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Farzadfar F.,Tehran University of Medical Sciences | Murray C.J.L.,University of Washington | Gakidou E.,University of Washington | Bossert T.,Harvard University | And 5 more authors.
The Lancet | Year: 2012

Background: Non-communicable diseases and their risk factors are leading causes of disease burden in Iran and other middle-income countries. Little evidence exists for whether the primary health-care system can effectively manage non-communicable diseases and risk factors at the population level. Our aim was to examine the effectiveness of the Iranian rural primary health-care system (the Behvarz system) in the management of diabetes and hypertension, and to assess whether the effects depend on the number of health-care workers in the community. Methods: We used individual-level data from the 2005 Non-Communicable Disease Surveillance Survey (NCDSS) for fasting plasma glucose (FPG) and systolic blood pressure (SBP), body-mass index, medication use, and sociodemographic variables. Data for Behvarz-worker and physician densities were from the 2006 Population and Housing Census and the 2005 Outpatient Care Centre Mapping Survey. We assessed the effectiveness of treatment on FPG and SBP, and associations between FPG or SBP and Behvarz-worker density with two statistical approaches: a mixed-effects regression analysis of the full NCDSS sample adjusting for individual-level and community-level covariates and an analysis that estimated average treatment effect on data balanced with propensity score matching. Results: NCDSS had data for 65 619 individuals aged 25 years or older (11 686 of whom in rural areas); of these, 64 694 (11 521 in rural areas) had data for SBP and 50 202 (9337 in rural areas) had data for FPG. Nationally, 39.2% (95% CI 37.7 to 40.7) of individuals with diabetes and 35.7% (34.9 to 36.5) of those with hypertension received treatment, with higher treatment coverage in women than in men and in urban areas than in rural areas. Treatment lowered mean FPG by an estimated 1. 34 mmol/L (0. 58 to 2. 10) in rural areas and 0.21 mmol/L (-0. 15 to 0. 56) in urban areas. Individuals in urban areas with hypertension who received treatment had 3.8 mm Hg (3.1 to 4.5) lower SBP than they would have had if they had not received treatment; the treatment effect was 2. 5 mm Hg (1.1 to 3.9) lower FPG in rural areas. Each additional Behvarz worker per 1000 adults was associated with a 0. 09 mmol/L (0.01 to 0. 18) lower district-level average FPG (p=0.02); for SBP this effect was 0. 53 mm Hg (-0.44 to 1.50; p=0.28). Our findings were not sensitive to the choice of statistical method. Interpretation: Primary care systems with trained community health-care workers and well established guidelines can be effective in non-communicable disease prevention and management. Iran's primary care system should expand the number and scope of its primary health-care worker programmes to also address blood pressure and to improve performance in areas with few primary care personnel. Funding: None. © 2012 Elsevier Ltd.


Stengel A.,Charité - Medical University of Berlin | Tache Y.,University of California at Los Angeles | Tache Y.,Digestive Diseases Research Center
Current Gastroenterology Reports | Year: 2012

Ingestion of food affects the secretion of hormones from specialized endocrine cells scattered within the intestinal mucosa. Upon release, these hormones mostly decrease food intake by signaling information to the brain. Although enteroendocrine cells in the small intestine were thought to represent the predominant gut-brain regulators of food intake, recent advances also established a major role for gastric hormones in these regulatory pathways. First and foremost, the gastric endocrine X/A-like cell was in the focus of many studies due to the production of ghrelin, which is until now the only known orexigenic hormone that is peripherally produced and centrally acting. Although X/A-cells were initially thought to only release one hormone that stimulates food intake, this view has changed with the identification of additional peptide products also derived from this cell, namely desacyl ghrelin, obestatin, and nesfatin-1. Desacyl ghrelin may play a counter-regulatory role to the food intake stimulatory effect of ghrelin. The same property was suggested for obestatin; however, this hypothesis could not be confirmed in numerous subsequent studies. Moreover, the description of the stomach as the major source of the novel anorexigenic hormone nesfatin-1 derived from the NUCB2 gene further corroborated the assumption that the gastric X/A-like cell products are not only stimulant but also inhibitors of feeding, thereby acting as so far unique dual regulator of food intake located in a logistically important place where the gastrointestinal tract has initial contact with food. © Springer Science+Business Media, LLC 2012.


