Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease

Recent studies have identified the genetic underpinnings of a growing number of diseases through targeted exome sequencing. However, this strategy ignores the large component of the genome that does not code for proteins, but is nonetheless biologically functional. To address the possible involvement of regulatory variation in congenital heart diseases (CHDs), we searched for regulatory mutations impacting the activity of TBX5, a dosage-dependent transcription factor with well-defined roles in the heart and limb development that has been associated with the HoltOram syndrome (hearthand syndrome), a condition that affects 1/100 000 newborns. Using a combination of genomics, bioinformatics and mouse genetic engineering, we scanned approximate to 700 kb of the TBX5 locus in search of cis-regulatory elements. We uncovered three enhancers that collectively recapitulate the endogenous expression pattern of TBX5 in the developing heart. We re-sequenced these enhancer elements in a cohort of non-syndromic patients with isolated atrial and/or ventricular septal defects, the predominant cardiac defects of the HoltOram syndrome, and identified a patient with a homozygous mutation in an enhancer approximate to 90 kb downstream of TBX5. Notably, we demonstrate that this single-base-pair mutation abrogates the ability of the enhancer to drive expression within the heart in vivo using both mouse and zebrafish transgenic models. Given the population-wide frequency of this variant, we estimate that 1/100 000 individuals would be homozygous for this variant, highlighting that a significant number of CHD associated with TBX5 dysfunction might arise from non-coding mutations in TBX5 heart enhancers, effectively decoupling the heart and hand phenotypes of the HoltOram syndrome.

Clinical Predictors Associated With Duration of Repetitive Transcranial Magnetic Stimulation Treatment for Remission in Bipolar Depression A Naturalistic Study

Repetitive transcranial magnetic stimulation (rTMS) has been widely tested and shown to be effective for unipolar depression. Although it has also been investigated for bipolar depression (BD), there are only few rTMS studies with BD. Here, we investigated 56 patients with BD who received rTMS treatment until remission (defined as Hamilton Depression Rating Scores <= 7). We used simple and multiple logistic regressions to identify clinical and demographic predictors associated with duration of treatment (defined as <15 vs. >15 rTMS sessions). Age, refractoriness, number of prior depressive episodes, and severe depression at baseline were associated with a longer rTMS treatment. In the multivariate analysis, refractoriness (likelihood ratio (LR) = 4.33; p < 0.01) and baseline severity (LR = 0.18, p < 0.01) remained significant predictors. Our preliminary study showed that, in remitted patients, refractoriness and severity of index episode are associated with the need of a longer rTMS treatment; providing preliminary evidence of important factors associated with rTMS parameters adjustment.

COMPARING RAINFALL INTENSITY DURATION RELATIONSHIPS FOR SITES OF THE STATE OF SAO PAULO

Rainfall intensity durations relationships are extremely important in the design of systems for mitigating runoff losses. The objective of this work was to compare rainfall depths generated by the PLUVIO 2.1 software, with depths from the standard intensity duration curves developed by MARTINEZ & MAGNI (1999). It was compared rainfall intensities of 10, 20, 30, 60, 120 and 1440 minute durations for 2, 5, 10, 50 and 100 year return periods for 30 sites in the state of Sao Paulo. The results showed that PLUVIO was effective, except in predicting the 24 hours rainfall from 100 year return period events in four locations in the central and eastern regions of the state.

Duration of dual antiplatelet therapy and outcomes after coronary stenting with the genous (TM) bio-engineered R stent (TM) in patients from the e-healing registry

Objective: We investigated the relation between duration of dual antiplatelet therapy (DAPT) and clinical outcomes up to 12 months after Genous (TM) endothelial progenitor cell capturing R stent (TM) placement in patients from the e-HEALING registry. Background: Cessation of (DAPT) has been shown to be associated with the occurrence of stent thrombosis (ST). After Genous placement, 1 month of DAPT is recommended. Methods: Patients were analyzed according to continuation or discontinuation of DAPT at a 30-day and 6-month landmark, excluding patients with events before the landmark. Each landmark was a new baseline, and outcomes were followed up to 12 months after stenting. The main outcome for our current analysis was target vessel failure (TVF), defined as target vessel-related cardiac death or myocardial infarction and target vessel revascularization. Secondary outcomes included ST. (Un)adjusted hazard ratios (HR) for TVF were calculated with Cox regression. Results: No difference was observed in the incidence of TVF [HR: 1.03; 95% confidence intervals (CI): 0.651.65, P = 0.89] in patients continuing DAPT (n = 4,249) at 30 days versus patients stopped (n = 309), and HR: 0.82 (95% CI: 0.551.23, P = 0.34) in patients continuing DAPT (n = 2,654) at 6 months versus patients stopped [n = 1,408] DAPT). Furthermore, no differences were observed in ST. Even after addition of identified independent predictors for TVF, adjusted TVF hazards were comparable. Conclusions: In a post-hoc analysis of e-HEALING, duration of DAPT was not associated with the occurrence of the outcomes TVF or ST. The Genous stent may be an attractive treatment especially in patients at increased risk for (temporary) cessation of DAPT or bleeding. (C) 2011 Wiley Periodicals, Inc.

