Malignancy-associated allelic losses on the X-chromosome in foregut but not in midgut endocrine tumours

Information on genetic changes involved in the progression of gastroenteropancreatic (GEP) endocrine tumours is scanty. On the other hand, the identification of molecular markers of malignancy could be crucial for the prognostic evaluation of these neoplasms, which is hardly predictable on the basis of conventional histological criteria. An association of X-chromosome deletions with malignancy has already been found in gastric endocrine tumours. To investigate this further, a comparative loss of heterozygosity (LOH) analysis was performed on 17 pancreatic endocrine tumours (PETs) and 17 intestinal (ten ileal, six appendiceal, and one rectal) carcinoids from female patients. The relationship of X-chromosome LOH with the ploidy status of the neoplasms was also investigated. LOH was found in six of eight malignant PETs (60% of the informative markers), but was infrequent in the nine benign ones (4.5%). In contrast, although retention of heterozygosity was consistently observed in benign midgut tumours, LOH was infrequent in malignant carcinoids (15%). No correlation was found between LOH and the ploidy status. These results indicate an association between X-chromosome LOH and malignancy in foregut endocrine tumours. The lack of such an association in midgut carcinoids suggests that different molecular mechanisms are involved in the progression of these two categories of endocrine neoplasms, which are otherwise considered to be closely related. These findings emphasize the need for further molecular studies on GEP endocrine tumours, carefully subdivided according to their anatomical site of origin.     

Susceptibility for homeostatic plasticity is down-regulated in parallel with maturation of the rat hippocampal synaptic circuitry

Homeostatic regulation, i.e. the ability of neurons and neuronal networks to adjust their output in response to chronic alterations in electrical activity is a prerequisite for the pronounced functional plasticity in the developing brain. Cellular mechanisms of homeostatic plasticity have mainly been studied in cultured preparations. To understand the developmental time frame and properties of homeostatic plasticity under more physiological conditions, we have here compared the effects of activity deprivation on synaptic transmission in acutely isolated and cultured hippocampal slices at different stages of development. We find that transmission at both glutamatergic and GABAergic synapses is strongly and rapidly (15 h) regulated in the opposite directions in response to inactivity during narrow, separated time windows early in development. Following this critical period of synaptic development, induction of the homeostatic response requires longer periods (40 h) of inactivity. At glutamatergic synapses, activity blockade led to an increase in the amplitude and frequency of mEPSCs, and the threshold for induction of this response was increased during development. In contrast, homeostatic regulation at GABAergic synapses was expressed in a qualitatively distinct manner at different developmental stages. Immature neurons responded rapidly to inactivity by regulating mIPSC frequency, while longer activity blockade led to a decrease in the mIPSC amplitude independent of the neuronal maturation. The susceptibility of immature networks to homeostatic regulation may serve as a safety mechanism against rapid runaway destability during the time of intense remodelling of the synaptic circuitry.     

A novel missense mutation in exon 3 of the COL4A5 gene associated with late-onset Alport syndrome

We have identified a novel missense transition (362G→A) in exon 3 of the COL4A5 gene in a male patient with late-onset Alport syndrome. We used non-isotopic single strand conformation polymorphism, heteroduplex analysis, and automated DNA sequencing. The mutation changes a conserved glycine at codon 54 for an aspartic acid (Gly54Asp), which abolishes a BstNI site. Using restriction analysis, we identified the heterozygous carrier status in the two daughters of the proband. Our findings are in keeping with the hypothesis that slower progressive forms of Alport syndrome are more often associated with missense mutations rather than large deletions or frameshifts. This is the first mutation described in the N-terminus triple helical 7S domain of the COL4A5 gene in an Alport syndrome patient.     

The ultrasonic detection of insulinomas during surgical exploration of the pancreas

The sensitivity of preoperative imaging was evaluated for the localization of insulinomas in 2 series of 54 and 17 patients, respectively. In the first series, diagnosis was obtained with ultrasonography (US) in 14.8%, with computed tomographic (CT) scan in 60%, and with arteriography and/or angio CT scan in 75% of patients. In the second series, US, CT scan, and arteriography were performed preoperatively showing a sensitivity of 53% of one or more of the imaging techniques. The last 17 patients all underwent intraoperative pancreatosonography, and the insulinoma was localized in each. Considering the high reliability of intraoperative ultrasonography, and the high costs and low benefits of other current diagnostic techniques, a new management plan is suggested for patients with a definite laboratory diagnosis of insulinoma.

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Resumen La sensibilidad de la imagenología preoperatoria para la localización de insulinomas fue evaluada en 2 series de 54 y 17 pacientes respectivamente. En la primera serie, el diagnóstico fue logrado con ultrasonografía en 14.8%, con escanografía computadorizada en 60%, y con arteriografía y/o angiografía con escanografía computadorizada en 75% de los casos. En la segunda serie, la ultrasonografía, la escanografía computadorizada, y la arteriografía fueron realizadas preoperatoriamente demostrando una sensibilidad de 53% en una o más de las técnicas de imagenología. En los últimos 17 pacientes se realizó pancreatosonografía, la cual permitió la localización del tumor en 100% de los casos.En consideración a la elevada confiabilidad de la ultrasonografía intraoperatoria, y los altos costos y bajo rendimiento de las técnicas corrientes de diagnóstico, se sugiere un nuevo plan de manejo para pacientes con un diagnóstico de laboratorio certero de insulinoma. Se fundamenta en la localización ultrasonográfica intraoperatoria del tumor, la cual puede ser aplicada en los más comprensivos centras médicos.