Laine L.,Yale University | Laine L.,VA Connecticut Healthcare System | Jensen D.M.,University of California at Los Angeles | Jensen D.M.,Digestive Diseases Research Center | Jensen D.M.,VA Greater Los Angeles Healthcare System
American Journal of Gastroenterology | Year: 2012

This guideline presents recommendations for the step-wise management of patients with overt upper gastrointestinal bleeding. Hemodynamic status is first assessed, and resuscitation initiated as needed. Patients are risk-stratified based on features such as hemodynamic status, comorbidities, age, and laboratory tests. Pre-endoscopic erythromycin is considered to increase diagnostic yield at first endoscopy. Pre-endoscopic proton pump inhibitor (PPI) may be considered to decrease the need for endoscopic therapy but does not improve clinical outcomes. Upper endoscopy is generally performed within 24h. The endoscopic features of ulcers direct further management. Patients with active bleeding or non-bleeding visible vessels receive endoscopic therapy (e.g., bipolar electrocoagulation, heater probe, sclerosant, clips) and those with an adherent clot may receive endoscopic therapy; these patients then receive intravenous PPI with a bolus followed by continuous infusion. Patients with flat spots or clean-based ulcers do not require endoscopic therapy or intensive PPI therapy. Recurrent bleeding after endoscopic therapy is treated with a second endoscopic treatment; if bleeding persists or recurs, treatment with surgery or interventional radiology is undertaken. Prevention of recurrent bleeding is based on the etiology of the bleeding ulcer. H. pylori is eradicated and after cure is documented anti-ulcer therapy is generally not given. Nonsteroidal anti-inflammatory drugs (NSAIDs) are stopped; if they must be resumed low-dose COX-2-selective NSAID plus PPI is used. Patients with established cardiovascular disease who require aspirin should start PPI and generally re-institute aspirin soon after bleeding ceases (within 7 days and ideally 1-3 days). Patients with idiopathic ulcers receive long-term anti-ulcer therapy. © 2012 by the American College of Gastroenterology.


Spiegel B.M.R.,VA Greater Los Angeles Healthcare System | Spiegel B.M.R.,University of California at Los Angeles | Spiegel B.M.R.,Digestive Diseases Research Center
Clinical Gastroenterology and Hepatology | Year: 2011

Although studies indicate that small intestinal bacterial overgrowth (SIBO) is prevalent in irritable bowel syndrome (IBS), it remains unclear whether SIBO causes IBS. This review presents an epidemiologic and evolutionary inquiry that questions the bacterial overgrowth hypothesis of IBS, as follows. (1) Although the hypothesis may be biologically plausible, there is also a strong rationale for competing hypotheses; it is unlikely that SIBO is the predominant cause of IBS in all comers, because competing explanations are sensible and defensible. Moreover, data indicate that the test used to promulgate the SIBO hypothesis - the lactulose hydrogen breath test - may not have measur ed SIBO in the first place. (2) We do not have evidence of SIBO being absent before IBS symptoms, and present after IBS emerges. (3) There is not a dose-response relationship between small intestinal microbiota and IBS symptoms. (4) The relationship between SIBO and IBS is highly inconsistent among studies. (5) Many effective IBS therapies do not address SIBO at all, yet have a more favorable "number needed to treat" than antibiotics. (6) IBS does not behave like a traditional infectious disease, suggesting that microbes may not principally cause the syndrome. (7) Other factors may confound the relationship between SIBO and IBS, including proton pump inhibitors. (8) Whereas the brain-gut hypothesis is evolutionary sensible, the bacterial hypothesis is harder to defend from an evolutionary perspective. The article concludes that bacteria may contribute to some IBS symptoms, but that bacteria cannot be the only explanation, and a causal link between SIBO and IBS is not secure. © 2011 AGA Institute.


