Enhancement of a modified Mediterranean-style, low glycemic load diet with specific phytochemicals improves cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia in a randomized trial

<p>Abstract</p> <p>Background</p> <p>As the worldwide dietary pattern becomes more westernized, the metabolic syndrome is reaching epidemic proportions. Lifestyle modifications including diet and exercise are recommended as first-line intervention for treating metabolic syndrome. Previously, we reported that a modified Mediterranean-style, low glycemic load diet with soy protein and phytosterols had a more favorable impact than the American Heart Association Step 1 diet on cardiovascular disease (CVD) risk factors. Subsequently, we screened for phytochemicals with a history of safe use that were capable of increasing insulin sensitivity through modulation of protein kinases, and identified hops <it>rho </it>iso-alpha acid and acacia proanthocyanidins. The objective of this study was to investigate whether enhancement of a modified Mediterranean-style, low glycemic load diet (MED) with specific phytochemicals (soy protein, phytosterols, <it>rho </it>iso-alpha acids and proanthocyanidins; PED) could improve cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia.</p> <p>Methods</p> <p>Forty-nine subjects with metabolic syndrome and hypercholesterolemia, aged 25–80, entered a randomized, 2-arm, 12-week intervention trial; 23 randomized to the MED arm; 26 to the PED arm. Forty-four subjects completed at least 8 weeks [MED (<it>n </it>= 19); PED (<it>n </it>= 25)]. All subjects were instructed to follow the same aerobic exercise program. Three-day diet diaries and 7-day exercise diaries were assessed at each visit. Fasting blood samples were collected at baseline, 8 and 12 weeks for analysis.</p> <p>Results</p> <p>Both arms experienced equal weight loss (MED: -5.7 kg; PED: -5.9 kg). However, at 12 weeks, the PED arm experienced greater reductions (<it>P </it>< 0.05) in cholesterol, non-HDL cholesterol, triglycerides (TG), cholesterol/HDL and TG/HDL compared with the MED arm. Only the PED arm experienced increased HDL (<it>P </it>< 0.05) and decreased TG/HDL (<it>P </it>< 0.01), and continued reduction in apo B/apo A-I from 8 to 12 weeks. Furthermore, 43% of PED subjects vs. only 22% of MED subjects had net resolution of metabolic syndrome. The Framingham 10-year CVD risk score decreased by 5.6% in the PED arm (<it>P </it>< 0.01) and 2.9% in the MED arm (<it>P </it>< 0.05).</p> <p>Conclusion</p> <p>These results demonstrate that specific phytochemical supplementation increased the effectiveness of the modified Mediterranean-style low glycemic load dietary program on variables associated with metabolic syndrome and CVD.</p

RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells

Background Telomeric 3’ overhangs can fold into a four-stranded DNA structure termed G-quadruplex (G4), a formation which inhibits telomerase. As telomerase activation is crucial for telomere maintenance in most cancer cells, several classes of G4 ligands have been designed to directly disrupt telomeric structure. Methods We exposed brain tumor cells to the G4 ligand 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) and investigated proliferation, cell cycle dynamics, telomere length, telomerase activity and activated c-Myc levels. Results Although all cell lines tested were sensitive to RHPS4, PFSK-1 central nervous system primitive neuroectodermal cells, DAOY medulloblastoma cells and U87 glioblastoma cells exhibited up to 30-fold increased sensitivity compared to KNS42 glioblastoma, C6 glioma and Res196 ependymoma cells. An increased proportion of S-phase cells were observed in medulloblastoma and high grade glioma cells whilst CNS PNET cells showed an increased proportion of G1-phase cells. RHPS4-induced phenotypes were concomitant with telomerase inhibition, manifested in a telomere length-independent manner and not associated with activated c-Myc levels. However, anti-proliferative effects were also observed in normal neural/endothelial cells in vitro and ex vivo. Conclusion This study warrants in vivo validation of RHPS4 and alternative G4 ligands as potential anti-cancer agents for brain tumors but highlights the consideration of dose-limiting tissue toxicities

Physicians' use of the 5As in counseling obese patients: is the quality of counseling associated with patients' motivation and intention to lose weight?

