Epidemiologie und Prävention von AIDS in der Bevölkerung

International Journal of Public Health - Die Übertragungswege des HIV, welche in der Bevölkerung eine Rolle spielen, sind heute bekannt. Neben der sexuellen Übertragung, der...     

Activity distribution of seven digestive enzymes along small intestine in calves during development and weaning

Ten groups of calves were used to study the changes in activity levels and distribution of seven hydrolases in the intestinal mucosa during development and weaning. The calves in the first group were sacrificed at birth while those in the remaining nine groups were either milk-fed until slaughter on days 2, 7, 28, 56, 70, and 119; or weaned between days 28 and 56 and then slaughtered on days 56, 70, and 119, respectively. The small intestine was immediately cut off and divided into five segments, ie, duodenum, proximal jejunum, median jejunum, distal jejunum, and ileum. In the milk-fed animals, the activity levels of aminopeptidases A and N, alkaline phosphatase, lactase, and isomaltase were maximum at 2 days of age, and then declined sharply between days 2 and 7 but did not change significantly thereafter. By contrast, the maltase activity increased between days 7 and 119, while no sucrase activity was detected. Weaning resulted in a decrease in the activity of lactase and an increase in that of aminopeptidase N, maltase, and isomaltase. The distribution of all these enzymes along the small intestine was slightly influenced by age but not at all by weaning.     

Ghrelin receptor conformational dynamics regulate the transition from a preassembled to an active receptor:Gq complex

How G protein-coupled receptor conformational dynamics control G protein coupling to trigger signaling is a key but still open question. We addressed this question with a model system composed of the purified ghrelin receptor assembled into lipid discs. Combining receptor labeling through genetic incorporation of unnatural amino acids, lanthanide resonance energy transfer, and normal mode analyses, we directly demonstrate the occurrence of two distinct receptor:Gq assemblies with different geometries whose relative populations parallel the activation state of the receptor. The first of these assemblies is a preassembled complex with the receptor in its basal conformation. This complex is specific of Gq and is not observed with Gi. The second one is an active assembly in which the receptor in its active conformation triggers G protein activation. The active complex is present even in the absence of agonist, in a direct relationship with the high constitutive activity of the ghrelin receptor. These data provide direct evidence of a mechanism for ghrelin receptor-mediated Gq signaling in which transition of the receptor from an inactive to an active conformation is accompanied by a rearrangement of a preassembled receptor:G protein complex, ultimately leading to G protein activation and signaling.G protein-coupled receptors (GPCRs), one of the largest cell surface receptor families, are involved in many cellular signaling processes (1). Based on this property, as well as their importance as drug targets, the molecular aspects of GPCR functioning have been extensively investigated. In particular, coupling to heterotrimeric G proteins has been the focus of numerous studies. Indeed, delineating the molecular mechanisms responsible for receptor:G protein interaction is absolutely required to better understand how signaling is controlled. Recent years have seen spectacular advances that have culminated in elucidation of the 3D structure of the β₂-adrenergic receptor:Gs complex (2). Nevertheless, the need for further progress remains, in particular to fully understand the dynamics of this interaction. This is a crucial question, given that how the receptor interacts with its G protein partner governs signaling, and thus biological and pathophysiological responses.To date, two different models for GPCR:G protein interaction have been proposed: collision coupling and preassembly. Originally, it was proposed that receptors and G proteins couple by collision (3, 4). One of the main features of this model is that only activated receptors interact with G proteins. Since then, alternative models of signaling have been developed. One of these, the preassembly model, proposes that the receptor and the G protein make a complex even in the absence of agonist (5–8). Discriminating between the two models is crucial. Indeed, signaling outputs, such as the kinetics of G protein activation, will be significantly different depending on whether the ligand-free receptor is always in complex with its G protein or must first be activated by the agonist to recruit the G protein and trigger signaling. Moreover, it has been shown that GPCR conformational dynamics (9–11) and signaling in the absence of ligand are key features of GPCR functioning (12). How receptor constitutive activity and conformational dynamics relate to their coupling to the G protein remains an open question.Here we used the purified ghrelin receptor GHS-R1a to analyze the way in which this GPCR interacts with its G protein partners. Ghrelin is a neuroendocrine peptide hormone that acts through its cognate GPCR to control important biological processes, such as growth hormone secretion, food intake, and reward-seeking behaviors (13). Among the GPCRs, GHS-R1a has been shown to have one of the highest basal Gq activation levels both in vitro (10, 14) and in vivo (15, 16). The physiological relevance of GHS-R1a basal activity is substantiated by the occurrence of a natural human mutation in the GHS-R1a gene (A²⁰⁴E substitution in the second extracellular loop of the receptor) that dramatically decreases constitutive activity and is associated with a short-stature phenotype (17). Along with its importance in drug design, GHS-R1a is a prototype for peptide-activated class A GPCRs.To delineate the way in which the ghrelin receptor interacts with G proteins, we used monomeric GHS-R1a reconstituted in a membrane-mimicking environment, lipid discs, and a combination of innovative biochemical [labeling with unnatural amino acid (UAA)] and biophysical [lanthanide resonance energy transfer (LRET) and normal mode (NM) analyses] approaches. By doing so, we provide the first direct evidence that ghrelin-mediated signaling involves a complex dialogue between the conformational dynamics of the receptor and its ability to interact with the different G protein subtypes to which it is coupled.     

