Fat oxidation in nonobese and obese adolescents: effect of body composition and pubertal development.

OBJECTIVES: To measure postabsorptive fat oxidation (F(ox)) and to assess its association with body composition (lean body mass [LBM] and body fat mass [BFM]) and pubertal development. DESIGN: We studied 235 control (male/female ratio = 116/119; age [mean +/- SD]: 13.1 +/- 1.7 years; weight: 45.3 +/- 10.5 kg; LBM: 34.3 +/- 7.1 kg; BFM: 11.0 +/- 4.5 kg) and 159 obese (male/female ratio = 93/66; age: 12.9 +/- 2.1 years; weight: 76.2 +/- 19.1 kg; LBM: 47.4 +/- 10.9 kg; BFM: 28.8 +/- 9.2 kg) adolescents. Postabsorptive F(ox) was calculated from oxygen consumption, carbon dioxide production, and urinary nitrogen as measured by indirect calorimetry and Kjeldahl's method, respectively. Body composition was determined by anthropometry. RESULTS: Postabsorptive F(ox) (absolute value and percentage of resting metabolic rate) was significantly (p < 0.001) higher in the obese adolescents (76.7 +/- 26.3 gm/24 hours, 42.3% +/- 18.7%) than in the control subjects (40.0 +/- 26.3 gm/24 hours, 28.7% +/- 17.0%), even if adjusted for LBM. F(ox) corrected for BFM was similar in control and in obese children, but was significantly lower in girls compared with boys (control male subjects: 62.1 +/- 29.1 gm/24 hours, control female subjects: 51.6 +/- 28.4 gm/24 hours, obese male subjects: 57.3 +/- 29 gm/24 hour, obese female subjects: 45.0 +/- 28.4 gm/24 hours). BFM and LBM showed a significant positive correlation with F(ox). By stepwise regression analysis the most important determinant of F(ox) was BFM in obese and LBM in control children. There was a significant rise in F(ox) during puberty; however, it was mainly explained by changes in body composition. CONCLUSIONS: Obese adolescents have higher F(ox) rates than their normal-weight counterparts. Both LBM and fat mass are important determinants of F(ox).

