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Biomedical subjects

M Löhr

Publications and source records attributed to M Löhr.

90 records · Page 5Linked to original sources
PubMed1989

Prostaglandin analogue protects pancreatic B-cells against cyclosporin A toxicity.

Cyclosporin A toxicity on pancreatic B-cells and its prevention by rioprostil, a prostaglandin E1 analogue, were studied in the model of the isolated perfused pancreas of rats treated with both compounds for 8 days. At toxic doses of cyclosporin (10 and 20 mg/kg b.wt), the B-cells showed severe hydropic degeneration of the endoplasmatic reticulum and slight degranulation of the B-cells. Accordingly, the insulin secretion was markedly impaired. Administration of rioprostil ameliorated the insulin secretion significantly, but not the ultrastructural changes. At therapeutic levels of cyclosporin (5 mg/kg b.wt), the hydropic degeneration and the drop in insulin secretion were completely prevented by rioprostil. This observation might have therapeutic implications in the treatment of patients, in particular those undergoing pancreatic transplantation.

Animals↗
PubMed1989

Cystic fibrosis associated islet changes may provide a basis for diabetes. An immunocytochemical and morphometrical study.

The pancreases of 23 patients (mean age 10.5 years, range 5-22) years dying of cystic fibrosis (CF) were evaluated at autopsy by routine histology and immunostaining for changes in their endocrine cell compartment. The severely altered pancreatic tissues showed end stage CF, with either a fibrotic pattern (CF-FIB, n = 14) or a lipoatrophic pattern (CF-LIP, n = 9) prevailing. In all specimens, irrespective of the dominating pattern, the islet system was affected by marked periinsular and intrainsular sclerosis. Quantitatively, the volume densities (relative tissue components) of the parenchymal, fibrotic, fatty and total endocrine compartments as well as the four islet cell types (B, A, D, PP) were determined by point counting. Compared with controls, the CF patients (including two patients with overt diabetes and glucose intolerance, respectively) had a significantly decreased insulin (B)-cell ratio (from 64.4 to 34%) with a concomitant rise in non-B-cells (A-cells: 23.2 to 35%; D-cells: 10.4 to 22%; PP-cells; 2 to 9%). Comparison of endocrine cell ratios in CF-FIB pancreases with CF-LIP pancreases revealed no significant differences. The reduction of approximately 50% of insulin cells in CF patients with advanced disease supports the concept that destruction of exocrine tissue with concomitant fibrous disorganization of islets gradually changes the proportional distribution of the endocrine cells in favor of the noninsulin cells. This slowly ongoing process probably provides the basis for islet dysfunction, i.e. diabetes, increasingly observed in final stage CF.

Adolescent↗
PubMed1989

Increase in B-cells in the pancreatic remnant after partial pancreatectomy in pigs. An immunocytochemical and functional study.

The regenerative and functional capacity of B-cells in the remaining pancreatic tissue after surgical removal of 40%, 60% and 80% of the pancreas was examined in 7 month old pigs (three animals in each group). Prior to resection and 1, 3 and 6 weeks after surgery, basal and glucose-stimulated levels of insulin and blood glucose were determined and compared with the preoperative data and that of sham-operated controls. For quantitative morphology, the volume of the resected specimen and the residual pancreatic tissue, 6 weeks after surgery, was determined and sections evaluated by immunocytochemistry (insulin, glucagon, somatostatin, pancreatic polypeptide) combined with morphometry. In the remaining pancreas, the volume density of the B-cells was increased by 19% (1.57-1.92 after 60% resection; p less than 0.02) and 56% (1.57-2.38 after 80% resection; p less than 0.02) 6 weeks after surgery, compared with the respective resected portion of the pancreas and the controls (n = 12). The non-B-cells gained between 0-10% (PP-cells), 10-20% (D-cells) and 30-40% (A-cells) in the different resection groups. As the number of B-cells per given islet area remained unchanged (mean 4.12 cells/0.25 mm2), the increased volume density was due to an increase in cell number rather than cell size. Insulin secretion (integrated values, 0-120 min), was not significantly impaired after 40% and 60% resection (2711 +/- 250 all preoperative samples; 3215 +/- 474 40% at 6 week intravenous glucose tolerance test (IV-GTT); 1677 +/- 109 60% at 6 week IV-GTT), although the glucose levels (integrated values) were increased during the IV-GTT. The 80% resected animals showed a significant decrease in the insulin response only 1 week after surgery (integrated values: 2711 +/- 250 all preoperative samples, compared with 1250 +/- 508 1 week IV-GTT; p less than 0.05), while the integrated glucose values during IV-GTT (0-120 min) were significantly elevated throughout the observation period. These results suggest a B-cell hyperplasia in the residual pancreas after resection, which may cope with a normal functional demand, but disclose functional abnormalities when challenged with an increased glucose load.

