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1.  An Automated Algorithm to Identify and Quantify Brown Adipose Tissue in Human 18F-FDG-PET/CT Scans 
Obesity (Silver Spring, Md.)  2013;21(8):1554-1560.
Objective
To develop an algorithm to identify and quantify BAT from PET/CT scans without radiologist interpretation.
Design and Methods
Cases (n = 17) were randomly selected from PET/CT scans with documented “brown fat” by the reviewing radiologist. Controls (n = 18) had no documented “brown fat” and were matched with cases for age (49.7 [31.0-63.0] vs. 52.4 [24.0-70.0] yrs), outdoor temperature at scan date (51.8 [38.9-77.0] vs. 54.9 [35.2-74.6] °F), sex (F/M: 15/2 cases; 16/2 controls) and BMI (28.2 [20.0-45.7] vs. 26.8 [21.4-37.1] kg/m2]). PET/CT scans and algorithm-generated images were read by the same radiologist blinded to scan identity. Regions examined included neck, mediastinum, supraclavicular fossae, axilla and paraspinal soft tissues. BAT was scored 0 for no BAT; 1 for faint uptake possibly compatible with BAT or unknown; and 2 for BAT positive.
Results
Agreement between the algorithm and PET/CT scan readings was 85.7% across all regions. The algorithm had a low false negative (1.6%) and higher false positive rate (12.7%). The false positive rate was greater in mediastinum, axilla and neck regions.
Conclusion
The algorithm's low false negative rate combined with further refinement will yield a useful tool for efficient BAT identification in a rapidly growing field particularly as it applies to obesity.
doi:10.1002/oby.20315
PMCID: PMC3910095  PMID: 23408435
2.  Preoperative weight gain might increase risk of gastric bypass surgery 
Background
Weight loss improves the cardiovascular and metabolic risk associated with obesity. However, insufficient data are available about the health effects of weight gain, separate from the obesity itself. We sought to determine whether the changes in body weight before open gastric bypass surgery (OGB) would have a significant effect on the immediate perioperative hospital course.
Methods
A retrospective chart review of 100 consecutive patients was performed to examine the effects of co-morbidities and body weight changes in the immediate preoperative period on the hospital length of stay and the rate of admission to the surgical intensive care unit (SICU).
Results
Of our class III obese patients undergoing OGB, 95% had ≥1 co-morbid condition and an overall SICU admission rate of 18%. Compared with the patients with no perioperative SICU admission, the patients admitted to the SICU had a greater degree of insulin resistance (homeostatic model analysis–insulin resistance 10.8 ± 1.3 versus 5.9 ± 0.5, P = .001), greater serum triglyceride levels (225 ± 47 versus 143 ± 8 mg/dL, P = .003), and had gained more weight preoperatively (.52 ± .13 versus .06 ± .06 lb/wk, P = .003). The multivariate analyses showed that preoperative weight gain was a risk factor for a longer length of stay and more SICU admissions lasting ≥3 days, as were a diagnosis of sleep apnea and an elevated serum triglyceride concentration.
Conclusion
The results of the present retrospective study suggest that weight gain increases the risk of perioperative SICU admission associated with OGB, independent of the body mass index. Sleep apnea and elevated serum triglyceride levels were also important determinants of perioperative morbidity. In view of the increasing epidemic of obesity and the popularity of bariatric surgical procedures, we propose that additional clinical and metabolic research focusing on the understanding of the complex relationship among obesity, positive energy balance, weight gain, and perioperative morbidity is needed.
doi:10.1016/j.soard.2010.09.009
PMCID: PMC3958941  PMID: 21111687
Morbid obesity; surgical risk; positive energy balance; hospital length of stay; perioperative morbidity
3.  Obesity and Cardiovascular Disease 
Circulation  2012;125(9):1178-1182.
