Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells.

Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasome-dependent reduction of p21(WAF1/CIP1) and p27(KIP1) protein levels, whereas little or no effect was observed on p21(WAF1/CIP1) or p27(KIP1) mRNAs. p21(WAF1/CIP1) silencing also increased MCF-10A cell proliferation, thus identifying p21(WAF1/CIP1) down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.

Inflammatory markers and blood pressure: sex differences and the effect of fat mass in the CoLaus Study.

Several studies have reported high levels of inflammatory biomarkers in hypertension, but data coming from the general population are sparse, and sex differences have been little explored. The CoLaus Study is a cross-sectional examination survey in a random sample of 6067 Caucasians aged 35-75 years in Lausanne, Switzerland. Blood pressure (BP) was assessed using a validated oscillometric device. Anthropometric parameters were also measured, including body composition, using electrical bioimpedance. Crude serum levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and ultrasensitive C-reactive protein (hsCRP) were positively and IL-1β (IL-1β) negatively (P<0.001 for all values), associated with BP. For IL-6, IL-1β and TNF-α, the association disappeared in multivariable analysis, largely explained by differences in age and body mass index, in particular fat mass. On the contrary, hsCRP remained independently and positively associated with systolic (β (95% confidence interval): 1.15 (0.64; 1.65); P<0.001) and diastolic (0.75 (0.42; 1.08); P<0.001) BP. Relationships of hsCRP, IL-6 and TNF-α with BP tended to be stronger in women than in men, partly related to the difference in fat mass, yet the interaction between sex and IL-6 persisted after correction for all tested confounders. In the general population, the associations between inflammatory biomarkers and rising levels of BP are mainly driven by age and fat mass. The stronger associations in women suggest that sex differences might exist in the complex interplay between BP and inflammation.

Trends in self-reported prevalence and management of hypertension, hypercholesterolemia and diabetes in Swiss adults, 1997-2007.

Switzerland has a low mortality rate from cardiovascular diseases, but little is known regarding prevalence and management of cardiovascular risk factors (CV RFs: hypertension, hypercholesterolemia and diabetes) in the general population. In this study, we assessed 10-year trends in self-reported prevalence and management of cardiovascular risk factors in Switzerland. data from three national health interview surveys conducted between 1997 and 2007 in representative samples of the Swiss adult population (49,261 subjects overall). Self-reported CV RFs prevalence, treatment and control levels were computed. The sample was weighted to match the sex - and age distribution, geographical location and nationality of the entire adult population of Switzerland. self-reported prevalence of hypertension, hypercholesterolemia and diabetes increased from 22.1%, 11.9% and 3.3% in 1997 to 24.1%, 17.4% and 4.8% in 2007, respectively. Prevalence of self-reported treatment among subjects with CV RFs also increased from 52.1%, 18.5% and 50.0% in 1997 to 60.4%, 38.8% and 53.3% in 2007 for hypertension, hypercholesterolemia and diabetes, respectively. Self-reported control levels increased from 56.4%, 52.9% and 50.0% in 1997 to 80.6%, 75.1% and 53.3% in 2007 for hypertension, hypercholesterolemia and diabetes, respectively. Finally, screening during the last 12 months increased from 84.5%, 86.5% and 87.4% in 1997 to 94.0%, 94.6% and 94.1% in 2007 for hypertension, hypercholesterolemia and diabetes, respectively. in Switzerland, the prevalences of self-reported hypertension, hypercholesterolemia and diabetes have increased between 1997 and 2007. Management and screening have improved, but further improvements can still be achieved as over one third of subjects with reported CV RFs are not treated.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Genetics of calcium homeostasis in humans: continuum between monogenic diseases and continuous phenotypes

