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Biomedical subjects

M J Zinner

Publications and source records attributed to M J Zinner.

At least 19 recordsLinked to original sources
PubMed1996

Amiloride inhibits meal-stimulated colonic absorption.

Meal-stimulated colonic absorption has recently been described, but the cellular transport mechanisms mediating this response are unknown. The purpose of this study was to determine the contribution of Na+ transport pathways to colonic proabsorption. Distal colonic Thiry-Vella loops were constructed in six dogs. Absorption was measured by infusing the loops with a physiological electrolyte solution containing [14C] polyethylene glycol as the impermeant marker. In the first set of experiments, the dose dependence of amiloride-induced inhibition of basal colonic absorption was determined. In the second set of experiments the effect of amiloride, which inhibits both Na+ channels and Na+/H+ exchange in colonocytes, on meal-stimulated colonic absorption was determined. Luminal amiloride inhibited basal colonic absorption in a dose-dependent manner, with significant reductions in Na+ absorption occurring with concentrations of 10(-2)M and higher. Infusion with 10(-3)M amiloride, a concentration that did not alter basal absorption, resulted in significant reductions in postprandial water, Na+, and Cl- absorption. These results suggest that meal-stimulated colonic absorption is mediated, at last in part, by transcellular Na+ absorptive pathways.

Amiloride↗
PubMed1996

Enterocyte functional adaptation following intestinal resection.

Following massive small bowel resection, the remaining intestine undergoes compensatory adaptation to maintain absorptive capacity. The purpose of this study was to determine the relative importance of mucosal hyperplasia and functional adaptation by individual enterocytes in this process. Distal ileum was harvested from rats 2 weeks following 70% small bowel resection or transection with reanastomosis. Transport parameters were determined in Ussing chambers. Short-circuit current (Isc) responses to additions of 3-0-methylglucose were measured to assess Na+/glucose cotransporter kinetics. Microvillus absorptive surface areas were calculated with computer-assisted morphometric modeling. These surface area values were used to normalize transport parameters. Ileal absorptive surface area was 70% greater in resection tissues than in transection tissues (P < 0.05). Na+ and Cl- fluxes were generally lower in the resection group. Na+/glucose cotransporter delta Isc max (an index of cotransporter quantity) for resection and transection tissues were 0.3 +/- 0.1 and 1.8 +/- 0.3, respectively (P < 0.05). Km (an index of cotransporter affinity for substrate) did not differ significantly. Following intestinal resection, ileal surface area increases; however, transport parameters, when normalized to absorptive surface area values, diminish. During early postresection adaptation, expansion of ileal absorptive surface area due to hyperplasia seems to play a greater role than upregulation of enterocyte Na+, Cl- , and glucose absorption.

Adaptation, Physiological↗
PubMed1996

The role of neoadjuvant therapy in surgically resectable esophageal cancer.

OBJECTIVE: To determine the effect of neoadjuvant therapy (NT) (preoperative chemotherapy, radiation therapy, or both) in surgically resectable esophageal cancer. DESIGN: A retrospective review over a 20-year period. SETTING: A tertiary academic medical center. PARTICIPANTS: All patients undergoing surgical resection for esophageal cancer (N = 316) over this time period. MAIN OUTCOME MEASURES: Perioperative morbidity and mortality, local and distant recurrences, and overall survival. RESULTS: Patients undergoing NT (n = 106) had prognostic factors similar to those treated with surgery alone (n = 210). No increase was noted in surgical morbidity with NT (anastomotic leaks, reoperation rates, complications, or extended hospital stays). Overall survival was not improved by NT (median survival, 14 months) except in the subset of patients (11/83) who responded completely (100% histological necrosis) to preoperative chemotherapy (median survival, 79.2 months; P < .02). Complete response to radiation therapy alone was not associated with improved survival. Partial necrosis of the primary tumor was seen in 13 (15%) of 83 patients but conferred no survival advantage. Complete response to preoperative chemotherapy was associated with squamous cell pathological features and excellent performance status as measured by preanesthesia evaluation. CONCLUSIONS: The addition of NT did not increase perioperative morbidity or mortality. Only the subset of patients who had a complete response to preoperative chemotherapy showed a survival advantage. Excellent performance status and squamous cell pathological features were associated with an increased chance of complete pathological response following preoperative chemotherapy.

