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The role of anorectal and defecatory dysfunction in opioid-related constipation is unclear. We aimed to evaluate the relationship between opioid use and rectal sensation, defecatory function, and balloon expulsion on anorectal physiology testing. This was a retrospective cohort study of consecutive adults undergoing high-resolution anorectal manometry (HRAM) at a tertiary center for constipation. Clinical characteristics, medication use, and HRAM findings were obtained. Statistical analyses were performed using Fisher-exact/student t-test for univariate analyses and logistic/general linear regression for multivariable analyses to compare patients with no opioid use, recent ( 3 months) use. 424 patients (49.8 ± 17.2 years; 85.6% female) were included. Compared to those without opioid history, patients with recent use had increased volumes for first rectal sensation (70.4 mL vs 59.4, p = 0.043), urge (120.5 mL vs 101.5, p = 0.017), and maximal tolerance (170.2 mL vs 147.2, p = 0.0018), but not patients with distant use. Recent opioid use was associated with increased risk of dyssynergic defecation (DD) (61.8% vs 46.4%, p = 0.035), but not failed balloon expulsion. On multivariable models controlling for potential confounders, recent opioid use, but not distant use, remained independently correlated with increased volumes for first rectal sensation (β-coefficient 9.78, p = 0.019), urge (β-coefficient 16.7, p = 0.0060), and maximal tolerance (β-coefficient 22.9, p = 0.0032), and higher risk for DD (aOR = 2.18, p = 0.026). Recent opioid use was an independent risk factor for rectal hyposensitivity and DD on HRAM in patients with constipation, but that effect may decrease with discontinuation of use. Anorectal physiology testing should be considered in patients with opioid-associated constipation.

The benefits of combination therapy with infliximab and azathioprine have been demonstrated in clinical trials of patients with ulcerative colitis (UC) and Crohn’s disease (CD). Concerns remain regarding the ideal duration and benefits of adding therapies in a sequential manner. We aim to compare long-term outcomes among patients with inflammatory bowel disease (IBD) treated with sequentially added combination therapy or monotherapy strategies . We performed a retrospective cohort study involving adult patients with UC and CD. One cohort included patients treated with infliximab, adalimumab, or a thiopurine as monotherapy. A second cohort included patients treated with sequentially added combination therapy including infliximab or adalimumab and a thiopurine. The primary outcome was the rate of IBD-related surgery. Among 462 patients, 181 (39 %) were treated with combination therapy. 12 % of patients treated with combination therapy underwent an IBD-related surgery compared to 18 % of patients treated with monotherapy (p = 0.091), with no overall difference in time to IBD-related surgery demonstrated (log-rank test, p = 0.063). When evaluating the subtypes of IBD, there was a significant benefit in time to IBD-related surgery among patients with CD treated with sequentially added combination therapy (HR 0.46, 95 % CI 0.25–0.85) but not UC (HR 0.82, 95 % CI 0.30–2.22). The benefits of sequentially added combination therapy seem blunted when evaluating long-term clinical outcomes. This may be due to a decreased effectiveness of sequential combination therapy, a loss of benefit over time, or a differential effect between subtypes of IBD.

Esophageal motility disorders are a broad category of diseases with a variety of symptoms, ranging from dysphagia to chest pain. The pathophysiology is not always fully understood, but may involve alterations in inhibitory or excitatory innervation of the smooth muscle of the distal esophagus and LES. High-resolution manometry is the gold standard for its diagnosis, and the Chicago classification offers an organizational framework for better evaluation and management. Major disorders of motility are generally pathologic, and include achalasia, EGJOO, DES, hypertensive esophagus, and diseases of absent peristalsis, such as scleroderma. Treatments are targeted at the particular diagnosis. In achalasia, endoscopic and surgical options are preferred. For the remaining motility diagnoses, medical management forms the mainstay of treatment, which can be limited by side effect profiles.

