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Background Schistosomiasis is a parasitic neglected tropical disease that ranks second only to malaria in terms of human suffering in the tropics and subtropics. Biomedical disease control interventions need to be complemented with effective prevention and health education strategies, that address the social and environmental determinants of disease. Malaria Consortium conducted an implementation research study between May 2014 and February 2016, in four districts of Nampula province, Mozambique, to test a Community Dialogue (CD) intervention to enhance schistosomiasis prevention and control. The study aimed to evaluate the acceptability and feasibility of using CD to improve communities’ level of knowledge, attitudes and practices, and engagement in wider schistosomiasis prevention and control efforts. Methods The feasibility and acceptability of the CD intervention was evaluated using qualitative and process evaluation data collected throughout the development and implementation phases. Qualitative data sets included key informant interviews (N = 4) with health system personnel, focus group discussions (N = 22) with Community Dialogue facilitators and participants, field observation visits (N = 11), training reports (N = 7), feedback meeting reports (N = 5), CD monitoring sheets (N = 1,458) and CD planning sheets (N = 152). Findings The CD intervention was found highly acceptable and feasible, particularly well-suited to resource poor settings. Non-specialist community volunteers were able to deliver participatory CDs which resulted in increased knowledge among participants and triggered individual and communal actions for improved disease prevention and control. The visual flipchart was a key aid for learning; the use of participatory communication techniques allowed the correction of misconceptions and positioned correct prevention and control practices as the community recommendations, through consensus building. Conclusion The Community Dialogue Approach should be embedded within neglected tropical disease control programmes and the health system to create long-lasting synergies between the community and health system for increased effectiveness. However, for behavioural change to be feasible, community engagement strategies need to be supported by improved access to treatment services, safer water and sanitation.

Background Across the developing world, countries are increasingly adopting the integrated community case management of childhood illnesses (iCCM) strategy in efforts to reduce child mortality. This intervention’s effectiveness is dependent on community adoption and changes in care-seeking practices. We assessed the implementation process of a theory-driven community dialogue (CD) intervention specifically designed to strengthen the support and uptake of the newly introduced iCCM services and related behaviours in three African countries. Methods A qualitative process evaluation methodology was chosen and used secondary project data and primary data collected in two districts of each of the three countries, in purposefully sampled communities. The final data set included 67 focus group discussions and 57 key informant interviews, totalling 642 respondents, including caregivers, CD facilitators community leaders, and trainers. Thematic analysis of the data followed the ‘Framework Approach’ utilising both a deduction and induction process. Results Results show that CDs contribute to triggering community uptake of and support for iCCM services through filling health information gaps and building cooperation within communities. We found it to be an effective approach for addressing social norms around child care practices. This approach was embraced by communities for its flexibility and value in planning individual and collective change. Conclusions Regular CDs can contribute to the formation of new habits, particularly in relation to seeking timely care in case of child sickness. This study also confirms the value of process evaluation to unwrap the mechanisms of community mobilisation approaches in context and provides key insights for improving the CD approach. Electronic supplementary material The online version of this article (doi:10.1186/s41043-017-0106-0) contains supplementary material, which is available to authorized users.

Face, content, and construct validity of robotic surgery simulators were confirmed in the literature by several studies, but elements to build a training program are still lacking. The aim of our study was to validate a progressive training program and to assess according to prior surgical experience the amount of training needed with a robotic simulator to complete the program.Exercises using the Da Vinci Skill Simulator were chosen to ensure progressive learning. A new exercise could only be started if a minimal score of 80% was achieved in the prior one. The number of repetitions to achieve an exercise was not limited. We devised a "performance index" by calculating the ratio of the sum of scores for each exercise over the number of repetitions needed to complete the exercise with at least an 80% score.The study took place at the François Baclesse Cancer Center. Participants all work at the primary care university Hospital located next to the cancer center.A total of 32 surgeons participated in the study- 2 experienced surgeons, 8 junior and 8 senior residents in surgery, 6 registrars, and 6 attending surgeons.There was no difference between junior and senior residents, whereas the registrars had better results (p0.0001). The registrars performed less exercise repetitions compared to the junior or senior residents (p = 0.012). Attending surgeons performed significantly more repetitions than registrars (p = 0.024), but they performed fewer repetitions than junior or senior residents with no statistical difference (p = 0.09). The registrars had a performance index of 50, which is the best result among all novice groups. Attending surgeons were between senior and junior residents with an index at 33.85.Choice of basic exercises to manipulate different elements of the robotic surgery console in a specific and progressive order enables rapid progress. The level of prior experience in laparoscopic surgery affects outcomes. More advanced laparoscopic expertise seems to slow down learning, surgeons having to "unlearn" to acquire a new technique.

