Second messengers, steroids and signaling cascades: Crosstalk in sperm development and function.

Signaling cascades control numerous aspects of sperm physiology, ranging from creation to fertilization. Novel aspects of several kinases and their influence on sperm development will be discussed in the first section and cover proliferation, chromatin remodeling and morphology. In the second section, protein kinases (A, B and C) that affect sperm function and their regulation by second messengers, cyclic-AMP and phosphoinositides, as well as steroids will be featured. Key areas of integration will be presented on the topics of sperm motility, capacitation, acrosome reaction and fertilization.

Dietary Supplement Use in Middle-aged and Older Adults.

OBJECTIVES: Despite limited evidence of clinical benefits, dietary supplement use is increasingly common among older adults. The aim of this study was to characterise the prevalence of dietary supplement use in a national sample of community-dwelling middle-aged and older adults and investigate factors associated with its use. DESIGN/SETTING/PARTICIPANTS: This was a cross-sectional study using data from the Health and Retirement Study (HRS), a biennial, nationally representative survey of individuals aged 50 years and older in the United States. This study combined data from the 2013/14 Health Care and Nutrition Survey (HCNS) and 2012 Core Survey. MEASUREMENTS: The primary outcome was the use of any dietary supplement at least once a week. Secondary outcomes were the use of multivitamins and specific vitamin and supplement types. Multivariable regression models were used to identify factors associated with any dietary supplement use. RESULTS: A total of 6045 participants (weighted n = 71,268,015) were included in the final analytical sample (mean age 67.7 years, 59.3% female). Of these, 84.6% (n=60,292,704) were regular dietary supplement users, with participants taking a mean of 3.2±0.1 different dietary supplements and 41.9% taking four or more. Multivitamins were the most common, used by 57.5% (n=41,147,146) of participants. Other commonly used dietary supplements were vitamin D, fish oil, calcium, vitamin C, and vitamin B12. Older age (75+ years), female sex, higher education, daily alcohol use, vigorous physical activity, regular medication use, and arthritis were associated with higher odds of dietary supplement use. CONCLUSIONS: In this sample of middle-aged and older Americans, more than 4 out of 5 used a dietary supplement. Certain demographic, behavioural, and clinical factors were associated with their use. Given the lack of evidence for improving health outcomes, our findings suggest potential overuse of dietary supplements in people over the age of 50.

The insulin-like growth factor (IGF) system and gonadotropin regulation: actions and interactions.

Insulin-like growth factors (IGF) are polypeptides that regulate growth, differentiation and survival in a multitude of cells and tissues. The IGF system consists of ligands, receptors, binding proteins and binding protein proteases. The influence of the IGF system on reproductive parameters, specifically gonadotropin release and interactions between the IGF system and other effectors of gonadotropin release will be examined in this review.

Corticosteroids and phosphatidylcholine biosynthesis in microsomal fractions from L5178Y lymphoma.

Microsomal fractions from mouse lymphoma L5178Y and from rat thymocytes were used to follow incorporation of radiolabel from cytidine diphosphate-[methyl-14C]choline into microsomal lipids. Dexamethasone, at concentrations ranging from 2.8 X 10(-6)M to 2.8 X 10(-5)M, partially inhibited this transfer reaction. Microsomes prepared from freshly isolated thymocytes were more sensitive to the effects of dexamethasone showing inhibition at concentrations of steroid as low as 2.8 X 10(-8)M. The inhibitory effect did not depend on the amount of the available endogenous diglycerides and was not related to a possible stimulation of cytidine diphosphate choline transferase back reaction by the steroid. The survey of a broad selection of different steroids revealed a lack of correlation between the known lymphocytolytic properties of steroids and their effects on cytidine diphosphate choline transferase. Dexamethasone was the only steroid of the glucocorticoid group that inhibited this reaction in microsomal fractions of L5178Y lymphoma. The structural requirement for the inhibitory effect was related to the absence of oxygen functions in positions 11 and 17 of the steroid and, possibly, to the presence of both C-20 and C-21 on the side chain.

Eclipse-induced wind changes over the British Isles on the 20 March 2015.

