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PMC3125654_02

Male

A 39-year-old HIV seropositive patient reported with breathlessness, fatigue, fever, and abdominal pain of five days' duration. On general examination the patient was well-oriented and conscious. The past medical history revealed that the patient was diagnosed as HIV seropositive (HIV 1 and 2) two months back. He was being treated for pulmonary tuberculosis (rifampacin 150 mg, isoniazid 300 mg) for the past two months. He was also on topical antibiotics for the past one month for the management of otitis media. Two weeks prior to reporting to us, he was started on HAART (lamivudine 150 mg, stavudine 30 mg and NVP 200 mg) and five days following this he developed mucocutaneous rash. There was no previous history of allergic reaction to drugs. Physical examination revealed generalized skin rashes on the neck and the trunk. Abdominal pain was thoroughly evaluated clinically by the physician. On intraoral examination, there was inflammation of the buccal mucosa and the palate. The labial mucosa was erythematous and tender. Oral Candidiasis (OC) was seen on the palate and the tongue [Figure 5]. The routine laboratory investigations showed an ESR of 49 mm/h, hemoglobin-9.2 g/dl and the differential count showed a raised eosinophil count to 6%. A clinical diagnosis of SJS and NVP-induced hepatitis was made based on the history and clinical presentation. HAART was discontinued and 2 ml dexamethasone (4 mg/ml) was given to manage mucocutaneous rashes and intravenous fluids were also administered. OC was treated with topical clotrimazole. Vitamin supplements were also prescribed. The patient was subsequently followed and discharged after one week, as his condition was stable. He was advised to continue ATT and vitamin supplements. Two months later ART was initiated with oral lamivudine 150 mg and efavirenz 600 mg, without rechallenge of NVP. A follow-up of the patient for six months confirmed that he was responding to ART and had not developed any drug reaction.

hiv, nevirapine, steven johnson syndrome, oral lesions, ulcers

PMC7555459_01

Female

A 26-year-old woman of Korean and Irish descent was evaluated for chronic hypercalcemia and complaints of fatigue, body and joint aches, and dental pain for ~4 years. She had no history of kidney stones or other medical problems except for multiple dental caries. Her mother had been treated for tuberculosis in Korea, and her maternal aunt had neck surgery in Korea at ~age 70 reportedly for a parathyroid problem. Physical examination revealed a BMI of 23.3, BP 114/68, P 68, weight 63.6 kg, and absence of dental or jaw lesions and was otherwise unremarkable. Laboratory studies 4 years prior to presentation revealed calcium levels of 10.3 mg/dL (8.4-10.2 mg/dL) and 10.8 mg/dL, phosphorus 2.4 mg/dL (2.5-4.5 mg/dL), 25 vit D 22 ng/dL (10 to 100 nM), albumin 4.4 g/L (3.4-5.4 g/dL), chloride 106 mM (96-106 mM), and creatinine 0.63 mg/dL (0.52-1.04 mg/dL). She underwent extensive evaluation over 2 years with results of blood and urine studies shown in Table 1 (daughter). Studies revealed mildly elevated calcium and calcitriol and low normal PTH. PPD and chest X-ray were negative, and urine testing favored FHH; however, she refused genetic testing citing the literature on the Internet, suggesting that PHPT is often misdiagnosed as FHH. CT imaging was performed to assess kidney stones, which were absent but, instead, showed a ~3 cm indeterminate lesion of the left iliac wing. It appeared benign on MRI (Figure 1(a)), and subsequent biopsy revealed results consistent with osteitis fibrosis cystica (Figures 1(b)-1(d)). This prompted concern for an atypical case of PHPT with low PTH levels. Further testing revealed low normal values for PTH by dilution, mid-molecule PTH, and PTHrp (Table 1). Dual-energy X-Rray absorptiometry (DXA-Hologic) revealed bone densities and Z scores of 0.717 (Z - 1.2), 0.81 (Z - 2.1), 0.797 (Z - 1.2), and 0.346 (Z - 1.4), in g/cm2, at the femoral neck, spine, hip, and ultra distal forearm, respectively. Parathyroid Tc-99 sestamibi revealed equivocal tracer retention in the right thyroid lobe, yet neck ultrasonography revealed several lymph nodes but no parathyroid adenoma. A 4D CT scan of the neck showed mild prominence of the parathyroid glands and unexpected bilateral mediastinal and hilar lymphadenopathy. Pulmonary lymph node biopsy revealed noncaseating granulomas consistent with sarcoidosis. A two-month trial of prednisone, 60 mg/d tapered to 20 mg/d, resulted in a normalization of calcitriol, 61 pg/mL and 37 pg/mL (18-72 pg/mL), at weeks 4 and 6, respectively, but no change in calcium, 10.9 mg/dL and 10.8 mg/dL, or PTH, 13 pg/mL and 16 pg/mL (10-65 pg/mL), respectively. Subsequent CT scanning of the chest revealed resolution of lymphadenopathy, and given the combination of elevated calcium, normal PTH, and low urine calcium, suspicion for FHH remained. The bone pathology was reviewed extensively and remained curious, yet its interpretation was not strictly limited to osteitis fibrosis cystica. At this time, she refused further medical evaluation and sought consultation from an endocrine surgeon. The case was presented and discussed at a multidisciplinary treatment conference, and the patient was counselled by the endocrine surgeon that parathyroid surgery was unproven in this scenario but could be considered based on her symptoms and she requested to proceed with parathyroidectomy. She underwent a subtotal parathyroidectomy with intraoperative PTH measurements, with a drop from 32 pg/mL to 9 pg/mL, 10 minutes after subtotal resection, leaving a remnant of approximately 20 mg of the left lower parathyroid gland. Intraoperatively, the parathyroid glands appeared minimally hyperplastic, and upon histologic review, they were each composed of 50-80% parathyroid epithelial cells with the rest composed of adipose tissue. Final pathology demonstrated that the left and right upper and left lower parathyroid glands weighed 20, 16, and 15 mg, respectively; two appeared histologically normal and one was hypercellular (Figures 1(g) and 1(h)). She developed postoperative hypoparathyroidism, with calcium 7.2 to 9.1 mg/dL and PTH < 3 to 5 pg/mL, but was maintained on calcitriol and reported an overall improvement in wellbeing and resolution of fatigue and body aches.

PMC7555459_02

Female

The patient referred her mother since she was noted to have hypercalcemia based on further inquiry. Her mother, a 62-year-old Korean woman with a history of treated tuberculosis, hypertension, and hyperlipidemia had mild asymptomatic hypercalcemia. Her calcium levels from 1997 to 2014 ranged from 10.2 mg/dL to 11.3 mg/dL, and further testing revealed similar findings to her daughter (Table 1, mother). CT imaging of the chest and abdomen did not reveal kidney stones or evidence of sarcoidosis, and the neck US revealed a thyroid nodule found to be benign on FNA. Surgery was discouraged, and she agreed to genetic testing revealing a novel heterozygous variant in the calcium-sensing receptor gene (CaSR) resulting in a serine to leucine substitution at position 147 (S147L). After this, her daughter agreed to testing which revealed the same heterozygous variant in the CaSR. On follow-up, the probands bony lesion was re-biopsied, 3 years after the initial biopsy and 1.5 years after surgery, revealing woven bone deposition and peritrabecular fibrosis, and it has been stable on imaging over 5.5 years. Repeat DXA (Hologic) 5.5 years after her initial one, and 3.5 years after parathyroid surgery, revealed increased bone density and Z scores of 0.798 (Z - 0.3), 0.927 (Z - 1.1), and 0.870 (Z - 0.5) in g/cm2 at the femoral neck, spine and hip, respectively, although the study was performed at a different location. Three years postoperatively, she continues to report a resolution in symptoms since her surgery, particularly in fatigue and mental clarity, yet remains hypoparathyroid (calcium 7.8 mg/dL; PTH 4 pg/mL) and on treatment with calcitriol and calcium. She had an uncomplicated pregnancy resulting in a healthy male child whose calcium so far has not been tested. Her mother remains asymptomatic.

PMC3514804_01

Male

A 23-year-old Caucasian male was admitted to the emergency department of our hospital due to severe left upper quadrant abdominal pain. His medical history was free, and no recent trauma was reported. Clinical examination revealed no pyrexia, heart rate at 90 per minute, and normal blood pressure. Upon physical examination, upper abdominal tenderness was revealed. On auscultation, abdominal sounds were present. Rectal examination showed an empty rectum. The emergent laboratory tests revealed the following: WBC 24350/mm3, hemoglobin 14,2 g/dl, platelets 278000/mm3, c-reactive protein 17 mg/dl, Tbil 1,9 mg/dl, Dbil 0,28, ast 27 IU/L, alt 42 IU/L, and creatinine and electrolytes were normal. An abdominal ultrasound showed splenomegaly (17,27 x 8,7 cm) and free fluid in the left iliac fossa and in pelvis (Figures 1 and 2). The urgent abdominal computerized tomography (CT) confirmed an enlarged spleen and showed a splenic hematoma with the presence of free fluid in the paracolic gutters and pelvis. There was a hyperdense component within the free fluid, indicating hemoperitoneum (Figure 3). The patient was managed conservatively because of his hemodynamic stability. The diagnosis of primary CMV infection was made with positive IgM anti-CMV antibodies. He was under close monitoring and surgical supervision. He was hemodynamically stable all the time, and two weeks later a new CT of the abdomen was arranged. CT demonstrated the same splenic hematoma and a little resolution of the peritoneal effusion (Figure 4). After a period of prolonged bed rest (twenty days), the patient was discharged from the hospital with the advice to avoid extreme sports and activities. Five months later, followup with ultrasound examinations showed progressive resolution of the splenic hematoma and complete resolution of the peritoneal effusion.

PMC4374200_01

Female

A 26-year-old young female with end-stage renal disease due to focal segmental glomerulosclerosis on maintenance hemodialysis was admitted for malignant hypertension to our Nephrology department. She was known to have tuberculous lymphadenitis and was on antituberculosis therapy for the preceding 4 months. On the day of admission, she had an episode of generalized tonic clonic seizures for which she was given 1 gram of phenytoin intravenously as loading dose and was continued on 300 mg PO daily. After 2 weeks, she was noted to have neutropenia (Absolute neutrophil count- <1000/mm3). She was evaluated for neutropenia and filgrastim 300 mcg was injected subcutaneously. Within a few hours of injection she reported itching around the site of injection and swelling of eyes, facial swelling, and itchy red rashes over the lips, face, upper and lower back [Figure 1]. Erythematous papules over legs, hands and several bullae and purpuric lesions over the palm, sole and feet were observed [Figure 2]. She developed desquamation of skin involving >80% of the skin surface and mucosa. There was no involvement of the eyes. So both phenytoin and filgrastim were withdrawn immediately. A skin biopsy was performed, which showed ulcerated epidermis with necrotic keratinocytes with acrosyringeal extension and few eosinophils overlying focally necrotic and edematous papillary dermis with neutrophil and lymphocytic infiltrate, melanin drop out along with perivascular lymphocytosis and adnexal structures. Subepidermal bulla was seen with focal in growth of epidermis [Figure 3]. It was suggestive of TEN. The patient was shifted to ICU and was treated with intravenous immunoglobulin (IVIG) 2 g/kg over 5 days and steroids with prophylactic antibiotics. Daily dressing was performed. She was continued on hemodialysis during the hospital stay and gradually her skin lesions improved significantly [Figure 4]. Presently she is doing well and is on maintenance hemodialysis.

end stage renal disease, filgrastim, hemodialysis, phenytoin, toxic epidermal necrolysis

PMC6503138_01

Female

A 40-year-old female came to our clinic with the chief complaint of inability to flex her right elbow. Her elbow motion limitation was accompanied by pain. Six months prior to her first visit to our clinic, she was involved in a motorcycle accident. She was immediately brought to a rural hospital and was diagnosed with open fracture (Gustillo-Anderson grade IIIA) of the right distal third of humerus (AO12.C3). According to the operation report, the patient underwent debridement and external fixation. Afterward, she was discharged from the hospital. Unfortunately, due to economic condition, she was unable to comply for regular post-operative visits to the outpatient clinic for follow-up. Six months later, the patient was referred to our hospital because there is no sign of healing at the fracture site and the patient was unable to flex her elbow with pain. At her first visit to our clinic, the examination revealed tenderness at the right distal third of the humerus with limited elbow flexion to only 30 . There was no sinus, pin tract infection or any sign of inflammation at the site of injury. The patient's expectation was to have her elbow pain-free and able to flex beyond 90 . A plain x-ray was made as shown in Fig. 1. From the x-ray, there was no sign of union or any bridging callus with some bone loss. No halo-sign was found in the pin or screw insertion sites. The patient underwent surgery of removal of all of the implants from the bone followed by debridement of the nonunion site. The viability of the bone ends and the surrounding soft tissue was examined intraoperatively. It revealed that the nonunion site was actually well-vascularized as shown by adequate surface bleeding. After thorough debridement, removal of devitalized tissues, and freshening of nonunion sites, a bone defect of 5-centimeter long was found. The necessary components of tissue engineering to treat the bone defect were prepared. Freeze-dried cancellous bone allograft (Fig. 2a) and autologous platelet-rich plasma (PRP) (Fig. 2b) were processed and prepared before the operation by the Biomaterial Center and Tissue Bank of our hospital. The freeze-dried cancellous bone allograft had been processed according to the standard protocols of American Association of Tissue Bank (AATB), European Association of Tissue Bank (EATB), and Asia Pacific Association of Surgical Tissue Bank (APASTB). Ten-milliliter aspirated bone marrow was retrieved from the patient's iliac crest. The bone defect was filled with the combination of bone marrow aspirate, cancellous bone allograft, and PRP (Fig. 2c and d). To secure it from leaking away, fibrin glue was used to seal the filled defect (Fig. 2e). Lastly, internal fixation with plate and screws was done to achieve stability of the nonunion site. (Fig. 2f). After the operation, the patient was regularly examined in the outpatient clinic to observe for any pain and sign of infection. The pain subsided as the healing progressed. There was no sinus or infection found at the surgical site. Radiographic images for three, six and twelve months were made to monitor callus formation (Fig. 3). As the healing progressed, the x-ray showed the formation of bridging callus at the defect site. The bone graft was slowly resorbed and replaced by the formation of new bridging callus. Twelve months after surgery, the x-ray showed thicker bone formation (Fig. 3c). The patient was really satisfied because she could finally flex her right elbow beyond 90 to her expectation (Fig. 4).

bone marrow aspirate, case series, critical-sized bone defect, tissue engineering

PMC7160763_01

Male

An 83-year-old man was admitted to our hospital for evaluation of general malaise. He had a 10-year history of chronic atrial fibrillation and hypertension and had been treated with candesartan (8 mg/day) and warfarin (2 mg/day). Two weeks before presentation, the patient had visited a urologist because of transient urinary tract hemorrhage. Detailed examination had shown no abnormalities of the urinary tract. He had been advised to drink enough water to prevent urinary obstruction by blood clots for 1-2 weeks. In response, the patient started drinking about 4 L of water per day. One week later, he became aware of fatigability and gait disturbance but continued drinking extra water. His symptoms gradually worsened until he was admitted to the general medicine department of our hospital. The patient had no relevant medical or family history. He was a non-smoker and non-drinker. On admission, the patient's weight was 58 kg and his blood pressure was 102/72 mmHg. He was alert and afebrile. The patient complained of gait disturbance, but physical and neurological examination showed no abnormalities. Electrocardiography showed atrial fibrillation. Plain computed tomography of the neck, chest, and abdomen showed no significant abnormalities. Notably, laboratory tests showed a markedly decreased serum sodium level (105 mEq/L, normal: 138-145 mEq/L). Plasma and urine osmolality were 225 and 140 mOsm, respectively. Urine sodium level was undetectable. Levels of plasma adrenocorticotropic hormone, cortisol, and antidiuretic hormone were normal, suggesting the possibility of water intoxication. The patient received 0.5 L of normal saline solution in the emergency department and was transferred to a general medicine bed 4 h after emergency department presentation. His serum sodium level increased by 4 mEq/L over 4 h. Administration of 5% glucose solution was started at a rate matching urine output to prevent a further increase in serum sodium level. On day 2, the patient's serum sodium level rose to 113 mEq/L. His serum sodium level on day 3 was 121 mEq/L. Thereafter his serum sodium level increased by 5 mEq/L per day. On day 5, the patient's serum sodium level was 130 mEq/L. He was alert and was improving. However, he suddenly developed twitching of the left arm lasting for 30 s, consistent with FIAS, followed by FTBTCS lasting for about 40 min. Assisted ventilation was started; intravenous diazepam (10 mg) was administered twice but was ineffective. Therefore, intravenous fosphenytoin sodium (1300 mg) was subsequently administered. FTBTCS stopped after administration of the first dose of fosphenytoin. However, intermittent twitching of the left arm with impaired awareness resulting from FIAS continued several times per hour, with each episode lasting more than 5 min. Moreover, the patient had five episodes of recurrent FTBTCS lasting for about 30 min each in the first 24 h with prolonged impaired awareness, despite the addition of continuous intravenous fosphenytoin (400 mg/day). Ictal electroencephalogram (EEG) during FTBTCS showed bilateral polyspikes but was obscured by artifact; ictal EEG during FIAS showed rhythmic 5-9 Hz theta activity in the right frontotemporal region (data not shown). EEG recorded during an interseizure period revealed irregular right frontal sharp waves with theta and delta activities (Figure 1). Magnetic resonance imaging (MRI) of the brain showed no obvious signs suggesting osmotic demyelination syndrome (ODS); however, marked atrophy of the hippocampus and temporal lobe was seen (Figure 2). Further questioning of the patient's family revealed that he had been diagnosed with AD 2 years before admission. Although atrophy of the hippocampus and temporal lobe has been associated with seizures in patients with AD, no symptomatic epileptic seizures had been recognized before hospitalization. On day 6, the frequency of FTBTCS decreased, but intermittent FIAS and FTBTCS did not completely disappear. Correction of hyponatremia was suspended to lower serum sodium to 125 mEq/L. Fosphenytoin administration was discontinued and was replaced with intravenous levetiracetam (1000 mg/day); however, FTBTCS continued intermittently. The addition of perampanel (4 mg/day) and clonazepam (3 mg/day) to levetiracetam was ineffective at controlling seizures. Administration of lamotrigine (200 mg/day), carbamazepine (600 mg/day), and levetiracetam (1000 mg/day) on day 7 was also ineffective. Continuous intravenous infusion of midazolam (5 mg/h) was introduced to treat SE on day 8. Thereafter, both FIAS and FTBTCS subsided. Repeat MRI of the brain on days 7, 14, and 28 revealed no obvious lesions suggesting ODS on diffusion-weighted, T2-weighted, or fluid attenuation inversion recovery imaging. Reduction of the midazolam dose was not possible because of relapsing seizures. The patient's general status gradually deteriorated; he died of aspiration pneumonia on day 58.

alzheimer’s disease, focal impaired awareness seizures, focal to generalized tonic-clonic seizures, hyponatremia, status epilepticus

PMC4753335_01

Male

A previously healthy 11-year-old boy was admitted to our hospital with a 20-day history of low back soreness and difficulty walking and sitting up. There was no history of trauma, tooth extraction, or spinal surgery, but the patient had reported an episode of fever (39 C) within the previous 3 weeks. On examination, he had no fever, complained of lumbar soreness which was exacerbated by forward flexion of the trunk, and presented paraspinal muscle spasms. The neurological examination was otherwise normal. Laboratory tests revealed a serum WBC count of 9,800 leucocytes/mm3 (normal range is 4,500-13,500 leucocytes/mm3), a CRP (C-reactive protein) level of 35 mg/L (normal < 10 mg/L), and an ESR (erythrocyte sedimentation rate) of 48 mm/h (normal range 0-10 mm/h). Lumbar radiographs did not show any spinal lesions (Figure 1). An MRI (magnetic resonance imaging) scan revealed an abscess in the L3 vertebral body with an adjacent vertebral body hyperintensity indicative of a bone marrow oedema. There was also an extension to the soft tissues, with an intense oedema visible at the level of the right psoas (Figure 2). These findings were suggestive of a vertebral osteomyelitis without infectious intervertebral disc (IVD) damage. Because tuberculosis or a bone tumour could not be definitively ruled out, a surgical navigation-assisted aspiration biopsy of the L3 vertebral body was performed using a posterior transpedicular approach (Figure 3). The patient was stepped down to i.v. Flucloxacillin (1 g three times daily) monotherapy as soon as the aspiration biopsy was realized. Three days after admission, standard blood culture was positive for methicillin-sensitive Staphylococcus aureus (MSSA), and cultures of vertebral bone aspirate yielded growth, thus confirming MSSA as the pathogen. Bacteriological investigations demonstrated that the responsible strain of MSSA was resistant to penicillin G but sensible to all other tested antibiotics (Flucloxacillin, Gentamicin, Ciprofloxacin, Clindamycin, Erythromycin, Cotrimoxazole, Fosfomycin, Rifampicin, Tetracycline, Vancomycin, Teicoplanin, and Linezolid). Imaging studies confirmed that there was no evidence of endocarditis. Three additional sets of postoperative monitoring blood cultures were also positive, continuing up until 8 days after the surgical procedure. A standard X-ray of the lumbar column was carried out 4 days after surgery and revealed a sudden 30% decrease in the height of the disk space, together with erosions of the adjacent vertebral endplates (Figure 4). The patient went on to complete a two-week course of i.v. Flucloxacillin (1 g three times daily), followed by a four-week course of orally administered Clindamycin (30 mg/kg/j). He responded well to antibiotics and body orthosis and showed clinical and laboratory improvement durably after the end of antibiotic treatment. Nevertheless, 2 months after surgery, a new X-ray revealed a considerable progression of the initial lesion which now included the vertebral body of L4 as well as the L3-L4 disk; there had been complete collapse of the disc and major erosion of the upper vertebral endplate of L4 (Figure 5). Nevertheless, the patient no longer reported low back soreness and he was able to move freely.

PMC9325874_01

Female

A 58-year-old woman admitted to an outpatient department with erythematosus and mild itching on her right cheek for six months was reported. She had type 2 diabetes and was being treated with metformin and glimepiride. Her fasting blood sugar remained slightly high, fluctuating around 8.0 mmol/L. She reported no personal or family history of tuberculosis. Further investigation revealed that she had stable, fingernail-sized erythema on her right cheek for 20 years. It did not change until six months ago, and her facial lesions expanded significantly. Physical examination of her right cheek revealed erythema, papules, and slight desquamation (Figure 1). The patient said there had been pustules and exudation when the disease worsened early. A T-cell spot test of MTB showed positive. Skin biopsy histopathology showed mild epidermal hyperplasia, with several epithelial cell masses of different sizes in the superficial and deep dermis. Lymphocytes were infiltrated around, and the boundary was clear. Caseous necrosis was not observed (Figure 2A and B). Direct immunofluorescence test showed that IgG basal membrane was suspiciously weak positive (+-), and IgM, IgA, and C3 were negative (-). Findings on computed tomographic (CT) scan of her chest were normal. The positive colonies that grew on the Lowenstein-Jensen medium tissue sample inoculated after 35 days at 37 C were identified as MTB by PCR and DNA sequencing and acid-fast bacilli staining (Figure 3). And the tissue samples were also inoculated on the Sabouraud dextrose agar (SDA) plate at 28 C. The positive colonies that grew on the medium after ten days were identified as Candida albicans (Figure 4). Microscopic examination of the local erythema fungus on the face showed positive hypha. Although infection of the face is a rare extrapulmonary manifestation of tuberculosis, it is exceptional to have a concurrent infection with Candida albicans at the same site. It is an essential consideration for a patient with type 2 diabetes who has a history of poor glycemic control. Itraconazole 0.2 g bid was administered for seven days, and rifampicin 0.45 g qd, isoniazid tablet 0.3 g qd, and ethambutol hydrochloride 0.25 g tid were administered for five months (Figure 5).

candida albicans, facial erythema, lupus vulgaris

PMC7365499_01

Female

We received a bone marrow biopsy measuring 2 cm in length in the Hematology Unit of the Department of Pathology along with the requisition form mentioning the following clinical details: 7-year-old girl, resident of New Delhi, India, and clinical features - fever on and off associated with weakness and abdominal distension for the past 3 weeks. Physical examination revealed pallor and hepatosplenomegaly with no significant lymphadenopathy. Laboratory data showed pancytopenia with a hemoglobin level of 8.7 g/dl, the total leukocyte count of 3400/mm3, and a platelet count of 44,000/mm3. Peripheral smear showed microcytic hypochromic blood picture. Bone marrow aspiration finding reported from an outside center was of hypocellular marrow. Human immunodeficiency virus serology, hepatitis B surface antigen, antibodies against hepatitis C virus, the Epstein-Barr virus, cytomegalovirus, measles, Widal test, K39 test for visceral leishmaniasis, and rapid diagnostic tests (RDTs) for malarial antigen were negative. Her blood, urine, sputum, and stool cultures were sterile. The chest X-ray and the cerebrospinal fluid study were normal. The bone marrow biopsy that we received was routinely histoprocessed and stained with hematoxylin and eosin stain. Low power microscopic examination of the sections revealed an adequate bone marrow in length with normal bony trabeculae. The marrow was normocellular for the age [Figure 1a]. High-power view of the trephine biopsy exhibited sheets and clusters of histiocytes. These were large cells with abundant pale staining bubbly cytoplasm and a small nucleus. No pleomorphism or any prominent nucleoli were seen. These histiocytes were seen admixed with an increased number of erythroid precursors and lymphocytes. The rest of the marrow hematopoietic elements were suppressed [Figure 1b]. Many of these marrow macrophages demonstrated phagocytosis of red cells, white cells, platelets as well as immature myeloid and erythroid cells (hemophagocytosis) [Figure 2a]. Some of these histiocytes also revealed the presence of a brown-colored pigment [Figure 2b]. Based on these findings, a tentative diagnosis of a mononuclear phagocytic system disorder/histiocytosis was made. Special stains and immunohistochemistry (IHC) were applied for ruling out various differentials under this category of disorder such as storage histiocytosis, dendritic cell-related, inflammatory, and malignant histiocytosis. On IHC, the histiocytes were positive for CD68 and negative for CD1a, S100, CD3, CD20, epithelial membrane antigen, and pancytokeratin, confirming the histiocytic nature of these large cells and ruling out the possibility of dendritic cell-related (Langerhans cell histiocytosis) and malignant histiocytosis [Figure 3a-c]. However, on IHC, a finding that was evident was the CD3 positive immunoexpression of the increased lymphocytes [Figure 3d]. Among the special stains, the periodic acid-Schiff (PAS) stain, Oil red O stain, and Perl's iron stain were put. These histiocytes were negative for both the PAS stain as well as the Oil red O stain [Figure 4a], thus ruling out any storage histiocytosis. Another finding that was revealed on Perl's iron stain was that not all histiocytes containing the brown pigment demonstrated hemosiderin, and in most of them, the brown pigment remained unstained [Figure 4b]. Based on all these findings, we arrived at a diagnosis of inflammatory histiocytosis HLH. A detailed clinical history as well as examination of the child was done as she came with her father to fetch the bone marrow report as her condition was deteriorating day by day. Her birth, family, and past medical or any treatment history was non-contributory. There was no history of contact with tuberculosis, measles, allergy, or any blood transfusion. Currently, she appeared lethargic and had fever with abdominal distention. On physical examination, she was febrile with a temperature of 39.5 C, pale, and had a palpable spleen (6 cm below the left costal margin) and a liver (liver span of 15 cm). The rest of the clinical examination was unremarkable. Her blood sample was taken for hematological investigations. The current complete blood count revealed pancytopenia with hemoglobin of 7.4 g/dL, total leukocyte count of 2500/mm3 (differential being N - 30%, L - 60%, M - 9%, and E - 1%), and a platelet count of 50,000/mm3. Other indices included were red blood cell count of 2.7 million/mm3, mean corpuscular volume - 59 fl, mean corpuscular hemoglobin (MCH) - 20.3 pg, MCH content - 27.8 g/dl, red cell distribution width - 20.7%, and a corrected reticulocyte count of 3.9%. The peripheral smear revealed fragmented red blood cells and on careful examination, schizonts of P. vivax [Figure 5a]. Biochemical tests revealed elevated ferritin (989 mg/dL) and lactate dehydrogenase levels (1022 mu/L) with high triglyceride at 4 mmol/L. Serum haptoglobin and plasma fibrinogen levels were reduced (0.02 g/l and 132 mg/dl, respectively). Glucose-6-phosphate dehydrogenase activity was normal. Renal function tests were normal; however, the liver function tests were deranged. Ultrasonography revealed enlarged liver and spleen. Meanwhile, the trephine biopsy was treated with alcoholic ammonium hydroxide, to which the brown pigment responded by getting bleached, hence, confirming the nature of this pigment to be that of malarial pigment (hemozoin) [Figure 5b]. Based on the clinical, hematological, histopathological, and immunohistochemical parameters, a final diagnosis of pancytopenia due to HLH as a result of P. vivax infection was estabilished. Due to the cost and unavailability, local perforin mutation studies and soluble interleukin (IL) level estimation tests were not performed. The child was administered oral chloroquine and primaquine along with iron supplements. Her condition dramatically improved within few days as she became afebrile, her laboratory parameters such as serum ferritin and fibrinogen levels improved gradually, and the liver and spleen reduced in size. She was discharged in a stable condition (hemoglobin of 10.8 g/dl, total leukocyte count of 10,600/mm3, and a platelet count of 198,000/mm3), and so far, her follow-up period has been uneventful.

bone marrow biopsy, plasmodium vivax, hemophagocytic lymphohistiocytosis, malaria, pancytopenia

PMC3620812_01

Male

A five-year-old boy presented to the emergency room (ER) with a 6-day history of fever, rhinorrhea, worsening cough, emesis, back and abdominal pain, decreased appetite, and headache. In the ER, he was found to have a temperature of 38.5 C-39.5 C, a respiratory rate of 60 breaths per minute, a heart rate of 140 beats per minute (bpm), blood pressure of 108/65, and an oxygen saturation of 96%-98% on 1/2 lpm of O2. He was tachypneic, with audible grunting, suprasternal retractions, a clear chest, mild tenderness at right upper and lower abdominal quadrants, but no guarding or rebound tenderness or hepatosplenomegaly, and no rashes. Laboratory values included a white blood cell count of 20 x 109/L, hemoglobin count of 122 g/L, platelet count of 462 x 09/L, absolute neutrophil count of 17 x 109/L, absolute lymphocyte count of 1.26 x 109/L, normal chemistry, elevated glucose of 9 mmol/L, urinalysis with glucose > 55 mmol/L and ketones. A chest X-ray (CXR) revealed right middle lobe pneumonia (Fig. 1). He was admitted to hospital and treated with intravenous ceftriaxone (75 mg/kg/day for 9 days), azithromycin (5 mg/kg/day po for 5 days) and vancomycin (20 mg/kg/day for 9 days, adjusted to a trough of 15-20). Twenty-four hours later, due to persistent respiratory distress and increased chest pain, a repeat CXR was done and revealed extensive parenchymal involvement, mediastinal shift and a large effusion (Fig. 2). Ultrasounds of the chest and abdomen confirmed the pleural effusion, and revealed mild splenomegaly. In contrast to the degree of effusion, this child exhibited initially only moderate distress and did not appear toxic. A chest tube was inserted because of progressively worsening distress, and straw-colored pus was drained. The fluid was sent for cell count (white blood cell (WBC) 315, neutrophils 57%, platelet 7.5% red blood cell (RBC) 1210), protein (26), albumin (16), lactate dehydrogenase (LDH; 1308), lipase (17), amylase (32), gram stain (negative), culture (negative), streptococcal pneumonia polymerase chain reaction (PCR; negative), fungal culture (negative), mycobacterial culture (negative), viral culture (negative), and TB culture (negative). Blood drawn at the same time revealed a lipase of 16, amylase of 23, LDH of 168, and protein of 54. Other tests included a negative throat culture, a negative stool viral culture, negative blood culture, negative nasopharyngeal aspirate for respiratory viruses, antistreptolysin O titer (ASOT) of 134, antideoxyri-bonuclease-B (DNase B) titer < 50, and EBV titers suggestive of past infection. Nasopharyngeal aspirate was positive for mycoplasma pneumonia by PCR. There was a gradual improvement in his respiratory status during the following week and he was discharged after 9 days on amoxicillin-clavulanate (45 mg/kg BID for 7 days), followed by amoxicillin prophylaxis (250 mg po BID). Past medical history was significant for recurrent skin and respiratory infections, including a left elbow abscess requiring drainage and oral antibiotic treatment (at the age of 5 months), pneumococcal bacteremia presenting with fever and emesis (at the age of 7 months), a retropharyngeal abscess (at the age of 9 months), and pneumonia (at the age of 3 years). Developmental history was unremarkable, and current weight was 17 kilograms (>15th percentile). The parents are second cousins of Moroccan origin, and there is a healthy older brother. Given the history of recurrent severe infections, he was initially evaluated at the age of 3 years by the immunology service at the Montreal Children's Hospital. His immune evaluation revealed a normal complete blood count (CBC), normal lymphocyte subsets, normal T cell proliferation to mitogens, normal serum IgG/A/M/E levels, and protective post-vaccination antibody titers to tetanus, diphtheria, hemophilus influenza, and streptococcus pneumonia. A dihydrorhodamine (DHR) test for phagocytic function was normal. Complement studies including CH50, AH50, C3, and C4 levels were normal, but there was absent activity through the mannose binding lectin (MBL) pathway for complement activation. With reproducible absence of functional MBL activity, DNA was sent for genetic analysis to identify known mutations associated with MBL deficiency. Results demonstrated a compound heterozygosity for two haplotypes in the MBL2 gene in this child. Both haplotypes identified, LYPB and LYQC, are associated with very low mannose binding protein levels. An additional polymorphism in the MBL promoter was also identified. Given the history of significant infections associated with genetic and functional diagnosis of MBL deficiency, recommendations for management included antibiotic chemoprophylaxis, optimization of protection through routine vaccination, prompt investigation and treatment of infections, and regular immunology clinic visits to reduce the risk of long-term complications. At the time of his current admission to hospital the child was taking no regular medication, and despite repeated attempts of the immunology service to contact the family, he had been lost to follow-up. As a result, the family was not fully aware of the implications of his immunodeficiency and did not relay his underlying diagnosis to the ER staff.

complement, immunodeficiency, innate immunity, mannose binding lectin, pneumonia

PMC4062235_01

Female

A 41-year-old Thai female presented to her primary physician with a history of right upper quadrant pain. While the pain had been present for several years, it had worsened considerably over the past year, prompting her to seek medical attention. The patient denied weight loss, but did complain of low-grade fevers and chills. Her past medical history was unremarkable. The patient was born in Thailand and had migrated to the United States 6 years ago. On physical examination, she was noted to be afebrile and his other vital signs were normal. There were no significant findings on examination of his lungs, heart, or abdomen. Her laboratory studies results were as follows: white blood cell count 7.4/mm (reference range: 3.8-10.8/mm), hemoglobin 11.8 g/dL (reference range: 13.2-17.1 g/dL). Her white blood cell differential count was normal. Her sedimentation rate was elevated at 45 mm/h (reference range: 0-20 mm/h). Other studies including serum chemistries, liver function tests, and blood cultures were non-revealing. Gastrointestinal tumor markers carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) were both within normal limits. Her chest radiograph was normal. On abdominal computed tomography (CT) scan demonstrated a 5.1 cm x 2.8 cm multi-loculated solid lesion in the head of the pancreas concerning for a primary malignancy along with several enlarged lymph nodes in the peripancreatic region. An endoscopic ultrasound (EUS) was performed which revealed a 4.3 cm x 2.5 cm hypoechoic, homogenous mass lesion with a cystic component within the pancreatic head (Fig. 1). In addition, an oval, 1.1 cm x 1.2 cm heterogeneous lymph node adjacent to mass was seen (Fig. 2). EUS- guided fine needle aspiration (EUS-FNA) of the lesion was performed with 25-G needle. Cytology from the mass revealed necrotizing granulomatous inflammation with no evidence of malignancy. The acid-fast bacilli (AFB) stain was negative. Subsequently, the AFB culture was found to be positive for Mycobacterium tuberculosis complex from the pancreatic mass cell block and found to susceptible to ethambutol, isoniazid, pyrazinamide and rifampin. She was treated with these 4 drugs for 2 months followed then rifampin and isoniazid for a further 7 months. At the end of therapy, her abdominal pain and fever had resolved and she maintained a normal appetite and weight.

endosonography, fine needle aspiration, tuberculosis

PMC3618090_01

Female

A 42-year-old woman was diagnosed with a KIT-positive high-risk GIST of the jejunum (18 cm diameter, 50 mitoses/50 high-power field) with synchronous peritoneal metastasis. She underwent segmental resection of the jejunum and duodenum, infragastric omentectomy, pelvic peritonectomy and excision of the bladder peritoneum resulting in complete removal of gross disease which was then confirmed by 18F-FDG-PET. She was put on postoperative IM 400 mg/day. Progressive recurrent peritoneal disease was diagnosed and resected 8 months later, followed by dose escalation of IM to 800 mg/day. At 16 months from initial diagnosis, 1 suspicious PET-positive supraclavicular lymph node was removed surgically and showed caseating granulomatous inflammation consistent with tuberculosis. PCR examination confirmed infection with Mycobacterium tuberculosis (fig. 1, fig. 2). Bronchoscopy with bronchoalveolar lavage (BAL) was performed, but PCR and culture were negative for M. tuberculosis. She was started on antituberculous triple therapy with isoniazid, rifabutin and pyrazinamide for 2 months, followed by isoniazid and rifabutin for an additional 4 months. Throughout, IM levels were monitored to ensure sufficient IM exposure during the antituberculous treatment. IM 800 mg was continued for a further 8 months and then had to be stopped because of intra-abdominal progression. During the next 15 months, the patient was switched to sunitinib, sorafenib and nilotinib because of progressive disease. There was no evidence of reactivation of tuberculosis until her death 29 months after initial diagnosis.

gastrointestinal stromal tumor, glivec, granuloma, imatinib mesylate, pet-ct, tuberculosis

PMC3618090_02

Male

A 62-year-old man underwent enucleation of a submucosal tumor of the stomach. Histological evaluation revealed an intermediate-risk GIST. He developed an abdominal recurrence 7 years later. After neoadjuvant IM treatment (400 mg/day) for 8 months, resection of the stomach antrum, gallbladder and atypical resection of the liver (segment III) was performed. One month later, a subcarinal lymph node with increased FDG uptake on PET-CT was detected and suggested metastatic disease. Mediastinoscopy was performed and lymph node biopsy showed granulomatous disease with focal necrosis suggestive of sarcoidosis or tuberculosis (fig. 1, fig. 2). During IM treatment, new lung lesions appeared leading to surgical removal of the lesions. Histological examination showed near totally regressing lung metastasis from GIST, but no evidence of granulomatous disease. He has since remained in continuous complete remission on IM for more than 38 months. The lymph nodes showed decreasing FDG uptake on follow-up FDG-PET-CT. Periodic CT scans did not show any new lymphadenopathy.

gastrointestinal stromal tumor, glivec, granuloma, imatinib mesylate, pet-ct, tuberculosis

PMC7657701_02

Male

The second patient was an 18-year-old male, who, actually, was a roommate to the first patient, and admitted because of fever (38 C), pharyngodynia, and arthritis of the ankles during the last five days. The patient was also of Pakistani descent, immigrant to Greece for the last six months, and currently is occupied as a field worker. His symptoms began three weeks after those of the first patient. He reported never receiving medical care since early childhood, while he denied any current or past alcohol abuse, herbal or supplements, and nasal or intravenous drug use. Clinical examination revealed pharyngitis, warm, swollen, and painful ankle joints, hepatomegaly (2 cm below the right subcostal margin), and a loud precordial systolic and diastolic murmur (3 out of 6, Levine scale). Laboratory work-up on admission revealed high serum levels of acute phase reactants, anemia, polyclonal hyperglobulinemia, and mild transaminasemia in both patients, while in the second case, additional cholestasis and hypoalbuminemia were recorded (Table 2). The remaining hematological, microbiological, and biochemical parameters including blood, stools, and urine cultures, as well as autoantibodies related to autoimmune rheumatic diseases including antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factors, antibodies against cyclic citrullinated peptides, and ferritin levels, were within normal limits in both patients. Multiple stool samples were also negative for ova and parasites such as Enterobius vermicularis, Entamoeba histolytica, Cryptosporidium, and Giardia species. Examination of the ankle joint synovial fluid showed increased neutrophil counts (patient 1: 21,600 neutrophils; patient 2: 24,000 neutrophils). X-rays of the chest and affected joints were unremarkable. Of note, patient 2 had an abnormal electrocardiogram (ECG) with third-degree atrioventricular block that, during hospitalization, interchanged with first-degree block and Mobitz I (Figure 1), even though he was completely asymptomatic. Accordingly, the differential diagnosis was built in three major pillars. The first included infectious diseases manifesting with arthritis according to our local endemicity, the young age, and the epidemiological background of the patients. Actually, a serological work-up for zoonosis (Brucella, Coxiella, Rickettsia, Borrelia, Leptospira, Leishmania, and other parasites including investigation for Trichinella, Entamoeba, and Echinococcus), sexually transmitted diseases (syphilis, N. gonorrhoeae, U. urealyticum, M. hominis, and C. trachomatis), viral hepatitis A, B, C, and E, and human immunodeficiency virus tested negative. Tropheryma Whipple infection (Whipple's disease), which can be presented with arthritis that predates gastrointestinal symptoms, was also excluded by a polymerase chain reaction (PCR) assay performed in the synovial fluid. Tuberculosis was also ruled out based on a negative chest X-ray, negative tuberculin test, and negative synovial fluid microscopy and culture. Furthermore, the presence of aseptic arthritis was confirmed on the basis of a negative 16sRNA PCR test as we described previously along with sterile synovial fluid cultures. The second pillar included diverse autoimmune rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, and ankylosing spondylitis which were excluded on the absence of several clinical and laboratory criteria. The third clinical entity which was considered highly likely in both cases was ARF with or without accompanied infectious endocarditis. In the first patient, infectious endocarditis was excluded based on repeatedly negative blood cultures and transesophageal echocardiogram (TOE) confirming the absence of structural valve disorders. The second patient had established valvular heart disease and possible endocarditis since TOE revealed bicuspid aortic valve with regurgitation (3+/4) and stenosis (peak gradient 67.2 mmHg) with possible presence of vegetation, mitral valve regurgitation (2+/4), and moderate stenosis along with moderately dilated left ventricle. However, multiple blood cultures were sterile though the safer way to exclude infectious endocarditis in patient 2 would be surgical excision and valve tissue culture. As expected, throat cultures and rapid antigen tests for GAS were negative in both patients. However, GAS was isolated in the pustular fluid culture from patient 1, while ASTO titers were elevated in both patients (Table 2). The diagnosis of ARF in the first patient was based on the presence of one major (polyarthritis) and two minor (fever >= 38.5 C, ESR >= 60 mm, and CRP >= 3 mg/dL) RJC while in the second patient was based on the presence of established RHD and two major (carditis and oligoarthritis) and two minor RJC (fever >= 38.5 C, ESR >= 60 mm, and CRP >= 3 mg/dL). With respect to treatment, patient 1 received intravenous vancomycin (15 mg/kg/bd) and ceftriaxone (2 g bid) till culture reports and oral indomethacin for 14 days for pain relief. He was discharged in good health with recommendation to receive benzathine penicillin G (1.200.000 IU) intramuscularly every twenty-eight days for at least 5 years in an attempt to prevent recurrent ARF episodes. Patient 2 received oral indomethacin for 14 days for pain relief along with intravenous ceftriaxone (2 g bid) and vancomycin (15 mg/kg/bd) for six weeks as endocarditis could not be safely excluded at the clinical ground. Subsequently, the patient submitted to aortic valve replacement with a mechanical valve. The presence of vegetation was not confirmed during surgery, and the tissue culture was sterile. The patient was discharged in good health with recommendation to receive lifelong chemoprophylaxis with azithromycin (250 mg qd) in an attempt to prevent recurrent ARF episodes. After one-year of follow-up, both patients are still in good health afebrile, without joint involvement or new ARF episode, while the laboratory markers are steadily normal. Both patients gave written informed consent for potential publication at the time of discharge.

PMC2919746_01

Female

Screening of household contacts at the mother's residence revealed a 12 year old female cousin with night-sweats, marked weight-loss and significantly productive cough for the previous six months. Her sputum was smear-positive for acid-fast bacilli. Culture revealed a fully susceptible M. tuberculosis strain on sputum culture and on fine needle aspirate biopsy of a lymph node. She was admitted to an in-patient TB hospital in Cape Town. All other household contacts tested negative for pulmonary TB. Household contacts at the father's residence in Hermanus could not be traced for testing.

PMC2919746_02

Male

The father of the index case was first diagnosed with pulmonary TB at a local clinic in Cape Town when the index case was 9 months old. Microscopy of his sputum showed 3+ acid-fast bacilli (AFB) and cultured M.tuberculosis, however drug susceptibility testing was not performed. He was started on standard 4-drug TB therapy but defaulted. One month after the index case had died, the father presented to a primary care clinic in Hermanus outside of Cape Town. At that assessment, his sputum showed 3+ AFB and cultured M.tuberculosis. However DST was again not requested even though the South African National TB Programme guidelines require DST in cases of retreatment due to previous non-compliance. Clinic staff empirically started him on regimen 2 (INH, rifampicin, pyrazinamide, ethambutol and streptomycin) because of his previous non-compliance. Clinic records confirmed daily attendance and adherence to TB therapy. A chest radiograph (CXR) was performed six months after starting regimen 2 because he was still severely symptomatic (productive cough, weight loss and night sweats). His CXR showed multiple cavities in his right upper lobe with bronchiectatic changes, and a right pleural effusion. This occurred despite documented directly observed compliance on regimen 2 for six full months. For the first time, his sputum was sent for TB culture and DST. Unfortunately, multiple sputum specimens did not culture M.tuberculosis, and therefore routine DST could not be done. Since he continued to deteriorate, and since his child had been proven to have had MDR-TB, he was empirically started on an MDR regimen (kanamycin, pyrazinamide, ofloxacin, ethambutol, ethionamide). Unfortunately he experienced significant side-effects and his MDR-TB regimen had to be interrupted. Team discussion regarding the possibility of a right pneumonectomy concluded that he was not a suitable candidate. He remains chronically breathless.

