Photocatalytic Synthesis of ß-Keto Primary Chlorides by Selective Chlorocarbonylation of Olefins.

Functionalized primary alkyl chlorides are precursors to a plethora of scaffolds but their access from chemical feedstocks remains challenging. Herein, we report a concise dual Ni/photoredox catalytic protocol for regioselective chlorocarbonylation of unactivated alkenes that enables rapid access to ß-keto primary chlorides. The catalytic process features an extensive substrate scope, scalability and functional group tolerance. The Ni/photocatalytic Cl⋅ generation and subsequent cross-coupling is implicated for the process based on the control experiments and DFT study. The synthetic utility of the protocol has been further corroborated through functionalization of complex substrates and modifications of the product.

Photochemical Oximesulfonylation of Alkenes Using Sulfonyl-Oxime-Ethers as Bifunctional Reagents.

Utilization of oxime ethers as bifunctional reagents remains unknown. Herein, we present a mechanistically distinct strategy that enables oximesulfonylation of olefins using sulfonyl-oxime-ethers as bifunctional reagents under metal-free photochemical conditions. Via concomitant C-S and C-C bond formation, the process permits incorporation of oxime and sulfonyl groups into olefins in a complete atom-economic fashion, providing rapid access to multi-functionalized ß-sulfonyl oxime ethers with good yields and stereoselectivity. The method is amenable to functionalization of complex bioactive molecules and is shown to be scalable. A radical chain mechanism initiated via photochemical Hydrogen Atom Transfer (HAT) mediated N-O bond cleavage is suggested for the process, based on our results on mechanistic investigations.

Study of Hepatic Dysfunction Associated with Dengue Epidemiology in a Tertiary Care Hospital, Kolkata.

Dengue is a common arthropod-borne life-threatening febrile illness. This disease affects liver functions with an imbalance of liver enzymes followed by other clinical manifestations. The dengue serotypes can cause asymptomatic infection to more severe versions of hemorrhagic fever and dengue shock syndrome in West Bengal and around the globe. The main aim of this study is to establish how different liver enzymes act in identifying markers for dengue prognosis for the early detection of severe dengue fever (DF). The diagnosis of dengue patients was confirmed by enzyme-linked immunosorbent assay, and associated clinical parameters [aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, total albumin, total protein, packed cell volume, and platelet count] were analyzed. Furthermore, the viral load estimation was also carried out by RT PCR analysis. The majority of these patients had elevated AST and ALT levels; ALT levels were higher than AST levels, which were partially observed in all non-structural protein 1 antigen- and dengue immunoglobulin M antibody-reactive patients. Almost 25% of patients had very low platelet count or thrombocytopenia. Furthermore, the viral load shows a significant association with all the clinical parameters with a p-value of <0.0001. All these liver enzymes are significantly correlated with an increased level of T.BIL, ALT, and AST. This study depicts that the intensity of hepatic involvement may play a critical role in the morbidity and mortality of DF patients. As a result, all of these liver parameters can be useful early markers for determining the severity of the disease, allowing for early detection of high-risk cases.

Photocatalytic Incorporation of an Oxime Ether Functional Group at Inert C(sp3)-H Bonds via HAT.

Herein, we describe a photocatalytic method for the direct incorporation of an oxime functional group at inert C(sp3)-H bonds of ethers, amides, alcohols, amines, and alkanes via HAT with photoexcited eosin Y under mild conditions using air and a blue LED. Many useful functional groups are tolerated in this process, and the reaction is scalable. A series of mechanistic studies were carried out to support the radical pathway proposed for the process.

Eliminating accidental deviations to minimize generalization error and maximize replicability: Applications in connectomics and genomics.

Replicability, the ability to replicate scientific findings, is a prerequisite for scientific discovery and clinical utility. Troublingly, we are in the midst of a replicability crisis. A key to replicability is that multiple measurements of the same item (e.g., experimental sample or clinical participant) under fixed experimental constraints are relatively similar to one another. Thus, statistics that quantify the relative contributions of accidental deviations-such as measurement error-as compared to systematic deviations-such as individual differences-are critical. We demonstrate that existing replicability statistics, such as intra-class correlation coefficient and fingerprinting, fail to adequately differentiate between accidental and systematic deviations in very simple settings. We therefore propose a novel statistic, discriminability, which quantifies the degree to which an individual's samples are relatively similar to one another, without restricting the data to be univariate, Gaussian, or even Euclidean. Using this statistic, we introduce the possibility of optimizing experimental design via increasing discriminability and prove that optimizing discriminability improves performance bounds in subsequent inference tasks. In extensive simulated and real datasets (focusing on brain imaging and demonstrating on genomics), only optimizing data discriminability improves performance on all subsequent inference tasks for each dataset. We therefore suggest that designing experiments and analyses to optimize discriminability may be a crucial step in solving the replicability crisis, and more generally, mitigating accidental measurement error.

