bluuebunny/crossref_metadata_2025 huggingface dataset:
A Cut-Point Value of Uncarboxylated to Carboxylated Index is Associated with Glycemic Status Markers in Type 2 Diabetes
Authors: Villafán-Bernal José Rafael , Llamas-Covarrubias Mara Anaís , Muñoz-Valle José Francisco , Rivera-León Edgar Alfonso , González-Hita Mercedes Elvira , Bastidas-Ramírez Blanca Estela , Gurrola-Díaz Carmen Magdalena , Armendáriz-Borunda Juan Socorro , Sánchez-Enríquez Sergio
Published: May 2016

Background

The uncarboxylated osteocalcin (ucOC) has been described as a regulator of glucose metabolism in mice, and it is decreased in human type 2 diabetes mellitus (T2D). Although inversely correlated with serum glucose, insulin, and glycated hemoglobin, it is unclear if ucOC decrement is caused by diabetes or plays a role in the pathogenesis and/or progression of the disease. Whatever the case may be, diabetes affects osteoblast gene expression, and possibly the proportion of ucOC over carboxylated OC (cOC). The association of ucOC/cOC index with glycemic status markers in patients with T2D has not been described before.

Objective

The objective of this study was to assess the ucOC/cOC index and its relationship with glycemic status markers in patients with T2D.

Methods

The ucOC/cOC index was determined by the quotient of ucOC and cOC serum levels in 80 T2D patients and 160 healthy subjects. The relationship between the ucOC/cOC index and glycemic status markers was evaluated.

Results

The ucOC/cOC index was low and negatively correlated to fasting plasma glucose and homeostasis assessment-insulin resistance model in T2D patients. The odds ratio for T2D patients with an ucOC/cOC index below the cut-point obtained by receiver operating characteristic analysis was 12.64 (confidence interval, 5.75–27.77; P < 0.001).

Conclusions

A value of ucOC/cOC index less than 0.3 is associated with markers of poor metabolic control in patients with T2D.
Pediatric Nephrologists’ Beliefs regarding Randomized Controlled Trials
Authors: Wightman Aaron G. , Oron Assaf P. , Symons Jordan M. , Flynn Joseph T.
Published: May 2016

Background

Pediatrics and pediatric nephrology lag behind adult medicine in producing randomized controlled trials (RCTs). Physician attitudes have been shown to play a significant role in RCT enrollment.

Methods

We surveyed members of the American Society of Pediatric Nephrology regarding beliefs about RCTs and factors influencing decisions to recommend RCT enrollment. Regression analyses were used to identify the effects of variables on an aggregate score summarizing attitudes toward RCTs.

Results

One hundred thirty replies were received. Sixty-six percent had enrolled patients in RCTs. Respondents in practice for more than 15 years were more likely to have recruited a patient to an RCT than those in practice for less than 5 years. Respondents were more willing to recommend RCT enrollment if the study was multicenter, patients were sicker or had a poorer prognosis, or if the parent or participant received a financial incentive versus the provider. In multiple regression analysis, history of enrolling patients in an RCT was the only significant predictor of higher aggregate RCT-friendly attitude.

Conclusions

Many pediatric nephrologists have never enrolled a patient in an RCT, particularly those in practice for less than 5 years. Respondents who have not enrolled patients in RCTs have a less RCT-friendly attitude. Provision of improved training and resources might increase participation of junior providers in RCTs.
Approaches to Preparing Young Scholars for Careers in Interdisciplinary Team Science
Authors: Begg Melissa D. , Crumley Gene , Fair Alecia M. , Martina Camille A. , McCormack Wayne T. , Merchant Carol , Patino-Sutton Cecilia M. , Umans Jason G.
Published: May 2016

To succeed as a biomedical researcher, the ability to flourish in interdisciplinary teams of scientists is becoming ever more important. Institutions supported by the Clinical and Translational Science Awards (CTSAs) from the National Institutes of Health have a specific mandate to educate the next generation of clinical and translational researchers. While they strive to advance integrated and interdisciplinary approaches to education and career development in clinical and translational science, general approaches and evaluation strategies may differ, as there is no single, universally accepted or standardized approach. It is important, therefore, to learn about the different approaches used to determine what is effective. We implemented a Web-based survey distributed to education leaders at the 60 funded CTSA institutions; 95% responded to the survey, which included questions on the importance of preparation for interdisciplinary team science careers, methods used to provide such training, and perceived effectiveness of these training programs. The vast majority (86%) of education leaders reported that such training is important, and about half (52%) of the institutions offer such training. Methods of training most often take the form of courses and seminars, both credit bearing and noncredit. These efforts are, by and large, perceived as effective by the training program leaders, although long-term follow-up of trainees would be required to fully evaluate ultimate effectiveness. Results from the survey suggest that CTSA education directors believe that specific training in interdisciplinary team science for young investigators is very important, but few methodologies are universally practiced in CTSA institutions to provide training or to assess performance. Four specific recommendations are suggested to provide measurable strategic goals for education in team science in the context of clinical and translational research.
The Positive Effect of Moderate Walking Exercise on Chemerin Levels in Portuguese Patients with Type 2 Diabetes Mellitus
Authors: Neuparth Maria João , Proença Jorge Brandão , Santos-Silva Alice , Coimbra Susana
Published: May 2016

Background

Physical exercise intervention is known to be crucial in the management of type 2 diabetes mellitus (T2DM). We aimed to evaluate, in patients with T2DM, the effect of regular moderate walking exercise on markers of oxidative stress, lipid metabolism, and inflammation.

