Viktor E. Eysselein

Circumferential ablation of Barrett's esophagus that contains high-grade dysplasia: a U.S. multicenter registry

BACKGROUND The management strategies for Barretts esophagus (BE) that contains high-grade dysplasia (HGD) include intensive endoscopic surveillance, photodynamic therapy, thermal ablation, EMR, and esophagectomy. OBJECTIVE To assess the safety and effectiveness of endoscopic circumferential balloon-based ablation by using radiofrequency energy for treating BE HGD. DESIGN Multicenter U.S. registry. SETTING Sixteen academic and community centers; treatment period from September 2004 to March 2007. PATIENTS Patients with histologic evidence of intestinal metaplasia (IM) that contained HGD confirmed by at least 2 expert pathologists. A prior EMR was permitted, provided that residual HGD remained in the BE region for ablation. INTERVENTION Endoscopic circumferential ablation with follow-up esophageal biopsies to assess the histologic response to treatment. OUTCOMES Histologic complete response (CR) end points: (1) all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD), (2) all biopsy specimens were negative for any dysplasia (CR-D), and (3) all biopsy specimens were negative for IM (CR-IM). RESULTS A total of 142 patients (median age 66 years, interquartile range [IQR] 59-75 years) who had BE HGD (median length 6 cm, IQR 3-8 cm) underwent circumferential ablation (median 1 session, IQR 1-2). No serious adverse events were reported. There was 1 asymptomatic stricture and no buried glands. Ninety-two patients had at least 1 follow-up biopsy session (median follow-up 12 months, IQR 8-15 months). A CR-HGD was achieved in 90.2% of patients, CR-D in 80.4%, and CR-IM in 54.3%. LIMITATIONS A nonrandomized study design, without a control arm, a lack of centralized pathology review, ablation and biopsy technique not standardized, and a relatively short-term follow-up. CONCLUSIONS Endoscopic circumferential ablation is a promising modality for the treatment of BE that contains HGD. In this multicenter registry, the intervention safely achieved a CR for HGD in 90.2% of patients at a median of 12 months of follow-up.

Protective effect of epidermal growth factor in an experimental model of colitis in rats

BACKGROUND/AIMS The role of epidermal growth factor (EGF) in the maintenance of mucosal integrity in the lower gastrointestinal tract is unknown. The aim of this study was to determine the effect of EGF in experimental colitis. METHODS Colitis was induced with 2,4,6-trinitrobenzenesulfonic acid/ethanol enemas. Rats were pretreated with intraperitoneal administration of recombinant human EGF (600 micrograms/kg) or vehicle 1 hour before induction of colitis and daily thereafter until killed at 8 hours, 48 hours, and 1 week. A separate group received an identical dosage and administration of EGF or vehicle for 1 week with treatment initiated 24 hours after the induction of colitis. Colonic tissue was evaluated macroscopically, histologically, and for myeloperoxidase activity. RESULTS Pretreatment with EGF reduced microscopic erosions at 8 and 48 hours by 74% and 54%, respectively (P < 0.05). At 1 week, microscopic ulcerations and myeloperoxidase activity were reduced by 65% in the EGF-pretreated group (P < 0.05). No significant difference in macroscopic injury, histological damage, or myeloperoxidase activity was noted when EGF treatment was initiated after the induction of colitis. CONCLUSIONS Systemic EGF administration reduces mucosal damage and inflammation in a trinitrobenzenesulfonic acid/ethanol model of colitis in rats through a mechanism involving mucosal protection.

Partial structure of a large canine cholecystokinin (CCK58): Amino acid sequence

A cholecystokinin molecule larger than any previously chemically characterized was purified from canine proximal small intestine mucosa. The purification procedure consisted of sequential steps of affinity chromatography, gel filtration, and high pressure liquid chromatography. Activity was detected and quantitated by radioimmunoassay with an antibody that recognized the carboxyl terminal sequence of porcine cholecystokinin. Microsequencing of the purified peptide revealed an amino terminal nonadecapeptide sequence (AQKVNSGEPRAHLGALLAR) not present in known cholecystokinin molecules followed by a nonadecapeptide sequence (YIQQARKAPSGRMSVIKNL) that corresponds exactly to the amino terminal sequence of porcine cholecystokinin 39 except for reversed positions of a Met and a Val residue. Based on the sequence analysis, immunoreactivity, and presence of biological activity in two bioassay systems, this peptide, tentatively named cholecystokinin 58, may be a biosynthetic precursor of the smaller forms previously characterized in gastrointestinal and brain tissues.