Stengel A.,Digestive Diseases Research Center | Stengel A.,Charité - Medical University of Berlin | Tachea Y.,Digestive Diseases Research Center
Current Pharmaceutical Design | Year: 2011

Postoperative gastric ileus develops after abdominal surgery and if prolonged leads to longer hospitalization times. Besides discomfort for the patient such as abdominal bloating and pain, this condition is associated with a great increase in healthcare costs. In order to develop new and effective treatment strategies to alleviate the ileus, a good understanding of the pathophysiological underlying mechanisms is necessary. Postoperative gastric ileus consists of two phases, a first neural/humoral phase and a second inflammatory phase. The present review will focus on the role of the orexigenic and prokinetic hormone ghrelin in the development of postoperative ileus. Although ghrelin and ghrelin mimetics have been used during the recent years in pre-clinical and a first clinical trial to alleviate symptoms of postoperative ileus, the regulation of this hormone under conditions of abdominal surgery has just recently begun to be explored. Growing evidence indicates that postoperative restoration of ghrelin signaling leads to an orexigenic effect whereas the gastroprokinetic actions seem to require supraphysiological doses. Since the expression of ghrelin-O-acyltransferase (GOAT), the only ghrelin acylating enzyme, is reduced after abdominal surgery, the stimulation of GOAT signaling may also be a new promising approach to restore levels of acyl ghrelin under these conditions and a potential useful addition to ghrelin mimetics. © 2011 Bentham Science Publishers Ltd.


Stengel A.,Charité - Medical University of Berlin | Tache Y.,Digestive Diseases Research Center
Hormone and Metabolic Research | Year: 2013

Hunger and satiety are regulated in a complex fashion by a few food intake stimulatory (orexigenic) and a multitude of inhibitory (anorexigenic) factors produced in the periphery (mainly in the gastrointestinal tract) or directly in the brain. Within the brain, the hypothalamus plays a pivotal role as a production site of food intake regulatory factors. Importantly, this site integrates peripheral and central signaling factors to orchestrate food intake and in the long term body weight. Our knowledge on these regulatory pathways is not static but rather rapidly changing as new factors as well as up- and downstream signaling pathways of already known transmitters are uncovered. Hypothalamic nucleobindin2 (NUCB2), the precursor of nesfatin-1, was first described in 2006 and nesfatin-1 found to be a novel anorexigenic modulator of food intake and body weight. The initial report stimulated several groups to investigate the biological actions of nesfatin-1 and subsequent studies delineated the underlying brain mechanisms involved in its food reducing effect. Of interest was the demonstration that NUCB2 also exerts its anorexigenic action in the paraventricular nucleus of the hypothalamus and is regulated at this site by changes in metabolic status with a diurnal rhythm inversely related to that of feeding in rats. The present review describes the current state-of-knowledge on central nesfatin-1's effects on food intake and body weight and highlights important missing links regarding cellular signaling mechanisms involved in nesfatin-1's action. © 2013 Georg Thieme Verlag KG Stuttgart New York.


Stengel A.,Digestive Diseases Research Center | Tache Y.,VA Greater Los Angeles Healthcare System
Current Protein and Peptide Science | Year: 2011

Several peptides are produced and released from endocrine cells scattered within the gastric oxyntic and the small intestinal mucosa. These peptide hormones are crucially involved in the regulation of gastrointestinal functions and food intake by conveying their information to central regulatory sites located in the brainstem as well as in the forebrain, such as hypothalamic nuclei. So far, ghrelin is the only known hormone that is peripherally produced in gastric X/A-like cells and centrally acting to stimulate food intake, whereas the suppression of feeding seems to be much more redundantly controlled by a number of gut peptides. Cholecystokinin produced in the duodenum is a well established anorexigenic hormone that interacts with ghrelin to modulate food intake indicating a regulatory network located at the first site of contact with nutrients in the stomach and upper small intestine. In addition, a number of peptides including leptin, urocortin 2, amylin and glucagon-like peptide 1 interact synergistically with CCK to potentiate its satiety signaling effect. New developments have led to the identification of additional peptides in X/A-like cells either derived from the pro-ghrelin gene by alternative splicing and posttranslational processing (obestatin) or a distinct gene (nucleobindin2/nesfatin-1) which have been investigated for their influence on food intake. © 2011 Bentham Science Publishers Ltd.


