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The advent of super‐resolution microscopy allowed for new insights into cellular and physiological processes of normal and diseased cells. In this study, we report for the first time on the super‐resolved DNA structure of buccal cells from patients with Alzheimer's disease (AD) versus age‐ and gender‐matched healthy, non‐caregiver controls. In this super‐resolution study cohort of 74 participants, buccal cells were collected and their spatial DNA organization in the nucleus examined by 3D Structured Illumination Microscopy (3D‐SIM). Quantitation of the super‐resolution DNA structure revealed that the nuclear super‐resolution DNA structure of individuals with AD significantly differs from that of their controls (p

Cells arrested in mitosis by inactivation of the APC/C complex sometimes manage to exit mitosis in a process called mitotic slippage, which helps cancer cells circumvent chemotherapy drugs. Balachandran et al. show that mitotic slippage occurs as a result of targeting of cyclin B1 for degradation by the ligase CRL2ZYG11., The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase is known to target the degradation of cyclin B1, which is crucial for mitotic progression in animal cells. In this study, we show that the ubiquitin ligase CRL2ZYG-11 redundantly targets the degradation of cyclin B1 in Caenorhabditis elegans and human cells. In C. elegans, both CRL2ZYG-11 and APC/C are required for proper progression through meiotic divisions. In human cells, inactivation of CRL2ZYG11A/B has minimal effects on mitotic progression when APC/C is active. However, when APC/C is inactivated or cyclin B1 is overexpressed, CRL2ZYG11A/B-mediated degradation of cyclin B1 is required for normal progression through metaphase. Mitotic cells arrested by the spindle assembly checkpoint, which inactivates APC/C, often exit mitosis in a process termed “mitotic slippage,” which generates tetraploid cells and limits the effectiveness of antimitotic chemotherapy drugs. We show that ZYG11A/B subunit knockdown, or broad cullin–RING ubiquitin ligase inactivation with the small molecule MLN4924, inhibits mitotic slippage in human cells, suggesting the potential for antimitotic combination therapy.

To critically analyze appropriate clinical studies to assess the relationship between health conditions and the frequency of private prayer. Private prayer is defined as individuals praying for themselves.Using PubMed and other search engines, we identified over 300 articles reporting relationships between prayer and health conditions. We identified 41 observational clinical studies that evaluated the relationship between private prayer and health conditions. Prayer scores of 5 to 1 were assigned to studies, with 5 being private prayer for health and 1 being prayer in combination with meditation or Bible study. Frequency scores ranged from 3 to 1 with 3 being twice daily or more and 0 when frequency was not assessed. Studies were ranked from 8 to 1 based on the sum of Prayer and Frequency Scores.Twenty-one studies had Prayer-Frequency scores of 5 to 8, indicating that they evaluated private prayer (praying for one's own health) of suitable frequency in association with health conditions. Nine of 11 studies indicated that private prayer was associated with a significantly lower prevalence of depression (P value,0.01). Optimism as well as coping were significantly improved by prayer in four studies (P value, P 0.01). In 10 studies of mental health conditions-including anxiety and confusion-there was a significant benefit associated with prayer (P 0.01), In the reviewed studies, prayer did not have a significant effect on physical health or blood pressure.The reported observational studies suggest that frequent private prayer is associated with a significant benefit for depression, optimism, coping, and other mental health conditions such as anxiety. Controlled clinical trials are required to critically assess the associations of private prayer and health conditions.

We develop a condition on a closed curve on a surface or in a 3-manifold that implies that the length function associated to the curve on the space of all hyperbolic structures on the surface or in the 3-manifold (respectively) completely determines the curve. Specifically, for an orientable surfaceSof negative Euler characteristic, we extend the known result that simple curves have this property to curves with self-intersection number one (with one exceptional case arising from hyperellipticity that we describe completely). For a large class of hyperbolizable 3-manifolds, we show that curves freely homotopic to simple curves on ∂Mhave this property.

Just as the type and duration of physical activity can have variable effects on the glucose levels and other cardiometabolic parameters among patients with type 2 diabetes mellitus (T2DM), so can the types of foods have variable effects as well. This 12-week randomized study of 51 study participants evaluated the impact of routine consumption of dark raisins versus alternative processed snacks on glucose levels and other cardiovascular risk factors among patients with type T2DM. In this study, compared to alternative processed snacks, those who consumed raisins had a significant 23% reduction in postprandial glucose levels (P = 0.024). Also compared to snacks, those who consumed raisins had a 19% reduction in fasting glucose and 0.12% reduction in hemoglobin A1c, although these latter findings did not achieve statistical significance. Regarding blood pressure, compared to alternative processed snacks, those who consumed raisins had a significant 8.7 mmHg reduction in systolic blood pressure (P = 0.035) (7.5% [P = 0.031]) but did not experience a significant reduction in diastolic blood pressure. Compared to alternative processed snacks, those who consumed raisins did not have a significant improvement in body weight, body mass index, waist circumference, fasting insulin, homeostatic model assessment of insulin resistance, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL), triglyceride, or non-HDL cholesterol levels. Overall, these data support raisins as a healthy alternative compare to processed snacks in patients with T2DM.

