Translational Medical Research Commons^™

The Interplay Of Obesity And Asthma, James Plumb, Rickie Brawer, Nancy Brisbon

Department of Family & Community Medicine Faculty Papers

The relationships, interactions, and association between obesity and asthma are complex, and are active sources of hypotheses and research. An association between obesity and asthma has been reported in many studies, although considerable debate about the existence of the association and its meaning still exists. Potential associative relationships may result from genetics, immune system modifications, and mechanical mechanisms. The rising prevalence of asthma and obesity in children and adults, and the significant morbidity from both, makes it imperative that clinicians recognize the importance of weight management in patients with and without asthma.

Oxpat/Pat-1 Is A Ppar-Induced Lipid Droplet Protein That Promotes Fatty Acid Utilization, Nathan E. Wolins, Benjamin K. Quaynor, James R. Skinner, Anatoly Tzekov, Michelle A. Croce, Matthew C. Gropler, Vijayalakshmi Varma, Aiwei Yao-Borengasser, Neda Rasouli, Philip A. Kern, Brian N. Finck, Perry E. Bickel

Clinical and Translational Science Faculty Publications

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family regulate cellular neutral lipid stores. We have studied a new member of this family, PAT-1, and found that it is expressed in highly oxidative tissues. We refer to this protein as "OXPAT." Physiologic lipid loading of mouse liver by fasting enriches OXPAT in the lipid droplet tissue fraction. OXPAT resides on lipid droplets with the PAT protein adipophilin in primary cardiomyocytes. Ectopic expression of OXPAT promotes fatty acid-induced triacylglycerol accumulation, long-chain fatty acid oxidation, and mRNAs associated with oxidative metabolism. Consistent with these observations, OXPAT is induced in mouse …

The Lipogenic Enzymes Dgat1, Fas, And Lpl In Adipose Tissue: Effects Of Obesity, Insulin Resistance, And Tzd Treatment, Gouri Ranganathan, Resat Unal, Irina D. Pokrovskaya, Aiwei Yao-Borengasser, Bounleut Phanavanh, Beata Lecka-Czernik, Neda Rasouli, Philip A. Kern

Clinical and Translational Science Faculty Publications

Acyl-coenzyme A:diacylglycerol transferase (DGAT), fatty acid synthetase (FAS), and LPL are three enzymes important in adipose tissue triglyceride accumulation. To study the relationship of DGAT1, FAS, and LPL with insulin, we examined adipose mRNA expression of these genes in subjects with a wide range of insulin sensitivity (S_I). DGAT1 and FAS (but not LPL) expression were strongly correlated with S_I. In addition, the expression of DGAT1 and FAS (but not LPL) were higher in normal glucose-tolerant subjects compared with subjects with impaired glucose tolerance (IGT) (P < 0.005). To study the effects of insulin sensitizers, subjects with IGT were treated with pioglitazone or metformin for 10 weeks, and lipogenic enzymes were measured in adipose tissue. After pioglitazone treatment, DGAT1 expression was increased by 33 ± 10% (P < 0.05) and FAS expression increased by 63 ± 8% (P < 0.05); however, LPL expression was not altered. DGAT1, FAS, and LPL mRNA expression were not significantly changed after metformin treatment. The treatment of mice with rosiglitazone also resulted in an increase in adipose expression of DGAT1 by 2- to 3-fold, as did the treatment of 3T3 F442A adipocytes in vitro with thiazolidinediones. These data support a more global concept suggesting that adipose lipid storage functions to prevent peripheral lipotoxicity.

Lipin Expression Is Attenuated In Adipose Tissue Of Insulin-Resistant Human Subjects And Increases With Peroxisome Proliferator-Activated Receptor Γ Activation, Aiwei Yao-Borengasser, Neda Rasouli, Vijayalakshmi Varma, Lesliie M. Miles, Bounleut Phanavanh, Tasha Starks, Jack Phan, Horace J. Spencer Iii, Robert E. Mcgehee Jr., Karen Reue, Philip A. Kern

Clinical and Translational Science Faculty Publications

Lipin-α and -β are the alternatively spliced gene products of the Lpin1 gene, whose product lipin is required for adipocyte differentiation. Lipin deficiency causes lipodystrophy, fatty liver, and insulin resistance in mice, whereas adipose tissue lipin overexpression results in increased adiposity but improved insulin sensitivity. To assess lipin expression and its relation to insulin resistance in humans, we examined lipin-α and -β mRNA levels in subjects with normal or impaired glucose tolerance. We found higher expression levels of both lipin isoforms in lean, insulin-sensitive subjects. When compared with normal glucose-tolerant subjects, individuals with impaired glucose tolerance were more insulin resistant, …

Photo Quiz - Pruritic Rash After Ocean Swim, James Studdiford

Department of Family & Community Medicine Faculty Papers

No abstract provided.

