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Background: Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use.Methods and Results: A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74-1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82-1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77-1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22-1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09-1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P=0.04 for interaction).Conclusions: The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications. [ABSTRACT FROM AUTHOR]

Abstract Background We report the development of a microarray platform for rapid and cost-effective genetic mapping, and its evaluation using rice as a model. In contrast to methods employing whole-genome tiling microarrays for genotyping, our method is based on low-cost spotted microarray production, focusing only on known polymorphic features. Results We have produced a genotyping microarray for rice, comprising 880 single feature polymorphism (SFP) elements derived from insertions/deletions identified by aligning genomic sequences of the japonica cultivar Nipponbare and the indica cultivar 93-11. The SFPs were experimentally verified by hybridization with labeled genomic DNA prepared from the two cultivars. Using the genotyping microarrays, we found high levels of polymorphism across diverse rice accessions, and were able to classify all five subpopulations of rice with high bootstrap support. The microarrays were used for mapping of a gene conferring resistance to Magnaporthe grisea, the causative organism of rice blast disease, by quantitative genotyping of samples from a recombinant inbred line population pooled by phenotype. Conclusion We anticipate this microarray-based genotyping platform, based on its low cost-per-sample, to be particularly useful in applications requiring whole-genome molecular marker coverage across large numbers of individuals.

Intestinal functions demonstrate circadian rhythms thought to be entrained, in part, by an organisms' intrinsic feeding and fasting periods as well as by the intestinal microbiome. Circadian disruption as a result of ill-timed nutrient exposure and obesogenic feeding poses an increased risk to disease. As such, the aim of this study was to assess the relationships between dietary timing, composition, and the microbiome with regard to rhythmic small intestinal structure and mucosal immunity. Rodent chow (RC)-mice exhibited time-dependent increases in small intestinal weight, villus height, and crypt depth as well as an increased proportion of CD8αα + cells and concomitant decrease in CD8αβ+ cells at the onset of the feeding period (p < 0.05-0.001). Western diet (WD)-animals displayed disrupted time-dependent patterns in intestinal structure and lymphocyte populations (p < 0.05-0.01). Antibiotic-induced microbial depletion abrogated the time- and diet-dependent patterns in both RC- and WD-mice (p < 0.05-0.001). However, although germ-free-mice displayed altered rhythms, fecal microbial transfer from RC-mice was generally unsuccessful in restoring structural and immune changes in these animals. This study shows that adaptive changes in the small intestine at the onset of the feeding and fasting periods are disrupted by WD-feeding, and that these changes are dependent, in part, on the intestinal microbiome., (© 2021. The Author(s).)

The abilities to mobilize and/or sequester excess ions within and outside the plant cell are important components of salt-tolerance mechanisms. Mobilization and sequestration of Na + involves three transport systems facilitated by the plasma membrane H + /Na + antiporter (SOS1), vacuolar H + /Na + antiporter (NHX1), and Na + /K + transporter in vascular tissues (HKT1). Many of these mechanisms are conserved across the plant kingdom. While Gossypium hirsutum (upland cotton) is significantly more salt-tolerant relative to other crops, the critical factors contributing to the phenotypic variation hidden across the germplasm have not been fully unraveled. In this study, the spatio-temporal patterns of Na + accumulation along with other physiological and biochemical interactions were investigated at different severities of salinity across a meaningful genetic diversity panel across cultivated upland Gossypium. The aim was to define the importance of holistic or integrated effects relative to the direct effects of Na + homeostasis mechanisms mediated by GhHKT1, GhSOS1 , and GhNHX1. Multi-dimensional physio-morphometric attributes were investigated in a systems-level context using univariate and multivariate statistics, randomForest , and path analysis. Results showed that mobilized or sequestered Na + contributes significantly to the baseline tolerance mechanisms. However, the observed variance in overall tolerance potential across a meaningful diversity panel were more significantly attributed to antioxidant capacity, maintenance of stomatal conductance, chlorophyll content, and divalent cation (Mg 2+ ) contents other than Ca 2+ through a complex interaction with Na + homeostasis. The multi-tier macro-physiological, biochemical and molecular data generated in this study, and the networks of interactions uncovered strongly suggest that a complex physiological and biochemical synergy beyond the first-line-of defense (Na + sequestration and mobilization) accounts for the total phenotypic variance across the primary germplasm of Gossypium hirsutum . These findings are consistent with the recently proposed Omnigenic Theory for quantitative traits and should contribute to a modern look at phenotypic selection for salt tolerance in cotton breeding., Competing Interests: MS was employed by BASF Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Cushman, Pabuayon, Hinze, Sweeney and de los Reyes.)