This study validates and expands on our previous work that assessed three-dimensional (3D) nuclear telomere profiling in buccal cells of Alzheimer's disease (AD) patients and non-AD controls (Mathur et al., J Alzheimers Dis 39, 35-48, 2014). While the previous study used age- and gender-matched caregiver controls, the current study consented a new cohort of 44 age- and gender-matched healthy non-caregiver controls and 44 AD study participants. 3D telomeric profiles of buccal cells of AD patients and their non-AD controls were examined with participant information blinded to the analysis. In agreement with our previous study, we demonstrate that 3D telomeric profiles allow for the distinction between AD and non-AD individuals. This validation cohort provides an indication that the total number of 3D telomeric signals and their telomere lengths may be a suitable biomarker to differentiate between AD and non-AD and between mild, moderate, and severe AD. Further studies with larger sample sizes are required to move this technology further toward the clinic.

Purpose To evaluate conventional brachytherapy (BT) plans using dose-volume parameters and high resolution (3 Tesla) MRI datasets, and to quantify dosimetric benefits and limitations when MRI-guided, conformal BT (MRIG-CBT) plans are generated. Material and methods Fifty-five clinical high-dose-rate BT plans from 14 cervical cancer patients were retrospectively studied. All conventional plans were created using MRI with titanium tandem-and-ovoid applicator (T&O) for delivery. For each conventional plan, a MRIG-CBT plan was retrospectively generated using hybrid inverse optimization. Three categories of high risk (HR)-CTV were considered based on volume: non-bulky (< 20 cc), low-bulky (> 20 cc and < 40 cc) and bulky (≥ 40 cc). Dose-volume metrics of D90 of HR-CTV and D2cc and D0.1cc of rectum, bladder, and sigmoid colon were analyzed. Results Tumor coverage (HR-CTV D90) of the conventional plans was considerably affected by the HR-CTV size. Sixteen percent of the plans covered HR-CTV D90 with the prescription dose within 5%. At least one OAR had D2cc values over the GEC-ESTRO recommended limits in 52.7% of the conventional plans. MRIG-CBT plans showed improved target coverage for HR-CTV D90 of 98 and 97% of the prescribed dose for non-bulky and low-bulky tumors, respectively. No MRIG-CBT plans surpassed the D2cc limits of any OAR. Only small improvements (D90 of 80%) were found for large targets (> 40 cc) when using T&O applicator approach. Conclusions MRIG-CBT plans displayed considerable improvement for tumor coverage and OAR sparing over conventional treatment. When the HR-CTV volume exceeded 40 cc, its improvements were diminished when using a conventional intracavitary applicator.

Raisins are widely recommended as good foods and preferred snacks because of their nutrient content. They are rich in dietary fiber, potassium, and many health-promoting phytonutrients and antioxidants. Raisins have a high dietary fiber score. Laboratory studies document that raisins rank in the upper quartile of foods for antioxidant content. Clinical research related to the potential health benefits of raisins has intensified over the past 10 y. Much of this research has focused on blood glucose and insulin responses to raisins compared to other foods or snacks. Meal studies indicate that raisins have a low to moderate glycemic index and a low insulinemic index. Longer term studies suggest that customary intake of raisins is associated with lower postprandial blood glucose values than with equicaloric control foods. Cross-sectional studies suggest that higher levels of dried fruit consumption are associated with lower systolic and diastolic blood pressure than seen with minimal dried fruit use. One clinical study documents that raisin intake over 12 wk is accompanied by a significant reduction in blood pressure. Preliminary results indicate that raisins are associated with increased satiety and decreased food consumption over an 8-h period, but the potential benefits of raisins for weight loss have not been assessed. Raisin intake is accompanied by reductions in serum low-density lipoprotein cholesterol, triglycerides, and oxidized low-density cholesterol values. Thus, raisins have the potential to significantly reduce the risk for developing diabetes or cardiovascular disease.

Aims: Cognitive decline disproportionately affects older adult type 2 diabetes. We tested whether randomized intensive glucose-lowering reduces the rate(s) of cognitive decline in adults with advanced type 2 diabetes (mean: age, 60 years; diabetes duration, 11 years) from the Veterans Affairs Diabetes Trial. Methods: A battery of neuropsychological tests (digit span, digit symbol substitution (DSym), and Trails-making Part B (TMT-B)) was administered at baseline in ~1700 participants and repeated at year 5. Thirty-six risk factors were evaluated as predictors of cognitive decline in multivariable regression analyses.Results: The mean age-adjusted, DSym or TMT-B declined significantly in all study participants (P < 0.001). Randomized intensive glucose-lowering did not significantly alter the rate of cognitive decline. The final model of risk factors associated with 5-year decline in age-adjusted TMT-B included as significant predictors: longer baseline diabetes duration (beta = -0.028; P = 0.0057), lower baseline diastolic blood pressure (beta = 0.028; P < 0.001), and baseline calcium channel blocker medication use (beta = -0.639; P < 0.001). Higher baseline pulse pressure was significantly associated with decline in age-adjusted TMT-B suggesting a role for both higher systolic and lower diastolic blood pressure. Baseline thiazide diuretic use (beta= -0.549; P =0.015) was an additional significant predictor of 5-year decline in age-adjusted digit symbol score. Post-baseline systolic blood pressure-lowering was significantly associated (P < 0.001) with decline in TMT-B performance. There was a significant inverse association between post-baseline plasma triglyceride- lowering (P = 0.045) and decline in digit symbol substitution task performance.Conclusions: A five-year period of randomized intensive glucose-lowering did not significantly reduce the rate of cognitive decline in older-aged adults with type 2 diabetes. Systolic and diastolic blood pressure as well as plasma triglycerides were modifiable risk factors of the rate of cognitive decline in older adult type 2 diabetes.

