Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.

Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities. BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited. METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism. RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF. CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

Outcome of subscapularis muscle release for shoulder contracture secondary to brachial plexus palsy at birth.

Children with unresolved brachial plexus palsy frequently develop a disabling internal rotation contracture of the shoulder. Several surgical options, including soft tissue procedures such as muscle releases and/or transfers, and bone operations such as humeral osteotomy are available to correct this deformity. This study describes the effect of subscapularis muscle release performed in isolation. Thirteen patients (5 boys, 8 girls) were reviewed at an average of 3.5 years after their surgery (range, 2-7 years). Their mean age at operation was 4.7 years (range, 1-8 years). Three children had C5-C6 palsies, 8 had C5-C7 palsies, and 2 had C5-C8 palsies. Postoperatively, patients presented significant gains in shoulder active lateral rotation (+49 degrees, from 5 to 54 degrees), active abduction (+30 degrees, from 63 to 93 degrees), active flexion (+46 degrees, from 98 to 144 degrees), and active extension (+23 degrees, from 7 to 30 degrees). Gains were also observed in passive range of motion, but of a lesser degree. Subscapularis muscle release is a procedure we found to have few significant complications and was highly effective in increasing active range of motion and restoring shoulder function.

Frailty and risk for heart failure in older adults: The health, aging, and body composition study.

OBJECTIVE: The aim of this study was to assess the association between frailty and risk for heart failure (HF) in older adults. BACKGROUND: Frailty is common in the elderly and is associated with adverse health outcomes. Impact of frailty on HF risk is not known. METHODS: We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC Battery) and the Gill index, and incident HF in 2825 participants aged 70 to 79 years. RESULTS: Mean age of participants was 74 ± 3 years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (HR 1.36, 95% CI 1.08-1.71) and severe frailty (HR 1.88, 95% CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC Battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95% CI 1.13-1.36 per SD decrease in score) and remained significant when controlled for death as a competing risk (HR 1.30; 95% CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC Battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95% CI 0.018-0.010) and appropriately reclassified 13.4% (net-reclassification-improvement 0.073, 95% CI 0.021-0.125; P = .006) of participants (8.3% who developed HF and 5.1% who did not). CONCLUSIONS: Frailty is independently associated with risk of HF in older adults.

A Small World Perspective on Urban Systems

The theory of small-world networks as initiated by Watts and Strogatz (1998) has drawn new insights in spatial analysis as well as systems theory. The theoryâeuro?s concepts and methods are particularly relevant to geography, where spatial interaction is mainstream and where interactions can be described and studied using large numbers of exchanges or similarity matrices. Networks are organized through direct links or by indirect paths, inducing topological proximities that simultaneously involve spatial, social, cultural or organizational dimensions. Network synergies build over similarities and are fed by complementarities between or inside cities, with the two effects potentially amplifying each other according to the âeurooepreferential attachmentâeuro hypothesis that has been explored in a number of different scientific fields (Barabási, Albert 1999; Barabási A-L 2002; Newman M, Watts D, Barabàsi A-L). In fact, according to Barabási and Albert (1999), the high level of hierarchy observed in âeurooescale-free networksâeuro results from âeurooepreferential attachmentâeuro, which characterizes the development of networks: new connections appear preferentially close to nodes that already have the largest number of connections because in this way, the improvement in the network accessibility of the new connection will likely be greater. However, at the same time, network regions gathering dense and numerous weak links (Granovetter, 1985) or network entities acting as bridges between several components (Burt 2005) offer a higher capacity for urban communities to benefit from opportunities and create future synergies. Several methodologies have been suggested to identify such denser and more coherent regions (also called communities or clusters) in terms of links (Watts, Strogatz 1998; Watts 1999; Barabási, Albert 1999; Barabási 2002; Auber 2003; Newman 2006). These communities not only possess a high level of dependency among their member entities but also show a low level of âeurooevulnerabilityâeuro, allowing for numerous redundancies (Burt 2000; Burt 2005). The SPANGEO project 2005âeuro"2008 (SPAtial Networks in GEOgraphy), gathering a team of geographers and computer scientists, has included empirical studies to survey concepts and measures developed in other related fields, such as physics, sociology and communication science. The relevancy and potential interpretation of weighted or non-weighted measures on edges and nodes were examined and analyzed at different scales (intra-urban, inter-urban or both). New classification and clustering schemes based on the relative local density of subgraphs were developed. The present article describes how these notions and methods contribute on a conceptual level, in terms of measures, delineations, explanatory analyses and visualization of geographical phenomena.

