Treatment of gastrointestinal stromal tumor after imatinib and sunitinib.

Purpose of review Tyrosine kinase inhibitors (TKIs), such as imatinib and sunitinib, have changed the outcome of patients with gastrointestinal stromal tumor (GIST) and prolonged survival by many-fold. Unfortunately, treatment failure and tumor progression seem inevitable over time and constitute an unresolved clinical challenge. This article reviews current efforts to overcome drug resistance and progression. Recent findings The major mechanism of resistance toward imatinib and sunitinib is the development of secondary resistance mutations in the kinase domain of KIT. Recent efforts aim at inhibitors with increased activity against resistance mutations or a broader spectrum of activity. Other strategies include indirect KIT inhibition by modulating KIT chaperone proteins or inhibition of KIT-dependent and independent signaling pathways. Summary dThe rapid improvement of our understanding of GIST biology as well as resistance mechanisms towards imatinib and sunitinib will greatly facilitate the development of novel treatment strategies. This article summarizes the results of recently reported third and fourth-line clinical trials in patients with resistant GIST and reviews data of important proof-of-concept studies.

Adolescent drinking patterns across countries: associations with alcohol policies.

Early consumption of full servings of alcohol and early experience of drunkenness have been linked with alcohol-related harmful effects in adolescence, as well as adult health and social problems. On the basis of secondary analysis of county-level prevalence data, the present study explored the current pattern of drinking and drunkenness among 15- and 16-year-old adolescents in 40 European and North American countries. Data from the 2006 Health Behavior in School Children survey and the European School Survey Project on Alcohol and other Drugs were used. The potential role of alcohol control and policy measures in explaining variance in drinking patterns across countries was also examined. Policy measures and data on adult consumption patterns were taken from the WHO Global Information System on Alcohol and Health, Eurostat and the indicator of alcohol control policy strength developed by Brand DA, Saisana M, Rynn LA et al. [(2007) Comparative analysis of alcohol control policies in 30 countries. PLoS Med 4:e151.]. We found that a non-significant trend existed whereby higher prices and stronger alcohol controls were associated with a lower proportion of weekly drinking but a higher proportion of drunkenness. It is important that future research explores the causal relationships between alcohol policy measures and alcohol consumption patterns to determine whether strict policies do in fact have any beneficial effect on drinking patterns, or rather, lead to rebellion and an increased prevalence of binge drinking.

Adult consequences of late adolescent alcohol consumption: a systematic review of cohort studies.

Alcohol is responsible for a significant portion of the global burden of disease. There is widespread concern reported in the media and other sources about drinking trends among young people, particularly heavy episodic or “binge” drinking. Prominent among policy responses, in the UK and elsewhere, have been attempts to manage antisocial behaviour related to intoxication in public spaces. Much less attention has been given to the longer term effects of excessive drinking in adolescence on later adult health and well-being. Some studies suggest that individuals “mature out” of late adolescent drinking behaviour, whilst others identify enduring effects on drinking and broader health and social outcomes in adulthood. If adolescent drinking does not cause later difficulties in adulthood then intervention approaches aimed at addressing the acute consequences of alcohol, such as unintentional injuries and anti-social behaviour, may be the most appropriate solution. If causal relationships do exist, however, this approach will not address the cumulative harms produced by alcohol, unless such intervention successfully modifies the long-term relationship with alcohol, which seems unlikely. To address this issue a systematic review of cohort studies was conducted, as this approach provides the strongest observational study design to evaluate evidence for causal inference.This resource was contributed by The National Documentation Centre on Drug Use.

The new EASL guidelines for the management of chronic hepatitis B infection adapted for Swiss physicians.

