Effectiveness and Safety of Short Course Liposomal Amphotericin B (AmBisome) as First Line Treatment for Visceral Leishmaniasis in Bangladesh

Background

Bangladesh is one of the endemic countries for Visceral Leishmaniasis (VL). Médecins Sans Frontières (MSF) ran a VL treatment clinic in the most endemic district (Fulbaria) between 2010 and 2013 using a semi-ambulatory regimen for primary VL of 15mg/kg Liposomal Amphotericin-B (AmBisome) in three equal doses of 5mg/kg. The main objective of this study was to analyze the effectiveness and safety of this regimen after a 12 month follow-up period by retrospective analysis of routinely collected program data. A secondary objective was to explore risk factors for relapse.

Methods and Principal Findings

Our analysis included 1521 patients who were initially cured, of whom 1278 (84%) and 1179 (77.5%) were followed-up at 6 and 12 months, respectively. Cure rates at 6 and 12 months were 98.7% (1262/1278) and 96.4% (1137/1179), respectively. Most relapses (26/39) occurred between 6 and 12 months after treatment. Serious adverse events (SAE) were recorded for 7 patients (0.5%). Odds of relapse at 12 months were highest in the youngest and oldest age groups. There was some evidence that spleen size measured on discharge (one month after initiation of treatment) was associated with risk of relapse: OR=1.25 (95% CI 1.01 to 1.55) per cm below lower costal margin (P=0.04).

Conclusions

Our study demonstrates that 15mg/kg AmBisome in three doses of 5mg/kg is an effective (>95% cure rate) and safe (<1% SAE) treatment for primary VL in Bangladesh. The majority of relapses occurred between 6 and 12 months, justifying the use of a longer follow-up period when feasible. Assessment of risk of relapse based on easily measured clinical parameters such as spleen size could be incorporated in VL treatment protocols in resource-poor settings where test-of-cure is not always feasible.     

Use of Smokeless Tobacco by Indian Women Aged 18–40 Years during Pregnancy and Reproductive Years

Objectives

This paper discusses patterns of daily smokeless tobacco (SLT) use and correlates of poly SLT use among married women aged 18–40 years in a Mumbai slum community with implications for tobacco control.

Methods

Using a mixed methods approach, the study included a structured survey with 409 daily SLT users and in-depth interviews with 42 women. Participants for the survey were selected using a systematic sampling procedure (one woman in every fourth eligible household). Univariate and bivariate analysis, and multiple logistic regressions were conducted to identify demographic and social factors associated with women’s use of poly SLT products. To illustrate survey results, in-depth interviews were analyzed using Atlas ti software.

Results

Sixty-four percent of the women surveyed used only one type of SLT; of these, 30% used mishri, 32% used pan with tobacco and the rest used chewed tobacco (11%), gul (17%) or gutkha (10%). Thirty-six percent used more than one type of SLT. Poly SLT users chewed or rubbed 50% more tobacco as compared to single users (mean consumption of tobacco per day: 9.54 vs. 6.49 grams; p<0.001). Women were more likely to be poly SLT users if they were illiterate as compared to literate (adjusted odds ratio [AOR]=1.67; 95% confidence interval [CI]=1.07-2.71), if they had lived in Mumbai for 10 years or more, versus less than ten years (AOR=1.67, 95% CI=1.03-2.71); and if their husband was a poly SLT user as compared to a non SLT user (AOR=2.78, 95% CI=1.63-4.76). No differences were noted between pregnant and non-pregnant women in SLT consumption patterns.

Conclusions

Tobacco control policies and programs must focus specifically on both social context and use patterns to address SLT use among women of reproductive age with special attention to poly SLT users, an understudied and vulnerable population.     

Novel SIRT1 activator MHY2233 improves glucose tolerance and reduces hepatic lipid accumulation in db/db mice

The NAD⁺-dependent deacetylase SIRT1, which is associated with the improvement of metabolic syndromes, such as type 2 diabetes, is a well-known longevity-related gene. Several in vitro and in vivo studies have shown the known protective effects of SIRT1 activators, such as resveratrol and SRT1720, on diabetes- or obesity-induced fatty liver and insulin resistance. Here, we newly synthesized 18 benzoxazole hydrochloride derivatives based on the structure of resveratrol and SRT1720. We performed an in vitro SIRT1 activity assay to identify the strongest SIRT1 activator. The assay confirmed MHY2233 to be the strongest SIRT1 activator (1.5-fold more potent than resveratrol), and docking simulation showed that the binding affinity of MHY2233 was higher than that of resveratrol and SRT1720. To investigate its beneficial effects, db/db mice were orally administered MHY2233 for 1?month, and various metabolic parameters were assessed in the serum and liver tissues. MHY2233 markedly ameliorated insulin signaling without affecting body weight in db/db mice. In particular, the mRNA expression of lipogenic genes, such as acetyl CoA carboxylase, fatty acid synthase, and sterol regulatory element-binding protein, which increased in db/db mice, decreased following oral treatment with MHY2233.In conclusion, the novel SIRT1 activator MHY2233 reduced lipid accumulation and improved insulin resistance. This finding may contribute toward therapeutic approaches for fatty liver disease and glucose tolerance.     