PMC7997763_01

Female

Our patient was a 9-year-old previously healthy girl who presented to the ED with a chief complaint of acute-onset obsessive-compulsive behavior. Eleven days prior to presentation, she became emotionally labile, manifested as sudden episodes of sadness, withdrawal, and unwillingness to participate in social events. Five days prior to admission, her parents observed her displaying ritualistic behaviors such as watching a YouTube commercial 75 times, walking in certain patterns, taking her pajamas on and off a certain amount of times before going to school, picking her lips, and banging her ankles and the side of her abdomen against the kitchen counter. These behaviors would occupy the patient for 4-6 hours, affecting her ability to function normally. She explained that if she did not engage in these behaviors, she would continue to think about them and was worried that something bad may happen to her or her parents. She was also described as having decreased concentration and difficulty performing simple mathematical equations. This was very unusual, as her parents described her as a highly spirited and functional child who is popular at school:participating in advanced math classes, piano, tennis, and gymnastics. Concerned with her behavior, she was taken to her primary doctor whose workup included Epstein-Barr virus (EBV) serology, anti-deoxyribonuclease (anti-DNase), antistreptolysin O (ASO), thyroid function tests (TFTs), complete blood count (CBC), comprehensive metabolic panel (CMP), thyroid-stimulating hormone/thyroxine (TSH/T4), and Lyme serology (all within normal limits). An impression of PANDAS was made, and she went home on amoxicillin and fluoxetine, which she took for two days prior to her presentation to our ED. The family considered stress as a possible contributing factor and spent a weekend away from home for a change in environment. In their hotel room, she would ritualize walking back and forth several times. If she failed to complete these rituals, it would result in emotional outbursts and a strong urge to repeat them. Her ability to eat and drink was also impaired, causing her to become dehydrated and prompting her parents to bring her to the ED. This process took five hours due to her extreme reluctance to leave the hotel room before completing her rituals. Review of systems was significant for the following: constitutional:negative for malaise and weight loss; skin:negative for rash, positive for bruising on ankles and waist; gastrointestinal:negative for vomiting and abdominal pain; neurologic:negative for weakness, neck pain, neck stiffness, paresthesia, and seizures. Family history was significant for anxiety in both parents. Socially, she was living with her parents with strong support from her grandparents who live nearby. No report of sexual abuse, physical abuse, or bullying at school. Her medications included fluoxetine and amoxicillin that were started two days prior to hospitalization by her pediatrician. Allergies included oseltamivir. On examination, she appeared well looking, in no apparent distress. Her vitals were normal; central nervous system (CNS):neck supple, pupils equal and round, reactive to light (PEARRL), cranial nerves II-XII intact, motor, sensation, and power normal; Her affect was normal, and her mood was congruent; Head, eyes, ears, nose, and throat (HEENT):mucous membranes dry; skin:healing bruises on her ankles and waist; cardiovascular, respiratory, and abdominal exams were normal. In the ED, she received maintenance intravenous fluids (IVF) and was admitted to the general pediatrics floor with a presumptive diagnosis of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). She continued to perform rituals in the hospital, requesting the participation of her parents to suppress them. When moving objects in the room, they would need to carry them over her in a certain way several times to complete the ritual without upsetting her. As her admission progressed, her urges became overwhelming, and she ultimately returned to performing the rituals herself. She paced several times across the hospital, resisting the urge to urinate until she had completed the task. This resulted in episodes of pain and distress attributed to acute urinary retention that resolved with voiding. She also regressed developmentally, showing more interest in cartoons targeted for younger children, and continued to refuse to drink, requiring IVF intermittently. Psychiatry, psychology, and neurology services were consulted to help guide the patient's evaluation and treatment. She underwent a series of tests to identify a secondary cause of her presentation. This included a CBC [mild microcytic anemia], CMP [normal], Lyme serology [normal], brain magnetic resonance imaging (MRI) [mild prominence of sulci likely secondary to dehydration], repeat brain MRI about 3 weeks from the first [normal], lumbar puncture (LP) with opening pressure [normal], cerebrospinal fluid (CSF) microscopy and chemistry [normal], CSF autoimmune profile [normal], electroencephalogram (EEG) [normal], serum autoimmune encephalopathy panel [positive for anti-GAD 65 at 0.05, resulted day 16], serum N-methyl D-aspartate (NMDA) antibodies [negative], and M. pneumoniae serum antibodies [IgG and IgM positive, resulted day 3] with confirmatory M. pneumoniae IgM indirect immunofluorescence assay (IFA) [positive, resulted day 3]. Amongst the consulting services, there were varying opinions regarding the diagnosis and treatment of the patient. Psychiatry cited case reports and experiences with patients with M. pneumoniae infections associated with OCD that responded to azithromycin. At their recommendation, azithromycin was initiated for a 30-day course. However, this was discontinued on day 13 because she developed diarrhea in the setting of underlying dehydration, in addition to a lack of clinical improvement. At this time, psychotropic medications were not started so as not to confound the possible response to azithromycin. Psychology attempted a reward system to encourage oral (PO) intake, but she continued to intermittently require IVF due to inadequate intake as a result of interference from her rituals. On day 9 of hospitalization, psychiatry recommended starting intravenous methylprednisolone (1.5 mg/kg/dose), however, no clinical response was observed after a 5-day course. Lorazepam was initiated as needed for agitation and ritual control at this time. Due to the lack of response to the above treatments (azithromycin, reward system, steroids), intravenous immunoglobulin (IVIG) was considered, however not initiated due to a national shortage. The ultimate decision to attempt plasmapheresis was made on day 16 of hospitalization when the anti-GAD 65 was found to be positive. After her first session of plasmapheresis, she showed some improvement: she was able to participate in Halloween activities (trick-or-treat), and her rituals were less repetitive with an improvement in her PO intake. She received a total of five rounds of plasmapheresis before her compulsions decreased significantly. Sertraline 10 mg daily was initiated on day 23 of hospitalization. She was ultimately discharged after about one month of inpatient care, and continued to follow up with her outpatient psychologist, psychiatrist, and pediatrician. Her outpatient psychiatrist increased her sertraline dosage to 15 mg and added Vitamin D 1000-2000 units daily. She also completed an outpatient intensive behavioral health program after her discharge. Within a few weeks of her discharge, her compulsions and intrusive thoughts had dissipated completely.

PMC6197143_01

Female

A 29-year-old woman, gravida 2, para 0, was hospitalized for abdominal pain in the lower part of the abdomen with no apparent cause at 32+2 weeks of gestation. Ultrasound showed MC triplet gestation with a difference in fetal weight estimates (two fetuses at 32 weeks and the other at 31 weeks). Placental function ranged between grades I and II. The umbilical cord of one fetus was once around the neck. Umbilical artery Doppler and a non-stress test showed no unusual symptoms. No distinct evidence of FFTS was observed during the entire pregnancy. After the woman was diagnosed with threatened premature delivery, she was treated with phloroglucinol for tocolysis and dexamethasone for promoting lung maturation of the three fetuses. The next day, the woman complained of continuous abdominal distension, while her previous abdominal pain was relieved. An ultrasound examination on the fourth day showed two fetuses with a weight estimated for 33 weeks and the other for 32 weeks of gestation. The non-stress test indicated slight abnormality. Therefore, conservative medical care was continuously implemented. At 4:30 am on the fifth day, the three fetal heartbeats stopped and fetal movement ceased. Thereafter, the three deceased fetuses weighted 1700, 2100 and 1800 g when they were delivered by caesarean section. An external examination showed that fetuses A and C were thin and pale, while fetus B was heavy and red (Figure 1). Observation of the internal organs showed that fetuses A and C suffered anaemic changes (Figure 2(A,C)). However, fetus B presented congestion and haemorrhage of the organs (Figure 2(B)). Examination of the MC placenta indicated that the umbilical cord of the recipient performed differently with the donor (Figure 3(A)). All three fetuses shared relatively symmetrical triple placental portions of the single placental disc. Two types of vascular anastomoses, including arterio-arterial anastomosis (AAA) and arterio-venous anastomosis (AVA), were observed in the placenta (Figure 3(B)). Microscopic examination of placental villi showed differences in anaemia and hyperaemia. We observed relatively large and immature villi with interstitial oedema in the anaemic area of the placenta (Figure 4(A,C)). In the hyperaemic area of the placenta, villi were mature with congestive interstitial telangiectasia. Furthermore, syncytiotrophoblast nuclei were degenerated, concentrated and gathered into multi-core nodules (Figure 4(B)). Laboratory studies showed that haemoglobin values of the fetuses were 58, 135 and 65 g/L for fetuses A, B and C, respectively.

feto-fetal transfusion syndrome, intrauterine fetal death, monochorionic triplet pregnancy, obstetrics, vascular anastomoses

PMC5377060_01

Male

The clinical diagnosis of meningitis was raised in a 67-year-old farmer when he presented with headaches, fever, nausea, and vomiting. The symptoms started 1 day prior to presentation. He was treated intravenously with ceftriaxone, amoxicillin, and acyclovir. His laboratory studies revealed an elevated white blood cell (WBC) count of 15,600/muL with 4.5% bands. His C-reactive protein level was 19.2 mg/L, and his erythrocyte sedimentation rate was 13 mm/h. Blood and urine culture yielded no growth of microorganisms. A computed tomography (CT) scan of the head showed no pathologic findings. CSF analysis revealed a WBC count of 244/muL (46/muL neutrophils and 198/muL lymphocytes), a protein level of 0.38 g/L and a glucose level of 3.86 mmol/L (in comparison to glucose in serum of 6.51 mmol/L and a CSF-serum ratio of 0.6). The results of a CSF culture for bacteria, fungi, and mycobacteria were negative. Polymerase chain reaction (PCR) analyses for herpes simplex virus (HSV) 1 and 2 and varicella zoster virus (VZV) in CSF were negative. Serological tests were negative for Borrelia burgdorferi, but reactive for TBEV (IgG positive, IgM negative). The results were consistent with his vaccine status, as he had been vaccinated against TBEV at 19, 18, and 5 months prior to referral. During the next 3 days, his encephalitic symptoms progressed. The patient showed persistent fever and was then transferred to our tertiary care hospital for further treatment. The patient had a medical history of rheumatoid arthritis, for which he was treated with prednisone (5 mg once daily) and methotrexate (20 mg once weekly). These compounds were not continued after first presentation. Of note, only the last vaccine against TBEV was administered while he was under immunosuppressive treatment. He had no significant family history, recent travel, or allergies. On admission to our hospital, his body temperature was 38.8 C, he was disoriented and somnolent [Glasgow Coma Score (GCS) 12], and he showed neck stiffness, increased tonicity of the upper and lower extremities, increased jerks of the lower limbs, and myoclonic movements. Repeated CSF analysis revealed a WBC count of 36/muL (99% lymphocytes) and repeated PCR tests for HSV 1, HSV 2, VZV, cytomegalovirus, enterovirus, and cryptococcal antigen remained negative. Screening for Mycoplasma antibodies and for vasculitis via multiple blood tests was negative, and a search for paraneoplastic causes by a CT scan of the chest and abdomen showed no pathologic results. Antimicrobial agents were stopped after microbiological investigations returned negative results. Multiple electroencephalograms (EEGs) showed generalized slow-wave activity (Figure 1A). Within 3 days, the patient became comatose and his GCS fell to 4. He developed a syndrome of inappropriate antidiuretic hormone secretion and severe peripheral axonal neuropathy. The initially preserved oculocephalic reflex with positive doll's eye phenomenon was soon abolished, and his GCS decreased to 3. The initial cranial magnetic resonance imaging (MRI) scan demonstrated no abnormal findings (Figure 2A) nor did the subsequent cranial CT scan on days 7 and 10. On day 9, periods of rhythmic epileptiform signal transients occurred with bifrontal localization. Antiepileptic medication was started with levetiracetam. Subsequent EEGs showed further slowing of background activity, with the appearance of triphasic signals (Figure 1B). Electroneuromyography demonstrated the absence of motor responses, even upon maximal electrical nerve stimulation, but the presence of somatosensory evoked potentials. The cranial MRI scan on day 16 showed slight hyperintensity in the region of the left lateral thalamus (Figures 2B-D). An open brain biopsy on day 15 showed scant infiltration of the cerebral cortex by CD3-positive T-lymphocytes and microglial activation (Figure 3). Immunostaining for HSV 1 and HSV 2 was negative. The findings were consistent with viral encephalitis with consecutive immune response or cellular infiltration in cerebral parenchyma due to an autoimmune disease. However, neither treatment with corticosteroids nor with plasmapheresis resulted in significant improvement of brain function or peripheral nerve function. On the basis of a high risk for persistent tetraplegia (extensive axonal peripheral motor denervation on electromyography with absence of motor responses on electrical stimulation) and for lifelong ventilator dependence and a poor cerebral prognosis, his family elected to provide comfort measures only. Four weeks after the onset of symptoms, the patient died. Shortly before the patient's demise, IgM antibodies against West Nile virus (WNV) were detected in the serum.

flavivirus, tick-borne encephalitis, tick-borne encephalitis vaccine, vaccine efficacy, vaccine failure

PMC6107029_01

Unknown

Glucocorticoids (GC) remain an important therapy in remission induction and maintenance. No RCTs have been published comparing different GC dosing. In life-threatening disease or those with major organ involvement, pulsed IV methylprednisolone 0.5-1 g/day for 3 consecutive days is recommended. Most adult guidelines recommend initial GC dose of 1 mg/kg/day and tapering to a desirable level of reaching a target GC dose of 10-12.5 mg by 3-5 month. In children (<15 years old), the initial dose of oral prednisone used is 1-2 mg/kg/day with a maximum of 60 mg/day. Daily calcium (500-1000 mg) and vitamin D (1000 IU) supplementation is recommended. Methotrexate (MTX) is recommended in combination with GC in those with limited or non-organ threatening AAV. In the NORAM trial (Non-renal Wegener's Granulomatosis Treated Alternatively with Methotrexate [MTX]), MTX was reported non-inferior to oral CYC in achieving remission induction but subsequent reports indicated less effective disease control than CYC-based induction therapy. Mycophenolate mofetil (MMF) was compared to IV CYC in non-severe GPA in MYCYC (mycophenolate mofetil versus cyclophosphamide for remission induction of ANCA-associated vasculitis) trial. MMF was noted to be non-inferior to CYC but was associated with a higher rate of relapse. The CanVasc as well as EULAR/ERA-EDTA recommends remission maintenance treatment with a combination of low-dose glucocorticoids and either azathioprine (AZA), rituximab, methotrexate or mycophenolate mofetil. This therapy for AAV be continued for at least 24 months following induction of sustained remission. In the Cyclophosphamide versus Azathioprine for Early Remission Phase of Vasculitis (CYCAZAREM) trial, AZA was shown to be equally efficacious as continuous CYC as maintenance treatment. This regime was also associated with fewer side-effects. MTX was shown to be well tolerated and effective in maintaining remission after induction with CYC and was proven to be of comparable efficacy to AZA. Leflunomide, though associated with increased frequency of adverse events, was found to be more effective than methotrexate in remission maintenance at a dose of 30 mg/day. Leflunomide can be used as an alternative agent in patients with intolerance to MTX and AZA. In the International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE) trial, MMF was shown to be less effective than azathioprine for maintaining disease remission. The role of RTX in maintenance therapy has been investigated in patients with AAV after inducing remission either with CYC or RTX. It is considered a safe and effective alternative to AZA. The MAINRITSAN (Efficacy Study of Two Treatments in the Remission of Vasculitis) was the first randomized trial comparing RTX (500 mg at remission, at 2 weeks and then once every 6 months till 18 months) to daily AZA (which was tapered after 12 months). Patients receiving RTX had sustained remission compared to AZA without significant adverse events. MAINRITSAN 2 (https://clinicaltrials.gov/ct2/show/NCT01731561) explores the RTX maintenance treatment based on ANCA estimation and CD19 lymphocytes. The RITAZAREM trial is planned to evaluate two remission-maintenance strategies of repeated doses of RTX compared to daily orally administered AZA for 24 months following induction with RTX. Both the CanVasc and EULAR/ERA-EDTA guidelines recommend switching from RTX to CYC and vice versa for relapsing AAV. In those who continue to have persistent active disease, intravenous immunoglobulin may be used as an adjunctive therapy. The role of PLEX in AAV is not well defined. It is recommended to be used for rapidly progressive glomerulonephritis in the setting of new or relapsing disease or for the treatment of severe diffuse alveolar hemorrhage. The largest trial investigating role of PLEX, the MEPEX trial (High-Dosage Methylprednisolone or Plasma Exchange as Adjunctive Therapy for Severe Renal Vasculitis) showed an increased rate of renal recovery in AAV patients presenting with renal failure when compared with intravenous methylprednisolone. However, this trial enrolled patients who were dialysis dependent or nearing end stage renal disease and it was unable to identify role of PLEX as an adjunctive to conventional therapies. Long-term follow-up of the same cohort failed to identify sustained benefit in PLEX group. PEXIVAS is an international study which enrolled patients with AAV with severe renal vasculitis and/or diffuse alveolar hemorrhage. This study aims to determine if the adjunctive plasma exchange with two oral glucocorticoid regimens (standard- and reduced-dose GC) with standard remission induction immunosuppression is effective in reducing death and end-stage renal disease. As mentioned above, clinical trials have not been conducted in pediatric GPA. The data from ARChiVe cohort highlights use of GC and CYC pulses most commonly used as a part of induction therapy (both for GPA and MPA) followed most frequently with methotrexate as a maintenance regime. However, most pediatric patients are now treated according to the adult recommendations. Many North American centers now prefers RTX as first-line remission induction therapy in children with severe GPA or MPA as it has low toxicity profile. PLEX should be considered in children with severe pulmonary hemorrhage or rapidly progressive renal disease responding inappropriately to GC and CYC or RTX. The better understanding of the pathogenesis of ANCA vasculitis from in vitro and animal studies have helped us to identify the targeted therapies focusing on components of innate and adaptive immune system. Belimumab (BEL) was investigated in a phase III, multicenter randomized double-blind trial evaluating its role the maintenance of remission in GPA and MPA in combination with AZA (BREVAS: NCT01663623). In BREVAS trial, addition of BEL to maintenance therapy with AZA did not reduce the risk of relapse. Fewer relapses of vasculitis was identified in RTX induced patients compared with placebo. Abatacept, a fusion protein co-stimulatory T cell blocker was evaluated in an open labeled study in non-severe relapsing GPA. Almost 90% patient had disease improvement and >70% patients could discontinue prednisone. The study was limited by a small sample size, continuing background DMARDS and prednisone early during the study. Abatacept is currently being investigated in a multicenter, phase III, double-blind, placebo-controlled trial in the treatment of non-severe AAV (ABROGATE: NCT02108860). The role of blocking complement component/receptor has been explored. Avacopan (CCX168/ selective C5a receptor inhibitor) was investigated in a phase II randomized, placebo-controlled trial (CLEAR: NCT01363388). Results from this study indicate both treatment groups receiving CCX168 were non-inferior to the standard induction and high-dose prednisone. These results highlight the importance of C5a as an important inflammatory mediator in AAV and can be used in future as an alternative to the use of oral glucocorticoids. The efficacy of Avacopan is now being evaluated in a larger phase III randomized, double-blind, active-controlled study (ADVOCATE: NCT02994927). Eculizumab is a long-acting humanized monoclonal antibody targeted against complement C5 and inhibits the deployment of the terminal complement system including the formation of membrane attack complex. It has been used successfully in a case report as an add-on treatment with an excellent clinical response with complete recovery of renal function. Gusperimus (15-deoxyspergualin) inhibits mainly T-cell maturation and cytotoxic T-cell proliferation. It was used in a small open labeled trial with high response rates in refractory GPA. Clinical trial assessing the efficacy of gusperimus compared to conventional treatment was prematurely terminated (SPARROW: NCT NCT01446211). IL-6 is expressed and produced at sites of active vasculitis and levels are increased in patients with AAV. Case reports of successful treatment with Tocilizumab have been published in literature. Clinical trial with TCZ and AAV is currently being considered. The mortality rates reported in pediatric series are low. The French registry reported a mortality of 10% as compared to none in a single center series reported by Noone et al. and James et al. in pediatric patients with predominant AAV associated glomerulonephritis and GPA respectively. The French vasculitis study group registry reported an increased incidence of ischemic abdominal pain and damage involving the upper respiratory tract. Childhood AAV relapse rates were also reported much higher requiring longer maintenance therapy compared to adult AAV. Important morbidity associated with AAV in pediatric patients includes nasal septal perforation with saddle nose deformity, chronic sinusitis, osteoporosis, chronic kidney disease, end stage renal disease, cystitis, infertility, and avascular necrosis. Recently published early treatment outcome data, reported under 50% of patients achieving remission at 12 months and 61% with inactive disease at 12 months. Improvement of PVAS score of at least 50% from time of diagnosis to post-induction was seen in 92% of patients. Vasculitis associated disease damage with PVDI scores >=1 was identified in more than 60% of the patient cohort early in their disease course.

anca—associated vasculitis, childhood vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, small vessel vasculitis

PMC6856949_01

Female

A 45-year-old Caucasian female born to first-cousin parents, with two healthy children and without any relevant family history record of prior diseases, was seen at the service of Dermatology (University of Coimbra, Coimbra, Portugal) in March 2014 because of persistent extensive, skin-colored, exuberant, and disfiguring warts in both feet and hands since the age of 10 years (Figure 1). Warts were refractory to treatment with keratolytic agents, cryosurgery, and excision, with minor improvement after treatment with acitretin in association with topical 50% urea cream. Apart from this, the patient did not describe recurrent infection-related episodes or diseases, except for past medical history of measles and mumps during her infancy and varicella infection during her first pregnancy, which all resolved without complications. Of note, such past history of infections is not rare among the patient age-matched Portuguese population since vaccination for these diseases was introduced in the Portuguese national vaccination program years after she was born (1969): in 1974 for measles, in 1987 for mumps, and in 2004 for varicella. In fact, outbreaks of measles and mumps have been reported in Portugal until the late 80s to mid-90s, with peaks of >10,000 cases per year. In addition, she referred allergic rhino-conjunctivitis treated with cetirizine and fluticasone, and chronic polyarthralgias in the absence of impaired functionality. Serological studies were negative for (severe) infections, including HIV 1/2, HTLV-1, and syphilis. In turn, she showed IgG antibodies for ubiquitous pathogens including CMV >250 arbitrary units (AU/ml) (positive threshold >6AU/ml) and Epstein-Barr virus VCA = 192 U/ml (positive threshold >20 U/ml) and EBNA = 24 U/ml (positive threshold >20 U/ml) in the absence of serum IgM antibodies for these pathogens (0.06 AU/ml; positive threshold >6AU/ml). Slightly increased serum IgG levels (IgG: 1,430 mg/dl), associated with normal IgA (278 mg/dl), IgM (67 mg/dl), C3 (1.4 g/L), C4 (0.33 g/L), and C1 inhibitor (0.318 g/L) serum levels, were detected. In addition, anti-neutrophil and anti-double-strand DNA autoantibodies were negative, while antinuclear autoantibodies were weakly positive. Screening for immunological alterations by flow cytometry (Supplementary Material) using the EuroFlow Primary Immunodeficiency Orientation Tube (PIDOT) showed an absolute defect of CD4-expressing T-cells (<0.01 cells/mul), with normal total T-cell, CD8+ TCRgammadelta- T-cell, and NK-cell (absolute) numbers, associated with consistently increased B-cell counts vs. age-matched normal reference values. Importantly, (TCRalphabeta+ TCRgammadelta-) DN T-cells were significantly expanded (Table 1). Signs/symptoms associated with primary immunodeficiency other than persistent warts in the feet and hands were not observed either at presentation or during the subsequently 5-year follow-up period. Of note, peripheral blood (PB) monocytes and DCs showed no cell surface expression of CD4. Since rare CD4 polymorphisms that abrogate reactivity of some monoclonal antibodies (MoAbs) with the CD4 molecule have been described, CD4 expression was evaluated using eight different MoAb clones. These eight CD4 MoAb clones were directed against five different epitopes located in two distinct domains of the CD4 protein (Supplementary Material; Figure 2A), as confirmed in competitive staining inhibition experiments (data not shown), in line with previous data in the literature. Detectable levels of either surface membrane (sm) or intracytoplasmic (cy) CD4 expression were observed in none of the cell lineages that usually express this protein in blood of healthy controls, such as T-cells, monocytes, and DCs (Figure 2B). A lack of CD4 expression was confirmed for both classical T-cells and invariant MAIT and iNKT cells (data not shown). In contrast, the expression of other molecules previously associated with CD4 lymphopenia, such as CD3 and HLA-DR, was normal and comparable to that observed in healthy donors (data not shown). Besides no cellular CD4 protein being detected, normal soluble CD4 levels in plasma were observed in the patient using an ELISA assay with a pair of antibodies directed against the extracellular domains of CD4 (amino acids 26-390; Table 2). CD4 gene sequencing of patient DNA revealed an isolated homozygous mutation (Figure 3; Supplementary Table 1) in the last bp of the 7-8 intron (NC_000012.12: g6818420 G>A), corresponding to the juxtamembrane domain of the CD4 protein. This alteration was considered by the Variant Effect Predictor Tool (VEP) as a splice acceptor variant with a high impact on CD4 protein transcription. No wild type CD4 DNA sequence was detected based on the analysis of the sequence of the amplicon products obtained after PCR amplification of DNA from the patient. Instead, two truncated forms of CD4 RNA/cDNA were detected. Both truncated forms of CD4 RNA presented with a frameshift deletion starting at the juxtamembrane region at the first bp of exon 8 and a premature stop codon associated with a truncated protein with normal extracellular domains in the absence of the anchoring domain to the membrane (Figure 3). The first frameshift deletion (NM_000616: c.1157_1278del) consisted of a complete deletion of exon 8 (122 pb), resulting in a 399-amino-acid protein. In turn, the second frameshift deletion produced a 430-amino-acid protein because of (only) a 29 bp deletion (NM_000616: c.1157_1185del) (Figure 3) that ended just before a 5 bp combination (TGCAG), homologous to the sequence observed at the end of the 7-8 intron (Figure 3). In order to investigate the origin of the mutation, DNA from four first-degree patient relatives (all asymptomatic) was also analyzed. Thus, the mutation identified in the patient (NC_000012.12: g6818420 G>A) was also found in heterozygosis in DNA from each of her two children and each of her parents. In contrast, her brother's DNA only showed wild type CD4 gene sequences. Further cDNA sequencing from her children and her parents revealed two CD4 mRNA sequences, one carrying the large deletion observed in the patient (NM_000616: c.1156_1278del) and another with the unmutated (wild type) CD4 allele sequence (Figure 3). These results are fully consistent with a germinal mutation in the patient inherited from her parents and transmitted to her children. In contrast, in the patient's brother, both alleles were found to be wild type. Analysis of CD4 protein levels by flow cytometry confirmed that, although normal CD4+ T-cell counts were observed in the patient's children and parents (Table 3), the amount of expression of the CD4 protein on CD4+ T-cells, monocytes, and pDCs was reduced to around half when compared to healthy controls (n = 3) and the patient's brother, stained in parallel (Supplementary Table 2). As described above, a lack of CD4 expression on patient T-cells was associated with abnormally expanded DN TCRgammadelta- TCRalphabeta+ T-cell counts in PB (>30% of all T-cells; Table 1), compared to age-matched normal reference values. Based on CD27, CD45RA, and CCR7 expression, these DN T-cells showed a similar distribution per maturation stage to that of CD4+ T-cells from age-matched healthy controls, both in relative and absolute numbers: (i) naive: 27% and 240 cells/mu (6-66% and 83-676 cells/mul), (ii) central memory: 66% and 587 cells/mul (18-71% and 235-589 cells/mul), and (iii) effector memory: 7% and 62 cells/mul (2-66% and 14-221 cells/mul). In addition, expanded DN T-cells showed a polyclonal TCRVbeta repertoire with a distribution per TCR family evaluated, fully consistent with reference TCRVbeta repertoire values observed in HLA class II-restricted CD4+ T-cells from healthy donors (Supplementary Figure 1). More extended phenotypic analysis of central/effector memory DN T-cells from the patient showed Treg and Th surrogate marker expression profiles for Tregs, TFH, Th1, Th2, Th17, and Th1/Th17 CD4+ helper T-cell to be present at frequencies similar to those observed for normal CD4+ T-cells (Table 1) from age-matched healthy donors (Botafogo et al., submitted). Short-term in vitro stimulation, for 4 and 6 h, showed that the expanded DN T-cells were capable of producing cytokines from the main Th patterns (e.g., IFNgamma, IL-4/IL-5, and IL-17A/IL-17F) at frequencies similar to CD4+ helper T-cells from age-matched healthy controls, when either polyclonal (i.e., PMA) or antigen-specific (i.e., CMV) stimuli that required antigen presentation were used (Table 4). In contrast, the percentage of DN T-cells expressing markers of cytotoxic T-cells (cyGranzyme B or cyPerforin) was decreased below <1% (normal age-matched range of <1-21% of DN T-cells). Normal total CD8+ T-cell, TCRgammadelta+ T-cell, and NK-cell counts were found in the patient blood, although the latter two were increased in some of the monitoring time points tested during the 5-year follow-up period. In contrast, consistently increased naive CD8+ T-cell counts (Table 1) vs. age-matched reference values, associated with normal central and effector memory CD8+ T-cell numbers, were found in the patient's blood at different time points. Expression of cytolytic enzymes (cyGranzyme B and cyPerforin) was detected in CD8+ T-cells (13 and 9% of CD8+ T-cells) and NK-cells (>99%) at normal values (15-65% and 10-53% of CD8+ T-cells, respectively; >99% of NK-cells). In addition, CD8+ TCRalphabeta+ T-cells also showed a normal polyclonal TCRVbeta repertoire (vs. normal age-matched reference values, shown in Supplementary Figure 1) and a normal cytokine production profile in response to PMA and CMV (Table 4). Detailed dissection of the PB B-cell compartment from the patient showed persistently increased total B-cell counts due to increased naive (CD21+) B-cells, IgG1-3 and IgA1 memory B-cells, and IgA1 plasmablasts, with normal immature/transitional B-cell numbers (Table 1), in line with the observed higher serum IgG levels. Analysis of circulating PB monocytes based on expression of CD14 (LPS receptor) and CD16 (low-affinity Fc IgG receptor) showed normal absolute counts for all subsets (Table 1), including: (1) CD14+ CD16- classical monocytes (cMo), (2) CD14+ CD16+ intermediate monocytes (iMo), and (3) CD14- CD16+ non-classical monocytes (ncMo). Further dissection of cMo and ncMo based on the expression of the CD62L and SLAN selectins, respectively, did not show significant differences vs. normal age-matched reference values. In addition, CD4-negative monocytes and DCs were capable of producing cytokines at frequencies similar to their CD4+ counterparts from age-matched healthy control blood, after stimulation with LPS and gamma-IFN (Supplementary Table 3).

cd4, cd4 lymphopenia, double-negative t-cells (dnts), idiopathic cd4 lymphocytopenia, warts

PMC9705775_01

Male

A 69-year-old man was diagnosed with post-hepatitis B cirrhosis for 20 years and presented with 2 weeks of fever. Two weeks before his admission, he developed pyrexia without obvious predisposing causes, and his highest temperature recorded was 39.6 C, with fever ocurring mainly in the afternoons. Furthermore, the patient suffered from asthenia, anorexia, mild cough, whitish sputum, and pain in the anterior chest wall without chills or abdominal pain. He had undergone a splenectomy for hypersplenism 16 years ago. During a physical examination, his temperature was 38.8 C. There were many spider angiomas in the anterior thoracic wall and decreased respiratory sound in both lungs, combined with shifting dullness and fist percussion over the liver. Laboratory tests revealed a C-reactive protein level of 84.36 mg/L (normal range <5 mg/L) and an erythrocyte sedimentation rate (ESR) level of 69 mm/h (normal range 0-43 mm/h). Liver function tests demonstrated a slight elevation of aspartate aminotransferase (AST) at 59.7 U/L, total bilirubin (TBIL) at 39.7 mmol/L, and a slight decrease of albumin at 31.4 g/L. Additionally, serum alpha-fetoprotein (AFP) level was markedly elevated to 1210 ng/ml (normal range 0-20 ng/mL). The serum adenosine deaminase (ADA) was mildly elevated to 24.4 U/L. However, an ascitic fluid examination demonstrated that ADA was normal. Negative test results were observed for purified protein derivative (PPD) and mycobacterium TB DNA. An interferon-gamma release assay (IGRA) test was positive. The results of coagulation function tests expressed that prothrombin time (PT) was 19.9 s (normal range 10-15 s), the international normalized ratio (INR) was 1.71, and there was 47.7% prothrombin time activity (PTA). An ultrasound (US) of the abdomen revealed signs of cirrhosis, a filling defect in the portal vein, and a large hypoechoic lesion with an irregular border and non-uniform internal echoes in the left lobe of the liver. Abdominal CT plain scans depicted a decompensated period of cirrhosis, a lobulated and inhomogeneous mass with a slightly lower density in the left lobe, measuring 13.5 cm x 6.8 cm, and the presence of ascites and bilateral pleural effusion (Figure 1). MRI, including T1- and T2-weighted imaging and contrast-enhanced with fat saturation and subsequent subtraction, revealed signs of cirrhosis and a huge mass in the left liver lobe, characterized by slightly higher non-uniform intensity, which was not significantly enhanced in the arterial phase, and mild to moderate delayed enhancement was found in the perifocal and internal septum of the venous phase and the delayed phase. In addition, the mass presented without a capsule surrounding it. The mass was hyperintense in DWI mapping. Moreover, a filling defect in the trunk of the portal vein was observed (Figure 2). The results led us to consider primary liver cancer and main portal vein tumor thrombus combined with decompensated cirrhosis. Although discovering a space-occupying lesion of the liver on MRI and that the AFP level in the peripheral blood was extremely elevated, the first diagnosis was probably HCC. Biopsy and histology may be considered the ultimate diagnostic tests, but needle biopsy was excluded because of a high risk of bleeding; in addition, the patient declined the procedure. To cope with fever, the patient was initially given broad-spectrum antibiotic treatment (3.0 g of cefoperazone-sulbactam every 8 h for 6 days and 0.5 g of levofloxacin every 24 h for 3 days, followed by 0.5 g of intravenous vancomycin every 12 h and 1 g of meropenem every 8 h via intravenous drip infusion for 3 days). After 12 days, the fever persisted (the highest temperature recorded was 38.2 C.). Although there was no direct evidence of TB infection, primary hepatic TB was suspected based on clinical symptoms, and an anti-TB therapeutic diagnosis was given. The patient was treated with 0.75 g of anti-TB oral ethambutol every 24 h and 0.6 g of amikacin every 24 h via intravenous drip infusion for 10 days; after that, the patient maintained a normal temperature (36.5 C). Anti-TB treatment continued at the same dosage for the following 15 days, with supplemental isoniazid at 0.3 g/24 h. In the days and weeks following the patient's coagulopathy correction, we repeatedly offered him a biopsy, but he declined it. The patient was then discharged from the hospital. The patient received tuberculostatic therapy with amikacin, isoniazid, and ethambutol for 6 months. The level of AFP had completely normalized upon review after stopping the medication for 20 weeks, and the imaging displayed that the mass on the left liver lobe had disappeared, the portal vein filling defect had markedly reduced, and ascites and bilateral pleural effusion reduced in the patient (Figure 3). At the 2-year follow-up, no evidence of recurrence was observed (Figure 4), and the patient had recovered well. The final diagnosis was predominantly that of hepatic TB based on the disappearance of the lesions, and the level of AFP gradually returned to normal after the patient had been given anti-TB therapy for 6 months.

case report, cirrhosis, hepatic tuberculosis, hepatitis b virus, hepatocellular carcinoma, portal vein thrombosis

PMC3860023_01

Male

Written informed consent was obtained from the patient for publication of this case report and accompanying images. In October 2011, a 69-year-old white man presented with 15% weight loss (22 kg), mental confusion, nocturnal fever, difficulty in ambulation, limb weakness and general fatigue experienced over the previous 9 months. Physical examination revealed hepatomegaly, palpable 3 cm below the right costal margin, without lymphadenopathy or splenomegaly. The results of the complete blood count were normal apart from mild leukocytosis (white blood cell count: 13,340/muL). The results of liver function tests were aspartate aminotransferase (AST): 58 U/L, alanine aminotransferase (ALT): 130 U/L, gamma-glutamyl transferase (GGT): 305 U/L, alkaline phosphatase (ALP): 601 U/L, total bilirubin (TB): 0.7 mg/dL and albumin: 3.4 g/dL. Lactate dehydrogenase (LDH) level was found to be 2648 U/L. Results of serologic tests for hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and human T-lymphotropic virus-1 were negative. FAN and VDRL were negative. Tumor markers levels are described as follows: carcinoembryonic antigen (CEA): 0.3 ng/mL, carbohydrate antigen 19-9 (CA 19.9): 7.0 U/mL, and alpha-fetoprotein (AFP): 4.58 ng/mL. Magnetic resonance imaging (MRI) findings showed a hypointense area on T1-weighted images sized of 13 cm x 9 cm x 11 cm, and hyperintense on T2-weighted images (Fig. 1a). There was no mediastinal lymphadenopathy or brain involvement on CT scan. Two ultrasonography-guided needle liver biopsies were found negative and the third one showed diffuse infiltration of large sized lymphoid cells. Immunohistochemistry (Fig. 2): positive CD45-LCA, positive CD20; positive Ki67 in 80% of atypical cells; CD99 positive; vimentin positive. CD3, CD15, CD30, ACT, CK, CRO, DES, HMB45, and S100 were all negative. The diagnosis of primary large cells non-Hodgkin B-cell lymphoma was made. Bone marrow aspiration and biopsy examination showed no evidence of diffuse large B-cell lymphoma. The patient received R-CHOP treatment (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) in 8 cycles throughout 12 months. Two sessions of radiotherapy were also implemented. In this case report, the patient showed a good response to treatment with mild side effects. After 6 months, the lesion decreased in size to 7 cm x 5 cm (Fig. 1b). After 24 months of follow-up, the patient remained asymptomatic. However, imaging studies have shown the persistence of a small calcified lesion of 3 cm x 1.5 cm (Fig. 1c). The patient has been regularly seen in an outpatient facility.

diagnosis, liver, primary lymphoma, treatment

PMC7727618_01

Male

An 81-year-old male patient with a history of well-controlled type 2 diabetes mellitus presented to the emergency room with a lesion on his left forehead, as well as periorbital swelling and erythema. Three days before presentation, he had injured his left forehead on a kitchen ventilator, resulting in a minor laceration. In the following days, he noticed a progressive rash and redness in the injured area, as well progressive left periorbital soft tissue swelling. Pain, itching, paraesthesia and vision impairment were absent. On physical examination, the patient's vital signs including temperature were normal. Cardiopulmonary examination was without pathological findings. The skin on his left forehead showed a dark crusty erosion and there was pronounced periorbital redness and swelling on both sides (Figs. 1 and 2). There were singular papules on the chin and upper chest (Fig. 3), as well as multiple erythematous papules without vesicles on the back. The lesions were painless. Trigeminal and facial palsies were absent. Blood tests showed an elevated C-reactive protein (36.1 mg/l, reference value <10.0 mg/l) with a normal white blood cell count with mild lymphopenia and monocytosis. Mild hyponatremia (129 mmol/l, reference value 135-145 mmol/l) and elevated creatinine (creatinine 115 mumol/l, reference value 49-97 mumol/l, corresponding to an estimated glomerular filtration rate of 51 ml/min/1.7) were present. A computed tomography scan of the head showed periorbital cellulitis on the left side without abscess formation (Fig. 4). Our initial hypothesis was cellulitis resulting from the previous head injury and we started the patient on intravenous antibiotic treatment with amoxicillin/clavulanic acid 2.2 g three times a day. Due to the atypical presentation and extension of the skin lesions to the trunk, we suspected a possible viral aetiology and started concomitant treatment with intravenous acyclovir 500 mg three times a day. Within the next 24 hours the patient was febrile (38.3 C) and a vesicular rash had developed. PCR testing of a swab of the vesicles on the forehead was positive for VZV (4,113,840,000 copies) and HSV-1 (396,500 copies). PCR testing of the vesicles on the trunk detected 312,000,000 copies of VZV and 600 copies of HSV-1. Serological studies were consistent with reactivation of the viruses (negative IgM, positive IgG antibodies for both VZV and HSV-1). Ophthalmological examination showed no evidence of herpes zoster ophthalmicus or acute retinal necrosis. We excluded underlying immunosuppressive diseases such as HIV infection and multiple myeloma. There were no clinical signs of reactivation of latent infections like cytomegalovirus or tuberculosis. In summary, we established the diagnosis of disseminated VZV infection with concomitant reactivation of HSV-1, triggered by a minor head injury. The clinical picture was more consistent with VZV reactivation than HSV-1 reactivation, as there were no signs of herpes labialis or genitalis, and no herpetic whitlow. According to the guidelines , we increased the dose of acyclovir to 750 mg intravenously three times a day. Within 3 days, a favourable clinical course was observed with regression of the facial oedema and crusting of the vesicles. After 7 days, we stopped therapy with both acyclovir and amoxicillin/clavulanic acid.

herpes simplex virus, head trauma, varicella zoster virus

PMC3881376_01

Female

An adult female patient with a chronological age of 19 years and 4 months and an ectomorphic body type reported to the Department of Orthodontics, Pushpagiri College of Dental Sciences, with the chief concern of unattractive facial appearance due to forwardly placed lower jaw and teeth. (Figures 1-4). Her parents pointed out that she was greatly dissatisfied by her looks. There was no relevant familial history pertaining to skeletal Class III malocclusion, nor any pertinent medical history. Extraoral clinical examination in frontal view exhibits the patient's face to be leptoprosopic (oval); paranasal areas were deficient; lips were potentially incompetent with excessive lower lip vermilion exposure, and facial asymmetry was evident with the lower border of mandible moderately shifted to the right. Her growth pattern was predominantly vertical and there was increased incisor and gingival visibility at smile. Examination of vertical facial proportions (Figure 2) revealed that both her midfacial and lower anterior facial heights were increased which corroborates an increased display of teeth and gingiva. Lateral view and oblique view showed pronounced mandibular prognathism, with a concave profile, an acute nasolabial angle, an everted and hypotonic lower lip, reduced labiomental fold, a long chin-throat length with a well-defined inferior border of the mandible, and an acute lip-chin-throat angle. Intraorally, the molar relationship was Class III with a complete anterior crossbite, along with a reverse overjet of 2 mm (Figure 3). There was generalized interdental spacing amongst her anterior teeth and the incisors were flared, combined with an anterior open bite. These characteristics may point to a large tongue. A lower dental midline discrepancy was present due to mandibular shift to the right. She had recently undergone endodontic treatment for her lower left first molar. Pretreatment radiographic records included lateral and posteroanterior (PA) cephalograms and orthopantomogram (OPG) (Figures 5-6). Cephalometric analysis (Table 1) revealed a Class III skeletal base with mandibular prognathism, increased maxillary skeletal and dental height, increased vertical chin height, and upper anterior proclination with compensatory lower anterior retroclination. After a joint clinic discussion with the Department of Oral and Maxillofacial Surgery, Pushpagiri College of Dental Sciences, Le Fort I maxillary impaction in combination with mandibular setback by bilateral sagittal split osteotomy (BSSO), with presurgical and postsurgical orthodontics, was planned in order to achieve facial aesthetics and a functionally optimum occlusion. During BSSO an asymmetrical setback with more orientation to the left was planned in order to correct the shift of the lower jaw and midline. Vertical reduction genioplasty for correction of the chin was considered, subjected to the changes, at the time of surgery or as a secondary procedure. Lower lip augmentation to reduce the thickness and vermillion display along with rhinoplasty later was planned, if needed, after thorough posttreatment evaluation. Therapeutic extractions of all third molars were to be done prior to surgery. After initial restorative and prophylactic measures, presurgical orthodontics was begun with 0.022'' x 0.028'' Roth preadjusted edgewise prescription appliance. Intra-arch levelling and aligning were achieved, and spaces were consolidated in both the arches. To achieve sufficient decompensation and ideal maxillary incisor inclination therapeutic extractions of upper first premolars were done, which was followed by controlled retraction of maxillary anterior segment with loop mechanics. Maxillary and mandibular arches were aligned up to 0.021'' x 0.025'' stainless steel wire and arch compatibility was established between upper and lower arches (Figures 7, 8, 9, and 10). In due course upper and lower third molars were extracted to facilitate the orthognathic surgery. At the end of the presurgical phase radiographic records were repeated and compared (Figures 11 and 12). In order to assess the practical considerations and further predict the results of the planned surgical approach, cephalometric prediction tracing was done both manually using the template method and with computer image prediction. In template method, skeletal profiles of maxilla and mandible were traced on an acetate paper. Profile tracing was then duplicated and transferred to a thin cardboard. This outline was then cut to produce a cardboard template. From these templates, trial sections were made until desirable location and amount for osteotomy were found. The cut sections of both maxilla and mandible were then fitted back to the tracing in desired occlusal relation. Finally, soft tissue outline can be traced in regard to the reference ratios, and the probable postsurgical changes were checked. Later, computer-based analysis was done wherein cephalometric landmarks were digitized and the surgical repositioning was monitorized. Measurements, calculations, and analyses were performed using Facad (Ilexis AB, Sweden). The obtained data was incorporated into prediction algorithms to provide single-line profile drawings predicting the final treatment goal (Figure 13). In the Maxilla, a 5 mm of superior repositioning along with an advancement of about 3 mm, was sufficient enough to reduce the gingival show and improve the para-nasal hollowing. In Mandible, 8 mm of setback brought about good posterior intercuspation with an aesthetically pleasing profile. Cast prediction or model surgery and fabrication of occlusal splints for use at surgery were the next steps in the planning sequence. Since both jaws were to be repositioned, the maxillary and mandibular dental casts were mounted on a semiadjustable articulator with the aid of facebow transfer (Figure 14(a)) and bite registration taken with the patient's jaws in the retruded contact position or centric relation. Model simulation of the anticipated surgical movement was performed next. The individual dental casts were repositioned, simulating the movements of the jaws as depicted by the manual and digital prediction. An intermediate acrylic occlusal splint was fabricated after the maxillary cast was repositioned on the articulator (Figure 14(b)). The mandibular cast was then repositioned to oppose the maxillary cast, simulating the final position of the jaws at surgery. Based on this position the final occlusal splint was then fabricated (Figure 14(c)).

