Interleukin-6-associated inflammatory processes in Alzheimer's disease: new therapeutic options

The cytokine interleukin-6 is consistently detected in the brains of Alzheimer's disease patients but not in the brains of nondemented elderly persons. Until recently it was unclear whether an interleukin-6-associated inflammatory mechanism is an early or late event in the pathological cascade of Alzheimer's disease. We investigated whether interleukin-6 could be detected in plaques of Alzheimer's disease patients prior to the onset of neuritic degeneration. We found interleukin-6 mostly in plaques where neuritic pathology has not yet developed. This indicates that the appearance of interleukin-6 may precede neuritic changes and is not just a consequence of neuritic degeneration. Therefore, one may hypothesize that activation of inflammatory mechanisms may cause neuritic degeneration in plaques. A suppression of interleukin-6 synthesis could, therefore, be of therapeutic value. Upon screening a number of substances, we found that a small number of nonsteroidal antiinflammatory drugs, including tenidap, were able to inhibit interleukin-6 synthesis in cultured human astrocytoma cells. These substances may be therapeutically useful in Alzheimer's disease and should be evaluated in clinical studies.     

Accuracy of subsampling mill for granular materials

A subsampling mill was constructed with 19 subsample spouts similar to the 1 or 2 subsample spouts on the conventional subsampling mills. Samples of peanuts, each of which contained 1 kernel made radioactive by neutron activation, were comminuted in the mill. For treatment M the discharge from each spout was kept separate. For treatment R, the discharge from all 19 spouts was blended together in a twin-shelled blender and subdivided with a riffle divider into 16 subsamples which averaged the same weight as the M subsamples. Radioactivity counts/gram of each subsample were measured. Eleven samples were comminuted for each treatment which produced a total of 209 M samples and 176 R samples. An analysis of variance on the pooled data from each treatment showed a mean square error of 1318.3 for the M treatment and 1278.6 for the R treatment. The null hypothesis that the mean square errors for the two treatments are equal was not rejected by the F test (P=0.421).     

Prevalence of epilepsy in children of Multnomah County, Oregon

The prevalence of epilepsy among children in the third grade in Multnomah County, Oregon, was investigated by use of a questionnaire similar to that used by Rose et al. (1973). Of the 7,039 potential respondents, 5,317 (75.5%) responded to the questionnaire. A stratified random sample of 161 children was drawn from the respondents, and of these 129 (80%) underwent physical and EEG examinations. This replication of the study by Rose et al. (1973) yielded prevalence estimates which were somewhat lower than those reported by Rose et al. for Washington County, Maryland. Our findings suggest that the questionnaire method of estimating the prevalence of epilepsy has promise; further investigation of the method is in progress.     

The kininogen gene family in obstructive uropathy

Because many patients present themselves for treatment with both craniofacial and craniocervical pain, 2 questions arise: (1) What are the sensory and motor consequences of dysfunction in either of these areas on the other? (2) Do craniofacial and craniocervical pain have a similar cause? These questions formed the impetus for this review article. The phenomenon of concurrent pain in craniofacial and cervical structures is considered, and clinical reports and opinions are presented regarding theories of cervical-to-craniofacial and craniofacial-to-cervical pain referral. Because pain referral between these 2 areas requires anatomic and functional connectivity between trigeminally and cervically innervated structures, basic neurophysiologic and neuroanatomic literature is reviewed. The published data clearly demonstrate neurophysiologic and structural convergence of cervical sensory and muscle afferent inputs onto trigeminal subnucleus caudalis nociceptive and non-nociceptive neurons. Moreover, changes in metabolic activity and blood flow in the brainstem and cervical dorsal horn of the spinal cord in both monkeys and cats have been demonstrated after electric stimulation of the V1-innervated superior sagittal sinus. In conclusion, the animal experimental data support the findings of human empiric and experimental studies, which suggest that strong connectivity exists between trigeminal and cervical motor and sensory responses.     

Genetic variation in the east Midlands

According to history, the population of the British Isles derives its genepool from a succession of invaders and immigrants. The settlement pattern of these invaders gave rise to a patchwork of genepools, shown in previous genetic surveys. Specimens from 1117 blood donors of regionally subdivided East Midlands (Derbyshire, Nottinghamshire and Leicestershire) were analysed for 18 conventional genetic systems (blood groups, serum proteins and red cell enzymes), according to place of residence. Significant differences exist among the five geographically defined sub-populations, and it is argued that these are derived from the historical settlement of continental European populations in the region, especially the Danes and the Vikings.     

Mifepristone. Auxiliary therapeutic use in cancer and related disorders

A pilot study was carried out to assess the safety and antigen-presenting properties of allogeneic or autologous dendritic cells (DCs) in six HLA-A2+, HIV-infected patients. Allogeneic DCs obtained from the peripheral blood of HLA-identical, HIV-seronegative siblings were pulsed with recombinant HIV-1 MN gp160 or synthetic peptides corresponding to HLA-A2-restricted cytotoxic epitopes of envelope, Gag, and Pol proteins. The antigen-pulsed cells were infused intravenously six to nine times at monthly intervals and HIV-specific immune responses were monitored. One allogeneic DC recipient with a CD4+ T cell count of 460/mm3 showed increases in envelope-specific CTL- and lymphocyte-proliferative responses, as well as in IFN-gamma and IL-2 production. Another allogeneic DC recipient with a CD4+ T cell count of 434/mm3 also showed an increase in HIV envelope-specific lymphocyte-proliferative responses. A recipient of autologous DCs with a CD4+ T cell count of 730/mm3 showed an increase in peptide-specific lymphocyte-proliferative responses after three infusions. Three other allogeneic DC recipients with CD4+ T cell counts <410/mm3 did not show increases in their HIV-specific immune responses. No clinically significant adverse effects were noted in this study and CD4+ T cell numbers and plasma HIV-1 RNA detected by RT-PCR of all six patients were stable during the study period. Thus, both allogeneic and autologous DC infusions were well tolerated and in patients with normal or near normal CD4+ T cell counts administration of these antigen-pulsed cells enhanced the immune response to HIV. However, since no effect on viral load was observed there was no evidence that this approach provided clinical benefit.     

CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation

The activity of cyclin-dependent kinase 2 (CDK2) is essential for progression of cells from G1 to the S phase of the mammalian cell cycle. CVT-313 is a potent CDK2 inhibitor, which was identified from a purine analog library with an IC50 of 0.5 microM in vitro. Inhibition was competitive with respect to ATP (Ki = 95 nM), and selective CVT-313 had no effect on other, nonrelated ATP-dependent serine/threonine kinases. When added to CDK1 or CDK4, a 8.5- and 430-fold higher concentration of CVT-313 was required for half-maximal inhibition of the enzyme activity. In cells exposed to CVT-313, hyperphosphorylation of the retinoblastoma gene product was inhibited, and progression through the cell cycle was arrested at the G1/S boundary. The growth of mouse, rat, and human cells in culture was also inhibited by CVT-313 with the IC50 for growth arrest ranging from 1.25 to 20 microM. To evaluate the effects of CVT-313 in vivo, we tested this agent in a rat carotid artery model of restenosis. A brief intraluminal exposure of CVT-313 to a denuded rat carotid artery resulted in more than 80% inhibition of neointima formation. These observations suggest that CVT-313 is a promising candidate for evaluation in other disease models related to aberrant cell proliferation.