Search PubMed⌕ Search

Biomedical subjects

J H Grendell

Publications and source records attributed to J H Grendell.

At least 37 records · Page 2Linked to original sources
PubMed1993

Effects of bile and pancreatic digestive enzymes on permeability of the pancreatic duct system in rabbits.

In order to reproduce what may occur during the initial phase of biliary acute pancreatitis, the rabbit pancreatic duct was perfused with preincubated mixtures of bile and different digestive enzymes at low physiologic pressure. Permeability of the pancreatic duct system, serum amylase, and histological appearance of pancreatic tissue were studied after orthograde duct perfusion in the anesthetized animal. The ductal permeability was estimated by recovery of fluoresceinated dextran (molecular weight 17,200) in central venous blood following duct perfusion with this substance. Perfusion with preincubated bile failed to increase permeability significantly (11.10 +/- 3.04 nmol/L compared to 5.80 +/- 2.71 nmol/L in the control group), whereas mixtures of bile and trypsin (27.19 +/- 5.21 nmol/L), bile and lipase (16.68 +/- 3.75 nmol/L), and bile and pancreatic juice (13.92 +/- 0.48 nmol/L) caused significant increases (p < 0.05). Similar observations were made regarding serum amylase and histology. Thus, the presence of mixtures of bile with pancreatic enzymes (following their prolonged common incubation) in the absence of elevated pressure, results in an increase in duct permeability for molecules up to the size range of pancreatic enzymes and thereby may contribute to the initiation of acute pancreatitis.

Acute Disease↗
PubMed1992

Diagnosis of pancreatic carcinoma. Imaging techniques and tumor markers.

In view of the increasing number of new imaging techniques and serum tumor markers, it is not well established which combination or which order of tests may provide the most information for diagnosis of pancreatic carcinoma. This review determines the diagnostic value of the various tests and evaluates which combination of tests may provide the most information and what may be considered to be a current rational approach to the diagnosis of pancreatic carcinoma. In the present analysis endoscopic retrograde cholangiopancreatography (ERCP) provided a 92% sensitivity that exceeded the 83% and 74% sensitivities calculated for computed tomography (CT) and ultrasound, respectively. The specificity of all three imaging techniques exceeded 90%. Serum determination of CA 19-9 yielded an 83% sensitivity, which was considerably higher than sensitivities of carcinoembryonic antigen and various other tumor markers. The combination of CA 19-9 and ultrasound improved the sensitivity of each test performed alone by 10-15%. Fine-needle biopsy allows diagnosis of pancreatic carcinoma with a sensitivity of 83% and an almost perfect specificity of 99%. On the basis of these data, the combination of ultrasound and determination of CA 19-9 is recommended as the initial tests when pancreatic carcinoma is suspected. CT also must be performed if ultrasound is indeterminant or inconsistent with the clinical evaluation, as well as in patients with negative ultrasound but abnormal CA 19-9. Negative results of CT, ultrasound, and CA 19-9 will exclude pancreatic carcinoma in most patients. A positive ultrasound or CT result usually leads to fine-needle biopsy, which helps avoid most diagnostic laparotomies. ERCP must be performed in patients where ultrasound, CT, and fine-needle biopsy do not clarify the diagnosis. In the majority of patients with pancreatic carcinoma, noninvasive imaging techniques such as ultrasound and CT also allow adequate staging. In some patients, however, laparoscopy and angiography may need to be performed for strategic planning of further therapy. Although modern imaging techniques and serum tumor markers allow diagnosis of pancreatic carcinomas as small as 2-3 cm and help avoid most diagnostic laparotomies, this improvement in diagnostic capability has as yet not significantly improved the prognosis.

Angiography↗
PubMed1992

Effects of antioxidants and free radical scavengers in three different models of acute pancreatitis.

