The interface between oral and systemic health: the need for more collaboration.

The focus of this review is to highlight the need for improved communication between medical and dental professionals in order to deliver more effective care to patients. The need for communication is increasingly required to capitalise on recent advances in the biological sciences and in medicine for the management of patients with chronic diseases. Improvements in longevity have resulted in populations with increasing special oral-care needs, including those who have cancer of the head and neck, those who are immunocompromised due to HIV/AIDS, advanced age, residence in long-term care facilities or the presence of life-long conditions, and those who are receiving long-term prescription medications for chronic conditions (e.g., anti-hypertensives, anticoagulants, immunosuppressants, antidepressants). These medications can cause adverse reactions in the oral cavity, such as xerostomia and ulceration. Patients with xerostomia are at increased risk of tooth decay, periodontal disease and infection. The ideal management of such individuals should involve the collaborative efforts of physicians, nurses, dentists and dental hygienists, thus optimising treatment and minimising secondary complications deriving from the oral cavity.

LAPATAX: A randomized phase II trial of FEC-docetaxel combined with lapatinib and/or trastuzumab as neoadjuvant therapy of HER2- positive breast cancer-EORTC 10054 trial.

Background: Patients with HER2 +ve breast cancer suitable for neoadjuvant chemotherapy (NAC) have been shown in a series of clinical trials to have the best outcome when treated with anthracyclines (A), taxanes (T), and trastuzumab (Tz). Recent evidence confirms that adjuvant Tz is more effective when given concomitantly rather than sequentially with T (Perez SABCS 2009). Whilst there remains uncertainty as to the most efficacious A-T regimen and duration of Tz, there is widespread use in Europe of FEC-D [3 cycles of 5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC100) followed by 3 cycles of docetaxel 100 mg/m2 (D) q3w] following the results of PACS-01. The advent of TKI anti-HER2 agents such as L could offer superior outcomes if combined with NAC. However, a phase I study in heavily pre-treated advanced breast cancer reported difficulties in combining lapatinib (L) with D 100 mg/m2 (LoRusso JCO 2008). Methods: EORTC 10054 is designed as a two-part study to compare FEC-D with either Tz, L or their combination as NAC for patients with HER2 +ve large operable or locally advanced breast cancer. Before and on-treatment frozen tumor and blood samples will be taken to better define which tumours are particularly sensitive to either Tz and/or L. Stage 1: (complete) a dose- finding study has confirmed that with primary prophylactic G-CSF, D 100 mg/m2 can be safely and effectively given with L 1,250 mg daily continuously. The dose-limiting toxicity was myelosuppression, and there was no significant diarrhoea or cardiac toxicity (ESMO 2009 abstr P- 5073). Stage 2: (opening Q1 2010) will enroll 150 patients from European centres into a 3-arm randomized trial whose primary endpoint is pathological complete response. All patients will receive FEC-D before primary surgery: 3 cycles of FEC (without anti-HER2 therapy) followed by 3 cycles of D plus either Tz (conventional weekly schedule), monotherapy L, or the combination of Tz and L, using doses based on the EGF100161 dose-finding study in 1st line metastatic therapy of D+L+Tz. After surgery all patients will receive standard 3-weekly Tz, radiotherapy and endocrine therapy as per local guidelines.

Neuropathies périphériques d'origine médicamenteuse [Drug-induced peripheral neuropathy].

Drug-induced peripheral neuropathies are common, secondary to multiple drug classes, in particular chemotherapeutic agents. They have an important impact on patients' quality of life. In recent years, significant progress has been made in the understanding of some pathophysiological mechanisms. The use of more objective assessment tools should allow the development of individualized and more effective therapeutic strategies.

Development of targeted therapies in advanced gastric cancer: promising exploratory steps in a new era.

