Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can cause neurological disease in humans, but little is known about the pathogenesis of SARS-CoV-2 infection in the central nervous system (CNS). Herein, using K18-hACE2 mice, we demonstrate that SARS-CoV-2 neuroinvasion and encephalitis is associated with mortality in these mice. Intranasal infection of K18-hACE2 mice with 10⁵ plaque-forming units of SARS-CoV-2 resulted in 100% mortality by day 6 after infection. The highest virus titers in the lungs were observed on day 3 and declined on days 5 and 6 after infection. By contrast, very high levels of infectious virus were uniformly detected in the brains of all the animals on days 5 and 6. Onset of severe disease in infected mice correlated with peak viral levels in the brain. SARS-CoV-2-infected mice exhibited encephalitis hallmarks characterized by production of cytokines and chemokines, leukocyte infiltration, hemorrhage and neuronal cell death. SARS-CoV-2 was also found to productively infect cells within the nasal turbinate, eye and olfactory bulb, suggesting SARS-CoV-2 entry into the brain by this route after intranasal infection. Our data indicate that direct infection of CNS cells together with the induced inflammatory response in the brain resulted in the severe disease observed in SARS-CoV-2-infected K18-hACE2 mice.     

ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project

The International Peripheral T-Cell Lymphoma Project is a collaborative effort designed to gain better understanding of peripheral T-cell and natural killer (NK)/T-cell lymphomas (PTCLs). A total of 22 institutions in North America, Europe, and Asia submitted clinical and pathologic information on PTCLs diagnosed and treated at their respective centers. Of the 1314 eligible patients, 181 had anaplastic large-cell lymphoma (ALCL; 13.8%) on consensus review: One hundred fifty-nine had systemic ALCL (12.1%) and 22 had primary cutaneous ALCL (1.7%). Patients with anaplastic lymphoma kinase–positive (ALK⁺) ALCL had a superior outcome compared with those with ALK^– ALCL (5-year failure-free survival [FFS], 60% vs 36%; P = .015; 5-year overall survival [OS], 70% vs 49%; P = .016). However, contrary to prior reports, the 5-year FFS (36% vs 20%; P = .012) and OS (49% vs 32%; P = .032) were superior for ALK^– ALCL compared with PTCL, not otherwise specified (PTCL-NOS). Patients with primary cutaneous ALCL had a very favorable 5-year OS (90%), but with a propensity to relapse (5-year FFS, 55%). In summary, ALK^– ALCL should continue to be separated from both ALK⁺ ALCL and PTCL-NOS. Although the prognosis of ALK^– ALCL appears to be better than that for PTCL-NOS, it is still unsatisfactory and better therapies are needed. Primary cutaneous ALCL is associated with an indolent course.     

Pangolin Indexing System: implications in forensic surveillance of large seizures

International Journal of Legal Medicine - Demand for pangolin scales in East Asia has increased dramatically in the past two decades, raising concern to the pangolin survival and bringing them to...     

Novel analogs of sulfasalazine as system xc− antiporter inhibitors: Insights from the molecular modeling studies

System x_c⁻ (Sx_c⁻), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sx_c⁻. However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood–brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure–activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sx_c⁻ antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sx_c⁻ inhibitory activity following in vitro Sx_c⁻ inhibition studies, showed moderately potent cytotoxicity in patient-derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT-ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.     

Gracilaria changii(Rhodophyta) alleviates bisphenol A-induced adverse reproductive abnormalities in mice

Objective: To evaluate the potential of Gracilaria changii extract in ameliorating the potential adverse effects of bisphenol A. Methods: The antioxidant capacity of Gracilaria changii extracted using different solvents(methanol, ethanol, and aqueous) was studied. The mice were administered by oral gavage with bisphenol A(60 mg/kg body weight) for 6 weeks with or without Gracilaria changii aqueous extract. Thereafter, the mice were either euthanized for histology and immunohistochemistry studies or mated to evaluate the pregnancy rate. Results: Gracilaria changii aqueous extract showed the highest antioxidant properties compared with extract using methanol and ethanol. The aqueous extract of Gracilaria changii improved the uterus index and uterine lipid peroxidation after bisphenol A exposure, although the uterine expressions of estrogen receptors and complement C3 were not improved. Histological evaluation of the uterus during the estrus stage has revealed that the extract could mitigate bisphenol A-induced adverse effects in the uterus as there was a lower percentage of mice showing abnormalities like decreased eosin staining in the myometrium, and decrease in the number of eosinophil and endometrial glands in the endometrium. Besides, Gracilaria changii aqueous extract improved the pregnancy rate of mice administered with bisphenol A. Conclusions: Gracilaria changii extract protects against bisphenol A-induced female reproductive abnormalities in mice which may be mediated via modulation of eosinophil migration, endometrial gland formation, and protein expressions associated with prostaglandins in the myometrium.     

Risk of Vancomycin-induced Nephrotoxicity in the Population With Chronic Kidney Disease

The antibiotic vancomycin has been available since the 1950s but has been used more commonly since the early 1980s because of the widespread appearance of methicillin-resistant Staphylococcus aureus. Infectious Diseases Society of America guidelines recommend achieving vancomycin trough levels of 10 to 20 μg/mL. Usage of vancomycin in high dosages especially ≥4 g/d has led to an increase in the incidence of vancomycin-induced nephrotoxicity, particularly in patients with chronic kidney disease (CKD). This review focuses on the impact of vancomycin-induced nephrotoxicity in patients with CKD. Patients with CKD are at increased risk of developing acute kidney injury and subsequently requiring renal replacement therapy. There is substantial need for vancomycin pharmacokinetic studies to be performed in the population with CKD to develop an optimum vancomycin nomogram in these patients. At present, tight monitoring of vancomycin trough levels in the population with CKD is recommended to help prevent acute kidney injury and its associated high morbidity, mortality and health care costs.     

Gestational diabetes mellitus: fetal liver length measurements between 21and 24 weeks' gestation

PURPOSE: To evaluate sonographic measurements of the fetal liver, fetal abdominal fat layer, interventricular septum, and Wharton's jelly area between 21 and 24 weeks' gestation in women with gestational diabetes mellitus (GDM). METHODS: A total of 123 consecutive healthy pregnant women underwent sonographic examination at 21-24 weeks' gestational age. The measurements included fetal biometry, detailed anomaly scan, and fetal body composition measurements (subcutaneous fat, liver size, cardiac muscle thickness, and Wharton's jelly area). GDM was confirmed by way of a 75-g oral glucose tolerance test using World Health Organization criteria within 1 week of the examination. RESULTS: Nineteen (15.4%) women were diagnosed with GDM, while 104 (84.6%) women were without GDM. The mean fetal liver length was 36 mm (95% CI 32-37) in women with GDM and 31 mm (95% CI 30-33) in women without GDM (p < 0.01). Liver enlargement was related to maternal fasting glucose levels and not 2-hour postprandial levels. There was no significant difference in the fetal biometric and other fetal body measurements between the 2 groups. CONCLUSIONS: The findings of this study suggest that midtrimester fetal liver length appears to be longer in GDM than in normal pregnancies. However, the fetal abdominal fat layer, interventricular septum, and Wharton's jelly were not affected. Nevertheless, further, larger randomized studies are required to confirm these findings.