Background The relation between central obesity and survival in community-dwelling adults with a normal body mass index (BMI) is not well known. Objectives To examine the risk of total and cardiovascular mortality associated with central obesity but normal BMI Design Stratified multistage probability design Setting Third National Health and Nutrition Examination Survey Participants We analyzed data on 15,184 people (52.3% women) aged 18 to 90 years.. Measurements We used multivariable Cox proportional hazards model to evaluate the relation of obesity patterns defined by BMI and WHR and total and cardiovascular mortality risk after adjustment for confounding factors. Results Persons with normal-weight central obesity had the worst long-term survival: a man with a normal BMI (22 kg/m2) and central obesity had greater total mortality risk than one with similar BMI but no central obesity (hazard ratio [HR], 1.87 [95% CI, 1.53–2.29]) and twice the mortality risk of participants who were overweight or obese by BMI only (HR, 2.24 [95% CI,1.52–3.32] and HR, 2.42 [95% CI, 1.30–4.53], respectively). Similarly, women with normal weight and central obesity had higher mortality risk than both women with similar BMI but no central obesity (HR, 1.48 [95% CI, 1.35–1.62]) and women who were obese by BMI only (HR, 1.32 [95% CI, 1.15–1.51]). Expected survival estimates were consistently lower for those with central obesity when controlled for age and BMI. Limitations Body fat distribution was assessed based on anthropometric indicators alone. Information on comorbidities was collected by self-report. Conclusion Normal-weight central obesity defined by WHR is associated with higher mortality than BMI–defined obesity, particularly in the absence of central fat distribution.

Background Body composition changes with aging lead to increased adiposity and decreased muscle mass, making the diagnosis of obesity challenging. Conventional anthropometry, including body mass index (BMI), while easy to use clinically may misrepresent adiposity. We determined the diagnostic accuracy of BMI using dual energy x-ray absorptiometry (DEXA) in assessing the degree of obesity in older adults. Methods The National Health and Nutrition Examination Surveys 1999–2004 were used to identify adults aged ≥60years with DEXA measures. They were categorized (yes/no) as having elevated body fat by gender (men≥25%; females ≥35%) and by body mass index (BMI) ≥25 and ≥30kg/m2. The diagnostic performance of BMI was assessed. Metabolic characteristics were compared in discordant cases of BMI/body fat. Weighting and analyses were performed per NHANES guidelines. Results We identified 4,984 subjects (men:2,453; female:2,531). Mean BMI and % body fat was 28.0kg/m2 and 30.8% in men, and 28.5kg/m2 and 42.1% in females. A BMI ≥30kg/m2 had a low sensitivity and moderately high specificity (men:32.9% and 80.8%, concordance index 0.66; females:38.5% and 78.5%, concordance 0.69) correctly classifying 41.0 and 45.1% of obese subjects. A BMI ≥25kg/m2 had a moderately high sensitivity and specificity (men:80.7% and 99.6%, concordance 0.81;females:76.9% and 98.8%, concordance 0.84) correctly classifying 80.8 and 78.5% of obese subjects. In subjects with BMI<30kg/m2 body fat was considered elevated in 67.1% and 61.5% of males and females, respectively. For a BMI≥30kg/m2, sensitivity drops from 40.3 to 14.5% and 44.5 to 23.4%, while specificity remains elevated (>98%),in males and females, respectively in those 60–69.9years to subjects aged ≥80years. Correct classification of obesity using a cutoff of 30kg/m2 drops from 48.1 to 23.9% and 49.0 to 19.6%, in males and females in these two age groups. Conclusions Traditional measures poorly identify obesity in the elderly. In older adults, BMI may be a suboptimal marker for adiposity.

