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Association of metabolic syndrome with non-thromboembolic adverse cardiac outcomes in patients with atrial fibrillation.
Polovina, M, Hindricks, G, Maggioni, A, Piepoli, M, Vardas, P, Ašanin, M, Ðikic, D, Ðuricic, N, Milinkovic, I, Seferovic, PM
European heart journal. 2018;(45):4030-4039
Abstract
AIMS: Evidence suggests an excess risk of non-thromboembolic major adverse cardiac events (MACE) associated with atrial fibrillation (AF), particularly in individuals free of overt coronary artery disease (CAD). Metabolic syndrome (MetS) increases cardiovascular risk in the general population, but less is known how it influences outcomes in AF patients. We aimed to assess whether MetS affects the risk of MACE in AF patients without overt CAD. METHODS AND RESULTS This prospective, observational study enrolled 843 AF patients (mean-age, 62.5 ± 12.1 years, 38.6% female) without overt CAD. Metabolic syndrome was defined according to the National Cholesterol Education Program. The 5-year composite MACE included myocardial infarction (MI), coronary revascularization, and cardiac death. Metabolic syndrome was present in 302 (35.8%) patients. At 5-year follow-up, 118 (14.0%) patients experienced MACE (2.80%/year). Metabolic syndrome conferred a multivariable adjusted hazard ratio (aHR) of 1.98 for MACE [95% confidence interval (CI), 1.23-3.16; P = 0.004], and for individual outcomes: MI (aHR, 2.00; 95% CI, 1.69-5.11; P < 0.001), revascularization (aHR, 2.33; 95% CI, 1.40-3.87; P = 0.001), and cardiac death (aHR, 2.59; 95% CI, 1.25-5.33; P = 0.011). Following the propensity score (PS)-adjustment for MetS, the association between MetS and MACE (PS-aHR, 1.87; 95% CI, 1.21-3.01; P = 0.012), MI (PS-aHR, 1.72; 95% CI, 1.54-5.00; P = 0.008), revascularization (PS-aHR, 2.18; 95% CI, 1.69-3.11; P = 0.015), and cardiac death (PS-aHR, 2.27; 95% CI, 1.14-5.11; P = 0.023) remained significant. CONCLUSION Metabolic syndrome is common in AF patients without overt CAD, and confers an independent, increased risk of MACE, including MI, coronary revascularization, and cardiac death. Given its prognostic implications, prevention and treatment of MetS may reduce the burden of non-thromboembolic complications in AF.
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Improving the comprehension of sarcopenic state determinants: An multivariate approach involving hormonal, nutritional, lifestyle and genetic variables.
da Silva, JRD, Freire, IV, Ribeiro, ÍJS, Dos Santos, CS, Casotti, CA, Dos Santos, DB, Barbosa, AAL, Pereira, R
Mechanisms of ageing and development. 2018;:21-28
Abstract
It is known that sarcopenia is a multifaceted phenomenon, which involves genetic, nutritional, hormonal and living habits aspects. Then, an integrated analysis, as a multivariate approach, could improve the comprehension about the determinants of sarcopenic state in old adults. The present study aimed to investigate the interaction among serum vitamin D, daily caloric and protein intake, lifestyle habits, ACE I/D gene polymorphism and sarcopenic state in community-dwelling old adults. One hundred one community-dwelling old adults were clinically stratified as sarcopenic or non-sarcopenic. Serum vitamin D, daily caloric and protein intake, lifestyle habits (smoking, physical activity level and sedentary behavior) and ACE I/D gene polymorphism were recorded. A multivariate logistic regression technique was applied to investigate the interaction among the selected independent variables and the sarcopenic state. The independent variables age, smoking, serum Vitamin D and ACE I/D polymorphism achieved the statistical criteria to be inserted in the multivariate analysis. After a stepwise procedure from the multivariate logistic regression, the variables age, serum Vitamin D and ACE I/D polymorphism remained, together, in the final model. Sarcopenic state was significantly associated to older age, II-genotype and low serum Vitamin D in old adults from 60 years old.
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Integration of sudden death syndrome resistance loci in the soybean genome.
