Zinsmeister, Alan R.

SummaryBackgroundRefractory coeliac disease is a severe complication of coeliac disease with heterogeneous outcome.AimTo create a prognostic model to estimate survival of patients with refractory coeliac disease.MethodsWe evaluated predictors of 5‐year mortality using Cox proportional hazards regression on subjects from a multinational registry. Bootstrap resampling was used to internally validate the individual factors and overall model performance. The mean of the estimated regression coefficients from 400 bootstrap models was used to derive a risk score for 5‐year mortality.ResultsThe multinational cohort was composed of 232 patients diagnosed with refractory coeliac disease across seven centres (range of 11–63 cases per centre). The median age was 53 years and 150 (64%) were women. A total of 51 subjects died during a 5‐year follow‐up (cumulative 5‐year all‐cause mortality = 30%). From a multiple variable Cox proportional hazards model, the following variables were significantly associated with 5‐year mortality: age at refractory coeliac disease diagnosis (per 20 year increase, hazard ratio = 2.21; 95% confidence interval, CI: 1.38–3.55), abnormal intraepithelial lymphocytes (hazard ratio = 2.85; 95% CI: 1.22–6.62), and albumin (per 0.5 unit increase, hazard ratio = 0.72; 95% CI: 0.61–0.85). A simple weighted three‐factor risk score was created to estimate 5‐year survival.ConclusionsUsing data from a multinational registry and previously reported risk factors, we create a prognostic model to predict 5‐year mortality among patients with refractory coeliac disease. This new model may help clinicians to guide treatment and follow‐up.

Abstract Background Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase ( HO 1) leads to loss of interstitial cells of Cajal and delayed gastric emptying ( GE ) in non‐obese diabetic mice. Our hypothesis was that hemin upregulation of HO 1 would restore normal GE in humans with gastroparesis. Aims To compare effects of hemin and placebo infusions on HO 1 activity and protein, GE , autonomic function, and gastrointestinal symptoms in diabetic gastroparesis. Methods In a single‐center, double‐blind, placebo‐controlled, randomized clinical trial, we compared intravenous hemin, prepared in albumin, or albumin alone (placebo) in 20 patients, aged 41 ± 5 ( SEM ) years with diabetic gastroparesis. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 additional weeks. Assessments included blood tests for HO 1 protein and enzyme activity levels, GE with 13 C‐spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks. Key Results Nine of 11 patients randomized to hemin completed all study procedures. Compared to placebo, hemin increased HO 1 protein on days 3 ( p = 0.0002) and 7 ( p = 0.008) and HO 1 activity on day 3 ( p = 0.0003) but not after. Gastric emptying, autonomic functions, and symptoms did not differ significantly in the hemin group relative to placebo. Conclusions & Inferences Hemin failed to sustain increased HO 1 levels beyond a week and did not improve GE or symptoms in diabetic gastroparesis. Further studies are necessary to ascertain whether more frequent hemin infusions or other drugs would have a more sustained effect on HO 1 and improve GE .

AbstractBackgroundDefecatory disorders (DD) are defined by clinical and objective features of impaired rectal evacuation. The epidemiology of DD in the population is unknown, partly because many constipated patients do not undergo anorectal tests. Our objectives were to estimate the incidence rate and clinical features of DD in the community.MethodsWe reviewed the medical records of all patients older than 16 years in Olmsted County, MN, who had constipation and underwent anorectal manometry from 1999 through 2008. Criteria for diagnosing DD were constipation for 6 months or longer and one of the following: (i) abnormal rectal balloon expulsion test; (ii) reduced or increased perineal descent; or (iii) two or more abnormal features with defecography or surface electromyography.Key ResultsOf 11 112 constipated patients, 516 had undergone anorectal tests; 245 of these (209 women, 36 men) had a DD. The mean (±SD) age at diagnosis was 44 years (±18) among women and 49 years (±19) among men. The overall age‐ and sex‐adjusted incidence rate per 100 000 person‐years was 19.3 (95% CI: 16.8–21.8). The age‐adjusted incidence per 100 000 person‐years was greater (p < 0.0001) in women (31.8, 95% CI: 27.4–36.1) than in men (6.6, 95% CI: 4.4–8.9). Prior to the diagnosis of DD, nearly 30% of patients had irritable bowel syndrome (IBS), 48% had a psychiatric diagnosis, 18% had a history of abuse, and 21% reported urinary and/or fecal incontinence.Conclusions & InferencesAmong constipated patients, DD are fourfold more common in women than men and often associated with IBS and psychiatric diagnoses.