Adult↗
PubMed1996

Cholecystokinin mediation of colonic absorption via peptide YY: foregut-hindgut axis.

Peptide YY (PYY), a 36-amino-acid polypeptide, is found in abundance in the colon, a region where its physiologic roles are unknown. Previous studies have revealed a substantial increase in plasma PYY after cholecystokinin (CCK) administration. PYY is released from the hindgut in response to a meal and inhibits CCK release. In this study we evaluated the effects of CCK and PYY on intestinal absorption of water and electrolytes. Colonic, ileal, or jejunal Thiry-Vella fistulas (TVFs) were created in 12 dogs, and intestinal continuity was reestablished. The TVFs were perfused with an isotonic buffer solution containing [14C] PEG as a volume marker. Electrolyte and water transport were measured every 15 minutes, and plasma PYY and CCK levels were measured by radioimmunoassay. Group 1 dogs received an intravenous bolus of MK329, a specific CCK receptor antagonist, at 20 nmol/kg after a standard mixed meal; group 2 colonic TVF dogs received a meal and an intravenous bolus of PYY polyclonal antibody at 1 mg/kg. Postprandially, all three regions of the bowel became significantly proabsorptive for water, sodium, and chloride. In the colon postprandial absorption was abolished by MK329 starting 60 minutes after a meal, whereas specific CCK receptor blockade blunted ileal absorption. CCK receptor blockade did not affect postprandial absorption in the jejunum. Postprandial PYY levels did not rise in MK329-treated animals. PYY antibody reduced colonic absorption during the postprandial phase. Reduction of meal-induced colonic absorption and PYY release by MK329 in awake dogs suggests an important foregut-hindgut hormonal feedback loop. Foregut-derived CCK stimulates hindgut PYY release, which in turn stimulates colonic absorption while inhibiting further CCK release.

Animals↗
PubMed1996

Endotoxin inhibitor prevents sepsis-induced alterations in intestinal ion transport.

BACKGROUND: The intestine is a target of septic insult. The aims of this study were to characterize sepsis-induced alterations in intestinal ion transport and to determine the role endotoxin plays in mediating these changes. METHODS: Rats underwent cecal manipulation alone (control), cecal ligation and puncture (CLP), or CLP plus intraperitoneal injection of 0.2 mg of a recently synthesized endotoxin inhibitor. At 24 hours, distal ileum was harvested, and transport parameters were determined. RESULTS: Cecal ligation and puncture produced a significant increase in short-circuit current (Isc) that was attributable to the induction of chloride secretion. There were no alterations in transepithelial resistance or fluxes of mannitol and sodium. The sepsis-induced increase in Isc was prevented by administration of the endotoxin inhibitor. CONCLUSIONS: In this model of sepsis, the primary alteration in ileal ion transport is an induction of electrogenic chloride secretion. Endotoxin inhibition may represent a strategy for prophylaxis against the intestinal effects of sepsis.

Animals↗
PubMed1996

Perioperative blood transfusions and decreased long-term survival in esophageal cancer.

We evaluated retrospectively the effect of perioperative blood transfusions on survival in esophageal cancer. The records of all patients who underwent esophageal resection (n = 316) at UCLA Medical Center from 1970 to 1993 were reviewed. Statistical analysis included univariate (log-rank chi 2) and multivariate (Cox proportional hazards) analyses with other known risk factors. High-volume blood transfusions (> 8 units) but not low-volume blood transfusions (1 to 8 units) were associated with a significant decrease in long-term survival (median survival: no transfusion, 22 months; low-volume blood transfusion, 14.5 months, versus high-volume blood transfusions, 6.5 months; p < 0.01). Multivariate analysis revealed that the shorter survival with high-volume blood transfusions was a result of an increased number of postoperative complications. High-volume blood transfusions were not associated with increases in tumor recurrence or infectious complications. The association between shorter survival and high-volume blood transfusions in esophageal cancer may, therefore, be because of the circumstances necessitating transfusion rather than any immunosuppressive effects of the transfused blood. These findings suggest that the transfusion of blood does not by itself decrease the chance of cure after esophageal resection.

Adenocarcinoma↗
PubMed1996

Nitric oxide regulates endothelium-dependent vasodilator responses in rabbit hindquarters vascular bed in vivo.