PMC4531957_01

Male

A 58-year-old man was admitted because of acute onset of non-productive cough, fever, myalgia and progressive dyspnea over a one-week period. This was associated with bilateral pulmonary infiltrates on chest PA. Prior to his illness, the patient had been completely well, without past history of either cardiac or respiratory disease. Of particular note, he was an ex-smoker who was unemployed and did not have hobbies which might have exposed him to possible harmful antigens. Neither the patient nor any of his close associates suffered from tuberculosis, and he denied taking drugs or exposing himself to noxious gases prior to his illness. On admission to hospital, he was distressed, tachypneic, and pyrexial with a respiratory rate of 35 per minute and a body temperature of 38 C. He was normotensive and his pulse rate was 90 beats per minute. The patient was not jaundiced. The head and neck were entirely normal. Examination of the chest revealed intercostal recession, but the respiratory excursion was equal bilaterally. The chest was resonant to percussion. The most striking feature on auscultation was the presence of extensive, bilateral, late inspiratory crepitations predominantly over the middle and lower lung zones. Vocal resonance was normal. Cardiac and abdominal examination were within normal limits. The chest radiographs showed multifocal and patchy distribution of opacities in the periphery of both lung zones (Fig. 1). Serial radiographs showed migratory natures of consolidations. High resolutional computed tomographic scan (HRCT) revealed nonsegmental and peribronchial distribution of alveolar consolidation and ground glass attenuation in the subpleural area, predominantly (Fig. 2). But, the consolidation had vertical zonal or anterior-posterior predominance. Several poorly defined centrilobular nodules and bronchial wall thickening with dilatation in the area of consolidation were seen. There was no evidence of pleural effusion or lymphadenopathy. Also, noted irregular lines were seen in both upper lung zones, suggestive due to previous centrilobular emphysema. Pulmonary function studies revealed an FVC of 3.28 L (88 percent predicted) and an FEV1 of 2.62 L (86 percent predicted) with an FEV1/FVC ratio of 98 percent. The patient's arterial blood gas levels (at room air) were as follows: pH; 7.48, PaCO2; 27.8mmHg, PaO2; 43.8mmHg and HCO3-; 21.1mmol/L. The ECG was normal. Laboratory findings disclosed the following values: erythrocyte sedimentation rate (ESR), 60mm/h; hemoglobin level 13.8g/dl; leukocyte count 22,100/mm3, with a normal differential cell count; platelet count, 473,000/mm3; BUN, 6mg/dl; creatinine, 0.8mg/dl; sodium 140mEq/L; potassium 3.8mEq/L; lactate dehydrogenase, 263.6 IU/L; alkaline phosphatase, 84.4 IU/L; GOT 16.2 IU/L; GPT 9.7 IU/dl. Levels of antinuclear antibody, rheumatoid factor and anticardiolipin antibody were all normal and complement levels were normal. Mycoplasma serology was negative. Cultures of blood and sputum were negative. Results of the urinalysis were normal. He underwent bronchoalveolar lavage that revealed 61x104/ml with 63 percent macrophages, 6 percent lymphocytes and 31 percent neutrophils. An open lung biopsy was performed on the fifth hospital day which showed BOOP. The section showed well demarcated areas of fibrosis involving air spaces in patchy distribution (Fig. 3). Fibrosis consisted of young fibroblasts and inflammatory cells in myxoid-matrix-forming fibroblast polyps. These fibroblast polyps occluded distal bronchioles, alveolar ducts and adjacent alveolar spaces and they were sometimes covered by a lining of bronchiolar or alveolar epithelial cells. Most bronchiolar lumens or air spaces were filled with fibrinous exudate containing granular eosinophilic necrotic cellular debris (Fig. 4). On the second hospital day, viral culture was performed from his throat swab in the National Institute of Health, Korea and adenovirus was isolated. He received supportive treatments including oxygen inhalation with partial rebreathing mask, without application of mechanical ventilation and PEEP. One day later, dyspnea subsided gradually. There was improvement in gas exchange and clearing of roentgenographic infiltrates without corticosteroid and antibiotics therapy. At discharge, arterial blood gas levels (at room air) were as follows: pH 7.46, PaCO2 37.8mmHg, PaO2 83.4mmHg; HCO3-, 23.8mmol/L. He has continued to do well two months following discharge and the follow-up HRCT scan after 2 months showed almost disappeared subpleural air-space consolidation with poorly defined nodule and nearly normalized bronchial wall thickening with dilatation.

High resolution computer tomography (HRCT) shows bilateral patchy involvement of alveolar consolidation in mainly both lower lobe and focal ground-glass lesion is also noted.

PMC5926488_01

Male

A 52-year-old man with a history of RA presented to the emergency department with a one-week history of fevers, chills, headache, nausea, vomiting, and diarrhea. He also reported having a nonproductive cough, fatigue, and one month of night sweats. His therapy for RA comprised weekly methotrexate, daily hydroxychloroquine, and sulfasalazine. His symptoms were well-controlled on this regimen. He also gave a history of receipt of rituximab for a year prior to presentation. Our patient is originally from Mexico but has lived in the United States for over forty years. Prior to moving to Colorado, he gave a history of residence in Ohio. He works as a truck driver and his route involves the Midwest states. He also gave a history of travel to California nearly a year ago. About one month before admission, he unloaded his truck in Kansas City during a rainstorm and shortly thereafter began having night sweats and a nonproductive cough. No known history of exposure to tuberculosis. On admission, he was afebrile but was found to have an oxygen saturation of 85% on room air and required 2-3 liters/minute of supplemental oxygen. Initial laboratory studies revealed a normal white blood cell count. Liver enzymes were elevated above his baseline (AST 74 U/L, ALT 60 U/L, and alkaline phosphatase 170 U/L). An abdominal ultrasound showed mild hepatosplenomegaly, and a chest X-ray showed a diffuse reticulonodular density with hilar lymphadenopathy. He received one dose of intravenous (IV) ceftriaxone and azithromycin and was started on empiric treatment with IV ceftriaxone, doxycycline, and metronidazole for community-acquired pneumonia. Additional negative studies included a respiratory viral PCR, Histoplasma urine antigen, Streptococcus pneumoniae urine antigen, Legionella urine antigen, human immunodeficiency virus (HIV) 4th generation antibody/antigen assay, acute hepatitis panel, serum herpes simplex virus (HSV) PCR, serum cytomegalovirus (CMV PCR), Mycobacterium tuberculosis (MTB) quantiferon gold, and sputum Pneumocystis jirovecii pneumonia (PJP) direct fluorescent antibody (DFA). Rheumatology recommended continuing hydroxychloroquine and stopping methotrexate and sulfasalazine in the setting of possible infection. A CT chest interstitial lung disease (ILD) showed diffuse micronodularity in all five pulmonary lobes in a perilymphatic and centrilobular distribution and few scattered calcified granulomas that suggested disseminated infection. The CT chest scan also showed mediastinal and hilar lymphadenopathy as well as splenomegaly (Figure 1). Diffuse micronodules had not been seen on previous CT chest scans six years prior and one month prior to presentation. His imaging findings suggested a miliary pattern. This combined with his clinical symptoms and environmental exposure history was concerning for an invasive fungal infection or tuberculosis (TB). Three sputum AFB cultures were collected and were smear negative. An MTB complex nucleic acid amplification test (NAAT) was performed on one of his AFB sputum samples and was not detectable. He underwent bronchoscopy and findings were notable for endobronchial nodules and plaques in the left upper lobe. Multiple biopsies were done and sent for standard aerobic, AFB and fungal cultures. An Aspergillus galactomannan antigen and PJP DFA in bronchoalveolar lavage fluid (BAL) were negative. Since all cultures remained negative, his antibiotics were stopped after 3 days. Infectious Diseases was consulted and recommended starting empiric anidulafungin and posaconazole combination therapy given concern for a fungal infection. Empiric combination therapy with an azole + echinocandin was chosen to cover possible endemic fungi and invasive aspergillosis. Posaconazole was chosen over voriconazole for the addition of Mucorales coverage. Assays for serum Histoplasma antigen enzyme immunoassay (EIA), urine Histoplasma galactomannan antigen quantitative EIA, serum Aspergillus galactomannan antigen, and serum Cryptococcus neoformans/gattii antigen were negative. T-SPOT interferon-gamma release assay was negative. Aspergillus fumigatus IgG was elevated at 13.03 U/mL. Pathology from bronchoscopy biopsy showed necrotizing granulomatous inflammation suggestive of infectious etiology. Acid-fast bacilli (AFB) and Grocott-Gomori methenamine silver (GMS) stains were negative. Periodic acid- Schiff (PAS) stain and hematoxylin and eosin (HE) stain were not done. Five days after bronchoscopy, Coccidioides antibody by complement fixation (CF) assay returned positive at 1 : 8, Coccidioides IgM by enzyme-linked immunosorbent assay (ELISA) was positive, and Coccidioides IgG by ELISA was negative. Coccidioides immitis antibody by immunodiffusion (ID) demonstrated a partial identity reaction indicating the presence of two different types of antibodies. One antibody was identical to the positive control, and the other antibody was unrelated and could be a cross-reactive antibody due to infection with other systemic fungi. His Coccidioides immitis antibody was repeated three days later and was reported as detectable. This pattern of serological data suggested active coccidioidomycosis. He was started on liposomal amphotericin B. Posaconazole and anidulafungin were discontinued. After one week of liposomal amphotericin B treatment, he was transitioned to oral fluconazole 400 mg daily. His hypoxia resolved, and he was discharged home. Nine days after discharge, our microbiology lab reported growth of mold from fungal lung tissue cultures. The isolate was preliminarily identified as Histoplasma capsulatum based on morphology (Figure 2) and was sent to a reference laboratory where it tested positive for Histoplasma capsulatum by DNA probe. A Histoplasma capsulatum DNA probe sent from his left upper lobe tissue culture was positive. On follow-up visit in the Infectious Diseases clinic, he was switched from fluconazole to itraconazole for the treatment of pulmonary histoplasmosis. A repeat chest CT showed improvement in the size and number of bilateral lung micronodules. One month after discharge, he reported resolution of shortness of breath. However, he described worsening of pain from RA in his shoulders, knees, wrists, and ankles. He was restarted on sulfasalazine and methotrexate after he had been on treatment for histoplasmosis for more than two months. Approximately eight months after presentation, his CT imaging continued to display multiple bilateral pulmonary nodules. Histoplasma antibodies by CF were checked and were negative (<1 : 8). He has been continued on his oral itraconazole treatment with plans to treat for at least one year.

PMC3561114_01

Female

A 49-year-old woman, born to nonconsanguineous parents in Laos, but who had lived in Canada for the past 30 years, presented in May 2010 with a 1-month history of weight loss, fatigue, cough, and intermittent low-grade fever. Her previous family and personal medical history were unremarkable. She could not recall being in contact with tuberculosis. Given that a 7-day course of levofloxacin treatment for presumed right lung pneumonia did not improve her symptoms, she was subjected to further examinations. An initial bronchoscopy showed friable, bleeding, and irregular mucosa of the right upper lobe entry. Biopsies were not feasible, but Ziehl-Neelsen and auramine stains of the bronchoalveolar lavage (BAL) were negative and cytology was normal. A thoracic computed tomography (CT) scan revealed atelectasis caused by an 8 x 7 cm irregular mass impacting the right superior lobar bronchus along with multiple mediastinal and hilar adenopathies (Figure 1a). Since the most probable diagnosis was a neoplastic process, the patient was discharged home to await a scheduled transthoracic biopsy (TTB). However, when a previous BAL culture was found to be positive for acid-fast bacilli (AFB), she was readmitted to rule out active tuberculosis. Upon presentation, she was afebrile and her vital signs were normal. There was no regional adenopathy, and the physical examination was normal except for reduced vesicular murmur sounds on auscultation over the right lung. The peripheral white blood cell count was 26 x 109/L, with 21 x 109/L neutrophils and 3 x 109/L lymphocytes. The inflammatory syndrome was considered important due to a serum C-reactive protein concentration of 111 mg/L and erythrocyte sedimentation rate of 25 mm/h. The procalcitonin concentration was 19 mug/L. The hemoglobin level was 71 g/L with a mean corpuscular volume of 73 fL, and the platelet count was at 766 x 109/L. Other routine biochemical tests were normal. Polymerase chain reaction (PCR) performed 3 days after admission, using morning sputum, was negative for Mycobacterium tuberculosis complex. On the fourth day, the patient developed fever with purulent expectorations. While other investigations were being pursued, treatment for post-obstructive pneumonia was initiated with piperacillin-tazobactam. An endobronchial ultrasound (EBUS) revealed purulent secretions and a diminished right superior lobar bronchus caliber. Multiple transbronchial needle aspirations of adenopathies were also performed. Two days later, the patient's condition necessitated her transfer to the intensive care unit (ICU), and vancomycin was added. The peripheral white blood cell count was 47 x 109/L and a chest X-ray film showed a new infiltration process affecting the right lower lobe and median lobe with an important pleural effusion. Analysis of the pleural fluid showed an uncomplicated exudative effusion (pH >7.2) with a predominance of lymphocytes. On the fourth day in the ICU, endotracheal intubation and support with amines were required for septic shock. The results of mediastinoscopy biopsies followed by a TTB of the mass lesion were non-diagnostic, showing only extensive fibrosis and unspecific acute and chronic reactive lymphoid infiltrates. Granuloma formation was not observed. On the eight day in the ICU, the first preliminary report of the initial BAL sample revealed that it was positive for M. colombiense, as shown by analyzing genomic deletions and rRNA 16S gene sequencing (Quebec Public Health Laboratory). As radiologic control had also deteriorated (Figure 1b), the decision to commence treatment on the same day with rifampicin, clarithromycin, and ethambutol was taken. Later sensitivity analysis by broth microdilution revealed that M.colombiense was susceptible to clarithromycin with a minimum inhibitory concentration (MIC) of 0.25 mg/L. Rifampin's MIC was 4 mg/L and ethambutol's MIC was >16 mg/L. Although ethambutol and rifampin are useful clinically in cases of Mycobacterium avium complex infections, breakpoints for determining susceptibility and resistance have not been established by the Clinical and laboratory standards institute M24-A2 (CLSI M24-A2). HIV tests were repeatedly negative. Two days later, multiple organ failure (MOF) developed. Since the previous mediastinoscopy culture was positive for a multiresistant Pseudomonas aeruginosa strain (Table 1), vancomycin was stopped and piperacillin-tazobactam was changed to doripenem and tobramycin. On the patient's 27th day in the ICU, administration of anti-Pseudomonas antibiotics was terminated because her clinical condition was stable. However, when 2 tracheal aspirates were found to be positive for susceptible P. aeruginosa (Table 1) and clinical deterioration was again noted, treatment with piperacillin-tazobactam and ciprofloxacin was started. Unfortunately, the patient died from septic shock with MOF on the 34th day in the ICU. Interestingly, almost every culture performed during the patient's hospitalization was positive for M. colombiense (Table 1). Although cytomegalovirus (CMV) serology was not performed for this patient before her death, samples from the final bronchoscopy grew CMV in fibroblast cell culture many days later (Table 1). The pathologist also identified CMV inclusions in the lungs, mediastinal adenopathies, thyroid gland, pancreas, and adrenal glands (Figure 2a). This observation was also confirmed by immunohistochemistry (Figure 2b). Post-mortem examination of the right lung revealed an organizing pneumonia, and the mediastinum contained a lot of adherence, fibrosis, and adenopathies with lymphoid hyperplasia. No granuloma formation was detected in the lungs or in any of the other organs examined. An immunologic investigation performed before the death of our patient revealed normal counts of lymphocyte populations (CD4+, CD8+, CD19+, CD56+) and normal levels of immunoglobulins. We concluded that a genetic immunological deficit was very unlikely because of the late presentation of symptoms:at the age of 49 years:and the absence of significant family or personal medical history. Instead, we suspected an acquired deficit; thus, we tested for the presence of anti-IFN-gamma autoantibodies in the patient's plasma. The IFN-gamma titer:defined as the dilution of a patient's plasma that inhibits 50% fixation of 125 pg/mL IFN-gamma in a standard IFN-gamma ELISA assay (eBioscience ELISA kit):was positive at 1:53725. Therefore, the final diagnosis was immunodeficiency secondary to the production of autoantibodies against IFN-gamma, which resulted in post-obstructive pneumonia caused by lymphadenitis and disseminated infection of M. colombiense. The clinical course was complicated by the presence of multiresistant P. aeruginosa infection post-EBUS mediastinitis, CMV pneumonitis with dissemination, and finally, susceptible P. aeruginosa ventilator-associated pneumonia with septic shock and MOF leading to death.

a; Thoracic CT scan at presentation. Irregular mass impacting the right superior lobar bronchus.

PMC3561114_01

Female

A 49-year-old woman, born to nonconsanguineous parents in Laos, but who had lived in Canada for the past 30 years, presented in May 2010 with a 1-month history of weight loss, fatigue, cough, and intermittent low-grade fever. Her previous family and personal medical history were unremarkable. She could not recall being in contact with tuberculosis. Given that a 7-day course of levofloxacin treatment for presumed right lung pneumonia did not improve her symptoms, she was subjected to further examinations. An initial bronchoscopy showed friable, bleeding, and irregular mucosa of the right upper lobe entry. Biopsies were not feasible, but Ziehl-Neelsen and auramine stains of the bronchoalveolar lavage (BAL) were negative and cytology was normal. A thoracic computed tomography (CT) scan revealed atelectasis caused by an 8 x 7 cm irregular mass impacting the right superior lobar bronchus along with multiple mediastinal and hilar adenopathies (Figure 1a). Since the most probable diagnosis was a neoplastic process, the patient was discharged home to await a scheduled transthoracic biopsy (TTB). However, when a previous BAL culture was found to be positive for acid-fast bacilli (AFB), she was readmitted to rule out active tuberculosis. Upon presentation, she was afebrile and her vital signs were normal. There was no regional adenopathy, and the physical examination was normal except for reduced vesicular murmur sounds on auscultation over the right lung. The peripheral white blood cell count was 26 x 109/L, with 21 x 109/L neutrophils and 3 x 109/L lymphocytes. The inflammatory syndrome was considered important due to a serum C-reactive protein concentration of 111 mg/L and erythrocyte sedimentation rate of 25 mm/h. The procalcitonin concentration was 19 mug/L. The hemoglobin level was 71 g/L with a mean corpuscular volume of 73 fL, and the platelet count was at 766 x 109/L. Other routine biochemical tests were normal. Polymerase chain reaction (PCR) performed 3 days after admission, using morning sputum, was negative for Mycobacterium tuberculosis complex. On the fourth day, the patient developed fever with purulent expectorations. While other investigations were being pursued, treatment for post-obstructive pneumonia was initiated with piperacillin-tazobactam. An endobronchial ultrasound (EBUS) revealed purulent secretions and a diminished right superior lobar bronchus caliber. Multiple transbronchial needle aspirations of adenopathies were also performed. Two days later, the patient's condition necessitated her transfer to the intensive care unit (ICU), and vancomycin was added. The peripheral white blood cell count was 47 x 109/L and a chest X-ray film showed a new infiltration process affecting the right lower lobe and median lobe with an important pleural effusion. Analysis of the pleural fluid showed an uncomplicated exudative effusion (pH >7.2) with a predominance of lymphocytes. On the fourth day in the ICU, endotracheal intubation and support with amines were required for septic shock. The results of mediastinoscopy biopsies followed by a TTB of the mass lesion were non-diagnostic, showing only extensive fibrosis and unspecific acute and chronic reactive lymphoid infiltrates. Granuloma formation was not observed. On the eight day in the ICU, the first preliminary report of the initial BAL sample revealed that it was positive for M. colombiense, as shown by analyzing genomic deletions and rRNA 16S gene sequencing (Quebec Public Health Laboratory). As radiologic control had also deteriorated (Figure 1b), the decision to commence treatment on the same day with rifampicin, clarithromycin, and ethambutol was taken. Later sensitivity analysis by broth microdilution revealed that M.colombiense was susceptible to clarithromycin with a minimum inhibitory concentration (MIC) of 0.25 mg/L. Rifampin's MIC was 4 mg/L and ethambutol's MIC was >16 mg/L. Although ethambutol and rifampin are useful clinically in cases of Mycobacterium avium complex infections, breakpoints for determining susceptibility and resistance have not been established by the Clinical and laboratory standards institute M24-A2 (CLSI M24-A2). HIV tests were repeatedly negative. Two days later, multiple organ failure (MOF) developed. Since the previous mediastinoscopy culture was positive for a multiresistant Pseudomonas aeruginosa strain (Table 1), vancomycin was stopped and piperacillin-tazobactam was changed to doripenem and tobramycin. On the patient's 27th day in the ICU, administration of anti-Pseudomonas antibiotics was terminated because her clinical condition was stable. However, when 2 tracheal aspirates were found to be positive for susceptible P. aeruginosa (Table 1) and clinical deterioration was again noted, treatment with piperacillin-tazobactam and ciprofloxacin was started. Unfortunately, the patient died from septic shock with MOF on the 34th day in the ICU. Interestingly, almost every culture performed during the patient's hospitalization was positive for M. colombiense (Table 1). Although cytomegalovirus (CMV) serology was not performed for this patient before her death, samples from the final bronchoscopy grew CMV in fibroblast cell culture many days later (Table 1). The pathologist also identified CMV inclusions in the lungs, mediastinal adenopathies, thyroid gland, pancreas, and adrenal glands (Figure 2a). This observation was also confirmed by immunohistochemistry (Figure 2b). Post-mortem examination of the right lung revealed an organizing pneumonia, and the mediastinum contained a lot of adherence, fibrosis, and adenopathies with lymphoid hyperplasia. No granuloma formation was detected in the lungs or in any of the other organs examined. An immunologic investigation performed before the death of our patient revealed normal counts of lymphocyte populations (CD4+, CD8+, CD19+, CD56+) and normal levels of immunoglobulins. We concluded that a genetic immunological deficit was very unlikely because of the late presentation of symptoms:at the age of 49 years:and the absence of significant family or personal medical history. Instead, we suspected an acquired deficit; thus, we tested for the presence of anti-IFN-gamma autoantibodies in the patient's plasma. The IFN-gamma titer:defined as the dilution of a patient's plasma that inhibits 50% fixation of 125 pg/mL IFN-gamma in a standard IFN-gamma ELISA assay (eBioscience ELISA kit):was positive at 1:53725. Therefore, the final diagnosis was immunodeficiency secondary to the production of autoantibodies against IFN-gamma, which resulted in post-obstructive pneumonia caused by lymphadenitis and disseminated infection of M. colombiense. The clinical course was complicated by the presence of multiresistant P. aeruginosa infection post-EBUS mediastinitis, CMV pneumonitis with dissemination, and finally, susceptible P. aeruginosa ventilator-associated pneumonia with septic shock and MOF leading to death.

b; Thoracic CT scan on the eighth day in the ICU. Extensive right pulmonary consolidation.

PMC3134955_02

Female

A 41-year-old Caucasian woman was admitted to the hospital in July 1998, because of Pneumocystis jiroveci pneumonia, oral candidiasis and pulmonary tuberculosis. HIV infection was diagnosed and ART with didanosine, stavudine and nevirapine was started. Two years later, progressive cholestasis appeared in blood test and infection with hepatitis B and hepatitis C virus was ruled out. In June 2003, the patient was admitted to the hospital because of bleeding from grade 2-3 esophageal varices. Sclerosis and banding ligation were performed, but main portal vein stent placement was required to connect the portal vein to inferior vena cava. Abdominal Doppler ultrasound showed massive ascites, left branch portal and splenoportal vein nonocclusive thrombosis, as well as chronic liver disease. Autoimmunity parameters disclosed slightly positive anti-smooth muscle and negative antinuclear, antimitochondrial and anti-liver kidney microsomal antibodies. She was evaluated for hypercoagulable state and was found to have low antithrombin III values at the time of hematemesis. Sixteen months later, low protein C and S values were found. A liver biopsy showed patchy sinusoidal dilatation and congestion, collapsed liver cell plates and nodular areas without extensive fibrosis, all of these findings being suggestive of nodular regenerative hyperplasia. In April 2005, ART was changed to abacavir/lamivudine and lopinavir/ritonavir booster (didanosine was removed), due to virological failure and according to resistance test. An abdominal ultrasound performed in March 2009 showed patent shunt. Eight months later, CD4 cell count was 1005/mcl (36 %), viral load was below 50 copies/ml, and the patient had a satisfactory general condition.

hiv, didanosine, portal hypertension

PMC9425879_01

Female

A 38-year-old South African woman presented to a district hospital in Durban, Kwa-Zulu Natal with progressive, painless bilateral visual loss since 10 March 2020. She had associated mild, intermittent headaches which were relieved by simple analgesia. Systemic enquiry was non-contributory. She was diagnosed with HIV infection in 2006 and began antiretroviral treatment (ART) in 2012. She was switched to second-line ART in 2020 after reports of virological failure secondary to default. She was seen initially at McCord's Provincial Eye Hospital (MPEH) on 10 March 2020 with a history of progressive loss of vision. She was noted to have bilateral panuveitis with macula oedema and disc pallor with non-perfused vessels. She was given topical and sub-Tenon's steroids as well as bilateral bevacizumab (Avastin) injections for the macula oedema, which resolved. Her viral load at presentation was 208,806 copies/mL (15 January 2020), which worsened to 237,000 copies/mL (15 March 2020) after which she was switched to second-line ART as a result of treatment default. Her cluster of differentiation (CD4) count on this presentation was 39 cells/microL. She was diagnosed with pulmonary tuberculosis (PTB) confirmed by typical chest radiographic changes and initiated on anti-TB treatment on 18 April 2020 after which she noticed worsening of the loss of vision in both eyes. She was then seen at MPEH on 25 May 2020 and was noted to have no perception of light (NPL) in both eyes. Fundus examination was still possible at this stage, which noted resolving macula oedema and disc pallor with non-perfused vessels. She was admitted to a district hospital in Durban for vision loss in February 2021. She reported compliance to her ART, and on admission her HIV viral load was 136 copies/mL, while her CD4 count was 132 cells/microL. She did not report any history of eye trauma. Her surgical, ophthalmological, and family histories were otherwise unremarkable. She had sober habits with a history of swimming in rivers. She was previously employed as a domestic worker with no history of toxic exposures and reported to have stayed on a farm and consumed cooked meat. General examination revealed an obese, middle-aged woman. Her vital signs, including blood pressure, were within normal limits. On examination, her Snellen Visual Acuity (VA) was measured as being 6/60 in the right eye and 1/60 in the left eye with no improvement with pinhole testing. Anterior segment examination revealed bilateral corneal pigmented keratic precipitates with cells in the anterior chamber and anterior vitreous humour and lenticular opacities. Fundus examination revealed bilateral optic disc pallor with striae and exudates at the macula and retinal vasculitis with extensive non-perfused vessels. The chest radiograph was normal. A computed tomography (CT) scan of the brain illustrated a small focus of nodular irregular thickening of the right retina just adjacent to the insertion of the optic nerve suggestive of an inflammatory lesion, non-benign lesion, haemorrhage or artefact. Clinically correlation was advised. There were no periventricular plaques, calcifications, infarcts, or pathological enhancements (Figures 1-3). Figure 4 shows tractional retinal detachment on the right eye. Figure 5 depicts the left eye with tractional bands and shows a 'double-walled sign' suggestive of echinococcal cystic cavity, causing traction on the retina. A full systemic work-up was performed to exclude systemic echinococcus and other infections. A lumbar puncture was within normal range (Table 1). Liver ultrasound revealed no cystic lesions. Parasitic serology revealed a cysticercosis ELISA IgG negative value of 0.2, while the Echinococcus ELISA IgG was positive with a value of 1.3. The full blood count revealed a white cell count of 7.26 x 109 with an eosinophilia of 5.70% (0.41 x 109). Her inflammatory markers, both C-reactive protein (CRP) and ertythrocyte sedimentation rate (ESR), were elevated at 47 mg/L and 93mm/hr, respectively. Non-specific markers in the form of Serum Angiotensin Converting Enzyme (SACE) and Rheumatoid Factor (RF) were weakly positive, at 101 U/L (8-52) and 13.0 IU/mL, respectively. Anti-nuclear antibodies and anti-nuclear factor were negative. Hepatitis screen was negative. Vitamin B12 and folate levels were normal. Syphilis serology tests were negative (Treponema pallidum haemagglutinin assay, fluorescent treponemal antibody absorption test). Herpes simplex virus (HSV) IgM result was negative. Both cytomegalovirus IgM result and Toxoplasma gondii IgM ELISA result were negative. Anaerobic and aerobic blood cultures showed no growth. The rest of the blood parameters were within normal limits. She was initiated on topical steroids and given bilateral orbital floor intravitreal steroid injections which resulted in decreased intraocular inflammation and dry maculae. Optical coherence tomography (OCT) revealed a central pre-injection macula thickness of 445 microm on the right and 446 microm on the left with intraretinal and subretinal fluid (Figure 6). Post-injection central macula thickness was 299 microm with scarring on the right. On the left, central macula thickness was reduced to 232 microm. At her 2-month clinic visit, she had no light perception and had developed cataracts with posterior synechiae which prevented fundal examination with intraocular pressures of 2 mmHg on the right eye and 3 mmHg on the left eye. After extensive work-up and ophthalmological expert consultation, she was initiated on long-term albendazole at a dose of 600 mg daily orally. She was continued on her ART for the HIV infection. She was provided with counselling by the social worker, referred to a society for the blind and a disability grant was initiated. By the fifth month after presentation, her visual acuity remained unchanged with no light perception bilaterally.

echinococcosis, south africa, hydatid disease, intraocular, parasitic disease

PMC9834524_01

Male

A 63-year-old Ecuadorian male patient with a history of type 2 diabetes mellitus (T2DM) and adult-onset Still's disease (AOSD) was admitted to a local hospital for presenting chronic fever and fatigue. AOSD was diagnosed approximately 3 years ago and treated with 2 cycles of Etanercept, oral corticosteroids, and methotrexate. His symptoms were attributed to the usage of monoclonal antibodies. However, after completing the treatment, his condition continues to decline with persistent daily fevers. On clinical examination, the patient presented Cushing's like fascia ("moon face") and subdermal nodules in the left hypochondrium and left forearm. A chest computed tomography (CT) scan revealed consolidation in the right lung vertex (Figure 1). Based on the patient's immunosuppression history, tuberculosis was initially suspected, but all test results were negative, including the sputum culture. Subsequently, a fiber bronchoscopy was performed with negative results, and the patient was started on a course of Piperacillin/tazobactam and quinolone. During hospitalization, the patient became lethargic and within less than 24 h he presented left-sided hemiparesis. The neurology department was consulted to assess for a cerebrovascular accident (CVA). The brain CT scan showed hypodense lesions at the level of the anterior limb of the internal capsule and right lenticular nucleus. A magnetic resonance imaging (MRI) of the brain revealed rounded lesions at basal ganglia and bilateral subcortical cortical lesions in the frontal, parietal, and temporal lobes with bilateral cerebellar lesions of different sizes on T2-weighted imaging (T2-WI) and Fluid-attenuated inversion recovery-weighted imaging (FLAIR-WI) (Figure 2). Based on the imaging findings, the diagnostic was leaning toward infection of the central nervous system or brain metastasis. His condition continued to decline to a state of stupor and was admitted to ICU. The patient was sedated and put on ventilatory support. Cerebrospinal fluid (CSF) reported adenosine deaminase (ADA): 11 UI/L, proteins: 110 g/dl, glucose: 82 mg/dL, Lactate Dehydrogenase (LDH): 35 U/L, negative liquid cultures, no growth in Chinese ink culture, C-reactive protein (CRP): negative for TB. In collaboration with the infectious diseases department, the patient received antituberculous drugs plus a course of broad-spectrum antibiotics. A control brain CT scan revealed an increase in size and number of the aforementioned lesions. Brain MRI with spectroscopy showed a peak of choline that confirmed neuro infection (Figure 3). Despite the treatment, fever persisted, and symptoms were not improving. After consulting the neurosurgery department, a CT-assisted stereotactic brain biopsy of the lesions was obtained with no apparent complications, and samples were analyzed with Kinyoun stain confirming the presence of filamentous gram-positive bacillus compatible with Nocardia (Figure 4). Molecular Biology study: Sanger method Sequencing of the 16 S rRNA gene confirmed 99.83% of Nocardia asiatica. Based on these results, a change in antibiotic treatment with trimethoprim/sulfamethoxazole (TMP-SMX) was decided upon. The patient presented partial improvement; however, further complications consequent to paralytic ileus led to multi-organ failure, and death.

nocardia asiatica, basal ganglia, case report, cerebral nocardiosis, immunodeficiency

PMC5937423_01

Male

A 62-year-old man attended a community hospital on April 16, 2012, due to a series of respiration symptoms such as cough and asthma with sputum. Chest X-rays showed a 2.8 cm anterior mediastinal mass and signs of pneumonia (Figures 1(a) and 1(b)). Afterwards, TBNA (transbronchial needle aspiration) failed to collect target tissues after two attempts. So he went to the First Affiliated Hospital of Nanjing Medical University for clear-cutting diagnosis on May 10, 2012. PET/CT scan was subsequently taken, and the SUV value of the lesion was as depicted by 2.4 (Figure 1(c)), which almost excluded the possibility of tumor. Considering his dissipating symptoms of pneumonia, the patient adopted the outpatient follow-up treatment for 7 months until November 27, 2012. In the meantime, the lesions showed no significant regression in computed tomography (CT) imaging during routine follow-ups. On December 4, 2012, the patient was admitted to the Department of Thoracic Surgery for lump resection surgery. The lesion was later pathologically diagnosed with thymoma, B2 type. On February 25, 2013, the patient was readmitted for recurrent respiratory infection. A series of detailed clinical analyses was further carried out, and the results were as follows: fasting blood glucose 7 mmol/l (3.9-6.1 mmol/L), HA1c 7.2% (4.0%-6.4%), positive autoantibodies of glutamic acid decarboxylase (GAD) and insulin autoantibody (IAA), globulin 19.7 g/L (20.0-40.0 g/L), and serum IgG 3.2 g/L (7.0-16.0 g/L), IgM 0.17 g/L (0.4-2.3 g/L), and IgA 0.37 g/L (0.7-4.0 g/L). Complement component 3 (C3) and complement component 4 (C4) results were within reference ranges. The results of routine blood test and blood biochemistry analysis were normal. Serum virus copy number detection including CMV, EBV, HIV, and HBV was negative. But his peripheral lymphocyte subsets were abnormal with low CD4+ T cells (16.2%; 30%-40%) and extremely low B cells (0.1%; 9%-14%). He also had slightly decreased muscle tension which improved after surgery. Moreover, this GS patient had mild diarrhea after thymoma resection, which improved without additional treatment. The combination of disrupted peripheral lymphocytes and immunoglobulin and a history of high blood sugar, as well as the diagnosis of thymoma, lead to the patient final diagnosis of GS. Immunoglobulin replacement was immediately and regularly applied to enhance postsurgery immunity supportive therapy until now. Between February 2012 and March 2017, the patient was readmitted several times to our hospital for recurrent respiratory infections due to high susceptibility to gram-negative bacilli or fungi of Candida albicans (July 7, 2013; August 19, 2013; May 14, 2015; and March 25, 2016). This GS patient often suffered from cough with sputum, fever of 39 C, and chest pain as well as signs of pneumonia identified via chest CT images. Doctors usually utilized combination therapy including antibiotics (levofloxacin tablets/imipenem/cefodizime) and antifungal (fluconazole) drug to prevent Candida albicans, as well as ambroxol for cough with sputum, which eliminated respiratory inflammation and prevented double infection (bacterial-fungal infections). Moreover, the routine monitoring of immunoglobulin, blood sugar, peripheral lymphocyte subsets, and immunoglobulin infusion is still ongoing every 3 months in our GS patient. A peripheral blood sample was collected on November 22, 2016 during a routine outpatient examination of a GS patient 4 years after thymectomy. At the time of sample collection, the patient did not show any obvious signs of respiratory infection, but he had a history of recurrent respiratory infections. The proportions of his peripheral immune cells were evaluated by flow cytometry. As shown in Figure 2, this GS patient had an elevated proportion of CD8+ T cells (55.6%) and a reduced proportion of CD4+ T cells (12.1%) compared with the corresponding levels in healthy control subjects (HCs); furthermore, B cells (1%) were nearly absent in this patient, and he also had an inverted ratio of CD4+/CD8+ cells. gammadeltaT cells play a crucial role in preventing bacterial and fungal infection and act as the first protective barrier of innate immunity. These cells are split into two subgroups based on the classification of the delta ligand: Vdelta1 T cells, which are almost located in the epithelial tissue, and Vdelta2 T cells, which account for 70% of the total gammadeltaT cells in the peripheral blood. Although the relative proportion of gammadeltaT cells in our GS patient was similar to that in HCs, the percentage of Vdelta2 T cells was particularly low (12.5% versus 66.45 +- 20.79%) in our GS patient. Accordingly, the percentage of Vdelta1 T cells in this patient was higher than that in the HCs (43.9% versus 19.12 +- 17.20%) (Figure 2(c)). This different distribution of gammadeltaT cell subsets may be related to the patient's recurrent respiratory infections. It is possible that the altered distribution of peripheral immune cells partly caused an inefficient peripheral immune response. Tregs modulate immune homeostasis that induced immune suppression effect in the peripheral blood. We further analyzed the proportions of five subtypes of Tregs with GS patient via flow cytometry. As shown in Figure 3, the percentages of CD4+CD25+Foxp3+ Treg cells (5.54% versus 1.46 +- 0.71%) and CD4+CD25+CTLA-4+ Treg cells (3.18% versus 0.66%) were higher in our GS patient compared with HCs. Surprisingly, the percentage of CD4+CD39+ Treg cells was 21.8% in our GS patient, which was much higher than that in the HCs (8.034 +- 1.868%). Recent studies indicated that CD8+ Treg cells are increased and associated with tumor stages in human ovarian cancer. As shown in Figure 4, the proportions of CD8+CD28- Treg cells and CD8+Foxp3+ Treg cells in our GS patient were 88.8% (HCs 38.66 +- 6.93%) and 2.3% (HCs 0.71 +- 0.29%), respectively. Additionally, the CD28 expression in our GS patient's immune cells was significantly lower than that in HCs. Thus, the excessive populations of various Treg cells in our GS patient's peripheral blood highlight the severe immune suppression status of this GS patient. Cell proliferation capacity is an essential index for assessing the presence of an effective immune response. We investigated the ex vivo proliferation of circuiting CD4+ T cells from our GS patient via flow cytometry. The result shows that CD4+ T cells from our GS patient underwent less proliferation than those from HCs (34.0% versus 80.8%) following stimulation by CD3/CD28; additionally, the cells from the GS patients had lower proliferation rates and fewer divisions (Figure 5). It has been widely reported that immune checkpoints, including programmed death receptor-1 (PD-1) and programmed death ligand-1 (PD-L1), participate in the progression of immune suppression, which also partly correlates with T cell activation and proliferation as well as cytokine secretion. In this study, our GS patient's peripheral CD4+ T cells expressed markedly higher levels of PD-1 (34.2% versus 4.2 +- 1.8%) but lower levels of PD-L1 (6.61% versus 10.1 +- 3.9%) than those reported for GS patients (Figure 6); this difference was similar to that reported by previous studies. These results suggest that both poor proliferation and increased PD-1 expression of circulating CD4+ T cells, along with a higher level of CTLA-4 expression, may be at least partly associated with the delayed immune reactions to infection in our GS patient. We detected the cellular IFN-gamma levels produced by ex vivo CD4+ T cells, CD8+ T cells, and gammadeltaT cells from our GS patient, and cells from 10 healthy volunteers were included as controls (Figure 7). The amount of IFN-gamma produced by CD4+ T cells was similar between our GS patient and the HCs (32.5% versus 31.08 +- 12.50%). In contrast, the amount of IFN-gamma secreted by CD8+ T cells was higher in our GS patient than in the HCs (71.1% versus 44.15 +- 12.49%), and the opposite trend was observed in gammadeltaT cells (15.1% versus 33.98 +- 12.26%). Additionally, we also found that the circuiting CD4+ T cells from our GS patient secreted slightly more IL-17A compared with those from the HCs (4.3% versus 2.62 +- 1.38%) (Figure 8). However, the levels of cellular IL-17A produced by CD8+ T cells and gammadeltaT cells were not significantly different between our GS patient and the HCs (1.20% versus 1.37 +- 0.91%; 2.70% versus 1.42 +- 0.41%, resp.). These results illustrate the abnormality of cellular cytokine levels in our GS patient, which may be linked to the recurrent respiratory infections suffered by this patient.

PMC4153222_01

Male

A 44-year old male residing at Howrah, West Bengal, India, businessman by profession, presented with severe respiratory distress, high grade fever and productive cough for the past 3 months. The patient was apparently well 3 months before, when he first noticed rise of temperature and left sided chest pain along with cough and expectoration. Fever was high from the beginning(104-105 F), intermittent in nature and not associated with chill or rigor that would relieve only after taking medications. Chest pain was pleuritic and localized in the left side. Cough was initially mild but it became severe within few days accompanying by thick, yellow and foul smell sputum about 50 ml per day. Afterwards, gradually increasing respiratory distress ensued, but it was not associated with hemoptysis. There was no history of weight loss during this period. He was admitted to a local hospital, where he received few intravenous antibiotics and was discharged almost asymptomatic with anti-tuberculosis drugs (ATD) on empirical basis. Thereafter, patient was apparently well for next two months. Meanwhile, he again suffered from high grade fever with chest pain over the same site along with productive cough. He was re-treated with some oral medications and subsequently fever subsided but other symptoms persisted, for which he was brought to our hospital for the first time and was immediately admitted. Clinical examination revealed polycythemia, mild cyanosis and grade 2 clubbing (Figure 1). There was no significant palpable lymph node anywhere in the body. Though he was hemodynamically stable, tachypnea persisted for long. Respiratory system examination revealed woody dullness over left infrascapular region on percussion and bronchial breath sound along with coarse crackles over the same area on auscultation. Blood biochemical examination revealed Hb = 18.9 mg/dl, TLC = 20200 ( Neu = 85%, Lymph = 12%,Eos = 1%), fasting blood sugar (FBS) = 71 mg/dl, urea = 23 mg/dl, creatinine = 1.1 mg/dl with normal serum electrolytes and liver function tests. Chest X-ray revealed left sided consolidation with pleural reaction and right sided diffuse pneumonitic changes (Figure 2). Repeated pleural tap was unsuccessful. Thoracic HRCT was suggestive of consolidation at left mid zone with pleural effusion at the base of the left lung (Figure 3). CT guided fine needle aspiration from left sided pleural effusion showed blood elements, a few foam cells and mesothelial cells. No malignant cell was seen. He was treated again with higher dosage of intravenous antibiotics and ATDs was also administered concomitantly. He was discharged with ATDs and advised bronchoscopy, as his coughs persisted. Since he got some relief from dyspnea and chest pain, he refused to undergo bronchoscopy. After an event free interval of 3 months he felt similar problem as in previous episodes. These symptoms were sudden onset and patient was rushed to the emergency department and admitted accordingly. Dyspnea was severe and fever was high, continuous and associated with chill. The amount of sputum was huge with whitish color and foul smell. On physical examination, cyanosis and clubbing were present with respiratory rate of 30/min, pulse rate of 110/min and BP of 110/80 mmHg. No lymph nodes were palpable throughout in the body. On respiratory system examination, trachea was central in position, chest movement was diminished in left side, breath sounds decreased in both sides (more at the left side), and coarse crepitation was present in both sides of chest. Other system examinations showed no abnormality except scrotal examination which revealed a hard mass involving right testis with loss of testicular sensation. Left testis was normal. He developed a new symptom, hyperpigmented macules over the lower lip, margin of tongue and buccal mucosa. This time, his baseline investigations showed higher level of hemoglobin with other parameters being within normal range. Results of biochemical analysis revealed normal serum levels of thyroid stimulating hormone (TSH), free thyroxin (FT4), alpha fetoprotein, sex hormone binding globulin, testosterone and estradiol, assayed on two different occasions. The levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin and angiotensin converting enzyme did not reveal any abnormality. The 24-hour urinary steroid excretion was normal. The serum estrogen level was undetectable. Serum LDH was 1254 U/L(N < 240 U/L),beta-hCG was 1.71 mIUv/ml(normal adult male/normal adult non pregnant female-0.1-5.7). HIV-COMB test to detect HIV antibody was non reactive. Apart from routine investigations, bronchoscopy was performed and broncho-alveolar lavage (BAL) fluid was cultured and diagnosed as Klebsiella pneumonia. Culture was negative for tuberculosis in BACTEC media and cytology could not detect malignant cells. Keeping in mind the newly developed oral mucosal pigmentations, Barium meal x-ray and follow-through was performed which showed gastric dilatation with sub-optimal mucosal coating; no obvious gastric polyps were seen. Upper gastrointestinal endoscopy was also inconclusive. However, colonoscopy detected multiple polyps (Figure 4) which upon histopathological examination were proved to be of hamartomatous nature without any malignant character, confirming the diagnosis of PJS. There was no history of exposure to any drugs and no family history of PJS. Antibiotics were administered according to the drug sensitivity report. Chest X-ray was taken showing left sided non resolving pneumonia. He was treated with injectable piperacillin, tazobactam and gentamicin, and nebulisation with salbutamol. Abdominal Ultrasound was normal, but scrotal ultrasound revealed a large (10cm X 7.8 cm) mixed echogenic mass lesion involving the whole right testicular substance with dispersed necrotic areas suggestive of testicular malignancy. Left testis and epididymis were normal. High inguinal orchidectomy on right side was performed and histopathological examination of biopsy specimen showed large cell calcifying Sertoli cell tumor (Figure 5). Immunohistochemistry showed tumor cells expressing Inhibin, Calretinin and CD 56 and were immune negative for CK-7 and EMA. The tumor also stained positively for erythropoietin. Thus, a testicular tumor secreting ectopic erythropoietin explained the polycythemia in this patient. The aromatase activity was measured in the testicular biopsies and the levels detected were as follows: right testis, 1183 pmol/h/g protein and left testis 1358 pmol/h/g protein. These values were much higher than what is found in normal adult testis (33 pmol/h/g protein). Chest CT revealed variegated mass lesion and CT-guided FNA from lung lesion showed evidence suggestive of metastasis from testicular tumor. Abdominal CT revealed no obvious peri-or para-aortic lymphadenopathy (skip metastasis) and brain CT appeared to be normal. The patient was put on a chemotherapy regimen comprising of bleomycin, etoposide and cisplatin. Though he tolerated the induction phase well, subsequently developed sepsis secondary to pancytopenia in the late consolidation phase and ultimately died despite all possible medical supportive therapy.

calcifying sertoli cell tumor, peutz-jeghers syndrome, skip metastasis, testis

Thoracic HRCT showing consolidation at left mid zone with pleural collection in left base.