Background Hepatorenal syndrome is defined as severe renal failure occurring in people with cirrhosis and ascites. Systematic reviews of randomised clinical trials found that, compared with placebo, terlipressin may reduce mortality and improve renal function in people with hepatorenal syndrome, but we need current evidence from systematic reviews on the benefits and harms of terlipressin versus other vasoactive drugs. Objectives To evaluate the beneficial and harmful effects of terlipressin versus other vasoactive drugs for people with hepatorenal syndrome. Search methods We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and Science Citation Index Expanded; conducted manual searches of references in relevant literature; and wrote to experts and pharmaceutical companies (date of last search November 2016). Selection criteria Randomised clinical trials comparing terlipressin versus any other type of vasoactive drugs for hepatorenal syndrome. We allowed albumin and other cointerventions if provided equally in the comparison groups. Data collection and analysis Three authors independently extracted data. The primary outcomes were mortality, hepatorenal syndrome (persistent hepatorenal syndrome despite treatment), and serious adverse events. We conducted meta-analyses and present the results as risk ratios (RR) with 95% confidence intervals (CI). We performed sensitivity, subgroup, and Trial Sequential Analyses and evaluated bias control based on the Cochrane Hepato-Biliary Group domains. Main results We included 10 randomised clinical trials with 474 participants. The trials compared terlipressin versus noradrenaline (seven trials), octreotide (one trial), midodrine and octreotide (one trial), or dopamine (one trial). All participants in both groups received albumin as cointervention. We classified two trials at low risk of bias and eight trials at high risk of bias in the assessment of mortality and all trials at high risk of bias for remaining outcomes. In five trials, investigators specifically stated that they did not receive funding from for-profit organisations. We had no information about the funding source from the remaining five trials. Terlipressin was not superior or inferior compared with other vasoactive drugs in regard to mortality when including the two trials with a low risk of bias (RR 0.92, 95% CI 0.63 to 1.36; 94 participants, very low quality evidence) or when including all 10 trials (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). One meta-analysis including nine trials suggested a beneficial effect of terlipressin on hepatorenal syndrome (RR 0.79, 95% CI 0.63 to 0.99; 394 participants; I² = 26%; very low quality evidence). Due to the high mortality of hepatorenal syndrome, the registration of other serious adverse events is uncertain, but comparing terlipressin and other vasoactive drugs we found no significant difference (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). Several trials did not report systematically of adverse events, but terlipressin seemed to increase the risks of diarrhoea or abdominal pain, or both (RR 3.50, 95% CI 1.19 to 10.27; 221 participants; 5 trials, I² = 0%). However, Trial Sequential Analyses found insufficient evidence to support or refute any differences between interventions for all outcomes. Considering reversal of hepatorenal syndrome, subgroup analyses on the type of other vasoactive drugs found that terlipressin was superior compared with midodrine and octreotide (RR 0.47, 95% CI 0.30 to 0.72) or octreotide alone (RR 0.56, 95% CI 0.33 to 0.96), but each subgroup only included one small trial. None of the remaining subgroup or sensitivity analyses found differences between terlipressin and other vasoactive drugs. We downgraded the evidence to very low quality because of the high risk of bias, imprecision, and the results of the Trial Sequential Analyses. Authors' conclusions This review found insufficient evidence to support or refute beneficial or harmful effects of terlipressin and albumin versus other vasoactive drugs and albumin. Additional research is needed to evaluate if clinically meaningful differences exist between interventions.

Background Hepatorenal syndrome is a potentially reversible renal failure associated with severe liver disease. The disease is relatively common among people with decompensated cirrhosis. Terlipressin is a drug that increases the blood flow to the kidneys by constricting blood vessels. The previous version of this systematic review found a potential beneficial effect of terlipressin on mortality and renal function in people with cirrhosis and hepatorenal syndrome. Objectives To assess the beneficial and harmful effects of terlipressin versus placebo/no intervention for people with cirrhosis and hepatorenal syndrome. Search methods We identified eligible trials through searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, and Science Citation Index Expanded, and manual searches until 21 November 2016. Selection criteria Randomised clinical trials (RCTs) involving participants with cirrhosis and type 1 or type 2 hepatorenal syndrome allocated to terlipressin versus placebo or no intervention. We allowed co-administration with albumin administered to both comparison groups. Data collection and analysis Two review authors independently extracted data from trial reports and undertook correspondence with the authors. Primary outcomes were mortality, hepatorenal syndrome, and serious adverse events. We conducted sensitivity analyses of RCTs in which participants received albumin, subgroup analyses of participants with type 1 or type 2 hepatorenal syndrome, and Trial Sequential Analyses to control random errors. We reported random-effects meta-analyses with risk ratios (RR) and 95% confidence intervals (CI). We assessed the risk of bias based on the Cochrane Hepato-Biliary Group domains. We graded the quality of the evidence using GRADE. Main results We included nine RCTs with a total of 534 participants with cirrhosis and ascites. One RCT had a low risk of bias for mortality and a high risk of bias for the remaining outcomes. All included trials had a high risk of bias for non-mortality outcomes. In total, 473 participants had type 1 hepatorenal syndrome. Seven RCTs specifically evaluated terlipressin and albumin. Terlipressin was associated with a beneficial effect on mortality when including all RCTs (RR 0.85, 95% CI 0.73 to 0.98; 534 participants; number needed to treat for an additional beneficial outcome (NNTB) 10.3 people; low-quality evidence). Trial Sequential Analysis including all RCTs also found a beneficial effect of terlipressin. Additional analyses showed a beneficial effect of terlipressin and albumin on reversal of hepatorenal syndrome (RR 0.63, 95% CI 0.48 to 0.82; 510 participants; 8 RCTs; NNTB 4 people; low-quality evidence). Terlipressin increased the risk of serious cardiovascular adverse events (RR 7.26, 95% CI 1.70 to 31.05; 234 participants; 4 RCTs), but it had no effect on the risk of serious adverse events when analysed as a composite outcome (RR 0.91, 95% CI 0.68 to 1.21; 534 participants; 9 RCTs; number needed to treat for an additional harmful outcome 24.5 people; low-quality evidence). Non-serious adverse events were mainly gastrointestinal, including diarrhoea (RR 5.76, 95% CI 2.19 to 15.15; 240 participants; low-quality evidence) and abdominal pain (RR 1.54, 95% CI 0.97 to 2.43; 294 participants; low-quality evidence). We identified one ongoing trial on terlipressin versus placebo in participants with cirrhosis, ascites, and hepatorenal syndrome type 1. Three RCTs reported funding from a pharmaceutical company. The remaining trials did not report funding or did not receive funding from pharmaceutical companies. Authors' conclusions This review suggests that terlipressin may be associated with beneficial effects on mortality and renal function in people with cirrhosis and type 1 hepatorenal syndrome, but it is also associated with serious adverse effects. We downgraded the strength of the evidence due to methodological issues including bias control, clinical heterogeneity, and imprecision. Consequently, additional evidence is needed.

