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Smith L.B.,Queens Medical Research Institute | Walker W.H.,University of Pittsburgh
Seminars in Cell and Developmental Biology | Year: 2014

Testosterone is essential for maintaining spermatogenesis and male fertility. However, the molecular mechanisms by which testosterone acts have not begun to be revealed until recently. With the advances obtained from the use of transgenic mice lacking or overexpressing the androgen receptor, the cell specific targets of testosterone action as well as the genes and signaling pathways that are regulated by testosterone are being identified. In this review, the critical steps of spermatogenesis that are regulated by testosterone are discussed as well as the intracellular signaling pathways by which testosterone acts. We also review the functional information that has been obtained from the knock out of the androgen receptor from specific cell types in the testis and the genes found to be regulated after altering testosterone levels or androgen receptor expression. © 2014 Elsevier Ltd.

Macnee W.,Queens Medical Research Institute
Annals of Medicine | Year: 2013

Chronic obstructive pulmonary disease (COPD) can no longer be considered as a disease affecting only the lungs. Increasing evidence supports the presence of a systemic inflammatory component which is thought to provide the link between COPD and the co-morbidities commonly associated with this disease. These include cardiovascular disorders, skeletal muscle dysfunction, diabetes, and osteoporosis. The majority of current therapies for COPD have been developed to improve airway obstruction or to target airway inflammation, leaving an unmet medical need with respect to the systemic inflammatory component of COPD and its extra-pulmonary manifestations. This review describes systemic biomarkers in COPD and their relationship with both the local lung and systemic manifestations of the disease. A summary is provided of the most promising biomarkers that have been investigated in COPD and its co-morbidities. Such biomarkers may be used to assess and manage the systemic effects of COPD, and may guide future development of novel therapeutic interventions to provide a more holistic approach to treating this multi-faceted disease. © 2013 Informa UK, Ltd.

Sharpe R.M.,Queens Medical Research Institute
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

The high incidence of low sperm counts in young (European) men and evidence for declining sperm counts in recent decades mean that the environmental/ lifestyle impact on spermatogenesis is an important health issue. This review assesses potential causes involving adverse effects on testis development in perinatal life (primarily effects on Sertoli cell number), which are probably irreversible, or effects on the process of spermatogenesis in adulthood, which are probably mainly reversible. Several lifestyle-related (obesity, smoking) and environmental (exposure to traffic exhaust fumes, dioxins, combustion products) factors appear to negatively affect both the perinatal and adult testes, emphasizing the importance of environmental/lifestyle impacts throughout the life course. Apart from this, public concern about adverse effects of environmental chemicals (ECs) (pesticides, food additives, persistent pollutants such as DDT, polychlorinated biphenyls) on spermatogenesis in adult men are, in general, not supported by the available data for humans. Where adverse effects of ECs have been shown, they are usually in an occupational setting rather than applying to the general population. In contrast, a modern Western lifestyle (sedentary work/lifestyle, obesity) is potentially damaging to sperm production. Spermatogenesis in normal men is poorly organized and inefficient so that men are poorly placed to cope with environmental/lifestyle insults. © 2010 The Royal Society.

Chapman K.,Queens Medical Research Institute | Holmes M.,Queens Medical Research Institute | Seckl J.,Queens Medical Research Institute
Physiological Reviews | Year: 2013

Glucocorticoid action on target tissues is determined by the density of "nuclear" receptors and intracellular metabolism by the two isozymes of 11 β-hydroxysteroid dehydrogenase (11 β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11 β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11 β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11 β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental "programming." The role of 11 β-HSD2 as a marker of programming is being explored. The 11 β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues. © 2013 the American Physiological Society.

