[Polypoid ulcerating endocarditis aortalis caused by Streptococcus viridans with perforation of the right atrium. Pathology and clinical aspects of 2 autopsy cases]. / Polypös-ulzeröse Endokarditis aortalis durch Streptococcus viridans mit Perforation in den rechten Vorhof. Pathologie und Klinik von 2 obduzierten Fällen.

We report two cases of patients (one 65 and one 43 years of age, respectively) who died of Streptococcus-viridans induced endocarditis of the aortic valve with perforation into the right atrium. Whereas perforation in Staphylococcus-induced endocarditis is a common complication, it occurs rarely in Streptococcus-induced endocarditis. Because of its uncharacteristic symptoms, the endocarditis was clinically unknown in both cases and was recognized to be the cause of death only at autopsy. To reduce the large number of complications in patients suffering from endocarditis, it is necessary to confirm the diagnosis as soon as possible if endocarditis might be suspected.

Expression of chromogranin A and B and secretoneurin immunoreactivity in neoplastic and nonneoplastic pancreatic alpha cells.

In the endocrine pancreas, chromogranins A and B as well as secretoneurin (a biologically active peptide processed endoproteolytically from secretogranin II) are most intensely expressed in alpha (glucagon) cells. We examined whether the functional status of neoplastic and nonneoplastic human alpha cells is reflected in the expression patterns of chromogranins/secretogranins. Neoplastic alpha cells were analysed immunocytochemically in six functioning glucagonomas and 37 nonfunctioning neuroendocrine tumours (29 with alpha cells) for their immunoreactivity to chromogranin A and B, as well as secretoneurin. There was no difference in the staining intensity for either peptide between glucagonomas and nonfunctioning, alpha cell containing tumours. Nonneoplastic alpha cells from patients with a functioning glucagonoma showed a decreased glucagon immunoreactivity, whereas the expression of chromogranin A (but not chromogranin B and secretoneurin) was as intense as in alpha cells not associated with glucagonoma syndrome. These results suggest that the expression of chromogranins/secretogranins in neoplastic alpha cells of the pancreas may be independently regulated from the cells' functional status. In nonneoplastic alpha cells there seems to be an association between glucagon production and chromogranin B and secretoneurin expression.

[Clinical relevance of malignant lateral branchial cyst]. / Klinische Relevanz der malignen lateralen Halszysten.

We analyzed 7 patients with so called "maligne lateral cervical cysts" regarding the controversies in the literature. Primary tumors of oropharyngeal sites were discovered in all these cases of "branchiogenic carcinoma" rising the final diagnosis of cystic metastases. Diagnostic tonsillectomy is supposed to be important to solve this problem of differential diagnosis. The issue of malignant transformation in cysts of branchial cleft origin has to be recognized as being an oncological artifact. We argue that the "maligne lateral cervical cyst" does'nt exist as a proper entity. In analogy to the principles of the treatment of oropharyngeal cancer ipsilateral neck dissection and wide local excision of the cyst followed by radiation therapy is the suggested plan of therapeutic management. Search for a possible unknown primary tumor within the oropharynx must be continued over years.

An immunohistochemical study of the breast using antibodies to basal and luminal keratins, alpha-smooth muscle actin, vimentin, collagen IV and laminin. Part II: Epitheliosis and ductal carcinoma in situ.

A detailed immunohistochemical study has been carried out on 63 breast lesions with epitheliosis, ductal carcinoma in situ and clinging carcinoma (lobular cancerization), using antibodies directed against keratins 5/14 and 14, 15, 16, 18, 19, vimentin, smooth muscle actin, collagen IV and laminin. The results have shown that epitheliosis on the one hand and ductal in situ and clinging carcinoma on the other are immunohistochemically different epithelial lesions. Epitheliosis appears to be epithelial hyperplasia with keratin 5/14 and keratin 14, 15, 16, 18, 19-positive cells. Compared to epitheliotic cells tumor cells of clinging carcinoma, lobular cancerization and ductal carcinoma in situ expressed only luminal keratins 14, 15, 16, 18, 19 in 85% of the cases studied; whereas in 15% there was a basal keratin expression. From our results we conclude that the clinging carcinoma (lobular cancerization) represents the initial morphological step in the development of ductal carcinoma in situ and thus may be interpreted as a minimal ductal neoplasia. With the immunohistochemical demonstration of basal and luminal keratins it may be possible in individual cases to differentiate between benign and malignant in situ lesions of the breast.

