bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin 8 Inhibition Enhanced Cholesterol Efflux in Acetylated Low-Density Lipoprotein–Stimulated THP-1 Macrophages
Authors: Chen Yandong , Wang Zheng , Zhou Lijun
Published: May 2016

Cholesterol efflux plays a major role in antiatherogenesis, and modification of this process may provide a new therapeutic approach to cardiovascular disease. Interleukin 8 (IL-8) is implicated in various aspects of atherosclerosis. However, the effect of IL-8 on cholesterol efflux is still unclear. Here, we used human IL-8–neutralizing antibody to inhibit IL-8 and analyze the function of IL-8 in cholesterol efflux from acetylated low-density lipoprotein–loaded THP-1 macrophages. Acetylated low-density lipoprotein loading resulted in an approximately 2.5-fold increase in both the mRNA and protein levels of IL-8 in THP-1 macrophages, when compared with nonloaded THP-1 macrophages ( P < 0.01). Five and 10 µg/mL of human IL-8–neutralizing antibody enhanced cholesterol efflux from THP-1–derived macrophages by 1.2- and 1.4-fold, respectively. Moreover, anti–IL-8–treated cells showed increased expression of peroxisome proliferator-activated γ, liver X receptor alpha, and ATP-binding cassette transporter A1 at both the mRNA and protein levels. Ten micromoles of SB203580, an inhibitor of p38, almost completely suppressed the production of IL-8 from acetylated low-density lipoprotein–loaded THP-1 macrophages and accelerated cholesterol efflux. Taken together, our results indicate that IL-8 exerts negative regulatory effects on cholesterol efflux from THP-1 cells and may thus represent a potential target for prevention and treatment of atherosclerosis.
Plasma Interleukin 33 Level in Patients with Osteonecrosis of Femoral Head
Authors: Zheng Liwen , Wang Wanchun , Ni Jiangdon , Li Zhihong , Xiao Tao , Zhang Qin , Mao Xinzhang , He Aiyong
Published: May 2016

Objectives

This study examines plasma interleukin 33 (IL-33) levels in patients with osteonecrosis of the femoral head (ONFH) and explores the possible use of IL-33 as a marker for early diagnosis and progression of ONFH.

Methods

One hundred twenty-five ONFH patients and 126 control subjects were recruited for this study. The plasma IL-33 levels were measured using a commercially available enzyme-linked immunosorbent assay kit. Effects of disease stage and risk factors on IL-33 level were also assessed.

Results

Plasma IL-33 levels were significantly higher in the 125 ONFH patients (174.33 [SD, 65.73] pg/mL) than in the 126 control subjects (90.50 [SD, 25.17] pg/mL, P < 0.001). Plasma IL-33 levels were significantly higher in patients with stage III/IV ONFH (184.17 [SD, 43.75] pg/mL) than in patients with stage I/II ONFH (158.24 [SD, 50.11] pg/mL, P < 0.001). There was no significant difference in IL-33 levels between alcohol-induced, idiopathic, and steroid-induced cases.

Conclusions

Plasma IL-33 may be an alarmin for ONFH, and its levels may be related to disease progression.
Ninety-Day Survival Rate of Patients with Sepsis Relates to Programmed Cell Death 1 Genetic Polymorphism rs11568821
Authors: Mansur Ashham , Hinz José , Hillebrecht Bronja , Bergmann Ingo , Popov Aron Frederik , Ghadimi Michael , Bauer Martin , Beissbarth Tim , Mihm Sabine
Published: May 2016

Background

Sepsis is a life-threatening condition. Programmed cell death 1 protein (PD-1), a negative costimulatory molecule, is suggested to be involved in pathogenesis as mortality is associated with high expression and as neutralizing antibodies improve survival in a mouse model. The PD-1 gene harbors an intronic single-nucleotide polymorphism, rs11568821, which is located in a transcription factor–binding site and supposed to affect PD-1 transcription.

Objective

This study aimed at investigating whether mortality (90-day) among patients with sepsis associates with PD-1 rs11568821 genotypes.

Methods

Adult white patients with sepsis from the surgical intensive care units of a university medical center were followed up for 90 days, and mortality was recorded as primary outcome variable. Blood samples were taken for PD-1 rs11568821 genotyping. Sequential Organ Failure Assessment scores increased at enrollment and during the observation period to monitor morbidity.

Results

Two hundred nineteen critically ill patients with sepsis were enrolled in this investigation. Ninety-day mortality was significantly higher among G homozygotes than among A allele carriers ( P = 0.0032). During intensive care unit stay, G homozygotes experienced higher Sequential Organ Failure Assessment scores ( P < 0.001) and a higher demand of vasopressor therapy ( P = 0.0107).

Conclusions

Data provide first associative evidence for PD-1 rs11568821 as a prognostic indicator in patients with sepsis.
Recommendations from the Investigational New Drug/Investigational Device Exemption Task Force of the Clinical and Translational Science Award Consortium: Developing and Implementing a Sponsor-Investigators Training Program
Authors: Holbein M. E. Blair , Berglund Jelena Petrovic , O'Reilly Erin K. , Hartman Karen , Speicher Lisa A. , Adamo Joan E. , O'Riordan Gerri , Brown Jennifer Swanton , Schuff Kathryn G.
Published: May 2016

Objective

The objective of this study was to provide recommendations for provision of training for sponsor and investigators at Academic Health Centers.

Background

A subgroup of the Investigational New Drug/Investigational Device Exemption (IND/IDE) Task Force of the Clinical and Translational Science Award (CTSA) program Regulatory Knowledge Key Function Committee was assembled to specifically address how clinical investigators who hold an IND/IDE and thus assume the role of sponsor-investigators are adequately trained to meet the additional regulatory requirements of this role.