The incretin glucagon-like peptide 1 (GLP-1) is secreted by the intestinal L cell upon nutrient ingestion. GLP-1 also exhibits a circadian rhythm, with highest release at the onset of the feeding period. Similarly, microbial composition and function exhibit circadian rhythmicity with fasting-feeding. The circadian pattern of GLP-1 release was found to be dependent on the oral route of glucose administration and was necessary for the rhythmic release of insulin and diurnal glycemic control in normal male and female mice. In mice fed a Western (high-fat/high-sucrose) diet for 16 weeks, GLP-1 secretion was markedly increased but arrhythmic over the 24-h day, whereas levels of the other incretin, glucose-dependent insulinotropic polypeptide, were not as profoundly affected. Furthermore, the changes in GLP-1 secretion were shown to be essential for the maintenance of normoglycemia in this obesogenic environment. Analysis of the primary L-cell transcriptome, as well as of the intestinal microbiome, also demonstrated time-of-day- and diet-dependent changes paralleling GLP-1 secretion. Finally, studies in antibiotic-induced microbial depleted and in germ-free mice with and without fecal microbial transfer, provided evidence for a role of the microbiome in diurnal GLP-1 release. In combination, these findings establish a key role for microbiome-dependent circadian GLP-1 secretion in the maintenance of 24-h metabolic homeostasis., (© 2020 by the American Diabetes Association.)

Background: Patients with stage 1 systolic hypertension have increased risk of cardiovascular disease (CVD) events., Methods: Using Cox models, we assess the effect of targeting an intensive SBP goal of less than 120 mmHg compared with standard SBP goal of less than 140 mmHg on the risk of CVD events in adults with stage 1 systolic hypertension with diabetes mellitus enrolled in Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial (ACCORD BP) (n = 1901) and without diabetes mellitus enrolled in Systolic Blood Pressure Intervention Trial (SPRINT) (n = 3484) that used identical SBP goal interventions., Outcomes: In ACCORD BP, the primary composite CVD outcome was the first occurrence of myocardial infarction, stroke, or CVD mortality. In SPRINT, the primary composite CVD outcome was the first occurrence of myocardial infarction, other acute coronary syndrome, stroke, heart failure, or CVD mortality., Results: In SPRINT, targeting an intensive SBP goal significantly reduced the risk of the primary CVD outcome [hazard ratio 0.75 (95% confidence interval, 0.58-0.98); events 1.78 vs. 2.37%/year]. In ACCORD BP, the relationships of SBP goal with the primary CVD outcome was modified by the glycemia goal intervention (interaction P = 0.039). In the standard glycemia subgroup (A1c target 7-7.9%), intensive SBP goal significantly reduced the risk of the primary CVD outcome [hazard ratio 0.61 (0.40-0.94); events 1.63 vs. 2.56%/year]. In the intensive glycemia subgroup (A1c target <6%), the risk of the primary CVD outcome was not significantly different between groups [hazard ratio 1.20 (0.76-1.89); events 1.91 vs. 1.60%/year]., Conclusion: Targeting an intensive SBP goal significantly reduced the risk of CVD events in patients with stage 1 systolic hypertension without diabetes and with diabetes on standard glycemia goal.