Characterization of PHO1 and PHO1;H1 gene function in Arabidopsis thaliana

Summary Phosphorus is one of the major macronutrients required for plant growth and development. Plant roots acquire phosphorus as inorganic phosphate (Pi), which is further distributed to the shoot, via the transpiration stream and root pressure, where Pi is imported again into cells. PHO1 in Arabidopsis has been identified as a protein involved in the loading of Pi into the root xylem. PHO1 does not have any homology to described Pi transporters including the Pht1 family of H+/ Pi cotransporters. PHO1 bears two domains, SPX and EXS domains, previously identified in Saccharomyces cerevisiae proteins involved in Pi transport and/or sensing, or in sorting proteins to endomembranes. Phylogenetic analysis of the PHO1 gene family revealed the presence of three clusters, with PHO1 and PHO1;H1 forming one cluster. The biological significance behind this cluster was demonstrated by the complementation of the pho1 mutant with only PHO1 and PHO1;H1, of all the PHO1 family members, when expressed under the PHO1 promoter. PHO1 has been shown to be expressed mostly in the root vascular cylinder and at low level in the shoot. PHO1;H1 had a different expression pattern, being expressed in both root and shoot vascular cylinder to the same level, with the levels in leaves increasing with the leaf maturity, suggesting additional role of PHO1;H1 in the Pi mobilization in leaves. In order to further explore the role of PHO1, Pi dynamics was studied on plants expressing PHO1 at different levels compared to the wild type: PHO1 overexpressors, PHO1 underexpressors and the pho1 mutant. Overexpression of the PHO1 protein in the shoot vascular tissue was shown to lead to increased Pi efflux out of the leaf cells and Pi accumulation in the shoot xylem apoplast compared to wild type, confirming the hypothesized role of PHO1 in xylem loading with Pi. The overexpression of PHO1 in the shoot was responsible far both changed Pi dynamic and stunted growth of PHO1 overexpressors, as shown by grafting experiments between wild type and PHO1 overexpressor. We found a ca. 2 fold decrease of shoot phosphorus and a 5-10 fold decrease in vacuolar Pi content in the PHO1 underexpressors and the pho1 null mutant compared to wild type, consistent with the role of PHO1 in the transfer of Pi from the root to the shoot. Shoot Pi deficiency results in a poor growth of the pho1 mutant. Grafting experiments between pho1 and wild type confirmed that both Pi deficiency and stunt growth of the pho1 mutant were dependent on the pho1 root, further supporting the importance of PHO1 in the root xylem loading with Pi. The pho1 mutant and the PHO1 underexpressors accumulated 8-15 fold more Pi in the root relative to wild type. In contrast to the pho1 mutant, the growth of PHO1 underexpressors was not impaired by the low shoat Pi content. This finding suggests that either PHO1 protein or root Pi concentration is important in Pi signaling and development of Pi deficiency symptoms leading to reduced growth. Résumé Le phosphore est l'un des nutriments essentiels à la croissance et au développement des plantes. Les racines absorbent le phosphore sous forme de phosphate inorganique (Pi) qui est dirigé, par la transpiration et la pression de la racine, vers les feuilles où le phosphate est acquis par les cellules. La protéine PHO1 a été démontrée indispensable au chargement du Pi dans le xylème des racines d'Arabidopsis. PHO1 ne démontre pas d'homologie aux transporteurs de Pi connus, incluant la famille Pht1 de cotransporteurs H+/Pi qui ont comme fonction le transport du phosphate à l'intérieur de la cellule. PHO1 contient deux domaines, SPX et EXS, aussi présents dans des protéines de Saccharomyces cerevisiae impliquées dans le transport ou la perception du phosphate, ou dans la localisation des protéines vers différentes membranes. Le génome d'Arabidopsis contient onze gènes homologues à PHO1. Neuf de ces homologues sont répartis en trois groupes. PHO1 et PHO1;H1 forment un de ces groupes. Nos travaux ont démontré que seuls PHO1;H1 et PHO1, sous contrôle du promoteur PHO1, peuvent complémenter le mutant pho1. PHO1 est exprimé principalement dans le cylindre vasculaire de la racine et faiblement dans la partie aérienne. Le degré d'expression de PHO1;H1 est similaire dans le cylindre vasculaire de la racine et des feuilles. Ceci suggère que PHO1;H1 est aussi impliqué dans la mobilisation du Pi dans les feuilles, en plus de son rôle dans le transfert du Pi dans le xylème des racines. Afin de mieux explorer le rôle de PHO1, la dynamique du phosphate a été observée dans trois lignées de plantes transgéniques: un sur-expresseur de PHO1, un sous-expresseur de PHO1 et le mutant pho1. La sur-expression de PHO1 dans le tissue vasculaire des feuilles a provoqué l'efflux du Pi vers l'espace apoplastic du xylème, ce qui confirme le rôle de PHO1 dans le chargement du Pi dans le xylème. La sur-expressìon de PHO1 dans la rosette est responsable d'un changement de la dynamique du Pi et de la diminution de la croissance, ce qui fut démontré par une expérience de greffe de la rosette du sur-expresseur de PHO1 sur les racines du sauvage. On a observé pour le sous-expresseur de PHO1 et le mutant pho1 une diminution du phosphore d'environ 2 fais au niveau des feuilles, et une diminution de 5-10 fois du Pi dans les vacuoles des feuilles, par rapport au sauvage. Ceci confirme le rôle proposé de PHO1 dans le transfert du Pi des racines aux feuilles. La carence de Pi chez pho1 implique une diminution de la taille de la rosette. Pour expliquer ce phénotype une autre expérience de greffe démontra que la cause de ce changement provenait des racines. Ceci renforce l'hypothèse de l'importance du rôle de PHO1 dans le xylème de la racine pour le chargement du Pi. Le mutant phot et le sous-expresseur de PHO1 accumulent 8-15 fois plus de Pi dans leurs racines comparé au sauvage. Cependant, contrairement au phot mutant, le sous-expresseur de PHO1 avait une croissance comparable au sauvage malgré le niveau bas du Pi dans les feuilles. Ceci suggère que la taille de la rosette lors d'une carence en Pi chez Arabidopsis serait la conséquence d'un changement de concentration de Pi dans les racines ou d'une influence de la protéine PHO1.

