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Zhu A.,Greater Los Angeles Veterans Affairs Healthcare System | Kaneshiro M.,Greater Los Angeles Veterans Affairs Healthcare System | Kaunitz J.D.,Greater Los Angeles Veterans Affairs Healthcare System | Kaunitz J.D.,University of California at Los Angeles | And 2 more authors.
Digestive Diseases and Sciences | Year: 2010

A substantial volume of the consultations requested of gastroenterologists are directed towards the evaluation of anemia. Since iron deficiency anemia often arises from bleeding gastrointestinal lesions, many of which are malignant, establishment of a firm diagnosis usually obligates an endoscopic evaluation. Although the laboratory tests used to make the diagnosis have not changed in many decades, their interpretation has, and this is possibly due to the availability of extensive testing in key populations. We provide data supporting the use of the serum ferritin as the sole useful measure of iron stores, setting the lower limit at 100 μg/l for some populations in order to increase the sensitivity of the test. Trends of the commonly obtained red cell indices, mean corpuscular volume, and the red cell distribution width can provide valuable diagnostic information. Once the diagnosis is established, upper and lower gastrointestinal endoscopy is usually indicated. Nevertheless, in many cases a gastrointestinal source is not found after routine evaluation. Additional studies, including repeat upper and lower endoscopy and often investigation of the small intestine may thus be required. Although oral iron is inexpensive and usually effective, there are many gastrointestinal conditions that warrant treatment of iron deficiency with intravenous iron. © 2009 Springer Science+Business Media, LLC.


Wang J.-H.,University of California at Los Angeles | Inoue T.,University of California at Los Angeles | Higashiyama M.,University of California at Los Angeles | Guth P.H.,Greater Los Angeles Veterans Affairs Healthcare System | And 7 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

Luminal nutrient chemosensing during meal ingestion is mediated by intestinal endocrine cells, which regulate secretion and motility via the release of gut hormones. We have reported that luminal coperfusion of L-Glu and IMP, common condiments providing the umami or proteinaceous taste, synergistically increases duodenal bicarbonate secretion (DBS) possibly via taste receptor heterodimers, taste receptor type 1, member 1 (T1R1)/R3. We hypothesized that glucose-dependent insulinotropic peptide (GIP) or glucagon-like peptide (GLP) is released by duodenal perfusion with L-Glu/IMP. We measured DBS with pH and CO 2 electrodes through a perfused rat duodenal loop in vivo. GIP, exendin (Ex)-4 (GLP-1 receptor agonist), or GLP-2 was intravenously infused (0.01-1 nmol/kg/h). L-Glu (10 mM) and IMP (0.1 mM) were luminally perfused with or without bolus intravenous injection (3 or 30 nmol/kg) of the receptor antagonists Pro 3GIP, Ex-3(9-39), or GLP-2(3-33). GIP or GLP-2 infusion dose-dependently increased DBS, whereas Ex-4 infusion gradually decreased DBS. Luminal perfusion of L-Glu/IMP increased DBS, with no effect of Pro 3GIP or Ex-3(9-39), whereas GLP-2(3-33) inhibited L-Glu/IMP-induced DBS. Vasoactive intestinal peptide (VIP)(6-28) intravenously or N G-nitro-L-arginine methyl ester coperfusion inhibited the effect of L-Glu/IMP. Perfusion of L-Glu/IMP increased portal venous concentrations of GLP-2, followed by a delayed increase of GLP-1, with no effect on GIP release. GLP-1/2 and T1R1/R3 were expressed in duodenal endocrine-like cells. These results suggest that luminal L-Glu/IMP-induced DBS is mediated via GLP-2 release and receptor activation followed by VIP and nitric oxide release. Because GLP-1 is insulinotropic and GLP-2 is intestinotrophic, umami receptor activation may have additional benefits in glucose metabolism and duodenal mucosal protection and regeneration. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A.


Kaunitz J.D.,Greater Los Angeles Veterans Affairs Healthcare System | Kaunitz J.D.,University of California at Los Angeles | Kaunitz J.D.,Brentwood Biomedical Research Institute | Akiba Y.,Greater Los Angeles Veterans Affairs Healthcare System | And 2 more authors.
Acta Physiologica | Year: 2011

The duodenum secretes HCO3 - as part of a multi-layered series of defence mechanisms against damage from luminal acid. In the 1980s, an alkaline surface layer was measured over the mucosa which correlated with the rate of HCO3 - secretion. As all biological processes are regulated, we investigated how the alkaline pH of the surface layer was maintained. As the ecto-phosphorylase alkaline phosphatase (AP) is highly expressed in the duodenal brush border, we hypothesized that its extreme alkaline pH optimum (~pH 8-9) combined with its ability to hydrolyse regulatory purines such as ATP was part of an ecto-purinergic signalling system, consisting also of brush border P2Y receptors and cystic fibrosis transmembrane regulator-mediated HCO3 - secretion. Extracellular ATP increases the rate of HCO3 - secretion through this purinergic system. At high surface pH (pHs), AP activity is increased, which then increases the rate of ATP hydrolysis, decreasing surface ATP concentration ([ATP]s), with a resultant decrease in the rate of HCO3 - secretion, which subsequently decreases pHs. This feedback loop is thus hypothesized to regulate pHs over the duodenal mucosa, and in several other HCO3 - secretory organs. As AP activity is directly related to pHs, and as AP hydrolyses ATP, [ATP]s and pHs are co-regulated. As many essential tissue functions such as ciliary motility and lipid uptake are dependent on [ATP]s, dysregulation of pHs and [ATP]s may help explain the tissue dysfunction characteristic of diseases such as cystic fibrosis. © 2010 No claim to original US government works. Journal compilation © 2010 Scandinavian Physiological Society.


