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Molecular Therapy 02/2013; 21(2):269-271. · 6.87 Impact Factor
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ABSTRACT: Bariatric surgery is a powerful treatment of severe obesity. During the past several years, a greater appreciation for the need for multidisciplinary care to optimize outcomes has developed, and a number of studies have been started to examine the role of postoperative interventions used in combination with surgery. The purpose of the present study was to investigate the hypothesis that the provision of postoperative dietary counseling, delivered by a registered dietitian, would lead to greater weight loss and more positive improvements in dietary intake and eating behavior compared with standard postoperative care. The study was performed at an academic medical center.
Eighty-four individuals who underwent bariatric surgery were randomly assigned to receive either dietary counseling or standard postoperative care for the first 4 months after surgery. The participants completed measures of macronutrient intake and eating behavior at baseline and 2, 4, 6, 12, 18, and 24 months after surgery.
The patients who received dietary counseling achieved greater weight loss than those who received standard postoperative care that did not involve this counseling, although this difference did not reach statistical significance. Patients in the dietary counseling arm did report significant changes in several eating behaviors believed to be important to successful long-term weight maintenance.
The results of our pilot study provide some support for the efficacy of early postoperative dietary counseling to improve outcomes after bariatric surgery.
Surgery for Obesity and Related Diseases 03/2012; 8(5):561-8. · 3.93 Impact Factor
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ABSTRACT: Improvements in psychosocial status are an important aspect of successful outcomes after bariatric surgery. Relatively few studies have investigated the changes in psychosocial functioning at a number of points in the first few postoperative years. The present study was undertaken to assess the changes in quality of life and body image after gastric bypass surgery. The present study was performed at an academic medical center.
A total of 200 men and women were enrolled in the study and completed psychometric measures of quality of life and body image before surgery and again 20, 40, and 92 weeks postoperatively.
The participants reported significant improvements in several domains of health- and weight-related quality of life, as well as changes in body image, after surgery. These changes were correlated with the percentage of weight loss.
Those who undergo gastric bypass surgery experienced significant improvements in quality of life and body image within the first few months after surgery. These changes were, with few exceptions, maintained into the second postoperative year.
Surgery for Obesity and Related Diseases 08/2010; 6(6):608-14. · 3.93 Impact Factor
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ABSTRACT: To investigate the relationship between preoperative eating behavior, postoperative dietary adherence and weight loss after gastric bypass surgery in a major, urban medical center with a comprehensive bariatric surgery program. Despite the significant weight loss and dramatic improvements in co-morbidities associated with bariatric surgery, a significant minority of patients appear to experience suboptimal weight loss. The reasons for this are not well understood, but the suboptimal weight loss is often attributed to preoperative psychosocial characteristics and/or eating behaviors, as well as poor adherence to the recommended postoperative diet.
A prospective investigation was performed of 200 female and male patients who were studied both preoperatively and 20, 40, 66, and 92 weeks postoperatively. All patients underwent either open or laparoscopic Roux-en-Y gastric bypass surgery. The measures were the percentage of weight loss, macronutrient intake, dietary adherence, and eating behavior.
Gender, baseline cognitive restraint, and self-reported adherence to the postoperative diet at postoperative week 20 were associated with the percentage of weight loss at postoperative week 92. Those high in dietary adherence had lost 4.5% more weight at postoperative week 92 than those low in dietary adherence.
Baseline cognitive restraint and adherence to the recommended postoperative diet were associated with the percentage of weight loss after gastric bypass surgery. These results suggest the potential utility of pre- and/or postoperative dietary counseling interventions to improve the postoperative outcomes.
