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Alterations in global DNA methylation have been observed in many cancers, but whether such alterations represent an epigenetic difference in susceptibility for the disease is unknown. The status of global DNA methylation also has not been reported in intact or specific types of cells involved in the carcinogenic process. To address these issues in lung carcinogenesis, we evaluated the status of global DNA methylation by using a monoclonal antibody specific for 5-methylcytosine (5-mc) in randomly selected lung specimens of 60 cigarette smokers who developed squamous cell carcinoma (SCC) and 30 cigarette smokers who did not. 5-mc immunostaining scores of DNA of SCC (0.61 +/- 0.42) and associated hyperplastic lesions (0.82 +/- 0.27) was significantly lower than those of DNA of histologically normal bronchial epithelial cells (0.99 +/- 0.52) and hyperplastic lesions (1.2 +/- 0.22) of noncancer specimens. The ratio of 5-mc scores between SCC and matched uninvolved bronchial epithelial cells was significantly associated with advanced stage and size of the tumor. The results suggest that alteration in global DNA methylation is an important epigenetic difference in susceptibility for the development of lung cancer. The reduced global DNA methylation in SCC compared with epithelial hyperplasia and its association with tumor size and disease stage is suggestive of its involvement in the progression of SCC. The results also indicate that normal methylation of DNA in epithelial hyperplastic lesions may prevent the transformation of these lesions to invasive cancer. If these results are confirmed, the status of DNA methylation in early lesions such as epithelial hyperplasia could be used to identify smokers who are at risk for the development of SCC.

We previously showed that a slow infectious strain of Creutzfeldt-Jakob Disease (CJD) can dramatically suppress the expression of a fast virulent agent injected intracerebrally 80days later. While the slow SY agent eventually produced disease at approximately 400days, there was little evidence of the fast FU agent. However, two of 18superinfected mice showed a minor increase in pathologic changes. To determine if FU was partially or completely suppressed, or if FU and SY agents formed a 'chimera' with intermediate incubation properties as predicted by prion theory, we passaged representative brains. All traces of FU were obliterated in typical brains of suppressed mice. The two aberrant mice however had mixed SY and FU infections, with FU reappearing at late stages of SY disease. Thus less virulent sporadic CJD infections in older people can conceal other agents such as variant CJD, the more recently evolved and virulent agent linked to bovine spongiform encephalopathy. This powerful model of agent-induced repression also implicates targets other than prion protein (PrP) in eliminating infection.

Regions where one type of epithelium replaces another (metaplasia) have a predilection for cancer formation. Environmental factors are closely linked to metaplastic carcinogenesis. In particular, cervical cancers associated with human papillomavirus (HPV) infection develop primarily at the transformation zone, a region where metaplastic squamous cells are detected in otherwise columnar epithelial-lined endocervical glands. Previously, we reported estrogen-induced multistage vaginal and cervical carcinogenesis in transgenic mice expressing HPV16 oncogenes in basal squamous epithelial cells. In the present study to investigate the threshold neoplastic response to exogenous estrogen, we treated groups of transgenic mice with lower hormone doses. A 5-fold reduction in estrogen dose induced squamous carcinogenesis solely at the cervical transformation zone compared with other reproductive tract sites. Further study delineated stages of transformation zone carcinogenesis, including formation of hyperplastic lower uterine glands and emergence of multiple foci of squamous metaplasia from individual stem-like glandular reserve cells, followed by neoplastic progression of metaplasia to dysplasia and squamous cancer. We propose that a combination of low-dose estrogen and low-level HPV oncogene expression biases transformation zone glandular reserve cells toward squamous rather than columnar epithelial fate decisions. Synergistic activation of proliferation by viral oncoprotein cell cycle dysregulation and estrogen receptor signaling, together with altered paracrine stromal-epithelial interactions, may conspire to support and promote neoplastic progression and cancer formation.

Changes in the manifestation of vulnerability to schizophrenia across the lifespan may hold important clues about aetiology. They may also illustrate some general principles about the nature of neurodevelopmental processes. Within the framework of a neural diathesis-stress model, we review findings on the precursors of schizophrenia and schizotypal personality disorder. The findings suggest that there are critical developmental periods for the manifestation of dysfunction and that, within certain domains of behaviour, there is a temporal disjunction between the onset of the neuropathology and its expression. It also appears that the diathesis for schizophrenia involves polymorphic behavioural expression, such that it can be manifested in multiple domains - motoric, cognitive and socio-emotional. Taken together, the data on the longitudinal course of schizophrenia indicate that the expression of the diathesis is moderated by central nervous system maturational processes. One putative moderating system, the hypothalamic-pituitary-adrenal (HPA) axis, is discussed, and implications for preventive intervention are explored.

Arteries predisposed and resistant to atherosclerosis development were studied. Arteries predisposed to atherosclerosis show a high degree of intima hyperplasia and various alterations of elastic structures. Hyperplasia of the vascular intima followed by disturbance of plasma perfusion through the arterial wall and increase of its cellularity (lymphocytes, monocytes/macrophages) determines possibility of atherosclerosis development (crucial factor of atherosclerosis pathogenesis) in man. Accumulation of lipids in the intima occurs not only in pronounced disturbances of lipid metabolism but at its "normal" indices as well this resulting in atherosclerosis development in all members of the population.

