Implication of Differential Surface Anisotropy on Biopharmaceutical Performance of Polymorphic Forms of Ambrisentan

The aim of the present study was to compare the dissolution rate and in vivo biopharmaceutical performance of 2 polymorphic forms (form I and II) of ambrisentan and correlate with their surface molecular environment. Dominance of various functionalities on the surface of specific crystal facets of both forms was predicted by Bravais-Friedel-Donnay-Harker method. Hirshfeld surface analysis maps and 2D fingerprint plots indicate a difference in shape index, curvedness, and relative percentage contribution of various contacts in both forms. Pre- and post-intrinsic dissolution compact studied by atomic force microscopy showed a significant difference in surface roughness and defects formation in form II as compared to form I which is attributed to the presence of more hydrophilic surfaces. The hydrophilic molecular surface environment of form II is ascribed to its improved intrinsic dissolution rate than form I. Furthermore, in vivo pharmacokinetic study also showed significantly higher AUC_0-24 and C_max in form II compared to form I. Overall, this study demonstrates that form I and II of ambrisentan exhibited the differential surface anisotropy which has significant implications on their biopharmaceutical performance.     

3CL hydrolase-based multiepitope peptide vaccine against SARS-CoV-2 using immunoinformatics

The present study provides the first multiepitope vaccine construct using the 3CL hydrolase protein of SARS-CoV-2. The coronavirus 3CL hydrolase (Mpro) enzyme is essential for proteolytic maturation of the virus. This study was based on immunoinformatics and structural vaccinology strategies. The design of the multiepitope vaccine was built using helper T-cell and cytotoxic T-cell epitopes from the 3CL hydrolase protein along with an adjuvant to enhance immune response; these are joined to each other by short peptide linkers. The vaccine also carries potential B-cell linear epitope regions, B-cell discontinuous epitopes, and interferon-γ-inducing epitopes. Epitopes of the constructed multiepitope vaccine were found to be antigenic, nonallergic, nontoxic, and covering large human populations worldwide. The vaccine construct was modeled, validated, and refined by different programs to achieve a high-quality three-dimensional structure. The resulting high-quality model was applied for conformational B-cell epitope selection and docking analyses with toll-like receptor-3 for understanding the capability of the vaccine to elicit an immune response. In silico cloning and codon adaptation were also performed with the pET-19b plasmid vector. The designed multiepitope peptide vaccine may prompt the development of a vaccine to control SARS-CoV-2 infection.     

The Impact of “COVID-19” and “Webinar Pandemic” on Plastic Surgery Practice in Teaching Institutes and Resident Training—A Multicentric Perspective

Introduction  The study was carried out to quantify the changes induced by the pandemic in plastic surgery practice and training and to study the impact of the webinars on plastic surgery education from a residents’ perspective. Methods  In this multicentric study, the number and type of surgeries, cause of injuries, and their regional variation during the coronavirus disease 2019 (COVID-19) period (February–September 2020) were compared with pre–COVID-19 time. An online survey on the impact of webinars was conducted for plastic surgery trainees across the country. Results  There was a significant reduction in total number of surgeries ( p = 0.003). The procedures for hand ( p = 0.156), faciomaxillary injuries ( p = 0.25), and replantations ( p = 0.46) were comparable; there was a significant reduction in combined orthopedic-plastic-surgical procedures ( p = 0.009) during the pandemic. There was a significant reduction in road accidents ( p = 0.007) and suicidal injuries ( p = 0.002) and increase in assault ( p = 0.03) and domestic accidents ( p = 0.01) during the COVID-19 period. A usefulness score of >8 was given for the webinars by 68.7% residents. There was no significant difference in perception of utility when correlated with the academic program at their institutes ( p = 0.109); 92% opined webinars should continue in post-COVID times. Conclusion  There was a drastic reduction in number of elective and emergency procedures during the COVID-19 time, negatively affecting resident training program. Majority of residents felt that webinars could prove a useful adjunct to training in formal training program in post-COVID-19 scenario.     