Surgery for Obesity and Related Diseases 07/2008; 4(5):640-6. · 3.93 Impact Factor
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American Journal of Roentgenology 01/2008; 189(6):1469-72. · 2.78 Impact Factor
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Peter Bell,
A David Moscioni,
Robert J McCarter,
Di Wu,
Guangping Gao,
Albert Hoang,
Julio C Sanmiguel,
Xun Sun,
Nelson A Wivel, Steven E Raper,
Emma E Furth,
Mark L Batshaw,
James M Wilson
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ABSTRACT: The present study reports on the frequency of liver tumors observed in a gene therapy study with AAV vectors in male mice of the B6C3F1 hybrid background, which are known to have a high frequency of spontaneous liver tumors. Male mice with mutations in their Otc gene and their wild-type siblings received AAV vectors expressing either the murine Otc or the LacZ gene. Untreated control animals were included in the study. All experimental groups, including wild-type and OTC-deficient animals not treated with vector, developed liver nodules, which in some cases were due to hepatocellular carcinoma. Vector DNA was lower in tumors than in adjacent normal liver. A statistical analysis of the data did not show an association between treatment with Otc vectors and formation of tumors in OTC-deficient mice. However, mice treated with LacZ vectors showed increased risks of tumor formation and hepatocellular carcinoma relative to untreated animals or animals that had received vectors with Otc as the transgene. It appears that AAV vectors alone do not contribute to the formation of tumors in these strains of mice although the expression of LacZ alone or in combination with vector may be problematic.
Molecular Therapy 08/2006; 14(1):34-44. · 6.87 Impact Factor
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David Moscioni,
Hiroki Morizono,
Robert J McCarter,
Adam Stern,
Juan Cabrera-Luque,
Albert Hoang,
Julio Sanmiguel,
Di Wu,
Peter Bell,
Guang-Ping Gao, Steven E Raper,
James M Wilson,
Mark L Batshaw
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ABSTRACT: The purpose of this study was to determine the efficacy of novel recombinant adeno-associated viral (AAV) vector constructs in correcting metabolic defects in the liver in two strains of ornithine transcarbamylase (OTC)-deficient mice (spf and spf-ash). AAV vectors expressing mouse OTC were produced with capsids from AAV2 and the novel serotypes AAV7, 8, and 9. OTC-deficient mice were infused with these vectors as well as a control AAV2/8 vector expressing LacZ. In vivo activity of OTC was assessed by measuring a surrogate marker, urine orotate. The novel vectors restored orotate levels to virtually normal 15 days after infusion, and each persisted to 1 year posttreatment. Liver OTC enzyme activity in spf mice was substantially higher in animals receiving novel vectors compared to those receiving AAV2 vectors. Animals receiving novel OTC-expressing vectors lived longer than those treated with AAV2 OTC or untreated controls, and they were tolerant to a challenge with NH3 at 21 days and beyond, which caused severe morbidity in control OTC-deficient animals. Numerous mice, representative of all treatment groups followed for +250 days, were observed to have either nodules or discrete tumors in the liver, the etiology of which is the subject of a companion paper.
Molecular Therapy 08/2006; 14(1):25-33. · 6.87 Impact Factor
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ABSTRACT: This study compared the psychosocial status and weight loss expectations of women with extreme (class III) obesity who sought bariatric surgery with those of women with class I-II obesity who enrolled in a research study on behavioral weight control.
Before treatment, all participants completed the Beck Depression Inventory-II and the Weight and Lifestyle Inventory. This latter questionnaire assesses several domains including symptoms of depression and low self-esteem, history of psychiatric complications, current stressors, and weight loss expectations.
Women with class III obesity, as compared with class I-II, reported significantly more symptoms of depression. Fully 25% of women in the former group appeared to have a significant mood disorder that would benefit from treatment. As compared with women with class I-II obesity, significantly more women with class III obesity also reported a history of psychiatric complications, which included physical and sexual abuse and greater stress related to their physical health and financial/legal matters. Both groups of women had unrealistic weight loss expectations. Those who sought surgery expected to lose 47.6 +/- 9.3% of initial weight, compared with 24.8 +/- 8.7% for those who enrolled in behavioral weight control.
These findings suggest that women with extreme obesity who seek bariatric surgery should be screened for psychosocial complications. Those determined to have significant psychiatric distress should be referred for behavioral or pharmacological treatment to alleviate their suffering. Long-term studies are needed to provide definitive guidance concerning the relationship between preoperative psychopathology and the outcome of bariatric surgery.