<p>Abstract</p> <p>Background</p> <p>Physicians are encouraged to counsel obese patients to lose weight, but studies measuring the quality of physicians' counseling are rare. We sought to describe the quality of physicians' obesity counseling and to determine associations between the quality of counseling and obese patients' motivation and intentions to lose weight, key predictors of behavior change.</p> <p>Methods</p> <p>We conducted post-visit surveys with obese patients to assess physician's use of 5As counseling techniques and the overall patient-centeredness of the physician.. Patients also reported on their motivation to lose weight and their intentions to eat healthier and exercise. One-way ANOVAs were used to describe mean differences in number of counseling practices across levels of self-rated intention and motivation. Logistic regression analyses were conducted to assess associations between number of 5As counseling practices used and patient intention and motivation.</p> <p>Results</p> <p>137 patients of 23 physicians were included in the analysis. While 85% of the patients were counseled about obesity, physicians used only a mean of 5.3 (SD = 4.6) of 18 possible 5As counseling practices. Patients with higher levels of motivation and intentions reported receiving more 5As counseling techniques than those with lower levels. Each additional counseling practice was associated with higher odds of being motivated to lose weight (OR 1.31, CI 1.11-1.55), intending to eat better (OR 1.23, CI 1.06-1.44), and intending to exercise regularly (OR 1.14, CI 1.00-1.31). Patient centeredness of the physician was also positively associated with intentions to eat better (OR 2.96, CI 1.03-8.47) and exercise (OR 26.07, CI 3.70-83.93).</p> <p>Conclusions</p> <p>Quality of physician counseling (as measured using the 5As counseling framework and patient-centeredness scales) was associated with motivation to lose weight and intentions to change behavior. Future studies should determine whether higher quality obesity counseling leads to improved behavioral and weight outcomes.</p

Accounting For Alignment Uncertainty in Phylogenomics

Uncertainty in multiple sequence alignments has a large impact on phylogenetic analyses. Little has been done to evaluate the quality of individual positions in protein sequence alignments, which directly impact the accuracy of phylogenetic trees. Here we describe ZORRO, a probabilistic masking program that accounts for alignment uncertainty by assigning confidence scores to each alignment position. Using the BALIBASE database and in simulation studies, we demonstrate that masking by ZORRO significantly reduces the alignment uncertainty and improves the tree accuracy

Glucose and Fatty Acid Metabolism in a 3 Tissue In-Vitro Model Challenged with Normo- and Hyperglycaemia

Nutrient balance in the human body is maintained through systemic signaling between different cells and tissues. Breaking down this circuitry to its most basic elements and reconstructing the metabolic network in-vitro provides a systematic method to gain a better understanding of how cross-talk between the organs contributes to the whole body metabolic profile and of the specific role of each different cell type. To this end, a 3-way connected culture of hepatocytes, adipose tissue and endothelial cells representing a simplified model of energetic substrate metabolism in the visceral region was developed. The 3-way culture was shown to maintain glucose and fatty acid homeostasis in-vitro. Subsequently it was challenged with insulin and high glucose concentrations to simulate hyperglycaemia. The aim was to study the capacity of the 3-way culture to maintain or restore normal circulating glucose concentrations in response to insulin and to investigate the effects these conditions on other metabolites involved in glucose and lipid metabolism. The results show that the system’s metabolic profile changes dramatically in the presence of high concentrations of glucose, and that these changes are modulated by the presence of insulin. Furthermore, we observed an increase in E-selectin levels in hyperglycaemic conditions and increased IL-6 concentrations in insulin-free-hyperglycaemic conditions, indicating, respectively, endothelial injury and proinflammatory stress in the challenged 3-way system

General practitioner advice on physical activity: Analyses in a cohort of older primary health care patients (getABI)

<p>Abstract</p> <p>Background</p> <p>Although the benefits of physical activity for health and functioning are recognized to extend throughout life, the physical activity level of most older people is insufficient with respect to current guidelines. The primary health care setting may offer an opportunity to influence and to support older people to become physically active on a regular basis. Currently, there is a lack of data concerning general practitioner (GP) advice on physical activity in Germany. Therefore, the aim of this study was to evaluate the rate and characteristics of older patients receiving advice on physical activity from their GP.</p> <p>Methods</p> <p>This is a cross-sectional study using data collected at 7 years of follow-up of a prospective cohort study (German epidemiological trial on ankle brachial index, getABI). 6,880 unselected patients aged 65 years and above in the primary health care setting in Germany were followed up since October 2001. During the 7-year follow-up telephone interview, 1,937 patients were asked whether their GP had advised them to get regular physical activity within the preceding 12 months. The interview also included questions on socio-demographic and lifestyle variables, medical conditions, and physical activity. Logistic regression analysis (unadjusted and adjusted for all covariables) was used to examine factors associated with receiving advice. Analyses comprised only complete cases with regard to the analysed variables. Results are expressed as odds ratios (ORs) with 95% confidence intervals (95% CI).</p> <p>Results</p> <p>Of the 1,627 analysed patients (median age 77; range 72-93 years; 52.5% women), 534 (32.8%) stated that they had been advised to get regular physical activity. In the adjusted model, those more likely to receive GP advice on physical activity were men (OR [95% CI] 1.34 [1.06-1.70]), patients suffering from pain (1.43 [1.13-1.81]), coronary heart disease and/or myocardial infarction (1.56 [1.21-2.01]), diabetes mellitus (1.79 [1.39-2.30]) or arthritis (1.37 [1.08-1.73]), and patients taking a high (> 5) number of medications (1.41 [1.11-1.80]).</p> <p>Conclusions</p> <p>The study revealed a relatively low rate of older primary health care patients receiving GP advice on physical activity. GPs appeared to focus their advice on patients with chronic medical conditions. However, there are likely to be many more patients who would benefit from advice.</p