PURPOSE OF REVIEW: Many chemotherapeutic drugs, including fluoropyrimidines, platinums, CPT-11, taxanes and adriamycin have single-agent activity in advanced gastric cancer. Although combination chemotherapy has been shown to be more effective than single agents, response rates between 30 and 50% have not fulfilled their promise as progression-free survival from the best combinations ranges between 3 and 7 months and overall survival between 8 and 11 months. The development of targeted therapies in gastric cancer clearly stays behind the integration of these novel agents into new treatment concepts for patients with colorectal cancer. This review summarizes the experience and major recent advances in the development of targeted therapies in advanced gastric cancer. RECENT FINDINGS: Recent publications on targeted therapies in gastric cancer are limited to nonrandomized phase I or II trials. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors epidermal growth factor receptor 1 and HER2. SUMMARY: Adequately powered, randomized phase III trials are necessary to define the clinical role of targeted therapies in advanced gastric cancer. Biomarker studies to correlate with treatment outcomes will be critical to identify patients who benefit most from chemotherapy and targeted therapy.

Whose DNA is this? How relevant a question? (a note for forensic scientists).

This communication seeks to draw the attention of researchers and practitioners dealing with forensic DNA profiling analyses to the following question: is a scientist's report, offering support to a hypothesis according to which a particular individual is the source of DNA detected during the analysis of a stain, relevant from the point of view of a Court of Justice? This question relates to skeptical views previously voiced by commentators mainly in the judicial area, but is avoided by a large majority of forensic scientists. Notwithstanding, the pivotal role of this question has recently been evoked during the international conference "The hidden side of DNA profiles. Artifacts, errors and uncertain evidence" held in Rome (April 27th to 28th, 2012). Indeed, despite the fact that this conference brought together some of the world's leading forensic DNA specialists, it appeared clearly that a huge gap still exists between questions lawyers are actually interested in, and the answers that scientists deliver to Courts in written reports or during oral testimony. Participants in the justice system, namely lawyers and jurors on the one hand and forensic geneticists on the other, unfortunately talk considerably different languages. It thus is fundamental to address this issue of communication about results of forensic DNA analyses, and open a dialogue with practicing non-scientists at large who need to make meaningful use of scientific results to approach and help solve judicial cases. This paper intends to emphasize the actuality of this topic and suggest beneficial ways ahead towards a more reasoned use of forensic DNA in criminal proceedings.

When "enough" is not enough: new perspectives on optimal methadone maintenance dose.

Some methadone maintenance treatment (MMT) programs prescribe inadequate daily methadone doses. Patients complain of withdrawal symptoms and continue illicit opioid use, yet practitioners are reluctant to increase doses above certain arbitrary thresholds. Serum methadone levels (SMLs) may guide practitioners dosing decisions, especially for those patients who have low SMLs despite higher methadone doses. Such variation is due in part to the complexities of methadone metabolism. The medication itself is a racemic (50:50) mixture of 2 enantiomers: an active "R" form and an essentially inactive "S" form. Methadone is metabolized primarily in the liver, by up to five cytochrome P450 isoforms, and individual differences in enzyme activity help explain wide ranges of active R-enantiomer concentrations in patients given identical doses of racemic methadone. Most clinical research studies have used methadone doses of less than 100 mg/day [d] and have not reported corresponding SMLs. New research suggests that doses ranging from 120 mg/d to more than 700 mg/d, with correspondingly higher SMLs, may be optimal for many patients. Each patient presents a unique clinical challenge, and there is no way of prescribing a single best methadone dose to achieve a specific blood level as a "gold standard" for all patients. Clinical signs and patient-reported symptoms of abstinence syndrome, and continuing illicit opioid use, are effective indicators of dose inadequacy. There does not appear to be a maximum daily dose limit when determining what is adequately "enough" methadone in MMT.