Obesity 04/2006; 14 Suppl 2:90S-98S. · 4.28 Impact Factor
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Steven E Raper
Surgery 06/2005; 137(5):487-92. · 3.10 Impact Factor
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ABSTRACT: The objective of these studies is to determine the effects of macrophage ablation on the course of acute viral pancreatitis. Macrophages secrete proinflammatory cytokines triggering local pancreatic and systemic inflammation in the acute phase of virus-induced pancreatitis. We hypothesized that ablation of macrophages should attenuate the host inflammatory response in a mouse model of adenovirus-induced pancreatitis.
Liposome-encapsulated dichloromethylene-diphosphonate, a macrophage-depleting agent, was used before direct pancreatic injection of a recombinant adenovirus expressing a marker gene in C57Bl/6 and IL-6 knockout (KO) mice.
C57Bl/6 mice depleted of macrophages had diminished pancreatic inflammation in the first 24 hours after vector administration. IL-6 KO mice depleted of macrophages had more severe inflammation than similarly treated C57Bl/6 mice. C57Bl/6 mice depleted of macrophages, and IL-6 KO mice had prolonged transgene expression and diminished cytotoxic T lymphocyte responses to adenoviral vector. Mortality was highest in IL-6 KO mice depleted of macrophages. Depletion of macrophages also prevented detectable serum IL-6, IL-10, or IL-12 levels in C57Bl/6 mice.
The data suggest that macrophages play a role in the acute inflammatory response to viral vector-induced pancreatitis and that IL-6 may be protective. Understanding of the mechanisms that initiate the host immune cascade will allow more effective use of adenoviral vector-based pancreatic gene delivery.
Surgery 06/2005; 137(5):545-51. · 3.10 Impact Factor
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ABSTRACT: Patients undergoing bariatric surgery are at risk for deep venous thrombosis (DVT) and fatal pulmonary embolus. In the presence of genetic hypercoagulable disorders, accepted methods of DVT prophylaxis utilizing sequential compression devices and subcutaneous unfractionated heparin may not be adequate to prevent DVT or fatal PE.
3 morbidly obese patients are described who underwent open Roux-en-Y gastric bypass and either had a previous diagnosis of Factor V Leiden or developed thrombosis in the presence of standard prophylaxis. Each was found to have the most common point mutation for Factor V Leiden, R506Q. All 3 patients had prophylactic inferior vena caval filters placed to prevent recurrent PE.
The presence of venous thromboembolism either without known risk factors or in the presence of standard perioperative prophylaxis for DVT should warrant a hypercoagulable work-up. Inferior vena caval filter placement is indicated in the presence of a hypercoagulable disorder prior to surgical intervention in the morbidly obese population. The recent literature is reviewed.
Obesity Surgery 05/2005; 15(4):561-4. · 3.29 Impact Factor
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American Journal of Roentgenology 04/2005; 184(3 Suppl):S65-6. · 2.78 Impact Factor
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ABSTRACT: The role of innate immunity in the development of acute viral pancreatitis is not well understood. The aim of the study was to characterize the role of the innate immune system, especially macrophages, natural killer (NK), and NK T (NKT) cells, in the generation of immune responses to intrapancreatic delivery of recombinant adenoviral vector.
Adenoviral vectors expressing beta-galactosidase or green fluorescent protein genes with viral capsid conjugated covalently with carbocyanine dye were directly injected into the pancreas of C57Bl/6 mice.
Fluorescent microscopy of the pancreas showed that 30 minutes after vector administration, adenoviral particles localized to cell membranes, internalized, and localized to the nucleus by 4 hours, and transgene expression began at 24 hours. Immunohistochemical staining showed macrophages entering the pancreas shortly after vector administration, with maximal infiltration at day 4, and then disappearing as antigen-expressing cells were eliminated. Intrapancreatic macrophages appeared to deliver viral capsid proteins to the spleen. Flow cytometry showed that NK and NKT cells migrate to the pancreas and persist. Serum cytokines IL-6, IL-10, and IL-12 were all elevated.
Macrophages and NK and NKT cells play a major role in the development of acute adenovirus-mediated pancreatitis.
