Testosterone Replacement Therapy in Aging Males

The U.S. Food and Drug Administration (FDA) cautions health care providers and patients regarding the use of testosterone replacement therapy products for the aging process, including a decrease in muscle strength, muscle mass, and lack of energy or sexual desire, due to an increased risk of heart attacks and strokes. Testosterone replacement therapy products are indicated for genetic defects, chemotherapy damage, or damage to the hypothalamus or pituitary gland, where testosterone is produced. A patient and his team of health care professionals must seriously consider the risks and benefits when using these products for other indications. Use of testosterone replacement therapy products for low testosterone due to natural aging has been on the rise due to disease state awareness, pharmaceutical marketing and media attention. Pharmacists can make a difference in patients\u27 lives by conducting patient education and counseling for these products

Consequences of <i>in vitro</i> benzyl butyl phthalate exposure for blubber gene expression and insulin-induced Akt activation in juvenile grey seals

Plastic and plasticiser pollution of marine environments is a growing concern. Although phthalates, one group of plasticisers, are rapidly metabolised by mammals, they are found ubiquitously in humans and have been linked with metabolic disorders and altered adipose function. Phthalates may also present a threat to marine mammals, which need to rapidly accumulate and mobilise their large fat depots. High molecular weight (HMW) phthalates may be most problematic because they can accumulate in adipose. We used blubber explants from juvenile grey seals to examine the effects of overnight exposure to the HMW, adipogenic phthalate, benzyl butyl phthalate (BBzP) on expression of key adipose-specific genes and on phosphorylation of Akt in response to insulin. We found substantial differences in transcript abundance of Pparγ, Insig2, Fasn, Scd, Adipoq and Lep between moult stages, when animals were also experiencing differing mass changes, and between tissue depths, which likely reflect differences in blubber function. Akt abundance was higher in inner compared to outer blubber, consistent with greater metabolic activity in adipose closer to muscle than skin, and its phosphorylation was stimulated by insulin. Transcript abundance of Pparγ and Fasn (and Adipoq in some animals) were increased by short term (30 min) insulin exposure. In addition, overnight in vitro BBzP exposure altered insulin-induced changes in Pparγ (and Adipoq in some animals) transcript abundance, in a tissue depth and moult stage-specific manner. Basal or insulin-induced Akt phosphorylation was not changed. BBzP thus acted rapidly on the transcript abundance of key adipose genes in an Akt-independent manner. Our data suggest phthalate exposure could alter seal blubber development or function, although the whole animal consequences of these changes are not yet understood. Knowledge of typical phthalate exposures and toxicokinetics would help to contextualise these findings in terms of phthalate-induced metabolic disruption risk and consequences for marine mammal health

Hypertrophic pulmonary osteoarthropathy secondary to bronchial adenocarcinoma and coexisting pulmonary tuberculosis: a case report

A 44-year-old man presented with painful swelling of wrists and ankles, severe pain at both tibiae, clubbing of fingers and toes and arthritis in wrist and ankle joints. The chest roentgenogram showed consolidation of the right lower lobe, whereas plain roentgenograms revealed solid periosteal reaction at both tibiae. CT and bronchoscopy confirmed the presence of adenocarcinoma of the right lower lobe. Moreover, mycobacterium of tuberculosis was isolated by culture of the patient's sputum

Predicting consequences of POP-induced disruption of blubber glucose uptake, mass gain rate and thyroid hormone levels for weaning mass in grey seal pups

Persistent organic pollutants (POPs) are endocrine disruptors that alter adipose tissue development, regulation and function. Top marine predators are particularly vulnerable because they possess large fat stores that accumulate POPs. However, links between endocrine or adipose tissue function disruption and whole animal energetics have rarely been investigated. We predicted the impact of alterations to blubber metabolic characteristics and circulating thyroid hormone (TH) levels associated with polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCPs) on suckling mass gain and weaning mass in wild grey seal pups. Glucose uptake by inner blubber was a strong predictor of whole animal mass gain rate, which in turn, resulted in heavier weaning mass. Weaning mass was predicted to increase by 3.7 ± 1.59 (sem) %, through increased mass gain rate, in the absence of the previously reported suppressive effect of dioxin-like PCB (DL-PCBs) on blubber glucose uptake. PBDEs were, conversely, associated with faster mass gain. Alleviation of this effect was predicted to reduce weaning mass by 6.02 ± 1.86% (sem). To better predict POPs effects on energy balance, it is crucial to determine if and how PBDEs promote mass gain in grey seal pups. Weaning mass was negatively related to total T3 (TT3) levels. A 20% (range = 9.3–31.7%) reduction in TT3 by DL-PCBs partially overcame the effect of DL-PCB -mediated reduction in blubber glucose uptake. Overall, DL-PCBs were thus predicted to reduce weaning mass by 1.86 ± 1.60%. Organohalogen impacts on whole-animal energy balance in grey seal pups appear to partially offset each other through opposing effects on different mechanisms. POP effects were generally minor, but the largest POP-induced reductions in weaning mass were predicted to occur in pups that were already small. Since weaning mass is positively related to first-year survival, POPs may disproportionately affect smaller individuals, and could continue to have population-level impacts even when levels are relatively low compared to historical values. Our findings show how in vitro experiments combined with measurements in vivo can help elucidate mechanisms that underpin energy balance regulation and help to quantify the magnitude of disruptive effects by contaminants and other stressors in wildlife