doi:10.1161/CIRCULATIONAHA.111.022541
PMCID: PMC3693443  PMID: 22392865
4.  Management of diabetes across the course of disease: minimizing obesity-associated complications 
Obesity increases the risk for developing type 2 diabetes mellitus (T2DM) and this in turn correlates with an elevated probability of long-term diabetes complications once diabetes is established. Interventions aimed at lowering weight via changes in diet and lifestyle have repeatedly been shown to improve glycemic control in patients with T2DM and even to reverse early disease. Weight gain, a potential side effect of treatment for patients with T2DM, is also an important concern, and it has been noted that weight increases associated with antidiabetes therapy may blunt cardiovascular risk reductions achieved by decreasing blood glucose. Among older agents, metformin and acarbose have the lowest risk for weight gain, while sulfonylureas, meglitinides, and thiazolidinediones are all associated with weight increases. Clinical trial results have also consistently demonstrated that treatment with glucagon-like peptide-1 receptor agonists and amylin lowers weight, and that dipeptidyl peptidase-4 inhibitors are weight neutral in patients with T2DM. Conventional human insulin formulations are known to increase weight in patients with T2DM. However, some insulin analogs, particularly insulin detemir, have lower liability for this adverse event. The use of both pharmacologic and surgical therapies aimed at treating obesity rather than lowering blood glucose have the potential to improve glycemic control and even resolve T2DM in some patients.
doi:10.2147/DMSO.S24022
PMCID: PMC3224657  PMID: 22135499
bariatric; diabetes; incretin; insulin; obesity; oral antidiabetes agents
5.  B lymphocytes in human subcutaneous adipose crown-like structures 
Obesity (Silver Spring, Md.)  2012;20(7):1372-1378.
Accumulation of macrophages and T cells within crown-like structures (CLS) in subcutaneous adipose tissue predicts disease severity in obesity related insulin resisance (OIR). While rodent data suggest the B cell is an important feature of these lesions, B cells have not been described within the human CLS. In order to identify B cells in the human subcutaneous CLS (sCLS) in obese subjects and determine if the presence of B cells predict insulin resistance, we examined archived samples of subcutaneous and omental fat from 32 obese men and women and related findings to clinical parameters. Using immunohistochemistry we identified B (CD19+) and T cells (CD3+) within the sCLS and perivascular space. B cell presence and density (B cells pHPF, T cells pHPF and B:T cell ratio) were compared with measures of insulin resistance (HOMA) and other variables. In sixteen of thirty-two subjects (50%) CD19+ B cells were localized within sCLS and were relatively more numerous than T cells. HOMA was not different between subjects with CD19+ vs. CD19− sCLS (5.5 vs. 5.3, p= 0.88). After controlling for diabetes and glycemia (HA1c), the B:T cell ratio correlated with current metformin treatment (r=0.89, p = 0.001). These results indicate that in human OIR, B cells are an integral component of organized inflammation in subcutaneous fat, and defining their role will lead to a better understanding of OIR pathogenesis and potentially impact treatment.
doi:10.1038/oby.2012.54
PMCID: PMC3682646  PMID: 22395812
Immunology; Type 2 Diabetes; insulin resistance; inflammation; subcutaneous adipose tissue
6.  Overweight in older children and adolescents: treatment or prevention? 
doi:10.1136/adc.2009.157677
PMCID: PMC2857966  PMID: 20040679
7.  Treating Diabetes and Prediabetes by Focusing on Obesity Management 
Current diabetes reports  2009;9(5):348-354.
Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes mellitus (T2DM). In obesity, the adipose cell releases non-esterified free fatty acids, hormones, adipocytokines, and other substances that are involved in insulin resistance. Under normal conditions, the pancreatic islet β cells increase production of insulin sufficiently to maintain normal blood glucose concentrations despite insulin resistance. However, in genetically predisposed patients, the β cells eventually become dysfunctional and T2DM develops. The development of T2DM can be delayed or sometimes prevented in individuals with obesity who are able to lose weight. Weight loss can be achieved medically with behavioral therapies that combine diet and exercise treatment or with behavioral therapies combined with weight-loss medications or weight-loss surgery. In this article, we summarize the evidence of obesity management in treating T2DM and prediabetes.
PMCID: PMC2857968  PMID: 19793504
8.  Arteriolar function in visceral adipose tissue is impaired in human obesity 
Objective
The purpose of this study was to characterize the relationship between adipose tissue phenotype and depot-specific microvascular function in fat.
Methods and Results
In 30 obese subjects (age 42±11 yr, BMI 46±11 kg/m2) undergoing bariatric surgery, we intra-operatively collected visceral and subcutaneous adipose tissue and characterized depot-specific adipose phenotypes. We assessed vasomotor function of the adipose microvasculature using videomicroscopy of small arterioles (75–250 μm) isolated from different fat compartments. Endothelium-dependent, acetylcholine-mediated vasodilation was severely impaired in visceral arterioles, compared to the subcutaneous depot (P<0.001 by ANOVA). Non-endothelium dependent responses to papaverine and nitroprusside were similar. Endothelial nitric oxide synthase (eNOS) inhibition with Nω-nitro-L-arginine methyl ester (L-NAME) reduced subcutaneous vasodilation but had no effect on severely blunted visceral arteriolar responses. Visceral fat exhibited greater expression of proinflammatory, oxidative stress-related, hypoxia-induced, and proangiogenic genes; increased activated macrophage populations; and higher capacity for cytokine production ex vivo.