Pancreas 04/2005; 30(2):122-9. · 2.39 Impact Factor
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Gary P Kobinger,
Shaoping Deng,
Jean-Pierre Louboutin,
Marko Vatamaniuk,
Victor M Rivera,
Moh-Moh Lian,
James F Markmann,
Tim Clackson, Steven E Raper,
Franz Matschinsky,
James M Wilson
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ABSTRACT: Transplantation of allogeneic islets can correct the metabolic abnormalities of Type I diabetes. Limited availability of donor pancreas tissues restricts the application of this therapeutic modality to a subset of eligible recipients. In an attempt to expand the utility of available donor human pancreas tissue, we developed a method to stimulate the proliferation of insulin-secreting beta-cells within human islets. A lentiviral vector was used to introduce into human islets chimeric signaling receptors that are activated to stimulate cell proliferation through interactions with a small-molecule drug called a chemical inducer of dimerization (CID). In vitro exposure of vector-transduced human islets to the CID expanded the number of cells and increased regulated insulin secretion. Transplantation of the regenerated islets into diabetic immunodeficient mice, followed by in vivo administration of the CID, corrected hyperglycemia. This strategy has the potential to reduce the quantity of human islets required for treatment of patients with Type I diabetes.
Molecular Therapy 02/2005; 11(1):105-11. · 6.87 Impact Factor
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ABSTRACT: This study investigated the psychiatric diagnoses and psychiatric treatment histories of 90 bariatric surgery candidates.
Prior to surgery, all participants completed the Weight and Lifestyle Inventory, the Questionnaire on Eating and Weight Patterns, and the Beck Depression Inventory-II. Participants also underwent a behavioral/psychological evaluation with a psychologist, which reviewed responses to the measures and provided further assessment of participants' psychiatric status. The evaluation also was used to produce a recommendation on the patients' psychological appropriateness for surgery.
Almost two-thirds of patients received a psychiatric diagnosis, the most common of which was major depressive disorder. Nearly two-fifths of all participants, and more than half of those given a psychiatric diagnosis, were engaged in some form of psychiatric treatment at the time of the evaluation. Nevertheless, 64% of patients were unconditionally approved for surgery; 31% were recommended for additional psychiatric or nutritional counseling prior to surgery. Three patients were not recommended for surgery.
Results of this study provide important information on the preoperative psychiatric status and treatment histories of bariatric surgery candidates. Given the increasing population of bariatric surgery patients, evaluation of patients' preoperative psychiatric status may play an important role in maximizing successful postoperative outcomes.
Obesity Surgery 11/2004; 14(9):1148-56. · 3.29 Impact Factor
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ABSTRACT: Hepatocyte growth/scatter factor (HGF/SF) is a pleiotropic cytokine originally identified as a potent mitogen for rat hepatocytes. Two HGF/SF knockout mouse models have been reported, both of which exhibit developmental abnormalities causing embryonic lethality. To circumvent this limitation, we created a mouse conditionally deficient in liver expression of HGF/SF to specifically investigate the role of this mitogen in the process of adult liver regeneration. Gene targeting technology was used to generate a mouse with loxP sites flanking exon 5 of the HGF/SF gene (ex5-flox). In the absence of cre recombinase activity, mice homozygous for ex5-flox were indistinguishable from wild-type littermates. To ablate HGF/SF gene expression in vitro, primary hepatocytes established from homozygous HGF(ex5-flox) mice were infected with a recombinant adenoviral vector coding for cre recombinase (AdCre1). PCR analyses of genomic DNA demonstrated greater than 90% ablation of the ex5-floxed gene sequence. In vivo, HGF(ex.5-flox) mice were administered AdCre1 vector and the ablation of the HGF gene confirmed by Southern blot analysis. To induce liver regeneration, mice were injected with the hepatotoxin carbon tetrachloride. The regenerative capacity of hepatocytes in mice administered cre recombinase was shown to be significantly reduced when compared with mice injected with an adenovirus expressing LacZ. A similar reduction in hepatocyte regeneration was observed in HGF(ex.5.flox) mice carrying the cre transgene under the control of the interferon-inducible (pI:pC) Mx1 promoter, as an alternative strategy to ablate the HGF/SF gene in liver. Our results confirm the mitogenic role of HGF/SF in liver regeneration.
