Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial

Background

Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India.

Methods

A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4–60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data.

Findings

The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: −1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens.

Conclusion

The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa.

Clinical Trials Registration

www.clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255567","term_id":"NCT00255567"}}NCT00255567     

Leptin Levels Are Negatively Correlated with 2-Arachidonoylglycerol in the Cerebrospinal Fluid of Patients with Osteoarthritis

Background

There is compelling evidence in humans that peripheral endocannabinoid signaling is disrupted in obesity. However, little is known about the corresponding central signaling. Here, we have investigated the relationship between gender, leptin, body mass index (BMI) and levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the serum and cerebrospinal fluid (CSF) of primarily overweight to obese patients with osteoarthritis.

Methodology/Principal Findings

Patients (20 females, 15 males, age range 44-78 years, BMI range 24-42) undergoing total knee arthroplasty for end-stage osteoarthritis were recruited for the study. Endocannabinoids were quantified by liquid chromatography – mass spectrometry. AEA and 2-AG levels in the serum and CSF did not correlate with either age or BMI. However, 2-AG levels in the CSF, but not serum, correlated negatively with CSF leptin levels (Spearman’s ρ -0.48, P=0.0076, n=30). No such correlations were observed for AEA and leptin.

Conclusions/Significance

In the patient sample investigated, there is a negative association between 2-AG and leptin levels in the CSF. This is consistent with pre-clinical studies in animals, demonstrating that leptin controls the levels of hypothalamic endocannabinoids that regulate feeding behavior.     

Characterization of plant phenotypes associated with loss-of-function of AtCNGC1, a plant cyclic nucleotide gated cation channel.

Of the 57 cation channel genes in the Arabidopsis genome, over a third encode cyclic nucleotide gated cation channels (CNGCs). CNGCs are ion channels regulated by cytosolic signaling molecules (cyclic nucleotides, calmodulin, and Ca(2+)), and which conduct Ca(2+) as well as K(+) and in some cases Na(+). Little is currently known about the role CNGCs may play in plant growth and development. Here, we examined the hypothesis that an Arabidopsis thaliana genotype containing a null mutation in one of the CGNC genes (AtCNGC1) would display cation uptake-related growth phenotype differences from wild type (WT) plants. We determined that AtCNGC1 protein is primarily expressed in the roots of Arabidopsis seedlings. Seedlings lacking this protein had slightly (6-22%) lower shoot Ca(2+) than WT plants. Primary roots of Atcngc1 mutant seedlings grew faster than roots of WT plants, and had larger angles of gravicurvature and less nitric oxide generation upon gravistimulation. We conclude that channels formed (at least in part) by AtCNGC1 contribute (along with other channels) to Ca(2+) uptake into plants, and that Ca(2+) uptake into roots through AtCNGC1 affects some aspects of growth in the primary root of Arabidopsis seedlings.     

Effect of 2, 4 -D on Seedling Physiology and Cytogenetical Studies in Triticum aestivum and Phalaris minor (Gramineae)

Effects of 2, 4 -D on seedling growth and chromosomal abnormalities were studied in Triticum aestivum and Phalaris minor. Seeds were soaked at different concentrations of 2, 4 -D (0.01%, 0.1%, 1.0%) for 4, 8, 12 and 16 hours. 2, 4 -D suppressed the germination more severely in P. minor than in T. aestivum. Shoot and root length was retarded with the increase of concentration and time of treatment in both species. Generally radical was more negatively affected than coleoptile and emergence of radical was not observed at 1.0% concentration at 8, 12, and 16 hours of treatment in T. aestivum while in P. minor there was a total lack of radical emergence at 1.0% concentration for all durations of treatment. Stiff and curled roots and undifferentiated callus like scutellar tissues were observed in T. aestivum, while in P. minor the coleoptile obtained was lean, pale green in colour and was lying flat on filter paper. Mitotic index decreased, while chromosomal abnormalities, bridges and laggards were increased with the increase of concentration and soaking time however, laggards were not observed in T. aestivum. Clumping and chain formation of chromosomes at metaphase was also noticed in P. minor.     

Reactive oxygen species damaged human serum albumin in patients with type 1 diabetes mellitus: biochemical and immunological studies

The role of hydroxyl radical (.OH) damaged human serum albumin (HSA) in type 1 diabetes has been investigated in the present study. Hydroxyl radical induced modification on HSA has been studied by UV absorption spectroscopy, ANS fluorescence and carbonyl estimation. Hydroxyl radical modified HSA was found to be highly immunogenic in rabbits as compared to native HSA. The binding characteristics of circulating autoantibodies in type 1 diabetes patients against native and modified HSA were assessed. Diabetes patients (n=31) were examined by direct binding ELISA and the results were compared with healthy age-matched controls (n=22). High degree of specific binding by 54.8% of patients sera towards .OH modified HSA, in comparison to its native analogue (p<0.05) was observed. Sera from those type 1 diabetes patients having smoking history, high aging with high degree of disease showed substantially stronger binding to .OH modified HSA over native HSA in particular. Normal human sera showed negligible binding with either antigen. Competitive inhibition ELISA reiterates the direct binding results. Gel retardation assay further substantiated the enhanced recognition of modified HSA by circulating autoantibodies in diabetes patients. The increase in total serum protein carbonyl levels in the diabetes patients was largely due to an increase in oxidized albumin. HSA of diabetes mellitus patients (DM-HSA) and normal subjects (normal-HSA) were purified on a Sephacryl S-200 HR column. Spectroscopic analysis confirmed that the DM-HSA samples contained higher levels of carbonyls than normal-HSA (p<0.001). DM-HSA was conformationally altered, with more exposure of its hydrophobic regions. Collectively, the oxidation of plasma proteins, especially HSA, might enhance oxidative stress in type 1 diabetes mellitus patients.     