Long-acting glucagon-like peptide-2 receptor (GLP-2R) agonists are well-established to increase intestinal growth in rodents and, most notably, humans with short bowel syndrome. Most of the trophic effects of GLP-2R agonists are reported to be mediated through increased growth of the crypt-villus axis, resulting in enhanced mucosal mass and improved intestinal function. The present study examined the effects of apraglutide, a novel GLP-2R agonist, on the growth of the small intestine and colon after 3, 7, and 10 weeks of treatment in male and female mice. Apraglutide (3 mg/kg; three times per week) significantly increased small intestinal weight ( P < 0.001) and length ( P < 0.001) after 3 weeks of administration, with a further increase in effectiveness after 10 weeks ( P < 0.01). Crypt depth and villus height were both markedly increased after 3 weeks of apraglutide administration ( P < 0.001) but did not show any further increase with duration of treatment, whereas crypt number and intestinal circumference were increased after 7 and 10 weeks ( P < 0.01) but not after 3 weeks of apraglutide treatment. Both the weight and the length of the colon were also enhanced by apraglutide treatment for 3 weeks ( P < 0.001), and these effects were maintained but did not improve further with continued apraglutide administration. The results of this study demonstrate that the novel, long-acting GLP-2R agonist, apraglutide, demonstrates an unexpected marked ability to increase intestinal length as well as exert time- and location-dependent specificity in its intestinotrophic actions. SIGNIFICANCE STATEMENT: The novel long-acting glucagon-like peptide 2 receptor agonist, apraglutide, enhances intestinal weight as well as intestinal length in a time- and site-dependent fashion., Competing Interests: SEW, MES and PLB have no conflicts of interest to declare. VD is a previous employee of GLyPharma Therapeutic, Inc. JAM has grants from the NIH, Crohn's and Colitis Foundation of America, Immunogenix, Allakos, DBV Technologies, and Cour. He has consulted for Vibrant Technologies, and Actobiotics., Innovate, Kanyos, Calypso, and Teva Pharma, and holds a patent US8617536, prevotella histicola, licensed to Evelo., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Circadian secretion of the incretin, glucagon-like peptide-1 (GLP-1), correlates with expression of the core clock gene, Bmal1, in the intestinal L-cell. Several SNARE proteins known to be circadian in pancreatic α- and β-cells are also necessary for GLP-1 secretion. However, the role of the accessory SNARE, Syntaxin binding protein-1 (Stxbp1; also known as Munc18-1) in the L-cell is unknown. The aim of this study was to determine whether Stxbp1 is under circadian regulation in the L-cell and its role in the control of GLP-1 secretion. Stxbp1 was highly-enriched in L-cells, and STXBP1 was expressed in a subpopulation of L-cells in mouse and human intestinal sections. Stxbp1 transcripts and protein displayed circadian patterns in mGLUTag L-cells line, while chromatin-immunoprecipitation revealed increased interaction between BMAL1 and Stxbp1 at the peak time-point of the circadian pattern. STXBP1 recruitment to the cytosol and plasma membrane within 30 minutes of L-cell stimulation was also observed at this time-point. Loss of Stxbp1 in vitro and in vivo led to reduced stimulated GLP-1 secretion at the peak time-point of circadian release, and impaired GLP-1 secretion ex vivo. In conclusion, Stxbp1 is a circadian regulated exocytotic protein in the intestinal L-cell that is an essential regulatory component of GLP-1 secretion., (© Endocrine Society 2020.)

The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reduced cardiovascular outcomes. We evaluated diabetes mellitus incidence in this randomized trial that compared intensive blood pressure strategy (systolic blood pressure <120 mm Hg) versus standard strategy (<140 mm Hg). Participants were ≥50 years of age, with systolic 130 to 180 mm Hg and increased cardiovascular risk. Participants were excluded if they had diabetes mellitus, polycystic kidney disease, proteinuria >1 g/d, heart failure, dementia, or stroke. Postrandomization exclusions included participants missing blood glucose or ≥126 mg/dL (6.99 mmol/L) or on hypoglycemics. The outcome was incident diabetes mellitus: fasting blood glucose ≥126 mg/dL (6.99 mmol/L), diabetes mellitus self-report, or new use of hypoglycemics. The secondary outcome was impaired fasting glucose (100-125 mg/dL [5.55-6.94 mmol/L]) among those with normoglycemia (<100 mg/dL [5.55 mmol/L]). There were 9361 participants randomized and 981 excluded, yielding 4187 and 4193 participants assigned to intensive and standard strategies. There were 299 incident diabetes mellitus events (2.3% per year) for intensive and 251 events (1.9% per year) for standard, rates of 22.6 (20.2-25.3) versus 19.0 (16.8-21.5) events per 1000 person-years of treatment, respectively (adjusted hazard ratio, 1.19 [95% CI, 0.95-1.49]). Impaired fasting glucose rates were 26.4 (24.9-28.0) and 22.5 (21.1-24.1) per 100 person-years for intensive and standard strategies (adjusted hazard ratio, 1.17 [1.06-1.30]). Intensive treatment strategy was not associated with increased diabetes mellitus but was associated with more impaired fasting glucose. The risks and benefits of intensive blood pressure targets should be factored into individualized patient treatment goals. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Culture-based methods to measure Escherichia coli ( E. coli ) are used by beach administrators to inform whether bacteria levels represent an elevated risk to swimmers. Since results take up to 12 h, statistical models are used to forecast bacteria levels in lieu of test results; however they underestimate days with elevated fecal indicator bacteria levels. Quantitative polymerase chain reaction (qPCR) tests return results within 3 h but are 2-5 times more expensive than culture-based methods. This paper presents a prediction model which uses limited deployments of qPCR tested sites with inter-beach correlation to predict when bacteria will exceed acceptable thresholds. The model can be used to inform management decisions on when to warn residents or close beaches due to exposure to the bacteria. Using data from Chicago collected between 2006 and 2016, the model proposed in this paper increased sensitivity from 3.4 percent to 11.2 percent-a 230 percent increase. We find that the correlation between beaches are substantial enough to provide higher levels of precision and sensitivity to predictive models. Thus, limited deployments of qPCR testing can be used to deliver better predictions for beach administrators at lower cost and less complexity.