Processus de reconnaissance et d'identification de personnes décédées

Recognition and identification processes for deceased persons. Determining the identity of deceased persons is a routine task performed essentially by police departments and forensic experts. This thesis highlights the processes necessary for the proper and transparent determination of the civil identities of deceased persons. The identity of a person is defined as the establishment of a link between that person ("the source") and information pertaining to the same individual ("identifiers"). Various identity forms could emerge, depending on the nature of the identifiers. There are two distinct types of identity, namely civil identity and biological identity. The paper examines four processes: identification by witnesses (the recognition process) and comparisons of fingerprints, dental data and DNA profiles (the identification processes). During the recognition process, the memory function is examined and helps to clarify circumstances that may give rise to errors. To make the process more rigorous, a body presentation procedure is proposed to investigators. Before examining the other processes, three general concepts specific to forensic science are considered with regard to the identification of a deceased person, namely, matter divisibility (Inman and Rudin), transfer (Locard) and uniqueness (Kirk). These concepts can be applied to the task at hand, although some require a slightly broader scope of application. A cross comparison of common forensic fields and the identification of deceased persons reveals certain differences, including 1 - reverse positioning of the source (i.e. the source is not sought from traces, but rather the identifiers are obtained from the source); 2 - the need for civil identity determination in addition to the individualisation stage; and 3 - a more restricted population (closed set), rather than an open one. For fingerprints, dental and DNA data, intravariability and intervariability are examined, as well as changes in these post mortem (PM) identifiers. Ante-mortem identifiers (AM) are located and AM-PM comparisons made. For DNA, it has been shown that direct identifiers (taken from a person whose civil identity has been alleged) tend to lead to determining civil identity whereas indirect identifiers (obtained from a close relative) direct towards a determination of biological identity. For each process, a Bayesian model is presented which includes sources of uncertainty deemed to be relevant. The results of the different processes combine to structure and summarise an overall outcome and a methodology. The modelling of dental data presents a specific difficulty with respect to intravariability, which in itself is not quantifiable. The concept of "validity" is, therefore, suggested as a possible solution to the problem. Validity uses various parameters that have an acknowledged impact on teeth intravariability. In cases where identifying deceased persons proves to be extremely difficult due to the limited discrimination of certain procedures, the use of a Bayesian approach is of great value in bringing a transparent and synthetic value. RESUME : Titre: Processus de reconnaissance et d'identification de personnes décédées. L'individualisation de personnes décédées est une tâche courante partagée principalement par des services de police, des odontologues et des laboratoires de génétique. L'objectif de cette recherche est de présenter des processus pour déterminer valablement, avec une incertitude maîtrisée, les identités civiles de personnes décédées. La notion d'identité est examinée en premier lieu. L'identité d'une personne est définie comme l'établissement d'un lien entre cette personne et des informations la concernant. Les informations en question sont désignées par le terme d'identifiants. Deux formes distinctes d'identité sont retenues: l'identité civile et l'identité biologique. Quatre processus principaux sont examinés: celui du témoignage et ceux impliquant les comparaisons d'empreintes digitales, de données dentaires et de profils d'ADN. Concernant le processus de reconnaissance, le mode de fonctionnement de la mémoire est examiné, démarche qui permet de désigner les paramètres pouvant conduire à des erreurs. Dans le but d'apporter un cadre rigoureux à ce processus, une procédure de présentation d'un corps est proposée à l'intention des enquêteurs. Avant d'entreprendre l'examen des autres processus, les concepts généraux propres aux domaines forensiques sont examinés sous l'angle particulier de l'identification de personnes décédées: la divisibilité de la matière (Inman et Rudin), le transfert (Locard) et l'unicité (Kirk). Il est constaté que ces concepts peuvent être appliqués, certains nécessitant toutefois un léger élargissement de leurs principes. Une comparaison croisée entre les domaines forensiques habituels et l'identification de personnes décédées montre des différences telles qu'un positionnement inversé de la source (la source n'est plus à rechercher en partant de traces, mais ce sont des identifiants qui sont recherchés en partant de la source), la nécessité de devoir déterminer une identité civile en plus de procéder à une individualisation ou encore une population d'intérêt limitée plutôt qu'ouverte. Pour les empreintes digitales, les dents et l'ADN, l'intra puis l'inter-variabilité sont examinées, de même que leurs modifications post-mortem (PM), la localisation des identifiants ante-mortem (AM) et les comparaisons AM-PM. Pour l'ADN, il est démontré que les identifiants directs (provenant de la personne dont l'identité civile est supposée) tendent à déterminer une identité civile alors que les identifiants indirects (provenant d'un proche parent) tendent à déterminer une identité biologique. Puis une synthèse des résultats provenant des différents processus est réalisée grâce à des modélisations bayesiennes. Pour chaque processus, une modélisation est présentée, modélisation intégrant les paramètres reconnus comme pertinents. À ce stade, une difficulté apparaît: celle de quantifier l'intra-variabilité dentaire pour laquelle il n'existe pas de règle précise. La solution préconisée est celle d'intégrer un concept de validité qui intègre divers paramètres ayant un impact connu sur l'intra-variabilité. La possibilité de formuler une valeur de synthèse par l'approche bayesienne s'avère d'une aide précieuse dans des cas très difficiles pour lesquels chacun des processus est limité en termes de potentiel discriminant.

