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Biomedical subjects

E P Passaro

Publications and source records attributed to E P Passaro.

At least 19 recordsLinked to original sources
PubMed1996

A 1.5-megabase physical map encompassing the multiple endocrine neoplasia type-1 (MEN1) locus on chromosome 11q13.

Linkage analysis and loss of heterozygosity studies have shown that the gene responsible for the multiple endocrine neoplasia type-1 (MEN1) syndrome localizes to a small interval between D11S427 and D11S460 on chromosome 11q13. As an initial step to clone this tumor suppressor gene, our group is the first to map the MEN1 region physically using yeast artificial chromosome, bacterial artificial chromosome (BAC), and cosmid contigs. The 1.5-Mb high-resolution, contiguous map extends from PYGM to 300 kb telomeric of D11S460. Of this, the 1.2-Mb interval between PYGM and D11S460 is isolated in cosmids and BACs and will be useful for the development of genomic sequences and transcription maps of this important region. Nine new sequence-tagged sites (STS) are also characterized from this region. The physical map and the STSs will be valuable tools for the cloning of the MEN1 gene.

Chromosome Mapping↗
PubMed1996

Prefabrication of a neo-endocrine organ: a rat model.

Previous work in the field of flap prefabrication has demonstrated that many tissues, including skin, bone, cartilage, muscle, and composite tissue, can be neovascularized with a carrier flap and transplanted to a distant site using microvascular technique. We have recently shown in a rat model that islets of Langerhans survive in large numbers when transplanted into a groin-based fasciovascular pedicled (FVP) flap. In the current study, we examined whether sufficient islet tissue can be transferred using microvascular free transfer of islet-containing flaps to reverse experimental diabetes. In the first phase of the experiment, islets from two Lewis rat donors were transplanted into the FVP flap of an isogeneic diabetic animal. Within 5 days, reversal of diabetes was noted in 4/4 experimental animals and in 0/4 control animals. In the second phase of the experiment, islet-FVP flaps were created in nondiabetic "carrier" animals. After 2 weeks the islet-containing flaps were harvested and transplanted to recipient diabetic Lewis rats using microvascular free transfer technique. Reversal of diabetes was noted within 10 days of free-flap transplant, and the diabetic state returned following removal of the flaps. Although preliminary, these results demonstrate that fasciovascular flaps can act as vehicles for the creation and transplantation of a functional neo-endocrine pancreas.

Animals↗
PubMed1994

Human islet isolation in 104 consecutive cases. Factors affecting isolation success.

One of the major steps toward successful islet transplantation for the treatment of type diabetes is to obtain islets of sufficient number and viability. Using a standardized method of isolating islets, the goal of this study was to analyze the factors influencing the outcome of islet isolation. A total of 104 cadaveric human pancreata were processed for islets by the same team. Data from the islet-processing charts were reviewed retrospectively. The two endpoints were the recovery of islets, viable after 2 days of culture (group V = viable, group NV = nonviable) and the islet yield. Viable islets were recovered in 61% of cases (n = 63). Minimal blood glucose recorded during hospitalization was very significantly lower in group V (124 +/- 5 vs. 148 +/- 9, P = 0.01). Lack of significant medical history in the donor was associated with better viability as compared with various donor predispositions (chi-2 4.21, P = 0.04). Cold ischemia time (8.1 +/- 0.5 hr in group V vs. 9.8 +/- 0.9 hr in group NV, P = 0.07) and collagenase lot (5 lots tested, chi-2 13.1, P = 0.01) also affected the recovery of viable islets. Hospital time was shorter in group V (65.3 +/- 6.8 vs. 80.9 +/- 17.9 hr, P = 0.35). Multivariate logistic regression analyses of viable islet recovery identified minimal blood glucose (P = 0.03) and collagenase lot (P = 0.06) as the most significant risk factors. However, the best multivariate predictive model--which includes blood glucose, collagenase lot, donor age and surgical procurement team--correctly predicted 66.2% of cases only. Multivariate analysis of final islet yield designed hospitalization length, cardiorespiratory arrest, surgical procurement team, and collagenase lot as the best predictors. These data obtained in a large series of pancreata emphasized several donor and technical factors that should target the attention of islet transplant researchers in order to improve islet yield and viability.

Adolescent↗
PubMed1994

Successful engraftment of autologous and allogeneic islets into the porcine thymus.

