Diabetes distress and depression are independently associated with gastrointestinal symptoms in type 2 diabetes in Bangladesh.

BACKGROUND AND AIMS: Gastrointestinal (GI) symptoms, common in type 2 diabetes (T2D), are typically bothersome, socially embarrassing, and impact negatively on quality of life. They may also contribute to diabetes distress (DD), but this has never been formally evaluated. We aimed to investigate the relationships between GI symptoms, DD and depressive symptoms in a large cohort of individuals with T2D in Bangladesh. MATERIALS AND METHODS: 1406 unselected T2D individuals (female 58.8%; mean age 51.0 ± 12.5 years) from four diabetes clinics in Bangladesh completed validated questionnaires evaluating GI symptoms (PAGI-SYM), DD (DDS-17) and depressive symptoms (PHQ-9). RESULTS: 31.1% of participants reported GI symptoms (36.2% females, 23.7% males), while 51.1% had elevated DD and 37.8% depressive symptoms. GI symptoms exhibited independent relationships with both DD and depressive symptoms, and their likelihood was higher among those with DD (OR: 3.6 [2.2-5.6] and with depressive symptoms (OR: 5.9 [3.5-9.9]). CONCLUSIONS: GI symptoms are independently associated with both DD and depressive symptoms in people with T2D in Bangladesh.

Lipid stimulation of fatty acid sensors in the human duodenum: relationship with gastrointestinal hormones, BMI and diet.

BACKGROUND AND AIMS: The small intestinal free fatty acid (FFA) sensors, FFA receptor 1 (FFAR1), FFAR4, G-protein receptor 119 (GPR119) and cluster of differentiation-36 (CD36), mediate the fat-induced release of gastrointestinal (GI) hormones. We investigated whether expression of duodenal FFA sensors in humans was (i) altered by intraduodenal (ID) lipid infusion, (ii) disordered in overweight or obese individuals, (iii) related to lipid-induced GI hormone secretion or (iv) affected by habitual dietary patterns. METHODS: Endoscopic duodenal biopsies were collected from 20 lean (body mass index (BMI): 22±1 kg m-2), 18 overweight (BMI: 27±1 kg m-2) and 19 obese (BMI: 35±1 kg m-2) participants at baseline, and following a 30 min ID Intralipid infusion (2 kcal min-1); FFA sensor expression was quantified by reverse transcription-PCR. On a separate day, participants underwent ID Intralipid infusion (2 kcal min-1) for 120 min, to assess GI hormone responses. Habitual diet was evaluated using food frequency questionnaires. RESULTS: Baseline FFAR1 and FFAR4 expression were lower, and CD36 was higher, in obese participants compared with lean participants. ID lipid increased GPR119 and FFAR1 expression equally across study groups, but did not alter FFAR4 or CD36 expression. Increased FFAR1 expression correlated positively with glucose-dependent insulinotropic polypeptide (GIP) secretion (r=0.3, P<0.05), whereas there was no relationship between habitual diet with the expression of FFA sensors. CONCLUSIONS: Obesity is associated with altered duodenal expression of FFAR1, FFAR4 and CD36, suggesting altered capacity for the sensing, absorption and metabolism, of dietary lipids. GPR119 and FFAR1 are early transcriptional responders to the presence of ID lipid, whereas FFAR1 may be an important trigger for lipid-induced GIP release in humans.

Effects of small intestinal glucose on glycaemia, insulinaemia and incretin hormone release are load-dependent in obese subjects.