An immunohistochemical study of the breast using antibodies to basal and luminal keratins, alpha-smooth muscle actin, vimentin, collagen IV and laminin. Part I: Normal breast and benign proliferative lesions.

The distribution of simple epithelial (K8/18/19) and basal (myoepithelial) (K5/14) keratins, alpha-smooth-muscle actin, vimentin, collagen IV and laminin in normal mammary glands and in benign proliferative lesions was studied using monoclonal antibodies (mAbs). These antibodies (Abs) identified myoepithelial cells and luminal cells specifically. In lesions with adenosis and papillomas, the two-layered formation resembled that of normal glands with a purely myoepithelial-epithelial differentiation. In scleradenotic lesions, the main cell was of myoepithelial immunophenotype with intermixed trabecular-tubular proliferations of simple-type epithelium. The sclerosis seems to be the result of an irregular basal lamina synthesis by the myoepithelial cells. In contrast to these lesions, epitheliosis represents a purely intraluminal cell proliferation of clearly simple epithelial immunophenotype and of cells with a basal keratin phenotype, lacking myoepithelial differentiation antigen actin. The basal keratin type epithelium may represent post-stem or intermediate cells developing into luminal epithelium. Epitheliosis appears to be a purely epithelial hyperplasia with striking similarity to the regeneration of normal breast epithelium. The different proliferative patterns may give an explanation for differences in potential cancer risks of patients with these lesions.

Combined subtotal pancreatectomy with selective streptozotocin infusion--a model for the induction of insulin deficiency in dogs.

Standardized models of type I diabetes-like insulin deficiency in larger laboratory animals hardly exist. It was therefore investigated whether stable long-term insulin deficiency in dogs can be induced by selective beta-cell destruction in a safe and reliable procedure without damage of other organs. In Beagle dogs, the diabetogenic response to systemic streptozotocin administration (38.5-28 mg/kg b.wt.) was tested. In addition, resection of corpus and cauda pancreatis in combination with selective streptozotocin perfusion (25 mg/kg b.wt.) of the remaining pancreas tissue was evaluated. Whereas systemic streptozotocin administration failed to destroy insulin secretion, but led to a variety of intoxication symptoms even in comparatively low doses (28 mg/kg b.wt.), the latter procedure resulted in a complete and persistent insulin depletion (basal serum immunoreactive insulin less than or equal to 3 microU/ml, no stimulated response) without toxic organ damage or other serious side effects. The dogs developed type I-like diabetes, which required continuous exogenous insulin substitution. From these results, subtotal pancreatectomy with selective streptozotocin perfusion of the remaining pancreas is proposed as a safe model of insulin deficiency in dogs, which should be further evaluated in experimental diabetology.

Inhibition of immune-mediated low-dose streptozotocin diabetes by agents which reduce vascular permeability.

Low-dose streptozotocin treatment in C57Bl/6J mice causes development of hyperglycemia within two weeks. Diabetes development is due to the specific loss of beta cells from pancreatic islets which can be blocked by immunosuppressive treatment. The role of vascular permeability in pancreatic islet destruction was studied by administration of methysergide or pargyline in addition to low-dose streptozotocin. Both drugs impair serotonin-enhanced vascular permeability. Administration of methysergide or pargyline during the first 11 days following streptozotocin treatment caused substantial suppression of diabetes development. These observations suggest a role of enhanced vascular permeability in immune-mediated beta cell destruction.

Recombinant interleukin 2 enhances spontaneous insulin-dependent diabetes in BB rats.

Treatment of BB rats with recombinant interleukin 2 (IL2) enhanced the development of spontaneous diabetes in these animals. A dose of 20 micrograms IL 2/kg body weight was administered twice daily for 80 days starting at 42 days of age. The rate of diabetes was doubled after IL 2 administration (53% vs. 23%) and the onset of diabetes was found to be accelerated by a mean of 18 days. Histological analysis showed enhanced inflammation of islets and in addition interstitial pancreatis. It is concluded that IL 2 has a regulatory effect on spontaneous organ-specific autoimmunity.

