Sidhartha R. Sinha

Health Technologies and Innovation in the Global Health Arena

Although many health technologies are indispensible to global health, many are inaccessible in developing countries. Yet most of the health technologies needed in such countries are not expensive, and there are ways to ensure their appropriate distribution.

A Thermo-Sensitive Delivery Platform for Topical Administration of Inflammatory Bowel Disease Therapies

Systemic therapies for inflammatory bowel disease are associated with an increased risk of infections and malignancies. Topical therapies reduce systemic exposure, but can be difficult to retain or have limited proximal distribution. To mitigate these issues, we developed a thermo-sensitive platform, using a polymer-based system that is liquid at room temperature but turns into a viscous gel on reaching body temperature. After rectal administration to mice with dextran sulfate sodium-induced colitis, the platform carrying budesonide or mesalamine becomes more viscoelastic near body temperature. Mice given the drug-containing platform gained more weight and had reduced histologic and biologic features of colitis than mice given the platform alone or liquid drugs via enema. Image analysis showed that enemas delivered with and without the platform reached similar distances in the colons of mice, but greater colonic retention was achieved by using the platform.

Enhanced imaging technologies in detecting dysplasia in IBD: narrowing or widening our options?

Nuzhat A. Ahmad, Philadelphia, PA Darren M. Brenner, Chicago, IL Andrew T. Chan, Boston, MA Francis K. L. Chan, Hong Kong, China Lin Chang, Los Angeles, CA Tsutomu Chiba, Kyoto, Japan Massimo Colombo, Milan, Italy B. Joseph Elmunzer, Ann Arbor, MI Timothy B. Gardner, Lebanon, NH Lauren B. Gerson, Stanford, CA Colin W. Howden, Chicago, IL W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Edward V. Loftus, Rochester, MN Josep M. Llovet, New York, NY Julian Panes, Barcelona, Spain Sameer Saini, Ann Arbor, MI Shiv K. Sarin, New Delhi, India Shamita B. Shah, Stanford, CA Amit Singal, Dallas, TX Jan Tack, Leuven, Belgium Michael L. Volk, Ann Arbor, MI Akbar Waljee, Ann Arbor, MI Kenneth K. Wang, Rochester, MN Alex Ford, Leeds, United Kingdom Joel H. Rubenstein, Ann Arbor, MI Alastair J. M. Watson, Norwich, UK

Effect of intratonsillar injection of steroids on the palatine tonsils of rabbits.

Nasal steroids may significantly improve nasal obstructive symptoms with a reduction of adenoid size in children, but they do not consistently yield the same concurrent effect on enlarged palatine tonsils. Failure of nasal steroids to decrease the size of palatine tonsils is believed to be attributable to location and washout by saliva. The purpose of this study was to determine if direct application of steroid via intratonsillar injection would reduce the size of palatine tonsils in the rabbit model.