BACKGROUND/OBJECTIVES: Studies concerning the glycaemic response to oral glucose, or meals in obesity have usually failed to account for gastric emptying. It has been suggested that the incretin effect may be diminished in obesity as a result of a reduction in glucagon-like peptide-1 (GLP-1) secretion. We sought to determine the effect of two different rates of intraduodenal glucose infusions on glycaemic, insulinaemic and incretin hormone responses in lean and obese subjects and compare the effects of oral and intraduodenal glucose in obese subjects. SUBJECTS/METHODS: Eleven obese subjects (age 37.5±4.1 years, body mass index (BMI) 35.7±1.4 kg m-2) and 12 controls (age 34.7±4.0 years, BMI 23.9±0.7 kg m-2) received intraduodenal infusions of glucose at 1 or 3 kcal min-1, or saline for 60 min (t=0-60 min), followed by intraduodenal saline (t=60-120 min). In obese subjects, an oral glucose tolerance test was performed. Blood glucose, serum insulin, plasma total GLP-1 and total gastric inhibitory polypeptide (GIP) were measured. RESULTS: In both the groups (P<0.001), the incremental areas under the curve (iAUC)0-60 min for glucose was greater with the 3 kcal min-1 than the 1 kcal min-1 infusion; the iAUC0-120 min for glucose during 3 kcal min-1 was greater (P<0.05), in the obese. Insulin responses to 1 kcal min-1 and, particularly, 3 kcal min-1 were greater (P<0.001) in the obese. Stimulation of GLP-1 and GIP were greater (P<0.001) in response to 3 kcal min-1, compared with 1 kcal min-1 and saline, without any difference between the groups. In the obese, glycaemic, insulinaemic and GIP, but not GLP-1, responses to oral and intraduodenal glucose were related (P<0.05). CONCLUSIONS: The rate of duodenal glucose delivery is a major determinant of glycaemia, insulinaemia and incretin hormone release in obese subjects. Obesity is not apparently associated with impaired GLP-1 secretion.

Occult upper gastrointestinal mucosal abnormalities in critically ill patients.

BACKGROUND: The objectives of this study were to estimate the frequency of occult upper gastrointestinal abnormalities, presence of gastric acid as a contributing factor, and associations with clinical outcomes. METHODS: Data were extracted for study participants at a single centre who had an endoscopy performed purely for research purposes and in whom treating physicians were not suspecting gastrointestinal bleeding. Endoscopic data were independently adjudicated by two gastroenterologists who rated the likelihood that observed pathological abnormalities were related to gastric acid secretion using a 3-point ordinal scale (unlikely, possible or probable). RESULTS: Endoscopy reports were extracted for 74 patients [age 52 (37, 65) years] undergoing endoscopy on day 5 [3, 9] of ICU admission. Abnormalities were found in 25 (34%) subjects: gastritis/erosions in 10 (14%), nasogastric tube trauma in 8 (11%), oesophagitis in 4 (5%) and non-bleeding duodenal ulceration in 3 (4%). The contribution of acid secretion to observed pathology was rated 'probable' in six subjects (rater #1) and five subjects (rater #2). Prior to endoscopy, 39 (53%) patients were receiving acid-suppressive therapy. The use of acid-suppressive therapy was not associated with the presence of an endoscopic abnormality (present 15/25 (60%) vs. absent 24/49 (49%); P = 0.46). Haemoglobin concentrations, packed red cells transfused and mortality were not associated with mucosal abnormalities (P = 0.83, P > 0.9 and P > 0.9 respectively). CONCLUSIONS: Occult mucosal abnormalities were observed in one-third of subjects. The presence of mucosal abnormalities appeared to be independent of prior acid-suppressive therapy and was not associated with reduced haemoglobin concentrations, increased transfusion requirements, or mortality.

Effects of sitagliptin on blood pressure and heart rate in response to intraduodenal glucose infusion in patients with Type 2 diabetes: a potential role for glucose-dependent insulinotropic polypeptide?

