Leila Neshatian

Long-term Follow-up Study of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection: A Multicenter Experience.

Goal:Our aim was to investigate fecal microbiota transplantation (FMT) efficacy in patients with severe and/or complicated Clostridium difficile infection (CDI). Background:FMT is successful for recurrent CDI, although its benefit in severe or complicated CDI has not specifically been evaluated. Study Methods:A multicenter long-term follow-up study was performed in patients who received FMT for severe and/or complicated CDI (diagnosed using standard criteria). Pre-FMT and post-FMT questionnaires were completed. Study outcomes included cure rates and time to resolution of symptoms. Results:A total of 17 patients (82% inpatients, 18% outpatients) were included (76.4% women; mean age, 66.4 y; mean follow-up, 11.4 mo). Patients had severe and complicated (76.4%) or either severe or complicated (23.6%) CDI. Sixteen patients (94.1%) had diarrhea, which resolved in 12 (75%; mean time to resolution, 5.7 d) and improved in 4 (25%) after FMT. Eleven patients (64.7%) had abdominal pain, which resolved in 8 (72.7%; mean time to resolution, 9.6 d) and improved in 3 (27.3%) after FMT. Two of 17 patients experienced early CDI recurrence (⩽90 d) after FMT (primary cure rate, 88.2%); and in 1 patient, a second FMT resulted in cure (secondary cure rate, 94.1%). Late CDI recurrence (≥90 d) was seen in 1 of 17 patients (5.9%) in association with antibiotics and was successfully treated with a repeat FMT. No adverse effects directly related to FMT occurred. Conclusions:FMT was successful and safe in this cohort of patients with severe or complicated CDI. Primary and secondary cure rates were 88.2% and 94.1%, respectively.

Macrophages in diabetic gastroparesis--the missing link?

Diabetic gastroparesis results in significant morbidity for patients and major economic burden for society. Treatment options for diabetic gastroparesis are currently directed at symptom control rather than the underlying disease and are limited. The pathophysiology of diabetic gastroparesis includes damage to intrinsic and extrinsic neurons, smooth muscle, and interstitial cells of Cajal (ICC). Oxidative damage in diabetes appears to be one of the primary insults involved in the pathogenesis of several complications of diabetes, including gastroparesis. Recent studies have highlighted the potential role of macrophages as key cellular elements in the pathogenesis of diabetic gastroparesis. Macrophages are important for both homeostasis and defense against a variety of pathogens. Heme oxygenase 1 (HO1), an enzyme expressed in a subset of macrophages has emerged as a major protective mechanism against oxidative stress. Activation of macrophages with high levels of HO1 expression protects against development of delayed gastric emptying in animal models of diabetes, while activation of macrophages that do not express HO1 are linked to neuromuscular cell injury. Targeting macrophages and HO1 may therefore be a therapeutic option in diabetic gastroparesis.

Ranolazine inhibits voltage-gated mechanosensitive sodium channels in human colon circular smooth muscle cells

Human jejunum smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs) express the SCN5A-encoded voltage-gated, mechanosensitive sodium channel NaV1.5. NaV1.5 contributes to small bowel excitability, and NaV1.5 inhibitor ranolazine produces constipation by an unknown mechanism. We aimed to determine the presence and molecular identity of Na(+) current in the human colon smooth muscle and to examine the effects of ranolazine on Na(+) current, mechanosensitivity, and smooth muscle contractility. Inward currents were recorded by whole cell voltage clamp from freshly dissociated human colon SMCs at rest and with shear stress. SCN5A mRNA and NaV1.5 protein were examined by RT-PCR and Western blots, respectively. Ascending human colon strip contractility was examined in a muscle bath preparation. SCN5A mRNA and NaV1.5 protein were identified in human colon circular muscle. Freshly dissociated human colon SMCs had Na(+) currents (-1.36 ± 0.36 pA/pF), shear stress increased Na(+) peaks by 17.8 ± 1.8% and accelerated the time to peak activation by 0.7 ± 0.3 ms. Ranolazine (50 μM) blocked peak Na(+) current by 43.2 ± 9.3% and inhibited shear sensitivity by 25.2 ± 3.2%. In human ascending colon strips, ranolazine decreased resting tension (31%), reduced the frequency of spontaneous events (68%), and decreased the response to smooth muscle electrical field stimulation (61%). In conclusion, SCN5A-encoded NaV1.5 is found in human colonic circular smooth muscle. Ranolazine blocks both peak amplitude and mechanosensitivity of Na(+) current in human colon SMCs and decreases contractility of human colon muscle strips. Our data provide a likely mechanistic explanation for constipation induced by ranolazine.

Advancing treatment options for chronic idiopathic constipation.

ABSTRACT Introduction: Chronic constipation is a global problem affecting all ages and associated with considerable morbidity and significant financial burden for society. Though formerly defined on the basis of a single symptom, infrequent defecation; constipation is now viewed as a syndrome encompassing several complaints such as difficulty with defecation, a sense of incomplete evacuation, hard stools, abdominal discomfort and bloating. Areas covered: The expanded concept of constipation has inevitably led to a significant change in outcomes in clinical trials, as well as in patient expectations from new therapeutic interventions. The past decades have also witnessed a proliferation in therapeutic targets for new agents. Foremost among these have been novel prokinetics, a new category, prosecretory agents and innovative approaches such as inhibitors of bile salt transport. In contrast, relatively few effective therapies exist for the management of those anorectal and pelvic floor problems that result in difficult defecation. Expert opinion: Though constipation is a common and often troublesome disorder, many of those affected can resolve their symptoms with relatively simple measures. For those with more resistant symptoms a number of novel, effective and safe options now exist. Those with defecatory difficulty (anismus, pelvic floor dysfunction) continue to represent a significant management challenge.