Health professionals are in need of more information about the weight-loss outcomes of using commercial weight-loss programs.A commercial behavioral intervention program using meal replacements, fruits, and vegetables (MR-FV) was compared with usual-care weight-loss counseling.Obese volunteers were randomly allocated to usual-care weight-loss counseling or participation in an MR-FV standardized behavioral education program. The MR-FV group attended weekly weight-loss classes for 16 weeks and weekly maintenance classes for 8 weeks.Obese women or men aged 20 to 65 years were recruited from the community through a commercial program provided at a university medical center.The control group (C group) received weight-management counseling from an experienced dietitian, while the intervention group (MR-FV group) participated in scheduled behavioral weight-loss classes. The MR-FV group participants were encouraged to consume 3 shakes, 2 entrées, and 5 servings of fruits or vegetables daily, and achieve physical activity goals (expend ≥ 8.4 mJ/week); they kept records and placed midweek phone calls. The C group was counseled at baseline, 8 weeks, and 16 weeks.Both groups were seen at baseline, and 8, 16, and 24 weeks for assessment of weight, risk factors, and side effects.The primary data analysis was intention to treat.Thirteen of 16 subjects (81.3%) in the C group and 18 of 22 subjects (81.8%) in the MR-FV group completed the 24-week study. Mean weight losses for the C group were: 1.3% (standard error [SE], 0.9) at 8 weeks; 0.7% (SE, 1.1) at 16 weeks; and 0.7% (SE, 1.1) or 0.7 kg at 24 weeks. Mean weight losses for the MR-FV group were: 8.5% (SE, 0.6) at 8 weeks, 12.5% (SE, 0.9) at 16 weeks, and 13.9% (SE, 1.1) or 13.7 kg at 24 weeks.A behavioral intervention with a low-energy diet including 5 meal replacements and 5 servings of fruits or vegetables enabled obese individuals to lose 13 kg more than control subjects over a 24-week period.

Many randomized controlled trials (RCTs) have assessed the effects of soy protein on serum lipoprotein risk factors for coronary heart disease (CHD). This review and meta-analysis assessed the quality of these RCTs and estimated the effects of soy protein consumption on serum lipoproteins.A comprehensive search using multiple databases was conducted for the years 1996 through 2008 to identify clinical trials related to soy protein intake and serum lipoprotein changes.RCTs were assessed that met these requirements: soy protein intake compared with nonsoy protein, provided information on serum low-density lipoprotein (LDL)-cholesterol values, provided no more than 65 g of soy protein daily, and obtained LDL-cholesterol measurements between 4 and 18 weeks of treatment. Randomized parallel and crossover studies were evaluated.Studies were graded for quality using 12 criteria with a possible maximum grade of 24. Net changes in lipoproteins with soy protein consumption compared with nonsoy control diets were analyzed by meta-analyses and funnel plots. Confidence intervals were constructed using inverse weighting. Analyses compared parallel to crossover studies and studies with lower and higher grades.Analyses included 20 parallel-design studies and 23 crossover studies. Parallel studies scored significantly higher (p0.001) in study quality, with a mean grade of 15.8 (95% confidence interval [CI], 14.3 to 17.3) compared with 10.1 (95% CI, 8.2 to 11.9) for crossover trials. Soy protein intake was associated with net changes in serum LDL-cholesterol values of -0.23 mmol/l (95% CI, -0.28 to -0.18 mmol/l) or a 5.5% reduction in parallel studies and -0.16 mmol/l (95% CI, -0.22 to -0.11 mmol/l) or a reduction of 4.2% with crossover studies (p0.001 for parallel vs crossover). In parallel studies, net serum HDL-cholesterol values were 3.2% higher (p0.007) with soy vs control, and fasting serum triacylglycerol values were 10.7% lower (p0.008) for soy vs control.Soy protein consumption with a median of 30 g/d was associated with a significant improvement in lipoprotein risk factors for CHD. Compared with crossover RCTs, parallel RCTs had significantly higher quality grades and were associated with significantly greater improvements in serum LDL-cholesterol values. Regular consumption of 1 to 2 servings of soy protein daily (15 to 30 g) has a significant favorable impact on serum lipoprotein risk factors for CHD.

Context: Ghrelin and peptide YY (PYY) are two hormones produced by the gastrointestinal tract that have effects on appetite. However, little is known about their secretion in response to meals high in individual macronutrients in prepubertal children. Objective: We sought to understand how meals high in carbohydrate, protein, and fat affect serum concentrations of total ghrelin and total PYY, hypothesizing that these macronutrients would exert differential effects on their secretion. Design and Setting: This was a cross-sectional study at one tertiary care center. Subjects: Subjects were 7- to 11-yr-old healthy normal-weight (NW) and obese (OB) volunteers recruited from local advertisements. Interventions: After an overnight fast, the subjects were given a breakfast high in carbohydrate, protein, or fat at 0800 h. Blood samples for total ghrelin and total PYY were taken at baseline, 30 min, and hourly from 0900 to 1200 h. Main Outcome Measure: We assessed postprandial ghrelin suppression and PYY elevation, as well as changes in reported hunger and satiety, after the three test meals. Results: After the high-protein meal, ghrelin declined gradually in both groups over the study period without subsequent increase, whereas ghrelin suppressed more rapidly to a nadir at 60 min after the high-carbohydrate meal in both NW and OB children, followed by rebound in ghrelin levels. Similarly, after the high-protein meal, PYY concentrations increased steadily over the course of the morning in both groups without decline, whereas PYY levels peaked 30 min after the high-carbohydrate meal in both NW and OB subjects with significant decline thereafter. Ghrelin and PYY responses to the high-fat meal were somewhat intermediate between that observed with high carbohydrate and high protein. The OB children reported higher hunger and lower satiety after the high-carbohydrate meal compared to the NW subjects, whereas appetite ratings were similar between the groups after the high-protein and high-fat meals. Additionally, within the OB group, area under the curve (AUC) analysis revealed significantly greater PYY response, as well as lower AUC hunger and higher AUC satiety, to the high-protein meal than the high-carbohydrate and high-fat meals. Conclusions: The patterns of secretion of ghrelin and PYY in our study of prepubertal children suggest that they may play a role in the effectiveness of high-protein/low-carbohydrate diets in promoting weight loss.