Aim To investigate whether adding bevacizumab to neoadjuvant carboplatin-paclitaxel (CP) helps achieve optimal debulking, measured by complete resection rate (CRR) at interval debulking surgery (IDS), in patients with initially unresectable International Federation of Gynecology and Obstetrics stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma. Methods Multicentre, open-label, non-comparative phase II study. Ninety-five patients randomised (2:1) to receive four cycles of neoadjuvant CP ±3 concomitant cycles of bevacizumab 15 mg/kg (BCP) followed by IDS. Primary objective is to evaluate the CRR at IDS in the BCP group (reference CRR rate defined as 45% CRR). A stopping rule based on bevacizumab-related adverse events (AEs) of special interest was implemented. Results In the BCP group (N = 58), IDS was performed in 40 (69%) patients, of whom 85% had a complete resection. The CRR of this group was therefore 58.6% (34 patients), statistically over pre-defined 45%. The CRR in the CP group was 51.4%: 22 (60%) patients underwent IDS (85% had a complete resection). Grade ≥3 adverse events occurred in 62% of the BCP-treated patients and 63% of the CP-treated patients: mainly blood and lymphatic, gastrointestinal and vascular disorders, without more toxicity with BCP. Postoperative complications (mainly wound, infectious and gastrointestinal complications) occurred in 28% and 36% of the patients, respectively. The pre-specified safety stopping rule was not reached. Conclusion The primary objective was met as the CRR with BCP was significantly higher than the reference rate. Bevacizumab may be safely added to a preoperative program in patients deemed non-optimally resectable, whatever the final surgical decision. Bevacizumab's role in this setting should be further investigated.

Background The Community Dialogue Approach is a promising social and behaviour change intervention, which has shown potential for improving health seeking behaviour. To test if this approach can strengthen prevention and control of schistosomiasis at community level, Malaria Consortium implemented a Community Dialogue intervention in four districts of Nampula province, Mozambique, between August 2014 and September 2015. Methodology/Principal findings Cross-sectional household surveys were conducted before (N = 791) and after (N = 792) implementation of the intervention to assess its impact on knowledge, attitudes and practices at population level. At both baseline and endline, awareness of schistosomiasis was high at over 90%. After the intervention, respondents were almost twice as likely to correctly name a risk behaviour associated with schistosomiasis (baseline: 18.02%; endline: 30.11%; adjusted odds ratio: 1.91; 95% confidence interval: 1.14–2.58). Increases were also seen in the proportion of people who knew that schistosomiasis can be spread by infected persons and who could name at least one correct transmission route (baseline: 25.74%; endline: 32.20%; adjusted odds ratio: 1.36; 95% confidence interval: 1.01–1.84), those who knew that there is a drug that treats the disease (baseline: 29.20%, endline: 47.55%; adjusted odds ratio: 2.19; 95% confidence interval: 1.67–2.87) and those who stated that they actively protect themselves from the disease and cited an effective behaviour (baseline: 40.09%, endline: 59.30%; adjusted odds ratio: 2.14; 95% confidence interval: 1.40–3.28). The intervention did not appear to lead to a reduction in misconceptions. In particular, the belief that the disease is sexually transmitted continued to be widespread. Conclusions/Significance Given its overall positive impact on knowledge and behaviour at population level, Community Dialogue can play an important role in schistosomiasis prevention and control. The intervention could be further strengthened by better enabling communities to take suitable action and linking more closely with community governance structures and health system programmes., Author summary Schistosomiasis is a parasitic neglected tropical disease that affects around 190 million people worldwide, causing chronic ill health and disability. Central to its prevention and control are the acceptance of health interventions such as the distribution of drugs on a mass scale and the adoption of good hygiene and sanitation practices in communities where the disease thrives. One promising method for promoting such behaviours is the Community Dialogue Approach, which involves training volunteers to host regular community meetings, where local health concerns are discussed and culturally appropriate solutions are agreed upon. In 2014/15, Malaria Consortium implemented a Community Dialogue intervention in four districts of Nampula province, Mozambique, to improve knowledge, attitudes and practices with regard to schistosomiasis prevention and control. To assess the effectiveness of the approach, two household surveys were conducted. Results show that before the intervention, knowledge of how schistosomiasis is acquired, transmitted, prevented and treated was low. After the intervention, knowledge and self-reported adoption of positive behaviours had improved substantially, demonstrating that Community Dialogue can play a central role in strengthening disease prevention and control. The approach could be strengthened by further empowering communities to take action and reducing deeply-held misconceptions.

