Madhusudan Grover

Cellular Changes in Diabetic and Idiopathic Gastroparesis

BACKGROUND & AIMS Cellular changes associated with diabetic and idiopathic gastroparesis are not well described. The aim of this study was to describe histologic abnormalities in gastroparesis and compare findings in idiopathic versus diabetic gastroparesis. METHODS Full-thickness gastric body biopsy specimens were obtained from 40 patients with gastroparesis (20 diabetic) and matched controls. Sections were stained for H&E and trichrome and immunolabeled with antibodies against protein gene product (PGP) 9.5, neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide, substance P, and tyrosine hydroxylase to quantify nerves, S100β for glia, Kit for interstitial cells of Cajal (ICC), CD45 and CD68 for immune cells, and smoothelin for smooth muscle cells. Tissue was also examined by transmission electron microscopy. RESULTS Histologic abnormalities were found in 83% of patients. The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers. On light microscopy, no significant differences were found between diabetic and idiopathic gastroparesis with the exception of nNOS expression, which was decreased in more patients with idiopathic gastroparesis (40%) compared with diabetic patients (20%) by visual grading. On electron microscopy, a markedly increased connective tissue stroma was present in both disorders. CONCLUSIONS This study suggests that on full-thickness biopsy specimens, cellular abnormalities are found in the majority of patients with gastroparesis. The most common findings were loss of Kit expression, suggesting loss of ICC, and an increase in CD45 and CD68 immunoreactivity. These findings suggest that examination of tissue can lead to valuable insights into the pathophysiology of these disorders and offer hope that new therapeutic targets can be found.

Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium.

Background  Cellular changes associated with diabetic (DG) and idiopathic gastroparesis (IG) have recently been described from patients enrolled in the Gastroparesis Clinical Research Consortium. The association of these cellular changes with gastroparesis symptoms and gastric emptying is unknown. The aim of this study was to relate cellular changes to symptoms and gastric emptying in patients with gastroparesis.

Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium: Clinical-histological associations in gastroparesis

Background  Cellular changes associated with diabetic (DG) and idiopathic gastroparesis (IG) have recently been described from patients enrolled in the Gastroparesis Clinical Research Consortium. The association of these cellular changes with gastroparesis symptoms and gastric emptying is unknown. The aim of this study was to relate cellular changes to symptoms and gastric emptying in patients with gastroparesis.

Small intestinal bacterial overgrowth in irritable bowel syndrome: association with colon motility, bowel symptoms, and psychological distress.

Abstract  Small intestinal bacterial overgrowth (SIBO) has been implicated in the pathogenesis of irritable bowel syndrome (IBS), although the issue is still under debate. The aim of this study was to determine the prevalence of SIBO in those with IBS and its association with colonic motility, bowel symptoms and psychological distress. Sucrose hydrogen and methane breath tests were performed in 158 IBS patients and 34 healthy controls (HC). Thresholds for pain and urgency were tested by barostat in the descending colon. The motility index (MI) was calculated as the average area under the curve for all phasic contractions. Questionnaires assessed psychological distress, IBS symptom severity (IBS‐SS), IBS quality of life (IBS‐QOL) and self‐reported bowel symptoms. Fifty‐two of 158 (32.9%) IBS patients had abnormal breath tests compared with six of 34 (17.9%) HC (χ2 = 0.079). SIBO (SIBO+) and non‐SIBO (SIBO−) patients did not differ in the prevalence of IBS subtypes, IBS‐SS, IBS‐QOL and psychological distress variables. IBS patients had a greater post‐distension increase in MI than HC, but there was no difference between SIBO+ and SIBO− patients. Predominant methane producers had higher urge thresholds (28.4 vs 18.3, P < 0.05) and higher baseline MI (461 vs 301.45, P < 0.05) than SIBO− IBS patients, and they reported more ‘hard or lumpy stools’ when compared with predominant hydrogen producers (P < 0.05) and SIBO− IBS patients (P < 0.05). SIBO is unlikely to contribute significantly to the pathogenesis of IBS. Methane production is associated with constipation.

Ultrastructural differences between diabetic and idiopathic gastroparesis

The ultrastructural changes in diabetic and idiopathic gastroparesis are not well studied and it is not known whether there are different defects in the two disorders. As part of the Gastroparesis Clinical Research Consortium, full thickness gastric body biopsies from 20 diabetic and 20 idiopathic gastroparetics were studied by light microscopy. Abnormalities were found in many (83%) but not all patients. Among the common defects were loss of interstitial cells of Cajal (ICC) and neural abnormalities. No distinguishing features were seen between diabetic and idiopathic gastroparesis. Our aim was to provide a detailed description of the ultrastructural abnormalities, compare findings between diabetic and idiopathic gastroparesis and determine if patients with apparently normal immunohistological features have ultrastructural abnormalities. Tissues from 40 gastroparetic patients and 24 age‐ and sex‐matched controls were examined by transmission electron microscopy (TEM). Interstitial cells of Cajal showing changes suggestive of injury, large and empty nerve endings, presence of lipofuscin and lamellar bodies in the smooth muscle cells were found in all patients. However, the ultrastructural changes in ICC and nerves differed between diabetic and idiopathic gastroparesis and were more severe in idiopathic gastroparesis. A thickened basal lamina around smooth muscle cells and nerves was characteristic of diabetic gastroparesis whereas idiopathic gastroparetics had fibrosis, especially around the nerves. In conclusion, in all the patients TEM showed abnormalities in ICC, nerves and smooth muscle consistent with the delay in gastric emptying. The significant differences found between diabetic and idiopathic gastroparesis offers insight into pathophysiology as well as into potential targeted therapies.