Methods

The participants who developed the recommendations were representatives of institutions with IND/IDE support programs. Through an informal survey, the task force determined that a variety and mix of models are used to provide support for IND/IDE holders within CTSA institutions. In addition, a CTSA consortium-wide resources survey was used. The participants worked from the models and survey results to develop consensus recommendations to address institutional support, training content, and implementation.

Recommendations

The CTSA IND/IDE Task Force recommendations are as follows: (1) Institutions should assess the scope of Food and Drug Administration–regulated research, perform a needs analysis, and provide resources to implement a suitable training program; (2) The model of training program should be tailored to each institution; (3) The training should specifically address the unique role of sponsor-investigators, and the effectiveness of training should be evaluated regularly by methods that fit the model adopted by the institution; and (4) Institutional leadership should mandate sponsor-investigator training and effectively communicate the necessity and availability of training.
Interleukin 1, Interleukin 6, Interleukin 10, and Tumor Necrosis Factor α in Active and Quiescent Systemic Lupus Erythematosus
Authors: Cigni Alessandro , Pileri Piera Veronica , Faedda Rossana , Gallo Paola , Sini Annalisa , Satta Andrea Ercole , Marras Riccardo , Carta Elisabetta , Argiolas Davide , Rum Iolanda , Masala Antonio
Published: May 2016

Objectives

Several studies have investigated the cytokine profile of patients with systemic lupus erythematosus (SLE); however, their role is still controversial, mostly because SLE has a heterogeneous disease manifestation. We measured 4 of the most important cytokines in patients with SLE after dividing them in uniform groups according to disease activity and organ involvement.

Materials and Methods

Eighty-two adult female patients with SLE were divided into 3 groups according to disease activity and organ involvement: Group A (SLE activity index [SLEDAI] score, 7 ± 0.4) included subjects with newly diagnosed, active SLE, investigated before starting therapy. Group B (SLEDAI score, < 6) included patients without renal involvement, treated with prednisone and azathioprine or hydroxychloroquine. Group C (SLEDAI score, < 6) included patients with lupus nephritis, treated with methylprednisolone and cyclophosphamide, reaching complete remission. Fourteen healthy females served as controls.

Results

Interleukin-1 levels were 1.0, 0.8, 0.7, and 0.25 pg/mL in groups A, B, C, and D, respectively. Interleukin-6 levels were 3.2, 3.6, 4.0, and 1.4 pg/mL in groups A, B, C, and D, respectively; Il-10 levels, 3.05, 1.1, 1.5, and 1.65; tumor necrosis factor-α levels, 8.75, 5.8, 5.4, and 3.6. Interleukin 1, IL-6, and tumor necrosis factor-α were significantly higher in the patients with SLE than in the healthy controls; IL-1 was significantly higher in group A than in group C. Interleukin 10 showed positive correlation with C-reactive protein, whereas it showed negative correlation with C3.

Conclusions

Data from our cohort, one of the largest so far reported, add to the evidence that proinflammatory cytokines such as Interleukin-1, Interleukin-6, Interleukin-10 and tumor necrosis factor-α are important in SLE pathogenesis.
Improvement in Insulin Sensitivity and Dyslipidemia in Protease Inhibitor-Treated Adult Male Patients after Switch to Atazanavir/Ritonavir
Authors: Busti Anthony J. , Bedimo Roger , Margolis David M. , Hardin Dana S.
Published: May 2016

Background

Treatment of human immunodeficiency virus (HIV) with protease inhibitors (PIs) is associated with insulin resistance, triglyceride-rich dyslipidemia, and fat redistribution. Atazanavir (ATV), a potent once-daily PI, has been recognized for its convenience to patients, and some studies describe improved lipid metabolism. However, its effects on insulin sensitivity have not been elucidated. We conducted this study to test the hypothesis that ATV improves insulin resistance and dyslipidemia.

Methods

We prospectively studied 9 HIV-infected men with dyslipidemia (median age, 53 years; baseline triglyceride level, >200 mg/dL) on stable PI-containing antiretroviral therapy who elected to change PI therapy to ritonavir-boosted ATV therapy, dose of 300/100 mg. We measured insulin resistance at baseline and after 12 weeks of therapy using a hyperinsulinemic euglycemic clamp (insulin dose, 200 mU/m2 minute). Fasting lipid profiles and body composition (whole-body dual energy x-ray absorptiometry) were also measured at baseline and after 12 weeks.

Results

All 9 patients completed the study and maintained undetectable viral loads (<50 copies/mL) and stable CD4 counts. After 12 weeks, insulin sensitivity significantly improved (+28%; P = 0.008) in all patients. Triglyceride levels also improved.

Conclusions

Using the gold-standard euglycemic clamp, ritonavir-boosted ATV therapy improved PI-induced insulin resistance among dyslipidemic HIV-infected men on PI-based antiretroviral therapy. These findings were not attributable to a change in body weight and provide further evidence for ATV's unique metabolic profile among the PIs.
The Antifibrogenic Potential of PPARγ Ligands in Pulmonary Fibrosis
Authors: Sime Patricia J.
Published: May 2016