BACKGROUND: Experience of seasonal malaria chemoprevention (SMC) is growing in the Sahel sub-region of Africa, though there remains insufficient evidence to recommend a standard deployment strategy. In 2012, a project was initiated in Katsina state, northern Nigeria, to design an appropriate and effective community-based delivery approach for SMC, in consultation with local stakeholders. Formative research (FR) was conducted locally to explore the potential feasibility and acceptability of SMC and to highlight information gaps and practical considerations to inform the intervention design. METHODS: The FR adopted qualitative methods; 36 in-depth interviews and 18 focus group discussions were conducted across 13 target groups active across the health system and within the community. Analysis followed the 'framework' approach. The process for incorporating the FR results into the project design was iterative which was initiated by a week-long 'intervention design' workshop with relevant stakeholders. RESULTS: The FR highlighted both supportive and hindering factors to be considered in the intervention design. Malaria control was identified as a community priority, the community health workers were a trusted resource and the local leadership exerted strong influence over household decisions. However, there were perceived challenges with quality of care at both community and health facility levels, referral linkage and supportive supervision were weak, literacy levels lower than anticipated and there was the potential for suspicion of 'outside' interventions. There was broad consensus across target groups that community-based SMC drug delivery would better enable a high coverage of beneficiaries and potentially garner wider community support. A mixed approach was recommended, including both community fixed-point and household-to-household SMC delivery. The FR findings were used to inform the overall distribution strategy, mechanisms for integration into the health system, capacity building and training approaches, supportive interventions to strengthen the health system, and the social mobilization strategy. CONCLUSIONS: Formative research played a valuable role in exploring local socio-cultural contexts and health system realities. Both opportunities and challenges for the introduction of SMC delivery were highlighted, which were appropriately considered in the design of the project.

Background Successful scale-up in the use of malaria rapid diagnostic tests (RDTs) requires that patients accept testing and treatment based on RDT results and that healthcare providers treat according to test results. Patient-provider communication is a key component of quality care, and leads to improved patient satisfaction, higher adherence to treatment and better health outcomes. Voiced or perceived patient expectations are also known to influence treatment decision-making among healthcare providers. While there has been a growth in literature on provider practices around rapid testing for malaria, there has been little analysis of inter-personal communication around the testing process. We investigated how healthcare providers and patients interact and engage throughout the diagnostic and treatment process, and how the testing service is experienced by patients in practice. Methods This research was conducted alongside a larger study which explored determinants of provider treatment decision-making following negative RDT results in a rural district (Kibaale) in mid-western Uganda, ten months after RDT introduction. Fifty-five patients presenting with fever were observed during routine outpatient visits at 12 low-level public health facilities. Observation captured communication practices relating to test purpose, results, diagnosis and treatment. All observed patients or caregivers were immediately followed up with in-depth interview. Analysis followed the ‘framework’ approach. A summative approach was also used to analyse observation data. Results Providers failed to consistently communicate the reasons for carrying out the test, and particularly to RDT-negative patients, a diagnostic outcome or the meaning of test results, also leading to confusion over what the test can detect. Patients appeared to value testing, but were frustrated by the lack of communication on outcomes. RDT-negative patients were dissatisfied by the absence of information on an alternative diagnosis and expressed uncertainty around adequacy of proposed treatment. Conclusions Poor provider communication practices around the testing process, as well as limited inter-personal exchange between providers and patients, impacted on patients’ perceptions of their proposed treatment. Patients have a right to health information and may be more likely to accept and adhere to treatment when they understand their diagnosis and treatment rationale in relation to their perceived health needs and visit expectations.

