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Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder characterized by tumors of parathyroid, anterior pituitary, and pancreatic islet cells. Pituitary adenomas in MEN1 can be aggressive and invade surrounding structures including the skull base. However, acute bacterial meningitis in patients with newly diagnosed macroprolactinomas is an exceptional finding. We present the case of a young man with suppurative meningitis complicating an invasive macroprolactinoma as the initial manifestation of MEN1. A 33-year-old male was admitted to the hospital with fever, headache, and nuchal rigidity and subsequently diagnosed with Haemophilus influenzae bacterial meningitis. Computed tomography (CT) and subsequent magnetic resonance imaging (MRI) of the sella turcica revealed a 5 x 3.5 cm pituitary mass invading both cavernous sinuses and the left sphenoid sinus. Laboratory evaluation was notable for significantly elevated serum prolactin level (2,484 ng/mL, 2.6-13.2) and evidence of hypopituitarism. Primary hyperparathyroidism was indicated by hypercalcemia (13.5 mg/dL, 8.5-10.5), low serum phosphorus (2.0 mg/dL, 2.5-4.9), and elevated intact parathyroid hormone (PTH) level (290 pg/mL, 15-60). No visual field deficits were identified. The patient was managed with hydrocortisone, levothyroxine, and cabergoline. However, cerebral spinal fluid (CSF) rhinorrhea compelled subtotal transsphenoidal resection of the tumor and repair of the CSF leak. Three-and-a-half gland parathyroid resection was performed after recovery from pituitary surgery and successfully treated hypercalcemia. Abdominal MRI revealed a 1.2 cm cystic mass in the neck of the pancreas, and pancreatic polypeptide was approximately fourfold elevated. A clinical diagnosis of MEN1 was made based on the occurrence of macroprolactinoma, multiple parathyroid adenomas, and pancreatic findings. This case appears to be the first in which bacterial meningitis was the initial presentation of an invasive macroprolactinoma in a patient with MEN1., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Bandaru et al.)

Breast cancer is the most prevalent cancer known worldwide in women. It is a heterogeneous, phenotypically diverse disease composed of several biologic subtypes that have distinct behavior and response to therapy. Hormone receptor-positive (i.e., estrogen [ER] and/or progesterone [PR] receptor-positive) breast cancers comprise the most common types of breast cancer, accounting for 75% of all cases. This makes endocrine therapy the standardized treatment for patients with ER+/PR+ breast cancer. Drugs that block estrogen receptors or that lower estrogen levels are the mainstay of treatment. High-risk patients benefit from the addition of ovarian function suppression (OFS)/ablation to either an aromatase inhibitor (AI) or tamoxifen. This case report discusses a 36-year-old premenopausal female who presented with an abnormal right breast lump in the upper outer quadrant of the right breast. Due to high suspicion of malignancy, a biopsy was performed which showed features of both lobular and ductal carcinoma with ER and PR positivity, HER 2 was negative. The patient underwent mastectomy with axillary lymph node removal due to concern for multifocal disease. No clinically relevant genetic mutations were present. Oncotype DX breast recurrence score was 16 and no chemotherapy was offered. Due to large tumor size, young age OFS with goserelin 3.6mg/28 days and letrozole 2.5 mg once daily was recommended. After 16 months of treatment, the patient developed a failure of goserelin-induced ovarian suppression. This case report highlights the possibility of the development of hormonal resistance after long-term use of goserelin., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Gupta et al.)

Malignant mesotheliomas (MM), as described are rare tumors that are mostly associated with occupational exposure to asbestos. They most commonly occur in the pleura. Other unfamiliar sites where they can occur are the peritoneum, pericardium, and tunica vaginalis. There is no significant correlation between the amount and duration of asbestos exposure to mesothelioma development as reported by various studies over the years. Apart from the environmental exposure, the development of malignant mesothelioma has been linked to a mutation in the BAP1 gene, which can predispose the patient to develop other malignancies associated with BAP1 mutation. We report a case of a 43-year-old man without any significant risk factors, who presented with a complaint of abdominal discomfort and was found to have malignant peritoneal mesothelioma (MPM). With a known familial history of mesothelioma and melanoma, our patient underwent genetic testing which revealed a mutation in BAP1, affirming the strong association with the development of MPM. Young patients who develop malignant mesothelioma without risk factors for MM should have germline testing for BAP1. This case report is unique and highlights a familial variant of mesothelioma, even rare with peritoneal mesothelioma in our patient., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Gupta et al.)