Methods

We studied 30 patients with T2DM who walked regularly during the last year and 53 patients with T2DM who did not perform any type of exercise. The patients were evaluated for chemerin, adiponectin, leptin, oxidized low-density lipoprotein, and C-reactive protein (CRP) levels.

Results

The active T2DM patients showed significantly lower body mass index, as compared with the inactive patients. The active T2DM patients showed significantly lower levels of chemerin and CRP than those of the inactive T2DM patients (CRP lost significance after adjustment for body mass index). The active patients, compared with the inactive, presented a trend toward higher levels of adiponectin and lower values of oxidized low-density lipoprotein. Leptin differed significantly between sexes, and the active women presented a trend toward lower levels as compared with the inactive women.

Conclusions

In the patients with T2DM, the practice of moderate walking in a regular basis was sufficient to reduce chemerin levels, which suggests that practice of regular physical exercise should be encouraged.
Triglyceride Glucose Index and Common Carotid Wall Shear Stress
Authors: Tripolino Cesare , Irace Concetta , Scavelli Faustina B. , de Franceschi Maria S. , Esposito Teresa , Carallo Claudio , Gnasso Agostino
Published: May 2016

Objectives

Alterations in wall shear stress contribute to both clinical and subclinical atherosclerosis. Several conditions such as hypertension, diabetes, and obesity can impair shear stress, but the role of insulin resistance has never been investigated. The present study was designed to investigate whether insulin resistance assessed by TyG Index associates with wall shear stress in the common carotid artery.

Methods

One hundred six individuals were enrolled. Blood pressure, lipids, glucose, and cigarette smoking were evaluated. TyG Index was calculated as log[fasting triglycerides × fasting glucose / 2]. Subjects underwent blood viscosity measurement and echo-Doppler evaluation of carotid arteries to calculate wall shear stress. The association between TyG Index and carotid wall shear stress was assessed by simple and multiple regression analyses.

Results

TyG Index was significantly and inversely associated with carotid wall shear stress both in simple ( r = −0.44, P < 0.001) and multiple regression analyses accounting for age, sex, and major cardiovascular risk factors. The association was further confirmed after exclusion of subjects with diabetes, dyslipidemia, fasting blood glucose greater than 100 mg/dL, and triglycerides greater than 150 mg/dL.

Conclusions

The present findings suggest that increasing insulin resistance, as assessed by TyG Index, associates with atherosclerosis-prone shear stress reduction in the common carotid artery.
Triglyceride–to–High-Density-Lipoprotein-Cholesterol Ratio is an Index of Heart Disease Mortality and of Incidence of Type 2 Diabetes Mellitus in Men
Authors: Vega Gloria Lena , Barlow Carolyn E. , Grundy Scott M. , Leonard David , DeFina Laura F.
Published: May 2016

Background

High triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) impart risk for heart disease. This study examines the relationships of TG/HDL-C ratio to mortality from all causes, coronary heart disease (CHD), or cardiovascular disease (CVD).

Subjects and Methods

Survival analysis was done in 39,447 men grouped by TG/HDL-C ratio cut point of 3.5 and for metabolic syndrome. National Death Index International Classification of Diseases ( ICD-9 and ICD-10) codes were used for CVD and CHD deaths occurring from 1970 to 2008. Incidence of type 2 diabetes mellitus (DM) according to ratio was estimated in 22,215 men. Triglyceride/HDL-C ratio and cross-product of TG and fasting blood glucose (TyG index) were used in analysis.

Results

Men were followed up for 581,194 person-years. Triglyceride/HDL-C ratio predicted CHD, CVD, and all-cause mortality after adjustment for established risk factors and non–HDL-C. Mortality rates were higher in individuals with a high ratio than in those with a low ratio. Fifty-five percent of men had metabolic syndrome that was also predictive of CHD, CVD, and all-cause mortality. Annual incidence of DM was 2 times higher in men with high TG/HDL-C ratio than in those with a low ratio. Individuals with high TG/HDL-C ratio had a higher incidence of DM than those with a low ratio. The TyG index was not equally predictive of causes of mortality to TG/HDL-C, but both were equally predictive of diabetes incidence.

Conclusions

Triglyceride/HDL-C ratio predicts CHD and CVD mortality as well as or better than do metabolic syndrome in men. Also, a high ratio predisposes to DM. The TyG index does not predict CHD, CVD, or all-cause mortality equally well, but like TG/HDL-C ratio, it predicts DM incidence.
Clinical Implications of the Interleukin 27 Serum Level in Breast Cancer
Authors: Lu Dapeng , Zhou Xiangyu , Yao Lutian , Liu Caigang , Jin Feng , Wu Yunfei
Published: May 2016

Introduction

Interleukin 27 (IL-27), belonging to the IL-12 family, exerts a critical role in immune regulation of infection, autoimmunity, and tumor. In this study, we aimed to investigate the roles of IL-27 and vascular endothelial growth factor (VEGF) in breast cancer.

Methods

The serum levels of IL-27 and VEGF in 150 patients with breast cancer and 90 control subjects were measured by an enzyme-linked immunosorbent assay. Estrogen receptor, progesterone receptor, and human epithelial growth factor receptor 2 were measured by immunohistochemistry. Clinical stage, tumor size, lymph node metastasis, grade, and histological type were also recorded.