Context: Antagonism of protein kinase Cβ (PKCβ) restores endothelial function in experimental models of diabetes and prevents vascular dysfunction in response to hyperglycemia in healthy humans. Objective: We tested the hypothesis that PKCβ antagonism would improve vascular function in subjects with type 2 diabetes compared with healthy control subjects. Design: The effect of PKCβ was evaluated in a randomized, placebo-controlled, double-blinded crossover trial. Setting: The study was performed in the outpatient setting of a university medical center. Participants: Thirteen subjects with type 2 diabetes without evidence of cardiovascular disease and 15 healthy control subjects were recruited via newspaper advertisement. Intervention: Subjects underwent a randomized, double-blind, crossover, placebo-controlled trial of the selective PKCβ antagonist ruboxistaurin mesylate. Subjects received each treatment for 14 d. Main Outcome Measure: Endothelium-dependent and endothelium-independent vasodilation of forearm resistance vessels was measured with mercury-in-silastic, strain-gauge plethysmography during intraarterial administration of methacholine chloride and verapamil, respectively. Markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress were measured after each treatment. Results: Endothelium-dependent vasodilation of forearm resistance vessels was attenuated in diabetic subjects when compared with healthy subjects (P = 0.001). Endothelium-independent vasodilation did not differ between groups (P value not significant). Ruboxistaurin did not significantly change endothelium-dependent or endothelium-independent vasodilation or blood-based markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress in either diabetic or healthy subjects. Conclusion: Endothelial dysfunction of forearm resistance vessels was not improved by 2 wk of selective PKCβ inhibition in patients with diabetes. These results suggest that PKCβ does not contribute significantly to vascular dysfunction in otherwise healthy patients with type 2 diabetes.

Food impaction has been described in both eosinophilic esophagitis and proton pump inhibitor-responsive esophageal eosinophilia. The association between endoscopic/histologic features of esophageal eosinophilia and food impaction remains unclear. We aimed to identify clinical, endoscopic, and histologic findings associated with a history of food impaction in esophageal eosinophilia. This was a retrospective cohort study of adult esophageal eosinophilia patients at a tertiary center in 6/2005–10/2014. Only patients with ≥15 eosinophils/high-power field on mucosal biopsies were included. Demographics, comorbidities, symptoms, endoscopic/histologic findings on initial endoscopy, and history of food impaction were reviewed. Statistical analyses were performed using Fisher’s exact test (univariate) and forward stepwise logistic regression (multivariate). 400 patients (42 ± 14 years, 61 % male) were included, with 78 (20 %) having food impaction history. On univariate analyses, rings (62 vs 42 %, p = 0.003), erosions (12 vs 5 %, p = 0.03), eosinophil density on biopsy (40 [IQR = 30–50] vs 30 [IQR = 15–50], p = 0.004), and dysphagia (88 vs 62 %, p