Conclusions
Our findings provide clinical evidence that the visceral microenvironment may be intrinsically toxic to arterial health providing a potential mechanism by which visceral adiposity burden is linked to atherosclerotic vascular disease. Our findings also support the evolving concept that both adipose tissue quality and quantity may play significant roles in shaping cardiovascular phenotypes in human obesity.
doi:10.1161/ATVBAHA.111.235846
PMCID: PMC3262114  PMID: 22095978
adiposity; endothelium; vasodilation; arteries; inflammation
9.  Reduced adipose tissue inflammation represents an intermediate cardiometabolic phenotype in obesity 
Objective
The purpose of this study was to determine whether obese individuals with reduced adipose tissue inflammation exhibit a more favorable cardiovascular risk profile.
Background
Obesity is associated with a low-grade state of chronic inflammation that may be causally related to cardiometabolic disease.
Methods
Using immunohistochemistry, we categorized obese individuals dichotomously as having inflamed fat (n=78) or non-inflamed fat (n=31) based on the presence (+) or absence (-) of macrophage crown-like structures (CLS) in subcutaneous abdominal fat biopsy samples. We compared their metabolic, vascular, and adipose tissue characteristics to lean subjects (n=17).
Results
Inflamed CLS+ obese individuals displayed higher plasma insulin, HOMA, triglycerides, glucose, blood pressure, hs-CRP, LDL-C, and lower HDL-C and brachial artery flow-mediated dilation (FMD) compared to leans (p<0.05). Adipose mRNA expression of inflammatory genes including CD68, leptin, MMP-9, CD163, and CD8A were significantly greater and VEGF lower in the CLS+ group (p<0.05). In contrast, obese subjects with non-inflamed fat exhibited a mixed clinical phenotype with lower insulin resistance, reduced proatherogenic gene expression, and preserved vascular function as in lean subjects. In multiple linear regression adjusting for age and gender, CLS status (beta = -0.28, p=0.008) and waist circumference (beta = -0.25, p =0.03) were independent predictors of FMD.
Conclusion
These findings lend support to the novel concept that factors in addition to absolute weight burden, such as qualitative features of adipose tissue, may be important determinants of cardiovascular disease. Therapeutic modulation of the adipose phenotype may represent a target for treatment in obesity.
doi:10.1016/j.jacc.2011.01.051
PMCID: PMC3132399  PMID: 21737012
obesity; endothelium; inflammation; vasodilation; vasculature
10.  THE ENDOCRINOPATHIES OF ANOREXIA NERVOSA 
Endocrine Practice  2008;14(8):1055-1063.
Objective
To describe the hormonal adaptations and alterations in anorexia nervosa.
Methods
We performed a PubMed search of the English-language literature related to the pathophysiology of the endocrine disorders observed in anorexia nervosa, and we describe a case to illustrate these findings.
Results
Anorexia nervosa is a devastating disease with a variety of endocrine manifestations. The effects of starvation are extensive and negatively affect the pituitary gland, thyroid gland, adrenal glands, gonads, and bones. Appetite is modulated by the neuroendocrine system, and characteristic patterns of leptin and ghrelin concentrations have been observed in anorexia nervosa. A thorough understanding of refeeding syndrome is imperative to nutrition rehabilitation in these patients to avoid devastating consequences. Although most endocrinopathies associated with anorexia nervosa reverse with recovery, short stature, osteoporosis, and infertility may be long-lasting complications. We describe a 20-year-old woman who presented with end-stage anorexia nervosa whose clinical course reflects the numerous complications caused by this disease.
Conclusions
The effects of severe malnutrition and subsequent refeeding are extensive in anorexia nervosa. Nutrition rehabilitation is the most appropriate treatment for these patients; however, it must be done cautiously.
PMCID: PMC3278909  PMID: 19095609
11.  The Relationship of Ectopic Lipid Accumulation to Cardiac and Vascular Function in Obesity and Metabolic Syndrome 
Obesity (Silver Spring, Md.)  2009;18(6):1116-1121.