Objective: To determine whether the effects of intensive (<120 mmHg) compared with standard (<140 mmHg) systolic blood pressure (SBP) treatment are different among those with prediabetes versus those with fasting normoglycemia at baseline in the Systolic Blood Pressure Intervention Trial (SPRINT)., Research Design and Methods: This was a post hoc analysis of SPRINT. SPRINT participants were categorized by prediabetes status, defined as baseline fasting serum glucose ≥100 mg/dL versus those with normoglycemia (fasting serum glucose <100 mg/dL). The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Cox regression was used to calculate hazard ratios for study outcomes with intensive compared with standard SBP treatment among those with prediabetes and normoglycemia., Results: Among 9,361 participants randomized (age 67.9 ± 9.4 years; 35.5% female), 3,898 and 5,425 had baseline prediabetes and normoglycemia, respectively. After a median follow-up of 3.26 years, the hazard ratio for the primary outcome was 0.69 (95% CI 0.53, 0.89) and 0.83 (95% CI 0.66, 1.03) among those with prediabetes and normoglycemia, respectively ( P value for interaction 0.30). For all-cause mortality, the hazard ratio with intensive SBP treatment was 0.77 (95% CI 0.55, 1.06) for prediabetes and 0.71 (95% CI 0.54, 0.94) for normoglycemia ( P value for interaction 0.74). Effects of intensive versus standard SBP treatment on prespecified renal outcomes and serious adverse events were similar for prediabetes and normoglycemia (all interaction P > 0.05)., Conclusions: In SPRINT, the beneficial effects of intensive SBP treatment were similar among those with prediabetes and fasting normoglycemia., (© 2017 by the American Diabetes Association.)

Importance: Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk., Objective: To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes., Design, Setting, and Participants: Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL (<55 mg/dL for women and African American individuals)., Interventions: Passive follow-up of study participants previously treated with fenofibrate or masked placebo., Main Outcomes and Measures: Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups., Results: The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n = 1445; 31%), nonwhite individuals (n = 1094; 21%), and those with preexisting cardiovascular events (n = 1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P = .25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P = .32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high-density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56-0.95)., Conclusions and Relevance: Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings., Trial Registration: clinicaltrials.gov Identifier: NCT00000620.

Study Objectives: Obstructive sleep apnea (OSA) and type 2 diabetes mellitus (T2DM) are prevalent disorders that pose increased risk of cardiovascular disease and death. The objective of this study was to clarify if continuous positive airway pressure (CPAP) therapy for OSA affects T2DM control and emergence., Methods: Point-of-care, comparative effectiveness study; cross-sectional and longitudinal analyses., Results: Our cohort included 928 consecutive patients; 13% were women; 36% were Caucasians and 61% African-Americans. OSA was diagnosed in approximately 738 patients and CPAP was initiated in 718 patients; median duration of therapy was 5 mo (25% to 75% interquartile range [IQR] 3-14). Patients with OSA used CPAP therapy for a median duration of 4.8 h, 34.5% of the nights. Adherence to CPAP was prespecified as follows: good (≥ 70% nights and ≥ 4 h/night), excellent (≥ 80% nights and ≥ 6 h/night) or outstanding (≥ 90% of nights and 8 h/night). Based on objective data, good, excellent, and outstanding compliance were found in only 30%, 20%, and 6%, respectively. Three percent of subjects without CPAP follow-up and less than 4% of those nonadherent to CPAP therapy (based on the established criteria) developed incident T2DM. Incident T2DM developed in only 0.8% of those with good compliance and in none (0%) of those in the excellent and outstanding groups. During follow-up, median weight change was +0.3 kg (IQR -1.8 to 2.7)., Conclusions: We found that an outstanding compliance to CPAP reduced fasting blood glucose in patients with OSA. Longitudinally, higher levels of therapeutic adherence may affect the rate of incident impaired fasting glucose, prediabetes, and T2DM, despite the observed weight gains., Commentary: A commentary on this article appears in this issue on page 365., (© 2017 American Academy of Sleep Medicine)

