Endothelin receptor antagonism ameliorates mast cell infiltration, vascular hypertrophy, and epidermal growth factor expression in experimental diabetes.

Vascular hypertrophy, a feature of experimental and human diabetes, has been implicated in the pathogenesis of the microvascular and macrovascular complications of the disease. In the present study, we sought to examine the role of endogenous endothelin and its relation to vascular growth factors in the mediation of vascular hypertrophy in experimental diabetes and to examine the contribution of mast cells to this process. Vessel morphology, endothelin, growth factor gene expression, and matrix deposition were studied in the mesenteric arteries of control and streptozotocin-induced diabetic Sprague-Dawley rats treated with or without the dual endothelin(A/B) receptor antagonist bosentan (100 mg x kg(-1) x d(-1)) during a 3-week period. Compared with control animals, diabetic animals had significant increases in vessel weight, wall-to-lumen ratio, mast cell infiltration, extracellular matrix deposition, and gene expression of epidermal growth factor (EGF) and transforming growth factor-beta(1). In diabetic, but not control, vessels, not only were EGF mRNA and endothelin present in endothelial cells, but also their expression was observed in adventitial mast cells. Immunoreactive endothelin was present in the media of mesenteric vessels of diabetic, but not control, animals. Bosentan treatment significantly reduced mesenteric weight, wall-to-lumen ratio, mast cell infiltration, matrix deposition, and EGF mRNA but did not prevent the overexpression of transforming growth factor-beta(1) mRNA in diabetic rats. These findings suggest that endogenous endothelin and EGF may play a role in diabetes-induced vascular hypertrophy and that mast cells may be pathogenetically involved in this process.

Regulation of c-Myb through protein phosphorylation and leucine zipper interactions.

c-Myb function is modulated in part by a negative regulation domain which encompasses a leucine zipper (LZ). When E. coli-expressed c-Myb with wild type or mutated LZ proteins are assessed for DNA binding activity, the mutant form is substantially better at DNA binding than the wild type (WT) form. In contrast, the DNA binding activity of the WT protein is increased to an equivalent level of activity of the LZ-mutant when both are expressed in rabbit reticulocyte lysates (RRL) or insect cells. The possibility that phosphorylation overcomes the negative influence of the LZ was investigated. E. coli-expressed mutant, but not wild type c-Myb proteins, were shown to be substrates for Casein Kinase II (CKII) and cAMP-dependent Protein Kinase (PKA). The phosphorylation sites for CKII and PKA were serines 11 and 12, and 8 and 116, respectively. Serines 11 and 12 were found to be phosphorylated in recombinant wild type and mutant c-Myb expressed in insect cells and DNA binding was markedly reduced following phosphatase treatment. Substitution of serines 11 and 12 with glutamic acid and alanine in E. coli-expressed Myb demonstrated that these amino terminal residues influence the negative effect on DNA binding exerted by the LZ. Collectively, these observations support the notion that phosphorylation of serines 11 and 12 positively modulate DNA binding.

A cell line (LIM 2463) derived from a tubulovillous adenoma of the rectum.

We describe a new epithelial cell line (LIM 2463) derived from tubulovillous adenoma of the rectum. The cells grow as organoids and secrete large amounts of mucus. The cells are polarized, with a microvillar brush border, and express dipeptidyl peptidase IV in a polarized manner. No staining was seen with 3 other antibodies directed against other brush-border hydrolases or disaccharidases. Focal polarized staining was obtained with 2 antibodies directed against other brush-border-associated peptides. The cells are aneuploid with a distinctive karyotype (48, XX, +9, +13). All attempts to clone the cells in semi-solid agar or to grow them as xenografts in nude athymic mice have failed.

Gastric carcinoma at Tygerberg Hospital, 1979-1983. A retrospective study.

A retrospective study was carried out on patients with histologically proven gastric carcinoma diagnosed at the Gastro-intestinal Clinic, Tygerberg Hospital, over a 5-year period--1979-1983. Fifty per cent of patients were coloured men. The overall median age was 65 years but the coloured patients were significantly younger than the white. The main symptoms were loss of appetite and weight, abdominal pain and vomiting. The median duration of symptoms in all patients was 3 months. An abdominal mass, anaemia and obvious weight loss were the most important physical signs. A normocytic, normochromic anaemia, an elevated erythrocyte sedimentation rate, raised liver enzyme levels and hypo-albuminaemia were the most important laboratory findings. In 96% of the 149 patients gastroscopy yielded a positive diagnosis of gastric carcinoma and barium meal examination showed abnormalities in 87%. In the majority of cases the carcinoma was poorly differentiated.

Hodgkin's disease and acute promyelocytic leukaemia. A case report.

A case of Hodgkin's disease is reported in which acute promyelocytic leukaemia developed within 5 months of initiation of chemotherapy. Only 3 other cases, possibly of a similar nature, were found in the literature; these had occurred 15, 77, and 226 months respectively after the initial diagnosis of Hodgkin's disease.

A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part IV. Preventive and prophylactic measures.

