Obesity: Jones D

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM, Anonymous00014. · No affiliation provided · Circulation. · Pubmed #18574054 links to  free full text

Abstract: Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM. · No affiliation provided · Hypertension. · Pubmed #18391085 links to  free full text

Abstract: Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Anonymous00057, Anonymous00058, Anonymous00059, Smith SC, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pearson T, Pfeffer MA, Taubert KA. · No affiliation provided · J Am Coll Cardiol. · Pubmed #16697342 No free full text.

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Smith SC, Blair SN, Bonow RO, Brass LM, Cerqueira MD, Dracup K, Fuster V, Gotto A, Grundy SM, Miller NH, Jacobs A, Jones D, Krauss RM, Mosca L, Ockene I, Pasternak RC, Pearson T, Pfeffer MA, Starke RD, Taubert KA. · No affiliation provided · J Am Coll Cardiol. · Pubmed #11691544 No free full text.

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Giger NJ, Richardson J, Jones D. · No affiliation provided · J Natl Black Nurses Assoc. · Pubmed #12242754 No free full text.

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Vicentic A, Lakatos A, Jones D. · Neuroscience Division, Yerkes National Primate Research Center of Emory University, Atlanta, GA 30329, USA. · Peptides. · Pubmed #16713658 No free full text.

Abstract: Previous evidence obtained from several behavioral and biochemical studies suggested the existence of multiple CART receptors. However, identification of CART receptor binding has been largely unsuccessful until recently. The first evidence of CART signaling properties came from a study demonstrating that CART 55-102 inhibited voltage-dependent intracellular calcium signaling. More recent studies showed CART-induced dose- and time-dependent activation of extracellular signal-regulated kinase (ERK) 1 and 2 in AtT20 cell line. The activation of ERK was blocked by pertussis toxin but not genisten suggesting the involvement of Gi/o linked cascade in CART's signaling properties in AtT20 cells. Shortly after these findings, the evidence of CART 61-102 specific binding was obtained from the same cell line. This study demonstrated that [(125)I]-CART 61-102 was displaced only by active CART peptide but not by inactive CART fragments or several other unrelated peptides or drugs. The [(125)I]-CART 61-102 binding was saturable and it had a high affinity for a single site in AtT20 cells. The binding was also dependent on time, pH, temperature and protein concentration. The average (+/-S.E.M.) B(max) and K(d) values were 101.4+/-8.8 fmol/mg protein and 21.9+/-8.0 pM, respectively. These data indicate the existence of specific CART receptor binding in AtT20 cells where CART signaling has been demonstrated. The identification of a receptor clone in these cells may help us elucidate CART receptors in other tissues. Because CART is implicated with several physiological functions including feeding, drug reward and stress, identification of a CART receptor would provide a novel target for the development of pharmacological tools and drugs for obesity and other disorders.

Hamza MA, Schneider BE, White PF, Recart A, Villegas L, Ogunnaike B, Provost D, Jones D. · Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, 5161 Harry Hines Boulevard, CS 2.282, Dallas, TX 75390, USA. · J Laparoendosc Adv Surg Tech A. · Pubmed #15772469 No free full text.

Abstract: BACKGROUND: Controversy exists regarding the efficacy of heated and humidified intraperitoneal gases in maintaining core body temperature. We performed a sham-controlled study to test the hypothesis that active warming and humidification of the insufflation gas reduces intraoperative heat loss and improves recovery outcomes. PATIENTS AND METHODS: Fifty morbidly obese patients undergoing laparoscopic Roux-en-Y gastric bypass procedures using a standardized anesthetic technique were randomly assigned to either a control (sham) group receiving room temperature insufflation gases with an inactive Insuflow (Lexion Medical, St. Paul, MN) device, or an active (Insuflow) group receiving warmed and humidified intraperitoneal gases. Esophageal and/or tympanic membrane temperature was measured perioperatively. Postoperative pain was assessed at 15 minute intervals using an 11-point verbal rating scale, with 0 = none to 10 = maximal. In addition, postoperative opioid requirements, incidence of nausea and vomiting, as well as the quality of recovery, were recorded. RESULTS: Use of the active Insuflow device was associated with significantly higher mean +/- standard deviation (SD) intraoperative core body temperatures (35.5 +/- 0.5 vs. 35.0 +/- 0.4 degrees C). Postoperative shivering (0 vs. 19%) and the requirement for morphine in the postanesthesia care unit (5 +/- 4 vs. 10 +/- 5 mg) were both significantly lower in the Insuflow vs. control groups. Patients in the Insuflow group also reported a higher quality of recovery 48 hours after surgery (15 vs. 13, P < 0.05). CONCLUSION: The Insuflow device modestly reduced shivering and heat loss, as well as the need for opioid analgesics in the early postoperative period. However, it failed to improve laparoscopic visualization due to fogging, and provided improvement in the quality of recovery only on postoperative day 2.