We Must Test The Blood For Antigens, Fred W. Markham Jr.

Department of Family & Community Medicine Faculty Papers

No abstract provided.

Pioglitazone Induces Apoptosis Of Macrophages In Human Adipose Tissue, Angela M. Bodles, Vijayalakshmi Varma, Aiwei Yao-Borengasser, Bounleut Phanavanh, Charlotte A. Peterson, Robert E. Mcgehee Jr., Neda Rasouli, Martin Wabitsch, Philip A. Kern

Clinical and Translational Science Faculty Publications

Metabolic syndrome and type 2 diabetes mellitus are associated with an increased number of macrophage cells that infiltrate white adipose tissue (WAT). Previously, we demonstrated that the treatment of subjects with impaired glucose tolerance (IGT) with the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone resulted in a decrease in macrophage number in adipose tissue. Here, adipose tissue samples from IGT subjects treated with pioglitazone were examined for apoptosis with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. TUNEL-positive cells were identified, and there was a significant 42% increase in TUNEL-positive cells following pioglitazone treatment. Overlay experiments with anti-CD68 antibody …

Research Annual Report 2005, Children's Mercy Hospital

Research Annual Reports

Annual report of the research at Children's Mercy Hospital in Kansas City MO, a pediatric medical center.

Gift Authorship Practices - History, Trends And Remedies, Saba Sohail

Department of Radiology

No abstract provided.

Bullous Eruption On The Posterior Thigh, James Studdiford, Amber Stonehouse

Department of Family & Community Medicine Faculty Papers

No abstract provided.

Expression Of Cd68 And Macrophage Chemoattractant Protein-1 Genes In Human Adipose And Muscle Tissues: Association With Cytokine Expression, Insulin Resistance, And Reduction By Pioglitazone, Gina B. Di Gregorio, Aiwei Yao-Borengasser, Neda Rasouli, Vijayalakshmi Varma, Tong Lu, Leslie M. Milrd, Gouri Ranganathan, Charlotte A. Peterson, Robert E. Mcgehee Jr., Philip A. Kern

Clinical and Translational Science Faculty Publications

To examine the role of adipose-resident macrophages in insulin resistance, we examined the gene expression of CD68, a macrophage marker, along with macrophage chemoattractant protein-1 (MCP-1) in human subcutaneous adipose tissue using real-time RT-PCR. Both CD68 and MCP-1 mRNAs were expressed in human adipose tissue, primarily in the stromal vascular fraction. When measured in the adipose tissue from subjects with normal glucose tolerance, covering a wide range of BMI (21-51 kg/m²) and insulin sensitivity (S_I) (0.6-8.0 × 10^-4 min^-1 · μU^-1 · ml^-1), CD68 mRNA abundance, which correlated with the number …

Research Annual Report 2004, Children's Mercy Hospital

Research Annual Reports

Annual report of the research at Children's Mercy Hospital in Kansas City MO, a pediatric medical center.

Improving Clinical Practice Using Clinical Decision Support Systems: A Systematic Review Of Trials To Identify Features Critical To Success, Kensaku Kawamoto, Caitlin A. Houlihan, E. Andrew Balas, David F. Lobach

School of Medical Diagnostics & Translational Sciences Publications

Objective To identify features of clinical decision support systems critical for improving clinical practice. Design Systematic review of randomised controlled trials.
Data sources Literature searches via Medline, CINAHL, and the Cochrane Controlled Trials Register up to 2003; and searches of reference lists of included studies and relevant reviews.
Study selection Studies had to evaluate the ability of decision support systems to improve clinical practice.
Data extraction Studies were assessed for statistically and clinically significant improvement in clinical practice and for the presence of 15 decision support system features whose importance had been repeatedly suggested in the literature.
Results Seventy studies …

Manuscripts Categorization And Their Accreditation, Jamshed Akhtar, Saba Sohail

Department of Radiology

No abstract provided.