Although increased serum histamine levels and H1R expression in the plaque are seen in atherosclerosis, it is not known whether H1R activation is a causative factor in the development of the disease, or is a host defense response to atherogenic signals. In order to elucidate how pharmacological inhibition of histamine receptor 1 (H1R) signaling affects atherogenesis, we administered either cetirizine (1 and 4 mg/kg. b.w) or fexofenadine (10 and 40 mg/kg. b.w) to ApoE-/- mice maintained on a high fat diet for three months. Mice ingesting a low dose of cetirizine or fexofenadine had significantly higher plaque coverage in the aorta and cross-sectional lesion area at the aortic root. Surprisingly, the higher doses of cetirizine or fexofenadine did not enhance atherosclerotic lesion coverage over the controls. The low dose of fexofenadine, but not cetirizine, increased serum LDL cholesterol. Interestingly, the expression of iNOS and eNOS mRNA was increased in aortas of mice on high doses of cetirizine or fexofenadine. This may be a compensatory nitric oxide (NO)-mediated vasodilatory mechanism that accounts for the lack of increase in the progression of atherosclerosis. Although the administration of cetirizine did not alter blood pressure between the groups, there was a positive correlation between blood pressure and lesion/media ratio at the aortic root in mice receiving the low dose of cetirizine. However, this association was not observed in mice treated with the high dose of cetirizine or either doses of fexofenadine. The macrophages or T lymphocytes densities were not altered by low doses of H1-antihistamines, whereas, high doses decreased the number of macrophages but not T lymphocytes. The number of mast cells was decreased only in mice treated with low dose of fexofenadine. These results demonstrate that chronic ingestion of low therapeutic doses of cetirizine or fexofenadine enhance progression of atherosclerosis.

Objective: Examine the effect of ABT-335 (fenofibric acid) on postprandial lipemia and susceptibility of plasma lipoproteins to Cu(++)-mediated oxidation in patients with metabolic syndrome., Methods and Results: This is a randomized double-blind, placebo-controlled study with cross-over and includes a 4-week wash-out period between the two treatment periods. At the end of each 8-week treatment period, subjects were challenged with a standardized mixed meal followed by blood collection over the ensuing 6 h. Plasma lipoproteins were isolated by a combination of ultracentrifugation and FPLC for the continuous monitoring of conjugated dienes formation as an assessment of oxidative susceptibility. Fasting plasma TG was reduced by 20% (p < 0.0002) and there was a modest reduction in hsCRP (6.1%, p < 0.06). There was no change in either HDLc or LDLc in these subjects. Postprandial lipemia was reduced with ABT-335 as demonstrated by a 28.5% reduction (p < 0.0005) in incremental area under the curve for TG during the 6-h period after the meal challenge. Lag times for both fasting LDL (+16%) and postprandial LDL (+28%) were increased with the ABT-335 therapy, suggestive of reduced oxidative susceptibility. Co-incubation with autologous HDL did not reduced LDL oxidative susceptibility in these patients., Conclusion: ABT-335 therapy reduced fasting and postprandial triglycerides in patients with metabolic syndrome. Autologous HDL may be dysfunctional in these patients as co-incubation with HDL failed to reduce oxidative susceptibility of LDL. During ABT-335 therapy, LDL was less susceptible to Cu(++)-mediated oxidative modification, in spite of the lack of changes in LDLc levels., (Published by Elsevier Ireland Ltd.)

Background/aims: The value of the Framingham equation in predicting cardiovascular risk in African Americans and patients with chronic kidney disease (CKD) is unclear. The purpose of the study was to evaluate whether the addition of CKD and race to the Framingham equation improves risk stratification in hypertensive patients., Methods: Participants in the ALLHAT were studied. Those randomized to doxazosin, older than 74 years, and those with a history of coronary heart disease were excluded. Two risk stratification models were developed using Cox proportional hazards models in a two-thirds developmental sample. The first model included the traditional Framingham risk factors. The second model included the traditional risk factors plus CKD, defined by estimated glomerular filtration rate categories, and stratification by race (black vs non-black). The primary outcome was a composite of fatal coronary heart disease, nonfatal myocardial infarction, coronary revascularization, and hospitalized angina., Results: There were a total of 19,811 eligible subjects. In the validation cohort, there was no difference in C-statistics between the Framingham equation and the ALLHAT model including CKD and race. This was consistent across subgroups by race and sex and among those with CKD. One exception was among Non-Black women where the C-statistic was higher for the Framingham equation (0.68 vs 0.65, P = .02). In addition, net reclassification improvement was not significant for any subgroup based on race and sex, ranging from -5.5% to 4.4%., Conclusion: The addition of CKD status and stratification by race does not improve risk prediction in high-risk hypertensive patients., (Copyright © 2012 Mosby, Inc. All rights reserved.)