Animals↗
PubMed1989

Nesidioblastosis of the pancreas in an adult with persistent hyperinsulinemic hypoglycemia.

The rare finding of pancreatic nesidioblastosis in an adult is described. A 43-year-old woman presented with a two-year history of hypoglycemic hyperinsulinism. Extensive diagnostic procedures revealed no insulinoma. Subtotal (75%) pancreatectomy relieved her symptoms; she has normal insulin levels 2.5 years after surgery. The pancreatic specimen revealed only discrete islet cell abnormalities, namely B-cells budding off ductular epithelium, islets in apposition to ducts, slight islet cell hypertrophy, and islet enlargement. Immunohistochemistry showed normal total endocrine cell content as well as normal proportions of islet cell subpopulations. Review of 20 cases in the literature and the authors' experience led to subtotal (75-90%) pancreatectomy as the treatment of choice. The authors conclude that the pediatric disease of nesidioblastosis may rarely occur in adults and that the paucity of histologic findings makes the exclusion of an insulinoma mandatory.

Adult↗
PubMed1989

Insulitis and diabetes are preceded by a decrease in beta cell volume in diabetes-prone BB rats.

Immunocytochemistry combined with morphometry was used to test the hypothesis that insulitis and diabetes are preceded by quantitative changes in the pancreas of diabetes-prone BB (DPBB) rats. Diabetes-resistant BB (DRBB) rats of the w-subline served as controls. In the first part of the study rats aged 15, 30, 45, and 60 days were studied. At 60 days preceding both insulitis and onset of diabetes, the DPBB rats demonstrated lower volumes of the entire pancreas, the parenchyma, the endocrine pancreas, and beta, A, and D cells. Body weights of the DPBB rats were lower than the DRBB rats from 15 days of age on. In the second part of the study, DP and DRBB rats were coreared by a foster mother to obtain weight-matched animals. Morphometric analysis at 70 days of age revealed a reduction in both the beta cell volume density and volume whereas no differences were seen in other pancreatic parameters. These results indicate that the appearance of insulitis and the later onset of insulin-dependent diabetes are preceded by a reduction in beta cell volume.

Animals↗
PubMed1989

Rioprostil, a new prostaglandin E1, prevents cyclosporin A-induced damage to endocrine and exocrine pancreas.

The possibility that rioprostil can prevent cyclosporin A-induced damage to the pancreas is investigated. Cyclosporin A is given to rats once daily intragastrically in doses of 5, 10 and 20 mg/kg body weight. These doses cause dose dependent significant reduction of insulin release and enzyme secretion from the arterially perfused isolated pancreas. The subcutaneous injection of rioprostil, 15 micrograms/kg twice daily, could completely prevent the effects of 5 mg/kg cyclosporin A on insulin release and could completely prevent the effects of 5 mg/kg cyclosporin A on insulin release and could completely prevent the effects of 5 mg/kg cyclosporin A on insulin release and could also afford significant protection from the effects of 10 and 20 mg/kg cyclosporin A on both insulin release and enzyme secretion. The cytoprotective action of rioprostil on the pancreas may have therapeutic implications.

Animals↗
PubMed1988

Differential sensitivity of rat exocrine and endocrine pancreas to cyclosporine.

