Inhibition of mitochondrial calcium transporters alters adp-induced platelet responses.

INTRODUCTION: ADP-stimulated elevation of cytosolic Ca2+ is an important effector mechanism for platelet activation. The rapidly elevating cytosolic Ca2+ is also transported to mitochondrial matrix via Mitochondrial Ca2+ Uniporter (MCU) and extruded via Na+/Ca2+/Li+ Exchanger (NCLX). However, the exact contribution of MCU and NCLX in ADP-mediated platelet responses remains incompletely understood. METHODS AND RESULTS: The present study aimed to elucidate the role of mitochondrial Ca2+ transport in ADP-stimulated platelet responses by inhibition of MCU and NCLX with mitoxantrone (MTX) and CGP37157 (CGP), respectively. As these inhibitory strategies are reported to cause distinct effects on matrix Ca2+ concentration, we hypothesized to observe opposite impact of MTX and CGP on ADP-induced platelet responses. Platelet aggregation profiling was performed by microplate-based spectrophotometery while p-selectin externalization and integrin αIIbß3 activation were analyzed by fluorescent immunolabeling using flow cytometery. Our results confirmed the expression of both MCU and NCLX mRNAs with relatively low abundance of NCLX in human platelets. In line with our hypothesis, MTX caused a dose-dependent inhibition of ADP-induced platelet aggregation without displaying any cytotoxicity. Likewise, ADP-induced p-selectin externalization and integrin αIIbß3 activation was also significantly attenuated in MTX-treated platelets. Concordantly, inhibition of NCLX with CGP yielded an accelerated ADP-stimulated platelet aggregation which was associated with an elevation of p-selectin surface expression and αIIbß3 activation. CONCLUSION: Together, these findings uncover a vital and hitherto poorly characterized role of mitochondrial Ca2+ transporters in ADP-induced platelet activation.

Low-grade adenosquamous carcinoma of the breast: A rare case presentation.

Low-grade adenosquamous carcinoma of the breast is a rare variant of metaplastic mammary carcinoma. It shows indolent behavior contrary to the usual aggressive nature of metaplastic carcinomas and has a good prognosis despite being triple negative. Recurrence rates tend to be high and a consequence of incomplete excision. Although this variant has an infiltrative growth pattern, owing to its bland cytologic features, it is liable to be confused with benign sclerosing adenotic breast lesions. We present here a case of a 55-year-old postmenopausal female, who presented with a painless, mobile, hard, and nontender lump in the lower outer quadrant of the left breast, with normal overlying skin and nipple-areola complex. No associated axillary lymphadenopathy was seen. On mammography, a high-density mass of architectural distortion, characterized as BIRADS category 4C, was found. Core-needle biopsy showed haphazard glands lined by a double layer of epithelium and nests of squamoid cells arranged in an infiltrative fashion within a fibromyxoid stroma. On immunohistochemistry, tumor cells showed a lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 receptor and were positive for CK 5/6 and CK7. There was counterintuitive, but characteristic positivity for myoepithelial markers calponin and CD 10 around the neoplastic nests and stromal cells expressed smooth muscle myosin. Subsequently, the patient underwent a wide local excision with free margins and sentinel lymph nodes were negative for tumor deposits. This patient remains well and free of recurrence well into follow-up.

Post-COVID Multisystem Inflammatory Syndrome-Adult (MIS-A) Presenting with Rhabdomyolysis and AKI.

Multisystem inflammatory syndrome is a rarely reported post-COVID (coronavirus disease) phenomenon in adults. Our understanding of the multisystem inflammatory syndrome- adult (MIS-A) is based on multiple case reports that have demonstrated heterogeneous clinical presentations and treatment options. Rhabdomyolysis is an unusual presentation of MIS-A. We report the case of a 61-year-old man who presented with rhabdomyolysis with acute kidney injury (AKI), acute inflammatory demyelinating polyneuropathy (AIDP), myocarditis, disseminated intravascular coagulation, and minimal respiratory symptoms. The patient was found to have post-COVID inflammatory syndrome and recovered with supportive treatment and intravenous immunoglobulin (2 g/kg over 5 days). COVID-19 (coronavirus disease 2019) antibody positivity played a significant role in making the diagnosis of MIS-A and in providing prompt treatment.

Tacrolimus-induced acute pancreatitis and diabetic ketoacidosis (DKA) in pediatric kidney transplant recipient.

BACKGROUND: Calcineurin inhibitors (CNIs) are often associated with abnormalities in glucose and lipid metabolism. Tacrolimus is the most potent CNI which is nowadays used almost universally as a part of triple-drug immunosuppression after kidney transplantation. Tacrolimus can cause islet cell damage and decrease in insulin secretion which can lead to post-transplant diabetes mellitus and rarely diabetic ketoacidosis. Although rare, acute pancreatitis has also been implicated by a few case reports to be associated with tacrolimus. However, tacrolimus-induced acute pancreatitis has not been reported in pediatric kidney transplant recipient till date. CASE DESCRIPTION: We report the first case of tacrolimus-induced acute pancreatitis in association with hypertriglyceridemia and DKA in a child early after kidney transplant. The patient was managed with supportive treatment, and tacrolimus was stopped for three days and then switched to cyclosporine-based regimen. The patient became euglycemic within 8 weeks of switching to cyclosporine and did not have any recurrence of pancreatitis. CONCLUSION: Tacrolimus-induced pancreatitis is rare in the setting of kidney transplants and prompt diagnosis and management can lead to a successful outcome.

Characteristics, maternal and neonatal outcomes of acute kidney injury in preeclampsia: A prospective, single-center study.

BACKGROUND: Preeclampsia is an important cause of pregnancy-related acute kidney injury (AKI). The objective of our study was to determine the incidence, characteristics, and maternal and neonatal outcomes of AKI in pregnant women with preeclampsia. MATERIALS AND METHODS: A prospective, observational, single-center study from January 2019 to January 2020. Patients admitted with preeclampsia were included. Patients with obstetric complications were excluded. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) 2012 criteria. RESULTS: Total number of patients with preeclampsia was 104, out of which 25% developed AKI. Among those with AKI, nulliparity (61.5%) was the most common risk factor for preeclampsia followed by prior history of preeclampsia (15.4%), pregestational hypertension (11.5%), pregestational diabetes mellitus (3.8%), and chronic kidney disease (3.8%). There was no significant difference in maternal mortality between those with AKI (15.4%) and without AKI (7.7%). Intermittent hemodialysis was needed in 15.4%. At the end of 90 days follow-up, complete recovery of renal function occurred in 53.8%, partial recovery in 23.1% and end-stage kidney disease (ESKD) in 7.7%. Perinatal death occurred in 26.9%, preterm birth in 23.1% and stillbirth in 7.7% of those with AKI and was not significantly different from those without AKI. The mean of birth weight in newborns delivered by patients with AKI (2.53 ± 0.73 kg) was significantly lower compared to those without AKI (2.82 ± 0.58 kg). CONCLUSION: AKI was associated with a lower mean birth weight of newborns. Complete recovery of renal function was seen in 53.8% of patients with AKI and preeclampsia.