Discovery of safe and orally effective 4-aminoquinaldine analogues as apoptotic inducers with activity against experimental visceral leishmaniasis

Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 μM). Of these, PP-9 and PP-10 were the most effective in vitro and demonstrated strong efficacies in vivo through the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistant Leishmania donovani strains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.     

Application of perineometer in the assessment of pelvic floor muscle strength and endurance: a reliability study

Despite different studies on the reliability of pelvic floor muscle assessment, there is still no general consensus on the most valid and reliable method. The purpose of this study was to investigate the intra-rater (within-day and between-days) reliability of perineometer in the assessment of pelvic floor muscle strength and endurance. Following ethical approval, 15 healthy women aged from 22 to 50-years old, with no history of low back pain were recruited. The Peritron perineometer instrument was used to measure pelvic floor muscle strength and endurance. Two measurements were taken on the same day with an hour interval to assess within-day reliability and the third measurement was taken five days later to determine between-days reliability. Intraclass Correlation Coefficients (ICCs) and the level of agreement between measurements were used for data analysis. The high ICC values (0.95 for strength and 0.94 for endurance) and high level of agreement between measurements indicated high within-day reliability for pelvic floor muscle strength and endurance. The perineometer was also shown to be reliable for between-days measurements with high ICC (0.88 for strength and 0.83 for endurance) and high level of agreement between measurements. The results demonstrated that the perineometer appears to be a highly reliable method of measuring pelvic floor muscle strength and endurance when measurements are taken in healthy subject by the same investigator.     

Apelin-13 Protects the Brain Against Ischemic Reperfusion Injury and Cerebral Edema in a Transient Model of Focal Cerebral Ischemia

The adipocytokine apelin is a peptide that was isolated from a bovine stomach for the first time. This peptide and its receptor are abundantly expressed in the nervous and cardiovascular systems. According to previous studies, apelin-13 protects cardiomyocytes from ischemic injury as well as apoptosis. In addition, this peptide has a neuroprotective effect on hippocampal and cultured mouse cortical neurons against NMDA receptor-mediated excitotoxicity. The present study was conducted to determine whether apelin-13 provides protection in transient focal cerebral ischemia. Focal ischemia was induced by 60-min middle cerebral artery occlusion (MCAO), followed by 23-h reperfusion. Saline as a vehicle and apelin-13 at doses of 25, 50, and 100 μg were injected intracerebroventriculary (ICV) at the beginning of ischemia. Infarct volume ,brain edema, motor dysfunction, and apoptosis were assessed 24 h after MCAO. Treatment with apelin-13 at doses of 50 and 100 μg ICV markedly reduced total infarct volumes by 45 and 55 %, respectively (P?P?>?0.05). In addition, apelin-13 at doses of 50 and 100 μg reduced brain edema (P?P?P?>?0.05).     

Profile of participants and genotype distributions of 108 polymorphisms in a cross-sectional study of associations of genotypes with lifestyle and clinical factors: a project in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study

Background

Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene–environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005.

Methods

We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay.

Results

The study group comprised 2124 men and 2395 women with a mean age of 55.8 ± 8.9 years (range, 35–69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency ≥0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P < 0.001).

Conclusions

This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene–environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available.Key words: allele frequency, cross-sectional studies, gene–environment interactions, Japan Multi-institutional Collaborative Cohort Study, polymorphism     

Endothelial to Mesenchymal Transition in the Cardiogenesis and Cardiovascular Diseases

Today, cardiovascular diseases remain a leading cause of morbidity and mortality worldwide. Endothelial to mesenchymal transition (EndMT) does not only play a major role in the course of development but also contributes to several cardiovascular diseases in adulthood. EndMT is characterized by down-regulation of the endothelial proteins and highly up-regulated fibrotic specific genes and extracellular matrix-forming proteins. EndMT is also a transforming growth factor-β-driven (TGF-β) process in which endothelial cells lose their endothelial characteristics and acquire a mesenchymal phenotype with expression of α-smooth muscle actin (α-SMA), fibroblast-specific protein 1, etc. EndMT is a vital process during cardiac development, thus disrupted EndMT gives rise to the congenital heart diseases, namely septal defects and valve abnormalities. In this review, we have discussed the main signaling pathways and mechanisms participating in the process of EndMT such as TGF-β and Bone morphogenetic protein (BMP), Wnt^#, and Notch signaling pathway and also studied the role of EndMT in physiological cardiovascular development and pathological conditions including myocardial infarction, pulmonary arterial hypertension, congenital heart defects, cardiac fibrosis, and atherosclerosis. As a perspective view, having a clear understanding of involving cellular and molecular mechanisms in EndMT and conducting Randomized controlled trials (RCTs) with a large number of samples for involving pharmacological agents may guide us into novel therapeutic approaches of congenital disorders and heart diseases.     

