Treatment of Morbid Obesity in Inner‐City Women

Objective: To explore the use of the very‐low‐calorie formula diet (VLCD) in the indigent population of Newark, NJ, with the goal of achieving 10% weight loss within a relatively short period of 10 weeks. Research Methods and Procedures: We accepted 131 morbidly obese indigent women into our study program. The study was limited to women only and the average starting weight was 292.3 ± 5.9 lbs (± SE; 50.3 ± 0.9 body mass index [kg/m²]). We used three treatment paradigms: total cost‐free program for 10 weeks; cost‐free, but compliance requirements; and a weekly charge of $25. The results obtained were compared with two control populations: women enrolled during the same recruitment period in a comparable suburban VLCD program and a historical control population of suburban women treated from 1985 through 1995. Results: In group A (total cost‐free), 79% of patients completed the 10‐week program, but only 18% of patients achieved the goal of 10% weight loss. In group B when attendance and weight loss requirements were imposed, the dropout rate accelerated such that only 37% of patients completed the 10‐week course, and 16% of the women were successful with their weight loss. In group C, imposing $25/wk financial outlay also accelerated dropouts but had little effect on weight loss success, which was 10% of the starting group. By comparison, the suburban patients and the historical control group exhibited 67% and 76% attendance rates after 10 weeks, and 33% and 55% success rates, respectively, in achieving the weight loss goal. Discussion: We conclude that inner‐city patients exhibit great interest in weight loss when financial barriers are removed. Successful weight loss was achieved in 10% to 18% of patients using the VLCD approach, approximately one‐half of that obtained in affluent suburban women. Imposing financial or compliance restrictions to the inner‐city patients served only to enhance dropouts.     

Vascular cell lines expressing SSAO/VAP-1: a new experimental tool to study its involvement in vascular diseases

Background information. PrAO (primary amine oxidase), also known as SSAO (semicarbazide‐sensitive amine oxidase)/VAP‐1 (vascular adhesion protein‐1), is an enzyme (EC 1.4.3.21) that is highly expressed in blood vessels and participates in many cell processes, including glucose handling or inflammatory leucocyte recruitment. High activity levels of this enzyme are associated with diabetes, atherosclerosis, AD (Alzheimer's disease) or stroke, among others, thus meaning that studies concerning SSAO as a therapeutic target are becoming more frequent. However, the study of this enzyme is difficult, owing to its loss of expression in cell cultures. Results. We have developed an endothelial cell line that stably expresses the human SSAO/VAP‐1 to be used as endothelial cell model for the study of this enzyme. The transfected protein is mainly expressed as a dimer in the membrane of these cells, and we demonstrate its specific localization in the lipid rafts of endothelial cells. The protein shows levels of enzymatic activity and kinetic parameters comparable with those observed in vivo by the same cell type. The transfected SSAO/VAP‐1 is also able to mediate the adhesion of leucocytes to the endothelium, a known function of this protein under inflammatory conditions. This distinctive function is not exerted by the SSAO/VAP‐1 transfected protein in a smooth muscle cell line that expresses 3‐fold higher protein levels. These differences have been widely reported to exist in vivo. Furthermore, using this endothelial cell model, we describe for the first time the involvement of the leucocyte‐adhesion activity of SSAO/VAP‐1 in the Aβ (amyloid β‐peptide)‐mediated pro‐inflammatory effect. Conclusions. The characterization of this new cell line shows the correct behaviour of the transfected protein and endorses the use of these cellular models for the in‐depth study of the currently poorly understood functions of SSAO/VAP‐1 and its involvement in the above‐mentioned pathologies. This cellular model will be also useful for the evaluation of potential compounds that could modulate its activity for therapeutic purposes.     

The Quantitative Relationship Between “The Metabolic Syndrome” and Abdominal Obesity in Women

Abdominal obesity is closely associated with the presence of metabolic risk factors and elevated blood pressure in selected materials. This has, however, never been analyzed quantitatively in a non-selected cohort. Therefore, in a population-based study of 1462 Swedish women, four selected risk factors for non-insulin dependent diabetes mellitus (NIDDM) and cardiovascular disease (CVD), serum triglycerides, blood glucose and systolic blood pressure and also serum insulin in a subsample, were examined in relation to regional and overall obesity. This was performed by subdividing the age adjusted sample into quintiles of waist to hip circumference ratio (WHR) or body mass index (BMI) as indicators of abdominal distribution of body fat and overall obesity, respectively. The risk factors serum triglycerides, blood glucose, blood pressure and serum insulin were defined as being elevated when the value of the risk factor was higher than the mean plus one or two standard deviations of the total age-adjusted cohort. The percentage of women with elevated risk factors according to this definition was then calculated in each of these quintiles. Having a risk factor which was elevated according to the definition was significantly correlated to WHR and BMI (p<0.0001) independent of age. The presence of one or several of these elevated risk factors was clearly higher than expected in the fifth quintile of WHR, and to a lesser extent in the fifth quintile of BMI while this was not the case in the lower quintiles of WHR and BMI. When studying the combination of the WHR and BMI, the presence of risk factors higher than the mean plus two standard deviations increased gradually with WHR in all five quintiles of BMI. A significant association was observed between WHR and presence of risk factors independent of BMI (p<0.0001) but BMI did not remain significantly correlated to presence of risk factors when controlling for WHR (p=0.09). These results indicate that abdominal distribution of body fat in women independently of general obesity is closely associated with metabolic risk factors including elevated blood pressure, a metabolic syndrome with increased risk for cardiovascular disease and non-insulin dependent diabetes mellitus.     