AIMS: To evaluate the effects of the dipeptidyl peptidase-4 inhibitor sitagliptin on blood pressure and heart rate, measured during a previously reported study, in which the effects of sitagliptin during intraduodenal glucose infusion at the rate of 2 kcal/min on glucose homeostasis were examined in patients with Type 2 diabetes. METHODS: A total of 10 people with Type 2 diabetes were studied on two different days, 30 min after oral ingestion of sitagliptin (100 mg) or placebo. Intraduodenal glucose was infused at 2 kcal/min (60 g over 120 min), and blood pressure, heart rate, plasma glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (total and intact), glucose, insulin and glucagon responses were evaluated. RESULTS: In response to intraduodenal glucose infusion, heart rate (treatment effect: P = 0.001) and serum insulin concentration (treatment × time interaction: P = 0.041) were higher after sitagliptin treatment than placebo, without a significant difference in blood pressure, plasma glucagon or glucose. During intraduodenal glucose infusion, there was a substantial increase in plasma total glucose-dependent insulinotropic polypeptide on both days (time effect: P < 0.001), but not in total glucagon-like peptide-1. After sitagliptin, plasma intact glucagon-like peptide-1 concentration increased slightly (treatment × time interaction: P = 0.044) and glucose-dependent insulinotropic polypeptide concentration increased substantially (treatment × time interaction: P = 0.003).The heart rate response to intraduodenal glucose was related directly to plasma intact glucose-dependent insulinotropic polypeptide concentrations (r = 0.75, P = 0.008). CONCLUSIONS: Sitagliptin increased the heart rate response to intraduodenal glucose infusion at 2 kcal/min in people with Type 2 diabetes, which was associated with augmentation of plasma intact glucose-dependent insulinotropic polypeptide concentrations. These observations warrant further clarification of a potential role for glucose-dependent insulinotropic polypeptide in the control of the 'gut-heart' axis.

The duodenal glucose load impacts the oral disposition index in healthy subjects.

AIM: In healthy subjects, the oral disposition index (ratio of insulin response to insulin sensitivity) is predictive of the development of Type 2 diabetes. Gastric emptying, which exhibits a substantial interindividual variation, is a major determinant of postprandial glycaemia in health and diabetes. We sought to determine whether the rate of intraduodenal glucose delivery affects the disposition index in people without diabetes. METHODS: Nineteen Caucasian males received glucose infusions via an intraduodenal catheter at either 2 kcal/min (ID2) or 4 kcal/min (ID4) for 120 min, on two separate days with measurements of blood glucose (G) and plasma insulin (I) at frequent intervals. The insulin response was estimated by the ratio of the change in insulin to that of change in glucose at 30 min (∆I(0-30)/∆G(0-30)) and 60 min (∆I(0-60)/∆G(0-60)). Insulin sensitivity was estimated as 1/fasting insulin. The oral disposition index (DI) was calculated as ∆I(0-30)/∆G(0-30) × 1/fasting insulin and ∆I(0-60)/∆G(0-60) × 1/fasting insulin. RESULTS: The overall glycaemic response was comparable on both days, but the insulin response was much greater at ID4 when calculated at either 30 or 60 min (P < 0.05). DI was also greater (P < 0.05) in response to ID4 than ID2. CONCLUSIONS: The rate of duodenal glucose delivery has a major impact on insulin release and, thereby, DI. This suggests that the rate of gastric emptying, which determines duodenal glucose delivery, is a determinant of DI.

Predictive factors for inadequate colon preparation before colonoscopy.

BACKGROUND: It could be helpful to ascertain which patients are at risk of poor bowel preparation prior to performing sedated colonoscopy. The aim of the present study was to identify the predictive factors for poor colon preparation prior to colonoscopy. METHODS: A prospective study was performed at Kaohsiung Chang Gung Memorial Hospital, Taiwan, from September 2011 to May 2013. Patient characteristics, food consumed within 2 days of colonoscopy, volume of polyethylene glycol (PEG) solution, interval between completing PEG and examination, number of bowel movements, and character of the last stool were evaluated. RESULTS: Seven hundred and three patients were enrolled (mean age 50.3 ± 11.6 years, 43 % female). In univariate analysis, character of the last stool (<0.001), body weight (p = 0.007), body mass index (p = 0.047), waist circumference (p = 0.008), buttock girth (p = 0.016), meal residue score (<0.001), and interval between end of PEG and colonoscopy (p = 0.01) were related to inadequate colon preparation. In multivariate analysis, waist circumference (p < 0.001), meal residue score (p < 0.001), and characteristics of last stool (p < 0.001) were variables that predicted poor colon preparation. CONCLUSIONS: Patients who have consumed a high residue diet and/or who report that their last stool is semisolid are likely to have poor bowel preparation, and consideration could be given to rescheduling the examination.

Endogenous amylin and glucagon-like peptide-1 concentrations are not associated with gastric emptying in critical illness.