Immune checkpoint inhibitors can cause immune side effects, with myasthenia gravis (MG) being relatively rare. With this review, we present 66-year-old man with melanoma treated with pembrolizumab who developed MG. With immuno-oncology (IO) single agent usage, 42 cases reported new-onset MG and 9 cases reported exacerbation of pre-existing MG. Among the patients who had new-onset MG after administration of programmed cell death protein 1 (PD-1) inhibitors, 14 patients (38.8%) developed severe respiratory failure and required intubation and 10 patients (27.02%) died. Among the patients with exacerbation of pre-existing MG after receiving PD-1 inhibitors, 1 patient (11.1%) required intubation, and no death was reported. Combination IO therapy-induced MG was reported in seven cases, with at least two cases complicated by respiratory failure and one death. Our observations suggest a possible difference in the severity of the disease and outcome among different IO therapy options., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Adrenal incidentalomas (AIs) are common incidental findings in medical practice with clinical significance. Although most AIs are nonsecretory and nonmalignant, they require a short course of follow-up over one to two years to rule out malignancy or hormonal secretion according to clinical practice guidelines. However, this can result in some adrenocortical carcinomas (ACCs) being missed if they transform at a later stage or evolve slowly. Here, we report one such case of an AI, which although remained indolent, eventually transformed into an ACC many years after the initial detection., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Kohli et al.)

A 54-year-old female presented with shortness of breath and cyanosis. Work up with chest X-ray and subsequent echocardiogram revealed an intracardiac bi-atrial mass leading to emergent cardiothoracic resection. Pathology was consistent with a primary cardiac high-grade osteosarcoma. Post-resection staging positron emission tomography-computed tomography (PET-CT) showed hypermetabolic mixed lytic and sclerotic lesion of T10 concerning for metastasis. She received five cycles of adriamycin and ifosfamide chemotherapy before discontinuation due to systolic dysfunction. Nine months later, she developed a high tumor burden with progressive disease and was treated with second-line gemcitabine/docetaxel with disappointing results. She is currently on treatment with cyclophosphamide and topotecan as third-line treatment with an excellent clinico-radiographic response. Osteosarcomas are aggressive with a high incidence of recurrence and metastasis. Fewer than 50 cases of primary cardiac osteosarcomas have been reported in the literature. Even though complete resection can be achieved in some cases, long-term results are usually poor. No standard therapy has been established., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Mhadgut et al.)

Lan is a high prevalence red blood cell antigen present in the majority of the populations that belong to the Lan (Langereis) blood group system. Anti-Lan antibody is an immunoglobulin G (IgG) antibody that is known to cause delayed hemolytic transfusion reactions in adults as well as hemolytic disease in fetuses and newborns, however with variable clinical significance ranging from mild to severe. We present a 58-year-old woman with diffuse abdominal pain and a large gastric ulcer causing gastric outlet obstruction. She underwent antrectomy and Billroth I reconstruction surgery without complications. The patient's hemoglobin upon presentation was 10g/dL and dropped acutely post-operatively to 6.4 g/dL requiring blood transfusion. The patient developed acute respiratory distress within minutes of starting a packed red blood cell (pRBC) transfusion, requiring discontinuation. Laboratory testing demonstrated pan-reactivity with additional reference testing demonstrating an anti-Lan antibody. The rarity of Lan negative pRBC units is a challenge in managing such patients requiring blood transfusions. Autologous blood donation or donation by a compatible family member is another option to consider in these rare cases., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Sharma et al.)

Survivorship care for a patient with cancer is often complex and requires a multidisciplinary approach. Cancer and its treatment can have late and long-term physical and psychosocial effects. After the acute and intense period of treatment and surveillance administered by oncology teams, cancer survivors slowly transition care to primary providers. Cancer survivors then enter into an extended phase of survivorship whether they are cancer-free, in remission, or living with cancer. In this phase, symptoms related to cancer and its treatment may vary over time. Developing a care plan can facilitate the transition of care between all providers taking care of cancer patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Manthri et al.)

Competing Interests: Competing interests: None declared.

Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino- N -(piperidin-4-yl)-1 H -pyrazolo[3,4- d ]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL., (This journal is © The Royal Society of Chemistry 2020.)

Primary hyperparathyroidism (PHPT) is the most common etiology of hypercalcemia in the ambulatory setting and usually presents with an intact parathyroid hormone (PTH) level that is elevated or inappropriately near the upper limit of the laboratory reference range. However, PHPT with low-normal PTH level is reported in the peer-reviewed literature, and this atypical presentation may delay diagnosis of PHPT. We present a case of PHPT with persistently low-normal PTH level in which the PTH dependence of hypercalcemia was demonstrated by the response to treatment with the calcimimetic agent cinacalcet., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Bandaru et al.)