Behaviorally Defined Patient-Centered Communication—A Narrative Review of the Literature

BACKGROUNDTouted by some as reflecting a better medical model and cited by the influential IOM report in 2000 as one of the six domains of quality care, patient-centered medicine has yet to fully establish its scientific attributes or to become mainstream. One proposed reason is failure to behaviorally define what the term ‘patient-centered’ actually means.OBJECTIVES(1) To identify patient-centered articles among all reported randomized controlled trials (RCT); (2) to identify those with specific behaviorally defined interventions; (3) to identify commonalities among the behavioral definitions; and (4) to evaluate the relationship of the well-defined RCTs to patient outcomes.DATA SOURCESMedline from April 2010 to 1975.ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONSRCTs having any specific, behaviorally defined patient-centered skill(s) in an intervention with some patient outcome involving real adult patients and providers in real clinical situations.APPRAISAL AND SYNTHESIS METHODSCritical appraisal via narrative review.RESULTSThe prevalence of any mention of patient-centeredness among 327,219 RCTs was 0.50% (1,475 studies), from which we identified only 13 studies (0.90%) where there were behaviorally-defined patient-centered skills in an intervention. Although there were too few studies to make clinical recommendations, we identified common features of the behavioral definitions used: all went well beyond identifying individual skills. Rather, skills were grouped, prioritized, and sequenced by virtually all, often describing a stepwise patient-centered approach to, variously, gather data, address emotions, or inform and motivate.LIMITATIONSThe inherent subjectivity of our method for identifying behaviorally-defined studies could under- or over-represent truly replicable such studies considerably. Also, studies were few and very heterogeneous with interventions of widely differing intensity and foci.CONCLUSIONS AND IMPLICATIONSRCTs identified as patient-centered were rare, and <1% of these were behaviorally defined and, therefore, possibly replicable. There were many common behavioral definitions in the studies reported, and these can guide us in identifying agreed-upon patient-centered interventions, the immediate next-step in advancing the field.

Atypical Antipsychotic Quetiapine in the Management of Severe Refractory Functional Gastrointestinal Disorders

Management of severe refractory functional gastrointestinal disorders (FGIDs) is difficult. Quetiapine, an atypical antipsychotic, may benefit patients by mitigating associated anxiety and sleep disturbances, augmenting the effect of antidepressants, and providing an independent analgesic effect. Outpatient records from a university-based FGID clinic were reviewed, and 21 patients with refractory symptoms who received quetiapine were identified and interviewed. Outcomes included global relief of symptoms, treatment efficacy questionnaire, and change in gastrointestinal (GI) and psychological symptoms. Eleven of 21 patients continued therapy at the time of interview. Six of 11 demonstrated global relief of symptoms, and 9 were satisfied with treatment. The remaining 10 of 21 discontinued therapy because of somnolence and lack of GI benefits. Quetiapine in low doses appeared beneficial in more than half of the adults with severe FGIDs who stayed on treatment. This response in otherwise refractory patients suggests quetiapine might augment the effectiveness of antidepressants in severe FGIDs.

Functional Abdominal Pain

Functional abdominal pain syndrome (FAPS) is a relatively less common functional gastrointestinal (GI) disorder defined by the presence of constant or frequently recurring abdominal pain that is not associated with eating, change in bowel habits, or menstrual periods (Drossman Gastroenterology 130:1377–1390, 2006), which points to a more centrally targeted (spinal and supraspinal) basis for the symptoms. However, FAPS is frequently confused with irritable bowel syndrome and other functional GI disorders in which abdominal pain is associated with eating and bowel movements. FAPS also differs from chronic abdominal pain associated with entities such as chronic pancreatitis or chronic inflammatory bowel disease, in which the pain is associated with peripherally acting factors (eg, gut inflammation or injury). Given the central contribution to the pain experience, concomitant psychosocial disturbances are common and strongly influence the clinical expression of FAPS, which also by definition is associated with loss of daily functioning. These factors make it critical to use a biopsychosocial construct to understand and manage FAPS, because gut-directed treatments are usually not successful in managing this condition.

On the fiftieth anniversary Postinfectious irritable bowel syndrome: mechanisms related to pathogens

Gastrointestinal (GI) infections resulting from bacterial, viral, and parasitic pathogens predispose to postinfectious irritable bowel syndrome (PI‐IBS) and other functional GI disorders. Existing literature supports the role of enterochromaffin cell hyperplasia, serotonin synthesis and reuptake, impaired barrier function, altered immune activation, and potentially mast cell activation in the pathophysiology of PI‐IBS.

Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases.

The effects of antidepressants on the gastrointestinal tract may contribute to their potential efficacy in functional dyspepsia and irritable bowel syndrome; buspirone, a prototype 5-HT1A agonist, enhances gastric accommodation and reduces postprandial symptoms in response to a challenge meal. Paroxetine, a selective serotonin reuptake inhibitor, accelerates small bowel but not colonic transit, and this property may not be relevant to improve gut function in functional gastrointestinal disorders. Venlafaxine, a prototype serotonin norepinephrine reuptake inhibitor, enhances gastric accommodation, increases colonic compliance and reduces sensations to distension; however, it is associated with adverse effects that reduce its applicability in treatment of functional gastrointestinal disorders. Tricyclic antidepressants reduce sensations in response to food, including nausea, and delay gastric emptying, especially in females. Buspirone appears efficacious in functional dyspepsia; amitriptyline was not efficacious in a large trial of children with functional gastrointestinal disorders. Clinical trials of antidepressants for treatment of irritable bowel syndrome are generally small. The recommendations of efficacy and number needed to treat from meta-analyses are suspect, and more prospective trials are needed in patients without diagnosed psychiatric diseases. Antidepressants appear to be more effective in the treatment of patients with anxiety or depression, but larger prospective trials assessing both clinical and pharmacodynamic effects on gut sensorimotor function are needed.