The effect of 5, 10, and 20 mg/kg bw cyclosporine on rat endocrine and exocrine pancreatic function was studied. Glucose-dependent insulin secretion from the endocrine pancreas was shown to be significantly impaired 8 days after cyclosporine was given once daily at a dose as low as 5 mg/kg. CCK-8-stimulated amylase and lipase secretion were less sensitive to the noxious effect of cyclosporine being impaired at a dose of 10 mg/kg. Trypsin secretion was shown to be impaired at 20 mg/kg cyclosporine only. Our results demonstrate that cyclosporine causes dose-dependent impairment of both pancreatic endocrine and exocrine functions: the endocrine pancreas being more sensitive to the noxious action than the exocrine pancreas.

Amylases↗
PubMed1988

Prevention of toxic effects of cyclosporin on pancreatic B-cells of rats by Rioprostil, a new prostaglandin analogue.

Cyclosporin 5, 10, and 20 mg/kg bw was given to rats once daily intragastrically and caused a dose dependent, significant decrease of glucose dependent insulin release from the arterially perfused isolated pancreas, without affecting animal behaviour, weight gain, microscopic appearances of the pancreas, or kidney function. Subcutaneous injection of a new synthetic prostaglandin analogue Rioprostil 7.5 micrograms/kg bw twice daily completely prevented the effect of cyclosporin 5 mg/kg bw and protected significantly against the effects of cyclosporin 10 and 20 mg/kg bw.

Animals↗
PubMed1987

Residual insulin positivity and pancreatic atrophy in relation to duration of chronic type 1 (insulin-dependent) diabetes mellitus and microangiopathy.

The relationship of residual insulin positivity in chronic Type 1 (insulin-dependent) diabetes and atrophy of the exocrine pancreas to duration of diabetes, age at onset and microangiopathy was studied in 26 patients (disease duration 2 to 54 years, mean 26 years). Islets containing insulin cells were found in 13/26 pancreata. In 5/13 pancreata insulin positive cells were detected in only one lobule, while in 8/13 insulin positivity was multifocal. All patients with diabetes duration less than 11 years had residual insulin cells; whereas, the rate of insulin positivity was near 40% with diabetes duration of more than 11 and 21 years, respectively. Survival of insulin cells was not clearly related to age at onset. HLA-DR expression on insulin cells was seen in one case. Insulitis was lacking. Pancreatic volume determined in 18 patients ranged from 14-110 ml (age adjusted mean 56.3 ml) and was significantly less than that of control subjects (age adjusted, mean 89.9 ml, p less than 0.0001). Computerized morphometry of the exocrine pancreas revealed severe acinar atrophy due to a reduction in size of acinar cells. Acinar atrophy correlated neither with the degree of insulin positivity, disease duration nor severity of microangiopathy. The findings suggest that in about 40% of patients with Type 1 diabetes a small population of insulin cells may escape autoimmune destruction, irrespective of disease duration or age at onset. Though exocrine atrophy and insulin deficiency are associated, the variable extent of pancreatic atrophy could not be related to such factors as amount of surviving insulin cells, duration of diabetes or microangiopathy.

Aging↗
PubMed1987

Morphometry and immunocytochemistry.

The use of morphometry (and stereology), especially in conjunction with immunocytochemistry, in surgical and experimental pathology is reviewed. The combined use of morphometry and immunocytochemistry permits the study of secretory products and the distinction between cells that produce them, e.g., as in the pancreas. Several examples to illustrate the application of immunocytochemical techniques in morphometry are presented. For example, using this approach on the pancreas, it was shown that not only B cells, but also A and D cells, seem to undergo pathologic changes in a prediabetic organism. Since morphologic alterations may be distributional as well as quantitative, a model for the assessment and statistical evaluation of the distribution of objects within an area is discussed. Similar procedures were used to analyze the distribution of cytochrome P-450 molecules along intracellular membranes; however, special labeling techniques were necessary for this quantification in the electron microscope. Immunoenzyme cytochemically stained secretions can also be studied morphometrically, and microdensitometry and microfluorometry can also be used to quantify immunocytochemical reactions, as is shown in the analysis of the intralobular distribution of NADPH-cytochrome P-450 reductase in the rat liver. Finally, the BIVAS semiautomatic system for morphometric measurements, developed at the Department of Pathology of the University of Basel, is briefly described.

