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Obesity, a global pandemic that debilitates millions of people and burdens society with tens of billions of dollars in health care costs, is deterred by exercise. Although it is presumed that the more strenuous a physical challenge the more effective it will be in the suppression of adiposity, here it is shown that 15 weeks of brief, daily exposure to high-frequency mechanical signals, induced at a magnitude well below that which would arise during walking, inhibited adipogenesis by 27% in C57BL/6J mice. The mechanical signal also reduced key risk factors in the onset of type II diabetes, nonesterified free fatty acid and triglyceride content in the liver, by 43% and 39%, respectively. Over 9 weeks, these same signals suppressed fat production by 22% in the C3H.B6-6T congenic mouse strain that exhibits accelerated age-related changes in body composition. In an effort to understand the means by which fat production was inhibited, irradiated mice receiving bone marrow transplants from heterozygous GFP⁺ mice revealed that 6 weeks of these low-magnitude mechanical signals reduced the commitment of mesenchymal stem cell differentiation into adipocytes by 19%, indicating that formation of adipose tissue in these models was deterred by a marked reduction in stem cell adipogenesis. Translated to the human, this may represent the basis for the nonpharmacologic prevention of obesity and its sequelae, achieved through developmental, rather than metabolic, pathways.

BACKGROUND: Simple criteria are needed to predict which patients with severe ulcerative colitis will respond poorly to intensive medical treatment and require colectomy. AIMS: To find out if the early pattern of change in inflammatory markers or other variables could predict the need for surgery and to evaluate the outcome of medical treatment during one year follow up. PATIENTS: 51 consecutive episodes of severe colitis (Truelove and Witts criteria) affecting 49 patients admitted to John Radcliffe Hospital, Oxford. METHODS: Prospective study monitoring 36 clinical, laboratory, and radiographic variables. All episodes treated with intravenous and rectal hydrocortisone and 14 of 51 with cyclosporine. RESULTS: Complete response in 21 episodes (< or = 3 stools on day 7, without visible blood), incomplete response in 15 (> 3 stools or visible blood on day 7, but no colectomy), and colectomy on that admission in 15. During the first five days, stool frequency and C reactive protein (CRP) distinguished between outcomes (p < 0.00625, corrected for multiple comparisons) irrespective of whether patients or the number of episodes were analysed. It could be predicted on day 3, that 85% of patients with more than eight stools on that day, or a stool frequency between three and eight together with a CRP > 45 mg/l, would require colectomy. For patients given cyclosporine, four of 14 avoided colectomy but two continued to have symptoms. After admission, complete responders remained in remission for a median nine months and had a 5% chance of colectomy. Incomplete responders had a 60% chance of continuous symptoms and 40% chance of colectomy. CONCLUSIONS: After three days intensive treatment, patients with frequent stools (> 8/day), or raised CRP (> 45 mg/l) need to be identified, as most will require colectomy on that admission. The role of cyclosporine for treating severe colitis has yet to be defined. After seven days' treatment, patients with > 3 stools/day of visible blood have a 60% chance of continuous symptoms and 40% chance of colectomy in the following months.

The prognostic significance of excess small bowel gas on a plain abdominal radiograph has been assessed in 75 patients with severe attacks of ulcerative colitis requiring intravenous hydrocortisone. The radiographs were reviewed without knowledge of the subsequent outcome. Small bowel distension was defined as the presence of three or more loops of gas filled small bowel. Forty two patients responded to medical treatment and 33 underwent colectomy. The two groups were comparable for age, sex, and length of history. The surgical group had more extensive disease. Of those who did well on medical therapy, 18 (42.9%) had small bowel distension compared with 24 of 33 (72.7%) who failed medical therapy. The difference was significant (p less than 0.05, odds ratio = 3.55, 95% confidence interval of 2.27-5.87). Of the 24 patients with small bowel distension who came to surgery, five had more than four loops of gas filled small bowel. This degree of distension was not seen in any of the patients settling on medical therapy. Thus the presence of small bowel distension on a plain abdominal radiograph in a patient with severe ulcerative colitis may predict a poor response to medical therapy.

Enteroclysis is now widely used for examining the jejunum and ileum. The technique is ideal for demonstrating the extent and severity of disorders that cause morphological changes to the small intestine. In this review many non-neoplastic small intestinal disorders as demonstrated by enteroclysis are described and illustrated.

We report a patient who presented with small intestinal ischaemia due to metastatic mesenteric disease from an oesophageal carcinoma. Enteroclysis suggested the diagnosis of small intestinal ischaemia, which was found at laparotomy to be due to compression of mesenteric veins by a nodal mass at the root of the small intestinal mesentery. Although this phenomenon has been described particularly in patients with carcinoid tumours, we believe that mesenteric venous ischaemia resulting from spread to the mesentery from an extra-abdominal primary neoplasm is extremely rare.