Objective: To characterize histologic, biochemical, and ultrastructural changes in the intestine of Irish Setters susceptible to gluten-sensitive enteropathy (GSE) during controlled oral challenge exposure with gluten after weaning., Animals: Six gluten-sensitive and 12 healthy Irish Setters and 3 healthy Greyhounds., Procedure: Jejunal biopsy specimens were taken at 4 and 12 months of age from the 6 gluten-sensitive Irish Setters, which had been reared on a gluten-free diet to which a controlled dose of gluten (0.5 g/kg of body weight/d) was added. Control specimens were obtained at 4 (n = 5) and 12 (7) months of age from the healthy Irish Setters, which had been fed a conventional gluten-containing diet, and at 4 months of age from the healthy Greyhounds fed the controlled dose of gluten. The specimens were subjected to histologic and ultrastructural examinations and assay of brush border enzymes., Results: Gluten-sensitive Irish Setters developed abnormalities characteristic of GSE at 4 months. Abnormalities were comparable to changes not seen previously until 12 months in dogs with GSE fed a conventional gluten-containing diet. In addition, microvilli were stunted and irregular, and a few were vesiculated and reduced in number; the glycocalyx was reduced or absent. By 12 months of age, there was improvement in morphologic and biochemical parameters, indicating partial recovery despite continued exposure to gluten., Conclusions: Relative early onset of intestinal damage, compared with that previously reported, and subsequent partial recovery suggestive of oral tolerance to gluten may be attributable to oral administration of gluten as a purified extract rather than in dietary cereal, but alternative explanations include differences in environment or genetic susceptibility to gluten.

Objective: To determine whether migraine in systemic lupus erythematosus (SLE) is associated with accentuated brain injury and disease activity., Methods: Forty SLE patients (11 without headache, 11 with non-migraine headache, and 18 with migraine) underwent clinical evaluation, magnetic resonance imaging (MRI), and spectroscopy (MRS)., Results: Recurrent headache occurred in 75% of SLE patients. MRI abnormalities and reduced N-acetylaspartate were common. However, migraine in SLE was not associated with increased disease activity or severity, neuropsychiatric manifestations, or end-organ involvement compared to patients without migraine (p > 0.05). There were no differences in the prevalence or severity of MRI or MRS abnormalities between SLE patients with migraine, with non-migraine headache, or without headache (p > 0.05)., Conclusions: Headache does not identify SLE patients at risk for brain injury, increased disease activity, or increased end-organ involvement. Aggressive immunosuppressive therapy for headache alone is not indicated in SLE.

Experimental allergic orchitis (EAO), the principle animal model of noninfectious testicular inflammatory disease, is a genetically determined phenotype. Classical EAO, induced by inoculation with testicular homogenate and the appropriate adjuvants, is characterized by inflammatory infiltrates in the testis (orchitis), epididymis (epididymitis), and vas deferens (vasitis). In this study, the genetic control of susceptibility and resistance to these three lesions was analyzed in the mouse. The results obtained with independent inbred strains and H2 congenic mice show that the genetic control of all three lesions is complex and involves both H2 and non-H2-linked genes. Whole-genome exclusion mapping was performed on a backcross population segregating for all three phenotypes. Permutation-derived thresholds provided experimentwise, chromosomewise, comparisonwise, and marker-specific chromosomewise thresholds for declaration of significant regions linked to marker loci. Unique loci were identified on chromosome 8 for orchitis, chromosome 16 for epididymitis, and chromosome 1 for vasitis and have been designated as Orch6, Epd1, and Vas1, respectively. These results show that autoimmune orchitis, epididymitis, and vasitis are immunogenetically distinct lesions.

Objective: To determine the prevalence of tumor diathesis (TD) in cervicovaginal smears from patients with squamous cell carcinoma (SQC)., Study Design: We reviewed all the cervical smears obtained no more than one year before a biopsy diagnosis of SQC. Patients who underwent irradiation to the cervix before the smear was taken were excluded from the analysis. The smears were rescreened by both authors, and the presence and extent of TD were recorded., Results: Twenty-eight smears from 19 patients with SQC fulfilled the study criteria. TD was seen in 15 of the 28 smears (54%). There was a positive correlation between the presence of TD and the depth of invasion., Conclusion: Although an important criterion of malignancy, TD is absent from some cases of SQC, particularly those that invade < 5 mm. A definite distinction between an intraepithelial lesion and a shallow invasive cancer may not be possible on cervicovaginal smears.

Clinical and pathologic features of 69 cases with primary hepatic lymphoma, 52 reported from Western countries and 17 cases from Japan, were summarized in terms of clinical findings including age and sex, past history, presenting symptoms, and physical findings, diagnostic procedures including imaging techniques and histopathology, and finally therapy and follow-up. The present cases included four patients with an acquired immunodeficiency syndrome and 12 with a history of chronic liver diseases. Histologically, all cases were non-Hodgkin's lymphoma with diffuse large cell type being the most common immunochemically about 80% were B-cell type. Follow-up showed that hepatic lymphoma had a relatively favourable prognosis provided early detection was possible.