Akiba Y.,Greater Los Angeles Veterans Affairs Healthcare System | Akiba Y.,University of California at Los Angeles | Akiba Y.,Brentwood Biomedical Research Institute | Kaunitz J.D.,Greater Los Angeles Veterans Affairs Healthcare System | And 2 more authors.
Digestive Diseases and Sciences | Year: 2010

Background: Luminal acid or CO2 induces a hyperemic response in the esophagus, via activation of acid sensors on capsaicin-sensitive afferent nerves (CSAN). Since disruption of the hyperemic response to luminal CO 2 acidifies the interstitium of the esophageal mucosa, the hyperemic response may maintain interstitial pH (pHint). We hypothesized that acid-related hyperemia maintains pHint, preventing acid-induced injury in the esophageal mucosa. Methods: We examined the effects of capsaicin (Cap) or lafutidine (Laf), a mucosal protective H2 antagonist, on the regulation of pHint and blood flow in rat esophagus using ratiometric microimaging and laser-Doppler measurements of the lower esophageal mucosa of living rats. The esophagus was topically superfused with pH 7.0 buffer, or a pH 1.0 or pH 1.0 + pepsin (1 mg/ml) solution with or without Laf. Results: Cap (30 or 100 μM) or Laf (0.1 or 1 mM) dose-dependently increased blood flow, accompanied by increased pHint. The pH 1.0 solution increased blood flow without pHint change, whereas Laf (1 mM) increased blood flow and pHint during acid exposure. The effects of Laf were abolished by ablation of CSAN. Perfusion of the acidified pepsin solution gradually decreased pHint, inhibited by Laf perfusion. Conclusions: Activation of CSAN by Laf with or without acid, accompanied by hyperemia, increased pHint, preventing acidified pepsin-induced interstitial acidification. Stimulation of the capsaicin pathway with compounds such as Laf enhances mucosal protection from acid-related injury in the upper gastrointestinal tract. © 2010 The Author(s).


Palileo C.,University of California at Los Angeles | Palileo C.,Brentwood Biomedical Research Institute | Kaunitz J.D.,Brentwood Biomedical Research Institute | Kaunitz J.D.,Digestive Diseases Research Center | Kaunitz J.D.,University of California at Los Angeles
Current Opinion in Gastroenterology | Year: 2011

Purpose of review: We have highlighted the recent findings relating to gastroduodenal mucosal defense, including elements that may contribute to the failure of defense systems and factors that enhance mucosal healing, focusing on findings that elucidate new pathophysiological mechanisms. Recent findings: Bicarbonate secretion is mediated by multiple types of prostaglandin E synthases, including membrane-bound prostaglandin E synthase-1. Mucins, growth factors, and trefoil factors are involved in accelerating gastric injury healing through epithelial reconstruction. A combination of NSAIDs and bile induce greater damage on the mucosa than if the two agents were acting alone. Proton pump inhibitors defend the mucosa from injury by promoting cellular restitution as well as inhibiting gastric acid secretion and reactive oxygen species (ROS) damage. Roxatidine, a novel H 2 receptor antagonist, acts through a mechanism that involves nitric oxide. Melatonin enhances angiogenesis through the upregulation of plasma levels of gastrin and matrix metalloproteinase expression. The mucosal protective drug polaprezinc exhibits ROS-quenching activities. Lipopolysaccharides induce oxidative stress mediated by p38 mitogen-activated protein kinase (p38 MAPK). Aging weakens gastroduodenal mucosal defense mechanisms. Summary: There is a wide array of pathways leading to gastroduodenal mucosal injury in addition to protective defense mechanisms that counteract them to maintain homeostasis. Increased understanding of these systems may help identify novel molecular targets for the prevention and treatment of mucosal injury. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Al-Jiboury H.,Cedars Sinai Medical Residency Program | Kaunitz J.D.,University of California at Los Angeles | Kaunitz J.D.,Digestive Diseases Research Center | Kaunitz J.D.,Brentwood Biomedical Research Institute
Current Opinion in Gastroenterology | Year: 2012

PURPOSE OF REVIEW: To review recent developments in the field of gastroduodenal mucosal defense. RECENT FINDINGS: Research in the field of gastroduodenal mucosal defense is shifting from animal models of mucosal injury towards the elucidation of molecular mechanisms that protect the mucosa at the cellular level. Accordingly, the recent literature is focused on endogenous antioxidants such as mitochondrial superoxide dismutase (SOD), and heme oxygenase-1, mucosal receptors such as the Toll-like receptors and protease-activated receptors, endogenous proteins with protective effects such as the matrix metalloproteinases, heat-inducible factors and trefoil factors, protective functions of submucosal mononuclear cells, junctional proteins affecting mucosal permeability, and hormone-mediated protective mechanisms mediated by estrogens, vasoactive peptides, and other hormones. SUMMARY: These new published findings contribute to our overall understanding of gastroduodenal defense and suggest innovative avenues of future research and possible novel therapeutic targets. © 2012 Wolters Kluwer Health Lippincott Williams & Wilkins.