Effects of Motivational Downshifts on Specific Pavlovian-Instrumental Transfer in Rats

BackgroundPavlovian stimuli predictive of appetitive outcomes can exert a powerful influence on the selection and initiation of action, a phenomenon termed outcome-selective Pavlovian-instrumental transfer (sPIT). Rodent studies suggest that sPIT is insensitive to motivational downshift induced by outcome devaluation, an effect that is, however, relatively underexplored.MethodsHere we examined in detail the effects of distinct shifts in motivation from hunger to a state of relative satiety on sPIT in rats.ResultsA motivational downshift by outcome-specific devaluation immediately prior to testing markedly reduced overall lever responding and magazine entries but left intact the sPIT effect. A motivational downshift prior testing by (1) giving ad libitum rather than restricted access to maintenance diet in the home cage for 24 hours or by (2) a systemic blockade of hormone secretagogue receptor subtype 1A receptors to inhibit orexigenic actions of ghrelin both reduced overall lever responding and magazine entries. Moreover, these latter motivational downshifts reduced the sPIT effect; however, the sizes of the sPIT effects were still large.ConclusionsCollectively, our rodent findings indicate that major effects of various motivational downshifts are overall inhibition of lever pressing and magazine approach, possibly reflecting reduced general motivation. The observed effects of motivational downshifts on sPIT have implications with regard to the role of general motivating effects in sPIT and to the contribution of Pavlovian-instrumental interactions to excessive food seeking as well as obesity in humans.     

Follow-up and management of patients exposed to a flawed automated endoscope washer-disinfector in a digestive diseases unit.

The possible transmission of pathogens to 236 persons exposed to an endoscope processed in a flawed automated endoscope washer-disinfector in a gastrointestinal endoscopy unit was investigated. During 6 months, 197 patients (83.5%) were followed up, and no cases of acute human immunodeficiency virus, hepatitis C virus, or hepatitis B virus infection were observed. This event created the conditions for improvements in safety procedures.     

Age-dependent variations of human and rat colon myofibroblasts in culture: Influence on their functional interactions with colon cancer cells

Epithelial-mesenchymal interactions play a pivotal role in colon cancer invasion and metastasis. We aimed at elucidating the impact of long-term cultivation on the phenotypic and functional characteristics of primary fibroblasts and their interaction with the human colon adenocarcinoma cell line LoVoC5. We used fibroblasts from human colon tumor tissue, normal human colon mucosa, rat normal colon and 2 rat colon-derived myofibroblast cell lines, MIC316 and MG. The following parameters were studied: cell shape and size, growth curve, intermediate filament expression and extracellular matrix synthesis. Coculture models with or without cell contacts were used to test the effects on LoVoC5 cell proliferation, spreading and adhesion. Irrespective of their origin, fibroblastic cells in primary cultures presented marked phenotypic and functional changes with time. Before passage 5, they presented as large, slow-growing cells expressing vimentin and alpha-smooth muscle actin; synthesizing laminin-1, fibronectin and collagens I and IV; and inducing LoVoC5 proliferation, spreading and adhesion. After passage 15, they presented as small, fast-growing cells inconstantly expressing alpha-smooth muscle actin and synthesizing mainly type I collagen. In coculture with or without cell contacts, they inhibited LoVoC5 proliferation and allowed only limited cell spreading and adhesion. Myofibroblastic cell lines presented as large, fast-growing cells expressing vimentin and alpha-smooth muscle actin and synthesizing mainly type I collagen. They had no significant effects on LoVoC5 proliferation, spreading and adhesion. Our results underline the importance of age-dependent variations in colon mesenchymal cells in culture and for the in vitro study of epithelial-mesenchymal interactions in colon cancer.     

