In search of susceptibility genes for schizophrenia

Zusammenfassung Nachdem in den letzten Jahren einige Kandidatenregionen der Schizophrenie auf mehreren Chromosomen gefunden und in Replikationstests bestätigt werden konnten, wurden in jüngster Zeit von verschiedenen Arbeitsgruppen erstmals Vulnerabilitätsgene für Schizophrenie identifiziert. Jede dieser Entdeckungen resultierte aus Assoziationsanalysen in chromosomalen Regionen, in welchen zuvor mittels Kopplungsanalysen Kopplungssignale gefunden wurden. Die in den letzten beiden Jahren entdeckten Vulnerabilitätsgene Neuregulin1, Dysbindin, D-Aminosäure-Oxidase (DAAO, D-amino-acid-oxidase) und G72 entfalten ihre Wirkung vermutlich durch Verminderung der Glutamat-Aktivität im Gehirn (wobei jeweils die mutierte Form die Glutamat-Aktivität vermindert) und stehen damit mit der so genannten „Glutamathypothese“, welche von einer Unterfunktion des glutamatergen Systems ausgeht, in Zusammenhang. Erwachsene mit VCFS (velo-cardio-faciales Syndrom) haben eine sehr hohe Inzidenz von Schizophrenie, wobei beim VCFS eine Deletion auf Chromosom 22q11 vorliegt. Diese 22q11-Deletion findet man außerdem bei 2 % der Patienten mit Schizophrenie. Mit zwei Genen auf Chromosom 22q11 innerhalb der VCFS-deletierten Region, der Prolin-Dehydrogenase (PRODH) und der Catechol-O-Methyltransferase (COMT), wurde ebenfalls eine signifikante Assoziation mit Schizophrenie gefunden. Prolin ist eine Vorstufe des Glutamat, dürfte aber darüber hinaus auch selbst ein Neuromodulator der glutamatergen Transmission im Gehirn sein. COMT ist eines der beiden Enzyme, die Katecholamine wie unter anderem Dopamin abbauen, und spielt damit eine besondere Rolle im kortikalen Dopamin-Stoffwechsel. Weiters wurde eine Assoziation der Schizophrenie mit dem Gen RGS4 (Regulator of G-Protein Signaling 4), einem Modulator der Funktion mehrerer G-Protein-gekoppelter Neurotransmitter-Rezeptoren, gefunden, wobei Gen-Expressions-Analysen von postmortem Großhirnrinden (präfrontal) darauf hinweisen, dass die Transkription von RGS4 bei Schizophrenen vermindert ist. In Übereinstimmung mit der Tatsache, dass die Schizophrenie eine Erkrankung mit multifaktorieller Verursachung ist, sollte festgehalten werden, dass die beschriebenen biologischen Risikofaktoren die Anfälligkeit für die Erkrankung möglicherweise erhöhen können, jeder für sich alleine jedoch die Krankheit keinesfalls auslösen kann.     

Volume-sensitive chloride channels (ICl,vol) mediate doxorubicin-induced apoptosis through apoptotic volume decrease in cardiomyocytes

Apoptosis is associated with early changes in cell volume through a mechanism called apoptotic volume decrease (AVD). As volume-sensitive chloride channels (I(Cl,vol)) are known to play a key role in the regulation of cell volume, this study investigated the role of I(Cl,vol) and AVD in doxorubicin-induced apoptotic cell death in adult rabbit ventricular cardiomyocytes. Exposure of cardiomyocytes to 1 microm doxorubicin induced a rapid and significant reduction in cell volume of cardiomyocytes (average of 15%), i.e. AVD as well as increases in the early markers of apoptosis, annexin V labeling and caspase-3 activity. Doxorubicin also induced the activation of a current characterized as I(Cl,vol) on the basis of the external chloride sensitivity and pharmacological properties with the patch clamp technique. Doxorubicin-induced AVD and apoptosis were both abolished when cardiomyocytes were exposed to the I(Cl,vol) inhibitors 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) (0.1 mM) or indanyloxyacetic acid 94 (IAA-94) (10 microM). The crucial role of I(Cl,vol) during AVD and apoptosis was confirmed using C(2)-ceramide, another pro-apoptotic compound. These results demonstrate that activation of I(Cl,vol) plays a major role in the mechanism leading to cell shrinkage and apoptosis-induced AVD by agents such as doxorubicin or C(2)-ceramide in adult cardiomyocytes.     