Storage of lipid in ectopic depots outside of abdominal visceral and subcutaneous stores, including within the pericardium and liver, has been associated with obesity, insulin resistance, and cardiovascular risk. We sought to determine whether anatomically distinct ectopic depots were physiologically correlated and site-specific effects upon cardiovascular function could be identified. Obese subjects (n = 28) with metabolic syndrome but without known atherosclerotic disease and healthy controls (n = 18) underwent magnetic resonance imaging (MRI) and proton MR spectroscopy (MRS) to quantify pericardial and periaortic lipid volumes, cardiac function, aortic compliance, and intrahepatic lipid content. Fasting plasma lipoproteins, glucose, insulin, and free-fatty acids were measured. Pericardial and intrahepatic (P < 0.01) and periaortic (P < 0.05) lipid volumes were increased in obese subjects vs. controls and were strongly and positively correlated (P ≤ 0.01) but independent of BMI (P = NS) among obese subjects. Intrahepatic lipid was associated with insulin resistance (P < 0.01) and triglycerides (P < 0.05), whereas pericardial and periaortic lipid were not (P = NS). Periaortic and pericardial lipid positively correlated to free-fatty acids (P ≤ 0.01) and negatively correlated to high-density lipoprotein (HDL) cholesterol (P < 0.05). Pericardial lipid negatively correlated to cardiac output (P = 0.03) and stroke volume (P = 0.01) but not to left ventricular ejection fraction (P = 0.46). None of the ectopic depots correlated to aortic compliance. In conclusion, ectopic storage of lipid in anatomically distinct depots appeared tightly correlated but independent of body size. Site-specific functional abnormalities were observed for pericardial but not periaortic lipid. These findings underscore the utility of MRI to assess individual differences in ectopic lipid that are not predictable from BMI.
doi:10.1038/oby.2009.363
PMCID: PMC3264050  PMID: 19875992
12.  Inducible Toll-like Receptor and NF-κB Regulatory Pathway Expression in Human Adipose Tissue 
Obesity (Silver Spring, Md.)  2008;16(5):932-937.
Objective
Inflammatory activity in fat tissue has recently been implicated in mechanisms of insulin resistance and obesity-related metabolic dysfunction. Toll-like receptors (TLRs) play a key role in innate immune responses and recent studies implicate the TLR pathway in mechanisms of inflammation and atherosclerosis. The aim of this study was to examine differential TLR expression and function in human adipose tissue.
Methods and Procedures
We biopsied subcutaneous abdominal fat from 16 obese subjects (age 39 ± 11 years, BMI 49 ± 14 kg/m2) and characterized TLR expression using quantitative real-time PCR and confocal immunofluorescence imaging. In tissue culture, we stimulated isolated human adipocytes with Pam3CSK4 and lipopolysaccharide (LPS) (TLR2 and TLR4 agonists, respectively) and quantified TLR activity, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production, and nuclear factor-κB (NF-κB) p65 nuclear activation using real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence.
Results
TLR1, 2, and 4 protein colocalized with adiponectin in human adipocytes with TLR4 exhibiting the highest immunohistochemical expression. Using real-time PCR, we confirmed higher level of gene expression for TLR4 as compared to other members of the TLR family (TLR1, 2, 7, 8) in human adipose depots (P < 0.001). In tissue culture, adipocyte TLR2/TLR4 mRNA expression and protein increased significantly following Pam3CSK4 and LPS (P < 0.001). TLR2/TLR4 stimulation was associated with NF-κB p65 nuclear translocation and proinflammatory cytokine production.
Discussion
The findings demonstrate that TLRs are inducible in adipose tissue and linked with downstream NF-κB activation and cytokine release. Adipose stores may play a dynamic role in the regulation of inflammation and innate immunity in human subjects via modulation of the TLR/NF-κB regulatory pathway.