The objective of this study was to determine whether nitric oxide (NO) could function as a negative feedback modulator of endothelium-dependent vasodilation in vivo. To this end, the influence of exogenous NO on vasodilator responses in the rabbit hindquarters vascular bed was determined. Previous in vitro studies have demonstrated that NO inhibits both neuronal NO synthase from rat cerebellum as well as NO synthase derived from bovine aortic endothelial cells. The present study was conducted in the rabbit hindquarters vascular bed under conditions of constant blood flow so that changes in pressure directly reflected changes in vascular resistance. Under these in vivo conditions, the NO donor agent S-nitroso-N-acetylpenicillamine (SNAP) reversibly attenuated responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin. In contrast, SNAP did not influence the endothelium-independent vasodilator response to SNAP itself or to 8-bromoguanosine 3',5'-cyclic monophosphate. These observations indicate clearly that NO interferes with endothelium-dependent vasodilator action and support the view that endogenous NO may actually play a physiological role in regulating vascular tone.

Acetylcholine↗
PubMed1996

Neuronal pathways involved in abdominal surgery-induced gastric ileus in rats.

The 20-min rate of gastric emptying of a noncaloric solution and c-fos expression detected by immunohistochemistry in the brain were monitored 3 h after abdominal surgery performed under 10-min enflurane anesthesia in rats. Abdominal surgery (laparotomy and 1-min manipulation of the cecum) decreased gastric emptying from 60.8 +/- 3.4 to 25.9 +/- 3.4%. Capsaicin applied to the celiac/superior mesenteric ganglia 2 wk before the experiment reduced the delay in gastric emptying induced by abdominal surgery (46.3 +/- 3.4%), whereas perivagal capsaicin application had no effect (23.6 +/- 7.9%). The corticotropin-releasing factor (CRF) antagonist [D-Phe12, Nle21,38,C alpha MeLeu37]CRF-(12--41) injected intracisternally (10-20 micrograms) prevented postoperative gastroparesis induced by surgery, while having no effect on basal gastric emptying. Abdominal surgery increased the number of Fos-positive cells in brain nuclei regulating autonomic outflow: the nucleus of the solitary tract, locus ceruleus, paraventricular nucleus, and supraoptic nucleus of the hypothalamus. These data indicate that capsaicin-sensitive splanchnic afferent fibers and activation of CRF receptors in the brain are part of the neuronal circuitry mediating gastric stasis 3 h after abdominal surgery.

Abdomen↗
PubMed1996

Peptide YY: a potential proabsorptive hormone for the treatment of malabsorptive disorders.

Peptide YY (PYY) is a 36 amino acid peptide that is released from the endocrine cells of the distal ileum, colon, and rectum following a meal. PYY is strongly proabsorptive in the small intestine. We studied the effects of intravenous PYY on colonic water and electrolyte transport in awake dogs. Dogs had 20 cm neurovascularly intact colon Thiry-Vella fistulas (TVS) surgically constructed. Colonic transport was studied in three experimental groups. Group 1 animals received a standard mixed meal. Group 2 animals were unfed and received intravenous PYY and 100 pmol/kg/hr for two hours. This dose of PYY has previously been shown to simulate the plasma levels of PYY normally seen after a meal. Group 3 received intravenous PYY at the same dose in addition to a mixed meal. Our study shows an increase in colonic water, Na+, and Cl- absorption after a meal (P < 0.05). Infusion of PYY at a 100 pmol/kg/hr was significantly proabsorptive beginning at 60 minutes (P < 0.01). Infusion of PYY in addition to a meal further increased absorption (P < 0.05). PYY is a potent proabsorptive agent in the colon of the conscious dog. PYY, or its analogs, may be useful clinical agents in intestinal malabsorptive disorders or after bowel resection.

Animals↗
PubMed1995

Pancreatic peptide YY mRNA levels increase during adaptation after small intestinal resection.