Since the arrival of several new antivirals and due to the growing molecular and clinical knowledge of hepatitis B virus (HBV) infection, therapy of hepatitis B has become complex. Clinical guidelines aim at streamlining medical attitudes: in this respect, the European Association for the Study of the Liver (EASL) recently issued clinical practice guidelines for the management of chronic hepatitis B. Guidelines made by international experts need however to be adapted to local health care systems. Here, we summarise the EASL guidelines with some minor modifications in order to be compatible with the particular Swiss situation, while discussing in more detail some aspects. Chronic hepatitis B is a complex disease with several phases where host and viral factors interact: the features of this continuous interplay need to be evaluated when choosing the most appropriate treatment. The EASL guidelines recommend, as first-line agents, using the most potent antivirals available with the optimal resistance profile, in order to abate HBV DNA as rapidly and as sustainably as possible. Once therapy has been started, the infection evolves and resistant viral strains may emerge. Rescue therapy needs to be started early with more potent agents lacking cross-resistance.

Biomphalaria tenagophila: dynamics of populations of resistant and susceptible strains to Schistosoma mansoni, with or without pressure of the parasite

Resistant (Taim, RS) and susceptible albino (Joinville, SC) Biomphalaria tenagophila populations were kept together, at different proportions, throughout a 18-month-period. Some of the snail groups were submitted to Schistosoma mansoni infection. The targets of this study were (a) to analyze the populational dynamics among resistant and susceptible individuals to S. mansoni; (b) to study the resistance phenotype in descendants of cross-breeding; (c) to observe whether the parasite could exert any kind of selection in those snail populations. Throughout the experiment it could be observed that the susceptible B. tenagophila strain (Joinville) underwent a selective pressure of the parasite that was negative, since the individuals showed a high mortality rate. Although B. tenagophila (Taim) population presented a higher mortality rate without pressure of the parasite, this event was compensated by a reproductive capacity. B. tenagophila Taim was more fecund than B. tenagophila Joinville and was able to transmit the resistance character to their descendants. F1 generation obtained by cross-breeding between resistant and susceptible lineages was completely resistant to S. mansoni infection, irrespective of the Taim proportion. Moreover, less than 5% of F2 progeny were susceptible to S. mansoni infection.

Genome-wide re-sequencing of multidrug-resistant Mycobacterium leprae Airaku-3.

Genotyping and molecular characterization of drug resistance mechanisms in Mycobacterium leprae enables disease transmission and drug resistance trends to be monitored. In the present study, we performed genome-wide analysis of Airaku-3, a multidrug-resistant strain with an unknown mechanism of resistance to rifampicin. We identified 12 unique non-synonymous single-nucleotide polymorphisms (SNPs) including two in the transporter-encoding ctpC and ctpI genes. In addition, two SNPs were found that improve the resolution of SNP-based genotyping, particularly for Venezuelan and South East Asian strains of M. leprae.

HIV-1 reverse transcriptase connection domain mutations: dynamics of emergence and implications for success of combination antiretroviral therapy.

BACKGROUND: Factors promoting the emergence of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) connection domain mutations and their effect on antiretroviral therapy (ART) are still largely undetermined. We investigated this matter by analyzing genotypic resistance tests covering 400 amino acid positions in the RT of HIV-1 subtype B viruses and corresponding treatment histories and laboratory measurements. METHODS: The emergence of connection domain mutations was studied in 334 patients receiving monotherapy or dual therapy with thymidine analogues at the time of the genotypic resistance test. Response to subsequent combination ART (cART) was analyzed using Cox regression for 291 patients receiving unboosted protease inhibitors. Response was defined by ever reaching an HIV RNA level <50 copies/mL during the first cART. RESULTS: The connection domain mutations N348I, R356K, R358K, A360V, and A371V were more frequently observed in ART-exposed than ART-naive patients, of which only N348I and A360V were nonpolymorphic (with a prevalence of <1.5% in untreated patients). N348I correlated with M184V and predominantly occurred in patients receiving lamivudine and zidovudine concomitantly. A360V was not associated with specific drug combinations and was found to emerge later than M184V or thymidine analogue mutations. Nonpolymorphic connection domain mutations were rarely detected in the absence of established drug resistance mutations in ART-exposed individuals (prevalence, <1%). None of the 5 connection domain mutations associated with treatment showed a statistically significant effect on response to cART. CONCLUSIONS: Despite their frequent emergence, connection domain mutations did not show large detrimental effects on response to cART. Currently, routine implementation of connection domain sequencing seems unnecessary for developed health care settings.