Accurate information about weight loss is not available for most commercial weight-loss programs. Our objective was to obtain accurate assessments of weight outcomes, behavioral data, and side effects for an intensive behavioral weight-loss program using low-energy diets. Weights, behavioral data, and side effects for 173 consecutive patients were assessed. Treatment options were Medically Supervised, using a minimum of five meal replacements per day, and Healthy Solutions, using meal replacements, fruits, and vegetables. Both options included weekly classes, daily records, midweek phone calls, and a minimum physical activity goal of 2,000 kcal/week. The primary outcome was change in body weight with secondary outcomes related to behavioral changes and side effects. Intention-to-treat (ITT) and completer analyses (completed 9 weeks of treatment) were performed. During 13 months, 173 patients met criteria for analysis. They selected either Healthy Solutions: 56 patients (ITT) and 37 completers; or Medically Supervised: 117 patients (ITT) and 93 completers. Mean (+/-standard error) weight losses were: Healthy Solutions: ITT=12.8+/-1.3 kg in 13 weeks and completers=17.0+/-1.4 kg in 18 weeks; Medically Supervised: ITT=16.6+/-1.0 kg in 16 weeks and completers=19.7+/-1.0 kg in 19 weeks. Mean use of meal replacements, fruits, and vegetables exceeded goals. Most side effects were mild and did not affect program continuation. An intensive behavioral weight-loss program using low-energy diets, including five meal replacements daily, is safe and effective.

Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro-opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo-controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of β-endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.

Background Prior clinical trials suggest that the Transcendental Meditation technique may decrease blood pressure of normotensive and hypertensive individuals but study-quality issues have been raised. This study was designed to assess effects of Transcendental Meditation on blood pressure using objective quality assessments and meta-analyses. Methods PubMed and Cochrane databases through December 2006 and collected publications on Transcendental Meditation were searched. Randomized, controlled trials comparing blood pressure responses to the Transcendental Meditation technique with a control group were evaluated. Primary outcome measures were changes in systolic and diastolic blood pressure after practicing Transcendental Meditation or following control procedures. A specific rating system (0-20 points) was used to evaluate studies and random-effects models were used for meta-analyses. Results Nine randomized, controlled trials met eligibility criteria. Study-quality scores ranged from low (score, 7) to high (16) with three studies of high quality (15 or 16) and three of acceptable quality (11 or 12). The random-effects meta-analysis model for systolic and diastolic blood pressure, respectively, indicated that Transcendental Meditation, compared to control, was associated with the following changes: -4.7 mm Hg (95% confidence interval (CI), -7.4 to -1.9 mm Hg) and -3.2 mm Hg (95% CI, -5.4 to -1.3 mm Hg). Subgroup analyses of hypertensive groups and high-quality studies showed similar reductions. Conclusions The regular practice of Transcendental Meditation may have the potential to reduce systolic and diastolic blood pressure by approximately 4.7 and 3.2 mm Hg, respectively. These are clinically meaningful changes.

Ten years have passed since the Food and Drug Administration (FDA) completed their review of the literature pertaining to the consumption of whole-oat sources of soluble fiber and a reduction in blood cholesterol concentrations. Since that time, data have continued to accumulate regarding oat-soluble fiber consumption, cholesterol, and other physiologic vectors related to cardiovascular health. The objective of this review was to compare the findings of more contemporary analyses of the oat and cholesterol-reduction literature to determine if newer information is consistent with the original conclusion reached by the FDA. A number of formal assessments have been conducted subsequent to the FDA review, and virtually all have reached the same conclusion, namely, consumption of oats and oat-based products significantly reduces total cholesterol and low-density lipoprotein cholesterol concentrations without adverse effects on high-density lipoprotein cholesterol or triglyceride concentrations. In addition, a number of new insights about the potential benefits of oats have emerged over the past 10 years. These more recent data indicate that including oats and oat-based products as part of a lifestyle management program may confer health benefits that extend beyond total cholesterol and low-density lipoprotein cholesterol reduction.

Orlistat, in the 60-mg over-the-counter dose, was recently approved by the FDA. This lipase inhibitor blocks absorption of ~25% of ingested fat and has ~85% of the efficacy of the 120-mg dose for weight loss. Over 16 weeks weight loss with diet and orlistat 60 mg averages ~5% of initial body weight. The 60-mg dose is better tolerated than the 120-mg dose and the gastrointestinal side effects are minimal when individuals consume < 30% of their energy from fat. In addition to facilitating modest weight loss, orlistat use decreases serum LDL-cholesterol values by ~10%. When taken three times daily before meals, orlistat 60 mg modifies lifestyle behavior, encourages lower fat-consumption and sets the stage for other healthy lifestyle changes.

