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Biomedical subjects
Publications and source records attributed to J Schade.
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In approximately 30% of the diabetics antigens of the diabetic glomerulosclerosis were found which were not observed in controls. This finding favours the view of altered composition of glomerular extracellular substances in diabetes.
The experimental animal model of human insulin-dependent diabetes mellitus (IDDM, type I diabetes), which was for the first time described by Like and Rossini (1976) for Charles River CD-1 mice and produced by the application of multiple subdiabetogenic streptozotocin (SZ) doses, has been reproduced in the mouse strain C57 Bl/KsJ which has been bred over several generations at the Central Institute for Diabetes Karlsburg (since 1975). Male mice were given subdiabetogenic intraperitoneal injections of SZ (40 mg/kg b.w.) on five days running.--The simultaneously performed metabolic, light and electron microscopical, histochemical, fluorescence microscopical, and morphometric examinations show that the small doses of SZ lead to a metabolic disturbance in the islets of Langerhans already on the third day of the experiment (after the first two SZ injections) which is associated with a high-degree reduction or an interruption of the insulin production. Subsequently, on the 8th day (three days after the last SZ injection) up to the 20th day an insulitis occurs which is characterized by a target cell reaction of lymphocytes against the beta cells and leads to the lysis of the majority of the beta cells. In the course and after the insulitis, a persisting insulin deficiency diabetes develops with lacking signs of an attempt to replace the perished beta cells. For the time being, the nature of this target beta cell destruction by lymphocytes remains unclear. According to the enzyme-histochemical and electron microscopical results, the involved lymphocytes are natural killer cells (NK cells) rather than T cells. The release of the target cell reaction is obviously effected by the initial metabolic disturbances in the beta cells intervening in the insulin synthesis. Virus bodies do not play any role in this process. The importance of this animal model to human insulin-dependent diabetes mellitus is discussed.
We compared morphologically newborn piglets of alloxan diabetic sows with those of control animals. There were no histochemically detectable marked differences between the two groups investigated. In particular no differences in glycogen content of the liver and heart were observed. In all cases the endocrine pancreas was immature with sporadic formation of islet structures. In both groups we were able to demonstrate A- and B-cells immunohistochemically but not a hyperplasia of the B-cell system. The results obtained correlate with the absence of hyperinsulinaemia in newborn pigs of alloxan diabetic sows. We were unable to demonstrate the morphological background or cause of the diminished glucose-induced insulin release in case of alloxan diabetes as was found in 8-day old piglets. Therefore, the changes in newborn pigs of alloxan diabetic sows do not correlate with those in diabetic fetopathy in human beings.
In human sera two methods of islet cell cytoplasmic antibody (ICA) detection (on Bouin-fixed or cryostate sections of human pancreas) and the islet cell surface antibody (ICSA) method on isolated rat islet cells were compared. The ICA detection on Bouin-fixed sections was more sensitive than that on cryostate sections. In two groups of subjects with putative islet cell autoimmunity ICA prevalence was higher than ICSA prevalence. However, a weak correlation between both types of antibodies was established. In one group of healthy subjects with cytotoxic serum against rat beta cells a high prevalence of ICSA was found, whereas none of them had ICA. Defined on the basis of a positive immunofluorescence on rat islet cells, ICSA positive sera of newly diagnosed IDDM patients reacted to a significantly higher percentage with beta cells than did normal controls. In conclusion, of all methods compared ICA detection on Bouin-fixed pancreas sections seems to be the most suitable method for the detection of an islet cell autoimmunity.
The examination of pancreas tissue is of essential necessity for special diagnostic problems and for the clarification of the etiology of pancreas diseases. The needle biopsy--mostly used--not always delivers sufficient material and is combined with uncontrollable complications. A new method is described in this paper which allows to obtain specimens of the pancreas during abdominal operations in a safty manner. Examples are demonstrated which establish the usefulness of the method for different examinations (light- and electron microscopy, immunhistology, histochemistry and biochemistry). In 48 cases no complications were observed.
Electron microscopical and immunohistological findings in small biopsies obtained at surgery from two subjects with longstanding type-I-diabetes [insulin-dependent diabetes mellitus (IDDM)] are described and demonstrated in relation to clinical data. The main findings are the first electron microscopical demonstration of A cells scattered as single cells in the exocrine pancreatic tissue and the detection of intermediate cells of the acinar-A cell type. Intermediate cells have never been reported before in the pancreas of diabetes in man.