Chang, HX, Roth, MG, Wang, D, Cianzio, SR, Lightfoot, DA, Hartman, GL, Chilvers, MI
TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik. 2018;(4):757-773
Abstract
Complexity and inconsistencies in resistance mapping publications of soybean sudden death syndrome (SDS) result in interpretation difficulty. This review integrates SDS mapping literature and proposes a new nomenclature system for reproducible SDS resistance loci. Soybean resistance to sudden death syndrome (SDS) is composed of foliar resistance to phytotoxins and root resistance to pathogen invasion. There are more than 80 quantitative trait loci (QTL) and dozens of single nucleotide polymorphisms (SNPs) associated with soybean resistance to SDS. The validity of these QTL and SNPs is questionable because of the complexity in phenotyping methodologies, the disease synergism between SDS and soybean cyst nematode (SCN), the variability from the interactions between soybean genotypes and environments, and the inconsistencies in the QTL nomenclature. This review organizes SDS mapping results and proposes the Rfv (resistance to Fusarium virguliforme) nomenclature based on supporting criteria described in the text. Among ten reproducible loci receiving our Rfv nomenclature, Rfv18-01 is mostly supported by field studies and it co-localizes to the SCN resistance locus rhg1. The possibility that Rfv18-01 is a pleiotropic resistance locus and the concern about Rfv18-01 being confounded with Rhg1 is discussed. On the other hand, Rfv06-01, Rfv06-02, Rfv09-01, Rfv13-01, and Rfv16-01 were identified both by screening soybean leaves against phytotoxic culture filtrates and by evaluating SDS severity in fields. Future phenotyping using leaf- and root-specific resistance screening methodologies may improve the precision of SDS resistance, and advanced genetic studies may further clarify the interactions among soybean genotypes, F. virguliforme, SCN, and environments. The review provides a summary of the SDS resistance literature and proposes a framework for communicating SDS resistance loci for future research considering molecular interactions and genetic breeding for soybean SDS resistance.
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Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men.
Rubinow, KB, Vaisar, T, Chao, JH, Heinecke, JW, Page, ST
Journal of clinical lipidology. 2018;(4):1072-1082
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BACKGROUND Exogenous testosterone decreases serum concentrations of high-density lipoprotein cholesterol (HDL-C) in men, but whether this alters cardiovascular risk is uncertain. OBJECTIVE To investigate the effects of testosterone and estradiol on HDL particle concentration (HDL-Pima) and metrics of HDL function. METHODS We enrolled 53 healthy men, 19 to 55 years of age, in a double-blinded, placebo-controlled, randomized trial. Subjects were rendered medically castrate using the GnRH receptor antagonist acyline and administered either (1) placebo gel, (2) low-dose transdermal testosterone gel (1.62%, 1.25 g), (3) full replacement dose testosterone gel (1.62%, 5 g) or (4) full replacement dose testosterone gel together with an aromatase inhibitor for 4 weeks. At baseline and end of treatment, serum HDL total macrophage and ABCA1-specific cholesterol efflux capacity (CEC), HDL-Pima and size, and HDL protein composition were determined. RESULTS Significant differences in serum HDL-C were observed with treatment across groups (P = .01 in overall repeated measures ANOVA), with increases in HDL-C seen after both complete and partial testosterone deprivation. Medical castration increased total HDL-Pima (median [interquartile range] 19.1 [1.8] nmol/L at baseline vs 21.3 [3.1] nmol/L at week 4, P = .006). However, corresponding changes in total macrophage CEC and ABCA1-specific CEC were not observed. Change in serum 17β-estradiol concentration correlated with change in total macrophage CEC (β = 0.33 per 10 pg/mL change in serum 17β-estradiol, P = .03). CONCLUSIONS Testosterone deprivation in healthy men leads to a dissociation between changes in serum HDL-C and HDL CEC. Changes in serum HDL-C specifically due to testosterone exposure may not reflect changes in HDL function.
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Maintenance of Lost Weight and Long-Term Management of Obesity.
Hall, KD, Kahan, S
The Medical clinics of North America. 2018;(1):183-197
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Weight loss can be achieved through a variety of modalities, but long-term maintenance of lost weight is much more challenging. Obesity interventions typically result in early weight loss followed by a weight plateau and progressive regain. This review describes current understanding of the biological, behavioral, and environmental factors driving this near-ubiquitous body weight trajectory and the implications for long-term weight management. Treatment of obesity requires ongoing clinical attention and weight maintenance-specific counseling to support sustainable healthful behaviors and positive weight regulation.
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ER-Mitochondria Microdomains in Cardiac Ischemia-Reperfusion Injury: A Fresh Perspective.