Improved nutritional habits are a major target in the treatment of dyslipidemias and atherosclerosis prevention. A number of newer approaches have been developed in the last few years, leading to a better knowledge of nutrients as well as of novel functional foods, supplements or nutraceuticals, which may provide an alternative to lipid-lowering drugs. Functional foods are fortified or enriched products with potential health benefits, whereas nutraceuticals can be defined as diet supplements that deliver a presumed bioactive food component in a nonfood matrix. Specific areas of current interest are those of dietary proteins with specific effects on cholesterolemia, also leading to the identification of absorbable peptides and changes in fat intake, resulting in a larger consumption of monounsaturated fatty acids. Both approaches represent an improvement compared with the classical method based on a low-lipid intake. Relevant nutraceuticals include plant sterols/stanols for cholesterol reduction and polyph...

James W Anderson University of Kentucky, Endocrine Division, Department of Internal Medicine, Room 524, Medical Science Building, College of Medicine, Lexington, KY 50536-0298, USA Tel.: +1 859 323 5822; Fax: +1 859 323 5707; jwandersmd@aol.com ‘...as no ‘blockbuster’ antiobesity drugs have appeared on the horizon, combinations of pharmaceutical agents, orlistat and lifestyle changes are likely to be recommended.’

We quantify the generation of free subgroups of surface mapping class groups by pseudo-Anosov mapping classes in terms of their translation distance and the distance between their axes in Teichmüller’s metric. The method makes reference to Teichmüller space only.

Recent studies suggest that obese individuals lose weight more rapidly and lose more total weight with soy protein than with animal protein as a major diet component. The purpose of the present study was to evaluate the weight-loss efficacy and changes in body composition, waist circumference, blood pressure, and levels of plasma glucose, insulin, serum lipids, C-reactive protein, and homocysteine from consumption of either 3 soy shakes or 3 casein shakes daily as part of a 16-week, energy-restricted diet for obese women. Forty-three women with body mass index values of 30 to 40 kg/m(2) were randomized to intensive dietary interventions using either casein (n = 21) or soy (n = 22) shakes. Subjects were instructed to consume 3 shakes, 1 prepackaged entrée, and 5 servings of fruits or vegetables daily to achieve an energy intake of 4.5 to 5.0 MJ/d. Subjects attended classes weekly or biweekly. Weight, body fat, lipid, and glucose measurements were obtained at baseline and at 8 and 16 weeks. For both groups combined, subjects lost 8.1% of initial body weight (7.7 kg) at 8 weeks and 13.4% (12.7 kg) at 16 weeks. Weight loss from baseline did not differ significantly by group and, for completing subjects, was 14.0% +/- 1.2% (mean +/- SE) for casein and 12.8% +/- 1.4% for soy. With the intention-to-treat analysis, weight losses at 16 weeks were 12.5% +/- 1.4% for casein and 11.3% +/- 1.2% for soy. Body fat losses were 23.7% +/- 2.0% for casein and 21.8% +/- 2.4% for soy and did not differ significantly. Both study groups lost significant amounts of weight with a highly structured behavioral program incorporating 4 meal replacements and vegetables and fruits. Differences in weight loss and body composition changes between casein and soy treatments were not significant.

Background: Lifestyle measures are considered the first line of therapy for treating overweight individuals, but many are unable to achieve a meaningful weight loss. Objective: To determine the efficacy and safety of orlistat 60 mg, given 3 times daily, for weight loss in mildly to moderately overweight individuals. Methods: A multicenter, 16 week, randomized, double-blind, placebo-controlled study was conducted in 391 overweight subjects at 20 US centers. The main outcome measure was change in weight from baseline to week 16; secondary measures included changes in body mass index, waist circumference, blood pressure, and fasting lipoprotein and glucose levels. Results: Subjects in both groups lost weight over the treatment period; however, orlistat-treated subjects lost significantly more weight than placebo-treated subjects beyond 2 weeks of treatment. Weight loss from baseline to week 16 was significantly greater in participants receiving orlistat versus those receiving placebo (3.05 vs 1.90 kg; p < 0.001, intent-to-treat analysis). Orlistat-treated subjects who completed 16 weeks of treatment lost 4.8 ± 0.35% (mean ± SE) of baseline weight compared with 3.1 ± 0.38% for the placebo group (p < 0.001). Orlistat-treated subjects, compared with those receiving placebo, also demonstrated a greater relative reduction in total (–4.4% vs 0.0%; p = 0.004) and low-density lipoprotein cholesterol (–7.2% vs -0.6%; p = 0.005) and both diastolic (-3.9% vs -0.5%; p = 0.001) and systolic blood pressure (-4.7% vs -1.8%; p = 0.004). Both groups showed a similar safety profile; gastrointestinal events were significantly more common in the orlistat-treated subjects. Conclusions: The use of orlistat 60 mg by mildly to moderately overweight individuals produced significant weight loss in conjunction with a reduced calorie diet and self-instructional materials. This amount of weight loss was associated with improvements in several weight-related risk factors. Orlistat 60 mg may be a useful adjunct to lifestyle measures and has the potential to contribute significantly to weight and risk factor improvement for overweight individuals.

Soy protein intake has favorable effects on body weight and fat distribution in experimental animals but these effects have not been demonstrated in humans. To compare effects of soy- vs. milk-based meal replacements (MR) we assessed weight loss and serum lipoproteins changes for obese subjects who consumed low-energy diets (LED) including either milk-based or soy-based MR.Overweight or obese women and men (body mass indices 27-40 kg/m(2)) were randomly assigned to LED providing 1200 kcal/day, with consumption of five soy-based or two milk-based liquid MR for a 12-week weight loss trial. Serum lipoprotein measurements were obtained at baseline, 6 and 12 weeks.For soy and milk MR groups, subject numbers were, respectively, 51 and 39 randomized and 30 and 22 completers. MR use averaged: soy, 3.7/day; and milk, 1.9/day. Weight losses for completers at 12 weeks were: soy MR, 9.0% of initial body weight (95% confidence intervals, 7.3-10.6%); and milk MR, 7.9% (5.8-8.8%) with no significant differences. Reductions from baseline in serum cholesterol and LDL-cholesterol values, respectively, at six weeks were significantly greater (P0.015) with soy MR (15.2% and 17.4%) than with milk MR (7.9% and 7.7%). Soy MR use was associated with significant reductions in serum triglycerides at 6 and 12 weeks while milk MR use was not.Soy MR use, as part of a low-energy diet, was associated with slightly but not significantly greater weight loss over a 12-week period than milk MR use. These observations confirm previous studies documenting the effectiveness of MR use for weight loss.

