PI 3-Kinase and the Histone Methyl-Transferase KMT2D Collaborate to Induce Arp2/3-Dependent Migration of Mammary Epithelial Cells.

Breast cancer develops upon sequential acquisition of driver mutations in mammary epithelial cells; however, how these mutations collaborate to transform normal cells remains unclear in most cases. We aimed to reconstitute this process in a particular case. To this end, we combined the activated form of the PI 3-kinase harboring the H1047R mutation with the inactivation of the histone lysine methyl-transferase KMT2D in the non-tumorigenic human mammary epithelial cell line MCF10A. We found that PI 3-kinase activation promoted cell-cycle progression, especially when growth signals were limiting, as well as cell migration, both in a collective monolayer and as single cells. Furthermore, we showed that KMT2D inactivation had relatively little influence on these processes, except for single-cell migration, which KMT2D inactivation promoted in synergy with PI 3-kinase activation. The combination of these two genetic alterations induced expression of the ARPC5L gene that encodes a subunit of the Arp2/3 complex. ARPC5L depletion fully abolished the enhanced migration persistence exhibited by double-mutant cells. Our reconstitution approach in MCF10A has thus revealed both the cell function and the single-cell migration, and the underlying Arp2/3-dependent mechanism, which are synergistically regulated when KMT2D inactivation is combined with the activation of the PI 3-kinase.

Features of trastuzumab-related cardiac dysfunction: deformation analysis outside left ventricular global longitudinal strain.

Background: Cancer therapy-related cardiac dysfunction due to trastuzumab has been well-known for many years, and echocardiographic surveillance is recommended every 3 months in patients undergoing trastuzumab treatment, irrespective of the baseline cardiotoxicity risk. However, the potential harm and cost of overscreening in low- and moderate-risk patients have become great concerns. Objectives: This study aimed to identify the incidence of early cancer therapy-related cardiac dysfunction (CTRCD) and the behaviours of left and right heart deformations during trastuzumab chemotherapy in low- and moderate-risk patients. Methods: We prospectively enrolled 110 anthracycline-naïve women with breast cancer and cardiovascular risk factors who were scheduled to receive trastuzumab. The left ventricular ejection fraction (LVEF), left ventricular global longitudinal strain (LV-GLS), and right ventricular and left atrial longitudinal strains were evaluated using echocardiography at baseline, before every subsequent cycle and 3 weeks after the final dose of trastuzumab. The baseline risk of CTRCD was graded according to the risk score proposed by the Heart Failure Association (HFA) Cardio-Oncology Working Group and the International Cardio-Oncology Society (ICOS). CTRCD and its severity were defined according to the current European Society of Cardiology (ESC) guidelines. Results: Twelve (10.9%) patients had asymptomatic CTRCD. All CTRCD occurred sporadically during the first 9 months of the active trastuzumab regimen in both low- and moderate-risk patients. While CTRCD was graded as moderate severity in 41.7% of patients and heart failure therapy was initiated promptly, no irreversible cardiotoxicity or trastuzumab interruption was recorded at the end of follow-up. Among the left and right heart deformation indices, only LV-GLS decreased significantly in the CTRCD group during the trastuzumab regimen. Conclusions: CTRCD is prevalent in patients with non-high-risk breast cancer undergoing trastuzumab chemotherapy. Low- and moderate-risk patients show distinct responses to trastuzumab. The LV-GLS is the only deformation index sensitive to early trastuzumab-related cardiac dysfunction.

Microfluidics-Enabled Isolation and Single-Cell Analysis of Circulating Tumor Cells.

Microfluidic platforms enable the enrichment and analysis of circulating tumor cells (CTCs), a potential biomarker for cancer diagnosis, prognosis, and theragnosis. Combined with immunocytochemistry/immunofluorescence (ICC/IF) assays for CTCs, microfluidics-enabled detection presents a unique opportunity to study tumor heterogeneity and predict treatment response, both of which can help cancer drug development. In this chapter, we detail the protocols and methods employed to fabricate and use a microfluidic device for the enrichment, detection, and analysis of single CTCs from the blood samples of sarcoma patients.

Longitudinal Study of Circulating Biomarkers in Patients with Resectable Pancreatic Ductal Adenocarcinoma.