Eribulin is a non-taxane microtubule inhibitor approved for the treatment of metastatic breast carcinoma after two prior chemotherapeutic regimens. We report a patient with extended progression-free survival (PFS) of more than 57 months with metastatic breast carcinoma treated with eribulin in the third-line setting. A 48-year-old lady was diagnosed with stage IIA (pT2N0M0), high grade, triple-negative, invasive ductal carcinoma (IDC) of the left breast on core needle biopsy. She underwent neoadjuvant chemotherapy with adriamycin, and cyclophosphamide followed by a negative sentinel lymph node (SLN) biopsy. Subsequent mastectomy and axillary lymph node dissection revealed a 2.5 cm, high grade, triple-negative IDC with three additional lymph nodes negative for metastatic carcinoma, consistent with the initial diagnosis. Eight months into the surveillance program, the patient developed a 2.8 cm right lower lobe (RLL) lung mass with standard uptake value (SUV) of 27 on positron emission tomography-computed tomography (PET/CT). Core needle biopsy of the lung lesion revealed sheets of poorly differentiated carcinoma, immunophenotypically compatible with the initial diagnosis of breast pathology. She then commenced single-agent paclitaxel in the 1st line metastatic setting with a significant decrease in RLL lung mass to less than 1 cm with an SUV of 1.7 noted. The patient developed progression after seven months and started 2nd line gemcitabine noting initial improvement and subsequent stable disease for a period of 12 months. Eventual progression of RLL lung nodule measuring 2.1 cm with SUV of 10 noted. Initiated 3rd line eribulin with a notable response on imaging studies within three months and with no evidence of disease (NED) on scans over the subsequent 57 months. Eribulin related mild neuropathy superimposed on previous paclitaxel associated grade 2 neuropathy required a 20% eribulin dose reduction. The patient is currently clinically and radiographically stable with plateaued serum tumor markers. Our patient has shown excellent response and tolerance to eribulin with PFS of over 57 months (nineteen times the norm) which is rare., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Manthri et al.)

Competing Interests: Competing interests: None declared.

Non-producing variant of plasma cell disorders with circulating plasma cells is an aggressive variant of plasma cell dyscrasias with relatively poor outcomes. A 75-year-old man was admitted due to anaemia (90 g/L) and thrombocytopenia (9×10 9 /L). Comprehensive metabolic panel showed creatinine of 1.34 mg/dL, total protein of 6 g/dL, and corrected calcium was normal. Peripheral smear review showed 8% circulating atypical plasmacytoid cells. Bone marrow biopsy (BMB) confirmed plasma cell myeloma involving 90%-95% of bone marrow cellularity. Serum protein electrophoresis showed no monoclonal protein. Due to aggressive biology of non-producer variant and outcomes based on circulating plasma cells, he was started on VD-PACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide) chemotherapy. BMB after cycle 1 chemotherapy showed no morphologic, immunophenotypic, or flow cytometric features of a plasma cell neoplasm. Given excellent treatment response cycle 2 was changed to VRD (bortezomib, lenalidomide and dexamethasone). Following two cycles of VRD, he underwent autologous haematopoietic cell transplantation. Day 80 BMB suggested stringent complete response., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Breast cancer is the most common cancer in a woman with a five-year survival of patients with metastatic disease is estimated at 23%. Ado-trastuzumab emtansine (T-DM1) is a HER2-antibody drug conjugate currently approved for the treatment of HER2-positive pre-treated metastatic breast cancer (BC). We report a case of recurrent metastatic breast cancer with unusually lengthy progression-free survival (PFS) on T-DM1 chemotherapy. She was diagnosed with Triple Positive Stage IIIC multifocal invasive ductal carcinoma of the left breast. After completing neoadjuvant chemotherapy, she underwent a bilateral mastectomy. Final pathology showed partial response. Postoperatively, she received adjuvant chemotherapy and radiation therapy. She was started on Q21 days trastuzumab following completion of adjuvant chemotherapy. Systemic imaging showed liver lesions and biopsy confirmed recurrence. She was started on T-DM1, endocrine therapy with anastrozole was continued. She is currently status post 45 cycles. T-DM1 was approved for the treatment (single-agent) of HER2-positive, metastatic BC based on phase III data from the EMILIA and TH3RESA study. Median PFS in the T-DM1 arm was 9.6 months. Herein, we present a case of a woman with recurrent triple positive metastatic BC with a lengthy progression-free survival on T-DM1 chemotherapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Manthri et al.)

A 67-year-old male patient presents to the hospital complaining of severe nausea and vomiting failing oral antiemetics. He carries the history of initial diagnosis of stage III prostate cancer. He underwent radical prostatectomy followed by external beam radiation. After 5 years of initial excellent control with androgen deprivation therapy (ADT), imaging study showed retroperitoneal adenopathy denoting ADT failure. His prostate-specific antigen continued to rise while on enzalutamide and then abiraterone reflecting disease progression. He maintained excellent functional capacity through 23 cycles of docetaxel however he started developing hip pain after the last cycle with imaging studies suggesting new hip metastatic disease. Following the first cycle of radium-223, the patient presented with intractable nausea and vomiting. MRI showed a high suspicion of leptomeningeal spread which was confirmed through a meningeal biopsy after lumbar puncture showed negative results. The patient had excellent symptomatic response to high-dose dexamethasone. After receiving whole-brain radiation, the patient opted to be on best supportive care and succumbed to his illness 3 months later., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum , is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the β5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the β4 and β5 proteasome subunits. This induced pocket exploits β4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials., Competing Interests: Conflict of interest statement: The following authors have shares in GlaxoSmithKline: C.-w.C., I.P., R.P.B., J.C., D.C., P.D.C., P.G., J. Howe, J.K., M.S.M., L.M-C., S.R., P.R., J.M.F., J.M., D.W.G., T.J.M., K.D.R., M.M., and P.G.W., (Copyright © 2019 the Author(s). Published by PNAS.)