Severe Iron Deficiency: Rare Etiology, Easy Treatment

A 23-year-old male with an over 10-year history of chronic iron-deficiency anemia and gastroschisis at birth was initially evaluated at an outpatient Gastroenterology clinic with complaints of generalized malaise and fatigue lasting for several days. Although he denied abdominal pain, he had experienced intermittent bloating and epigastric discomfort for several years. He also reported chronic diarrhea, which he described as foul smelling, loose stools that occurred three to six times per day for several years. He denied fevers, chills, nausea, vomiting, hematemesis, or rectal bleeding. Additionally, he denied dyspnea on exertion or chest discomfort. On examination, tachycardia and normotension were noted. A hemoglobin of 4.4 g/dL prompted admission for further evaluation. His past medical history included asthma. The patient had been hospitalized for 3 months after birth (at 36 weeks gestation), largely due to an inability to tolerate oral intake, having received total parenteral nutrition prior to being discharged tolerating oral feeds. Charts from that time noted that he ‘‘...had gastroschisis with intestine, spleen and stomach outside of the abdomen.’’ A few days after birth, he underwent non-resective surgical repair. Intraoperatively, there was no evidence of intestinal atresia. At the age of five, he had one episode of a small bowel obstruction that resolved with medical management. An upper gastrointestinal series (UGIS) with small bowel follow through (SBFT) at that time showed slightly dilated small bowel segments with normal transit time throughout. In 1994, at the age of six, his hemoglobin and mean corpuscular volume (MCV) were within normal limits. Nevertheless, even in 2001, the patient had a history of heme-positive stool, along with bloating, diarrhea, and anemia (hemoglobin 9.1 g/dL and MCV 60). His anemia was evaluated at that time with panendoscopy without abnormal findings. The duodenum was reported as being ‘‘patulous.’’ Biopsies revealed mild chronic active gastritis (antral biopsies were negative for Helicobacter pylori), mild reflux esophagitis, and a normal duodenum. Biopsies throughout the right and left colon were normal. Overall, his endoscopic evaluation did not reveal any abnormalities that explained his anemia. He was prescribed oral iron replacement therapy, which, however, was not tolerated and thus not taken regularly. Given his history of asthma and poor growth as a child, he was evaluated for cystic fibrosis (CF) with sweat chloride and genetic testing which were normal. In 2001 another UGIS with SBFT showed a somewhat dilated distal jejunum. Pancreatic enzyme supplements were prescribed for unclear reasons, which, however, initially improved his bloating and diarrhea. By 2004, the diarrhea recurred with non-bloody, loose stools reported two to three times a week. There was no clear explanation for the patient’s diarrhea, anemia, or hemepositive stools; he was lost to follow-up until being seen at our institution. The patient’s social history was unremarkable in that he denied any drug, alcohol, or tobacco use. He also denied foreign travel or unusual environmental exposures. He did not have any pertinent family history; his three siblings S. R. Sinha (&) G. Triadafilopoulos N. Shah Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 300 Pasteur Dr., Always Bldg. M211, Stanford, CA 94305-5187, USA e-mail: sidsinha@stanford.edu

Age-Related Changes in Gut Microbiota Alter Phenotype of Muscularis Macrophages and Disrupt Gastrointestinal Motility

Figure 1. Microbiota from old mice alte were co-housed with either young or old m from GF mice showed reduced expres (FIZZ1), C-type lectin domain family 10 me and (C) statistically significantly increased sponded to (D) increased levels of TNFa sentative of 3 independent experiments. (F stool. Whole-gut transit times (WGTTs) w statistically significant reduction in transit before and after Abx treatment, which was independent experiments. n 5 for each g Bonferroni multiple comparisons test. Dat muscularis macrophages (MMs) in the gut muscularis externa modulate gut homeostasis including neuromuscular function. Through neuroimmune cross-talk, MMs may sense cues in the microenvironment from the microbiota or extrinsic sympathetic neurons and relay this information to enteric neurons. We showed that aging shifts the phenotype of MMs from an M2 to an M1 polarization state, which is associated with chronic, low-grade inflammation in the enteric nervous system and delayed intestinal transit. The objective of this study was to evaluate whether alterations in gut microbiota contribute to age-related

The use of Tumor Necrosis Factor Alpha Inhibitors for Inflammatory Bowel Disease Patients with Concurrent Heart Failure

Background Prescribing information for tumor necrosis factor alpha (TNFα) inhibitors, a mainstay of treatment for moderate to severe inflammatory bowel disease (IBD), instructs cautious use in those with heart failure (HF). However, the limited data behind these warnings are inconclusive and should be weighed against mounting evidence demonstrating worse cardiac outcomes in active IBD.

Mo1700 Targeted Topical Therapy to Treat Inflammatory Bowel Disease Using a Novel Thermosensitive Drug Delivery Platform

by hyperemia and mucosal thickness and weight lose. On day 3 after colitis induction, 66% and 16% of Desnosumab-DSS-treated mice had weight loss and mucosal thickening respectively, compared to 100% and 66% of vehicle DSS-treated mice (p<0.05). Composite macroscopic score was 41% lower in Desnosumab-DSS-treated mice than in vehicle DSStreated mice (p<0.05). All four markers including diarrhea, hyperemia, thickness and adhesion were decreased. Denosumab treatment decreased the colonic MPO activity (p<0.05). Colonic IL-1b levels decreased from 41.1±1.7 in vehicle-DSS-treated mice to 13.11±1.3 pg/ mg of tissue in Denosumab-DSS-treated mice (p<0.05). Conversely, no effect was evident on colonic IL-6 levels. In control mice (without colitis) Denosumab did not affect any inflammatory marker. Conclusions: These results support the hypothesis that preventative treatment with Denosumab modulates intestinal inflammation in a murine model of colitis. This provides a rationale for considering Denosumab as a therapy in CD.