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Résumé La sensibilité de l'imagerie pré-opératoire permettant la localisation des insulinomes a été étudiée dans 2 séries de 54 et 17 sujects. Dans la première série le diagnostic fut posé par l'échographie dans 14.8% des cas, par la tomodensitométrie dans 60% des cas, par l'artériographie et/ou l'angiotomodensitométrie dans 75% des cas. Dans la seconde série, l'échographie, la tomodensitométrie et l'artériographie furent pratiquées avant l'intervention avec une sensibilité de 53% pour l'une ou pour plusieurs techniques. Chez les 17 derniers malades l'échographie opératoire fut systématiquement pratiquée et permit la localisation de la tumeur dans 100% des cas.Considérant la haute fiabilité de l'échographie opératoire, le coût élevé et les faibles résultats des autres techniques de diagnostic, un nouveau plan d'investigation est proposé pour explorer les malades qui présentèrent certains signes biologiques d'insulinome. Il repose sur la localisation per-opératoire de la tumeur par l'échographie, méthode qui peut être pratiquée dans des centres spécialisés.

     

Endoscopic internal drainage for the management of leak,fistula, and collection after sleeve gastrectomy: our experience in 617 consecutive patients

BackgroundEndoscopy plays a pivotal role in the management of adverse events (AE) following bariatric surgery. Leaks, fistulae, and post-operative collection after sleeve gastrectomy (SG) may occur in up to 10% of cases.ObjectivesTo evaluate the efficacy and safety of endoscopic internal drainage (EID) for the management of leak, fistula, and collection following SG.SettingRetrospective, observational, single center study on patients referred from several bariatric surgery departments to an endoscopic referral center.MethodsEID was used as first-line treatment for the management of leaks, fistulae, and collections. Leaks and fistulae were treated with double pigtail stent (DPS) deployment in order to guarantee internal drainage and second intention cavity obliteration. Collections were treated with endoscropic ultrasound (EUS)–guided deployment of DPS or lumen apposing metal stents.ResultsA total of 617 patients (83.3% female; mean age, 43.1 yr) were enrolled in the study for leak (n = 300, 48.6%), fistula (n = 285, 46.2%), and collection (n = 32, 5.2%). Median follow-up was 19.5 months. Overall clinical success was 84.7% whereas 15.3% of cases required revisional surgery after EID failure. Clinical success according to type of AE was 89.5%, 78.5%, and 90% for leak, fistula, and collection, respectively. A total of 10 of 547 (1.8%) presented a recurrence during follow-up. A total of 28 (4.5%) AE related to the endoscopic treatment occurred. At univariate logistic regression predictors of failure were: fistula (OR 2.012), combined endoscopic approach (OR 2.319), need for emergency surgery (OR 1.755), and previous endoscopic treatment (OR 4.818).ConclusionEarly EID for the management of leak, fistula, and post-operative collection after SG seems a safe and effective first-line approach with good long-term results.     

Endothelial leukocyte adhesion molecule-1-dependent adhesion of colon carcinoma cells to vascular endothelium is inhibited by an antibody to Lewis fucosylated type I carbohydrate chain.

Endothelial leukocyte adhesion molecule-1 (ELAM-1) has been determined to be the mediator of adhesion of colon carcinoma cells to interleukin-1 (IL-1)-activated endothelial cells. To identify ELAM-1 ligand in colon carcinoma cells, we have screened a series of 11 monoclonal antibodies directed to these cells and found that only one MBr8 was able to inhibit the IL-1-induced increment in adhesion of HT29 and of SW948 colon carcinoma lines to endothelial cells. In contrast, MBr8 did not bind to polymorphonuclear cells, monocytes, and lymphocytes and did not inhibit polymorphonuclear adhesion to IL-1-activated endothelial cells. As expected, an ELAM-1 monoclonal antibody strongly inhibited IL-1 induced increment of adhesion of HT29, SW948, and polymorphonuclear cells. As negative control, MG63 osteosarcoma cells were used. These cells adhere more efficiently to IL-1 activated endothelial cells but MBr8 and ELAM-1 monoclonal antibodies did not affect their adhesion. The effect of MBr8 was also tested in an experimental system in vivo. As described previously, radiolabeled HT29 cell retention in the lung of nude mice was increased in animals given IL-1. MBr8 administration to nude mice or pretreatment of tumor cells with it inhibited this effect. These data suggest that cell adhesion to ELAM-1 might be mediated by different, cell type specific, sugar ligands.     

Neurohumoral control of gallbladder motility in healthy subjects and diabetic patients with or without autonomic neuropathy

Patients affected by diabetes mellitus are reported to have an increased incidence of gallbladder abnormalities. The pathophysiologic mechanisms for this phenomenon are unclear. In the present study ultrasonography was used to determine gallbladder emptying in response to a meal or separate cephalic or hormonal stimulation in 21 diabetic patients and 10 healthy subjects. Gallbladder emptying and refilling after a meal were similar in diabetic patients and healthy subjects. When diabetics were divided according to the presence or absence of cardiac autonomic neuropathy (AN), a significant reduction of gallbladder emptying in response to cephalic stimulation was found in diabetics with AN (P<0.01 in comparison with diabetics without AN or healthy subjects). A dose-response curve of gallbladder emptying in response cerulein, a cholecystokinin analog, at concentrations of 0.25, 1, and 4 g/kg/min was evaluated. No differences of gallbladder emptying were found in the three groups of subjects, indicating that gallbladder sensitivity to hormonal stimulation is not changed in diabetic patients with or without AN. Diabetic patients with AN have a significant reduction of gastric acid output and pancreatic polypeptide (PP) secretion in response to cephalic stimulation (P<0.05 in comparison with diabetic patients without AN or healthy subjects). Cerulein-induced PP secretion was similar in all three groups of subjects (P>0.05). This study indicates that in diabetic patients with AN, gallbladder emptying as well as gastric acid and PP secretions induced by neural stimulation are markedly reduced in comparison to diabetics without AN.