Tokugoro Tsunematsu

Antinuclear antibodies in healthy aging people: a prospective study

In order to evaluate the expression of antinuclear antibodies (ANA) in normal elderly individuals over time and clinical significance, a cross-sectional ANA testing in healthy Japanese was performed, followed by annual evaluations of ANA positive aged (> or = 65 years) and a control group. ANA was more prevalent in the aged (11.4% vs. 3.8%) and most were persistent after 4 years. Anti-ssDNA and anti-histone antibodies were increased in aged ANA positive as compared to ANA negative controls. Except for a history of spontaneous abortion, there was no differences in clinical findings. HLA DRB1*0901 and the DQB1*0602 + 0302 + 0303 set of alleles were increased in ANA positive. Therefore, ANA in the aged were persistent, apparently directed toward chromatin elements, and shared MHC associations with autoimmune diseases. Longer follow-up may be necessary to improve the evaluation of clinical significance of ANA in the aged.

Improvement of Cerebral Blood Flow and Cognitive Function following Pacemaker Implantation in Patients with Bradycardia

We investigated the effects of pacemaker implantation on cerebral blood flow and cognitive function in 14 severely bradycardic patients (mean age 75.2 years). Cerebral blood flow and verbal intelligence improved after the pacemaker implantation. Systolic and mean arterial blood pressure was significantly reduced after the implantation. Changes in cerebral blood flow significantly correlated with changes in heart rate in polynomial regression analysis, but not with changes in cardiac output. Before the implantation, verbal cognitive function was lower in bradycardic patients than in age-matched control subjects, and brain CT showed significant advanced atrophy in these patients. However, verbal cognitive function was also improved after the implantation. Pacemaker implantation in the severe bradycardic elderly should be beneficial not only for cardiac function but also for brain function. We concluded that these results suggest that heart rate is one of the important factors in the regulation of cerebral circulation in patients with severe bradycardia. Pacemaker implantation in the elderly improved quality of life and may prevent mental deterioration.

Prevalence of Parkinson's disease in Izumo City, Japan.

The prevalence of Parkinsons disease was studied in Izumo City, the Shimane prefecture having the largest population of the elderly in the country. The adult population of Izumo City (56,869 people over 20 years of age) were screened by means of questionnaires sent by mail and by other methods. A total of 66 people, 18 males and 48 females, were found to have Parkinsons disease. The prevalence of this disease was 82.0/100,000 population, the highest reported in Japan to date. Of the patients affected, 17.1% showed apparent dementia. Those with dementia were older and were classified at a more advanced Yahr stage than were the nondemented cases. The prevalence of Parkinsons disease in the growing geriatric population has major medical and socioeconomic implications.

Effect of smoking on regional cerebral blood flow in the normal aged volunteers

The effects of long-term cigarette smoking on regional cerebral blood flow (rCBF) were studied in 67 normal male volunteers. All subjects were healthy volunteers without any past history of cerebral and pulmonary disease. rCBF decreased significantly with advancing age. Although there was no significant difference in rCBF between young smokers and nonsmokers, elderly smokers showed significantly lower rCBF than elderly nonsmokers. There was no difference in vital capacity and FEV 1.0% between smokers and nonsmokers in both young and elderly groups. The smokers, however, showed significantly lower V50 than the nonsmokers. PeCO2 in smokers was significantly lower than in nonsmokers. No significant differences were seen in hematocrit, antithrombin III, aggregating platelet, serum lipids and blood pressure between smokers and nonsmokers in both age groups. There was a significantly positive correlation between rCBF and PeCO2 in all groups. These results suggest that long-term smoking may reduce rCBF by means of hypocapnia, resulting from latent small airway disturbances, not by advancing cerebral arteriosclerosis.

Effect of Aging on Collateral Circulation via Pial Anastomoses in Cats

The effect of aging on collateral circulation via pial anastomoses after middle cerebral artery occlusion was investigated in young and aged cats. The reduction of blood flow and electroencephalography power were greater and collateral vessel resistance was higher in the aged group than the young group. Electroencephalography power after the occlusion was correlated with collateral resistance and blood flow in the two groups. These results suggest that collateral function deteriorates with aging and the high vulnerability to ischemic insult in aged brain may be caused in part by the poor collateral function.

Familial Occurrence of impaired interleukin-2 activity and increased peripheral blood B cells actively secreting immunoglobulins in systemic lupus erythematosus

PURPOSE We tested the hypothesis that some abnormalities of immune functions are genetically controlled in patients with systemic lupus erythematosus (SLE). SUBJECTS AND METHODS We used a phytohemagglutinin-induced interleukin-2 (IL-2) activity assay and a spontaneous plaque-forming cell assay to evaluate T-cell and B-cell function, respectively, in 34 clinically healthy family members of six SLE probands. RESULTS Impaired IL-2 activity was found in 15 of the 29 consanguineous relatives. There was no relation between the household relatives and the nonhousehold relatives; none of the five nonconsanguineous household persons had abnormal results. Results for the B-cell assay were abnormal in 22 of the 29 consanguineous relatives. The B-cell abnormalities were more commonly observed in the consanguineous household relatives; four of the five nonconsanguineous household relatives also had abnormal assay results. CONCLUSION The findings indicate that the impaired IL-2 activity in relatives appears to strongly correlate with a genetic relationship. Although the evidence favors a genetic basis for the B-cell abnormalities, environmental effects may also contribute to the familial occurrence of these abnormalities.