Subclinical Inflammatory Response: Accelerated versus Standard Corneal Cross-Linking

Purpose: To compare the subclinical inflammatory response (as measured by anterior chamber flare) induced after standard (3 mW/cm², 30 min) and accelerated (18 mW/cm², 5 min) corneal cross-linking (CXL).

Methods: In this comparative, non-randomized study, patients with progressive keratoconus who underwent standard or accelerated CXL were studied. Laser flare photometery (FM-600; Kowa, Tokyo, Japan) was used to measure anterior chamber flare preoperatively and at 1 week, 1 month, 3 months, and 6 months after the procedure.

Results: Sixty eyes of 60 patients were studied; 30 eyes in each group. Mean baseline flare values were 4.15 ± 1.19 and 4.57 ± 2.17 ph/ms in standard and accelerated groups, respectively (p = 0.228).and after surgery increased in all follow-up measurements in the both groups similarly (P > 0.05).

Conclusion: Both standard and accelerated CXL results in induction of a subclinical inflammatory response that persists up to 6 month. The response was similar between the two groups.     

The Effects of Lysine Analogs During Pelvic Surgery: A Systematic Review and Meta-Analysis

Pelvic vasculature is complex and inconsistent while pelvic bones impede access to pelvic organs. These anatomical characteristics render pelvic surgery inherently difficult, and some of these procedures are frequently associated with blood loss that necessitates blood transfusion. The aim of this study was to review the literature on the use of lysine analogs to prevent bleeding and blood transfusion during pelvic surgery. The objective of this study was to assess the safety and efficacy of lysine analogs during pelvic surgery. A systematic literature search was performed using Medline, Cochrane Register of Clinical Trials, Embase, and the reference lists of relevant articles. Randomized controlled trials or observational cohort studies comparing a lysine analog to placebo or standard care were included. Outcomes collected were blood transfusion, blood loss, thromboembolic adverse events (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism), nonthromboembolic adverse events, and death. There were no language limitations. Fifty-six articles reported on 68 comparisons between a lysine analog and an inactive comparator, involving a total of 7244 patients published between 1961 and 2013. Thirty-nine studies evaluated urologic procedures, and 21 evaluated gynecologic procedures. Thirty-six studies (60%) were published before 1980. Of the 43 randomized comparisons, only 30 (44%) had a score of 3 or higher on Jadad's 5-point scale of methodological quality. Among randomized trials, lysine analogs reduced the risk of blood transfusion (pooled odds ratio [OR], 0.47; 95% confidence interval [CI], 0.35-0.64) and blood loss (pooled OR, 0.22; 95% CI, 0.18-0.27). There was a small statistically insignificant increased risk of thromboembolic events (pooled OR, 1.07; 95% CI, 0.72-1.59) and no-thrombotic serious adverse events (pooled OR, 1.11; 95% CI, 0.67-1.83). In the 17 randomized trials published since the year 2000, only 6 thrombotic events were reported, 4 of which occurred in the placebo arm. Lysine analogs did not increase risk of death (pooled OR, 0.91; 95% CI, 0.34-2.48). These results are significant as they indicate that lysine analogs significantly reduce blood loss and blood transfusion during pelvic surgery. Although there does not appear to be a large increase in the risk of thromboembolic and nonthrombotic adverse events, more data are required to definitively assess these outcomes. Based on this review, lysine analogs during pelvic surgery seem to reduce bleeding and blood transfusion requirements. Although there does not seem to be a significant risk of adverse effects, larger studies would help clarify risks, if any, associated with lysine analog use.     

Does l -carnitine supplementation affect serum levels of enzymes mainly produced by liver? A systematic review and meta-analysis of randomized controlled clinical trials

l-carnitine supplementation is proposed to reduce liver enzymes levels; however, previous findings were equivocal. The current systematic review and meta-a