The British Isles benefits from dense meteorological observation networks, enabling insights into the still-unresolved effects of solar eclipse events on the near-surface wind field. The near-surface effects of the solar eclipse of 20 March 2015 are derived through comparison of output from the Met Office's operational weather forecast model (which is ignorant of the eclipse) with data from two meteorological networks: the Met Office's land surface station (MIDAS) network and a roadside measurement network operated by Vaisala. Synoptic-evolution relative calculations reveal the cooling and increase in relative humidity almost universally attributed to eclipse events. In addition, a slackening of wind speeds by up to about 2 knots in already weak winds and backing in wind direction of about 20° under clear skies across middle England are attributed to the eclipse event. The slackening of wind speed is consistent with the previously reported boundary layer stabilization during eclipse events. Wind direction changes have previously been attributed to a large-scale 'eclipse-induced cold-cored cyclone', mountain slope flows, and changes in the strength of sea breezes. A new explanation is proposed here by analogy with nocturnal wind changes at sunset and shown to predict direction changes consistent with those observed.This article is part of the themed issue 'Atmospheric effects of solar eclipses stimulated by the 2015 UK eclipse'.

Atmospheric changes from solar eclipses.

This article reviews atmospheric changes associated with 44 solar eclipses, beginning with the first quantitative results available, from 1834 (earlier qualitative accounts also exist). Eclipse meteorology attracted relatively few publications until the total solar eclipse of 16 February 1980, with the 11 August 1999 eclipse producing the most papers. Eclipses passing over populated areas such as Europe, China and India now regularly attract scientific attention, whereas atmospheric measurements of eclipses at remote locations remain rare. Many measurements and models have been used to exploit the uniquely predictable solar forcing provided by an eclipse. In this paper, we compile the available publications and review a subset of them chosen on the basis of importance and novelty. Beyond the obvious reduction in incoming solar radiation, atmospheric cooling from eclipses can induce dynamical changes. Observations and meteorological modelling provide evidence for the generation of a local eclipse circulation that may be the origin of the 'eclipse wind'. Gravity waves set up by the eclipse can, in principle, be detected as atmospheric pressure fluctuations, though theoretical predictions are limited, and many of the data are inconclusive. Eclipse events providing important early insights into the ionization of the upper atmosphere are also briefly reviewed.This article is part of the themed issue 'Atmospheric effects of solar eclipses stimulated by the 2015 UK eclipse'.

The National Eclipse Weather Experiment: an assessment of citizen scientist weather observations.

The National Eclipse Weather Experiment (NEWEx) was a citizen science project designed to assess the effects of the 20 March 2015 partial solar eclipse on the weather over the United Kingdom (UK). NEWEx had two principal objectives: to provide a spatial network of meteorological observations across the UK to aid the investigation of eclipse-induced weather changes, and to develop a nationwide public engagement activity-based participation of citizen scientists. In total, NEWEx collected 15 606 observations of air temperature, cloudiness and wind speed and direction from 309 locations across the UK, over a 3 h window spanning the eclipse period. The headline results were processed in near real time, immediately published online, and featured in UK national press articles on the day of the eclipse. Here, we describe the technical development of NEWEx and how the observations provided by the citizen scientists were analysed. By comparing the results of the NEWEx analyses with results from other investigations of the same eclipse using different observational networks, including measurements from the University of Reading's Atmospheric Observatory, we demonstrate that NEWEx provided a fair representation of the change in the UK meteorological conditions throughout the eclipse. Despite the simplicity of the approach adopted, robust reductions in both temperature and wind speed during the eclipse were observed.This article is part of the themed issue 'Atmospheric effects of solar eclipses stimulated by the 2015 UK eclipse'.