Chronic insulitis after partial islet damage by passive insulin antibody transfer.

The effect of passive insulin antibody transfer into recipient mice was reevaluated. Mice of inbred strains BALB/c, C57Bl/6 and DBA/2 received 10 injections of hyperimmune guinea pig insulin antiserum within 2 weeks. Ten days later the animals were sacrificed. It was found that up to 40% of animals had developed chronic lymphocytic infiltrations of pancreatic islets (insulitis) without showing diabetic symptoms. It is concluded that repeated damaging of islet tissue by passive insulin antibody transfer may result in chronic, possibly autoimmune insulitis. Our observation supports the concept that partial damage of pancreatic islets by environmental factors may trigger an organ-specific progressive islet cell destruction process mediated by immune cells.

Cell mediated immunity to islet cells: lessons from animal studies.

As a pathogenic factor of type I (insulin-dependent) diabetes cell mediated immunity to pancreatic islet cells, i.e. lymphocytic insulitis has been studied in mice with spontaneous lupus-like autoimmune disease, in mice with experimentally induced immune dysregulation and in mice treated with multiple low doses of streptozotocin or with alloxan. The following conclusions have been reached: Autoimmunity to B-islet cells requires a disturbed immune system. Autoimmune insulitis requires altered B-islet cells. Cellular immunity to B-islet cells apparently involves two different mechanisms: The intrainsular invasion of single lymphocytes and macrophages and the mostly periinsular/periductular infiltration of large numbers of lymphocytes and macrophages. Some observations indicate a primary role of helper and suppressor T lymphocytes as well as of macrophages in B-islet cell destruction. In this paper an attempt will be made to combine observations on the induction and course of insulitis in several animal models in a general scheme of pathological events. Several conclusions on the mechanism of islet autoimmunity have been reached. At the time being however, these "lessons" must be regarded as hypotheses, which may be helpful in understanding the pathogenesis of human type I diabetes.

Insulitis as a consequence of immune dysregulation: further evidence.

Lymphocytic infiltrations in pancreatic islets (insulitis) have been shown previously to occur in mice with spontaneous or experimentally induced immune disorders. We now have studied which type of immune dysregulation leads to insulitis. Immune disorders were induced by treatment with cyclophosphamide (Cy) or phenytoin and by graft versus host reactions (GVHR) across minor or major histocompatibility barriers. Histological analysis of immune disturbed animals revealed insulitis after phenytoin treatment and as a consequence of GVHR. Insulitis during GVHR is only observed in certain mouse strain combinations. Treatment with Cy in a large dose range does not lead to lymphocytic infiltration of pancreatic islets. It is concluded that cellular immunity to islet cells can occur spontaneously during certain types of immune dysregulation. Since phenytoin treatment and GVHR stimulate lymphocytes reactive with major histocompatibility antigens, such structures may also be part of target antigens on islet cells.

What's new in diabetes? Etiological and pathogenetic aspects of juvenile-onset (type I) diabetes.

In recent years research on the pathogenesis of juvenile-onset, insulin-dependent diabetes mellitus (now called type I) has considerably expanded, a development that is documented by an impressive number of conferences and symposia held on this topic every year. In the present review the authors will discuss new insights into the etiology of type I diabetes. Additional information is available in several recently published reviews.

Strain dependency of the transfer of experimental immune insulitis in mice.

Multiple treatment with low doses of streptozotocin induces hyperglycaemia with concomitant lymphocytic infiltrations into pancreatic islets (insulitis) in several mouse strains. The transfer of cellular immune reactions against islet cells by means of spleen cells was tested in two congeneic and five allogeneic strain combinations. Donor mice were treated on 5 consecutive days with 40 mg streptozotocin per kg body weight. Three weeks later, 5 x 10(7) live spleen cells were transferred into thymusless recipient mice. Insulitis which had developed in about 70% of the donors was only transferable from C57B1/6J to congeneic thymusless mice. In a second congeneic and in all allogeneic strain combinations, cellular immune reactions against pancreatic islets could not be transferred. In none of the recipients of spleen cells from diabetic donors was hyperglycaemia observed. As streptozotocin-induced cellular immune reactions against pancreatic islet cells were only transferable in one congeneic and in no allogeneic strain combinations, it is concluded that there is a genetic restriction both on the levels of donor and recipient mice.

