Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report

This study prospectively examined changes in cognition in hypogonadal men given testosterone (T) or older hypogonadal men given dihydrotestosterone (DHT) gel. A battery of cognitive tests assessing verbal and spatial memory, language, and attention was administered at baseline (prior to medication) and again at days 90 and 180 of treatment for men receiving T gel and at baseline and days 30 and 90 of treatment for men receiving DHT gel. For men receiving T gel, circulating total T and estradiol (E(2)) were significantly raised compared with baseline, and a significant improvement in verbal memory was observed. For men receiving DHT gel, serum DHT levels increased and T levels decreased significantly compared with baseline, and a significant improvement in spatial memory was observed. The results suggest that beneficial changes in cognition can occur in hypogonadal men using T replacement levels and DHT treatment, and these changes in cognition can be reliably measured during a relative steady-state dose level. Further, our results suggest that aromatization of T to E(2) may regulate verbal memory in men, whereas nonaromatizable androgens may regulate spatial memory.     

Treatment of dementia with neurotransmission modulation

The prevalence of dementia is growing in developed countries where elderly patients are increasing in numbers. Neurotransmission modulation is one approach to the treatment of dementia. Cholinergic precursors, anticholinesterases, nicotine receptor agonists and muscarinic M(2) receptor antagonists are agents that enhance cholinergic neurotransmission and that depend on having some intact cholinergic innervation to be effective in the treatment of dementia. The cholinergic precursor choline alfoscerate may be emerging as a potential useful drug in the treatment of dementia, with few adverse effects. Of the anticholinesterases, donepezil, in addition to having a similar efficacy to tacrine in mild-to-moderate Alzheimer's disease (AD), appears to have major advantages; its use is associated with lower drop-out rates in clinical trials, a lower incidence of cholinergic-like side effects and no liver toxicity. Rivastigmine is efficacious in the treatment in dementia with Lewy bodies, a condition in which the other anticholinesterases have not been tested extensively to date. Galantamine is an anticholinesterase and also acts as an allosteric potentiating modulator at nicotinic receptors to increase the release of acetylcholine. Pooled data from clinical trials of patients with mild-to-moderate AD suggest that the benefits and safety profile of galantamine are similar to those of the anticholinesterases. Selective nicotine receptor agonists are being developed that enhance cognitive performance without influencing autonomic and skeletal muscle function, but these have not yet entered clinical trial for dementia. Unlike the cholinergic enhancers, the M(1) receptor agonists do not depend upon intact cholinergic nerves but on intact M(1) receptors for their action, which are mainly preserved in AD and dementia with Lewy bodies. The M(1) receptor-selective agonists developed to date have shown limited efficacy in clinical trials and have a high incidence of side effects. A major recent advancement in the treatment of dementia is memantine, a non-competitive antagonist at NMDA receptors. Memantine is beneficial in the treatment of severe and moderate-to-severe AD and may also be of some benefit in the treatment of mild-to-moderate vascular dementia. Drugs that modulate 5-HT, somatostatin and noradrenergic neurotransmission are also being considered for the treatment of dementia.     

A fully automated [35S]GTPgammaS scintillation proximity assay for the high-throughput screening of Gi-linked G protein-coupled receptors

The diversity of physiological functions mediated by the GPCR superfamily provides a rich source of molecular targets for drug discovery programs. Consequently, a variety of assays have been designed to identify lead molecules based on ligand binding or receptor function. In one of these, the binding of [(35)S]GTPgammaS, a nonhydrolyzable analogue of GTP, to receptor-activated G-protein alpha subunits represents a unique functional assay for GPCRs and is well suited for use with automated HTS. Here we compare [(35)S]GTPgammaS scintillation proximity binding assays for two different G(i)-coupled GPCRs, and describe their implementation with automated high-throughput systems.     

Role of arteries in oxygen induced vaso-obliteration

In mice the retinal vasculature develops in the first postnatal week by spreading from the optic nerve head towards the retinal periphery. During this growth period, exposure to hyperoxia causes vaso-obliteration of capillaries in the retinal center but not in peripheral regions. High oxygen levels lead to downregulation of vascular endothelial growth factor (VEGF), an important survival factor for vascular endothelial cells, which could explain the vaso-obliteration caused by hyperoxia. However, it is not clear why only capillaries in the center of the retina are affected. We therefore investigated how capillary obliteration correlates with VEGF mRNA distribution by in situ hybridization in retinal whole mount preparations. In mouse pups reared under normoxic conditions VEGF mRNA was detectable across the entire vascular network but was virtually absent in the immediate vicinity of arteries. This was true along developing retinal arteries but also around the optic nerve head through which the entire arterial blood supply for the retinal and hyaloid vasculature passes. In these areas capillaries were absent, resulting in so-called capillary free zones. Exposure to hyperoxia caused an expansion of areas with low VEGF mRNA which correlated with capillary obliteration in these regions. Combined capillary obliteration around the optic nerve head and along retinal arteries lead to a large capillary free zone in the center of the retina. Thus, our observations suggest that hyperoxia affects the retinal vasculature by reducing VEGF mRNA levels near arteries and causing a widening of capillary free zones.     