The present studies were done to evaluate the therapeutic potential of several antioxidants and free radical scavengers in three different models of acute pancreatitis. (a) Edematous pancreatitis with acinar cells necrosis was induced by seven hourly intraperitoneal injections of 50 micrograms of caerulein per kg in mice. (b) Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet in mice. (c) Hemorrhagic pancreatitis was induced by retrograde infusion of 0.6 ml of 5% sodium taurocholate into the pancreatic duct in rats. The following antioxidants and free radical scavengers were given at various doses intravenously, subcutaneously, or intraperitoneally before the onset of pancreatitis: Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], superoxide dismutase, catalase, deferoxamine (Desferal), dimethyl sulfoxide, or allopurinol. The severity of pancreatitis was assessed at various times after its onset by determination of serum amylase and pancreatic weight (edema), by grading of histological alterations, and by determination of survival (survival determined in models of hemorrhagic pancreatitis). In general, free radical scavengers and antioxidants ameliorated edema and inflammation to a greater degree than necrosis and the increase in serum amylase. Superoxide dismutase (as did Ebselen in previous studies) exerted beneficial effects on survival in diet-induced pancreatitis in the absence of marked effects on pancreatic necrosis, suggesting that these beneficial effects are due to amelioration of extrapancreatic complications that often contribute to mortality in acute pancreatitis. None of the antioxidants had major beneficial effects in taurocholate-induced hemorrhagic pancreatitis. Thus, formation of free radicals may be important for progression and outcome in diet-induced and, to a lesser degree, in caerulein-induced pancreatitis but not at all in taurocholate-induced pancreatitis. Different models of pancreatitis may, therefore, involve different degrees and mechanisms of free radical formation. Despite the amelioration of edema and the beneficial effects on mortality seen for some antioxidants in some of the models, antioxidants and free radical scavengers appear to have only a limited potential for treatment of acute pancreatitis.

Acute Disease↗
PubMed1992

Acute experimental hemorrhagic-necrotizing pancreatitis induced by feeding a choline-deficient, ethionine-supplemented diet. Methodology and standards.

The present work evaluates the methodology and standards of acute hemorrhagic-necrotizing pancreatitis induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet to mice. The diet model appears to be a good approximation of severe necrotizing human pancreatitis. Both the gross and histological appearance of the pancreatic and peripancreatic inflammation as well as the clinical and biochemical course of diet-induced pancreatitis resemble human disease. By limiting the period of feeding the diet, one can control the mortality at any desired level between 0 and 100%. Ascites, acidosis, hypoxia and hypovolemia occur in this model as well as in human pancreatitis. The time course of the morphological and biochemical alterations have extensively been studied and are, thus, well defined in this model. Despite the differences in pathogenesis of pancreatitis induced in this model versus human disease, the experimental pancreatitis and clinical pancreatitis share several pathophysiologic features. Therefore, the model is suitable to study pathophysiologic aspects of this disease. The diet model is particularly well suitable to study the potential for new therapeutic substances. The small size of the animals used, however, is a limitation for the evaluation of surgical procedures and of new diagnostic tools. Several pitfalls and problems have to be considered in order to obtain valuable data. The amount of injury produced by the CDE diet depends critically on sex, age and weight of the mice. Special care has to be taken to guarantee that the intake of the CDE diet is identical between different experimental groups. Therefore, each set of experiments needs to include a separate control group of mice which receive the CDE diet without any other special treatment. The potential benefit of an experimental therapy can be assessed by measuring survival, various biochemical and histological features, and alterations in hematocrit, pH and blood gases.

Acute Disease↗
PubMed1992

Glutathione monoethyl ester ameliorates caerulein-induced pancreatitis in the mouse.

Studies in animal models suggest that oxygen radicals may be important in the pathogenesis of acute pancreatitis. Because glutathione is an essential component of the defense against radical-mediated cellular injury, we investigated whether pancreatic glutathione content is influenced by inducing acute pancreatitis and whether augmenting the intracellular supply of glutathione would alter the course of pancreatitis. Caerulein, a decapeptide cholecystokinin analogue, induces acute necrotizing pancreatitis in mice when given in high doses (50 micrograms/kg per h) over a period of 6 h. The pancreatic glutathione content (total, GSH + GSSG) in mice treated with high-dose caerulein fell to 17% of normal within 4 h of beginning caerulein and recovered toward normal after discontinuing caerulein treatment. Mice treated with glutathione monoethyl ester (20 mmol/kg 1 h before caerulein, 10 mmol/kg 3 and 7 h after starting caerulein) were found to have blunted depletion of pancreatic glutathione, diminished histologic evidence of pancreatitis (necrosis, inflammation, and vacuolization), and lower serum amylase values compared with mice treated with caerulein alone. These findings suggest that the profound depletion of pancreatic glutathione caused by hyperstimulation of the pancreas with caerulein is critically important in the pathogenesis of acute caerulein-induced pancreatitis.