Cellular immune reactions against pancreatic islets as a consequence of graft versus host disease.

We studied autoimmune reactions against pancreatic islets occurring as a consequence of defects of the immune system rather than after pathological changes in the endocrine organ itself. Immune dysregulation was induced by transfer of parental lymphocytes into semi-allogeneic F1 recipient mice (graft versus host reaction, GVHR). Recipients were killed 1 month after the induction of the disease. Pancreatic islets were screened by light microscopy for signs of lymphocytic infiltration (insulitis). Severe insulitis was found in all mice undergoing GVHR. The cytotoxic activity of lymphocytes was apparent in electron microscopic studies and affected only B cells. Infiltrations were not seen in the exocrine part of the pancreas nor in heart, liver or kidneys at this early stage of GVHR. It is concluded that non-specific disorders of the immune system induced by GVHR may lead to specific cellular autoimmune reactions against B cells of pancreatic islets.

Spontaneous autoimmune reactions against pancreatic islets in mouse strains with generalized autoimmune disease.

The spontaneously autoimmune mouse strains NZB, NZB X NZW, MRL and BXSB have been examined for signs of autoimmune reactions against islet cells. Between 15 and 55 animals of each strain were tested. Infiltrates of lymphocytes and fibroblasts into pancreatic islets were found in more than 80% of NZB mice, in about 50% of MRL and NZB X NZW mice, and in less than 20% of BXSB mice. Infiltrates were not found in the exocrine portion of pancrea. All NZB mice had abnormal glucose tolerance. In the three other strains between 20 and 50% of animals had abnormal glucose tolerance. All mice had fasting normoglycaemia. The lesions in NZB mice were studied in more detail. It was found by ultrastructural analysis that in young mice pancreatic infiltrates consisted of lymphocytes and fibroblasts. Single lymphocytes were also seen outside the main infiltration area. After 2 to 5 months of age another type of infiltrate, consisting of lymphocytes and macrophages was observed. B-cell destruction by lymphocytes was apparent in both young and adult NZB mice. It is concluded that cellular autoimmune reactions against pancreatic islets may occur spontaneously as a consequence of immunological disorders in NZB, NZB X NZW and MRL mice.

Transfer of experimental autoimmune insulitis by spleen cells in mice.

We have tested whether experimental insulitis induced by multiple subdiabetogenic injections of streptozotocin can be transferred by lymphocytes to normal recipients. C57BL/6J mice were treated on 5 consecutive days with 40 mg streptozotocin/kg body weight. 5 X 10(7) nucleated spleen cells from 20 animals which had developed hyperglycaemia with concomitant insulitis three weeks after the first streptozotocin-injection, were transferred into congenic thymusless C57BL/6J-nu/nu mice. The cell transfer led to lymphocytic infiltrations of pancreatic islets in 75% of the recipients. Hyperglycaemia was not observed. It is concluded that low-dose streptozotocin treatment induces cellular immune reactions against pancreatic islets.

[Wound healing after surgery by laser, scalpel and thermocautery (author's transl)]. / Vergleichende Beobachtungen zur Wundheilung nach Laser, Skalpell- und Thermokauterschnitt.

Laser-, thermocautery- and scalpelsurgery when compared in respect to their wound healing procedure have qualified as prepared for clinical application. On minipigs wound healing of skin scissions has been followed up morphologically in light microscopy and by testing the stress resistance of 16 days old scars. The fastest wound healing occurs after scalpel incision resulting in an almost perfect reconstruction of subepethelial tissue architecture at the 20th postoperative day. The initial tendency of laser incisions to dilate, which is still more pronounced in thermocautery wounds, causes a flat funnel shaped deformation of the scars, again more distinct after thermocautery. This is reflected in a still remaining slight disarrangement of the subepithelial collagenous fibres at the 20 postoperative day. Stress resistance is maximal in thermacautery scars, i. e. almost 30% higher than in scalpel and laser scars.