Preserved tissue-type plasminogen activator release and endothelium-dependent vasodilation in postmenopausal women with NIDDM

We have recently shown that the net release of tissue-type plasminogen activator (t-PA) antigen can be rapidly enhanced by the muscarinic receptor stimulation in healthy males. Since diabetes mellitus has been associated with endothelial dysfunction, the aim of the present study was to compare the endothelium-derived local net release of t-PA with vasodilation in response to muscarinic receptor stimulation by metacholine (Mch) and fluid shear stress in a group of postmenopausal women with non-insulin-dependent diabetes mellitus (NIDDM), and to elucidate the influence of estrogen on this process. Six postmenopausal women with NIDDM were in randomized order exposed to step-wise intra-arterial infusions of Mch (0.1-0. 8-4.0 microg/min) and nitroprusside (SNP; 0.5-2.5-10.0 microg/min). Forearm blood flow (FBF) was assessed by plethysmography. The infusions with Mch and SNP were repeated during simultaneous intra-arterial infusion of 17-beta estradiol (E; 20 ng/min). During placebo infusion, FBF increased significantly in response to Mch and SNP (p<0.001), but no differences between Mch and SNP were found. In parallel to the blood flow increase in response to Mch stimulation, the t-PA net release was increased over 30 times (p<0.001). Estrogen did not produce any change in blood flow or net release of t-PA at baseline or in response to either drug (Mch or SNP). The present study demonstrates a preserved endothelium-dependent vasodilation and stimulated tissue-type plasminogen activator release in NIDDM postmenopausal women in response to Mch stimulation. Acute intra-arterial infusion of 17-beta estradiol did not affect the vasodilation or the t-PA net release.     

Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.     

The effects of zinc supplementation on serum zinc concentration and protein catabolic rate in hemodialysis patients.

OBJECTIVE: To examine the effect of zinc sulfate supplementation on serum zinc concentrations and protein catabolic rate (PCR) in hemodialysis (HD) patients. DESIGN: Randomized, double-blind, before-after trial. SETTING: Outpatient dialysis center in a large metropolitan city. PATIENTS: Twenty-eight maintenance HD patients were selected. Twenty (15 women, 5 men) subjects completed the study. Subjects were identified for inclusion in the study by the following criteria: a history of low PCR (<0.09 g/kg body weight), HD treatment for a minimum of 6 months, no signs of gastrointestinal disorders, and no record of hospitalizations for reasons other than access complication within the last 3 months. INTERVENTIONS: Patients consumed 7.7 pmol zinc sulfate (2,200 microg) or a cornstarch placebo capsule daily for 90 days. In addition, patients completed a 2-day food record representative of 1 dialysis day and 1 nondialysis day. MAIN OUTCOME MEASURE: Fasting, predialysis serum samples were collected on days 0, 40, and 90 to determine serum zinc concentration and PCR. Dietary parameters including intake of zinc, protein, and energy were analyzed on Days 0 and 90. RESULTS: Initial analysis at Day 0 of serum zinc concentration indicated subjects were below the normal range for serum zinc standards (12.2 micromol/L [80 microg/dL]). After supplementation, subjects in the zinc-supplemented group showed significant increases in serum zinc concentrations from 12.2 micromol/L (80 microg/dL) at Day 0 to 15.3 pmol/L (100 microg/dL) at Day 90. A significant positive correlation (r = +0.61) was shown between PCR and serum zinc concentrations at the end of the study. Reported dietary protein intake did not change with zinc supplementation. CONCLUSION: Low serum zinc concentrations are reversible with zinc supplementation. Improvement in serum zinc concentration increases the PCR of HD patients.     

Systemic levels and preportal organ release of tissue-type plasminogen activator are enhanced by PEEP in the pig

BACKGROUND: Endothelium-derived tissue-type plasminogen activator, t-PA, is the key enzyme in the initiation of endogenous thrombolysis. Plasma levels of t-PA increase in response to sympatho-adrenergic activation. In the mesenteric vascular bed an increased norepinephrine spillover has been observed during positive end-expiratory pressure ventilation, PEEP. This experimental study examines the effects of PEEP-induced alterations on regional release rates and systemic levels of t-PA in vivo. METHODS: The protocol included measurements of arterio-venous concentration gradients of t-PA and the respective plasma flow across the pulmonary, coronary, hepatic and preportal vascular beds, in pigs, during zero-PEEP and at 2, 4 and 10 min after the application of a PEEP of 10 cm H2O. Both total plasma t-PA antigen (ELISA with a porcine t-PA standard) and active t-PA (spectrophotometric functional assay) were determined. RESULTS: During zero-PEEP, a high preportal basal net release and hepatic net uptake of total t-PA was observed. With PEEP, the magnitude of the preportal net release of t-PA was markedly enhanced (+24+/-5%), as was hepatic net uptake (+21+/-8%), simultaneously to a significant decrease in liver plasma flow (-30+/-2%). PEEP-induced alterations in active t-PA mirrored those observed in total t-PA. No significant net fluxes of total or active t-PA were observed across the coronary or the pulmonary vascular beds. CONCLUSIONS: Clinically used levels of PEEP induce increases in net release of endothelially derived t-PA within preportal organs. The application of PEEP is associated with increased systemic levels of total and active t-PA, in spite of a simultaneous increase in hepatic net uptake, indicating that the preportal vascular bed can not account for the systemic t-PA response.     

Genetic variation in complement component C3 shows association with ischaemic stroke

Background and purpose: The aim of this study was to investigate whether genetic variation at the third complement component (C3) locus is associated with ischaemic stroke (IS). Methods: The Sahlgrenska Academy Study on Ischaemic Stroke comprises 844 patients with IS, and 668 healthy controls. Sixteen SNPs were analyzed. Results: Two SNPs, rs2277984 and rs3745565, showed a significant association with overall IS. The SNP rs2277984 also showed association with the IS subtype cryptogenic stroke. These associations were independent of hypertension, diabetes, and smoking. The independent association between rs3745565 and overall IS withstands correction for multiple testing. Conclusion: In this sample of patients with IS, genetic variation in C3 is associated with IS.     

A Reassessment of the Possible Effects of the Serotonin Transporter Gene Linked Polymorphism 5-HTTLPR on Premature Ejaculation

A population-based sample of 1673 (valid phenotypic and genotypic data were available from 1412 individuals) Finnish male twins and siblings of twins aged 18–45 years provided questionnaire data regarding ejaculatory function as well as saliva samples for genotype analyses. Genotypic analyses were conducted controlling for between-subjects dependence. No significant association was found between the 5-HTTLPR polymorphism and a composite variable measuring premature ejaculation or between this polymorphism and a self-report measure of ejaculation latency time. Previously conducted studies have found contradicting results regarding the possible role of 5-HTTLPR in premature ejaculation. Methodological inconsistencies have been pointed out in these studies, which have all been conducted on rather small samples. While differences in terms of measurement of ejaculatory function could partly explain why positive findings from some earlier studies could not be replicated, the present study, given the large sample size and multifactorial measures used, indicated that the 5-HTTLPR polymorphism has a limited, if any, impact on ejaculatory function.