Targeted disruption of the pituitary adenylate cyclase-activating polypeptide gene results in early postnatal death associated with dysfunction of lipid and carbohydrate metabolism.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hormone belonging to the glucagon superfamily of hormones. These hormones are known to play important roles in metabolism and growth. PACAP is a neuropeptide that causes accumulation of cAMP in a number of tissues and affects the secretion of other hormones, vasodilation, neural and immune functions, as well as the cell cycle. To determine whether PACAP is essential for survival and to evaluate its function(s), we have generated mice lacking the PACAP gene via homologous recombination. We found that most PACAP null mice died in the second postnatal week in a wasted state with microvesicular fat accumulation in liver, skeletal muscle, and heart. Gas chromatography-mass spectrometry showed that fatty acid beta-oxidation in liver mitochondria of PACAP(-/-) mice was not blocked based on the distribution of 3-hydroxy-fatty acids (C6-16) in the plasma. Instead, increased metabolic flux through the beta-oxidation pathway was suggested by the presence of ketosis. Also, serum triglycerides and cholesterol were significantly higher (2- to 3-fold) in PACAP null mice than littermates. In the fed state, both serum insulin and blood glucose were normal in 5-d-old null mice compared with their littermates. In contrast, fasted PACAP null pups had a significant increase in insulin, but a decrease in blood glucose compared with littermates. Glycogen in the liver was reduced. These results suggest PACAP is a critical hormonal regulator of lipid and carbohydrate metabolism.

Characteristics predicting incorrect metered-dose inhaler technique in older subjects.

OBJECTIVE: To determine whether cognitive status, hand strength, and demographic variables are predictive of correct use of metered-dose inhalers by older subjects. METHODS: Clinic patients (n = 29) and healthy volunteers (n = 42) older than 50 years with no previous or limited metered-dose inhaler use were enrolled. After cognitive (Mini-Mental State Examination) and hand strength assessments, subjects received extensive instruction in proper metered-dose inhaler technique. Technique was independently assessed by two evaluators immediately after instruction and 1 week later. Correct technique was defined as (1) activating the canister in the first half of inhalation, (2) continuing to inhale slowly and deeply, and (3) holding breath at full inspiration (5 seconds). Data for the two subject groups were pooled for analyses. RESULTS: The mean age of the subjects was 69.7 years. Forty subjects (56%) demonstrated correct metered-dose inhaler technique at 1 week. Logistic regression showed that hand strength measurement (odds ratio, 0.68; 95% confidence interval, 0.55 to 0.84), Mini-Mental State Examination score less than 24 (odds ratio, 3.66; 95% confidence interval, 1.07 to 12.4), and male gender (odds ratio, 5.01; 95% confidence interval, 1.07 to 23.5) were significant predictors of incorrect inhaler use. Correct use of the metered-dose inhaler was unrelated to age, education, or subject status. CONCLUSIONS: Clinicians should consider cognitive status and hand strength when metered-dose inhaler therapy is initiated for an older adult. Patients with cognitive impairment and hand strength deficits may require more extensive training, frequent follow-up, or alternative dosage forms.

Factors affecting choice of community residential care setting.

UNLABELLED: To investigate factors associated with residents' choice of type of Medicaid-funded community residential care setting in western Washington State. METHOD: Prospective cohort design including residents new to any of three setting types (264 residents entering 170 different facilities), using data from state and Medicaid databases and in-person interviews. The authors used analysis of variance and multinomial logistic regression to examine bivariate associations and estimate effects of resident and facility characteristics on choice of facility type at baseline. RESULTS: Several resident characteristics appear to be associated with choice of community residential care setting, including age, marital status, education, functional status, and reported memory and behavior problems. Facility policies differ significantly among types of facilities and also appear to be associated with choice of setting. DISCUSSION: Selection processes operate in choice of community residential care setting, with residents choosing facility type based on the fit of their needs with facility characteristics.

Assessment of interrater and intrarater reliability in the evaluation of metered dose inhaler technique.

STUDY OBJECTIVE: To determine if a training session using videotaped metered dose inhaler (MDI) performances can result in high interrater and intrarater reliability of five evaluators assessing MDI technique. DESIGN: Five evaluators (three pharmacists, two pulmonary fellows) were trained to evaluate MDI technique during a 2-h training session. The training session consisted of verbal instruction and practical experience in evaluating MDI technique using video-taped MDI performances of six nonstudy subjects. After the training session, the evaluators independently observed the same videotaped MDI demonstrations of 14 subjects on two occasions separated by a 7- to 10-day interval. Interrater and intrarater reliability was determined for individual steps by calculating percent agreement and intraclass correlation (ICC) coefficient. RESULTS: Interrater. The interrater reliability for individual steps ranged from 29 to 86 percent (ICC coefficient = 0.13 to 0.81). Steps in which evaluators were in agreement for less than 9 of the 14 subjects were shaking the inhaler before inhalation, exhaling, continuing to inhale slowly, and adequate breath hold. Intrarater: The overall percent agreement by step ranged from 74 to 97 percent. Exhaling to functional residual volume (76 percent) and continuing to inhale slowly and deeply (74 percent) had the lowest overall agreement between the first and second observation day. The consistency of evaluating a step between the two observation days varied considerably depending on the step and evaluator. CONCLUSIONS: High interrater and intrarater reliability in MDI evaluation is difficult to obtain. Clinicians and researchers involved in MDI evaluation and education should be trained to achieve consistency. A single training session using videotaped MDI demonstrations was not adequate in achieving consistency among evaluators. To improve accuracy of research results, researchers should include at least two evaluators to assess MDI technique or take other measures to show and report reliability.