Housewife or working mum--each to her own? The relevance of societal factors in the association between social roles and alcohol use among mothers in 16 industrialized countries.

Aims To investigate whether differences in gender-income equity at country level explain national differences in the links between alcohol use, and the combination of motherhood and paid labour. Design Cross-sectional data in 16 established market economies participating in the Gender, Alcohol and Culture: An International Study (GenACIS) study. Setting Population surveys. Participants A total of 12 454 mothers (aged 25-49 years). Measurements Alcohol use was assessed as the quantity per drinking day. Paid labour, having a partner, gender-income ratio at country level and the interaction between individual and country characteristics were regressed on alcohol consumed per drinking day using multi-level modelling. Findings Mothers with a partner who were in paid labour reported consuming more alcohol on drinking days than partnered housewives. In countries with high gender-income equity, mothers with a partner who were in paid labour drank less alcohol per occasion, while alcohol use was higher among working partnered mothers living in countries with lower income equity. Conclusion In countries which facilitate working mothers, daily alcohol use decreases as female social roles increase; in contrast, in countries where there are fewer incentives for mothers to remain in work, the protective effect of being a working mother (with partner) on alcohol use is weaker. These data suggest that a country's investment in measures to improve the compatibility of motherhood and paid labour may reduce women's alcohol use.

