthy parenchyma in the right pulmonary base, configuring a pattern of aberrant systemic artery feeding a normal lung (Figures 4-6). Other congenital anomalies that appear to be related to pulmonary sequestration were absent; in particular, pulmonary venous drainage was regular through the pulmonary veins, there was no communication between the bronchus and the oesophagus, and no diaphragmatic defects or other gross pulmonary anomalies were identified either. Our patient responded well to antitubercular antibiotic therapy and his clinicians, together with his family, decided to keep him under control with clinical follow-up, avoiding surgery for the moment.

PMC9453015_01

Male

A 61-year-old man with underlying hypertension and anxiety disorder presented with backache and left lower chest pain since end of year 2020 and later was diagnosed with MM with left T8-T11 paravertebral plasmacytoma in March 2021. There was no bone marrow examination because patient refused. CT-guided biopsy of left lower thoracic paravertebral mass showed plasmacytoma with lambda light chain restriction (Figure 1). MRI thoracic spine showed left T8-T11 posterior mediastinal soft tissue mass, with a size of 6.8 x 3.8 x 10.0 cm, with intraspinal extension and infiltration into left posteromedial segment of 10th and 11th rib (Supplementary Data (available here)). Serum protein electrophoresis (SPE) and immunofixation (IF) showed IgA lambda of 10 g/L without immunoparesis, while urine protein electrophoresis (UPE) and IF did not show evidence of paraprotein. Serum free light chain (sFLC) showed reduced kappa:lambda ratio of 0.10 (13.2 mg/L:132.7 mg/dL). Other investigations were normal:beta2-microglobulin 1.7 mg/L, albumin 42 g/L, Hb 15.7 g/dL, TWC 4.547 x 109/L, PLT 219.9 x 109/L, creatinine 83 micromol/L, eGFR 87 mL/min/1.73 m2, corrected Ca 2.37 mmol/L, and LDH 172 micro/L within normal range. Patient developed major depressive disorder since the diagnosis of MM on top of the preexisting anxiety disorder. Despite psychological therapy, both conditions waxed and waned following the condition of MM. Hence, throughout the follow-up, it is difficult to manage this patient, especially on the evaluation of certain subjective symptoms. Dexamethasone was started at the end of March 2021 while waiting for the results of the investigations above. Bortezomib-dexamethasone plus zoledronic acid (VD + Z) was started in the middle of April 2021 instead of the usual triplet with addition of cyclophosphamide, thalidomide, or lenalidomide (R) due to patient's concern on potential adverse effect of all drugs and to keep the number of drug minimum with intention to increase to triplet once proven he was tolerable to VD + Z. In early May 2021, MRI thoracic spine showed progression of the paravertebral plasmacytoma, with a size of 8.2 x 5.8 x 15 cm, without significant change in the involvement at T9/10 and T10/11 foramina and intraspinal extension (Supplementary Data). In the middle of May 2021, local radiotherapy to the left paraspinal plasmacytoma, 30 Gy in10 fractions, was completed, while systemic MM treatment was changed to RVD + Z. Retrospective investigation of the initial paravertebral plasmacytoma sample revealed that about 30% of the tumour cells showed aberrant nuclear p53 protein expression (Figure 1), positivity for fluorescent in situ hybridisation (FISH) TP53 deletion (nuc ish (DLEU x 2,TP53 x 1)(200)) (Figure 1), and positivity for FISH IGH rearrangement (nuc ish (IGH x 3,BCL x 2)(51/200)) (Figure 1). After 2nd cycle of RVD + Z at the end of June 2021, patient achieved at least a partial response (PR). SPE showed IgA lambda of <1 g/L. UPE showed a faint band at fast moving gamma region. sFLC showed normal ratio of 1.04 (18.8 mg/L:18.0 mg/L). MRI and PETCT showed reduction of the paravertebral mass (Supplementary Data). After 4th cycle of RVD + Z in the middle of August 2021, patient achieved a very good PR (VGPR) or near complete response (CR). SPE and IF were negative, while UPE showed a faint restriction band at fast moving gamma region for which IF did not reveal any abnormality. sFLC showed normal ratio of 1.22 (15.4 mg/L:12.6 mg/L). MRI and PETCT showed further reduction of the paravertebral mass (Supplementary Data). The patient was a heavy smoker. During treatment of MM, imaging showed occurrence of lung changes which were progressive (Supplementary Data). He was investigated and treated as smear-negative pulmonary tuberculosis (PTB) due to clinical suspicion and endemicity of PTB in the region. Anti-TB was started in August 2021, while MM treatment was changed to lenalidomide maintenance. The lung changes improved with anti-TB (Supplementary Data). In November 2021, SPE/IF, UPE/IF, and sFLC remained negative and PETCT showed stable left paraspinal mass. His anti-TB was continued until the diagnosis of leptomeningeal myelomatosis in February 2022. His backache and peripheral sensory neuropathy worsened around December 2021. He was diagnosed with sciatica due to nerve root compression and received a steroid injection to left L4/4 facet joint at the end of December 2021, but the injection did not improve his condition. Lenalidomide maintenance was off in the middle of January because worsening drug-induced peripheral neuropathy was suspected while anti-TB, which could also cause drug-induced peripheral neuropathy, was continued to ascertain the main causative agent and in view of the importance of complete anti-TB regimen. However, symptoms were not improved and motor weakness at right wrist and fingers appeared in February 2022. MRI brain and whole spine in the middle of February 2022 showed multiple nodular lesions at leptomeningeal at the cerebrum, cerebellum, spinal cord, cauda equina, and bilateral internal auditory canals (Supplementary Data). CSF analysis showed protein 1.83 g/L, glucose 3.3 mmol/L, cell count 113 x 106/L with all mononuclear cells, cytology of abundant large atypical plasmacytoid cells in loose clusters along with singly dispersed cells, and immunophenotyping of lambda-restricted plasma cells (Figure2). SPE showed reappearance of M-protein <1 g/L. He was treated as MM-CNS at relapse/progression in this case given the tempo of the worsening CNS symptoms which appeared more than a year after initial diagnosis of MM, although MM-CNS at diagnosis could not be confidently ruled out because no CNS assessment was done. After the diagnosis of leptomeningeal myelomatosis, he received intravenous methylprednisolone 1 g daily for three days which improved the symptoms partially. He decided to take traditional treatment, which did not improve the symptoms further instead the symptoms started to worsen after a week. At the end of March 2022, he and his family members agreed for chemotherapy. Before the start of chemotherapy, he was wheelchair and bed bound with lower limbs' power of grade 3 at the right and 4 at the left and upper limbs' power of 3-4 at the right and 4-5 at the left. Finger-nose test was positive. He was delirious and had visual and auditory hallucination. MRI showed worsening of leptomeningeal lesions (Figure 3). Dara-PVPD (daratumumab, pomalidomide, vincristine, procarbazine, and dexamethasone) was started. His condition was rapidly improved. He was able to stand and walk with walking frame after two cycles of treatment. At the time of writing, he completed the 4th cycle in the middle of May 2022. Between the 2nd and 3rd cycle, he developed an abscess at left gluteal ischial tuberosity region which resolved with antibiotic and local surgical drainage but resulted a week delay to the commencement of the 3rdcycle. The peripheral sensory neuropathy worsened from fingertips to whole palms and soles after the 2nd cycle needing dose modification. The detail of Dara-PVPD given from the 1st to 4th cycle is shown in Supplementary Data. He achieved a VGPR3 after the 4th cycle. CSF analysis in the middle of the 4th cycle showed protein 0.58 g/L, glucose 3.2 mmol/L, cell count 6 x 106/L, cytology of low cellularity with no malignant cell seen, and immunophenotyping of no evidence of clonal plasma cells and myeloma involvement. MRI showed disappearance of leptomeningeal lesion in the cerebrum, cerebellum, spinal cord, and cauda equina, except PR at left internal auditory canal and left external capsule (Supplementary Data). He completed 6th cycle in the middle of June 2022. Assessment post-6th cycle showed further CNS improvement:CR with CSF and other MRI lesions except stable external capsule lesion as compared to MRI post-4th cycle. At the time of writing, he was undergoing peripheral blood haematopoietic stem cell collection and planned for thiotepa-based autologous haematopoietic stem cell transplantation in the middle of July 2022.