Mode of action of monoclonal-nonspecific suppressor factor (MNSF) produced by murine hybridoma

Monoclonal-nonspecific suppressor factor (MNSF), a product of murine T cell hybridoma, suppresses antibody response to lipopolysaccharide. In an attempt to clarify the functional mechanisms in vitro, we investigated the mode of action of MNSF. This factor inhibited the antibody response by B cells (depleting T cells and Mø), thereby indicating that the lymphokine acts directly on B cells, without interaction between B and T cells or Mø. MNSF activity was absorbed by mitogen-stimulated T or B cells, but not by resting lymphocytes. Proliferative responses to T cell and B cell mitogens were inhibited dose dependently by the addition of MNSF. Kinetic studies showed that MNSF suppressed the antibody response, in all culture periods, thereby indicating that immunoglobulin secretion and proliferation were inhibited. The effect of growth factor on MNSF-mediated suppression was investigated to search for a possible suppression of MNSF action. Interleukin 2 (IL-2) remarkably inhibited MNSF activity, and the effect of IL-1 or IL-4 was less. IL-2 was most effective when added on the fourth day of culture. MNSF also inhibits division in the plasmacytoma line MOPC-31C or in thymoma EL4, but not in L929 fibroblasts. Tumor necrosis factor (TNF) inhibits cell division of various tumor cells and suppresses the pokeweed mitogen-induced antibody response, without cytotoxic action, as does MNSF. While MNSF and TNF have similar biochemical and physiochemical properties, the cross-reaction tests showed that both are antigenically discrete lymphokines. Although MNSF lacks TNF activity, the concomitant addition of both factors to L929 increases the cytotoxic action, a finding indicative of a synergistic effect.

Characterization of cell-surface receptors for monoclonal-nonspecific suppressor factor (MNSF)☆

Abstract Monoclonal-nonspecific suppressor factor (MNSF) is a lymphokine derived from murine T cell hybridoma. The target tissues are both LPS-stimulated B cells and Con A-stimulated T cells. Since the action of MNSF may be mediated by its binding to specific cell surface receptors, we characterized the mode of this binding. The purified MNSF was labeled with 125 I, using the Bolton-Hunter reagent. The labeled MNSF bound specifically to a single class of receptor (300 receptors per cell) on mitogen-stimulated murine B cells or T cells with an affinity of 16 p M at 24 °C, in the presence of sodium azide. Competitive experiments showed that MNSF bound to the specific receptor and that the binding was not shared with IL2, IFN-γ, and TNF. Various cell types were surveyed for the capacity to specifically bind 125 I-MNSF. 125 I-MNSF bound to MOPC-31C (a murine plasmacytoma line) and to EL4 (a murine T lymphoma line). The presence of specific binding correlates with the capacity of the cells to respond to MNSF. These data support the view that like other polypeptide hormones, the action of MNSF is mediated by specific cell surface membrane receptor protein. Identification of these receptors will provide insight into the apparently diverse activities of MNSF.

Effect of Single Oral Administration of Nilvadipine on Cerebral Blood Flow in Chronic Cerebral Infarction

The effect of nilvadipine, a newly developed calcium antagonist, on regional cerebral blood flow (rCBF) was investigated in 7 patients with chronic cerebral infarction. rCBF was measured by the 133Xenon inhalation method. Patients were given a single dose of 4 mg of nilvadipine after the first measurement of rCBF, and the second measurement was done one hour after the administra tion. All patients had hemiparesis and 2 of them had mild to moderate mental deterioration, but all patients could walk to the outpatient clinic by themselves. Results: (1) rCBF of the affected side significantly increased by 22.7% after single oral administration of nilvadipine (p<0.05). The increase of rCBF was significantly marked in frontal regions of the affected hemispheres. (2) No sig nificant changes in blood pressure or end tidal partial pressure of carbon diox ide were observed during the examination. These results indicate that nilvadipine has a potent selective vasodilatory action on the cerebral arteries in patients with cerebral infarction.

The Effects of FK-506 and Cyclosporin A on the Proliferation of PHA - Stimulated T Cells in Response to IL-2, IL-4 or IL-6

Stimulated by PHA, the T cells responded well to exogenous IL-2, IL-4 or IL-6, but the responses were inhibited by FK-506 or cyclosporin A (Cs A). In contrast, when stimulated by PMA, the T cells responded to IL-2 and IL-4, but not to IL-6 and the responses were not inhibited by FK-506 and Cs A. Kinetic studies showed that FK-506 and Cs A had no inhibitory effects on T cell proliferation in response to IL-2 and IL-4 after the resting T cells were pulsed with PHA alone for a certain time. However, the response of the PHA-pulsed T cells to IL-6 was still inhibited by FK-506 or Cs A, but the inhibitory effect gradually decreased as the time in which the PHA-pulsed T cells interacted with IL-6 was prolonged. In a control system, the proliferation of the T cells that were treated with FK-506 or Cs A for 3 h and washed 3 times was not inhibited when the T cells were stimulated with PHA in combination with either IL-2, IL-4 or IL-6. Our data suggest that FK-506 and Cs A interfere with the early steps of T cell proliferation after stimulation of PHA, but not PMA. It is likely that the two drugs inhibit the expression of lymphokine receptors, by interfering Ca(2+)-related signals and that IL-6 induces T cell proliferation in a different way than IL-2 and IL-4, which are FK-506- and Cs A-sensitive.