To review international nutrition recommendations with a special emphasis on carbohydrate and fiber, analyze clinical trial information, and provide an evidence-based recommendation for medical nutrition therapy for individuals with diabetes. Relevant articles were identified by a thorough review of the literature and the data tabulated. Fixed-effects meta-analyses techniques were used to obtain mean estimates of changes in outcome measures in response to diet interventions. Most international organizations recommend that diabetic individuals achieve and maintain a desirable body weight with a body mass index of/=25 kg/m(2). For diabetic subjects moderate carbohydrate, high fiber diets compared to moderate carbohydrate, low fiber diets are associated with significantly lower values for: postprandial plasma glucose, total and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. High carbohydrate, high fiber diets compared to moderate carbohydrate, low fiber diets are associated with lower values for: fasting, postprandial and average plasma glucose; hemoglobin A(1c); total, LDL-cholesterol, HDL-cholesterol and triglycerides. Low glycemic index diets compared to high glycemic index diets are associated with lower fasting plasma glucose values and lower glycated protein values. Based on these analyses we recommend that the diabetic individual should be encouraged to achieve and maintain a desirable body weight and that the diet should provide these percentages of nutrients: carbohydrate,/=55%; protein, 12-16%; fat,30%; and monounsaturated fat, 12-15%. The diet should provide 25-50 g/day of dietary fiber (15-25 g/1000 kcal). Glycemic index information should be incorporated into exchanges and teaching material.

Obesity is a major risk factor for development of diabetes, and excessive energy intake is a major contributor to poor glycemic control in Type 2 diabetes. The impact of obesity on risk for diabetes as well as coronary heart disease (CHD) risk factors and the benefits of weight loss in decreasing risk for developing diabetes and improving glycemia and CHD risks were reviewed. A systematic review of the medical literature to assess the impact of obesity and weight gain on risk for diabetes and CHD was done. We performed a meta-analysis of the effects of weight loss for obese diabetic individuals. Controlled clinical trials assessing lifestyle changes on risk for developing diabetes and weight loss effects on glycemia and CHD risk factors were reviewed. Obesity and weight gain can increase risk for diabetes by greater than ninetyfold and CHD by about sixfold. Very-low-energy diets (VLED) decrease fasting plasma glucose values by approximately 50% within two weeks and these changes are sustained with continued energy restriction. Twelve weeks of energy-restricted diets were associated with these significant decreases: body weight, 9.6%; fasting plasma glucose, 25.7%; serum cholesterol, 9.2%; serum triglycerides, 26.7%; systolic blood pressure, 8.1%; and diastolic blood pressure, 8.6%. Larger weight losses were associated with larger reductions in these values. The reviewed data suggest that US health care providers should endorse the American Heart Association's and European diabetes associations' recommendations that diabetic persons achieve and maintain a BMI of

Based on what is known of the components of plant-based diets and their effects from cohort studies, there is reason to believe that vegetarian diets would have advantages in the treatment of type 2 diabetes. At present there are few data on vegetarian diets in diabetes that do not in addition have weight loss or exercise components. Nevertheless, the use of whole-grain or traditionally processed cereals and legumes has been associated with improved glycemic control in both diabetic and insulin-resistant individuals. Long-term cohort studies have indicated that whole-grain consumption reduces the risk of both type 2 diabetes and cardiovascular disease. In addition, nuts (eg, almonds), viscous fibers (eg, fibers from oats and barley), soy proteins, and plant sterols, which may be part of the vegetarian diet, reduce serum lipids. In combination, these plant food components may have a very significant impact on cardiovascular disease, one of the major complications of diabetes. Furthermore, substituting soy or other vegetable proteins for animal protein may also decrease renal hyperfiltration, proteinuria, and renal acid load and in the long term reduce the risk of developing renal disease in type 2 diabetes. The vegetarian diet, therefore, contains a portfolio of natural products and food forms of benefit for both the carbohydrate and lipid abnormalities in diabetes. It is anticipated that their combined use in vegetarian diets will produce very significant metabolic advantages for the prevention and treatment of diabetes and its complications.