Animals↗
PubMed1985

Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited.

The present review draws attention to the diversity of islet lesions seen in human type 1 and type 2 diabetes. This heterogeneity of islet changes is best demonstrated by immunocytochemistry. In type 1 diabetes the endocrine pancreas is characterized by selective loss of B cells, which most likely results from a slowly acting autoimmune process depending on the presence of both genetic and environmental factors. The process starts years before overt diabetes develops and manifests when the B-cell volume is reduced by about 80%. In type 2 diabetes B cells are always present, regardless of the duration and severity of the disease, but lack any signs of functional activity. This reflects a secretory defect of the B cells which obviously becomes evident under the conditions of obesity, hyperinsulinism and insulin resistance. Obese but non-diabetic subjects show, in parallel to their hyperinsulinism, an increased B cell volume, suggesting that under prediabetic conditions the B cells have still the capacity to respond to increased functional demands by enhanced proliferation. In manifest diabetes the B cells have lost their proliferative potential. Whether this is due to an inherent defect or the consequence of a functional disturbance, is not clear. The development of islet amyloidosis most likely represents an associated functional abnormality of the B cell.

Autoimmune Diseases↗
PubMedDate not supplied

Effects of inorganic divalent cations on the renal basolateral transport system for organic anions.

Recent work demonstrated that the heavy metal ion Cd2+ increases the transport of p-aminohippuric acid (PAH) across the basolateral membrane of microdissected non-perfused rabbit kidney S2 proximal tubule segments. Usually, such ions induce damage of various renal transport systems, therefore the effects of divalent metal ions Zn2+, Co2+ and Ni2+ on this transporter were investigated. Addition of Ni2+ or Zn2+ to the bathing solution leads to a significant reduction of basolateral PAH transport, with IC50 values of 2 x 10(-5) and 10(-6) M, respectively, whereas Co2+ failed to inhibit PAH accumulation. Simultaneous incubation with thrombin (10(-9)M), which is known to increase [Ca2+]i, abolished the effects of the divalent ions. Our results indicate that Ni2+ and Zn2+ reduce cellular PAH uptake. Because Ni2+ and Zn2+ are calcium channel blockers, these effects are probably due to a reduction of [Ca2+]i by an interaction of these metals with binding sites in the calcium channel, whereas Co2+ does not affect these binding sites. This finding is supported by the fact that thrombin abolished the cation effects.

Animals↗
PubMedDate not supplied

Portal vein erosion and acute abdominal hemorrhage as a complication of acute pancreatitis.

The case of a 35-year-old male with portal vein erosion and acute life-threatening abdominal hemorrhage as a complication of acute pancreatitis is reported. Erosion of arterial walls is the most common complication of pancreatitis and pancreatic pseudocysts, and erosion of the portal vein leading to a fistula between the pancreas and the portal vein is very rare. Diagnosis was made by multislice spiral computed tomography, and nonsurgical treatment was elected, leading to complete recoverage.

Acute Disease↗
PubMedDate not supplied

Release of hyaluronan and laminin into pancreatic secretions.

