Social-structural contexts of needle and syringe sharing behaviours of HIV-positive injecting drug users in Manipur, India: a mixed methods investigation

<p>Abstract</p> <p>Background</p> <p>Few investigations have assessed risk behaviours and social-structural contexts of risk among injecting drug users (IDUs) in Northeast India, where injecting drug use is the major route of HIV transmission. Investigations of risk environments are needed to inform development of effective risk reduction interventions.</p> <p>Methods</p> <p>This mixed methods study of HIV-positive IDUs in Manipur included a structured survey (n = 75), two focus groups (n = 17), seven in-depth interviews, and two key informant interviews.</p> <p>Results</p> <p>One-third of survey participants reported having shared a needle/syringe in the past 30 days; among these, all the men and about one-third of the women did so with persons of unknown HIV serostatus. A variety of social-structural contextual factors influenced individual risk behaviours: barriers to carrying sterile needles/syringes due to fear of harassment by police and "anti-drug" organizations; lack of sterile needles/syringes in drug dealers' locales; limited access to pharmacy-sold needles/syringes; inadequate coverage by needle and syringe programmes (NSPs); non-availability of sterile needles/syringes in prisons; and withdrawal symptoms superseding concern for health. Some HIV-positive IDUs who shared needles/syringes reported adopting risk reduction strategies: being the 'last receiver' of needles/syringes and not a 'giver;' sharing only with other IDUs they knew to be HIV-positive; and, when a 'giver,' asking other IDUs to wash used needles/syringes with bleach before using.</p> <p>Conclusions</p> <p>Effective HIV prevention and care programmes for IDUs in Northeast India may hinge on several enabling contexts: supportive government policy on harm reduction programmes, including in prisons; an end to harassment by the police, army, and anti-drug groups, with education of these entities regarding harm reduction, creation of partnerships with the public health sector, and accountability to government policies that protect IDUs' human rights; adequate and sustained funding for NSPs to cover all IDU populations, including prisoners; and non-discriminatory access by IDUs to affordable needles/syringes in pharmacies.</p

An electrostatic interaction between TEA and an introduced pore aromatic drives spring-in-the-door inactivation in Shaker potassium channels

Slow inactivation of Kv1 channels involves conformational changes near the selectivity filter. We examine such changes in Shaker channels lacking fast inactivation by considering the consequences of mutating two residues, T449 just external to the selectivity filter and V438 in the pore helix near the bottom of the selectivity filter. Single mutant T449F channels with the native V438 inactivate very slowly, and the canonical foot-in-the-door effect of extracellular tetraethylammonium (TEA) is not only absent, but the time course of slow inactivation is accelerated by TEA. The V438A mutation dramatically speeds inactivation in T449F channels, and TEA slows inactivation exactly as predicted by the foot-in-the-door model. We propose that TEA has this effect on V438A/T449F channels because the V438A mutation produces allosteric consequences within the selectivity filter and may reorient the aromatic ring at position 449. We investigated the possibility that the blocker promotes the collapse of the outer vestibule (spring-in-the-door) in single mutant T449F channels by an electrostatic attraction between a cationic TEA and the quadrupole moments of the four aromatic rings. To test this idea, we used in vivo nonsense suppression to serially fluorinate the introduced aromatic ring at the 449 position, a manipulation that withdraws electrons from the aromatic face with little effect on the shape, net charge, or hydrophobicity of the aromatic ring. Progressive fluorination causes monotonically enhanced rates of inactivation. In further agreement with our working hypothesis, increasing fluorination of the aromatic gradually transforms the TEA effect from spring-in-the-door to foot-in-the-door. We further substantiate our electrostatic hypothesis by quantum mechanical calculations

Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations

Background: Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion. Objectives: To study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods: Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed. Results: Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 µmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified. Conclusion: Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations

Diabetic Muscle Infarction - A Case Report

Diabetic muscle infarction is a rare complication in patients of longstanding diabetes mellitus with multiple end organ microvascular sequelae. A case of a 69 year old lady with a 10 year history of diabetes mellitus, with sudden onset of right thigh pain is described here. This case illustrates the need for increasing awareness among clinicians for early recognition of diabetic muscle infarction.Key words: Diabetic complications; Muscle infarctio

PREDOMINANCE AND INFLUENCE OF VITAMIN D DEFICIENCY ON GLYCEMIC AND LIPID INDICES IN TYPE 2 DIABETES SUBJECTS: A CASE CONTROL STUDY

Objective To investigate the existence of vitamin D deficiency (VDD) among type 2 diabetes, non-diabetes subjects and its effect on both glycemic and lipid profiles.MethodsA case control study was conducted on 200 subjects of both gender (100 type 2 diabetes and 100 non-diabetes individuals) aged 40 to 60 years. Fasting serum 25(OH) D levels, Fasting Blood Sugar (FBS), HbA1C, lipid profile including total cholesterol, triglycerides, high density lipoprotein, low density lipoprotein TC/HDL and very low density lipoprotein were estimated. Atherogenic Index of Plasma (AIP) was calculated. Group comparisons were done by one way ANOVA followed by post hoc Tukey's test and Student's independent T test. Chi-square test was performed for categorical variables. Correlation was done by Pearson's analysis. P &lt; 0.05 was considered significant.Results The average serum 25(OH) D levels were significantly (p&lt;0.001) low in diabetes group. The prevalence of VDD and the percentage of insufficient and sufficient categories was significantly (p&lt;0.001) high and low respectively in diabetes group. In the deficient category diabetes group had severe VDD with significantly low HDL and elevated triglycerides and there was an insignificant but negative association between serum vitamin D levels, FBS, HbA1c, TC, TG, LDL, TC / HDL and AIP among diabetes subjects.ConclusionThe occurrence of severe vitamin D deficiency coupled with the independent association of the same with the glycemic and lipid profiles in type 2 diabetes may further add to the aggravation of complications Keywords: Vitamin D deficiency, Type 2 diabetes, Glycemic and lipid indice

Predicting Enzyme–Substrate Specificity with QM/MM Methods: A Case Study of the Stereospecificity of d‑Glucarate Dehydratase

The stereospecificity of d-glucarate dehydratase (GlucD) is explored by QM/MM calculations. Both the substrate binding and the chemical steps of GlucD contribute to substrate specificity. Although the identification of transition states remains computationally intensive, we suggest that QM/MM computations on ground states or intermediates can capture aspects of specificity that cannot be obtained using docking or molecular mechanics methods

Prevalence of and Barriers to Dual-Contraceptive Methods Use among Married Men and Women Living with HIV in India

Objective. To describe the prevalence and correlates of dual-contraceptive methods use (condoms and an effective pregnancy prevention method) and barriers to their use among married persons living with HIV (PLHIV) in India. Methods. We conducted a quantitative survey (93 men, 97 women), 25 in-depth interviews, seven focus groups, and five key informant interviews. Results. Prevalence of dual- contraceptive method use increased from 5% before HIV diagnosis to 23% after diagnosis (P < 0.001). Condoms were the most common contraceptive method, with prevalence increasing from 13% before diagnosis to 92% after diagnosis (P < 0.001). Barriers to using noncondom contraceptives were lack of discussion about noncondom contraceptives by health care providers, lack of acceptability of noncondom contraceptives among PLHIV, and lack of involvement of husbands in family planning counseling. Conclusion. There is a need for interventions, including training of health care providers, to increase dual-contraceptive methods use among married PLHIV

Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin

Pyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty-acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd-chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood–brain-barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal-onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI-brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up-titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long-chain triglycerides were restricted, with fat-soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post-exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well-tolerated and appeared efficacious during 2 years' follow-up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C