Regression of canine oral papillomas is associated with infiltration of CD4+ and CD8+ lymphocytes

Canine oral papillomavirus (COPV) infection is used in vaccine development against mucosal papillomaviruses. The predictable, spontaneous regression of the papillomas makes this an attractive system for analysis of cellular immunity. Immunohistochemical analysis of the timing and phenotype of immune cell infiltration revealed a marked influx of leukocytes during wart regression, including abundant CD4+ and CD8+ cells, with CD4+ cells being most numerous. Comparison of these findings, and those of immunohistochemistry using TCRalphabeta-, TCRgammadelta-, CD1a-, CD1c-, CD11a-, CD11b-, CD11c-, CD18-, CD21-, and CD49d-specific monoclonal antibodies, with previously published work in the human, ox, and rabbit models revealed important differences between these systems. Unlike bovine papillomavirus lesions, those of COPV do not have a significant gamma/delta T-cell infiltrate. Furthermore, COPV lesions had numerous CD4+ cells, unlike cottontail rabbit papillomavirus lesions. The lymphocyte infiltrate in the dog resembled that in human papillomavirus lesions, indicating that COPV is an appropriate model for human papillomavirus immunity.     

Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease

Two closely related genes, the presenilins ( PS ), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile AD). We performed a systematic mutation analysis of all coding and 5'-non-coding exons of PS -1 and PS -2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene ( APP ) had previously been excluded. Four different PS -1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50-78 years). One PS -2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS -1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS -1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5'-non-coding region of PS -1 and in intronic and exonic sequences of PS -2 that will be useful in genetic association studies.      

Social support and life events in working class women. Stress buffering or independent effects?

Several authors have suggested that social support reduces the risk of psychiatric disorder by providing a "buffer" against the adverse effects of stressful events. Others have proposed, in contrast, that social support is beneficial irrespective of life stress. We addressed this issue in a community survey of 193 working class mothers by measuring social support, threatening life events, psychiatric symptomatology, and psychological well-being via a detailed assessment combining a standardized interview and case-identification procedure with self-report questionnaires yielding continuous measures of distress and well-being. Subject selection minimized confounding between support and events. The effects of life stress and social support were found to be largely independent of one another, although detailed analysis suggested that the conclusions drawn in such studies are affected by the measures and statistics used.     

SC phocomelia syndrome, premature centromere separation, and congenital cranial nerve paralysis in two sisters, one with malignant melanoma

Two middle age sisters had most manifestations of the SC phocomelia syndrome including postnatal growth retardation, symmetric limb deficiencies with radial aplasia and absent thumbs, facial anomalies with microcephaly, microphthalmia, hypoplastic nasal alae, and borderline to mild mental retardation. Unusual findings included congenital paralysis of some cranial nerves in both patients and malignant melanoma in the proposita. Cultured lymphocytes from both patients, and skin fibroblasts, Epstein Barr virus-transformed lymphocytes, and tumor cells from the proposita demonstrated premature separation of centromeric heterochromatin (PCS) of many chromosomes, a finding noted previously in the SC phocomelia syndrome and the similar but more severe Roberts syndrome. Extensive overlap of the phenotypes of the sisters and 15 other patients with either syndrome and PCS confirms that these are either allelic conditions or the same disease--designated Roberts-SC phocomelia syndrome. The role of PCS in the syndrome(s) remains uncertain since some patients with the characteristic clinical phenotypes are reported to lack it.     

Sites of [3H]taurine Uptake in the Rat Substantia Nigra in Relation to the Release of Taurine from the Striatonigral Pathway

The autoradiographic localization of radiolabelled taurine taken up in the rat substantia nigra in vivo together with conditions of release of the [3H]taurine taken up into brain slices were studied to determine whether they are consistent with the hypothesis that taurine may act as a neurotransmitter in the striatonigral pathway. At the light microscopic level the main cellular elements that became radiolabelled following the injection of [3H]taurine into the substantia nigra could be identified as glial cells. Electron microscope autoradiography confirmed that a subpopulation of glial cells including astrocytes, pericytes, and oligodendrocytes were radiolabelled and that neuronal perikarya were not radiolabelled. In addition, axonal elements including both terminal and preterminal boutons were found to have silver grains overlying them and were thus considered to be radiolabelled. This was supported by a quantitative analysis of the distribution of the silver grains; whereas glial elements had a significantly higher number of grains associated with them than with any other structure, axonal elements had a significantly greater number of grains than dendritic structures. Release of the preloaded [3H]taurine from superfused slices of substantia nigra occurred in response to veratridine, was calcium-dependent and was sensitive to inhibition by high magnesium concentrations or tetrodotoxin. Following the destruction of neurons in the striatum by ibotenic acid injections, although the weight of the ipsilateral substantia nigra was reduced, the uptake of [3H]taurine was not altered. In contrast to this, the veratridine-stimulated release was markedly attenuated, implying that the destruction of striatal neurons causes the loss of sites in the substantia nigra from which exogenous taurine is released. These results add further support to previous suggestions that taurine might act as a neurotransmitter or neuromodulator in the striatonigral pathway.     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Transfection of the mullerian inhibiting substance gene inhibits local and metastatic tumor-growth

Mullerian Inhibiting Substance (MIS), a gonadal growth factor important in sexual differentiation, has antiproliferative activity against several human carcinoma cell lines. In this study, we examine the effect of MIS-transfection on the growth characteristics of Chinese hamster ovary (CHO) and human ocular melanoma (OM431) cells, compared to wild-type lines and a CHO line transfected with a noncleavable, inactive MIS mutant. MIS-transfection inhibited proliferation of CHO cells in double-layer agarose, tumor spheroid, and murine subrenal capsule assays, as well as growth of CHO and OM431 cells in pulmonary metastasis studies. These results anticipate further study of targeted gene therapy of certain human tumors with MIS gene constructs.     

EFFICACY OF SUCRALFATE IN PREVENTING GASTROINTESTINAL SIDE EFFECTS OF NSAIDs

To find out the efficacy of sucralfate in preventing gastrointestinal side effects of non-steroidal anti-inflammatory drugs (NSAIDs) a prospective, randomised single blind study was conducted from 1989 to 1992. Patients with osteoarthritis, rheumatoid arthritis and other long standing painful conditions, who were expected to receive NSAIDs for over three months, were recruited into the study. All medicines were discontinued for a period of 10–15 days prior to initial endoscopic assessment. NSAID therapy was started and the patients were randomised to receive either placebo (group A) or sucralfate (group B) in addition. Patient were reassessed clinically every week and an endoscopic examination was repeated after 6–8 weeks of follow-up. A total of 176 patients were studied in group A (n=91) and group B (n=85). At the end of 8 weeks gastrointestinal symptoms were present in 30.6% and 26.4% patients of group A and B respectively. Endoscopic assessment showed superficial lesions in 36.5% and 18.7% while endoscopic ulcer in 2.4% and 1.1% patients of groups A and B respectively. Thus in patients receiving chronic NSAID therapy, simultaneous administration of sucralfate reduces the incidence of superficial gastric lesions but has no significant effect on symptoms or ulcer formation.KEY WORDS: Gastropathy, Sucralfate, Nonsteroidal anti-inflammatory drugs