The content of multinuclear endothelial cells and the ability of cells to incorporate 3H-thymidine were studied in primary cultures isolated from zones of low (LP) and high (HP) probability of atherosclerosis of adult human aortas. It was found that the percentage of multinuclear EC was at mean 2-fold higher in cultures from HP zones compared to LP zones of the same vessels. In primary cultures and in the first passage cultures only small mononuclear EC were able to incorporate 3H-thymidine. A significant decrease in the thymidine index (TI) was found only in cultures from HP zones of atherosclerotic aortas. In cultures of EC from the LP zones of these aortas the TI was as high as in cultures from the LP and HP zones from grossly normal vessels.

Intragranular and supragranular mossy fibers arise from granule cells and are present in the dentate gyrus of hippocampi from kindled and epileptic animals. The intragranular fibers often appear as fibers perpendicular to the long axis of the granule cell layer at periodic intervals. Rats and gerbils were analyzed to determine whether such mossy fibers are also associated with nongranule cells (including the basket cells), which send their apical dendrites through this layer with a periodicity similar to that of mossy fibers. The results for rats and both epileptic and nonepileptic gerbils show that many intragranular mossy fibers are apposed to the surfaces of the somata and apical dendrites of basket cells where they form asymmetric synapses. This plexus of mossy fiber axons appears to follow the dendrites of these neurons into the inner molecular layer. Based on previous data indicating that basket cells are GABAergic inhibitory neurons, the present findings in normal rats and both types of gerbils suggest that intragranular and supragranular mossy fibers provide additional circuitry for feedback inhibition to granule cells. It is possible that under pathological conditions, such as denervation or kindling, these fibers sprout and form synapses with granule cells.

Patients with hypertension frequently have vague complaints of dizziness and many other symptoms experienced by healthy individuals with motion sickness. We examined vestibular function in patients with essential hypertension, and we determined whether patients with essential hypertension are more prone to motion sickness using Coriolis stress testing. Vestibular function and Coriolis stress susceptibility were measured in 12 normotensive (NT) and seven asymptomatic patients with mild essential hypertension (HT). The Coriolis stress susceptibility index (CSSI) was calculated from the number of head movements in the four cardinal directions an individual could complete while being rotated in a computerized chair at increasing velocity before they developed motion sickness. The patients with hypertension had normal vestibular function and normal vestibuloocular responses as measured by standard techniques. Subjects with hypertension had significantly decreased Coriolis stress susceptibility scores compared to normotensive subjects (NT, 29.70 +/- 4.8; v HT, 5.48 +/- 2.0, P less than .001) and significantly decreased suppression of postrotatory nystagmus (NT, 44.5% +/- 3.8; v HT, 19.1% +/- 6.9, P less than .05). Medical treatment of hypertension did not result in an increased tolerance to provocative stimuli for motion sickness. It is suggested from our data that an increased susceptibility to motion sickness and abnormal vestibular responses to normal motion may account for many of the vague symptoms of "dizziness" reported by a large number of hypertensive patients.

The investigations conducted on Syrian hamsters have revealed that multiple enteral infusions of cold inactivated (t = -10 degrees C) O. felineus metacercariae resulted in the formation of immunocompetent cell and fibroblast infiltrations around the branches of the portal vein. The infestation of animals by viable pathogens led to reduced accommodation of helminths and suppressed cell infiltration in the liver. It is assumed that the native population of the foci become tolerant to the disease with the penetration of noninvasive Opisthorchis larvae into their body and the development of latent forms of helminthiasis.

In guinea pigs and noninbred white mice, infected subcutaneously with anthrax which resulted in their death, characteristic generalized infection with the hematogenic contamination of their organs and the signs of intoxication and shock could be observed. In inbred white rats (Fisher 344) the invasion and dissemination of B. anthracis are relatively slightly pronounced, the phenomena of intoxication and shock being clearly prevalent.

Epidemiological data indicate that patients suffering from diabetes, hypothyroidism, obesity, or following prolonged treatment with antibiotics, corticosteroids or oral contraceptives, have an increased tendency to develop cutaneous candidiasis. Since it is generally believed that attachment of microorganisms to host cells is an initial step in the evolution of infection, the aim of the present study was to investigate whether cells from susceptible individuals have increased capacity to bind the fungus. Corneocytes collected from the forearms of individuals of these susceptible groups were exposed in vitro to Candida albicans and adhesion to the cells was evaluated in comparison with adherence to cells from a non-susceptible population. Adherence in vitro was assayed microscopically and evaluated quantitatively by two parameters: 1) percentage of adherence - number of corneocytes with adhering yeasts on their surface, and 2) the total number of adhered yeasts. Results of the study revealed that the mean percentage of adherence and the mean total number of yeasts adhering to cells from individuals of the susceptible populations was twice as high as values in a healthy population. Statistical analysis of the data by Student's t-test indicated that the difference was significant (p less than 0.001).