PMC4756263_01

Female

Between November 2013 and early 2015, 62 patients with HCV cirrhosis underwent OLT at the Cleveland Clinic, of whom, five patients developed recurrence of HCV post-OLT in the form of severe FCH. All five patients were treated with the regimen of sofosbuvir and simeprevir (SOF-SMV) for 24 weeks. All liver biopsies were reviewed by two expert pathologists, and the diagnosis of FCH was made according to definition proposed by the International Liver Transplantation Society. Case 1 A 68-year-old white female presented with end-stage liver disease due to chronic HCV genotype 1b infection (Table 1). HCV was likely contracted after a blood transfusion approximately 30 years before. Prior to transplantation, the patient failed previous treatment with regular interferon and ribavirin in 1999 for HCV infection. Her liver disease progressed over years and was complicated by jaundice, refractory ascites and esophageal varices. At the time of transplantation, she had a laboratory Models for End-Stage Liver Disease (MELD) score of 40. Post-operatively, the patient received triple immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil (MMF) and prednisone. Prednisone was discontinued on post-operative day 21 while remained on tacrolimus and MMF with complete normalized liver function tests. Two months following OLT, the patient presented with fatigue and worsening jaundice. Liver chemistry tests were noted to be markedly abnormal with rise in the total bilirubin (TB) levels to 16.2 mg/dL, aspartate aminotransferase (AST) to 530 U/L, alanine aminotransferase (ALT) to 284 U/L, alkaline phosphate (ALP) to 1467 U/L, and gamma-glutamyl transpeptidase (GGT) to 749 U/L. Vascular ultrasound imaging of the liver showed patent hepatic vasculature and no intra- or extra-hepatic biliary duct dilation. A liver biopsy was performed and showed marked lobular and portal inflammation with hepatocyte swelling, focal cholestasis and patchy bile duct injury. Importantly, there was no portal or central vein endotheliitis. No significant fibrosis was seen on the trichrome stain (Fig 1). This histologic features were concerning for evolving recurrent cholestatic hepatitis C. The patient's HCV viral load prior to the biopsy was 40,500,000 RNA IU/mL. Given the clinical and pathologic findings the decision was made to start anti-viral therapy with SOF-SMV. Shortly after initiating anti-viral therapy, liver biochemical tests started to drift down (Table 2). However, three weeks later the liver enzymes went-up again and her TB reached a level of 52.2 mg/dL; the patient was feeling more fatigue. A repeated liver biopsy showed plasma cell-rich, immune-mediated hepatitis with prominent bile duct injury, favoring acute cellular rejection vs. plasma cell hepatitis. During that event, tacrolimus level was noted to be on the lower side of 2-4 ng/mL. The dose of tacrolimus was increased accordingly and the patient was started on high doses of intravenous steroid, followed by prednisone tapering. The patient responded well to the treatment and immunosuppression was continued with prednisone, tacrolimus and MMF. Anti-viral therapy was continued without interruption throughout the course. Tacrolimus trough level remained stable (8-10 ng/mL) during the rest of the treatment course and no dose changes were made. The HCV viral load decreased to 596 IU/mL at week four of the therapy, then became undetectable at week 12, and remained undetectable to at least 12 weeks after completion of the treatment. The patient had a delayed but remarkable biochemical improvement. The course of the treatment was complicated by mild episode of acute pancreatitis that responded well to intravenous hydration and conservative management. The etiology of acute pancreatitis remained indeterminate. The treatment was also complicated by pruritus, which was refractory to medical therapy, and the patient underwent frequent sessions of plasmapheresis to relieve her symptoms. After completing the treatment, the patient's pruritus resolved and plasmapheresis was no longer needed. The liver biopsy performed 12 weeks after the completion of SOF-SMV demonstrates near normal histology with no evidence of ongoing hepatic injury. There was no evidence of acute or chronic rejection, no chronic portal or lobular inflammation. The bile ducts were normal without evidence of chronic cellular rejection. Additionally, there was no residual fibrosis seen on the trichrome stain. Case 2 A 56-year-old female with HCV genotype 1a infection who previously failed treatment with interferon monotherapy in 1996 presented to our clinic for further management. After the diagnosis of a 2-cm hepatocellular carcinoma (HCC), she received a MELD upgrade to 22 points and received a liver from a cardiac-dead donor. The post-transplantation immunosuppression regimen consisted of tacrolimus, MMF and prednisone. Prednisone was discontinued on post-operative day 21 while MMF was stopped six months following OLT. The patient remained on tacrolimus monotherapy six months post-OLT. Six months post-OLT, a routine protocol liver biopsy showed mild lobular inflammation and mild steatosis, suggestive of early recurrent HCV. The patient remained asymptomatic until nine months post-OLT. Her liver chemistry gradually trended up. Ultrasonography of the liver was normal with no lesions. No intra- or extra-hepatic biliary duct dilation was seen. A repeated liver biopsy demonstrated diffuse hepatocyte swelling and cholestasis. The trichrome stain demonstrates periportal fibrosis with focal pericellular and perisinusoidal fibrosis. The findings were compatible with fibrosing cholestatic recurrence of HCV. The HCV viral load at this time was 9,120,000 IU/mL. We decided to initiate treatment with SOF-SMV. Tacrolimus dosage needed to be increased to keep the level in the range of 4-6 ng/mL. HCV viral load improved to <43 IU/mL at week four, then became undetectable at week eight and remained undetectable at week 12 and at the end of the treatment. The patient had a complete normalization of liver enzymes at week two of the treatment. Her liver chemistry continued to be within normal limits and the patient has completed 24 weeks of therapy. She has experienced no adverse events. The patient achieved SVR with undetectable HCV RNA at 12 weeks after treatment completion. An additional liver biopsy performed three months after initiation of the therapy, showed resolution of the cholestatic changes and hepatocellular injury with only minimal inflammation without significant peri-sinusoidal fibrosis. Comparison of the patient's previous liver biopsy, prior to SOF-SMV, demonstrated a significant histologic improvement with anti-viral therapy. Case 3 The third patient was a 62-year-old male with multiple medical problems included HCV genotype 1a, coronary artery disease, hypertension and type 2 diabetes mellitus. He developed liver cirrhosis and HCC secondary to HCV infection. With exceptional MELD points granted for HCC the patient received a liver from a brain-dead donor. Prior to transplantation, the patient failed treatment with pegylated interferon and ribavirin. After two months of transplantation, the patient had worsening jaundice and was frequently complaining of abdominal pain. AST and ALT were elevated and serum TB was reached 22.1 mg/dL. The patient underwent ERCP that showed a focal biliary stricture in the post-transplantation anastomosis. A liver biopsy at this time demonstrated focal mild portal and lobular inflammation with mild ductular reactive without changes of cellular rejection. Additionally there was no definite hepatocellular injury or fibrosis. Biliary sphincterotomy with dilatation and stenting of the anastomotic stricture were performed but did not alleviate patient's symptoms. He continued to have a worsening jaundice despite a repeated ERCP and successfully replacing the stent. A liver biopsy performed four months post-OLT revealed diffuse hepatocyte swelling with associated hepatocyte injury, and no evidence of endotheliitis. The trichrome stain confirmed the presence of periportal and perilobular fibrosis with rare fibrous bridge. These features were consistent with fibrosing cholestatic hepatitis C. His HCV viral load was >69,000,000 IU/mL. Treatment for HCV was started with SOF-SMV. HCV viral load decreased to 3200 IU/mL at week two and became undetectable at week six of the treatment. His liver biochemistries improved markedly at week six of the treatment. However, the patient developed recurrent abdominal pain, nausea and vomiting that required two ER visits. Liver ultrasonography was concerning for hepatic artery stenosis. Hepatic angiogram showed marked stenosis suggesting transplanted hepatic artery thrombosis. Paracentesis was performed for new ascites and fluid analysis showed severe leukocytosis and cultures later grew E. coli. He went into respiratory failure, required endotracheal intubation and stayed in the ICU for three days. He died of sepsis and multiorgan failure, which complicated his ICU stay. Case 4 The fourth patient was a 44-year-old male with chronic infection with hepatitis B virus (HBV) and history of HCV-HIV co-infection. With a MELD score of 31, the patient received OLT from a matched 68-year-old donor. Post-OLT immunosuppression included tacrolimus, MMF and steroids. Prior to transplantation, his CD4 count was 194 and HBV DNA was undetectable. His antiviral therapy for HIV and HBV were continued post-OLT. This included emcitrabine 200 mg daily, tenofovir 300 mg daily, etravirin 200 mg twice daily, and raltegravir 400 mg twice daily. His liver enzymes were slowly trending up at 4.5 months post-OLT. A liver biopsy showed lobular architecture that was distorted by cholestatic changes with ballooning hepatocytes, lobular inflammation, and multiple acidophilic bodies. Portal tracts demonstrated moderate chronic inflammation with focal interface activity. There was only focal mild bile ductal injury. The trichrome stain highlighted mild portal expansion. These findings were consistent with HCV recurrence with FCH. Treatment for FCH was started with SOF-SMV; his HIV and HBV therapy were continued. HCV RNA viral load was 8,970,000 IU/mL prior to SOF-SMV treatment. It improved to 44 IU/mL at week four of the treatment. His liver chemistry improved slowly throughout the treatment course. At week 12 of the treatment, his TB decreased to 2.9 mg/dL, AST to 42 U/L, ALT to 49 U/L, ALP to 180 U/L, and GGT to 144 U/L. The patient completed 24 weeks and his HCV viral load remained undetectable. HCV viral load was also checked at week 12 after completion of the treatment and the patient successfully achieved SVR. No side effects were reported throughout the course of the treatment. Case 5 The fifth patient was a 30-year-old female with a history of alpha1 antitrypsin deficiency for which she underwent OLT in 1987. Her course was complicated with HCV genotype 1a infection that was likely acquired at the time of OLT. She developed cirrhosis post-OLT secondary to HCV infection and subsequently received a second liver transplantation in June 2014. Post-OLT immunosuppression included tacrolimus, MMF and prednisone. The last drug was discontinued on post-operative day 21. Two months after the second transplantation, the patient was admitted to the hospital with elevated liver enzymes and abdominal pain. Abdominal imaging was unremarkable. Liver biopsy showed evidence of recurrent HCV in the form of FCH. There were marked diffuse hepatocyte swelling with cholestasis, mild steatosis and scattered lobular inflammatory cell infiltrates. There was no portal vein endotheliitis, and bile duct damage was minimal. Trichrome stain demonstrated portal fibrous expansion with focal pericellular fibrosis. She was subsequently started on SOF-SMV therapy for HCV infection. HCV RNA prior to the treatment viral load of 1,280,000 IU/mL decreased to 59 IU/mL at week eight of the treatment, then became undetectable at week 12 of the treatment. Liver function tests prior to the treatment were as following: TB of 2.4 U/L, AST of 204 U/L, ALT of 55 U/L, ALP of 231 U/L, and GGT of 841 U/L. After two weeks of the treatment, her TB trended up to 5.2 U/L; however, all of her other liver functions improved remarkably; AST decreased to 14 U/L, ALT to 13 U/L, ALP to 189 U/L, and GGT to 73 U/L. The patient's bilirubin dropped thereafter and reached normal limits at week six of the treatment. She had a complete normalization of her liver tests at week eight, and this was maintained at week 12 and week 24 of the treatment. The patient completed 24 weeks of therapy with no significant adverse events; she achieved SVR with undetectable HCV viral load 12 weeks after completion of the treatment.

fibrosis, hepacivirus, jaundice, liver cirrhosis, liver transplantation, pancreatitis, pruritus, obstructive

PMC3543951_01

Male

A 66-year-old man was admitted to our hospital because of dyspnea on mild exertion for 3 days. He was a smoker and had a 10-year history of hypertension with medication. He had no known history of diabetes, pulmonary tuberculosis, or hepatitis. He had no medication history except for antihypertensive agents. His family history was non-specific. On arrival, his vital signs included temperature, 36.3C; blood pressure, 140/90 mmHg; pulse rate, 88 beats/min; and respiratory rate, 32 beats/min. The patient showed an acutely ill appearance at the time of admission. On physical examination, he had increased jugular venous pressure of 10 cm H2O. Auscultation in the left upper sternal area revealed a normal S1 and a loud P2 with a grade IV systolic ejection murmur in the pulmonic area. No abdominal tenderness or organomegaly was noted. His neurological examination was normal. Peripheral edema was not observed. Arterial blood gas analysis revealed pH, 7.429; pCO2, 33.6 mmHg; pO2, 72.2 mmHg; HCO3-, 21.8 mmol/L; and O2 saturation, 94.5c. His complete blood cell count results were white cells, 11,200/mm3; hemoglobin, 14.5 mg/dL; hematocrit, 40.8%; and platelets, 157,000/mm3. The coagulation profile included activated partial-thromboplastin time, 39.2 seconds (range, 26.5 to 41); prothrombin time, 11.8 seconds (range, 9.8 to 13); fibrinogen, 284.9 mg/dL (range, 180 to 350); fibrinogen degradation products, 8.9 microg/mL (range, 0 to 5); and D-dimer, 0.72 mg/L (range, 0 to 0.3). His creatinine level had increased to 1.9 mg/dL (range, 0.5 to 1.2). The lipid profile results showed low density lipoprotein-cholesterol, 121 mg/dL (range, 0 to 120); triglycerides, 133 mg/dL (range, 50 to 150); and lipoprotein(a), 10 mg/dL (range, 0 to 30). The levels of cardiac biomarkers were elevated: troponin I, 0.35 ng/mL (range, 0 to 0.05); C-reactive protein, 1.6 mg/dL (range, 0.1 to 1); and N-terminal prohormone brain natriuretic peptide, 3,106 pg/mL (range, < 262). The estimated creatinine clearance rate using the Cockcroft-Gault formula was 33.92 mL/min/1.73 m2. An electrocardiogram revealed sinus rhythm at a rate of 65 beats per minute and ST-T segment changes over leads III, aVF, and V1-3. Chest radiography revealed no definitive abnormalities such as cardiomegaly, pulmonary congestion, or pneumonic infiltration. For further evaluation of the dyspnea, we performed transthoracic echocardiography, which revealed a D-shaped left ventricle due to right ventricular pressure overload (Fig. 1A). The right ventricular ejection fraction estimated by tricuspid annular plane systolic excursion had decreased to 33%. Moderate pulmonary hypertension (right ventricular systolic pressure, 61.63 mmHg) was observed (Fig. 1B). These echocardiographic findings suggested acute PTE. We performed chest computed tomography (CT) to confirm the PTE. Multiple PTE in both lobar and main pulmonary arteries were observed on chest CT (Fig. 2). After transferring the patient to the intensive care unit, we performed fibrinolysis with a continuous infusion of tissue plasminogen activator (actylase) 100 mg over 2 hours to dissolve the pulmonary arterial thrombi. An ultrasonogram of the lower extremity venous system revealed no evidence of venous thrombosis. Renal ultrasonography was performed to evaluate the decreased renal function. Multiple cystic lesions in both kidneys were observed on ultrasonography. We performed further biochemical and immunological examinations to assess the possible thrombophilic cause of the PTE. Vitamin B12 and urine methylmalonic acid levels were within normal limits. The folate level had decreased to 6.31 nmol/L (range, > 12.19). The Hcy level was >50 micromol/L (range, 4.72 to 14.05). Protein C, protein S, and antithrombin III levels were within normal limits. The laboratory results for coagulation factors were: factor V, 65% (range, 60 to 140); factor VIII, 169.4% (range, 50 to 150); and factor XII, 37% (range, 60 to 140). The factor V leiden mutation was not detected. Anticardiolipid antibody and antiphospholipid antibody tests were negative. The homozygous point mutation of the methyltetrahydrofolate reductase (MTHFR) gene (677C>T substitution) was identified. Thus, we finally diagnosed PTE caused by severe hyperhomocysteinemia, polycystic kidney disease, and known hypertension. One-week later, a second transthoracic echocardiography showed remarkable improvement of the impaired right ventricular function and moderate pulmonary hypertension. At 2 weeks after fibrinolysis, a ventilation-perfusion lung scan, performed instead of a follow-up chest CT scan, revealed no significant segmental perfusion defect in either lung field. The patient received anticoagulation therapy after discharge, with daily supplements of 100 mg of vitamin B6 and 2 mg of folate to prevent recurrence of the PTE. The serum level of Hcy decreased to 12.05 micromol/L, and PTE had not recurred after 6 months of clinical follow-up. A recent revolution has occurred in the field of venous thromboembolism (VTE), which encompasses deep venous thrombosis and PTE. VTE-related deaths have been estimated at 300,000 annually in the United States. Although less common in certain regions such as Asia, VTE is a worldwide problem, particularly in people with known risk factors. Hcy is a sulfhydryl amino acid derived from the metabolic conversion of methionine, which is dependent on vitamins (folic acid, B12, and B6) as cofactors or cosubstrates. It is clear that hyperhomocysteinemia promotes atherosclerosis and thrombosis in susceptible animal models, but the pathophysiological mechanisms of these effects are less well understood. The overall prevalence of hyperhomocysteinemia in the total population is 5% to 7%. Several clinical studies have reported that elevated levels of Hcy are associated with an increased risk for coronary artery disease and VTE. A meta-analysis found that for every increase of 5 micromol/L in plasma Hcy concentration, there was an average increase of 60% (odds ratio, 16; 95% confidence interval, 1.1 to 2.34) in the incidence of VTE. Plasma levels of Hcy increase with age, are lower in fertile women than in men, and increase after menopause. Major determinants of plasma Hcy levels include genetic abnormalities, diet (vitamin B2, B6, B12, and folate intake), renal function, cigarette smoking, and coffee and tea consumption. The most frequent cause of severe hyperhomocysteinemia (characterized by fasting plasma levels of Hcy > 100 micromol/L) is a homozygous deficiency of cystathione beta-synthase. The prevalence of this deficiency in the general population is approximately one in 335,000, varying between one in 65,000 (Ireland), and one in 900,000 (Japan). Approximately 5% to 10% of severe hyperhomocysteinemia cases are caused by inherited defects in remethylation. The homozygous point mutation of MTHFR (677C>T substitution), which catalyzes the reduction of methylene-tetrahydrofolate to methyltetrahydrofolate, is the most common inherited defect of the remethylation pathway. The homozygous MTHFR point mutation leads to a thermolabile enzyme variant with decreased basal enzymatic activity. It has been found in a large proportion of both normal subjects (5%) and patients with vascular disease (17%) in Western countries. Moon et al. reported that the proportion of patients with a homozygous MTHFR C677T gene mutation in Korea was 14% to 20%. Homozygous Korean patients with the MTHFR mutation and coronary artery disease had significantly higher fasting Hcy levels than those in the wild-type enzyme (homozygotes, 18.83 +- 6.37 micromol/L; wild type, 12.36 +- 3.21 micromol/L; p < 0.01). Three meta-analyses related to the association between MTHFR 677TT (homozygous deficiency) and VTE showed that the TT genotype is associated with increased risk for VTE compared with the wild-type homozygous genotype. It is unclear whether correcting mild to moderate hyperhomocysteinemia reduces the risk for VTE. However, there is clear evidence that the very high VTE risk of patients with severe hyperhomocysteinemia is due to cystathione beta-synthase deficiency; this deficiency decreases dramatically with vitamin supplementation, thereby lowering the very high plasma Hcy levels. No side effects have been reported in trials in which folic acid with or without other vitamins were used for various indications. In our patient, severe hyperhomocysteinemia was the most possible causative factor for the PTE. The severe hyperhomocysteinemia was associated with old age, smoking, folate deficiency, renal insufficiency, and a homozygous MTHFR C677T gene mutation. With the administration of folate and vitamin B6, the Hcy level decreased to 12.05 micromol/L within 3 months, and the patient had no evidence of PTE recurrence during a 6-month clinical follow-up. This patient with PTE due to severe hyperhomocysteinemia associated with the MTHFR gene mutation was successfully managed with antithrombotics, folate, and vitamin B6. Although it is uncertain whether treatment with vitamins in patients with mild to moderate hyperhomocysteinemia decreases the risk for PTE, we should bear in mind that a patient with a PTE due to severe hyperhomocysteinemia precipitated by a homozygous MTHFR C677T gene mutation can be successfully managed with inexpensive and safe vitamin supplementation.

folate, hyperhomocysteinemia, pulmonary embolism

Chest computed tomography at admission revealed multiple pulmonary thromboemboli in the right lobar. arrow), and.

PMC6557744_01

Male

A 76-year-old man with a 37.5 pack-year history of smoking was admitted to our hospital for the assessment of a right upper lung mass observed on chest CT (Fig. 1A). The chest CT also revealed right axillary lymphadenopathy and diffuse small pulmonary nodules (Fig. 1B), indicating extra- and intrapulmonary metastases. Biopsy of the axillary lymph nodes revealed lung adenocarcinoma. He was treated with carboplatin and nab-paclitaxel as the first line chemotherapy. After four weeks of treatment, his chest radiography revealed rapid enlargement of a right axillary lymph node (Fig. 2A), suggesting progression of the lung cancer. Immunohistochemistry performed with 22C3 pharmDx (Agilent, Tokyo, Japan) on the tumor biopsy specimen revealed a programmed death-ligand 1 (PD-L1) tumor proportion score of >=95%. Based on these results, second-line treatment with pembrolizumab (2 mg/kg, every 3 weeks) was initiated. Although the lesions appeared to increase in size as revealed by chest radiographs obtained during the first course, this radiological finding was thought to represent pseudo-progression, and treatment with pembrolizumab was continued. During the second course, chest radiography revealed reduction in the lesion size, and the treatment with pembrolizumab was continued for a total of five courses. After the fifth course, the patient started experiencing dry cough. His body temperature was 36.7 C, blood pressure was 140/63 mmHg, heart rate was 88 bpm, and percutaneous oxygen saturation was 97%. Physical examination, including chest auscultation, was unremarkable. Peripheral blood and serum tests results indicated slight inflammation based on the elevated serum C-reactive protein levels; however, the patient's white blood cell count and serum Krebs von den Lungen-6 levels were normal (Table 1). Pulmonary function tests results indicated the worsening of obstruction [FVC, 2.57 L (83.0%); FEV1, 1.51 L/s; FEV1/FVC, 58.8%; %FEV1, 60.5%] compared with the results before treatment with pembrolizumab [FVC, 2.99 L (96.6%); FEV1, 1.99 L/s; FEV1/FVC, 66.6%; %FEV1, 79.5%]. Chest CT revealed diffuse micronodules (Fig. 2B), suggesting diffuse bronchiolitis. The patient was treated with azithromycin for 3 days; however, neither his cough nor the micronodules on chest radiography improved. Bronchoscopy was performed, and cytology of the bronchoalveolar lavage fluid (BALF) revealed an increased number of neutrophils in the BALF. Histologically, transbronchial lung biopsy specimens contained inflammatory cell infiltrates in the bronchioles, including lymphocytes; however, there were no specific histological characteristics of OP, NSIP, DAD, or diffuse panbronchiolitis (DPB) (Fig. 2C). No bacteria, including acid-fast bacilli and Mycobacterium tuberculosis, were isolated from the BALF or sputum. Based on all these findings, the patient was diagnosed with bronchiolitis type of ICI-ILD. Treatment with pembrolizumab was discontinued, and he was treated with low-dose erythromycin (400 mg/day). As the patient complained of persistent cough, he was treated with a long-acting muscarinic antagonist and a long-acting beta2 agonist. An inhaled corticosteroid was subsequently administered when the cough only slightly improved. With this regimen, the cough finally resolved. The lung mass decreased in size, and the micronodules suggesting bronchiolitis also improved (Fig. 3).

bronchiolitis, immune checkpoint inhibitors-related lung disease, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2 agonist, lung cancer

Chest computed tomography before treatment showing right upper lung mass and diffuse small pulmonary nodules.

PMC10089361_01

Unknown

"We rely on the lecturer's skills and knowledge rather than set curricula. Some of our modules are taught based on translated textbooks that are 30 and 35 years old which are far from being related to the health needs of our people or even the research community." Senior faculty member of an academic institute "We are not used to conducting research, we have a lot to tell, but we are not even trained on how to write a scientific paper. We need interventions for our cadres rather than on our facilities and infrastructure." Representative of a governance body Political level. The unstable state of security, 'polarisation', and 'politicisation' of MEHPT were the major factors impacting support channels and reaching out to donors. Participants felt these issues were a real impediment to achieving a stable base for development work. "It is time now to neutralise medical education work, as we were able to neutralise medical relief and humanitarian work when the situation and the context necessitated it, now it is time to do this for medical education because the situation and the context necessitates." Representative of a national NGO Governance level. Participants expressed major challenges facing them on the governance level due to the weak internal decision-making capacity of local governance bodies. The reliance on external funding channels from donors and non-governmental organisations (NGOs) has caused a lack of autonomy and independence of these bodies. Furthermore, this has been the cause for complexities related to the requirements of donor-related reporting, red tape, and logistics. Participants also described this as the reason for a 'hesitance to initiate change': "There is no unified governance structure that can coordinate efforts, set plans, achieve standardisation, achieve effective external partnerships, and approach funders. This creates negative competitiveness between the local bodies for funding opportunities which come and go, and projects are hugely dependent on the presence of external funding, as long as there is a donor organisation implementing the project and providing funds, the project will continue, as soon as it stops, the work ends. This is a waste of local efforts, and a source of disappointment." Representative of a governance body Given the subsequent lack of holistic and systematic need assessment studies to inform the initiation and distribution of support programmes, there is a lack of effective coordination and communication towards standardisation of curricula, assessments, evaluations, and quality control procedures. "Lack of local accreditation is a significant issue in northwest Syria, there is a focus on international recognition and external accreditation, at the expense of the local accreditation:I will only accredit your graduates if you accredit my graduates." Director of academic institute Despite the multi-level challenges facing actors, participants perceived significant opportunities within the MEHPT sector. They said they believed the MEHPT has high levels of resilience. They also expressed a belief in a dominant culture of proactivity and creating positive changes which they felt would be the catalyst for future development work. They also professed a strong sense of loyalty to MEHPT and mutual hope in bettering the future of health and creating peace for the local population. These feelings stemmed from their joint experiences during the ten plus years of "sacrifice", "enduring extreme violence" and operating within limited or absent resource-settings: "We work in a uniquely complex context, we have been able to establish institutions from scratch under shelling, what we need now is to look at medical education and training from a different lens, we need to go beyond short intermittent courses to the space of building systems and strengthening institutions. We need to re-think medical education and training as a peace building pillar for our community." Key individual The extensive efforts of the Syrian diaspora were seen as a significant pillar of support which "broadened horizons" for local actors. Additionally, innovation and technology made it possible to coordinate remote training and capacity strengthening activities for local staff by experts from international institutions. This was perceived to have created the potential to network and establish more stable and sustainable partnerships with international academic institutions. The participants suggested several recommendations for future work in the field of MEHPT in northwest Syria. Firstly, they perceived the political neutralization of MEHPT as the main pillar for future development. They explained that this may include lining up around "a core body" or "a core alliance" which is able to overcome the polarisation and political sensitivities within the context and hence guarantee representation, independence, and collective decision making in MEHPT towards achieving sustainable and effective external partnerships. Secondly, strengthening the local MEHPT governance bodies to enable improved leadership, ownership, coordination, accreditation, and decision making. They suggested this may be achieved by gradually shifting power from external support systems (including NGOs and donors) to local governance systems, together with holistic capacity strengthening approaches and programmes in leadership, conflict resolution, management, strategic planning, information technology, needs assessment, public health planning, research and quality improvement, communication, "common value-building", and English language skills. Thirdly, networking with neighbouring and international academic institutions and establishing sustainable academic partnerships and capacity building programmes with local academic bodies, including training senior leadership and teaching staff especially in areas such as assessments, teaching strategies, curriculum design, and English language.