Extracellular calcium participates in several key physiological functions, such as control of blood coagulation, bone calcification or muscle contraction. Calcium homeostasis in humans is regulated in part by genetic factors, as illustrated by rare monogenic diseases characterized by hypo or hypercalcaemia. Both serum calcium and urinary calcium excretion are heritable continuous traits in humans. Serum calcium levels are tightly regulated by two main hormonal systems, i.e. parathyroid hormone and vitamin D, which are themselves also influenced by genetic factors. Recent technological advances in molecular biology allow for the screening of the human genome at an unprecedented level of detail and using hypothesis-free approaches, such as genome-wide association studies (GWAS). GWAS identified novel loci for calcium-related phenotypes (i.e. serum calcium and 25-OH vitamin D) that shed new light on the biology of calcium in humans. The substantial overlap (i.e. CYP24A1, CASR, GATA3; CYP2R1) between genes involved in rare monogenic diseases and genes located within loci identified in GWAS suggests a genetic and phenotypic continuum between monogenic diseases of calcium homeostasis and slight disturbances of calcium homeostasis in the general population. Future studies using whole-exome and whole-genome sequencing will further advance our understanding of the genetic architecture of calcium homeostasis in humans. These findings will likely provide new insight into the complex mechanisms involved in calcium homeostasis and hopefully lead to novel preventive and therapeutic approaches. Keyword: calcium, monogenic, genome-wide association studies, genetics.

CUBN is a gene locus for albuminuria.

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR) gene.

Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.

Association of PCK1 with Body Mass Index and Other Metabolic Features in Patients With Psychotropic Treatments.

Weight gain is a major health problem among psychiatric populations. It implicates several receptors and hormones involved in energy balance and metabolism. Phosphoenolpyruvate carboxykinase 1 is a rate-controlling enzyme involved in gluconeogenesis, glyceroneogenesis and cataplerosis and has been related to obesity and diabetes phenotypes in animals and humans. The aim of this study was to investigate the association of phosphoenolpyruvate carboxykinase 1 polymorphisms with metabolic traits in psychiatric patients treated with psychotropic drugs inducing weight gain and in general population samples. One polymorphism (rs11552145G > A) significantly associated with body mass index in the psychiatric discovery sample (n = 478) was replicated in 2 other psychiatric samples (n1 = 168, n2 = 188), with AA-genotype carriers having lower body mass index as compared to G-allele carriers. Stronger associations were found among women younger than 45 years carrying AA-genotype as compared to G-allele carriers (-2.25 kg/m, n = 151, P = 0.009) and in the discovery sample (-2.20 kg/m, n = 423, P = 0.0004). In the discovery sample for which metabolic parameters were available, AA-genotype showed lower waist circumference (-6.86 cm, P = 0.008) and triglycerides levels (-5.58 mg/100 mL, P < 0.002) when compared to G-allele carriers. Finally, waist-to-hip ratio was associated with rs6070157 (proxy of rs11552145, r = 0.99) in a population-based sample (N = 123,865, P = 0.022). Our results suggest an association of rs11552145G > A polymorphism with metabolic-related traits, especially in psychiatric populations and in women younger than 45 years.

Internet-Based Brief Intervention to Prevent Unhealthy Alcohol Use among Young Men: A Randomized Controlled Trial.

Alcohol use is one of the leading modifiable morbidity and mortality risk factors among young adults. 2 parallel-group randomized controlled trial with follow-up at 1 and 6 months. Internet based study in a general population sample of young men with low-risk drinking, recruited between June 2012 and February 2013. Intervention: Internet-based brief alcohol primary prevention intervention (IBI). The IBI aims at preventing an increase in alcohol use: it consists of normative feedback, feedback on consequences, calorific value alcohol, computed blood alcohol concentration, indication that the reported alcohol use is associated with no or limited risks for health. Intervention group participants received the IBI. Control group (CG) participants completed only an assessment. Alcohol use (number of drinks per week), binge drinking prevalence. Analyses were conducted in 2014-2015. Of 4365 men invited to participate, 1633 did so; 896 reported low-risk drinking and were randomized (IBI: n = 451; CG: n = 445). At baseline, 1 and 6 months, the mean (SD) number of drinks/week was 2.4(2.2), 2.3(2.6), 2.5(3.0) for IBI, and 2.4(2.3), 2.8(3.7), 2.7(3.9) for CG. Binge drinking, absent at baseline, was reported by 14.4% (IBI) and 19.0% (CG) at 1 month and by 13.3% (IBI) and 13.0% (CG) at 6 months. At 1 month, beneficial intervention effects were observed on the number of drinks/week (p = 0.05). No significant differences were observed at 6 months. We found protective short term effects of a primary prevention IBI. Controlled-Trials.com ISRCTN55991918.