Recalcitrant Grain Legume Vigna radiata, Mung Bean, Made to Regenerate on Change of Hormonal and Cultural Conditions

Induction of shoots is possible from cotyledonary node of Vigna radiata seedlings by culturing them on a low concentration of thidiazuron (TDZ 1.0 μM). Interestingly, flooding the seedlings with the same concentration of TDZ considerably enhanced this effect and also led to the induction of shoots from the epicotyl – an unexpected and significant finding. Even plain mineral medium evoked this response on flooding. But seedlings raised on TDZ and flooding with mineral medium was not so effective. Instead seedlings raised on TDZ (1.0 μM) medium as well as flooding with it had synergistic effect. In a comparative study TDZ (1.0 μM) was found to be more effective than BAP (10 μM). Marked repression of root formation and expansion of shoot–apex were noted in seedlings raised on TDZ or BAP, particularly in cultures that were flooded.     

Effect of 2,4-D on Seedling Physiology and Cytogenetical Studies in Triticum aestivum and Phalaris minor ( Gramineae )

Effects of 2, 4 -D on seedling growth and chromosomal abnormalities were studied in Triticum aestivum and Phalaris minor. Seeds were soaked at different concentrations of 2,4 -D （0.01%, 0.1%, 1.0% ） for 4, 8, 12 and 16 hours. 2,4-D suppressed the germination more severely in P. minor than in T. aestivum. Shoot and root length was retarded with the increase of concentration and time of treatment in both species. Generally radical was more negatively affected than coleoptile and emergence of radical was not observed at 1.0% concentration at 8, 12, and 16 hours of treatment in T. aestivum while in P. minor there was a total lack of radical emergence at 1.0% concentration for all durations of treatment. Stiff and curled roots and undifferentiated callus like scutellar tissues were observed in T. aestivum, while in P. minor the coleoptile obtained was lean, pale green in colour and was lying flat on filter paper. Mitotic index decreased, while chromosomal abnormalities, bridges and laggards were increased with the increase of concentration and soaking time however, laggards were not observed in T. aestivum. Clumping and chain formation of chromosomes at metaphase was also noticed in P. minor.     

Giving the silent majority a stronger voice? Initiatives to empower Muslim women as part of the UK's ‘War on Terror’

Abstract

This article provides a gendered analysis of the ‘War on Terror’ in the UK context. Specifically it looks at initiatives to empower Muslim women, which were part of New Labour's Preventing Violent Extremism (PVE) agenda, the impetus for which stemmed from the idea that, as ‘the silent majority’, women need to be given a ‘stronger voice’. Based on analysis of qualitative interviews, this article situates these initiatives within a broader policy landscape of debates on multiculturalism, community cohesion and Britishness. It explores interviewees' understandings of Muslim women's silence in relation to those suggested by policy discourse, considering the ways in which the state's attempt to ‘give voice’ worked in practice. I argue that the operation of such initiatives continued to constrain Muslim women's voices, restricting ‘voice’ to a narrow range of speakers speaking about a narrow range of issues.     

A Comprehensive Insight into Binding of Hippuric Acid to Human Serum Albumin: A Study to Uncover Its Impaired Elimination through Hemodialysis

Binding of hippuric acid (HA), a uremic toxin, with human serum albumin (HSA) has been examined by isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), molecular docking, circular dichroism (CD) and fluorescence spectroscopy to understand the reason that govern its impaired elimination through hemodialysis. ITC results shows that the HA binds with HSA at high (K_b ∼10⁴) and low affinity (K_b ∼10³) sites whereas spectroscopic results predict binding at a single site (K_b∼10³). The HA form complex with HSA that involves electrostatic, hydrogen and hydrophobic binding forces as illustrated by calculated thermodynamic parameters. Molecular docking and displacement studies collectively revealed that HA bound to both site I and site II; however, relatively strongly to the later. Esterase-like activity of HSA confirms the involvement of Arg410 and Tyr411 of Sudlow site II in binding of HA. CD results show slight conformational changes occurs in the protein upon ligation that may be responsible for the discrepancy in van’t Hoff and calorimetric enthalpy change. Furthermore, an increase in and is observed from DSC results that indicate increase in stability of HSA upon binding to HA. The combined results provide that HA binds to HSA and thus its elimination is hindered.