Amylases↗
PubMed1991

Effect of octreotide on refractory AIDS-associated diarrhea. A prospective, multicenter clinical trial.

OBJECTIVE: To determine the efficacy and safety of octreotide for treatment of refractory, profuse diarrhea in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: A prospective, open-label study. SETTING: Inpatient metabolic units of four university medical centers. PATIENTS: Fifty-one patients infected with human immunodeficiency virus (HIV) who had uncontrolled diarrhea (greater than or equal to 500-mL liquid stool per day) despite treatment with maximally tolerable doses of antidiarrheal medications. INTERVENTION: After initial baseline studies, patients received octreotide, 50 micrograms every 8 hours for 48 hours. If stool volume was not reduced to less than 250 mL/d, the dose of octreotide was increased stepwise to 100, 250, and 500 micrograms. MAIN RESULTS: Fifty men and one woman (mean age, 36.3 +/- 1.1 years) entered and completed the 28-day protocol (14 days of inpatient therapy and 14 days of outpatient therapy). Stool frequency and volume decreased significantly (6.5 +/- 0.5 stools per day on day 0 compared with 3.8 +/- 0.3 stools per day on day 21 [P less than 0.001] and 1604 +/- 180 mL/d on day 0 compared with 1084 +/- 162 mL/d on day 14 [P less than 0.001], respectively). Twenty-one patients (41.2%) were considered to be partial or complete responders (reduction in daily stool volume by greater than or equal to 50% of initial collections or reduction to less than or equal to 250 mL/d). Of the 21 responders, 14 (67%) had no identifiable pathogens at initial screening compared with 9 of 30 (30%) nonresponders (P less than 0.01). CONCLUSION: Patients with AIDS-associated refractory watery diarrhea, especially those without identifiable pathogens, may respond favorably to subcutaneously administered octreotide. This drug deserves further study in a randomized, placebo-controlled trial.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Effects of the seleno-organic substance Ebselen in two different models of acute pancreatitis.

This study evaluated the effects of the seleno-organic substance Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] in two models of acute hemorrhagic and acute edematous pancreatitis. Ebselen is known to catalyze glutathione peroxidase-like reactions and to inhibit lipid peroxidation. Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet to mice for 66 h. Edematous pancreatitis was induced by 7-h subcutaneous injections of 50 micrograms/kg of cerulein in mice. Ebselen was given from the beginning of the CDE diet either as a subcutaneous injection of 100 mg/kg at 6-h intervals or was mixed in with the CDE diet to yield a daily dose of 100 mg/kg of Ebselen. In further experiments, Ebselen was given at various time intervals after the beginning of the CDE diet as subcutaneous injections of 100 mg/kg at 6-h intervals. In the cerulein model, Ebselen was given 5 min prior to each cerulein injection at doses from 10-500 mg/kg. Prophylactic administration of Ebselen given orally or subcutaneously significantly improved survival from 38.5% in the control group of saline-injected CDE-fed mice to 61.9 and 65.0%, respectively. Ebselen also reduced increases in serum amylase and pancreatic weight in the diet model. Therapeutic administration of Ebselen significantly increased survival only when injections were started 20 h after the beginning of the CDE diet (64%), but not when started after 40 h (44%). Similarly, increases in serum amylase and pancreatic weight due to the CDE diet were significantly reduced by Ebselen only when injections were started after 20 h but not when started after 40 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1990

Pancreatic exocrine secretion in acute experimental pancreatitis.