Pulmonary fibrosis is characterized by the accumulation of fibroblasts, myofibroblasts, collagen, and other extracellular matrix proteins in the interstitium of the lung, with subsequent scarring and destruction of the alveolar capillary interface. In some cases, pulmonary fibrosis is preceded by lung inflammation and can be treated with anti-inflammatory therapies. However, idiopathic pulmonary fibrosis is characterized by a relative paucity of underlying inflammation and currently has no effective treatment. There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor (PPAR) γ plays an important role in controlling cell differentiation and that PPARγ ligands can modify inflammatory and fibrotic responses. Peroxisome proliferator-activated receptor γ ligands, including the thiazolidinedione class of antidiabetic drugs and novel triterpenoid compounds derived from oleanic acid, inhibit TGF-β-stimulated profibrotic differentiation of lung fibroblasts in vitro and reduce lung scarring in animal models of fibrosis. The mechanism of action of the PPARγ ligands is under investigation but seems to involve both PPARγ-dependent and PPARγ-independent pathways. These in vitro and in vivo data highlight the potentially exciting role of PPARγ ligands as novel therapies for fibrosis of the lung and other organ systems prone to scarring. Many of the synthetic PPARγ ligands are orally active, and several are currently available and Food Drug Administration approved for use in therapy of type 2 diabetes. Further research is urgently required to more clearly elucidate the mechanism of action of these drugs and to develop more potent antifibrotic agents for patients with scarring diseases for whom there are currently few effective therapies.
Peroxisome Proliferator-Activated Receptor γ and Lung Cancer Biology
Authors: Roman Jesse
Published: May 2016

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of transcriptional modulators. In addition to their known roles in regulation of metabolism and inflammation, PPARs have also been implicated in carcinogenesis based on studies showing their ability to modulate cellular differentiation, proliferation, and apoptosis. Of the 3 PPARs identified to date (PPARα, PPARβ/δ, and PPARγ), PPARγ has been studied the most in part because of the availability of PPARγ agonists (also known as PPARγ ligands). In many tumor cells, including lung carcinoma cells, activation of PPARγ results in decreased cellular proliferation; this is particularly true for non-small cell lung carcinoma, the most common malignant lung tumor in the United States. Studies performed in xenograft models of lung cancer also show decreased tumor growth and progression in animals treated with PPARγ ligands. More recently, data are emerging from retrospective clinical studies that suggest a protective role for PPARγ ligands on the incidence of lung cancer. This review summarizes the available data that implicate PPARs in lung carcinogenesis while focusing on PPARγ as a potential target for the development of novel anti-lung cancer treatment strategies.
Immunomodulatory Role of PPAR-γ in Alveolar Macrophages
Authors: Reddy Raju C.
Published: May 2016

The lung is constantly exposed to inhaled pathogens and toxins yet totally dependent on the integrity of a delicate alveolar-capillary interface for its function. Much of the balance between protection and collateral damage rests on the alveolar macrophage, which not only phagocytoses inhaled particles but also modulates the activity of both innate and acquired immune systems to limit unnecessary or exuberant inflammation. In its resting state, the alveolar macrophage secretes anti-inflammatory mediators while limiting antigen presentation to the adaptive immune system. The alveolar macrophage's state of activation is regulated by a variety of factors, including the activity of the nuclear receptor peroxisome proliferator-activated receptor γ (PPAR-γ). Peroxisome proliferator-activated receptor γ agonists reduce the ability of inflammatory stimuli to activate the alveolar macrophage while simultaneously stimulating phagocytosis of both opsonized and unopsonized particles, via the Fcγ and CD36 receptors, respectively. All known endogenous PPAR-γ ligands are fatty acid derivatives, and macrophage-specific knockout of the enzyme that converts esterified fatty acids to free fatty acids results in severe lung inflammation. Peroxisome proliferator-activated receptor γ expression is reduced in alveolar macrophages from patients with pulmonary sarcoidosis and alveolar proteinosis, suggesting that the deficiency may play a role in pathogenesis of these diseases. In summary, these observations point to PPAR-γ in the context of the alveolar macrophage as a crucial factor in limiting excessive and possibly injurious inflammation in the lung.
Renal Injury, Abnormal Vitamin D Metabolism and Bone Homeostasis in Aged Rats with Insulin Resistance or Type 2 Diabetes Mellitus
Authors: Chang-Quan Huang , Bi-Rong Dong , Qian Xiao , Ping He , Qun-Fang Ding , Zhen-Chan Lu , Xiao-Dong Peng
Published: May 2016

Objective

The study aimed to explore the relationship among renal injury, abnormal vitamin D metabolism, and bone homeostasis in insulin resistance (IR) or type 2 diabetes mellitus (T2DM).

Design and Methods

The animal models of IR, T2DM, and T2DM treated with 1-alpha hydroxyvitamin D (1-α(OH)D) were established on 18-month-old male Wistar rats. Glucose infusion rates (GIR) and levels of urinary albumin (UA), serum 25-hydroxyvitamin D (25-(OH)D), serum 1,25-dihydroxyvitamin D (1,25-(OH)2D), and bone mineral density (BMD) in lumbar vertebrae and femoral bone were measured.

Results

Urinary albumin level in the rats with T2DM significantly increased, and there existed a significant and negative correlation between GIR and UA level in the rats with T2DM or IR. The levels of serum 25-(OH)D in all models were similar. The levels of serum 1,25-(OH)2D and BMD in the rats with IR were significantly higher than those in the rats with T2DM and were lower than those in normal control rats. In the aged rats with T2DM, administration of 1-α(OH)D had no effect on serum 25-(OH)D level although significantly increased the levels of serum 1,25-(OH)2D and BMD. There existed a negative correlation between the levels of serum 1,25-(OH)2D and UA in the rats with T2DM or IR.