Stearoyl-CoA Desaturase 1 (SCD1) is a central enzyme that catalyzes the biosynthesis of monounsaturated fatty acids from saturated fatty acids. SCD1 is an emerging target in obesity and insulin resistance due to the improved metabolic profile obtained when the enzyme is genetically inactivated. Here, we have investigated if the pharmacological inhibition of SCD1 could elicit the same profile. We have identified a small molecule, GSK993 and characterized it as a potent and orally available SCD1 inhibitor. In Zuckerfa/fa rats, GSK993 exerted a marked reduction in hepatic lipids as well as a significant improvement of glucose tolerance. Furthermore, in a diet-induced insulin resistant rat model, GSK993 induced a very strong reduction in Triton-induced hepatic Very Low Density Lipoprotein-Triglyceride production. In addition, following a hyperinsulinemic–euglycemic clamp in GSK993-treated animals, we observed an improvement in the whole body insulin sensitivity as reflected by an increase in the glucose infusion rate. Taken together, these findings demonstrate that the pharmacological inhibition of SCD1 translates into improved lipid and glucose metabolic profiles and raises the interest of SCD1 inhibitors as potential new drugs for the treatment of insulin resistance.

The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR). Using HepG2 human hepatoma cells, we found that BBR inhibits cholesterol and TG synthesis in a similar manner to the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide 1-beta-ribofuranoside (AICAR). Significant increases in AMPK phosphorylation and AMPK activity were observed when the cells were incubated with BBR. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK, correlated with a subsequent increase in fatty acid oxidation. All of these effects were abolished by the mitogen-activated protein kinase kinase inhibitor PD98059. Treatment of hyperlipidemic hamsters with BBR decreased plasma LDL cholesterol and strongly reduced fat storage in the liver. These findings indicate that BBR, in addition to upregulating the LDLR, inhibits lipid synthesis in human hepatocytes through the activation of AMPK. These effects could account for the strong reduction of plasma TGs observed with this drug in clinical trials.

International audience; The industrial development of active immunotherapy based on live-attenuated bacterial vectors has matured. We developed a microsyringe for antigen delivery based on the type III secretion system (T3SS) of P. aeruginosa. We applied the "killed but metabolically active" (KBMA) attenuation strategy to make this bacterial vector suitable for human use. We demonstrate that attenuated P. aeruginosa has the potential to deliver antigens to human antigen-presenting cells in vitro via T3SS with considerable attenuated cytotoxicity as compared with the wild-type vector. In a mouse model of cancer, we demonstrate that this KBMA strain, which cannot replicate in its host, efficiently disseminates into lymphoid organs and delivers its heterologous antigen. The attenuated strain effectively induces a cellular immune response to the cancerous cells while lowering the systemic inflammatory response. Hence, a KBMA P. aeruginosa microsyringe is an efficient and safe tool for in vivo antigen delivery.

Rationale: A noninvasive tool allowing the detection of vulnerable atherosclerotic plaques is highly needed. By combining nanomolar affinities and fast blood clearance, nanobodies represent potential radiotracers for cardiovascular molecular imaging. Vascular cell adhesion molecule-1 (VCAM1) constitutes a relevant target for molecular imaging of atherosclerotic lesions. Objective: We aimed to generate, radiolabel, and evaluate anti-VCAM1 nanobodies for noninvasive detection of atherosclerotic lesions. Methods and Results: Ten anti-VCAM1 nanobodies were generated, radiolabeled with technetium-99m, and screened in vitro on mouse and human recombinant VCAM1 proteins and endothelial cells and in vivo in apolipoprotein E–deficient (ApoE −/− ) mice. A nontargeting control nanobody was used in all experiments to demonstrate specificity. All nanobodies displayed nanomolar affinities for murine VCAM1. Flow cytometry analyses using human human umbilical vein endothelial cells indicated murine and human VCAM1 cross-reactivity for 6 of 10 nanobodies. The lead compound cAbVCAM1-5 was cross-reactive for human VCAM1 and exhibited high lesion-to-control (4.95±0.85), lesion-to-heart (8.30±1.11), and lesion-to-blood ratios (4.32±0.48) ( P −/− mice were successfully identified by single-photon emission computed tomography imaging. 99m Tc-cAbVCAM1-5 binding specificity was demonstrated by in vivo competition experiments. Autoradiography and immunohistochemistry further confirmed cAbVCAM1-5 uptake in VCAM1-positive lesions. Conclusions: The 99m Tc-labeled, anti-VCAM1 nanobody cAbVCAM1-5 allowed noninvasive detection of VCAM1 expression and displayed mouse and human cross-reactivity. Therefore, this study demonstrates the potential of nanobodies as a new class of radiotracers for cardiovascular applications. The nanobody technology might evolve into an important research tool for targeted imaging of atherosclerotic lesions and has the potential for fast clinical translation.