Zhou, H, Wang, S, Hu, S, Chen, Y, Ren, J
Frontiers in physiology. 2018;:755
Abstract
The mitochondrial and endoplasmic reticulum (ER) homeostasis is pivotal to the maintenance of an array of physiological processes. The physical contact and association between ER and mitochondria, known as the ER-mitochondria microdomains or mitochondria-associated ER membrane (MAM), temporally and spatially regulates the mitochondria/ER structure and function. More evidence suggests a role for MAMs in energy production, cellular contraction and mobility, and normal extracellular signal transmission. In pathological states, such as cardiac ischemia-reperfusion (I/R injury), this ER-mitochondria microdomains may act to participate in the cellular redox imbalance, ER stress, mitochondrial injury, energy deletion, and programmed cell death. From a therapeutic perspective, a better understanding of the cellular and molecular mechanisms of the pathogenic ER-mitochondria contact should help to identify potential therapeutic target for cardiac I/R injury and other cardiovascular diseases and also pave the road to new treatment modalities pertinent for the treatment of reperfusion damage in clinical practice. This review will mainly focus on the possible signaling pathways involved in the regulation of the ER-mitochondria contact. In particular, we will summarize the downstream signaling modalities influenced by ER-mitochondria microdomains, for example, mitochondrial fission, mitophagy, calcium balance, oxidative stress, and programmed cell death in details.
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Arterial Stiffness: A Prognostic Marker in Coronary Heart Disease. Available Methods and Clinical Application.
Bonarjee, VVS
Frontiers in cardiovascular medicine. 2018;:64
Abstract
Multiple biomarkers may predict short and long-term prognosis in patients with coronary heart disease, but their impact is limited when used in addition to established risk factors such blood pressure, cholesterol levels, diabetes mellitus, smoking as well as age and sex. Arteries are an integral part of the cardiovascular (CV) system. Arterial stiffness has been shown to be a predictor of cardiovascular events and mortality independent of traditional risk factors. It has also been shown that increased arterial stiffness may predict cardiovascular events in asymptomatic individuals without overt cardiovascular disease. Measuring arterial stiffness may, therefore, identify patients at risk at an early stage. Antihypertensive treatment has been shown to reduce arterial stiffness beyond its antihypertensive effect. Arterial stiffness could, therefore, be a surrogate marker of treatment that relates to prognosis. Arterial stiffness has mostly been used in research protocols, and its use as a prognostic indicator in clinical practice is still uncommon. Several methods exist that can determine parameters related to arterial stiffness, both local and in specific artery beds such as the aorta. In this brief review we present methods to evaluate arterial stiffness, their clinical utility, limitations and the advantages of a novel method, the Cardio-Ankle Vascular Index. Easier and more reproducible methods to evaluate arterial stiffness may increase the use of parameter as a risk factor for coronary heart disease in common clinical practice.
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In silico prediction of nonpermissive HLA-DPB1 mismatches in unrelated HCT by functional distance.
Arrieta-Bolaños, E, Crivello, P, Shaw, BE, Ahn, KW, Wang, HL, Verneris, MR, Hsu, KC, Pidala, J, Lee, SJ, Fleischhauer, K, et al
Blood advances. 2018;(14):1773-1783
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In silico prediction of high-risk donor-recipient HLA mismatches after unrelated donor (UD) hematopoietic cell transplantation (HCT) is an attractive, yet elusive, objective. Nonpermissive T-cell epitope (TCE) group mismatches were defined by alloreactive T-cell cross-reactivity for 52/80 HLA-DPB1 alleles (TCE-X). More recently, a numerical functional distance (FD) scoring system for in silico prediction of TCE groups based on the median impact of exon 2-encoded amino acid polymorphism on T-cell alloreactivity was developed for all DPB1 alleles (TCE-FD), including the 28/80 common alleles not assigned by TCE-X. We compared clinical outcome associations of nonpermissive DPB1 mismatches defined by TCE-X or TCE-FD in 8/8 HLA-matched UD-HCT for acute leukemia, myelodysplastic syndrome, and chronic myelogenous leukemia between 1999 and 2011 (N = 2730). Concordance between the 2 models was 92.3%, with most differences arising from DPB1*06:01 and DPB1*19:01 being differently assigned by TCE-X and TCE-FD. In both models, nonpermissive mismatches were associated with reduced overall survival (hazard ratio [HR], 1.15, P < .006 and HR, 1.12, P < .03), increased transplant-related mortality (HR, 1.31, P < .001 and HR, 1.26, P < .001) as well as acute (HR, 1.16, P < .02 and HR, 1.22, P < .001) and chronic (HR, 1.20, P < .003 and HR, 1.22, P < .001) graft-versus-host disease (GVHD). We show that in silico prediction of nonpermissive DPB1 mismatches significantly associated with major transplant outcomes is feasible for any DPB1 allele with known exon 2 sequence based on experimentally elaborated FD scores. This proof-of-principle observation opens new avenues for developing HLA risk-prediction models in HCT and has practical implications for UD searches.
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Safety and Efficacy of Fludrocortisone in the Treatment of Cerebral Salt Wasting in Patients With Tuberculous Meningitis: A Randomized Clinical Trial.