PMC9795948_01

Female

A 48-year-old Colombian female, Caucasian, without relevant personal or familiar medical history, who had been diagnosed with early T cell precursor ALL, with high-risk criteria due to her age and malignancy subtype who was initially treated with the PETHEMA ALL AR 2011 protocol, and with prophylactic intrathecal chemotherapy, starting in January of 2022. During her initial hospital stay, she presented with fever, along with chest computed tomography findings of ground-glass nodules in the lungs (Fig. 1) and was started on Voriconazole, due to a high suspicion of invasive pulmonary aspergillosis infection. The assessment of serum galactomannan was negative. Subsequently she exhibited a rise in aminotransferase levels over 6 times the upper limit of normal, along with conjugated hyperbilirubinemia. After performing magnetic resonance imaging, autoantibody tests, serologies for hepatotropic viruses and a liver biopsy, which ruled out fungal infection or infiltration due to her hematologic malignancy, it was concluded that she was experiencing drug toxicity due to her antifungal treatment. Therapy was changed to Isavuconazole which was administered for about 2 weeks. Despite these efforts, the patient had recurrent fever episodes and lung nodules persisted. A bronchoscopy with bronchoalveolar lavage was performed, but no relevant pathogens where isolated in the samples. SARS-COV-2, Tuberculosis molecular assays, Galactomannan and fungal cultures were negative. Multiple cervical lymphadenopathies of several centimeters in diameter where later detected. A biopsy was performed to rule out possible T cell lymphoblastic leukemia or a systemic mycosis, which had not been identified up to that moment. Ziehl-Neelsen stain and polymerase chain reaction assays for tuberculosis were negative, but the histopathologic study exhibited chronic necrotizing granulomatous inflammation, with large areas of liquefactive necrosis, containing Paracoccidioides brasiliensis yeasts (Figs. 2, 3). Following this, infectious disease specialists determined treatment with Liposomal Amphotericin B, and after 1 week of treatment fever seized, cervical lymph node size gradually reduced, and 3 weeks later, lung nodules disappeared. Regarding ALL, the treatment was resumed and after completion of the chemotherapy regimen, flow cytometry was performed in a bone marrow sample, which reported 0.4% of lymphoblasts, and MPO deficiency, depicted in Fig. 4, where flow cytometry shows different white cell populations as polymorphonuclear neutrophils and monocytes negative for MPO fluorescence, as an incidental finding as shown. This discovery correlates with the presence of Large Unstained Cells (LUC)/false neutropenia in the complete blood count, with a normal peripheral blood smear. As part of the treatment of the ALL a haploidentical allogenic stem cell transplant process was later initiated. During this process, she had multiple infectious complications, intestinal bleeding, and cholestasis, which lead to the discontinuation of liposomal amphotericin B. Antifungal treatment was stopped for 2 weeks and was later restarted using Trimethoprim/Sulfamethoxazole as indicated by the infectious diseases specialist. By that time, a control chest computed tomography did not report any lung nodules. During her bone marrow transplant recovery and engraftment, findings consistent with resolution of the MPO deficiency were noted (increase in the number of positive MPO neutrophils in the blood count). Finally, after making a complete recovery, she was discharged, and treatment with Trimethoprim/Sulfamethoxazole was continued for 12 additional months. Two weeks after discharge, a new blood count was obtained, which showed MPO positive neutrophils and stability of the graft.

acute lymphoblastic leukemia lymphoblastic, case report, enzymatic deficiency, myeloperoxidase deficiency, paracoccidioidomycosis

PMC4735505_01

Male

The return-to-sport rate from this study is similar to others seen in the literature in that 92.1% of baseball pitchers returned to the same or higher level of function. An interesting finding of this study was the breakdown in athletic level of patients who underwent UCLR. The majority of patients in this study were collegiate (51.6%) and high school (36.2%) athletes. Although this procedure has been common in collegiate athletes for some time, the number of high school athletes undergoing UCLR is somewhat concerning. There has been a trend in the literature toward younger patients undergoing UCLR, with a recent increase in the percentage of high school athletes compared with other levels. A recent study on national trends in UCLR between 2007 and 2011 using the Pearl Diver database showed that UCLR was most commonly performed in 15- to 19-year-old patients; 57% of all patients undergoing UCLR fell into this age group. Although injury prevention programs have been instituted over the past decade to protect adolescent athletes from injury, these programs have yet to yield a significant decline in injury rates. Interestingly, this study did not show a significant difference in the yearly timing of UCLR. One could postulate that pitchers are at greater risk for injuries during the beginning of the season, as they have not yet returned to game shape, but this does not appear to be accurate based on this study. The implications of this finding are that preventative programs aimed at reducing injuries at the beginning of the season may not be effective given the relatively even distribution of yearly UCLR timing seen in this study. Further research into injury prevention is crucial to slow the increase in UCLR, specifically in the high school athlete population. There is a relative paucity of literature regarding the use of allograft in UCLR. Savoie et al reported the largest series of allograft UCLR in which 116 patients (a mixture of high school, college, and professional athletes involved in baseball, softball, and javelin) underwent UCLR with hamstring allograft and found that 94.8% of players had returned to play, 88% of whom returned to play at an equal or higher level. Allograft alleviates the issue of donor site morbidity but introduces foreign human tissue into the young athlete's elbow, and there may be substantial variability in the quality of the allograft tissue. Allografts are expensive, but the overall cost related to the procedure may be offset by avoiding autograft harvest and wound closure. The results of our study are consistent with the prior study and suggest that allograft UCLR is a reasonable option for surgeons after appropriate patient and family consent. While graft choice is an important aspect of UCLR, treatment of the ulnar nerve is also important and has become controversial. Some authors recommend routine anterior subcutaneous transposition while others do not transpose the nerve at all. All the authors in this study treated the ulnar nerve with the same philosophy of management. If the patient had preoperative ulnar nerve symptoms such as paresthesia in the small and ring fingers, wasting of the interossi muscles of the hand, a positive Tinel sign at the elbow, or subluxation of the nerve, an anterior subcutaneous ulnar nerve transposition was performed as part of the index procedure. However, if the patient did not have any of the above preoperative symptoms, the ulnar nerve was not formally transposed but rather simply identified for protection and decompressed in situ. Of the 188 elbows in this study, 7 (3.7%) underwent subsequent ulnar nerve transposition for persistent ulnar nerve symptoms during the routine follow-up period. Vitale and Ahmad reviewed the literature on UCLR and found postoperative ulnar neuropathy in 3% to 8% of patients depending on the technique used (excluding the Jobe technique, which had a 20% rate of postoperative ulnar neuropathy after submuscular transposition). Hence, to date, there is no literature to strongly support any 1 practice over another, and as such, recommendations on how best to treat the ulnar nerve cannot be made at this time. In our study, the ulnar nerve was transposed subcutaneously in 79 (41.8%) patients, with an additional 7 (3.7%) requiring subsequent ulnar nerve transposition. Theoretically, if all patients underwent systematic ulnar nerve transposition, more than 50% of our patients would have been unnecessarily exposed to the potential added complications and adverse events associated with the subcutaneous ulnar nerve transposition. The 1 patient in this series who required a revision UCLR was initially treated as a high school pitcher via the standard docking technique with a hamstring autograft and subcutaneous ulnar nerve transposition. He retore his UCL 4 months after surgery while in college and underwent a subsequent revision UCLR via the standard docking technique utilizing a palmaris longus allograft. As this was the only patient in this series to require a revision UCLR, it is difficult to determine whether there are any risk factors for retearing a UCL after UCLR. Other studies have shown that risk factors for sustaining an initial UCL tear include growing up in warm weather climates and pitching while fatigued (including pitching for multiple teams at a time, pitching more than 100 innings per season, pitching more than 9 months of the year, etc). Interestingly, throwing breaking pitches at early ages has not been shown to correlate with UCL injuries, which is a common misconception among athletes, parents, and coaches. The patients in this study did not routinely undergo elbow arthroscopy at the time of UCLR unless there was documented or suspected intra-articular pathology. This is in contrast to some studies in which patients routinely undergo elbow arthroscopy at the time of UCLR to confirm instability at the medial elbow and address any intra-articular pathology. The authors believe that, while some patients necessitate an arthroscopic evaluation and treatment for various intra-articular pathologies including osteochondritis dissecans and/or posteromedial osteophytes, the vast majority of patients do not need an arthroscopic evaluation. Using the combination of history (overhead athletes with medial elbow pain), physical examination (positive moving valgus stress test or milking maneuver), and diagnostic imaging (MRI or MRA), the authors feel comfortable diagnosing and treating UCL tears and associated pathology through a direct open approach without arthroscopy in the vast majority of patients. Although this study was the largest cohort of double-docking UCLR and second largest overall cohort of UCLR patients reported in the literature to date for the patient demographics, there are several limitations. First, the patients did not have preoperative clinical scores to compare with postoperative scores. The surgical data were extracted from the electronic medical record, which may have been incomplete. There were patients who were unable to be contacted, and this could have affected the results, specifically falsely lowering the rate of postoperative ulnar neuropathy or falsely elevating the rate of return to sport. Furthermore, the study is subject to recording and recall bias as patients may not have recalled their complications or their complications may not be recorded in the electronic medical record. Similarly, they may have reported better results to the lead author (B.J.E.) on the phone in comparison with them completing a questionnaire. Patient physical examinations were not performed, so range of motion, strength, and valgus stress of the elbow were unable to be assessed, and performance measures were not evaluated. The KJOC questionnaire was administered over the phone, and it is possible that this introduced some recording or recall bias as this was administered by one of the study personnel. Furthermore, this questionnaire has not been validated for over-the-phone use, and although the patients seemed comfortable when answering the questions, this could have affected the results. Finally, although the patients in the standard docking group all had the graft fixed in the same manner, there were 7 surgeons who performed these surgeries. While all the surgeons were fellowship-trained sports, shoulder/elbow, or hand surgeons, there may have been some subtle differences in their techniques. However, in comparing the patients of each surgeon with the others, we were unable to find any statistically significant differences in outcomes or complications.

tommy john, baseball, elbow, injury, pitcher, surgical treatment, ulnar collateral ligament reconstruction (uclr)

PMC4856911_03

Male

Patient 3. A 40-year-old diabetic patient was admitted with severe cellulitis of the feet after walking bare-footed on the sand. His diabetes is poorly controlled with HBA1C 15.5 (mmol/mol). His course was complicated by neuropathy and retinopathy. He also admitted to (R) knee swelling of two years duration. Multiple aspirations and injections of the knee resulted in temporary relief. There was no history of fever or night sweats. He had contact with animals but did not consume raw milk. The (R) knee was swollen, hot, and tender with restricted range of movement. Admission WBC was 8.7, CRP 38 mg/mL, albumin 24 g/dL, and alkaline phosphatase 220 mu/L. CT scan showed moderate to large effusion of the right knee with associated synovial thickening and osteoarthritic changes (Figure 4). Synovial fluid showed WBC of 9.9 x 109 with 50.5% polymorphs. AFB smears and PCR for tuberculosis were negative. Synovial cultures isolated Brucella species but blood culture was negative. Brucella serology in the blood was high; it was 1 : 10240 and dropped to 1 : 640 on treatment. He received two weeks of streptomycin and completed a 3-month course of rifampicin and doxycycline.

PMC4856911_04

Male

Patient 4. A 68-year-old man presented with (R) knee swelling and back pain for 4 months. He was initially diagnosed as OA and spondylitis. He is known to have DM, HTN, and IHD with a permanent pacemaker. CT scan showed degenerative spinal canal stenosis at L4-L5 with mild degree of bilateral SI joints degeneration. He had received epidural injection of steroid and (R) knee injection with temporary improvement. There was no history of fever or contact with TB patients; however, there was strong history of animal contact. He received one month of antibiotics prior to presentation but without improvement. General examination was normal but the (R) knee was swollen, tender, and with decreased ROM (10-15). CT scan showed moderate to large effusion of the (R) knee with associated synovial thickening and OA changes (Figure 4). The WBC was normal, ESR 70 mm/hr., and CRP 47 mg/mL, and rheumatoid factor was negative. The blood urea and creatinine was raised at 16.8 mmol/L and 140 mumol/L. Synovial fluid cultures were positive for Brucella species but the blood culture was negative. Blood serology for brucella was 1 : 10240. He received 3/12 of doxycycline rifampicin with full functional recovery.

PMC4074181_02

Female

She had pulmonary tuberculosis at the age of 26. She took oral contraceptives, and she underwent surgery and blood transfusion for endometriosis at age 47. She had surgery without transfusion for osteoarthritis of the right knee and removal of colonic polyps, at 68 and 75 years old, respectively. Hypertension, hypercholesterolemia, and hypertrophic cardiomyopathy were diagnosed at age 56, 56, and 66, respectively, but no treatments were given. She did not have a past history of rheumatoid arthritis and had never received hemodialysis. She never smoked or drank alcohol. She was not a drug abuser, and no tattoo was found. At the time of admittance to our hospital, she was not taking any medications. Her father had esophageal cancer and alcoholic liver dysfunction, and her sister had skin cancer. Although several clinical tests were performed at the outpatient clinic during a 6-month period, as the cause of her liver dysfunction remained unknown, she was then admitted to our hospital. Contrast-enhanced computed tomography (CT) revealed hepatomegaly with narrow portal vein, hepatic vein, and mild splenomegaly (Figure 1A-C). Although the association of liver and cardiac involvement is frequent, as her electrocardiogram and echocardiography showed normal cardiac movement (left ventricular ejection fraction, 75%) and no dilatation of the inferior vena cava, we did not consider the possibility of cardiac involvement. Renal function was within normal range as late as 2 months before her death. Fluorine-18 (18F) labeled FDG PET/CT was performed. The FDG uptake into the liver but not into the spleen was observed (Figure 1D), although the mean standard uptake value was not so high (2.0 in the left lobe of the liver; 1.8-2.0 in the right lobe; and 1.3-1.4 in the spleen). Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography revealed narrowed intrahepatic bile ducts with smooth walls (Figure 2). Upper gastrointestinal endoscopy showed no abnormal gross findings, but a biopsy specimen from the duodenal bulb mucosa exhibited amyloid deposition in the interspace of smooth muscles (not shown); macroglossia was observed. Eosinophilic amorphous depositions positive for Dylon staining that were resistant to potassium permanganate treatment and positive for amyloid P component were found. These results strongly suggested AL amyloidosis. A liver biopsy was performed. The specimen was occupied by a diffuse eosinophilic amorphous structure, and any cellular component could not be found, suggesting hepatic amyloidosis (Figure 3). The biopsy specimen had the appearance of inappropriate material, but we later confirmed the hepatic involvement of primary systemic AL amyloidosis. Her general condition was too poor to allow aggressive treatment. She died 4 months after first admission to our hospital. Necropsy showed cardiac, renal, and hepatic involvement of amyloidosis.

fdg pet, amyloidosis, diagnosis, hepatic involvement

PMC6345080_01

Female

A 51-year-old Portuguese female visited A&E with a headache and vomiting. She had a transurethral resection for superficial bladder cancer 2 years ago and a pacemaker for mobitz-type-2 heartblock. She had a 35-pack-year smoking history and drank 10 units of alcohol per week. Over the preceding 3 weeks she had several hospital attendances with epigastric pain and vomiting. Investigations had been normal:she was diagnosed with gastroenteritis and discharged. This occasion, she reported ongoing epigastric pain, vomiting and new postural headaches associated with neck pain and photophobia. She had noticed progressive vision loss and unsteady gait. She denied fevers or weight-loss. On examination her GCS was 15, she had bilateral papilloedema and visual acuity reduced to hand-movement on the left. The rest of the cranial nerves III-XII and peripheral neurological examination were unremarkable, apart from an ataxic gait. She had normal observations, blood tests and x-rays. CT head and lumbar puncture were performed and she was commenced on antibiotics and antivirals to cover infective meningitis. CT head revealed a contrast-enhancing lesion in the left pre-pontine region, likely to be a trigeminal schwannoma or metastatic deposit (Fig. 1). Lumbar puncture found clear CSF, normal opening pressures, WCC 4, raised protein 2.51 and low glucose 0.3. Since the CT findings did not explain the clinical picture, an MRI head was recommended. This had to be performed at another trust since we did not have a pacemaker-compatible scanner. The patient was reviewed by neurology, infectious-diseases, ophthalmology and microbiology. Differentials included infective (particularly TB and fungal), inflammatory and neoplastic diseases. CT-venography showed no evidence of venous sinus thrombosis. Further tests included: B12/folate, LDH, ESR, hormones, ACE, immunoglobulins, complement, autoimmune and porphyria screen, tumour markers, myeloma-screen, TB ellipspot, hepatitis, HIV, CMV, cryptococcal, aspergillus, toxoplasmosis and Borrelia burgdorferi. All results were unremarkable. Further CSF results revealed no bacterial, acid-fast-bacilli or fungal growth, viral and TB PCR were negative. CSF cytology showed malignant cells (Fig. 2). CT chest, abdomen and pelvis found a solitary 15 mm parenchymal lung nodule and a 5 mm endobronchial lesion in the right lower lobe. In light of these findings; antimicrobials were stopped, dexamethasone plus a proton-pump-inhibitor started and an MRI spine, head and orbits requested. The working diagnosis was malignant meningitis of unknown primary cancer. Bronchoscopy confirmed an endobronchial tumour. The patient was transferred to oncology while awaiting histology. Further examination found no lymphadenopathy, suspicious skin or ophthalmic lesions. She had left nipple inversion (longstanding), but no breast lumps or skin changes. An urgent breast clinic appointment and mammogram were arranged and ER/PR/HER-2 status requested on CSF. During this time she deteriorated with confusion (GCS 14) and rapidly progressive neurology: tinnitus, hearing loss and bilateral proximal lower limb weakness (power 3-4/5). She lost 5 kg of weight in 2 weeks. The patient became agitated and complained of severe headaches. She had decreased vision in the right eye and complete blindness in the left. She developed worsening leg weakness (power 2/5) and urinary incontinence. Detailed neurological examination became difficult due to confusion and agitation. Morphine and Midazolam were started for comfort. On Day 10 her GCS decreased to 12 and symptoms progressed further. Despite best efforts, she was too unwell to attend the MRI appointment. Histopathological analysis revealed melanoma (cells expressed: S100p, Melan A and HMB45 and were immunonegative for: AE1/3, p63 and TTF1) (Figs 3-5). Given her poor performance-status and rapid decline, the patient was not fit for any cancer treatment. She was transferred to a hospice on Day 12.

PMC7677042_01

Male

A 72-year-old male patient presented with shortness of breath and fever of ten days duration. He was diagnosed with stage IV bronchogenic carcinoma and lymphangitis carcinomatosis five months prior to his presentation. On the initial assessment, he appeared uncomfortable, dyspneic, tachypneic and cachetic. The blood pressure was 140/85 mmHg, heart rate: 124 beats/min, oxygen saturation: 79%, and body temperature: 37.7 Co. Chest expansion was reduced as well as the air entry on the left side of the chest; course crepitation on auscultating the other side. The chest radiograph showed left sided with multiple right sided chest opacifications demonstrating a massive pleural effusion (Fig. 1). Chest thoracostomy tube was inserted on the left side, draining a clear serous fluid. Fluid sample was sent for cytology, acid fast bacilli culture, biochemistry, and Gram-stain culture and sensitivity. The patient was admitted to the thoracic ward for gradual chest decompression. He was maintained on antibiotics, and analgesia. Due to COVID-19 pandemic, the patient was sent for a CT scan of the chest, and PCR for COVID-19 to look for any evidence of COVID-19. The PCR was obtained from two sites (nasopharyngeal, and oropharyngeal). Unsurprisingly, the PCR test came back positive for COVID-19. The CT chest showed multiple ground glass opacifications on both lungs, and pleural effusion on the left side with irregular hilar mass (Fig. 2). The patient condition deteriorated; he became dyspneic and his oxygen saturation never exceeded 85% despite oxygen supply on the ward. He was transferred to ICU for ventilatory support. After three days, the result of pleural cytology was negative for metastasis, and AFB was negative for tuberculosis. The patient's condition gradually deteriorated in the following days with elevated renal parameters and progressive hypoxia. On the sixth, the patient unfortunately passed away due to severe hypoxia that led to a cardiac arrest.

bronchogenic carcinoma, covid-19, coronavirus, lung cancer, pleural effusion

CT scan of chest in day two post-intervention, showed multiple ground glass opacifications on both lungs, and pleural effusion on the left side with irregular hilar mass.

PMC6830201_01

Female

A 31-year-old female presented in the emergency room with intermittent epigastric pain for two weeks. The pain was burning in type with no radiation and was worsened by food intake. she also reported nausea usually during the pain but denied any symptoms of vomiting. The rest of the review of the system was negative. She had multiple visits to the emergency room in the last six months for similar complaints. Past medical history was only significant for cholecystectomy for cholelithiasis four years back. Vital signs at presentation were normal, and the rest of the physical examinations were within normal limits except for mild epigastric tenderness without any rebound, guarding or rigidity. Lab tests were significant for normocytic normochromic anemia with hemoglobin of 10.7 g/dL and hematocrit of 33.7%, normal serum lipase of 48 U/L (normal 22-52 U/L). Serum calcium was 8.7 mg/dL (normal 8.9-10.3 mg/dL). The rest of the complete blood count and metabolic panel were normal. An abdominal sonogram was unremarkable. Computed tomography (CT) scan of the abdomen showed normal abdominal findings with 7 mm pulmonary nodule in the right lower lobe. A subsequent CT scan of the chest showed multiple bilateral pulmonary nodules with enlarged mediastinal and hilar lymph nodes. After admission, the patient underwent esophagogastroduodenoscopy (EGD) that revealed mild gastritis while antral biopsy showed acute and chronic inflammation with non-caseating granuloma. Subsequent bronchoscopy with transbronchial biopsy showed benign lung tissue with non-necrotizing granuloma. However, Serum angiotensin-converting enzyme level (ACE) was normal 49 U/L (normal 14-82 U/L). Based on compatible clinical symptoms and histological evidence of non-caseating granuloma; the patient was diagnosed to have active gastric sarcoidosis (Figure 1) with the simultaneous presence of inactive pulmonary sarcoidosis (Figures 2 and 3). Other potential causes of granuloma including Helicobacter pylori, Mycobacterium tuberculosis, fungal organisms, etc. were excluded on histology. Later, she was started on Prednisone 40 mg per day with a progressive resolution of her GI symptoms. Subsequently, pulmonary function test was also performed during admission which showed normal spirometry compatible with asymptomatic pulmonary sarcoidosis. She was discharged on a tapering dose of prednisone with no recurrence of symptoms at 3 months of follow up.

gastric sarcoidosis, granuloma, pulmonary sarcoidosis

Computed Tomography (CT) showing hilar lymphadenopathy.

PMC9282704_01

Male

A 50-year-old gentlemanpresented with 2 ulcers over the glans penis for 10 days. They started as minimally painful papules which rapidly ulcerated with increase in size. There was no history of discharge, bleeding, fluid-filled lesions, trauma, recurrent oral ulcers, redness of eyes, joint pains, gastrointestinal symptoms, urethral discharge, fever, loss of weight, or appetite. The patient was married and gave a history of multiple extramarital contacts with commercial sex workers, last contact being 15 days before the onset of the ulcers. There was no history of sexually transmitted disease (STD) in partner. He was a known diabetic on irregular treatment for 5 years. General examination was unremarkable. Peripheral pulses were palpable. There was no lymphadenopathy. Glans penis had two well-defined tender, indurated ulcers with necrotic grayish-white slough, regular margins, undermined edges, erythematous border- measuring 3 cm x 2 cm and 0.5 cm x 0.5 cm [Figure 1a]. They did not bleed on touch. Rest of the mucosa, skin, palms, soles were normal. Gram's stain revealed multiple polymorphonuclear leukocytes, no organisms. Tzanck smear showed no multinucleated giant cells or acantholytic cells. Screening for HIV, Hepatitis B and C, syphilis (VDRL and TPHA), and herpes simplex virus serology were nonreactive. His fasting, postprandial sugars, and HbA1c were elevated (314 mg/dl, 362 mg/dl, and 7.3%, respectively). Pus culture for Haemophilus ducreyi was sterile. The Mantoux test was positive (15 mm x 17 mm). Skin biopsy [Figure 1b] showed acanthosis, fibrinoid necrosis in vessels, acute inflammatory cell infiltrate, and granulation tissue in the dermis along with necrotic debris. There was no evidence of dysplasia or malignancy. Repeat biopsy showed large areas of ulceration. Dermis showed granulation tissue with dense mixed inflammatory infiltrate of neutrophils, lymphocytes, and occasional plasma cells; there is no evidence of vasculitis, epithelioid cell granuloma, Crohn's disease, or malignancy [Figure 1c]. Ziehl-Neelsen staining did not show acid-fast bacilli, and culture for typical, atypical mycobacteria and tissue CBNAAT were negative. Chest X-ray was normal and contrast-enhanced computed tomography abdomen showed 16 mm x 10 mm right inguinal lymph node; no other significant abnormality. Pathergy test, stool for occult blood, and ANA were negative. Serum protein electrophoresis was normal. With the initial acute presentation and history of high risk behavior, considering a differential diagnosis of primary chancre with mixed anerobic infection, chancroid, or herpes genitalis, we empirically treated him with local cleansing and oral antibiotics (metronidazole and ciprofloxacin). Metformin and teneligliptin were started. After ruling out STD, we considered differentials of noduloulcerative genital tuberculosis, atypical mycobacterial ulcer, malignancy, and PG. We diagnosed PG based on clinical findings and exclusion of other causes. We started him on dapsone 100 mg once daily and colchicine 0.5 mg thrice daily. After an initial response, the patient discontinued treatment by himself and developed another ulcer near the meatal opening. He was restarted on dapsone and colchicine. Prednisolone was added for 6 weeks with a maximum of 40 mg daily with which he showed rapid improvement [Figure 1d].

nonsexually acquired genital ulcer, penile ulcers, pyoderma gangrenosum

PMC7683282_01

Male

An otherwise healthy 20-year-old male working at a construction site was carrying a metal gutter, which contacted a transformer and overhead wires resulting in both electrical contact injury and flame burns from electrothermal discharge igniting his clothing. He developed pulseless ventricular dysrhythmia and received thirteen minutes of CPR by coworkers and first responders. He was defibrillated with return of spontaneous circulation en route to an outside hospital. He was intubated and transferred to this Burn Center. The care of this patient from admission to discharge is chronicled in Fig. 1. On arrival, his primary survey was significant for an established airway with an endotracheal tube and adequate oxygenation on mechanical ventilation. He had a heart rate of 108, blood pressure of 153/94, and a GCS of 3T. Total burn area was calculated to be 45.5% TBSA of mixed deep partial- and full-thickness burns to his back, left flank, and bilateral upper and lower extremities. He sustained a full-thickness circumferential burn to the right lower extremity with palpable distal pulses. Intravenous fluid resuscitation with lactated ringer's (LR) was guided by the consensus formula, which totaled 16.6 L during the first 24 h from burn injury (4 mL/kg/%TBSA). Fresh frozen plasma was used as a colloid adjunct. A Foley catheter placed on admission returned dark urine that was positive for myoglobin (Fig. 2). Laboratory results on arrival were as follows: WBC 28.6 K/muL; Hgb 17.8 g/dL; Hct 52.4%; Platelets 342 K/muL; Potassium 5.3 mmol/L; Calcium 5.9 mmol/L; Bicarbonate 11 mmol/L; Creatinine 0.84 mg/dL; pH 7.09; pCO2 45 mmHg; pO2 166 mmHg; Carboxyhemoglobin 0.0%; Base Deficit -16.1 mmol/L. Creatinine Kinase peaked within 24 h at 33,760 units/L. Whole-body X-ray was significant for metallic foreign bodies in the airway (Fig. 3). Computed tomography (CT) localized the objects to the right bronchus intermedius (Fig. 4A-B). Retrieval attempted with flexible bronchoscopy in the trauma bay was unsuccessful. Persistent acidosis despite resuscitation and diminishing pulses raised suspicion for compartment syndrome of the right lower extremity, prompting emergent operative intervention. A four-compartment fasciotomy revealed dusky bulging muscles responsive to electrocautery stimulation. Subsequently, rigid bronchoscopy was performed with successful retrieval of two metallic screws (Fig. 5). The airway was noted to be erythematous, attributed to repeated instrumentation. Continuous RRT was initiated for persistent acidosis and electrolyte derangements secondary to rhabdomyolysis. Burn wound excision began on post-burn day (PBD) 2 and was complete by PBD67. On PBD3 he developed acute hypoxic respiratory failure. Flexible bronchoscopy revealed edematous and erythematous airways, copious secretions, and mucosal sloughing. This inhalation injury was caused by the aspiration of super-heated air and metal screws held in the patient's mouth at the moment of electrothermal discharge, and was not clear during initial management of the foreign bodies. He was diagnosed with grade III inhalation injury, initiated on protocolized nebulized pharmacotherapy (acetylcysteine, albuterol, bicarbonate, heparin) and placed in the prone position. Tracheotomy was performed (PBD14) given prolonged ventilator requirement. He required right lower extremity below knee amputation secondary to non-salvageable myonecrosis. He exhibited renal recovery and his tracheotomy was decannulated prior to discharge. He recovered well and was cleared to return to work just before the one year anniversary of his injury.

burns, case report, compartment syndrome, electrical injury, foreign body aspiration, inhalation injury

(A,B): Computed tomography (CT) images localizing foreign bodies to the right bronchus intermedius.

PMC7683282_01

Male

An otherwise healthy 20-year-old male working at a construction site was carrying a metal gutter, which contacted a transformer and overhead wires resulting in both electrical contact injury and flame burns from electrothermal discharge igniting his clothing. He developed pulseless ventricular dysrhythmia and received thirteen minutes of CPR by coworkers and first responders. He was defibrillated with return of spontaneous circulation en route to an outside hospital. He was intubated and transferred to this Burn Center. The care of this patient from admission to discharge is chronicled in Fig. 1. On arrival, his primary survey was significant for an established airway with an endotracheal tube and adequate oxygenation on mechanical ventilation. He had a heart rate of 108, blood pressure of 153/94, and a GCS of 3T. Total burn area was calculated to be 45.5% TBSA of mixed deep partial- and full-thickness burns to his back, left flank, and bilateral upper and lower extremities. He sustained a full-thickness circumferential burn to the right lower extremity with palpable distal pulses. Intravenous fluid resuscitation with lactated ringer's (LR) was guided by the consensus formula, which totaled 16.6 L during the first 24 h from burn injury (4 mL/kg/%TBSA). Fresh frozen plasma was used as a colloid adjunct. A Foley catheter placed on admission returned dark urine that was positive for myoglobin (Fig. 2). Laboratory results on arrival were as follows: WBC 28.6 K/muL; Hgb 17.8 g/dL; Hct 52.4%; Platelets 342 K/muL; Potassium 5.3 mmol/L; Calcium 5.9 mmol/L; Bicarbonate 11 mmol/L; Creatinine 0.84 mg/dL; pH 7.09; pCO2 45 mmHg; pO2 166 mmHg; Carboxyhemoglobin 0.0%; Base Deficit -16.1 mmol/L. Creatinine Kinase peaked within 24 h at 33,760 units/L. Whole-body X-ray was significant for metallic foreign bodies in the airway (Fig. 3). Computed tomography (CT) localized the objects to the right bronchus intermedius (Fig. 4A-B). Retrieval attempted with flexible bronchoscopy in the trauma bay was unsuccessful. Persistent acidosis despite resuscitation and diminishing pulses raised suspicion for compartment syndrome of the right lower extremity, prompting emergent operative intervention. A four-compartment fasciotomy revealed dusky bulging muscles responsive to electrocautery stimulation. Subsequently, rigid bronchoscopy was performed with successful retrieval of two metallic screws (Fig. 5). The airway was noted to be erythematous, attributed to repeated instrumentation. Continuous RRT was initiated for persistent acidosis and electrolyte derangements secondary to rhabdomyolysis. Burn wound excision began on post-burn day (PBD) 2 and was complete by PBD67. On PBD3 he developed acute hypoxic respiratory failure. Flexible bronchoscopy revealed edematous and erythematous airways, copious secretions, and mucosal sloughing. This inhalation injury was caused by the aspiration of super-heated air and metal screws held in the patient's mouth at the moment of electrothermal discharge, and was not clear during initial management of the foreign bodies. He was diagnosed with grade III inhalation injury, initiated on protocolized nebulized pharmacotherapy (acetylcysteine, albuterol, bicarbonate, heparin) and placed in the prone position. Tracheotomy was performed (PBD14) given prolonged ventilator requirement. He required right lower extremity below knee amputation secondary to non-salvageable myonecrosis. He exhibited renal recovery and his tracheotomy was decannulated prior to discharge. He recovered well and was cleared to return to work just before the one year anniversary of his injury.

burns, case report, compartment syndrome, electrical injury, foreign body aspiration, inhalation injury

(A,B): Computed tomography (CT) images localizing foreign bodies to the right bronchus intermedius.

PMC5167287_01

Male

A 45-year-old businessman was hospitalized for 5 days for dengue fever in 2011 during the peak of a dengue epidemic in Pakistan. He was managed with supportive treatment. Other than controlled hypertension, his past medical and family histories were unremarkable. A week post-discharge, he re-presented with left-sided chest pain, exertional dyspnoea, cough and a medium-sized, multi-loculated left-sided pleural effusion. Baseline haematological, coagulation and biochemical profiles were normal. A diagnostic pleural aspiration revealed a straw-coloured lymphocyte-predominant exudate. Bronchoscopy and bronchial washings were non-informative. A closed Abrams' biopsy yielded only non-specific pleural inflammation. A chest tube was inserted and 1.3 L of fluid was removed. In accordance with local practice for undiagnosed lymphocytic effusions, he was given an empirical trial of quadruple anti-tuberculosis (TB) therapy for TB pleuritis which he took for 4 months before being lost to follow-up. He re-presented in June 2015 with "heaviness" in his chest. A chest X-ray (CXR) and computed tomography (CT; Fig. 1) showed a large left-sided pleural-based low-density mass resembling a pleural effusion. The previous loculated residual pleural fluid collections had resolved. There was visceral pleural thickening but no abnormality was seen in the lung parenchyma or cardiovascular structures. He underwent a video-assisted thoracoscopic surgery (VATS), which identified a huge, firm-to-hard, pleural-based mass that was completely excised following conversion to a thoracotomy. The mass (Fig. 2A), which weighed 2.2 kg, occupied the anterior mediastinal recess at the level of left internal mammary artery and involved the second and third intercostal recessions. The mass was parietal pleural-based but also extended into the chest wall and was adherent to the visceral pleura, thus requiring non-anatomical lung resection for removal. The histopathology was unusual. An opinion was sought from the multi-disciplinary thoracic oncology meeting of a quaternary centre of pleural disease/mesothelioma. Tissue block and slides were examined by a specialist pleural pathologist (S. M. Chai). The morphology and immunohistochemistry of the tumour were diagnostic for desmoid-type fibromatosis. The lesional tissue showed bland spindle-shaped cells arranged in intersecting fascicles (Fig. 2B). The cells were set in variably dense collagenous stroma, with patches of myxoid change. The spindle-shaped cells had oval nuclei, small nucleoli and delicate pale eosinophilic to amphophilic cytoplasm. Scattered mitotic figures were present without any necrosis or cellular atypia. At the periphery of the tumour, the spindle-shaped cells infiltrated and surrounded individual skeletal muscle fibres. There was patchy cytoplasmic staining for smooth muscle actin and nuclear staining for beta-catenin (Fig. 2C). The lesional cells were negative for desmin, S-100, calretinin, MNF 116, D2-40, AE1 + 3, CK7 and CD34 immunostains. The patient made an uneventful recovery and had no signs of tumour recurrence after 9 months of follow-up.

desmoid, effusion, mesothelial, pleura

PMC9932685_01

Male

The patient is a 33-year-old male, an automobile factory worker with a bachelor's degree, who presented to cognitive impairment clinic on 15 September 2021 with the chief compliant of "memory declines for 3 years and progressive deterioration for 5 months". Three years before admission, the patient developed memory decline without obvious inducement, mainly in recent memory impairment. He was found to have reduced responsiveness during communication and sometimes was reluctant to communicate with others, occasionally incoherent, but he was still able to fulfill his job. His family noticed that he was emotionally indifferent, did not concerned about his family and family affairs as much as he had been in the past, and was emotionally depressed. Two years ago, the patient had visited the neurology outpatient department because of the above symptoms and underwent cranial magnetic resonance imaging (MRI) examination on 17 December 2019, which showed encephalomalacia in the right basal ganglia, frontal lobe and cerebral atrophy (Figures 1A-C). Five months ago, the patient felt that his memory loss was worsening, manifested by an inability to recall the events of the previous day, as well as to remember newly learned lyrics and melodies (he used to be good at music), and occasional transient difficulty typing on his mobile phones. Seven days prior to admission, the MRI (31 August 2021) results showed that the encephalomalacia foci had expanded to bilateral frontal lobe, right insula, and right temporo-occipital junction as compared to previous findings (Figures 1D-F). The pressure of cerebrospinal fluid (CSF) by lumbar puncture was normal, the CSF appearance was colorless and transparent, the routine examination was normal, and the biochemical and immune examinations were normal. His symptoms were not significantly improved after treatment with nutritional nerve and intellectual promotion, and he was later transferred to our cognitive impairment clinic and admitted to the neurology department. He had no significant medical history, denying arterial hypertension, diabetes, coronary heart disease (CHD), cerebrovascular disease, and other chronic diseases. Denied any history of infectious diseases such as hepatitis, tuberculosis and malaria; history of trauma and blood transfusion; history of food and drug allergy. He had been depressed after suffering an emotional trauma in 2011. A history of dog bite and rabies vaccination in 2018. Smoking history of 10 years, 20 cigarettes/day; no history of alcohol consumption. His uncle died and began to show signs of memory impairment at the age of 50. Denied any other family history of genetic problems. Physical examination: T 36.5 C, P 52 times/min, R 17 times/min, BP 127/87 mmHg (1 mmHg = 0.133 kPa), no deformity in the chest, lungs breath sounds clear, no wet and dry rales. The heart sounds were strong and rhythmic, and there were no pathological murmurs in the auscultation area of each valve. The abdomen was soft, without tenderness, and the liver and spleen cannot be palpable under the ribs. There was no swelling in the lower limbs, and no deformity of the spinal limbs. Neurological examination: clear in consciousness, fluent in language, time, place, character orientation are normal, calculation is normal, declined in recent memory, bilateral pupils equal in size, left: right for 3 mm:3 mm, pupillary light reflex was present, central eye position, ocular motility was normal, no diplopia or nystagmus, bilateral nasolabial sulcus were symmetrical, central tongue extension, soft palate elevation were normal, pharyngeal reflex (+), limbs muscle strength grade V, normal muscle tone, tendon reflex (++), bilateral Babinski sign (-), bilateral symmetric sensory examination, bilateral limbs ataxia examination were stable and accurate. The frontal lobe release signs of palm-grasping reflex, rooting reflex and sucking reflex were all negative. The routine blood, coagulation function, serum immune function, liver and kidney function, lipids, blood glucose, high sensitive C-reactive protein, homocysteine, thyroid function, folic acid, vitamin B12, ferritin, immune panel (hepatitis A, hepatitis B, hepatitis C, syphilis and HIV), urine routine and stool routine showed no significant abnormalities. The electrocardiogram showed sinus rhythm and normal. No arrhythmias were detected by ambulatory electrocardiography (AECG). Cardiac color doppler ultrasound showed mild regurgitation of aortic valve, mitral valve and tricuspid valve. No intracardiac right-to-left shunts was detected by right heart contrast echocardiography. Color doppler ultrasound of abdomen and urinary system showed no abnormalities. Brain MRI (22 September 2021) results showed punctate hyperintensity on diffusion-weighted imaging (DWI) of the right cerebellum, suggesting an acute cerebral infarction, cerebral atrophy and encephalomalacia foci in different degree (Figure 1G). Brain magnetic resonance angiography (MRA) (22 September 2021) showed no significant abnormalities in the vascular morphology and structure (data not shown). The neuropsychological assessment showed multidomain cognitive decline, highlighted by delayed recall deficits, as well as emotional apathy and sleep disturbances (Table 1). The Dr. Brain tool was used to automatically perform brain tissue segmentation and extract multiparameter volumetric measurements of different brain regions for analysis (https://cloud.drbrain.net, registration number: 20212210359). The artificial intelligence brain structure imaging analysis showed that the proportion of gray matter and white matter to intracranial volume decreased, and the proportion of bilateral thalamus, caudate nucleus, putamen, bilateral frontal lobe, parietal lobe, occipital lobe, and temporal lobe decreased, especially reduced in the cerebellum regions (Table 2).

wfs1 gene mutation, cognitive impairment (ci), ischemic cerebral infarction, neurodegeneration, wolframin protein

PMC8227459_01

Female

A 51-year-old woman was admitted with 3 weeks of cough, initially dry then productive of a small amount of clear sputum, and 6 days of subjective fevers, chills and dyspnea on exertion. On the day prior to admission, she experienced worsening malaise, fatigue and dyspnea. Her past medical history included HIV infection diagnosed 2 years earlier, with a CD4 cell count of 220 cells/ul measured 2 months prior to admission, cervical dysplasia with cone biopsy 8 months earlier and chronic anemia. She reported no recent travel history or sick exposures. Her ART regimen was lamivudine/zidovudine plus lopinavir/ritonavir, with TMP/SMX 800/160 mg 3 times weekly for PCP prophylaxis. On physical examination, the patient was in no acute distress. She was febrile at 102 F, pulse was 84 beats/minute, and respirations were 22 breaths/minute. Blood pressure was 86/50 mm Hg and oxygen saturation was 99% on room air. Lungs were clear, with bilateral breath sounds. There was no palpable lymphadenopathy. Laboratory values were significant for a lactate dehydrogenase level of 217 U/L (100-190), albumin 2.0 g/dl, hemoglobin 10.7g/dl, and white blood cell count 7.9 cells/ul, with differential: 71.1% neutrophils, 15.9% lymphocytes, 12.1% monocytes, 0.4% eosinophils and 0.8% basophils. Computed Tomography (CT) of the chest revealed subcarinal, prevascular and right hilar lymphadenopathy. Multiple masses and nodules were scattered throughout both lungs, the largest cavitating and abutting the major fissure in the left upper lobe measuring 4.2 x 4.2 cm, with another large mass at the right cardiophrenic angle measuring 2.2 x 4.6 cm. There were also bilateral pleural effusions with associated compressive atelectasis of the lower lobes and fibrotic changes in the left apical region, (Fig. 1). The patient was admitted with the diagnosis of pneumonia of uncertain etiology, placed on airborne isolation for tuberculosis, and was started on ceftriaxone 1g Intravenous (IV) daily, azithromycin 500 mg IV daily and TMP/SMX 2 double strength tablets orally every 8 hours. Sputum Gram stain and bacterial culture, 3 Acid-Fast Bacilli sputum smears and purified protein derivative testing were negative. The patient continued to have intermittent fevers 101-102 F for the next 4 days, then became afebrile and started feeling overall better. She experienced nausea and vomiting as a side effect of TMP/SMX. Five days after admission, the patient underwent fiberoptic bronchoscopy under moderate sedation. There were no abnormalities in the airways, and Bronchoalveolar Lavage (BAL) of the lingula as well as 5 Transbronchial Biopsies (TBBx) of the left upper lobe were performed. All cultures and smears were negative. Cytology was negative for malignancy and PCP. The TBBx of the left upper lobe showed benign bronchial tissue and a fragment of lung parenchyma with interstitial fibrosis. TMP/SMX was discontinued in view of negative results for PCP while azithromycin and ceftriaxone were continued. Three days later, fever and malaise restarted, and because of suspicion for nocardiosis, TMP/SMX was restarted. CT of the head showed maxillary, frontal and ethmoid sinus disease, without other pathology. That day, 2 transthoracic core needle biopsies were performed in the left upper lung cavitating pleural-based mass. Pathology revealed lung parenchyma and bronchial tissue with acute inflammation and fibrosis, and granulomas with coagulation necrosis with organisms within morphologically consistent with Pneumocystis jiroveci noted on Gomori methenamine silver (GMS) stain by direct microscopy, and negative Acid-Fast Bacilli stain, (Fig. 2). Azithromycin and ceftriaxone were stopped. The patient was restarted on oral TMP/SMX and again became afebrile; malaise and fatigue improved. Due to persistent nausea and vomiting, therapy was switched to IV formulation. She continued to improve and felt back to baseline and was discharged 1 week later on oral clindamycin and primaquine. CT of the chest 3 months later revealed nearly complete resolution of the previous findings, with a significantly improved cavitating left upper lobe nodule, multiple peripheral bilateral sub-cm non calcified pulmonary nodules, and resolution of bilateral pleural effusions and mediastinal lymphadenopathy (Fig. 1).

antiretroviral therapy, biopsy, diagnosis, granulomatous, human immunodeficiency virus, lung mass, pneumocystis jiroveci pneumonia

Admission Computed Tomography scan (CT) of the chest, showing:. Pleural based large cavitating lung mass in the left upper lobe measuring 4.2 x 4.2 cm, and.