The discovery, synthesis and biological evaluation of a novel series of 7-isoxazoloquinolines is described. Several analogs are shown to increase ApoA1 expression within the nanomolar range in the human hepatic cell line HepG2.

Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.

Background In France outpatient centres for the care of alcoholics are healthcare establishments providing medical, psychological and social support. Although they meet the practical needs of these patients, their degree of use in each of these domains and the respective mobilisation of different skills by the care team are not well understood. Our aim was therefore to determine in detail the management involved as a function of the severity of alcohol dependence. For this purpose, all the procedures involved were compiled in a thesaurus describing its type (psychological, medical, social, reception), its scheduled or unscheduled nature, its method (face-to-face, telephone, letter) and its duration. The severity of dependence was evaluated using the Addiction Severity Index (ASI). Results 45 patients were included and followed-up during 291 ± 114 days. The mean initial ASI scores (± SD) were: medical (M) = 0.39 ± 0.3, working-income (ER) = 0.5 ± 0.3, alcohol (A) = 0.51 ± 0.2, illicit drugs (D) = 0.07 ± 0.08, legal (L) = 0.06 ± 0.13, familial and social environment (FS) = 0.34 ± 0.26, psychological (P) = 0.39 ± 0.22. The total number of procedures was 1341 (29.8 per patient) corresponding to 754.4 hours (16.7 per patient). The intensity of management peaked during the first month of treatment, and then declined rapidly; the maximum incidence of abstinence was observed during the 3rd month of management. Interviews with patients, group therapy and staff meetings represented 68.7%, 9.9% and 13.9% of all procedures, respectively. In patients with severe dependence, as compared to moderate, management was twice as intense in the psychological and social domains, but not in the medical domain. The ASI questionnaire was completed a second time by 24 patients, after an average of 3.2 months. The improvement was significant in the M, A, D and P domains only. Conclusion This study provided an overview of the methods employed in managing a sample of patients consulting an alcoholism centre in line with standards for medical, psychological and social establishments. The predominance of the social and psychological domains over the medical domain was clearly established. Relapses were common after the third month of treatment, but a remobilisation of teams made it possible to contain them. These results provide a framework for discussions on the organisation of healthcare systems and highly suggest that staff need to maintain a constant level of care throughout the treatment process.

We analysed liver histology findings in a large cohort of patients with chronic hepatitis C and in roughly half of them their response to interferon-alpha-based on iron parameters and HFE status. Histological activity and virological response to antiviral therapy (n = 146) were analysed in 273 immunocompetent and nonalcoholic patients with chronic hepatitis C, in terms of serum iron load, intrahepatic iron load (n = 110) and HFE mutations. Patients who were heterozygous for the C282Y and H63D mutations exhibited higher iron serum parameters than subjects without these mutations. The intrahepatic iron load was higher in H63D patients only. No association was observed between HFE mutations and histological activity. Increased iron parameters were associated with liver disease severity by univariate analysis only. Genotype 1 and ferritinaemia were associated with a poor response to antiviral therapy, whereas the H63D mutation emerged as a positive predictive factor for end of treatment and sustained antiviral response. Therefore, in chronic hepatitis C patients serum and intrahepatic iron levels were weakly correlated with histological activity, while HFE mutations were not. As for the response to interferon-alpha, elevated ferritinaemia constituted a negative predictive factor whereas the H63D mutation was a positive one. The H63D mutation might form part of an immunogenetic profile influencing the response to interferon therapy.