Eosinophilic esophagitis (EoE) is an increasingly diagnosed, immune-mediated disease characterized by inflammation of the esophagus in both children and adult, causing significant morbidity. Adults typically present with dysphagia and a history of food impaction. Diagnosis should be considered in patients with histological evidence of eosinophilia (≥15 eosinophils per high-power field) on esophageal biopsy. More recently, it has been observed that a significant percentage of patients with esophageal eosinophilia respond both clinically and histologically to PPI therapy. This disorder has been named PPI-responsive esophageal eosinophilia (PPI-REE). Recent studies suggest that patients with PPI-REE have similar clinical and endoscopic features of patients with EoE. Specifically, both PPI-REE and EoE patients have a strong disposition to allergy compared to patients without eosinophilia. As such, PPI-REE may represent a subset or variant of EoE. Effective treatment of EoE requires a multidisciplinary approach with gastroenterologists, pathologists, allergists, and nutritionists. Treatments include elimination and elemental diets, topical glucocorticoids (fluticasone and budesonide), and endoscopic dilation.

Short bowel syndrome (SBS) is a state of malabsorption resulting from physical or functional loss of large portions of the small intestine, and is the most common cause of intestinal failure. The average length of a human’s small intestine is between 3 and 8 m, depending on the type of measurements made (surgical, radiologic, or autopsy); SBS occurs when less than 200 cm of small bowel remains. SBS may be congenital (intestinal atresia) or acquired. Physical losses usually occur from surgical resection for Crohn disease (CD), vascular insufficiency, radiation, malignancy, trauma, or volvulus. The site of intestinal resection helps to determine the degree of intestinal capacity. Functional losses, on the other hand, are less common and occur in the setting of a nonfunctioning, but intact, small intestine. Examples include radiation enteritis, congenital defects, and inflammatory bowel disease (IBD). This review addresses the epidemiology, pathophysiology and pathogenesis, clinical manifestations, treatment, complications, and prognosis of SBS. A figure shows sites of intestinal nutrient absorption. A table lists potential complications of SBS in patients receiving parenteral nutrition (PN). This review contains 1 highly rendered figure, 1 table, and 67 references.

Reduced glucose utilization and energy metabolism occur early in the course of Alzheimer's disease (AD) and correlate with impaired cognition. Glucose utilization and energy metabolism are regulated by insulin and insulin-like growth factor I (IGF-I), and correspondingly, studies have shown that cognitive impairment may be improved by glucose or insulin administration. Recently, we demonstrated significantly reduced levels of insulin and IGF-I polypeptide genes and their corresponding receptors in advanced AD relative to aged control brains. The abnormalities in gene expression were accompanied by impaired survival signaling downstream through PI3 kinase-Akt. The present work characterizes the abnormalities in insulin and IGF gene expression and receptor binding in brains with different Braak stage severities of AD. Realtime quantitative RT-PCR analysis of frontal lobe tissue demonstrated that increasing AD Braak Stage was associated with progressively reduced levels of mRNA corresponding to insulin, IGF-I, and IGF-II polypeptides and their receptors, tau, which is regulated by insulin and IGF-I, and the Hu D neuronal RNA binding protein. In contrast, progressively increased levels of amyloid beta protein precursor (AbetaPP), glial fibrillary acidic protein, and the IBA1/AIF1 microglial mRNA transcripts were detected with increasing AD Braak Stage. Impairments in growth factor and growth factor receptor expression and function were associated with increasing AD Braak stage dependent reductions in insulin, IGF-I, and IGF-II receptor binding, ATP levels, and choline acetyltransferase (ChAT) expression. Further studies demonstrated that: 1) ChAT expression increases with insulin or IGF-I stimulation; 2) ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons; and 3) ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD. Together, these data provide further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus (? Type 3) and progresses with severity of neurodegeneration.

Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars. AGEs are prevalent in the diabetic vasculature and contribute to the development of atherosclerosis. The presence and accumulation of AGEs in many different cell types affect extracellular and intracellular structure and function. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Activation of RAGE by AGEs causes upregulation of the transcription factor nuclear factor-κB and its target genes. Soluble AGEs activate monocytes, and AGEs in the basement membrane inhibit monocyte migration. AGE-bound RAGE increases endothelial permeability to macromolecules. AGEs block nitric oxide activity in the endothelium and cause the production of reactive oxygen species. Because of the emerging evidence about the adverse effects of AGEs on the vasculature of patients with diabetes, a number of different therapies to inhibit AGEs are under investigation.