BACKGROUND: In health, the hormones amylin and glucagon-like peptide-1 (GLP-1) slow gastric emptying (GE) and modulate glycaemia. The aims of this study were to determine amylin and GLP-1 concentrations in the critically ill and their relationship with GE, glucose absorption and glycaemia. METHODS: In fasted critically ill and healthy subjects (n = 26 and 23 respectively), liquid nutrient, containing 100 mg (13) C-sodium octanoate and 3 g 3-O-methlyglucose (3-OMG), was administered via a nasogastric tube. Amylin, GLP-1, glucose and 3-OMG concentrations were measured in blood samples taken during fasting, and 30 min and 60 min after the 'meal'. Breath samples were taken to determine gastric emptying coefficient (GEC). Intolerance to intragastric feeding was defined as a gastric residual volume of ≥ 250 ml and/or vomiting within the 24 h prior to the study. RESULTS: Although GE was slower (GEC: critically ill 2.8 ± 0.9 vs. health, 3.4 ± 0.2; P = 0.002), fasting blood glucose was higher (7.0 ± 1.9 vs. 5.7 ± 0.2 mmol/l; P = 0.005) and overall glucose absorption was reduced in critically ill patients (3-OMG: 9.4 ± 8.0 vs. 17.7 ± 4.9 mmol/l.60 min; P < 0.001), there were no differences in fasting or postprandial amylin concentrations. Furthermore, although fasting [1.7 (0.4-7.2) vs. 0.7 (0.3-32.0) pmol/l; P = 0.04] and postprandial [3.0 (0.4-8.5) vs. 0.8 (0.4-34.3) pmol/l; P = 0.02] GLP-1 concentrations were increased in the critically ill and were greater in feed intolerant when compared with those tolerating feed [3.7 (0.4-7.2) vs. 1.2 (0.7-4.6) pmol/l; P = 0.02], there were no relationships between GE and fasting amylin or GLP-1 concentrations. CONCLUSION: In the critically ill, fasting GLP-1, but not amylin, concentrations are elevated and associated with feed intolerance. Neither amylin nor GLP-1 appears to substantially influence the rate of GE.

A randomised trial of enteric-coated nutrient pellets to stimulate gastrointestinal peptide release and lower glycaemia in type 2 diabetes.

AIMS/HYPOTHESES: Glucagon-like peptide-1 (GLP-1), an important mediator of postprandial glycaemia, could potentially be stimulated by delivering small quantities of nutrient to a long length of distal gut. We aimed to determine whether enteric-coated pellets, releasing small amounts of lauric acid throughout the ileum and colon, could reduce glycaemic responses to meals in type 2 diabetes, associated with stimulation of GLP-1. METHODS: Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting. After an overnight fast, patients consumed 5 g active pellets (47% lauric acid by weight) or placebo with breakfast (T = 0 min) and lunch (T = 240 min), in a crossover design with order randomised by the hospital pharmacy and allocation concealed by numbered containers. Patients and investigators making measurements were blinded to the intervention. Blood was sampled frequently for blood glucose (the primary outcome) and hormone assays. RESULTS: Eight patients were randomised (four to receive either intervention first), and all completed the study without adverse effects. Blood glucose was lower after breakfast (T = 0-240 min, area under the curve (AUC) 2,075 ± 368 vs 2,216 ± 163 mmol/l × min) and lunch (T = 240-480 min, AUC 1,916 ± 115 vs 2,088 ± 151 mmol/l × min) (p = 0.02 for each) after active pellets than after placebo. Plasma GLP-1 concentrations were higher after breakfast (p = 0.08) and lunch (p = 0.04) for active pellets. While there were no differences in insulin or glucose-dependent insulinotropic polypeptide concentrations, glucagon concentrations were higher after breakfast and lunch (p = 0.002 for each) for active pellets. CONCLUSIONS/INTERPRETATION: Delivering small amounts of nutrient to the ileum and colon can stimulate substantial endogenous GLP-1 release and attenuate postprandial glycaemia. This novel approach has therapeutic potential in type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000600842. FUNDING: The study was funded by Meyer Nutriceuticals.

Prognosis of diabetic gastroparesis--a 25-year evaluation.