Peptide YY (PYY) is a 36-amino-acid peptide known to inhibit pancreatic and gastrointestinal secretion. Immediately following small bowel resection, intestinal PYY mRNA and plasma PYY levels rise. The purpose of this study was to determine whether PYY expression changes in the pancreas during the adaptive period after extensive small bowel resection. Female Sprague-Dawley rats (250 g) underwent 70% small intestinal resection or transection alone as control. Animals were sacrificed at 6 hr, 24 hr, 1 week, or 2 weeks following operation (N = 5/time group). Pancreatic tissue was harvested and RNA was isolated by the guanididium-thiocyanate method. PYY mRNA was analyzed by reverse transcriptase PCR, standardized to glyceraldehyde-3-phosphate dehydrogenase, and semiquantitated by Southern blotting and 32P cpm. Ribonuclease protection assay was used to confirm PCR results. PYY mRNA expression was increased 9 1/2-fold beginning 6 hr after resection compared to transection (P < 0.05). PYY mRNA levels remain elevated, 2 1/4-fold greater than control after 2 weeks (P < 0.05) as analyzed by reverse transcriptase PCR and ribonuclease protection assay. Quantitation by ribonuclease protection assay reveals a gradual elevation of PYY mRNA levels in transected animals compared to a nonoperated rat starting at 1 and 2 weeks. Pancreatic PYY mRNA levels increase rapidly after extensive intestinal resection and remain elevated 2 weeks postoperatively. These results confirm for the first time that the increase in PYY seen after extensive intestinal resection also occurs in extraintestinal sites. In the pancreas, elevated PYY levels may inhibit exocrine secretion, reducing luminal volume, and thereby facilitating intestinal adaptation.

Adaptation, Physiological↗
PubMed1995

Amino acids mediate postprandial jejunal proabsorption.

Ingestion of a meal stimulates small intestinal ion and water transport. Current evidence suggests that this response, termed proabsorption, is primarily mediated by the apical Na+/glucose cotransporter. Like glucose, the majority of amino acid absorption occurs by Na(+)-dependent, secondary active transport. The purpose of this study was to determine the role of amino acid transport in meal-induced jejunal ion and water absorption in vivo. Exteriorized, neurovascularly intact jejunal loops measuring 25 cm were created in six female mongrel dogs, and the dogs were allowed to recover for 2 weeks. After an overnight fast, the loops were perfused with a standard buffer containing 10 mM aspartate, leucine, glycine, or lysine. Net water and electrolyte absorption before and after a mixed meal was calculated using [14C]polyethylene glycol as a volume marker. Aspartic acid, leucine, glycine, and lysine are each transported by a separate transporter system. Except for lysine, each amino acid significantly (P < 0.05) potentiated sodium and water absorption after a meal. In addition, this effect was at least as great as that seen with 10 mM glucose. These results demonstrate that amino acid transporter, like the Na+/glucose cotransporter, mediates meal-induced jejunal sodium and water absorption and may be as important in the proabsorptive response.

Amino Acids↗
PubMed1995

A novel synthetic analog of peptide YY, BIM-43004, given intraluminally, is proabsorptive.

Peptide YY (PYY), a proabsorptive hormone, is released into the circulation and lumen of the small intestine after a meal. We have recently found that intraluminal PYY is proabsorptive in the ileum. The purpose of this study was to examine the effects of intraluminal administration of a new substituted PYY (22-36) analog on intestinal absorption of electrolytes and water. Twelve conditioned 20-kg dogs had 25-cm jejunal, 25-cm ileal, or 20-cm colonic Thiry-Vella fistulas (TVF) surgically constructed under general anesthesia (jejunal and ileal TVF, N = 6, and colonic TVF, N = 6). After a 2-week recovery period, the animals received the intraluminal PYY analog, BIM-43004, in the ileum (200 pmole/kg) or colon (300 pmole/kg) for 60 min after a 90-min steady-state basal period was confirmed. The TVF were perfused with an isotonic buffer solution containing [14C]polyethylene glycol as a volume marker. Ion and water transport were measured every 15 min. Net water absorptions were significant in the ileum and colon but not in the jejunum upon intraluminal administration of the PYY analog, BIM-43004. Colonic water absorptions were increased more than twofold above basal absorption rates and ileal absorptions were increased more than 1.5-fold upon addition of intraluminal BIM-43004. Sodium and chloride ion absorption in the colon and ileum paralleled water fluxes. We are describing for the first time a synthetic peptide analog of PYY that produces significant water and electrolyte absorption in the ileum and colon when administered luminally. This synthetic analog may have therapeutic potential in patients with malabsorptive disorders.

Animals↗
PubMed1995

Na+/H+ exchange mediates postprandial ileal water and electrolyte transport.

