Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice.

Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-ß-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-ß-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-ß-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-ß-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT.

Constipation and a low-fiber diet are not associated with diverticulosis.

BACKGROUND & AIMS: Asymptomatic diverticulosis is commonly attributed to constipation caused by a low-fiber diet, although evidence for this mechanism is limited. We examined the associations between constipation and low dietary fiber intake with risk of asymptomatic diverticulosis. METHODS: We performed a cross-sectional study that analyzed data from 539 individuals with diverticulosis and 1569 without (controls). Participants underwent colonoscopy and assessment of diet, physical activity, and bowel habits. Our analysis was limited to participants with no knowledge of their diverticular disease to reduce the risk of biased responses. RESULTS: Constipation was not associated with an increased risk of diverticulosis. Participants with less frequent bowel movements (<7/wk) had reduced odds of diverticulosis compared with those with regular bowel movements (7/wk) (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.40-0.80). Those reporting hard stools also had reduced odds (OR, 0.75; 95% CI, 0.55-1.02). There was no association between diverticulosis and straining (OR, 0.85; 95% CI, 0.59-1.22) or incomplete bowel movement (OR, 0.85; 95% CI, 0.61-1.20). We found no association between dietary fiber intake and diverticulosis (OR, 0.96; 95% CI, 0.71-1.30) in comparing the highest quartile with the lowest (mean intake, 25 vs 8 g/day). CONCLUSIONS: In our cross-sectional, colonoscopy-based study, neither constipation nor a low-fiber diet was associated with an increased risk of diverticulosis.

What should be done with a dilated bile duct?

Current methods for imaging the biliary tree include ultrasound, CT, MRI, endoscopic retrograde cholangiography, and endoscopic ultrasound (EUS). Bile duct abnormalities may be identified during evaluation of patient symptoms or laboratory abnormalities, or incidentally during imaging for another problem. Biliary dilatation, when identified, may be separated into obstructive or nonobstructive causes. Clinical presentation should guide decisions on which, if any, additional investigations are necessary. Choledocholithiasis is the most common cause of obstructive dilatation and frequently requires decompression. Nonobstructive causes include cystic dilatation, aging, and possibly post-cholecystectomy state. Data are limited regarding the yield of further investigations in patients with incidentally identified modest ductal dilatation without symptoms or laboratory abnormalities. Additional investigations are more likely to identify clinically relevant findings in patients with more pronounced dilatation. EUS is highly accurate, low-invasive, and useful in this setting, whereas ERC should be reserved for cases likely to require therapeutic intervention.

Palliative use of percutaneous endoscopic gastrostomy and percutaneous endoscopic cecostomy tubes.

Percutaneous endoscopic gastrostomy (PEG) tubes are most commonly placed for feeding purposes with the intention of maintenance or improvement in nutritional status; however, they may also be used in a palliative role in patients who have terminal illnesses for feeding or decompression. Percutaneous endoscopic cecostomy (PEC) tubes can be used to decompress malignant and functional bowel disorders with accepted morbidity and mortality. This article reviews the use of PEG and PEC tubes for palliative use.

Endoscopic ultrasound with tissue sampling is accurate in the diagnosis and subclassification of gastrointestinal spindle cell neoplasms.

BACKGROUND AND OBJECTIVES: Mesenchymal (spindle cell) neoplasms (SCN) of the gastrointestinal (GI) tract are an important subtype of subepithelial lesions that need subclassification to assess their malignant potential. Reported success rates of accurate subclassification with endoscopic ultrasound (EUS)-guided biopsies are variable. Our goal was to analyze our experience using EUS-guided TruCut biopsy (EUS-TCB) in the majority of patients. METHODS: Retrospective analysis in patients who underwent EUS with biopsies for suspected SCN at our tertiary referral center between 2004 and 2013. RESULTS: A total of 146 patients with suspected SCN underwent EUS with tissue acquisition. Thirteen patients were excluded from analysis because tissue acquisition established a definite diagnosis other than SCN. In the remaining 133 patients, tissue acquisition was diagnostic of SCN in 118 (88.7%) and nondiagnostic in 15 (11.3%). Subclassification based on immunohistochemistry (IHC) was possible in 109 of the 133 cases (81.9%). The final diagnosis was GI stromal tumor in 64, leiomyoma in 39, and schwannoma in 6 cases. The percentage of patients who were subclassified by the various EUS-guided techniques together was 72.18%, and the percentage of patients who were subclassified specifically with EUS-TCB was 61.65%. Tissue specimens that enabled a specific diagnosis based on histological or cytological characteristics in conjunctions with IHC were obtained with EUS core biopsy in 83 (TCB in 82 and ProCore needle biopsy in 1), fine-needle aspiration in 13, mucosal resection in 10, and forceps biopsies (bite-on-bite) in 3 cases. CONCLUSION: EUS with endoscopic tissue acquisition is accurate in the diagnosis and subclassification of SCN. In experienced hands, the EUS-TruCut needle is a valuable tool with a high success rate for this indication.