Frier B.M.,Queens Medical Research Institute
Nature Reviews Endocrinology | Year: 2014

Hypoglycaemia is a frequent adverse effect of treatment of diabetes mellitus with insulin and sulphonylureas. Fear of hypoglycaemia alters self-management of diabetes mellitus and prevents optimal glycaemic control. Mild (self-treated) and severe (requiring help) hypoglycaemia episodes are more common in type 1 diabetes mellitus but people with insulin-treated type 2 diabetes mellitus are also exposed to frequent hypoglycaemic events, many of which occur during sleep. Hypoglycaemia can disrupt many everyday activities such as driving, work performance and leisure pursuits. In addition to accidents and physical injury, the morbidity of hypoglycaemia involves the cardiovascular and central nervous systems. Whereas coma and seizures are well-recognized neurological sequelae of hypoglycaemia, much interest is currently focused on the potential for hypoglycaemia to cause dangerous and life-threatening cardiac complications, such as arrhythmias and myocardial ischaemia, and whether recurrent severe hypoglycaemia can cause permanent cognitive impairment or promote cognitive decline and accelerate the onset of dementia in middle-aged and elderly people with diabetes mellitus. Prevention of hypoglycaemia is an important part of diabetes mellitus management and strategies include patient education, glucose monitoring, appropriate adjustment of diet and medications in relation to everyday circumstances including physical exercise, and the application of new technologies such as real-time continuous glucose monitoring, modified insulin pumps and the artificial pancreas. © 2014 Macmillan Publishers Limited. All rights reserved.

Hadoke P.W.,Queens Medical Research Institute
Current atherosclerosis reports | Year: 2013

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/inhibition causes hypertension, whereas deficiency/inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis.

Low birthweight, a marker of an adverse in utero environment, is associated with cardiometabolic disease and brain disorders in adulthood. The adaptive changes made by the fetus in response to the intra-uterine environment result in permanent changes in physiology, structure and metabolism, a phenomenon termed early life programming. One of the key hypotheses to explain programming, namely over exposure of the developing fetus to glucocorticoids, was proposed nearly two decades ago, following the observation that the fetus was protected from high glucocorticoid levels in the mother by the actions of the placental barrier enzyme, 11β-hydroxysteroid dehydrogenase, which converts active glucocorticoids into inactive products. Numerous mechanistic studies in animal models have been carried out to test this hypothesis using manipulations to increase maternal glucocorticoids. Overall, these have resulted in offspring of lower birthweight, with an activated hypothalamic-pituitary-adrenal (HPA) axis and an adverse metabolic profile and behavioural phenotype in adulthood. Altered glucocorticoid activity or action is a good candidate mechanism in humans to link low birthweight with cardiometabolic and brain disorders. We have carried out detailed studies in men and women showing that high levels of endogenous glucocorticoids, or treatment with exogenous glucocorticoids, is associated with an adverse metabolic profile, increased cardiovascular disease and altered mood and cognitive decline. Our laboratory carried out the first translational studies in humans to test the glucocorticoid hypothesis, firstly demonstrating in studies of adult men and women, that low birthweight was associated with high fasting cortisol levels. We went on to dissect the mechanisms underlying the high fasting cortisol, demonstrating activation of the HPA axis, with increased cortisol responses to stimulation with exogenous adrenocorticotrophin hormone, lack of habituation to the stress of venepuncture, and increased cortisol responses to psychosocial stress. We have developed new dynamic tests to dissect the mechanisms regulating HPA axis central negative feedback sensitivity in humans, and demonstrated that this may be altered in obesity, one component of the metabolic syndrome. There are now studies in humans demonstrating that high circulating levels of maternal cortisol during pregnancy correlate negatively with birthweight, suggesting that excess glucocorticoids can by-pass the placental barrier. Deficiencies in the barrier enzyme, potentially increasing fetal glucocorticoid exposure, can also arise in association with maternal stress, malnutrition and disease, and can be inhibited by consumption of liquorice, which contains glycyrrhizin, an HSD inhibitor. Importantly, studies in humans have now demonstrated that high maternal cortisol in pregnancy and/or inhibition of HSD2 are associated with programmed outcomes in childhood including higher blood pressure, behavioural disorders as well as altered brain structure. We are investigating this further, using novel magnetic resonance imaging techniques to study the developing fetal brain in utero. The translational studies in support of the glucocorticoid hypothesis, and demonstrating that glucocorticoids are both mediators and targets of programming, are exciting and raise the question of whether this information can be used to identify those individuals most at risk of later life disease. In a recent study we showed that alterations in DNA methylation at genes important in regulating cortisol levels, tissue glucocorticoid action, blood pressure and fetal growth, are present in adulthood in association with both early life parameters and cardiometabolic risk factors. These preliminary data add to the limited literature in humans indicating a persisting epigenetic link between early life events and subsequent disease risk. Such findings open novel avenues for further exploration of the contribution of glucocorticoids to later life disease. © 2012 Elsevier Ltd.