Improved oral intake after palliative duodenal stenting for malignant obstruction: a prospective multicenter clinical trial.

OBJECTIVES:We sought to test the hypothesis that placement of a new nitinol duodenal self-expandable metallic stent (SEMS) for palliation of malignant gastroduodenal obstruction is effective and safe in allowing patients to tolerate an oral diet.METHODS:In a prospective multicenter study, SEMSs (Duodenal WallFlex, Boston Scientific) were placed to alleviate gastroduodenal obstruction in inoperable patients without the ability to tolerate solid food. The primary study end point was improvement in oral intake monitored according to the 4-point Gastric Outlet Obstruction Scoring System (GOOSS) up to 24 weeks after stent placement.RESULTS:Forty-three patients received SEMSs, which were successfully deployed on the first attempt in 41 cases (95%) and the second attempt in two (5%). Within 1 day and 7 days after SEMS placement, 52% and 75% of patients, respectively, benefited from a GOOSS increase ≥1. Resumption of solid food intake (GOOSS 2–3) was attained by 56% of patients within 7 days and 80% by 28 days. Of the patients attaining GOOSS 2–3, 48% remained on solid food until death or last follow-up. Device-related adverse events included stent occlusion/malfunction in 9% of patients and perforation in 5% of patients.CONCLUSIONS:Duodenal WallFlex stent placement promptly improves oral intake in a majority of inoperable patients with malignant gastroduodenal obstruction. In approximately half the patients achieving GOOSS 2–3, the capacity for solid food intake endures until death or last follow-up.

The ADH3*2 and CYP2E1 c2 alleles increase the risk of alcoholism in Mexican American men

To identify the association between the polymorphisms of genes encoding alcohol metabolizing enzymes and alcoholism, the alcohol dehydrogenase 2 (ADH2), alcohol dehydrogenase 3 (ADH3), aldehyde dehydrogenase 2 (ALDH2), and cytochrome P450 2E1 (CYP2E1) genes were studied in 101 male Mexican American alcoholics. One hundred and four Mexican American nonalcoholic males served as controls. The allele frequency of ADH2*2 (4.3%) and ALDH2*2 (0%), which are considered as protective alleles against alcohol drinking, is very low in Mexican Americans and no association is found between these alleles and alcohol dependence. A strong association was found between ADH3 genotype and alcoholism; the percentage of subjects who carry the ADH3*2 allele was significantly higher in alcoholics (64.4%) than controls (50%). Association was also found between the CYP2E1 RsaI c2 allele and alcohol dependence; the percentage of subjects who carry the RsaI c2 allele was significantly higher in alcoholics (34.7%) than in nonalcoholics (22.1%). The subjects whose alcohol drinking onset age is younger than 25 have much higher CYP2E1 c2 allele frequency than those whose alcohol drinking onset age is older than 25 (22.1% vs 15.7%). Among 101 alcoholics, only 18 subjects carry neither ADH3*2 nor CYP2E1 c2 alleles. For those subjects who have an ADH*1/*1 background, a strong association is found between CYP2E1 RsaI/DraI genotype and alcoholism; the CYP2E1 RsaI c2 and DraI C allele frequencies are much higher in alcoholics than in nonalcoholics (26.4% vs 9.6% for c2 and 27.8% vs 13.5% for C allele). Taken together, ADH3*2 and CYP2E1 c2/C alleles might independently contribute to the development of alcoholism in Mexican American men.

Calcitonin gene-related peptide and substance P decrease in the rabbit colon during colitis. A time study