Competing Interests: Competing interests: None declared.

Families and patients receive emotional support and better care planning after palliative care consultations., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.

Influenza A associated with rhabdomyolysis has become more commonly recognized in recent years. It requires prompt recognition and treatment in order to prevent heme pigment-induced acute kidney injury. Here we report a 50-year-old female without a significant past medical history who presented with a one-week history of fevers, chills, fatigue, and generalized body aches. She was on no prior medication. Laboratory studies were significant for leukocytosis and elevated creatinine kinase up to a peak of 28,216 IU/L. Rapid influenza antigen testing was positive for influenza A virus. The patient was diagnosed with influenza A-induced rhabdomyolysis. According to our literature review, we are the first to report a case of influenza A-induced rhabdomyolysis in the 2017-2018 flu season. This case highlights the importance of considering rhabdomyolysis as a manifestation of an influenza infection., Competing Interests: The authors have declared that no competing interests exist.

Acute pericarditis as a presenting sign of adrenal insufficiency is rarely reported. We present a rare case that highlights pericarditis as a clinical presentation of secondary adrenal insufficiency later complicated by cardiac tamponade. A 44-year-old lady who presented to the hospital with a one-day history of pleuritic chest pain and shortness of breath. In the emergency room, she had a blood pressure of 70/35 mmHg. Laboratory evaluation revealed white blood cell count of 16.08 k/cumm with neutrophilia, normal renal function and elevated troponin (0.321 ng/mL, normal 0.000-0.028). An electrocardiogram (EKG) showed sinus tachycardia, low voltage, PR suppression and ST changes consistent with acute pericarditis. Echocardiogram showed small pericardial effusion without tamponade physiology. Infectious workup was negative; she was thought to have acute adrenal insufficiency likely secondary to viral pericarditis. We treated the patient with high dose nonsteroidal anti-inflammatory drugs (NSAIDS) and hydrocortisone. Three weeks later, she presented to emergency room with complaints of persistent nausea, vomiting, chills, weakness. Her blood pressure was 49/23 mmHg. Random serum cortisol level was <1.2 mcg/dl (normal A.M. specimens 3.7-19.4 mcg/dl). Echocardiogram showed loculated pericardial fluid adjacent to the right ventricle with echocardiographic evidence of tamponade. Emergent pericardiocentesis yielded 250 ml of straw color fluid. Blood pressure improved after the procedure. The patient was initially started on IV stress dose steroids, but following clinical stabilization, hydrocortisone was switched to a physiological dose of 15 mg in am and 10 mg in pm. Although the mechanism of pericarditis in adrenal failure is unknown, this clinical presentation may help early diagnosis of adrenal failure and pericarditis. Early recognition and prompt treatment of this rare presentation are critical to prevent morbidity and mortality., Competing Interests: The authors have declared that no competing interests exist.

Empyema necessitans (EN) is a rare phenomenon that refers to an insidious extension of the empyema through parietal pleura and subsequent dissection into subcutaneous tissue of the chest wall. A 29-year-old man presented to the hospital with fever and chills a few days after an inadvertent needle stick while injecting heroin. His left forearm was warm with an area of fluctuance. He underwent incision and drainage of the left forearm abscess with fluid submitted for Gram stain and culture. His condition rapidly deteriorated due to sepsis, and he required transfer to the intensive care unit. A new 4 × 3 cm area over the left pectoralis muscle had become increasingly indurated, fluctuant, and erythematous. CT of the chest demonstrated extensive cavitary lung lesions and a large loculated left-sided pleural effusion with extension through the chest wall. TEE revealed a 3 cm complex lesion on the superior septal leaflet of the tricuspid valve. The patient underwent incision and drainage of the pectoralis major EN with placement of a drain. Blood and sputum cultures grew methicillin-susceptible Staphylococcus aureus (MSSA) at which time antibiotic therapy was tailored to oxacillin. Our case highlights a rare occurrence of EN due to MSSA in a patient with intravenous drug use (IDU) and underscores the importance of prompt diagnosis and treatment.