T cells are important mediators of autoimmune inflammation in relapsing-remitting multiple sclerosis (RRMS). Previous studies found that deferiprone, an iron chelator, suppressed disease activity in a mouse model of multiple sclerosis, and inhibition of T cell proliferation was implicated as a putative mechanism. The objective of the present study was to examine the effects of deferiprone on suppressing in vitro responses of T cells from control and RRMS subjects. Peripheral blood T cells were co-stimulated with anti-CD3+anti-CD28 and cultured with or without interleukin 2 (IL-2). Proliferating CD4+ T cells from control and RRMS subjects, cultured with or without IL-2, decreased in response to 75 μM deferiprone, although the extent of decreased proliferation of CD4+ T cells from RRMS subjects was less than for control subjects. Proliferating CD8+ T cells from control subjects, cultured with or without IL-2, also decreased in response to 75 μM deferiprone, and this decrease was seen in proliferating CD8+ T cells from RRMS cultured with IL-2. CD4+CD25+ and CD8+CD25+ cells from control subjects, cultured with or without IL-2, declined in 75 μM deferiprone, but the decrease was smaller than for the CD4+ and CD8+ proliferative responses. CD4+CD25+ and CD8+CD25+ cells from RRMS subjects showed more variability than for control subjects, but CD4+CD25+ cultured with IL-2 and CD8+CD25+ cells cultured without IL-2 significantly declined in 75 μM deferiprone. CD4+FoxP3+ and CD4+CD25+FoxP3+ cells tended to remain constant or increase. In summary, deferiprone induced declines in proliferative responses at a dosage that is within peak serum pharmacological concentrations., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Summary Histamine is a well-recognized modulator of vascular inflammation. We have shown that histamine, acting via H1 receptors (H1R), synergizes lipopolysaccharide (LPS)-induced production of prostaglandin I(2) (PGI(2)), PGE(2) and interleukin-6 (IL-6) by endothelial cells. The synergy between histamine and LPS was partly attributed to histamine -induced expression of Toll-like receptor 4 (TLR4). In this study, we examined whether LPS stimulates the H1R expression in human coronary artery endothelial cells (HCAEC) with resultant enhancement of histamine responsiveness. Incubation of HCAEC with LPS (10-1000 ng/ml) resulted in two-fold to fourfold increases in H1R mRNA expression in a time-dependent and concentration-dependent fashion. In contrast, LPS treatment did not affect H2R mRNA expression. The LPS-induced H1R mRNA expression peaked by 4 hr after LPS treatment and remained elevated above the basal level for 20-24 hr. Flow cytometric and Western blot analyses revealed increased expression of H1R protein in LPS-treated cells. The specific binding of [(3)H]pyrilamine to H1R in membrane proteins from LPS-treated HCAEC was threefold higher than the untreated cells. The LPS-induced H1R expression was mediated through TLR4 as gene silencing by TLR4-siRNA and treatment with a TLR4 antagonist inhibited the LPS effect. When HCAEC were pre-treated with LPS for 24 hr, washed and challenged with histamine, 17-, 10- and 15-fold increases in PGI(2), PGE(2) and IL-6 production, respectively, were noted. Histamine-induced enhancement of the synthesis of PGI(2), PGE(2) and IL-6 by LPS-primed HCAEC was completely blocked by an H1R antagonist. The results demonstrate that LPS, through TLR4 activation, up-regulates the expression and function of H1R and amplifies histamine-induced inflammatory responses in HCAEC., (© 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.)

Objective: To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial., Design: Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics., Participants: Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A(1C)) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control., Outcome Measures: Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia., Results: 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia., Conclusion: Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued., Trial Registration: NCT00000620.

Background: Comparing findings from separate trials is necessary to choose among treatment options, however differences among study cohorts may impede these comparisons., Purpose: As a case study, to examine the overlap of study cohorts in two large randomized controlled clinical trials that assess interventions to reduce risk of major cardiovascular disease events in adults with type 2 diabetes in order to explore the feasibility of cross-trial comparisons, Methods: The Action for Health in Diabetes (Look AHEAD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials enrolled 5145 and 10,251 adults with type 2 diabetes, respectively. Look AHEAD assesses the efficacy of an intensive lifestyle intervention designed to produce weight loss; ACCORD tests pharmacological therapies for control of glycemia, hyperlipidemia, and hypertension. Incidence of major cardiovascular disease events is the primary outcome for both trials. A sample was constructed to include participants from each trial who appeared to meet eligibility criteria and be appropriate candidates for the other trial's interventions. Demographic characteristics, health status, and outcomes of members and nonmembers of this constructed sample were compared., Results: Nearly 80% of Look AHEAD participants were projected to be ineligible for ACCORD; ineligibility was primarily due to better glycemic control or no early history of cardiovascular disease. Approximately 30% of ACCORD participants were projected to be ineligible for Look AHEAD, often for reasons linked to poorer health. The characteristics of participants projected to be jointly eligible for both trials continued to reflect differences between trials according to factors likely linked to retention, adherence, and study outcomes., Limitations: Accurate ascertainment of cross-trial eligibility was hampered by differences between protocols., Conclusions: Despite several similarities, the Look AHEAD and ACCORD cohorts represent distinct populations. Even within the subsets of participants who appear to be eligible and appropriate candidates for trials of both modes of intervention, differences remained. Direct comparisons of results from separate trials of lifestyle and pharmacologic interventions are compromised by marked differences in enrolled cohorts.