Divergent Effects Of Peroxisome Proliferator-Activated Receptor Γ Agonists And Tumor Necrosis Factor Α On Adipocyte Apoe Expression, Lili Yue, Neda Rasouli, Gouri Ranganathan, Philip A. Kern, Theodore Mazzone

Clinical and Translational Science Faculty Publications

ApoE is expressed in multiple mammalian cell types in which it supports cellular differentiated function. In this report we demonstrate that apoE expression in adipocytes is regulated by factors involved in modulating systemic insulin sensitivity. Systemic treatment with pioglitazone increased systemic insulin sensitivity and increased apoE mRNA levels in adipose tissue by 2-3-fold. Treatment of cultured 3T3-L1 adipocytes with ciglitazone increased apoE mRNA levels by 2-4-fold in a dose-dependent manner and increased apoE secretion from cells. Conversely, treatment of adipocytes with tumor necrosis factor (TNF) α reduced apoE mRNA levels and apoE secretion by 60%. Neither insulin nor a peroxisome …

Insulin Sensitivity Following Agent Orange Exposure In Vietnam Veterans With High Blood Levels Of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin, Philip A. Kern, Sufyan Said, William G. Jackson Jr., Joel E. Michalek

Clinical and Translational Science Faculty Publications

Our objective was to determine whether insulin sensitivity was related to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Vietnam veterans exposed to Agent Orange. Air Force veterans of Operation Ranch Hand, the unit responsible for spraying Agent Orange and other herbicides in Vietnam from 1962 to 1971, and comparison veterans who did not spray herbicides were included. We measured insulin sensitivity (S_I) using a frequently sampled iv glucose tolerance test in a matched study of 29 matched pairs of veterans and a quantitative insulin sensitivity check index (QUICKI) based on fasting glucose and insulin in 71 matched pairs. No group differences were …

Translation Research: From Accurate Diagnosis To Appropriate Treatment, Craig P. Webb, Harvey I. Pass

Wayne State University Associated BioMed Central Scholarship

Abstract

This review article focuses on the various aspects of translational research, where research on human subjects can ultimately enhance the diagnosis and treatment of future patients. While we will use specific examples relating to the asbestos related cancer mesothelioma, it should be stressed that the general approach outlined throughout this review is readily applicable to other diseases with an underlying molecular basis. Through the integration of molecular-based technologies, systematic tissue procurement and medical informatics, we now have the ability to identify clinically applicable "genotype"-"phenotype" associations across cohorts of patients that can rapidly be translated into useful diagnostic and treatment …

Research Annual Report 2003, Children's Mercy Hospital

Research Annual Reports

Annual report of the research at Children's Mercy Hospital in Kansas City MO, a pediatric medical center.

Transgenic Mice Expressing Lipoprotein Lipase In Adipose Tissue: Absence Of The Proximal 3′-Untranslated Region Causes Translational Upregulation, Lori L. Hensley, Gouri Ranganathan, Elke M. Wagner, Brian D. Wells, Joseph C. Daniel, Diane Vu, Clay F. Semenkovich, Rudolf Zechner, Philip A. Kern

Clinical and Translational Science Faculty Publications

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein and adipocyte metabolism. Defects in LPL can lead to hypertriglyceridemia and the subsequent development of atherosclerosis. The mechanisms of regulation of this enzyme are complex and may occur at multiple levels of gene expression. Because the 3′-untranslated region (UTR) is involved in LPL translational regulation, transgenic mice were generated with adipose tissue expression of an LPL construct either with or without the proximal 3′-UTR and driven by the aP2 promoter. Both transgenic mouse colonies were viable and expressed the transgene, resulting in a 2-fold increase in LPL activity in white adipose …

Adiponectin Expression From Human Adipose Tissue: Relation To Obesity, Insulin Resistance, And Tumor Necrosis Factor-Α Expression, Philip A. Kern, Gina B. Di Gregorio, Tong Lu, Negah Rassouli, Gouri Ranganathan