OBJECTIVE—To assess the effect of insulin resistance and the benefit of the fibrate, gemfibrozil, on the incidence of major cardiovascular events in subjects with low HDL cholesterol and a broad range of triglyceride values who participated in the Veterans Affairs High Density Lipoprotein Intervention Trial (VA-HIT). RESEARCH DESIGN AND METHODS—This intention-to-treat analysis, specified as a secondary objective in VA-HIT, determined using Cox proportional hazards models the 5-year combined incidence of nonfatal myocardial infarction, coronary heart disease (CHD) death, or stroke in relation to the presence or absence of insulin resistance (defined by the highest tertile of the homeostasis model assessment of insulin resistance, HOMA-IR) in conjunction with lower and higher levels of HDL cholesterol and triglycerides. The study population consisted of 2,283 men with known coronary heart disease (CHD), treated with either placebo or gemfibrozil, who could be subdivided into groups with diabetes with or without insulin resistance, with no diabetes but insulin resistance, and with neither diabetes nor insulin resistance. RESULTS—With insulin resistance there was a significantly higher relative risk (RR) of a cardiovascular event both with diabetes (RR of 1.62 with 95% CI of 1.28–2.06) and without diabetes (RR of 1.43 with 95% CI of 1.03–1.98) than without insulin resistance. Throughout both lower and higher ranges of HDL cholesterol and triglycerides, the rate of new cardiovascular events and the reduction of events with gemfibrozil was greater in subjects with insulin resistance than without, despite the finding that an increase in HDL cholesterol and a decrease in triglycerides with gemfibrozil was less with insulin resistance than without insulin resistance. CONCLUSIONS—Results show that in VA-HIT the occurrence of a new cardiovascular event and the benefit of fibrate therapy was much less dependent on levels of HDL cholesterol or triglycerides than on the presence or absence of insulin resistance.

Aims: To evaluate the efficacy of a lifestyle intervention programme including meal replacements and increased physical activity upon body weight, diabetes control and other cardiovascular risk factors in obese, poorly controlled, insulin-treated, type-2-diabetic individuals and to assess the impact of concomitant rosiglitazone (RSG) therapy. Methods: This 6-month intervention study included 21 patients with type 2 diabetes mellitus (DM) requiring insulin therapy with haemoglobin A1c (HbA1c) > 7% and with a body mass index (b.m.i.) > 27. All subjects were enrolled in a 6-month lifestyle intervention programme and randomized to placebo or RSG 4 mg/day. Participation in the lifestyle programme included meal replacements, increased intake of fruits and vegetables and increased daily physical activity. Measured end-points included body weight, waist circumference, blood pressure, HbA1c and serum lipids, before entry into the study. Results: The baseline mean b.m.i. was 36.4 and the mean HbA1c was 9.0%. The greatest weight losses occurred during the first 12 weeks (19 lbs for RSG, 13.4 lbs for placebo) with a greater weight loss at each point for the group receiving RSG. Waist circumference declined by 2.8 and 4.0 inches for the placebo and RSG groups. Systolic BP declined 16.2 mmHg in the placebo group and 14.3 mmHg in the RSG group. Diastolic blood pressure decreased by 12.8 mmHg in the placebo group. HbA1c was reduced significantly by 1.3% for the placebo group and 1.1% in the RSG group. Discussion: This study demonstrates the benefits of lifestyle intervention using meal replacements and increased physical activity with resultant modest weight loss in long-standing, poorly controlled type 2 diabetes. RSG did not impede weight loss and, in fact, amplified some of the positive benefits of lifestyle intervention.

OBJECTIVE—The purpose of this study was to assess the effect of orlistat, a gastrointestinal lipase inhibitor, on body weight, glycemic control, and cardiovascular risk factors in metformin-treated type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A 1-year multicenter, randomized, double-blind, placebo-controlled trial of 120 mg orlistat t.i.d. (n = 249) or placebo (n = 254) combined with a reduced-calorie diet was conducted in overweight and obese patients with suboptimal control of type 2 diabetes. RESULTS—After 1 year of treatment, mean (±SE) weight loss was greater in the orlistat than in the placebo group (−4.6 ± 0.3% vs. −1.7 ± 0.3% of baseline wt, P < 0.001). Orlistat treatment caused a greater improvement in glycemic control than placebo, as evidenced by a greater reduction in serum HbA1c, adjusted for changes in metformin and sulfonylurea therapy (−0.90 ± 0.08 vs. −0.61 ± 0.08, P = 0.014); a greater proportion of patients achieving decreases in HbA1c of ≥0.5 and ≥1.0% (both P < 0.01); and a greater reduction in fasting serum glucose (−2.0 ± 0.2 vs. −0.7 ± 0.2 mmol/l, P = 0.001). Compared with the placebo group, patients treated with orlistat also had greater decreases in total cholesterol, LDL cholesterol, and systolic blood pressure (all P < 0.05). Although more subjects treated with orlistat experienced gastrointestinal side effects than placebo (83 vs. 62%, P < 0.05), more subjects in the placebo group withdrew prematurely from the study than in the orlistat group (44 vs. 35%, P < 0.05). CONCLUSIONS—Orlistat is a useful adjunctive treatment for producing weight loss and improving glycemic control, serum lipid levels, and blood pressure in obese patients with type 2 diabetes who are being treated with metformin.

The subfornical organ (SFO) has been repeatedly identified as a CNS site that plays a critical role in sensing multiple physiological variables of the ‘milieu interieur’ and, through efferent projections to other CNS sites, initiating physiological responses to change. Many recent in vitro patch-clamp studies have examined the cellular mechanisms underlying the sensory abilities of these specialized CNS neurons. The primary limitation of these studies, however, has been the inability to identify homogeneous groups of SFO neurons for such investigation. We report here the development of techniques to permit patch clamp recording from dissociated SFO neurons identified according to their in vivo projection site. SFO neurons were labeled by injection of fluorescently labeled, retrogradely transported microspheres into the hypothalamic paraventricular nucleus (PVN) 3 days prior to cell dissociation. Patch-clamp recordings from these SFO-PVN neurons revealed both sodium currents, potassium currents, action potentials, input resistance and membrane potential which were all similar to SFO cells prepared from animals with no prior tracer injection. Labeled SFO→PVN cells were also found to be osmosensitive and responsive to angiotensin II, suggesting specific functional roles for this anatomically defined group of SFO neurons. Intriguingly, our post hoc analysis also demonstrated that all labeled neurons demonstrated a unique electrophysiological profile dominated by a large transient potassium conductance such that the transient/sustained potassium current ratio, or degree of inactivation was, on average, greater than 4.0. Utilization of these tracing techniques to permit the in vitro recording from cells with known in vivo connections will permit study of intrinsic mechanisms that underlie physiological responses of anatomically defined populations of neurons.