Little is known about exocrine pancreatic secretory function in patients with acute pancreatitis, in particular during the early phase of the disease. Therefore, this study evaluates basal and stimulated pancreatic secretion in vivo and in vitro in four different models of acute pancreatitis which reflect its clinical spectrum of severity: (a) edematous pancreatitis induced in the rat by seven IP injections of 50 micrograms/kg cerulein at hourly intervals; (b) edematous pancreatitis with cellular necrosis induced in the mouse by seven IP injections of 50 micrograms/kg cerulein at hourly intervals; (c) hemorrhagic pancreatitis induced in the mouse by feeding an ethionine-supplemented, choline-deficient diet for 66 hours; and (d) hemorrhagic pancreatitis induced in the rat by retrograde infusion of 0.6 mL 5% sodium taurocholate into the pancreatic duct. Secretory studies were performed in vivo and in vitro at various times after onset of pancreatitis. The results show that the exocrine pancreas gradually became resistant to cholecystokinin stimulation after the onset of acute pancreatitis in all four animal models. Cholecystokinin-stimulated secretion was almost abolished in vivo and in vitro at the time of maximal histological damage. In vivo basal secretion was also reduced. In vitro there was an increase in basal release of amylase from isolated acini that was not caused by an increase in luminal secretion but by enzyme release from damaged cells. The time course of improvement of secretory function after acute experimental pancreatitis depended on the severity of the pancreatitis. Recovery of secretory capacity took longer after severe necrotizing pancreatitis than after edematous pancreatitis. However, the ultimate resolution of secretory function was remarkable, in particular after severe hemorrhagic pancreatitis. In all four models, secretory capacity became indistinguishable from normal before the morphological alterations had completely resolved. The present experimental data suggest that pancreatic secretion, and particularly pancreatic secretory response to cholecystokinin, may also be reduced in patients early after the onset of acute pancreatitis.

Acute Disease↗
PubMed1990

Cytomegalovirus-associated acute pancreatic disease in patients with acquired immunodeficiency syndrome. Report of two patients.

Pancreatic disease has been infrequently reported in patients with acquired immunodeficiency syndrome. Over the last 3 years at our hospital, two patients with the acquired immunodeficiency syndrome and acute pancreatic or biliary disease, demonstrated at autopsy to be secondary to cytomegalovirus infection of the pancreas, have been evaluated. However, pancreatic disease was not recognized antemortem in our two patients because of their underlying diseases and the atypical presentation. Cytomegalovirus infection of the pancreas may cause acute symptomatic disease in patients with acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Growing pancreatic acinar cells (postpancreatitis and fetal) express a ductal antigen.

Monoclonal antibodies specific for luminal plasma membranes of acinar and duct cells of the exocrine pancreas were used to investigate changes in antigen expression during regeneration of the pancreas after acute pancreatitis and during fetal pancreatic development in mice. During regeneration after acute pancreatitis induced by supramaximal injections of cerulein or by a choline-deficient, ethionine-supplemented diet, morphologically identifiable acinar cells expressed the ductal antigen on their luminal surface, but at a lower level than this antigen is expressed on duct cells. As the pancreas regenerated, the ductal antigen was lost from acinar cells and was found only on duct cells. Characteristic tubular complexes formed in both pancreatitis models and were positive for the acinar antigen, demonstrating their acinar origin. In fetal pancreas, acinar cells between prenatal days 3 through 1, when zymogen granules were already abundant, expressed the duct-cell antigen on their luminal surface. By birth duct antigen was mostly present on ducts with only occasional label on acinar cells. The presence of a ductal antigen on acinar cells is associated with acinar-cell growth during regeneration and during fetal development and may reflect a less differentiated state.

Animals↗
PubMed1990

Effects of long-term CCK stimulation and CCK blockade on pancreatic and intestinal growth, morphology, and function.