Self-expanding plastic stents in treatment of benign esophageal conditions.

BACKGROUND: Recently, self-expanding plastic stents (SEPSs) have been proposed for the treatment of benign esophageal disease. OBJECTIVES: Our purpose was to review our experience with SEPSs in patients with benign esophageal conditions. DESIGN: This was a retrospective case review of patients who underwent SEPS placement for benign esophageal disease, including (1) benign stricture, including reflux disease, ischemia, and idiopathic, (2) radiation-induced strictures, (3) anastomotic strictures, and (4) esophageal leak/fistulae. PATIENTS: Nineteen male and 11 female patients (average age 52.1 years, range 11-87 years) underwent SEPS placement. INTERVENTIONS: SEPS placement. MAIN OUTCOME MEASUREMENTS: Initial complications, stent migration, long-term complications, and treatment success according to clinical symptoms, follow-up endoscopy, or imaging. RESULTS: Eighty-three of 84 SEPS placements were successful. The most common complications were chest pain, dysphagia, nausea, and vomiting. No deaths were reported from stent placement. Stent migration was more frequent in proximal (30/44 stents, 68.1%) and distal (19/27 stents, 70.4%) compared with mid esophageal (3/10 stents, 30%). Migration was more frequent in stents placed for benign strictures (18/22 stents, 81.8%), anastomotic strictures (18/24 stents, 75%), and fistulae/leak (13/22 stents, 59.1%) compared with radiation-induced strictures (4/14 stents, 28.6%). Only 5 of 83 interventions (6%) resulted in long-term improvement after stent removal. LIMITATIONS: This was a retrospective review, and patients were selected from a tertiary medical center. CONCLUSION: Use of SEPSs for benign esophageal conditions resulted in frequent stent migration and few cases of long-term improvement. Further investigation is warranted to identify optimal patient populations and to guide future recommendations for the use of SEPSs.

Cytoskeletal modulation of sodium current in human jejunal circular smooth muscle cells.

A Na(+) current is present in human jejunal circular smooth muscle cells. The aim of the present study was to determine the role of the cytoskeleton in the regulation of the Na(+) current. Whole cell currents were recorded by using standard patch-clamp techniques with Cs(+) in the pipette to block K(+) currents. Cytochalasin D and gelsolin were used to disrupt the actin cytoskeleton and phalloidin to stabilize it. Colchicine was used to disassemble the microtubule cytoskeleton (and intermediate filaments) and paclitaxel to stabilize it. Acrylamide was used to disrupt the intermediate filament cytoskeleton. Perfusion of the recording chamber at 10 ml/min increased peak Na(+) current recorded from jejunal smooth muscle cells by 27 +/- 3%. Cytochalasin D and gelsolin abolished the perfusion-induced increase in Na(+) current, whereas incubation with phalloidin, colchicine, paclitaxel, or acrylamide had no effect. In conclusion, the Na(+) current expressed in human jejunal circular smooth muscle cells appears to be regulated by the cytoskeleton. An intact actin cytoskeleton is required for perfusion-induced activation of the Na(+) current.

Sodium current in human jejunal circular smooth muscle cells.

BACKGROUND & AIMS: Sodium channels are key regulators of neuronal and muscle excitability. However, sodium channels have not been definitively identified in gastrointestinal smooth muscle. The aim of the present study was to determine if a Na(+) current is present in human jejunal circular smooth muscle cells. METHODS: Currents were recorded from freshly dissociated cells using patch-clamp techniques. Complementary DNA (cDNA) libraries constructed from the dissociated cells were screened to determine if a message for alpha subunits of Na(+) channels was expressed. Smooth muscle cells were also collected using laser-capture microdissection and screened. RESULTS: A tetrodotoxin-insensitive Na(+) channel was present in 80% of cells patch-clamped. Initial activation was at -65 mV with peak inward current at -30 mV. Steady-state inactivation and activation curves revealed a window current between -75 and -60 mV. The Na(+) current was blocked by lidocaine and internal and external QX314. A cDNA highly homologous to SCN5A, the alpha subunit of the cardiac Na(+) channel, was present in the cDNA libraries constructed from dissociated cells and from smooth muscle cells collected using laser-capture microdissection. CONCLUSIONS: Human jejunal circular smooth muscle cells express a tetrodotoxin-insensitive Na(+) channel, probably SCN5A. Whether SCN5A plays a role in the pathophysiology of human gut dysmotilities remains to be determined.