Tegaserod pharmacokinetics are similar in patients with severe renal insufficiency and in healthy subjects

Tegaserod (HTF 919), a selective 5-HT4 receptor partial agonist with promotile activity throughout the gastrointestinal tract, is in development for the treatment of irritable bowel syndrome. In an open-label, parallel-group study, the pharmacokinetics of a single 12-mg oral dose of tegaserod in patients with severe renal insufficiency requiring hemodialysis were compared with data obtained from healthy subjects matched for age, weight, height, and gender (n = 10, both). The pharmacokinetics of tegaserod were similar in both groups (AUC(0h-tz), ng.h/ml: 14.6 +/- 8.5 vs. 14.3 +/- 7.1; Cmax, ng/ml: 4.6 +/- 2.3 vs. 5.1 +/- 2.2; tmax, h: 1.0, for both). Tegaserod had similar tolerability in renally impaired patients and healthy volunteers, with adverse events largely related to the gastrointestinal pharmacological actions of the drug. Therefore, no dose adjustment of tegaserod is necessary for patients with renal insufficiency.     

Alcohol use and related harm among older adolescents treated in an emergency department: the importance of alcohol status and college status

OBJECTIVE: Patients treated in an urban emergency department were studied to determine if college status, gender and having alcohol as a reason for medical treatment were related to alcohol use and related problem behaviors. METHOD: Patients ages 18-19 years (N = 250; 55% men) who had or had not been drinking alcohol prior to the event that precipitated their medical treatment were assessed on their alcohol use, alcohol-related problems and drug use. RESULTS: There were high levels of alcohol use, tobacco use and other drug use in the sample, regardless of the reason for medical treatment. Analyses consistently showed that patients treated for alcohol-related reasons had more severe drinking patterns and problems than patients who were alcohol negative. Patients not enrolled in college showed similar patterns of alcohol consumption as their college-attending peers, but bad more severe alcohol-related behaviors and problems. Few gender differences were found and no interactions were found between gender, alcohol status and college status. CONCLUSIONS: Findings indicate that older adolescents who receive medical treatment for alcohol use are not inexperienced drinkers. Furthermore, in this convenience sample, college students did not appear to be at greater risk for substance use or problems. Findings underscore the potential usefulness of alcohol intervention programs for alcohol-involved medical patients, and the need to attend to the alcohol and drug use of nonstudent populations.     

"It wasn't the plague we expected." Parents' perceptions of the health and environmental impact of opencast coal mining

This paper explores the health and environmental concerns of parents living close to opencast coal mines in the UK and characterises parental risk perceptions in relation to children's asthma status. This qualitative research was undertaken in tandem with an epidemiological investigation aiming to establish whether opencast coal mining adversely affected children's respiratory health. Using a social construction approach, the centrality of health claims in environmental health disputes becomes apparent for a number of claims-makers. We focus on claims of non-activist participants in an epidemiological study, hitherto unknown and unexplored. In all but one case health claims were anticipated rather than realised. No link was found between children's asthma and exacerbation of the condition although some parents of children with asthma had greater concerns during the opencast planning stage. In fact, parents' discourses on children's health largely mirrored the epidemiological findings which showed increased dust, no increase in asthma prevalence but higher rates of general practitioner (GP) consultations for respiratory conditions suggesting that the commonly observed lack of convergence between lay and expert knowledge should not be taken for granted. In spite of this overall lack of an experienced health effect, the sociological data highlight respondents' recognition of the place-specificity of exposures, hence, the reasons why opencast proposals are likely to continue to be met with opposition. Environmental health studies which incorporate epidemiological and social approaches simultaneously have a better chance of arriving at conclusions meaningful to affected communities and facilitate greater understanding of environmental disputes.     

The quality of life of spouse dementia caregivers: changes associated with yielding to formal care and widowhood

The focus of the study was the effect on spouse dementia caregivers of relinquishing care. The study used a longitudinal design, in which a group of 150 dementia caregivers were interviewed 2 years apart (designated Time 1 and Time 2), with data collected from both continuing caregivers and those who had relinquished care. The aims were to determine the extent to which changes over time in quality of life differed between continuing caregivers, those who had yielded to formal care, and those who had been widowed; and to examine whether change in quality of life variables was associated with time since yielding to formal care and time since death of the spouse. Quality of life was defined in terms of health status, psychological well-being, and activity participation. All participants were interviewed in their own homes. Three groups of participants were identified at Time 2: those who continued to provide care for their spouses (n=60); those who had yielded their caregiver role by admitting their spouses to permanent residential care (n=53); and those who had admitted their spouses to permanent institutional care, but whose spouse had then died (n=37). Different patterns of quality of life changes were observed between the three groups, with both positives and negatives associated with disengagement from the caregiving role. Positive changes were particularly evident in psychological well-being and activity participation. These findings were discussed in terms of their relevance for a life transitions approach to the relinquishment of caregiving.