Conclusions

In IR or T2DM, abnormal vitamin D metabolism is characterized by 1,25-(OH)2D deficiency and is related to renal injury, and there also existed bone loss. In T2DM, both 1,25-(OH)2D deficiency and bone loss can be reversed by 1-α(OH)D.
Acute Suppression of Circulating sCD40L during Hyperglycemia and Euglycemic-Hyperinsulinemia in Healthy Young Males
Authors: Oliver Stacy R. , Flores Rebecca L. , Pontello Andria M. , Rosa Jaime S. , Zaldivar Frank P. , Galassetti Pietro R.
Published: May 2016

sCD40L is a proatherogenic cytokine, part of the tumor necrosis factor (TNF) superfamily and consistently associated with obesity, diabetes, and increased cardiovascular risk. Although the role of sCD40L in the onset/progression of cardiovascular complications of dysmetabolic diseases may be modulated by acute and/or chronic fluctuations of plasma insulin and glucose, very little has been done to clarify this interaction. The kinetic profile of sCD40L (and, in an exploratory manner, of several immunomodulatory factors), were measured during hyperglycemia and euglycemic-hyperinsulinemia in a group of 10 healthy young males (26.8 ± 1.4 years). After an overnight fast, intravenous (iv) catheters were placed in antecubital veins of both arms for blood drawing and dextrose/insulin iv infusions. Procedures lasted 240 minutes including baseline ( t = 0-60), hyperglycemia ( t = 60-150; plasma glucose ∼220 mg/dL via iv dextrose infusion), and euglycemic-hyperinsulinemia ( t = 150-240; glucose infusion continued to clamp glycemic levels between 80 and 110 mg/dL; constant insulin infusion at 1.5 mU/kg/minute).

Plasma for cytokine assays was sampled at 12 separate time-points. Plasma levels of sCD40L were significantly reduced ( P < 0.01) during hyperglycemia and euglycemic-hyperinsulinemia, paralleling the kinetic profiles of free fatty acids and ketone bodies. This pattern was also observed in other immunomodulatory factors (notably cortisol and epidermal growth factor), while (interleukin [IL]-1α, IL-4, IL-6, IL-9, IL-10, TNF-α, Eotaxin) did not change significantly. Significant reductions of the proatherogenic cytokine sCD40L were observed during endogenous and exogenous hyperinsulinemia, independent of prevailing glucose concentration, in young healthy males. Our data suggest a mechanism by which correct insulin action may exert a beneficial protective role against inflammation, independent of its immediate glucose-lowering effect.
Fibrogenic Polymorphisms (TGF-β, PAI-1, AT) in Mexican Patients with Established Liver Fibrosis. Potential Correlation with Pirfenidone Treatment
Authors: Armendáriz-Borunda Juan , Rincón Ana Rosa , Muñoz-Valle José Francisco , Bueno-Topete Miriam , Oregón-Romero Edith , Islas-Carbajal María Cristina , Medina-Preciado David , González-García Ignacio , Bautista C. Alfredo , García-Rocha Sergio , Godoy Jesús , Vázquez-Del Mercado Mónica , Troyo-SanRoman Rogelio , Arellano-Olivera Inmaculada , Lucano Silvia , Álvarez-Rodríguez Adriana , Salazar Adriana
Published: May 2016

Background/Aim

The aim of this work was to establish a potential correlation between specific polymorphisms and presence of hepatic fibrosis in Mexican patients with established liver fibrosis (ELF). Second, necroinflammatory index improvement was correlated with Pirfenidone (PFD) treatment response and the same polymorphisms.

Methods

We analyzed TGF-β polymorphisms in codon 25, a single basepair guanine insertion-deletion polymorphism (4G/5G) for PAI-1 and angiotensin AT-6 single nucleotide polymorphism located in -6 promoter region. Twenty patients infected with either hepatitis C virus (HCV) (n = 13) or affected by alcohol consumption (n= 7) were included. Thirty subjects with no hepatic damage were included in control group. Blood samples for genomic DNA were obtained and plasminogen activator inhibitor-1 polymorphisms were done by polymerase chain reaction-artificial introduction of a restriction site, TGF-β by polymerase chain reaction-amplification refractory mutation system and AT by polymerase chain reaction-restriction fragment length polymorphisms. Liver biopsies were obtained at baseline and after 12 months of PFD treatment.

Results

Established liver fibrosis patients had the homozygote G/G TGF-β genotype, which has been associated with increased development of fibrosis. None of our patients had the G/C genotype. All pure HCV and pure alcohol abuse subjects carried G/G TGF-β genotype (100% vs 37% control) ( P = 0.0006). The odds of having TGF-β G/G genotype was 19.5 for HCV patients and 10.83 for alcohol consumption patients as compared with healthy subjects ( P < 0.001). Established liver fibrosis patients had an improvement in necroinflammatory index after PFD treatment when correlated with plasminogen activator inhibitor-1 and angiotensinogen-6 genotypes.

Conclusion

Our data suggested that a combination of inherited polymorphisms increased the risk of advanced fibrosis in ELF patients. Pure HCV and pure alcohol consumption patients which were homozygous G/G carriers had 19.5- and 10.8-fold higher risk to develop advanced fibrosis respectively. Abbreviations: TGF-β, transforming growth factor β; RAS, renin angiotensin system
Advanced Glycation End Products Increase Transglutaminase Activity in Primary Porcine Tenocytes
Authors: Rosenthal Ann K. , Gohr Claudia M. , Mitton Elizabeth , Monnier Vincent , Burner Todd
Published: May 2016

Objectives

Tendon abnormalities, such as increased stiffness, thickness, and excess calcification, occur commonly in patients with diabetes mellitus and cause considerable disability. These changes are frequently attributed to increased cross-linking of extracellular matrix components by advanced glycation end-products (AGEs). However, cellular effects of AGEs, such as increased activity of the cross-linking transglutaminase (Tgase) enzymes, could also contribute to altered tissue biomechanics and calcification in diabetic tendons. We determined the effect of AGE-modified protein on tenocyte Tgase activity.

Research Design and Methods

Primary porcine tenocytes were exposed to Nε- carboxymethyl-lysine (CML)-modified type I collagen in high or normal glucose media. Protein and mRNA levels of the Tgase enzymes and Tgase activity levels were measured, as were markers of apoptosis. We also determined the effect of antioxidants on CML-collagen mediated Tgase activity.