Results

The serum levels of IL-27 and VEGF were significantly greater in breast cancer patients than in the control group. In addition, there was a significant correlation between IL-27 and VEGF, and serum IL-27 and VEGF levels were associated with the clinical stage of breast cancer. Moreover, the serum levels of IL-27 were especially elevated in breast cancer patients who were estrogen receptor–positive and progesterone receptor–positive. Furthermore, the serum levels of IL-27 and VEGF decreased after patients with breast cancer had modified radical mastectomy.

Conclusion

Interleukin 27 may be a new prognostic biomarker of breast cancer and a promising target to limit both angiogenesis and tumor growth.
Asthma and Obstructive Sleep Apnea: Clinical and Pathogenic Interactions
Authors: Puthalapattu Swathy , Ioachimescu Octavian C.
Published: May 2016

Asthma and obstructive sleep apnea (OSA) are among the most prevalent chronic human diseases of the 21st century. They share several risk and aggravating factors such as obesity, smoking, gastroesophageal reflux, sinonasal disease or upper airway involvement, systemic inflammation, etc. Although the association between OSA and chronic obstructive pulmonary disease or “overlap syndrome” is better known and characterized, the association of asthma and OSA or “alternative overlap syndrome” is less clearly defined and understood. Nevertheless, their coexistence has synergistic effects on patient symptoms, response to therapy, and general outcomes. Taxonomically, asthma and OSA are syndromically defined entities that are quite heterogeneous, being characterized by a plethora of clinical phenotypes. The complex interactions between these conditions should take into account more specific etiopathogenic mechanisms or distinct disease endotypes. The potential clinical, pathogenic, and therapeutic significance of the disease endotypes is still emerging and needs further evaluation. We present here a review on the bidirectional relationships between asthma and OSA, including their clinical, pathophysiologic, and therapeutic connections. Furthermore, we propose here to look at these interactions beyond the development of comprehensive inventories of genotypes, clinical and pathophysiologic phenotypes, but in the larger context of obstructive lung and airway disorders, with the goal to reassess meaningful syndromes based on natural history and predictable patient outcomes, which will help us better stratify therapy in an era of personalized medicine.
Evaluation of Feasible Timing of Elective Noncardiac Procedure after Antiplatelet Discontinuation in Patients Treated with Antiplatelet Agents
Authors: Joo Min Sun , Ahn Byung Moo , Kim Hee Jun , Mun Hee-Sun , Kang Min Kyung , Choi Seong Hoon , Park Min Jeong , Song Won Keun , Lee Nam Ho , Cho Jung Rae
Published: May 2016

Background

The current standard of care is to delay noncardiac procedure (NCP) 5 to 7 days after discontinuation of antiplatelet agents (APAs) in patients with coronary stents. However, it is often difficult to follow because of concerns over stent thrombosis. The point-of-care aspirin/P2Y12 assay (VerifyNow; Accumetrics Inc, San Diego, CA) is useful to evaluate platelet reactivity in conjunction with APAs. In this study, we evaluated the feasible timing after discontinuation of APAs.

Methods and Results

Sixty-two patients taking APAs, who were scheduled to undergo elective NCP, were enrolled. All patients took either aspirin 100 mg or aspirin 100 mg plus clopidogrel 75 mg daily. The aspirin-reactivity unit (ARU) and P2Y12-reactivity unit (PRU) were measured from 0 days (day 0, no discontinuation) to as long as 5 days (day 5, 5 days after discontinuation) depending on each procedure schedule. For 15 patients, baseline ARU and PRU (592 and 288) before aspirin/clopidogrel loading at index percutaneous coronary intervention were collected as control. For ARU after discontinuation of APA, days 0 to 5 values progressively increased over time (489.4 ± 85.3, 512.6 ± 77.0, 589.9 ± 58.8, 613.6 ± 47.3, 632.6 ± 49.2, 662.0 ± 4.2). Likewise, for PRUs, days 0 to 5 values also increased over time (245.0 ± 96.9, 253.9 ± 80.9, 270.9 ± 45.8, 289.0 ± 68.6, 306.5 ± 29.2, 351.0 ± 8.5). The ARU and PRU well correlated with days after APA discontinuation by linear regression analysis ( y = 490.897 + 39.238 * x, R2 = 0.43, P < 0.001; y = 241.739 + 16.701 * x, R2 = 0.092, P = 0.018, respectively). Assuming baseline ARU and PRU as 592 and 288, the mean days after complete reversal of platelet reactivity by APAs are 2.6 and 2.8, respectively.

Conclusions

The feasible timing of NCP after discontinuation of APAs showed less than 5 days. VerifyNow is useful in the evaluation of antiplatelet reversal after discontinuation of APAs.
The Effect of a Disease Management Algorithm and Dedicated Postacute Coronary Syndrome Clinic on Achievement of Guideline Compliance: Results from the Parkland Acute Coronary Event Treatment Study
Authors: Yorio Jeff , Viswanathan Sundeep , See Raphael , Uchal Linda , McWhorter Jo Ann , Spencer Nali , Murphy Sabina , Khera Amit , de Lemos James A. , McGuire Darren K.
Published: May 2016

Background

The application of disease management algorithms by physician extenders has been shown to improve therapeutic adherence in selected populations. It is unknown whether this strategy would improve adherence to secondary prevention goals after acute coronary syndromes (ACSs) in a largely indigent county hospital setting.