This study evaluated the effects of long-term cholecystokinin (CCK) stimulation and blockade on pancreatic and intestinal growth, function, and morphology. CCK release was induced by feeding of the protease inhibitor camostate and CCK blockade by feeding of the CCK antagonist CR 1409. Four groups of NMRI-mice received the following diets for 9 months (each group consisting of 36 mice): (1) chow (control); (2) chow + 100 mg/kg/day camostate; (3) chow + 50 mg/kg/day CR 1409; (4) chow + 100 mg/kg/day camostate + 50 mg/kg/day CR 1409. Long-term feeding of camostate greatly increased pancreatic weight by induction of marked hypertrophy (increase in protein content) and moderate hyperplasia (increase in DNA content). Camostate feeding also increased secretory capacity of the exocrine pancreas. Despite camostate-induced growth neither hyperplastic nor neoplastic nodules developed. The CCK-antagonist CR 1409 markedly inhibited the effects of camostate which are therefore mainly mediated by CCK. Neither long-term CCK stimulation nor CCK blockade altered morphology or composition of duodenal mucosa. Feeding of CR 1409 alone (i.e., without camostate) slightly but significantly decreased pancreatic content of protein and secretory capacity of enzymes when compared to the chow-fed control; pancreatic weight and DNA content remained unchanged after long-term administration of CR 1409. Thus, long-term, continuous and effective blockade of the CCK-receptor only slightly inhibited pancreatic growth and secretory capacity. CCK is, therefore, not an essential growth factor for the pancreas, although increases of endogenous CCK stimulate pancreatic growth and secretory capacity.

Animals↗
PubMed1990

Idiopathic acute pancreatitis.

In most patients presenting with acute pancreatitis, the cause can be established on the basis of initial history, physical examination, laboratory studies, and abdominal sonography. Patients with unexplained pancreatitis at that point are often considered to have idiopathic disease. However, a cause and, often, effective treatment to prevent recurrent pancreatitis are possible in many of these patients if an aggressive diagnostic approach is taken to discover undiagnosed hyperlipidemia, occult gallstones, abnormalities of the bile and pancreatic ducts, sphincter of Oddi dysfunction, pancreatic cancer and other tumors, and cystic fibrosis (in children and young adults).

Acute Disease↗
PubMed1989

Comparative effects of CCK receptor antagonists on rat pancreatic secretion in vivo.

The present experiments evaluate in vivo effects of recently described cholecystokinin (CCK) receptor antagonists on rat pancreatic secretion. Pancreaticobiliary secretion was studied after bile duct cannulation in anesthetized rats. After two basal 10-min fractions were selected, secretion was stimulated by intravenous caerulein (0.1-30.0 micrograms/kg) or secretin, and collected for seven further 10-min fractions. Peptide antagonists (CR 1409, CR 1392, and CR 1505) and nonpeptide antagonists (asperlicin and L364,718) were given intravenously 10 min before agonists. Increasing doses of antagonists gradually reduced secretion of protein and enzymes stimulated by submaximal and maximal doses of caerulein. The antagonists did not alter nonstimulated or secretin-stimulated secretion, indicating their specificity for the CCK receptor. Except for proglumide and asperlicin, all antagonists were able to abolish caerulein-stimulated pancreatic secretion, as evaluated by the mean integrated 1-h response to a near-maximal dose of caerulein. The caerulein dose-response curve was gradually shifted to the right by increasing doses of CR 1409, indicating competitive-like kinetics. Inhibition of secretion due to supramaximal doses of caerulein, however, could be reversed by doses of CR 1409 smaller than expected from extrapolating truely competitive kinetics from an in vitro situation to the in vivo situation. The rank order of potency of the compounds to antagonize caerulein-stimulated secretion in vivo agreed with their relative potencies to antagonize caerulein-stimulated amylase secretion from pancreatic acini in vitro as well as with their affinity to bind to peripheral CCK receptors in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1988

Therapeutic regimens in acute experimental hemorrhagic pancreatitis. Effects of hydration, oxygenation, peritoneal lavage, and a potent protease inhibitor.