Results

Carboxymethyl-lysine-collagen increased Tgase activity in tenocytes 2.3- to 5.6-fold over unmodified collagen controls in both normal and high glucose media, without altering enzyme protein levels. Anti-oxidant treatment reduced the effect of CML-collagen on Tgase activity. Deoxyribonucleic acid laddering and annexin V protein levels were not altered by CML-collagen exposure.

Conclusions

Carboxymethyl-lysine-collagen increased Tgase activity in tenocytes, likely posttranslationally. Increased levels of Tgase-mediated cross-links may contribute to the excess calcification and biomechanical pathology seen in diabetic tendons.
Effects of Diet and Gemfibrozil on Posttransplant Hyperlipidemia in Renal Transplant Recipients
Authors: Sapan Muzaffer , Ozben Beste , Yakupoglu Gulsen , Suleymanlar Gultekin , Ozben Tomris
Published: May 2016

Background

Posttransplant hyperlipidemia increases cardiovascular morbidity and mortality rate in renal transplant recipients. It also leads to graft loss due to atherosclerosis and glomerular damage. It is essential to control hyperlipidemia in renal transplant recipients to prevent these events.

Methods

In our study, we determined lipid profiles in 59 renal transplant recipients. Twenty of the recipients had hyperlipidemia; 9 had type IV, and 11 had type II hyperlipoproteinemia. Randomly selected 14 of 20 hyperlipidemic patients consisted of the diet group and were treated with American phase 3 diet for 1 month. Randomly selected 6 of the 20 hyperlipidemic patients received their regular diet as the control group. Five diet-resistant patients in the American phase 3 diet group were given diet plus placebo for another 1 month and then they were given diet plus Gemfibrozil (600 mg twice a day) for 2 months.

Results

Lipid profile was normalized in 9 of the 14 patients on American phase 3 diet. The lipid profile of 5 patients in the American phase 3 diet group did not change significantly after 1-month diet. These 5 diet-resistant patients were given diet plus placebo for another 1 month, and their lipid levels again did not change significantly. Afterward, they were treated with Gemfibrozil (600 mg twice a day) plus American phase 3 diet for 2 months. At the end of this therapy period, their cholesterol level and triglyceride level decreased significantly. No change was observed in low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels.

Conclusions

We conclude that American phase 3 diet and/or Gemfibrozil are effective in controlling posttransplant hyperlipidemia in renal transplant recipients.
Training Interdisciplinary Scientists for Systems Biology
Authors: Facciotti Marc T.
Published: May 2016

The rise of interdisciplinary research programs in recent years has spawned numerous questions regarding the best way to organize interdisciplinary programs and how to best train new interdisciplinary scientists in ways that will catalyze novel discoveries in biology. Systems biology, a relatively new branch of science, can be considered in many respects a poster child for modern interdisciplinary science. It not only requires that people from different traditional disciplines work closely together but it also requires the development of unique training environments to educate the next generation of systems biologists. The unique scientific and training challenges associated with the development of systems biology are certainly faced across the spectrum of interdisciplinary endeavors. Therefore, it is useful for scientists interested in building interdisciplinary research programs to consider the merits of successful systems biology initiatives. Institute for Systems Biology is one such example, and in the following, several key aspects of Institute for Systems Biology that make it both a unique and successful interdisciplinary science and training center are discussed.
Strategies for Innovation and Interdisciplinary Translational Research
Authors: Benedyk Mark , Berglund Lars , Facciotti Marc , Mobley William , Zucker Deborah
Published: May 2016

Following is a portion of the proceedings of the panel and audience discussion from the AFMR-Translational Medical Research Development Workshop at EB08.
Social Environmental Stressors, Psychological Factors, and Kidney Disease
Authors: Bruce Marino A. , Beech Bettina M. , Sims Mario , Brown Tony N. , Wyatt Sharon B. , Taylor Herman A. , Williams David R. , Crook Errol
Published: May 2016

Kidney disease is one of the most striking examples of health disparities in American public health. Disparities in the prevalence and progression of kidney disease are generally thought to be a function of group differences in the prevalence of kidney disease risk factors such as diabetes, hypertension, and obesity. However, the presence of these comorbidities does not completely explain the elevated rate of progression from chronic kidney disease (CKD) to end-stage renal disease among high-risk populations such as African Americans. We believe that the social environment is an important element in the pathway from CKD risk factors to CKD and end-stage renal disease. This review of the literature draws heavily from social science and social epidemiology to present a conceptual frame specifying how social, economic, and psychosocial factors interact to affect the risks for and the progression of kidney disease.
Association of Transforming Growth Factor β1 Gene Polymorphisms and Asbestos-Induced Fibrosis and Tumors
Authors: Helmig Simone , Belwe Alexandra , Schneider Joachim
Published: May 2016

Aim

Inhaled asbestos fibers are known to cause progressive lung or pleural fibrosis and malignancies such as lung cancer or diffuse malignant mesothelioma. Transforming growth factor β1 (TGF-β1), a multifunctional cytokine, regulates the proliferation and differentiation of cells. Transforming growth factor β1 is known to promote the pathogenesis of lung fibrosis and acts as a tumor suppressor in normal cells. Two genetic polymorphisms in codons 10 (Leu10Pro) and 25 (Arg25Pro) of the TGF-β1 gene are suggested to be associated with a different TGF-β1 protein production. Therefore, we examined an association between the 2 TGF-β1 gene polymorphisms and asbestos-induced lung fibrosis and lung cancer.