Methods

Patients admitted for ACS were randomized at the time of discharge to usual follow-up care versus the same care with the addition of a physician extender visit. Physician extender visits were conducted according to a treatment algorithm based on contemporary practice guidelines. Groups were compared using the primary end point of achievement of low-density lipoprotein treatment goals at 3 months after discharge and achievement of additional evidence-based practice goals.

Results

One hundred forty consecutive patients were randomized. A similar proportion of patients returned for study follow-up in both groups at 3 months (54 [79%]/68 in the usual care group vs 57 [79%]/72 in the intervention group; P = 0.97). Among those completing the 3-month visit, a low-density lipoprotein cholesterol level less than 100 mg/dL was achieved in 37 (69%) of the usual care patients compared with 35 (57%) of those in the intervention group ( P = 0.43). There was no statistical difference in implementation of therapeutic lifestyle changes (smoking cessation, cardiac rehabilitation, or exercise) between groups. Prescription rates of evidence-based therapeutics at 3 months were similar in both groups.

Conclusion

The implementation of a post-ACS clinic run by a physician extender applying a disease management algorithm did not measurably improve adherence to evidence-based secondary prevention treatment goals. Despite initially high rates of evidence-based treatment at discharge, adherence with follow-up appointments and sustained implementation of evidence-based therapies remains a significant challenge in this high-risk cohort.
Serum Ghrelin Concentrations are Increased in Children with Growth Hormone Insensitivity and Decrease during Long-Term Insulinlike Growth Factor-I Treatment
Authors: Uckun-Kitapci Aysin , Haqq Andrea M. , Purnell Jonathan Q. , Newcomb Kenneth , Gulkesen Hakan , Underwood Louis E.
Published: May 2016

Background

Ghrelin increases food intake, body weight, and growth hormone (GH) secretion. Serum concentrations of ghrelin are low in obese hyperinsulinemic persons, are reduced by infusion of insulin into normal-weight subjects, and are increased in underweight hypoinsulinemic patients with anorexia nervosa. Laron syndrome is an autosomal recessive disorder of GH insensitivity that results in decreased insulinlike growth factor-I (IGF-I) synthesis and growth failure. These patients have elevated GH levels, excess adipose tissue, and are insulin resistant. Because IGF-I has insulinlike actions and patients with GH insensitivity syndrome (GHIS) exhibit excess adiposity, we sought to determine whether ghrelin levels were elevated in these patients and potentially regulated by IGF-I replacement.

Methods

Thirteen children with GHIS and 20 normal control children matched for age, sex, and body mass index underwent complete physical examination and a fasting blood draw at baseline. The GHIS subjects then underwent follow-up fasting blood draws during therapy with human recombinant IGF-I (80-120 μg/kg, given subcutaneously twice daily). Fasting glucose, insulin, and IGF-I concentrations were measured at the time of collection. Fasting total ghrelin levels were measured on stored serum samples.

Results

The GHIS subjects had 2-fold higher fasting ghrelin levels (2926 ± 1869 pg/mL) compared with the normal control children (1492 ± 493 pg/mL; P = 0.009), and mean ghrelin values were reduced 56% during 6.4 ± 0.2 years of IGF-I replacement ( P < 0.05).

Conclusions

Growth hormone resistance and low IGF-I levels are associated with elevated ghrelin levels, which may potentiate GH secretion and adiposity in these children. Suppression of ghrelin during IGF-I treatment suggests a novel mechanism potentially regulating ghrelin levels.
PPARγ: A Novel Molecular Target in Lung Disease
Authors: Hart C. Michael , Roman Jesse , Reddy Raju , Sime Patricia J.
Published: May 2016

Interest in peroxisome proliferator-activated receptors (PPARs) has steadily increased over the past 15 years. The recognition that subclasses of this receptor played critical roles in regulation of metabolism led to the development of synthetic ligands and their widespread application in the treatment of type 2 diabetes. At the same time, emerging evidence demonstrated that the influence of PPARs extends well beyond metabolism and diabetes. A salient example of this can be seen in studies that explore the role of PPARs in lung cell biology. In fact, current literature suggests that PPAR receptors may well represent exciting new targets for treatment in a variety of lung disorders. In an attempt to keep the scientific and medical communities abreast of these developments, a symposium sponsored by the American Federation for Medical Research entitled “PPARγ: A Novel Molecular Target in Lung Disease” was convened on April 29, 2007, at the Experimental Biology Meeting in Washington, DC. During that symposium, 4 speakers reviewed the latest developments in basic and translational research as they relate to specific lung diseases. Jesse Roman, MD, professor and director of the Emory University Division of Pulmonary, Allergy, and Critical Care Medicine, reviewed the role of PPARγ in the pathogenesis of lung cancer and its implications for therapy. Raju Reddy, MD, assistant professor of Medicine at the University of Michigan, presented data regarding the immunomodulatory role of PPARγ in alveolar macrophages. Patricia J. Sime, MD, associate professor of Medicine, Environmental Medicine, and Oncology at the University of Rochester School of Medicine, discussed the antifibrogenic potential of PPARγ ligands in pulmonary fibrosis. Finally, C. Michael Hart, MD, professor of Medicine at Emory University and chief of the Atlanta Veterans Affairs Medical Center Pulmonary Section, reviewed the role of PPARγ in pulmonary vascular disease. This brief introduction to the symposium will provide background information about PPARs to facilitate the general reader's appreciation of the more in-depth and disease-specific discussions that follow.
Elevated Gluconeogenesis and Lack of Suppression by Insulin Contribute to Cystic Fibrosis-Related Diabetes
Authors: Hardin Dana S. , Ahn Chul , Rice Julie , Rice Mark , Rosenblatt Randall
Published: May 2016

The incidence of diabetes is high in cystic fibrosis (CF) and is an important cause of morbidity and mortality. Understanding the pathophysiology is imperative. Studies have documented increased endogenous (mostly hepatic) glucose production (HGP) but have not distinguished the relative contribution of gluconeogenesis (GNG). The purpose of this study was to quantitate GNG, to determine its contribution to high HGP, and to measure insulin's suppression of GNG.