While patients with resectable pancreatic ductal adenocarcinoma (PDAC) show improved survival compared to their non-resectable counterparts, survival remains low owing to occult metastatic disease and treatment resistance. Liquid biopsy based on circulating tumor cells (CTCs) and cell-free DNA (cfDNA) has been shown to predict recurrence and treatment resistance in various types of cancers, but their utility has not been fully demonstrated in resectable PDAC. We have simultaneously tracked three circulating biomarkers, including CTCs, cfDNA, and circulating tumor DNA (ctDNA), over a period of cancer treatment using a microfluidic device and droplet digital PCR (ddPCR). The microfluidic device is based on the combination of filtration and immunoaffinity mechanisms. We have measured CTCs, cfDNA, and ctDNA in a cohort of seven resectable PDAC patients undergoing neoadjuvant therapy followed by surgery, and each patient was followed up to 10 time points over a period of 4 months. CTCs were detectable in all patients (100%) at some point during treatment but were detectable in only three out of six patients (50%) prior to the start of treatment. Median cfDNA concentrations remained comparable to negative controls throughout treatment. ddPCR was able to find KRAS mutations in six of seven patients (86%); however, these mutations were present in only two of seven patients (29%) prior to treatment. Overall, the majority of circulating biomarkers (81% for CTCs and 91% for cfDNA/ctDNA) were detected after the start of neoadjuvant therapy but before surgery. This study suggests that a longitudinal study of circulating biomarkers throughout treatment provides more useful information than those single time-point tests for resectable PDAC patients.

Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis.

Bacteria inhabit diverse environmental niches and consequently must modulate their metabolism to adapt to stress. The nucleotide second messengers guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) (collectively referred to as (p)ppGpp) are essential for survival during nutrient starvation. (p)ppGpp is synthesized by the RelA-SpoT homologue (RSH) protein family and coordinates the control of cellular metabolism through its combined effect on over 50 proteins. While the role of (p)ppGpp has largely been associated with nutrient limitation, recent studies have shown that (p)ppGpp and related nucleotides have a previously underappreciated effect on different aspects of bacterial physiology, such as maintaining cellular homeostasis and regulating bacterial interactions with a host, other bacteria, or phages. (p)ppGpp produced by pathogenic bacteria facilitates the evasion of host defenses such as reactive nitrogen intermediates, acidic pH, and the complement system. Additionally, (p)ppGpp and pyrophosphorylated derivatives of canonical adenosine nucleotides called (p)ppApp are emerging as effectors of bacterial toxin proteins. Here, we review the RSH protein family with a focus on its unconventional roles during host infection and bacterial competition.

Evaluation of the effect of 3D porous Chitosan-alginate scaffold stiffness on breast cancer proliferation and migration.

Breast cancer (BCa) is one of the most common cancers for women and metastatic BCa causes the majority of deaths. The extracellular matrix (ECM) stiffens during cancer progression and provides biophysical signals to modulate proliferation, morphology, and metastasis. Cells utilize mechanotransduction and integrins to sense and respond to ECM stiffness. Chitosan-alginate (CA) scaffolds have been used for 3D culture, but lack integrin binding ligands, resulting in round cell morphology and limited cell-material interaction. In this study, 2, 4, and 6 wt% CA scaffolds were produced to mimic the stages of BCa progression and evaluate the BCa response to CA scaffold stiffness. All three CA scaffold compositions highly porous with interconnected pores and scaffold stiffness increased with increasing polymer concentration. MDA-MB-231 (231) cells were cultured in CA scaffolds and 2D cultures for 7 d. All CA scaffold cultures had similar cell numbers at 7 d and the 231 cells formed clusters that increased in size during the culture. The 2 wt% CA had the largest clusters throughout the 7 d culture compared with the 4 and 6 wt% CA. The 231 cell migration was evaluated on 2D surfaces after 7 d culture. The 6 wt% CA cultured cells had the greatest migration speed, followed by 4 wt% CA, 2D cultures, and 2 wt% CA. These results suggest that 231 cells sensed the stiffness of CA scaffolds without the presence of focal adhesions. This indicates that a non-integrin-based mechanism may explain the observed mechanotransduction response.

Exosome isolation using nanostructures and microfluidic devices.