doi:10.1038/oby.2008.25
PMCID: PMC3264059  PMID: 18292749
13.  Elevated Proinflammatory Cytokine Production by a Skewed T Cell Compartment Requires Monocytes and Promotes Inflammation in Type 2 Diabetes 
An appropriate balance between proinflammatory (Th17 and Th1) and anti-inflammatory (regulatory T cells [Tregs] and Th2) subsets of T cells is critical to maintain homeostasis and avoid inflammatory disease. Type 2 diabetes (T2D) is a chronic inflammatory disease promoted by changes in immune cell function. Recent work indicates T cells are important mediators of inflammation in a mouse model of T2D. These studies identified an elevation in the Th17 and Th1 subsets with a decrease in the Treg subset, which culminates in inflammation and insulin resistance. Based on these data, we tested the hypothesis that T cells in T2D patients are skewed toward proinflammatory subsets. Our data show that blood from T2D patients has increased circulating Th17 cells and elevated activation of Th17 signature genes. Importantly, T cells required culture with monocytes to maintain Th17 signatures, and fresh ex vivo T cells from T2D patients appeared to be poised for IL-17 production. T cells from T2D patients also have increased production of IFN-γ, but produce healthy levels of IL-4. In contrast, T2D patients had decreased percentages of CD4+ Tregs. These data indicate that T cells in T2D patients are naturally skewed toward proinflammatory subsets that likely promote chronic inflammation in T2D through elevated cytokine production. Potential therapies targeted toward resetting this balance need to be approached with caution due to the reciprocal relationship between Th17 cells and Tregs. Understanding the unique aspects of T2D T cells is essential to predict outcomes of such treatments.
doi:10.4049/jimmunol.1002615
PMCID: PMC3089774  PMID: 21169542
14.  Maladaptive enlargement of the brachial artery in severe obesity is reversed with weight loss 
Maladaptive peripheral arterial remodeling, which leads to large arteries with low shear stress, may be associated with increased cardiovascular risk. We tested the hypothesis that arterial enlargement in severe obesity represents maladaptive remodeling and that weight reduction would reverse this process. We evaluated brachial arterial diameter and flow using ultrasound in 244 severely obese patients (age 44 ± 11 years, 80% female, body mass index (BMI) 46 ± 9 kg/m) at baseline and in a group of 67 subjects who experienced weight loss at 1 year. Higher BMI was associated with larger brachial artery diameter (p = 0.01) and lower shear stress (p = 0.008), indicating maladaptive remodeling. Significant (≥ 10%) weight reduction was associated with a decrease in resting arterial diameter (−0.19 ± 0.47 mm, p = 0.02) along with a trend toward increased shear stress. Decreased systemic inflammation was associated with weight loss-induced reverse remodeling of the brachial artery. Our findings demonstrate the presence of maladaptive arterial remodeling in advanced obesity that was ameliorated by significant weight loss.
doi:10.1177/1358863X10362831
PMCID: PMC3077113  PMID: 20375126
inflammation; obesity; remodeling; risk factors; ultrasonography; vascular diseases
15.  Validation of a web-based dietary questionnaire designed for the DASH (Dietary Approaches to Stop Hypertension) diet: the DASH Online Questionnaire 
Public health nutrition  2009;13(5):615-622.
Objective
With the upsurge in online dietary modification programmes, online dietary assessment tools are needed to capture food intake. Although the DASH (Dietary Approaches to Stop Hypertension) diet is recommended by the US Department of Agriculture, there are no online instruments that capture DASH food servings. Our objective was to assess the validity of a new, short, online dietary questionnaire developed to capture intake of DASH food servings. The DASH Online Questionnaire (OLQ) was validated against the well-known Block Food Frequency Questionnaire (FFQ).
Design
This was a cross-sectional validation of the DASH OLQ, which contained eleven food groups (breakfast cereals; dairy; drinks; fats and oils; fruits; grains and snacks; meat, fish and poultry; mixed dishes; sweets; vegetables; and nuts, seeds and legumes). Each subject completed a DASH OLQ once weekly for four weeks and one 98.2 Block FFQ (110 questions) between weeks 2 and 4. DASH OLQ were averaged and then compared with the Block FFQ for nutrient intakes as well as intakes of DASH food groups.
Setting
Boston University Medical Center, Boston, Massachusetts.
Subjects
One hundred and ninety-one faculty and staff at Boston University Medical Center aged 20–70 years.
Results
There were significant positive correlations between the Block FFQ and the DASH OLQ for all food groups ranging from r=0·8 for the nuts/seeds/legumes category to r = 0·3 for vegetables and mixed dishes. A comparison of nutrient intakes found strong positive correlations in all nutrient categories. Of particular interest in the DASH diet and the web-based nutrition and physical activity programme were total fat (r=0·62), total carbohydrate (r=0·67), total K (r=0·68), total Ca (r =0·69), total vitamin C (r=0·60) and total energy intake (r=0·68).