Effort‐Related Calf Pain in the Obese and Long‐Term Changes after Surgical Obesity Treatment**

Objective: To compare the prevalence of effort‐related calf pain in an obese and a general population and to analyze the incidence of and recovery from such pain after surgical and conventional obesity treatment. Research Methods and Procedures: A random sample of 1135 subjects from a general population was compared with 6328 obese subjects in the Swedish Obese Subjects study. Obese subjects were followed longitudinally, and information about calf pain was obtained from surgically and conventionally treated patients for up to 6 years. Results: In both sexes, self‐reported calf pain was more common in the obese than in the general population [odds ratios (ORs) 5.0 and 4.0 in men and women, respectively, p < 0.001]. Obese patients undergoing surgery had a lower 6‐year incidence of calf pain compared with the conventionally treated control group (ORs 0.39 and 0.61, p < 0.05). Among subjects reporting symptoms at baseline, the 6‐year recovery rate was higher in the surgical group compared with the control group (ORs 15.3 and 5.9, p < 0.001). Discussion: Obese subjects have markedly more problems with effort‐related calf pain than the general population. Surgical obesity treatment reduces the long‐term risk of developing claudication symptoms and increases the likelihood of recovering from such symptoms.     

Leptin Responses to Weight Loss in Postmenopausal Women: Relationship to Sex‐Hormone Binding Globulin and Visceral Obesity

Objective: Leptin concentrations increase with obesity and tend to decrease with weight loss. However, there is large variation in the response of serum leptin levels to decreases in body weight. This study examines which endocrine and body composition factors are related to changes in leptin concentrations following weight loss in obese, postmenopausal women. Research Methods and Procedures: Body composition (DXA), visceral obesity (computed tomography), leptin, cortisol, insulin, and sex hormone‐binding globulin (SHBG) concentrations were measured in 54 obese (body mass index [BMI] = 32.0 ± 4.5 kg/m²; mean ± SD), women (60 ± 6 years) before and after a 6‐month hypocaloric diet (250 to 350 kcal/day deficit). Results: Body weight decreased by 5.8 ± 3.4 kg (7.1%) and leptin levels decreased by 6.6 ± 11.9 ng/mL (14.5%) after the 6‐month treatment. Insulin levels decreased 10% (p < 0.05), but mean SHBG and cortisol levels did not change significantly. Relative changes in leptin with weight loss correlated positively with relative changes in body weight (r = 0.50, p < 0.0001), fat mass (r = 0.38, p < 0.01), subcutaneous fat area (r = 0.52, p < 0.0001), and with baseline values of SHBG (r = 0.38, p < 0.01) and baseline intra‐abdominal fat area (r = ?0.27, p < 0.06). Stepwise multiple regression analysis showed that baseline SHBG levels (r² = 0.24, p < 0.01), relative changes in body weight (cumulative r² = 0.40, p < 0.05), and baseline intra‐abdominal fat area (cumulative r² = 0.48, p < 0.05) were the only independent predictors of the relative change in leptin, accounting for 48% of the variance. Discussion: These results suggest that obese, postmenopausal women with a lower initial SHBG and more visceral obesity have a greater decrease in leptin with weight loss, independent of the amount of weight lost.     

Combined experimental and computational analysis of DNA damage signaling reveals context‐dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress

Following DNA damage, cells display complex multi‐pathway signaling dynamics that connect cell‐cycle arrest and DNA repair in G1, S, or G2/M phase with phenotypic fate decisions made between survival, cell‐cycle re‐entry and proliferation, permanent cell‐cycle arrest, or cell death. How these phenotypic fate decisions are determined remains poorly understood, but must derive from integrating genotoxic stress signals together with inputs from the local microenvironment. To investigate this in a systematic manner, we undertook a quantitative time‐resolved cell signaling and phenotypic response study in U2OS cells receiving doxorubicin‐induced DNA damage in the presence or absence of TNFα co‐treatment; we measured key nodes in a broad set of DNA damage signal transduction pathways along with apoptotic death and cell‐cycle regulatory responses. Two relational modeling approaches were then used to identify network‐level relationships between signals and cell phenotypic events: a partial least squares regression approach and a complementary new technique which we term ‘time‐interval stepwise regression.’ Taken together, the results from these analysis methods revealed complex, cytokine‐modulated inter‐relationships among multiple signaling pathways following DNA damage, and identified an unexpected context‐dependent role for Erk in both G1/S arrest and apoptotic cell death following treatment with this commonly used clinical chemotherapeutic drug.