In this study we evaluated the effects of hydration, oxygenation, peritoneal lavage, and the protease inhibitor gabexate mesilate in acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented diet. Different groups of mice were kept at various concentrations of O2 (21%, 35%, and 45% O2), or were treated by either s.c. injections or i.p. injections of electrolyte solution at various doses (0, 4, 6, or 8 ml/day). Further groups were treated either with i.p. lavage, lavage with 1.5 mg/ml of gabexate, or i.p. injections of 100 mg/kg of gabexate without lavage. The potential benefits of the various regimens were assessed by measuring survival, various biochemical and histologic features, and alterations in hematocrit, pH, and blood gases. Increasing O2 concentrations reversed hypoxemia and acidosis, but had no effect on biochemical or morphologic alterations and did not improve survival. However, hydration by s.c. fluid markedly improved survival and normalized the hematocrit without having major effects on biochemical or morphologic alterations. Intraperitoneal fluid did not improve survival. Gabexate injections without lavage had a slight effect on survival and serum amylase concentration and very little effect on histology. Lavage without gabexate had a greater effect on survival, serum amylase, and histology. Addition of gabexate to the lavage fluid increased the beneficial effect of lavage. Increases in amylase and activated trypsin in ascites were markedly reduced by lavage and even more so by lavage with addition of gabexate. We conclude that sufficient hydration appears to be an important factor in supportive care for severe acute pancreatitis, whereas oxygenation without sufficient hydration has no major benefit. Peritoneal lavage with gabexate showed the greatest benefit of the various regimens for acute severe pancreatitis and is worthy of clinical trials.

Acute Disease↗
PubMed1988

Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment.

The appearance of vacuoles inside acinar cells characterizes an early stage of development in different models of acute pancreatitis and, possibly, also in human disease. The vacuoles have been shown to contain both digestive and lysosomal enzymes. This abnormal admixture may have important implications for the pathogenesis of pancreatitis because the lysosomal enzyme cathepsin B can activate trypsinogen and may, by this way, trigger pancreatic autodigestion. For the activation process of trypsinogen by cathepsin B, however, an acidic pH is required. This study, therefore, looked for evidence of vacuole acidification in two different models of acute pancreatitis. Edematous pancreatitis was induced in rats by hyperstimulation with cerulein and hemorrhagic pancreatitis was induced in mice by feeding a choline-deficient, ethionine-supplemented diet. Pancreatic acinar cells were isolated at different times after induction of pancreatitis and incubated with 50 microM of acridine orange to identify acidic intracellular compartments. As shown in previous work, zymogen granules are the main acidic compartment of normal acinar cells; they remained acidic throughout the course of pancreatitis in both models. Vacuoles became increasingly more frequent in both models as pancreatitis progressed. Throughout development of pancreatitis, vacuoles accumulated acridine orange indicating an acidic interior. Addition of a protonophore (10 microM monensin or 5 microM carbonyl cyanide m-chlorophenylhydrazone [CCCP] or a weak base (5 mM NH4Cl) completely and rapidly abolished acridine orange fluorescence inside both zymogen granules and vacuoles providing further evidence for an acidic interior. The acidification of vacuoles seen in two different models of pancreatitis may be an important requirement for activation of trypsinogen by cathepsin B and thus for the development of acute pancreatitis.

Acute Disease↗
PubMed1987

Sucralfate suspension versus titrated antacid for the prevention of acute stress-related gastrointestinal hemorrhage in critically ill patients.

Seventy-four medical and surgical patients having a minimum of two risk factors for stress-related gastric mucosal bleeding were prospectively selected randomly to receive prophylaxis by antacid titration (to maintain a gastric pH of more than 4) or with sucralfate suspension (1 g/10 ml every four hours). Gastric aspirates were monitored every two hours for pH and overt and occult bleeding. Despite a significantly greater severity of illness in the sucralfate group (p less than 0.01), no significant difference in overt or occult bleeding between the groups could be demonstrated. Low-grade occult blood loss occurred frequently in both groups, but only one of the 74 patients (four risk factors, sucralfate group) had significant stress-related bleeding as defined by preset criteria and documented by endoscopy. The effectiveness of sucralfate appeared unrelated to acid neutralization in keeping with its classification as a cytoprotective agent. There were eight antacid-related side effects (four severe diarrhea, four hypermagnesemia), and none related to sucralfate. Sucralfate suspension was safe and effective and had fewer side effects than antacid titration for the prophylaxis of stress-related bleeding in critically ill patients.

Adult↗