BACKGROUND: Development of fibrosis characterizes chronic pancreatitis. As it results from deposition of extracellular matrix (ECM) proteins such as hyaluronan (HA) or laminin, the release of these ECM components into blood or pancreatic secretion may be enhanced during the course of chronic pancreatitis. PATIENTS, MATERIAL AND METHODS: Using immunoassays for HA and laminin, the concentration for these ECM components was measured in pancreatic juice and serum samples from 20 patients with and 20 patients without chronic pancreatitis. Pancreatic calculi of varying size and weight obtained from 13 patients with chronic pancreatitis were also examined for the content of ECM components. Tissue samples from normal pancreas and those showing chronic pancreatitis were investigated immunocytochemically with an antibody to HA synthetase (HAS). RESULTS: After stimulation with secretin high levels of ECM components were found in the initial washout period in chronic pancreatitis patients as well as in controls. HA levels, however, were seen seven times higher in patients with chronic pancreatitis (mean +/- SEM; 734 +/- 301 vs. 95 +/- 15 microg/l; p < 0.01). Serum HA levels correlated with the duration of chronic pancreatitis and with the levels of HA in pancreatic juice. HA and laminin were detected in the supernatants of pancreatic calculi (laminin 0.70 +/- 0.30 U/l; HA 275 +/- 85 microg/l). Immunocytochemically, strong staining for HAS was found in the duct epithelium and in centroacinar cells of chronic pancreatitis specimens. CONCLUSION: Demonstration of increased amounts of HA in pancreatic juice of chronic pancreatitis patients stimulated with secretin suggests enhanced production of this ECM component in the chronically inflamed pancreas. The source of HA appears to be the pancreatic ductal epithelium.

Calculi↗
PubMedDate not supplied

Human pancreatic cancer cell lines express the CCKB receptor.

BACKGROUND/AIMS: The gastrointestinal peptide gastrin might be a stimulatory effector of the growth of human pancreatic cancer cell lines. Several authors suggest that this effect is mediated by CCKB receptors. However, no studies have examined human pancreatic cells for CCKB receptor expression. The study was designed to evaluate cell lines from human pancreatic cancer (n = 6), or normal pancreatic ducts (n = 2), pancreatic tumor and control tissues (n = 9) for CCKB receptor expression. METHODOLOGY: RNA from cell lines and tissues was subject to DNAse digestion, reverse transcription and amplification using CCKB receptor cDNA sequence specific oligonucleotides via polymerase chain reaction (PCR). After confirmation of CCKB receptor sequence, the products were examined using southern blot analysis. The relative expression was determined by photodensitometrical quantification and normalization to the housekeeping gene beta-actin. RESULTS: Six pancreatic tumor cell lines expressed the CCKB receptor. Amplification of CCKB receptor cDNA from 2 cell lines derived from non-malignant human pancreatic duct cell lines resulted in products with a significantly lower copy number. Tissues like stomach and brain served as positive controls. CONCLUSIONS: These results provide evidence that most human pancreatic cancer cell lines of ductal origin express CCKB receptor mRNA. Malignant pancreatic tissue may overexpress these receptors in comparison with normal tissue.

Adenocarcinoma↗
PubMedDate not supplied

Serum levels of extracellular matrix in acute pancreatitis.

BACKGROUND/AIMS: Elevated levels of serum markers of extracellular matrix, i.e., the amino-terminal procollagen-III-peptide, hyaluronic acid and laminin are found in various diseases. The study aims to examine a panel of these parameters in patients with acute pancreatitis and correlate them with the course and severity of the disease. METHODOLOGY: We prospectively examined the time-course of procollagen-III-peptide, hyaluronic acid and laminin in 24 consecutive patients with acute necrotizing (n = 13) or edematous (n = 11) pancreatitis. Patients with chronic pancreatitis with (n = 10) or without (n = 17) acute pain, and 6 patients in complete remission after an episode of acute pancreatitis as well as healthy individuals served as controls. In addition, serum levels of collagen VI and undulin were followed in 10 and 9 patients with acute necrotizing pancreatitis, respectively. RESULTS: The serum concentrations of procollagen-III-peptide, hyaluronic acid and laminin were significantly higher at the onset of acute necrotizing pancreatitis compared to edematous pancreatitis and the controls. They returned to almost normal levels during the course of the disease when the patient recovered, but remained elevated in patients with a lethal course. Laminin allowed us to discriminate between patients with necrotizing pancreatitis from all other forms of pancreatitis on admission (specificity 82%, sensitivity 92%, PPV 86%, NPV 90%). Collagen type VI levels were 2-3-fold higher in sera of patients with acute pancreatitis than in healthy controls, whereas the results for undulin were inconclusive. CONCLUSIONS: Since markers of matrix metabolism (especially laminin) are differently elevated in acute necrotizing versus edematous pancreatitis, we suggest that they might be used as parameters for the outcome.

Acute Disease↗