We recruited 31 adult CF subjects (age, 26.2 ± 7.9 years; 12 female subjects) and quantified GNG by measuring the incorporation of 2H into the second and fifth carbons of glucose. Hepatic glucose production was measured using [6,6-2H2]glucose. Protein breakdown was measured using [1-13C]leucine. Data were compared with that from 11 healthy volunteers (age, 27.5 ± 7.0 years) who underwent both GNG and clamp studies. Thirteen CF subjects and all controls had a hyperinsulinemic euglycemic clamp during measures of GNG. Other measures included glucose tolerance and glucagon and cortisol levels.

Rate of GNG was higher in CF subjects than controls and comprised a greater percentage of fasting HGP (GNG as percent of HGP: CF = 68%; controls = 44%; P = 0.034). Suppression of GNG by insulin was significantly lower in CF than in controls and was lower in CF subjects with abnormal glucose tolerance than in those with normal glucose tolerance. Gluconeogenesis correlated with protein breakdown.

These studies suggest that high HGP in CF is mostly from elevated rates of GNG and that resistance to insulin's suppression of GNG may contribute to abnormal glucose tolerance in CF.
Clopidogrel Use in Coronary Heart Disease and Percutaneous Coronary Intervention
Authors: Atiemo Andrew D. , Williams Marlene S.
Published: May 2016

Antiplatelet therapy has proven efficacy in the management of atherothrombosis. Clopidogrel, a thienopyridine, is a potent antiplatelet agent that achieves its antiplatelet effects by inhibiting the binding of adenosine 5’ diphosphate to its platelet receptor. Large clinical trials have demonstrated a role for clopidogrel in the management of symptomatic atherosclerosis, acute coronary syndromes, and patients undergoing percutaneous coronary intervention. In this review, we discuss the pharmacology of clopidogrel including the mechanism of action, review the major clinical trials that have defined the current role of clopidogrel in coronary heart disease and percutaneous coronary intervention, and, finally, examine the concept of clopidogrel resistance and its potential clinical implications.
Central Role of Rho Kinase in Lipopolysaccharide-Induced Platelet Capture on Venous Endothelium
Authors: Slotta Jan E. , Braun Oscar Ö. , Menger Michael D. , Thorlacius Henrik
Published: May 2016

Background

Platelet-endothelial cell interactions play a key role in hemostasis and pathological coagulation and are dependent on different surface molecules that are expressed upon activation (eg, mediated by lipopolysaccharide [LPS]). Recently, we have shown that Rho kinase plays a central role in LPS-mediated leukocyte-endothelial cell interactions. We investigated the role of Rho-kinase in inflammatory interactions between platelets and the endothelium in femoral veins in vivo.

Methods

Mice were injected intravenously with LPS (0.5 mg/kg)/D-galactosamine (900 mg/kg), and Rho kinase was blocked with fasudil 15 minutes before LPS application. Four hours after LPS administration, intravital fluorescence microscopy of the femoral vein was performed, and primary and secondary platelet-endothelial cell interactions were visualized after in vivo platelet staining with rhodamine 6G.

Results

Intravital microscopy showed a significant increase in platelet tethering, rolling, and firm adhesion as well as platelet secondary capture in LPS-treated mice. Rho-kinase inhibition by fasudil significantly reduced platelet tethering, rolling, and firm adhesion. Interestingly, functional blockade of Rho kinase was also able to diminish secondary platelet capture by 79%.

Conclusions

From our data, we conclude that Rho-kinase signaling plays a central role in the regulation of LPS-induced platelet-endothelial cell interactions in large veins in vivo. Thus, Rho-kinase inhibition might be useful in prevention or treatment of pathological inflammation and endotoxin-mediated hypercoagulation.
Effects of Additive Therapy with Spironolactone on Proteinuria in Diabetic Patients Already on ACE Inhibitor or ARB Therapy: Results of a Randomized, Placebo-Controlled, Double-Blind, Crossover Trial
Authors: Saklayen Mohammad G. , Gyebi Leonard K. , Tasosa Joseph , Yap Jayson
Published: May 2016

Introduction

Aldosterone seems to have deleterious effects on the kidneys. Many animal studies and a few clinical trials have shown that suppression of aldosteroneby aldosterone receptor blockers ameliorates these effects.

Method

In a double-blind crossover study, patients with diabetic nephropathy who were already receiving either angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) were given spironolactone or matching placebo with 1 month of washout in between. Blood pressure (BP), serum creatinine, serum potassium, and spot urine protein/creatinine were measured at the beginning and end of each study period.