Work in rodents has shown that injection of pancreatic islets of Langerhans into the thymus can induce donor-specific unresponsiveness to islets subsequently transplanted to extrathymic sites. The overall objective of our investigation is to test this in a large animal (pig) model. In the current study we examined whether autologous and allogeneic adult or fetal islets survive in the porcine thymus. Collagenase-digested adult and fetal porcine islets were injected into the thymic lobes of 5- to 13-month-old, normal pigs. Pigs receiving allografts were given either a standard triple regimen of oral cyclosporine, azathioprine, and prednisone or intravenous anti-lymphocyte globulin (ALG) for immunosuppression. Two pigs of each group that received an allograft or autograft were given no immunosuppression. Biopsies of the grafts were taken at 4, 6, or 12 weeks for examination. Islet survival was assessed by histology with hematoxylin and eosin and insulin staining and by measurement of tissue insulin content using acid alcohol extraction and radioimmunoassay. The insulin content of control thymus was found to be 0.71 +/- 0.29 microU/mg (n = 5). The insulin content of the islet-grafted thymic tissues ranged from 1.57 to 10.65 microU/mg. Since the amounts of injected islets were not equal and not distributed evenly, and only a part of the graft site was used for determination of tissue insulin, thymic insulin contents higher than 1.4 microU/mg (twice that of the control value) were considered to demonstrate the presence of viable islets. With this criterion, we concluded that islets were found to be viable in seven of nine pigs and two pigs which were treated with ALG were shown to be marginally positive. On histological examination, islets were found in the thymus as well as under the thymic capsule, except for the above two pigs. These results demonstrate that the pig thymus supports fetal and adult islet transplants.

Animals↗
PubMed1993

Heterogeneous distribution of gastric mucosal blood flow with restraint stress in the rat.

Cold water immersion restraint (CWIR) is associated with gastric hypercontractility and gastric corpus erosions in the rat. Because the gastric blood flow response to CWIR has not been well defined, we performed the following study. Rats were implanted with force transducers, subjected to CWIR for 2 hr, and then blood flow was determined by the iodo[14C]antipyrine autoradiographic (IAP) technique. When compared to control animals, the CWIR-treated animals displayed foci of gastric corpus hyperemia with a marked and significant increase in blood flow in all layers of the gastric corpus. There was approximately a 100% increase in the mucosa and a 50% increase in the muscularis externa. The hyperemia was not uniform, but rather alternated every 2.1 +/- 0.2 mm with regions of low blood flow. Blood flow in the antrum and duodenum was unaffected by CWIR. We conclude that CWIR is associated with alternating regions of high and low blood flow only in the gastric corpus. Reduction of corpus mucosal blood flow might be due to the powerful gastric contractions associated with CWIR.

Animals↗
PubMed1992

Spectrum of injury produced in the duodenum by perfusion with luminal acid in the rat.

The dose and time dependence of duodenal mucosal injury by luminal acid perfusion was studied. Saline, 0.01, 0.05, 0.15, and 0.3N HCl, were perfused through the proximal duodena of rats for 5, 15, or 30 minutes and then harvested for histological examination. In a second set of studies, after a 30-minute perfusion, duodena were harvested either immediately or 2, 4, 8, or 24 hours after the perfusion to study the recovery from injury. Acid disappearance (acid delivered minus acid recovered) was measured in all groups. Duodena were examined grossly, then fixed, stained, and scored histologically. Whereas no gross mucosal injury was noted, there was graded histological injury proportional to acid concentration. Injury occurred early in the perfusion and changed little with increased perfusion durations. The initial injury lead to an acid disappearance rate that was proportional to acid concentration and, therefore, the degree of injury. After the initial injury occurred, the rate of acid neutralization was unchanged by increased duration of acid perfusion. This acid neutralization protected against further injury despite the continued presence of acid. Recovery from injury was complete with physiological (0.01 and 0.05N HCl) but not pharmacological (0.15 and 0.3N HCl) concentrations of acid. It is concluded that acid-induced duodenal injury occurs within 5 minutes of exposure, is proportional to the acid concentration, and results in acid neutralization that protects against extension of the injury with continued acid exposure.

Animals↗
PubMed1991

Elevated intracranial pressure stimulates gastric contractility in the rat.

The gastric contractile response to elevated intracranial pressure (ICP) was studied in conscious rats. Elevation of intracranial pressure to 20 mm Hg was associated with a marked increase in the amplitude of gastric contractions (70-90% over baseline) without any change in contractile frequency (5.2 +/- .5 contractions per min). The increase in contractility continued for 45 min following release of the pressure. Vagotomy completely blocked the increase in gastric contractility seen with elevation in ICP. We conclude that acute elevation of intracranial pressure in rats results in increased force of gastric contractions. The forceful contractions persist despite release of the pressure and the increased contractile force is vagally mediated.