Symons JD, McMillin SL, Riehle C, Tanner J, Palionyte M, Hillas E, Jones D, Cooksey RC, Birnbaum MJ, McClain DA, Zhang QJ, Gale D, Wilson LJ, Abel ED. · College of Health, University of Utah School of Medicine, 30 N 2030 E, Salt Lake City, UT 84132, USA. · Circ Res. · Pubmed #19342603 No free full text.

Abstract: Impaired insulin signaling via phosphatidylinositol 3-kinase/Akt to endothelial nitric oxide synthase (eNOS) in the vasculature has been postulated to lead to arterial dysfunction and hypertension in obesity and other insulin resistant states. To investigate this, we compared insulin signaling in the vasculature, endothelial function, and systemic blood pressure in mice fed a high-fat (HF) diet to mice with genetic ablation of insulin receptors in all vascular tissues (TTr-IR(-/-)) or mice with genetic ablation of Akt1 (Akt1-/-). HF mice developed obesity, impaired glucose tolerance, and elevated free fatty acids that was associated with endothelial dysfunction and hypertension. Basal and insulin-mediated phosphorylation of extracellular signal-regulated kinase 1/2 and Akt in the vasculature was preserved, but basal and insulin-stimulated eNOS phosphorylation was abolished in vessels from HF versus lean mice. In contrast, basal vascular eNOS phosphorylation, endothelial function, and blood pressure were normal despite absent insulin-mediated eNOS phosphorylation in TTr-IR(-/-) mice and absent insulin-mediated eNOS phosphorylation via Akt1 in Akt1-/- mice. In cultured endothelial cells, 6 hours of incubation with palmitate attenuated basal and insulin-stimulated eNOS phosphorylation and NO production despite normal activation of extracellular signal-regulated kinase 1/2 and Akt. Moreover, incubation of isolated arteries with palmitate impaired endothelium-dependent but not vascular smooth muscle function. Collectively, these results indicate that lower arterial eNOS phosphorylation, hypertension, and vascular dysfunction following HF feeding do not result from defective upstream signaling via Akt, but from free fatty acid-mediated impairment of eNOS phosphorylation.

Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M. · Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. · Am J Hum Genet. · Pubmed #17236139 links to  free full text

Abstract: We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.

Villegas L, Schneider B, Provost D, Chang C, Scott D, Sims T, Hill L, Hynan L, Jones D. · Southwestern Center for Minimally Invasive Surgery, University of Texas Southwestern Medical Center at Dallas, TX, USA. · Obes Surg. · Pubmed #15018749 No free full text.

Abstract: BACKGROUND: Routine cholecystectomy is often performed at the time of gastric bypass for morbid obesity. The aim of our study was to determine the incidence of gallstone formation requiring cholecystectomy following a laparoscopic Roux-en-Y gastric bypass (LRYGBP). METHODS: 289 LRYGBP were performed between November 1999 and May 2002. 60 patients (21%) who had prior cholecystectomy were excluded. If gallstones were identified by intra-operative ultrasound (IOUS), simultaneous cholecystectomy was performed. Patients without gallstones were prescribed ursodiol for 6 months and scheduled for follow-up with transabdominal ultrasound. RESULTS: During LRYGBP, gallstones were detected in 40 patients using IOUS (14%) and simultaneous cholecystectomy was performed. Of 189 patients with no stones identified by IOUS, 151 patients (80%) had a postoperative ultrasound after 6 months. 39 patients developed gallstones (22%) and 12 developed sludge (8%), as demonstrated by ultrasound at the time of follow-up. 11 patients had gallstone-related symptoms and subsequently underwent cholecystectomy (7%). 106 patients (70%) were gallstone-free at the time of ultrasound follow-up. Ursodiol compliance was found to be significantly lower for patients developing stones than for gallstone-free patients (38.9% vs 58.3%, z =-2.00, P = 0.045). CONCLUSIONS: There is a low incidence of symptomatic gallstones requiring cholecystectomy after LRYGBP. Prophylactic ursodiol is protective. Routine IOUS and selective cholecystectomy with close patient follow-up is a rational approach in the era of laparoscopy.