Elliptocytosis is commonly seen as a hereditary condition. We present a case of myelodysplastic syndrome (MDS) del(q20) variant with concomitant acquired elliptocytosis. A 73-year-old male with a history of prostate cancer presented to the hospital for evaluation of bleeding gums. Initial evaluation showed Hgb of 9.3 gm/dl, hematocrit of 28%, platelet count of 36,000 K/cmm, and WBC of 1.8 K/cmm with an ANC of 0.8 K/cmm. A slightly elevated bilirubin of 1.2 mg/dl spurred a hemolytic workup. Peripheral smear showed frequent elliptocytes, teardrop cells, schistocytes, and occasional spherocytes. Bone marrow biopsy did not show significant fibrosis to explain the elliptocytosis. Cytogenetics showed 20q deletion, and later, he was started on therapy for intermediate risk MDS. Bone marrow biopsy after completion of 6 cycles showed complete cytogenetic remission with significant improvement in elliptocytosis. Elliptocytosis in the setting of MDS has rarely been reported, and association with 20q deletion is even rarer. Animal studies have shown that haploinsufficiency of L3MBTL1 contributes to some (20q-) myeloproliferative neoplasms and myelodysplastic syndromes by affecting erythroid differentiation. Our case report raises interesting questions: Does MDS with rarely reported elliptocytosis indicate a disease process that is different from the usual 20q deletion? Is haploinsufficiency of L3MBTL1 responsible for this manifestation?

Cetuximab-induced nephrotoxicity is very rare, occurring in less than 1% of colorectal cancer patients and not defined in other populations. We report a rare case of crescentic diffuse proliferative glomerulonephritis (GN) that developed in close temporal association with cetuximab treatment. A 65-year-old female recently completed chemotherapy with cetuximab treatment for moderately differentiated oral squamous cell carcinoma. She was admitted with acute renal failure and nephrotic-range proteinuria. Laboratory data showed serum creatinine of 6.6 mg/dl and urinalysis showed proteinuria, moderate hemoglobinuria, hyaline casts (41/LPF), WBC (28/HPF), and RBC (81/HPF). Serologic studies were negative for ANA, anti-GBM, ANCA, hepatitis B, and hepatitis C. Serum C3 and C4 level were normal. Renal biopsy showed crescentic diffuse proliferative GN with focal features of thrombotic microangiopathy. Patient was started on cyclophosphamide and steroids. Her renal function did not improve on day 8 and she was started on hemodialysis. Previous reports suggest that EGFR-targeting medications can possibly trigger or exacerbate an IgA-mediated glomerular process leading to renal failure. This case suggests that cetuximab therapy may have triggered or exacerbated a severe glomerular injury with an unfavorable outcome. Treating physicians should maintain a high degree of caution and monitor renal function in patients on EGFR inhibitors.

Multiple brain abscesses in an immunocompetent patient is a challenging clinical problem in the medical world despite advances in imaging techniques, laboratory diagnostics, surgical interventions, and antimicrobial treatment. It is a clinical entity that typically tends to occur in the presence of known predisposing factors. Clinicians seek to determine the potential risk factors responsible for the development of brain abscess because it is very crucial for management of this life-threatening condition. At times, like in our case, there are clinical situations where it is difficult to reveal any traditional risk factors. We report a case of multiple brain abscesses in a 51-year-old female with a past medical history significant only for factor V Leiden mutation, and deep vein thrombosis on chronic anticoagulation. She underwent thorough evaluation but no predisposing factors were found. Based on our extensive literature review, this is the index case of multiple brain abscesses in a patient with history of factor V Leiden mutation and the absence of any conventional risk factors. We also postulate a possible mechanism of infection in such patients., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Violence against sex workers can heighten their vulnerability to HIV and other sexually transmitted infections (STIs). Evidence suggests the risk of acquiring STI/HIV infections among female sex workers (FSWs) who have experienced violence to be almost three-times higher than FSWs, who have not experienced violence. Moreover, an experience of physical and sexual violence makes it difficult for them to negotiate safer sex with their partners and often act as a barrier to utilization of prevention services., Methods: This study utilizes data from 2785 FSWs aged 18 years and above who participated in a cross-sectional behavioural study conducted during 2013-14 in Thane district, Maharashtra. A probability-based two-stage cluster sampling method was used for data collection. This study assesses the effect of physical violence on self-reported STI symptoms (any STI and multiple STIs) and treatment seeking for the last STI symptom using propensity score matching method., Results: About 18% of sampled FSWs reported physical violence at the time of the survey. The likelihood of experiencing such violence was significantly higher among FSWs who solicited clients at public places, engaged in other economic activities apart from sex work, had savings, and reported high client volume per week. FSWs experiencing violence were also inconsistent condom users while engaging in sex with regular partners and clients. The average adjusted effect of violence clearly depicted an increase in the risk of any STI (11%, p<0.05) and multiple STIs (8%, p<0.10) and reduction in treatment seeking (10%, p<0.05)., Conclusions: This study demonstrates a significant effect of physical violence on reporting of any STI symptom and treatment seeking. Findings call for the immediate inclusion of strategies aimed to address violence related challenges in HIV prevention program currently being provided at Thane district. Such strategies would further help in enhancing the access to tailored STI prevention and care services among FSWs in the district.