Patrones de consumo de alcohol en la adolescencia

Este estudio analiza los patrones de consumo de alcohol y el papel de la influencia social y la percepción de peligrosidad de esta sustancia en dicho consumo en una muestra de 1.624 estudiantes de Secundaria de Girona con edades comprendidas entre los 12 y los 18 años (49,4% chicos). Losresultados muestran que un 20,9% de los adolescentes se consideran consumidores habituales de alcohol, y que el consumo se incrementa con la edad, independientemente del género. Un porcentaje elevado de consumidores supera el umbral de alto riesgo para la salud, principalmente entre las chicas debido a las diferencias de género en la metabolización alcohólica. Asimismo se confirma la influencia del entorno (amigos y familiares) y de la percepción de peligrosidad del alcohol tanto en el consumo de esta sustancia como en su uso de alto riesgo. Alcohol consumption patterns in adolescence

Styles de vie, besoins de santé et utilisation des services de soins des adolescents porteurs d'affections chroniques

Résumé Contexte et objectifs Le premier volet a comme objectif d'évaluer la prévalence de l'affection chronique (AC) parmi les adolescents en Suisse, de décrire leurs comportements (loisirs, sexualité, conduites à risque) et de les comparer aux adolescents non porteur d'AC afin d'évaluer l'impact de l'AC sur leur bien-être. Le second volet a comme objectif d'explorer leur réseau de soutien, leur mode d'adaptation et leur perception de la prise en charge dont ils bénéficient par les équipes soignantes. Chacun des objectifs est traité dans un article : - « Chronic illness, life style and emotional health in adolescence: results of a cross-sectional survey on the health of 15-20-year-olds in Switzerland » Eur J Pediatr (2003) 162: 682-689 - « Adolescents porteurs d'affections chroniques: la parole aux patients » Med Hyg 2004 ; 62 : 2224-9. Méthode Première partie: les données ont été obtenues par analyse secondaire de l'enquête sur la santé des adolescents en Suisse, réalisée en 1993-1994 auprès d'un échantillon de 9268 jeunes de 15 à 20 ans (6% de la population visée), à l'aide d'un questionnaire auto administré de 100 questions environ. Le programme SPSS a été utilisé pour effectuer les analyses bi- et multi-variées. Seconde partie: la commission d'éthique de la Faculté de médecine de l'Université de Lausanne a donné son accord permettant la réalisation d'un focus group (discussion en petit groupe) de 12 jeunes. Ils ont participé à une discussion de 2 heures, conduite par un modérateur entraîné à cette méthode. Résultats Premier volet : 11.4% des filles et 9.6% des garçons se déclarent porteurs d'une AC. 25% des filles porteuses d'une AC (versus 13% de non porteur; p=0.007) et 38% des garçons porteurs d'une AC (versus 25% de non porteur; p=0.002) déclarent ne pas utiliser la ceinture de sécurité quand ils conduisent. 6.3% des filles (versus 2.7% ; p= 0.000) disent avoir conduit en étant ivres. 43% des filles (versus 36% ; p= 0.004) et 47% des garçons (versus 39% ; p=0.001) sent fumeurs de cigarettes. 32% des garçons (versus 27% p=0.02) rapportent avoir consommé du cannabis. 