An Efficient Rice Transformation System Utilizing Mature Seed-derived Explants and a Portable,Inexpensive Particle Bombardment Device

We developed a practical and efficient gene transfer system for indica rice utilizing mature-seed derived explants and a simple bombardment device which uses compressed helium for accelerating DNA-coated metal particles. Unlike instruments which have been described in the literature previously, this new bombardment device, which is an improvement of the particle inflow concept, does not require vacuum. This attribute simplifies the transformation procedure significantly and it makes rice transformation technology accessible to laboratories which may not have the resources to invest in more expensive particle bombardment instruments. We determined experimentally that we could recover transgenic rice plants utilizing three different particle bombardment instruments at comparable frequencies.     

The tyrosinase inhibitory effects of isoxazolone derivatives with a (Z)-β-phenyl-α, β-unsaturated carbonyl scaffold

Thirteen (Z)-4-(substituted benzylidene)-3-phenylisoxazol-5(4H)-ones were designed to confirm the geometric effect of the double bond of the β-phenyl-α, β-unsaturated carbonyl scaffold on tyrosinase inhibitory activity. Compounds 1a–1m, which all possessed the (Z)-β-phenyl-α, β-unsaturated carbonyl scaffold, were synthesized using a tandem reaction consisting of an isoxazolone ring formation and a Knoevenagel condensation, and three starting materials, ethyl benzoylacetate, hydroxylamine and benzaldehydes. Some of the compounds showed inhibitory activity against mushroom tyrosinase as potent as compounds containing the “(E)”-β-phenyl-α, β-unsaturated carbonyl scaffold. Compounds 1c and 1m showed greater inhibitory activity than kojic acid: IC₅₀?=?32.08?±?2.25?μM for 1c; IC₅₀?=?14.62?±?1.38?μM for 1m; and IC₅₀?=?37.86?±?2.21?μM for kojic acid. A kinetic study indicated that 1m inhibited tyrosinase in a competitive manner and that it probably binds to the enzyme’s active site. In silico docking simulation supported binding of 1m (?7.6?kcal/mol) to the active site of tyrosinase with stronger affinity than kojic acid (?5.7?kcal/mol). Similar results were obtained using cell-based assays, and in B16F10 cells, compound 1m dose-dependently inhibited tyrosinase activity and melanogenesis. These results indicate the anti-melanogenic effect of compound 1m is due to the inhibition of tyrosinase and (Z)-isomer of the β-phenyl-α, β-unsaturated carbonyl scaffold can, like its congener the (E)-isomer, act as an excellent scaffold for tyrosinase inhibition.     

Length‐weight and length‐length relationships of two gobiid fishes Eleotris fusca (Forster, 1801) and Odontamblyopus rubicundus (Hamilton, 1822) from the Payra River,southern Bangladesh

The present study provides the estimates of length‐weight relationships (LWRs) and length‐length relationships (LLRs) of two gobiid fishes Eleotris fusca and Odontamblyopus rubicundus from the Payra River, southern Bangladesh. Fish samples were collected from the set bagnet (mesh size <2 mm) fishers of the Payra River in July 2016. Allometric coefficient (b) values were 2.95 for E. fusca and 2.76 for O. rubicundus. Additionally, the LLRs were highly significant with r² ≥ .955. While the estimate of the LWR for O. rubicundus includes a substantial larger sample size and thus provides a more reliable LWR than the one published so far, the LWR for E. fusca must be considered as tentative because the sample includes only juveniles for a fish that reaches a maximum standard length more than three times as much. Additional studies are needed to further improve our LWR knowledge base for these fish species.     

Cdc14 Phosphatase Promotes TORC1-Regulated Autophagy in Yeast

Cdc14 protein phosphatase is critical for late mitosis progression in budding yeast, although its orthologs in other organisms, including mammalian cells, function as stress-responsive phosphatases. We found herein unexpected roles of Cdc14 in autophagy induction after nutrient starvation and target of rapamycin complex 1 (TORC1) kinase inactivation. TORC1 kinase phosphorylates Atg13 to repress autophagy under nutrient-rich conditions, but if TORC1 becomes inactive upon nutrient starvation or rapamycin treatment, Atg13 is rapidly dephosphorylated and autophagy is induced. Cdc14 phosphatase was required for optimal Atg13 dephosphorylation, pre-autophagosomal structure formation, and autophagy induction after TORC1 inactivation. In addition, Cdc14 was required for sufficient induction of ATG8 and ATG13 expression. Moreover, Cdc14 activation provoked autophagy even under normal conditions. This study identified a novel role of Cdc14 as the stress-responsive phosphatase for autophagy induction in budding yeast.     

Hybridization studies in the genusSilene sectt.Siphonomorpha andAuriculatae (Caryophyllaceae)

Ten species in the genusSilene sectt.Siphonomorpha andAuriculatae were crossed artificially involving 612 crosses to test inter- and infraspecific, intervarietal and intersectional crossability. In sect.Siphonomorpha all interspecific crosses (between diploids) failed due to cross- or seed-incompatibility; however, intervarietal crosses betweenS. gigantea var.gigantea andS. gigantea var.incana produced hybrids. In sect.Auriculatae hybrids were produced betweenS. vallesia andS. boryi, both tetraploids, but crosses between these and the diploid species were unsuccessful. The delimitation and status of the species in both sections was supported by the crossing results.