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BackgroundVLA-4 and CD38 predict a poor clinical outcome in chronic lymphocytic leukemia (CLL). We used CLL samples with discordant VLA-4/CD38 risk to address their individual roles in human bone marrow infiltration (BM), CLL cell homing to murine BM, and in supportive CLL cell-stromal cell interactions.MethodsVLA-4, CD38, and Ki-67 expression was measured in CLL cells from peripheral blood (PB) and bone marrow (BM) aspirates. CLL BM infiltration rates, routinely determined by Pathology, were correlated to VLA-4 and CD38 expression. Short-term homing capacity of CLL cells was evaluated by adoptive transfer experiments. CLL cell viability and adhesion in stromal cell co-culture was determined.ResultsAbout 20% of CLL samples in our cohort displayed discordant VLA-4 and CD38 risk, with either high VLA-4 and low CD38 risk or vice versa. Using particularly such samples, we observed that VLA-4, and not CD38, was responsible for recirculation of CLL cells to murine BM. Human BM infiltration was also significantly higher in patients with high VLA-4 risk but not high CD38 risk. However, both molecules acted as independent prognostic markers. While both VLA-4 and CD38 expression were increased in BM-derived CLL cells, and VLA-4+ and CD38+ subpopulations showed enriched Ki-67 expression, VLA-4 did not contribute to CLL cell protection by stromal cells in vitro.ConclusionsOur data argue for a prominent role of VLA-4 but not CD38 expression in the homing of CLL cells to BM niches and in human BM infiltration,but only a limited role in their protection by stromal cells.

Aims/hypothesis To examine the association of serum cystatin C with the incidence of type 2 diabetes mellitus over a 15-year follow-up period. Methods The 15-year cumulative incidence of diabetes was measured in a cohort of Beaver Dam Eye Study participants (n=3472, 1988–2003). A person was defined as developing diabetes (a positive history of diabetes mellitus treated with insulin, oral hypoglycemic agents and/or diet, or had elevations in glycosylated hemoglobin levels) in the absence of diabetes at baseline. The relation of cystatin C and other risk factors to incident type 2 diabetes was determined using discrete time extension of the proportional hazards model. Results The 15-year cumulative incidence of diabetes was estimated to be 9.6%. After controlling for age, sex, body mass index, smoking status, glycosylated hemoglobin, proteinuria, chronic kidney disease status, and hypertension status, serum cystatin C at baseline was associated with the 15-year cumulative incidence of type 2 diabetes (Odds Ratio per log of cystatin C unit 2.19, and 95% Confidence Interval 1.02, 4.68). Conclusions/interpretation These findings show a positive relationship of serum cystatin C levels with the incidence of type 2 diabetes mellitus independently of confounding risk factors. The findings strongly suggest the need for further evaluation of the potential importance of cystatin C in pathogenesis of type 2 diabetes mellitus.

Background/ObjectiveAdiponectin exerts beneficial effects by reducing inflammation, and improving lipid metabolism and insulin-sensitivity. Although adiponectin is lower in obese individuals, whether weight gain reduces adiponectin expression in humans is controversial. We sought to investigate the role of weight gain, and consequent changes in leptin, on altering adiponectin expression in humans.Methods/ResultsForty four normal-weight healthy subjects were recruited (mean age 29 years; 14 women) and randomized to either gain 5% of body weight by 8-weeks of overfeeding (n=34) or maintain weight (n=10). Modest weight gain of 3.8 ± 1.2 kg resulted in increased adiponectin (p=0.03) while weight maintenance resulted in no changes in adiponectin. Further, changes in adiponectin correlated positively with changes in leptin (p=0.0085). In-vitro experiments using differentiated human white preadipocytes showed that leptin increased adiponectin mRNA and protein expression, while a leptin-antagonist had opposite effects. To understand the role of leptin in established obesity, we compared adipose tissue samples obtained from normal weight versus obese subjects. We noted, first, that leptin activated cellular signaling pathways and increased adiponectin mRNA in adipose tissue from normal-weight participants, but did not do so in adipose tissue from obese participants; and second, that obese subjects had increased caveolin-1 expression, which attenuates leptin-dependent increases in adiponectin.ConclusionsModest weight gain in healthy individuals is associated with increases in adiponectin, which correlate positively with changes in leptin. In-vitro, leptin induces adiponectin expression which is attenuated by increased caveolin-1 expression. Additionally, adipose tissue from obese subjects shows increased caveolin-1 expression, and impaired leptin signaling. This leptin signal impairment may prevent concordant increases in adiponectin in obese subjects despite their high levels of leptin. Therefore, impaired leptin signaling may contribute to low adiponectin expression in obesity and may provide a target for increasing adiponectin expression, hence improving insulin sensitivity and cardio-metabolic profile in obesity.

Background-Data from longitudinal studies suggest that biomarkers of inflammation and endothelial dysfunction are associated with development of hypertension. None of these studies have examined the association of these markers with hypertension risk in persons with diabetes. We examined the associations of inflammatory and endothelial dysfunction markers with long-term hypertension incidence in persons with type 1 diabetes mellitus.

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