Genetic Background Analysis of Protein C Deficiency Demonstrates a Recurrent Mutation Associated with Venous Thrombosis in Chinese Population

Background: Protein C (PC) is one of the most important physiological inhibitors of coagulation proteases. Hereditary PC deficiency causes a predisposition to venous thrombosis (VT). The genetic characteristics of PC deficiency in the Chinese population remain unknown. Methods: Thirty-four unrelated probands diagnosed with hereditary PC deficiency were investigated. PC activity and antigen levels were measured. Mutation analysis was performed by sequencing the PROC gene. In silico analyses, including PolyPhen-2, SIFT, multiple sequence alignment, splicing prediction, and protein molecular modeling were performed to predict the consequences of each variant identified. One recurrent mutation and its relative risk for thrombosis in relatives were analyzed in 11 families. The recurrent mutation was subsequently detected in a case (VT patients)-control study, and the adjusted odds ratio (OR) for VT risk was calculated by logistic regression analysis. Results: A total of 18 different mutations, including 12 novel variants, were identified. One common mutation, PROC c.565C.T (rs146922325:C.T), was found in 17 of the 34 probands. The family study showed that first-degree relatives bearing this variant had an 8.8-fold (95%CI = 1.1–71.6) increased risk of venous thrombosis. The case-control (1003 vs. 1031) study identified this mutation in 5.88 % patients and in 0.87 % controls, respectively. The mutant allele conferred a high predisposition to venous thrombosis (adjusted OR = 7.34, 95%CI = 3.61–14.94). The plasma PC activity and antigen levels i

Preferential Entry of Botulinum Neurotoxin A Hc Domain through Intestinal Crypt Cells and Targeting to Cholinergic Neurons of the Mouse Intestine

Botulism, characterized by flaccid paralysis, commonly results from botulinum neurotoxin (BoNT) absorption across the epithelial barrier from the digestive tract and then dissemination through the blood circulation to target autonomic and motor nerve terminals. The trafficking pathway of BoNT/A passage through the intestinal barrier is not yet fully understood. We report that intralumenal administration of purified BoNT/A into mouse ileum segment impaired spontaneous muscle contractions and abolished the smooth muscle contractions evoked by electric field stimulation. Entry of BoNT/A into the mouse upper small intestine was monitored with fluorescent HcA (half C-terminal domain of heavy chain) which interacts with cell surface receptor(s). We show that HcA preferentially recognizes a subset of neuroendocrine intestinal crypt cells, which probably represent the entry site of the toxin through the intestinal barrier, then targets specific neurons in the submucosa and later (90–120 min) in the musculosa. HcA mainly binds to certain cholinergic neurons of both submucosal and myenteric plexuses, but also recognizes, although to a lower extent, other neuronal cells including glutamatergic and serotoninergic neurons in the submucosa. Intestinal cholinergic neuron targeting by HcA could account for the inhibition of intestinal peristaltism and secretion observed in botulism, but the consequences of the targeting to non-cholinergic neurons remains to be determined

The impact of statins on health services utilization and mortality in older adults discharged from hospital with ischemic heart disease: a cohort study

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease (CVD) carries a high burden of morbidity and mortality and is associated with significant utilization of health care resources, especially in the elderly. Numerous randomized trials have established the efficacy of cholesterol reduction with statin medications in decreasing mortality in high-risk populations. However, it is not known what the effect of the utilization of these medications in complex older adults has had on mortality and on the utilization of health services, such as physician visits, hospitalizations or cardiovascular procedures.</p> <p>Methods</p> <p>This project linked clinical and hospital data from the Improving Cardiovascular Outcomes in Nova Scotia (ICONS) database with administrative data from the Population Health Research Unit to identify all older adults hospitalized with ischemic heart disease between October 15, 1997 and March 31, 2001. All patients were followed for at least one year or until death. Multiple regression techniques, including Cox proportional hazards models and generalized linear models were employed to compare health services utilization and mortality for statin users and non-statin users.</p> <p>Results</p> <p>Of 4232 older adults discharged alive from the hospital, 1629 (38%) received a statin after discharge. In multivariate models after adjustment for demographic and clinical characteristics, and propensity score, statins were associated with a 26% reduction in all- cause mortality (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.63-0.88). However, statin use was not associated with subsequent reductions in health service utilization, including re-hospitalizations (HR, 0.98, 95% CI 0.91-1.06), physician visits (relative risk (RR) 0.97, 95% CI 0.92-1.02) or coronary revascularization procedures (HR 1.15, 95% CI 0.97-1.36).</p> <p>Conclusion</p> <p>As the utilization of statins continues to grow, their impact on the health care system will continue to be important. Future studies are needed to continue to ensure that those who would realize significant benefit from the medication receive it.</p