A decrease in physical activity affects appetite, energy, and nutrient balance in lean men feeding ad libitum

BACKGROUND: It is not clear how decreased activity quantitatively affects energy balance (EB) in subjects feeding ad libitum. OBJECTIVE: We assessed the effect of an imposed sedentary routine on appetite, energy intake (EI), EB, and nutrient balance in lean men for 7 d. DESIGN: Six men with a mean (+/-SD) age of 23.0 +/- 2.3 y, weight of 69.2 +/- 11.4 kg, and height of 1.76 +/- 0.07 m were each studied twice during a sedentary [1.4 x resting metabolic rate (RMR)] and a moderately active (1.8 x RMR) regimen. During each treatment, they resided in the whole-body indirect calorimeter for the 7 d and had ad libitum access to a medium-fat diet of constant, measurable composition. Meal size, frequency, and composition were continually monitored. Motivation to eat was recorded during waking hours. Subjects were weighed in light clothing each morning, and their weight was corrected to nude. RESULTS: Energy expenditure was 9.7 and 12.8 MJ/d [P < 0.01; SE of the difference between means (SED) = 0.41] during the sedentary and active regimens, respectively. EI was 13.5 and 14.4 MJ/d (P = 0.463, SED = 1.06), respectively. There was no regimen effect on hunger, appetite, or body weight. By day 7, cumulative EB was 26.3 and 11.1 MJ, respectively. CONCLUSIONS: Reducing a level of physical activity from 1.8 to 1.4 x RMR can markedly affect EB. A sedentary routine does not induce a compensatory reduction of EI and leads to a significantly positive EB, most of which is stored as fat.     

The relationship between self-reported emotional health, demographics, and perceived satisfaction with prenatal care

Aims to describe pregnant women with poor emotional health and the relationship between self-reported emotional health and prenatal care satisfaction. To this end, 1,265 women who delivered a live-born singleton infant were interviewed and information abstracted from prenatal records. Concludes that patient assessment of satisfaction with prenatal care may be related to both self-reported emotional health and delivery of medical care. Identifying and addressing emotional health of prenatal patients may improve compliance with medical recommendations, ultimately improving health outcomes.     

Stress, trauma, and risky sexual behaviour among American Indians in young adulthood

This paper examines the relationship of risky sexual behaviour to stress and trauma-often the mediators of the content and structure of everyday life-among young American Indians. School, work, social life, and home life bring about demands and stresses for youth; choices young people make may depend on the quantity and content of those demands. Traumatic events or highly distressing situations may shatter fragile (or even resilient) systems of external and internal support from which youth may draw. American Indians live in some of the most impoverished areas of the country, where everyday life includes a heavy burden of stress and trauma. Using data from a representative sample of youth from a Northern Plains tribe, bivariate and adjusted ordered logit models are used to show that stress and trauma do play a role in the sexual decision-making of young people, especially young women. For example, young women who have experienced a trauma have a 20% probability of having had multiple casual partners in the prior year compared to 9% for those who have not experiences a trauma. Types and levels of stress and trauma also make a difference by gender.     