Heteroarylation of Ethers, Amides, and Alcohols with Light and O2.

An efficient protocol for the Cα-H heteroarylation of ethers, amides, and alcohols using air and light under mild conditions is described. The reaction is applicable to a wide spectrum of functional groups. The generation of C-radicals via photoinduced aerobic oxidation of ethers, amides, and alcohols is the key feature of the process. Control experiments suggest a radical pathway for the reaction.

Retraction: Association Between 5-HTR2C -759C/T (rs3813929) and -697G/C (rs518147) Gene Polymorphisms and Risperidone-Induced Insulin Resistance Syndrome in an Indian Population.

The above article from the Journal of Clinical Pharmacology, first published online on 22 September 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement among the authors, the journal Editor in Chief, Joseph Bertino, and Wiley Periodicals, Inc. The retraction has been agreed upon due to the article having been submitted by the lead author without agreement from all co-authors. Having been alerted to this irregularity, the journal was also advised by the Senior Author of inaccuracies in the genotyping data. Reference Das, S., Dey, J. K., Prabhu SS, N., David, S., Kumar, A., Braganza, D. and Shanthi FX, M. (2017), Association Between 5-HTR2C -759C/T (rs3813929) and -697G/C (rs518147) Gene Polymorphisms and Risperidone-Induced Insulin Resistance Syndrome in an Indian Population. The Journal of Clinical Pharmacology. doi:10.1002/jcph.1012.

Efficacy and Safety of Patiromer in Hyperkalemia: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients at the highest risk of hyperkalemia are those with chronic kidney disease (CKD) stages 3 and 4. OBJECTIVE: To evaluate the efficacy and safety of patiromer in hyperkalemia in patients with heart failure or CKD. METHODS: The Cochrane Renal Group's Specialized Register was searched through contact with the Trials' Search Coordinator. We aimed at including randomized controlled trials with patiromer in patients with developed or risks of developing hyperkalemia, comparing against an active comparator or placebo. Three studies matched our inclusion and exclusion criteria, which we included in the meta-analysis. All-cause mortality, reduction in hospitalization, episodes of hypokalemia or hyperkalemia, and cardiovascular and gastrointestinal adverse events during the treatment period were our primary outcomes. Serial change in serum potassium (K+) until end of treatment or follow-up during the trial period and all other reported adverse reactions during the treatment period were our secondary outcomes. Meta-analysis (RevMan version 5.3.5) and descriptive statistics were used. RESULTS: There was a non-significant improvement in all-cause mortality and serious cardiovascular events with patiromer than placebo. Hospitalization data were unavailable. Although serious gastrointestinal events were more common with placebo, there was a significant reduction ( P = .02) in the risk of non-serious gastrointestinal events with placebo. Patiromer lowered serum K+ more than placebo, and there were more patients developing hyperkalemia with placebo. High-dose patiromer was associated with better efficacy in some parameters but with more adverse events. CONCLUSION: Although patiromer seems promising, more trials with active comparator are essential to finalize its indication and use in hyperkalemia.

Inhibition by tadalafil of contractility of isolated nonpregnant human myometrium.

OBJECTIVE: To investigate the inhibitory effect of tadalafil on the contractility of isolated nonpregnant human myometrium. MATERIALS AND METHODS: The ability of tadalafil (25, 40, and 63 µM) to inhibit 55 mM KCl-induced contractility of isolated nonpregnant human myometrium was studied. The ability of the ATP-sensitive potassium channel blocker glibenclamide (10 µM) and the calcium-sensitive potassium channel (BKCa) blocker iberiotoxin (100 nM) to reverse the inhibitory effect of 40 µM tadalafil on 55 mM KCl-induced myometrial contractility was also studied. RESULTS: Tadalafil produced a concentration-dependent inhibition of myometrial contractility that was statistically significant at 40 and 63 µM concentrations of tadalafil. The inhibition by tadalafil of myometrial contractility was statistically significantly reversed by the concurrent administration of glibenclamide and iberiotoxin. CONCLUSIONS: These results suggest that tadalafil inhibits human myometrial contractility by opening ATP-sensitive potassium channels and BKCa channels. The opening of these channels could have been due to the action of raised intracellular levels of cGMP due to inhibition of PDE-5 by tadalafil. The results suggest that tadalafil could be investigated for use in clinical conditions requiring relaxation of the myometrium.

A case of montelukast induced hypercholesterolemia, severe hypertriglyceridemia and pancreatitis.

Montelukast sodium is a leukotriene inhibitor, and competitively antagonizes cys-LT1 receptor and used widely and effectively in treating allergic rhinitis, bronchial asthma and allied respiratory conditions. This case report outlines a rare case of montelukast induced hypercholesterolemia, severe hypertriglyceridemia and acute pancreatitis in a 22 years old male patient. The patient was taking 10 mg oral montelukast daily for allergic rhinitis. Although his symptoms improved considerably, after 2 months of therapy, he experienced unusual weight gain and got admitted with severe pain abdomen. Clinical and other relevant investigation findings revealed the presence of acute pancreatitis with associated hypercholesterolemia and severe hypertriglyceridemia. There were no evidences of any other possible hereditary, surgical, metabolic, infective, organic or other pathologic causes giving rise to these conditions. De-challenge was done and the patient was treated conservatively resulting in reversal of the diseased state. Naranjo adverse drug reaction probability scale suggested that it was 'probable' that oral administration of montelukast was responsible for the acute pancreatitis associated with hypercholesterolemia and severe hypertriglyceridemia. There is only a singular and confirmed reported case of montelukast induced hypertriglyceridemia from India. For patients taking montelukast for a long duration, routine lipid profile monitoring should be done, and if these patients present with symptoms of epigastric and periumbilical pain with vomiting, provisions for screening acute pancreatitis might be warranted.

Roxithromycin-induced toxic epidermal necrolysis.

This case report highlights a very rare adverse drug reaction of oral roxithromycin causing toxic epidermal necrolysis (TEN). A 54-year-old male patient diagnosed with upper respiratory tract infection was prescribed oral roxithromycin 150 mg twice daily for 7 days. On the 10th day, the patient was admitted to the emergency with sore throat, redness, watering of eyes, painful micturition, and severe skin lesions. The skin lesions were multiple, severely painful, burning, coalesced, and filled with fluid-producing large blisters appearing on the lip, face, and trunk and then gradually spreading to legs, arms, palms, hands, and feet extensively involving much >30% of body surface area. Clinical examination, blood investigation, and histopathological examination of the skin confirmed the diagnosis of TEN. There was no history of any concomitant medications, drug allergy, burn injury, recent graft, or transplant or any coexisting infections such as herpes simplex. Other resembling skin diseases were eliminated after proper dermatological examination. This episode of TEN was probably drug (roxithromycin) induced. The drug was immediately stopped, and the patient was treated meticulously resulting in gradual reversal of the diseased state. Naranjo adverse drug reaction probability scale suggested the likelihood that oral administration of roxithromycin was responsible for the TEN was 'probable.'

Oral pantoprazole-induced acute pancreatitis in an 11-year-old child.

This case report highlights a very rare adverse drug reaction caused by oral pantoprazole resulting in acute pancreatitis. An 11-year-old boy was diagnosed with gastroesophageal reflux disease. Apart from general advice for lifestyle and dietary changes, he was symptomatically prescribed oral pantoprazole 40 mg once daily 30 minutes before meals for 4 weeks. The symptoms of gastroesophageal reflux disease were improving gradually, but the patient developed progressive symptoms of acute pancreatitis and was admitted in the emergency department with acute abdominal pain. Relevant investigations were done, and it was diagnosed as a case of acute pancreatitis. There was no evidence of any other possible hereditary, traumatic, surgical, metabolic, infective, organic, or pathologic causes giving rise to this condition, and this acute pancreatitis was probably drug (pantoprazole) induced. Dechallenge was done, and the patient was treated conservatively resulting in reversal of the diseased state. Naranjo adverse drug reaction probability scale suggested that the likelihood that oral administration of pantoprazole was responsible for the acute pancreatitis was 'probable.'

Entomophthoromycosis in South Bengal (Eastern India): a 9 years study.

Subcutaneous mycoses caused by the family Entomophthoraceae is very rare type of disease and is being reported sporadically from various Tropical countries including India. Here we report 8 cases of rhinoentomophthoromycosis caused by Conidiobolous coronatus and 7 cases of chronic subcutaneous phycomycosis caused by Basidiobolus ranarum. Cases were detected during a span of 9 years between 1991 to 1999, from 9 districts in and around Kolkata (Eastern India). Former type of lesions were detected among 20 to 65 age group of healthy individuals, predominantly males (7:1). In the latter type, male-female ratio was 2:5, and except for one all cases belonged to below 20 years age group of healthy individuals. Several cases were detected only after examination of repeat biopsy samples. With high degree of clinical suspicion, right approach is needed for laboratory confirmation of diagnosis.