PMC8227459_01

Female

A 51-year-old woman was admitted with 3 weeks of cough, initially dry then productive of a small amount of clear sputum, and 6 days of subjective fevers, chills and dyspnea on exertion. On the day prior to admission, she experienced worsening malaise, fatigue and dyspnea. Her past medical history included HIV infection diagnosed 2 years earlier, with a CD4 cell count of 220 cells/ul measured 2 months prior to admission, cervical dysplasia with cone biopsy 8 months earlier and chronic anemia. She reported no recent travel history or sick exposures. Her ART regimen was lamivudine/zidovudine plus lopinavir/ritonavir, with TMP/SMX 800/160 mg 3 times weekly for PCP prophylaxis. On physical examination, the patient was in no acute distress. She was febrile at 102 F, pulse was 84 beats/minute, and respirations were 22 breaths/minute. Blood pressure was 86/50 mm Hg and oxygen saturation was 99% on room air. Lungs were clear, with bilateral breath sounds. There was no palpable lymphadenopathy. Laboratory values were significant for a lactate dehydrogenase level of 217 U/L (100-190), albumin 2.0 g/dl, hemoglobin 10.7g/dl, and white blood cell count 7.9 cells/ul, with differential: 71.1% neutrophils, 15.9% lymphocytes, 12.1% monocytes, 0.4% eosinophils and 0.8% basophils. Computed Tomography (CT) of the chest revealed subcarinal, prevascular and right hilar lymphadenopathy. Multiple masses and nodules were scattered throughout both lungs, the largest cavitating and abutting the major fissure in the left upper lobe measuring 4.2 x 4.2 cm, with another large mass at the right cardiophrenic angle measuring 2.2 x 4.6 cm. There were also bilateral pleural effusions with associated compressive atelectasis of the lower lobes and fibrotic changes in the left apical region, (Fig. 1). The patient was admitted with the diagnosis of pneumonia of uncertain etiology, placed on airborne isolation for tuberculosis, and was started on ceftriaxone 1g Intravenous (IV) daily, azithromycin 500 mg IV daily and TMP/SMX 2 double strength tablets orally every 8 hours. Sputum Gram stain and bacterial culture, 3 Acid-Fast Bacilli sputum smears and purified protein derivative testing were negative. The patient continued to have intermittent fevers 101-102 F for the next 4 days, then became afebrile and started feeling overall better. She experienced nausea and vomiting as a side effect of TMP/SMX. Five days after admission, the patient underwent fiberoptic bronchoscopy under moderate sedation. There were no abnormalities in the airways, and Bronchoalveolar Lavage (BAL) of the lingula as well as 5 Transbronchial Biopsies (TBBx) of the left upper lobe were performed. All cultures and smears were negative. Cytology was negative for malignancy and PCP. The TBBx of the left upper lobe showed benign bronchial tissue and a fragment of lung parenchyma with interstitial fibrosis. TMP/SMX was discontinued in view of negative results for PCP while azithromycin and ceftriaxone were continued. Three days later, fever and malaise restarted, and because of suspicion for nocardiosis, TMP/SMX was restarted. CT of the head showed maxillary, frontal and ethmoid sinus disease, without other pathology. That day, 2 transthoracic core needle biopsies were performed in the left upper lung cavitating pleural-based mass. Pathology revealed lung parenchyma and bronchial tissue with acute inflammation and fibrosis, and granulomas with coagulation necrosis with organisms within morphologically consistent with Pneumocystis jiroveci noted on Gomori methenamine silver (GMS) stain by direct microscopy, and negative Acid-Fast Bacilli stain, (Fig. 2). Azithromycin and ceftriaxone were stopped. The patient was restarted on oral TMP/SMX and again became afebrile; malaise and fatigue improved. Due to persistent nausea and vomiting, therapy was switched to IV formulation. She continued to improve and felt back to baseline and was discharged 1 week later on oral clindamycin and primaquine. CT of the chest 3 months later revealed nearly complete resolution of the previous findings, with a significantly improved cavitating left upper lobe nodule, multiple peripheral bilateral sub-cm non calcified pulmonary nodules, and resolution of bilateral pleural effusions and mediastinal lymphadenopathy (Fig. 1).

antiretroviral therapy, biopsy, diagnosis, granulomatous, human immunodeficiency virus, lung mass, pneumocystis jiroveci pneumonia

CT of the chest 3 months later, showing:. Persistent but much smaller cavitating left upper lobe nodule, and.

PMC8604635_01

Female

A 35-year-old female presented to our clinic with slightly tender lumps and hyperpigmented depressed scars on both lower legs. The first lesions appeared ten years ago as erythematous macules and nodules. Some lesions became ulcerated and healed as hard hyperpigmented atrophic scars. Four months prior to consultation, new lumps appeared on both legs. There was no history of injuries, contact with TB patients, or symptoms of pulmonary or extrapulmonary TB. The patient was overweight while other aspects of general examination were within normal limit. Deep atrophy of the skin resulted in asymmetrical lower leg shape without movement disability (Figure 1). Varicose veins were observed on popliteal fossa (Figure 1). Dermatological examination revealed erythematous-violaceous, deep-seated nodules and macules, as well as hyperpigmented plaques on one-third distal portion of both lower legs. Some skin lesions showed superficial ulcers on deep skin atrophy covered with crusts and scales (Figure 1). Histopathological examination showed lobular panniculitis (Figure 2A) without vasculitis and granulomatous inflammation (Figure 2B) which consisted of caseous necrosis (red circle), epithelioid cells, and multinucleated giant cells (red arrow). There were no thickened collagen bundles, mucin deposition, and hyalinization. Direct immunofluorescence on skin lesion reveals no deposit of immunoglobulin or complement. The results of chest radiograph and sputum smear did not support the diagnosis of pulmonary TB. Tuberculin skin test (TST) was positive with a 20-mm induration after 48 hours. Polymerase chain reaction (PCR) examination using GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) on specimen obtained from skin biopsy was positive for deoxyribonucleic acid (DNA) of MTB. Nuclear 99mTc-ethambutol scintigraphy was positive for tuberculosis infection in the one-third distal portion of the left lower leg (Figure 3). Based on those results, the diagnosis of EIB was established. The patient was therefore treated with fixed-dose combination (FDC) of anti-tuberculosis drugs. After 6 months of treatment, the nodules regressed and healed, and no new skin lesions occurred (Figure 4).

mycobacterium tuberculosis, erythema induratum of bazin, panniculitis

PMC5109569_01

Female

An 84-year-old woman had a 3-year history of hypertension, a femoral neck fracture 1 year previously, and a left radial fracture 1 month previously. She had no family history of renal disease or dialysis. She was noted to have renal dysfunction of unknown etiology 1 year prior to admission. She visited a regional clinic for edema and was observed to have renal dysfunction [serum creatinine (Cr), 2.7 mg/dL] and anemia 2 months prior to admission. Since that time, she had developed marked edema and progressive renal dysfunction (serum Cr, 3.7 mg/dL) and was referred to our hospital for further evaluation and treatment. On physical examination, her temperature was 37.1C, and her blood pressure was 168/63 mmHg. She showed marked abdominal distention due to ascites and also had lower extremity edema without dyspnea. Chest radiography revealed cardiac enlargement and bilateral pleural effusions, and an abdominal computed tomography (CT) scan revealed massive ascites and bilateral kidney enlargement (Fig. 1). The following laboratory results were obtained: white blood cell (WBC) count, 5,400 WBC/mm3; red blood cells (RBC) count, 250x104 RBC/mm3; hemoglobin (Hb), 8.2 g/dL; hematocrit (Ht), 24.0%; platelet count (plt), 15.8x104 plt/mm3; total protein (TP), 5.6 g/dL; albumin (Alb), 2.8 g/dL; blood urea nitrogen (BUN), 45 mg/dL; serum Cr; 3.9 mg/dL; sodium (Na), 140 mEq/L; potassium (K), 3.2 mEq/L; chloride (Cl), 104 mEq/L; C-reactive protein (CRP), 0.5 mg/dL; plasma glucose, 142 mg/dL; hemoglobin A1c (HbA1c), 4.8%; aspartate aminotransferase (AST), 38 IU/L; alanine aminotransferase (ALT), 18 IU/L; alkaline phosphatase (ALP), 787 IU/L; gamma glutamyl transpeptidase (gammaGT), 239 IU/L; IgG, 828 mg/dL; IgM, 700 mg/dL; and IgA, 148 mg/dL. Cryoglobulin was negative and an immunoglobulin (Ig) M (kappa) spike was identified on immunoelectrophoresis. The third complement component (C3) level was 59 mg/dL (normal 50-130 mg/dL); the fourth component (C4) level was 10.5 mg/dL (normal 10-50 mg/dL); hemolytic complement activity via the classical pathway (CH50) was 13 U/mL (normal 25.0-48.0 U/mL); and antinuclear antibody (ANA) was negative. Myeloperoxidase antibodies (MPO), proteinase 3 antibodies (PR3), antineutrophil cytoplasmic antibodies (ANCA), and anti-glomerular basement membrane (anti-GBM) antibodies were not detected. A urinalysis showed 1.17 g protein/g creatinine and 30-49 RBC/high-power field (HPF). The urinary beta-2 microglobulin (beta-2MG) level was 25,150 ng/mL. Bence Jones protein was negative in the urine. A bone marrow aspirate clot showed hypercellular bone marrow with 3% plasma cells. At the time of hospitalization, a percutaneous kidney biopsy was not performed because of the patient's massive ascites. A percutaneous kidney biopsy was performed 1 month later after several paracentesis procedures, allowing the patient to lie in a prone position. Histological findings revealed tubular dilatation, primarily involving the distal tubules, with extensive fibrosis in the interstitium, consistent with nephronophthisis-medullary cystic disease complex(NPH-MCKD). There were no remarkable glomerular changes except for global sclerosis consistent with the patient's age (Fig. 2). Immune deposits of IgG, IgA, IgM, C1q, C3, and fibrinogen were absent, despite the IgM kappa M protein detected in the serum. Electron microscopy revealed irregularities, thinning and disintegration of the tubular basement membrane (TBM). However, it was difficult to explain the patient's massive ascites and rapidly progressive renal dysfunction according to the histological findings. Considering her advanced age (84 years of age) and symptomatic relief after paracentesis, no further investigation was done and she was discharged with a serum Cr level of 5.1 mg/dL 2 months after admission. She began hemodialysis therapy 1 month after discharge.

PMC5109569_02

Female

A 74-year-old woman was started on antihypertensive therapy 1 year prior to admission when she was noted to have a mild renal impairment with a serum Cr level of 1.1 mg/dL. She was status post-appendectomy at 20 years of age, had a history of ulcerative colitis with rectal cancer at 61 years of age, and a cataract at 68 years of age. She had no family history of renal disease or dialysis. Although her blood pressure was well controlled, her serum Cr level rapidly increased to 1.5 mg/dL at 3 months after the start of antihypertensive therapy and 2.4 mg/dL at 5 months after the start of therapy. She was subsequently referred to our hospital for further evaluation and treatment. On physical examination, her temperature was 36.5C, and her blood pressure was 150/79 mmHg. Her conjunctivae were pale and she had lower extremity edema. The following laboratory results were obtained: WBC count, 6,800 WBC/mm3; RBC count, 248x104 RBC/mm3; Hb, 7.3 g/dL; Ht, 21.7%; Plt, 18.2x104/mm3; TP, 7.1 g/dL; Alb, 4.1 g/dL; BUN, 30 mg/dL; Cr, 3.6 mg/dL; Na, 138 mEq/L; K, 5.3 mEq/L; Cl, 107 mEq/L; CRP, 0.21 mg/dL; plasma glucose, 107 mg/dL; HbA1c, 5.1%; IgG, 1,326 mg/dL; IgM, 76 mg/dL; IgA, 239 mg/dL; C3, 91 mg/dL; C4, 24.7 mg/dL; and CH50, 13 U/mL. Cryoglobulin was negative. ANA was negative, and MPO, PR3, ANCA, and anti-GBM were not detected. A urinalysis showed 1.23 g protein/g creatinine and 6 RBC/HPF. Urinary beta-2MG was 27,708 ng/mL. Abdominal CT showed bilateral kidney enlargement that was not seen on an earlier CT exam 1 year previously. Serial CT images are shown in Fig. 3. Magnetic resonance images (MRI) are shown in Fig. 4. MRI, including coronal magnetic resonance images, did not reveal multiple microcysts in the enlarged kidneys, however, a careful observation revealed multiple cysts along the corticomedullary boundary. A percutaneous renal biopsy was performed on day 2. Of seven glomeruli, two were globally sclerotic, one was segmentally sclerotic, and two showed glomerular cysts. The other glomeruli were essentially normal. The distal tubules were also dilated, consistent with MCKD, and there was mild interstitial fibrosis and inflammatory cell infiltration (Fig. 5). Electron microscopy revealed irregular layering, spheroidizing, thinning, and partial rupture of the TBM. The patient was treated with corticosteroids [prednisolone (PSL) 30 mg/day] in view of the significantly elevated urinary beta-2MG level and interstitial cell infiltration. Immediately after PSL administration, a slight reduction in the serum Cr level was noted and her anemia improved. However, the serum Cr level gradually increased and the Hb level gradually decreased 2 months later, when PSL was tapered. Three months after the start of PSL therapy, the patient developed gastrointestinal bleeding and was found to have a serum Cr level of 7 mg/dL. The gastrointestinal bleed may have been an adverse effect of PSL therapy. However, no apparent bleeding source was detected by gastroscopy, colonoscopy, or enteroscopy. Anemia was corrected with blood transfusions, however, the patient's renal function did not improve and she began hemodialysis therapy 5 months after referral. We also performed immunohistochemical staining in both cases for CD10, cytokeratin 7 (CK7), epithelial membrane antigen (EMA), E-cadherin, and cytokeratin (34 beta E12) to identify the level of tubular dilatation (Fig. 6). In case 1, the dilated tubules were negative for CD10, a marker of proximal tubules. In contrast, immunostaining results for CK7, EMA, and E-cadherin, markers of the distal tubules and collecting ducts, were positive. Immunostaining results for CK (34 beta E12), a marker of collecting ducts, were also positive, indicating that the cysts predominantly arose from collecting ducts in case 1. In case 2, the dilated tubules were positive for CK7 and EMA and weakly positive for E-cadherin and CK (34 beta E12).

PMC5727653_01

Female

A 49-year-old woman with no significant past medical or surgical history other than sporadic migraines presented to the emergency room at Jackson Memorial Hospital complaining of a 2-week episode of abdominal distention and flank pain. Initial examination revealed an otherwise normal female with vital signs within normal limits and discomfort in the right flank, suspicious for a kidney stone. As part of her initial workup, the patient had an abdominal CT scan that revealed a 15 cm right adrenal mass (Figure 1(a)). No stones or signs of hydronephrosis or pyelonephritis were identified. Laboratory workup, including serum determination of cortisol (5.7 mcg/dL, normal range: 4.3-22.4 mcg/dL at 8 am), aldosterone (<4.0 ng/dL, reference: <=21 ng/dL), and adrenocorticotropic hormone (12 pg/mL, reference: <47 pg/mL), was unremarkable. The patient underwent surgical excision of the mass. The resected specimen consisted of a well-encapsulated oval mass with a bright golden-yellow parenchyma. The right adrenal gland was found adjacent to the mass (Figure 1(b)). Microscopic examination of the tumor after formalin fixation demonstrated a neoplasm composed of large oncocytic cells (Figure 1(c)) with focal areas of nuclear pleomorphism (Figure 1(c), insert). The presence of increased intracytoplasmic mitochondria was confirmed by electron microscopy (Figure 1(d)). Mitotic figures were not observed. According to the proposed classification by Bisceglia et al., the tumor size and the absence of mitoses, necrosis, capsular, and sinusoidal invasion indicate that this AON could harbor borderline malignant potential. The patient's postsurgical course was unremarkable and no further treatment was required. Currently, four years after surgery, the patient is alive, tumor-free, and in her normal state of health. In order to assess the expression of TSPO we obtained additional unstained slides from formalin-fixed paraffin-embedded (FFPE) tissue including a representative section of the tumor with adjacent normal adrenal gland (internal control) of the patient. Two slides were deparaffinized after incubation at room temperature (RT, 24 C) in xylene (twice for 10 minutes). The deparaffinized tissue sections were then rehydrated with a graded series of ethanol (100%, 100%, 70%, 70%, and 50%) and incubated in phosphate buffered saline (PBS) for 15 minutes at RT. After incubation, slides were stained for TSPO by immunofluorescence as previously described. Primary antibody to detect TSPO (FL-169, Santa Cruz Biotechnology, Inc., Dallas, Texas, cat# 20120) was used at 1 : 75 dilution, according to the manufacturer instructions. Fluorescent HRP-conjugated secondary antibody (Alexa Flour-488 goat anti-rabbit IgG (H+L)) was used at 1 : 200 dilutions. The slides were reviewed with a Zeiss LSM510/UV Axiovert 200 M confocal microscope (Carl Zeiss, Peabody, MA, USA). Multiple images captured from tumor cells and normal adrenal gland showed strong immunofluorescence positivity in the normal adjacent adrenal gland (Figure 2(a)) and significant loss of TSPO expression in the tumor cells (Figure 2(b)). To more precisely evaluate the loss of nuclear and cytoplasmic TSPO expression in tumor cells and confirm the immunofluorescence findings, we dissected mapped tumor and normal adrenal tissue from FFPE unstained slides and performed immunoblots. Briefly, FFPE tissue sections were deparaffinized by incubation at RT in xylene (twice for 10 minutes). The deparaffinized tissue sections were then rehydrated with a graded series of ethanol (100%, 100%, 70%, 70%, and 50%) and incubated at RT in PBS for 15 minutes. After incubation, tumor and normal adrenal tissue were dissected off the slides and placed in two separate plastic tubes. The tubes were pelleted at 16,000 xg for 5 minutes, and the incubation/centrifugation steps were repeated twice. Tissue samples were briefly air-dried in a fume hood. The cell pellet was resuspended in 200 mul cold buffer A, consisting of 10 mM HEPES (pH 7.9), 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 muM dithiothreitol (DTT), and a complete protease inhibitor cocktail (Roche, Mannheim, Germany). The pellet was then incubated on ice for 15 minutes to allow cells to swell, after which 15 mul of 10% NP-40 was added, and the sample was vortexed thoroughly for 40 seconds and centrifuged at 3,000 rpm for 3 minutes at 4 C. The resulting supernatant was used for cytosolic TSPO measurement (equal amount of protein, 12.4 mug was loaded on an SDS-polyacrylamide gel and Western blot analysis with TSPO antibody was performed as described previously) and the pellet (nuclear fraction) was resuspended in 30 mul cold buffer B consisting of 20 mM HEPES (pH 7.9), 0.4 M NaCl, 1 mM EDTA, 1 mM EGTA, 1 muM DTT, and protease inhibitors. The pellet was then incubated on ice and vortexed for 15 seconds every 2 min for up to 15 min. The nuclear extract was then centrifuged at 13,000 rpm for 5 minutes at 4 C. Equal amounts of protein (21.6 mug) from the supernatant (containing the nuclear extract) were loaded and Western blot analysis with TSPO antibody was performed as described above. The quality of the nuclear extract was analyzed by propidium iodide staining, which indicated a purity of 92-96%. Primary TSPO antibody (Santa Cruz Biotechnology, Inc., Dallas, Texas, cat# 20120) was used at 1 : 1000 dilution. Beta actin (ACTBD11B7, sc-81178, Santa Cruz Biotechnology, Dallas, TX, USA) and lamin a/c (Cell Signaling Technology, Beverly, MA, USA) antibodies were used at 1 : 5000 and 1 : 750, respectively. Anti-rabbit and anti-mouse secondary antibodies (Vector Laboratories, Burlingame, CA, USA) were used at 1 : 3000 dilution. Optical density of the bands was determined with the Chemi-Imager (Alpha Innotech, San Leandro, CA, USA) digital imaging system and the results were quantified with the Sigma Scan Pro (Jandell Scientific, San Jose, CA, USA) program as a proportion of the signal of housekeeping protein bands (lamin a/c and beta-actin, nuclear and cytosolic markers, resp.). The experiment was performed using 4 different tissue sections from the same sample and the mean intensity of Western blot bands was subjected to Tukey's multiple comparison test. Statistical significance was set at p value = 0.05. As illustrated in Figures 2(a) and 2(b) (cytosolic fraction) and Figures 2(c) and 2(d) (nuclear fraction), the representative semiquantitative immunoblots from two different tumor sections show a significant decrease in TSPO expression in the tumor sample of 72.4 and 72.8% decrease in the cytosol and 77.1 and 76.8% decrease in the nuclear fraction as compared to respective controls (p = 0.03).

PMC3205552_01

Male

A 40-year-old male patient presented to us with a history of severe head injury in a bus accident while traveling in it. Initial Glasgow Coma Scale (GCS) was about 6/15 with bilateral normal. There was no focal neurological deficit, deep tendon jerks (DTR) were absent in all the limbs and computerized tomography (CT) scan of head was grossly normal without any surgical lesion. Conservative management was started considering the case as diffuse axonal injury (DAI). Though there was some improvement in neurological status after few weeks, he went on to a vegetative state, i.e. remained unconscious with GCS about 9/15 and without any specific motor and verbal function. He could occasionally open eyes and move limbs spontaneously, but there was no verbal function, no purposeful limb movement, no bowel and bladder control and he did not respond to any verbal command. Finally, he developed generalized spasticity. Considering an appropriate candidate, ITB was planned. Baclofen injection was not available in Nepal and ITB therapy was never used before in this country. Fortunately, Prof. Taira had brought a few ampoules of injection baclofen from Japan and gave them to us as a gift. But, we did not have baclofen pump and other accessories for ITB. Therefore, an epidural catheter, which is used by an anesthetist for spinal anesthesia or for continuous lumbar drainage [Figure 1], was inserted into the thecal sac at second and third lumbar space and was fixed. The catheter was placed in situ throughout the ITB period and baclofen was injected everyday through it with aseptic precaution. Patency of catheter was confirmed every time before ITB by free flow of cerebrospinal fluid (CSF). We injected 50 mug of baclofen intrathecally everyday for the first 2 weeks and then increased the dose to 100 mug everyday. Oral baclofen was stopped. Patient was placed in lying position during ITB and bedside physiotherapy was continued. In due course of time with ITB, his limbs became less stiff and clonus improved significantly. His higher mental function also showed signs of improvement, and he started producing few words and sounds, followed verbal commands and moved limbs purposefully. Occasionally, he also started showing his emotion in terms of agitation and irritation especially with his family members. Slowly, we increased physiotherapy, made him sit on wheel chair few times a day, started catheter clamping for his bladder training. His higher mental function improved day by day, could speak a few sentences, followed verbal commands well, and understood and recognized his surroundings and family members. However, we had to stop ITB after about 5 weeks due to CSF leakage through skin puncture site. By the time he was discharged from the hospital after about 2.5 months of hospital stay, he was fully conscious, i.e. he was well oriented, could speak appropriately and walk with support. He did not have any neurological deficit except for squint due to internuclear ophthalmoplegia that he had developed immediately after trauma and mild spasticity of limbs. Bladder catheter was removed and he could pass urine by himself. He had some behavioral problem, occasionally used to get agitated and violent and also had some psychotic features. Therefore, he was referred to a psychiatrist. Electroencephalogram (EEG) done in 2 months of follow-up was normal.

intrathecal baclofen, nepal, spasticity, vegetative state

PMC8599444_01

Male

A lesion was found on the left scrotal wall of a 67-year-old man 11 months ago, followed by ulceration at the surface of the lesion 6 months later. The patient was in good health before and had no history of hepatitis, diabetes, tuberculosis, or cancer. He had no history of medical, family, psychosocial, or genetic problem neither. Hard and diffuse eczematous changes and ulcerations were revealed on his left scrotum by physical examination ( Figure 1 ). Palpations of his testis and epididymis were normal, along with no swelling or palpable mass in his bilateral groins. Nothing notable was found from bloodwork and conventional chest CT. The bloodwork did however show syphilis-specific antibodies. According to the physical examination and patient history, it was initially diagnosed with a common skin disease, such as dermatitis or eczema. Since no response to a diagnostic therapy of topical ointment was found thereafter, further examinations were subsequently ordered. With relevant guidelines and regulations complied, the work was approved by the Ethical Committee of Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine and informed consents were obtained from the patient. The conventional high-frequency US examination of the lesion was performed, using the Philips iU22 Ultrasound machine (Philips Healthcare, Bothell, WA, USA) with the L12-5 linear array transducer (frequency range, 5.0-12.0 MHz). An isoechoic to hypoechoic lesion measuring 3.6 x 2.9 x 1.4 cm was found on his left-sided scrotal wall, with an infiltrative margin and cutaneous invasion (including epidermis, dermis, and hypodermis invasion). Color Doppler ultrasound showed a profuse signal of intralesional vascularity, and the resistance index was 0.76. Elastography was performed to assess the lesion stiffness, which was valued to be hard in a score of 4 according to the Itoh score system. No abnormality was found in the testis, epididymis, or bilateral groins. A lesion with hypointensity on T1WI and heterogeneous hyperintensity on T2WI was found at his left scrotal wall by magnetic resonance (MR) (1.5 T, SIGNA Explorer, GE, Tianjin, China). However, the extent of lesion invasion was not accurately measured in such uneven location. Subsequently, CEUS was performed with the L9-3 linear array transducer (frequency range, 3.0-9.0 MHz) and low acoustic power (mechanical index, 0.06) for further confirming the extent of the lesion before surgery. The examination was carried out by an experienced radiologist after intravenous bolus injection of 4.8 ml SonoVue (Bracco Diagnostics Inc., Italy), flushed with 10 ml of a physiological saline solution. Rapid enhancement of the lesion was shown in CEUS, which indicated a malignant tumor. The lesion measuring 5.6 x 4.9 x 1.4 cm with hyper-enhancement in the main area and non-enhancement in the superficial area was shown in all stages, which was larger than that shown on conventional US. Then, we made marks on the skin before surgical resection. Based on all clinical data and imaging findings, it was highly suspected as a skin malignant tumor before surgery, such as squamous cell carcinoma or adenocarcinoma of skin. Dermatosis associated with syphilis was also a possibility. Finally, a histopathological result of EMPD was confirmed after conducting biopsy on the excised lesion. It found scattered epidermal Paget cells with a pleomorphic and hyperchromatic nucleus and abundant clear cytoplasm, which were located throughout the epidermis in nest-like structures, involving full skin layers and subcutaneous soft tissue (including nerves and blood vessels). The present case showed all morphologic features of EMPD including positive immunohistochemical staining for CEA, CK7, and GCDFP-15. Moreover, the volume of the lesion on the gross specimen was 5.5 x 5.0 x 1.3 cm, which matched the result of CEUS. The patient did not receive radiotherapy or chemotherapy after surgery and has been closely followed up to now.

contrast-enhanced ultrasound (ceus), conventional ultrasonography (us), extramammary paget disease (empd), imaging findings, scrotum

PMC9425876_01

Male

A 25-year-old man presented with fatigue, recurrent episodes of fever and infectious symptoms, night sweats, and inappetence. In addition, dyspnea and chest pain during inspiration were reported. Furthermore, rash on both arms was described. Hematologic workup revealed leukocytosis of undifferentiated cells, which were characterized as myeloid progenitors by immunophenotyping. Bone marrow (BM) aspiration and biopsy confirmed the diagnosis of acute myeloid leukemia (AML) (Figure 1(a)). Cytogenetic analysis revealed an NF1-deletion (del17q11). No other genetic abnormalities were detected using routine molecular analysis methods [fragment length analysis and amplicon-based next generation sequencing (NGS)]. Induction chemotherapy with 60 mg/m2 daunorubicin (day 3-5) and 100 mg/m2 cytarabine (day 1-7) (DA) was initiated. As the patient complained of chest pain and newly onset of fever episodes, computed tomography (CT) of the thorax was performed on day 6 of DA, depicting a large mediastinal tumor and ground-glass opacities. 18Fluorodesoxy-glucose positron emission tomography/computed tomography ( FDG-PET/CT) demonstrated mediastinal vital tissue [maximum standardized uptake value (SUVmax) 5.3; Figure 2(b1)]. Hence, a biopsy of the tumor was conducted, revealing residual leukemic blasts embedded in necrotic tissue through histologic workup, being the first verified extramedullary site of the patient's AML (Figure 2(a1)). BM assessment at day 15 showed moderate response and positive cytogenetic measurable residual disease (MRDpos) with persisting del17q11 detection. A second cycle of DA was initiated leading to cytomorphologic and cytogenetic complete remission (CR). Follow-up CT showed the mediastinal tumor unchanged in diameter. No further extramedullary manifestation (EM) sites were traced in clinical examination and by imaging. The patient underwent allogeneic hematopoietic cell transplantation (alloHCT) from a matched sibling donor after receiving myeloablative conditioning with 120 mg/kg cyclophosphamide and 12 Gy fractionated total body irradiation (TBI), which was tolerated without unexpected toxicities. Graft versus host disease (GvHD) prophylaxis consisted of methotrexate (MTX) and cyclosporin (CsA). On day +8, the patient reported sudden and severe chest pain again and imaging revealed the mediastinal tumor with unchanged diameters. The patient developed full donor chimerism until day +56 and remained in cytomorphologic and cytogenetic CR. Immunosuppression was tapered rapidly and discontinued 6 months after transplantation. Eighteen months later, the patient noticed progressive jaundice. Abdominal ultrasound revealed a large tumor of the pancreaticoduodenal region causing cholestasis. Endoscopy revealed a tumor of the duodenum obstructing the common hepatic duct with the need of stent insertion (Figure 2(b2)). Biopsies were obtained, again demonstrating leukemic infiltration and defining AML relapse (Figure 2(a2)). Cytogenetic evaluation of the duodenal tumor was indicative for the known NF1-deletion. In addition, 18FDG-PET/magnetic resonance imaging (MRI) was further suspicious for localized iliac EM (SUVmax 5.4), while the initial mediastinal tumor (SUVmax 3.5-5.2) and the duodenal tumor (SUVmax 3.7) also showed metabolic activity. Surprisingly, BM aspiration showed a persisting CR (Figure 1(b)) without cytogenetic or molecular abnormalities and full donor chimerism. Reinduction with 3000 mg/m2 BID high-dose cytarabine (day 1-3) and 5 mg/m2 mitoxantrone (day 3-5, dose reduction because of pancreatitis) was started, which induced a metabolic CR of the EM according to 18FDG-PET/MRI. At the time of referral to the transplantation ward for second alloHCT, the patient reported about a cutaneous tumor on the chest that rapidly grew within the last few days. A punch biopsy verified again leukemic infiltration in this lesion (Figure 2(a3)). Myeloablative conditioning with 12.8 mg/kg busulfan and 150 mg/m2 fludarabine was applied prior to allografting from an alternative matched unrelated donor (MUD). MTX and CsA were applied as GvHD prophylaxis. Full donor chimerism was achieved again; no further sites of chloroma appeared. BM aspirate revealed persisting CR. The patient developed acute GvHD grade III of the upper and lower gastrointestinal tract and the skin, which required repetitive escalation of immunosuppression. However, a follow-up 18FDG-PET/MRI demonstrated relapse of the mediastinal mass 1 month after the second transplantation (SUVmax 6.6). Local radiation therapy of the mediastinal tumor with a cumulative dose of 40 Gy was conducted leading to a significant shrinking of the mediastinal tumor burden. Three months later, the patient showed new signs of progression, this time with multiple EMs detected below the left kidney causing urinary obstruction, paravertebrally, and in the coeliac trunk (SUVmax 4, Figure 2(b4)). Again, myelosarcoma was histologically confirmed after biopsy (Figure 2(a4)). Therapy with azacitidine and venetoclax was initiated, resulting in a morphologically complete response after two cycles of chemotherapy as per 18FDG-PET/MRI. To study the clonal landscape of this aggressive and refractory course of extramedullary disease, we performed amplicon-based NGS of AML tumor tissue and compared it with genetic characteristics of the patient's BM AML.

aml, allogeneic stem cell transplantation, clonal landscape, extramedullary

PMC7656864_01

Male

A 72-year-old man had clinical gradual hip pain in both hips for 1 year. He was diagnosed with osteonecrosis of the femoral head in both hips by X-ray. His X-ray presented Ficat-Arlet classification stage III for the left hip and stage II for the right hip (Figure 1). Seven months later, there was a sudden and progressive increase in pain in the left hip. X-ray showed marked, progressive collapse of the left femoral head and arthritis change of the acetabulum (Figure 2). He had no fever or any symptoms of infection; however, an investigation for infection was performed, due to acute-onset and rapid progressive radiographic changes. The results of his serum work-up were a white blood cell count of 10,370/muL, hematocrit of 37.9%, hemoglobin of 13 g/dL, polymorphonuclear neutrophils (PMN) of 70.7%, lymphocyte of 19.6%, eosinophil of 3.5%, monocyte of 5.7% and platelets of 500,000/muL. The erythrocyte sedimentation rate (ESR) was 66 mm/h (normal value, 0-15 mm/h), and the C-reactive protein (CRP) was 9.6 mg/dL (normal value, <0.6 mg/dL). Ultrasound of the left hip revealed minimal fluid in the hip joint. Hip joint fluid aspiration under ultrasound guidance was performed only on the left side for microbiology study and yielded negative results. The patient was scheduled for THA in the next 3 months due to tight surgical queue. Preoperative laboratory ESR and CRP decreased to nearly a normal value. At the scheduled admission for THA, the patient was afebrile and had no sign of inflammation, with normal skin condition at the left hip joint. Cloxacillin (1 g) was used for prophylaxis against surgical site infection 30 min before starting the operation and continued for 3 days after the operation. Intraoperatively, there was collapse of the femoral head, with erosion of acetabular cartilage in addition to rice body synovitis. Soft tissue and bone samples were sent for microbiology and pathology assessment due to a suspicion of infection. Cementless THA was successfully performed using the standard technique (Figure 3). The laboratory results were positive for acid-fast bacilli (AFB), negative for gram stain, negative for aerobic bacterial culture and negative for tuberculous culture. A pathological tissue diagnosis reported chronic inflammation, with an area of granulomatous inflammation. Post-operatively, the patient received anti-TB drugs for 9 months: isoniazid, rifampicin, pyrazinamide and etambutol for the first 2 months and then isoniazid and rifampicin for 7 months (2IRZE/7IR regimen). Other TB work-ups, such as chest X-ray and 3 days of morning sputum for AFB, were negative. After surgery, he was able to walk with full weight-bearing without gait support and able to do daily life activities as normal. At his latest follow-up visit, at 2 years, his clinical condition was good and his Harris hip score was 97. X-ray of his hips is shown in Figure 4.

orthopedics, occupational therapy, rehabilitation

PMC5259930_01

Male

A 42-year-old male patient visited the emergency room of our hospital in November 2013 with fever, sore throat, and diarrhea. He was a known seropositive patient for HIV and syphilis and a frequent traveler to Guangxi, China, and Hong Kong. Laboratory testing on admission showed a white blood cell count of 9600/muo (8764/muh, neutrophils, 470/muh lymphocytes), 7.0 g/dL hemoglobin, and 86 K/muh platelets. The peripheral CD4+ T lymphocyte count was 25 cells/mup. Computed tomography (CT) scans revealed bilateral septal thickening and micronodules of both the lungs, severe hepatosplenomegaly, and multiple enlarged lymph nodes in the chest and abdominal cavity, with tuberculosis or malignancy, especially lymphoma, suspected. Bronchoscopy revealed multiple micronodules in the wall of the right bronchi. Bronchoscopic biopsy and washing cytology with concurrent supraclavicular lymph node biopsy were performed. The bronchial washing cytology was diffuse and cellular smear contained mixed inflammatory infiltrate, including numerous histiocytes, lymphocytes, some eosinophils, and neutrophils. Most histiocytes were packed with many yeast-like organisms measuring 3mm in diameter that stained dark brown on methenamine silver (GMS) stain [Figure 1]. Focusing up and down through histiocytes, the organisms appeared to have a central dot-like structure. Bronchoscopic biopsy revealed anergic tissue reactions with histiocytic infiltration. In Hematoxylin and eosin (H and E)-stained sections, the organisms were seen as nonbudding round-to-oval spherules within the histiocytes in the submucosa of bronchi [Figure 2]. These organisms were also observed extracellularly but not in bronchial epithelial cells. In the lymph node, there was lymphoid depletion with diffuse proliferation of histiocytes engorged with many organisms. On the basis of cytologic and histologic findings, the initial cytopathologic interpretation suggested histoplasmosis. Two days after admission, the mycelial form presented in an interim report on a fungal culture obtained from the blood. Given its dimorphic feature and the patient's history of travel to endemic areas, penicilliosis was suspected and a polymerase chain reaction assay was positive for P. marneffei. We reviewed the bronchial washing and biopsy findings. In the cytologic specimen, while intracellular organisms appeared to be uniform yeasts of 3 mus in size, extracellular fungi were elongated and up to 8 mui in length (sausage form). The most characteristic feature was a central transverse septum that was transparent with Papanicolaou stain but highlighted by GMS stain [Figure 1]. The size, shape, and distribution of the organisms were similar in both biopsy and cytologic specimens, except that central dots and septa were more readily identified on cytologic smears. After amphotericin B administration, the patient exhibited clinical and radiologic improvement. Amphotericin B was changed to oral itraconazole 400 mg/day after 2 weeks. Toxoplasma IgG, influenza, and pneumococcal-conjugated (PCV 13) vaccines were also prescribed to prevent opportunistic infections. The patient continues to visit the outpatient clinic without any specific problems.

bronchial washing cytology, hiv, penicilliosis

PMC9924590_02

Male

A 61-year-old competitive male cyclist presented to these authors' clinic with a history of insidious onset pain in the left perineal area which occurred during cycling. Shortly prior to seeking medical attention, he noted a tender mass in his perineum. No visible abnormality was detected. On palpation, a nodule of approximately 1 cm in transverse and 4 cm in longitude was noted adjacent to the left ischial tuberosity. It was firm and rubbery in consistency, mildly tender on palpation, and not fixed to the underlying muscle or bone. The patient was referred for diagnostic high-resolution ultrasound. High-resolution greyscale ultrasound demonstrated a well-defined, heterogeneous, predominately cystic mass inferior to the left scrotum. It measured 5.0 x 2.4 x 4.0 cm and contained hypoechogenic material within it, with no increased vascularity. Based on the imaging and clinical findings, it was diagnosed as an ischial hygroma. The patient was reluctant to undergo surgery and specifically requested conservative management. A comprehensive assessment of his cycling biomechanics and saddle contact point was performed. Pre-fitting and static kinematics were performed using ErgoFiTTM (http://www.sciencetosport.com/ergofit) software and kinematic tools. Saddle pressure mapping was performed using Gebiomized dynamic saddle pressure mapping systems (http://www.gebiomized.de). Salient findings were that underwear was being worn under the cycling-specific garment and that the cycling-specific garments were of relatively low quality, with chronic wear demonstrated on the padding material. The kinematic assessment demonstrated excessive saddle height (static knee flexion angle (KFA) of 22 using the Holmes10 method) and excessive saddle setback (10.5 cm). This was confirmed on initial saddle pressure mapping by a front: rear pressure balance ratio of 62:38. After correction of the kinematics (KFA of 31 and saddle setback of 6.8 cm) a series of minor adjustments were made and numerous different saddle types were tested to achieve the most favourable saddle pressure mapping possible (pre- and post-pressure mapping are shown in Fig.4). Pre- and post-changes (Table 1) improved overall pressure distribution by: Improving front: rear pressure balance ratio from 62:38 to 46:54 Increasing loaded area in left ischial area from 4300 mm2 to 5325 mm2 Reducing peak pressure from 923 mbar to 724 mbar The patient returned to cycling activity and has subsequently not experienced any recurrence of symptoms at two-year follow-up.

cycling, perineal injury

PMC3513220_08

Female

Subject 8, a mother (26-year-old-female; genotypes: CYP2D6 *2/*4, CYP2C9 *1/*1, CYP2C19 *2/*17), was initially prescribed paroxetine for stress. On paroxetine, she experienced an uncharacteristic episode of rage and attempted suicide by inhalation of carbon monoxide from a car exhaust, so she stopped taking it. Two years later, she was prescribed paroxetine again and reassured about its safety. The second time she experienced intense restlessness, surges of rage and anger, marital troubles, panic attacks, impulsive spending sprees, and constant suicidal ideation. She reasoned that her low self-esteem, insomnia, and suicidal behavior were due to difficulties with her in-laws. She overdosed and was admitted to hospital where paroxetine was increased. She tried to kill herself again and was diagnosed with an "adjustment disorder," a stress-induced state. She was switched to venlafaxine, 37.5 mg/day and it was increased to 300 mg/day over 3 months. Each upward dose adjustment occasioned a week spent in bed with exhaustion, as she was unable to get up (akinesia). Her mental state deteriorated and violent outbursts and suicidal ideation became frequent and severe. Unable to stay in one place, she drove several hundred miles with her children and tried to kill them and herself by car exhaust. A few days later she tried to kill her children and herself again. There were no interacting drugs in her regimen, however, her genotype for 2D6 (*2/*4) places her in the intermediate metabolizer category, for which there is evidence of at least twofold increases in serum-venlafaxine levels in both single dose and steady-state studies. Moreover, case reports have documented serious venlafaxine-related adverse events, which are either suspected or confirmed to have resulted from above-therapeutic-range serum-venlafaxine levels; the events ranged from psychosis to hallucination, psychomotor agitation, and delirium. The subject pleaded diminished responsibility to four charges of attempted murder and was not required to complete time in prison. She recovered fully on withdrawal. Wyeth has provided the following information in product information for venlafaxine, Effexor XR, including homicidal ideation, since 2005. (Note: frequent is 1/10; infrequent, 1/100; rare, 1/1000; suicide attempts and homicidal thinking are catastrophic effects, irrespective of frequency.) Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, thinking abnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor, suicidal ideation; Rare: abnormal/changed behavior, adjustment disorder, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial paralysis, abnormal gait, Guillain-Barre Syndrome, homicidal ideation, hyperchlorhydria, hypokinesia, hysteria, impulse control difficulties, libido increased, motion sickness, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, torticollis. Common: Abnormal dreams, decreased libido, dizziness, dry mouth, increased muscle tonus, insomnia, nervousness, paraesthesia, sedation, tremor. Uncommon: Apathy, hallucinations, myoclonus. Rare: Convulsion, manic reaction, neuroleptic malignant syndrome (NMS), serotonergic syndrome. Very little of the above-quoted information appears in Australian product information for Efexor . It contains no black box warning, denies differences in metabolism between poor and extensive metabolizers, and lists only for nervous system:

cyp1a2, cyp2c19, cyp2c9, cyp3a4 cyp2d6, adverse drug reaction, drug metabolism, drug therapy, human rights, public health, safety pharmacogenetics, suicide, violence

PMC9626822_01

Female

A 20-year-old woman was presented to the emergency clinic with fever and sore throat for one week and joint pain, weakness in limbs, and slight numbness of fingertips and tongue. She denied any tobacco or alcohol (illicit drugs) use, and her family history was not notable. After admission, she continued to experience a high fever (Tmax 40 C). One week after her admission, scattered congestive pinpoint itching rashes appeared on her chest, abdomen, back, and limbs, without ulceration or scaling, accompanied by liver function abnormalities (alanine aminotransferase, ALTmax 227 IU/L, reference range of 7-40 IU/L; aspartate transaminase, ASTmax 193 IU/L, reference range of 13-35 IU/L). The rash was noticeable when the body temperature rose and faded when the body temperature dropped. Inflammatory markers such as serum ferritin (max to >7,500 ng/ml, reference range 11-306.8 ng/ml), erythrocyte sedimentation rate (ESR, max to 50 mm/h, reference range 0-20 mm/h), C-reactive protein (CRP, max to 104 mg/L, normal <5 mg/L), and lactate dehydrogenase (LDH, max to 900 IU/L, reference range 100-240 IU/L) were all significantly elevated. The lymph node ultrasound revealed extensive enlarged superficial lymph nodes (Figure 1). The clinical diagnosis of AOSD is generally reached by exclusion while investigating a patient with a fever of unknown origin. We carried out detailed screenings for infectious diseases, autoimmune diseases, and tumors. Laboratory examinations for common pathogens (respiratory pathogens, such as influenza virus, mycoplasma, chlamydia, legionella, adenovirus, etc.) and specific disease-related pathogens (cytomegalovirus/Epstein-Barr virus, mycobacterium tuberculosis, rickettsia of typhus, Coxiella burnetii of Q fever, Salmonella typhi, Brucella, etc.) were all negative. The blood culture was repeatedly negative, and screening tests for AIDS, hepatitis B, hepatitis C, and syphilis were negative. Antibodies that indicate some autoimmune diseases, such as the anti-double-stranded DNA antibody, antineutrophil cytoplasmic antibodies (ANCA), anti-extractable nuclear antigen (ENA) antibodies, immunoglobulins, protein electrophoresis, immunofixation electrophoresis, complements, rheumatoid factor were all no meaningful found. No significant findings were found in tumor markers, bone marrow biopsy, and imaging examinations of underlying malignant tumors. According to the Yamaguchi criteria, the patient was diagnosed with AOSD. Methylprednisolone (60 mg Q.D.) was administrated as starting dose with subsequent tapering. After glucocorticoid treatment, her main symptoms were relieved, and inflammatory markers rapidly decreased, but the paresthesia and decreased sensation in her extremities decreased muscle strength with MRC (Medical Research Council) grades 2-3, tendon reflexes diminished to the disappearance, and imbalance progressed remarkably so that she was not able to walk or write; even words started slurring in the third week. We ordered an MRI of the spine with no positive findings, excluding the possibility of the patient's lumbosacral ganglion compression. Heavy metal and toxicants blood tests were negative. Head MRI and cerebrospinal fluid (CSF) examination were normal. The anti-ganglioside GQ1b antibody was negative in both serum and cerebrospinal fluid. Polymyositis antibodies, and paraneoplastic syndrome-related antibodies (Hu, Yo, and Ri antibodies) showed no meaningful findings. We performed the electrophysiological examination, and nerve and muscle biopsy revealed immune-mediated extensive peripheral nerve injury (Supplementary Figures 1-3). Intriguingly, electron microscopy images of nerve biopsy demonstrate the typical manifestation of distal axonal degeneration due to nerve injury:Wallerian degeneration (Figure 2). Paresthesia, muscle weakness, and tendon reflexes were fully recovered with MRC grades five after 9 months of glucocorticoid therapy in the patient, and slight numbness of the fingers and toes remained. She got fully recovered after more than 3 years of regular follow-up.

wallerian degeneration, adult-onset still's disease, delayed aggravation, innate-immune response, sensory ganglionopathy, sensory neuropathy