Residues from anabolic preparations after good veterinary practice.

The purpose of this study was to determine the endogenous concentrations of estrogens, particularly estradiol-17beta (E2beta, in edible tissues of beef cattle (females and intact and neutered males) and the concentrations of E2beta, and trenbolone beta and alpha (betaTb, alphaTb) after an E2beta and/or trenbolone acetate (TA) ear implant. Radioimmunoassays were validated for quantitation of E2beta (active isomer), E2alpha, estrone (E1), betaTb and alphaTb for bovine muscle, liver, kidney and fat tissues. The criteria of accuracy, precision, specificity and sensitivity were applied according to the standards of the U.S. Food & Drug Administration. In steer tissues, endogenous E2beta was <15 ppt, as was heifer muscle; but heifer liver and kidney were 3-fold greater. An E2beta implant in steers had no effect on muscle E2beta concentration, but increased E2beta in liver and fat 4- and 3-fold, respectively, but by 24 h post-implant removal, E2beta had fallen by half. Tissue E1 concentrations in cyclic females were similar to E2beta, but rose many fold greater than did E2beta during gestation; E2beta rose 3-fold during gestation. After E2beta/TA implant, steer tissues had E2beta concentrations equal to (for muscle and fat) and one-half (for liver) the E2beta measured in E2beta implant only steers; betaTb was in a low range (250-380 ppt) in muscle, liver and fat and alphaTb was even lower, except in liver (800-1500 ppt). An implant of TA only (no E2beta) resulted in betaTb and alphaTb concentrations 2-3-fold greater in liver, kidney and fat, but no greater in muscle than betaTb in tissues of E2beta/TA implant steers. In conclusion, anabolic implants in steers resulted in tissue E2beta concentrations less than the FDA allowable increment and betaTb in the lowest quartile (0.25) of a part per billion 30 days after implant.

Effect of a single dose of diazepam on balance measures in older people.

OBJECTIVE: This study examines the effect of a single dose of diazepam on a spectrum of balance measures in healthy older subjects. The measures include static (postural sway), dynamic (anterior tibialis muscle activation latency), and a complex self-initiated task of balance (functional reach) in addition to neuropsychological tests of attention. DESIGN: A double-blind, two-period, cross-over trial. SETTING: The community surrounding a university hospital. PARTICIPANTS: Community-dwelling, nonsmoking volunteers 65 years of age and older. MEASUREMENTS: Measures included response to unexpected perturbation (platform/EMG muscle latency), self-initiated perturbation (functional reach), and a static measure of balance (postural sway). Neurocognitive tests (digital symbol substitution test, card sorting) were included to document the cognitive effect. RESULTS: Twelve nonsmoking healthy subjects (average age = 70.4 years (66-76 years)) participated. The anterior tibalis muscle latency increased in response to a sudden perturbation with diazepam compared with placebo (TA latency 149 ms vs 142 ms, P < .001). Neurocognitive tests were adversely affected for 90 minutes after diazepam administration compared with placebo (P < .05). Other measures did not demonstrate significant effect of diazepam. CONCLUSIONS: This is among the first reports showing that benzodiazepines affect neuromuscular processing related to balance control. Increased muscle latency to sudden perturbations may represent an effect of diazepam upon the oligosynaptic spinal reflex distinct from the sedation. Surface electromyography may be a valuable noninvasive tool for future studies of drug effect on balance and falls risk among older people.

Measured versus estimated creatinine clearance in a high-functioning elderly sample: MacArthur Foundation Study of Successful Aging.