With the disc size independent method, for a group of patients with primary open angle glaucoma (POAG) and a control group, the authors calculated the vertical CDR and, based on a histogram plot of the control group, concluded that the vertical CDR is not normally distributed. The optimal confidence interval may be selected rationally using an ROC curve constructed from different confidence intervals: the optimal test criterion is a confidence interval of 72% (sensitivity 90.2%, specificity 92.3%) (Fig 1 B) which yields a predictive value, V+ = 19.3%.

The principles underlying composite material behavior during metallographic preparation of coating cross-sections are generally not well understood. This study of the effect of extended fine polishing on apparent porosity shows that adequate polishing times, using a fine abrasive (3 mu m) and low force, are required to remove prior deformation in the section surface and to reveal the true porosity of the underlying composite material. Insufficient polishing times can result in considerable underestimation of porosity. A model is described which proposes that the deformation induced in the material during grinding and polishing, even at low applied force, results in smearing of material into voids that exist in the plane of the section.

IntroductionChronic diarrhoea occurs frequently as a result of excess faecal bile acid (BA) loss. Secondary bile acid diarrhoea (SBAD) is common in Crohn's disease with ileal inflammation and/or resection. The normal ileum produces Fibroblast Growth Factor 19 (FGF19) in response to BA absorption and farnesoid X receptor (FXR) activation. FGF19 acts as a hormonal regulator of hepatic BA synthesis. We showed previously in 10 patients with primary bile acid diarrhoea, diagnosed by 7d SeHCAT retention <10%, that the semi-synthetic BA and potent FXR agonist obeticholic acid (OCA) significantly increased low FGF19 levels producing significant clinical improvement. We aimed to see if these findings could be extended to patients with SBAD due to Crohn's and in idiopathic diarrhoea controls.MethodsOut of 32 patients recruited to this pilot trial, 8 SBAD patients (6F:2M, median age 45, ileal resection 0-48 cm, median 22.5 cm, and/or SeHCAT <11%), and 7 controls (2F:5M, SeHCAT 16-35%, median 25%) received OCA 25 mg daily for 2w after a 2w run-in period. BA sequestrants were discontinued. Symptoms were recorded and a stool index calculated from frequency, stool form and loperamide use. On the first and last days of OCA therapy, blood samples were assayed for FGF19, total BA levels and the BA precursor, 7 alpha OH-4-cholesten-3-one (C4) in fasting and for 6h after OCA and meals.ResultsIn the SBAD group, 7 out of 8 patients showed positive but variable changes in stool form and stool index (both p = 0.07, Wilcoxon). Pain frequency (p = 0.05) and severity (p = 0.07) improved. Ileal resection length was related to the change in stool number (r = 0.78, p = 0.01, Spearman), index (r = 0.63, p = 0.05) and urgency (r = 0.68, p = 0.03) so that those with the smallest resections had the greatest improvements. Increases in FGF19 fasting and post-prandial levels were relatively small except in 2 patients, but were associated with improvements in urgency (r=-0.93, p < 0.01). The reductions in post-prandial BA response (p = 0.01), fasting and peak BA values were significantly greater in those with shorter resections. C4 was related inversely to FGF19 and positively to the resection length. By contrast in the diarrhoea controls, there were no significant changes in clinical symptoms or FGF19. However BA responses were lower (p = 0.03) and significant relationships between FGF19 and BA responses were found.ConclusionThis pilot study has shown that OCA produces clinical benefit in many patients with chronic diarrhoea including those with SBAD, particularly with short resections, but not in idiopathic controls. Further trials are warranted.Disclosure of InterestNone Declared.