Villegas L, Schneider B, Provost D, Chang C, Scott D, Sims T, Hill L, Hynan L, Jones D. · Southwestern Center for Minimally Invasive Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. · Obes Surg. · Pubmed #14980035 No free full text.

Abstract: BACKGROUND: Routine cholecystectomy is often performed at the time of gastric bypass for morbid obesity.The aim of this study was to determine the incidence of gallstone formation requiring cholecystectomy following a laparoscopic Roux-en-Y gastric bypass (LRYGBP). METHODS: 289 LRYGBP were performed between November 1999 and May 2002. 60 patients (21%) who had prior cholecystectomy were excluded. If gallstones were identified by intra-operative ultrasound (IOUS), simultaneous cholecystectomy was performed. Patients without gallstones were prescribed ursodiol for 6 months and scheduled for follow-up with transabdominal ultrasound. RESULTS: During LRYGBP, gallstones were detected in 40 patients using IOUS (14%) and simultaneous cholecystectomy was performed. Of 189 patients with no stones identified by IOUS, 151 patients (80%) had a postoperative ultrasound after 6 months. 33 patients developed gallstones (22%) and 12 developed sludge (8%) as demonstrated by ultrasound at the time of follow-up. 11 patients had gallstone-related symptoms and subsequently underwent cholecystectomy (7%). 106 patients (70%) were gallstone-free at the time of ultrasound follow-up. Ursodiol compliance was found to be significantly lower for patients who developed stones than for gallstone-free patients (38.9% vs 58.3%, z =-2.00, P = 0.045). CONCLUSIONS: There is a low incidence of symptomatic gallstones requiring cholecystectomy after LRYGBP. Prophylactic ursodiol is protective. Routine IOUS and selective cholecystectomy with close patient follow-up is a rational approach in the era of laparoscopy.

Juhaeri, Stevens J, Chambless LE, Nieto FJ, Jones D, Schreiner P, Arnett D, Cai J. · Department of Epidemiology, School of Public Health, CB# 7400 McGavran-Greenberg Hall, University of North Carolina Chapel Hill, 27599-740, USA. · Prev Med. · Pubmed #12634024 No free full text.

Abstract: BACKGROUND: To examine associations of weight loss and changes in fat distribution with changes in blood pressure and the remission of hypertension in a community-based sample. METHODS: Participants were 3245 white and African-American men and women, 45-64 years of age, who participated in the Atherosclerosis Risk in Communities Study over an average of 9 years. Mixed models analyses were used to examine the associations of weight loss and changes in fat distribution with changes in blood pressure. Proportional hazard models with time-dependent covariates were used to examine the associations of weight loss and changes in fat distribution with the remission of hypertension. RESULTS: Weight loss was associated with a decrease in systolic blood pressure and diastolic blood pressure and with an increased rate of remission of hypertension. Hazard ratios of the remission of hypertension associated with 1-kg increment in annual weight loss were 2.04 (95% confidence interval [CI]: 1.62-2.59), 1.38 (95% CI: 1.14-1.67), 1.84 (95% CI: 1.47-2.29), and 1.53 (95% CI: 1.14-2.05) for white women, African-American women, white men, and African-American men, respectively. Changes in fat distribution were associated with the remission of hypertension in younger (45-54 years) participants. CONCLUSIONS: Weight loss was associated with a decrease in blood pressure and with remission of hypertension in white and African-American men and women.

Jones D. · No affiliation provided · Nat Rev Drug Discov. · Pubmed #19043439 No free full text.

Abstract: A wave of terminations of development programmes for cannabinoid receptor 1 blockers for obesity indicates the demise of a drug class that was once anticipated to yield blockbusters. Nevertheless, lessons learned might help salvage something for future such approaches.

Jones D. · No affiliation provided · Nat Rev Drug Discov. · Pubmed #17821827 No free full text.

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