New active series of growth hormone secretagogues

New growth hormone secretagogue (GHS) analogues were synthesized and evaluated for growth hormone releasing activity. This series derived from EP-51389 is based on a gem-diamino structure. Compounds that exhibited higher in vivo GH-releasing potency than hexarelin in rat (subcutaneous administration) were then tested per os in beagle dogs and for their binding affinity to human pituitary GHS receptors and to hGHS-R 1a. Compound 7 (JMV 1843, H-Aib-(d)-Trp-(d)-gTrp-formyl) showed high potency in these tests and was selected for clinical studies.(1)     

Epidemiologie und Pr?vention von AIDS in der Bev?lkerung

Zusammenfassung Die Übertragungswege des HIV, welche in der Bevölkerung eine Rolle spielen, sind heute bekannt. Neben der sexuellen Übertragung, der Infektion durch Austausch von Injektionsnadeln bei Drogenabhängigen, den akzidentellen Blutkontakten wird vor allem auch die Übertragung von der schwangeren Mutter auf ihr Kind beobachtet. Die Anzahl Neuinfektionen ist abhängig von der Anzahl Infizierter, der Ausbreitungsgeschwindigkeit und dem Ausbreitungspotential. Die Ausbreitungsgeschwindigkeit kann unter Drogenabhängigen sehr gross werden, können sich doch mehrere Abhängige durch Spritzentausch gleichzeitig infizieren. In der Gesamtbevölkerung besitzt die sexuelle Übertragung das grösste Ausbreitungspotential. Die Aids-Prävention in der Schweiz beinhaltet Ziele, welche einerseits Neuinfektionen verhindern und andererseits Solidarität aufbauen sollen. Mit der STOP-AIDS Kampagne wurde in der Schweiz eine gute Breitenwirkung erreicht. Es gilt nun in Zukunft vermehrt Tiefenwirkungen bei bestimmten Zielgruppen weiter zu fördern, sowie vermehrt individuelle Beratungen anzubieten.

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Epidemiology and prevention of AIDS in the population

Summary Routes of transmission of HIV which play an important role in the population are known. Sexual transmission, infection through needle sharing by i.v. drug addicts, accidental blood contacts and transmission from the infected pregnant mother to her child are seen. The number of new infections depends on the number of already infected individuals, the rapidity of spread and the spread potential. The infection can be rapidly spread among drug addicts, several drug users may be infected at the same time through needle sharing. In the general population the spread potential through sexual transmission is high. The AIDS prevention campaign in Switzeland aims at preventing new infections and at building up solidarity. With the STOP-AIDS campaign a broad effect in the population could be reached. The most important goals in the near future are to have an effect in depth in some target groups and to promote individual counselling.

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Epidémiologie et prévention du SIDA dans la population

Résumé Les voies de transmission du HIV qui jouent un rôle dans la population sont connues aujourd'hui. La transmission par voie sexuelle, les infections chez les drogués par l'échange des aiguilles, les contacts de sang accidentels et la transmission de la mère enceinte à l'enfant sont connus. Le nombre de nouvelles infections dépend du nombre des infectés, de la rapidité de propagation et du potentiel de propagation. La rapidité de propagation peut être très grande chez les drogués, étant donné que plusieurs peuvent être infectés en même temps par échange des seringues. Le potentiel de propagation par voie sexuelle est très grand dans la population générale. La prévention du SIDA en Suisse a deux objectifs: prévenir de nouvelles infections et établir une solidarité. La campagne STOP-SIDA a eu un effet très large dans la population. Dans le proche futur il faudra agir en profondeur sur les groupes cibles et promouvoir les consultations individuelles.

     

The Salto Total Ankle Arthroplasty: Survivorship and Analysis of Failures at 7 to 11 years

Background  

Despite the appearance of new-generation, mobile-bearing, cementless prostheses, total ankle arthroplasty remains controversial. Among the criteria guiding the choice between arthrodesis and arthroplasty, the long-term survival and postoperative function are of critical importance. The mobile-bearing Salto prosthesis has been used in Europe since 1997, but only 2 to 5 years of followup data have been reported.