Results

Mean systolic BP on spironolactone went down from 153.64 (±25.95) at the beginning to 141.60 (±16.54) at the end of study ( P = 0.01). Diastolic BP during spironolactone therapy did not change significantly. The urine protein/creatinine increased from 1.24 (±1.13) to 1.57 (±2.13) on placebo ( P = 0.35) and decreased from 1.80 (±1.78) to 0.79 (±0.99) during spironolactone therapy ( P = 0.004). In other words proteinuria increased by 24% during the placebo treatment period but decreased by half (57%) during the active treatment. Serum potassium increased from 4.29 (±0.47) to 4.64 (±0.55) during spironolactone therapy ( P = 0.002), no significant change with placebo. Whereas serum creatinine did not change on placebo, it increased from 1.35 (±0.54) to 1.56 (±0.62) on spironolactone ( P = 0.006). Glomerular filtration rate decreased from 61.91 (±23.4) to 53.94 (±23.58) on spironolactone ( P = 0.0001) but not on placebo.

Conclusions

Addition of a modest dose of spironolactone to a regimen of ACEI or ARB in patients with diabetic proteinuria causes further reduction in proteinuria and also lowers the systolic BP. As with ACEI or ARB, spironolactone modestly reduces the glomerular filtration rate and raises serum potassium.
Do Surrogate Markers for Adiposity Relate to Cytokines in Adolescents?
Authors: Rubin Daniela A. , McMurray Robert G. , Harrell Joanne S. , Hackney Anthony C. , Haqq Andrea M.
Published: May 2016

Purpose

To determine the associations between field-collected surrogates of adiposity and concentrations of resistin, tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and adiponectin in youth.

Methods

Cross-sectional data from 60 normal weight and 60 overweight adolescents, ages 10-14 years, were retrospectively examined. Body mass index (BMI) percentile, sum of subscapular and triceps skinfolds (SSF), and waist circumference (WC) were used to classify weight status (BMI) or adiposity (SSF and WC). Percentiles for each surrogate were used for comparison groups. Fasting TNF-α, IL-6, resistin, and adiponectin concentrations were measured in plasma.

Results

Multiple regression models, controlling for sex and ethnicity, indicated that TNF-α was associated with BMI percentile ( R2 = 0.107, P < 0.05) and SSF ( R2 = 0.085, P < 0.05), whereas resistin was associated with SSF ( R2 = 0.118, P < 0.05). Adiponectin was associated with all 3 adiposity markers: BMI percentile ( R2 = 0.298, P < 0.05), SSF ( R2 = 0.297, P < 0.05), and waist ( R2 = 0.278, P < 0.05). Analyses of variance indicated higher TNF-α and lower adiponectin concentrations in youth with a BMI higher than the 95th percentile ( P = 0.014; P < 0.001) or SSF higher than the 95th percentile ( P = 0.025; P < 0.001). Youth with WC higher than the 90th percentile had higher resistin ( P = 0.029), higher IL-6 ( P = 0.028), and lower adiponectin ( P < 0.001) concentrations.

Conclusions

Of the 3 surrogates examined, differences in cytokine concentrations were mostly observed in youth who had WC percentiles higher than the 90th percentiles versus WC lower than the 75th percentiles. Alternatively, from the multiple-regression models SSF, an estimate of subcutaneous adiposity was the surrogate most consistently related to all cytokines, although the degrees of associations were low. The results suggest that although some surrogates were more strongly associated to certain cytokines, WC and SSF seemed more closely associated with cytokines than a BMI percentile indicating obesity.
Evaluation of Risk Factors and Seroprevalence of Hepatitis B and C in Diabetic Patients in Kutahya, Turkey
Authors: Gulcan Aynur , Gulcan Erim , Toker Aysun , Bulut İsmet , Akcan Yusuf
Published: May 2016

Aim

To assess the prevalence of hepatitis B and C viruses among Turkish patients with type 1 and type 2 diabetes mellitus and to determine the risk factors affecting the prevalence in these patient groups.

Methods

This study included 630 diabetic and 314 nondiabetic patients. Serologic testing for anti-hepatitis C virus (anti-HCV) and HbsAg was done using a third-generation commercial enzyme-linked immunosorbent assay, and samples positive for anti-HCV and HbsAg were confirmed by a polymerase chain reaction assay. Diabetic patients were classified by HbsAg and anti-HCV status and were evaluated according to demographic features, diabetic characteristics and nondiabetic general risk factors, harmful habits, and aminotransferase (alanine aminotransferase and aspartate aminotransferase) levels.

Results

HbsAg and anti-HCV seropositivity rates were 5.1% and 3.2% in diabetic patients and were 3.8% and 1.3% in control group, respectively. There was no statistically significant difference between the 2 groups with respect to either marker. Shared risk factors for both hepatitis infections were increased aminotransferase levels and history of hospital admission. In addition, long duration of diabetes mellitus, poor diabetic regulation, and insulin treatment usage were found to relate to HbsAg, whereas a history of blood transfusions and surgical procedures were found to associate with anti-HCV seropositivity.

