Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis.

BACKGROUND: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic process. In a previous work, we demonstrated that the insulin receptor isoform A (IRA) and its association with the insulin-like growth factor-I receptor (IGF-IR) confer a proliferative advantage to VSMCs. However, the role of IR and IGF-IR in VSMC migration remains poorly understood. METHODS: Wound healing assays were performed in VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR-/- VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs). To study the role of IR isoforms and IGF-IR in experimental atherosclerosis, we used ApoE-/- mice at 8, 12, 18 and 24 weeks of age. Finally, we analyzed the mRNA expression of total IR, IRB isoform, IGF-IR and IGFs by qRT-PCR in the medial layer of human aortas. RESULTS: IGF-I strongly induced migration of the four cell lines through IGF-IR. In contrast, insulin and IGF-II only caused a significant increase of IRA VSMC migration which might be favored by the formation of IRA/IGF-IR receptors. Additionally, a specific IGF-IR inhibitor, picropodophyllin, completely abolished insulin- and IGF-II-induced migration in IRB, but not in IRA VSMCs. A significant increase of IRA and IGF-IR, and VSMC migration were observed in fibrous plaques from 24-week-old ApoE-/- mice. Finally, we observed a marked increase of IGF-IR, IGF-I and IGF-II in media from fatty streaks as compared with both healthy aortas and fibrolipidic lesions, favoring the ability of medial VSMCs to migrate into the intima. CONCLUSIONS: Our data suggest that overexpression of IGF-IR or IRA isoform, as homodimers or as part of IRA/IGF-IR hybrid receptors, confers a stronger migratory capability to VSMCs as might occur in early stages of atherosclerotic process.

Usefulness of biodegradable polydioxanone stents in the treatment of postsurgical colorectal strictures and fistulas.

Benign colonic strictures and fistulas are a growing problem presenting most commonly after bowel resection. Standard treatment is with endoscopic bougies or, more usually, balloon dilation. When these approaches are not successful, other solutions are available and different endoscopic and surgical approaches have been used to treat fistulas. We present an additional option--biodegradable stents--for the treatment of colonic strictures and fistulas that have proven refractory to other endoscopic interventions. We analyzed the results from 10 patients with either a postsurgical colorectal stricture (n =7) or rectocutaneous fistula (n =3) treated with the biodegradable SX-ELLA esophageal stent (covered or uncovered). Stents were successfully placed in nine patients, although early migration subsequently occurred in one. Placement was impossible in one patient due to deformity of the area and the fact that the stricture was approximately 30cm from the anus. The fistulas were successfully closed in all patients, although symptoms reappeared in one patient. In the six patients who received stents for strictures, symptoms resolved in five; in the remaining patient, the stent migrated shortly after the endoscopy. Treatment of colonic strictures and rectocutaneous fistulas with biodegradable stents is an effective alternative in the short-to-medium term. The stent does not have to be removed and is subject to very few complications. The drawbacks of this approach are the need to repeat the procedure in some patients and the lack of published series on efficacy.

Colonic stenting as a bridge to surgery in malignant large-bowel obstruction: a report from two large multinational registries.

OBJECTIVES: To date, this is the largest prospective series in patients with malignant colorectal obstruction to evaluate the effectiveness and safety of colonic self-expanding metal stents (SEMSs) as an alternative to emergency surgery. SEMSs allow restoration of bowel transit and careful tumor staging in preparation for elective surgery, hence avoiding the high morbidity and mortality associated with emergency surgery and stoma creation. METHODS: This report is on the SEMS bridge-to-surgery subset enrolled in two multicenter international registries. Patients were treated per standard of practice, with documentation of clinical and procedural success, safety, and surgical outcomes. RESULTS: A total of 182 patients were enrolled with obstructive tumor in the left colon (85%), rectum (11%), or splenic flexure (4%). Of these patients, 86% had localized colorectal cancer without metastasis. Procedural success was 98% (177/181). Clinical success was 94% (141/150). Elective surgery was performed in 150 patients (9 stomas) and emergency surgery in 7 patients for treatment of a complication (3 stomas). The overall complication rate was 7.8% (13/167), including perforation in 3% (5/167), stent migration in 1.2% (2/167), bleeding in 0.6% (1/167), persistent colonic obstruction in 1.8% (3/167), and stent occlusion due to fecal impaction in 1.2% (2/167). One patient died from complications related to surgical management of a perforation. CONCLUSIONS: SEMSs provide an effective bridge to surgery treatment with an acceptable complication rate in patients with acute malignant colonic obstruction, restoring luminal patency and allowing elective surgery with primary anastomosis in most patients.

Efficacy of pediatric colonoscopy used as push enteroscopy in the management of capsule endoscopy findings.