Congenital disorder of glycosylation type Id (CDG Id): phenotypic, biochemical and molecular characterization of a new patient.

Congenital disorders of glycosylation (CDG) are a family of multisystem inherited disorders caused by defects in the biosynthesis of N- or O-glycans. Among the many different subtypes of CDG, the defect of a mannosyltransferase encoded by the human ALG3 gene (chromosome 3q27) is known to cause CDG Id. Six patients with CDG Id have been described in the literature so far. We further delineate the clinical, biochemical, neuroradiological and molecular features of CDG Id by reporting an additional patient bearing a novel missense mutation in the ALG3 gene. All patients with CDG Id display a slowly progressive encephalopathy with microcephaly, severe psychomotor retardation and epileptic seizures. They also share some typical dysmorphic features but they do not present the multisystem involvement observed in other CDG syndromes or any biological marker abnormalities. Unusually marked osteopenia is a feature in some patients and may remain undiagnosed until revealed by pathological fractures. Serum transferrin screening for CDG should be extended to all patients with encephalopathy of unknown origin, even in the absence of multisystem involvement.

Association of ECG abnormalities and incident heart failure events

Background: With the aging of the population, the heart failure (HF) incidence and prevalence trends are expected to significantly worsen unless concentrated prevention efforts are undertaken. ECG abnormalities are common in the elderly but data are limited for their association with HF risk. Objective: To assess whether baseline ECG abnormalities or dynamic changes are associated with an increased risk of HF. Method: A prospective cohort study of 2915 participants aged 70 to 79 years without a preexisting HF followed for a median period of 11.4 (IQR 7.0-11.7) years from the Health Aging and Body Composition study. The Minnesota Code was used to define major and minor ECG abnormalities at baseline and at 4-year. Main outcome measure was adjudicated incident HF events. Using Cox models, the (1) the association between ECG abnormalities and incident HF and (2) incremental value of adding ECG to the Health ABC HF Risk Score, was assessed. Results: At baseline, 380 participants (13.0%) had minor and 620 (21.3%) had major ECG abnormalities. During follow-up, 485 (16.6%) participants developed incident HF. After adjusting for the eight clinical variables in the Health ABC HF Risk Score, the hazard ratio (HR) was 1.27 (95% confidence interval [CI] 0.96-1.68) for minor and 1.99 (CI 1.61-2.44) for major ECG abnormalities (P for trend <0.001) compared to no ECG abnormalities. The association did not change according to presence of baseline CHD. At 4-year, 263 participants developed new and 549 had persistent abnormalities and both were associated with increased HF risk (HR = 1.94, CI 1.38-2.72 for new and HR=2.35, CI 1.82-3.02 for persistent compared to no ECG abnormalities). Baseline ECG correctly reclassified 10.6% of overall participants across the categories of the Health ABC HF Risk Score. Conclusion: Among older adults, baseline ECG abnormalities and changes in them over time are common; both are associated with an increased risk of HF. Whether ECG should be incorporated in routine screening of older adults should be evaluated in randomized controlled trials.

Serum resistin concentrations and risk of new onset heart failure in older persons: the health, aging, and body composition (Health ABC) study.