AIMS: Although the prevalence of alcohol problems amongst detainees is suspected to be high, often only more flagrant problems are detected, restricting the possibilities for intervention in alcohol misuse and reducing opportunities for preventive efforts. This study examined the re-test reliability of AUDIT (the Alcohol Use Disorder Identification Test) in screening prisoners METHODS: AUDIT was administered for the first time on the day of entry to prison and again about 15 days later. The results were analysed according to two AUDIT thresholds: a score of 8 or higher and 12 or higher. RESULTS: Of 75 consecutive entrants tested, 47 male prisoners completed the study. At the first administration, 19.1% of these 47 men met criteria for a probable alcohol problem but this percentage rose to 59.6% on the second occasion (P = 0.0001). The proportion of subjects with a score 12 or higher (probably dependent) was 10.6% the first time versus 42.6% the second time (P = 0.0001). In the 19 who scored positive at the second administration only, changes in answers to the 10 items were coherent with a total score growing from 3.0 to 18.1 (P = 0.0001). No prisoner had a lower AUDIT score on the second administration. As alcohol problems are not routinely considered during the medical and biological examination at entry, no confirmation of the AUDIT results could be obtained, although those obtained at the second administration fitted well with the prevalence rates in previous reports. CONCLUSIONS: AUDIT, for the purpose of giving a prevalence estimate or to enter appropriate prisoners into more detailed assessment or interventions, should not be conducted immediately at entry, but some weeks later.

Information on the position of private practitioners faced with the problem of alcoholism mainly concerns the role of the general practitioner in the follow-up of these patients and there is little information from private specialists, hence the need for new dataAll the general practitioners and specialists in the Languedoc-Roussillon area were interviewed through a mailed questionnaire regarding their opinion on alcohol consumption and public health; their definition of the risks; moderate consumption and health; how they approached the question of drinking during consultations and their involvement in training and prevention.Six hundred sixty-five practitioners (12.4% of those interviewed) returned the questionnaire. The profile of those who replied was identical to that of the whole population surveyed. The medical corps is clearly aware of the need to fight against alcohol abuse, but this is associated with a relative ignorance of the basics of alcoholism, a non-systematic approach of the question of drinking during consultations, little involvement in its management, limited use of the specialised structures and limited training on the question. The specialists are less involved than the general practitioners, but appear more at ease when approaching the question of drinking with their patients and resort more frequently to specialised structures than the general practitioners. Continued medical training on alcoholism only concerned a minority of practitioners and its practical impact was low.With regard to alcoholism, the practitioners fulfill their role in providing medical care, within the limits of available therapeutic resources, but their role with regard to the reduction of the risks, i.e., primary or early prevention is more or less disregarded.

A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d -amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d -serine, a potent activator of N -methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N -methyl- d -aspartate receptor regulation pathway in schizophrenia.

Ovarian cancers are addicted to Bcl-xL and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-xL can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naïve and had undergone surgery were prospectively exposed ex vivo to ABT-737 ± carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression (via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value = 0.019 by Fisher's test and sensitivity = 93%, (95% confidence interval, 66-100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737).

— Aims: While it was thought that all alcoholic beverages share a similar liver toxicity when drunk at a high level, recent epidemiological surveys have suggested that wine drinking might decrease the risk of alcoholic cirrhosis in heavy drinkers. Therefore, we performed a study aiming to analyse the type and the intake levels of alcoholic beverages in heavy drinkers according to the severity of the liver disease. Methods: This is a case–control study enrolling 42 cirrhotic and 60 non-cirrhotic patients. Liver status was assessed using clinical, biological, histological and ultrasonographic procedures. Alcohol consumption was recorded using the Lifetime Drinking History method. Results: We did not find any significant differences in total alcohol consumption between cases and controls and, moreover, in our series, the relative percentage of pure alcohol drunk in wine was significantly higher in cirrhotic, than in non-cirrhotic, patients. Conclusions: Our results confirm that the absence of a link between the type of alcoholic beverage and the occurrence of cirrhosis is still valid.