BACKGROUND: recent advances in endoscopy have enabled us to explore the small intestine more efficiently, both with capsule endoscopy and double-balloon enteroscopy. However, these methods are not available in all hospitals. Therefore, when capsule endoscopy reveals proximal jejunal lesions, a possible alternative for treatment could involve push enteroscopy combined with colonoscopy. Lesions can thus be marked for subsequent monitoring. OBJECTIVES: to describe the efficacy of pediatric colonoscopy for diagnosis, the marking of the area explored, and therapeutic options. MATERIAL AND METHODS: between October 2007 and September 2008 a total of 21 enteroscopies were performed using a pediatric colonoscope. Nine of these were used to take jejunal biopsy samples due to suspected disease of the mucosa. In 10 of the remaining 12, capsule endoscopy revealed lesions (vascular malformations or jejunal bleeding), and in 2 intestinal transit time was analyzed due to suspected jejunal stenosis. We used a PENTAX EC-3470-LK pediatric colonoscope, whose 11.6-mm sectional diameter and 3.8-mm working channel make it possible to administer all the usual endoscopic treatments. RESULTS: therapeutic endoscopy was performed on 7 men and 5 women (mean age 63.3 years). Jejunal lesions were observed in 10 cases (5 cases of angiodysplasia, 2 cases of jejunal stenosis, 1 case of nonmalignant thickened jejunal folds, 1 eroded submucosal tumor, and 1 case of duodenal and jejunal varices). The most distal area was marked with India ink (2), hemoclips (4), or both to help locate the lesions using simple abdominal radiography or capsule endoscopy. CONCLUSIONS: jejunal enteroscopy enabled a firm diagnosis to be made in most of the patients studied. We were able to treat 58% of patients and mark the areas explored for subsequent follow-up. With hemoclips we were able to locate the most distal point explored using simple abdominal radiography.

The Role of Insulin Receptor Isoforms in Diabetes and Its Metabolic and Vascular Complications.

The insulin receptor (IR) presents by alternative splicing two isoforms: IRA and IRB. The differential physiological and pathological role of both isoforms is not completely known, and it is determinant the different binding affinity for insulin-like growth factor. IRB is more abundant in adult tissues and it exerts mainly the metabolic actions of insulin, whereas IRA is mainly expressed in fetal and prenatal period and exerts mitogenic actions. However, the change in the expression profile of both IR isoforms and its dysregulation are associated with the development of different pathologies, such as cancer, insulin resistance, diabetes, obesity, and atherosclerosis. In some of them, there is a significant increase of IRA/IRB ratio conferring a proliferative and migratory advantage to different cell types and favouring IGF-II actions with a sustained detriment in the metabolic effects of insulin. This review discussed specifically the role of IR isoforms as well as IGF-IR in diabetes and its associated complications as obesity and atherosclerosis. Future research with new IR modulators might be considered as possible targets to improve the treatment of diabetes and its associated complications.

Esophagoenteral stents in patients with recurrent gastric adenocarcinoma.

One of the problems that can appear in patients with total gastrectomy for adenocarcinoma with esophagoenteral anastomosis is the appearance of a stenosis of the anastomosis. These stenosis are frequently malignant due to relapse of neoplasia. The therapeutic possibilities available are the surgical bypass or palliative treatment. There is very little experience described in the literature (21 cases) on the placing of self-expandable metal stents as a palliative treatment for the symptoms of stenosis.We present our experience of 3 patients, in whom 4 esophageal stents were fitted (1 covered and 3 uncovered) with good results. The dysphagia disappeared or improved, it allowed the ingestion of a soft diet and meant an improvement in the quality of life and at the same time stopped the weight loss. It seems an effective palliative treatment as a treatment for dysphagia in patients with tumoral relapse in the anastomosis of total gastrectomies.

Long-term outcome of patients with non-cardiac chest pain.

OBJECTIVE: To assess long-term outcome for patients with chest pain in our environment, to estimate direct resource use, and to evaluate the influence of patient views regarding pain origin on outcome. PATIENTS AND METHODS: All patients referred to our Department between 1994 and 1998 to undergo pH-metry as a result of chest pain were identified. Those detected were subjected to a structured direct interview on the telephone. RESULTS: 104 patients with a follow-up period (since pH-metry) of 3.76 years were evaluated. Thirty nine percent of patients were free from pain (37.5%), and one had died from a seemingly unrelated cause (1%), whereas the rest still suffered from pain. The mean number of visits per patient during the last year was 2.83 to their general practitioner, 1.04 to an specialist, and 0.99 to an Emergency Unit; hospitalisations were 0.26, and ICU admissions 0.09. Patients who trusted medical diagnoses showed better outcomes than those who did not trust or understand them, in association with lower resource use, particularly Emergency Unit use. CONCLUSION: Patients with chest pain had a favourable life prognosis, but 60% still suffer from pain after nearly 4 years of follow-up, which entails a relevant use of health-care resources. Trust in medical diagnosis seemingly influences outcome, and the use of diagnostic procedures to determine pain origin is thus likely beneficial for patient.