Misra, UK, Kalita, J, Kumar, M
JAMA neurology. 2018;(11):1383-1391
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IMPORTANCE Tuberculous meningitis is associated with high frequency of cerebral salt wasting. There is a paucity of objective information regarding the best method of treatment of this condition. OBJECTIVE To evaluate the efficacy and safety of fludrocortisone in the treatment of cerebral salt wasting in patients with tuberculous meningitis. DESIGN, SETTING, AND PARTICIPANTS This is a single-center, open-label, randomized clinical trial conducted from October 2015 to April 2017 in India. Patients were randomized in a 1:1 ratio to arms receiving saline only or saline plus fludrocortisone, in addition to a standard treatment of 4 antitubercular drugs, prednisolone, and aspirin. The 2 arms were matched for demographic, clinical, and magnetic resonance imaging findings. The patients were followed up for at least 6 months. INTERVENTIONS Patients were randomized to a 0.9% solution of intravenous saline with 5 to 12 g per day of oral salt supplementation, with or without the addition of 0.1 to 0.4 mg of fludrocortisone per day. MAIN OUTCOMES AND MEASURES The primary end point was the time needed to correct serum sodium levels; secondary end points were in-hospital deaths, disability at 3 months, disability at 6 months, occurence of stroke, and serious adverse reactions. RESULTS Ninety-three patients with suspected tuberculous meningitis were recruited; 12 did not meet the inclusion criteria, including 4 with alternate diagnoses. A total of 37 patients with cerebral salt wasting were eligible for the study. One refused to participate, and therefore 36 patients were included, with 18 randomized to each group. The median (range) age was 30 (20-46) years, and 19 were male (52.8%). Those receiving fludrocortisone regained normal serum sodium levels after 4 days, significantly earlier than those receiving saline only (15 days; P = .004). In an intention-to-treat analysis, hospital mortality, disability at 3 months, and disability at 6 months did not differ significantly, but fewer infarcts occurred in the deep border zone in the group receiving fludrocortisone (1 of 18 [6%]) vs those in the control arm (6 of 18 [33%]; P = .04). Fludrocortisone was associated with severe hypokalemia and hypertension in 2 patients each, and pulmonary edema occurred in 1 patient. These adverse reactions necessitated discontinuation of fludrocortisone in 2 patients. CONCLUSIONS AND RELEVANCE Fludrocortisone results in earlier normalization of serum sodium levels, but did not affect outcomes at 6 months. Fludrocortisone had to be withdrawn in 2 patients because of severe adverse effects. This study provides class II evidence on the role of fludrocortisone in treatment of hyponatremia associated with cerebral salt wasting in patients with tuberculous meningitis. TRIAL REGISTRATION Clinical Trials Registry of India (ctri.nic.in) Identifier: CTRI/2017/10/010255.
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Phase II Clinical Trial of First-line Eribulin Plus Trastuzumab for Advanced or Recurrent HER2-positive Breast Cancer.
Sakaguchi, K, Nakatsukasa, K, Koyama, H, Kato, M, Sakuyama, A, Matsuda, T, Tsunoda, N, Fujiwara, I, Yamaguchi, M, Tanaka, H, et al
Anticancer research. 2018;(7):4073-4081
Abstract
BACKGROUND/AIM: Eribulin mesylate has been approved for advanced or metastatic breast cancers subjected to at least two previous chemotherapy regimens. The present multicenter, phase II, single-arm study assessed the efficacy and safety of a first-line regimen of eribulin plus trastuzumab for untreated advanced or metastatic HER2-positive breast cancer. PATIENTS AND METHODS Enrolled patients received eribulin (1.4 mg/m2 intravenously; I.V.) on days 1 and 8 of each 21-day cycle, an initial trastuzumab dose (8 mg/kg I.V.) on day 1, and 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. The primary endpoint was the response rate (RR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Twenty-eight patients (median age: 62.5 years) received a median of 12 (range: 2-53) cycles of eribulin plus trastuzumab. RESULTS The RR was 53.6% [complete response (CR), 4; partial response (PR), 11] with a median PFS of 344 days. The clinical benefit rate was 64.0%. Grade 3/4 adverse events were observed in 12 (42.9%) patients. For details, neutropenia in 8 (28.6%) patients, peripheral neuropathy in 2 (7.1%) patients, interstitial pneumonia in 1 (3.6%) patient, ALT elevation in 1 (3.6%) patient, osteonecrosis of the jaw in 1 (3.6%) patient, and fatigue in 1 (3.6%) patient. The patient with osteonecrosis received denosumab, too. No symptomatic congestive heart failure was observed. CONCLUSION Combination therapy of eribulin plus trastuzumab is acceptable in efficacy and safety, and a capable option for first-line advanced or recurrent HER2-positive breast cancer.