AIM: To evaluate the prognosis of diabetic gastroparesis. METHODS: Eighty-six patients with diabetes had measurements of gastric emptying of a mixed meal using a dual isotope test of solid and liquid meal components, mean blood glucose levels, HbA1c , upper gastrointestinal symptoms and autonomic nerve function performed in 1984-1989. These patients were followed up in 2011, after a mean period of ~25 years. RESULTS: Of the 86 patients, gastric emptying of solid (the percentage remaining in the stomach at 100 min) was delayed in 35 (41%), and of liquid (the time taken for 50% of the liquid to empty) was delayed in 38 (44%). In 2011, 53 patients were known to be alive, 29 had died and four were lost to follow-up. In those who had died, both age at baseline (P < 0.001) and the score for autonomic nerve dysfunction (P < 0.001) were greater than those who were alive, while there was no difference in emptying of either the solid or liquid between the two groups. When patients with delayed gastric emptying were divided according to the median value ('delayed' and 'markedly delayed'), mortality tended to be greater in the 'markedly delayed' group for both solids (P = 0.12) and liquids (P = 0.09). Of the 82 patients who could be followed up, 23 of the 35 (66%) with delayed gastric emptying of solid and 25 of 38 (66%) with delayed gastric emptying of liquid were alive. After adjustment for age and autonomic dysfunction, there was no association between gastric emptying of either solid or liquid and death. CONCLUSIONS: Over a period of ~25 years, diabetic gastroparesis is apparently not usually associated with a poor prognosis, or increased mortality. ABBREVIATIONS: T100 min, the percentage remaining in the stomach at 100 mins; T50%, the time taken for 50% of the liquid to empty.

Effects of rectal administration of taurocholic acid on glucagon-like peptide-1 and peptide YY secretion in healthy humans.

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), secreted by enteroendocrine L-cells located most densely in the colon and rectum, are of fundamental importance in blood glucose and appetite regulation. In animal models, colonic administration of bile acids can stimulate GLP-1 and PYY by TGR5 receptor activation. We evaluated the effects of taurocholic acid (TCA), administered as an enema, on plasma GLP-1 and PYY, as well as gastrointestinal sensations in 10 healthy male subjects, and observed that rectal administration of TCA promptly stimulated secretion of both GLP-1 and PYY, and increased fullness, in a dose-dependent manner. These observations confirm that topical application of bile acids to the distal gut may have potential for the management of type 2 diabetes and obesity.

Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes.

AIMS: Postprandial glucagon-like peptide-1 (GLP-1) secretion and the 'incretin effect' have been reported to be deficient in Type 2 diabetes, but most studies have not controlled for variations in the rate of gastric emptying. We evaluated blood glucose, and plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) responses to intraduodenal glucose in Type 2 diabetes, and compared these with data from healthy controls. METHODS: Eight males with well-controlled Type 2 diabetes, managed by diet alone, were studied on four occasions in single-blind, randomized order. Blood glucose, and plasma insulin, GLP-1, and GIP were measured during 120-min intraduodenal glucose infusions at 1 kcal/min (G1), 2 kcal/min (G2) and 4 kcal/min (G4) or saline control. RESULTS: Type 2 patients had higher basal (P < 0.0005) and incremental (P < 0.0005) blood glucose responses to G2 and G4, when compared with healthy controls. In both groups, the stimulation of insulin and GLP-1 by increasing glucose loads was not linear; responses to G1 and G2 were minimal, whereas responses to G4 were much greater (P < 0.005 for each) (incremental area under the GLP-1 curve 224 ± 65, 756 ± 331 and 2807 ± 473 pmol/l.min, respectively, in Type 2 patients and 373 ± 231, 505 ± 161 and 1742 ± 456 pmol/l.min, respectively, in healthy controls). The GLP-1 responses appeared comparable in the two groups. In both groups there was a load-dependent increase in plasma GIP with no difference between them. CONCLUSIONS: In patients with well-controlled Type 2 diabetes, blood glucose, insulin and GLP-1 responses are critically dependent on the small intestinal glucose load, and GLP-1 responses are not deficient.

Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes.

