Prostaglandins, masculinization and its disorders:effects of fetal exposure of the rat to the cyclooxygenase inhibitor- indomethacin

Recent studies have established that masculinization of the male reproductive tract is programmed by androgens in a critical fetal ‘masculinization programming window’ (MPW). What is peculiar to androgen action during this period is, however, unknown. Studies from 20 years ago in mice implicated prostaglandin (PG)-mediation of androgen-induced masculinization, but this has never been followed up. We therefore investigated if PGs might mediate androgen effects in the MPW by exposing pregnant rats to indomethacin (which blocks PG production by inhibiting cyclooxygenase activity) during this period and then examining if androgen production or action (masculinization) was affected. Pregnant rats were treated with indomethacin (0.8 mg/kg/day; e15.5–e18.5) to encompass the MPW. Indomethacin exposure decreased fetal bodyweight (e21.5), testis weight (e21.5) and testicular PGE2 (e17.5, e21.5), but had no effect on intratesticular testosterone (ITT; e17.5) or anogenital index (AGI; e21.5). Postnatally, AGI, testis weight and blood testosterone were unaffected by indomethacin exposure and no cryptorchidism or hypospadias occurred. Penis length was normal in indomethacin-exposed animals at Pnd25 but was reduced by 26% (p<0.001) in adulthood, an effect that is unexplained. Our results demonstrate that indomethacin can effectively decrease intra-testicular PGE2 level. However, the resulting male phenotype does not support a role for PGs in mediating androgen-induced masculinization during the MPW in rats. The contrast with previous mouse studies is unexplained but may reflect a species difference

Rapid Reactivation of Extralymphoid CD4 T Cells during Secondary Infection

After infection, extralymphoid tissues are enriched with effector and memory T cells of a highly activated phenotype. The capacity for rapid effector cytokine response from extralymphoid tissue-memory T cells suggests these cells may perform a ‘sentinel’ function in the tissue. While it has been demonstrated that extralymphoid CD4+ T cells can directly respond to secondary infection, little is known about how rapidly this response is initiated, and how early activation of T cells in the tissue may affect the innate response to infection. Here we use a mouse model of secondary heterosubtypic influenza infection to show that CD4+ T cells in the lung airways are reactivated within 24 hours of secondary challenge. Airway CD4+ T cells initiate an inflammatory cytokine and chemokine program that both alters the composition of the early innate response and contributes to the reduction of viral titers in the lung. These results show that, unlike a primary infection, extralymphoid tissue-memory CD4+ T cells respond alongside the innate response during secondary infection, thereby shaping the overall immune profile in the airways. These data provide new insights into the role of extralymphoid CD4+ T cells during secondary immune responses

Circumstellar discs: What will be next?

This prospective chapter gives our view on the evolution of the study of circumstellar discs within the next 20 years from both observational and theoretical sides. We first present the expected improvements in our knowledge of protoplanetary discs as for their masses, sizes, chemistry, the presence of planets as well as the evolutionary processes shaping these discs. We then explore the older debris disc stage and explain what will be learnt concerning their birth, the intrinsic links between these discs and planets, the hot dust and the gas detected around main sequence stars as well as discs around white dwarfs.Comment: invited review; comments welcome (32 pages

Dynamics of Viral Evolution and CTL Responses in HIV-1 Infection

Improved understanding of the dynamics of host immune responses and viral evolution is critical for effective HIV-1 vaccine design. We comprehensively analyzed Cytotoxic T-lymphocyte (CTL)-viral epitope dynamics in an antiretroviral therapy-naïve subject over the first four years of HIV-1 infection. We found that CTL responses developed sequentially and required constant antigenic stimulation for maintenance. CTL responses exerting strong selective pressure emerged early and led to rapid escape, proliferated rapidly and were predominant during acute/early infection. Although CTL responses to a few persistent epitopes developed over the first two months of infection, they proliferated slowly. As CTL epitopes were replaced by mutational variants, the corresponding responses immediately declined, most rapidly in the cases of strongly selected epitopes. CTL recognition of epitope variants, via cross-reactivity and de novo responses, was common throughout the period of study. Our data demonstrate that HIV-specific CTL responses, especially in the critical acute/early stage, were focused on regions that are prone to escape. Failure of CTL responses to strongly target functional or structurally critical regions of the virus, as well as the sequential cascade of CTL responses, followed closely by viral escape and decline of the corresponding responses, likely contribute to a lack of sustainable viral suppression. Focusing early and rapidly proliferating CTL on persistent epitopes may be essential for durable viral control in HIV-1 infection

Accreting Millisecond X-Ray Pulsars

Accreting Millisecond X-Ray Pulsars (AMXPs) are astrophysical laboratories without parallel in the study of extreme physics. In this chapter we review the past fifteen years of discoveries in the field. We summarize the observations of the fifteen known AMXPs, with a particular emphasis on the multi-wavelength observations that have been carried out since the discovery of the first AMXP in 1998. We review accretion torque theory, the pulse formation process, and how AMXP observations have changed our view on the interaction of plasma and magnetic fields in strong gravity. We also explain how the AMXPs have deepened our understanding of the thermonuclear burst process, in particular the phenomenon of burst oscillations. We conclude with a discussion of the open problems that remain to be addressed in the future.Comment: Review to appear in "Timing neutron stars: pulsations, oscillations and explosions", T. Belloni, M. Mendez, C.M. Zhang Eds., ASSL, Springer; [revision with literature updated, several typos removed, 1 new AMXP added

β-Cells with Relative Low HIMP1 Overexpression Levels in a Transgenic Mouse Line Enhance Basal Insulin Production and Hypoxia/Hypoglycemia Tolerance

