Heterozygosity for a mutation in the growth hormone-releasing hormone receptor gene does not influence adult stature, but affects body composition

CONTEXT: Biallelic mutations in the GHRH receptor (GHRHR) gene (GHRHR) are a frequent cause of isolated GH deficiency (IGHD). Although heterozygous carriers of these mutations appear normal, we hypothesized that heterozygosity for a GHRHR mutation might be associated with a subclinical phenotype. METHODS: We studied members of a large Brazilian kindred with IGHD (Itabaianinha cohort) caused by a homozygous null GHRHR mutation. We compared 76 adult subjects (age, 25-75 yr) heterozygous for the mutation (WT/MT) with 77 sex-matched controls from the same population who are homozygous for the wild-type GHRHR allele (WT/WT). RESULTS: We found no difference in adult height and sd score for serum IGF-I between the two groups. Body weight, body mass index, skin folds, waist and hip circumferences, and lean mass were all reduced in WT/MT subjects. Percentage fat mass and waist/hip ratio were similar in the two groups. Fasting insulin and homeostasis model assessment of insulin resistance were lower in WT/MT. The other biochemical parameters [total and fractionated cholesterol, triglycerides, lipoprotein (a), and C-reactive protein] were not different between the two groups. CONCLUSIONS: Heterozygosity for a null GHRHR mutation is not associated with reduction in adult stature or in serum IGF-I but is associated with changes in body composition and possibly an increase in insulin sensitivity. These effects do not seem to be modulated by changes in circulating IGF-I.     

Magnesium intake, glucose and insulin serum levels in pre-school very-low-birth weight pre-term children

AimsTo evaluate cross-sectional associations between dietary magnesium intake and the metabolic pattern of very-low-birth-weight (VLBW, <1500 g) pre-term children, in pre-school years (>2 and < 6 years).Methods and resultsFifty-eight Italian children without major congenital malformations/conditions were enrolled; dietary intakes, clinical and (in 34 cases) laboratory characteristics were evaluated. Subjects with lower magnesium intake showed significantly higher fasting glucose, insulin and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) levels. At simple regression analysis, fasting glucose was significantly associated with magnesium intake (inversely) and catch-up growth (CUG). Fasting insulin and HOMA-IR values were inversely associated with intakes of magnesium and fibres, and directly with Body Mass Index (BMI) and CUG. In a multiple regression model, after adjusting for multiple confounders and fibre intake, magnesium intake was inversely associated with glucose (β = − 0.018; 95%CI −0.026 to −0.010), but not with insulin or HOMA-IR levels. In the same model, dietary fibres remained inversely associated with insulin (β = − 0.075; −0.14 to −0.008) and HOMA-IR levels (β = − 0.06; −0.11 to −0.01).ConclusionThese results suggest a significant association between reduced magnesium intake and fasting glucose, and between reduced fibre intake and insulin resistance and this is present even in earlier childhood, and independently of BMI and growth characteristics.     

Arginine transport in human erythroid cells: discrimination of CAT1 and 4F2hc/y+LAT2 roles

Since arginine metabolites, such as nitric oxide and polyamines, influence the expression of genes involved in erythroid differentiation, the transport of the cationic amino acid may play an important role in erythroid cells. However, available data only concern the presence in these cells of CAT1 transporter (system y⁺), while no information exists on the role of the heterodimeric transporters of system y⁺L (4F2hc/y⁺LAT1 and 4F2hc/y⁺LAT2) which operates transmembrane arginine fluxes cis-inhibited by neutral amino acids in the presence of sodium. Using erythroleukemia K562 cells and normal erythroid precursors, we demonstrate here that arginine transport in human erythroid cells is due to the additive contributions of a leucine-sensitive and leucine-insensitive component. In both cell types, leucine inhibition of arginine influx is much less evident in the absence of sodium, a hallmark of system y⁺L. In K562 cells, N-ethylmaleimide, a known inhibitor of CAT transporters (system y⁺), suppresses only a fraction of arginine influx corresponding to leucine-insensitive uptake. Moreover, in Xenopus oocytes coexpressing 4F2hc and y⁺LAT2, leucine exerts a marked inhibition of arginine transport, partially dependent on sodium, while no inhibition is seen in oocytes expressing CAT1. Lastly, silencing of SLC7A6, the gene for y⁺LAT2, lowers arginine transport and doubles the intracellular content of the cationic amino acid in K562 cells. We conclude that arginine transport in human erythroid cells is due to both system y⁺ (CAT1 transporter) and system y⁺L (4F2hc/y⁺LAT2 isoform), which mainly contribute, respectively, to the influx and to the efflux of the cationic amino acid.     