OBJECTIVE: To assess the validity of several equations for estimating creatinine clearance in a large sample of high-functioning, community-dwelling elderly. DESIGN: Serum and 12-hour urine samples were collected and assayed for creatinine using the Jaffe total chromagen method. Fifteen clearance-estimating equations were evaluated for bias, accuracy, correlation with measured clearance values, and frequency of erroneous placement into renal function categories. Stepwise regression modeling and reliability testing were performed on a split sample to construct and assess a novel creatinine-clearance-estimating equation. SETTING: New Haven, Connecticut, East Boston, Massachusetts, and a five-county region in and around Durham, North Carolina. PARTICIPANTS: A subsample of community-dwelling men and women (age range 70-79 years) from the Established Populations for Epidemiological Studies of the Elderly was screened for physical and cognitive functioning and placed into high-, medium-, and low-functioning groups (n = 1354). High-functioning respondents who provided blood and complete urine samples (n = 762) were included in the present study. RESULTS: In general, estimated creatinine clearance was more closely correlated to measured values in males than in females. Most equations underestimated creatinine clearance, with average bias ranging from -33.1 mL/min to +19.6 mL/min. Predictive accuracy ranged from 18.2 mL/min to 38.0 mL/min. Equations were variable in their erroneous placement of individuals into renal function categories. Regression modeling yielded an equation which contained novel components but failed to provide better estimates of creatinine clearance than those already available. CONCLUSIONS: The equations evaluated here provide unacceptable predictions of creatinine clearance in normally aging individuals. We advocate the use of serum drug concentration measurements when available and encourage investigation into timed urine collections of short duration as alternatives to clearance-estimating equations in the elderly.

Adverse drug events in hospitalized elderly.

BACKGROUND: The study objectives were (a) to describe the occurrence, types, and preventability of adverse drug events (ADEs) in hospitalized patients 70 years of age and older; (b) to examine the association between potential risk factors and ADEs; and (c) to examine the relationship of an ADE occurrence and hospital length of stay (LOS) and functional decline. METHOD: Consecutive general medical admissions (n = 157) of community-dwelling persons were prospectively monitored daily for ADE occurrence. Admission assessment included demographic factors, cognition, preadmission medication use, and functional status. Discharge assessment included functional status. LOS, discharge diagnoses, and medication use during the hospitalization. RESULTS: Twenty-three patients (14.6%) experienced 28 probable ADEs, of which 54.2% (13/24) were judged to be potentially preventable. Patients experiencing an ADE had a significantly lower mean Mini-Mental State Examination score (23.6 +/- 4.3 vs 25.5 +/- 3.6, p = .039) and were prescribed significantly more new inpatient medications (4.0 +/- 2.3 vs 2.6 +/- 1.7, p = .01) compared to non-ADE patients. Age, gender, functional status prior to admission, percent with more than four active diagnoses, or number of preadmission medications were not associated with ADE status. Upon discharge, 50.0% of ADE patients experienced a decline in one or more activities of daily living (ADLs), compared with 24.1% of non-ADE patients (p = .017). ADE patients had a longer LOS (8.7 +/- 4.9 vs 6.6 +/- 3.0 days, p = .022) compared to non-ADE patients. CONCLUSIONS: ADEs were associated with number of new inpatient medications and admission cognitive status, but not demographic, disease, or physical function variables. Patients experiencing an ADE were more likely to experience a longer LOS and to decline in ADL function. ADEs may be one factor contributing to functional decline during hospitalization. Future research in this area should include larger samples and multivariable analyses controlling for potential confounders.

Drug-induced cognition disorders in the elderly: incidence, prevention and management.