PMC6796648_01

Male

A 57-year-old man presented with jaundice. There was no past history of hepatitis or blood transfusion. Blood tests showed high levels of bilirubin, protein induced by vitamin K absence or antagonist-II (PIVKA-II) and carbohydrate antigen 19-9 (CA19-9). The indocyanine green retention test (ICGR15) could not be evaluated due to obstructive jaundice (Table 1a). Computed tomography (CT) scans showed a tumor 40 mm in diameter located in segment 6 with TT in the common hepatic bile duct (Fig. 1). Endoscopic retrograde cholangiography (ERCP) showed TT in the right hepatic duct and the common bile duct (Fig. 1). An endoscopic nasobiliary drainage (ENBD) tube was inserted in the left liver. ENBD was performed instead of percutaneous transhepatic biliary drainage (PTBD) due to the risk of tumor dissemination and bleeding, and insufficient dilation of the left intrahepatic bile duct. The level of total bilirubin in the bile (LTB) from the left liver as a future remnant liver was calculated at 1 week and 2 weeks after ENBD. LTB was calculated by multiplying bile density and volume obtained by ENBD. One week after ENBD, the total bilirubin density was 16.9 mg/dL and the bile volume was 205 ml. Two weeks after ENBD, the total bilirubin density was 46.0 mg/dL and the bile volume was 235 ml. The LTB from the left liver increased from 34.6 mg to 108.1 mg. However, bleeding from the TT and cholangitis occurred so thatneither the patient's general condition nor the serum level of bilirubin improved. One month after admission, the patient underwent thrombectomy in the bile duct, transection of the right hepatic bile duct and ligation of the right hepatic artery due to bleeding from the thrombus (Fig. 2). The bilirubin level immediately improved, and he was discharged from the hospital (Fig. 3). However, TT in the right portal vein developed (Fig. 4) and he was admitted to the hospital for a second operation. The serum level of total bilirubin was 1.3 mg/dl and ICGR15 was 34% at the second admission. Although the volume of bile could not be measured, the total bilirubin density in the bile from the left liver by ERCP was 40 mg/dL (Table 1b). 99mT-galactosyl human serum albumin (99mTc-GSA) scintigraphy revealed a reduced accumulation of GSA in the right liver. In addition, left liver hypertrophy was observed on GSA scintigraphy (Fig. 4). We judged that right hepatectomy was possible because of the following reasons: (1) decrease in the serum level of total bilirubin, (2) hypertrophy of the left liver similar to portal vein embolization, (3) sufficient future remnant liver function on the basis of the total bilirubin density in the bile from the left liver. The patient underwent right hepatectomy for HCC. The total operation time was 326 min, and the total blood loss was 6264 g. The pathological findings yielded a diagnosis of moderately differentiated HCC with macroscopic portal vein and bile duct TT (Fig. 5). There was no intrahepatic metastasis, and the surgical margin was negative. The patient's postoperative course was uneventful, and he was discharged on postoperative day 30 and he is well without recurrence 10 years after surgery.

biliary drainage, hemobilia, tumor thrombus in the bile duct

PMC5337757_01

Female

A 68-year-old female, a resident of Karnal (Haryana, North India), a known case of diabetes mellitus (for 5 years on diet control), and chronic liver disease (for 3 years) presented with complaints of cough, generalized weakness, and significant weight loss since one month. The cough was insidious in onset, dry in nature, and not associated with any aggravating or relieving factor. She was diagnosed with chronic liver disease 3 years ago and an evaluation was done earlier for the same and was found to be cryptogenic in origin. There were no similar complaints among her family members. On examination, she was thin built and pale. The patient was afebrile and haemodynamically stable. There were no palpable lymph nodes. Systemic examination was unremarkable. Initial blood investigations revealed anaemia (haemoglobin 10.2 g/dl), total leucocyte count 12x109 cells/l, platelet count 150x109 cells/l, erythrocyte sedimentation rate 59 mm/hour and differential count was neutrophil 41%, lymphoctes 27% and eosinophils 32%. Mean corpuscular volume and mean corpuscular haemoglobin concentration were 84 fL and 32 g/dl, respectively. Peripheral blood smear showed normocytic normochromic anaemia with eosinophilia (figure 1). Absolute eosinophil count was 4x109 cells/l. Hepatic functions were normal except for hypoalbuminemia (2.78 g/dl). Renal function tests were normal. ELISA for HIV-1 and HIV-2, anti-hepatitis C antibody, hepatitis B surface antigen were negative. Reaction to the tubercular skin test was less than 10 mm. Chest radiograph showed increased bronchovascular markings with right hilar prominence (figure 2). Stool samples tested two times but did not reveal any ova or parasite. Ultrasound abdomen showed coarse liver echotexture. During the course of hospital stay, the patient continued to have a dry cough and generalized weakness. The patient was given deworming measures (albendazole and diethylcarbamazine). Repeat blood counts revealed persistent eosinophilia. Test for echinococcus serology was negative. Anti-filarial antibodies were negative. Tests for anti-nuclear and anti-neutrophil cytoplasmic antibodies were negative. Echocardiography was normal with no evidence of vegetation. A contrast-enhanced CT of the thorax and abdomen was done, which revealed enlarged non-necrotic mediastinal lymph nodes with features suggestive of chronic liver disease. Microscopic examination of needle-aspirated bone marrow and biopsy examination revealed increased eosinophilic precursors with no abnormal cells. Endoscopic bronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes was consistent with tubercular inflammation with acid-fast stain positive for bacilli. Acid-fast bacilli culture grew Mycobacterium tuberculosis over a period of 3 weeks in the BACTEC medium. The patient was started on anti-tubercular treatment (isoniazid, rifampicin, ethambutol, and pyrazinamide) and her eosinophil counts gradually returned to normal levels with in 1 week.

eosinophilia, lymph nodes, tuberculosis

PMC3919839_01

Female

A 42-year-old Moroccan female was admitted to the hospital with fever lasting one month, night sweats and left cervical lymphadenopathy. Laboratory exams showed leukocytes 3300/mm3, erythrocytes 4.370.000/mm3, hemoglobin 12.7 g/dl, thrombocytes 156.000/mm3, LDH 843U/l (normal values: 230-460). Other laboratory findings were all within normal ranges. Serologic investigations excluded viral, bacterial and parasitic infections, including syphilis and cytomegalovirus, Epstein-Barr virus, HIV, Rickettsia coronii, Brucella spp, Salmonella typhi, Salmonella paratyphi, toxoplasma, Leishmania donovani infections. Blood and throat cultures were negative. QuantiFERON TB Gold (ESAT-6, CFP-10, TB7.7 antigens) was negative. Chest X-ray was normal. Chest computed tomography (CT) showed multiple, small-sized bilateral hilar and mediastinal lymphadenopathies. Abdominal CT revealed additional small interaortocaval, para-aortic mesentheric and iliac lymphadenopathies. Due to the presence of multiple lymphadenopathies, a bone marrow biopsy was performed to exclude a lymphoma. Bone marrow examination was considered normal. Histology showed a mild reactive T lymphocytosis, consisting of a regular number of interstitial lymphocytes which showed mainly a CD3+, CD 20-phenotype. Bronchial aspiration with microbiologic cultures for Mycobacterium tuberculosis were negative. A cervical lymph node biopsy was performed. The lymph node structure was completely effaced by diffuse necrotic areas with abundant karyorrhectic debris (Figure 1); the search for DNA of Mycobacterium tuberculosis was negative. A mediastinal lymph node biopsy and a liver biopsy showed normal histological findings. At this time a definitive diagnosis was not available. After two months new laboratory investigations showed a leukocyte count of 3830/mm3, erythrocytes 3360000/mm3, Hgb 9,2 g/dL, thrombocytes 353.000/mm3, AST 44 U/I, ALT 45 U/I, LDH 138 U/l. Since the patient developed recurrent papulo-squamous lesions on her scalp, ears, face, and trunk, she was referred to the dermatology department. Skin examination showed papular and scaly plaques on the face, the scalp, the V-area of the neck, upper chest, back and shoulder in a photodistributed pattern. No malar rash was noted. Skin lesions were biopsied with a presumptive diagnosis of lupus. At histology, the epidermis was thinned and displayed focal parakeratosis and vacuolar degeneration of basal keratinocytes, with occasional cytoid bodies. The dermis showed conspicuous interstitial mucin deposits, dense perivascular and perifollicular lymphocytic infiltrates with interface dermatitis (Figure 2) and superficial nuclear debris with karyorrhexis. Direct immunofluorescence failed to demonstrate immunoglobulin or complement deposits along the dermoepidermal junction or around the vessels. Immunologic serum investigations showed absence of antinuclear antibodies, antibodies (anti)-LA/SS-B, anti-ds DNA, anti-phospholipids, anti-pANCA, anti-Jo1, anti-Scl-70, anti-RNP. Antibodies anti-Ro/SS-A (E.I.A) were 59 (normal value: 0-10), ENA (E.I.A) 18.7 (normal value: 0-3). The patient's complement levels were low with C3 71 mg/dL (normal values: 88-201 mg/dL), C4 5 mg/dL (normal values: 16-47 mg/dL). On the basis of clinical, laboratory and histology findings, a diagnosis of SCLE was made. The patient was given prednisone 25 mg per day and hydroxychloroquine. Skin lesions improved rapidly and healed without scarring. The dosage of corticosteroids was gradually tapered without relapse of skin lesions. After 38-month follow up the patient is free of skin and systemic symptoms. Now she is taking hydroxychloroquine 400 mg/day. Laboratory investigations are all within normal value, except for persistent complement deficiency in C3 and C4.

kikuchi-fujimoto disease, lymphadenitis, skin

PMC9034561_02

Female

Participant 2: Miss O.P, 32-year-old single seamstress admitted with recurrent fever of three months, cough, weight loss and then right sided weakness of one day. She was not a known patient with haemoglobinopathy, hypertension, or diabetes mellitus. No history of significant alcohol consumption, cigarette smoking or use of illicit drugs. She had recurrent diarrhoea for about two months with a positive history of multiple sexual partners. On admission, she had hyperpigmented skin, dehydrated, febrile to touch (temperature- 38 C), anicteric and pale (PCV 22%). There was right hemiparesis, with power of 4 in the right upper limb and 2 in the right lower limb, with chest signs of consolidation on the right side, confirmed on chest radiograph. There was hepatomegaly of 2-4cm, with a tipped spleen. Her blood pressure was 90/60 mmHg. There were hemic murmurs with tachycardia of 102bpm. Blood was sterile on culture. The random blood glucose was 76mg/dl, with normal plasma lipids profile. Aside a hyponatraemia of 131mmol/l her renal assessment was normal. A computerized tomography (CT) scan was not done for financial reasons. She had stroke care, rehydration and systematic antibiotics. A follow-up chest X-ray after antibiotics reveal underlined features suggestive of tuberculosis. Even though she had a smear-negative sputum examination, her genexpert examination was positive. Outcome: she improved remarkably, had anti tuberculosis treatment, and was enrolled in the adult HIV services and had ART.

hiv-positive, nigeria, stroke in the young

PMC9582237_01

Female

A 55-year-old woman with no significant medical history initially presented with several months of right-sided flank pain. A computed tomography (CT) of the abdomen and pelvis revealed severe right-sided hydroureteronephrosis and right cortical atrophy of the right kidney. A CT urogram demonstrated a soft tissue mass involving the distal right ureter near the ureterovesical junction as well as enlarged right external iliac lymph nodes. She underwent cystoscopy which identified tumor arising from the right ureteral orifice. A transurethral resection of bladder tumor (TURBT) was performed which revealed invasive high-grade, poorly differentiated papillary urothelial carcinoma that extended into the lamina propria but did not invade into the muscularis propria. A biopsy of the right external iliac lymph node was positive for malignancy. The patient was thus initially diagnosed with stage IIIA disease (pT1N1M0) and started on neoadjuvant dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC). She eventually underwent a radical nephroureterectomy, partial cystectomy, and pelvic lymph node dissection. At the time of surgery, she was found to have microscopic foci of malignancy with negative surgical margins and negative lymph nodes in the nine total lymph nodes examined. Adjuvant therapy was not indicated given the pathologic findings of pTaN0Mx, and the patient proceeded with surveillance. Four months after surgery, she was found to have a new 3.1 cm right inguinal lymph node and 1.3 cm anterior aortocaval lymph node on re-staging CT imaging. Biopsy of the right inguinal lymph node was positive for recurrent urothelial carcinoma. There was concern for platinum resistance given her prior neoadjuvant ddMVAC therapy. The patient was therefore started on intravenous pembrolizumab 200 mg every 3 weeks instead of a cisplatin-based regimen. Re-staging CT imaging after approximately three months of pembrolizumab indicated decreasing size of the inguinal and pelvic lymph nodes. After five months of pembrolizumab (eight cycles), repeat imaging indicated no evidence of disease. However, CT chest imaging at this time revealed interval development of bilateral ground glass opacities in the lungs. At this time, the patient did not report any respiratory symptoms such as shortness of breath, dyspnea on exertion, or cough. However, pembrolizumab was held given the concern for immune-mediated pneumonitis. She eventually developed acute-onset shortness of breath and fever for which she presented to the hospital where she was found to have progressive bilateral ground glass opacities involving all of the lobes. Infectious workup including Pneumocystis jirovecii was negative. She was then started on a prolonged steroid taper for grade 3 immune-mediated pneumonitis. One month after starting steroids, she had improvement in respiratory symptoms. An interval CT chest at this time demonstrated improvement in the bilateral opacities. The patient completed her steroids over two months with complete resolution of her pulmonary symptoms. Approximately 4 weeks later (3 months after her last dose of pembrolizumab), she developed several recurrent episodes of red eyes, styes, and eyelid tenderness involving both eyes. She had pre-existing myopia and age-related presbyopia but did not have any changes in visual acuity. The patient did not have any blurry vision or ocular pain. Given that her symptoms persisted despite conservative measures, she was evaluated by an optometrist. Visual acuity examination was stable. Tear breakup time (TBUT) was low suggesting tear film instability. The patient was also noted to have thin tear meniscus in both eyes. Digital expression of the meibomian glands revealed thick, turbid meibum. Infrared meibography revealed bilateral grade 2 meibomian gland atrophy (Figure 2). Taken together, she was diagnosed with meibomian gland dysfunction (MGD). Management was started with warm compresses, lid massages, oil-based eye drops, as well as dietary omega-3 fatty acid supplementation. With these measures, the patient had significant improvement in her eye symptoms. Pembrolizumab was not continued after eight cycles given that her interval staging scans did not show any evidence of cancer or recurrence and since she had experienced severe pulmonary toxicity. At a follow-up two years after completing pembrolizumab, the patient was doing well clinically without evidence of cancer on repeat imaging. She continued to have mild eye symptoms and persistent meibomian gland atrophy on meibography. However, her symptoms were well-managed with continued MGD therapies.