Visceral leishmaniasis is an important parasitic disease of the developing world with a limited arsenal of drugs available for treatment. The existing drugs have significant deficiencies so there is an urgent need for new and improved drugs. In the human host, Leishmania are obligate intracellular parasites which poses particular challenges in terms of drug discovery. To achieve sufficient throughput and robustness, free-living parasites are often used in primary screening assays as a surrogate for the more complex intracellular assays. We and others have found that such axenic assays have a high false positive rate relative to the intracellular assays, and that this limits their usefulness as a primary platform for screening of large compound collections. While many different reasons could lie behind the poor translation from axenic parasite to intracellular parasite, we show here that a key factor is the identification of growth slowing and cytostatic compounds by axenic assays in addition to the more desirable cytocidal compounds. We present a screening cascade based on a novel cytocidal-only axenic amastigote assay, developed by increasing starting density of cells and lowering the limit of detection, and show that it has a much improved translation to the intracellular assay. We propose that this assay is an improved primary platform in a new Leishmania screening cascade designed for the screening of large compound collections. This cascade was employed to screen a diversity-oriented-synthesis library, and yielded two novel antileishmanial chemotypes. The approach we have taken may have broad relevance to anti-infective and anti-parasitic drug discovery.

Background: An effective emergency referral transport system is the link between the home of the pregnant woman and a health facility providing basic or comprehensive emergency obstetric care. This study attempts to explore the role of emergency transport associated with maternal deaths in Unnao district, Uttar Pradesh (UP)., Methods: A descriptive study was carried out to assess the causes of and factors leading to maternal deaths in Unnao district, UP, through community based Maternal Death Review (MDR) using verbal autopsy, in a sample of 57 maternal deaths conducted between June 1, 2009, and May 31, 2010. A facility review was also conducted in 15 of the 16 block level and district health facilities to collect information on preparedness of the facilities for treating obstetric complications including referral transportation. A descriptive analysis was carried out using ratios and percentages to analyze the availability of basic facilities which may lead to maternal deaths., Results: It was found that there were only 10 ambulances available at 15 facilities against 19 required as per Indian Public Health Standards (IPHS). About 47% of the deaths took place in a facility, 30% enroute to a health facility and 23% at home. Twenty five percent of women were taken to one facility, 32% were taken to two facilities, and 25% were taken to three facilities while 19% were not taken to any facility before their death. Sixteen percent of the pregnant women could not arrange transportation to reach any facility. The mean time to make arrangements for travel from home to facility-1 and facility-2 to facility-3 was 3.1 hours; whereas from facility-1 to facility-2 was 9.9 hours. The mean travel time from home to facility-1 was 1 hour, from facility-1 to facility-2 was 1.4 hours and facility-2 to facility-3 was 1.6 hours., Conclusion: The public health facility review and MDR, clearly indicates that the inter-facility transfers appropriateness and timeliness of referral are major contributing factor for maternal deaths in Unnao district, UP. The UP Government, besides strengthening Emergency Obstetric and Newborn Care (EmONC) and Basic Emergency Obstetric and Newborn Care (BEmONC) services in the district and state as a whole, also needs to focus on developing a functional and effective referral system on a priority basis to reduce the maternal deaths in Unnao district.

Background: Uttar Pradesh (UP) is the most populous state in India with the second highest reported maternal mortality ratio in the country. In an effort to analyze the reasons for maternal deaths and implement appropriate interventions, the Government of India introduced Maternal Death Review guidelines in 2010., Methods: We assessed causes of and factors leading to maternal deaths in Unnao District, UP, through 2 methods. First, we conducted a facility gap assessment in 15 of the 16 block-level and district health facilities to collect information on the performance of the facilities in terms of treating obstetric complications. Second, teams of trained physicians conducted community-based maternal death reviews (verbal autopsies) in a sample of maternal deaths occurring between June 1, 2009, and May 31, 2010., Results: Of the 248 maternal deaths that would be expected in this district in a year, we identified 153 (62%) through community workers and conducted verbal autopsies with families of 57 of them. Verbal autopsies indicated that 23% and 30% of these maternal deaths occurred at home and on the way to a health facility, respectively. Most of the women who died had been taken to at least 2 health facilities. The facility assessment revealed that only the district hospital met the recommended criteria for either basic or comprehensive emergency obstetric and neonatal care., Conclusions: Life-saving treatment of obstetric complications was not offered at the appropriate level of government facilities in a representative district in UP, and an inadequate referral system provided fatal delays. Expensive transportation costs to get pregnant women to a functioning medical facility also contributed to maternal death. The maternal death review, coupled with the facility gap assessment, is a useful tool to address the adequacy of emergency obstetric and neonatal care services to prevent further maternal deaths.