Exosomes contain cargoes of proteins, lipids, micro-ribonucleic acids, and functional messenger RNAs, and they play a key role in cell-to-cell communication and hold valuable information about biological processes such as disease pathology. To harvest their potentials in disease diagnostics, prognostics, and therapeutics, exosome isolation is a crucial first step in providing pure and intact samples for both research and clinical purposes. Unfortunately, conventional methods for exosome separation suffer from low purity, low capture efficiency, long processing time, large sample volume requirement, the need for dedicated equipment and trained personnel, and high cost. In the last decade, microfluidic devices, especially those that incorporate nanostructures, have emerged as superior alternatives for exosome isolation and detection. In this review, we examine microfluidic platforms, dividing them into six categories based on their capture mechanisms: passive-structure-based affinity, immunomagnetic-based affinity, filtration, acoustofluidics, electrokinetics, and optofluidics. Here, we start out exploring the research and clinical needs that translate into important performance parameters for new exosome isolation designs. Then, we briefly introduce the conventional methods and discuss how their failure to meet those performance standards sparks an intense interest in microfluidic device innovations. The essence of this review is to lead an in-depth discussion on not only the technicality of those microfluidic platforms, but also their strengths and weaknesses with regards to the performance parameters set forth. To close the conversation, we call for the inclusion of exosome confirmation and contamination evaluation as part of future device development and performance assessment process, so that collectively, efforts towards microfluidics and nanotechnology for exosome isolation and analysis may soon see the light of real-world applications.

Prescription of Potentially Harmful Drugs in Young Adults With Heart Failure and Reduced Ejection Fraction.

According to national guidelines and statements drugs that can cause or exacerbate heart failure (HF) are considered potentially harmful and should be avoided if possible in patients with a diagnosis of heart failure with reduced ejection fraction (HFREF). To evaluate the prevalence of potentially harmful drug (PHD) prescription among patients with a diagnosis of systolic heart failure we conducted a retrospective cohort study using Truven Health MarketScan Commercial database from 2011 to 2014. Prescription of PHD as defined by American Heart Association Statement was examined among patients with a HFREF diagnosis in: (1) Two outpatient encounters, (2) One inpatient encounter as primary diagnosis and/or (3) one inpatient encounter any position and one outpatient encounter. Among 40,966 patients, 24.2% were prescribed with at least 1 drug with the potential to cause or exacerbate heart failure. Of the 9,954 patients prescribed with PHD, nonsteroidal anti-inflammatory agents were the most frequent category prescribed (67.4%), followed by antihypertensive (24%), diabetes mellitus (23.3%), neurological and psychiatric (21%) and antiarrhythmic medications (12.6%). After multivariable analysis female patients, the presence of a comorbidity associated with a PHD use and polypharmacy were more frequently prescribed a PHD. In conclusion almost » of adult patients with a diagnosis of HFREF have a prescription of a drug with a potential to cause or exacerbate heart failure as defined by current heart failure guidelines.

Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial.

Background: Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial. Patients and methods: Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated. Results: Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ≥2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level. Conclusions: In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC. ClinicalTrials.gov number: NCT01375842.

Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling.

Mutations in the DYNAMIN2 (DNM2) gene are frequently detected in human acute T-cell lymphoblastic leukemia (T-ALL), although the mechanisms linking these mutations to disease pathogenesis remain unknown. Using an ENU-based forward genetic screen for mice with erythroid phenotypes, we identified a heterozygous mouse line carrying a mutation in the GTPase domain of Dnm2 (Dnm2V265G) that induced a microcytic anemia. In vitro assays using the V265G mutant demonstrated loss of GTPase activity and impaired endocytosis that was comparable to other DNM2 mutants identified in human T-ALL. To determine the effects of DNM2 mutations in T-ALL, we bred the Dnm2V265G mice with the Lmo2 transgenic mouse model of T-ALL. Heterozygous Dnm2 mutants lacking the Lmo2 transgene displayed normal T-cell development, and did not develop T-ALL. In contrast, compound heterozygotes displayed an accelerated onset of T-ALL compared with mice carrying the Lmo2 oncogene alone. The leukemias from these mice exhibited a more immature immunophenotype and an expansion in leukemic stem cell numbers. Mechanistically, the Dnm2 mutation impaired clathrin-mediated endocytosis of the interleukin (IL)-7 receptor resulting in increased receptor density on the surface of leukemic stem cells. These findings suggest that DNM2 mutations cooperate with T-cell oncogenes by enhancing IL-7 signalling.