Neurogenic Bowel Dysfunction in Patients with Neurogenic Bladder

Patients with primary neurologic conditions often experience urinary and bowel dysfunction due to loss of sensory and/or motor control. Neurogenic bowel dysfunction is frequently characterized by both constipation and fecal incontinence. In general, the management of neurogenic bowel dysfunction has been less well studied than bladder dysfunction despite their close association. It is widely accepted that establishment of a multifaceted bowel regimen is the cornerstone of conservative management. Continuing assessment is necessary to determine the need for more invasive interventions. In the clinical setting, the Urologist may be the principle provider addressing bowel concerns in addition to bladder dysfunction, and furthermore, treatment of one often impacts the other. Future directions should include development of follow-up and management guidelines that address the comprehensive care of this patient population.

Irritable bowel syndrome patients have SCN5A channelopathies that lead to decreased NaV1.5 current and mechanosensitivity

The SCN5A-encoded voltage-gated mechanosensitive Na+ channel NaV1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian irritable bowel syndrome (IBS) patient cohorts, 2-3% of patients have SCN5A missense mutations that alter NaV1.5 function and may contribute to IBS pathophysiology. In this study we examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, compared them with IBS-negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%) IBS patients had six rare SCN5A mutations that were absent in 377 IBS-negative controls. Six of six (100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%) IBS-associated SCN5A mutations (R225W, R433C, R986Q, and F1293S) resulted in altered NaV1.5 mechanosensitivity. In this racially and ethnically diverse cohort of IBS patients, we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function. NEW & NOTEWORTHY The voltage-gated Na+ channel NaV1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed irritable bowel syndrome cohort, 2% had mutations in the NaV1.5 gene SCN5A. These mutations were absent in irritable bowel syndrome-negative controls. Most mutant NaV1.5 channels were loss of function in voltage dependence or mechanosensitivity.

The assessment and management of defecatory dysfunction: a critical appraisal

Purpose of review To summarize the advances in diagnostic modalities and management options for defecatory dysfunction and highlight the areas in need of further research. Recent findings The diagnostic utility of high-resolution anorectal manometry (ARM), which has emerged as a promising tool for the diagnosis of defecatory dysfunction, appears to be questionable in differentiating disease from normal physiology. There also seems to be discrepancy between results of various tests of anorectal function in the diagnosis of defecatory dysfunction. New revisions in diagnostic criteria for defecatory dysfunction by Rome IV consortium, may enhance its diagnostic yield. Biofeedback remains to be the most effective evidence-based treatment option for patients with defecatory dysfunction. Anorectal pressure profile cannot predict or mediate the success of biofeedback. Biofeedback may improve the symptoms through central effects. Summary Despite the advances in the ARM and defecography techniques, no one test has been able to be considered as the ‘gold standard’ for diagnosis of defecatory dysfunction. The mechanism of action of biofeedback in defecatory dysfunction remains poorly understood.

A Hidden Cause of Dysphagia

Gastroentero Question: A 78year-old man was referred to our clinic for progressive esophageal dysphagia. He had first noted intermittent difficulty with swallowing solids 6 months before the visit. His symptoms had worsened progressively over the past 2 months to both solids and liquids. He had a 10 pounds loss over this time period. His past medical history was significant for coronary artery disease and history of bypass grafting 15 years before the presentation. He had a remote history of smoking (>30 years ago). There was no pertinent finding in the physical examination. Routine blood tests were unremarkable, except for slightly elevated lactate dehydrogenase at 228. His local evaluation with upper endoscopy revealed a moderate stenosis measuring 6 cm in length 25 cm from the incisors. The mucosa was intact with the inner diameter 1 cm. The mucosal biopsies were normal. The remainder of the esophagus, the entire stomach and duodenum were normal. Barium esophagography (Figure A) showed a 6 cm area of smooth narrowing of the mid esophagus. CT of the chest (Figure B, arrow) showed a circumferential esophageal thickening with soft tissue infiltration involving the esophagus starting at the level of the carina. There were slightly enlarged lymph nodes in the adjacent mediastinum. He underwent endoscopic ultrasonography (EUS), which confirmed the diffuse esophageal wall thickening. Yet again the mucosal biopsies and a lymph node fine needle aspiration (FNA) were negative. At this point, the patient was referred to our institution. What is your diagnosis? Look on page 550 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

Abdominal pain and bloating in an auto mechanic.

Gastroenterology 2014;146:1610–1611 Question: A 56-yearold auto mechanic man presented with a 6-week history of fever, chills, drenching night sweats, malaise, nausea, abdominal pain, and distention associated with a 15kg weight loss. His past medical history was significant for ileocolonic Crohn’s disease, diagnosed 20 years ago, asymptomatic onmercaptopurine for the past 10 years. He had remote history of 30 pack-years of smoking, but stopped smoking 20 years ago. Pertinent physical examination findings included mild pallor and a distended, soft abdomen, which was mildly tender to palpation. He was not jaundiced. There was no distinct palpable mass or evidence of ascites. Laboratory tests revealed hemoglobin, 8.5 g/dL; mean corpuscular volume, 98; platelets, 790 10/L; erythrocyte sedimentation rate, 134; International Normalized Ratio, 1.8; total protein, 5.6 g/dL; and albumin, 1.8 g/dL. Electrolytes, creatinine, and liver enzymes were otherwise normal. Computed tomography (CT) of the abdomen and pelvis is shown in Figures A and B. CT-guided biopsy was performed and the pathology result is shown in Figures C and D. What is the diagnosis? Look on page 1611 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.