Nonspecific PCR amplification by high-fidelity polymerases: implications for next-generation sequencing of AFLP markers.

High-fidelity 'proofreading' polymerases are often used in library construction for next-generation sequencing projects, in an effort to minimize errors in the resulting sequence data. The increased template fidelity of these polymerases can come at the cost of reduced template specificity, and library preparation methods based on the AFLP technique may be particularly susceptible. Here, we compare AFLP profiles generated with standard Taq and two versions of a high-fidelity polymerase. We find that Taq produces fewer and brighter peaks than high-fidelity polymerase, suggesting that Taq performs better at selectively amplifying templates that exactly match the primer sequences. Because the higher accuracy of proofreading polymerases remains important for sequencing applications, we suggest that it may be more effective to use alternative library preparation methods.

Emergency Department Use by oldest-old Patients Between 2005 And 2010 in a Swiss University Hospital

Introduction: Population ageing challenges Emergency Departments (ED) with a population shift toward higher age groups. Patients aged 85+, represent the fastest growing segment, leading to more prevalent complex situations within ED. Method: Retrospective analysis of 56'162 ED visits of patients at the University of Lausanne Medical Center (CHUV), from 2005 to 2010. Results: ED visits of 65+ patients increased from 8'228 to 10'390/year, representing 6 patients/day more (+26%). 85+ Patients increased by +46% vs +20% for the 65-84 (+20% ED visits of people 18-64y). Median age of the 65+ ED patients increased from 78.7 to 79.3 years. 85+ patients were more likely than 65-84y patients to come from a NH setting (13% vs 4%) and to be hospitalised (70% vs 59%). Median length of stay difference between both age groups extended from 2 hours 08 min in 2005 to 2 hours 45 min in 2010. First reason to visit ED was fall/injury for 85+ patients (27%; 65-84: 18%) and a cardiovascular disorder for patients aged 65-84y (18%; 85+: 16%). Part of high degree of emergency cases (42%) and readmission to ED within 30 days (8%) were similar for both age classes (similar proportions in 2005 and 2010 for these 3 issues). Conclusion: Patients aged 85+ are the fastest growing group admitted to ED. Compared to younger counterparts, they use more ED ressources and the differences are increaseing overtime. ED addressing specific needs of geriatric patients would improve their care and lead to a better use of available resources.

Mutations in the DNA-binding domain of NR2E3 affect in vivo dimerization and interaction with CRX.