The most studied members of the calpain protease superfamily are CAPN1 and 2, which are conserved across vertebrates. Another similar family member called mu/m-CAPN has been identified in birds alone. Here, we establish that mu/m-CAPN shares one-to-one orthology with CAPN11, previously described only in eutherians (placental mammals). We use the name CAPN11 for this family member and identify orthologues across vertebrate lineages, which form a monophyletic phylogenetic clade directly ancestral to CAPN1 and 2. In lineages branching before therians (live-bearing mammals), the CAPN11 coding region has evolved under strong purifying selection, with low nonsynonymous (d(N)) versus synonymous (d(S)) substitution rates (d(N)/d(S) = 0.076 across pretherians), and its transcripts were detected widely across different tissues. These characteristics are present in CAPN1 and 2 across vertebrate lineages and indicate that pretherian CAPN11 likewise has conserved a wide physiological function. However, an approximately 7-fold elevation in d(N)/d(S) is evident along the CAPN11 branch splitting eutherians from platypus, paralleled by a shift to "testis-specific" gene regulation. Estimates of d(N)/d(S) in eutherians were approximately 3-fold elevated compared with pretherians and coding and transcriptional-level evidence suggests that CAPN11 is functionally absent in marsupials. Many CAPN11 sites are functionally constrained in eutherians to conserve a residue with radically different biochemical properties to a fixed state shared between pretherian CAPN11 and CAPN1 and 2. Protein homology modeling demonstrated that many such eutherian-specific residue replacements modify or ablate interactions with the calpain inhibitor calpastatin that are observed in both pretherian orthologues and CAPN1/2. We propose a model akin to the Dykhuizen-Hartl effect, where inefficient purifying selection and increased genetic drift associated with a reduction in effective population size, drove the fixation of mutations in regulatory and coding regions of CAPN11 of a common marsupial-eutherian ancestor. A subset of these changes had a cumulative adaptive advantage in a eutherian ancestor because of lineage-specific aspects of sperm physiology, whereas in marsupials, no advantage was realized and the gene was disabled. This work supports that functional divergence among gene family member orthologues is possible in the absence of widespread positive selection.

The typical calpain proteases are a subset of a wider superfamily and regulate a broad spectrum of physiological processes. Here we characterised Atlantic halibut complete-coding orthologues of calpain-1, calpain-2-like, "muscle-specific" calpain-3, plus calpain-11, a recently recognised vertebrate-wide family member. Phylogenetic analysis established the relationship of each sequence within a comprehensive framework of vertebrate calpains, including teleost paralogues. This approach provided significant insight into the evolution of teleost calpains. For example, teleost sequences considered calpain-2 orthologues formed a monophyletic clade external to sister clades for tetrapod calpain-2 and vertebrate calpain-8. Thus, teleost "calpain-2" is likely not directly orthologous to tetrapod calpain-2 and represents a calpain-2-like protein. The characteristic domain structure of typical calpains was observed in each halibut sequence, although calpain-3, as for other teleosts, retained only one (IS2) of three further domains found in human calpain-3 (NS, IS1 and IS2). Transcripts for capn1, capn2-like and capn11 were widely detected across eleven halibut tissues, whereas capn3 was detected in striated muscles, spleen and ovary, but absent or relatively less abundant in other tissues. We assessed the transcript expression of each calpain gene in fast-twitch skeletal muscle where nutritional state was altered with 60days feed restriction, followed by 60days satiation refeeding. Measured by quantitative real-time PCR, capn1 transcript levels were highest during maximal fasting and then steadily decreased with refeeding, where muscle was in net positive protein balance. Conversely capn2-like showed little response, whereas capn3 and capn11 transcript levels were lowest at maximal fasting before being strongly constitutively upregulated with subsequent refeeding. Halibut capn3 transcript abundance was on average 6.5, 23.7 and 5.9 fold greater than capn1, capn2-like and capn11 respectively in skeletal muscle across nutritional states. In turn, transcript levels of capn1 and capn11 were invariably higher than capn2-like, but were dependent on nutritional state compared to each other. The differential regulation of these genes in response to nutritional status suggests distinct roles for typical calpain family members in regulating the balance between catabolism and growth in teleost skeletal muscle., (2010 Elsevier B.V. All rights reserved.)

We recently suggested a novel site-specific N-glycosylation mechanism in Trypanosoma brucei whereby some protein N-glycosylation sites selectively receive Man9GlcNAc2 from Man9GlcNAc2-PP-Dol while others receive Man5GlcNA(2 from Man5GlcNAc2-PP-Dol. In this paper, we test this model by creating procyclic and bloodstream form null mutants of TbALG3, the gene that encodes the alpha-mannosyltransferase that converts Man5GlcNAc2-PP-Dol to Man6GlcNAc2-PP-Dol. The procyclic and bloodstream form TbALG3 null mutants grow with normal kinetics, remain infectious to mice and tsetse flies, respectively, and have normal morphology. However, both forms display aberrant N-glycosylation of their major surface glycoproteins, procylcin, and variant surface glycoprotein, respectively. Specifically, procyclin and variant surface glycoprotein N-glycosylation sites that are modified with Man9GlcNAc2 and processed no further than Man5GlcNAc2 in the wild type are glycosylated less efficiently but processed to complex structures in the mutant. These data confirm our model and refine it by demonstrating that the biantennary glycan transferred from Man5GlcNAc2-PP-Dol is the only route to complex N-glycans in T. brucei and that Man9GlcNAc2-PP-Dol is strictly a precursor for oligomannose structures. The origins of site-specific Man5GlcNAc2 or Man9GlcNAc2 transfer are discussed and an updated model of N-glycosylation in T. brucei is presented.

