Low alanine aminotransferase and higher cardiovascular events in type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Aims Non-alcoholic fatty liver disease (NAFLD) is common in type 2 diabetes and associated with higher risk of cardiovascular disease. This study aimed to determine whether alanine aminotransferase (ALT) or gamma-glutamyltransferase (GGT), as markers of liver health and NAFLD, might predict cardiovascular events in this population. Methods Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (nonfatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years. Results ALT had a linear inverse relationship with the first cardiovascular event on study. After adjustment, for every standard deviation higher baseline ALT (13.2U/L), the risk of an event was 7%(95%CI 4–13, P=0.02) lower. Participants with ALT below and above the reference range 8–41 U/L for women and 9–59 U/L for men, had a hazard ratio of an event of 1.86(95%CI, 1.12–3.09) and 0.65(95%CI, 0.49–0.87), respectively (P=0.001). No relationship was found for GGT. Conclusions The data may indicate that in type 2 diabetes — associated with higher ALT due to prevalent NAFLD — lower ALT is a marker of hepatic or systemic frailty rather than health

X-Linked Genes and Risk of Orofacial Clefts: Evidence from Two Population-Based Studies in Scandinavia

Background: Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers. Methodology/Principal Findings: We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample. Conclusions: The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits

Leukocytospermia and sperm preparation - a flow cytometric study

Reprod Biol Endocrinol. 2009 Nov 19;7:12

Insulin-like growth factor binding protein 5 enhances survival of LX2 human hepatic stellate cells

ABSTRACT: BACKGROUND: Expression of insulin-like growth factor binding protein 5 (IGFBP5) is strongly induced upon activation of hepatic stellate cells and their transdifferentiation into myofibroblasts in vitro. This was confirmed in vivo in an animal model of liver fibrosis. Since IGFBP5 has been shown to promote fibrosis in other tissues, the aim of this study was to investigate its role in the progression of liver fibrosis. METHODS: The effect of IGFBP5 was studied in LX2 cells, a model for partially activated hepatic stellate cells, and in human primary liver myofibroblasts. IGFBP5 signalling was modulated by the addition of recombinant protein, by lentiviral overexpression, and by siRNA mediated silencing. Furthermore, the addition of IGF1 and silencing of the IGF1R was used to investigate the role of the IGF-axis in IGFBP5 mediated effects. RESULTS: IGFBP5 enhanced the survival of LX2 cells and myofibroblasts via a >50% suppression of apoptosis. This effect of IGFBP5 was not modulated by the addition of IGF1, nor by silencing of the IGF1R. Additionally, IGFBP5 was able to enhance the expression of established pro-fibrotic markers, such as collagen Ialpha1, TIMP1 and MMP1. CONCLUSION: IGFBP5 enhances the survival of (partially) activated hepatic stellate cells and myofibroblasts by lowering apoptosis via an IGF1-independent mechanism, and enhances the expression of profibrotic genes. Its lowered expression may, therefore, reduce the progression of liver fibrosi

Deletion of Genes Implicated in Protecting the Integrity of Male Germ Cells Has Differential Effects on the Incidence of DNA Breaks and Germ Cell Loss

Infertility affects approximately 20% of couples in Europe and in 50% of cases the problem lies with the male partner. The impact of damaged DNA originating in the male germ line on infertility is poorly understood but may increase miscarriage. Mouse models allow us to investigate how deficiencies in DNA repair/damage response pathways impact on formation and function of male germ cells. We have investigated mice with deletions of ERCC1 (excision repair cross-complementing gene 1), MSH2 (MutS homolog 2, involved in mismatch repair pathway), and p53 (tumour suppressor gene implicated in elimination of germ cells with DNA damage).We demonstrate for the first time that depletion of ERCC1 or p53 from germ cells results in an increased incidence of unrepaired DNA breaks in pachytene spermatocytes and increased numbers of caspase-3 positive (apoptotic) germ cells. Sertoli cell-only tubules were detected in testes from mice lacking expression of ERCC1 or MSH2 but not p53. The number of sperm recovered from epididymes was significantly reduced in mice lacking testicular ERCC1 and 40% of sperm contained DNA breaks whereas the numbers of sperm were not different to controls in adult Msh2 -/- or p53 -/- mice nor did they have significantly compromised DNA.These data have demonstrated that deletion of Ercc1, Msh2 and p53 can have differential but overlapping affects on germ cell function and sperm production. These findings increase our understanding of the ways in which gene mutations can have an impact on male fertility

Later life sex and Rubin’s ‘Charmed Circle'

Gayle Rubin’s now classic concept of the ‘charmed circle’ has been much used by scholars of sexuality to discuss the ways in which some types of sex are privileged over others. In this paper, I apply the concept of the charmed circle to a new topic– later life – in order both to add to theory about later life sex and to add an older-age lens to thinking about sex hierarchies. Traditional discursive resources around older people’s sexual activities, which treat older people’s sex as inherently beyond the charmed circle, now coexist with new imperatives for older people to remain sexually active as part of a wider project of ‘successful’ or ‘active’ ageing. Drawing on the now-substantial academic literature about later life sex, I discuss some of the ways in which redrawing the charmed circle to include some older people’s sex may paradoxically entail the use of technologies beyond the charmed circle of ‘good, normal, natural, blessed’ sex. Sex in later life also generates some noteworthy inversions in which types of sex are privileged and which treated as less desirable, in relation to marriage and procreation. Ageing may, furthermore, make available new possibilities to redefine what constitutes ‘good’ sex and to refuse compulsory sexuality altogether, without encountering stigma

Characterization of Mullite Ceramic Membranes and their Application in the Removal Escherichia Coli

This paper aims the morphological and structural characterization of ceramic membranes of mullite and their application in the removal of Escherichia coli. A complex irregular structure presented by the pores of the membrane was verified by scanning electron microscopy (SEM). The average pore size and distribution were determined by mercury intrusion porosimetry. The average pore size of the material presented was 0,39 μm. Microfiltration tests resulted in a protein retention of 46, 76 and 89% for trypsin (TR), egg albumin (EA) and bovine serum albumin (BSA), proving the efficiency of the membrane microfiltration tests for molecular weight of 69 kDa. The application of the membranes on the retention of gram-negative bacterium E. coli resulted in a 66% efficiency at a pressure of 200 kPa and a 98% efficiency when applied a pressure of 50 kPa. Therefore, the use of mullite membranes show limited efficiency towards bacteria retention. Nevertheless, they present fluxes similar to other materials proposed in the literature

Spermatozoal sensitive biomarkers to defective protaminosis and fragmented DNA

Human sperm DNA damage may have adverse effects on reproductive outcome. Infertile men possess substantially more spermatozoa with damaged DNA compared to fertile donors. Although the extent of this abnormality is closely related to sperm function, the underlying etiology of ensuing male infertility is still largely controversial. Both intra-testicular and post-testicular events have been postulated and different mechanisms have been proposed to explain the presence of damaged DNA in human spermatozoa. Three among them, i.e. abnormal chromatin packaging, oxidative stress and apoptosis, are the most studied and discussed in the present review. Furthermore, results from numerous investigations are presented, including our own findings on these pathological conditions, as well as the techniques applied for their evaluation. The crucial points of each methodology on the successful detection of DNA damage and their validity on the appraisal of infertile patients are also discussed. Along with the conventional parameters examined in the standard semen analysis, evaluation of damaged sperm DNA seems to complement the investigation of factors affecting male fertility and may prove an efficient diagnostic tool in the prediction of pregnancy outcome

Pathogen-Specific Circulating Plasmablasts in Patients with Pneumonia

Peer reviewe