Animals↗
PubMed1991

Resuscitation. Revival should be the first priority.

During resuscitation, it is important to distinguish between those maneuvers directed at patient revival and those directed at examination and measurement. Revival should always be the top priority. The steps for revival are easily remembered as ABCDEF: Airway, Breathing, Circulation, Decompression, Elimination, and Fluids. Once these steps have been completed, vital functions can be assessed and measurements to aid in diagnosis can be taken.

Blood Circulation↗
PubMed1991

Strong gastric contractions cause mucosal ischemia.

Contractions of a segment of bowel result in alterations of its blood flow. However, the precise temporal and spacial relationships between contractions and mucosal blood flow are unknown. Rats were fitted with strain gauge force transducers and implanted with silver wire electrodes into the muscularis externa of the stomach. In vivo microscopic observation of motility and of the gastric mucosal blood flow was performed during electrical field-stimulated contractions. Contractions originated in the midcorpus, were 0.237 +/- 0.018 cm wide, traveled along the corpus at 0.133 +/- 0.024 cm/s, and had a duration of 5.9 +/- 0.1 s. Antral contractions were 0.174 +/- 0.032 cm wide, traveled at 0.070 +/- 0.009 cm/s, and had a duration of 5.6 +/- 0.7 s. During the contraction, capillary flow velocity in the corpus decreased from a basal value of 410 +/- 105 to 206 +/- 104 microns/s at the peak of a contraction. Five seconds after the contraction was released hyperemia was observed with the flow velocity increasing to 570 +/- 102 microns/s. In the antrum, flow stopped completely during the contraction irrespective of the initial flow velocity and no hyperemia occurred with release of the contraction; rather, flow velocity slowly returned to baseline values. In both regions the flow reductions were in phase with the contractions as measured by the force transducers. These studies provide direct evidence that strong gastric contractions can effectively reduce or stop gastric mucosal blood flow.

Animals↗
PubMed1990

Postoperative ileus.

Postoperative ileus follows any operation. Although worsened if the peritoneum is entered, the length and duration of surgery does not influence the severity of postoperative ileus. Inhibitory alpha 2-adrenergic reflexes with peptidergic afferents contribute to postoperative ileus. Clinically, treatment of ileus centers around symptomatic relief with nasogastric suction. Trials of adrenergic blockade combined with cholinergic stimulation have met with limited success. Prokinetic drugs have not been proved effective in the treatment of this disorder. Two types of ileus exist: postoperative and paralytic. Postoperative ileus resolves spontaneously after two to three days, and probably reflects inhibition of colonic motility. Paralytic ileus is more severe, last more than three days, and seems to represent inhibition of small bowel activity. No discrete structural changes cause postoperative ileus and the role of peptidergic neuronal systems of the enteric nervous system has not been elucidated. Possible central or humoral mechanisms have not been studied extensively. The possible direct inhibition of enteric or spinal nerves by anesthetic agents not cleared from these tissues remains to be studied. Also in need of study is the potential alteration of neurotransmitter receptor activity within the enteric nervous plexus after manipulation of the bowel.

Gastrointestinal Motility↗
PubMed1989

Vasoactive intestinal polypeptide receptor binding sites in the human gastrointestinal tract: localization by autoradiography.

Vasoactive intestinal polypeptide (VIP) is a putative neurotransmitter in both the brain and peripheral tissues. To define possible target tissues of VIP we have used quantitative receptor autoradiography to localize and quantify the distribution of [125I]VIP receptor binding sites in histologically normal human surgical specimens. While the distribution of VIP binding sites was different for each gastrointestinal segment examined, specific vasoactive intestinal polypeptide binding sites were localized to the mucosa, the muscularis mucosa, the smooth muscle of submucosal arterioles, the circular and longitudinal smooth muscle of the muscularis externa, the myenteric plexus, and lymph nodules. In most segments, the mucosal layer expressed the highest concentration of VIP binding sites, with the duodenal and jejunal mucosa showing the highest density of receptors. These results identify putative VIP target tissues in the human gastrointestinal tract. In correlation with physiological data, VIP binding sites appear to be involved in the regulation of a variety of gastrointestinal functions including mucosal ion transport, gastric secretion, hemodynamic regulation, gastric and intestinal motility, neuronal excitability, and modulation of the immune system.

Digestive System↗
PubMed1988

Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease.