AbstractBackgroundA 50% or greater reduction in the frequency of fecal incontinence (FI) recorded with daily bowel diaries is the primary endpoint in clinical trials of FI. Whether this difference is clinically important is unknown. The relationship between FI symptoms recorded with daily and weekly instruments is unknown. The contribution of psychological factors to quality of life (QOL) in FI is unclear.MethodsFecal incontinence severity was assessed with daily bowel diaries and periodic questionnaires (fecal incontinence severity score [FISS], FIQOL, 36‐Item Short Form Health Survey [SF‐36], and hospital anxiety and depression scales) for 4 weeks before and during double‐blind randomization to placebo or clonidine in 44 women with FI. The reduction in FI frequency was compared to the minimal clinically important difference (MCID) computed from the FISS. Endpoints of FI were compared between daily and weekly diaries.Key ResultsThe FISS exceeded the MCID in 75% and 83% of patients in whom the FI frequency declined by 50–74% and ≥75% respectively. Parameters of FI measured with daily and weekly instruments were significantly correlated. The daily parameters explained 71% of the inter‐patient variation in the FISS. The SF‐36 health scores, rather than the FISS rating, explained a majority of the inter‐subject variation in FIQOL.Conclusions & InferencesMost patients who report a ≥50% reduction in FI frequency experience a clinically important improvement. Weekly questionnaires accurately assess the severity of FI. Self‐reported physical and mental health explained a greater proportion of the variance in FIQOL than FI symptom severity.

Abstract Background Gastrointestinal infections are risk factors for irritable bowel syndrome ( IBS ) and functional dyspepsia ( FD ). We investigated whether non‐enteric infections and antibiotic exposure are also associated with the development of functional gastrointestinal disorders ( FGID s). Methods In a nested case–control study, random samples of Olmsted County, MN , were mailed valid self‐report questionnaires from 1988 through 1994, and then follow‐up questionnaires from 1995 through 2003. Survey responders who did not report any FGID symptoms at baseline, but then reported such symptoms in at least one subsequent survey, were classified as new‐onset cases. Age‐matched controls were individuals who did not have symptoms at either the initial or subsequent surveys. Key Results The overall response rate was 78% to the initial survey and 52% to the follow‐up survey. Based on the responses, 316 participants had a new onset of an FGID (43 IBS constipation, 95 IBS diarrhea, 25 IBS mixed, and 153 other FGID s, including FD ) and 250 did not (controls). Around 76% (241/316) of cases reported a non‐enteric infection vs 66% (166/250) of the controls. The frequency of enteric infections was similar between the two groups. Of the new FGID cases, 83% had a non‐enteric infection that was treated with antibiotic. In a logistic regression model, treatment with antibiotics for a non‐gastrointestinal infection was associated with the development of an FGID (odds ratio = 1.90; 95% CI : 1.21–2.98; p = 0.005), after adjusting for age and sex. Conclusions & Inferences Based on a case–control study, treatment of a non‐gastrointestinal infection with antibiotics appears to be a risk factor for development of an FGID .

AbstractBackgroundCurrently, anorectal manometry (ARM), which is used to diagnose defecatory disorders and identify anal weakness in fecal incontinence (FI) is generally conducted in specialized laboratories. Our aims were to compare anorectal functions measured with high‐resolution manometry (HRM) and a novel portable manometry device.MethodsAnal pressures at rest, during squeeze, and simulated evacuation, and rectal sensation were evaluated with portable and HRM in 20 healthy women, 19 women with constipation, and 11 with FI. The relationship between anal pressures measured with portable and HRM was assessed by the concordance correlation coefficient (CCC), Bland Altman test, and paired t‐tests.Key ResultsAnal pressures at rest (CCC 0.45; 95% CI: 0.29, 0.58) and during squeeze (CCC 0.60; 95% CI: 0.46, 0.72) measured with portable and HRM were correlated and inversely associated with the risk of FI. During simulated evacuation, the CCC for rectal pressure (0.62; 95% CI: 0.43, 0.76) was greater than that for anal pressure (CCC 0.22; 95% CI: 0.04, 0.39) and the rectoanal gradient (CCC 0.22; 95% CI: 0.02, 0.41). Rectal sensory thresholds for first sensation, the desire to defecate, and urgency measured by portable and HRM were also significantly correlated between techniques. For several parameters, differences between portable and HRM were statistically significant and the Bland Altman test was positive.Conclusions & InferencesAnorectal pressures and rectal sensation can be conveniently measured by portable manometry and are significantly correlated with high‐resolution manometry.