BACKGROUND: NR2E3 (PNR) is an orphan nuclear receptor essential for proper photoreceptor determination and differentiation. In humans, mutations in NR2E3 have been associated with the recessively inherited enhanced short wavelength sensitive (S-) cone syndrome (ESCS) and, more recently, with autosomal dominant retinitis pigmentosa (adRP). NR2E3 acts as a suppressor of the cone generation program in late mitotic retinal progenitor cells. In adult rod photoreceptors, NR2E3 represses cone-specific gene expression and acts in concert with the transcription factors CRX and NRL to activate rod-specific genes. NR2E3 and CRX have been shown to physically interact in vitro through their respective DNA-binding domains (DBD). The DBD also contributes to homo- and heterodimerization of nuclear receptors. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed NR2E3 homodimerization and NR2E3/CRX complex formation in an in vivo situation by Bioluminescence Resonance Energy Transfer (BRET(2)). NR2E3 wild-type protein formed homodimers in transiently transfected HEK293T cells. NR2E3 homodimerization was impaired in presence of disease-causing mutations in the DBD, except for the p.R76Q and p.R104W mutant proteins. Strikingly, the adRP-linked p.G56R mutant protein interacted with CRX with a similar efficiency to that of NR2E3 wild-type and p.R311Q proteins. In contrast, all other NR2E3 DBD-mutant proteins did not interact with CRX. The p.G56R mutant protein was also more effective in abolishing the potentiation of rhodospin gene transactivation by the NR2E3 wild-type protein. In addition, the p.G56R mutant enhanced the transrepression of the M- and S-opsin promoter, while all other NR2E3 DBD-mutants did not. CONCLUSIONS/SIGNIFICANCE: These results suggest different disease mechanisms in adRP- and ESCS-patients carrying NR2E3 mutations. Titration of CRX by the p.G56R mutant protein acting as a repressor in trans may account for the severe clinical phenotype in adRP patients.

Production endogène de Nortestostérone chez l'homme et influence de l'activité physique et du régime alimentaire