PMC4848873_01

Female

A forty-nine year old homeless woman with a 35 pack year cigarette smoking history and no significant medical problems presented to primary medical care with complaints of painful oral ulcerations on her gums and palate that had been present for at least 6 months. Her review of systems was unremarkable including an absence of constitutional symptoms, infectious symptoms, rheumatologic symptoms, lymphadenopathy, or history of recurrent infections, as well as a lack of history of or risk factors for HIV or immunosuppression. Her physical exam was notable for hypertrophic gums, a 1 cm ulceration adjacent to the right upper incisor, and a palatal ulceration near the left upper molars. She did not have palpable adenopathy, hepatosplenomegaly, rashes, joint tenderness, or joint effusions. Her differential diagnosis at time of presentation included trauma (necrotizing sialometaplasia), infection (herpes simplex virus/HSV, coxsackie virus, human immunodeficiency virus/HIV, syphilis, tuberculosis), autoimmune (systemic lupus erythematosus, Behcet syndrome, reactive arthritis, Crohn disease orofacial granulomatosis variant, Sweet syndrome, granulomatosis with polyangiitis, mucous membrane pemphigoid), carcinoma (squamous cell, malignant salivary gland tumor), or hematologic malignancy (B-cell lymphoma, T-cell leukemia/lymphoma). Diagnostic studies included a normal complete blood count and differential with exception of a mild lymphopenia at 950 cells/muL, normal basic metabolic panel, normal liver function test and lactate dehydrogenase, negative autoimmune screen (antinuclear antibody, anti-neutrophil cytoplasmic antibodies), and negative serologies for HIV and viral hepatitis. Her EBV screen by polymerase chain reaction (PCR) of serum was also negative. Computed tomography (CT) of neck, chest, abdomen, and pelvis demonstrated bilateral diffuse lymphadenopathy in the neck with the largest lymph node measuring 2.4 cm (Fig. 1), but no adenopathy in the hilum, mediastinum, axilla, abdomen, retroperitoneum, pelvis, or inguinal region. The spleen size was normal at 9.2 cm and the abdominal viscera appeared radiographically normal. The patient was referred to oral surgery for biopsy of her right maxillary perimolar lesion and left palatal lesion. Pathologic findings are demonstrated in Fig. 2 and Table 1. Extensive mucosal ulceration was noted with an underlying dense infiltration of small lymphocytes and frequent admixed large atypical lymphocytes including rare Hodgkin and Reed-Sternberg (HRS)-like forms that were positive for CD30 (strong), PAX5 (uniform), CD20 (variable), EBER (uniform), and negative for CD3, CD15, and CD79a. Molecular studies demonstrated a clonal immunoglobulin gene rearrangement. The overall findings were consistent with a clonal EBV-driven, B-cell lymphoproliferative disorder. The diagnostic considerations included EBV-positive mucocutaneous ulcer (EBVMCU) and other EBV-positive B-cell lymphomas including EBV-positive diffuse large B-cell lymphoma, however the patient declined excisional biopsy of cervical lymph nodes and bone marrow biopsy. Given CD20 expression on the large atypical lymphocytes, the patient received four weekly doses of rituximab (375 mg/m2) with immediate improvement of symptoms and ulcer regression. Unfortunately this response was short-lived. Within 3 months of completion of rituximab therapy the oral ulcers recrudesced and she declined additional diagnostic studies. Over the next 15 months the oral ulcers increased in extent, with multiple maxillary teeth spontaneously loss, increasing pain, and difficulty opening her mouth resulting in an inability to tolerate solid food, a 36-kilogram unintentional weight loss, and aspiration pneumonia and sepsis. Repeat CT (Fig. 3) demonstrated irregular enhancing soft tissue deep to the left nasolabial region and anterior premaxilla, encroaching on the left nasal vestibule. The tumor invaded the left maxilla. There was diffuse enhancement around the maxilla, palate, and upper oral mucosa. There were shotty bilateral cervical lymph nodes and small subcentimeter bilateral retropharyngeal nodes, but none clearly pathologic. On clinical exam, there was obvious left facial swelling along the left medial cheek and premaxillary region extending into the lip (Fig. 4a). She had limited oral opening due to pain. An ulcerative indurated mass was visible eroding the left maxilla and palate (Fig. 4b, c). It extended to the hard palate-soft palate junction with normal appearing soft palate mucosa. There was fullness and induration suggestive of submucosal extension to the sublabial region and to the buccal mucosa from the lip commisure back to the retromolar trigone. A second ulcer was apparent on the right upper inner gum line extending from the incisors to molars (Fig. 4d) with gum hypertrophy (Fig. 4e) and induration of the right buccal mucosa extending about halfway back. The oral tongue appeared normal. A swab of her ulcers was negative for HSV by PCR and her screen for HIV and EBV was again negative by PCR of peripheral blood. She continued to be resistant to repeat biopsy and bone marrow evaluation. Given the brief response to prior rituximab therapy, four weekly infusions of rituximab dosed at 375 mg/m2 were administered; however, the patient failed to experience treatment response. Her oral ulcers persisted and increased in size resulting in an almost total inability to tolerate oral intake with subsequent worsening weight loss, lethargy, and weakness. Her large left palatal ulcer was biopsied with overall pathologic findings similar to that seen in her initial biopsy. Again noted was ulcerated mucosa with underlying dense inflammatory infiltrate of small lymphocytes, eosinophils, neutrophils, histiocytes, and scattered large atypical lymphocytes with rare HRS-like forms. Sheets of large cells were not seen. Large atypical lymphocytes were uniformly positive for CD30, PAX5, MUM1, EBER, EBV LMP (Fig. 5), and negative for CD3, CD10, and CD20 (in the setting of recent rituximab exposure). The Ki-67 proliferation rate of the atypical lymphocytes was 70-80 %. Given the absence of lymphadenopathy or other systemic involvement of disease, a diagnosis of EBVMCU was rendered. Although HIV testing had been repeatedly negative and the patient had no prior history of recurrent infections or exposure to immunosuppressive agents, a potential underlying immunodeficiency syndrome was considered. Quantitative immunoglobulin (Ig) and T-cell subset analysis was performed and her IgG and IgM were found to be mildly depressed at 544 mg/dL (reference range 620-1490 mg/dL) and 29 mg/dL (reference range 40-350 mg/dL), respectively, while her IgA was normal at 122 mg/dL (reference range 65-420 mg/dL). Her mild hypogammaglobulinemia was likely secondary to recent rituximab exposure, although pre-treatment quantitative immunoglobulins had not been evaluated. Interestingly her CD4 and CD8 T-cell counts were both depressed with an absolute CD4 T-lymphocyte count of 125 cells/muL (reference range 733-2250 cells/muL) and an absolute CD8 T-lymphocyte count of 168 cells/muL (reference range 250-1240 cells/muL). Her CD4/CD8 ratio was relatively preserved at 0.73. Rituximab can cause B-lymphocyte depletion and subsequent hypogammaglobulinemia, however it is generally not observed to cause either primary of secondary T-cell depletion. Unfortunately T-cell subset analysis was not performed in our patient prior to rituximab exposure, and we were unable to determine whether she had an underlying immunodeficiency. Given our patient's poor response to recent systemic therapy, radiotherapy was considered as a therapeutic option given case report of excellent clinical response to radiation. Details of radiotherapy including dose were not described; however, extrapolating from radiation approaches with other lymphoproliferative conditions such as low grade lymphomas, we expected doses in the range of 20-45 Gy in conventional fractionation (1.8-2 Gy per fraction) to be associated with a high rate of clinical response and local control with a favorable toxicity profile. Regional nodal dissemination is not characteristic of EBVMCU, so elective nodal irradiation was not deemed necessary. Our patient received external beam radiation therapy using a three-dimensional conformal plan and a three-field approach (opposed lateral and anteroposterior fields; Fig. 6). The gross disease in the oral cavity was treated to 30 Gy in 15 fractions. She experienced a very brisk and complete clinical response with resolution of all oral ulcers and gum hypertrophy (Fig. 7) durable to 6 months.

b-cell neoplasm, epstein–barr virus, epstein–barr virus-positive mucocutaeneous ulcer disease, immunosenescence, lymphoproliferative disorder, radiation therapy, rituximab

PMC5225697_01

Male

An 11-year-old male child presented with a history of drooping of both the eyelids for 5 days with associated headache and ataxia for 2 days. He had no history of fever, convulsion, or loss of vision. There was a history of contact with a case of TB in the neighborhood. Clinical examination revealed bilateral symmetrical ptosis [Figure 1], but the movement of both the eyeballs was normal in all the directions with normal pupillary size and reaction bilaterally. Other cranial nerves were essentially normal. Dysdiadochokinesia and ataxia were noted on the right side. No weakness was found in any of the limbs. Deep tendon jerks were bilaterally normal with a normal plantar response. Investigations revealed normal blood counts and raised erythrocyte sedimentation rate. Mantoux test was negative and chest radiograph was normal. Magnetic resonance imaging (MRI) of the brain revealed single ring-like enhancing lesion in the dorsal part of the midbrain with significant perifocal edema in adjacent parts of the brainstem, right cerebellar peduncle, adjacent thalamocortical tract, and periventricular region [Figure 2]. MRS at the site of the lesion showed increased lipid peak, decreased N-acetylaspartate (NAA) peak with increased choline/creatinine ratio, suggestive of tuberculoma [Figure 3]. He was started on four drugs antitubercular treatment (ATT) (isoniazid [10 mg/kg/day], rifampicin [10 mg/kg/day], ethambutol [25 mg/kg/day], and pyrazinamide [35 mg/kg/day] - all thrice a week) along with intravenous dexamethasone (0.6 mg/kg/day in 4 divided doses). Later, dexamethasone was switched over to oral prednisolone at 1 mg/kg/day which was tapered after 6 weeks. Ataxia and headache responded within 2 days of starting the treatment, whereas drooping of eyelids improved gradually after 4 weeks of treatment. No worsening of symptoms was noted. ATT was continued for 12 months (2 months intensive phase with four drugs, followed by 10 months continuation phase with isoniazid and rifampicin) and the child is doing well without any symptom at 12 and 18 months follow-up.

ataxia, magnetic resonance spectroscopy, midbrain, ptosis, tuberculoma

PMC8418180_01

Male

Central nervous system (CNS) tuberculosis is one of the most devastating manifestations of tuberculosis and a leading cause of morbidity in developing countries. Its main pathological manifestations include meningoencephalitis, tuberculomas, and less frequently, abscesses. The involvement of ventricles is rare and the occurrence of intraventricular tuberculous abscess has been reported in literature only one time so far. Thus, without any specific clinical and radiological signs, the diagnosis of such condition can be very challenging. In this report, we describe the case of a ruptured tubercular abscess of the third ventricle in a 56-year-old man presenting with an atypical radiological image mistaken for a ventricular cystic tumor.

tuberculosis, brain abscess, case report, cerebral ventricles, intracranial hypertension

PMC8418180_02

Male

Patient information: a 56-years-old man, without any pathological background, presented with a one-month history of walk imbalance, urinary incontinence, and signs of increased intracranial pressure consisting of intense headaches, vomiting, and episodes of brief consciousness loss. Clinical findings: the physical examination found a conscious patient, afebrile, with gait apraxia and distal postural tremor. The cranial nerves examination was normal, and neither motor nor sensory deficits were detected. Diagnostic assessment: a cranial computed tomography scan (CT scan) revealed an isodense mass within the third ventricle obstructing the foramen of Monro bilaterally and extending to the left frontal horn with a mild rim contrast enhancement and small calcifications, associated with an obstructive hydrocephalus (Figure 1). Magnetic resonance imaging (MRI) disclosed a bilobate lesion including a cystic part of 23mm of diameter extending from the third ventricle to both of the foramen of Monro and a second heterogenous part in the left frontal horn of the lateral ventricle. The cystic part in the third ventricle contained three components on high, middle and low signal intensity on both T1 and T2-weighted images with a fluid-fluid level. There was a mild peripheral enhancement after gadolinium administration. In addition to the obstructive hydrocephalus, there were deposits in the occipital horns of the lateral ventricles (Figure 1). Apart from a deep hyponatremia of 117mEq/l and a quantitative C-reactive protein of 15mg/L, baseline blood investigations were within normal range. The chest X-ray was unremarkable. Based on clinical and radiological grounds, a presumptive diagnosis of cystic neoplasm, as colloid cyst or craniopharyngioma, was initially considered. Therapeutic intervention: right frontal craniotomy, transcortical transventricular approach to the lesion was performed one week after admission, combining both microscope and endoscope. On endoscopic visualization, the lesion was spherical, extending from the septum pellucidum to the third ventricle and encompassing the foramens of Monro (Figure 2). There was a yellowish and gelatinous fluid inside the ventricles. After microsurgical cauterization and opening of the cystic wall that was highly vascularized, a yellowish pus was evacuated by puncture and aspiration. The lesion was highly adherent to the fornix, preventing a complete excision of the wall (Figure 3). The part of the lesion within the left frontal horn was also punctured through the septum pellucidum with the help of the endoscope. After washing out the ventricles, an external ventricular drain was left on the right lateral ventricle. On bacterial examination of the pus, ZN staining demonstrated acid-fast bacilli (AFB). The histopathological examination of the cystic wall revealed vascular granulations with non-specific inflammatory reaction. GeneXpert was positive for mycobacterium tuberculosis. HIV serology, performed after this finding, was negative. The antituberculosis therapy was started immediately, including rifampicin, isoniazid, pyrazinamide and ethambutol, as recommended by the national guidelines. Follow-up and outcomes: post-operatively, the patient experienced a rapid neurologic improvement. The external ventricular drain was removed after seven days, and the patient was discharged from hospital ten days after surgery. Considering the risk of ventricular septation inherent to central nervous system (CNS) tuberculosis and recurrence of hydrocephalus, the patient and his family were advised to consult at the slightest worsening, in order to perform a ventriculoperitoneal shunt if necessary. But the patient was almost symptom-free at the first month follow-up examination, with only a mild memory disturbance, and the control blood tests were normal. Three months later, the patient was hospitalized again in another institution for a jaundice and altered general state. A drug-induced fulminant hepatitis was suspected, and unfortunately, he died a few days later.

tuberculosis, brain abscess, case report, cerebral ventricles, intracranial hypertension

PMC4661164_01

Male

A 25-year-old man was referred after excision of a painful 2-cm nodule in the left infrapatellar region. Pathological diagnosis was synovial sarcoma (Fig. 1a). Because of positive margin, pre-operative radiotherapy and subsequent re-excision were performed. The whole patellar tendon, infrapatellar fat pad, inferior one-third of the patella, and the tibial tuberosity were removed together with 6 x 12 cm of the skin including previous operation scar. Using an oblique osteotomy, nearly the whole original patellar-femoral joint surface of the patella was preserved. Following resection, BPTB allograft was harvested and shaved to fit the osteotomy sites. Then, the allograft was fixed to the residual patella and proximal tibia with screws and a stainless steel Dall-Miles 2-mm Cable and Sleeve Set (Stryker Australia Pty., Ltd.) tightened at 30 knee flexion (Fig. 1b). The soft tissue defect was covered with a free ipsilateral antero-lateral thigh (ALT) flap. Post-operative course was uneventful without wound complication or infection. The operated knee was kept straight in splint for the first 3 months, and then gentle passive and active range-of-motion (ROM) exercise was started. Full weight bearing (FWB) was tolerated immediately after surgery but only in the setting of using crutches for the first 6 weeks. Three months after surgery, progressive ROM exercise and FWB without splint were allowed. Both bone-bone junctions were united 11 months post-operatively (Fig. 1c). After both bone-bone junctions were united, sports activity, including fun skiing, was permitted. At 67 months after surgery, the patient was continuously free of disease. His left knee function was virtually normal, with no extension lag and knee flexion of 130 (Fig. 2; Additional file 1: Movie S1). Quadriceps manual muscle test was 5/5. Musculoskeletal Tumor Society (MSTS) score was 30/30 (Enneking et al.).

allograft, knee extension mechanism, patellar tendon, reconstruction, soft tissue sarcoma

PMC4661164_02

Male

A 56-year-old man was referred after unplanned excision of an infrapatellar 35-mm nodule. The pathological diagnosis was clear cell sarcoma. After pre-operative radiotherapy, the same area as in patient 1 was removed because of similar tumor location, BPTB allograft was fashioned to fit the defect, and the allograft was covered by the free contralateral ALT flap. Post-operative course was uneventful. Post-operative management was similar to Patient 1, with the reduced period of the knee brace maintained in straight of 8 weeks, reflecting on the slightly limited ROM in the previous case. Bone union was completed 1 year after surgery. At 48 months post-operatively, the patient was continuously free of disease and his knee function was satisfactory, with minor knee extension lag (<5 ), knee flexion of 145 , full muscle strength and MSTS score of 30/30.

allograft, knee extension mechanism, patellar tendon, reconstruction, soft tissue sarcoma

PMC4661164_03

Male

A 28-year-old man was referred after unplanned excision of an infrapatellar 4-cm nodule. The pathologic diagnosis was extraskeletal Ewing's sarcoma. After neo-adjuvant chemotherapy and radiotherapy, re-excision and reconstruction with BPTB allograft and ALT flap were performed, similar to patients 1 and 2. Post-operative management was similar to the previous 2 cases, with the reduced period of the knee brace maintained in straight of 6 weeks. Post-operative course was uneventful. Bone union was completed 1 year after surgery. At 30 months after surgery, the patient was continuously free of disease. The bone-bone junctions were united, and his knee function was satisfactory, with minor knee extension lag (<5 ), knee flexion of 135 , full muscle strength and MSTS score of 30/30.

allograft, knee extension mechanism, patellar tendon, reconstruction, soft tissue sarcoma

PMC4661164_04

Male

A 72-year-old man presented with a 9-cm painless mass in the right knee just lateral to the distal end of patellar tendon. The tumor was located subcutaneously and intra-muscularly but partially invaded into the lateral cortex of the proximal tibia (Fig. 3a). Core needle biopsy confirmed the diagnosis of synovial cell sarcoma. After pre-operative radiotherapy, wide resection included the lower one-third of the patella, the whole patellar tendon, infrapatellar fat pad, anterior lateral knee joint capsule, and one anterior-lateral third in axial section of the proximal tibia extending more distal than the previous cases. After resection, BPTB allograft was fixed to the residual patella and proximal tibia with screws. A lateral proximal tibial plate and screws were added but no cable wire was added because the suitable hole site for cable wiring, just distal to the tibial tuberosity, was resected (Fig. 3b). Post-operatively, we managed this patient similar to the previous patients, maintaining the operated knee straight in splint for the first 8 weeks. Five months post-operatively, an increasingly painful stress fracture of the proximal tibia was diagnosed (Fig. 3c). The fracture was fixed with another plate. Bone union between the implanted allograft and host bones was completed 1 year after surgery. At 18 months after the initial surgery, the fracture site was united, FWB was tolerated, but the knee ROM was restricted with -10 of extension and 115 of flexion. MSTS score was 28/30 (93 %).

allograft, knee extension mechanism, patellar tendon, reconstruction, soft tissue sarcoma

PMC3425248_01

Male

A 28-year-old man working in a local factory was admitted to the Department of Medicine with the diagnosis of acute dengue infection from where he was referred to the Psychiatry outpatient department of the University College of Medical Sciences and associated Guru Tegh Bahadur Hospital with the complaint of altered behavior. Detailed psychiatric evaluation was performed. There was reported history of talking more than usual, feeling happy, increased activity, increased self-confidence, decreased need for sleep, and food, irritability, outbursts of aggression with grandiosity for a period of 5 days. Three days prior to onset of psychiatric illness, he developed fever (40.6 C) associated with severe headache, transient spells of altered consciousness, generalized body ache, anorexia, and occasional vomiting. There was no history of neck rigidity, photophobia, seizure, and covert or overt bleeding. General and systemic examinations were unremarkable. The patient's blood pressure and pulse rate were 114/76 mm Hg and 110-120 per minute respectively. Investigations were done on the third day of fever. His IgM ELISA for dengue was positive; other investigations revealed a platelet count of 26,000/mul, total leukocyte count: 5400/cmm with lymphocytes 46%. Blood electrolytes, blood sugar, lipid profile, and renal function tests were within normal range. Liver function tests were also normal except for aspartate transaminase (258 IU/ml) and alanine transaminase (366 IU/ml). The blood smear was found to be negative for malarial parasite. Prothrombin time was 13 seconds but bleeding time was increased (9 minutes). He was diagnosed as a case of dengue fever with thrombocytopenia. The patient received three units of platelet concentrates transfusion and was kept under observation and received only supportive therapy. On the third day of dengue fever, the patient exhibited discernable symptoms (mentioned above) of a manic episode. His past, personal, and family history was noncontributory. Mental status examination revealed a young man of average built, wearing bright yellow colored shirt and green trousers with a pink hat with a string of beads round his neck. He appeared authoritative. While talking, it was difficult to interrupt him. He refused to sit despite being requested to do so by the examiner. He continued to move about in the examination room chanting some mantras and in between making claims of possessing special superhuman abilities like ability to engulf the sun, to trap the air, so on and so forth. No amount of explanation could shake him off his grandiose delusions rather it increased his irritability. There was no evidence of any formal thought disorder. Higher mental functions were found to be within normal limits. His abstract thinking was intact on formal assessment. The judgment was found to be impaired with insight of grade 1. His young mania rating scale (YMRS) score was 29. Mini Mental State Examination revealed no cognitive impairment with score of 28/30. Computed tomography scan of the head was found to be normal. He was started on tablet divalproex sodium 1500 mg/day and risperidone 6 mg/day to which he responded successfully within 3 weeks. Subsequent blood investigations conducted on day 18 of admission were within normal limits and he was followed up in the outpatient department of psychiatry for 3 months and did not develop the symptoms of mania.

dengue, mania, psychiatric complications

PMC10277496_01

Male

A man aged 33 years was taken to the hospital after colliding with a car while riding his moped. There had been no loss of consciousness. There were no abnormal neurological findings. A CT brain scan was normal, and he was discharged after 6 h. The same night, he became confused, unable to see clearly, unsteady, and vomiting. He was brought back to the hospital but discharged again after a few hours. He was admitted 4 days later with increasingly aggressive behavior and numbness and weakness down his left side. A T9 compression fracture was treated with a brace. In the hospital, 7 days following the accident, he began to develop tics, first as minor oral movements, progressing over a matter of days to substantial vocal and motor spasms, the latter affecting his head, neck, trunk, and upper limbs. He also complained of headaches, visual disturbances, slurred speech, word-finding difficulties, and short-term memory impairment. Brain MRI was normal, and he was discharged. When examined at our institution 2 months later, he was virtually housebound with a florid syndrome of tics and involuntary vocalizations. Abnormal movements included a stammer, humming, facial grimacing, and shoulder shrugging. Vocalizations involved clang associations "tick tock, rock rock" and repeated profanities. All were suppressible for short periods at the expense of extreme discomfort and emotional upset. All were exacerbated by anxiety and partially relieved by distraction. He was walking on crutches. MRIs of the brain and spine were unremarkable. There was no family history of Tourette syndrome. Over the next 3 years, his tics were undiminished. There were no objective neurological findings, and there was broad agreement between neurology and psychiatry that his symptoms were largely functional. He was reviewed by the ophthalmology service, who recorded grossly disordered eye movements and grossly restricted visual fields but no papilledema. His premorbid personality had been boisterous and outgoing. After the accident, his mood varied between elation and depression, with outbursts of anger. With time, he became apathetic, fatigued, and withdrawn. His weight increased, and he noticed reduced facial hair and libido. Pituitary function tests were all normal except that gonadotrophin levels were not increased in the face of low testosterone levels. He was started on testosterone replacement therapy. He developed polydipsia, which was attributed after investigation to a constant sensation of dryness in his mouth. With intractable symptoms and our group's interest in disordered cerebrospinal fluid (CSF) dynamics and cerebral venous outflow obstruction, he underwent CT venography. This showed normal intracranial venous sinuses but marked narrowing of both jugular veins between the styloid processes of the skull and the transverse processes of the C1 vertebra (Figure 1A). Lumbar puncture revealed an opening pressure of 20 cm H2O, and his headache responded temporarily to cerebrospinal fluid (CSF) drainage, although tics were unchanged. Catheter venography confirmed the jugular narrowings, each associated with a 3 cm H2O gradient (Figure 2A). He had bilateral jugular venoplasty (Figure 2B) with no immediate effect, but over the following week, his physical and vocal tics were greatly reduced. His headache had improved. His demeanor was calmer. His head felt clearer, and his memory was improved. Within 2 weeks, all symptoms had returned (see Supplementary Videos S1, S2). He was diagnosed with cranial venous outflow insufficiency and, following appropriate counseling, had resections of the left styloid process and of the left C1 transverse process in a single procedure (Figure 1B). The next day, barring the occasional facial tic, all his abnormal vocalizations and abnormal movements had resolved. His headaches, balance, and mood improved. At ophthalmology review 6 weeks later, his vision had returned to normal. His headache reoccurred in the months following surgery, and there was residual mood and cognitive disturbance, as well as profound fatigue. He responded to repeat venoplasty, but further surgical and stenting procedures were not successful in effecting any further reduction in jugular narrowing or seemingly any lasting clinical benefit. A review of his notes 2 years after his initial intervention revealed a brief mention of a fluid discharge from his nose around the time of the accident. This was not addressed by his treating physician at the time, but now, on direct questioning, his partner recalled copious volumes of clear fluid coming from his nose on the night of the accident, adding to the distress experienced by the family on his arrival home. Then, over the next 3 years, this nasal discharge was repeated frequently, with no obvious precipitating factor, sometimes, for example, when they were sitting together watching television. However, none of this was revealed in numerous follow-up medical consultations, and at no time prior to surgery was the possibility of a CSF leak considered. Following surgery, these discharges were substantially reduced in frequency and volume, and late attempts to establish the presence or likely origin of a CSF leak were unsuccessful. Then, at around 3 years post-surgery, they ceased altogether, this coinciding with a pronounced improvement in his general health and restoration of his premorbid affect, although headache and fatigue have persisted, if less severe than previously (see Supplementary Video S3).

tourette syndrome, cerebrospinal fluid leak, functional neurological disorder, jugular vein stenosis, whiplash injury

PMC9194441_01

Male

The proband is a 4-month-old male infant, the second affected child of healthy non-consanguineous parents. His elder brother experienced similar symptoms and died 5 years ago at the age of 4 months. The proband was born at term with a birth weight of 2.53 kg following a normal pregnancy. On the second day after birth, the patient presented with frequent apneas and cyanosis, and was transferred to our hospital. He presented with hypotonia and marked muscle weakness. His blood oxygen level was reduced to 77% (normal range for newborns: 93-100%), and the heart rate dropped to 110-120 beats/min (normal range for newborns:120-140 beats/min). The peripheral blood glucose fluctuated between 4.0 and 6.0 mmol/L (normal range: 3.9-6.1 mmol/L) during this period. Nasal continuous positive airway pressure (NCPAP) was used to maintain airway patency. A CT scan of the brain revealed an existing subarachnoid hemorrhage. Laboratory investigations revealed plasma lactate concentration fluctuated between normal and abnormal. Blood acylcarnitine analysis and urinary organic acid profiling showed no abnormality. Laboratory tests revealed total bilirubin (TBIL) of 170.8 mumol/L (normal range: 0-23 mumol/L) and direct bilirubin (DBIL) of 11.1 mumol/L (normal range: 0-4 mumol/L), and renal functions were basically normal. After being hospitalized for 5 days in our hospital, the child was transferred to a provincial hospital for more than 2 months. During this period, the child underwent a number of examinations and no clear cause was determined. At said hospital, no pathogenic mutations or copy number variations were found in genes related to the disease.

aifm1, fatal encephalomyopathy, mitochondrial disease, novel intronic mutation, whole-exome sequencing

PMC9194441_02

Male

At roughly 4 months old, the child was sent to the emergency department of our hospital due to spit-up and cyanosis at home. He had gone into a sudden respiratory and cardiac arrest. After rescue, the child's complexion gradually turned rosy, and his spontaneous heartbeat was restored. Considering that the child's breathing was unstable after successful cardiopulmonary resuscitation, advanced life support treatment was still needed, so he was transferred to PICU under the condition of tracheal intubation and resuscitation bag positive pressure ventilation for further monitoring and treatment. Later, despite the use of non-invasive respiratory support, the child still had repeated apneas, accompanied by mental fatigue, drowsiness, and sudden hypotension. The lactic acid was always high, fluctuating at 5-12.9 mmo/L (normal range: 0.5-2.2 mmol/L), showing a progressive increase. A brain magnetic resonance imaging (MRI) examination was performed and revealed a bilateral hyperintensity of basal ganglia (Figure 1A). Hydrocephalus was suggested by a moderately enlarged ventricle system, centered on each side of the ventricle and a widened extracerebral space in the temporal part of both sides. The patient's lactate peak was distinctly discernible as an inverted doublet at TE = 144 ms by single voxel magnetic resonance spectroscopy (MRS) of the left basal ganglia (Figure 1B). Multiple basic symmetrical abnormal signals, combined with MRS can be seen in the bilateral basal ganglia, brainstem, thalamus, frontal lobe, parietal lobe, bilateral limbic lobe, and temporal cortex, suggesting mitochondrial encephalopathy. Finally, the proband died due to respiratory failure after the parents ceased treatment. The peripheral blood samples were obtained from the patient and his family members after informed consent was obtained. Whole Exome Sequencing (WES) was performed to analyze the coding exons and the exon-intron boundaries of protein-coding genes by the Novogene Bioinformatics Institute (Tianjin, China). The American College of Medical Genetics and Genomics (ACMG) guidelines were also used to classify this variant. The 3D models of the normal and mutant protein are predicted by the I-TASSER server1 and visualization was carried out by PyMOL. RNA sequencing was conducted by the Novogene Bioinformatics Institute (Beijing, China). Preparation of sample is followed by the RNA library preparation. RNA library is formed by polyA capture (or rRNA removal) and reverse transcription of cDNA. Illumina PE150 technology is employed to sequence the sample and the final stage involves the bioinformatics analysis. Quadricep muscle and skin biopsies were obtained from the patient. Age- and gender-matched specimens of normal human muscle and skin were obtained from a patient during surgery. For the use of biomedical studies, fibroblasts were cultured and harvested from the biopsies. We preformed reverse transcription-polymerase chain reaction (RT-PCR) on mRNA extracted from the patient's fibroblasts in order to evaluate the potential effect of this variant on splicing. The cDNA obtained was amplified by PCR, using a set of primers: the forward primer aligning on exon 10 (5'-CAGCAACTGGACCATGGAAA-3') and the reverse primer aligning on exon 12 (5'-GCTCTGCATTTACCCGGAAG-3') of AIFM1 gene. The PCR products were gel-purified and ligated into the pMD19-T vector and transformed into E. coli DH5alpha. The colonies were picked and screened by PCR, and the positive clones were sent for sequencing (Sangon Biotech, Shanghai, China). The relative mRNA expression levels of AIFM1 in the fibroblasts of the patient and control normal individual were compared by real-time quantitative polymerase chain reaction (RT-qPCR). Four pairs of primers were designed to detect the mRNA level of AIFM1. Each experiment was performed in triplicate, and expression data were normalized to beta-actin as an internal reference gene. The 2-DeltaDeltaCt method was used for quantification by comparing the Ct values. Fibroblasts were trypsinied, centrifuged at 1000 g for the duration of 5 min, followed by solubilizing in RIPA buffer with protease inhibitors. For muscle tissues, ice-cold lysis buffer was rapidly added to the samples, followed by homogenizing with an electric homogenizer and rinsing the blade twice with another 2 x 300 muL lysis buffer. The samples were then kept at 4 C for 2 h with continual agitation. Immunoblot analysis was performed with the ECL-chemiluminescence kit in accordance with manufacturer's protocol. A mouse monoclonal anti-GAPDH (4A Biotech Co., Ltd., Shanghai, China, Cat. No. 4ab030004) and mouse monoclonal anti-AIFM1 antibody binding to the C-terminus of human AIF (Boster Biological Technology, Wuhan, China, Cat. No. M01571-1) were used. The HRP-conjugated Affinipure Goat Anti- Rabbit IgG (H + L) was used as secondary antibody (Proteintech, Illinois, IL, United States, Cat. No. SA00001-2). For immunofluorescence, cells were fixed in 4% paraformaldehyde and permeabilized in 0.25% Triton X-100. Subsequently, cells were blocked and immunostained with antibodies in 5% goat serum and treated with 4',6-Diamidino-2-phenylindole (DAPI) staining solution (Beyotime Biotechnology, Shanghai, China) before mounting. Anti-TOMM20 (Millipore, Bedford, MA, United States) was used at 1/200 dilution for mitochondria localization. Images were visualized using Nikon Eclipse Ti-S Phase Contrast Fluorescence Inverted Microscope (Nikon, Tokyo, Japan). The level of NAD+ in fibroblasts was determined using NAD+ /NADH assay kit (Beyotime, S0175, Shanghai, China) with WST-8 according to the manufacturer's instructions. Human Cytochrome C Oxidase (COX) of cell culture supernatant were measured using the Human COX ELISA kit (RX105095H, Ruixin Biotech, Quanzhou, Fujian, China) according to instruction of the manufacturer.

aifm1, fatal encephalomyopathy, mitochondrial disease, novel intronic mutation, whole-exome sequencing

PMC6580309_01

Female

A 6-month-old girl presented to the pediatric emergency department with four days of intermittent fever, tachypnea, and persistent cough. According to the patient's mother, she had not experienced previous nausea, vomiting, dyspnea, or peripheral edema; but she did exhibit poor oral intake and general failure to thrive. Her mother reported no history of trauma, birth complications, or evidence of other congenital malformations and a thorough review of systems was otherwise negative. Her mother was a 23-year-old woman who denied any personal or family history of chronic disease, sick contacts (including anyone infected with tuberculosis), and reported a negative HIV status. She was seen by a physician prenatally but did not receive routine ultrasound. Physical examination revealed a small female infant with low body weight (4.8 kg, <5 percentile weight for age), breathing at a rate of 52 breaths/min, with a heart rate of 145 beats/min, and blood pressure of 126/111 mmHg. She was afebrile. Abdominal evaluation was soft and nontender. Chest auscultation was notable for diffuse bilateral rhonchi and rales, though cardiac sounds were normal. She was not cyanotic. Preoperative labs demonstrated anemia (HgB: 10.2 g/dL) but no leukocytosis (WBC: 9.4 x 103/muL). Echocardiography was reported as normal. An initial chest radiograph (Fig. 1) showed dilated loops of bowel located centrally in the thoracic cavity, obscuring the cardiac silhouette, with opacification of the lower lobe of the left lung. These findings were suspicious for CDH, which was confirmed by a thoracic CT scan (Fig. 2). Plans for corrective surgery were made with the preoperative diagnosis of a likely Morgagni-type CDH. The patient was taken to the operating room and underwent a left thoracotomy. It was readily apparent that there was no hernia sac or loops of bowel within either pleural cavities. However, the pericardium was grossly enlarged and ballotable. We carefully incised the pericardium, from which drained roughly 20 ml of serous fluid. Within the pericardium we found the hernia sac, which was also incised, revealing loops of small bowel that were incarcerated, but not strangulated (Fig. 3). The heart itself was visualized directly without overlying pericardium. On two occasions during manipulation of the hernia contents the heart became asystolic. Each time systole was quickly restored with direct cardiac massage. We proceeded to reduce 10 cm of small bowel, and corrected the 2 cm defect in the cardiac portion of the central tendon of the diaphragm. The remainder of the diaphragm was intact, the abdominal wall was intact, the great vessels entering and leaving the heart were grossly normal, and we found no evidence of any other congenital malformations within the thorax. We closed the pericardium, leaving a small defect to prevent future pericardial effusion. We subsequently closed the thoracic cavity in layers, leaving a 28 French chest tube draining the pleural cavity by gravity under water seal. Postoperative management included treatment with furosemide for acute pulmonary edema on post-operative day one. On the second post-operative day, the patient developed a new leukocytosis and fever. A chest radiograph demonstrated bilateral opacification of the lung fields. She was given penicillin, acetaminophen, and salbutamol and a follow-up chest radiograph demonstrated clear lung fields and no evidence of hernia. The patient was discharged seven days after her operation, breastfeeding normally clinically stable. Despite attempts to contact the mother, the patient was lost to follow up and not seen in our surgical clinic.

case report, congenital diaphragmatic hernia, pediatric surgery, pericardium, thoracic surgery

PMC9479181_02

Female

The Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) was used to evaluate the general intellectual ability of the patient when she was 78 months old. The full-scale intelligence quotient was 78, which is at the lower limit of the normal range. The scores of verbal comprehension, perceptual reasoning, working memory, and processing speed subtests were 81, 79, 85, and 79, respectively. Detailed neurological features are shown in Table 1. To detect disease-causing mutations, genomic DNA was extracted from the peripheral blood samples of the patient and her parents using the Gentra Puregene Blood Kit (Qiagen, Hilden, Germany), according to the manufacturer's protocol. Whole-exome capture was performed using an Agilent SureSelect V6 enrichment capture kit (Agilent Technologies, Inc., Woburn, MA, United States), according to the manufacturer's instructions. The captured library was sequenced using the Illumina HiSeq 2500 System (Illumina, Inc., San Diego, CA, United States). Original sequencing data were assessed using FastQC (version 0.11.2) for quality control. The Burrows Wheeler alignment tool v0.2.10 was used for sequencing data alignment to the Human Reference Genome (NCBI build 37, hg 19). Single-nucleotide variants and small indels were identified using the Genome Analysis Toolkit. All variants were saved in VCF format and uploaded to the Ingenuity Variant Analysis (Ingenuity Systems, Redwood City, CA, United States) and TGex (Translational Genomics Expert) platforms for biological analysis and interpretation, as previously reported. Variants detected by next-generation sequencing were confirmed by Sanger sequencing. Whole-exome sequencing revealed a novel frame-shift variant, c.2128_2129del, p.Leu710Valfs x 42, in the last exon of SATB1 (NM_001195470.2). Sanger sequencing confirmed the variant as well as the wild-type status of her father and mother (Figure 1B). The control population database (gnomAD) and our local control cohort database did not have reports on the detected variant. The frame-shift variant is classified as a pathogenic variant according to the ACMG guidelines for variant interpretation.

satb1, anti-epileptic drugs, epilepsy, neurodevelopmental delay, protein-truncating variants

PMC10352806_01

Female

A 30-year-old Chinese female was admitted to our hospital with persistent fever and cough as well as and chest and back pain (lasting for 8 and 3 months, respectively). The maximum body temperature was 39.4 C, the fever was irregular. No other symptoms or signs of organ involvement was present. She had been initially admitted and treated at a local hospital. An examination at the local hospital showed an erythrocyte sedimentation rate of 59 mm/h. The HIV test yielded negative results; the results of the purified protein derivative test and interferon-gamma release assay, which used the ELISA, were normal. The results of the acid-fast bacillus (AFB) test, smear, and cultures of the sputum and bronchoalveolar lavage fluid did not reflect any abnormalities. Even after 21-day antibiotic therapy (cefoperazone sulbactam), the patient showed no improvement. Considering her symptoms and the imaging features (Figure 1A) observed in her chest CT, she was prescribed anti-tuberculosis treatment comprising isoniazid, rifampicin, pyrazinamide, and ethambutol on December 15, 2021. She was non-responsive to the medications for up to six months. Meanwhile, her condition deteriorated, and she started experiencing chest and back pain. 2-deoxy-2-[fluorine-18] fluoro-D-glucose positron emission tomography/X-ray computed tomography (18F-FDG PET/CT) indicated that the thoracic (T-6) vertebral body showed low metabolism (Figure 2A), and the left upper lobe of the lung indicated high metabolism (Figure 2B). Chest CT scans showed some osteolytic damage in the vertebrae (Figure 2C). The patient was then transferred to our hospital for further diagnosis and treatment. The patient had no history of unprotected sex or blood transfusions. In addition, there was no history of other personal or hereditary diseases. She also denied traveling to any area except her hometown over the past 10 years. The vital signs during the initial examination were as follows: body temperature, 37.3 C; blood pressure, 107/74 mmHg; heart rate, 107 beats/min; and respiratory rate: 20 breaths/min. Physical examination was normal, except for tenderness at the 5/6 thoracic spine level. Initial laboratory examinations reported the following: white blood cell count, 13.83 x 109/L; red blood cell count, 3.03 x 1012/L; hemoglobin level, 77 g/L; neutrophil percentage, 95.4%; lymphocyte percentage, 2.8%; and albumin level, 35.9 g/L. C-reactive protein (112.00 mg/L), procalcitonin (17.70 ng/mL), and interleukin-6 (26.40 pg/mL) levels and erythrocyte sedimentation rate (110.00 mm/h) showed significant elevation. Multiple peripheral blood cultures yielded normal results. The possibility of bacterial infection was first considered based on the clinical characteristics and auxiliary examinations. The physician intravenously administered piperacillin-sulbactam and levofloxacin to the patient. However, the patient was feverish, with a maximum temperature of approximately 39 C. Owing to the poor response of the patient to antibiotic and anti-tuberculosis therapy, we further searched for potential evidence of any other kind of infection. The beta-1,3-D-glucan test, Aspergillus galactomannan test, Cryptococcus antigen test, Pneumocystis japonicum DNA test, repeated purified protein derivative test, interferon-gamma release assay (using the ELISPOT assay), and acid-fast staining and sputum culture were all negative for their associated infections. Table 1 presents immunological reports of the patient under investigation. Chest CT scans showed scattered patches, nodules, and ground-glass shadows in the left upper lobe with ill-defined borders and thickening of some interlobular septa (Figure 1B). White blood cell count and C-reactive protein levels continuously increased, while hemoglobin and plasma albumin levels progressively decreased. Upon testing for them, we did not find any of the following antibodies in the patient: antinuclear antibodies, anti-double stranded DNA antibodies, anti-cyclic citrullinated peptide antibody, anti-keratin antibody, anti-neutrophil cytoplasmic antibodies, and HLA-B27. In conclusion, the diagnosis remained unclear. On the fifth day after admission to our hospital, the patient's blood pressure decreased to 70/42 mmHg, and she developed asthenia. A large amount of fluid was administered for rehydration; and the blood pressure was not raised significantly with fluid resuscitation. Vasoactive drug (m-hydroxyamine 50mg) was used to raise blood pressure, her blood pressure then increased to 90/60 mmHg, and we adjusted her treatment to intravenous meropenem and levofloxacin. A percutaneous lung biopsy was performed after the patient's condition had slightly improved, which showed granulomatous inflammation. Some pathogens were observed in the macrophages and interstitium suspiciously. Hexamine silver (Figure 3A) and periodic acid-Schiff (PAS) staining (Figure 3B) were positive suspiciously, whereas AFB, mucous card red staining, and TB-qPCR were negative. Tumors were not detected. Due to scarce availability of lung tissue and denial by the patient's family, biopsy specimens were not sent for culturing. Eventually, we performed mNGS, which detected 1655 reads of Talaromyces spp. (Illumina NextSeq 550, Chengdu, China), including 1160 reads of T. marneffei, 435 reads of Human gamma herpesvirus 4 (EBV), no other bacteria and parasite had been detected. The MRI of spine showed the lesions of thoracic vertebra (Figure 1E). Thoracic cone biopsy was also performed to identify any thoracic vertebral lesions. mNGS of bone tissue revealed no pathogens. Pathological examination of the bone and bone marrow showed focal granuloma formation, and AFB smear, silver hexamine, PAS staining, and TB-qPCR results were negative. We could finally confirm T. marneffei infection via PCR amplification targeting the rDNA internal transcribed spacer region followed by a BLAST sequence comparison (https://blast.ncbi.nlm.nih.gov/Blast.cgi; GenBank accession no. MN700106.1, coverage 97%, identity 99.23%) (Figure 4A). These results showed that the patient was infected with T. marneffei. Anti-fungal therapy with amphotericin B was immediately initiated. She was treated with intravenous amphotericin B (0.6-1.0 mg/kg.d, ivgtt) as standard initial therapy. After 3 days of the antifungal treatment, the patient's body temperature normalized, and the talarmycosis-associated clinical symptoms were relieved. ELISA confirmed that the patient had a high titer of anti-IFN-gamma autoantibodies (1:2500), the value of optical density (OD) was 1.149, which was much higher than negative control (Figure 4B). During the antifungal treatment, the patient's renal function was impaired. After discussing it with her family, we adjusted the antifungal therapy to liposomal amphotericin B (30 mg/d, ivgtt). Chest CT scans showed that the lesions in the left upper lobe of the lung had been absorbed after 2 weeks of cumulative treatment with amphotericin B (Figure 1C). The MRI of spine showed the lesions of thoracic vertebra were absorbed (Figure 1F). The main clinical diagnosis was severe T. marneffei pneumonia, spine T. marneffei infection, septic shock. Oral itraconazole was administered successively. Five months after discharge, there was no recurrence, which was confirmed via a telephonic follow-up, and Chest CT scans of the local hospital showed that the lesions in the left upper lobe of the lung had been absorbed furthermore (Figure 1D). A timeline of the patient with relevant data on the episodes and interventions is presented in Figure 5.

hiv-negative patient, talaromyces marneffei, anti-interferon gamma autoantibodies, metagenomic next-generation sequencing, septic shock