17% des filles (versus 13°h ; p=0.013) et 43% des garçons (versus 36% ; p= 0.002) disent boire de l'alcool. Le fait d'être porteur d'AC a aussi des conséquences psychologiques : 7.7% des filles (versus 3.4% ; p= 0.000) et 4.9% des garçons (versus 2% ; p=0.000) ont effectué un tentamen durant les 12 mois précédents. Deuxième volet: Sur oui peuvent-ils compter ? Avant tout sur eux-mêmes, puis sur leurs parents ou leurs amis. Les pairs, l'équipe soignante, les autres malades et les enseignants ont chacun des rôles à jouer à des moments précis de l'évolution de l'AC. Leurs modes d'adaptation: prendre du recul, faire preuve d'humour et demander de l'aide à leurs proches. Ils s'évadent dans l'écriture, les pensées ou la musique. Demande aux médecins une prise en charge globale qui permette une compréhension de l'ensemble de leurs besoins plutôt que focalisée seulement sur leur AC. Le respect, la possibilité d'un soutien et d'explications précises leur paraissent importants. Conclusions Les conduites dites à risque ne sont pas moins fréquentes chez les adolescents porteurs d'AC que chez leurs pairs Elles peuvent être expliquées par le besoin de tester leurs limites tant sur le plan des consommations que du comportement. Une prévention et une attention spécifiques des équipes soignantes sont nécessaires. Un réseau social diversifié paraît nécessaire aux jeunes souffrant d'AC. Les médecins devraient avoir une vision globale de leur patient, les aider à se situer dans le monde de l'adolescence, leur permettre de nommer leurs émotions et anticiper les questions difficiles à poser. Abstract The objective was to evaluate the prevalence of chronic conditions (CC) in adolescents in Switzerland; interval to describe their behaviour (leisure, sexuality, risk taking behaviour) and to compare them to those in adolescents who do not have CC in order to evaluate the impact of those conditions on their well-being. The data were obtained from the Swiss Multicentre Adolescent Survey Introduction on Health, targeting a sample of 9268 in-school adolescents aged 15 to 20 years, who answered a self-administered questionnaire. Some 11.4% of girls and 9.6% of boys declared themselves carriers of a CC. Of girls suffering from a CC, 25% (versus 13% of non carriers; P = 0.007) and 38% of boys (versus 25%; P=0.002) proclaimed not to wear a seatbelt whilst driving. Of CC girls, 6.3% (versus 2.7%; P= 0.000) reported within the last 12 months to have driven whilst drunk. Of the girls, 43% (versus 36%; P=0.004) and 47% (versus 39%; P=0.001) were cigarette smokers. Over 32% of boys (versus 27%; P=0.02) reported having ever used cannabis and 17% of girls (versus 13%; P=0.013) and 43% of boys (versus 36%; P=0.002) admitted drinking alcohol. The burden of their illness had important psychological consequences: 7.7% of girls (versus 3.4%; P=0.000) and 4.9% of boys (versus 2.0%; P=0.000) had attempted suicide during the previous 12 months. Conclusion: Experimental behaviours are not rarer in adolescents with a chronic condition and might be explained by a need to test their limits both in terms of consumption and behaviour. Prevention and specific attention from the health caring team is necessary.