RESUME Depuis les années 1980, les stéroïdes androgéniques anabolisants (SAA) sont restés les produits dopants les plus utilisés par les sportifs. Les propriétés principales attribuées à ces substances sont une augmentation de la masse et de la force musculaire ainsi qu'une agressivité supérieure pouvant s'avérer bénéfique lors des entraînements ou des compétitions. En plus de cette "tradition" liée à la consommation des SAA, une autre problématique est apparue dans le monde antidopage suite à la fulgurante expansion de l'utilisation des compléments alimentaires par les athlètes professionnels et amateurs. Dès la fin des années 1990, une recrudescence de cas positifs de dopage aux SAA a été attribuée à la contamination des compléments alimentaires par des composés anabolisants tels que la testostérone ou la nandrolone ou par des prohormones se situant en amont dans le métabolisme de certains SAA et conduisant à la présence, dans les urines, de traces de substances interdites par l'Agence Mondiale Antidopage (AMA). Afin de mettre en garde les autorités antidopage ainsi que les athlètes quant aux problèmes liés aux compléments alimentaires, le Laboratoire Suisse d'Analyse du Dopage (LAD) a décidé d'étudier de manière plus précise la composition d'une centaine de produits accessibles en Suisse par l'intermédiaire d'internet. Cette étude a permis de mettre en évidence un taux de non conformité des produits avoisinant les 20%, avec une contamination plus importante des produits contenant des hormones ou des prohormones. La consommation de doses journalières recommandées des produits contaminés a mené à la détection dans les urines de la présence de substances interdites par l'AMA. Ces résultats confirment ainsi que l'usage de compléments alimentaires peut s'avérer dangereuse dans le cadre de contrôles antidopage et que les effets sur l'état physique et mental des athlètes peuvent dépasser les effets désirés et être dramatiques pour la poursuite d'une carrière sportive. D'autre part, cela démontre que l'alimentation peut mener à la présence urinaire de substances proscrites telles que les métabolites de la nandrolone, la 19-norandrostéreone (19-NA) et la 19-norétiocholanolone (19-NE). Afin de démontrer un effet potentiel de l'exercice physique sur l'excrétion urinaire des métabolites de la nandrolone, une première étude clinique a été réalisée avec 34 volontaires. Deux doses orales de nandrolone marquée avec deux atomes de C13 ont été administrées aux sujets. Les urines ont été récoltées durant les 5 jours suivant les prises orales (études d'excrétion) ainsi qu'avant et après les 8 séances d'entraînements du protocole. Les analyses des études d'excrétion ont permis d'établir une variabilité intra- et inter-individuelle du métabolisme et de la pharmacocinétique de la 19-NA et de la 19-NE. En dépit de la rapide élimination urinaire des métabolites de la nandrolone C13, les analyses des échantillons prélevés avant et après les différents efforts n'ont pas révélé une influence nette de l'exercice physique sur les concentrations urinaires de la 19-NA et 19-NE. Une seconde étude clinique a été effectuée, avec la participation de 30 volontaires. Il s'agissait de déterminer si la consommation de multiples doses orales d'un décanoate de testostérone, de 19-norandrostenedione (un précurseur de la nandrolone) ou de placebo durant un mois, pouvait avoir des effets bénéfiques sur la récupération et la performance physique. En parallèle, les sujets étaient soumis à un entrainement d'endurance intense et individualisé. Divers paramètres physiologiques ont été étudiés dans le sérum et les urines afin de mettre en évidence une meilleure récupération de l'organisme. Aucun de ses paramètres n'a permis de conclure que la consommation orale de SAA est favorable pour optimaliser les capacités de récupération des athlètes. De plus, les performances physiques ont été évaluées avant et après l'entraînement et le traitement. Aucune différence significative n'a été démontrée entre les trois groupes de volontaires. L'état psychologique des volontaires a été évalué à l'aide de questionnaires (short Profile of Mood State, sPOMS) remplis à trois reprises au cours du protocole. De manière générale, l'évolution observée est une augmentation de la fatigue avec une diminution de la vigueur. Des analyses statistiques ont révélé que des prises orales de testostérone, et dans une moindre mesure de 19-norandrostenedione, ont une légère influence sur cette évolution générale en diminuant les effets de l'entrainement sur le profil psychologique. Les urines récoltées durant le protocole ont été analysées par GC/C/IRMS et GCMS afin de détecter les variations des concentrations des hormones liées au métabolisme de la testostérone. Les résultats ont démontré une variabilité interindividuelle du métabolisme de la testostérone qui implique que les critères de positivité imposés par l'AMA ne sont pas forcément valables pour tous les individus. La détection de la 19-NA et de la 19-NE, issus du métabolisme in vivo de la 19norandrostenedione, a confirmé les résultats obtenus sur la pharmacocinétique et le métabolisme de la nandrolone C13 obtenus lors de la première étude clinique. Ce travail a permis de clarifier certains points en lien avec l'abus de la nandrolone dans le sport et notamment