EBV BMRF-2 facilitates cell-to-cell spread of virus within polarized oral epithelial cells

We previously reported that the Epstein-Barr virus (EBV) BMRF-2 protein plays an important role in EBV infection of polarized oral epithelial cells by interacting with β1 and αv family integrins. Here we show that infection of polarized oral epithelial cells with B27-BMRF-2^low recombinant virus, expressing a low level of BMRF-2, resulted in significantly smaller plaques compared with infection by parental B95-8 virus. BMRF-2 localized in the trans-Golgi network (TGN) and basolateral sorting vesicles and was transported to the basolateral membranes of polarized epithelial cells. Mutation of the tyrosine- and dileucine-containing basolateral sorting signal, YLLV, in the cytoplasmic domain of BMRF-2 led to the failure of its accumulation in the TGN and its basolateral transport. These data show that BMRF-2 may play an important role in promoting the spread of EBV progeny virions through lateral membranes of oral epithelial cells.     

Cardiovascular changes during maximal breath-holding in elite divers

During maximal breath-holding six healthy elite breath-hold divers, after an initial “easy-going” phase in which cardiovascular changes resembled the so-called “diving response”, exhibited a sudden and severe rise in blood pressure during the “struggle” phase of the maneuver. These changes may represent the first tangible expression of a defense reaction, which overrides the classic diving reflex, aiming to reduce the hypoxic damage and to break the apnea before the loss of consciousness.     

Treadmill training for ataxic patients: a single-subject experimental design

OBJECTIVE: To investigate changes in gait quality, balance and mobility associated with treadmill training for ataxic individuals. DESIGN: Single-subject ABA design. Baseline phases (A) lasted three weeks and intervention (B) lasted four weeks. SETTING: University rehabilitation clinic. SUBJECTS: A woman (25 years) and a man (53 years) with chronic ataxia due to head trauma. INTERVENTION: Three 20-minute treadmill training sessions each week with progression in velocity and step length. MAIN MEASURES: Rivermead Visual Gait Assessment, Timed Up and Go, time to complete a balance task, walking speed, cadence, and stride length assessments three times a week during the 10 weeks. Data were analysed with the celeration line technique and two standard deviation band. RESULTS: Both individuals demonstrated gains in all parameters over initial baseline and subsequent phases, with performance increases ranging from 26% to 233% when first and last assessments were compared. Significantly superior effects of treadmill training over baseline conditions on cadence were detected (P<0.05). Gains in walking speed were not significantly better during intervention, but intervention withdrawal produced deceleration of performance gains. Gains in Timed Up and Go, step length and balance were not consistent and were possibly caused by a learning effect of the association between repeated testing and treadmill training. Rivermead Visual Gait Assessment gains reached significance only for subject 2 (P<0.05), probably because of increased variability of performance of subject 1. Results suggest that the association between repeated testing and treadmill training might have been responsible for the observed gains in the two ataxic patients.     

Do Perfluoroalkyl Compounds Impair Human Semen Quality?

Background

Perfluoroalkyl acids (PFAAs) are found globally in wildlife and humans and are suspected to act as endocrine disruptors. There are no previous reports of PFAA levels in adult men from Denmark or of a possible association between semen quality and PFAA exposure.

Objectives

We investigated possible associations between PFAAs and testicular function. We hypothesized that higher PFAA levels would be associated with lower semen quality and lower testosterone levels.

Methods

We analyzed serum samples for levels of 10 different PFAAs and reproductive hormones and assessed semen quality in 105 Danish men from the general population (median age, 19 years).

Results

Considerable levels of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid were found in all young men (medians of 24.5, 4.9, and 6.6 ng/mL, respectively). Men with high combined levels of PFOS and PFOA had a median of 6.2 million normal spermatozoa in their ejaculate in contrast to 15.5 million among men with low PFOS–PFOA (p = 0.030). In addition, we found nonsignificant trends with regard to lower sperm concentration, lower total sperm counts, and altered pituitary–gonadal hormones among men with high PFOS–PFOA levels.

Conclusion

High PFAA levels were associated with fewer normal sperm. Thus, high levels of PFAAs may contribute to the otherwise unexplained low semen quality often seen in young men. However, our findings need to be corroborated in larger studies.