Conclusions

We determined that hepatitis B virus and hepatitis C virus infections were slightly but not significantly higher in diabetic patients compared with a normal population. If it is considered that different results might be obtained in various countries or even in various regions of same country, it may be concluded that multicenter and comprehensive studies are needed to elucidate true infection rates and to identify other risk factors affecting the prevalence of these infections.
Behavior and Obesity in Women across the Life Span
Authors: Keitt Sarah K. , Resnick Eileen M. , Simon Viviana R. , Iskikian Sara O. , Marts Sherry A.
Published: May 2016

In October 2006, the Society for Women's Health Research convened a workshop that focused on the behavioral and social influences on obesity in women across the life span with an emphasis on ethnicity, socioeconomic status, and mental health. The purposes of the workshop were to examine the current state of the science related to behavioral influences on obesity in women across the life span; to determine the mechanisms, methods, and technical advances required for research progress in this area; and to develop an agenda for future research on behavioral influences on obesity in women. The workshop participants included psychologists, social scientists, clinicians, health educators, health services researchers, nutrition specialists, and epidemiologists, among others, who have expertise in obesity at critical life stages in women (childhood, adolescence, pregnancy, menopause, and older age). Discussions during the workshop focused on 4 specific topics: (1) the relationship between mental or emotional health and obesity in women; (2) the impact of social, cultural, and environmental factors on obesity in women; (3) the improvement of obesity research methodology; and (4) the development of obesity prevention and intervention strategies. Based on these discussions, participants proposed recommendations for future research.
How to Launch a Successful Career in Clinical Research
Authors: Toto Robert D.
Published: May 2016

Preparing for a career in academic medicine is both challenging and rewarding. Most trainees need guidance to successfully navigate the period of training and early years as a faculty member. An important aspect for young investigators is learning how to avail themselves of resources they will need to build a research program. This article provides some timely and valuable tips on how to lay the groundwork for long-term success as a clinical/translational researcher.
“Ignoramics” in Medical and Premedical Education
Authors: Witte Marlys H. , Crown Peter , Bernas Michael , Garcia Francisco A.R.
Published: May 2016

As physician-essayist Lewis Thomas has urged, ignorance-based courses and curricula are urgently needed in medical education to prepare future generations of scientific physicians and physician-scientists for the uncertain, rapidly changing world ahead. This article reviews the evolving concept of ignorance in general and specifically in medicine and its relationship to knowledge. Issues about goals, content, and assessment of such ignorance-based courses are discussed along with the experience of the University of Arizona's National Institutes of Health-sponsored Summer Institute on Medical Ignorance for medical student researchers and disadvantaged high school students. Summer Institute on Medical Ignorance activities can be readily replicated or adopted in their entirety or partially in both live and Internet-based formats. These will serve to introduce medical ignoramics and questioning as a way to balance the information-overloaded medical curriculum.
Reporting of Multivariable Methods in the Medical Literature
Authors: Tetrault Jeanette M. , Sauler Maor , Wells Carolyn K. , Concato John
Published: May 2016

Background

Multivariable models are frequently used in the medical literature, but many clinicians have limited training in these analytic methods. Our objective was to assess the prevalence of multivariable methods in medical literature, quantify reporting of methodological criteria applicable to most methods, and determine if assumptions specific to logistic regression or proportional hazards analysis were evaluated.

Methods

We examined all original articles in Annals of Internal Medicine, British Medical Journal, Journal of the American Medical Association, Lancet, and New England Journal of Medicine, from January through June 2006. Articles reporting multivariable methods underwent a comprehensive review; reporting of methodological criteria was based on each article's primary analysis.

Results

Among 452 articles, 272 (60%) used multivariable analysis; logistic regression (89 [33%] of 272) and proportional hazards (76 [28%] of 272) were most prominent. Reporting of methodological criteria, when applicable, ranged from 5% (12/265) for assessing influential observations to 84% (222/265) for description of variable coding. Discussion of interpreting odds ratios occurred in 13% (12/89) of articles reporting logistic regression as the primary method and discussion of the proportional hazards assumption occurred in 21% (16/76) of articles using Cox proportional hazards as the primary method.

Conclusions

More complete reporting of multivariable analysis in the medical literature can improve understanding, interpretation, and perhaps application of these methods.
Tumor Necrosis Factor α-308 and -238 Polymorphisms in Rheumatoid Arthritis. Association with Messenger RNA Expression and sTNF-α
Authors: Oregón-Romero Edith , Vázquez-Del Mercado Mónica , Ruiz-Quezada Sandra Luz , Navarro-Hernández Rosa Elena , Rangel-Villalobos Héctor , Martínez-Bonilla Gloria , Bernard-Medina Ana Guilaisne , Armendáriz-Borunda Juan , García-Bañuelos Jesús , Muñoz-Valle José Francisco
Published: May 2016

Background

Rheumatoid arthritis (RA) is characterized by a progressive joint damage mediated mainly by tumor necrosis factor α (TNFα). We investigated the relationship of TNFα-308 and -238 polymorphisms with messenger RNA (mRNA) expression and soluble TNFα (sTNFα) in 50 RA and 100 healthy subjects (HS).

Methods

Clinical and laboratory assessments were performed. Spanish Health Assessment Questionnaire Disability Index, Spanish version of Arthritis Impact Measurement Scales and Disease Activity Score using 28 joint count indices were applied to RA patients. The TNFα-308 and -238 polymorphisms were performed by polymerase chain reaction and restriction fragment length polymorphism techniques. The mRNA expression of TNFα was quantified by real-time polymerase chain reaction. The sTNFα levels were measured by enzyme-linked immunosorbent assay.