The aetiology of cognitive impairment is multifactorial; however, drugs are an important cause of delirium and dementia. Several factors may increase the risk of drug-induced cognition disorders in the elderly including imbalances in neurotransmitters (e.g. acetylcholine), age-related alterations in pharmacokinetics and pharmacodynamics, and high levels of medication use. Nearly any drug can cause cognitive impairment in susceptible individuals; however, certain classes are more commonly implicated. Benzodiazepines, opioids, anticholinergics, and tricyclic antidepressants are probably the worst offenders. Older antihypertensive agents (reserpine, clonidine) have negative effects on cognition; however, large clinical trials in the elderly indicate that commonly used agents [e.g. thiazide diuretics, calcium antagonists (amiodipine, diltiazem), ACE inhibitors (captopril, enalapril) and beta-blockers (atenolol)] have minimal effects on cognition. Newer antidepressants such as selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) and reversible inhibitors of monoamine oxidase A have not been shown to have negative effects on cognition. Although some drugs have shown low risk for causing cognition disorders in research studies, risk may be increased in frail older adults taking several medications and each case should be reviewed carefully. Identification of drug-induced cognitive impairment is crucial to early detection and resolution of symptoms. Preventive strategies directed at avoiding high risk medications when possible, appropriately adjusting doses based on age-related changes and close follow-up may prevent these conditions.

Actions and interactions of the IGF system in Alzheimer's disease: review and hypotheses.

Insulin-like growth factors (IGF) are pleiotrophic polypeptides affecting all aspects of growth and development. The IGF system, including ligands, receptors, binding proteins and proteases is also involved in pathophysiological conditions, such as cancer and degenerative conditions. In this review, the actions and interactions of the IGF system as it relates to Alzheimer's disease will be investigated.

Predictors of nutritional supplement use by the elderly.

We conducted a population survey to describe patterns and determine predictors of the use of nutritional supplements and single-ingredient vitamins and minerals among elderly living in five adjacent urban and rural counties in the Piedmont area of North Carolina. The stratified random sample consisted of 3939 black and white participants age 65 or older from the Duke Established Populations for Epidemiologic Studies of the Elderly. The use of nutritional supplements within the previous 2 weeks was determined during an in-home interview. Multivariate analyses, using weighted data adjusted for sampling design, were conducted to assess the association between nutritional supplement use and predisposing, need, and enabling factors. Nutritional supplement use was reported by 26.2% of participants and was more likely for those who were white women, were high school educated, were underweight, took prescription drugs, had five or more health visits in the previous year, and had supplemental health insurance. It was less likely for those with poor self-rated health. The majority (71.5%) of nutritional supplement users took at least one single-ingredient supplement. Use of such products was more likely in those who were white, born and raised in an urban area, and high school educated, and was less likely in those with impaired functional status. Nutritional supplement use is prevalent in community-dwelling elderly and is more commonly associated with demographic factors and access to health care than with need factors.

Management of older adults with hypercholesterolaemia.

Although the strength of total cholesterol levels as a relative risk factor for coronary heart disease (CHD) declines with age, the prevalence of CHD increases dramatically with age. Data from cholesterol treatment trials, although sparse in older adults, suggest that dyslipidaemia treatment has the potential to prevent CHD. In particular, dyslipidaemia treatment appears to be most beneficial in older adults with a history of CHD or who have several other CHD risk factors. Dyslipidaemia screening should be selective in the elderly, reserved for those whose health status would be amenable to nutritional or pharmacological therapy, and in whom several CHD risk factors or a history of CHD are present. Since high density lipoprotein cholesterol (HDL) levels retain their inverse association CHD in old age, cholesterol subfractions should be measured in persons being screened in order to adequately assess the severity of dyslipidaemia. Treatment decisions should be guided by the patient's dyslipidaemic class, which is determined by the cholesterol subfractions and serum triglycerides (TG). As in younger persons, nutritional therapy remains the first step in dyslipidaemia management in high risk, nondebilitated older adults. An array of cholesterol modifying medications are available which vary widely in treatment effects, adverse effects and cost. Extra care needs to be taken in prescribing these agents in older adults because of greater potential for adverse effects and interactions with other medications. The cost-effectiveness of pharmacological treatment decreases with age and increases with the severity of dyslipidaemia, a history of CHD, or the presence of multiple CHD risk factors. When comparing elderly to middle-aged adults, the relative cost-effectiveness of different cholesterol-lowering medications may be altered due to age-related changes in therapeutic efficacy and adverse effects.

Measurement of leptin and insulin-like growth factor-I in seminal plasma from different species.

The multi-functional proteins, insulin-like growth factor-I (IGF-I) and leptin were present in seminal plasma from different species. Concentrations of IGF-I in equine and porcine semen were 20 and 17.5 ng/ml, respectively. Seminal plasma concentrations of leptin were 1 ng/ml in human and 11 ng/ml in porcine samples.