Large-scale diversification without genetic isolation in nematode symbionts of figs.

Diversification is commonly understood to be the divergence of phenotypes accompanying that of lineages. In contrast, alternative phenotypes arising from a single genotype are almost exclusively limited to dimorphism in nature. We report a remarkable case of macroevolutionary-scale diversification without genetic divergence. Upon colonizing the island-like microecosystem of individual figs, symbiotic nematodes of the genus Pristionchus accumulated a polyphenism with up to five discrete adult morphotypes per species. By integrating laboratory and field experiments with extensive genotyping of individuals, including the analysis of 49 genomes from a single species, we show that rapid filling of potential ecological niches is possible without diversifying selection on genotypes. This uncoupling of morphological diversification and speciation in fig-associated nematodes has resulted from a remarkable expansion of discontinuous developmental plasticity.

Effect of the CYP3A5 and ABCB1 genotype on exposure, clinical response and manifestation of toxicities from sunitinib in Asian patients.

The objective of this study was to determine the effect of the CYP3A5 and ATP binding cassette subfamily B member 1 (ABCB1) single-nucleotide polymorphisms on the disposition of sunitinib and SU12662, on clinical response, and on the manifestation of toxicities in Asian metastatic renal cell carcinoma patients. At week 4 of each treatment cycle, toxicities and plasma steady-state levels were assessed. Clinical response was assessed after two cycles. Genotyping was performed by using the PCR restriction fragment length polymorphism method. The CC genotype for ABCB1 was associated with a higher sunitinib exposure (76.81 vs 56.55 ng ml(-1), P=0.03), higher risk of all-grade rash (RR 3.00, 95% CI 1.17-7.67) and mucositis (RR 1.60, 95% CI 1.10-2.34) and disease progression than compared with the CT/TT genotype. There was a lack of association observed between the CYP3A5 polymorphism and exposure, response and toxicities. The polymorphism of ABCB1 (C3435T) has an important role in the manifestation of toxicities and drug exposure, but not polymorphism of CYP3A5.

Polyoxygenated steroids from the gorgonian Menella woodin with capabilities to modulate ROS levels in macrophages at response to LPS.

Four new polyoxygenated sterol derivatives (1-4) along with the compounds (5-7) previously known from other biological sources were isolated from the gorgonian Menella woodin, collected from the Vietnamese waters. Structures of 1-4 were elucidated by the detailed NMR spectroscopic and mass-spectrometric analyses as well as comparison with those reported in literature data. Compounds 1, 4, and 6 decrease the production of reactive oxygen species (ROS) by the murine macrophages of RAW 264.7 line at induction by endotoxic lipopolysaccharide (LPS) from Escherichia coli.

Estimating the burden of fungal disease in Vietnam.

Data regarding the prevalence of fungal infections in Vietnam are limited yet they are likely to occur more frequently as increasingly sophisticated healthcare creates more iatrogenic risk factors. In this study, we sought to estimate baseline incidence and prevalence of selected serious fungal infections for the year 2012. We made estimates with a previously described actuarial method, using reports on the incidence and prevalence of various established risk factors for fungal infections from Vietnam, or similar environments, supplemented by personal communications. Global data were used if local data were unavailable. We estimated 2,352,748 episodes of serious fungal infection occurred in Vietnam in 2012. Frequent conditions included recurrent vaginal candidiasis (3893/100,000 women annually), tinea capitis (457/100,000 annually) and chronic pulmonary aspergillosis (61/100,000/5 year period). We estimated 140 cases of cryptococcal meningitis, 206 of penicilliosis and 608 of Pneumocystis jirovecii pneumonia. This is the first summary of Vietnamese fungal infections. The majority of severe disease is due to Aspergillus species, driven by the high prevalence of pulmonary tuberculosis. The AIDS epidemic highlights opportunistic infections, such as penicilliosis and cryptococcosis, which may complicate immunosuppressive treatments. These estimates provide a useful indication of disease prevalence to inform future research and resource allocation but should be verified by further epidemiological approaches.

Mortality gradient across the labour market core-periphery structure: a 13-year mortality follow-up study in north-eastern France.