How accurate is glucose analysis in the presence of multiple interfering substances in the neonate? (glucose analysis and interfering substances)

Whole blood glucose testing by reagent sticks is inaccurate at low plasma glucose concentrations and with varying hemalocrit. Both conditions are frequently seen in newborn infants. Therefore plasma glucose analysis is the preferred method for newborn glucose monitoring. We encountered unanticipated difficulties in plasma glucose measurement by the automated hexokinase method caused by the combinations of plasma free hemoglobin, bilirubin, and plasma triglycerides, which are frequently elevated in newborn plasma. We determined the adverse effects of various combinations of these interfering substances on glucose analysis by the hexokinase method and demonstrated that accurate analysis is possible by a 1:1 plasma dilution only at high plasma glucose levels but not at the more critical low plasma glucose concentration. The dilution reduced the number of repeat specimen required in newborns. But 1:1 plasma dilution overestimated the glucose levels at low plasma glucose values, and therefore this automated hexokinase method is not suitable for glucose analysis in the newborn. Glucose-oxidase remains the method of choice for plasma glucose analysis in neonates. This information is important because using this hexokinase methodology, one might miss hypoglycemia in the newborn. © 1996 Wiley-Liss, Inc.     

Marcus Gunn Jaw Winking Phenomenon with Cortical Malformation

Indian Journal of Pediatrics -     

Broad and specific caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions evaluated by radiolabeled annexin A5 imaging.

OBJECTIVES: The purpose of this study was to evaluate the role of caspase inhibitors on acute resolution of apoptosis in atherosclerotic lesions as evaluated by imaging with annexin A5. BACKGROUND: Extensive apoptosis of macrophages has been reported at the site of plaque rupture in patients dying of acute coronary syndrome. METHODS: Of 31 New Zealand White atherosclerotic rabbits, 6 received broad caspase, 3 received caspase-1, 3 received caspase-3, 3 received caspase-8, and 4 received caspase-9 inhibitors; 12 animals did not receive any caspase inhibitors (treatment control group). Six unmanipulated rabbits were used for comparison (disease control group). Technetium-99m-labeled annexin A5 was used for imaging atherosclerotic lesions; 6 of the 12 uninhibited atherosclerotic rabbits received (99m)Tc-labeled mutant annexin A5 (radiotracer control group). Gamma images were obtained, and quantitative radiotracer uptake was compared with pathologic findings. RESULTS: Atherosclerotic lesions were best visible in untreated atherosclerotic rabbits. Quantitative annexin uptake, defined as the percent of injected dose per g of abdominal aorta tissue, was significantly higher in untreated atherosclerotic animals (mean +/- SD = 0.0515 +/- 0.0099) compared with the normal rabbits (0.0065 +/- 0.0008; p < 0.0001) or atherosclerotic rabbits receiving mutant annexin (0.014 +/- 0.0024; p < 0.0001). Among all caspase inhibitor-treated rabbits, uptake was 39% lower (0.0314 +/- 0.0151) than in untreated atherosclerotic animals (p < 0.01). Uptake was also significantly lower in rabbits receiving broad caspase (0.0206 +/- 0.0058; p < 0.0001) or caspase-1, -3, or -9 (0.0272 +/- 0.0088, p < 0.01; 0.0286 +/- 0.0095, p < 0.01; 0.0300 +/- 0.0021, p < 0.01, respectively) inhibitors. Caspase-8 inhibitor did not affect apoptosis (0.0618 +/- 0.0047; p = NS). Upon histologic characterization, a substantial decrease in macrophage apoptosis was observed in caspase-inhibited animals. CONCLUSIONS: Molecular imaging, using radiolabeled annexin A5, allows the detection of acute resolution of apoptosis as a result of caspase inhibition in experimental atherosclerosis. If proven clinically, this may allow development of novel intervention strategies in acute vascular events.     

Pathology of calcific aortic stenosis

With the aging of the general population in industrialized nations, calcific aortic stenosis (CAS) is becoming an increasingly important medical problem. The etiology is for the most part, dependent on the age at presentation; the two predominant causes in the western world are calcific aortic valve disease arising in a tricuspid aortic valve and bicuspid aortic valve (BAV). CAS is a progressive disease, exhibiting a spectrum of pathologic findings, ranging from valvular sclerosis to severe nodular calcification. Aortic valve replacement is the recommended treatment for severe disease but tissue valves may also calcify over time. Various atherosclerotic risk factors have been linked to aortic stenosis and there are mechanistic similarities between atherosclerosis and CAS. The precise pathologic mechanisms underlying aortic stenosis are poorly understood.