Evidence for independent heritability of the glycation gap (glycosylation gap) fraction of HbA1c in nondiabetic twins

OBJECTIVE: HbA(1c) (A1C) is substantially determined by genetic factors not shared in common with glucose. Fractions of the variance in A1C, the glycation gap (GG; previously called the glycosylation gap) and the hemoglobin glycosylation index, correlate with diabetes complications. We therefore tested whether GG (measured A1C - A1C predicted from glycated serum proteins [GSPs]) was genetically determined and whether it accounted for the heritability of A1C. RESEARCH DESIGN AND METHODS: We conducted a classic twin study on A1C and GSP collected in 40 and 46 pairs of monozygotic and dizygotic healthy female twins, respectively. The predicted A1C was based on the regression line between A1C and GSP in a separate population spanning the pathophysiologic range. RESULTS: GG was more strongly correlated between monozygotic (r = 0.65) than dizygotic (r = 0.48) twins, adjusted for age and BMI. The best-fitting quantitative genetic model adjusted for age and BMI showed that 69% of population variance in GG is heritable, while the remaining 31% is due to unique environmental influences. In contrast, GSP was similarly correlated between monozygotic (r = 0.55) and dizygotic (r = 0.49) twins, hence not genetically determined. GG was strongly correlated to A1C (r = 0.48), attributable mostly to genetic factors. About one-third of the heritability of A1C is shared with GG; the remainder is specific to A1C. CONCLUSIONS: Heritability of the GG accounts for about one-third of the heritability of A1C. By implication, there are gene(s) that preferentially affect erythrocyte lifespan or glucose and/or nonenzymatic glycation or deglycation in the intracellular, rather than extracellular, compartment.     

High-dose tranexamic acid reduces blood loss in postpartum haemorrhage

Introduction

Our purpose in conducting this study was to determine whether administration of high-dose tranexamic acid (TA) at the time of diagnosis of postpartum haemorrhage (PPH) could reduce blood loss.

Methods

This was a randomised, controlled, multicentred, open-label trial. Women with PPH >800 mL following vaginal delivery were randomly assigned to receive TA (loading dose 4 g over 1 hour, then infusion of 1 g/hour over 6 hours) or not. In both groups, packed red blood cells (PRBCs) and colloids could be used according to French guidelines. The use of additional procoagulant treatments was permitted only in cases involving intractable bleeding. The primary objective was to assess the efficacy of TA in the reduction of blood loss in women with PPH, and the secondary objectives were the effect of TA on PPH duration, anaemia, transfusion and the need for invasive procedures.

Results

A total of 144 women fully completed the protocol (72 in each group). Blood loss between enrolment and 6 hours later was significantly lower in the TA group than in the control group (median, 173 mL; first to third quartiles, 59 to 377) than in controls (221 mL; first to third quartiles 105 to 564) (P = 0.041). In the TA group, bleeding duration was shorter and progression to severe PPH and PRBC transfusion was less frequent than in controls (P < 0.03). Invasive procedures were performed in four women in the TA group and in seven controls (P = NS). PPH stopped after only uterotonics and PRBC transfusion in 93% of women in the TA group versus 79% of controls (P = 0.016). Mild, transient adverse manifestations occurred more often in the TA group than in the control group (P = 0.03).

Conclusions

This study is the first to demonstrate that high-dose TA can reduce blood loss and maternal morbidity in women with PPH. Although the study was not adequately powered to address safety issues, the observed side effects were mild and transient. A larger international study is needed to investigate whether TA can decrease the need for invasive procedures and reduce maternal morbidity in women with PPH.

Trial registration

Controlled Trials ISRCTN09968140.     

The Complexity of Characteristics,Diagnoses and Treatment of Older Patients With Pulmonary Hypertension

Background

Older patients with pulmonary hypertension (PH) are more likely to have complex comorbidity than younger patients with pulmonary arterial hypertension (PAH). The best approach to the evaluation and management of these patients is unclear.

Impact of comorbid conditions on disease-specific quality of life in older men and women with atrial fibrillation

Quality of Life Research - Older persons with atrial fibrillation (AF) experience significant impairment in quality of life (QoL), which may be partly attributable to their comorbid diseases. A...     