immune-related adverse events, immunotherapy, immunotherapy adverse reactions, meibomian gland dysfunction, ocular toxicity

PMC3917411_01

Male

In February, 2012, a 52-year-old Caucasian man with no underlying disease (but a cigarette smoker) was admitted to the intensive care unit of a Dutch hospital, with high fever, shortness of breath, electrolyte imbalance, diarrhea, and neurological symptoms. Chest radiography showed areas of consolidation in both his lungs and confirmed the diagnosis of pneumonia. He was treated with intravenous ciprofloxacin (400mg daily), intravenous cefuroxime (6 days, 1000mg every 8 hours), and doxycycline oral (3 days, 200mg twice daily). Following negative results for both a L. pneumophila urinary antigen test, and a polymerase chain reaction (PCR) assay that targeted the 5S ribosomal deoxyribonucleic acid (DNA) gene performed on a sputum sample (DNA extraction by NucliSENS easyMAG , bioMerieux, Durham, USA), treatment with intravenous ciprofloxacin was stopped after 4 days. Two days later, both PCR and culture of a bronchial lavage sample were found positive for L. pneumophila (serogroup 3), and the treatment with intravenous ciprofloxacin was continued for another 10 days. The patient left the intensive care unit after 13 days, recovered and left the hospital after 23 days. In accordance with the National Legionella Outbreak Detection Programme that was installed in the Netherlands in 2002, an investigation was performed to find the source of infection. During the source investigation, two potential sources were identified: (1) the house of the patient where he had used taps and shower, and (2) the metal processing company where he worked and was exposed to water-based cutting fluids, and a pressure test pump (Figure 1) that uses water to evaluate the quality of the produced industrial iron molds. With this manually operated pressure test pump, molds are tested for leakages by pushing water through the mold with increasing air pressure. When a leak is present, respirable water aerosols are sprayed around by the pump, and the pressure drops. Samples were taken from the patient's home (taps and shower), from the cutting-fluids and water reservoir of the pump at the company. All nine samples from his home were negative, but one of the five samples from the company was positive for L. pneumophila. The sample from the water reservoir of the pressure test pump contained 9 8x103 colony forming units/L. Both L. pneumophila serogroup 1 and serogroup 3 were isolated from this sample. Sequence-based typing (SBT) showed the same sequence type (ST93) for both the clinical and environmental L. pneumophila serogroup 3 strains. This sequence type was previously reported for only 29 clinical and 15 environmental isolates according to the European Working Group for Legionella Infections SBT database which contains sequence types of over 6600 L. pneumophila strains. The high pressure pump was dismantled and thoroughly cleaned and rinsed several times, and control measures and changes in the working procedure were implemented. Employees are now required to wear filtering facepiece 2 respirator masks when operating the pump and the water reservoir is emptied and dried after every use. No other cases of LD related to this company were reported among the other employees.

PMC4672610_01

Female

In July 2014, a 59-year-old women was admitted in into the infectious disease department of the University Hospital in Marseille for swollen, erythematous, painful breasts with purulent discharge from surgical wound of left breast prosthesis implantation. Fifteen months after weight-loss surgery and advanced diet per bariatric surgery nutritional procedure for morbid obesity (body mass index 41 kg/m2), she has significant loss of 43 kg (body mass index weight 20 kg/m2). There was nothing else notable in her medical history. Four weeks before her admission, she underwent breast prosthesis implantation, mastopexy and arm lifting surgery in private clinics in the region. One week after surgery, she presented with thoracic pain and purulent discharge from surgical wound. The laboratory investigations revealed high C-reactive protein levels (74 mg/l; normal values <=5 mg/l), elevated leukocyte count (12,000 muL-1, predominantly neutrophil granulocytes), low hemoglobin concentration (10 g/l; normal = 135-175 g/l), and normal platelet count (480,000 muL-1). The culture of the fluid obtained by percutaneous drainage was positive of Pseudomonas aeruginosa. Symptoms persisted despite of 10 days of oral therapy by ciprofloxacin. Breast prosthesis implant have been removed and intravenous antimicrobial treatment of amikacin and ceftazidime was begun. Fifteen day later, she had been admitted in our unit for persistent of swelling, reddish, painful left breast and purulent discharge from surgical wound of left breast implant. Her body temperature was 37 C, her pulse was 74 beats/min, and her blood pressure was 127/70 mmHg. Laboratory investigations revealed normal values for C-reactive protein (1 mg/l; normal values <=5 mg/l) and normal leukocyte count (5000 muL-1), low hemoglobin concentration (10 g/l; normal = 135-175 g/l), and normal platelet count (300,000 muL-1). Magnetic resonance imaging (MRI) has shown an inflammation of anterior chest wall in the left side with sternal osteitis (Fig. 1a and b). She was treated by surgical lavage with debridement, a fistulectomy with costal-chondral resection of infected tissue. The necrotic periosteum and perichondrium tissues and hypovascularized rib were removed (Fig. 1c). A removal of 3rd and 4th left ribs and a partial sternal resection was performed (Fig. 1d). Bacterial cultures of the deep sample were negative. Analyses for S. aureus and M. tuberculosis by PCR and 16S RNA testing were negative. She was discharged one week after surgery. She received 90 days of treatment with imipenem/cilastatin and ciprofloxacin.

bacteria, breast implant infection, human, pseudomonas aeruginosa, rib osteomyelitis, sternum osteomyelitis

PMC9887667_01

Female

A 37-year-old white woman presented to our clinic with symptoms, including reduced physical capacity (NYHA II), strong recurrent dizziness (i.e. near-syncope), fatigue, and diffuse arthralgias as well as myalgias, which commenced approximately 4 years prior. Besides recurrent episodes of depression, treated with 60 mg/day fluoxetine p.o., her past medical history was unremarkable. The patient denied consumption of alcohol, tobacco or drugs. Her family history revealed that her grandfather received a pacemaker at the age of 50, for reasons that could not be further specified. Other familial diseases, including relevant genetic aberrations, were unknown. Preceding admission to our clinic, an electrocardiogram performed by her cardiologist revealed complex conduction abnormalities, including a right bundle branch block, left anterior hemi-block, and atrioventricular block 1 (Figure 1A and B). While echocardiographic left ventricular (LV) volume appeared normal, LV-function was mildly impaired (LVEF 51%). Therefore, treatment with 1.25 mg/day Ramipril p.o. was initiated. Additionally, the interventricular septum was thickened (IVSd 13 mm; LVPWd 10 mm; LVIDd 50 mm). Consecutive cardiac magnetic resonance imaging (CMR), performed due to suspicion of cardiac amyloidosis, unveiled focal septal scarring as possible aetiology of the combined conduction defect, with no signs of active inflammation. Our patient then underwent cardiac catheterization with extraction of four endomyocardial biopsies (EMB) for further diagnostic workup. Histology of those EMBs demonstrated signs of inflammatory cardiomyopathy. In the meantime, negative results for IgG- and IgM-antibodies against Borrelia burgdorferi excluded concerns about potential Lyme-disease, following a tick bite 10 years prior. Upon admission to our clinic, thorough physical examination of our patient revealed no abnormalities. Blood analyses showed elevated NT-proBNP (157 ng/L) but normal levels of high-sensitivity Troponin T (6 ng/L) and Myoglobin (<21 mug/L). Relative (18.3%) and absolute (0.99/nL) lymphocyte count were also abnormally low, implying a possible viral aetiology of the patient's myocardial inflammation. However, a consecutive PCR-screening for cardiotropic viruses proved inconclusive. Biomarkers of rheumatic diseases, suspected due to the patient's diffuse joint and muscular pain, were also inconspicuous (ANA negative; c-ANCA <0.5; P-ANCA 1.0). Moreover, levels of soluble Interleukin-2 Receptor (sIL-2R) and serum angiotensin-converting enzyme (ACE), both established biomarkers of sarcoidosis, were normal (383.0 IU/mL and 23.7 U/L, respectively). Additionally, genetic analysis for variants of the alpha-galactosidase gene, which may cause conduction defects and thickened left ventricular walls by predisposing to Morbus Fabry, were negative. Despite negative biomarker results, sarcoidosis remained our working diagnosis due to the prevalence of complicated conduction abnormalities in a young patient, histological evidence of inflammatory cardiomyopathy and typical septal scarring in the absence of signs for acute myocarditis on CMR. Based on strong suspicion of CS with long-standing complex conduction abnormalities as the most probable cause for our patients recurrent near-syncopes, she underwent implantation of a dual-chamber pacemaker-defibrillator (DDD-ICD) given the risk of ventricular arrhythmias and sudden cardiac death in CS. This decision was reached in accordance with indications for device therapy in CS outlined in the HRS expert consensus statement for the management of arrythmias associated with CS published by Birnie et al. in 2014 (i.e. 'unexplained near-syncope, felt to be arrhythmic in nature'; Class IIa) and our patient's wish. Subsequently, positron emission tomography with 18F-fluorodeoxyglucose integrated with computed tomography (18F-FDG-PET-CT) was performed to screen for hypermetabolic lesions, which indicate active inflammation (Figure 2A, D, G, and J). Our patient followed a special high-fat low-carbohydrate diet to suppress physiological myocardial 18F-FDG uptake. Intense hypermetabolic myocardial lesions were found in the septum, anterior wall, and proximal pulmonary trunk:a pattern indicative of active cardiac sarcoidosis. Moreover, multiple pulmonary, hepatic, splenic, and spinal lesions were found along with various hypermetabolic peripheral lymph nodes. Although these findings were highly suggestive of systemic sarcoidosis in light of the patient's clinical presentation, co-existent disseminated malignancies (i.e. lymphoma) could not be excluded securely until the diagnosis would be confirmed through biopsy of an easily accessible lesion. Therefore, bronchoscopy with real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed. No signs of malignancy were observed. Two samples of suspicious pulmonary tissue and three samples of 18F-FDG-PET-responsive mediastinal lymph nodes were obtained and sent for histopathological assessment. Additionally, 150 mL of bronchoalveolar lavage (BAL) specimen was extracted and sent for microbiological and cytological examination. Infections with Mycobacterium tuberculosis, other mycobacteria or fungi could be excluded through negative QuantiFERON-tests, cultivation, MOTT-PCR, as well as PAS-stains of the BAL and tissue samples, respectively. Cytological analysis revealed an elevated CD4/CD8 T-cell ratio (4.3), indicative of sarcoidosis. Histopathological evaluation identified characteristic infiltrates with non-caseating epithelioid granulomas in one of the obtained tissue samples. Given the exclusion of other granulomatous diseases, that finding provided sufficient proof of sarcoidosis. Due to the lack of associated symptoms and limited inflammatory activity observed in pulmonary tissue samples, it was concluded that pulmonary sarcoidosis is currently inactive in our patient, while CS prevails. Supporting this conclusion, spirometry results indicated sustained lung function regarding VC (103%), TLC (112%), FEV1 (80%), FVC (89%), and FEV1/FVC (91%) with no signs of restriction or obstruction. Confirmation of sarcoidosis was followed by prompt initiation of immunosuppressive treatment with 50 mg/day prednisolone p.o.. A tapering strategy, reducing daily prednisolone doses by 10 mg/week until a dose of 20 mg/day was reached and further reductions of 2.5 mg/week after that, was followed to a maintenance dose of 5 mg/day. Additionally, our patient was advised to substitute vitamin D3 (1000 IE/day) and take pantoprazole (40 mg/day) to reduce the prednisolone-related risk of osteoporosis and gastric ulcer. In consideration of our patient's extensive organ involvement and data indicating significantly reduced relapse rates for combined steroid and immunosuppressive therapy, prednisolone therapy was augmented with 1000 mg cyclophosphamide i.v., which was administered once a month for a duration of 6 months in an inpatient setting under gonadal protection through subcutaneous administration of gonadotropin-releasing hormone analogues.Cyclophosphamide was chosen over the more widely used corticosteroid-sparing agent methotrexate, based on data from patients with neurosarcoidosis and clinical observations made by the treating team in previous CS patients, indicating superior long-term outcomes. A benefit of cyclophosphamide was later also reported by Cacoub and colleagues, who demonstrated significantly lower relapse rates for intravenous cyclophosphamide than for methotrexate in CS. The combined immunosuppressive therapy was well-tolerated and induced significant improvements in subjective physical capacity and quality of life within three months of initiation. In contrast, a control 18F-FDG-PET-CT indicated that most sarcoid lesions remained morphologically and metabolically unchanged at that time point (Figure 2B, E, H, and K). Yet, the therapeutic scheme was retained, as one of the pulmonary lesions appeared to be metabolically normalized, indicating partial response to treatment. Following six cyclophosphamide cycles with a cumulative dose of 6000 mg, a maintenance regimen featuring weekly subcutaneous injections of 15 mg methotrexate, which would facilitate relatively uncomplicated outpatient treatment, was initiated. Methotrexate was chosen for therapeutic maintenance to reduce the risk of sterility posed by the well-established cumulative dose-dependent gonadotoxicity of cyclophosphamide, since our patient still had a strong wish to have children, as outlined above. Treatment duration could not be finally defined at the time of initiation, as it depends on the course of the disease. Specifically, an approach where the methotrexate dose is maintained for at least 6 months upon achievement of remission, followed by a tapering attempt reducing the weekly methotrexate dose by 2.5-5 mg every three months, was applied. Eventually, a second control 18F-FDG-PET-CT performed 9 months after treatment initiation (Figure 2C, F, I, and L) indicated good overall response with full regression of lymph node and osseous lesions and slight residual activity at most in anteroseptal regions of the heart and in the liver. Solely the splenic lesions remained clearly hypermetabolic. The rate of ventricular stimulation recorded at a pacemaker interrogation approximately 9 months after treatment initiation was still 86%. However, partial recovery of our patient's conduction abnormalities, including the 1 AV-block and left anterior hemi-block, could be noted in an electrocardiographic follow-up approximately one year after initiation of treatment (Figure 1C and D). Both pulmonary and cardiac function remained stable throughout the course of treatment, as assessed by serial spirometry and echocardiographic examinations.