Methods

Detection of the 2 polymorphisms was performed by rapid capillary polymerase chain reaction, with melting curve analysis, using fluorescence-labeled hybridization probes. To investigate the association between TGF-β1 gene polymorphisms in codons 10 and 25 and the susceptibility to asbestos-induced diseases, association studies were performed with healthy control subjects (n = 83), patients with pulmonary fibrosis (n = 591), and patients with bronchial carcinoma (n = 147).

Results

Compared with a healthy control group, odds ratio (OR) analysis revealed an inverse relationship for the proline allele at codon 10 or 25 with pulmonary fibrosis (higher risk) and lung cancer (lower risk). The proline allele at codon 10 or 25 is significantly associated with a higher risk for fibrotic lung diseases (ORcrude, 1.46; 95% confidence interval [CI], 1.01-2.11; P = 0.045 and ORadjusted, 1.76; 95% CI, 1.14-2.72; P = 0.011, respectively, for codon 10; OR, 2.13; 95% CI, 1.33-3.99; P = 0.019 and ORadjusted, 2.27; 95% CI, 1.14-4.52; P = 0.02, respectively, for codon 25) when compared with patients with lung cancer. A significant association for the proline allele is also revealed when comparing patients with asbestosis (ORcrude, 3.01; 95% CI, 1.44-6.29; P = 0.003 and ORadjusted, 3.72; 95% CI, 1.56-8.85; P = 0.011) with patients with asbestos-induced lung cancer.

Conclusions

In summary, the results confirm the hypothesis that TGF-β1 polymorphisms are associated with asbestos-induced fibrotic or malignant lung diseases in whites.
Hepatitis B Virus and Hepatitis C Virus Seroprevalence in the Elderly Living in Nursing Homes
Authors: Maral Isil , Dogruman-Al Funda , Bakar Coskun , Ilhan Mustafa Necmi , Yalinay-Cirak Meltem , Bumin Mehmet Ali
Published: May 2016

Background

Communal living situations such as nursing homes create a risk for the spread of hepatitis B virus and hepatitis C virus (HCV). The aim of this study was to determine the seroprevalence of hepatitis B virus and HCV in the elderly living in 2 nursing homes in Ankara, Turkey.

Methods

A total of 227 persons (mean age, 76.11 ± 8.55 years) participated in this cross-sectional study. All individuals were investigated seroprevalence for hepatitis B surface antigen (HBsAg), anti-HBs immunoglobulin G (IgG), anti-hepatitis B core IgG, and anti-HCV IgG.

Results

Positive seroprevalence was 11.9% for HBsAg, 48.0% for anti-HBs IgG, 25.1% for anti-hepatitis B core IgG, and 2.5% for anti-HCV IgG. Hepatitis B surface antigen positivity was 12.4% in males and 11.5% in females ( P > 0.05); and the seroprevalence was 10.4% for those living in nursing homes for 1 year or less and 13.0% for those living in nursing homes for more than 1 year ( P > 0.05).

Conclusions

The fact that nearly half of those living in nursing homes had not encountered hepatitis B infection or had not received hepatitis B vaccination indicates the need for administering hepatitis B vaccines in this group.
P-Selectin and P-Selectin Glycoprotein Ligand 1 Mediate Rolling of Activated CD8+ T Cells in Inflamed Colonic Venules
Authors: Asaduzzaman Muhammad , Mihaescu Andrada , Wang Yusheng , Sato Tohru , Thorlacius Henrik
Published: May 2016

Background

Activated T cells regulate inflammatory diseases in the intestinal tract; however, the adhesive mechanisms governing CD8+ T-cell recruitment in the colon are not known.

Methods

Herein, we used a graft-versus-host disease (GvHD) model to study CD8+ T-cell rolling and adhesion in the large intestine by use of intravital fluorescence microscopy. Graft-versus-host disease was induced by transferring 50 × 106 allogeneic donor splenocytes from BDF1, B6, H-2b mice to recipient BDF1, H-2bxd mice. After 8 days, rhodamine-labeled CD8+ T cells (4 × 106) from healthy and GvHD mice were injected into both healthy and GvHD recipient mice, and CD8+ T-cell-endothelium interactions were studied in the colon.

Results

Activated CD8+ T cells from GvHD mice expressed higher levels of P-selectin ligand and decreased levels of L-selectin. Immunoneutralization of P-selectin and P-selectin glycoprotein ligand 1 reduced CD8+ T-cell rolling and adhesion in inflamed colonic venules by more than 71%. Inhibition of E-selectin had no effect on GvHD-induced CD8+ T-cell-endothelium interactions.

Conclusions

We conclude that P-selectin and P-selectin glycoprotein ligand 1 are dominating molecules in supporting adhesive interactions of CD8+ T cells in inflamed colonic venules and may be useful targets to protect against pathological inflammation in the large bowel.
It Takes Two to Tango: Combined Amylin/Leptin Agonism as a Potential Approach to Obesity Drug Development
Authors: Chan Jean L. , Roth Jonathan D. , Weyer Christian
Published: May 2016

The discovery of leptin in 1994 was a seminal event in obesity research. It helped to establish that body weight is tightly regulated by a complex neurohormonal feedback system and that obesity should be viewed as a disorder with a strong biological basis rather than simply the result of poor lifestyle choices and lack of willpower.

Leptin, secreted from adipocytes, acts as a prototypic long-term (tonic) adiposity signal. Although nonclinical and clinical studies have provided unequivocal evidence that leptin plays a unique, pivotal role in body weight regulation, efforts to develop recombinant leptin (metreleptin) as a monotherapy for obesity have proven unsuccessful. Amylin, secreted from pancreatic β-cells, fulfills the criteria for a short-term (episodic) satiety signal. The amylin analog pramlintide elicits sustained reductions in food intake and body weight in obese rodents and humans.