PH01 gene family in Arabidopsis thaliana and Physcomitrella patens

Summary Inorganic phosphate (Pi) is a main limiting nutrient to the growth and production yield of plants in many agro-ecosystems. Plants have evolved a series of metabolic and developmental adaptations to cope with low Pi availability. PH01 has been identified as a protein involved in the loading of Pi into the xylem of roots in Arabidopsis. In this study, the PHO1 gene family in both higher plant Arabidopsis and lower plant Physcomitrella was characterized. Additional ten PHO1 homologues in Arabidopsis and three homologues in Physcomitrella were identified. All proteins harbor a SPX tripartite domain in the N-terminal hydrophilic portion and an EXS domain in the highly conserved C-terminal hydrophobic portion. RT-PCR analysis of the Arabidopsis PHO1 genes revealed a broad pattern of expression in leaves, roots, stems, and flowers for most genes, although two genes are expressed exclusively in flowers, indicating their potential roles not only in Pi transport but also in Pi homeostasis within the Arabidopsis plant. The regulation of gene expression by different nutrient-starvations showed that some genes are strongly up-regulated by elements other than Pi, e.g. by NO3, Mg, and Zn starvation. Northern blot and RT-PCR analysis showed distinct expression patterns of the three Physcomitrella PHO1 genes. The investigation of Pi starvation effects on some Pi-deprivation responsive genes demonstrates that Physcomitrella has evolved a similar mechanism as higher plants to respond to Pi deficiency. Promoter activity analysis for the Physcomitrella PHO1 family genes using promoter-GUS fusions revealed their expression in protonemata and gametophores but at different levels and with different patterns, suggesting these genes may play distinct roles in Pi transport and/or Pi homeostasis in the moss plant. Single knockout mutants of the three genes were generated by gene targeting and one of them displayed a reduced Pi content in the protonemata under Pi starvation. The evolution of the PHO1 family in land plants was also discussed. Together, these findings indicate that the PHO1 family genes, present in a broad range of plant species from lower plants to flowering plants, play important roles in Pi transport and homeostasis. Résumé Le phosphate inorganique (Pi) est un nutriment essentiel à la croissance des plantes et au rendement de la production végétale. Dans beaucoup d'agro-écosystèmes, ce nutriment est limitant. Les plantes ont développé des adaptations métaboliques et développementales pour palier à la faible disponibilité du Pi. Il a été démontré que la protéine PHOI est indispensable au transfert du Pi dans le xylème des racines d' Arabidopsis. Cette étude porte sur la famille de gènes définie par PHO1 ; ceci, dans deux organismes modèles : la plante Arabidopsis pour les végétaux supérieurs, et la mousse Physcomitrella pour les végétaux inférieurs. Dix homologues à PHOI dans Arabidopsis et trois homologues dans Physcomitrella ont été identifiés. Toutes les protéines encodées présentent un domaine tripartite SPX dans leur partie N terminale hydrophile et un domaine EXS dans la partie C terminale hydrophobe hautement conservée d'entre eux. L'analyse par RT-PCR de l'expression des gènes PHO1 dans Arabidopsis révèle une expression ectopique pour la plupart, à l'exception de deux gènes dont l'expression est uniquement florale ; ceci suggère l'implication de cette famille non seulement dans le transport mais aussi dans l'homéostasie du Pi dans Arabidopsis. L'observation de l'expression de ces gènes en fonction de l'absence de différents nutriments montre que certains gènes sont fortement régulés lors de carences en NO3, Mg et Zn. L'analyse par northern blot et RT-PCR met en évidence des profils d'expression distincts pour les trois gènes de Physcomitrella. Les effets de la carence en Pi sur Physcomitrella ont été étudiés par le biais de gènes dépendants connus pour Arabidopsis, les résultats suggèrent un mode de réponse à cette carence conservé entre les végétaux inférieurs et supérieurs. La localisation tissulaire de l'expression de la famille PHO1 dans la mousse a été étudiée au moyen du gène rapporteur GUS fusionné aux différents promoteurs. Ceci a révélé leur expression dans les protonemata et les gametophores, mais à des intensités et avec des profils différents, ce qui suggère des implications distinctes dans le transport et/ou l'homéostasie du Pi dans la mousse. Des simples mutants knockout ont été générés pour chaque gène de mousse ; l'un d'eux présente une diminution du contenu protonemal en Pi lorsque soumis à une carence en Pi. L'évolution de la famille PHO1 dans les plantes terrestres est également discutée. Ensemble, ces résultats indiquent que les gènes de la famille PHO1 sont présents dans une large gamme de plantes allant des végétaux inférieurs aux supérieurs, et cette étude démontre que leur conservation se justifie potentiellement par le fait qu'ils sont probablement impliqués dans des mécanismes conservés de transport et d'homéostasie du Pi.

Potential role of pathogen signaling in multitrophic plant-microbe interactions involved in disease protection.

Multitrophic interactions mediate the ability of fungal pathogens to cause plant disease and the ability of bacterial antagonists to suppress disease. Antibiotic production by antagonists, which contributes to disease suppression, is known to be modulated by abiotic and host plant environmental conditions. Here, we demonstrate that a pathogen metabolite functions as a negative signal for bacterial antibiotic biosynthesis, which can determine the relative importance of biological control mechanisms available to antagonists and which may also influence fungus-bacterium ecological interactions. We found that production of the polyketide antibiotic 2,4-diacetylphloroglucinol (DAPG) was the primary biocontrol mechanism of Pseudomonas fluorescens strain Q2-87 against Fusarium oxysporum f. sp. radicis-lycopersici on the tomato as determined with mutational analysis. In contrast, DAPG was not important for the less-disease-suppressive strain CHA0. This was explained by differential sensitivity of the bacteria to fusaric acid, a pathogen phyto- and mycotoxin that specifically blocked DAPG biosynthesis in strain CHA0 but not in strain Q2-87. In CHA0, hydrogen cyanide, a biocide not repressed by fusaric acid, played a more important role in disease suppression.