Kemmerly T.,Cedars Sinai Medical Residency Program | Kaunitz J.D.,University of California at Los Angeles | Kaunitz J.D.,Brentwood Biomedical Research Institute
Nutrition in Clinical Practice | Year: 2014

We describe a case in which a patient receiving parenteral nutrition (PN) developed hypophosphatemia. Due to lack of availability of parenteral phosphate supplements, we chose to restore phosphate using diluted hypertonic sodium phosphate enemas. Due to the recent shortages of parenteral minerals and vitamins, such an alternate means of repletion is of increasing importance. Diluted hypertonic sodium phosphate enemas are inexpensive, easy to administer, and effective since phosphate is readily absorbed across the rectal mucosa. We hope that through this type of repletion, life-threatening hypophosphatemia among patients receiving PN can be avoided. © 2014 American Society for Parenteral and Enteral Nutrition.


Kaunitz J.D.,University of California at Los Angeles | Kaunitz J.D.,Digestive Diseases Research Center | Kaunitz J.D.,Brentwood Biomedical Research Institute
Digestive Diseases and Sciences | Year: 2013

Background: The lumen of the gastrointestinal tract contains many substances produced from the breakdown of foodstuffs, from salivary, esophageal, intestinal, hepatic, and pancreatic secretions, and from sloughed cells present in the gastrointestinal lumen. Although these substances were traditionally regarded as waste products, there is increasing realization that many can be biologically active, either as signalling compounds or as nutrients. For example, proteins are broken down into amino acids, which are then sensed by nutrient receptors. The gut microbiome, which is at highest abundance in the ileocecum, has powerful metabolic activity, digesting and breaking down unabsorbed carbohydrates, proteins, and other ingested nutrients into phenols, amines, volatile organic compounds, methane, carbon dioxide, hydrogen, and hydrogen sulfide into volatile fatty acids, also called short-chain fatty acids (SCFAs). Conclusion: These latter substances are the topic of this review. In this review, we will briefly discuss recent advances in the understanding SCFA production, signalling, and absorption, followed by a detailed description and discussion of trials of SCFAs, probiotics, and prebiotics in the treatment of gastrointestinal disease, in particular ulcerative colitis (UC), pouchitis, short bowel syndrome, and obesity. © 2013 Springer Science+Business Media New York (Outside the USA).


Kemmerly T.,Cedars SinaiMedical Residency Program | Kaunitz J.D.,University of California at Los Angeles | Kaunitz J.D.,Digestive Diseases Research Center | Kaunitz J.D.,Brentwood Biomedical Research Institute
Current Opinion in Gastroenterology | Year: 2014

Purpose of review: To review recent developments in the field of gastroduodenal mucosal defense. Recent findings: Research in the field of gastroduodenal mucosal defense has focused on continued elucidation of molecular mechanisms that protect the mucosa and influence healing at the cellular level. Review of literature over the past year reveals that familiar proteins and mediators, such as nitric oxide, toll-like receptors, nucleotidebinding oligomerization domain-containing proteins (NOD2), β-defensins, macrophages, dendritic cells, mucins, autophagy, and the influence of aging and diet, are still subjects of study, but also brings into light new processes and mediators, such as dual oxidases, defense against radiation injuries, and novel proteins such as ZBP-89. Summary: These new published findings contribute to our overall understanding of gastroduodenal defense and suggest innovative avenues of future research and possible novel therapeutic targets. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Kemmerly T.,Cedars Sinai Medical Center | Kaunitz J.D.,University of California at Los Angeles | Kaunitz J.D.,Digestive Diseases Research Center | Kaunitz J.D.,Brentwood Biomedical Research Institute
Current Opinion in Gastroenterology | Year: 2013

Purpose of Review: To review recent developments in the field of gastroduodenal mucosal defense. Recent Findings: Research in the field of gastroduodenal mucosal defense has focused on continued elucidation of molecular mechanisms that protect the mucosa and influence healing at the cellular level. Review of literature over the past year reveals focus on familiar processes such as superoxide dismutase, nitric oxide, heme oxygenase-1, neutrophil infiltration, cysteamine, mucin, hydrogen sulfide, ghrelin, adiponectin and the influence of Helicobacter pylori, but also brings into light new processes such as the balance between apoptosis and cellular proliferation, as well as the influence of other organ systems such as the bone marrow and central nervous system on the gastrointestinal tract. Summary: These new published findings contribute to our overall understanding of gastroduodenal defense and suggest innovative avenues of future research and possible novel therapeutic targets. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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