DNA and Cell Biology 10/2004; 23(9):592-603. · 2.07 Impact Factor
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Surgery 04/2004; 135(3):352-4. · 3.10 Impact Factor
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ABSTRACT: Type I diabetes is caused by an autoimmune-mediated elimination of insulin-secreting pancreatic islets. Genetic modification of islets offers a powerful molecular tool for improving our understanding of islet biology. Moreover, efficient genetic engineering of islets could allow for evaluation of new strategies aimed at preventing islet destruction. The present study evaluated the ability of a human immunodeficiency virus (HIV)-based lentiviral vector pseudotyped with various viral envelopes to target human islets ex vivo, with the goal of improving efficiency while minimizing toxicity. Transfer of the enhanced green fluorescent protein reporter gene in human islets was first evaluated with an HIV-based vector pseudotyped with the vesicular stomatitis virus (VSV), murine leukemia virus, Ebola, rabies, Mokola, or lymphocytic choriomeningitis virus (LCMV) envelope glycoprotein to optimize transduction efficiency. Results indicated that LCMV-pseudotyped vector transduced insulin-secreting beta cells with the highest efficiency. Moreover, toxicity associated with transduction of islets was found to be lower with LCMV-pseudotyped vector than with VSV-G-pseudotyped vector, the second most efficient vector for islet transduction. Overall, our study describes an improved methodology for achieving safe and efficient gene transfer into cells of human islets.
Human Gene Therapy 03/2004; 15(2):211-9. · 4.22 Impact Factor
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ABSTRACT: Recent advances in molecular genetics and biotechnology will revolutionize the practice of medicine and surgery during the next decade. Surgeons must understand and begin to use the new technologies in the study of surgical biology and patient care. A brief overview of the principles of gene transfer and how this technology is used for treating metabolic disease is presented. Two examples of how recombinant viruses (vectors) can be used to study fundamental biology in the liver and pancreas are given. Familial hypercholesterolemia is used as a paradigm for a clinical gene transfer study and underscores the importance of surgeons in the development of novel therapeutic strategies.
World Journal of Surgery 08/2002; 26(7):838-42. · 2.36 Impact Factor
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Steven E Raper,
Marc Yudkoff,
Narendra Chirmule,
Guang-Ping Gao,
Fred Nunes,
Ziv J Haskal,
Emma E Furth,
Kathleen J Propert,
Michael B Robinson,
Susan Magosin,
Heather Simoes,
Lisa Speicher,
Joseph Hughes,
John Tazelaar,
Nelson A Wivel,
James M Wilson,
Mark L Batshaw
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ABSTRACT: Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis that has been considered as a model for liver-directed gene therapy. Current treatment has failed to avert a high mortality or morbidity from hyperammonemic coma. Restoration of enzyme activity in the liver should suffice to normalize metabolism. An E1- and E4-deleted vector based on adenovirus type 5 and containing human OTC cDNA was infused into the right hepatic artery in adults with partial OTCD. Six cohorts of three or four subjects received 1/2 log-increasing doses of vector from 2 x 10(9) to 6 x 10(11) particles/kg. This paper describes the experience in all but the last subject, who experienced lethal complications. Adverse effects included a flu-like episode and a transient rise in temperature, hepatic transaminases, thrombocytopenia, and hypophosphatemia. Humoral responses to the vector were seen in all research subjects and a proliferative cellular response to the vector developed in apparently naive subjects. In situ hybridization studies showed transgene expression in hepatocytes of 7 of 17 subjects. Three of 11 subjects with symptoms related to OTCD showed modest increases in urea cycle metabolic activity that were not statistically significant. The low levels of gene transfer detected in this trial suggest that at the doses tested, significant metabolic correction did not occur.
Human Gene Therapy 02/2002; 13(1):163-75. · 4.22 Impact Factor