Conclusions
The DASH OLQ captures food and nutrient intake well in relation to the more established Block FFQ.
doi:10.1017/S1368980009991996
PMCID: PMC2859196  PMID: 19912673
Diet; Dietary pattern; Food frequency; Food intake; Energy intake; Dietary assessment; Questionnaire; Validation; Internet; Online; Web-based; DASH diet; Block FFQ
16.  Best Practice Updates for Multidisciplinary Care in Weight Loss Surgery 
Obesity (Silver Spring, Md.)  2009;17(5):871-879.
The objective of this study is to update evidence-based best practice guidelines for multidisciplinary care of weight loss surgery (WLS) patients. We performed systematic search of English-language literature on WLS, patient selection, and medical, multidisciplinary, and nutritional care published between April 2004 and May 2007 in MEDLINE and the Cochrane Library. Key words were used to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence-based models. A total of 150 papers were retrieved from the literature search and 112 were reviewed in detail. We made evidence-based best practice recommendations from the most recent literature on multidisciplinary care of WLS patients. New recommendations were developed in the areas of patient selection, medical evaluation, and treatment. Regular updates of evidence-based recommendations for best practices in multidisciplinary care are required to address changes in patient demographics and levels of obesity. Key factors in patient safety include comprehensive preoperative medical evaluation, patient education, appropriate perioperative care, and long-term follow-up.
doi:10.1038/oby.2008.580
PMCID: PMC2859198  PMID: 19396065
17.  Long-term Successful Weight Loss Improves Vascular Endothelial Function in Severely Obese Individuals 
Obesity (Silver Spring, Md.)  2010;18(4):754-759.
Obesity is associated with increased cardiovascular risk. Although short-term weight loss improves vascular endothelial function, longer term outcomes have not been widely investigated. We examined brachial artery endothelium-dependent vasodilation and metabolic parameters in 29 severely obese subjects who lost ≥10% body weight (age 45 ± 13 years; BMI 48 ± 9 kg/m2) at baseline and after 12 months of dietary and/or surgical intervention. We compared these parameters to 14 obese individuals (age 49 ± 11 years; BMI 39 ± 7 kg/m2) who failed to lose weight. For the entire group, mean brachial artery flow-mediated dilation (FMD) was impaired at 6.7 ± 4.1%. Following sustained weight loss, FMD increased significantly from 6.8 ± 4.2 to 10.0 ± 4.7%, but remained blunted in patients without weight decline from 6.5 ± 4.0 to 5.7 ± 4.1%, P = 0.013 by ANOVA. Endothelium-independent, nitroglycerin-mediated dilation (NMD) was unaltered. BMI fell by 13 ± 7 kg/m2 following successful weight intervention and was associated with reduced total and low-density lipoprotein cholesterol, glucose, hemoglobin A1c, and high-sensitivity C-reactive protein (CRP). Vascular improvement correlated most strongly with glucose levels (r = −0.51, P = 0.002) and was independent of weight change. In this cohort of severely obese subjects, sustained weight loss at 1 year improved vascular function and metabolic parameters. The findings suggest that reversal of endothelial dysfunction and restoration of arterial homeostasis could potentially reduce cardiovascular risk. The results also demonstrate that metabolic changes in association with weight loss are stronger determinants of vascular phenotype than degree of weight reduction.
doi:10.1038/oby.2009.482
PMCID: PMC2857970  PMID: 20057371
18.  Adipose Macrophage Infiltration is Associated with Insulin Resistance and Vascular Endothelial Dysfunction in Obese Subjects 
Objective
Experimental studies suggest that adipose inflammation is etiologically linked to obesity-induced systemic disease. Our goal was to characterize the state of inflammation in human fat in relation to vascular function and metabolic parameters in obese individuals.
Methods and Results
We collected subcutaneous abdominal fat in 77 obese subjects (BMI ≥30 kg/m2) and quantified adipose macrophage population using targeted immunohistochemistry. Brachial artery vasodilator function was examined using high-resolution vascular ultrasound. In 50 subjects, an inflamed adipose phenotype characterized by tissue macrophage accumulation in crown-like structures was associated with systemic hyperinsulinemia and insulin resistance (HOMA-IR 5.5 ± 4.5 vs. 2.6 ± 1.9, p=0.002), and impaired endothelium-dependent, flow-mediated vasodilation (8.5 ± 4.4% vs. 10.8 ± 3.8%, p<0.05), as compared to subjects with quiescent non-inflamed adipose architecture (n=27). Macrophage retention in fat was linked to upregulated tissue CD68 and TNF-α mRNA expression in addition to increased plasma hs-CRP.