Endoscopic resection of large colorectal polyps.

BACKGROUND: Endoscopic polypectomy is a common technique, but there are discrepancies over which treatment--surgical or endoscopic--to follow in case of polyps of 2 cm or larger. OBJECTIVES: To analyse the efficacy and complications of colonoscopic polypectomy of large colorectal polyps. PATIENTS AND METHODS: 147 polypectomies were performed on 142 patients over an eight-year period. The technique used was that of submucosal adrenaline 1:10000 or saline injection at the base of the polyp, followed by resection of the polyp using a diathermic snare in the smallest number of fragments. Remnant adenomatous tissue was fulgurated with an argon plasma coagulator. Lately, prophylactic hemoclips have been used for thick-pedicle polyps. Complete removal was defined as when a polyp was completely resected in one or more polypectomy sessions. Polypectomy failure was defined as when a polyp could not be completely resected or contained an invasive carcinoma. RESULTS: The mean patient age was 67.9 years (range, 4-90 years), with 68 men and 79 women. There were 74 sessile polyps, and the most common location was the sigmoid colon. The most frequent histology was tubulovillous. Most of the polyps (96.6%), were resected and cured. This was not achieved in four cases of invasive carcinoma, and a villous polyp of the cecum. All pedunculated polyps were resected in one session, whereas the average number of colonoscopies for sessile polyps was 1.35 +/- 0.6 (range, 1-4). The polypectomy was curative in all of the in situ carcinomata except one. As for complications, 2 colonic perforations (requiring surgery) and 8 hemorrhages appeared, which were controlled via endoscopy. There was no associated mortality. CONCLUSIONS: Endoscopic polypectomy of large polyps (> or =2 cm) is a safe, effective treatment, though it is not free from complications. Complete resection is achieved in a high percentage, and there are few relapses. It should be considered a technique of choice for this type of polyp, except in cases of invasive carcinoma.

Thiopurine methyltransferase activity in a Spanish population sample: decrease of enzymatic activity in multiple sclerosis patients.

The present study was performed in order to obtain the thiopurine methyltransferase (TPMT) activity frequency distribution histogram in a Spanish population. A total of 3640 Spanish clinical laboratory samples were evaluated, which included 1249 patients with Crohn's disease, 589 with ulcerative colitis, 348 with multiple sclerosis (MS), 487 with several autoimmune diseases different from the above-mentioned diseases and 967 a donor group. We have measured the TPMT activity in red blood cells (RBCs) by a radiochemical method, using S-adenosyl-L-[methyl-3H]methionine as methyl donor. The different groups present in their entirety a normal distribution histogram and a wide range of TPMT activity from 0 to 41 U/ml RBCs. The differences found between the Spanish population TPMT activity frequency distribution histogram and the pattern previously described in a North American population were not due to azathioprine treatment or gender. The effect of autoimmune diseases on TPMT activity was evaluated: the enzymatic activity was similar in the donor group (19.9 +/- 6.3 U/ml RBCs) and in the patients with Crohn's disease (20.0 +/- 5.8 U/ml RBCs) and ulcerative colitis (19.7 +/- 6.1 U/ml RBCs); however, it decreased significantly (p<0.0001) in MS patients (17.1 +/- 6.1 U/ml RBCs) with respect to the donor group. In conclusion, our results show that the Spanish population TPMT distribution is closer to that of the Jewish population of Israel than to North American populations, and that in MS the enzymatic activity of TPMT decreases significantly. This observation may take into account the usage of azathioprine as therapeutic agent in Spanish MS patients.

Determination of thiopurine methyltransferase activity in human erythrocytes by high-performance liquid chromatography: comparison with the radiochemical method.

The current article describes a new assay to measure thiopurine methyltransferase (TPMT) activity from red blood cells. This method is based on the measurement of the reaction product 6-methylmercaptopurine (6-MMP) by high-performance liquid chromatography (HPLC). 6-MMP is extracted by ethyl acetate with recoveries of 85%, 80%, 80%, and 92% for 50, 250, 500, and 1,000 ng/100 microL packed red blood cells, respectively. 6-MMP was identified and measured by a Zorbax CN column installed in an HPLC system. The chromatograms were resolved using a mobile phase consisting of 40 mmol/L sodium phosphate buffer (pH 3) and methanol in a gradient from 1% to 20% of methanol. Under these conditions 6-MMP is well resolved from substrates (6-mercaptopurine and S-adenosyl-L-methionine) and endogenous peaks. When the TPMT activity from 20 patients was measured by the HPLC-linked assay and the classic radiochemical method, a linear correlation was obtained between both procedures ( y = 0.99x + 0.33; x-axis, radiochemical assay; y-axis, HPLC-linked assay; r = 0.98). In conclusion, the current report describes a new, reliable, safe, and nonradioactive method to measure TPMT activity that is shorter and simpler than the previously described ones.