International Standardisation and Local Participatory Dynamics : The INTERNORM Project

This paper presents a pilot project (INTERNORM) funded by the University of Lausanne (2010 - 2013) to support the involvement of civil society organisations (CSO) in international standard setting bodies such as the ISO. It analyses how a distinct participatory mechanism can influence the institutional environment of technical diplomacy in which standards are shaped. The project is an attempt to respond to the democratic deficit attested in the field of international standardisation, formally open to civil society participation, but still largely dominated by expert knowledge and market players. Many international standards have direct implications on society as a whole, but CSOs (consumers and environmental associations, trade unions) are largely under-represented in negotiation arenas. The paper draws upon international relations literature on new institutional forms in global governance and studies of participation in science and technology. It argues that there are significant limitations to the rise of civil society participation in such global governance mechanisms. The INTERNORM project has been designed as a platform of knowledge exchange between CSO and academic experts, with earmarked funding and official membership to a national standardisation body. But INTERNORM cannot substitute for a long- established lack of resources in time, money and expertise of CSOs. Despite high entry costs into technical diplomacy, participation thus appears as less a matter of upstream engagement, or of procedure only, than of dedicated means to shift the geometry of actors and the framing of socio-technical change.

Identification of psychological dysfunctions and eating disorders in obese women seeking weight loss: cross-sectional study.

Objective. The aim of this study is to analyse associations between eating behaviour and psychological dysfunctions in treatment-seeking obese patients and identify parameters for the development of diagnostic tools with regard to eating and psychological disorders. Design and Methods. Cross-sectional data were analysed from 138 obese women. Bulimic Investigatory Test of Edinburgh and Eating Disorder Inventory-2 assessed eating behaviours. Beck Depression Inventory II, Spielberger State-Trait Anxiety Inventory, form Y, Rathus Assertiveness Schedule, and Marks and Mathews Fear Questionnaire assessed psychological profile. Results. 61% of patients showed moderate or major depressive symptoms and 77% showed symptoms of anxiety. Half of the participants presented with a low degree of assertiveness. No correlation was found between psychological profile and age or anthropometric measurements. The prevalence and severity of depression, anxiety, and assertiveness increased with the degree of eating disorders. The feeling of ineffectiveness explained a large degree of score variance. It explained 30 to 50% of the variability of assertiveness, phobias, anxiety, and depression. Conclusion. Psychological dysfunctions had a high prevalence and their severity is correlated with degree of eating disorders. The feeling of ineffectiveness constitutes the major predictor of the psychological profile and could open new ways to develop screening tools.

The impact of cyclin D1 mRNA isoforms, morphology and p53 in mantle cell lymphoma: p53 alterations and blastoid morphology are strong predictors of a high proliferation index.

BACKGROUND: Mantle cell lymphoma is a clinically heterogeneous disease characterized by overexpression of cyclin D1 protein. Blastoid morphology, high proliferation, and secondary genetic aberrations are markers of aggressive behavior. Expression profiling of mantle cell lymphoma revealed that predominance of the 3'UTR-deficient, short cyclin D1 mRNA isoform was associated with high cyclin D1 levels, a high "proliferation signature" and poor prognosis. DESIGN AND METHODS: Sixty-two cases of mantle cell lymphoma were analyzed for cyclin D1 mRNA isoforms and total cyclin D1 levels by real-time reverse transcriptase polymerase chain reaction, and TP53 alterations were assessed by immunohistochemistry and molecular analysis. Results were correlated with proliferation index and clinical outcome. RESULTS: Predominance of the short cyclin D1 mRNA was found in 14 (23%) samples, including four with complete loss of the standard transcript. TP53 alterations were found in 15 (24%) cases. Predominance of 3'UTR-deficient mRNA was significantly associated with high cyclin D1 mRNA levels (P=0.009) and more commonly found in blastoid mantle cell lymphoma (5/11, P=0.060) and cases with a proliferation index of >20% (P=0.026). Both blastoid morphology (11/11, P<0.001) and TP53 alterations (15/15, P<0.001) were significantly correlated with a high proliferation index. A proliferation index of 10% was determined to be a significant threshold for survival in multivariate analysis (P=0.01). CONCLUSIONS: TP53 alterations are strongly associated with a high proliferation index and aggressive behavior in mantle cell lymphoma. Predominance of the 3'UTR-deficient transcript correlates with higher cyclin D1 levels and may be a secondary contributing factor to high proliferation, but failed to reach prognostic significance in this study.