Introduction Primary (idiopathic) bile acid diarrhoea (PBAD) is a common chronic diarrhoeal condition, affecting ~1% of the population, and a large proportion of patients otherwise diagnosed with IBS-D. We showed that the ileal hormone Fibroblast Growth Factor 19 (FGF19), which decreases hepatic bile acid (BA) synthesis, is reduced in this condition, resulting in excess BA production and faecal BA loss. FGF19 is secreted in response to the natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA). Obeticholic acid (OCA), 6-ethyl CDCA, is a semi-synthetic derivative with ~100x greater FXR agonist potency. We aim to determine the FGF19, BA and clinical response to OCA in PBAD patients. Methods After a 2-week run in period, 10 patients (7F:3M, median age 47, range 24–74) with PBAD (SeHCAT 7d retention < 10%, median 4.8%), received oral OCA 25mg daily, for 2 weeks. Bile acid sequestrants were discontinued; loperamide was allowed as rescue therapy. Patients completed symptom diaries including stool frequency and Bristol Stool-form Scale (BSFS); a diarrhoea index ([stool frequency * mean BSFS] + loperamide use [weekly mg*3]) was calculated. Fasting serum FGF19 and total BA were measured before the first dose of OCA and after 2w treatment. Postprandial FGF19 and BA (6h area-under-curve, AUC) were determined after the first and last OCA dose. Data (expressed as medians) were analysed by Wilcoxon paired tests and Spearman correlation. Results OCA increased fasting FGF19 from 133 to 237 pg/ml (p = 0.007) at 2w. Most patients had an increase > 60% in fasting FGF19 and a large OCA first dose/postprandial response. Fasting BA reduced from 1.5 to 0.9 µmol/l (p = 0.13) and postprandial BA AUC was lower after the 2 w OCA treatment (from 4.9 to 3.0 µmol/l, p = 0.02). Clinical improvements were found in all patients, including in stool frequency (23 to 14/wk, p = 0.02), BSFS (5.15 to 4.34, p = 0.05) and the diarrhoea index (113 to 76, p = 0.005). The reduction in BA AUC (p = 0.02) and the increase in fasting FGF19 (p = 0.03) both correlated with the reduction in stool frequency. Symptoms of abdominal pain, urgency and bloating also tended to be less on OCA treatment. OCA was well tolerated and no adverse events were reported of clinical concern. Conclusion This study has shown for the first time that rational therapy with the FXR agonist OCA in PBAD is well tolerated and effective, stimulating serum FGF19 and reducing postprandial BA, resulting in clinical improvements in stool frequency and type. We propose larger, randomised, controlled trials of OCA. [EudraCT 2011–003777–28] Disclosure of Interest None Declared.

IntroductionPrimary (idiopathic) bile acid diarrhoea (PBAD) is a common chronic diarrhoeal condition, affecting ~1% of the population, and a large proportion of patients otherwise diagnosed with IBS-D. We showed that the ileal hormone Fibroblast Growth Factor 19 (FGF19), which decreases hepatic bile acid (BA) synthesis, is reduced in this condition, resulting in excess BA production and faecal BA loss. FGF19 is secreted in response to the natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA). Obeticholic acid (OCA), 6-ethyl CDCA, is a semi-synthetic derivative with ~100x greater FXR agonist potency. We aim to determine the FGF19, BA and clinical response to OCA in PBAD patients.MethodsAfter a 2-week run in period, 10 patients (7F:3M, median age 47, range 24-74) with PBAD (SeHCAT 7d retention < 10%, median 4.8%), received oral OCA 25mg daily, for 2 weeks. Bile acid sequestrants were discontinued; loperamide was allowed as rescue therapy. Patients completed symptom diaries including stool frequency and Bristol Stool-form Scale (BSFS); a diarrhoea index ([stool frequency * mean BSFS] + loperamide use [weekly mg*3]) was calculated. Fasting serum FGF19 and total BA were measured before the first dose of OCA and after 2w treatment. Postprandial FGF19 and BA (6h area-under-curve, AUC) were determined after the first and last OCA dose. Data (expressed as medians) were analysed by Wilcoxon paired tests and Spearman correlation.ResultsOCA increased fasting FGF19 from 133 to 237 pg/ml (p = 0.007) at 2w. Most patients had an increase > 60% in fasting FGF19 and a large OCA first dose/postprandial response. Fasting BA reduced from 1.5 to 0.9 mu mol/l (p = 0.13) and postprandial BA AUC was lower after the 2 w OCA treatment (from 4.9 to 3.0 mu mol/l, p = 0.02). Clinical improvements were found in all patients, including in stool frequency (23 to 14/wk, p = 0.02), BSFS (5.15 to 4.34, p = 0.05) and the diarrhoea index (113 to 76, p = 0.005). The reduction in BA AUC (p = 0.02) and the increase in fasting FGF19 (p = 0.03) both correlated with the reduction in stool frequency. Symptoms of abdominal pain, urgency and bloating also tended to be less on OCA treatment. OCA was well tolerated and no adverse events were reported of clinical concern.ConclusionThis study has shown for the first time that rational therapy with the FXR agonist OCA in PBAD is well tolerated and effective, stimulating serum FGF19 and reducing postprandial BA, resulting in clinical improvements in stool frequency and type. We propose larger, randomised, controlled trials of OCA. [EudraCT 2011-003777-28]Disclosure of InterestNone Declared.