A translational research program aimed at elucidating the interaction between different islet-, gut-, and adipocyte-derived hormones led to the discovery that combined amylin/leptin agonism induces marked, synergistic, fat-specific weight loss in leptin-resistant diet-induced obese rodents. In obese humans, combination treatment with pramlintide/metreleptin led to an approximately 13% weight loss after 24 weeks, significantly more than after treatment with pramlintide or metreleptin alone.

Collectively, these findings suggest that combined amylin/leptin agonism may have therapeutic utility as part of an integrated, neurohormonal approach to obesity pharmacotherapy.
Central Leptin Receptor Action and Resistance in Obesity
Authors: Bjørbæk Christian
Published: May 2016

The discovery of leptin in 1994 has led to remarkable advances in obesity research. We now know that leptin is a cytokinelike hormone that is produced in adipose tissue and plays a pivotal role in regulation of energy balance and in a variety of additional processes via actions in the central nervous system. This symposium review covers current understandings of neuronal leptin receptor signaling and mechanisms of obesity-related leptin resistance in the central nervous system and provides recent insights into the regulation of peripheral glucose balance by central leptin action in rodents.
Insulin Resistance and Triglycerides
Authors: Glueck Charles J. , Khan Naseer A. , Umar Muhammad , Uppal Muhammad S. , Ahmed Waqas , Morrison John A. , Goldenberg Naila , Wang Ping
Published: May 2016

In 1385 adults with primary untreated hyperlipidemia and in a population study of 339 adults (Princeton Follow-up Study [PFS]), we hypothesized that homeostasis model assessment (HOMA) insulin resistance (IR) was a significant explanatory variable for triglycerides (TG) and that IR rose in a stepwise fashion, independent of age, race, sex, and body mass index (BMI), whereas TG categories rose from less than 150 to 150 to 200, to 200 to 500, and to more than 500 mg/dL. A third hypothesis was that TG, BMI, and the ratio of TG to high-density lipoprotein cholesterol (TG/HDL-C) were significant explanatory variables for IR and that IR was inversely associated with HDL-C quintiles and positively associated with non-HDL-C quintiles. By stepwise multiple regression with age, race, sex, BMI, and IR as explanatory variables, in the 1385 patients, positive explanatory variables for TG included BMI (partial R2 = 1.3%, P < 0.0001), sex (men higher, partial R2 = 1.1%, P = 0.0001), and IR (partial R2 = 0.4%, P = 0.012). In the 339 PFS subjects, positive explanatory variables for TG were IR (partial R2 = 11.4%, P < 0.0001), race (whites higher, partial R2 = 2.1%, P = 0.005), and sex (men higher, partial R2 = 1.4%, P = 0.019). After adjusting for age, race, sex, and BMI, in 1385 patients, HOMA IR rose while TG categories rose, with least square means of 2.64 for the TG category less than 150 mg/dL, 3.27 for 150 to 200 mg/dL, 3.85 for 200 to 500 mg/dL, and 4.12 for more than 500 mg/dL. Similarly, in the PFS, while TG categories rose, the least square means of HOMA IR rose, with 1.68 for the TG category less than 150 mg/dL, 2.34 for 150 to 200 mg/dL, and 3.03 for 200 to 500 mg/dL. Body mass index, TG, and TG/HDL-C were significant explanatory variables for IR. Homeostasis model assessment IR is a significant, potentially reversible explanatory variable for TG in patients referred because of hyperlipidemia and in population subjects.
Association between T102C Polymorphism of Serotonin 2A Receptor Gene and Urinary Incontinence in Older Women
Authors: Noronha Jorge Antônio Pastro , Schwanke Carla Helena Augustin , Machado Denise Cantarelli , Braga Rafael , Lubianca Jeremia Mistrello , Sesti Fabiane Lorenzoni , de Toledo Aloysio Floriano , da Cruz Ivana Beatrice Mânica
Published: May 2016

Background

The bladder's regulatory function is influenced by central serotonergic modulation. T102C polymorphism of the serotonin 2A (5-HT2A) receptor gene is associated with urinary incontinence (UI) that has been reported by older community dwellers. We analyzed the association between 5-HT2A receptor gene polymorphism and urodynamic tests for UI in older women.

Methods

A case-control study was performed with 68 older women submitted to urodynamic evaluation and 162 older women without urinary problems (self-reported), all community dwellers enrolled in the Gravataí-GENESIS Project, Brazil. Clinical interviews, complete urodynamic evaluation following the International Continence Society Report on Good Urodynamic Practice (case group), and molecular analyses were performed (case and control groups). Serotonin 2A receptor gene genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism using the restriction enzyme HpaII. We excluded patients with diabetes mellitus, neurologic damage, and diuretic intake.

Results

The subjects' mean (SD) age was 68.1 (6.5) years (range, 60-92 years). We found an association between the TT genotype versus CC + CT genotypes and UI ( P = 0.013; odds ratio, 2.69; 95% confidence interval, 1.37-5.29) and, in addition, an association with urgency UI, maximal cystometric capacity (TT, 349 mL; CC + CT, 429.5 mL [ P = 0.047]), detrusor pressure at maximum cystometric capacity (TT, 11 cm H2O; CC + CT, 6.75 cm H2O [ P = 0.032]), and detrusor compliance (TT, 34 mL/cm H2O; CC + CT, 61.25 mL/cm H2O [ P = 0.006]).

Conclusions

We confirmed our previous findings of a genetic influence of the TT genotype on UI involving the serotonergic pathway among older women. Further investigations including 5-HT2A expression in the bladder, pelvic floor, and striated sphincter muscle must be performed.
Effect of Month-Long Treatment with Oral N-Acetylcysteine on the Oxidative Stress and Proteinuria in Patients with Diabetic Nephropathy a Pilot Study
Authors: Saklayen Mohammad G. , Yap Jayson , Vallyathan Val
Published: May 2016

Introduction

Oxidative stress plays an important role in the pathogenesis of diabetic nephropathy (DN). This study examined if use of N-acetylcysteine for a month in moderate doses would reduce the oxidative stress in patients with DN and reduce the proteinuria.