Earlier experimental studies indicated that the integrity of vagal pathway was required to confer gastric protection against damaging agents. Several peptides located in the brainstem initially identified to influence vagal outflow to the stomach, as assessed by electrophysiological approach or by vagal dependent alterations of gastric secretory and motor function, were investigated for their influence in the vagal regulation of the resistance of the gastric mucosa to injury. Thyrotropin releasing hormone (TRH), or its stable TRH analog, RX-77368, injected at low doses into the cisterna magna or the dorsal motor nucleus (DMN) was the first peptide reported to protect the gastric mucosa against ethanol injury through stimulation of vagal cholinergic pathways, inducing the release of gastric prostaglandins/ nitric oxide (NO) and the recruitment of efferent function of capsaicin sensitive afferent fibers containing calcitonin-gene related peptide (CGRP). Activation of endogenous TRH-TRH1 receptor signaling located in the brainstem plays a role in adaptive gastric protection against damaging agents. Since then, an expanding number of peptides, namely peptide YY, CGRP, adrenomedullin, amylin, glugacon-like peptide, opioid peptides acting on μ, δ1 or δ2 receptors, nocicpetin, nocistatin, ghrelin, leptin and TLQP-21, a peptide derived from VGF prohormone, have been reported to act in the brainstem to afford gastric protection against ethanol injury largely through similar peripheral effectors mechanisms than TRH. Therefore gastric prostaglandins and CGRP/NO pathways represent a common final mechanism through which brain peptides confer vagally mediated gastroprotection against injury. A better understanding of brain circuitries through which these peptides are released will provide new strategies to recruit integrated and multifaceted gastroprotective mechanisms. © 2012 Bentham Science Publishers.


Stengel A.,Digestive Diseases Research Center | Goebel M.,Digestive Diseases Research Center | Wang L.,Digestive Diseases Research Center | Tache Y.,Digestive Diseases Research Center
Peptides | Year: 2010

Abdominal surgery-induced postoperative gastric ileus is well established to induce Fos expression in specific brain nuclei in rats within 2-h after surgery. However, the phenotype of activated neurons has not been thoroughly characterized. Nesfatin-1 was recently discovered in the rat hypothalamus as a new anorexigenic peptide that also inhibits gastric emptying and is widely distributed in rat brain autonomic nuclei suggesting an involvement in stress responses. Therefore, we investigated whether abdominal surgery activates nesfatin-1-immunoreactive (ir) neurons in the rat brain. Two hours after abdominal surgery with cecal palpation under short isoflurane anesthesia or anesthesia alone, rats were transcardially perfused and brains processed for double immunohistochemical labeling of Fos and nesfatin-1. Abdominal surgery, compared to anesthesia alone, induced Fos expression in neurons of the supraoptic nucleus (SON), paraventricular nucleus (PVN), locus coeruleus (LC), Edinger-Westphal nucleus (EW), rostral raphe pallidus (rRPa), nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM). Double Fos/nesfatin-1 labeling showed that of the activated cells, 99% were nesfatin-1-immunoreactive in the SON, 91% in the LC, 82% in the rRPa, 74% in the EW and VLM, 71% in the anterior parvicellular PVN, 47% in the lateral magnocellular PVN, 41% in the medial magnocellular PVN, 14% in the NTS and 9% in the medial parvicellular PVN. These data established nesfatin-1 immunoreactive neurons in specific nuclei of the hypothalamus and brainstem as part of the neuronal response to abdominal surgery and suggest a possible implication of nesfatin-1 in the alterations of food intake and gastric transit associated with such a stressor.


Stengel A.,Digestive Diseases Research Center | Tache Y.,Digestive Diseases Research Center
Experimental Biology and Medicine | Year: 2010

Stress may cause behavioral and/or psychiatric manifestations such as anxiety and depression and also impact on the function of different visceral organs, namely the gastrointestinal and cardiovascular systems. During the past years substantial progress has been made in the understanding of the underlying mechanisms recruited by stressors. Activation of the corticotropin-releasing factor (CRF) signaling system is recognized to be involved in a large number of stress-related behavioral and somatic disorders. This review will outline the present knowledge on the distribution of the CRF system (ligands and receptors) expressed in the brain and peripheral viscera and its relevance in stress-induced alterations of gastrointestinal and cardiovascular functions and the therapeutic potential of CRF1 receptor antagonists. Copyright © 2010 by the Society for Experimental Biology and Medicine.

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