par rapport à la consommation de compléments alimentaires. Les deux études cliniques n'ont pas véritablement apporté les réponses souhaitées aux hypothèses de départ. Cependant certains aspects intéressants en relation avec le métabolisme des SAA ont été découverts et pourront peut-être permettre à la lutte antidopage d'évoluer vers une meilleure efficacité. SUMMARY Since 1980's, anabolic androgenic steroids (AAS) are still the most used doping agents in sports. The main properties attributed to these substances are an increase of muscle mass and strength and also a higher aggressiveness that could be beneficial during trainings and competitions. In addition to this "tradition" linked to the AAS intake, another problematics has raised in the antidoping field. Indeed, nutritional supplements have been more and more used by professional and amateur athletes. Since the end of the 1990's, an outburst of positive doping cases with AAS has been attributed to nutritional supplements contaminations with anabolic compounds like testosterone or nandrolone or with prohormones located above in the metabolism of some AAS and prompting urinary traces of forbidden compounds by the World Antidoping Agency (WADA). In order to inform the antidoping authorities and the athletes about the problems linked to the nutritional supplements, the Swiss Laboratory for Doping Analyses (LAD) decided to investigate more precisely the composition of about hundred products accessible in Switzerland through different web sites. This study showed that about 20% of the products were not conformed to the composition announced by the manufacturers. The oral intake of daily recommended doses of the contaminated products revealed the presence in urines of forbidden substances by the WADA. Hence, these results confirm that the use of nutritional supplements can lead to adverse analytical findings in antidoping controls and that the effects on athletes' physical and mental state could be different from the ones desired and could be dramatic for the continuation of an athlete's career. Moreover, this demonstrates that the diet can lead to the presence in urines of proscribed substances like nandrolone metabolites, i.e. 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE). To put forward a potential effect of physical exercise on urinary nandrolone metabolites excretion rate, a first clinical study was done with 34 volunteers. Two oral doses of nandrolone labelled with two C13 atoms were administered to the subjects. The urines were collected during the 5 days following the treatment (excretion studies) and before and after the 8 exercise sessions of the protocol. The analyses of excretion studies revealed an intra- and inter-individual variability of the metabolism and the pharmacokinetics of 19-NA and 19-NE. In spite of the rapid urinary elimination of the nandrolone C13 metabolites, the analyses of the urine samples gathered before and after efforts did not show a clear influence of physical exercise on the urinary 19-NA and 19-NE concentrations. A second clinical study was done with the participation of 30 volunteers. The main aim was to determine if multiple oral doses of testosterone undecanoate, 19-norandrostenedione (a nandrolone precursor) or placebo during one month, could have beneficial effects on recovery and physical performance. Meanwhile, the individuals had to follow an intense and personalized endurance training program. Several physiological parameters were investigated in serum and urines in order to demonstrate a better organism's recovery. None of these parameters lead to the conclusion that oral intake of AAS is useful to optimise the recovery capacities of athletes. In addition, physical performances were evaluated before and after the training and treatment month. No significant difference was shown between the three volunteers groups. The psychological state of the volunteers was assessed through questionnaires (short Profile of Mood State, sP4MS) filled three times during the protocol. The global evolution is an increase of fatigue with an decrease of vigour. Statistical analyses revealed that the oral intake of testosterone, and to a lesser extent of 19= norandrostenedione, have a small influence on this general evolution in decreasing the effect of training on the psychological profile. The urines collected during the protocol were analysed by GC/C/IRMS and GCMS to detect concentrations variations of hormones related to the testosterone metabolism. The results revealed an interindividual variability of testosterone metabolism which implies that the guidance concerning endogenous steroids prescribed by the WADA are not uniformly valid for all individuals. Detection of 19-NA and 19-NE, coming from the in vivo metabolism of 19norandrostenedione, confirmed the results previously obtained on the pharamcokinetics and metabolism of the nandrolone C13 in the first clinical study. This work allowed to clarify some aspects linked to nandrolone abuse in sports and noteworthy related to nutritional supplements intake. The two clinical studies did not really bring plain answers to the basal hypotheses but some interesting aspects in relation with AAS metabolism were put forth and would perhaps allow an evolution of a more effective fight against doping.