Bioequivalence study of two perindopril erbumine tablet formulations in healthy volunteers

The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 20 healthy adult male and female subjects under fasting conditions. In this study, one subject withdrew from the study and one reserve subject did not appear at both periods. The pharmacokinetic parameters were assessed based on the concentrations of perindopril (CAS 82834-16-0) and perindoprilat (CAS 95153-31-4) because perindopril has litte pharmacologic activity until hydrolized in the liver into its active metabolite, perindoprilat. The blood samples from 18 subjects were analyzed for plasma concentrations of perindopril and perindoprilat. In each of the two study periods (separated by a washout of three weeks) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 192 h (AUC), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t(1/2)). The geometric mean ratios (90% CI) of the test drug/reference drug for perindopril and perindoprilat were 106.59% (92.97-122.20%) and 100.56% (94.11-107.46%) for AUC,, 106.64% (93.39-121.77%) and 100.88% (95.30-106.80%) for AUCinfo, and 101.23% (87.39-117.27%) and 99.30% (90.42-109.05%) for Cmax, respectively. The 90% confidence intervals calculated for AUCt and Cmax of perindopril and perindoprilat were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two perindopril erbumine tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.     

Severe Hypothyroidism From Iodine Deficiency Associated With Parenteral Nutrition

Parenteral nutrition is crucial for supply of nutrients in children who cannot tolerate a full enteral diet. In the United States, it is not standard of care to give iodine to children dependent on parenteral nutrition, hence iodine is not routinely included in the micronutrient package. Herein, we present a case of a boy with hypothyroidism secondary to iodine deficiency after prolonged exclusive use of parenteral nutrition. Our case highlights the importance of screening for iodine deficiency and administering timely iodine supplementation in these at‐risk children to prevent iatrogenic hypothyroidism.     

The effect of calcium fluoride (CaF(2)) on the chemical solubility of an apatite-mullite glass-ceramic material.

OBJECTIVE: To assess the effect of varying CaF(2) on the chemical solubility of apatite-mullite glass-ceramic (G-C) materials in both the glassy and crystallized states. METHODS: Apatite-mullite forming glasses used in this study are ionomer cement derivatives based on the general formula (4.5SiO(2)-3Al(2)O(3)-1.5P(2)O(5)-3CaO-XCaF(2)). Six glass formulations were produced where X=0.5, 1, 1.5, 2, 2.5 and 3, and called HG1-6, respectively. Batches were melted in covered silliminite crucibles in a furnace overnight at 1050 degrees C, then at 1450 degrees C for 2h, before quenching in water. The six glass compositions were analyzed using differential thermal analysis (DTA), X-ray diffraction (XRD) and X-ray fluorescence spectrometry (XRF). Thirty discs (2mm thick and 12 mm diameter) were produced per glass using the lost wax casting technique. Ten were left as cast and 10 heat treated to either apatite or apatite-mullite. Solubility testing was carried out according to International Standard BS EN ISO 6872 1999 and the mass difference in solubility calculated as mug/cm(2). A lithium disilicate G-C system was used as a control material. RESULTS: All compositions formed glasses and on heat treatment could form apatite and apatite-mullite. The as-cast glass samples were the most soluble followed by the apatite samples. The apatite-mullite G-C was significantly less soluble than the other two phases (p<0.05) for all six compositions. The control material was significantly less soluble than all the HG glass-ceramic compositions for every phase (p<0.05). Decreasing the CaF(2) content (3-0.5 mol%) led to a decrease in solubility, without affecting the ability of the material to form apatite and apatite-mullite phases. SIGNIFICANCE: Increasing the CaF(2) content increases the chemical solubility for the glass, apatite G-C and apatite-mullite G-C phases. The solubility values obtained show that all the compositions, as cast and heat treated would be suitable for use as core ceramics.     

Effects of riluzole on N-methyl- -aspartate-induced tyrosine phosphorylation in the rat hippocampus

Since increased tyrosine phosphorylation has been observed in response to brain ischemia, we investigated whether riluzole (an inhibitor of glutamate neurotransmission with neuroprotective properties) affects tyrosine phosphorylation stimulated by N-methyl- -aspartate (NMDA) in rat hippocampal slices. Riluzole produced an extremely potent concentration-related inhibition of NMDA (1 mM)-stimulated protein tyrosine phosphorylation (IC₅₀=0.5±0.03 μM, mean±S.D.), but failed to affect that evoked by phorbol 12-myristate 13-acetate (PMA, an activator of protein kinase C, 0.1 and 1 μM). These results suggest that inhibition of tyrosine phosphorylation may contribute to the neuroprotective effects of riluzole against excitotoxic injury.