XX males SRY negative: a confirmed cause of infertility

BACKGROUND: SOX9 is a widely expressed transcription factor playing several relevant functions during development and essential for testes differentiation. It is considered to be the direct target gene of the protein encoded by SRY and its overexpression in an XX murine gonad can lead to male development in the absence of Sry. Recently, a family was reported with a 178 kb duplication in the gene desert region ending about 500 kb upstream of SOX9 in which 46,XY duplicated persons were completely normal and fertile whereas the 46,XX ones were males who came to clinical attention because of infertility. METHODS AND RESULTS: We report a family with two azoospermic brothers, both 46,XX, SRY negative, having a 96 kb triplication 500 kb upstream of SOX9. Both subjects have been analyzed trough oligonucleotide array-CGH and the triplication was confirmed and characterised through qPCR, defining the minimal region of amplification upstream of SOX9 associated with 46,XX infertile males, SRY negative. CONCLUSIONS: Our results confirm that even in absence of SRY, complete male differentiation may occur, possibly driven by overexpression of SOX9 in the gonadal ridge, as a consequence of the amplification of a gene desert region. We hypothesize that this region contains gonadal specific long-range regulation elements whose alteration may impair the normal sex development. Our data show that normal XX males, with alteration in copy number or, possibly, in the critical sequence upstream to SOX9 are a new category of infertility inherited in a dominant way with expression limited to the XX background

Primary Prevention Of Cardiovascular Risk In Octogenarians By Risk Factors Control

Primary prevention of cardiovascular events in older adults is a relevant problem, because of lack of evidence for safe and efficacious therapy, its costs and elderly quality of life, Italy's aging population is constantly increasing, so cardiovascular disease (CVD) primary prevention in the elderly is a prime objective. Life expectancy has dramatically increased over the last 2 decades,the proportion of individuals aged 80 years and older has grown rapidly in Europe and United States,but cost / effective ratio of CVD prevention through risk factors control is debated. It is therefore important to implement cardiovascular risk factors estimation in the elderly to maximize quality of life of patients and to lengthen their healthy life expectancy, choosing the better treatment for each patient sharing the choice with himself when it is possible, always remembering that elderly patients often have multiple co-morbidities that require a high number of concurrent medications; this may increase the risk for drug-drug interactions, thereby reducing the potential benefits of CVD prevention therapy. Anyway CVD are not an inevitable concomitant of aging. Sometimes autopsy in the elderly reveals atheroma-free coronary arteries,a normal-sized heart and unscarred valves. All primary prevention strategy decisions should consider estimated life expectancy and overall function not only cardiovascular event risks, magnitude and time to benefit or harm, potentially altered adverse effect profiles, and informed patient preferences.CVD primary prevention need to be more implemented in the elderly, this might contribute to improve health status and quality of life in this growing population if correctly performed

Highly Conserved Non-Coding Sequences and the 18q Critical Region for Short Stature: A Common Mechanism of Disease?

Background. Isolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD) are heterogeneous disorders with several different etiologies and they are responsible for most cases of short stature. Mutations in different genes have been identified but still many patients did not present mutations in any of the known genes. Chromosomal rearrangements may also be involved in short stature and, among others, deletions of 18q23 defined a critical region for the disorder. No gene was yet identified. Methodology/Principal Findings. We now report a balanced translocation X;18 in a patient presenting a breakpoint in 18q23 that was surprisingly mapped about 500 Kb distal from the short stature critical region. It separated from the flanking SALL3 gene a region enriched in highly conserved non-coding elements (HCNE) that appeared to be regulatory sequences, active as enhancers or silencers during embryonic development. Conclusion. We propose that, during pituitary development, the 18q rearrangement may alter expression of 18q genes or of X chromosome genes that are translocated next to the HCNEs. Alteration of expression of developmentally regulated genes by translocation of HCNEs may represent a common mechanism for disorders associated to isolated chromosomal rearrangements. © 2008 Rizzolio et al

Galectin-3 Serum Levels Are Independently Associated With Microalbuminuria in Chronic Heart Failure Outpatients

Background: Galectin-3 (Gal-3) is a novel biomarker reflecting inflammation status and fibrosis involving worsening of both cardiac and renal functions. Objectives: The aim of this study was to evaluate the relationship between Gal-3 serum levels and microalbuminuria in a group of chronic heart failure (CHF) outpatients. Patients and Methods: We enrolled CHF outpatients having stable clinical conditions and receiving conventional therapy. All patients underwent clinical evaluation, routine chemistry analysis, echocardiography, and evaluation of the urinary albumin/creatinine ratio (UACR). Results: Among the patients enrolled, 61 had microalbuminuria (UACR, 30-299) and 133 normoalbuminuria (UACR, < 30). Patients with normoalbuminuria showed significantly higher levels of Gal-3 than those without (19.9 ± 8.8 vs. 14.6 ± 5.5 ng/mL). The stepwise regression analysis indicated that Gal-3 was the first determinant of microalbuminuria (odds ratio [OR]: 1.08; 95% confidence interval [CI]: 1.02 - 1.14, P = 0.012), followed by diabetes (OR 2.14; 95% CI: 1.00 - 4.57; P = 0.049) and high central venous pressure (OR 2.80; 95% CI: 1.04 - 7.58; P= 0.042). Conclusions: Our findings indicate an independent association between Gal-3 levels and microalbuminuria, an early marker of altered renal function. This suggests the possible role of Gal-3 in the progression of cardiorenal syndrome in CHF outpatients

an application of the cox aalen model for breast cancer survival

Semiparametric hazard function regression models are among the well studied risk models in survival analysis. The Cox proportional hazards model has been a popular choice in modelling data from epidemiological settings. The Cox-Aalen model is one of the tools for handling the problem of non-proportional effects in the Cox model. We show an application on Piedmont cancer registry data. We initially fit standard Cox model and with the help of the score process we detect the violation of the proportionality assumption. Covariates and risk factors that, on the basis of clinical reasoning, best model baseline hazard are then moved into the additive part of the Cox-Aalen model. Multiplicative effects results are consistent with those of the Cox model whereas only the Cox-Aalen model fully represents the timevarying effect of tumour size

Nutraceuticals and dyslipidaemia: Beyond the common therapeutics

Dyslipidaemia accelerates the atherosclerotic process and its morbid consequences; statins represent the evidence-based treatment of choice for reducing low-density lipoprotein cholesterol levels and decreasing cardiovascular events. Unfortunately, statins are frequently not available for several reasons, including intolerance, side effects or, simply, patient preference. Nutraceuticals and functional food ingredients that are beneficial to vascular health may represent useful compounds that are able to reduce the overall cardiovascular risk induced by dyslipidaemia by acting parallel to statins or as adjuvants in case of failure or in situations where statins cannot be used. The mechanisms underlying such actions are not fully understood but may be related to reducing 7a-hydroxylase, increasing faecal excretion of cholesterol, decreasing 3-hydroxy-3-methylglutaryl-CoA reductase mRNA levels or reducing the secretion of very low-density lipoprotein. This contribution provides an overview of the mechanism of action of nutraceuticals and functional food ingredients on lipids and their role in the management of lipid disorders