Results

The TNFα-308 polymorphism showed an increased frequency of guanine (G)/adenine (A) genotype in RA versus HS ( P = 0.03; 95% confidence interval, 1.05-8.08; odds ratio, 2.9) and also the A allele was more frequent in RA patients versus HS ( P = 0.04; 95% confidence interval, 1.01-7.29; odds ratio, 2.7). The G/G genotype and also the G allele were more frequent in HS. No significant difference was observed in TNFα-238 polymorphism. Rheumatoid arthritis patients showed high TNFα mRNA expression (1.33-fold). The G/G genotype was associated with high mRNA and sTNFα levels in both TNFα polymorphisms. The correlation of sTNFα levels with C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, Spanish Health Assessment Questionnaire Disability Index, and Spanish version of Arthritis Impact Measurement Scales, was observed.

Conclusion

The TNFα-308 polymorphism is a susceptibility marker to RA. The G/G genotype is associated with a high mRNA and soluble TNFα expression.
Rapamycin Inhibits Growth Factor-Induced Cell Cycle Regulation in Pancreatic β Cells
Authors: Aronovitz Amy , Josefson Jami , Fisher Amanda , Newman Marsha , Hughes Elizabeth , Chen Fei , Moons David S. , Kiyokawa Hiroaki , Lowe William L.
Published: May 2016

A progressive decline in islet function is a major obstacle to the success of islet transplantation. The cause of this decline in islet function is unclear, but immunosuppressive agents may contribute. Insulin-like growth factor-I (IGF-I) and betacellulin are important for islet cell survival and/or proliferation. In the present study, we performed studies in INS-1 cells and murine islets to define the effect of IGF-I and betacellulin on progression of islet cells through the cell cycle and the impact of immunosuppressive agents. Treatment of INS-1 cells for 24 hours with 20 ng/mL betacellulin or 50 ng/mL IGF-I increased cells in S phase by ∼2-fold. Treatment of INS-1 cells with IGF-I or betacellulin also increased cyclin D1 expression and nuclear exclusion of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1. In INS-1 cells and islets, betacellulin- and IGF-I increased Akt, extracellular signal-related kinase, and p70S6 kinase phosphorylation. Rapamycin, an immunosuppressant which inhibits mammalian target of rapamycin, inhibited the increase in p70S6 kinase phosphorylation stimulated by betacellulin- and IGF-I in INS-1 cells. Rapamycin also inhibited betacellulin- and IGF-I-induced entry of cells into S phase and 5′-Bromo-2′-deoxyuridine incorporation as well as the effect of betacellulin and IGF-I on cyclin D1 expression and nuclear exclusion of p21Cip1 and p27Kip1. Together, these data suggest that the effect of betacellulin and IGF-I on islet cell growth and proliferation is mediated, in part, via signaling through mammalian target of rapamycin. As rapamycin is used to treat islet transplant recipients, these results suggest that rapamycin could have deleterious effects on islet proliferation and function over time.
Clinical Research from Proposal to Implementation
Authors: Rivera Suzanne M.
Published: May 2016

The conduct of clinical trials is a complicated process involving a myriad of regulations and enforcement entities. To protect the rights and welfare of study participants, a system of oversight bodies called institutional review boards has been established in the US. This article describes how institutional review boards work and explains what clinical researchers need to know about federally mandated human subject protection requirements.
ACE Insertion/Deletion, but Not −240A>T Polymorphism, Modulates the Severity in Heart Failure
Authors: Fatini Cinzia , Sticchi Elena , Marcucci Rossella , Said Abdihakim Abdullahi , Del Pace Stefano , Verdiani Valerio , Nozzoli Carlo , Gensini Gian Franco , Abbate Rosanna
Published: May 2016

Objective

ACE gene is reported to be a candidate gene in heart failure. The insertion/deletion (I/D) polymorphism has been observed to be a predictor of mortality in this disease, but no data are available concerning the role of ACE −240A>T polymorphism. In this study, we investigated the role of ACE I/D and −240A>T polymorphisms in influencing both severity and clinical outcomes in patients with heart failure, according to New York Heart Association (NYHA) class.

Patients

We studied 323 patients with heart failure (258 men/65 women; age, 70.8 ± 11.5 years) followed-up for 11.9 ± 6.6 months.

Results

The ACE D and −240T allele frequency significantly increased according to the NYHA functional class ( P = 0.0002 and P < 0.0001, respectively). No significant difference in ACE polymorphism genotype distribution and allele frequency according to N-terminal pro-brain natriuretic peptide tertiles was observed. At multinomial regression analysis, ACE D but not −240T allele has been evidenced to be a significant and independent predictor of severity for both NYHA III and IV classes ( P = 0.01 and P = 0.004, respectively). The ACE D allele prevalence was higher, even if not significantly in both death and rehospitalization groups in comparison with survivors and nonrehospitalized ( P = 0.6 and P = 0.9, respectively). No difference in −240T allele frequency has been observed for the ACE −240A>T polymorphism, in relation to both death and rehospitalization ( P = 0.1 and P = 0.6, respectively).

Conclusions

This study suggests that ACE I/D polymorphism might represent a predisposing factor to severe heart failure, independently of well-known prognostic markers.
Designer Natriuretic Peptides
Authors: Lee Candace Y. W. , Lieu Hsiao , Burnett John C.
Published: May 2016

Designer natriuretic peptides (NPs) are novel hybrid peptides that are engineered from the native NPs through addition, deletion, or substitution of amino acid(s) with a goal toward optimization of pharmacological actions while minimizing undesirable effects. In this article, selected peptides that were designed in our laboratory are reviewed, and future directions for research and development of designer NPs are discussed.