The human prion diseases, Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler syndrome (GSS), are neurodegenerative diseases that are unique in being both infectious and genetic. Transmission of both diseases and the animal spongiform encephalopathies (for example, scrapie and bovine spongiform encephalopathy) to experimental animals by intracerebral inoculation with brain homogenates is well documented. Despite their experimental transmissibility, missense and insertional mutations in the prion protein gene are associated with both GSS and familial CJD, demonstrating that the human familial cases are autosomal dominant diseases. More than 80% of CJD cases occur sporadically, however, and are not known to be associated with mutations. Here we report that 21 of 22 sporadic CJD cases and a further 19 of 23 suspected sporadic CJD cases are homozygous at the polymorphic amino-acid residue 129; 51% of the normal population are heterozygous at this site. We argue that homozygosity predisposes towards sporadic CJD and that this directly supports the hypothesis that interaction between prion protein molecules underlies the disease process.
One of the fundamental problems posed by multiple sclerosis is concerned with the distribution of the pathological lesions called plaques. The The fixed cerebral hemispheres were cut coronally at 1 cm. intervals, the first cut being made immediately in front of the mammillary bodies. This procedure is the usual practice in the Department of Pathology, and the resulting coronal slices anterior to the first cut are called Al, 2, 3, etc. and those posterior P1, 2, 3, etc. The inspection of these 1 cm. coronal slices formed the basis of our investigation and it was not thought to be invalidated by the exclusion of small plaques occurring between cuts and the appearance of large plaques in more than one slice.The cut coronal slices were photographed from the posterior aspect. On life size prints each plaque was outlined in ink, and its position recorded (Fig. 1). Every plaque was then represented by a dot on one of a series of photographs of normal coronal brain slices (Figs. 2 to 15). The dot was placed in the position of the apparent centre of the plaque, and in this way every plaque from all the cases was assigned to an anatomical situation. The amassed dots were then counted and assigned to various topographical categories, the first division being into left and right hemispheres. Four broad divisions were then made, namely, cortex, white matter, central grey matter, and the junction of cortex with white matter. Plaques were assigned to the last category only when they clearly appeared to be astride the boundary. These categories were further divided first into lobes and subsequently into named gyri. RESULTSThe total number of plaques counted was 1,594, making the average for each case 72. Their relative distribution is recorded in Tables I and lI. The percentages for the right and left hemispheres were 51 and 49, and this equality appeared not only in the totals but also in every anatomical structure considered.In order to compare the incidence of plaques in the various lobes of the cerebrum the area occupied TABLE
Purpose: Akt is a signal transduction protein that plays a central role in inhibiting apoptosis in a variety of cell types including human cancer cells. In cell lines derived from human non-small cell lung cancers (NSCLCs), Akt has been shown to confer chemoresistance by inhibition of apoptosis in response to different chemotherapeutic agents including platinum-based agents, which are often the first-line therapy for NSCLCs. Only 20% to 30% of patients with NSCLC treated with chemotherapy have clinical evidence of response. The purpose of this study is to determine whether or not overexpression of activated Akt [i.e., phosphorylated Akt (pAkt)] is correlated with survival.Experimental Design: We studied tumors from 61 patients with NSCLC in three tissue microarrays. All patients were followed for a period of 10 years or until death. The arrays were studied immunohistochemically with antibodies against pAkt, p53, and Ki-67.Results: There was a statistically significant difference in survival between the 14 patients with strong pAkt staining and the 47 patients with weak to absent pAkt staining both by log-rank (P ؍ 0.0416) and Breslow analysis (P ؍ 0.0446). Difference in survival time with respect to pAkt status was also statistically significant even after accounting for stage at diagnosis (P ؍ 0.004). Neither p53 nor Ki-67 was a statistically significant prognostic factor.Conclusions: Overexpression of pAkt is an independent prognostic factor. Additional studies of human NSCLCs are warranted to drive the development of targeted tumorspecific antineoplastic therapies.
Sixty-five malignant gliomas (astrocytomas grade 3 and 4 and glioblastomas) were examined by means of immunoperoxidase staining on frozen tissue using various monoclonal antibodies directed against macrophages, lymphocytes and natural killer cells. Depending on the antibody used, the presence of macrophages in tumours ranged from 85%-100%. Many of the tumours contained substantial numbers of macrophages not only, as expected, in necrotic areas but also in intact tumour tissue. Eighty-nine percent of 39 tumours tested contained Fc receptor-bearing mononuclear cells in viable tumour. In 100% of 44 tumours tested for HLADR class 2 major histocompatibility complex antigen this antigen was detected in the macrophages. In 40% of these 44 cases, HLADR antigen was also present on the tumour cells. Eighty-eight percent of 53 tumours tested contained T cells in viable tumour and the majority of these cells were T cytotoxic/suppressor (T8). Twenty-four percent of 33 tumours contained no T helper/inducer (T4) lymphocytes and in the other 76% there were few positive cells. Only 9% of 21 tumours contained natural killer cells (NK). B cells were absent from 88% of 61 tumours and almost all of the remainder contained only a small number of B cells. The findings are discussed with reference to a possible host immune response to gliomas and relevant literature is reviewed.
Samples of tissue from the central nervous system (cns), the lymphoreticular system (lrs) and the rectal mucosa of a large number of scrapie-exposed sheep, with and without signs of clinical disease, were examined immunohistochemically for evidence of disease-associated prion protein (PrP(d)). The rectal mucosa has received almost no attention so far in scrapie diagnosis, despite its abundant rectoanal mucosa-associated lymphoid tissue, and its accessibility. The scrapie-confirmed cases included 244 with clinical disease, of which 237 (97.1 per cent) were positive in the rectal mucosa, and 121 apparently healthy sheep, of which 104 (86 per cent) were positive in the rectal mucosa. PrP(d) was detected in 86.4 to 91.5 per cent of the other lrs tissues of the healthy sheep examined and in 77.7 per cent of their cns tissues. The stage of infection, therefore, affected the probability of a positive result in the rectal mucosa, whereas the breed, PrP genotype, age and sex had little or no independent effect. Accumulations of PrP(d) were observed in the rectal mucosa and other lrs tissues of vrq/arr sheep with preclinical and clinical scrapie, albeit with a lower frequency and magnitude than in sheep of other PrP genotypes. Western immunoblotting analyses of samples of rectal mucosa gave the characteristic PrP glycoprofile, with a sensitivity similar to that of immunohistochemistry.
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