Optimized Duration of Clopidogrel Therapy Following Treatment with the Endeavor Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) Trial: Rationale and design of a large-scale, randomized, multicenter study

Background Current recommendations for antithrombotic therapy after drug-eluting stent (DES) implantation include prolonged dual antiplatelet therapy (DAPT) with aspirin and clopidogrel >= 12 months. However, the impact of such a regimen for all patients receiving any DES system remains unclear based on scientific evidence available to date. Also, several other shortcomings have been identified with prolonged DAPT, including bleeding complications, compliance, and cost. The second-generation Endeavor zotarolimus-eluting stent (E-ZES) has demonstrated efficacy and safety, despite short duration DAPT (3 months) in the majority of studies. Still, the safety and clinical impact of short-term DAPT with E-ZES in the real world is yet to be determined. Methods The OPTIMIZE trial is a large, prospective, multicenter, randomized (1: 1) non-inferiority clinical evaluation of short-term (3 months) vs long-term (12-months) DAPT in patients undergoing E-ZES implantation in daily clinical practice. Overall, 3,120 patients were enrolled at 33 clinical sites in Brazil. The primary composite endpoint is death (any cause), myocardial infarction, cerebral vascular accident, and major bleeding at 12-month clinical follow-up post-index procedure. Conclusions The OPTIMIZE clinical trial will determine the clinical implications of DAPT duration with the second generation E-ZES in real-world patients undergoing percutaneous coronary intervention. (Am Heart J 2012;164:810-816.e3.)

Sleep duration in elderly obese patients correlated negatively with intake fatty

Study objectives: The purpose of the present study was to evaluate the relationship between sleep duration and dietary habits in elderly obese patients treated at an institute of cardiology. Methods: The fifty-eight volunteers were elderly patients with obesity (classified as obese according to BMI) of both genders, between 60 and 80 years of age. All participants were subjected to assessments of food intake, anthropometry, level of physical activity, and duration of sleep. Results: The men had significantly greater weight, height, and waist circumference than women. Sleep durations were correlated with dietary nutrient compositions only in men. We found a negative association between short sleep and protein intake (r = -0.43; p = 0.02), short sleep and monounsaturated fatty acids intake (r = -0.40; p = 0.03), and short sleep and cholesterol dietary intake (r = -0.50; p = 0.01). Conclusions: We conclude that mainly in men, volunteers that had short sleep duration showed a preference for high energy-density as fatty food, at least in part, may explain the relationship between short sleep duration and the development of metabolic abnormalities.

Effect of the rest interval duration between contractions on muscle fatigue

Background: We aimed to investigate the effect of rest interval, between successive contractions, on muscular fatigue. Methods: Eighteen subjects performed elbow flexion and extension (30 repetitions) on an isokinetic dynamometer with 80 degrees of range of motion. The flexion velocity was 120 degrees/s, while for elbow extension we used 5 different velocities (30, 75, 120, 240, 360 degrees/s), producing 5 different rest intervals (2.89, 1.28, 0.85, 0.57 and 0.54 s). Results: We observed that when the rest interval was 2.89 s there was a reduction in fatigue. On the other hand, when the rest interval was 0.54 s the fatigue was increased. Conclusions: When the resting time was lower (0.54 s) the decline of work in the flexor muscle group was higher compared with different rest interval duration.

The impact of psychiatric diagnosis on treatment adherence and duration among victimized children and adolescents in Sao Paulo, Brazil

OBJECTIVE: Despite the high prevalence of substance abuse and mood disorders among victimized children and adolescents, few studies have investigated the association of these disorders with treatment adherence, represented by numbers of visits per month and treatment duration. We aimed to investigate the effects of substance abuse and mood disorders on treatment adherence and duration in a special programfor victimized children in Sao Paulo, Brazil. METHODS: A total of 351 participants were evaluated for psychiatric disorders and classified into one of five groups: mood disorders alone; substance abuse disorders alone; mood and substance abuse disorders; other psychiatric disorders; no psychiatric disorders. The associations between diagnostic classification and adherence to treatment and the duration of program participation were tested with logistic regression and survival analysis, respectively. RESULTS: Children with mood disorders alone had the highest rate of adherence (79.5%); those with substance abuse disorders alone had the lowest (40%); and those with both disorders had an intermediate rate of adherence (50%). Those with other psychiatric disorders and no psychiatric disorders also had high rates of adherence (75.6% and 72.9%, respectively). Living with family significantly increased adherence for children with substance abuse disorders but decreased adherence for those with no psychiatric disorders. The diagnostic correlates of duration of participation were similar to those for adherence. CONCLUSIONS: Mood and substance abuse disorders were strong predictive factors for treatment adherence and duration, albeit in opposite directions. Living with family seems to have a positive effect on treatment adherence for patients with substance abuse disorders. More effective treatment is needed for victimized substance-abusing youth.

The impact of psychiatric diagnosis on treatment adherence and duration among victimized children and adolescents in São Paulo, Brazil

OBJECTIVE: Despite the high prevalence of substance abuse and mood disorders among victimized children and adolescents, few studies have investigated the association of these disorders with treatment adherence, represented by numbers of visits per month and treatment duration. We aimed to investigate the effects of substance abuse and mood disorders on treatment adherence and duration in a special program for victimized children in São Paulo, Brazil. METHODS: A total of 351 participants were evaluated for psychiatric disorders and classified into one of five groups: mood disorders alone; substance abuse disorders alone; mood and substance abuse disorders; other psychiatric disorders; no psychiatric disorders. The associations between diagnostic classification and adherence to treatment and the duration of program participation were tested with logistic regression and survival analysis, respectively. RESULTS: Children with mood disorders alone had the highest rate of adherence (79.5%); those with substance abuse disorders alone had the lowest (40%); and those with both disorders had an intermediate rate of adherence (50%). Those with other psychiatric disorders and no psychiatric disorders also had high rates of adherence (75.6% and 72.9%, respectively). Living with family significantly increased adherence for children with substance abuse disorders but decreased adherence for those with no psychiatric disorders. The diagnostic correlates of duration of participation were similar to those for adherence. CONCLUSIONS: Mood and substance abuse disorders were strong predictive factors for treatment adherence and duration, albeit in opposite directions. Living with family seems to have a positive effect on treatment adherence for patients with substance abuse disorders. More effective treatment is needed for victimized substance-abusing youth