Vulnerability to adverse consequences of drinking and problem drinker status as predicted by risky drinking behaviours, drug use, sex differences and affect : a test of multiple models /

Although alcohol problems and alcohol consumption are related, consumption does not fully account for differences in vulnerability to alcohol problems. Therefore, other factors should account for these differences. Based on previous research, it was hypothesized that risky drinking behaviours, illicit and prescription drug use, affect and sex differences would account for differences in vulnerability to alcohol problems while statistically controlling for overall alcohol consumption. Four models were developed that were intended to test the predictive ability of these factors, three of which tested the predictor sets separately and a fourth which tested them in a combined model. In addition, two distinct criterion variables were regressed on the predictors. One was a measure of the frequency that participants experienced negative consequences that they attributed to their drinking and the other was a measure of the extent to which participants perceived themselves to be problem drinkers. Each of the models was tested on four samples from different populations, including fIrst year university students, university students in their graduating year, a clinical sample of people in treatment for addiction, and a community sample of young adults randomly selected from the general population. Overall, support was found for each of the models and each of the predictors in accounting for differences in vulnerability to alcohol problems. In particular, the frequency with which people become intoxicated, frequency of illicit drug use and high levels of negative affect were strong and consistent predictors of vulnerability to alcohol problems across samples and criterion variables. With the exception of the clinical sample, the combined models predicted vulnerability to negative consequences better than vulnerability to problem drinker status. Among the clinical and community samples the combined model predicted problem drinker status better than in the student samples.

The dual role of students with behavioural problems: an analysis of their experiences as bullies and victims /

The present study examined the bullying experiences of a group of students, age 10-14 years, identified as having behaviour problems. A total often students participated in a series of mixed methodology activities, including self-report questionnaires, story telling exercises, and interview style joumaling. The main research questions were related to the prevalence of bully/victims and the type of bullying experiences in this population. Questionnaires gathered information about their involvement in bullying, as well as about psychological risk factors including normative beliefs about antisocial acts, impulsivity, problem solving, and coping strategies. Journal questions expanded on these themes and allowed students to explain their personal experiences as bullies and victims as well as provide suggestions for intervention. The overall results indicated that all of the ten students in this sample have participated in bullying as both a bully and a victim. This high prevalence of bully/victim involvement in students from behavioural classrooms is in sharp contrast with the general population where the prevalence is about 33%. In addition, a common thread was found that indicated that these students who participated in this study demonstrate characteristics of emotionally dysregulated reactive bullies. Theoretical implication and educational practices are discussed.

Leisure-time physical activity in individuals with osteoporosis : associations with psychological well-being

With approximately 16% of the Canadian population living with osteoporosis, and rates expected to increase (Osteoporosis Canada, 2009), cost-effective treatment modalities that improve bone health and psychological well-being reflect an important public health agenda. Physical activity has been implicated as one non-pharmaceutical mechanism to help improve psychological well-being in the general population (Fox, Stathi, McKenna, & Davis, 2007) and in people diagnosed with osteoporosis (Osteoporosis Canada, 2007). The purpose of this investigation was to determine the association between leisure-time physical activity (LTP A) and well-being in people diagnosed with osteoporosis. A secondary purpose, using Basic Needs Theory (BNT; Deci & Ryan, 2002) was to determine if the fulfillment of three psychological needs (i.e., competence, autonomy and relatedness) mediated the relationship between LTP A and well-being. People diagnosed with osteoporosis (N= 190; Mage = 68.14; SDage = 11.54) were asked to complete a battery of questionnaires assessing L TP A, hedonic and eudaimonic well-being and perceived psychological need satisfaction in physical activity contexts. Bivariate correlations revealed a pattern of negligible (r's -0.02 to 0.35) to small correlations between LTP A and well-being with contextual positive affect (r = 0.24) and subjective vitality (r = 0.22) demonstrating statistical significance (p < .01). Results of the multiple mediation analysis indicated that perceived satisfaction of the three psychological needs mediated the relationship between LTPA and well-being with perceived competence emerging as a unique mediator. As such, LTP A was positively associated with well-being in people who are diagnosed with osteoporosis, and the fulfillment of the three psychological needs may be the mechanism through which this 111 effect is carried. Health promotion specialists and practitioners should encourage patients with osteoporosis to engage in LTP A, and support their needs for competence, autonomy and relatedness. Practical implications for researchers and health promotion specialists are discussed in terms ofthe results of this investigation.