The sensory neuropeptides, substance P and calcitonin gene-related peptide, have been implicated in inflammatory reactions in several tissues. An immune-complex model of colitis was used in rabbits to determine the colonic content (nmol/g protein) of immunoreactive substance P and calcitonin gene-related peptide at various times after induction of inflammation to assess changes in these neuropeptides during the inflammatory response. Calcitonin gene-related peptide content was decreased by 66% 4 hours after induction of inflammation and reached a maximum of 80% at 48 hours. The substance P content was decreased at 8 hours, with a maximum decrease of 64% at 48 hours. Substance P decrease was detected in the muscle layer. The amounts of substance P in the mucosal/submucosal layer extracts were too low to allow accurate measurements. Calcitonin gene-related peptide decreased both in the muscle and the mucosal-submucosal layers. Immunohistochemical analysis showed that calcitonin gene-related peptide and substance P innervation patterns were comparable in normal and inflamed colon, even though there appeared to be a decrease in density and intensity of the staining, particularly for calcitonin gene-related peptide at 48 hours. The early decrease of calcitonin gene-related peptide and substance P during the time course of colitis might be due to release from nerve terminals of the gut during the inflammatory response. The profound changes in colonic calcitonin gene-related peptide and substance P content during colitis may have important implications during inflammation and subsequent tissue repair and may also lead to disturbances in gut motility.

Selective ablation of spinal afferent neurons containing CGRP attenuates gastric hyperemic response to acid

The gastric mucosa, in particular submucosal blood vessels, are innervated by afferent neurons containing neuropeptides such as calcitonin gene-related peptide. Stimulation of sensory neurons innervating the gastric mucosa increases submucosal blood flow. Since sensory neurons supplying the stomach are of dual origin from nodose and dorsal root ganglia, we examined the effect of selective ablation of either the vagal or spinal sensory innervation to the upper gastrointestinal tract on the increase in gastric mucosal blood flow in response to acid back diffusion into the gastric mucosa. Perineural application of capsaicin to the celiac/superior mesenteric ganglia, but not to the vagus nerves, significantly inhibited by 53% the hyperemic response to acid back diffusion. Tissue levels of immunoreactive calcitonin gene-related peptide in the gastric corpus were significantly reduced (by 73%) by periceliac capsaicin treatment, but unaffected by perivagal capsaicin treatment. These data suggest that spinal capsaicin-sensitive afferents containing calcitonin gene-related peptide immunoreactivity are involved in mediating increases in gastric mucosal blood flow. This increase in gastric mucosal blood flow mediated by sensory neurons may act as a protective mechanism against mucosal injury, similar to responses seen in other tissues such as skin.

Commercial Recombinant Human β‐Nerve Growth Factor and Adult Rat Dorsal Root Ganglia Contain an Identical Molecular Species of Nerve Growth Factor Prohormone

Abstract: Examination of commercial recombinant human β‐nerve growth factor (rh‐β‐NGF) preparations with polyclonal antibodies specific to 13‐kDa NGF and pro‐NGF‐specific domains revealed the presence of high‐molecular‐mass immunoreactive proteins, including a 60‐kDa NGF prohormone. On incubation with a mixture of N‐ and O‐specific glycosidases, the 60‐kDa NGF prohormone generated a 32‐kDa protein corresponding to the molecular size of NGF precursor predicted by the cloned human NGF cDNA. Highly sensitive chemiluminescence immunoblot analysis of adult rat dorsal root ganglia, spinal cord, and colon tissues with NGF‐ and pro‐NGF domain‐specific antibodies also revealed the presence of high‐molecular‐mass proteins, including the 60‐kDa NGF prohormone. Based on the presence of the 60‐kDa NGF prohormone in dorsal root ganglia and its efferent tissues, we suggest that proteolytically unprocessed, glycosylated NGF prohormone may mediate interactions between neurons and the tissues they innervate.

Acute liver injury induced by weight-loss herbal supplements

We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.

Keratinocyte Growth Factor Ameliorates Dextran Sodium Sulfate Colitis in Mice

Keratinocyte growth factor (KGF) is emerging asan important mediator of mucosal defense and repair inthe colon. The aim of the present study was to evaluateand further characterize the effects of exogenous KGF administration utilizing the dextran sodiumsulfate (DSS) model of colitis in mice. Colitis wasinduced via oral administration of DSS (5 g/100 ml) toBalb/c mice for eight days. Intraperitonealadministration of KGF (5 mg/kg, once daily) or vehicle (VEH)was initiated 1 hr prior to the induction of the colitis(N = 10, each group). Mucosal injury of the entire colonwas histologically assessed and graded. An approximately fourfold reduction in the cryptdamage score was noted in the KGF group when compared tocontrols (VEH) (2.8 ± 1.03 and 11.4 ±0.78, respectively). The significant reduction ofmucosal injury in KGF treated mice confirms that KGF isa key mediator maintaining the integrity of the colonicmucosa.