Clinical and Translational Science Faculty Publications

Adiponectin is a 29-kDa adipocyte protein that has been linked to the insulin resistance of obesity and lipodystrophy. To better understand the regulation of adiponectin expression, we measured plasma adiponectin and adipose tissue adiponectin mRNA levels in nondiabetic subjects with varying degrees of obesity and insulin resistance. Plasma adiponectin and adiponectin mRNA levels were highly correlated with each other (r = 0.80, P < 0.001), and obese subjects expressed significantly lower levels of adiponectin. However, a significant sex difference in adiponectin expression was observed, especially in relatively lean subjects. When men and women with a BMI2were compared, women had a twofold higher percent body fat, yet their plasma adiponectin levels were 65% higher (8.6 ± 1.1 and 14.2 ± 1.6 μg/ml in men and women, respectively; P < 0.02). Plasma adiponectin had a strong association with insulin sensitivity index (S_I) (r = 0.67, P < 0.0001, n = 51) that was not affected by sex, but no relation with insulin secretion. To separate the effects of obesity (BMI) from S_I, subjects who were discordant for S_I were matched for BMI, age, and sex. Using this approach, insulin-sensitive subjects demonstrated a twofold higher plasma level of …

Research Annual Report 2002, Children's Mercy Hospital

Research Annual Reports

Annual report of the research at Children's Mercy Hospital in Kansas City MO, a pediatric medical center.

The Translational Regulation Of Lipoprotein Lipase By Epinephrine Involves An Rna Binding Complex Including The Catalytic Subunit Of Protein Kinase A, Gouri Ranganathan, Dan Phan, Irina D. Pokrovskaya, Joan E. Mcewen, Chunling Li, Philip A. Kern

Clinical and Translational Science Faculty Publications

The balance of lipid flux in adipocytes is controlled by the opposing actions of lipolysis and lipogenesis, which are controlled primarily by hormone-sensitive lipase and lipoprotein lipase (LPL), respectively. Catecholamines stimulate adipocyte lipolysis through reversible phosphorylation of hormone-sensitive lipase, and simultaneously inhibit LPL activity. However, LPL regulation is complex and previous studies have described translational regulation of LPL in response to catecholamines because of an RNA-binding protein that interacts with the 3′-untranslated region of LPL mRNA. In this study, we identified several protein components of an LPL RNA binding complex. Using an LPL RNA affinity column, we identified two of …

Regulation Of Lipoprotein Lipase By Protein Kinase Cα In 3t3-F442a Adipocytes, Gouri Ranganathan, Wei Song, Nicholas Dean, Brett Monia, Steven W. Barger, Philip A. Kern

Clinical and Translational Science Faculty Publications

Lipoprotein lipase (LPL) is an important enzyme in adipocyte and lipid metabolism with complex cellular regulation. Previous studies demonstrated an inhibition of LPL activity and synthesis following depletion of protein kinase C (PKC) isoforms with long term treatment of 3T3-F442A adipocytes with 12-O-tetradecanoylphorbol-13-acetate. To identify the specific PKC isoforms involved, we treated cells with antisense oligonucleotides that block expression of specific PKC isoforms. An antisense oligonucleotide to PKCα inhibited LPL activity by 78 ± 8%, whereas antisense oligonucleotides directed against PKCδ or PKCε had no effect on LPL activity. The change in LPL activity was maximal at 72 …

Optimisation Of Bile Production During Normothermic Preservation Of Porcine Livers., Charles J. Imber, Shawn D. St Peter, Inigo Lopez De Cenarruzabeitia, Hugh Lemonde, Mike Rees, Andrew Butler, Peter T. Clayton, Peter J. Friend

Manuscripts, Articles, Book Chapters and Other Papers

Machine perfusion of livers may provide a mechanism for extended preservation of marginal donor organs before transplantation, as well as a method for viability assessment. It has proved possible in a series of experimental porcine liver perfusions to maintain liver viability for up to 72 h. However, a reduction in bile production with associated histological evidence of cholestasis was seen after 10 h of perfusion, damaging the biliary canaliculi during the preservation period and leaving these organs in an unacceptable condition for transplantation. It was proposed that reduction in bile production was the result of a relentless depletion of available …

The Hiv Protease Inhibitor Saquinavir Impairs Lipid Metabolism And Glucose Transport In Cultured Adipocytes, S. Ranganathan, Philip A. Kern