cardiac magnetic resonance imaging, cardiac sarcoidosis, case report, heart arrhythmia, positron emission tomography, sarcoidosis

PMC4927661_01

Male

A-48-year-old man was admitted to our hospital because of dyspnea. His sputa were strongly smear-positive and the mycobacteria obtained from culture were identified as Miliary tuberculosis. Routine blood tests showed white blood cell count of 12800/mm3, platelets of 35.0 x 104/mm3, C-reactive protein of 22.0 mg/dl, albumin level of 1.9 g/dl and a negative HIV ELISA test. His chest X-ray and computed tomography showed diffuse bilateral infiltration and cavity (Fig. 1A, B), and blood gas test showed PaO2/FiO2 131.0. This patient was initially hospitalized in the ICU and noninvasive positive-pressure ventilation started. Anti-tuberculosis drugs, including isoniazid, refampicin, streptomycin and pyrazinamide; antibiotics including meropenem and ciprofloxacin; and intravenous methylprednisolone (1.0 mg/kg/day) were introduced. Six days later, further deterioration of gas exchange prompted the decision to intubate and steroid pulse therapy consisting of intravenous methylprednisolone (1000 mg/day for 3 days) followed by intravenous methylprednisolone (1.0 mg/kg/day) was administered. However, on the 3rd day of intubation arterial blood gas analyses showed severe hypoxemia (PaO2/FiO2 60.4) refractory to conventional MV, and we decided to administer veno-venous ECMO. Ventilator settings were adjusted to provide lung rest (pressure controlled ventilation with peak pressure of 20 cmH2O, PEEP of 10 cmH2O, and ventilation frequency of 8 per minute). Hemoptysis was observed on day 27 after the start of ECMO but ceased with adjustment to a lower dosage of heparin. No other ECMO-related major complications were evident during treatment. The pulmonary infiltrate and oxygenation status gradually improved (Fig. 1C, D, E, F), and the systemic corticosteroid was tapered. ECMO was discontinued on day 52 and we successfully weaned the patient from MV 106 days after the start of administration of ECMO. After a hospital stay and rehabilitation of 10 months, he was discharged from our hospital without severe disability.

ards, ards, acute respiratory distress syndrome, ecmo, ecmo, extracorporeal membrane oxygenation, icu, intensive care unit, mv, mechanical ventilation, ptb, pulmonary tuberculosis, pulmonary tuberculosis

PMC5491825_01

Male

A 72-year-old Japanese man visited our hospital with bilateral wrist pain and swelling. The symptoms began about one month prior to his visit. Two weeks before presentation, he had consulted a local orthopedist. At the orthopedic clinic, he had bilateral wrist swelling and showed positive findings for rheumatoid factor (RF). The doctor suspected that he had RA and referred him to our hospital for further examinations. The patient was a farmer who smoked 30 cigarettes/day for 40 years and drank alcohol occasionally. He had ulcerative colitis and had been treated with mesalazine (3.6 g/day) and prednisolone (5 mg/day); the disease was relatively well controlled. At the first visit, the patient's physical examination showed a blood pressure of 104/64 mmHg, a pulse rate of 101 beats/min, and a body temperature of 36.6 C. A musculoskeletal examination revealed marked swelling on both the dorsal and palmar surfaces of the left wrist (Fig. 1) and tenderness in both wrists. Sensation was attenuated in the palm of the left hand. Tinel's sign and Phalen's test were both positive in the left hand, indicating carpal tunnel syndrome. No skin trauma or lesions were noted. No particular findings were noted in any other systems. Laboratory tests revealed the following: white blood cells, 9,040/mm3 (normal range, 3,500-9,000/mm3); C-reactive protein, 4.78 mg/dL (normal range, 0-0.3 mg/dL); matrix metalloproteinase-3, 199.2 ng/mL (normal range, 36.9-121 ng/mL); positive RF, 63 IU/mL (normal range, 0-15 IU/mL); negative anti-citrullinated protein antibody, 0.7 U/mL (normal range, 0-4.4 U/mL); and beta-D glucan, 9.1 pg/mL (normal range, 0-20 pg/mL). Serum urea, electrolytes, creatinine, and glucose levels were within the normal range. Wrist radiographs showed swelling of the soft tissue around the left wrist, but no bone erosions. The gray-scale image obtained from MSUS showed marked thickening of the flexor and extensor tendon sheaths in the left wrist. In addition, marked power Doppler signals were detected in the margin of the tendon sheath (Fig. 2a). The tenosynovium was filled with rice bodies (Fig. 2b). A small amount of straw-colored, cloudy synovial fluid was drained by joint-puncture from the left wrist. Neither crystals nor microorganisms were detected. Mycobacterium tuberculosis DNA was not detected by a polymerase chain reaction analysis of the synovial fluid. Given the above clinical history and findings, he did not have typical RA and was instead suspected of having other diseases, including chronic infection. To identify the cause of the swelling in the left wrist and to relieve the carpal tunnel symptoms, we performed surgical synovectomy of the dorsal and palmar surfaces of the left wrist. Macroscopically, the extensor and flexor tendon sheaths were markedly thickened (Fig. 3a). The inside of the tendon sheaths showed marked hyperplastic synovium filled with abundant rice bodies that compressed the median nerve. In contrast, the synovia of the radiocarpal and midcarpal joints were almost intact. A histopathological examination of the resected tenosynovium revealed granulomatous tissue accompanied by plasma cell and lymphocyte infiltrations (Fig. 3b). No bacteria were found through Gram staining or Ziehl-Neelsen staining. However, Grocott's methenamine silver (GMS) stain detected a small number of oval-shaped yeasts (Fig. 4). The resected synovial tissue culture was positive for Sporothrix schenckii, and sporotrichal tenosynovitis was diagnosed. Initially, saturated solution potassium iodide, the standard therapy for sporotrichosis, was administered. However, shortly after starting the treatment, the patient developed hypothyroidism. The treatment was promptly changed to itraconazole, an anti-fungal drug, which he continued for a total of six months without any adverse effects. Two years following completion of treatment, the patient has shown no sign of recurrence or a change in the wrist radiography findings.

fungal infection, musculoskeletal ultrasonography, rheumatoid arthritis, sporotrichosis, tenosynovitis

PMC9577071_01

Female

A 32-year-old woman presented to the Ear, Nose and Throat clinic with a tender lump on her right side of the upper neck that had appeared for 2 weeks. She had a mild fever initially but did not have a loss of appetite, weight loss or night sweats. She also did not experience any cough, chest pain, nasal obstruction or otologic symptoms. There was no recent contact history of tuberculosis. She was treated for cervical lymphadenitis with amoxicillin by a general practitioner before coming to us. However, her neck lump persisted. On examination, there was a firm 1.5 x 1 cm right upper neck lump which was mildly tender. We performed nasal endoscopy, which showed a nasopharyngeal mass almost obliterating the fossa of Rosenmuller on both sides (Figure 1). The surface of the mass looked irregular with yellowish secretions on it. The rest of the ear, nose and throat examinations were unremarkable. Our working diagnosis was NPC with neck metastasis. We ordered an ultrasound scan of the neck and fine needle aspiration cytology (FNAC) of the neck lump. A biopsy of the nasopharyngeal mass was taken. The ultrasound scan reported multiple hypoechoic enlarged cervical nodes bilaterally with distortion of the fatty hilum. A computed tomography (CT) scan of the nasopharynx and neck was ordered to further evaluate the neck lump and nasopharyngeal mass. The FNAC was reported as showing 2 foci of atypical cells arranged in a sheet, composed of enlarged hyperchromatic nuclei. The nuclear membranes were found to be irregular with moderate cytoplasm in the background of abundant polymorphous lymphoid cells and red blood cells. The Ziehl-Neelsen (ZN) stain of the FNAC was negative for acid-fast bacilli (AFB). Metastatic carcinoma of the neck node was suspected. The CT scan showed a heterogeneously enhancing soft tissue mass measuring 2 x 1.4 x 3.9 cm in the nasopharynx, obliterating the bilateral fossa of Rosenmuller and extending inferiorly to the upper part of the oropharynx (Figure 2). Multiple enlarged, homogenously enhancing cervical nodes were seen on both sides. The visualized apical lungs showed minimal consolidation and centrilobular nodules with tree-in-bud appearances. The radiologist's impression from the CT scan finding was that of nasopharyngeal cancer with multiple cervical lymphadenopathy. Lesions in the lung apices were suspected of being active lung infections. Histopathological examination of the nasopharyngeal mass biopsy revealed necrotizing granulomatous inflammation with epithelioid histiocytes and multinucleated giant cells. No malignant cells were seen. Stains for AFB and Grocott methenamine silver (GMS) stain for fungal hyphae were negative. A repeat biopsy of the nasopharyngeal mass was sent due to strong suspicion of nasopharyngeal cancer with neck metastasis. The repeat biopsy showed caseating granuloma with dense chronic inflammatory cells forming lymphoid follicles and the ZN stain demonstrated a few AFB (Figure 3(a)-(c)). Malignant cells were again not detected and GMS staining was negative for fungal hyphae. The repeat biopsy was again negative for malignant cells and fungal hyphae. We ordered sputum smears for microscopy and a chest x-ray to exclude pulmonary tuberculosis. The chest x-ray was normal, but her sputum smears for AFB tested positive. Her white blood cell (WBC) count was 6.99 x 109/L, neutrophil count 70.4%, lymphocyte count 19%, Hb level was 12.2 g/dL, erythrocyte sedimentation rate was (ESR) 60 mm/h and anti HIV and HBsAg tests were negative. A diagnosis of nasopharyngeal tuberculosis secondary to pulmonary tuberculosis was made. We referred her to a pulmonologist colleague who put her on first-line anti-tubercular drugs. The patient was admitted to the tuberculosis ward for 2 weeks to be observed for any drug reactions and acute side-effects as per the protocol. The patient responded well to standard treatment of a 2 months intensive phase (isoniazid, rifampicin, pyrazinamide, ethambutol), and a 4 months continuation phase (isoniazid and rifampicin). Her neck node was not palpable after 2 months of treatment and the nasopharyngeal mass disappeared in 3 months. She remained asymptomatic at 6 months follow-up.

nasopharyngeal tuberculosis, acid-fast bacilli, extrapulmonary tuberculosis, nasopharyngeal carcinoma, nasopharyngeal mass