Body fat distribution in white and black women: different patterns of intraabdominal and subcutaneous abdominal adipose tissue utilization with weight loss.

BACKGROUND: Intraabdominal adipose tissue (IAAT) is the body fat depot most strongly related to disease risk. Weight reduction is advocated for overweight people to reduce total body fat and IAAT, although little is known about the effect of weight loss on abdominal fat distribution in different races. OBJECTIVE: We compared the effects of diet-induced weight loss on changes in abdominal fat distribution in white and black women. DESIGN: We studied 23 white and 23 black women, similar in age and body composition, in the overweight state [mean body mass index (BMI; in kg/m(2)): 28.8] and the normal-weight state (mean BMI: 24.0) and 38 never-overweight control women (mean BMI: 23.4). We measured total body fat by using a 4-compartment model, trunk fat by using dual-energy X-ray absorptiometry, and cross-sectional areas of IAAT (at the fourth and fifth lumbar vertebrae) and subcutaneous abdominal adipose tissue (SAAT) by using computed tomography. RESULTS: Weight loss was similar in white and black women (13.1 and 12.6 kg, respectively), as were losses of total fat, trunk fat, and waist circumference. However, white women lost more IAAT (P < 0.001) and less SAAT (P < 0.03) than did black women. Fat patterns regressed toward those of their respective control groups. Changes in waist circumference correlated with changes in IAAT in white women (r = 0.54, P < 0.05) but not in black women (r = 0.19, NS). CONCLUSIONS: Despite comparable decreases in total and trunk fat, white women lost more IAAT and less SAAT than did black women. Waist circumference was not a suitable surrogate marker for tracking changes in the visceral fat compartment in black women.

Prevalence and risk of Down syndrome in monozygotic and dizygotic multiple pregnancies in Europe: implications for prenatal screening.

OBJECTIVE: To determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome. DESIGN: Population-based prevalence study based on EUROCAT congenital anomaly registries. SETTING: Eight European countries. POPULATION: 14.8 million births 1990-2009; 2.89% multiple births. METHODS: DS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases. MAIN OUTCOME MEASURES: Relative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome. STATISTICAL ANALYSIS: Poisson and logistic regression stratified for maternal age, country and time. RESULTS: Overall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53-0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25-0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23-1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50-0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27-0.59]). CONCLUSIONS: The risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening.

Idiopathic chiasmal neuritis: clinical features and prognosis.

OBJECTIVES: To describe the clinical features of idiopathic chiasmal neuritis in a large cohort of patients and to report their visual and neurologic outcomes. DESIGN: A retrospective medical record review of consecutive patients with chiasmal neuritis at a single institution. Patients with clinical or radiographic evidence of inflammation involving the intraorbital optic nerve and patients with a systemic inflammatory or neoplastic disorder were excluded. RESULTS: Twenty patients were identified (14 female, 6 male; mean age, 37 years). Visual acuity at initial examination ranged from 20/15 to light perception. Progressive visual loss beyond 1 month was documented in 1 patient. Twelve of 15 patients who underwent magnetic resonance imaging demonstrated chiasmal enlargement and/or enhancement; 6 patients had 1 or more white matter lesions. Follow-up time ranged from 2 weeks to 22 years, with a mean of 5.7 years. The final median visual acuity was 20/20 (range, 20/15-20/50) and visual fields were normal or improved. Of 15 patients with a minimum follow-up interval of 1 year, 6 developed multiple sclerosis. CONCLUSIONS: The demographic and clinical features of idiopathic chiasmal neuritis resemble those of idiopathic optic neuritis. Visual prognosis is excellent. In this series, 40% of patients subsequently developed multiple sclerosis.

Intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency.

OBJECTIVE: To compare the prevalence of intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency (oPOI) and in controls. DESIGN: Observational study. SETTING: Division of Infertility and Service of Genetic Medicine, Geneva University Hospitals. PATIENT(S): The study group consisted of 27 infertile women with oPOI referred by infertility specialists for FMR1 testing in 2005-6 because of unexplained poor response to controlled ovarian hyperstimulation or altered hormonal profiles. The control group consisted of 32 women undergoing genetic testing for conditions unrelated to mental retardation or ovarian function. The DNA samples were anonymized. INTERVENTION(S): In the study group, data were collected concerning reproductive/family history, hormonal markers, possible fertility treatment outcomes, and results of karyotype and FMR1 testing. In the control group, FMR1 gene testing was done. The only clinical data available in controls were sex and indication for genetic testing. MAIN OUTCOME MEASURE(S): Distribution of FMR1 alleles. RESULT(S): Six (22%) of 27 women with oPOI had FMR1 alleles of >40 repeats (intermediate to premutation range), compared with one (3%) of 32 controls. CONCLUSION(S): These results suggest that women with oPOI might be at risk of carrying alleles in the intermediate and premutation range.

Partnership for fragility bone fracture care provision and prevention program (P4Bones): study protocol for a secondary fracture prevention pragmatic controlled trial.

ABSTRACT: BACKGROUND: Fractures associated with bone fragility in older adults signal the potential for secondary fracture. Fragility fractures often precipitate further decline in health and loss of mobility, with high associated costs for patients, families, society and the healthcare system. Promptly initiating a coordinated, comprehensive pharmacological bone health and falls prevention program post-fracture may improve osteoporosis treatment compliance; and reduce rates of falls and secondary fractures, and associated morbidity, mortality and costs.Methods/design: This pragmatic, controlled trial at 11 hospital sites in eight regions in Quebec, Canada, will recruit community-dwelling patients over age 50 who have sustained a fragility fracture to an intervention coordinated program or to standard care, according to the site. Site study coordinators will identify and recruit 1,596 participants for each study arm. Coordinators at intervention sites will facilitate continuity of care for bone health, and arrange fall prevention programs including physical exercise. The intervention teams include medical bone specialists, primary care physicians, pharmacists, nurses, rehabilitation clinicians, and community program organizers.The primary outcome of this study is the incidence of secondary fragility fractures within an 18-month follow-up period. Secondary outcomes include initiation and compliance with bone health medication; time to first fall and number of clinically significant falls; fall-related hospitalization and mortality; physical activity; quality of life; fragility fracture-related costs; admission to a long term care facility; participants' perceptions of care integration, expectations and satisfaction with the program; and participants' compliance with the fall prevention program. Finally, professionals at intervention sites will participate in focus groups to identify barriers and facilitating factors for the integrated fragility fracture prevention program.This integrated program will facilitate knowledge translation and dissemination via the following: involvement of various collaborators during the development and set-up of the integrated program; distribution of pamphlets about osteoporosis and fall prevention strategies to primary care physicians in the intervention group and patients in the control group; participation in evaluation activities; and eventual dissemination of study results.Study/trial registration: Clinical Trial.Gov NCT01745068Study ID number: CIHR grant # 267395.