During the Crimean-Congo haemorrhagic fever (CCHF) outbreak at Tygerberg Hospital a particular problem existed: a simultaneous influenza epidemic complicated the screening of contacts because of its very similar clinical picture to that of early CCHF. The methods of identifying and screening contacts are described. Of 459 listed CCHF contacts, 7 (1,5%) developed the disease; 6 were contacts of the index case and only 1 a contact of a secondary case. Two of the 7 CCHF patients had no direct contact with the index case; this caused great concern about the dissemination, despite the otherwise full protective measures. Four of 46 blood contacts (8,7%) and 3 of 9 needle contacts (33%) developed the disease. Prophylactic interferon therapy had to be discontinued because of side-effects mimicking the symptoms of CCHF. Ribavirin was used prophylactically in 6 of the 9 inoculation contacts. One of the patients on ribavirin had a mild clinical course while 5 others who received the drug developed neither clinical CCHF nor antibodies to the virus. Two of the 3 needle contacts not treated with ribavirin had a severe clinical course. One contact with needle inoculation and 42 proven blood contacts who had not received ribavirin did not become infected. No firm conclusion can therefore be made about the protective value of prophylactic ribavirin.

Gastric juice carcino-embryonic antigen estimation. A useful additional test in the diagnosis of gastric carcinoma?

There is a high incidence of gastric carcinoma in the coloured population of the Western Cape. Diagnostic tests other than barium meal examination or gastroscopy were investigated. In this study 50 patients were assessed and grouped according to the gastroscopic and histological findings. Twenty-five patients with gastric carcinoma and 25 with benign gastric ulcer and/or chronic atrophic gastritis and/or intestinal metaplasia were tabulated. The gastric juice and plasma carcino-embryonic antigen (CEA) levels were evaluated and compared in the two groups. The gastric juice CEA level was more useful than the plasma CEA level as an aid in diagnosing malignant gastric lesions. No correlation was evidence between CEA values and the extent of the gastric carcinoma and or histological typing. An elevated gastric juice CEA level was an additional aid in diagnosing gastric carcinoma. Markedly elevated values may also identify the high-risk patient who is prone to develop gastric carcinoma.

Lack of an association between carcinoma of the stomach and the major histocompatibility complex (HLA) in Cape Coloureds.

A possible genetic contribution to the high incidence of gastric carcinoma in the Cape Coloured population of the Western Cape region of South Africa was investigated. The HLA-A, B, C, DR and DQ antigens were determined with a microcytotoxicity assay, and their frequencies compared in 124 individuals with gastric carcinoma and 4,560 controls. No significant difference was found, thus supporting the view that a genetic component has a minor, if any, role in gastric carcinogenesis.

Familial dilated (congestive) cardiomyopathy. Occurrence in two brothers and an overview of the literature.

Two young White brothers had dilated (congestive) cardiomyopathy. The elder came to autopsy after a chronic course of congestive cardiac failure, the younger underwent repeated cardiac catheterization and transvenous right ventricular endomyocardial biopsy specimens demonstrated histopathological features in keeping with a diagnosis of idiopathic dilated cardiomyopathy. These brothers may have the familial form of the disease, although post-viral myocarditis cardiomyopathy cannot be entirely excluded. The literature relating to familial dilated (congestive) cardiomyopathy is reviewed.

A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part II. Management of patients.

During the outbreak of Crimean-Congo haemorrhagic fever (CCHF) at Tygerberg Hospital 8 patients were diagnosed positive. CCHF was diagnosed in another patient several months later. The treatment of these 9 cases is outlined. When it became evident that CCHF could present with a spectrum of severity, treatment was adjusted according to each patient's requirements. The essential components consisted of correction of haematological abnormalities combined with hyperimmune serum; the latter is particularly important for the severely ill patient with no antibodies to CCHF. The antiviral agents ribavirin and interferon were used but evidence to substantiate their application in future cases was inconclusive. Interferon was discontinued because of severe side-effects, many of which simulated the clinical features of CCHF. Objective improvement after corticosteroid treatment was noted in only 1 patient, but some of her symptoms could have been due to a transfusion reaction. Antibiotics were not routinely used. The 2 patients who died were diagnosed late, did not receive hyperimmune serum, and eventually developed multi-organ failure. The course of CCHF can probably be modified if the diagnosis is made early, if antiserum is given, and if the haematological abnormalities are promptly corrected.

A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part I. Clinical features.

Crimean-Congo haemorrhagic fever (CCHF) is a rare disease in South Africa. From 1981 to September 1984, 8 sporadic primary cases were reported. An outbreak of CCHF in a large university hospital is described; of 8 patients diagnosed 2 died (the index and a secondary case). Four patients were seriously ill and 2 had a mild illness. Problems were encountered in diagnosing the disease, which presents initially with influenza-like symptoms, differing only in severity from influenza. However, petechiae and other manifestations of a bleeding tendency distinguished it from influenza in the later phase of the disease. Special investigations, especially those revealing leucopenia and thrombocytopenia, were critically important in early diagnosis. The dilemma of handling this highly contagious disease is that definite virological diagnosis is time-consuming and is conducted in only one high-security laboratory 1600 km distant. A further case was admitted 3 months later from a different locality and confirmed virologically but no secondary cases could be confirmed or traced.