PMC7720070_01

Female

A 20-year old woman was diagnosed at birth as having TSC. She developed epilepsy at the age of 15 months. Brain magnetic resonance imaging (MRI) revealed a SEGA and cortical tubers. Other typical manifestations that appeared progressively over time included multiple renal AMLs, cardiac rhabdomyoma, facial angiofibromas, hypomelanotic macules and ungueal fibromas. No genetic testing was performed in the patient, but genetic analysis in both parents did not detect any TSC1 or TSC2 mutation. At the age of 14, the gradual growth of the SEGA led to hydrocephalus, which was treated by ventriculoperitoneal shunting and fenestration of the septum pellucidum. Due to recurrent intracranial hypertension, incomplete surgical removal of the tumor was performed 3 months later, and the diagnosis of SEGA was confirmed at histopathology. At the age of 15, a growing right renal mass suspect of AML led to selective arterial renal embolization and concomitant needle biopsy. Despite careful histopathological examination and external review, it was not possible to discriminate between epithelioid AML and papillary renal cell carcinoma, and regular imaging follow-up was instituted. A chest high-resolution CT (HRCT) revealed numerous small pulmonary nodules randomly distributed throughout both lungs. At first visit to our Department, the patient was a non-smoker and had no respiratory symptoms. Lung auscultation was unremarkable. Pulmonary function tests showed normal lung volumes and carbon monoxide transfer coefficient. There was no feature suggesting an infection, including tuberculosis. In the absence of cystic lung lesions on HRCT, LAM was ruled out. Follow-up HRCT at 6, 12 and 18 months showed stability in the number, size and density of all pulmonary nodules, thus reducing the likelihood of metastatic disease and suggesting MMPH. Moreover, the renal mass remained stable for 2 years after embolization, thus reinforcing the hypothesis of AML. At the age of 18, owing to progressive SEGA growth and increased seizure frequency, the patient was started on everolimus 10 mg daily. The treatment was well tolerated. Brain MRI after 3 months showed a significant reduction in SEGA size, which subsequently remained stable at 8 and 11 months of treatment. A follow-up chest HRCT performed 3 months after everolimus initiation (and 3 years after the first thoracic imaging) showed a remarkable decrease in density of all pulmonary MMPH lesions, without obvious change in size (Fig. 1A-C). We measured the diameter and density of the 8 most easily perceptible solid nodules on the 4 HRCT performed before everolimus, and the last one on everolimus. As shown in Fig. 1D, long and short axis (axial view) of all 8 nodules did not change over time either before or after everolimus therapy. In contrast, the density of all 8 nodules decreased after everolimus initiation, suggesting a therapeutic effect of everolimus on these lesions. Abdominal HRCT at 3 months of treatment also demonstrated a decreased density of all AMLs.

alveolar epithelial cells, everolimus, lung, mechanistic target of rapamycin, multifocal micronodular pneumocyte hyperplasia, tuberous sclerosis

PMC10316131_01

Female

An immunocompetent 45-year-old female presented with a 2-week history of progressive lower back pain, paresthesias, and paraparesis. Within a few days, the patient progressed from 3/5 to 1/5 lower extremity weakness; her neurological findings also included diffuse hyperreflexia, bilateral Babinski signs, and urinary retention. The magnetic ressonance imaging (MRI) of the spine demonstrated an intramedullary expansive lesion at the T8-T9 level that markedly enhanced with contrast [Figures 1 and 2]. Moreover, an MRI of the brain revealed no intraparenchymal lesions, and the computed tomography of the chest/abdomen failed to reveal any other focus of histoplasmosis (i.e., specifically no pulmonary involvement). A lumbar puncture for cerebrospinal fluid (CSF) analysis revealed; 94 cells; 84% neutrophils; 1% glucose; proteins 1779; and lactic acid 13.4 mmol/L. The serology was negative for: toxoplasmosis immunoglobulin M (IgM), human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B surface antigen (HBsAg), venereal disease research laboratory (VDRL), and the patient denied a history of tuberculosis. Notably, the patient had a longstanding history of requiring a ventriculoperitoneal shunt (with multiple revisions), and later, a ventriculoatrial shunt, despite an undiagnosed or apparent cause. Utilizing neuronavigation, an operative microscope, and intraoperative monitoring, the patient underwent a T8-10 laminectomy. As soon as the dura and arachnoid were opened, an expansile intramedullary cord lesion was visualized, and xanthochromic/purulent fluid immediately drained under increased pressure. A well-demarcated cleavage plane between the lesion and cord facilitated gross-total lesion resection. The pathological analysis was diagnostic for histoplasmosis [Figure 3]. Postoperatively, the patient's paraparesis markedly improved, with full recovery of the motor/sensory deficits, and sphincter function.

histoplasmosis, neurosurgery, spine, spine infection, spine surgery

PMC7415454_01

Male

A 47-year-old male patient, diagnosed with AS 25 years ago with a main presenting complaint of gradually progressive neck and back pain. This was associated with morning stiffness, lasting more than 1 hour, affecting his daily activity with limited range of motion and improving on non-steroidal anti-inflammatory drugs (NSAIDs). He had no other joints' involvement, ocular pain, redness or any acute visual disturbance, no shortness of breath, chest pain, abdominal pain, or bowel disturbances. There was no skin rash or lesions. He was not known to have any medical illnesses before. He sought multiple medical advice and was diagnosed with AS based on bilateral sacroiliitis on MRI. He is HLA-B27 positive. Initially, he was started on methotrexate by a rheumatologist for 1 year hoping that it might help his back pain. There was no significant improvement in his symptoms. Another rheumatologist shifted him to adalimumab 40 mg per 2 weeks due to the persistence of pain and lack of efficacy of methotrexate. He showed significant improvement with adalimumab. Later on, after 2 years of treatment, adalimumab was discontinued, and he was started on etoricoxib 60 mg once daily alternating with celecoxib 200 mg twice daily and topical diclofenac with minimal improvement. Adalimumab was resumed by his rheumatologist after 6 months due to an active disease, patient had considerable improvement and he remained on this regimen with avid exercise with no mentionable changes of complications. He had a flare of his disease in 2011 despite being on adalimumab and he was switched to etanercept 50 mg per week, during this time he suffered from recurrent infections in the form of skin abscesses and recurrent sinusitis. There were episodes of holding the treatment until his infections were cured and then resuming etanercept. His recurrent infections were bothering, and subsequently, he was started on secukinumab 150 mg per week for a total of five loading doses and he did not notice a major improvement in his symptoms then it was increased to 300 mg once monthly in May 2019. Later on, in Nov 2019 and after a total of 11 doses, he presented to an ophthalmologist with cloudy vision and painful red eye. He was diagnosed with the first episode of anterior uveitis. He denied any previous similar complaints or symptoms and after excluding all other infectious causes such as TB, syphilis, and HSV he was started on local corticosteroid eye drops for 2 months. The patient was reluctant to initiate systemic corticosteroid and he was maintained on secukinumab 150 mg once monthly with close monitoring in the clinics. His eye symptoms started to improve by the first week of local treatment and by the fifth week, his uveitis was totally resolved. His disease remained controlled while he was maintained on secukinumab. He showed no major limitations in movement. His C-reactive protein (CRP) was normal. His disease was mainly monitored based on symptoms and other objective measures such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). His BASDAI score was 0.9. Physical examination in his last visit in Feb 2020 showed limitation of his lumbar spine flexion with a positive modified Schober test. He also demonstrated mild limitation in lateral flexion, chest expansion, and occiput to wall distance of 5 cm. His medication was maintained even during the era of COVID-19 pandemic and he had no more ocular symptoms.

il-17a inhibitors, ankylosing spondylitis, biologics, iritis, secukinumab, spondyloarthritis, uveitis

PMC7189823_01

Female

A 28-year-old woman with a 33-week pregnancy presented to our ED with acute left groin pain of increasing severity, which started at noon on the same day and spread to the left side of her abdomen. According to the patient's declaration, she had her first pregnancy acquired by intrauterine insemination (IUI) in another center. A complete review of her medical history revealed no record of a disease, drug use, or surgery. The patient's vital signs were unremarkable except for tachycardia. Physical examination revealed defense musculaire and rebound tenderness on the left lower quadrant of the abdomen. On admission, she was given intravenous hydration and symptomatic treatment for the preliminary diagnosis of acute abdomen. In laboratory studies, complete blood count revealed leukocytosis (13.100/muL), neutrophilia (12.150/muL), and anemia (hemoglobin: 11.3 g/dL), whereas urine analysis showed no abnormal findings. A complete abdominal USG examination performed by a radiologist showed the presence of fetal heartbeat and bilateral multicystic (each with an average size of 4 cm x 5 cm) ovaries with dimensions of 9 cm x 10 cm. However, ovarian blood flow was not clearly demonstrated by Doppler USG. Due to the absence of a diagnostic result by USG and a progression of symptoms despite treatment, noncontrast MRI was scheduled after obtaining informed consent. MRI showed cysts that may be secondary to IUI, reaching 6.5 cm in the right ovary and 6 cm in the left ovary [Figure 1]. In addition, MRI showed signs suggestive of OT in the left ovary, including peripherally arranged cysts, microcysts harboring the peripheral hypointense hemosiderin ring, marked stromal edema, free fluid in the inferior part of the ovary, and suspected whirlpool sign in the vascular pedicle [Figures 2 and 3]. Finally, the patient was diagnosed with OT and transferred to the department of obstetrics and gynecology. The patient underwent an emergency operation and was discharged after 3 days of hospitalization.

abdominal pain, magnetic resonance imaging, ovary, pregnancy, torsion

PMC4572465_01

Male

A 25-year-old man with no significant past medical history presented with persistent fever and nonproductive cough of two-week duration. His symptoms were initially treated as an outpatient one week prior to presentation with amoxicillin/clavulanic acid due to concern for pneumonia; however, his symptoms progressively worsened. Upon presentation, his initial vital signs were as follows: T: 100.8, P: 108, BP: 120/73, RR: 20, and oxygen saturation: 95% on room air. Within 24 hours he developed increased oxygen requirements requiring three liters of supplemental oxygen, orthopnea, and voluminous blood-tinged, frothy sputum. Physical examination was remarkable for mild respiratory distress and diminished heart and lung sounds. Initial basic metabolic panel and complete blood count were normal. NTproBNP was elevated at 513, troponin-t was elevated at 0.04, and inflammatory markers were elevated (ESR 55, CRP 13.4). Respiratory viral reverse transcriptase polymerase chain reaction (PCR) was positive only for hMPV using a nasopharyngeal swab. Chest X-ray showed new cardiomegaly and bilateral opacities, as compared to a normal chest X-ray 6 months earlier, suggesting pulmonary edema. Our differential diagnosis at this point included acute heart failure, pulmonary infection, and diffuse alveolar haemorrhage. Pulmonary medicine was consulted and a computed tomography (CT) of the chest demonstrated bilateral opacities. Echocardiogram demonstrated a severely depressed ejection fraction of 25% with severely enlarged left atrial volume and severely dilated left ventricle. Cardiac magnetic resonance imaging (MRI) showed septal wall enhancement compatible with myocarditis (Figure 1). The patient was transferred to the cardiac intensive care unit and started on intravenous diuretics and afterload and preload reducing agents (furosemide 80 mg IV BID, captopril 3.125 mg TID, metoprolol tartrate 12.5 mg BID, and isosorbide dinitrate 10 mg TID). Over the course of seven days the patient improved. He was net negative eight liters from admission and was discharged home on lisinopril 5 mg and metoprolol succinate 25 mg daily. On hospital day 4, the national reference laboratory's report of respiratory pathogen testing of a nasal swab collected on admission was positive for hMPV but negative for pathogens most commonly causing pulmonary infection, including influenza A and influenza B, parainfluenza, respiratory syncytial virus, adenovirus, tuberculosis, and mycoplasma.