PMC9577386_01

Male

An 18-year-old male patient with a history of redness, pain, watering, foreign body sensation and diminution of vision in his right eye for the past month was referred to us. The patient had a prior history of trauma to the right eye with dust particles, subsequent to which he had put honey in the eye for symptomatic relief. The application of honey in the eye could be a source of keratitis. On presentation, the Snellen visual acuity was hand motion close to the face with accurate projection of rays in the right eye and 6/6 in the left eye. Slit-lamp examination revealed a near total epithelial defect with corneal infiltrates of 8x8 mm extending up to 1/2 of corneal thickness with circumciliary congestion and lid edema (Figure 1 (Fig. 1)). Corneal scrapings were taken for smear and culture, and Staphylococcus aureus was isolated in bacterial culture, which was sensitive to moxifloxacin, gatifloxacin, cefazolin, and vancomycin. Confocal microscopy was performed, which revealed the presence of fungal hyphae (Figure 2 (Fig. 2)). Posterior segment examination on ultrasonography did not reveal any evidence of presence of vitreous exudates or retinal detachment. Treatment was started with topical voriconazole 1% (prepared my mixing 20 mL ringer lactate to 200 mg voriconazole lyophilised powder), natamycin 5% (commercially prepared eye drops), vancomycin 5% (500 mg of vancomycin powder was reconstituted with 2 mL sterile water and then added to 8 mL of artificial tears), administered every hour with homatropine hydrobromide 2% QID and oral voriconazole at a dosage of 200 mg twice daily. After 3 days, the lesion had not progressed, but there was no change in corneal infiltration or epithelial defect, and the patient had worsened symptomatically. The culture report was negative for fungus and Acanthamoeba. At one week, there was a further increase in symptoms and no reduction in infiltrates. The patient was subsequently switched from concentrated vancomycin to topical 0.5% moxifloxacin. The epithelial defect remained unchanged. Meanwhile, a corneal scrape GeneXpert sample to rule out atypical mycobacterium also turned out to be negative. GeneXpert is a cartridge-based nucleic acid amplification test (NAAT) for rapid diagnosis of tuberculosis and atypical mycobacteria. In view of the poor response with clinical worsening on day 14 of starting the treatment, we decided to replace topical natamycin with topical caspofungin acetate 0.5%, applied every hour. To prepare the eyedrops, 1 vial of 50 mg of caspofungin acetate was diluted in 10.5 mL of sterile normal saline; all eyedrops were freshly prepared weekly, kept at 4 C, and protected from light. Three days later, clinical improvement was observed. Following the commencement of the treatment, healing of the corneal epithelium and resolution of the corneal infiltrate were observed from the periphery towards the centre with evidence of vascularisation, and the patient showed commendable clinical response (Figure 3 (Fig. 3)). At 6 weeks of follow-up, the ulcer had healed completely. Although the patient initially had limbus to limbus corneal infiltrates, the scarring was less dense and involved superficial cornea with relative peripheral corneal sparing (Figure 4 (Fig. 4)). The patient attained an uncorrected visual acuity of 6/36 in the right eye, which improved to 6/12 with a trial of rigid gas permeable (RGP) contact lens.

caspofungin, corneal ulcer healing, echinocandins, fungal corneal ulcer, recalcitrant fungal keratitis

PMC3414247_02

Female

This was a woman with depression who responded well to a selective serotonin reuptake inhibitor. She was described as cheerful and precise and had been maintaining a diary that she had written in every day for 10 years. She never missed school and was a member of the basketball and softball teams. After graduating from school, she worked in a home for the aged, taking care of the elderly. She was taking piano lessons, learning to perform the Japanese tea ceremony, and enjoyed writing. At the age of 29 years, she became lethargic, depressed, and frequently needed to rest at work. After 2 months, she became withdrawn and could no longer go to work, eat, or bathe herself. She would lie in bed, sobbing and complaining, "I am hopeless and tired". She felt discomfort in her chest and developed irregular menstruation. At the same time, she was diagnosed with cataracts. She visited our hospital at the age of 30 years (7 months after the onset of her symptoms) and was diagnosed with major depressive disorder. MRI findings showed atrophy of the hippocampus and diffuse mild ischemic changes in the cerebral white matter (Figure 1B). The patient's psychomotor slowness and depressed mood improved 3 months after treatment with a selective serotonin reuptake inhibitor (fluvoxamine 12.5 mg/day). Her symptoms resolved and she quickly became cheerful, optimistic, and resumed eating by the age of 31 years.

alzheimer’s disease, down syndrome, acute neuropsychiatric disorders

PMC6125799_01

Female

A 61-year-old woman was evaluated because of 2 days of anuria, fever, anorexia, and progressive decline in mental status. Her medical history included cerebral palsy, and neurogenic bladder without diabetes, and not hypertension, type 2 diabetes, depression, and immunodeficiency. She was treated with indwelling bladder catheter to relieve urinary retention for ten years. She had no medication. The patient was evaluated by her primary care provider at her house. She had a temperature of 38.7C. Her consciousness level was Glasgow coma scale (GCS) E2V2M4. After two hours, she was admitted to the hospital because of fever with a disturbance of consciousness for further evaluation. On examination, she appeared confused with a GCS score of 8/15 (E2V2M4). Her temperature was 37.8C, blood pressure 151/81 mmHg, heart rate regular at 95 beats per minute, percutaneous oxygen saturation 96% (room air), and respiration rate 26 per minute. The patient mentioned a discomfort in the suprapubic region. Her breath did not smell of alcohol, acetone, and ammonia. Bulbar (palpebral) conjunctivae were not injected or congested without icterus or pallor. The respiratory examination was unremarkable and abdominal examination revealed no stigmata of chronic liver disease or focal tenderness in the suprapubic area or costovertebral angles. A large, non-tender cystic mass was palpable in the suprapubic region. The patient`s neurologic examination revealed that she was slow to answer questions and follow commands, was hard of hearing, and had no asterixis. She could not give any details of her history or symptoms and did not say that she had a headache or stiff neck. The nursing staff noted that there was no urine in her urine bag. Laboratory analysis at the time of admission are shown in Table 1. Urinalysis showed marked pyuria, a pH of 8.0, specific gravity 1.009, protein >4+, with numerous bacteria, >100 white blood cells, 10-19 red blood cells, 1-4 ammonium magnesium phosphate crystals, and 1-4 epithelial cells per high-power field in the sediment. The white blood cell count was 25,200 /mm3, with 93% neutrophils, 15% band forms, 2% lymphocyte, 1% monocyte; hemoglobin, 11.5 g/dL; hematocrit, 34.6%; and platelet count was 132,000 /mm3. Coagulation test revealed prothrombin time INR 1.44; the serum fibrinogen 447.5 mg/dL, fibrin/fibrinogen degradation products (FDP) 37.5 mug/mL. Biochemical analysis showed aspartate aminotransferase (AST) 43 IU/L, alanine aminotransferase (ALT) 23 IU/L, lactate dehydrogenase (LDH) 275 IU/L, alkaline phosphatase (ALP) 240 IU/L, total bilirubin (TB) 1.09 mg/dL, urea nitrogen (UN) 43.2 mg/dL, creatinine 1.2 mg/dL, creatine kinase (CK) 1222 IU/L, sodium 144 mEq/L, potassium 3.1 mEq/L, and C-reactive protein (CRP) 16.97 mg/dL. Blood ammonia level was elevated (176 mug/dL). Head computed tomography (CT) and magnetic resonance imaging (MRI) revealed no factor responsible for consciousness disturbance, and chest CT showed no pneumonitis. Abdominal CT and ultrasonography revealed bilateral hydronephrosis and bladder fullness with wall thickness in spite of indwelling bladder catheter, however, no sign of liver cirrhosis (Fig. 1). Sepsis was diagnosed on the basis of qSOFA criteria (GCS < 15 and respiratory rate >=22) on admission and a bladder catheter exchange was performed. Her indwelling bladder catheter on admission was obstructed by blood clots. Before antimicrobial therapy was begun, two blood samples and one urine sample had been obtained for cultures. Tazobactam / Piperacillin, 2.25 g intravenously, was administered q6h. Approximately 10 h later, the patient had a temperature of 39.8C, her systolic blood pressure 60/30 mmHg, heart rate at 120 beats per minute, respiration rate 30 per minute, and she appeared ill. Extracellular fluid was administered for volume resuscitation. In addition, intravenous continuous infusion noradrenaline and methylprednisolone was administered. However, her mean arterial pressure (MAP) was 55 mmHg (<65), and lactate was 20 mg/dL (>2 mmol/L). Volume resuscitation, cardiovascular support, antimicrobial administration, and bladder catheterization were continued. Seven days later from admission, two blood cultures, blood clots culture, and one urine culture detected Proteus mirabilis. The P. mirabilis isolates from our patients was susceptible to Cefazolin, Cefotiam, Cefotaxime, Ceftazidime, Ceftriaxone, Cefepime, Piperacillin, Sulbactam / Ampicillin, Tazobactam / piperacillin, Gentamicin, Amikacin, Imipenem, Meropenem, Levofloxacin, and trimethoprim, but less to minocycline. The patient's level of consciousness and general condition improved rapidly and ammonia level had normalized (46 mug/dL). After she received rehabilitation, she was discharged on the 28th hospital day.

hyperammonaemia, obstructive urinary tract infection, proteus mirabilis

PMC8281055_01

Female

A 51-year-old woman with a one-month history of redness and swollen left knee joint was transferred to our general intensive care unit (ICU) due to persistent high fever (up to 39.5 C) and sudden hypotension. After being diagnosed with dermatomyositis 2 years ago, she continued medication treatment on prednisone tablets with a 25 mg daily dose and cyclosporine capsule with a 75 mg dose twice per day. Last month, the results of blood culture and bacterial culture of joint cavity pus as obtained from other medical institutions were shown to be negative, with no special microbiological examination performed. When the patient visited the rheumatology department for appointment with a doctor, she coughed up sputum intermittently and her body temperature reached up to 40 C. Physical examination revealed that the left knee was red and swollen with positive floating patellar test, along with red rash in the V area of face and neck. The right dark yellow pleural effusion displayed exudate and negative bacterial culture. Vancomycin was thus prescribed to reduce infection, and 20 mg of methylprednisolone was applied twice a day. Four days later, she was transferred to ICU due to hypotension (the detailed clinical course is shown in Figure 1). The patient exhibited low blood pressure and high heart rate, which was accompanied by elevated procalcitonin and multiple organ failure. Broad-spectrum anti-infective therapy (imipenem/cilastatin + linezolid) was initiated within the first hour of highly suspected septic shock. ECG suggested cardiac infarction and high myocardial enzyme index. In order to rule out the occurrence of acute cardiovascular event, no infarction was detected immediately after coronary angiography. Given the EF value of 30% for the patient, septic heart disease was suspected. At the same time, the patient suffered acute liver injury, acute renal injury and thrombocytopenia. After the patient was transferred to ICU, joint cavity pus was also taken for culture in addition to blood culture samples (ultrasound: Figures 2A,B, MRI: Figures 2C,D). Considering that the patient had negative culture multiple times in the previous month, the NGS examination was conducted for joint cavity pus and blood samples at the same time. Subsequently, NGS results indicated that the pathogen was "M. tuberculosis," with acid-fast bacilli unexpectedly visible in articular cavity effusion. After an inquiry made about her medical history, it was known that the patient had a history of contact with pulmonary tuberculosis, and such symptoms as night sweating, coughing and expectoration were manifested since around the last month. Thus, the septic shock associated with M. tuberculosis was suspected. Five combinations of anti-tuberculosis drugs (HRZEO: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol, Ofloxacin) were prescribed, while imipenem/cilastatin was downgraded to piperacillin/tazobactam and vitamin B6 was prescribed as a supplement. The bronchoalveolar lavage fluid was found negative for acid-fast staining. The T-SPOT results of the patients remained negative. The T lymphocyte count of the patient was shown to be extremely low. After about 10 days of anti-tuberculosis treatment, the body temperature improved, the ST segment of ECG decreased, myocardial enzymes returned to normal, shock was alleviated, and the count of platelets increased. Unfortunately, liver function deteriorated for the patient gradually. Five days after the adjustment made to anti-tuberculosis drugs, the patients showed such tuberculosis poisoning symptoms as high fever and shock, norepinephrine of 1.2 ug/kg/kg min, which was accompanied by a decline in the count of platelet again. Afterwards, both liver function and cardiac function further deteriorated. Re-examination of blood NGS remained suggestive of M. tuberculosis. Our advice against further treatment was rejected by her family members.

mycobacterium tuberculosis, bloodstream infection, intensive care unit, sepsis, septic shock

PMC8660025_03

Female

An 89-year-old woman with systemic hypertension presented with a history of multiple episodes of hypertensive anterior uveitis in the RE after uneventful cataract surgery two years before. Extensive systemic investigations had been unrevealing, ruling out tuberculosis, syphilis and sarcoidosis, among other infections/noninfectious conditions. The ultrasound biomicroscopy showed a well-placed intracapsular intraocular lens with no ciliary touch. Empiric treatment with topical and systemic corticosteroids led to the initial improvement, followed by recurrence of intraocular inflammation in the RE. Continuous use of timolol, dorzolamide and brimonidine drops in the RE was then necessary. At presentation, BCVA was 20/40 in the RE and 20/20 in the LE. Slit-lamp examination of the RE showed white medium-sized coin-shaped central/paracentral keratic precipitates, connected by a fibrin network adhered to the corneal endothelium. The anterior chamber of the RE had 3+ cells and 1+ flare and the iris displayed focal atrophy inferonasally (Figure 3). A topic (in-the-bag) single-piece-intraocular lens (IOL) was also seen in both eyes. The anterior segment of the LE and the fundus examination of both eyes were otherwise unremarkable. In face of the suspicion of an herpes virus etiology, an AC tap for PCR of aqueous humor, as well as serological tests for herpesviruses were performed. Results were positive for CMV DNA in aqueous humor, and for specific IgG anti-HSV, VZV and CMV in the serum. The specular microscopy revealed an endothelial cell count of 1,035 and 1,720 cells/mm2 in the RE and the LE, respectively. Topical 2% ganciclovir eye drops 5x/day and topical 0.15% ganciclovir gel at bedtime were then started, in addition to 1% prednisolone drops in a tapering regimen. The intraocular inflammation progressively improved, with no further crises of intraocular inflammation after six months of follow-up.

PMC8442530_01

Male

A 63-year-old man was admitted to our hospital with altered cognition for the previous 4 months. He was disoriented in time and space and unable to recall any words after 3 min; in addition, he had a progressive headache with nausea and vomiting for 1 week. He had no history of underlying diseases. The day after admission, he entered a state of stupor [Glasgow Coma Scale (GCS): E2V2M2] with respiratory failure. Laboratory tests, including malignancy workup [i.e., Ri, Yo, Hu, Ma2/Ta (PNMA2), LGI1, CV2/CRMP5, amphiphysin, NMDAR, GABAR, recoverin, CASPR2, and AMPAR2] and vasculitis workup (i.e., ESR, CRP, RF, ANA, C3, C4, CH 50, ANCA, RPR/VDRL, protein electrophoresis) yielded negative results. Brain MRI (T2-FLAIR) revealed abnormal hyperintensity with expansion in the hippocampi, temporal cortex, medial thalami, right insular cortex, left pulvinar, and left parietal lobe, without restricted diffusion (not shown) or contrast enhancement (Figures 1A,B). Brain MRI (T2-FLAIR) demonstrates the disappearance of hyperintense and expansion lesions after treatment for autoimmune encephalitis, especially in the medial thalami, right insular cortex, and left pulvinar. Brain MRI (T2-FLAIR) also shows T2-FLAIR hyperintensity with atrophy in the left medial temporal lobe (white arrow), right medial temporal lobe (white arrowhead), and left parietal lobe (Figures 1C-F). A lumbar puncture showed no evidence of infection (white blood cells: 0 cells/muL) or malignant cells. Blood culture, urine culture, and CSF were negative for HSV-1, HSV-2, HHV-3, HHV-6, HHV-7, HHV-8, Epstein-Barr virus, cytomegalovirus, Enterovirus, HBV, HIV, HTLV, Treponema pallidum, human polyomavirus 2, Mycobacterium tuberculosis, Borrelia burgdorferi, Anaplasma phagocytophilum, tick-borne encephalitis virus, and polyomavirus BK. The CSF was also negative for antibodies, including Ri, Yo, Hu, Ma2/Ta (PNMA2), LGI1, CASPR2, recoverin, Sox1, Titin, Zic4, DNER/Tr, amphiphysin, CV2/CRMP5, GAD65, NMDAR, GABAR, IgLON5, AMPAR2, DPPX, glycine receptor, and mGluR5. Finally, additional auto-antibody detecting tests were performed to check for an AE with the patient's serum. A tissue-based assay was initially performed to screen for AE. Then, cell-based immunoassay and immunoblotting were performed to detect synaptic and intracellular auto-antibodies. In cases of an unknown auto-antibody being identified in the tissue-based assay, further tests were performed by staining cultured neuronal cells with the patients' serum. In addition, immunoprecipitation and mass spectrometry were performed to identify novel specific antigens. Despite this extensive testing of AE, no auto-antibodies were identified. We suspected antibody-negative AE and started first-line treatment with high-dose intravenous methylprednisolone (1,000 mg) for 5 days, followed by oral prednisolone (Figure 1G). However, the patient's status deteriorated; he presented with episodes of right facial grimacing and right upper limb contraction, consistent with faciobrachial dystonic seizures. Continuous electroencephalogram demonstrated rhythmic sharp-and-waves arising from the left temporo-occipital lobe. These alterations were controlled with levetiracetam, valproic acid, and lacosamide. The patient further deteriorated to a comatose state (GCS: E1VtM1) with generalized tonic-clonic seizures, requiring intravenous immunoglobulin (IVIg, 1 mg/kg for 5 days) on hospital day 16. His arousal level plateaued (GCS: E1VtM1) after receiving IVIg for 2 weeks. We then administered a second-line treatment, rituximab (IV, 375 mg/m2, once weekly x 4 doses); before rituximab administration, we checked the patient's B-cell counts (CD19+/CD20+) on hospital day 28. CD19+/CD20+ counts of total lymphocytes in the peripheral blood were 15.3 and 15.1%, respectively (Figure 1G). After receiving rituximab for 3 weeks, the patient's mental status started improving (GCS: E4VtM5), and follow-up brain MRI findings were markedly improved (Figures 1C-F). The patient was discharged to a rehabilitation center (GCS: E4VtM6). At the last follow-up 5 months later, CD19+/CD20+ B-cells both remained at 0% (GCS: E4V5M6).

cd19+/cd20+, antibody-negative, autoimmune encephalitis, brain mri, rituximab, treatment

PMC2660695_01

Female

Avian influenza (H5N1) had not been reported in humans in Laos until February 27, 2007. Our patient was a 15-year-old adolescent girl who lived in a suburb of Vientiane where an outbreak of influenza (H5N1) in poultry had been confirmed on February 7, 2007. Influenza-like symptoms developed in the patient on February 10. She was hospitalized in Vientiane with fever and respiratory symptoms on February 15. On February 17, her parents brought her to a private hospital in Nong Khai Province, Thailand. Oseltamivir was prescribed on February 19. On February 20, she was transferred to the Nong Khai Provincial Hospital because of rapid, progressive, severe pneumonia with acute respiratory distress syndrome. When we suspected avian influenza in this patient, clinical specimens were tested. A diagnosis of infection with avian influenza (H5N1) was based on positive results obtained by reverse transcription-PCR (RT-PCR), viral isolation in MDCK cells inoculated with an endotracheal suction specimen collected on February 22, and a 4-fold increase in neutralizing antibody titers from 80 to 320 in paired blood specimens collected on February 25 and March 1, as assayed against autologous virus. This virus isolate was named A/Laos/Nong Khai 1/07(H5N1). Subsequent samples were collected on February 25 and March 7 (day of death). Results of RT-PCR were positive for the sample collected on February 25 only; virus isolation results were negative for both samples. The virus was screened for a novel reassorted gene by a multiplex RT-PCR and 8 primer pairs specific for each genomic segment of genotype Z, clade 1 virus. All segments except the polymerase A (PA) segment were amplified, which indicated that the new virus was different from genotype Z viruses. The viral genome was sequenced and submitted to GenBank (accession nos. EU499372-EU499379 for hemagglutinin, nonstructural protein, matrix protein, nucleoprotein, PB1, PB2, neuraminidase, and PA genes, respectively). Phylogenetic analysis showed that this virus belonged to genotype V (Appendix Figure, panel B); phylogenetic analysis of the hemagglutinin gene (www.who.int/csr/disease/avian_influenza/smaltree.pdf) showed that it belonged to clade 2.3.4 (Appendix Figure, panel A). Protein sequence at the hemagglutinin cleavage site harbored many basic amino acids (RERR_RKR). One amino acid deletion and 1 amino acid change were found when compared with RERRRKKR, which is present in most avian influenza viruses (H5N1). There was no change in receptor binding site. This virus had glutamic acid at aa 627 in the PB2 protein, aspartic acid at aa position 92 in nonstructural protein 1, and 5 aa deletions at positions 80-84 in the nonstructural protein 1. Analysis of the neuraminidase gene showed a 20-aa deletion in the stalk protein; there was no mutation of histidine to tyrosine at aa position 274, a position shown to be the oseltamivir resistance marker in the neuraminidase 1 viral genome. Mutations in the matrix 2 gene showed that amantadine resistance was not present in our virus. Our in vitro assay showed that this virus was sensitive to oseltamivir and amantadine. Since 2003, genotype V influenza viruses (H5N1) have been reported in some East Asian countries. Genetic diversity in the hemagglutinin gene has classified those genotype V viruses into distinct clades. Viruses from avian species in South Korea in 2003 and Japan in 2004 belong to clade 2.5. A/chicken/Shanxi/2/2006 isolate belonged to clade 7. Human cases in People's Republic of China, i.e., A/China/GD01/06, A/Shenzhen/406H/06, A/Jiangsu/1/2007, and A/Jiangsu/2/2007, belong to clade 2.3.4, the same clade as A/chicken/Thailand/NP-172/2006 and the virus from our study. Highly pathogenic avian influenza viruses (H5N1) that caused outbreaks in Thailand since 2004 belong to genotype Z, clade 1. Introduction of genotype V clade 2.3.4 virus, A/chicken/Thailand/NP-172/2006, to Nakhon Phanom Province occurred in November 2006, the same year that clade 2.3.4 virus was introduced into Laos (Appendix Figure, panel A). On the basis of hemagglutinin gene phylogeny, A/Laos/Nong Khai 1/2007 is closely related to A/chicken/Nong Khai/NIAH 400802/2007 and A/chicken/Thailand/NP-172/2006. Phylogenetic analysis suggested that viruses from these 2 countries shared the same origin. There was extensive movement across the Mekong River even before the bridge linking Nong Khai from Vientiane was opened. However, the route of transmission of genotype V viruses from east Asian to Southeast Asian countries could not be elucidated.

PMC3095885_01

Female

A 21-year-old female presented with history of fever, anterior neck swelling, and weight loss of 3.5 kg for 3-4 months. The family history was significant for tuberculosis in one brother. On examination, she had marked swelling of anterior neck with no lymphadenopathy. Clinically, she was euthyroid. The systemic examination was unremarkable. Her complete blood count was normal with an ESR of 25 mm/1st hour. Mantoux test was positive. The routine biochemistry were all within the normal limits. Biochemically, she was also euthyroid. Her Technetium 99 thyroid scintigraphy revealed cold nodule in the lower aspect of right thyroid lobe. Fine-needle aspiration cytology (FNAC) showed caseation necrosis, and pus from nodule did not show AFB, but pus culture was positive for Tubercle Bacilli. Therefore, she was started on antituberculous treatment (ATT) with four drugs regimen for first 3 months followed by 3 drugs regimen for the next 6 months. After treatment, she had complete resolution of swelling (Figures 1(a) and 1(b)).

PMC3095885_02

Female

A 51-year-old female presented with history of left thyroid lobe swelling for 3-4 years, which was gradually increasing in size with no compressive or any associated symptoms. On examination, she had a left thyroid nodule which was nontender and moving with swallowing with no palpable lymph node. The systemic examination was unremarkable, and she was clinically euthyroid. Her initial workup included FNAC of left thyroid lobe which showed follicular lesion with prominent Hurthle cell. Her Technetium 99 thyroid scintigraphy revealed cold nodule in left lobe of thyroid. Ultrasound of thyroid showed a left sided hypoechoic nodule measuring 3.3 x 2.4 cm with minimal peripheral vascularity. The right lobe was normal in size with few small solid and cystic nodules. Her chest X-ray was normal. Her complete blood count and routine biochemistry were essentially normal. She underwent total thyroidectomy, and her histopathology report showed, follicular adenomaoncocytic variety (Hurthle cell adenoma), foci of granulomatous inflammation in the left lobe, and benign nodular hyperplasia with foci of chronic granulomatous inflammation along with necrosis with possibility of tuberculosis in the right lobe. She was started on ATT with four drug regimen for the first three months followed by three drugs regimen for the next six months along with Thyroxine 100 ug daily. She completed her treatment and remained asymptomatic as she was before.

PMC3095885_03

Male

A 32-year-old male presented with a solitary nodule over the right side of lower neck for three months with progressive enlargement. He had no systemic symptoms. On examination, there was a solitary, nontender, and firm swelling on the right side of neck with no evidence of lymphadenopathy. Systemic examination was unremarkable, and clinically, he was euthyroid. His complete blood count, ESR, and routine biochemistry were within normal limits. Biochemically, he was euthyroid. His Technetium 99 thyroid scintigraphy revealed multinodular goiter involving both lobes. Ultrasound of thyroid revealed multinodular goiter with the largest nodule (4 x 4 cm) in the right lobe of thyroid. Ultrasound-guided FNAC revealed extensive caseous necrosis suggestive of tuberculosis. His X-ray chest was within normal limits. He was started on ATT with four-drug regimen for three months followed by three-drug regimen for the next six months. Followup examination after six months revealed remarkable regression of the size of the nodule (Figures 2(a) and 2(b)).

PMC6411511_01

Female

A 59-year-old Caucasian woman presented with non-specific abdominal discomfort. Clinical examination revealed a palpable abdominal mass. There was no other abdominal symptoms of significance or unintentional weight loss nor constitutional symptoms. She had no significant past medical history and was not on any regular medications. She was a current smoker with a 30-pack year history. She had no known occupational or environmental exposure to asbestos. Computed tomography (CT) of the abdomen demonstrated extensive peritoneal omental caking with infiltration to the anterior abdominal wall (Fig. 1). Ultrasound-guided biopsy of the abdominal mass revealed large, pleomorphic epithelioid cells, within fibrous stroma. These cells stained positively with AE1/3, CK7, CK5/6, WT1, calretinin and D2 40. The cells were negative for BerEP4, PAX8, CA125, ER, CD34, ERG, P63, P40, Melan A, Gata3 and mammaglobin. The morphology and immunohistochemical profile supported a diagnosis of epithelioid malignant mesothelioma. (figure -2a). The patient subsequently presented with exertional dyspnoea. A CT scan of chest revealed moderate right sided pleural effusion, bilateral hilar and mediastinal lymphadenopathy, extensive bilateral pulmonary parenchymal & interstitial opacity along with interlobular septal thickening, suggestive of lymphangitic spread. (Fig. 3). A bone scan and a Brain CT were negative for distant metastases. Pleural fluid examination showed it was an exudative effusion, cytological examination was inconclusive. Bacterial cultures and acid fast bacilli were negative. In order to obtain a definitive diagnosis of the pulmonary infiltrates, she underwent a bronchoscopy with trans-bronchial lung biopsy (TBLB). Bronchial washing and lavage did not reveal malignant cells and was negative for microbial or fungal elements. The TBLB confirmed pulmonary epithelioid malignant mesothelioma, demonstrating lung tissue with infiltrating cells, similar to that of initial peritoneal biopsy, also stained positively with CK7, calretinin, WT1 and D2 40. They were negative for Napsin A, TTF1 and P40 confirming pulmonary metastatic malignant epithelioid mesothelioma (Fig. 2b). The TBLB biopsy samples were small and did not contain muscle/fat tissue, hence no invasion into muscle/fat were demonstrated. Lymphovascular invasion was not seen either. Although TBL biopsy did not did not demonstrate lymphangitic invasion, however, the CT scan findings were highly suggestive of lymphangitic spread. Unfortunately the patient had an aggressive course of disease and died within three months of initial presentation, prior to the initiation of any systemic treatment.

asbestos, malignant mesothelioma, peritoneal mesothelioma, pleural effusion, trans-bronchial lung biopsy

PMC5164904_01

Female

A 32-year-old female presented to our hospital's emergency service with progressive, painless vision loss in her left eye lasting for 2 days. She was diagnosed with FMF based on her clinical complaints, familial history, and physical and laboratory examinations 2 months ago. She was started on oral colchicine therapy. She had no other history of systemic and ocular disease. Her best-corrected visual acuity (BCVA) was 20/20 in the right and there was light perception in the left eye, respectively. Intraocular pressure was in normal limits in both eyes. Slit lamp examination disclosed few cells in anterior chamber (+1) and anterior vitreous (+1) in the left eye. Fundus examination revealed perivascular, white, severe, and continuous sheathing of vascular structures starting from optic disc and extending to periphery. Veins were dilated and tortuous. Intraretinal hemorrhages in all quadrants, papillary edema, and subhyaloid hemorrhage in macular area were also observed (Figure 1). The ophthalmologic examination of the right eye was normal. Fluorescein angiography (FA) revealed dilated and tortuous veins and blockage of fluorescein due to retinal hemorrhages. Arteriovenous transit time was in normal limits. FA showed no venous stasis/occlusion and dye leakage at earlier phases. Later phases of FA could not be displayed because the patient had syncope and systemic hypotension at the second minute of FA. Laboratory investigations, including complete blood count, electrolytes, plasma proteins, urea, creatinine, angiotensin converting enzyme, C-reactive protein, erythrocyte sedimentation rate (ESR), autoimmune markers (anti-cardiolipin antibodies, anti-neutrophil cytoplasmic antibodies, antinuclear antibody, antimitochondrial antibody, rheumatoid factor, anti-double-stranded DNA, anti-single-stranded DNA, anti-scl-70 antibodies, and anti-jo-1 antibodies), and antibody titers for HIV, CMV, HSV, EBV, syphilis, rubella, and toxoplasmosis were performed. Herpes simplex type 1 Ig G and rubella Ig G were positive. ESR was slightly high. Results of all other tests were in normal limits or negative. Cranial magnetic resonance imaging and chest X-ray were also normal. Genetic investigation revealed homozygous MEFV gene mutation (M964V) supporting FMF diagnosis. She had no clinical and laboratory signs of lymphoma, leukemia, sarcoidosis, tuberculosis, multiple sclerosis, systemic lupus erythematosus, Behcet's disease, and other autoimmune diseases. Systemic treatment of 64 mg/day oral methylprednisolone was started. Two days after the treatment, visual acuity of the left eye increased to 20/400. Cellular reaction of anterior chamber and vitreous disappeared. However, vascular sheathing, retinal hemorrhages, and subhyaloid premacular hemorrhage had no obvious change. One week after previous visit, fundus examination revealed significant improvement in the papillary edema, sheathing of vascular structures, and retinal hemorrhages. Visual acuity had no change due to subhyaloid premacular hemorrhage (Figure 2). Argon laser posterior hyaloidotomy was performed to the inferior part of the subhyaloid hemorrhage and the blood flowed through the hyaloidotomy to the vitreous cavity. Just after that the laser therapy visual acuity was 20/60. One week after hyaloidotomy, visual acuity significantly improved to 20/20 and dislocated intravitreal hemorrhage disappeared. Methylprednisolone was gradually tapered to 4 mg/day over 2 months. Four months after first FBA attack, she presented to our retina department with a complaint of blurred vision for 2 days. Her BCVA was 20/20 in the right and 20/25 in the left eye, respectively. Biomicroscopy of anterior segment revealed anterior chamber (cells +1) and anterior vitreous inflammation (cells +1) in the left eye. Vascular sheathing and preretinal and intraretinal hemorrhages that were limited to superior peripheral retina were noted in the left eye (Figure 3). Oral methylprednisolone dosage was increased to 64 mg/day. Because the patient developed a "moon face" due to corticosteroid use and a recurrence of retinal vasculitis occurred, a decision for immunosuppressive therapy has been made. Corticosteroid treatment was combined with azathioprine 150 mg and methylprednisolone dosage was gradually tapered. Clinical findings of retinal vasculitis subsided over time and no other recurrences were noted during subsequent follow-ups. At her last visit performed in the 12th month of follow-up, the BCVA was 20/25 in the left eye. Biomicroscopy of anterior segment was normal. Fundus examination and optic coherence tomography showed epiretinal membrane formation around the fovea.

PMC7684549_01

Male

Our patient was a 29-year-old Srilankan male, with no known previous comorbidities. On October 31, 2018, he presented to the emergency department of Hamad General Hospital. He had a history of a heavy object falling on his back. He complained of severe back pain and the inability to move his lower limbs. He was able to move both of his upper limbs; however, the power of his lower limbs was 0/5. His sensations were intact, the anal tone was weak, the perianal sensation was intact, and bulbocavernosus reflex was+ve. A CT scan and MRI were performed and showed a burst fracture of the L2 vertebral body with retropulsion, which compromised the spinal canal, causing severe spinal cord injury. On October 31, 2018, he underwent urgent tbl12-L4 transpedicular screw fixation and a tbl12 and L1 laminectomy. He was kept postoperatively in the trauma ICU for observation. A follow-up X-ray of his spine showed satisfactory alignment and placement of the screws. The patient was reviewed by the rehabilitation physician, who agreed to move the patient to the Qatar Rehabilitation Institute for an active rehabilitation program. On November 8, 2018, the patient was transferred from the neurosurgery ward to QRI. The patient underwent rehabilitation by a multidisciplinary team in a spinal cord injury rehabilitation unit. On admission to QRI, the patient was paraplegic ASIA B level L2. He had no power in both lower limbs but had intact sensations. He was dependent for activities of daily living with a functional independence measure (FIM) score of 69/126. He was on gabapentin 300 mg, three times a day, for neuropathic pain in his lower limbs. He was also taking dalteparin sodium, senna, and a multivitamin. His pain score was a numeric rating score (NRS) 6/10. His pain was not relieved but was increasing. On November 13, 2018 (day 13 postinjury), the dose of gabapentin was increased to 600 mg, three times a day. On the next day, (day 14 postinjury), he complained of increased lower limb and whole-body pain of NRS 8/10. On examination, he had severe muscle tenderness throughout his whole body, including his upper and lower limbs (NRS 9-10/10). He was observed for a few days presuming that the pain was due to exercise and the preexisting pain. When his pain had not improved, an internal medicine consultation was performed. A blood workup was sent on suspicion of myositis on 5th December 2019 and returned with the following results: serum creatine kinase (CK) was high- 747 U/L (reference range, 39-308 U/L), myoglobin was high- 152 ng/ml (reference range, 28-72 ng/ml), C-reactive protein(CRP) was high- 22.9 mg/L (reference range, 0-5 mg/L), ALT was high- 75 U/L (reference range, 0-41 U/L), AST was high- 46 U/L (reference range, 0-40 U/L), and the creatinine level was normal. Unfortunately, his CK and myoglobin levels before the increase of gabapentin dose were not available. A diagnosis of gabapentin-induced myositis was made from the background of blood investigations (increase CK and myoglobin), clinical profile (new-onset generalized muscle pain and tenderness), and Adverse Drug Reaction Probability Scale (Naranjo algorithm) score of 6 of gabapentin. The Naranjo algorithm score of 6 indicated that gabapentin is the probable cause of myositis. Other medications- senna, dalteparin sodium, and the multivitamin were excluded as causes of myositis by their negative Naranjo algorithm scores (senna -2, dalteparin sodium -2, and multivitamin -2). On December 12, 2018 (day 42 postinjury), gabapentin was discontinued. His severe muscle pain of the whole body reduced dramatically in the next three days after discontinuation of the gabapentin. His follow-up blood workup on December 19, 2018 (day 49 postinjury) showed a CK of 203 U/L (previously 747 459 U/L) and myoglobin 90 ng/ml (previously 152 ng/ml). After discontinuation of gabapentin, his pain was managed effectively with paracetamol 1000 mg, when necessary, three times daily (if pain NRS 4/10 or more). On January 16, 2019 (day 77 postinjury), the patient was discharged from QRI. On discharge, the patient was ASIA C level L2. He was on selfintermittent catheterization and was wheelchair bound (self-propelled) for indoor and outdoor mobility. His FIM score was 111/126 (FIM on admission to QRI: 69/126). There were no adverse effects after discontinuing gabapentin. He was followed up in an outpatient rehabilitation program. Table 1 describes the timeline of important clinical developments of the case.

gabapentin, myositis, neuropathic pain, spinal cord injury

PMC4712975_01

Unknown

The prevalence of ADHD in adults aged >=50 years is a question yet to be answered. In a large, epidemiological study by Kessler et al, the prevalence of ADHD in adults was estimated to be 4.4%. This important study did not include patients older than 44 years old. In contrast to this, in a European population-based study, 50% of the study sample was older than 45 years (range: 18-75 years), and the prevalence of ADHD in this sample was 1.0%-2.5%. Some recent studies have investigated the prevalence of ADHD in adults aged >=50 years and found prevalence rates below the previous estimates for adult ADHD (Table 1). In a Dutch epidemiological study, 1,419 adult participants aged 55-85 years were studied. The prevalence of syndromatic ADHD was 2.8% and symptomatic ADHD was 4.2%. The results also showed that younger elderly adults (60-70 years) reported more ADHD symptoms than the older group (71-94 years). The Australian PATH Through Life Project also found that older-age adults (68-74 years) reported significantly lower levels of ADHD symptoms as measured by ASRS screener than middle-aged adults (48-52 years). Approximately 2.2% of the older-age adults met the suggested cut-off for the Adult ADHD Self-Report Scale (ASRS)-screener score that has been linked to a clinical diagnosis of ADHD, versus 6.2% in the middle-aged group. In a Swedish population-based study of 2,500 persons aged 65-80 years, the authors found the prevalence of self-rated childhood ADHD to be 3.3%. A methodological problem in this study is the dependence on retrospectively experienced childhood symptoms recalled 50-70 years later. The risk for recall bias, and both under- and overestimation of symptoms, is probably high. These three epidemiological studies indicate that the prevalence of ADHD symptoms appears to decline to 1.0%-2.8% in the oldest ages. Some authors discuss the impact of lower life length expectancy in patients with ADHD, due to greater rates of accidents, substance abuse, mood disorders, and other health issues, resulting in a relative decline of people with ADHD by age. The lack of age-appropriate diagnostic criteria for adult ADHD may also explain some of the apparent decline in ADHD prevalence in older adults, as discussed by several authors. Simon et al discuss in their meta-analysis the problem with validity of DSM criteria for diagnosing adult ADHD and assume that a strict use of the criteria may lead to an underestimation of the prevalence of ADHD in adults. Another factor is the occurrence of health-related issues in adults aged >=50 years, making the differential diagnostic assessment related to an ADHD diagnosis difficult. Examples of such issues are mild cognitive impairment (MCI), dementia, and other neurodegenerative disorders, increasing polypharmacy, sleep disturbances, chronic pain and other physical conditions, and impaired vision and hearing. Despite the lack of research on ADHD in adults aged >=50 years, and many unanswered questions about prevalence and persistence of ADHD throughout the life span, there is reason to believe that ADHD or residual ADHD persists into middle age and late adulthood in a large number of patients. A number of recent studies from different countries using national registers and prescription databases have shown that a growing number of patients aged >=50 years are assessed and treated for ADHD worldwide. A systematic search was conducted in the databases Medline/PubMed and PsycINFO to identify studies regarding ADHD in adults aged >=50 years. Search terms were "ADHD AND older adults" published up to date. The resulting list of papers was screened to find papers for this review, and the reference lists in the relevant papers were further screened to find other papers of relevance. The core symptoms of ADHD are persisting inattentiveness, impulsivity, and hyperactivity. Despite the persistence of symptoms, the presentation of symptoms will often change over the course of development. The overt signs of hyperactivity and impulsivity in children with ADHD will often decline with increasing age, while symptoms of inattentiveness often will continue unchanged. The motor hyperactivity in children with ADHD is in adults often replaced by an "inner" hyperactivity in the form of restlessness, excessive fidgeting and talking, inability to relax, and difficulty to sit quietly for long periods. Impulsivity in adulthood may appear as outbursts of anger, impatience, careless driving, and making decisions without thinking. Inattention will manifest as disorganization, forgetfulness, poor performance in planning and completion of tasks, task shifting, and time management. Because of this developmental change in symptom expression, many adults will not fully exhibit the criteria for the diagnosis, while still remaining significantly impaired. In addition to the core symptoms, ADHD in adults is strongly associated with emotional dysregulation (ED). The concept of ED includes symptoms such as increased irritability, low tolerance for frustration and stress, and emotional lability. Recent research indicates, however, that ED is not as specific for ADHD as previously assumed. ADHD in all ages is associated with the presence of psychiatric comorbidity. Studies have shown that comorbidity can have a negative impact on treatment outcome in ADHD across the life span. Recent studies indicate that psychiatric comorbidity mostly occurs during childhood and adolescence, and more seldom have onset after the age of 20 years. A recent study by Rasmussen et al suggests that living longer without receiving central stimulant (CS) treatment may lead to an increase in comorbid psychiatric problems. The comorbid disorders most strongly associated with adult ADHD are anxiety disorders, mood disorders, antisocial personality disorder, and substance use disorders. Most studies of comorbidity in adult ADHD are done in samples of young adults up to 40 years. The developmental alteration of comorbid disorders into middle-aged and older samples is poorly understood. We have identified only a few studies presenting data on comorbidity in samples of adults aged >=50 years. A Dutch study, with average sample age 71 years (range: 60-94 years), found that participants with ADHD had more depressive and anxiety symptoms than participants without ADHD. In another paper presenting data from the same study, the authors found that older adults with ADHD had significantly lower self-esteem and sense of mastery, and higher levels of neuroticism and social inadequacy, than older adults without ADHD. Self-esteem and sense of mastery partly explained the association between ADHD and depressive symptoms. Semeijn et al found that the risk of depression in older adults with ADHD was partly explained by serious conflicts and adverse life events. In this study, lower cognitive functioning was also explained by depressive symptoms. In a sample of adults aged >=50 years with ADHD from Norway (mean age: 55.7 years), 46.7% of the participants reported psychiatric comorbidity, depression 36.7%, anxiety 26.5%, and bipolar disorder 24.5%. The sample was recruited from the national ADHD organization, and not necessarily representative for adults aged >=50 years with ADHD. In a small study of 27 patients from the US, recruited from psychiatrists in private practice, 63% of the participants reported having other mental health conditions, depression 54%, anxiety 42%, and bipolar disorder 8%. In the older population, the prevalence of dementia increases steadily with advancing age. MCI is a diagnosis designed as a predictor of prodromal degenerative dementia, and its prevalence in the geriatric population is estimated to 16%. MCI includes cognitive problems in older ages that do not meet the criteria for dementia, and results in no or minimal functional impairment. In a review by Ivanchak et al, the authors discuss the role of ADHD as a predisposing factor for MCI and more manifest degenerative disease in late life, but conclude that such an association is less than convincing. On the contrary, a clinical study from Argentina found an association between childhood ADHD and dementia with Lewy bodies, but not with Alzheimer's disease. The authors have no explanation for this association between ADHD and dementia with Lewy bodies, but discuss the role of dopaminergic dysfunction in both diseases. There has been a growing interest in somatic comorbidity in ADHD. A number of somatic diseases have been found to have an association to ADHD in children, adolescence, and young adults, such as obesity, musculoskeletal pain, asthma, and allergy. The association between somatic diseases and ADHD in older adults is largely unknown. In Lensing et al's study of 149 adults aged >=50 years with ADHD, 46.6% reported co-occurring somatic disorders. Hypothyroidism 20.6%, hypertension 19.1%, fibromyalgia 16.2%, and arthritis 16.2% were the most common disorders. Another finding from the same sample showed that 73.7% of the patients reported moderate-to-severe pain/discomfort on EuroQoL, in comparison to 43.8% in the age- and sex-matched population norm. In a small sample of eleven clinically recruited patients with mean age 61.6 years, 55% had somatic disorders like hypertension, type 2 diabetes, and ischemic heart disease. In a study comparing 23 older adults with 208 controls without ADHD, the authors could not find significant differences in a number of somatic diseases, like chronic lung disease, cardiovascular disease, diabetes, arthritis, and cancer. In an adjusted regression analysis, they found, however, that the number of ADHD symptoms was associated with the presence of chronic lung disease, cardiovascular disease, and number of somatic diseases. Interestingly, the authors found no association between ADHD and an unhealthy lifestyle. A number of controlled follow-up studies have shown that ADHD in young adults is associated with impairment in several life domains, such as academic, occupational, and social functioning. In a study of 148 adults aged >=50 years with ADHD (mean age 55.7 years), compared to an age group-matched reference sample, the ADHD patients were significantly more often single (41.5% versus 25.2%) and less frequently employed (48.8% versus 69.2%). Surprisingly, in this study the level of education was not different between groups. The study showed that adults aged >=50 years with ADHD reported significantly reduced quality of life compared to population norms. A Dutch study that recruited patients with a mean age 68 years also found a significantly higher level of divorced/never married in the ADHD group compared to the non-ADHD group (26.1% versus 10.1%). They also found that ADHD was associated with having fewer family members in their network and experiencing emotional loneliness. Because of the presence of only a few studies, relatively small samples, and different age groups, it is not possible to draw definitive conclusions about impairment in adults aged >=50 years with ADHD. However, the results indicate that the negative impact of ADHD seems to persist into late adulthood. In a paper based on a study of 24 clinically referred older adults with ADHD, Brod et al found that the quality of life suffers from the accumulated negative impact of ADHD symptoms and impairments on their professional, economic, social, and emotional well-being. At the same time, none of the patients in this study indicated worsening of ADHD symptoms with aging, and some stated that living with ADHD got easier with age. Similar findings are also described by the patients in the paper by Henry and Jones.

adhd, adults, central stimulants, older adults, pharmacotherapy

PMC6818345_01

Male

A 67-year-old man was referred to our department after his local doctor detected a 15-mm nodular shadow in the upper lobe of his right lung. The nodule had remained unchanged for 10 months (Fig. 1A and B). The patient's temperature was 36.5 C, his heart rate was 78 beats per minute, and percutaneous arterial oxygen saturation was 98% in room air. Symptoms such as cough, sputum, shortness of breath, and weight loss were not observed. His medical history included hypertension, chronic obstructive pulmonary disease, dyslipidemia, and internal carotid artery stenosis, and he had a history of smoking 20 cigarettes a day for 43 years. His family history was unremarkable. He had no history of pet ownership, overseas travel, or excessive exposure to dust. Laboratory results on admission included a white cell count of 6610/mm3 (reference range 3300-8600/mm3) with white blood cell differentiation ratios of 72.5% neutrophils (reference range 35%-73.0%), 18.3% lymphocytes (reference range 20.0%-52%), 4.2% eosinophils (reference range 0.0%-11.0%), 0.4% basophils (reference range 0.0%-2.0%), 4.6% monocytes (reference range 0.0%-13.0%), and hemoglobin 14.3 g/dL (reference range 13.5-17.0 g/dL), platelet count 192,000/mm3 (reference range 150,000-350,000/mm3), C-reactive protein 0.03 mg/dL (reference range 0.0-0.3 mg/dL), carcinoembryonic antigen 4.26 ng/mL (reference range 0.0-5.00 ng/mL), and cytokeratin-19 fragments 3.3 ng/mL (reference range 0.0-2.8 ng/mL). An interferon-gamma (IFNgamma)-releasing assay (IGRA) (QuantiFERON-TB GoldR) was positive at 0.49 IU/mL. Tests for cryptococcus antigen and HIV antibodies were negative. Chest computed tomography (CT) revealed a 15-mm nodular shadow with slightly irregular margins in the upper lobe of the right lung (Fig. 1). Only normal bacterial flora were detected via sputum culture, and Mycobacterium smear, tuberculosis (Tb)-polymerase chain reaction (PCR), and MAC-PCR were negative, as was acid-fast bacilli culture. Ultrasound-guided bronchoscopy confirmed the locations of the lesions, then transbronchial biopsy, bronchial brushing, and bronchial lavage were performed. Histological investigations did not reveal any indications of malignancy or granuloma, and the cytological results of bronchial washing and brushing were negative for malignancy. Bronchial lavage culture only yielded normal bacterial flora, and a Mycobacterium smear was negative in the culture test as were Tb-PCR, MAC-PCR, and acid-fast bacilli culture tests. Based on these results no definitive diagnosis was reached with regard to the nodular shadow in the upper lobe of the right lung, and therefore the patient was instructed to comply with careful monitoring on an outpatient basis. The patient was monitored as an outpatient for 18 months, during which time no changes in the size or characteristics of the nodular shadow in the right upper lobe of the lung were observed (Fig. 2A). A small 5-mm node appeared as a new lesion in the left lung apex, however, and it gradually increased to 10 mm over the course of 10 months (Fig. 2B). Enlargement of the right axillary lymph node was also observed. No enhancement effect was detected via contrast CT (Fig. 2C). Accumulation was detected in the left lung apex and right axillary lymph node via positron emission tomography-CT (Fig. 2D), but no accumulation was depicted in the right lung nodule. The patient had no fever, cough, or sputum which could suggest disseminated MAC, and the right axillary lymph node was not painful, therefore blood culture tests for acid-fast bacteria were not performed. QuantiFERON-TB GoldR was slightly elevated at 0.93 IU/mL, and anti-MAC antibodies were positive at 1.51 U/mL (reference range 0.0-0.69 U/mL). Angiotensin-converting enzyme level was 1.9 U/L (reference range 8.3-21.4 U/L) and soluble interleukin-2 receptor level was 478 U/mL (reference range 122-496 U/mL). Combined with the fact that no bilateral hilar lymphadenopathy or skin, ocular, or cardiovascular complications were observed, it was surmised that sarcoidosis was unlikely to be the cause of the lung nodule and enlargement of the right axillary lymph nodes. The new lesion, which was depicted as a small nodular shadow in the left lung apex, was in contact with the proximal subclavian artery, and performing a surgical lung biopsy to achieve a definitive diagnosis would have been difficult. Hence, a biopsy was obtained from the right axillary lymph node under local anesthesia for diagnostic purposes. Large numbers of epithelioid granulomas and multinucleated giant cells were detected in the biopsy tissue (Fig. 3). M. intracellulare was identified via mycobacterium culture of the biopsy needle aspirate fluid from the right axillary lymph node, therefore lymphadenitis caused by M. intracellulare was diagnosed. Multidrug antimicrobial therapy including clarithromycin was considered, but at the patient's request, his condition was monitored on an outpatient basis instead. Interestingly the nodule in the left upper lobe gradually shrunk over the course of one year, as did the right axillary lymph nodes (Fig. 4A and B). The nodule had almost disappeared after 18 months (Fig. 4C). Anti-MAC antibody was not increased after the left lung apex lesion had disappeared compared to the level recorded when right lymphangitis had appeared (1.45 U/mL vs. 1.51 U/mL; range 0.0-0.69 U/mL). No relapse was observed throughout the 18 months following the biopsy. During the subsequent follow-up period the lesion in the right upper lobe did not exhibit any changes in size or other characteristics (Fig. 1).

axillary lymphadenitis, mycobacterium avium complex infection, mycobacterium intracellulare

Chest computed tomography of the nodule in the upper lobe of the right lung. No change was observed during the course of observation. A. The nodule when it was first detected.

