John E. Craighead

Diabetes Mellitus: Induction in Mice by Encephalomyocarditis Virus

Hyperglycemia and lesions of the pancreatic islets of Langerhans developed in some, but not all, adult mice infected with a variant of the encephalomyocarditis virus. Large amounts of virus were recovered from the pancreas during acute stages of infection. At this time blood glucose concentrations were markedly elevated and the islets of Langerhans exhibited focal necrosis and degranulation of beta cells. Evidence of abnormal glucose metabolism persisted for varying periods after recovery from the infection. The islets of Langerhans of chronically hyperglycemic mice were distorted and decreased in size, and the beta cells were degranulated. Encephalomyocarditis virus appears to cause diabetes mellitus by reducing the mass of functional beta cells of the islets of Langerhans.

Cytomegalovirus Infection and Cytomegalic Inclusion Disease in Renal Homotransplant Recipients

Abstract Cytomegalic inclusion disease (CID) was found at autopsy in eight of twenty-five (32 per cent) renal homotransplant recipients who had been given drugs (azathioprine, prednisone, azaserine and actinomycin C, in various combinations) to suppress immunologic rejection of the graft. The disease occurred only in patients who survived transplantation for one or more months. A review of autopsy material from transplant recipients who died at the Peter Bent Brigham Hospital since 1951 showed conclusively that the disease was associated with immunosuppressive drug treatment. Cytomegalovirus (CMV) was recovered at autopsy from six patients. Generalized infection was demonstrated in five of the six; substantial amounts of virus were found in the lungs, salivary glands, pancreas and transplanted kidney. However, the virus titer of the tissues did not correlate well with the relative numbers of histologically evident cytomegalic cells containing inclusion bodies or the occurrence of lesions directly attributable to infection. Cytomegalovirus was isolated from the urine or oropharyngeal secretions of seven of ten adult homotransplant recipients given immunosuppressive drugs. Five children treated similarly failed to yield the virus. Several patients excreted virus for extended periods of time. Illness due to infection was not observed. Cytomegalovirus infection is a common complication of renal homotransplantation when immunosuppressive drugs are used and the resulting cytomegalic inclusion disease occasionally is responsible for death. The evidence, although incomplete, suggests that these drugs activate latent virus. The possibility that the infection is acquired by person-to-person spread remains to be excluded.

Fatal disease of swine due to encephalomyocarditis virus.

Encephalomyocarditis virus was isolated from the organs of swine dying during an outbreak of an acutely fatal disease occurring on a farm in Panama. The outstanding lesion was severe myocarditis. Pigs inoculated with the viral isolate developed a systemic infection with myocarditis.

Current views on the etiology of insulin-dependent diabetes mellitus.

THE pathogenesis of diabetes mellitus has long been an enigma. Because of its familial pattern of transmission and the subtle chronicity of the disease, diabetes has been considered a degenerative ...

Mechanisms of asbestos carcinogenesis

Abstract A striking synergistic effect on tumor induction is seen when asbestos and polycyclic hydrocarbons (PCH) are inhaled by or instilled intratracheally into rodents. This observation supports the results of epidemiologic studies indicating that the incidence of bronchogenic carcinoma is increased substantially in smokers occupationally exposed to asbestos. To determine the mechanisms of asbestos-induced carcinogenesis at the cellular level, cell and organ cultures of tracheobronchial epithelium were examined morphologically and biochemically after their exposure to asbestos with and without the adsorption of PCH to its surfaces. Asbestos was phagocytized by the basal cells of the epithelium. The mineral stimulated cellular division, hyperplastic and metaplastic changes, and induction of Na+K+ ATPase, a marker enzyme for the plasma membrane. The metabolism of 3-methyl-cholanthrene (3 MC), as determined by aryl hydrocarbon hydroxylase (AHH) activity in monolayers of epithelial cells after their exposure to both asbestos and 3 MC, was potentiated. A hypothetical construct depicting the role of asbestos in carcinogenesis of the respiratory tract is presented.

Interstitial associations of cells lining air spaces in human pulmonary fibrosis

An ultrastructural study of the cells that line air spaces in human pulmonary fibrosis is reported. Intimate associations between these cells and cellular elements in the interstitium were consistently found in biopsies from 25 cases. Cytoplasmic extensions of cuboidal pneumocytes protruded through discontinuities in the subjacent basement membrane. Attenuated cells having structural properties of fibroblasts were situated on connective tissue that formed the walls of numerous air spaces. In this situation, a basement membrane was not demonstrable. These heretofore undescribed features suggest a dynamic interaction between certain mesenchymal and epithelial elements in the fibrotic lung.

Long-Term Maintenance of Differentiated Respiratory Epithelium in Organ Culture I. Medium Composition

Summary Six commercially prepared, chemically defined media were tested in the presence and absence of serum to assess their influence on the maintenance of viable hamster respiratory epithelium over extended periods of time in vitro. Unique proliferation of epithelial elements was observed in organ cultures maintained in “complex” media containing serum, whereas use of these media in the absence of serum produced disorganized epithelial changes resembling squa-mous metaplasia. Minimum essential media at low serum concentrations preserved the columnar structure of the normal tracheal epithelium for 8 wk and longer in vitro.

Comparative effects of fibrous and nonfibrous minerals on cells and liposomes

Abstract The comparative effects of chrysotile asbestos, silica, talc, kaolinite, and montmorillonite on cellular and artificial membranes were examined using three test systems—monolayer cultures of tracheal epithelial cells, suspensions of sheep erythrocytes (RBC), and preparations of phospholipid-cholesterol vesicles. The four minerals caused perturbations in each system, although to varying degrees. Membrane alterations induced by chrysotile asbestos and the clay mineral montmorillonite were more striking than those caused by other dusts. The results obtained with the three test systems were consistent. Electron microscopic observations indicated that the particles were phagocytized by cultured epithelial cells of hamster tracheal origin and developed intimate associations with the RBC plasma membrane. These interactions are discussed with regard to possible mechanisms of cellular injury and their relevance to pulmonary disease.

Studies on the Mechanism of Mucin Secretion by Cells of the Porcine Tracheal Epithelium

Abstract The effects of selected pharmacological agents on mucin secretion by the tracheal epithelium of piglets were studied using organ culture. Mucin release into the culture medium was reduced, and mucin retention by secretory cells of the mucosa and submucosal glands was increased, by colchicine, vinblastine sulfate, and cytochalasin B. Dibutyryl cyclic AMP had no significant effect. Although these agents have diverse and poorly understood influences on cell functions, the results suggest a possible role for mi-crotubules and microfilaments in the intracellular movement and release of mucin.

Virus-induced diabetes in mice☆

Abstract As recently reported, a variant of the encephalomyocarditis virus can induce a diabetic syndrome in mice. Forty-six animals were inoculated and followed by urinary glucose every other day. Eighteen of 30 which survived the infection were sacrificed on the 4th, 8th, 12th, and 24th postinfection day. Six of 30 non-infected mice served as controls. The parameters measured were blood glucose, immunoreactive insulin and pancreatic insulin. Four days after inoculation hyperinsulinemia was apparent, without alteration in blood glucose or pancreatic insulin content. Hyperglycemia and glycosuria were present at 8, 12, and 24 days, associated with a reduction of pancreatic insulin. Serum insulin was significantly below control levels only at 12 days following infection. These biochemical findings support the histological evidence that a variant of the encephalomy-ocarditis virus produces pancreatic islet lesions in mice, resulting in a diabetic syndrome.