Several lines of evidence indicate that tachykinin neuropeptides [substance P (SP), substance K (SK), and neuromedin K (NK)] play a role in regulating the inflammatory and immune responses. To test this hypothesis in a human inflammatory disease, quantitative receptor autoradiography was used to examine possible abnormalities in tachykinin binding sites in surgical specimens from patients with inflammatory bowel disease. Surgical specimens of colon were obtained from patients with ulcerative colitis (n = 4) and Crohn disease (n = 4). Normal tissue was obtained from uninvolved areas of extensive resections for carcinoma (n = 6). In all cases, specimens were obtained less than 5 min after removal to minimize influences associated with degradation artifacts and were processed for quantitative receptor autoradiography by using 125I-labeled Bolton-Hunter conjugates of NK, SK, and SP. In the normal colon a low concentration of SP receptor binding sites is expressed by submucosal arterioles and venules and a moderate concentration is expressed by the external circular muscle, whereas SK receptor binding sites are expressed in low concentrations by the external circular and longitudinal muscle. In contrast, specific NK binding sites were not observed in any area of the human colon. In colon tissue obtained from ulcerative colitis and Crohn disease patients, however, very high concentrations of SP receptor binding sites are expressed by arterioles and venules located in the submucosa, muscularis mucosa, external circular muscle, external longitudinal muscle, and serosa. In addition, very high concentrations of SP receptor binding sites are expressed within the germinal center of lymph nodules, whereas the concentrations of SP and SK binding sites expressed by the external muscle layers are not altered significantly. These results demonstrate that receptor binding sites for SP, but not SK or NK, are ectopically expressed in high concentrations (1000-2000 times normal) by cells involved in mediating inflammatory and immune responses. These data suggest that SP may be involved in the pathophysiology of inflammatory bowel disease and might provide some insight into the interaction between the nervous system and the regulation of inflammation and the immune response in human inflammatory disease.

Autoradiography↗
PubMed1986

Technetium 99m-DTPA microcapsules: a new preparation for gastric emptying studies.

Technetium 99m-DTPA microcapsules have been developed to measure gastric emptying. Such capsules not only provide high labeling efficiency in vitro, but demonstrate limited dissociation in vivo, resulting in decreased error during measurement. In normal control subjects, the half-life ranged from 40 to 80 minutes under the aforementioned conditions.

Adult↗
PubMed1983

Pathological acid secretion not due to gastrinoma.

There are few detailed studies of patients with pathological hypergastrinaemia of antral origin. We have identified four patients with severe acid hypersecretion associated with peptic ulcer disease and in whom no evidence for gastrinoma or isolated retained antrum could be found. Three of these patients also had hypergastrinaemia. In two patients, one with gastric ulcers and one with duodenal ulcer disease, the hypergastrinaemia appeared to be due to antral gastrin cell hyperfunction and there was also evidence for mild antral gastrin cell hyperplasia. In the other hypergastrinaemic patient, a primary intestinal gastrin cell hyperfunction syndrome was suspected, but a hidden gastrinoma could not be excluded. The remaining patient had nearly fatal hypersecretory ulcer disease and cimetidine failed to control the hypersecretory state. In this patient the hypersecretion responded to a more potent H2 antagonist with resolution of a metabolic encephalopathy. No general pathophysiological mechanism could be identified in these patients or in larger groups of patients with gastric or duodenal ulcer disease.

Adult↗
PubMed1982

Evidence for vagus-dependent pancreatic polypeptide-releasing factor in the antrum: studies with the autotransplanted dog pancreas.

Pancreatic polypeptide (PP) response to food is suppressed by truncal vagotomy, antral vagotomy, and antrectomy. The inhibitory effect of antral vagotomy and of antrectomy may be due to inadvertent vagal denervation of the pancreas, disruption of antropyloric neural reflexes, or inhibition of release of a PP-releasing factor from the antrum. In this study we examined the latter hypothesis by achieving total extrinsic pancreatic denervation by orthotopic autotransplantation of the entire pancreas in four dogs. Total extrinsic pancreatic denervation, which abolished the pancreatic juice protein response to insulin, did not significantly alter plasma PP response to a meal (peak 30-minute PP of 696 +/- 192 pg/ml before transplantation versus 961 +/- 80 pg/ml after transplantation). Therefore, postprandial release of PP is, to a large extent, not mediated either by direct vagal innervation of the pancreas or by neural communications between the pancreas and antrum or the pancreas and the small intestine. In two of the dogs with pancreatic transplants, subsequent antral vagotomy resulted in greater than 80% inhibition of postprandial PP response. These findings are consistent with the hypothesis that a PP-releasing factor is present in the antrum and that the release of this factor is dependent on intact antral vagal innervation.

Animals↗