Three members of a peptide family are differentially distributed and elicit differential state-dependent responses in a pattern generator-effector system

C-type allatostatins (AST-Cs) are pleiotropic neuropeptides that are broadly conserved within arthropods; the presence of three AST-C isoforms, encoded by paralog genes, is common. However, these peptides are hypothesized to act through a single receptor, thereby exerting similar bioactivities within each species. We investigated this hypothesis in the American lobster, Homarus americanus, mapping the distributions of AST-C isoforms within relevant regions of the nervous system and digestive tract, and comparing their modulatory influences on the cardiac neuromuscular system. Immunohistochemistry showed that in the pericardial organ, a neuroendocrine release site, AST-C I and/or III and AST-C II are contained within distinct populations of release terminals. Moreover, AST-C I/III-like immunoreactivity was seen in midgut epithelial endocrine cells and the cardiac ganglion (CG), whereas AST-C II-like immunoreactivity was not seen in these tissues. These data suggest that AST-C I and/or III can modulate the CG both locally and hormonally; AST-C II likely acts on the CG solely as a hormonal modulator. Physiological studies demonstrated that all three AST-C isoforms can exert differential effects, including both increases and decreases, on contraction amplitude and frequency when perfused through the heart. However, in contrast to many state-dependent modulatory changes, the changes in contraction amplitude and frequency elicited by the AST-Cs were not functions of the baseline parameters. The responses to AST-C I and III, neither of which is COOH-terminally amidated, are more similar to one another than they are to the responses elicited by AST-C II, which is COOH-terminally amidated. These results suggest that the three AST-C isoforms are differentially distributed in the lobster nervous system/midgut and can elicit distinct behaviors from the cardiac neuromuscular system, with particular structural features, e.g., COOH-terminal amidation, likely important in determining the effects of the peptides. NEW & NOTEWORTHY Multiple isoforms of many peptides exert similar effects on neural circuits. In this study we show that each of the three isoforms of C-type allatostatin (AST-C) can exert differential effects, including both increases and decreases in contraction amplitude and frequency, on the lobster cardiac neuromuscular system. The distribution of effects elicited by the nonamidated isoforms AST-C I and III are more similar to one another than to the effects of the amidated AST-C II

Long-Term Effects of Traffic-Related Air Pollution on Mortality in a Dutch Cohort (NLCS-AIR Study)

BACKGROUND: Several studies have found an effect on mortality of between-city contrasts in long-term exposure to air pollution. The effect of within-city contrasts is still poorly understood. OBJECTIVES: We studied the association between long-term exposure to traffic-related air pollution and mortality in a Dutch cohort. METHODS: We used data from an ongoing cohort study on diet and cancer with 120,852 subjects who were followed from 1987 to 1996. Exposure to black smoke (BS), nitrogen dioxide, sulfur dioxide, and particulate matter < or = 2.5 microm (PM(2.5)), as well as various exposure variables related to traffic, were estimated at the home address. We conducted Cox analyses in the full cohort adjusting for age, sex, smoking, and area-level socioeconomic status. RESULTS: Traffic intensity on the nearest road was independently associated with mortality. Relative risks (95% confidence intervals) for a 10-microg/m(3) increase in BS concentrations (difference between 5th and 95th percentile) were 1.05 (1.00-1.11) for natural cause, 1.04 (0.95-1.13) for cardiovascular, 1.22 (0.99-1.50) for respiratory, 1.03 (0.88-1.20) for lung cancer, and 1.04 (0.97-1.12) for mortality other than cardiovascular, respiratory, or lung cancer. Results were similar for NO(2) and PM(2.5), but no associations were found for SO(2). CONCLUSIONS: Traffic-related air pollution and several traffic exposure variables were associated with mortality in the full cohort. Relative risks were generally small. Associations between natural-cause and respiratory mortality were statistically significant for NO(2) and BS. These results add to the evidence that long-term exposure to ambient air pollution is associated with increased mortality

What do young people who self-harm find helpful? A comparative study of young people with and without experience of being looked after in care: What do young people who self-harm find helpful?

BackgroundSelf‐harm amongst young people is an increasing problem, with looked‐after young people at higher risk. Despite this, little research exists on what young people who self‐harm find helpful.MethodOne hundred and twenty‐six 11–21 year olds (53 who had experience of the care system and 73 who did not) were recruited from the community and NHS. All participants had self‐harmed in the past 6 months. Participants completed an Audio Computer‐Assisted Self‐interview (ACASI) regarding their views about the support they had received, how helpful it was, and what further help they felt they needed.ResultsLooked‐after young people reported the three most helpful sources of support were Child and Adolescent Mental Health Services (CAMHS), friends and pets and the least helpful were CAMHS, Accident and Emergency (A&E) and Social services. For non‐looked‐after young people, CAMHS, counselling and Harmless (user‐led support service for self‐harm) were most helpful and CAMHS, cognitive behavioural therapy (CBT) and general practitioner (GP) were the least. Compared with the other group, more looked‐after young people had received help from A&E and CAMHS, whereas more non‐looked‐after young people had accessed GPs, parents, psychological therapies, self‐help books and websites. More looked‐after young people found support groups helpful, and more non‐looked‐after young people reported that distraction techniques, medication and their siblings were helpful.ConclusionYoung people who self‐harm have mixed views about CAMHS. Differences in the pattern of access and preferences for support between looked‐after and non‐looked‐after young people should be reflected in service availability and commissioning

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p&lt;0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p&lt;0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p&lt;0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology