Synthesis of a peptidyl 2,2-difluoro-4-phenylbutyl ketone and its evaluation as an inhibitor of interleukin-1β converting enzyme.

An efficient way of preparing the peptidyl 2,2,-difluoro-4-phenylbutyl ketone (1) is described that utilizes condensation of the 2,2-difluoro-5-phenylpentanoyl chloride (6) with the oxazolone derivative 9, followed by isomerization and decarboxylation to provide the difluoro compound 12. Treatment of the ketone 12 with NaBH₄ followed by 6% Na/Hg afforded the amino lactone 14. This amino lactone was coupled to N-(3-phenylpropionyl)valylalanine to provide the lactone 15. Hydrolysis of the lactone 15 and oxidation of the resulting alcohol afforded the target compound 1 in good yield.     

Correlation between SERT polymorphisms and Venlafaxine response in major depression patients

Major depression (MD) has a complex multifactorial aetiology with genetic and environmental factors contributing to this disorder. As with all antidepressant treatments, there is variability in drug response because of heredity, and this leads us to focus on the genetic polymorphism of the drug’s metabolising transporter genes. The serotonin transporter (5-HTT) gene is a particularly important candidate for genetic involvement in MD disorders owing to its key role in the regulation of serotonergic transmission and is therefore considered an interesting candidate in the mechanism of antidepressant drugs. Here, we studied the associations between genetic polymorphisms in two regions of the 5-HTT gene (5-HTTLPR and VNTR) to understand venlafaxine response. Venlafaxine was found to be effective in MD patients based on their HAM-D and CGI scores (p<0.05). Although the results did not yield a significant difference between the frequencies of the SS, LS, LL, 9/9, 10/10, 12/12 and 10/12 genotypes and venlafaxine response, venlafaxine dose was increased in patients with Stin2.12 and S alleles. These alleles might have a predisposition to mood disorders. Further studies with more patients are required to confirm this clinical association.     

Measurement of multiple cytokines for discrimination and risk stratification in patients with Chagas’ disease and idiopathic dilated cardiomyopathy

Chagas’ disease (CD), caused by the hemoflagellate protozoan, Trypanosoma cruzi, is endemic in most countries of Latin America. Heart failure (HF) is often a late manifestation of chronic CD, and is associated with high morbidity and mortality. Inflammatory processes mediated by cytokines play a key role in the pathogenesis and progression of CD. Keeping in view the inflammatory nature of CD, this study investigated the possible role of 21 different inflammatory cytokines as biomarkers for prediction and prognosis of CD. The plasma concentration of these cytokines was measured in a group of patients with CD (n = 94), and then compared with those measured in patients with dilated cardiomyopathy (DCM) from idiopathic causes (n = 48), and with control subjects (n = 25). Monovariately, plasma levels of cytokines such as stem cell growth factor beta (SCGF beta), hepatocyte growth factor (HGF), monokine induced by interferon gamma (CXCL9), and macrophage inhibitory factor (MIF) were significantly increased in CD patients with advanced HF compared to control group. None of the cytokines could demonstrate any prognostic potency in CD patients, and only MIF and stromal derived factor-1 alpha (CXCL12) showed significance in predicting mortality and necessity for heart transplant in DCM patients. However, multivariate analysis prognosticated a large proportion of CD and DCM patients. In CD patients, HGF and Interleukin-12p40 (IL-12p40) together separated 81.9% of 3-year survivors from the deceased, while in DCM patients, CXCL12, stem cell factor (SCF), and CXCL9 together discriminated 77.1% of survivors from the deceased. The significant increase in plasma concentrations of cytokines such as HGF and CXCL9 in CD patients, and the ability of these cytokines to prognosticate a large proportion of CD and DCM patients multivariately, encourages further studies to clarify the diagnostic and prognostic potential of cytokines in such patients.     

Phosphatidylinositol Labelling in Response to Activation of Muscarinic Receptors in Bovine Adrenal Medulla

Abstract: The secretion of catecholamines and the labelling of phospholipids with ³²P_i has been studied in slices of bovine adrenal medulla. Both nicotinic and muscarinic drugs provoked catecholamine secretion, but only muscarinic activation was accompanied by the increased labelling of phosphatidylinositol and phosphatidic acid.     

Influencing relatives to respect donor autonomy: Should we nudge families to consent to organ donation?

Refusing consent to organ donation remains unacceptably high, and improving consent rates from family or next‐of‐kin is an important step to procuring more organs for solid organ transplantation in countries where this approval is sought. We have thus far failed to translate fully our limited understanding of why families refuse permission into successful strategies targeting consent in the setting of deceased organ donation, primarily because our interventions fail to target underlying cognitive obstacles. Novel interventions to overcome these hurdles, incorporating an understanding of cognitive psychology and behavioral change therapy, may be beneficial. One potential intervention is to use the concept of nudge theory, where decision‐making is influenced by encouraging positive reinforcement and indirect suggestion. Purposefully nudging families to given consent for organ donation by understanding, and then overcoming, their inherent cognitive biases is novel but also controversial. This article explores the roles of relatives in decisions about organ donation, how nudge theory translates to organ donation and discusses the arguments for and against its application.     

Electromagnetic-Induced Transparency and Slow Light in Plasmonic Metasurfaces

Plasmonics - We report numerically electromagnetic-induced transparency (EIT) and Fano resonances in simple plasmonic metasurfaces consisting of gold nanobars arranged in pi, H, and four-shaped...     

Melatonin and vitamin E alleviate homocysteine‐induced oxidative injury and apoptosis in endothelial cells

Molecular Biology Reports - A relationship exists between hyperhomocysteinemia and cardiovascular diseases, although the underlying mechanisms are still incompletely defined. One possibility...