Horne A.W.,Queens Medical Research Institute
Expert reviews in molecular medicine | Year: 2012

Ectopic pregnancy is defined as a pregnancy implanted outside the uterus, and >98% implant in the Fallopian tube. It has a major clinical and socioeconomic impact worldwide. The diagnosis of ectopic pregnancy is often difficult and resource intensive owing to a lack of accurate biomarkers, and there is a need for improved medical management of ectopic pregnancy using new or adjuvant treatments. The aetiology of ectopic pregnancy is uncertain, but tubal implantation is probably due to retention of the embryo in the Fallopian tube owing to impaired embryo-tubal transport and alterations in the tubal microenvironment. This comprehensive review of the literature supporting current understanding of the endocrinology of Fallopian tube biology and tubal implantation focuses on genes expressed in the Fallopian tube regulated by oestrogen and progesterone and discusses their potential functions. It concludes with a discussion of how advances in this field are enabling the development of novel biomarkers and could lead to the identification of potential new treatments for ectopic pregnancy.

Dean A.,Queens Medical Research Institute | Sharpe R.M.,Queens Medical Research Institute
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Male reproductive disorders evident at birth or in young adulthood are remarkably common. They are hypothesized to comprise a testicular dysgenesis syndrome (TDS), with a fetal origin involving mild androgen deficiency. Evidence Acquisition: Testing this hypothesis requires "seeing back in time." Two ways have been proposed: measurement of anogenital distance (AGD), or measurement of the 2:4 digit length ratio. This review assesses the evidence that they reflect fetal androgen exposure and might be used to provide insight into the origin of TDS disorders. Evidence Synthesis: Supporting evidence for AGD derives from rat experimental studies that identified a fetal masculinization programming window, within which androgen action determines adult reproductive organ size, TDS disorders, and AGD. In humans, AGD is positively correlated to testis size, sperm count/fertility, penis length, and T levels, consistent with rat experimental data. The 2:4 digit ratio also shows associations with these parameters, but inconsistently between studies; evidence that the 2:4 digit ratio accurately reflects fetal androgen exposure is also equivocal. Conclusions: AGD appears to provide a reliable guide to fetal androgen exposure, although available data are limited. The next steps are to: standardize AGD measurement; obtain age-specific population data; and use AGD to evaluate the importance of fetal androgens in determining reproductive disorders and variation in testis/penis size and sperm count in the normal population. These studies should identify what, if any, clinical applications of AGD measurement are feasible - for example, its ability to predict adult-onset reproductive function and disorders. Copyright © 2013 by The Endocrine Society.

Noy R.,Yeshiva University | Pollard J.W.,Yeshiva University | Pollard J.W.,Queens Medical Research Institute
Immunity | Year: 2014

The tumor microenvironment is a complex ecology of cells that evolves with and provides support to tumor cells during the transition to malignancy. Among the innate and adaptive immune cells recruited to the tumor site, macrophages are particularly abundant and are present at all stages of tumor progression. Clinical studies and experimental mouse models indicate that these macrophages generally play a protumoral role. In the primary tumor, macrophages can stimulate angiogenesis and enhance tumor cell invasion, motility, and intravasation. During monocytes and/or metastasis, macrophages prime the premetastatic site and promote tumor cell extravasation, survival, and persistent growth. Macrophages are also immunosuppressive, preventing tumor cell attack by natural killer and Tcells during tumor progression and after recovery from chemo- or immunotherapy. Therapeutic success in targeting these protumoral roles in preclinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment. © 2014 Elsevier Inc.

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