OBJECTIVE: Resistin is associated with inflammation and insulin resistance and exerts direct effects on myocardial cells including hypertrophy and altered contraction. We investigated the association of serum resistin concentrations with risk for incident heart failure (HF) in humans. METHODS AND RESULTS: We studied 2902 older persons without prevalent HF (age, 73.6+/-2.9 years; 48.1% men; 58.8% white) enrolled in the Health, Aging, and Body Composition (Health ABC) Study. Correlation between baseline serum resistin concentrations (20.3+/-10.0 ng/mL) and clinical variables, biochemistry panel, markers of inflammation and insulin resistance, adipocytokines, and measures of adiposity was weak (all rho <0.25). During a median follow-up of 9.4 years, 341 participants (11.8%) developed HF. Resistin was strongly associated with risk for incident HF in Cox proportional hazards models controlling for clinical variables, biomarkers, and measures of adiposity (HR, 1.15 per 10.0 ng/mL in adjusted model; 95% CI, 1.05 to 1.27; P=0.003). Results were comparable across sex, race, diabetes mellitus, and prevalent and incident coronary heart disease subgroups. In participants with available left ventricular ejection fraction at HF diagnosis (265 of 341; 77.7%), association of resistin with HF risk was comparable for cases with reduced versus preserved ejection fraction. CONCLUSIONS: Serum resistin concentrations are independently associated with risk for incident HF in older persons.

Association of major and minor ECG abnormalities with coronary heart disease events.

CONTEXT: In populations of older adults, prediction of coronary heart disease (CHD) events through traditional risk factors is less accurate than in middle-aged adults. Electrocardiographic (ECG) abnormalities are common in older adults and might be of value for CHD prediction. OBJECTIVE: To determine whether baseline ECG abnormalities or development of new and persistent ECG abnormalities are associated with increased CHD events. DESIGN, SETTING, AND PARTICIPANTS: A population-based study of 2192 white and black older adults aged 70 to 79 years from the Health, Aging, and Body Composition Study (Health ABC Study) without known cardiovascular disease. Adjudicated CHD events were collected over 8 years between 1997-1998 and 2006-2007. Baseline and 4-year ECG abnormalities were classified according to the Minnesota Code as major and minor. Using Cox proportional hazards regression models, the addition of ECG abnormalities to traditional risk factors were examined to predict CHD events. MAIN OUTCOME MEASURE: Adjudicated CHD events (acute myocardial infarction [MI], CHD death, and hospitalization for angina or coronary revascularization). RESULTS: At baseline, 276 participants (13%) had minor and 506 (23%) had major ECG abnormalities. During follow-up, 351 participants had CHD events (96 CHD deaths, 101 acute MIs, and 154 hospitalizations for angina or coronary revascularizations). Both baseline minor and major ECG abnormalities were associated with an increased risk of CHD after adjustment for traditional risk factors (17.2 per 1000 person-years among those with no abnormalities; 29.3 per 1000 person-years; hazard ratio [HR], 1.35; 95% CI, 1.02-1.81; for minor abnormalities; and 31.6 per 1000 person-years; HR, 1.51; 95% CI, 1.20-1.90; for major abnormalities). When ECG abnormalities were added to a model containing traditional risk factors alone, 13.6% of intermediate-risk participants with both major and minor ECG abnormalities were correctly reclassified (overall net reclassification improvement [NRI], 7.4%; 95% CI, 3.1%-19.0%; integrated discrimination improvement, 0.99%; 95% CI, 0.32%-2.15%). After 4 years, 208 participants had new and 416 had persistent abnormalities. Both new and persistent ECG abnormalities were associated with an increased risk of subsequent CHD events (HR, 2.01; 95% CI, 1.33-3.02; and HR, 1.66; 95% CI, 1.18-2.34; respectively). When added to the Framingham Risk Score, the NRI was not significant (5.7%; 95% CI, -0.4% to 11.8%). CONCLUSIONS: Major and minor ECG abnormalities among older adults were associated with an increased risk of CHD events. Depending on the model, adding ECG abnormalities was associated with improved risk prediction beyond traditional risk factors.

Subclinical hypothyroidism and functional mobility in older adults.