Conclusions
In a cohort of obese subjects, we demonstrate that proinflammatory changes in adipose tissue are associated with systemic arterial dysfunction and insulin resistance. These findings suggest that adipose inflammation may be linked to vascular injury and increased cardiovascular risk in obese subjects.
doi:10.1161/ATVBAHA.108.170316
PMCID: PMC2728436  PMID: 18566296
obesity; endothelium; inflammation; insulin; vasculature
19.  Weight, Blood Pressure, and Dietary Benefits After 12 Months of a Web-based Nutrition Education Program (DASH for Health): Longitudinal Observational Study 
Background
The dietary habits of Americans are creating serious health concerns, including obesity, hypertension, diabetes, cardiovascular disease, and even some types of cancer. While considerable attention has been focused on calorie reduction and weight loss, approaches are needed that will not only help the population reduce calorie intake but also consume the type of healthy, well-balanced diet that would prevent this array of medical complications.
Objective
To design an Internet-based nutrition education program and to explore its effect on weight, blood pressure, and eating habits after 12 months of participation.
Methods
We designed the DASH for Health program to provide weekly articles about healthy nutrition via the Internet. Dietary advice was based on the DASH diet (Dietary Approaches to Stop Hypertension). The program was offered as a free benefit to the employees of EMC Corporation, and 2834 employees and spouses enrolled. Enrollees voluntarily entered information about themselves on the website (food intake), and we used these self-entered data to determine if the program had any effect. Analyses were based upon the change in weight, blood pressure, and food intake between the baseline period (before the DASH program began) and the 12th month. To be included in an outcome, a subject had to have provided both a baseline and 12th-month entry.
Results
After 12 months, 735 of 2834 original enrollees (26%) were still actively using the program. For subjects who were overweight/obese (body mass index > 25; n = 151), weight change at 12 months was -4.2 lbs (95% CI: -2.2, -6.2; P < .001). For subjects with hypertension or prehypertension at baseline (n = 62), systolic blood pressure fell 6.8 mmHg at 12 months (CI: -2.6, -11.0; P < .001; n = 62). Diastolic pressure fell 2.1 mmHg (P = .16). Based upon self-entered food surveys, enrollees (n = 181) at 12 months were eating significantly more fruits, more vegetables, and fewer grain products. They also reduced consumption of carbonated beverages. Enrollees who had visited the website more often tended to have greater blood pressure and weight loss effect, suggesting that use of the DASH for Health program was at least partially responsible for the benefits we observed.
Conclusions
We have found that continued use of a nutrition education program delivered totally via the Internet, with no person-to-person contact with health professionals, is associated with significant weight loss, blood pressure lowering, and dietary improvements after 12 months. Effective programs like DASH for Health, delivered via the Internet, can provide benefit to large numbers of subjects at low cost and may help address the nutritional public health crisis.
doi:10.2196/jmir.1114
PMCID: PMC2629362  PMID: 19073541
Weight loss; blood pressure; hypertension; health education; diet; Internet; behavior change
20.  Obesity prevalence from a European perspective: a systematic review 
BMC Public Health  2008;8:200.
Background
Obesity has been recognised as an important contributing factor in the development of various diseases, but comparative data on this condition are limited. We therefore aimed to identify and discuss current epidemiological data on the prevalence of obesity in European countries.
Methods
We identified relevant published studies by means of a MEDLINE search (1990–2008) supplemented by information obtained from regulatory agencies. We only included surveys that used direct measures of weight and height and were representative of each country's overall population.
Results
In Europe, the prevalence of obesity (body mass index ≥ 30 kg/m2) in men ranged from 4.0% to 28.3% and in women from 6.2% to 36.5%. We observed considerable geographic variation, with prevalence rates in Central, Eastern, and Southern Europe being higher than those in Western and Northern Europe.