ObjectiveTo examine the association of gene variants of uncoupling proteins (UCP)‐2 and −3 with obesity and gastrointestinal (GI) traits.MethodsIn 255 overweight or obese adults, the associations of gene variants in UCP‐2 (−3474, rs659366) and UCP‐3 (rs1626521, rs2075577, rs15763) with body weight (BW) and GI traits were studied. Gene variants were genotyped by TaqMan® assay. The associations of genotypes with BW and GI traits (gastric emptying, gastric volume, satiety by buffet meal, satiation by nutrient drink test and GI hormones) were assessed using ANOVA corrected for false detection rate (FDR).ResultsA novel UCP‐3 gene variant, rs1626521, was identified; it was associated with BW (P = 0.039), waist circumference (P = 0.035), and significantly higher postprandial gastric volume (P = 0.003) and calories ingested at buffet meal (P = 0.006, both significant with FDR). In a subgroup of 11 participants, rs1626521 was also associated with reduced mitochondrial bioenergetics efficiency in skeletal muscle (P = 0.051). In an in vitro study in HEK293 cells, rs1626521 reduced UCP‐3 protein expression (P = 0.049). Associations detected between other genotypes and GI traits were nonsignificant with FDR.ConclusionsA newly identified functional variant (rs1626521) in UCP‐3 affects postprandial gastric functions and satiety and may contribute to weight gain and alter human mitochondrial function.

To compare the effects of the κ-opioid agonist asimadoline and placebo on visceral sensation and gastrointestinal (GI) motor functions in humans, 91 healthy participants were randomized in a double-blind fashion to 0.15, 0.5, or 1.5 mg of asimadoline or placebo orally twice a day for 9 days. We assessed satiation (nutrient drink test), colonic compliance, tone, perception of colonic distension (barostat), and whole gut transit (scintigraphy). Treatment effect was assessed by analysis of covariance. Asimadoline increased nutrient drink intake ( P = 0.03). Asimadoline decreased colonic tone during fasting ( P = 0.03) without affecting postprandial colonic contraction, compliance, or transit. Gas scores in response to colonic distension were decreased with 0.5 mg of asimadoline at low levels (8 mmHg above operating pressure) of distension ( P = 0.04) but not at higher levels of distension. Asimadoline at 1.5 mg increased gas scores at 16 mmHg of distension ( P = 0.03) and pain scores at distensions of 8 and 16 mmHg ( P = 0.003 and 0.03, respectively) but not at higher levels of distension. Further studies of this compound in diseases with altered satiation or visceral sensation are warranted.

Colonic transit is slowed in patients with disordered rectal evacuation, but the mechanism of this phenomenon is unclear. Our objective was to investigate rectocolonic inhibitory reflexes in humans to provide potential insight into patients with obstructed defecation. In 30 healthy subjects, a barostat-manometric assembly recorded colonic tone and phasic activity in the descending colon during rectal distension and recorded rectal tone during colonic distension. Phasic distensions were 8, 16, and 32 mmHg above balloon operating pressure, and staircase inflations were comprised of balloon inflation then deflation in 2-mmHg increments at 30-s intervals from 0 to 36 mmHg. Colonic balloon volumes increased to a similar extent during phasic rectal distensions 8, 16, and 32 mmHg above operating pressure, reflecting reduced colonic tone; balloon volumes also increased and phasic pressure activity decreased during staircase rectal distensions. In contrast, rectal balloon volume declined, reflecting increased tone during phasic and staircase colonic distensions. Thus rectal distension inhibited colonic motor activity, indicative of a viscerovisceral inhibitory reflex.