OBJECTIVE: Nutrient feedback from the small intestine modulates upper gastrointestinal function and energy intake; however, the molecular mechanism of nutrient detection is unknown. In the tongue, sugars are detected via taste T1R2 and T1R3 receptors and signalled via the taste G-protein alpha-gustducin (G alpha(gust)) and the transient receptor potential ion channel, TRPM5. These taste molecules are also present in the rodent small intestine, and may regulate gastrointestinal function. SUBJECTS AND METHODS: Absolute transcript levels for T1R2, T1R3, G alpha(gust) and TRPM5 were quantified in gastrointestinal mucosal biopsies from subjects with and without type 2 diabetes; immunohistochemistry was used to locate G alpha(gust). Effects of luminal glucose on jejunal expression of taste molecules were also quantified in mice. RESULTS: T1R2, T1R3, G alpha(gust) and TRPM5 were preferentially expressed in the proximal small intestine in humans, with immunolabelling for G alpha(gust) localised to solitary cells dispersed throughout the duodenal villous epithelium. Expression of T1R2, T1R3, TRPM5 (all p<0.05) and G alpha(gust) (p<0.001) inversely correlated with blood glucose concentration in type 2 diabetes subjects but, as a group, did not differ from control subjects. Transcript levels of T1R2 were reduced by 84% following jejunal glucose perfusion in mice (p<0.05). CONCLUSIONS: Taste molecules are expressed in nutrient detection regions of the proximal small intestine in humans, consistent with a role in "tasting". This taste molecule expression is decreased in diabetic subjects with elevated blood glucose concentration, and decreased by luminal glucose in mice, indicating that intestinal "taste" signalling is under dynamic metabolic and luminal control.

Relationships of upper gastrointestinal motor and sensory function with glycemic control.

Acute changes in the blood glucose concentration have a major reversible effect on esophageal, gastric, intestinal, gallbladder, and anorectal motility in both healthy subjects and diabetic patients. For example, gastric emptying is slower during hyperglycemia than euglycemia and accelerated during hypoglycemia. Acute hyperglycemia also affects perceptions arising from the gastrointestinal tract and may accordingly, be important in the etiology of gastrointestinal symptoms in diabetes. Elevations in blood glucose that are within the normal postprandial range also affect gastrointestinal motor and sensory function. Upper gastrointestinal motor function is a critical determinant of postprandial blood glucose concentrations by influencing the absorption of ingested nutrients. Interventions that reduce postprandial hyperglycemia, by modulating the rate of gastric emptying, have the potential to become mainstream therapies in the treatment of diabetes.

Comparative effect of intraduodenal and intrajejunal glucose infusion on the gut-incretin axis response in healthy males.

The region of enteral nutrient exposure may be an important determinant of postprandial incretin hormone secretion and blood glucose homoeostasis. We compared responses of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon, and blood glucose to a standardised glucose infusion into the proximal jejunum and duodenum in healthy humans. Ten healthy males were evaluated during a standardised glucose infusion (2 kcal min(-1) over 120 min) into the proximal jejunum (50 cm post pylorus) and were compared with another 10 healthy males matched for ethnicity, age and body mass index who received an identical glucose infusion into the duodenum (12 cm post pylorus). Blood was sampled frequently for measurements of blood glucose and plasma hormones. Plasma GLP-1, GIP and insulin responses, as well as the insulin:glucose ratio and the insulinogenic index 1 (IGI1) were greater (P<0.05 for each) after intrajejunal (i.j.) than intraduodenal glucose infusion, without a significant difference in blood glucose or plasma glucagon. Pooled analyses revealed direct relationships between IGI1 and the responses of GLP-1 and GIP (r=0.48 and 0.56, respectively, P<0.05 each), and between glucagon and GLP-1 (r=0.70, P<0.001). In conclusion, i.j. glucose elicits greater incretin hormone and insulin secretion than intraduodenal glucose in healthy humans, suggesting regional specificity of the gut-incretin axis.

Long-term results of low-dose intravenous ciclosporin for acute severe ulcerative colitis.