Safety of a new algorithm for the management of childhood illness (Almanach) to improve quality of care and rational use of drugs

Introduction New evidence from randomized controlled and etiology of fever studies, the availability of reliable RDT for malaria, and novel technologies call for revision of the IMCI strategy. We developed a new algorithm based on (i) a systematic review of published studies assessing the safety and appropriateness of RDT and antibiotic prescription, (ii) results from a clinical and microbiological investigation of febrile children aged <5 years, (iii) international expert IMCI opinions. The aim of this study was to assess the safety of the new algorithm among patients in urban and rural areas of Tanzania.Materials and Methods The design was a controlled noninferiority study. Enrolled children aged 2-59 months with any illness were managed either by a study clinician using the new Almanach algorithm (two intervention health facilities), or clinicians using standard practice, including RDT (two control HF). At day 7 and day 14, all patients were reassessed. Patients who were ill in between or not cured at day 14 were followed until recovery or death. Primary outcome was rate of complications, secondary outcome rate of antibiotic prescriptions.Results 1062 children were recruited. Main diagnoses were URTI 26%, pneumonia 19% and gastroenteritis (9.4%). 98% (531/541) were cured at D14 in the Almanach arm and 99.6% (519/521) in controls. Rate of secondary hospitalization was 0.2% in each. One death occurred in controls. None of the complications was due to withdrawal of antibiotics or antimalarials at day 0. Rate of antibiotic use was 19% in the Almanach arm and 84% in controls.Conclusion Evidence suggests that the new algorithm, primarily aimed at the rational use of drugs, is as safe as standard practice and leads to a drastic reduction of antibiotic use. The Almanach is currently being tested for clinician adherence to proposed procedures when used on paper or a mobile phone

Tumor sensitizing function and mechanism of action of a RasGAP derived peptide

Cancer is the second cause of death after cardio-vascular diseases in economically developed countries. Two of the most commonly used anti-cancer therapies are chemo and radiotherapy. Despite the remarkable advances made in term of delivery and specificity of these two anti-tumor regimens, their toxicity towards healthy tissue remains a limitation. A promising approach to overcome this obstacle would be the utilization of therapeutic peptides that specifically augment the sensitivity of tumoral cells to treatments. Lower therapeutical doses would then be required to kill malignant cells, limiting toxic effects on healthy tissues. It was previously shown in our laboratory that the caspase-3 generated fragment N2 of RasGAP is able to potentiate the genotoxin-induced apoptosis selectively in cancer cells. In this work we show that fragment N2 strictly requires a cytoplasmic localization to deliver its pro-apoptotic effect in genotoxin-treated cancer cells. The tumor sensitizing capacity of fragment N2 was found to reside within the 10 amino acid sequence 317-326. Our laboratory earlier demonstrated that a peptide corresponding to amino acids 317 to 326 of RasGAP fused to the TAT cell permeable moiety, called TAT-RasGAP317.326, is able to sensitize cancer cells, but not normal cells, to genotoxin-induced apoptosis. In the present study we describe the capacity of TAT-RasGAP 317.326 to sensitize tumors to both chemo and radiotherapy in an in vivo mouse model. The molecular mechanism underlying the TAT-RasGAP 317.326-mediated sensitization starts now to be elucidated. We demonstrate that G3BP1, an endoribonuclease binding to amino acids 317-326 of RasGAP, is not involved in the sensitization mechanism. We also provide evidence showing that TAT-RasGAP3 17-326 potentiates the genotoxin-mediated activation of Bax in a tBid-dependent manner. Altogether our results show that TAT-RasGAP 317.326 could be potentially used in cancer therapy as sensitizer, in order to improve the efficacy of chemo and radiotherapy and prolong the life expectancy of cancer patients. Moreover, the understanding of the TAT-RasGAP317.326 mode of action might help to unravel the mechanisms by which cancer cells resist to chemo and radiotherapy and therefore to design more targeted and efficient anti-tumoral strategies.