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Compared with control animals with a normal metabolism, rats with insulinopenic diabetes generally show an increase in glomerular deposition of complement-fixing immune complexes after immunization with bovine albumin and bovine gamma-globulin. Compared with the control group, the serum of the diabetic animals showed a reduction in the titers of IgM-isotype antibodies, which have a lower affinity. The concentration of the circulating immune complexes is the same. The increased frequency of glomular deposits in experimental diabetes can be explained by an increase in capillary permeability and by the formation of qualitatively different immune complexes.
8 rabbits were immunized with isolated fractions of renal glomerular basement membrane of 18 human diabetics and 18 human controls. The antisera were tested with the indirect immunofluorescence at frozen kidney sections of 31 longtime diabetics and 31 controls. One part of the sera was absorbed with isolated glomerular basement membrane of both groups before. In 30% of the diabetics we found antigens which were not observed in controls. Therefore, we conclude that a part of the diabetics produce not only too much but also a changed extracellular matrix in the glomeruli.
An insulin-deficient diabetes of long duration was induced by intravenous injection of alloxanmonohydrate (200 mg/kg and 100 mg/kg body mass, respectively) in 23 pigs (Landrace, Duroc) of 20-44 kg body mass. The dose of 200 mg/kg body mass was too high and there were fatal outcomes only. With the dose of 100 mg/kg and an initial body mass of 30-35 kg it is possible to induce a chronic diabetes mellitus in the pig. As complications we observed intoxications caused by alloxan, hypoglycemic situations from the 6th hour after application of alloxan with possible hypoglycemic damages, and septic complications by the intravenous catheter. Five out of 23 animals are still alive, 2 animals for 31 months and the others for 19 months. All the living animals have plasma glucose levels between 11 and 17 mmol/1 with very low values of plasma insulin. The serum triglycerides increased slightly in some cases, but not the serum cholesterol. The weight gain is retarded.
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Metabolic disorders and immunological factors are discussed in connection with the pathogenesis of diabetic microangiopathy. Renal biopsies were obtained from 22 diabetics (8 women aged 18 to 53, 14 men aged 15 to 52). 7 of the 22 patients had been suffering from diabetes for 2 weeks to 3 years, 10 for 7 to 25 years, 2 showed a pathological glucose-tolerance test, i.e., they had been "latent" diabetics, and 3 patients, had been so-called "potential" subjects of diabetes due to hereditary traits or delivery of big babies. They were examined by light miroscopy as well as by immunofluorescence microscopy. A number of cases were chosen for the differentiation and counting of glomerular cells (n=8) as well as for electron microscopic (n=7) and polarizing-microscopic (n=6) examinations. Histologically, focal proliferations of mesangial cells as well as an increase in mesangial substance in the glomeruli was found in all cases, although in a varying degree of intensity. These results were confirmed by both the glomuerular cell count and electron-microscopic examination. Immunofluorescence microscopy made it possible to detect frequently both IgA (9/17) and IgG (9/17), usually in either linear or mesangial arrangements whereas it was less frequently possible to detect IgM (1/17) and albumin (1/8) and impossible to detect beta1C in the glomerulus. Labeled insulin was detected five times in the glomerulus. Polarizing-microscopic measurements made in order to discover possible submicroscopic variations in the structure of GBM showed deviations in the average values of anisotropic indices from the controls in the group of long-term diabetics only. The pathogenesis of diabetic microangiopathy may be described as an inflow of immunoglobulins and serum proteins into the mesangium because of an alteration of the capillary endothelium, the mesangial cell being thus caused to overfunction, proliferate and produce an excess of mesangial matrix. In prolonged diabetes the mesangial cell, so far as its own metabolism is concerned, will finally be affected to the point where its power of synthesis is modified in the sense of an excess and/or faulty composition of GBM (glomerular basement membrane).
No diabetic angiolopathy was found in the retinas, kidneys and skeletal muscles of protodiabetic and overtly diabetic sand rats. The terminal blood vessels were investigated using histological, enzyme histochemical, immunofluorescence microscopic, autoradiographic and electron microscopic methods. There seems to be little or no connection in sand rats between the diabetic metabolism syndrome and the metabolic process leading to angiolopathy.
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