BACKGROUND: Intravenous ciclosporin for acute, severe colitis is usually administered in a dose of 4 mg/kg/day, with concurrent intravenous steroids. This is associated with considerable morbidity. We have been using a low-dose regimen, most commonly without concurrent steroids, for seven years, and present the outcome. METHODS: Records of all patients admitted for severe ulcerative colitis, treated by one physician over seven years, were reviewed. RESULTS: Thirty-one patients received low-dose intravenous ciclosporin (2 mg/kg/day) for a median 8 days. Eleven early patients received concurrent intravenous corticosteroids. Three patients had hypertension requiring dose reduction, one elevated creatinine and one elevated liver enzymes (all transient), and four experienced infection (two arm cellulitis, one perianal abscess, one post-operative wound infection). Twenty-four patients (77%) avoided urgent colectomy, and were discharged on oral ciclosporin and azathioprine. After a median 18 months (range 3-77), 14 patients (45% of total) avoided colectomy, of whom eight had flares responding to medical therapy and two had persistent, mildly active disease. CONCLUSIONS: Low-dose intravenous ciclosporin (2 mg/kg/day), usually used as a monotherapy and followed by azathioprine, achieves similar long-term efficacy to higher dose ciclosporin combined with steroids in severe acute ulcerative colitis. Morbidity appears to be low.

Azathioprine dose escalation in inflammatory bowel disease.

BACKGROUND: Forty per cent of patients with inflammatory bowel disease fail to respond to standard dose azathioprine (2 mg/kg/day). AIMS: To evaluate the efficacy and safety of increasing the azathioprine dose according to a fixed schedule and guided by clinical response and adverse effects. METHODS: We reviewed the records of all patients with inflammatory bowel disease treated by a single clinician over 6 years, unresponsive to at least 3 months treatment with standard dose azathioprine, and whose dose was subsequently increased. RESULTS: Forty patients (27 male; 24 Crohn's, 16 ulcerative colitis) with chronic active disease or recurrent flares despite standard dose azathioprine for a median 8 months (range 3-114) increased their dose from a median 2.02 (1.61-3.19) mg/kg/day to 2.72 (2.37-3.99) mg/kg/day in one to four increments of 0.5 mg/kg/day, and were followed over a median 6 (0.5-54) months. Eleven of the 40 patients (seven Crohn's, four ulcerative colitis) responded or had reduced frequency of flare-ups at the end of follow-up, while 17 of the 40 patients had no benefit. Response was more likely for maximum doses < or =2.5 mg/kg/day (six of 11 patients) than for doses >2.5 mg/kg/day (five of 29 patients) (P = 0.042). Twelve patients (11 of whom received maximum doses >2.5 mg/kg/day) were unable to maintain an increased azathioprine dose because of leukopenia in eight, nausea in three, and raised liver enzymes in one (all transient and reversible). CONCLUSIONS: Increasing the azathioprine dose up to 2.5 mg/kg/day appears beneficial in patients who have not responded to 2 mg/kg/day. Further increase above 2.5 mg/kg/day is less likely to be efficacious, and is associated with a substantial risk of adverse reactions.

Osseous sarcoidosis--a magnetic resonance imaging diagnosis.

Bone involvement in sarcoidosis is not uncommon but may be overlooked as a cause of symptoms. Magnetic resonance imaging (MRI) is emerging as a sensitive diagnostic tool for osseous sarcoid. We document a case in which MRI suggested the diagnosis in the absence of abnormality with more conventional imaging techniques.

Gastroparesis: prevalence, clinical significance and treatment.

The application of novel techniques to quantify gastric motor function and gastric emptying has yielded important insights into the prevalence, pathogenesis and clinical sequelae of gastroparesis. Both acute and chronic gastroparesis occur frequently; gastric emptying of solids is delayed in 30% to 50% of patients with diabetes mellitus, functional dyspepsia and gastroesophageal reflux disease. While many patients with gastroparesis experience upper gastrointestinal symptoms that adversely affect quality of life, the concept that symptoms are inevitably the direct outcome of delay in gastric emptying is now recognized to be overly simplistic. In contrast, the potential impact of gastroparesis on oral drug absorption and blood glucose control in patients with diabetes mellitus has probably been underestimated. While the use of prokinetic drugs (cisapride, domperidone, metoclopramide and erythromycin) forms the mainstay of therapy in symptomatic patients with gastroparesis, a number of novel pharmacological therapies are being evaluated, and preliminary studies using gastric pacing show promise.