Conclusion
In Europe, obesity has reached epidemic proportions. The data presented in our review emphasise the need for effective therapeutic and preventive strategies.
doi:10.1186/1471-2458-8-200
PMCID: PMC2441615  PMID: 18533989
21.  Relation of Cumulative Weight Burden to Vascular Endothelial Dysfunction in Obesity 
Although excess fat mass is broadly linked to increased cardiovascular risk, the relation between vascular phenotype and degree of obesity in extreme weight categories is unknown. We examined brachial artery vasomotor responses using ultrasound in 203 consecutive patients mainly afflicted with severe obesity (mean age 44 ± 11 yr; body mass index (BMI) 46 ± 9 kg/m2, range 30–72 kg/m2; and body weight 128 ± 29kg, range 69–207 kg). We studied a unique population with >70% of subjects characterized as morbidly obese (BMI ≥ 40) including a 31% group of super-obese individuals (BMI ≥ 50). Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) were examined as measures of endothelium-dependent and -independent dilation, respectively, in relation to clinical, hemodynamic, and metabolic parameters. Endothelial function was significantly impaired in the highest as compared to lowest tertile of body weight (FMD 6.5 ± 4.6 vs. 9.8 ± 4.8%, p<0.001), whereas NMD was similar in all groups. Univariate correlates of FMD were gender, weight, waist circumference, BMI, diastolic blood pressure, and creatinine. In multivariate analysis, weight was a strong independent significant predictor of FMD (β= −0.23, p=0.005) in addition to gender. Within an overweight population, cumulative weight burden remains strongly linked to progressive arterial dysfunction. In conclusion, these results suggest that cardiovascular risks intensify with escalating obesity, and underscore the importance of therapeutic weight loss interventions in the context of the expanding obesity epidemic.
doi:10.1016/j.amjcard.2007.07.055
PMCID: PMC2199378  PMID: 18157973
endothelium; obesity; vasculature
22.  A Randomized, Phase 3 Trial of Naltrexone SR/Bupropion SR on Weight and Obesity-related Risk Factors (COR-II) 
Obesity (Silver Spring, Md.)  2013;21(5):935-943.
Objective
To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight-related risk factors in overweight and obese participants.
Design and Methods
CONTRAVE Obesity Research-II (COR-II) was a double-blind, placebo-controlled study of 1,496 obese (BMI 30-45 kg/m2) or overweight (27-45 kg/m2 with dyslipidemia and/or hypertension) participants randomized 2:1 to combined naltrexone sustained-release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) or placebo for up to 56 weeks. The co-primary endpoints were percent weight change and proportion achieving ≥5% weight loss at week 28.
Results
Significantly (P < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (−6.5% vs. −1.9%) and week 56 (−6.4% vs. −1.2%). More NB32-treated participants (P < 0.001) experienced ≥5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant-reported weight-related quality of life, and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. NB was not associated with increased events of depression or suicidality versus placebo.
Conclusion
NB represents a novel pharmacological approach to the treatment of obesity, and may become a valuable new therapeutic option.
doi:10.1002/oby.20309
PMCID: PMC3739931  PMID: 23408728
23.  Self-Monitoring of Blood Glucose with Finger Tip Versus Alternative Site Sampling: Effect on Glycemic Control in Insulin-Using Patients with Type 2 Diabetes 
Abstract
Objective
This study compared glycemic control in finger tip versus forearm sampling methods of self-monitoring of blood glucose (SMBG).
Research Design and Methods
One hundred seventy-four insulin-using patients with type 2 diabetes were randomized to SMBG using either finger-tip testing (FT) or forearm alternative site testing (AST) and followed up for 7 months. Hemoglobin A1C (HbA1C) was measured at baseline, month 4, and month 7. The study was designed to test the noninferiority of the AST method for the primary end point of change in HbA1C from baseline to month 7. Adherence with the testing schedule and frequency of hypoglycemic episodes were also measured.
Results
The FT (n = 85) and AST (n = 89) groups each had significant decreases in mean HbA1C from baseline to month 7 (FT, −0.4 ± 1.4%, P = 0.008; AST, −0.3 ± 1.2%, P = 0.045), and noninferiority between groups was demonstrated with a margin of equivalence of 0.5 (P = 0.043). There was no observable difference in HbA1C change between the groups (P = 0.442). Adherence was better in the FT (87%) than the AST (78%) group (P = 0.003), which may have been because of the difficulty some subjects had in obtaining blood samples for AST. The number of hypoglycemic episodes was too small to assess for a difference between groups.
Conclusions
SMBG by the AST, rather than FT, method did not have a detrimental effect on long-term glycemic control in insulin-using patients with type 2 diabetes. Although adherence with testing was expected to be better in the AST group, it was actually better in the FT group.
doi:10.1089/dia.2008.0060
PMCID: PMC3196050  PMID: 19344196

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