Genetics of chloroquine-resistant malaria: a haplotypic view

The development and rapid spread of chloroquine resistance (CQR) in Plasmodium falciparum have triggered the identification of several genetic target(s) in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76), are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria.

From Opacity to Transparency? The Place of Organized Interests within the European Institutions

Regulació dels Grup d'interès en la governança europea és crucial per a una comprensió completa de com s'exerceix el poder a la Unió Europea (UE) i per a una descripció més precisa de com funciona el sistema polític de la UE (i dels seus principis subjacents). Un dels temes principals aquí és com els interessos privats o particulars comprometre amb un interès general o públic encarnat en una forma o altra per aquells que actuen per a la UE. Donada la varietat de temes sensibles en joc, no és d'estranyar que la qüestió de la regulació es troba amb una resistència considerable, sobre tot en la Comissió. No obstant això, els recents obstacles a la integració europea han tingut l'efecte de rellançar un debat que fa que l'ètica i la transparència de les peces centrals de l'agenda. Dinàmiques polítiques actuals semblen donar testimoni d'una creixent receptivitat de la UE a les reivindicacions del moviment ALTER-EU que busca un entorn molt més regulat per cabilderos i funcionaris comunitaris.

Hypertension and microvascular remodelling

In the present review, microvascular remodelling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Folkow's contribution made half a century ago. We then move to some basic concepts on the biomechanics of blood vessels, and explicit the definitions proposed by Mulvany for specific forms of remodelling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodelled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodelling is described, again with emphasis on human data. Some details are given on the three studies to date which point to remodelling of subcutaneous resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remodelling in the pathogenesis of end-organ damage and in the perpetuation of hypertension.

Essstörungen bei Adipositas und Diabetes mellitus [Eating disorders associated with obesity and diabetes].

Binge eating disorder is one of the most frequent comorbid mental disorders associated with overweight and obesity. Binge eating disorder patients often suffer from other mental disorders and longitudinal studies indicate a continuous weight gain during the long-term course. As in other eating disorders gender is a risk factor, but the proportion of male binge eating disorder patients is surprisingly high.In young women with type 1 diabetes the prevalence of subclinical types of bulimia nervosa is increased. In addition, insulin purging as a characteristic compensatory behavior in young diabetic women poses a considerable problem. In patients with type 1 diabetes, disturbed eating and eating disorders are characterized by insufficient metabolic control and early development of late diabetic sequelae. Patients with type 2 diabetes are often overweight or obese. Binge eating disorder does not occur more frequently in patients with type 2 diabetes compared to healthy persons. However, the comorbidity of binge eating disorder and diabetes type 2 is associated with weight gain and insulin resistance. Especially in young diabetic patients a screening procedure for disturbed eating or eating disorders seems to be necessary. Comorbid patients should be offered psychotherapy.

Cardiovascular patterns associated with appetitive and defensive activation during affective picture viewing

Descriptors: cardiovascular patterns, emotion, affective pictures In this study we assessed blood pressure (BP), heart rate (HR), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) in response to 13 picture series in 18 men and 19 women in order to investigate their hemodynamic responses associated with activation of the appetitive and defensive motivational systems underlying emotional experience. Skin conductance level (SCL) was also recorded. BP and SV increased with increasing self-rated arousal both for appetitive and defensive activation, whereas HR decelerated more in response to negative than positive and neutral pictures. TPR showed a general increase from baseline to picture processing but was unrelated to self-rated valence and arousal. These findings suggest that affective modulation of the cardiovascular response to affective pictures is primarily myocardial. The observed response pattern is consistent with a configuration of cardiac sympathetic-parasympathetic coactivation. The relationships between self-reported arousal, BP and SV were mainly exhibited by men suggesting that increases in the sympathetic inotropic effect to the heart with increasing self-rated arousal might be larger in men than in women. In contrast, SCL covaried positively with self-rated arousal both in men and women. This suggests that sex differences in the affective modulation of the responses to pictures may be restricted to specific cardiovascular parameters and support the contention that the sympathetic nervous system does not discharge as a whole.

Being Drunk to Have Fun or to Forget Problems? Identifying Enhancement and Coping Drinkers Among Risky Drinking Adolescents

Prevention programs in adolescence are particularly effective if they target homogeneous risk groups of adolescents who share a combination of particular needs and problems. The present work aims to identify and classify risky single-occasion drinking (RSOD) adolescents according to their motivation to engage in drinking. An easy-to-use coding procedure was developed. It was validated by means of cluster analyses and structural equation modeling based on two randomly selected subsamples of a nationally representative sample of 2,449 12- to 18-year-old RSOD students in Switzerland. Results revealed that the coding procedure classified RSOD adolescents as either enhancement drinkers or coping drinkers. The high concordance (Sample A: kappa - .88, Sample B: kappa - .90) with the results of the cluster analyses demonstrated the convergent validity of the coding classification. The fact that enhancement drinkers in both subsamples were found to go out more frequently in the evenings and to have more satisfactory social relationships, as well as a higher proportion of drinking peers and a lower likelihood to drink at home than coping drinkers demonstrates the concurrent validity of the classification. To conclude, the coding procedure appears to be a valid, reliable, and easy-to-use tool that can help better adapt prevention activities to adolescent risky drinking motives.