Dopamine D3 receptors as a therapeutic target for methamphetamine dependence

Background: Methamphetamine (MA) use disorders are major public health problems nationally and worldwide and treatment remains an unmet need. Objectives: (1) To review preclinical and clinical studies identifying the dopamine D3 receptor as a therapeutic target for substance use disorders (SUDs), including MA dependence, (2) to consider buspirone (Buspar®) as a potential medication based on its dopamine D3 receptor antagonist properties, and (3) to evaluate the safety and initial efficacy of buspirone in a pilot study of MA-dependent individuals. Methods: Literature on the dopamine D3 receptor as a therapeutic target and on the potential of buspirone as a novel therapy for MA dependence was reviewed. The cardiovascular and subjective effects of intravenous MA challenge were assessed in five non-treatment seeking individuals. Participants met DSM-IV criteria for MA dependence and were treated subacutely (9 days) with buspirone (60?mg daily). Results: The literature identified the dopamine D3 receptor as a therapeutic target for MA dependence, a safe and approved medication, and a valuable opportunity to re-purpose buspirone for treating MA dependence and perhaps other SUDs. Pilot data (n?=?5) indicated that buspirone is safe in MA-using individuals and comparison against historical placebo data from this laboratory suggested that at least some aspects of the subjective properties of MA may be diminished during buspirone treatment. Conclusion: Future studies should include a small-scale, placebo-controlled Phase IIa trial of buspirone in MA dependence.     

Multimorbidity's research challenges and priorities from a clinical perspective: The case of ‘Mr Curran’

Older patients, suffering from numerous diseases and taking multiple medications are the rule rather than the exception in primary care. A manifold of medical conditions are often associated with poor outcomes, and their multiple medications raise additional risks of polypharmacy. Such patients account for most healthcare expenditures. Effective approaches are needed to manage such complex patients in primary care. This paper describes the results of a scoping exercise, including a two-day workshop with 17 professionals from six countries, experienced in general practice and primary care research as well as epidemiology, clinical pharmacology, gerontology and methodology. This was followed by a consensus process investigating the challenges and core questions for multimorbidity research in primary care from a clinical perspective and presents examples of the best research practice. Current approaches in measuring and clustering multimorbidity inform policy-makers and researchers, but research is needed to provide support in clinical decision making. Multimorbidity presents a complexity of conditions leading to individual patient's needs and demanding complex processes in clinical decision making. The identification of patterns presupposes the development of strategies on how to manage multimorbidity and polypharmacy. Interventions have to be complex and multifaceted, and their evaluation poses numerous methodological challenges in study design, outcome measurement and analysis. Overall, it can be seen that complexity is a main underlying theme. Moreover, flexible study designs, outcome parameters and evaluation strategies are needed to account for this complexity.     

A synthesis of a vocational assessment system and an information system of technical aids

Purpose : In vocational rehabilitation, the selection and tailoring of the work place is tightly bound with the integration or reintegration of people with disabilities into the work environment. Instruments which ease this task are assessment systems as well as information systems of technical aids. To date, these instruments are separated from one another in practice. They also necessitate a broad transfer capacity between the results of an assessment system and the selection of technical aids for a work place design suited for people with disabilities. Method/Results : Therefore, when employing assessment system, immediate access to information concerning technical aids would ease the work of experts in the area of vocational rehabilitation. This information should also provide a commentary concerning which aids have been utilized to date in concrete cases of suitably designing work places for people with disabilities. Conclusions : This article describes the synthesis of a vocational assessment system with an information system of technical aids from the aspect of frequency of use.     

Dietary studies of children from a biracial population: intakes of vitamins in 10- and 13-year-olds.

Impact of vitamin supplements upon dietary intakes of eight vitamins was examined in 10- and 13-year-old children randomly selected from a biracial community, Bogalusa, LA. More younger children reported taking supplements daily (17%) than did adolescents (12%). Over 90% of the children surveyed had dietary intakes of vitamin E and niacin that met or exceeded the RDA. One-half to two-thirds of children using supplements had adequate intakes of ascorbic acid from diet alone. Children who most needed ascorbic acid supplements were the least likely to take them. One-quarter to one-half of the children did not consume the RDA levels of vitamin A, thiamine, and riboflavin. Adolescents had less adequate vitamin A intakes than younger children. In all surveys, a higher proportion of girls than boys had intakes that did not meet the RDA for vitamins B6 and B12. Vitamin intakes of Bogalusa children and adolescents were comparable to other U.S. surveys. Inclusion of vitamin E and niacin in supplements may be unnecessary.     

Sex-specific mating pheromones in the nematode Panagrellus redivivus

Nematodes use an extensive chemical language based on glycosides of the dideoxysugar ascarylose for developmental regulation (dauer formation), male sex attraction, aggregation, and dispersal. However, no examples of a female- or hermaphrodite-specific sex attractant have been identified to date. In this study, we investigated the pheromone system of the gonochoristic sour paste nematode Panagrellus redivivus, which produces sex-specific attractants of the opposite sex. Activity-guided fractionation of the P. redivivus exometabolome revealed that males are strongly attracted to ascr#1 (also known as daumone), an ascaroside previously identified from Caenorhabditis elegans hermaphrodites. Female P. redivivus are repelled by high concentrations of ascr#1 but are specifically attracted to a previously unknown ascaroside that we named dhas#18, a dihydroxy derivative of the known ascr#18 and an ascaroside that features extensive functionalization of the lipid-derived side chain. Targeted profiling of the P. redivivus exometabolome revealed several additional ascarosides that did not induce strong chemotaxis. We show that P. redivivus females, but not males, produce the male-attracting ascr#1, whereas males, but not females, produce the female-attracting dhas#18. These results show that ascaroside biosynthesis in P. redivivus is highly sex-specific. Furthermore, the extensive side chain functionalization in dhas#18, which is reminiscent of polyketide-derived natural products, indicates unanticipated biosynthetic capabilities in nematodes.