PURPOSE: This study explores mortality related to temporary employment, about which very little is known to date. METHODS: In 1996, a health survey was carried out in the French region of Lorraine, and all members of 8,000 randomly chosen households were followed up for mortality over a 13-year period. Mortality of subjects in relation to their employment situation at baseline was analysed using a Cox survival regression. RESULTS: In comparison with permanent workers, for unemployed men, we found age and occupation-adjusted hazard ratios (HR) of 4.1 for all-causes of death and 3.9 for non-violent causes, and for male temporary workers a HR of 2.2 for both all-causes and non-violent causes of death. Bad health, tobacco smoking and alcohol misuse explained 17 % of the excess risk for the unemployed and 41 % of that for temporary workers. CONCLUSION: The observation of large mortality inequalities across the labour market core-periphery structure has important policy implications, particularly in terms of prevention focused on unhealthy behaviours among male unemployed and temporary workers.

A phase II study of sunitinib in recurrent and/or metastatic adenoid cystic carcinoma (ACC) of the salivary glands: current progress and challenges in evaluating molecularly targeted agents in ACC.

BACKGROUND: Vascular endothelial growth factor (VEGF) and c-kit are highly expressed in adenoid cystic carcinoma (ACC) and associated with biologic aggressiveness. This study aimed to assess the antitumor activity of sunitinib, a multi-targeted inhibitor of vascular endothelial growth factor receptor, c-kit, platelet-derived growth factor receptor, ret proto-oncogene (RET) and FMS-like tyrosine kinase 3 (FLT3), in ACC of the salivary gland. PATIENTS AND METHODS: Patients with progressive, recurrent and/or metastatic ACC were treated with sunitinib 37.5 mg daily in this single-arm, two-stage phase II trial. Response was assessed every 8 weeks. RESULTS: Fourteen patients were enrolled on to the study. Among 13 assessable patients, there were no objective responses, 11 patients had stable disease (SD), 8 patients had SD ≥ 6 months and 2 patients had progressive disease as best response. Median time to progression was 7.2 months. Median overall survival was 18.7 months. Toxic effects occurring in at least 50% of patients included fatigue, oral mucositis and hypophosphatemia usually of mild to moderate severity. CONCLUSIONS: Although no responses were observed, sunitinib was well tolerated, with prolonged tumor stabilization of ≥ 6 months in 62% of assessable patients. The lack of responses is comparable with other trials of molecularly targeted agents in ACC and highlights the need for novel strategies in phase II clinical trial design.

Gender differences in the association between depressive mood and mortality: a 12-year follow-up population-based study.

BACKGROUND: Depressive mood has been associated with all-cause mortality in both men and women. This study aimed at exploring gender differences in the association between depressive mood and specific causes of mortality as well as factors that may account for it, including education, marital status, social support, health behaviors, and chronic diseases. METHODS: A population-based survey including 6043 subjects (2892 men and 3151 women) was conducted in 1996 in the north-east of France with a questionnaire covering education, marital status, social support, health behaviors (smoking status, alcohol consumption, body mass index), and chronic diseases. Depressive mood was measured using the Duke Health Profile questionnaire. Cox regression models were used to examine its association with subsequent natural all-cause mortality, and cardiovascular and cancer mortality. RESULTS: During a follow-up of 12.5 years, 406 men and 303 women died from a natural cause. Adjusting for all covariates, depressive mood predicted natural mortality in both men [Hazard Ratio (HR)=1.30; 95% confidence interval (CI): 1.00-1.69] and women (HR=1.37; 95% CI: 1.06-1.77). However, this association was significant for cardiovascular mortality in men (HR=1.63; 95% CI: 1.00-2.65) whereas it was significant for cancer mortality in women (HR=1.71; 95% CI: 1.11-2.64). LIMITATIONS: Baseline data were self-reported and the response rate was low. DISCUSSION: Preventive strategies aiming at reducing the increased mortality associated with depressive mood should take gender into account. Depressed men may warrant a better screening for cardiovascular risk factors and diseases, whereas depressed women may benefit from better cancer prevention measures.

Gender and age disparities in the associations of occupational factors with alcohol abuse and smoking in the French working population.