Clinical and Translational Science Faculty Publications

Treatment of HIV infection using protease inhibitors is frequently associated with lipodystrophy and impaired lipid and glucose metabolism. We examined the effect of saquinavir, one of the protease inhibitors, on lipid metabolism and glucose transport in cultured adipocytes. Saquinavir inhibited lipoprotein lipase (LPL) activity in 3T3-F442A and 3T3-L1 adipocytes. The inhibition of LPL was 81% at a concentration of 20 μg/ml. Another closely related drug, indinavir, had a small inhibitory effect. Saquinavir also inhibited the biosynthesis of lipids from [¹⁴C]-acetate. Saquinavir increased the lipolysis. Saquinavir had no significant effect on the cellular protein synthesis or protein content. Saquinavir …

Cigarette Sources For Teens By Grade: Implications For Prevention And Intervention, Netra M. Thakur, Michael P. Rosenthal, Priscilla Latta, Jamie L. Robinson, James Diamond

Department of Family & Community Medicine Faculty Papers

Objective: To identify at-risk teen populations and their sources of cigarettes, in order to help target future efforts in prevention of teen smoking. Methods: Analysis of smoking behavior questions for students in grades 6, 7, 9 and 12 from the 1997 Pennsylvania Biennial Youth Risk Survey. Results: Current smoking prevalence was 20.9% overall. The number of ninth grade smokers was almost five times higher than the number of sixth grade smokers (30.6% vs. 6.6%). Seventy-three percent of the teens identified friends as a source of tobacco. Stores became the most common source for twelfth graders only. Conclusion: Teenage smoking remains …

Beyond Pain Management: A Primer For Providing Quality End-Of-Life Care, Linda P. Tomko, Terri L. Maxwell

Department of Family & Community Medicine Faculty Papers

Providing excellent care for a dying patient is something all patients deserve. Hospices and palliative care centers exist in many areas to aid primary care physicians and patients through this difficult time. It is important to remember that most patients want to prepare for death, if at all possible. Everyone does this in his or her own way, but oftentimes concern about pain and symptom management interfere with this very involved and valuable process. Being prepared to treat these symptoms as well as addressing your patient's emotional needs is imperative. Referral to a hospice, if possible, will only strengthen the …

The Translational Regulation Of Lipoprotein Lipase In Diabetic Rats Involves The 3′-Untranslated Region Of The Lipoprotein Lipase Mrna, Gouri Ranganathan, Chunling Li, Philip A. Kern

Clinical and Translational Science Faculty Publications

Adipose tissue lipoprotein lipase (LPL) activity is decreased in patients with poorly controlled diabetes, and this contributes to the dyslipidemia of diabetes. To study the mechanism of this decrease in LPL, we studied adipose tissue LPL expression in male rats with streptozotocin-induced diabetes. Heparin releasable and extractable LPL activity in the epididymal fat decreased by 75-80% in the diabetic group and treatment of the rats with insulin prior to sacrifice reversed this effect. Northern blot analysis indicated no corresponding change in LPL mRNA levels. However, LPL synthetic rate, measured using [³⁵S]methionine pulse labeling, was decreased by 75% in …

Research Vision 2000, Children's Mercy Hospital

Research Annual Reports

Describes some of the research at Children's Mercy Hospital in Kansas City MO, a pediatric medical center, along with the vision for building its research efforts over the long term.

Exposure To 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (Tcdd) Is Associated With Hyperinsulinemia And Insulin Resistance, Morris Cranmer, Shirley Louie, Richard H. Kennedy, Philip A. Kern, Vivian A. Fonseca

Clinical and Translational Science Faculty Publications

High exposures of Vietnam veterans to 2,3,7,8-Tetrachlorodibenzo-p- dioxin, a dioxin contained in the herbicide mixture Agent Orange, have previously been demonstrated to be associated with an increased prevalence of diabetes and hyperinsulinemia in non-diabetic subjects. Sixty-nine persons were identified who were in good health and had normal glucose levels during glucose tolerance testing. These subjects lived within 25 miles of the Vertac/Hercules Superfund site located in Jacksonville, Arkansas. The blood sera lipid concentrations of TCDD for the 69 subjects ranged between 2 and 94 ppt. When subjects with blood sera lipid TCDD levels in the top 10% (TCDD > 15 ppt, …