Association between Body Iron Status and Leukocyte Telomere Length,a Biomarker of Biological Aging,in a Nationally Representative Sample of US Adults

Background

Excess iron levels can induce oxidative stress and could therefore affect telomere attrition. However, little is known about the impact of body iron status on telomere length.

Relationship between plasma insulin and left ventricular mass in normotensive participants of the Gubbio Study

BACKGROUND: There is substantial but not conclusive evidence that insulin resistance is related to left ventricular mass (LVM) in hypertensive individuals. To what extent this association is mediated by the relationship between plasma insulin and body size and build is still debated, and is poorly explored in nonhypertensive people. OBJECTIVE: To explore the relationship between insulin or insulin resistance and LVM in a population-based sample of nonhypertensive participants of the Gubbio Study. METHOD: Echocardiographic LVM was determined in 91 nondiabetic, nonhypertensive individuals aged 45-54 years, participating in a population-based screening. LVM normalized for height2.7 was used in the analyses; LV hypertrophy was defined as a value of > or = 50 g/m2.7 in men or > or = 47 g/m2.7 in women. Fasting plasma insulin and glucose were measured and the Homeostasis Model Assessment (HOMA) index was used as a measure of insulin resistance. RESULTS: LVM was positively and significantly correlated with body mass index (BMI) (P < 0.01), waist circumference (P < 0.01) and HOMA index (P < 0.05), whereas correlations with plasma glucose and triglycerides did not reach statistical significance (P = 0.07 for both); all correlations were offset after adjusting for BMI. Fasting plasma insulin and HOMA index were not significantly different in subjects with or without LV hypertrophy (70.8 +/- 27.8 vs. 77.7 +/- 29.6 pmol/l and 2.2 +/- 1.0 vs. 2.6 +/- 1.4, respectively). Bivariate analysis performed stratifying participants above or below the 75th percentile of the sex-specific distribution for BMI (29.1 and 29.4 kg/m2 for males and females, respectively) and plasma insulin (84 pmol/l for either gender), did not result in appreciable differences in LVM due to insulin levels. Similar results were obtained replacing the HOMA index for insulin in the analysis. CONCLUSION: In nonhypertensive individuals left ventricular mass is not associated with plasma insulin independently of body mass index.     

Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane

The liver is the major source of reduced glutathione (GSH) in blood plasma. The transport protein mediating the efflux of GSH across the basolateral membrane of human hepatocytes has not been identified so far. In this study we have localized the multidrug resistance protein 4 (MRP4; ABCC4) to the basolateral membrane of human, rat, and mouse hepatocytes and human hepatoma HepG2 cells. Recombinant human MRP4, expressed in V79 hamster fibroblasts and studied in membrane vesicles, mediated ATP-dependent cotransport of GSH or S-methyl-glutathione together with cholyltaurine, cholylglycine, or cholate. Several monoanionic bile salts and the quinoline derivative MK571 were potent inhibitors of this unidirectional transport. The K(m) values were 2.7 mmol/L for GSH and 1.2 mmol/L for the nonreducing S-methyl-glutathione in the presence of 5 micromol/L cholyltaurine, and 3.8 micromol/L for cholyltaurine in the presence of 5 mmol/L S-methyl-glutathione. Transport of bile salts by MRP4 was negligible in the absence of ATP or without S-methyl-glutathione. These findings identify a novel pathway for the efflux of GSH across the basolateral hepatocyte membrane into blood where it may serve as an antioxidant and as a source of cysteine for other organs. Moreover, MRP4-mediated bile salt transport across the basolateral membrane may function as an overflow pathway during impaired bile salt secretion across the canalicular membrane into bile. In conclusion, MRP4 can mediate the efflux of GSH from hepatocytes into blood by cotransport with monoanionic bile salts.     

Early detection by the Tei index of carvedilol-induced improved left ventricular function in patients with heart failure

Twenty-two patients (19 men) with heart failure (16 ischemic, 6 dilated cardiomyopathy; mean age of 67 +/- 6 years) in New York Heart Association classes I (2 patients), II (18 patients), and III (2 patients) under optimal therapy were strictly monitored after carvedilol supplementation. The Tei index decreased significantly from 0.87 +/- 0.17 to 0.53 +/- 0.29 (p <0.03). Conversely, the ejection fraction and transmitral Doppler flow analysis did not show significant improvement, despite a trend toward the amelioration of the ejection fraction, the E-/A-wave ratio, and atrial contribution. The Tei index could represent an earlier marker to evaluate drug-induced left ventricular function improvement in patients with heart failure and could represent a more sensitive tool to monitor left ventricular function during drug interventions.     

Four new cases of congenital secondary hypothyroidism due to a splice site mutation in the thyrotropin-beta gene: phenotypic variability and founder effect

Isolated TSH deficiency is a rare cause of congenital hypothyroidism. We here report four children from two consanguineous Turkish families with isolated TSH deficiency. Affected children who were screened at newborn age had an unremarkable TSH result and a low serum TSH level at diagnosis. Age at diagnosis and clinical phenotype were variable. All affected children carried an identical homozygous splice site mutation (IVS2 + 5 G--> A) in the TSHbeta gene. This mutation leads to skipping of exon 2 and a loss of the translational start codon without ability to produce a TSH-like protein. However, using specific monoclonal antibodies, we detected a very low concentration of authentic, heterodimeric TSH in serum, indicating the production of a small amount of correctly spliced TSH mRNA. By genotyping all family members with polymorphic markers at the TSHbeta locus, we show that the mutation arose on a common ancestral haplotype in three unrelated Turkish families indicating a founder mutation in the Turkish population. These results suggest that this TSHbeta mutation is among the more common TSHbeta gene mutations and stress the need for a biochemical and molecular genetic workup in children with symptoms suggestive of congenital hypothyroidism, even when the neonatal TSH screening is normal.