Atlantic salmon (Salmo salar L.) were fed to satiety and reared from approximately 60 g to 5000 g at ambient seawater temperatures. The effect of photoperiod manipulation on muscle growth was investigated from the start of the first sea winter. Continuous light treatment in winter/spring (1 November to 18 June) improved growth performance in fish, resulting in a 30% increase in mean body mass relative to the ambient photoperiod fish by 12 August, but had no effect on sexual maturation. Significant increases in body mass in the continuous light groups were observed after 126 days (P<0.01). The number of fast muscle fibres per trunk cross-section was determined in a subset of the fish and was 28.5% higher in the continuous light (799 x 10(3)) than the natural day length (644 x 10(3)) groups after only 40 days, corresponding to the period of decreasing natural day length. Subsequent rates of fibre recruitment were similar between treatments. At the end of the fibre recruitment phase of growth (combined June and August samples), the maximum number of fast muscle fibres was 23% higher in fish from the cages receiving continuous light (881 x 10(3)+/-32 x 10(3); N=19) than in the ambient photoperiod cages (717 x 10(3)+/-15 x 10(3); N=20) (P<0.001). Continuous light treatment was associated with a shift in the distribution of fibre diameters, reflecting the altered patterns of fibre recruitment. However, the mean rate of fibre hypertrophy showed no consistent difference between treatments. There was a linear relationship between the myonuclear content of isolated single fibres and fibre diameter. On average, there were 27% more myonuclei in 150 microm-diameter fibres in the continuous light (3118 myonuclei cm(-1)) than the ambient photoperiod (2448 myonuclei cm(-1)) fish. After 40 days, continuous light treatment resulted in a transient increase in the density of myogenic progenitor cells, identified using a c-met antibody, to a level 70% above that of fish exposed to natural light. It is suggested that short days inhibited the proliferation of myogenic progenitor cells and that this was overcome by transferring fish to continuous light, causing an increase in the number of times the myogenic precursor cells divided and/or a decrease in cell cycle time. The net increase in myogenic progenitor cells resulted in proportional increases in the number and myonuclear content of fibres. The subsequent hypertrophy of these additional fibres can explain the delayed increase in body mass observed with continuous light treatment.

The influence of freshwater environment on muscle growth in seawater was investigated in an inbred population of farmed Atlantic salmon (Salmo salar L.). The offspring from a minimum of 64 families per group were incubated at either ambient temperature (ambient treatment) or in heated water (heated treatment). Growth was investigated using a mixed-effect statistical model with repeated measures, which included terms for treatment effect and random fish effects for individual growth rate (alpha) and the instantaneous growth rate per unit change in temperature (gamma). Prior to seawater transfer, fish were heavier in the heated (61.6+/-1.0 g; N=298) than in the ambient (34.1+/-0.4 g; N=206) treatments, reflecting their greater growth opportunity: 4872 degree-days and 4281 degree-days, respectively. However, the subsequent growth rate of the heated group was lower, such that treatments had a similar body mass (3.7-3.9 kg) after approximately 450 days in seawater. The total cross-sectional area of fast muscle and the number (FN) and size distribution of the fibres was determined in a subset of the fish. We tested the hypothesis that freshwater temperature regime affected the rate of recruitment and hypertrophy of muscle fibres. There were differences in FN between treatments and a significant age x treatment interaction but no significant cage effect (ANOVA). Cessation of fibre recruitment was identified by the absence of fibres of <10 micro m diameter. The maximum fibre number was 22.4% more in the ambient (9.3 x 10(5)+/-2.0 x 10(4) than in the heated (7.6 x 10(5)+/-1.5 x 10(4)) treatments (N=44 and 40 fish, respectively; P<0.001). For fish that had completed fibre recruitment, there was a significant correlation between FN and individual growth rate, explaining 35% of the total variation. The density of myogenic progenitor cells was quantified using an antibody to c-met and was approximately 2-fold higher in the ambient than in the heated group, equivalent to 2-3% of the total muscle nuclei. The number of myonuclei in isolated fibre segments showed a linear relationship with fibre diameter. On average, there were 20.6% more myonuclei in 200-microm-diameter fibres isolated from the ambient (3734 myonuclei cm(-1)) than from the heated (3097 myonuclei cm(-1)) treatments. The maximum fibre diameter was greater in heated than in ambient groups, whereas the age x treatment interaction was not significantly different (ANCOVA). There were also no consistent differences in the rate of hypertrophy of muscle fibres between treatments. It was concluded that freshwater temperature regime affected fibre number and the nuclear content of fast muscle in seawater but not the rate of fibre hypertrophy. The mechanisms and life history consequences of developmental plasticity in fibre number are discussed.