Elevated serum cholesterol is a known risk factor for the development of coronary artery disease. Circulating cholesterol is a product of both cholesterol absorption from the gut and cellular cholesterol production. Ezetimibe is a novel cholesterol-lowering drug that acts at the brush border of the small intestine. Recent studies have further identified the molecular target as the Niemann-Pick C1-like transporter. Ezetimibe blocks the absorption of dietary and biliary cholesterol and plant sterols resulting in intracellular cholesterol depletion. Clinical studies have demonstrated beneficial improvements in the lipid profile with ezetimibe as monotherapy, but dramatic effects are seen when ezetimibe is combined with other lipid-lowering drugs, particularly 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Combination studies of ezetimibe with statins, bile acid sequestrants, fenofibrate and niacin all demonstrate significant total and low density lipoprotein cholesterol lowering. An excellent safety and tolerability profile combined with once-daily dosing make this attractive adjunct therapy for the treatment of hypercholesterolemia.

Objective: Hypertension (HTN) is a major risk factor for cardiovascular disease (CVD) in the setting of diabetes. There is no consensus on how best to treat hypertension among those with diabetes. Here we describe the characteristics of a cohort of hypertensive adults with diabetes who are part of a large prospective blood pressure study. This study will help clarify the treatment of HTN in the setting of diabetes., Research Design and Methods: The Antihypertensive and Lipid-Lowering high-risk hypertensive participants, ages > or = 55 years, designed to determine whether the incidence of fatal and nonfatal coronary heart disease (CHD) and combined cardiovascular events (fatal and nonfatal CHD, revascularization surgery, angina pectoris, congestive heart failure, and stroke) differs between diuretic (chlorthalidone) treatment and three alternative antihypertensive therapies: a calcium channel blocker (amlodipine), an ACE inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). The planned follow-up is an average of 6 years, to be completed March 2002., Results: There are 15,297 diabetic individuals in the ALLHAT study (36.0% of the entire cohort). Of these individuals, 50.2% are male, 39.4% are African-American, and 17.7% are Hispanic. Demographic and laboratory characteristics of the cohort are similar to those of other studies of the U.S. elderly population with HTN. The sample size has 42 and 93% confidence, treatments for the two study outcomes., Conclusions: The diabetic cohort in ALLHAT wil be able to provide valuable information about the treatment of hypertension in older diabetic patients at risk for incident CVD.

Large numbers of observational studies have described a decrease in the incidence of cardiovascular disease in women taking hormone replacement therapy (HRT). The potential mechanisms for this effect are numerous, including direct effects on lipid levels and lipid metabolism, cardiovascular dynamics, and endothelial reactivity. The beneficial effects of HRT are probably affected by various factors, including the age of onset of therapy, the presence of coronary artery disease, the type of estrogen and whether it is used in combination with progesterone, concurrent modification of other cardiac risk factors, and duration of therapy. Until further prospective clinical trials are done, HRT should be considered in those women for whom the potential benefits exceed the potential risks, on the basis of an individualized patient evaluation.

Purpose: The purpose of the study was to compare the powder and the bar forms of cholestyramine to determine efficacy and patient compliance., Subjects and Methods: A prospective, randomized trial was conducted that included 83 healthy men and women with hyperlipidemia greater than the 90th percentile for low-density lipoprotein (LDL) or total cholesterol. Patients were randomly assigned to receive either cholestyramine powder, two packets (8 g), twice daily, or cholestyramine confectionery bar, in maple or mint flavors, two bars (8 g), twice daily. Fasting serum total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured at baseline, after 6 to 8 weeks of following the American Heart Association Step I diet alone, and after 8 weeks of taking either the cholestyramine bar or powder., Results: Total cholesterol decreased significantly (p less than 0.01) by 16% in the bar group and 17% in the powder group. LDL cholesterol decreased by 28% and 29% in the bar and powder groups, respectively (p less than 0.01). There was no significant change in HDL cholesterol. Triglycerides increased in both groups, by 29% in the bar group and by 25% in the powder group. There was no difference between bar and powder in the effect on blood lipids. The majority of the lipid-lowering effect was seen within 14 days. Mean patient endpoint compliance with the therapy was 91.8 +/- 3.6% in the bar group and 94.8 +/- 2.1% in the powder group. There was no difference between groups., Conclusion: The cholestyramine confectionery bar is as effective as cholestyramine powder in the treatment of hyperlipidemia. The majority of the lipid-lowering effect is seen within 14 days of therapy. Although patient compliance is comparable between the two forms, gastrointestinal side effects were slightly greater with the bar form. Therefore, although the bar offers an alternative form of therapy, there appears to be no advantage with regard to patient compliance or palatability.