BACKGROUND: This study assessed the associations of short-term employment, physical and psychological occupational demands, and job dissatisfaction with alcohol abuse (using the Audit-C test) and daily smoking among working French men and women in different age groups. METHODS: The sample included 13,241 working people, 18-29, 30-39, and 40-59-years-old, randomly selected in France and interviewed by phone. Occupation, type of employment, physical demands, psychological demands, job dissatisfaction, gender, age, educational level, and income were considered. Data were analyzed with logistic models. RESULTS: Alcohol abuse affected 20.4% of men and 7.5% of women; smoking 32.1% and 24.2%, respectively. Their patterns of association with the occupational factors varied with gender and age. Job dissatisfaction was the leading factor among young men (adjusted odds ratio for alcohol abuse and smoking: 1.71 and 2.02), whereas short-term employment was the leading factor among young women (1.69 and 1.58), this pattern being reversed in older generations. The pattern of associations of physical and psychological demands with outcomes is more complex, but overall psychological demands were more important for women (especially the younger ones) than men, especially for smoking (OR>1.6). Smoking within 5 min after waking was much more common among male and female smokers with these occupational factors, suggesting a potential dependency. CONCLUSIONS: Workers with short-term employment and occupational demands are subject to a higher risk for alcohol abuse and smoking with high gender and age disparities. Gender and age should be considered when designing measures to prevent substance abuse related to occupation.

Suicidal ideation among young French adults: association with occupation, family, sexual activity, personal background and drug use.

BACKGROUND: To assess associations among young adults between suicidal ideation in the previous year and adverse childhood events, occupation, education, tobacco use, alcohol abuse, cannabis use in the previous month, illicit drug use, sexual orientation and activity, depression, physical violence in the previous year, and lifetime forced sexual intercourse. METHODS: A subsample of 4075 French adults aged 18-30 years was drawn from a random national telephone survey in 2005. Major depressive episode and alcohol abuse were assessed using CIDI-SF and AUDIT-C (score above 4). Data were analysed with logistic regressions. RESULTS: Suicidal ideation affected 5.7% of men and 4.9% of women. Among men depression had the highest adjusted odds ratio (ORa=8.06, 5.07-12.79), followed by homosexual intercourse (3.37, 1.62-7.04), absence of sexual activity (2.83, 1.80-4.44); ORa between 1.6 and 2.0 were observed for living alone, daily tobacco smoking, being unemployed, serious health event concerning the father, age 26-30 and bad relationships between parents. Among women, depression had the highest ORa (7.60, 4.70-12.29), followed by lifetime experience of forced sexual intercourse (5.37, 2.89-9.96), having consumed illicit drugs other than cannabis (4.01, 1.48-10.89); ORa between 1.7 and 2.5 were observed for living alone, being unemployed, bad relationship between parents and age 26-30. LIMITATIONS: Cross-sectional survey, sexual orientation inferred from sexual activity. CONCLUSION: Suicide prevention should integrate the fact that besides depression, unemployment, family history, age, and sexual activity and orientation are specific risk factors among men, whereas illicit drug use, violence and forced sexual intercourse are more important among women.

Relationship between job, lifestyle, age and occupational injuries.

BACKGROUND: Physical job demands (PJD), age, disability and lifestyle may influence the risk of occupational injury. AIM: To assess the relationships between PJD, lifestyle and injury in workers of various ages. METHODS: A total of 2888 randomly selected workers from northeastern France, aged >or=15, completed a postal questionnaire. The PJD score was defined as the total number of the following reported job demands: using pneumatic tools, other vibrating hand tools, hammers, machine tools or vibrating platforms and exposure to manual handling tasks, awkward postures, high pace of work, high physical workload, work at heights, work in adverse climates or exposure to noise, cold or heat. Data were analysed using logistic regression. RESULTS: Nine per cent of subjects reported an injury during the previous 2 years. The PJD score was related to the injury rate for workers aged >or=45: crude odds ratio (OR) 3.5 (95% confidence interval = 1.5-8.0) for PJD = 1, 5.0 (2.2-11.3) for PJD = 2-3 and 14.5 (6.5-32.2) for PJD >or=4, versus PJD = 0. Lower ORs were found for those aged <30 (1.4, 4.2 and 9.9, respectively) and 30-44 (1.5, 4.4 and 6.5, respectively). The differences between age groups remained when controlling for all factors studied. Obesity, smoking and musculoskeletal disorders were associated with injury risk in workers aged >or=45 (adjusted ORs 1.7-2.6). Smoking was also an injury risk factor for workers aged <30. CONCLUSIONS: PJD and lifestyle have a higher impact on injury rates among older workers than among younger ones. Injury prevention should address reducing PJD and improving relevant lifestyle factors, especially for older workers.