ANDERSON, JAMES W. AND ELIZABETH C. KONZ. Obesity and disease management: effects of weight loss on comorbid conditions. Obes Res. 2001;9:326S‐334S. Objective: This review is designed to quantitate the effects of obesity and weight gain on risk for coronary heart disease (CHD) and to review the effects of weight loss on CHD risk factors. Research Methods and Procedures: After a comprehensive review of the literature related to body weight and weight gain on CHD risk, the relative risks (RRs) were tabulated. Values were averaged and meta-analysis techniques were used to estimate the variance-adjusted RR. Results: Young persons with higher body mass index values have a significantly higher risk for CHD than do slender young people. For every 1% above a desirable body mass index, the risk for CHD increases by 3.3% for women and by 3.6% for men. Every kilogram of weight gain after high school increases risk for CHD by 5.7% for women and 3.1% for men. Weight loss significantly decreases major CHD risk factors. For every kilogram of weight loss the following favorable changes occur: fasting serum cholesterol, 21.0%; low-density lipoprotein cholesterol, 20.7%; triglycerides, 21.9%; high-density lipoprotein cholesterol, 10.2%; systolic blood pressure, 20.5%; diastolic blood pressure, 20.4%; and blood glucose, 20.2 mM. Discussion: Obesity and/or weight gain are associated with major risk for CHD. Weight loss significantly improves serum lipid parameters, blood pressure, and fasting blood glucose values. Effective treatment approaches are available for most overweight or obese individuals but a major challenge is to enable these individuals to engage in these programs. Professional and consumer education is essential for advancing effective intervention strategies for overweight individuals.

BACKGROUND Current perception is that participants of a structured weight-loss program regain all of their weight loss within 5 y. OBJECTIVE The objective was to examine the long-term weight-loss maintenance of individuals completing a structured weight-loss program. DESIGN Studies were required to 1) have been conducted in the United States, 2) have included participants in a structured weight-loss program, 3) have provided follow-up data with variance estimates for > or =2 y. Primary outcome variables were weight-loss maintenance in kilograms, weight-loss maintenance as a percentage of initial weight loss, and weight loss as a percentage of initial body weight (reduced weight). RESULTS Twenty-nine studies met the inclusion criteria. Successful very-low-energy diets (VLEDs) were associated with significantly greater weight-loss maintenance than were successful hypoenergetic balanced diets (HBDs) at all years of follow-up. The percentage of individuals at 4 or 5 y of follow-up for VLEDs and HBDs were 55.4% and 79.7%, respectively. The results for VLEDs and HBDs, respectively, were as follows: weight-loss maintenance, 7.1 kg (95% CI: 6.1, 8.1 kg) and 2.0 (1.5, 2.5) kg; percentage weight-loss maintenance, 29% (25%, 33%) and 17% (13%, 22%); and reduced weight, 6.6% (5.7%, 7.5%) and 2.1% (1.6%, 2.7%). Weight-loss maintenance did not differ significantly between women and men. Six studies reported that groups who exercised more had significantly greater weight-loss maintenance than did those who exercised less. CONCLUSIONS Five years after completing structured weight-loss programs, the average individual maintained a weight loss of >3 kg and a reduced weight of >3% of initial body weight. After VLEDs or weight loss of > or =20 kg, individuals maintained significantly more weight loss than after HBDs or weight losses of

The purpose of this note is to present a criterion for an infinite collection of distinct hyperbolic 3-manifolds to be commensurably infinite. (Here, a collection of hyperbolic 3-manifolds is commensurably infinite if it contains representatives from infinitely many commensurability classes.) Namely, such a collection M is commensurably infinite if there is a uniform upper bound on the volumes of the manifolds in M.

The constancy of plasma osmolality demands that salt and water concentration within the extracellular fluid be constantly monitored and regulated within a few percentage points. The circumventricular organs in general, and the subfornical organ in particular, have long been proposed to be the site of the osmosensitivity. Isolated subfornical organ neurons of male rats were studied using the whole-cell patch-clamp technique and both action potential frequency and whole cell currents were measured as bath osmolality was changed, from 240 to 330 mOsm, by altering the amount of mannitol and maintaining the concentrations of electrolytes constant. Out of 64 cells, 66% responded to changes in bath osmolality in a predictable manner, exhibiting a hyperpolarization and decrease in spike frequency in hypo-osmotic solutions and a depolarization and increase in action potential frequency during hyperosmotic exposure. Cells (34%) defined as non-responders exhibited no significant modulation during identical changes in extracellular osmolality. The responses to changing extracellular osmolality were dose dependent; the activity of subfornical organ neurons was significantly modulated by changes in extracellular osmolality of less than 10 mOsm. By regression analysis, this osmosensitivity was approximately 0.1 Hz/mOsm change throughout a ±10 mOsm range and was maintained throughout the range of osmolalities studied (270–330 mOsm). The mechanism underlying this osmosensitivity remains unclear, although the non-selective cation conductance and the volume-activated chloride conductance do not seem to be involved. This intrinsic osmosensitivity of subfornical organ within the normal physiological range supports the view that this circumventricular structure plays a role in normal osmoregulation.