Medically eligible women who do not use HAART: the importance of abuse, drug use, and race

OBJECTIVES: We investigated the prevalence and characteristics of HIV-positive women who do not report highly active antiretroviral therapy (HAART) use. METHODS: We analyzed HAART use among 1165 HIV-positive participants in the Women's Interagency HIV Study. RESULTS: Between October 1, 2000, and March 31, 2001, 254 women with clinical indications for HAART reported not using it, 635 reported HAART use, and 276 had no clinical indications. In multivariate analysis, using crack/cocaine/heroin and a history of abuse decreased the likelihood of using HAART, whereas being White increased it. CONCLUSIONS: One of 4 women for whom HAART was indicated reported not using HAART. Childhood sexual abuse prevention, more intensive abuse treatment, and continuing drug treatment may enhance HIV disease treatment of women.     

The view from two sides: a qualitative study of community and medical perspectives on screening for colorectal cancer using FOBT

BACKGROUND: Population-wide screening for people at average risk of colorectal cancer (CRC) by faecal occult blood test (FOBT) is under consideration in Australia. METHODS: Qualitative methods were used to examine the views of community members who did (n = 18) or did not (n = 12) participate in a pilot program of FOBT screening. In addition, views were obtained from general practitioners (GPs) and specialist gastroenterologists directly involved in the implementation of the program. Two focus group sessions were conducted with screening participants and interviews were conducted with nonparticipants, GPs and gastroenterologists. RESULTS: The findings suggest that CRC screening by FOBT distributed to households by mail was well accepted by the community and by the medical practitioners involved in its implementation. The trial had little negative effect on general practice. Both medical practitioners and consumers raised concerns about the efficacy of FOBT screening. Medical practitioners were also concerned about the potential burden mass screening could place on the public (government-funded) health care sector. CONCLUSIONS: It would seem that CRC screening using FOBT will not enjoy unqualified support from the community or from medical practitioners involved in the continuum of screening. Information about the objectives of screening programs, in general, and the efficacy of FOBT screening in particular, needs to be provided to the community to ensure informed individual choice.     

In vitro and ex vivo evidence for modulation of P-glycoprotein activity by progestins

The well known gender-related differences in drug action may partly be explained by changes in activity and expression of drug metabolising enzymes, but also by modulation of active drug transport systems (e.g. P-glycoprotein, Pgp) by sexual steroids, which is yet not well investigated. Because many women are using hormones (e.g. as oral contraceptives) we investigated the influence of different synthetic progestins on Pgp activity. Pgp inhibition of progesterone, medroxyprogesterone, chlormadinone, cyproterone, levonorgestrel, norethisterone, desogestrel, and norgestimate was measured in vitro in two Pgp over-expressing cell lines (L-MDR1, P388/dx cells) and the corresponding parental cell lines by means of calcein assay, and ex vivo in human peripheral blood mononuclear cells (PBMCs) by rhodamine123 efflux. For most progestins tested, concentrations needed to double baseline fluorescence (f2) in L-MDR1 cells were similar to that of the potent Pgp inhibitor quinidine, whereas levonorgestrel and norethisterone did not reach f2. The results in P388/dx cells essentially confirmed our findings in L-MDR1 cells. Additionally, Pgp inhibitory activity of all progestins tested was also shown ex vivo in PBMCs. The potent Pgp inhibition by several synthetic progestins in vitro and ex vivo suggests that such an interaction might be clinically relevant despite generally low plasma concentrations of progestins. The results may be of particular importance for Pgp substrates, such as protease inhibitors and chemotherapeutic agents, for which intracellular concentrations are critical.     

Aspochalamins A-D and aspochalasin Z produced by the endosymbiotic Fungus aspergillus niveus LU 9575. I. Taxonomy, fermentation, isolation and biological activities

Aspochalamins A-D, a family of new cytochalasan antibiotics have been isolated from Aspergillus niveus, an endosymbiotic fungus isolated from the gut of a woodlouse belonging to the family Trichoniscidae. Besides aspochalamins, aspochalasin Z, a new member of the aspochalasin family, as well as the known mycotoxins aspochalasin D and citreoviridins A/C and B were isolated from the mycelium. Aspochalamins showed cytostatic effects towards various tumor cell lines and a weak antibacterial activity against Gram-positive bacteria.