BACKGROUND: Health risks associated with subclinical hypothyroidism in older adults are unclear. Our objective was to compare the functional mobility of people aged 70 to 79 years by thyroid function categorized by thyrotropin (TSH) level as euthyroid (>or=0.4 to <4.5 mIU/L), mild subclinical hypothyroid (>or=4.5 to <7.0 mIU/L), or moderate subclinical hypothyroid (>or=7.0 to <or=20.0 mIU/L with a normal free thyroxine level) cross-sectionally and over 2 years. METHODS: A total of 2290 community-dwelling residents participating in the year 2 clinic visit (July 1998-June 1999) of the Health, Aging, and Body Composition (Health ABC) Study, who had measured TSH level, had the capacity to walk 20 m unaided, and were not taking thyroid medication or had TSH levels consistent with hyperthyroidism or hypothyroidism. Main outcome measures included self-reported and performance-based measures of mobility (usual and rapid gait speed and endurance walking ability) assessed at study baseline (year 2) and 2 years later. RESULTS: In age- and sex-adjusted analyses, the mild subclinical hypothyroid group (vs the euthyroid group) demonstrated better mobility (faster mean usual and rapid gait speed [1.20 vs 1.15 m/s and 1.65 vs 1.56 m/s, respectively; P < .001] and had a higher percentage of those with good cardiorespiratory fitness and reported walking ease [39.2% vs 28.0% and 44.7% vs 36.5%, respectively; P < .001]). After 2 years, persons with mild subclinical hypothyroidism experienced a similar decline as the euthyroid group but maintained their mobility advantage. Persons with moderate subclinical hypothyroidism had similar mobility and mobility decline as the euthyroid group. CONCLUSION: Generally, well-functioning 70- to 79-year-old individuals with subclinical hypothyroidism do not demonstrate increased risk of mobility problems, and those with mild elevations in TSH level show a slight functional advantage.

Role of Staphylococcus aureus coagulase and clumping factor in pathogenesis of experimental endocarditis.

The pathogenic role of staphylococcal coagulase and clumping factor was investigated in the rat model of endocarditis. The coagulase-producing and clumping factor-producing parent strain Staphylococcus aureus Newman and a series of mutants defective in either coagulase, clumping factor, or both were tested for their ability (i) to attach in vitro to either rat fibrinogen or platelet-fibrin clots and (ii) to produce endocarditis in rats with catheter-induced aortic vegetations. In vitro, the clumping factor-defective mutants were up to 100 times less able than the wild type strain to attach to fibrinogen and also significantly less adherent than the parents to platelet-fibrin clots. Coagulase-defective mutants, in contrast, were not altered in their in vitro adherence phenotype. The rate of in vivo infection was inoculum dependent. Clumping factor-defective mutants produced ca. 50% less endocarditis than the parent organisms when injected at inoculum sizes infecting, respectively, 40 and 80% (ID40 and ID80, respectively) of rats with the wild-type strain. This was a trend at the ID40 but was statistically significant at the ID80 (P &lt; 0.05). Coagulase-defective bacteria were not affected in their infectivity. Complementation of a clumping factor-defective mutant with a copy of the wild-type clumping factor gene restored both its in vitro adherence and its in vivo infectivity. These results show that clumping factor plays a specific role in the pathogenesis of S. aureus endocarditis. Nevertheless, the rate of endocarditis with clumping factor-defective mutants increased with larger inocula, indicating the contribution of additional pathogenic determinants in the infective process.

Use of a dynamic foot pressure index to monitor the effects of treatment for equinus gait in children with cerebral palsy.

The purpose of this study is to introduce and describe a newly developed index using foot pressure analysis to quantify the degree of equinus gait in children with cerebral palsy before and after injection with botulinum toxin. Data were captured preinjection and 12 weeks postinjection. Ten children aged 2(1/2) to 6(1/2) years took part (5 boys and 5 girls). Three of them had a diagnosis of spastic diplegia and 7 of congenital hemiplegia. In total, 13 limbs were analyzed. After orientation and segmentation of raw pedobarographic data, we determined a dynamic foot pressure index graded 0 to 100 that quantified the relative degree of heel and forefoot contact during stance. These data were correlated (Pearson correlation) with clinical measurements of dorsiflexion at the ankle (on a slow and fast stretch) and video observation (using the Observational Gait Scale). Pedobarograph data were strongly correlated with both the Observational Gait Scale scores (R = 0.79, P < 0.005) and clinical measurements of dorsiflexion on a fast stretch, which is reflective of spasticity (R = 0.70, P < 0.005). We demonstrated the index's sensitivity in detecting changes in spasticity and good correlation with video observations seems to indicate this technique's potential validity. When manipulated and segmented appropriately, and with the development of a simple ordinal index, we found that foot pressure data provided a useful tool in tracking changes in patients with spastic equinus.