Feeding stimulates fluid and electrolyte absorption in the small intestine. Previous studies have suggested that Na+/glucose cotransport is important in initiating this response in the jejunum. The purpose of this study was to determine whether Na+/H+ exchange plays a role in meal-induced absorption. Exteriorized, neurovascularly intact jejunal and ileal loops (25 cm) were constructed in dogs. Following a two-week period of postoperative recovery, the loops of awake dogs were perfused with standard buffer alone or with increasing concentrations of amiloride, a Na+/H+ exchange inhibitor. Water, sodium, and chloride fluxes were calculated following a meal using [14C]PEG as a volume marker. The meal significantly increased absorption in both the jejunum (P < 0.001) and ileum (P < 0.01) in those animals perfused with buffer alone. More significantly, amiloride suppressed the increased absorption seen following a meal in the ileum (P < 0.001) but not the jejunum. The response in the ileum was dose dependent. These findings suggest that a major mediator of postprandial sodium and water absorption in the ileum is the Na+/H+ exchanger.

Amiloride↗
PubMed1995

Changes in the surgical management of esophageal cancer from 1970 to 1993.

PURPOSE: To evaluate the changes since 1970 in the management and outcome of esophageal resection for cancer. METHODS: The records of all 316 patients who underwent esophageal resection for cancer at University of California Los Angeles Medical Center during the years 1970 to 1993 were reviewed. RESULTS: When records from 1984 to 1993 were compared to those from 1970 to 1983, significant decreases were seen in operative mortality (10% to 3%, P < 0.01), morbidity (72% to 60%, P < 0.05), anastomotic leaks (12% to 5%, P < 0.03), and reoperations (20% to 8%, P < 0.003). Time spent in hospital and in intensive care decreased 40%. These improvements in short-term outcome were most evident in patients with disease in later stages. The 5-year survival rate increased (12% to 21%, P < 0.01). A greater percentage of tumors presented in early stages (21% versus 37%). CONCLUSIONS: Short-term outcome of surgical resection for esophageal carcinoma improved between 1970 and 1993, in part because of changes in perioperative and surgical management. Long-term survival improved, probably due to earlier detection of tumors.

Adenocarcinoma↗
PubMed1995

Solid and papillary neoplasms of the pancreas.

Solid and papillary neoplasms of the pancreas are rare, low-grade malignant tumors histologically distinct from usual ductal adenocarcinomas and islet cell tumors and amendable to cure by surgical excision. Because these lesions have been incorrectly diagnosed in the past as adenocarcinomas or cystadenocarcinomas, they may have contributed to reports with confusing survival statistics following resections for malignant neoplasms of the pancreas. In young women with large, relatively asymptomatic tumors of the pancreas, solid and papillary neoplasms should be high on the list of the differential diagnoses.

Adenocarcinoma↗
PubMed1995

Early regional expression and secretion of peptide YY and enteroglucagon after massive resection of small bowel.

BACKGROUND: Previous studies suggest that peptide YY (PYY) and enteroglucagon have an important role in intestinal adaptation after massive small bowel resection. This study was done to define the mechanisms, timing, and anatomic distribution of the PYY and enteroglucagon response. STUDY DESIGN: Lewis rats underwent resection of 70 percent of the small bowel (leaving equal segments of jejunum and ileum), transection, or laparotomy alone. Jejunum, ileum, and colon were compared in resected, transected, and control bowel six hours, 24 hours, one week, and two weeks postoperatively. RESULTS: Analysis of DNA, RNA, and protein per cm of bowel demonstrated hyperplastic changes. Radioimmunoassay revealed plasma PYY and enteroglucagon to be significantly elevated 24 hours after resection and they remained so through week two. In contrast, tissue PYY and enteroglucagon content decreased significantly in all tissues (p < 0.05) after resection. Reverse transcriptase polymerase chain reaction and Southern blot analysis demonstrated an immediate and sustained increase in PYY messenger RNA (mRNA) in both the ileum (fourfold) and in the colon (2.5-fold) at six hours (p < 0.05). A gradual increase in PYY mRNA was also demonstrated in the jejunum with significance at two weeks (p < 0.05). Proglucagon mRNA was significantly higher in the jejunum, compared with the ileum and colon, at 24 hours, one week, and two weeks postresection. CONCLUSIONS: Alterations in PYY and enteroglucagon synthesis occur early in the ileum and colon after massive small bowel resection. The residual jejunum, however, is primarily responsible for the adaptive hyperenteroglucagonemia. These findings suggest that although PYY and enteroglucagon are colocalized to the same cell type, there is a gene-specific response for these two peptides after resection.

Adaptation, Physiological↗
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↗