International differences in alcohol use according to sexual orientation.

Most research on sexual orientation and alcohol use in the United States has found higher rates of alcohol use and abuse among gay men and lesbians. Studies from other countries have found smaller or no differences between sexual minority and heterosexual women and men. The present study used general population survey data from 14 countries to examine high-volume and risky single-occasion drinking by sexual orientation. Data from 248 gay men and lesbians and 3720 heterosexuals were analyzed in a case-control design. In several countries partnered or recently partnered gay men and lesbians had no greater risk of heavy drinking or engaging in heavy drinking than heterosexual controls. Only lesbians in North America showed higher risk for both indicators. Future general population health research should include larger samples of gays and lesbians and use more comprehensive measures of sexual orientation for investigating the prevalence of health risk factors.

Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density.

CONTEXT: In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk. OBJECTIVE: The aim of the study was to identify factors associated with greater efficacy during ZOL 5 mg treatment. DESIGN, SETTING, AND PATIENTS: We conducted a subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. Intervention: A single infusion of ZOL 5 mg or placebo was administered at baseline, 12, and 24 months. MAIN OUTCOME MEASURES: Primary endpoints were new vertebral fracture and hip fracture. Secondary endpoints were nonvertebral fracture and change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups were age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index, and concomitant osteoporosis medications. RESULTS: Greater ZOL induced effects on vertebral fracture risk were seen with younger age (treatment-by-subgroup interaction, P = 0.05), normal creatinine clearance (P = 0.04), and body mass index >or= 25 kg/m(2) (P = 0.02). There were no significant treatment-factor interactions for hip or nonvertebral fracture or for change in BMD. CONCLUSIONS: ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women, and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.

Management of faecal incontinence and constipation in adults with central neurological diseases.

BACKGROUND: People with neurological disease have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine line between the two conditions, with any management intended to ameliorate one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical with a limited research base. OBJECTIVES: To determine the effects of management strategies for faecal incontinence and constipation in people with neurological diseases affecting the central nervous system. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 26 January 2005), the Cochrane Central Register of Controlled Trials (Issue 2, 2005), MEDLINE (January 1966 to May 2005), EMBASE (January 1998 to May 2005) and all reference lists of relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised trials evaluating any types of conservative or surgical measure for the management of faecal incontinence and constipation in people with neurological diseases were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction were also considered. DATA COLLECTION AND ANALYSIS: Two reviewers assessed the methodological quality of eligible trials and two reviewers independently extracted data from included trials using a range of pre-specified outcome measures. MAIN RESULTS: Ten trials were identified by the search strategy, most were small and of poor quality. Oral medications for constipation were the subject of four trials. Cisapride does not seem to have clinically useful effects in people with spinal cord injuries (three trials). Psyllium was associated with increased stool frequency in people with Parkinson's disease but did not alter colonic transit time (one trial). Prucalopride, an enterokinetic did not demonstrate obvious benefits in this patient group (one study). Some rectal preparations to initiate defaecation produced faster results than others (one trial). Different time schedules for administration of rectal medication may produce different bowel responses (one trial). Mechanical evacuation may be more effective than oral or rectal medication (one trial). There appears to be a benefit to patients in one-off educational interventions from nurses. The clinical significance of any of these results is difficult to interpret. AUTHORS' CONCLUSIONS: There is still remarkably little research on this common and, to patients, very significant condition. It is not possible to draw any recommendation for bowel care in people with neurological diseases from the trials included in this review. Bowel management for these people must remain empirical until well-designed controlled trials with adequate numbers and clinically relevant outcome measures become available.

Brief alcohol intervention as pragmatic intervention: Who is voluntarily taking an offered intervention?

Brief alcohol interventions (BAI) have shown the potential to decrease problematic alcohol use among adolescents and young adults. Most of the BAI studies have been efficacy trials designed to achieve high internal validity but have raised questions regarding the feasibility of large-scale implementation. Providing interventions for those voluntarily wanting them might offer an alternative, and studies using this design would be more similar to effectiveness studies. The present research compares randomly selected 20-year-old men who took part in a scientific trial (efficacy) with those who voluntarily sought an intervention (effectiveness). Sampling took place during army recruitment procedures that are mandatory for all males in Switzerland. At-risk drinking (20+ drinks per week, or more than one risky drinking occasion of 6+ drinks per month) was determined a posteriori; there was no screening. There were a higher percentage of at-risk drinkers in the volunteer arm at baseline, but at-risk drinkers did not differ from those in the trial arm on any of the assessed alcohol measures. This suggests that offering BAI on a large-scale, voluntary basis may reach at-risk drinkers as effectively as do more scientifically oriented trials, without needing to adhere to screening and stringent research procedures. Nevertheless, BAI was more effective for at-risk drinkers who were invited for trial participation versus those who volunteered. This could be due to behavior that is already consolidated and is difficult to change. Lacking further modifications, real-world implementations of BAI for young men may be less effective than randomized controlled trials designed to test the efficacy of BAI.