Bone speed of sound in overweight and normal-weight girls and adolescents

Over the last two decades, the prevalence of obesity in the general population has been steadily increasing. Obesity is a major issue in scientific research because it is associated with many health problems, one of which is bone quality. In adult females, adiposity is associated with increased bone mineral density, suggesting that there is a protective effect of fat on bone. However, the association between adiposity and bone strength during childhood is not clear. Thus, the purpose of this study was to compare bone strength, as reflected by speed of sound (SOS), of overweight and obese girls and adolescents with normal-weight age-matched controls. Data from 75 females included normal-weight girls (G-NW; body fat:::; 25%; n = 21), overweight and obese girls (GOW; body fat ~ 28%; n = 19), normal-weight adolescents (A-NW, body fat:::; 25%; n = 13) and overweight and obese adolescents (A-OW; body fat ~ 28%; n = 22). Nutrition was assessed with a 24-hour recall questionnaire and habitual physical activity was measured for one week using accelerometry. Using quantitative ultrasound (QUS; Sunlight Omnisense™), bone SOS was measured at the distal radius and mid-tibia. No differences were found between groups in daily total energy, calcium or vitamin D intake. However, all groups were below the recommended daily calcium intake of 1300 mg (Osteoporosis Canada, 2008). Adolescents were significantly less active than girls (14.7 ± 0.6 vs. 6.3 ± 0.6% active for G and A, respectively). OW accumulated significantly less minutes of moderate-to-very vigorous physical activity per day (MVPA) than NW in both age groups (114 ± 6 vs. 57 ± 5 min/day for NW and OW, i respectively). Girls had significantly lower radial SOS (3794 ± 87 vs. 3964 ± 64 mls for G-NW and A-NW, respectively), and tibial SOS (3678 ± 86 vs. 3878 ± 52 mls for G-NW and A-NW, respectively) than adolescents. Radial SOS was similar in the two adiposity groups within each age group. However, tibial SOS was lower in the two overweight groups (3601 ± 75 mls vs. 3739 ± 134 mls for G-OW and A-OW, respectively) compared with the age-matched normal-weight controls. Body fat percentage negatively correlated with tibial SOS in the study sample as a whole (r = -0.30). However, when split into groups, percent bo~y fat correlated with tibial SOS only in the A-OW group (r = -0.53). MVPA correlated with tibial SOS (r = 0.40), once age was partialed out. In conclusion, in contrast withthe higher bone strength characteristic of obese adult women, overweight and obese girls and adolescents are characterized by low tibial bone strength, as assessed with QUS. The differences between adiposity groups in tibial SOS may be at least partially due to the reduced weight-bearing physical activity levels in the overweight girls and adolescents. However, other factors, such as hormonal influences associated with high body fat may also playa role in reducing bone strength in overweight girls. Further research is required to reveal the mechanisms causing low bone strength in overweight and obese children and adolescents.

Teaching persons with intellectual disabilities and limited receptive and expressive communication how to recognize and assert their human rights

Persons with intellectual disabilities (ID) are far more likely to be abused than the general population, but there is little research on teaching people with ID about their rights. The goal of this study was to teach four participants with ID and limited communication abilities about their human rights by training them on specific rights topics. The training program included icebreaker activities, instruction on rights concepts, watching and answering questions about videotaped scenarios of rights restrictions, watching and answering questions about role pl ay scenarios of rights restrictions, and responding to brief, low risk in situ rights restrictions imposed by the researchers. Participant performance did not improve significantly or consistently from baseline to training on the questions asked about the videotaped or the role play scenarios, but two of three participants demonstrated defmite improvements in responding to in situ rights restrictions.

An Exploration of Male Adolescents' Body Image Perceptions

There has been an increasing concern among researchers and the general population of our culture's increasing emphasis on "ideal" physical attractiveness-for both females and males. Despite this growing concern, research on body image has focused primarily on women and girls, with little research aimed specifically for males. Prior research (Grogan & Richards, 2002; Hargreaves & Tiggemann, 2006) stated that body image was a "feminine" or a "gay" issue, according to men and boys. The present study investigates this issue, particularly within the theoretical framework of multiple selves and gender theories. This exploratory case study involved semi-structured interviews with six male adolescents between the ages of 13 and 18 years. Researcher's fieldnotes were taken after the interviews. Content analysis of the interviews and fieldnotes revealed that for these six male adolescents, body image is not relevant to them, as they think about and discuss their issues of physical appearance with family and close peers. Traditional stereotypic notions of masculinity and what it means to be an adolescent male for the participants are discussed within the context of developmentally appropriate and gender-inclusive curriculum.