To test alterations in plasma potassium and magnesium levels with maximal exercise, 15 sedentary, healthy men (mean age 29 years) participated in a double-blind crossover study for 11 weeks with propranolol, atenolol, and placebo. Maximal exercise tests were done at baseline and after placebo and beta-blockade phases. Blood for analysis was collected via indwelling brachial vein angiocatheters at baseline and during and after testing. Plasma potassium and magnesium levels increased at peak exercise with atenolol, propranolol, and placebo. There was no difference among groups in baseline recovery for magnesium (mean 28 minutes, range 24 to 30 minutes). Potassium levels returned to baseline more rapidly (compared with magnesium) in the placebo and atenolol groups (mean 10 minutes); however, recovery time was prolonged with propranolol (26 minutes) compared with placebo and atenolol (p less than 0.01). In conclusion, plasma magnesium and potassium levels increased significantly with maximal exercise and are unaffected by atenolol or propranolol beta-blockade. Propranolol, however (compared with atenolol and placebo), prolongs the time of return to baseline of plasma potassium after exercise.

To evaluate the effects of exercise testing, training and beta blockade on serum potassium, 40 normal subjects (24 men, 16 women, mean age 33 years) had 4 maximal exercise tests with venipuncture for serum potassium before and less than or equal to 40 seconds after each test. After initial exercise testing, they were randomized to atenolol 50 mg daily, atenolol 100 mg daily, propranolol 80 mg twice daily or placebo. All began a 9-week dynamic exercise program for 8 weeks followed by a 1-week drug-free washout period. Tests were done after weeks 1, 8 and 9. A significant mean increase (p less than 0.05) in serum potassium occurred with maximal exercise in the atenolol 50 mg and propranolol groups after 1 week of treatment (mean +/- standard deviation, 4.78 +/- 0.29 to 5.09 +/- 0.43 mEq/liter and 4.81 +/- 0.55 to 5.30 +/- 0.33 mEq/liter). By week 8 after training, all beta blockade groups showed an increase in postmaximal exercise test serum potassium (atenolol 50 mg, 4.78 +/- 0.29 to 5.11 +/- 0.26 mEq/liter; atenolol 100 mg, 4.95 +/- 0.41 to 5.16 +/- 0.36 mEq/liter; propranolol, 4.81 +/- 0.55 to 5.05 +/- 0.29 mEq/liter). After washout, only the placebo group showed an increase in postmaximal test serum potassium (4.99 +/- 0.46 to 5.35 +/- 0.27 mEq/liter). Data indicate that hyperkalemia with maximal exercise testing increases after training with atenolol and propranolol compared to placebo and that this effect resolves once treatment is discontinued.

Comparisons of the WISC-R and WAIS-R were made in a sample of male delinquents (N = 80) to determine whether they would show differences in the degree to which the P greater than V sign occurred on them. A larger split between mean Verbal and mean Performance IQ was found on the WISC-R than on the WAIS-R. Frequency analyses revealed no differences in the number of persons who showed the P greater than V sign on each test. Age and the P greater than V sign were not related significantly. Results suggest that the WISC-R and WAIS-R may not be equivalent measures of this sign, and caution should be exercised in applying results of research on the WISC and WAIS to the revisions of those tests.

To determine whether or not a training effect can be achieved with beta-adrenergic blockade and whether there is a difference between selective and nonselective therapy, we recruited 40 healthy subjects (16 women, 24 men) to participate in a 9-week exercise training program. After a baseline exercise treadmill test, subjects were randomized to oral therapy groups of atenolol, 50 mg daily (AT 50), atenolol, 100 mg daily (AT 100), propranolol, 80 mg twice a day (Prop), or placebo. Repeat exercise tests were performed at week 1, week 8, and at week 9, with week 8 to 9 being a 1-week drug-free washout period. At week 8, maximal oxygen consumption (Max VO2), when compared with baseline levels, was increased slightly in AT 50 (4.2%) and Prop (2.4%), decreased in AT 100 (5.3%), and increased significantly in the placebo group (12.7%). After washout, Max VO2 increased significantly compared with baseline in AT 50, AT 100, and Prop (9.8%, 10.8%, and 9.8%, respectively). We conclude that there is no significant difference between selective and nonselective beta-blockade therapy in the development of a training effect. This effect, however, may not become apparent until the drug is withdrawn.