PMC6818345_01

Male

A 67-year-old man was referred to our department after his local doctor detected a 15-mm nodular shadow in the upper lobe of his right lung. The nodule had remained unchanged for 10 months (Fig. 1A and B). The patient's temperature was 36.5 C, his heart rate was 78 beats per minute, and percutaneous arterial oxygen saturation was 98% in room air. Symptoms such as cough, sputum, shortness of breath, and weight loss were not observed. His medical history included hypertension, chronic obstructive pulmonary disease, dyslipidemia, and internal carotid artery stenosis, and he had a history of smoking 20 cigarettes a day for 43 years. His family history was unremarkable. He had no history of pet ownership, overseas travel, or excessive exposure to dust. Laboratory results on admission included a white cell count of 6610/mm3 (reference range 3300-8600/mm3) with white blood cell differentiation ratios of 72.5% neutrophils (reference range 35%-73.0%), 18.3% lymphocytes (reference range 20.0%-52%), 4.2% eosinophils (reference range 0.0%-11.0%), 0.4% basophils (reference range 0.0%-2.0%), 4.6% monocytes (reference range 0.0%-13.0%), and hemoglobin 14.3 g/dL (reference range 13.5-17.0 g/dL), platelet count 192,000/mm3 (reference range 150,000-350,000/mm3), C-reactive protein 0.03 mg/dL (reference range 0.0-0.3 mg/dL), carcinoembryonic antigen 4.26 ng/mL (reference range 0.0-5.00 ng/mL), and cytokeratin-19 fragments 3.3 ng/mL (reference range 0.0-2.8 ng/mL). An interferon-gamma (IFNgamma)-releasing assay (IGRA) (QuantiFERON-TB GoldR) was positive at 0.49 IU/mL. Tests for cryptococcus antigen and HIV antibodies were negative. Chest computed tomography (CT) revealed a 15-mm nodular shadow with slightly irregular margins in the upper lobe of the right lung (Fig. 1). Only normal bacterial flora were detected via sputum culture, and Mycobacterium smear, tuberculosis (Tb)-polymerase chain reaction (PCR), and MAC-PCR were negative, as was acid-fast bacilli culture. Ultrasound-guided bronchoscopy confirmed the locations of the lesions, then transbronchial biopsy, bronchial brushing, and bronchial lavage were performed. Histological investigations did not reveal any indications of malignancy or granuloma, and the cytological results of bronchial washing and brushing were negative for malignancy. Bronchial lavage culture only yielded normal bacterial flora, and a Mycobacterium smear was negative in the culture test as were Tb-PCR, MAC-PCR, and acid-fast bacilli culture tests. Based on these results no definitive diagnosis was reached with regard to the nodular shadow in the upper lobe of the right lung, and therefore the patient was instructed to comply with careful monitoring on an outpatient basis. The patient was monitored as an outpatient for 18 months, during which time no changes in the size or characteristics of the nodular shadow in the right upper lobe of the lung were observed (Fig. 2A). A small 5-mm node appeared as a new lesion in the left lung apex, however, and it gradually increased to 10 mm over the course of 10 months (Fig. 2B). Enlargement of the right axillary lymph node was also observed. No enhancement effect was detected via contrast CT (Fig. 2C). Accumulation was detected in the left lung apex and right axillary lymph node via positron emission tomography-CT (Fig. 2D), but no accumulation was depicted in the right lung nodule. The patient had no fever, cough, or sputum which could suggest disseminated MAC, and the right axillary lymph node was not painful, therefore blood culture tests for acid-fast bacteria were not performed. QuantiFERON-TB GoldR was slightly elevated at 0.93 IU/mL, and anti-MAC antibodies were positive at 1.51 U/mL (reference range 0.0-0.69 U/mL). Angiotensin-converting enzyme level was 1.9 U/L (reference range 8.3-21.4 U/L) and soluble interleukin-2 receptor level was 478 U/mL (reference range 122-496 U/mL). Combined with the fact that no bilateral hilar lymphadenopathy or skin, ocular, or cardiovascular complications were observed, it was surmised that sarcoidosis was unlikely to be the cause of the lung nodule and enlargement of the right axillary lymph nodes. The new lesion, which was depicted as a small nodular shadow in the left lung apex, was in contact with the proximal subclavian artery, and performing a surgical lung biopsy to achieve a definitive diagnosis would have been difficult. Hence, a biopsy was obtained from the right axillary lymph node under local anesthesia for diagnostic purposes. Large numbers of epithelioid granulomas and multinucleated giant cells were detected in the biopsy tissue (Fig. 3). M. intracellulare was identified via mycobacterium culture of the biopsy needle aspirate fluid from the right axillary lymph node, therefore lymphadenitis caused by M. intracellulare was diagnosed. Multidrug antimicrobial therapy including clarithromycin was considered, but at the patient's request, his condition was monitored on an outpatient basis instead. Interestingly the nodule in the left upper lobe gradually shrunk over the course of one year, as did the right axillary lymph nodes (Fig. 4A and B). The nodule had almost disappeared after 18 months (Fig. 4C). Anti-MAC antibody was not increased after the left lung apex lesion had disappeared compared to the level recorded when right lymphangitis had appeared (1.45 U/mL vs. 1.51 U/mL; range 0.0-0.69 U/mL). No relapse was observed throughout the 18 months following the biopsy. During the subsequent follow-up period the lesion in the right upper lobe did not exhibit any changes in size or other characteristics (Fig. 1).

axillary lymphadenitis, mycobacterium avium complex infection, mycobacterium intracellulare

Chest computed tomography of the nodule in the upper lobe of the right lung. No change was observed during the course of observation. B. Ten months after the time from 1A.

PMC6818345_01

Male

A 67-year-old man was referred to our department after his local doctor detected a 15-mm nodular shadow in the upper lobe of his right lung. The nodule had remained unchanged for 10 months (Fig. 1A and B). The patient's temperature was 36.5 C, his heart rate was 78 beats per minute, and percutaneous arterial oxygen saturation was 98% in room air. Symptoms such as cough, sputum, shortness of breath, and weight loss were not observed. His medical history included hypertension, chronic obstructive pulmonary disease, dyslipidemia, and internal carotid artery stenosis, and he had a history of smoking 20 cigarettes a day for 43 years. His family history was unremarkable. He had no history of pet ownership, overseas travel, or excessive exposure to dust. Laboratory results on admission included a white cell count of 6610/mm3 (reference range 3300-8600/mm3) with white blood cell differentiation ratios of 72.5% neutrophils (reference range 35%-73.0%), 18.3% lymphocytes (reference range 20.0%-52%), 4.2% eosinophils (reference range 0.0%-11.0%), 0.4% basophils (reference range 0.0%-2.0%), 4.6% monocytes (reference range 0.0%-13.0%), and hemoglobin 14.3 g/dL (reference range 13.5-17.0 g/dL), platelet count 192,000/mm3 (reference range 150,000-350,000/mm3), C-reactive protein 0.03 mg/dL (reference range 0.0-0.3 mg/dL), carcinoembryonic antigen 4.26 ng/mL (reference range 0.0-5.00 ng/mL), and cytokeratin-19 fragments 3.3 ng/mL (reference range 0.0-2.8 ng/mL). An interferon-gamma (IFNgamma)-releasing assay (IGRA) (QuantiFERON-TB GoldR) was positive at 0.49 IU/mL. Tests for cryptococcus antigen and HIV antibodies were negative. Chest computed tomography (CT) revealed a 15-mm nodular shadow with slightly irregular margins in the upper lobe of the right lung (Fig. 1). Only normal bacterial flora were detected via sputum culture, and Mycobacterium smear, tuberculosis (Tb)-polymerase chain reaction (PCR), and MAC-PCR were negative, as was acid-fast bacilli culture. Ultrasound-guided bronchoscopy confirmed the locations of the lesions, then transbronchial biopsy, bronchial brushing, and bronchial lavage were performed. Histological investigations did not reveal any indications of malignancy or granuloma, and the cytological results of bronchial washing and brushing were negative for malignancy. Bronchial lavage culture only yielded normal bacterial flora, and a Mycobacterium smear was negative in the culture test as were Tb-PCR, MAC-PCR, and acid-fast bacilli culture tests. Based on these results no definitive diagnosis was reached with regard to the nodular shadow in the upper lobe of the right lung, and therefore the patient was instructed to comply with careful monitoring on an outpatient basis. The patient was monitored as an outpatient for 18 months, during which time no changes in the size or characteristics of the nodular shadow in the right upper lobe of the lung were observed (Fig. 2A). A small 5-mm node appeared as a new lesion in the left lung apex, however, and it gradually increased to 10 mm over the course of 10 months (Fig. 2B). Enlargement of the right axillary lymph node was also observed. No enhancement effect was detected via contrast CT (Fig. 2C). Accumulation was detected in the left lung apex and right axillary lymph node via positron emission tomography-CT (Fig. 2D), but no accumulation was depicted in the right lung nodule. The patient had no fever, cough, or sputum which could suggest disseminated MAC, and the right axillary lymph node was not painful, therefore blood culture tests for acid-fast bacteria were not performed. QuantiFERON-TB GoldR was slightly elevated at 0.93 IU/mL, and anti-MAC antibodies were positive at 1.51 U/mL (reference range 0.0-0.69 U/mL). Angiotensin-converting enzyme level was 1.9 U/L (reference range 8.3-21.4 U/L) and soluble interleukin-2 receptor level was 478 U/mL (reference range 122-496 U/mL). Combined with the fact that no bilateral hilar lymphadenopathy or skin, ocular, or cardiovascular complications were observed, it was surmised that sarcoidosis was unlikely to be the cause of the lung nodule and enlargement of the right axillary lymph nodes. The new lesion, which was depicted as a small nodular shadow in the left lung apex, was in contact with the proximal subclavian artery, and performing a surgical lung biopsy to achieve a definitive diagnosis would have been difficult. Hence, a biopsy was obtained from the right axillary lymph node under local anesthesia for diagnostic purposes. Large numbers of epithelioid granulomas and multinucleated giant cells were detected in the biopsy tissue (Fig. 3). M. intracellulare was identified via mycobacterium culture of the biopsy needle aspirate fluid from the right axillary lymph node, therefore lymphadenitis caused by M. intracellulare was diagnosed. Multidrug antimicrobial therapy including clarithromycin was considered, but at the patient's request, his condition was monitored on an outpatient basis instead. Interestingly the nodule in the left upper lobe gradually shrunk over the course of one year, as did the right axillary lymph nodes (Fig. 4A and B). The nodule had almost disappeared after 18 months (Fig. 4C). Anti-MAC antibody was not increased after the left lung apex lesion had disappeared compared to the level recorded when right lymphangitis had appeared (1.45 U/mL vs. 1.51 U/mL; range 0.0-0.69 U/mL). No relapse was observed throughout the 18 months following the biopsy. During the subsequent follow-up period the lesion in the right upper lobe did not exhibit any changes in size or other characteristics (Fig. 1).

axillary lymphadenitis, mycobacterium avium complex infection, mycobacterium intracellulare

Chest computed tomography of the nodule in the upper lobe of the right lung. No change was observed during the course of observation. C. Eighteen months after the time from 1B (the same period represented in Fig.

PMC6818345_01

Male

A 67-year-old man was referred to our department after his local doctor detected a 15-mm nodular shadow in the upper lobe of his right lung. The nodule had remained unchanged for 10 months (Fig. 1A and B). The patient's temperature was 36.5 C, his heart rate was 78 beats per minute, and percutaneous arterial oxygen saturation was 98% in room air. Symptoms such as cough, sputum, shortness of breath, and weight loss were not observed. His medical history included hypertension, chronic obstructive pulmonary disease, dyslipidemia, and internal carotid artery stenosis, and he had a history of smoking 20 cigarettes a day for 43 years. His family history was unremarkable. He had no history of pet ownership, overseas travel, or excessive exposure to dust. Laboratory results on admission included a white cell count of 6610/mm3 (reference range 3300-8600/mm3) with white blood cell differentiation ratios of 72.5% neutrophils (reference range 35%-73.0%), 18.3% lymphocytes (reference range 20.0%-52%), 4.2% eosinophils (reference range 0.0%-11.0%), 0.4% basophils (reference range 0.0%-2.0%), 4.6% monocytes (reference range 0.0%-13.0%), and hemoglobin 14.3 g/dL (reference range 13.5-17.0 g/dL), platelet count 192,000/mm3 (reference range 150,000-350,000/mm3), C-reactive protein 0.03 mg/dL (reference range 0.0-0.3 mg/dL), carcinoembryonic antigen 4.26 ng/mL (reference range 0.0-5.00 ng/mL), and cytokeratin-19 fragments 3.3 ng/mL (reference range 0.0-2.8 ng/mL). An interferon-gamma (IFNgamma)-releasing assay (IGRA) (QuantiFERON-TB GoldR) was positive at 0.49 IU/mL. Tests for cryptococcus antigen and HIV antibodies were negative. Chest computed tomography (CT) revealed a 15-mm nodular shadow with slightly irregular margins in the upper lobe of the right lung (Fig. 1). Only normal bacterial flora were detected via sputum culture, and Mycobacterium smear, tuberculosis (Tb)-polymerase chain reaction (PCR), and MAC-PCR were negative, as was acid-fast bacilli culture. Ultrasound-guided bronchoscopy confirmed the locations of the lesions, then transbronchial biopsy, bronchial brushing, and bronchial lavage were performed. Histological investigations did not reveal any indications of malignancy or granuloma, and the cytological results of bronchial washing and brushing were negative for malignancy. Bronchial lavage culture only yielded normal bacterial flora, and a Mycobacterium smear was negative in the culture test as were Tb-PCR, MAC-PCR, and acid-fast bacilli culture tests. Based on these results no definitive diagnosis was reached with regard to the nodular shadow in the upper lobe of the right lung, and therefore the patient was instructed to comply with careful monitoring on an outpatient basis. The patient was monitored as an outpatient for 18 months, during which time no changes in the size or characteristics of the nodular shadow in the right upper lobe of the lung were observed (Fig. 2A). A small 5-mm node appeared as a new lesion in the left lung apex, however, and it gradually increased to 10 mm over the course of 10 months (Fig. 2B). Enlargement of the right axillary lymph node was also observed. No enhancement effect was detected via contrast CT (Fig. 2C). Accumulation was detected in the left lung apex and right axillary lymph node via positron emission tomography-CT (Fig. 2D), but no accumulation was depicted in the right lung nodule. The patient had no fever, cough, or sputum which could suggest disseminated MAC, and the right axillary lymph node was not painful, therefore blood culture tests for acid-fast bacteria were not performed. QuantiFERON-TB GoldR was slightly elevated at 0.93 IU/mL, and anti-MAC antibodies were positive at 1.51 U/mL (reference range 0.0-0.69 U/mL). Angiotensin-converting enzyme level was 1.9 U/L (reference range 8.3-21.4 U/L) and soluble interleukin-2 receptor level was 478 U/mL (reference range 122-496 U/mL). Combined with the fact that no bilateral hilar lymphadenopathy or skin, ocular, or cardiovascular complications were observed, it was surmised that sarcoidosis was unlikely to be the cause of the lung nodule and enlargement of the right axillary lymph nodes. The new lesion, which was depicted as a small nodular shadow in the left lung apex, was in contact with the proximal subclavian artery, and performing a surgical lung biopsy to achieve a definitive diagnosis would have been difficult. Hence, a biopsy was obtained from the right axillary lymph node under local anesthesia for diagnostic purposes. Large numbers of epithelioid granulomas and multinucleated giant cells were detected in the biopsy tissue (Fig. 3). M. intracellulare was identified via mycobacterium culture of the biopsy needle aspirate fluid from the right axillary lymph node, therefore lymphadenitis caused by M. intracellulare was diagnosed. Multidrug antimicrobial therapy including clarithromycin was considered, but at the patient's request, his condition was monitored on an outpatient basis instead. Interestingly the nodule in the left upper lobe gradually shrunk over the course of one year, as did the right axillary lymph nodes (Fig. 4A and B). The nodule had almost disappeared after 18 months (Fig. 4C). Anti-MAC antibody was not increased after the left lung apex lesion had disappeared compared to the level recorded when right lymphangitis had appeared (1.45 U/mL vs. 1.51 U/mL; range 0.0-0.69 U/mL). No relapse was observed throughout the 18 months following the biopsy. During the subsequent follow-up period the lesion in the right upper lobe did not exhibit any changes in size or other characteristics (Fig. 1).

axillary lymphadenitis, mycobacterium avium complex infection, mycobacterium intracellulare

Chest computed tomography of the nodule in the upper lobe of the right lung. No change was observed during the course of observation. 4A). D. Twelve months after the time represented in Fig. 1C (the same period represented in Fig.

PMC6818345_01

Male

A 67-year-old man was referred to our department after his local doctor detected a 15-mm nodular shadow in the upper lobe of his right lung. The nodule had remained unchanged for 10 months (Fig. 1A and B). The patient's temperature was 36.5 C, his heart rate was 78 beats per minute, and percutaneous arterial oxygen saturation was 98% in room air. Symptoms such as cough, sputum, shortness of breath, and weight loss were not observed. His medical history included hypertension, chronic obstructive pulmonary disease, dyslipidemia, and internal carotid artery stenosis, and he had a history of smoking 20 cigarettes a day for 43 years. His family history was unremarkable. He had no history of pet ownership, overseas travel, or excessive exposure to dust. Laboratory results on admission included a white cell count of 6610/mm3 (reference range 3300-8600/mm3) with white blood cell differentiation ratios of 72.5% neutrophils (reference range 35%-73.0%), 18.3% lymphocytes (reference range 20.0%-52%), 4.2% eosinophils (reference range 0.0%-11.0%), 0.4% basophils (reference range 0.0%-2.0%), 4.6% monocytes (reference range 0.0%-13.0%), and hemoglobin 14.3 g/dL (reference range 13.5-17.0 g/dL), platelet count 192,000/mm3 (reference range 150,000-350,000/mm3), C-reactive protein 0.03 mg/dL (reference range 0.0-0.3 mg/dL), carcinoembryonic antigen 4.26 ng/mL (reference range 0.0-5.00 ng/mL), and cytokeratin-19 fragments 3.3 ng/mL (reference range 0.0-2.8 ng/mL). An interferon-gamma (IFNgamma)-releasing assay (IGRA) (QuantiFERON-TB GoldR) was positive at 0.49 IU/mL. Tests for cryptococcus antigen and HIV antibodies were negative. Chest computed tomography (CT) revealed a 15-mm nodular shadow with slightly irregular margins in the upper lobe of the right lung (Fig. 1). Only normal bacterial flora were detected via sputum culture, and Mycobacterium smear, tuberculosis (Tb)-polymerase chain reaction (PCR), and MAC-PCR were negative, as was acid-fast bacilli culture. Ultrasound-guided bronchoscopy confirmed the locations of the lesions, then transbronchial biopsy, bronchial brushing, and bronchial lavage were performed. Histological investigations did not reveal any indications of malignancy or granuloma, and the cytological results of bronchial washing and brushing were negative for malignancy. Bronchial lavage culture only yielded normal bacterial flora, and a Mycobacterium smear was negative in the culture test as were Tb-PCR, MAC-PCR, and acid-fast bacilli culture tests. Based on these results no definitive diagnosis was reached with regard to the nodular shadow in the upper lobe of the right lung, and therefore the patient was instructed to comply with careful monitoring on an outpatient basis. The patient was monitored as an outpatient for 18 months, during which time no changes in the size or characteristics of the nodular shadow in the right upper lobe of the lung were observed (Fig. 2A). A small 5-mm node appeared as a new lesion in the left lung apex, however, and it gradually increased to 10 mm over the course of 10 months (Fig. 2B). Enlargement of the right axillary lymph node was also observed. No enhancement effect was detected via contrast CT (Fig. 2C). Accumulation was detected in the left lung apex and right axillary lymph node via positron emission tomography-CT (Fig. 2D), but no accumulation was depicted in the right lung nodule. The patient had no fever, cough, or sputum which could suggest disseminated MAC, and the right axillary lymph node was not painful, therefore blood culture tests for acid-fast bacteria were not performed. QuantiFERON-TB GoldR was slightly elevated at 0.93 IU/mL, and anti-MAC antibodies were positive at 1.51 U/mL (reference range 0.0-0.69 U/mL). Angiotensin-converting enzyme level was 1.9 U/L (reference range 8.3-21.4 U/L) and soluble interleukin-2 receptor level was 478 U/mL (reference range 122-496 U/mL). Combined with the fact that no bilateral hilar lymphadenopathy or skin, ocular, or cardiovascular complications were observed, it was surmised that sarcoidosis was unlikely to be the cause of the lung nodule and enlargement of the right axillary lymph nodes. The new lesion, which was depicted as a small nodular shadow in the left lung apex, was in contact with the proximal subclavian artery, and performing a surgical lung biopsy to achieve a definitive diagnosis would have been difficult. Hence, a biopsy was obtained from the right axillary lymph node under local anesthesia for diagnostic purposes. Large numbers of epithelioid granulomas and multinucleated giant cells were detected in the biopsy tissue (Fig. 3). M. intracellulare was identified via mycobacterium culture of the biopsy needle aspirate fluid from the right axillary lymph node, therefore lymphadenitis caused by M. intracellulare was diagnosed. Multidrug antimicrobial therapy including clarithromycin was considered, but at the patient's request, his condition was monitored on an outpatient basis instead. Interestingly the nodule in the left upper lobe gradually shrunk over the course of one year, as did the right axillary lymph nodes (Fig. 4A and B). The nodule had almost disappeared after 18 months (Fig. 4C). Anti-MAC antibody was not increased after the left lung apex lesion had disappeared compared to the level recorded when right lymphangitis had appeared (1.45 U/mL vs. 1.51 U/mL; range 0.0-0.69 U/mL). No relapse was observed throughout the 18 months following the biopsy. During the subsequent follow-up period the lesion in the right upper lobe did not exhibit any changes in size or other characteristics (Fig. 1).

axillary lymphadenitis, mycobacterium avium complex infection, mycobacterium intracellulare

Chest computed tomography of the nodule in the upper lobe of the right lung. No change was observed during the course of observation. 4B). E. Eighteen months after the time from Fig. 1C (the same period represented in Fig. 4C).

PMC6818345_01

Male

A 67-year-old man was referred to our department after his local doctor detected a 15-mm nodular shadow in the upper lobe of his right lung. The nodule had remained unchanged for 10 months (Fig. 1A and B). The patient's temperature was 36.5 C, his heart rate was 78 beats per minute, and percutaneous arterial oxygen saturation was 98% in room air. Symptoms such as cough, sputum, shortness of breath, and weight loss were not observed. His medical history included hypertension, chronic obstructive pulmonary disease, dyslipidemia, and internal carotid artery stenosis, and he had a history of smoking 20 cigarettes a day for 43 years. His family history was unremarkable. He had no history of pet ownership, overseas travel, or excessive exposure to dust. Laboratory results on admission included a white cell count of 6610/mm3 (reference range 3300-8600/mm3) with white blood cell differentiation ratios of 72.5% neutrophils (reference range 35%-73.0%), 18.3% lymphocytes (reference range 20.0%-52%), 4.2% eosinophils (reference range 0.0%-11.0%), 0.4% basophils (reference range 0.0%-2.0%), 4.6% monocytes (reference range 0.0%-13.0%), and hemoglobin 14.3 g/dL (reference range 13.5-17.0 g/dL), platelet count 192,000/mm3 (reference range 150,000-350,000/mm3), C-reactive protein 0.03 mg/dL (reference range 0.0-0.3 mg/dL), carcinoembryonic antigen 4.26 ng/mL (reference range 0.0-5.00 ng/mL), and cytokeratin-19 fragments 3.3 ng/mL (reference range 0.0-2.8 ng/mL). An interferon-gamma (IFNgamma)-releasing assay (IGRA) (QuantiFERON-TB GoldR) was positive at 0.49 IU/mL. Tests for cryptococcus antigen and HIV antibodies were negative. Chest computed tomography (CT) revealed a 15-mm nodular shadow with slightly irregular margins in the upper lobe of the right lung (Fig. 1). Only normal bacterial flora were detected via sputum culture, and Mycobacterium smear, tuberculosis (Tb)-polymerase chain reaction (PCR), and MAC-PCR were negative, as was acid-fast bacilli culture. Ultrasound-guided bronchoscopy confirmed the locations of the lesions, then transbronchial biopsy, bronchial brushing, and bronchial lavage were performed. Histological investigations did not reveal any indications of malignancy or granuloma, and the cytological results of bronchial washing and brushing were negative for malignancy. Bronchial lavage culture only yielded normal bacterial flora, and a Mycobacterium smear was negative in the culture test as were Tb-PCR, MAC-PCR, and acid-fast bacilli culture tests. Based on these results no definitive diagnosis was reached with regard to the nodular shadow in the upper lobe of the right lung, and therefore the patient was instructed to comply with careful monitoring on an outpatient basis. The patient was monitored as an outpatient for 18 months, during which time no changes in the size or characteristics of the nodular shadow in the right upper lobe of the lung were observed (Fig. 2A). A small 5-mm node appeared as a new lesion in the left lung apex, however, and it gradually increased to 10 mm over the course of 10 months (Fig. 2B). Enlargement of the right axillary lymph node was also observed. No enhancement effect was detected via contrast CT (Fig. 2C). Accumulation was detected in the left lung apex and right axillary lymph node via positron emission tomography-CT (Fig. 2D), but no accumulation was depicted in the right lung nodule. The patient had no fever, cough, or sputum which could suggest disseminated MAC, and the right axillary lymph node was not painful, therefore blood culture tests for acid-fast bacteria were not performed. QuantiFERON-TB GoldR was slightly elevated at 0.93 IU/mL, and anti-MAC antibodies were positive at 1.51 U/mL (reference range 0.0-0.69 U/mL). Angiotensin-converting enzyme level was 1.9 U/L (reference range 8.3-21.4 U/L) and soluble interleukin-2 receptor level was 478 U/mL (reference range 122-496 U/mL). Combined with the fact that no bilateral hilar lymphadenopathy or skin, ocular, or cardiovascular complications were observed, it was surmised that sarcoidosis was unlikely to be the cause of the lung nodule and enlargement of the right axillary lymph nodes. The new lesion, which was depicted as a small nodular shadow in the left lung apex, was in contact with the proximal subclavian artery, and performing a surgical lung biopsy to achieve a definitive diagnosis would have been difficult. Hence, a biopsy was obtained from the right axillary lymph node under local anesthesia for diagnostic purposes. Large numbers of epithelioid granulomas and multinucleated giant cells were detected in the biopsy tissue (Fig. 3). M. intracellulare was identified via mycobacterium culture of the biopsy needle aspirate fluid from the right axillary lymph node, therefore lymphadenitis caused by M. intracellulare was diagnosed. Multidrug antimicrobial therapy including clarithromycin was considered, but at the patient's request, his condition was monitored on an outpatient basis instead. Interestingly the nodule in the left upper lobe gradually shrunk over the course of one year, as did the right axillary lymph nodes (Fig. 4A and B). The nodule had almost disappeared after 18 months (Fig. 4C). Anti-MAC antibody was not increased after the left lung apex lesion had disappeared compared to the level recorded when right lymphangitis had appeared (1.45 U/mL vs. 1.51 U/mL; range 0.0-0.69 U/mL). No relapse was observed throughout the 18 months following the biopsy. During the subsequent follow-up period the lesion in the right upper lobe did not exhibit any changes in size or other characteristics (Fig. 1).

axillary lymphadenitis, mycobacterium avium complex infection, mycobacterium intracellulare

A. Chest computed tomography (CT) revealed a 15-mm irregularly shaped nodule in the upper lobe of the right lung. The nodule shadow was unchanged after 10 months of observation.

PMC6818345_01

Male

A 67-year-old man was referred to our department after his local doctor detected a 15-mm nodular shadow in the upper lobe of his right lung. The nodule had remained unchanged for 10 months (Fig. 1A and B). The patient's temperature was 36.5 C, his heart rate was 78 beats per minute, and percutaneous arterial oxygen saturation was 98% in room air. Symptoms such as cough, sputum, shortness of breath, and weight loss were not observed. His medical history included hypertension, chronic obstructive pulmonary disease, dyslipidemia, and internal carotid artery stenosis, and he had a history of smoking 20 cigarettes a day for 43 years. His family history was unremarkable. He had no history of pet ownership, overseas travel, or excessive exposure to dust. Laboratory results on admission included a white cell count of 6610/mm3 (reference range 3300-8600/mm3) with white blood cell differentiation ratios of 72.5% neutrophils (reference range 35%-73.0%), 18.3% lymphocytes (reference range 20.0%-52%), 4.2% eosinophils (reference range 0.0%-11.0%), 0.4% basophils (reference range 0.0%-2.0%), 4.6% monocytes (reference range 0.0%-13.0%), and hemoglobin 14.3 g/dL (reference range 13.5-17.0 g/dL), platelet count 192,000/mm3 (reference range 150,000-350,000/mm3), C-reactive protein 0.03 mg/dL (reference range 0.0-0.3 mg/dL), carcinoembryonic antigen 4.26 ng/mL (reference range 0.0-5.00 ng/mL), and cytokeratin-19 fragments 3.3 ng/mL (reference range 0.0-2.8 ng/mL). An interferon-gamma (IFNgamma)-releasing assay (IGRA) (QuantiFERON-TB GoldR) was positive at 0.49 IU/mL. Tests for cryptococcus antigen and HIV antibodies were negative. Chest computed tomography (CT) revealed a 15-mm nodular shadow with slightly irregular margins in the upper lobe of the right lung (Fig. 1). Only normal bacterial flora were detected via sputum culture, and Mycobacterium smear, tuberculosis (Tb)-polymerase chain reaction (PCR), and MAC-PCR were negative, as was acid-fast bacilli culture. Ultrasound-guided bronchoscopy confirmed the locations of the lesions, then transbronchial biopsy, bronchial brushing, and bronchial lavage were performed. Histological investigations did not reveal any indications of malignancy or granuloma, and the cytological results of bronchial washing and brushing were negative for malignancy. Bronchial lavage culture only yielded normal bacterial flora, and a Mycobacterium smear was negative in the culture test as were Tb-PCR, MAC-PCR, and acid-fast bacilli culture tests. Based on these results no definitive diagnosis was reached with regard to the nodular shadow in the upper lobe of the right lung, and therefore the patient was instructed to comply with careful monitoring on an outpatient basis. The patient was monitored as an outpatient for 18 months, during which time no changes in the size or characteristics of the nodular shadow in the right upper lobe of the lung were observed (Fig. 2A). A small 5-mm node appeared as a new lesion in the left lung apex, however, and it gradually increased to 10 mm over the course of 10 months (Fig. 2B). Enlargement of the right axillary lymph node was also observed. No enhancement effect was detected via contrast CT (Fig. 2C). Accumulation was detected in the left lung apex and right axillary lymph node via positron emission tomography-CT (Fig. 2D), but no accumulation was depicted in the right lung nodule. The patient had no fever, cough, or sputum which could suggest disseminated MAC, and the right axillary lymph node was not painful, therefore blood culture tests for acid-fast bacteria were not performed. QuantiFERON-TB GoldR was slightly elevated at 0.93 IU/mL, and anti-MAC antibodies were positive at 1.51 U/mL (reference range 0.0-0.69 U/mL). Angiotensin-converting enzyme level was 1.9 U/L (reference range 8.3-21.4 U/L) and soluble interleukin-2 receptor level was 478 U/mL (reference range 122-496 U/mL). Combined with the fact that no bilateral hilar lymphadenopathy or skin, ocular, or cardiovascular complications were observed, it was surmised that sarcoidosis was unlikely to be the cause of the lung nodule and enlargement of the right axillary lymph nodes. The new lesion, which was depicted as a small nodular shadow in the left lung apex, was in contact with the proximal subclavian artery, and performing a surgical lung biopsy to achieve a definitive diagnosis would have been difficult. Hence, a biopsy was obtained from the right axillary lymph node under local anesthesia for diagnostic purposes. Large numbers of epithelioid granulomas and multinucleated giant cells were detected in the biopsy tissue (Fig. 3). M. intracellulare was identified via mycobacterium culture of the biopsy needle aspirate fluid from the right axillary lymph node, therefore lymphadenitis caused by M. intracellulare was diagnosed. Multidrug antimicrobial therapy including clarithromycin was considered, but at the patient's request, his condition was monitored on an outpatient basis instead. Interestingly the nodule in the left upper lobe gradually shrunk over the course of one year, as did the right axillary lymph nodes (Fig. 4A and B). The nodule had almost disappeared after 18 months (Fig. 4C). Anti-MAC antibody was not increased after the left lung apex lesion had disappeared compared to the level recorded when right lymphangitis had appeared (1.45 U/mL vs. 1.51 U/mL; range 0.0-0.69 U/mL). No relapse was observed throughout the 18 months following the biopsy. During the subsequent follow-up period the lesion in the right upper lobe did not exhibit any changes in size or other characteristics (Fig. 1).

axillary lymphadenitis, mycobacterium avium complex infection, mycobacterium intracellulare

B. Chest CT revealed a small new 5-mm nodular lesion in the left lung apex, which gradually increased in size over the course of 10 months (red arrow).

PMC6818345_01

Male

A 67-year-old man was referred to our department after his local doctor detected a 15-mm nodular shadow in the upper lobe of his right lung. The nodule had remained unchanged for 10 months (Fig. 1A and B). The patient's temperature was 36.5 C, his heart rate was 78 beats per minute, and percutaneous arterial oxygen saturation was 98% in room air. Symptoms such as cough, sputum, shortness of breath, and weight loss were not observed. His medical history included hypertension, chronic obstructive pulmonary disease, dyslipidemia, and internal carotid artery stenosis, and he had a history of smoking 20 cigarettes a day for 43 years. His family history was unremarkable. He had no history of pet ownership, overseas travel, or excessive exposure to dust. Laboratory results on admission included a white cell count of 6610/mm3 (reference range 3300-8600/mm3) with white blood cell differentiation ratios of 72.5% neutrophils (reference range 35%-73.0%), 18.3% lymphocytes (reference range 20.0%-52%), 4.2% eosinophils (reference range 0.0%-11.0%), 0.4% basophils (reference range 0.0%-2.0%), 4.6% monocytes (reference range 0.0%-13.0%), and hemoglobin 14.3 g/dL (reference range 13.5-17.0 g/dL), platelet count 192,000/mm3 (reference range 150,000-350,000/mm3), C-reactive protein 0.03 mg/dL (reference range 0.0-0.3 mg/dL), carcinoembryonic antigen 4.26 ng/mL (reference range 0.0-5.00 ng/mL), and cytokeratin-19 fragments 3.3 ng/mL (reference range 0.0-2.8 ng/mL). An interferon-gamma (IFNgamma)-releasing assay (IGRA) (QuantiFERON-TB GoldR) was positive at 0.49 IU/mL. Tests for cryptococcus antigen and HIV antibodies were negative. Chest computed tomography (CT) revealed a 15-mm nodular shadow with slightly irregular margins in the upper lobe of the right lung (Fig. 1). Only normal bacterial flora were detected via sputum culture, and Mycobacterium smear, tuberculosis (Tb)-polymerase chain reaction (PCR), and MAC-PCR were negative, as was acid-fast bacilli culture. Ultrasound-guided bronchoscopy confirmed the locations of the lesions, then transbronchial biopsy, bronchial brushing, and bronchial lavage were performed. Histological investigations did not reveal any indications of malignancy or granuloma, and the cytological results of bronchial washing and brushing were negative for malignancy. Bronchial lavage culture only yielded normal bacterial flora, and a Mycobacterium smear was negative in the culture test as were Tb-PCR, MAC-PCR, and acid-fast bacilli culture tests. Based on these results no definitive diagnosis was reached with regard to the nodular shadow in the upper lobe of the right lung, and therefore the patient was instructed to comply with careful monitoring on an outpatient basis. The patient was monitored as an outpatient for 18 months, during which time no changes in the size or characteristics of the nodular shadow in the right upper lobe of the lung were observed (Fig. 2A). A small 5-mm node appeared as a new lesion in the left lung apex, however, and it gradually increased to 10 mm over the course of 10 months (Fig. 2B). Enlargement of the right axillary lymph node was also observed. No enhancement effect was detected via contrast CT (Fig. 2C). Accumulation was detected in the left lung apex and right axillary lymph node via positron emission tomography-CT (Fig. 2D), but no accumulation was depicted in the right lung nodule. The patient had no fever, cough, or sputum which could suggest disseminated MAC, and the right axillary lymph node was not painful, therefore blood culture tests for acid-fast bacteria were not performed. QuantiFERON-TB GoldR was slightly elevated at 0.93 IU/mL, and anti-MAC antibodies were positive at 1.51 U/mL (reference range 0.0-0.69 U/mL). Angiotensin-converting enzyme level was 1.9 U/L (reference range 8.3-21.4 U/L) and soluble interleukin-2 receptor level was 478 U/mL (reference range 122-496 U/mL). Combined with the fact that no bilateral hilar lymphadenopathy or skin, ocular, or cardiovascular complications were observed, it was surmised that sarcoidosis was unlikely to be the cause of the lung nodule and enlargement of the right axillary lymph nodes. The new lesion, which was depicted as a small nodular shadow in the left lung apex, was in contact with the proximal subclavian artery, and performing a surgical lung biopsy to achieve a definitive diagnosis would have been difficult. Hence, a biopsy was obtained from the right axillary lymph node under local anesthesia for diagnostic purposes. Large numbers of epithelioid granulomas and multinucleated giant cells were detected in the biopsy tissue (Fig. 3). M. intracellulare was identified via mycobacterium culture of the biopsy needle aspirate fluid from the right axillary lymph node, therefore lymphadenitis caused by M. intracellulare was diagnosed. Multidrug antimicrobial therapy including clarithromycin was considered, but at the patient's request, his condition was monitored on an outpatient basis instead. Interestingly the nodule in the left upper lobe gradually shrunk over the course of one year, as did the right axillary lymph nodes (Fig. 4A and B). The nodule had almost disappeared after 18 months (Fig. 4C). Anti-MAC antibody was not increased after the left lung apex lesion had disappeared compared to the level recorded when right lymphangitis had appeared (1.45 U/mL vs. 1.51 U/mL; range 0.0-0.69 U/mL). No relapse was observed throughout the 18 months following the biopsy. During the subsequent follow-up period the lesion in the right upper lobe did not exhibit any changes in size or other characteristics (Fig. 1).

axillary lymphadenitis, mycobacterium avium complex infection, mycobacterium intracellulare

D. Positron emission tomography-CT depicting 18F-fluorodeoxyglucose uptake in the left lung apex and right axillary lymph nodes. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article. ).

PMC2896840_01

Male

In September 2007, an 8.5-year-old red-necked male wallaby (Macropus rufogriseus) displaying severe neurological signs, including head tremor, lethargy, unresponsiveness, and weakness (see Figure 1) was presented to the veterinary surgeon of the Zoo of Hamm, (59065, Germany). Physical examination revealed pyrexia (39 C), neurological and ophthalmic signs including nystagmus and bilateral epiphora. Serum biochemical abnormalities included increased LDH- and AST-levels, hyperproteinaemia, and reduced ALT-, ALP-, and creatinine-levels. Despite immediate supportive therapy with antibiotics (enrofloxacin, 10 mg/kg body weight, s.c., Baytril, Bayer) and corticosteroids (dexamethasone, 0.1 mg/kg body weight, s.c., Medistar-Dexamethason, Medistar), there was no improvement. After one week of stagnation, a tentative diagnosis of toxoplasmosis was made. For confirmation, blood samples were taken for serological analysis. The wallaby was found serologically positive for T. gondii, showing high antibody titres (>=1 : 1024) in the indirect haemagglutination (IHA) test (Cellognost-Toxoplasmosis H, Dade Behring). Neither T. gondii- nor Neospora caninum-DNA was detected in the EDTA-blood samples by specific PCR. After confirmation of toxoplasmosis, appropriate treatment of the wallaby was initiated. Subcutaneous injections of trimethoprim/sulfadoxin (15 mg/kg body weight daily for 10 days, Sulphix, Bela-Pharm) were administered. Three days after initiation of therapy, amelioration of neurological signs was noted in the wallaby and after 7 days the majority of the clinical signs were no longer apparent. As the infected animal shared premises with two other wallabies and T. gondii infection of these could not be excluded, respective blood samples were analysed serologically as well. Both wallabies, which showed no clinical signs of disease, also had high antibody titres (>=1 : 1024) against T. gondii. Toxoplasmosis has been reported in captive macropods from various zoos worldwide. As red-necked wallabies (Macropus rufogriseus) are herbivores, they presumably acquire T. gondii by the oral uptake of sporulated oocysts shed from stray cats or other felids. Transplacental and transmammary infections are also reported in joeys. In red-necked wallabies, generalized T. gondii infections may be associated with nonsuppurative meningoencephalitis, hepatitis, myositis, myocarditis, keratitis, uveitis, choroidoretinitis, endophthalmitis, or severe enteritis. As such, a broad range of clinical signs, such as depression, lethargy, ataxia, cataracts, unresponsiveness, weakness, diarrhoea, and weight loss have been described. The neurological findings seen in this report, such as depression, nystagmus, and head tremor may reflect an acute meningoencephalitis, bilateral epiphora, and ophthalmic disorders. Serum biochemical abnormalities detected in the sick wallaby, such as hyperproteinaemia, could also indicate an inflammatory process. Increased LDH-levels are often seen in myositis/myocarditis, which have been reported in acute toxoplasmosis in wallabies. Subclinical T. gondii infections, as reported in the other species, have also been documented in macropods. Acute toxoplasmosis in this wallaby might have been triggered by individual additional factors, for example, stress. The wallaby mentioned in this report most probably became infected by the ingestion of sporulated oocysts of T. gondii spread on the ground of the premises. Interestingly, the premises flanked a local allotment garden area with a stable stray cat population. For many years stray cats have been observed at the Zoo of Hamm and, as in other zoos, they are suspected to be the most likely source of T. gondii-oocysts contamination. The case reported here indicates that toxoplasmosis should be considered as a differential diagnosis in cases of neurological disorders in wallabies. T. gondii infection can be confirmed rapidly by serology, and immediate therapy may reduce clinical illness and fatality of the disease within captive macropods. The treatment with trimethoprim/sulfonamide has been described to be effective against T. gondii and may be used prophylactically in macropods during toxoplasmosis outbreaks. Additionally, the successful treatment with atovaquone in wallabies suffering from ocular toxoplasmosis has recently been described.