Methods

Fifteen volunteers with DN participated in the study. Participants took capsule form of N-acetylcysteine 1 gm twice a day for a month. Spot urines were collected and tested for protein/creatinine on days 1 and 30. Sera were collected on days 1, 15, 30, and 60 and tested for several oxidative stress biomarkers.

Results

There was no significant change in proteinuria or any of the oxidant stress markers at any point: protein-creatinine ratio (day 1, 1.6 ± 1.8; day 30, 1.3 ± 1.3), 8-isoprostane (day 1, 5.9 ± 4.2 pg/mL; day 15, 4.67 ± 2.4 pg/mL; day 30, 5.1 ± 2.8 pg/mL; and day 60, 4.7 ± 1.9 pg/mL), total antioxidant status (day 1, 1.5 ± 0.1 mM; day 15, 1.6 ± 0.2 mM; day 30, 1.5 ± 0.1 mM; and day 60, 1.5 ± 0.2 mM), aconitase (day 1, 7.9 ± 5.9 mU/mL; day 15, 10.1 ± 5.9 mU/mL; day 30, 8.9 ± 6.2 mU/mL; and day 60, 7.8 ± 5.5 mU/mL), glutathione peroxidase (day 1, 261.4 ± 56.4 mU/mL; day 15, 263.9 ± 57.2 mU/mL; day 30, 269.2 ± 66.0 mU/mL; and day 60, 257.5 ± 48.2 mU/mL), and superoxide dismutase (day 1, 242.6 ± 79.3 mU/mL; day 15, 252.1 ± 68.1 mU/mL; day 30, 262.0 ± 73.3 mU/mL; and day 60, 255.7 ± 61.5). However, 4 patients with initial high isoprostane levels showed nonsignificant decline at each subsequent time point.

Conclusions

N-acetylcysteine in moderate doses given over a month did not have significant effect on the overall oxidative stress in patients with DN and did not reduce proteinuria.
Intron 4 VNTR Polymorphism of eNOS Gene is Protective for Cardiac Syndrome X
Authors: Sinici Incilay , Atalar Enver , Kepez Alper , Hayran Mutlu , Aksoyek Serdar , Tokgozoglu Lale , Ozmen Ferhan
Published: May 2016

Microvascular abnormalities caused by endothelial dysfunction seem to be responsible for the myocardial ischemia in patients with cardiac syndrome X (CSX). Nitric oxide is a key mediator of endothelial function and is synthesized by endothelial nitric oxide synthase (eNOS). We investigated if the 3 potential polymorphisms of the eNOS gene (VNTR in intron 4, T786C polymorphism in the promoter region, and G894T polymorphism in exon 7) are independent risk factors for CSX. Sixty-nine patients with CSX and 73 healthy controls were studied. Genotypes were determined through polymerase chain reaction with or without restriction endonuclease digestions. Genotype distribution was significantly different between patients with CSX and controls for intron 4aa (allele for 4 repeats of 27 bp), intron 4aa genotype frequency being 3.2% and 6.8%, respectively. The presence of intron 4a is 3.2 (odds ratio) times protective (95% confidence interval, 1.5-6.8) for the risk of CSX disease. The protective effect of intron 4a polymorphism also holds after adjustment for age and sex and when the study group is limited to those without hypertension and hyperlipidemia. No significant difference was observed in genotype distribution of G894T and T786C polymorphism between patients with CSX and controls. In conclusion, intron 4aa genotype of eNOS gene is protective for CSX. No association was found between promoter and exon 7 polymorphisms of eNOS gene and CSX.
Screening and Evaluation of Study Subjects in Patient-Oriented Research
Authors: Toto Robert D.
Published: May 2016

This article describes practical aspects of screening and evaluation of potential study subjects for patient-oriented research. Screening and evaluation comprise the crucial initial steps in the process of any patient-oriented research study. Appropriate infrastructure, operations, and documentation of the procedures needed to efficiently and effectively conduct screening and evaluation are described. A stepwise approach for screening and evaluating potential study subjects for determination of study eligibility is described. The design and conduct of screening and evaluation procedures should be protocol driven and compliant with regulatory requirements.
Neutrophil Gelatinase-Associated Lipocalin Levels in Patients with Crohn Disease Undergoing Treatment with Infliximab
Authors: Bolignano Davide , Della Torre Anna , Lacquaniti Antonio , Costantino Giuseppe , Fries Walter , Buemi Michele
Published: May 2016

Increased levels of neutrophil gelatinase-associated lipocalin (NGAL), a small 25-kd stress protein released by several injured cells, have been reported in different pathological conditions such as kidney and chronic inflammatory bowel diseases. As NGAL is also emerging as a biomarker for monitoring the response to different types of treatment, the aims of this pilot study were to analyze urinary NGAL levels in a small cohort of patients affected by Crohn disease and to evaluate the eventual impact of the intravenous administration of infliximab on these levels.

Crohn disease patients presented increased NGAL values compared with controls (210.5 ng/mL [88.3-1100.0 ng/mL] vs 7.6 [4.4] ng/mL; P = 0.001); the infusion of a single high dose of infliximab induced an impressive reduction in these levels to 80.1 ng/mL (38.6-400.2 ng/mL; P = 0.006) with a mean reduction ratio of 62.1%. These findings suggest a pivotal role of NGAL in the systemic adaptations to Crohn disease, also confirming the potential usefulness of NGAL measurement in the evaluation of early responses to therapy or in predicting different clinical outcomes.