PMC10460097_01

Male

A 65-year-old male came to our hospital complaining of abdominal pain in the right lumbar region for 2 months with lethargy. He had history of loss of appetite for one month with no history of fever, diabetes, tuberculosis, weight loss, or any surgeries. He has been a chronic alcoholic for the last 30 years. He had a history of dark-colored stools for a week. The patient did not receive BCG vaccination at his birth. Pallor was present in the palpebral conjunctiva, cardiovascular and respiratory system has no abnormality. On abdominal examination, mild tenderness in the right lumbar region otherwise the abdomen was soft on palpation with no organomegaly. His haemoglobin level was 8%, peripheral smear showed normocytic, normochromic anemia with few microcytes, and stool examination revealed occult blood. HIV and HBsAg tests were negative. Colonoscopy showed a circumferential ulcerated, narrowed ileocecal valve with a pulled-up caecum suggestive of abdominal tuberculosis. Multiple biopsies were taken to rule out dysplasia. The anal canal, rectum, sigmoid colon, descending colon, transverse colon, and ascending colon were visualized and their mucosa appeared normal. Computed tomography of abdomen showed mesenteric lymph node enlargement suggestive of intestinal tuberculosis. Interferon-gamma release assay, polymerase chain reaction, and Mantoux test were positive suggestive of tuberculosis, and fecal calprotectin level was normal. Chest X-ray revealed no abnormalities. The patient started with antitubercular therapy (ATT) according to national protocol i.e. rifampicin, isoniazid, pyrazinamide, and ethambutol were prescribed for four months, followed by rifampicin and isoniazid for two months along with vitamin B6.

gastrointestinal tuberculosis, colonoscopy, interferon-gamma release assay

PMC3675223_01

Female

A 43-year-old Vietnamese-American woman was referred for evaluation of dyspnea. Six months prior to presentation, left-sided chest pain radiating to her shoulder had developed, and she also noted nonproductive cough and decreased exercise tolerance. These symptoms resolved spontaneously after 10 days, and she returned to her usual state of good health. Within a few weeks began the insidious onset of progressive exertion-related dyspnea. She denied fevers, night sweats, weight loss, cough, sputum production, hemoptysis, wheezing, or recurrent chest pain. She was seen by her primary care physician who started her on loratadine, 10 mg/d, and albuterol by metered-dose inhaler. When her symptoms failed to improve, she was referred to our institution. Her medical history was significant for hypertension, hyperlipidemia, and polycystic kidney disease. Her medications at the time of presentation to our center included hydrochlorothiazide, simvastatin, lansoprazole, and loratadine. She was a lifetime nonsmoker, denied recent travel, and had no risk factors for tuberculosis. There was no known family history of polycystic kidney or parenchymal lung disease. On physical examination, vital signs were normal and pulse-derived oxygen saturation was 98% on room air. Lung auscultation revealed diminished breath sounds bilaterally, but without crackles, wheeze, or rhonchi. She was not clubbed, nor did she have peripheral edema, rash, or skin lesions. Neurologic examination was unremarkable. Results for CBC count, chemistry panel, liver tests, and coagulation studies were normal. Room air, resting blood gas showed pH 7.45, PaCO2 of 33 mm Hg, and PaO2 of 71 mm Hg. Urinalysis was normal. Spot urine protein/creatinine ratio was 0.1. Spirometry showed the following: FVC, 3.67 L (86% of predicted); FEV1, 2.92 L (85% of predicted); and FEV1/FVC, 0.80. Lung volumes measured by body plethysmograph revealed total gas volume of 4.01 L (123% of predicted), residual volume of 3.25 L (171% of predicted), and total lung capacity of 6.82 L (118% of predicted). Diffusion capacity of the lung for carbon monoxide unadjusted for hemoglobin was 90% of predicted. High-resolution CT of the chest and unenhanced CT scans of the abdomen and pelvis were performed (Fig 1, 2).

PMC9709846_01

Female

A 14-year-old adolescent female was referred to our department in July 2021 with generalized pustular and erythematous on the trunk and extremities for a week. She did not complain of chills, fever or arthralgia, but complained of swelling and pain and mild itching in the lesions. During the history collection, the patient reported a history of recurrent pustules on the distal portion of the middle finger of her right hand since 2015, which had been diagnosed as onychomycosis and treated with oral and topical antifungal in local hospitals for half a year but failed in 2017. In the summer of 2019, pustules gradually developed to multiple fingers of her both hands (Figure 1A), she visited our clinic and had a biopsy, bacterial culture was sterile and the pathologic results confirmed the diagnosis of ACH (Figure 1B and C). Since then she received intermittently treatment with oral thiamphenicol, compound glycyrrhizin, minocycline, and traditional Chinese medicine (TCM), and so on, combined with topical halometasone and tazarotene cream. The treatment response was still poor and more fingers were involved. She returned to our out-patient three months ago. According to the patient's previous treatment response, in order to improve the treatment effect, taking into account the patient's age and economic status, oral cyclosporine (150mg/day, 4mg/kg/day) was given, but there was no improvement after one month of adherence, so she stopped the medication on her own. However, about half a month after she stopped cyclosporine, the symptoms of her fingers became worse and pustules also appeared on some of the toes of both feet, and erythema and pustules immediately appeared on the trunk and extremities. She was admitted and diagnosed with acute GPP at a local hospital where she had received detailed examination ruled out latent infections such as tuberculosis and hepatitis B. Then, she was treated with adalimumab (80mg at first dose). The erythema and pustules all over her body quickly subsided within a week after first injection. However, she did not receive subsequent injections, mistakenly believing that the disease had healed, and GPP relapsed a month after she stopped taking adalimumab. Then she was given adalimumab with an 80mg dose again at the local hospital, but her symptoms were still active a week later. After a second injection of 40mg adalimumab, instead of improving, her symptoms got worse. In desperation, she stopped further adalimumab injections and came to our out-patient again. Physical examination revealed widespread erythema and dense pustules on the trunk and limbs (Figure 2A-E). The erythema, swelling, crusting, focal erosion, and pustules were present on distal portions of all fingers (except the index and middle fingers of the right hand), as well as the fourth toe of the right foot and the third toe of the left foot. Nails of these fingers and toes were dystrophic and the nail plate were also studded with pustules (Figure 3A and B). Routine laboratory testing revealed white blood cell count of 15,860/muL (normal range, 4000-11,000/muL), neutrophil count of 12,670/muL (normal range, 2500-7000/muL) and neutrophil percentage of 79.9% (normal range, 50-70%), the count and percentage of eosinophils were both normal, serum levels of C-reactive protein (CRP) of 78.32 mg/L (normal range, 0-2 mg/L) and TNF-alpha of 162.00ng/mL (normal range, 7.4-15.4 ng/mL). The immunological laboratory tests including antinuclear antibodies, thyroid autoantibodies, rheumatoid factors, complement and so on were all normal. The thorax scanned by computed tomography (CT) and abdominal ultrasound showed no obvious abnormalities. Tuberculin purified protein derivative (PPD) skin test was normal. Hepatitis-virus-related tests were also normal. The family history of the patient was unremarkable for psoriasis or other inflammatory pathologies. Based on the patient's history of ACH, skin lesion characteristics and laboratory examination, the diagnosis of acute GPP was clear, with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) total score of 4. Based on her previous experience with adalimumab, the patient and her guardians strongly refused to be treated with any biologics again. Therefore, we formulated a regular regimen of NB-UVB phototherapy combined with oral acitretin (20mg/day), which was accepted by the patient and her guardians. Due to lack of suitable skin areas for UVB minimal erythema dose (MED) testing, the patient was treated with NB-UVB (SS-10, Shanghai Sigma High Technology Co., LTD.) with an empirical starting dose of 300 mJ/cm2 (on the basis of Fitzpatrick skin type III), 3 times a week, and the dose is increased by 0-100 mJ/cm2 each time, depending on the skin reaction after each irradiation, and the maximum single dose did not exceed 3000 mJ/cm2. Surprisingly, the erythema and pustules on her trunk and extremities almost disappeared after two weeks of treatment. The patient was satisfied with the treatment response and was willing to continue the treatment. After another two weeks of treatment, the lesions all over her body had totally subsided, leaving only pigmentation (Figure 2a-e). Symptoms of fingers and toes also improved (Figure 3a and b). The GPPGA total score had been reduced to 1. NB-UVB was then reduced to once a week and the dose of acitretin was reduced to 10mg/day. There has been no recurrence of eruptions after more than 1 year of follow up.

acitretin, acrodermatitis continua of hallopeau, acute generalized pustular psoriasis, adalimumab, narrowband ultraviolet b

PMC6206516_01

Female

A 56-year-old woman with end-stage renal disease (ESRD) on hemodialysis (HD) was diagnosed with upper extremity deep vein thrombosis (DVT) one month prior to presentation and started on apixaban presented with dyspnea and left-sided pleuritic chest pain for two weeks that have been progressing slowly. She denied any other respiratory symptoms such as hemoptysis and cough and had no history of falls nor trauma. There was no weight loss, fever, night sweats, or recent travels. She has history of hypertension, diabetes mellitus, and prosthetic mitral valve replacement and she takes lisinopril, carvedilol simvastatin, and aspirin. Physical examination revealed tachypnea and dullness to percussion of the posterior left hemithorax along with decrease in tactile fremitus; she remained hemodynamically stable throughout her hospital stay. Laboratory tests on admission revealed the following: prothrombin time (PT) of 11.5 seconds, international normalized ratio (INR) of 1.03, activated partial thromboplastin time (aPTT) of 30.4 seconds, and hemoglobin of 7.0 g/dL. Chest radiograph (CXR) showed opacification of two-thirds of the left hemithorax with tracheal deviation to the contralateral side consistent with pleural effusion (Figure 1). Bedside ultrasound of left hemithorax revealed hypoechoic fluid without loculations. Even though she was transfused one unit of packed red blood cells (PRBC), her Hb dropped to 6.7 g/dL on the second day of admission. Apixaban was held for 48 hours and bedside ultrasound-guided thoracentesis was performed on the third day of admission. One liter of bloody fluid was drained and sent for testing (Figure 2). Pleural fluid analysis was as follows: hematocrit (Hct) 22%, red blood cells (RBC) 126,000/mm3, white blood cells (WBC) 1,400/mm3; bacterial gram-stain, culture, and acid-fast bacilli smear were negative for bacteria and tuberculosis, respectively, and cytology negative for malignant cells. Serum Hct was 25% at the time of the thoracentesis. The finding of pleural fluid analysis was consistent with hemothorax (pleural Hct to serum Hct ratio 88%). A chest computed tomography (CT) with intravenous contrast was done to rule out active bleeding, vascular malformations, and other causes of spontaneous hemothorax (Figure 3). A 12-Fr pigtail catheter was inserted and another one liter was drained in the first 2 hours which then slowed down to 300ml in the next 24 hours and afterwards 20-30ml daily for 2 days. CXR after drainage showed near-total resolution of the pleural effusion (Figure 4). The catheter was then removed and patient was discharged without complications.

PMC3437073_01

Male

A 55-year-old male presented with a gradually increasing mass on the left lateral lower chest and upper abdomen over a period of one year. He had no other medical problems and no history of contact with a tuberculous patient. On examination, a lobulated subcutaneous mass measuring about 7 cm in diameter, soft to cystic in consistency, immobile and attached to the skin which was tense and slightly red, tender but not warm, not pulsating, and with no bruit was found on the left lower chest and upper abdomen laterally. The spleen was enlarged 8 cm below the costal margin. Other systems were normal. Chest X-rays showed a calcified lesion near the hilum of the right lung suggestive of an old pulmonary tuberculosis. Abdominal radiographs showed calcified lesions in the left upper quadrant (Figure 1). Ultrasound of the abdomen indicated an enlarged spleen with areas of calcification. CT scan of the abdomen revealed a splenic abscess communicating with another subcutaneous abscess through the lower chest wall (Figure 2). Based on these data, a complicated tuberculous splenic abscess was the most probable diagnosis. Under general anesthesia, the subcutaneous abscess was incised and drained, and splenectomy was performed simultaneously. The spleen was found to be enlarged, fibrotic, and adherent to the lower chest wall. There was an abscess cavity within the spleen communicating with the subcutaneous abscess through a small tract in the lower chest wall below the insertion of the diaphragm. The abscesses contained thick pus and necrotic material. Histopathology of the spleen revealed the characteristic tuberculoid granuloma with epithelioid cells, Langhans' multinucleated giant cells, and caseation necrosis (Figure 3). Acid fast bacilli staining, tuberculous and bacterial cultures were all negative. The patient was started on Isoniazid (INH) 300 mg OD, Rifampin 600 mg OD, Ethambutol 600 mg OD and Pyrazinamide 500 mg OD for 5 weeks, then maintained on the former two drugs. The patient's condition improved on anti-tuberculous medications and showed good clinical progress at one-year follow-up.

abscess, spleen, tuberculous

PMC4782454_01

Male

Seventeen-year-old male, youngest of four siblings, staying with parents and three elder sisters, was brought by mother for behavioural disturbances and anger outbursts. Since 3 years, he stole sisters' undergarments and used them for masturbation. This was recurrent and persistent despite warning by parents. He had started using these clothes out of curiosity, but later got arousal and gratification only on using the inner garments for genital stimulation. He sometimes dressed up in the inner garments during masturbation but it was not necessary for arousal. Other paraphilic behaviours like attempts to rub his genitals against the sister while she was asleep, watching females taking bath, exhibitionistic behaviour were also present. Gender identity was male and had sexual fantasies towards females. He denied fantasizing himself as a female during these episodes nor desire to become female. Anger and aggressive behaviour over family members when confronted for such behaviour was present. Patient's scholastic performance was poor since childhood and further deteriorated since 7th grade. Since 1 year, there were complaints from school that patient misbehaved with girls and tried to touch them inappropriately. Physical examination was unremarkable. Secondary sexual characteristics were well-developed. Intelligence quotient (IQ) assessment revealed mild mental retardation (IQ-57). Ultrasonography (USG) abdomen ruled out any adrenal pathology. Patient was diagnosed as mild MR with paraphilia and started on sodium valporate at 20 mg/kg in view of behavioural disturbances. Psychoeducation about appropriate sexual behaviour was done. At 12 weeks, family reported mild improvement in anger and no further episodes of paraphilic behaviour.

cross-dressing, paraphilia, transvestism