Rodent pancreatic β-cells that naturally lack hypoglycemia/hypoxia inducible mitochondrial protein 1 (HIMP1) are susceptible to hypoglycemia and hypoxia influences. A linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 is suggested in a recent study using transformed β-cells lines. To further illuminate this linkage, we applied mouse insulin 1 gene promoter (MIP) to control HIMP1-a isoform cDNA and have generated three lines (L1 to L3) of heterozygous HIMP1 transgenic (Tg) mice by breeding of three founders with C57BL/6J mice. In HIMP1-Tg mice/islets, we performed quantitative polymerase chain reaction (PCR), immunoblot, histology, and physiology studies to investigate HIMP1 overexpression and its link to β-cell function/survival and body glucose homeostasis. We found that the HIMP1 level increased steadily in β-cells of L1 to L3 heterozygous HIMP1-Tg mice. HIMP1 overexpression at relatively lower levels in L1 heterozygotes results in a negligible decline in blood glucose concentrations and an insignificant elevation in blood insulin levels, while HIMP1 overexpression at higher levels are toxic, causing hyperglycemia in L2/3 heterozygotes. Follow-up studies in 5–30-week-old L1 heterozygous mice/islets found that HIMP1 overexpression at relatively lower levels in β-cells has enhanced basal insulin biosynthesis, basal insulin secretion, and tolerances to low oxygen/glucose influences. The findings enforced the linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 in β-cells, and show a potential value of HIMP1 overexpression at relatively lower levels in modulating β-cell function and survival

The risk of cryptorchidism among sons of women working in horticulture in Denmark: a cohort study

<p>Abstract</p> <p>Background</p> <p>Androgens are crucial for normal testicular descent. Studies show that some pesticides have estrogenic or antiandrogenic effects, and that female workers exposed to pesticides have increased risk of having a boy with cryptorchidism. The main objective of the present study was to investigate whether pregnant women exposed to pesticides due to their work in horticulture experience excess risk of having sons with cryptorchidism.</p> <p>Methods</p> <p>We conducted a cohort study of pregnant women working in horticulture using four cohorts including one cohort established with data from the departments of occupational medicine in Jutland and Funen and three existing mother-child cohorts (n = 1,468). A reference group was established from the entire Danish population of boys born in the period of 1986-2007 (n = 783,817). Nationwide Danish health registers provided information on birth outcome, cryptorchidism diagnosis and orchiopexy. The level of occupational exposure to pesticides was assessed by expert judgment blinded towards outcome status. Risk of cryptorchidism among exposed horticulture workers compared to the background population and to unexposed horticulture workers was assessed by Cox regression models.</p> <p>Results</p> <p>Pesticide exposed women employed in horticulture had a hazard ratio (HR) of having cryptorchid sons of 1.39 (95% CI 0.84; 2.31) and a HR of orchiopexy of 1.34 (0.72; 2.49) compared to the background population. Analysis divided into separate cohorts revealed a significantly increased risk of cryptorchidism in cohort 2: HR 2.58 (1.07;6.20) and increased risk of orchiopexy in cohort 4: HR 2.76 (1.03;7.35), but no significant associations in the other cohorts. Compared to unexposed women working in horticulture, pesticide exposed women had a risk of having sons with cryptorchidism of 1.34 (0.30; 5.96) and of orchiopexy of 1.93 (0.24;15.4).</p> <p>Conclusions</p> <p>The data are compatible with a slightly increased risk of cryptorchidism in sons of women exposed to pesticides by working in horticulture.</p

Excessive Food Intake, Obesity and Inflammation Process in Zucker fa/fa Rat Pancreatic Islets

Inappropriate food intake-related obesity and more importantly, visceral adiposity, are major risk factors for the onset of type 2 diabetes. Evidence is emerging that nutriment-induced β-cell dysfunction could be related to indirect induction of a state of low grade inflammation. Our aim was to study whether hyperphagia associated obesity could promote an inflammatory response in pancreatic islets leading to ß-cell dysfunction. In the hyperphagic obese insulin resistant male Zucker rat, we measured the level of circulating pro-inflammatory cytokines and estimated their production as well as the expression of their receptors in pancreatic tissue and β-cells. Our main findings concern intra-islet pro-inflammatory cytokines from fa/fa rats: IL-1β, IL-6 and TNFα expressions were increased; IL-1R1 was also over-expressed with a cellular redistribution also observed for IL-6R. To get insight into the mechanisms involved in phenotypic alterations, abArrays were used to determine the expression profile of proteins implicated in different membrane receptors signaling, apoptosis and cell cycle pathways. Despite JNK overexpression, cell viability was unaffected probably because of decreases in cleaved caspase3 as well as in SMAC/DIABLO and APP, involved in the induction and amplification of apoptosis. Concerning β-cell proliferation, decreases in important cell cycle regulators (Cyclin D1, p35) and increased expression of SMAD4 probably contribute to counteract and restrain hyperplasia in fa/fa rat islets. Finally and probably as a result of IL-1β and IL-1R1 increased expressions with sub-cellular redistribution of the receptor, islets from fa/fa rats were found more sensitive to both stimulating and inhibitory concentrations of the cytokine; this confers some physiopathological relevance to a possible autocrine regulation of β-cell function by IL-1β. These results support the hypothesis that pancreatic islets from prediabetic fa/fa rats undergo an inflammatory process. That the latter could contribute to β-cell hyperactivity/proliferation and possibly lead to progressive β-cell failure in these animals, deserves further investigations