Spinocerebellar degeneration with prominent involvement of the motor neuron system: Autopsy report of a sporadic case

Summary A sporadic case of spinocerebellar degeneration with prominent involvement of the motor neuron system is reported. A Japanese male without contributing family history, developed cerebellar ataxia at the age of 52, followed by generalized amyotrophy and ophthalmoplegia, and died aged 58. The clinical findings were pathologically verified as degeneration of the spino-ponto-cerebellar system and the motor neuron system, the latter almost identical to those of amyotrophic lateral sclerosis. Additional subclinical changes were found in the dentate nucleus and substantia nigra. Brain-stem nuclei subserving eye movements were well preserved, suggesting a supranuclear basis for the ophthalmoplegia. This unusual combination of system degenerations has on rare occasions been reported in the heredofamilial cerebellar disorders. As a sporadic case, however, this may be the first autopsy case of spinocerebellar degeneration with severe concurrent involvement of the motor neuron system.     

Histochemical study of the vascular endothelium of the synovial membrane of rheumatoid arthritis and osteoarthritis by Ulex europaeus agglutinin I (UEA-I)

The Ulex europaeus agglutinin-I binding sites were significantly more distributed on the capillary endothelium of the synovium of rheumatoid arthritis (12 of 24 cases, positive) than of osteoarthritis (2 of 14 cases, positive). The distribution was not related to that of factor VIII related antigen nor IgG or IgM.     

Irrelevance of the mutated p53 gene product to tumor rejection antigen in 3-methylcholanthrene-induced fibrosarcomas

The relevance of mutated p53 to in vivo rejection of MC-induced fibrosarcomas and/or in vitro CTL activity against these tumors was investigated. p53 gene was found to be altered in nine MC-induced fibrosarcomas of BALB/c origin. The mutated p53 cDNA derived from several MC-induced fibrosarcomas was transduced into CMS8 which lacks p53 expression. Immunization of mice with these mutated p53 transfectants failed to protect them from original MC-induced fibrosarcomas from which mutated p53 genes were derived. CTL lines specific for these MC-induced fibrosarcomas destroyed the original MC-induced fibrosarcomas, but not CMS8 transduced with mutated p53 genes derived from the same lines. A series of 9mer peptides consisting of mutated amino acid residues of p53 of Meth A, CMS17 and CMS9 were prepared, and target P1HTR cells were pulsed with them. None of CTLs for these fibrosarcomas were reactive with P1HTR pulsed with these peptides. In conclusion, peptides derived from mutated p53 genes may serve as target antigens for CD8(+) MHC class I restricted CTL as reported, but may often not contribute as target antigens to the rejection of MC-induced fibrosarcomas.     

Expression of hepatocyte growth factor(hgf) and C-met gene in human gastric-cancer cell-lines

Tissue P-glycoprotein immunostaining was performed in seventy one patients with follicular large, mixed, or small cell non-Hodgkin's lymphomas. Only six patients (8.5%) demonstrated positive immunostaining for P-glycoprotein. All patients had complete and durable responses to initial therapy. P-glycoprotein (MDR) fails to predict for primary drug resistance in follicular lymphomas and is constitutionally expressed in only a few follicular lymphomas at present.     

Antioxidative activity of indenestrol A, a diethylstilbestrol metabolite.

To elucidate the various activities of synthetic estrogens, the antioxidative activities of diethylstilbestrol (DES) and related metabolic analogs were examined. The antioxidative activities were assessed in terms of the inhibitory effect on Fe2+(-) and ascorbic acid-induced peroxidation of egg phosphatidylcholine (egg PC), and also superoxide scavenging ability using cyclic voltammetry. Moreover, after in vivo administration of the test compounds to mice, the animals were subjected to hyperoxia, and catalase, glutathione peroxidase and superoxide dismutase activities in the brain, lungs and liver were measured. The results indicated that indenestrol A, one of the metabolites of DES, had the strongest antioxidative activity among the test compounds under both in vivo and in vitro conditions.     

Association of a single nucleotide polymorphism in the steroid and xenobiotic receptor (SXR) gene (IVS1-579A/G) with bone mineral density

Vitamin K2 plays an important role in the bone metabolism. The steroid and xenobiotic receptor (SXR) as a nuclear receptor activated by vitamin K2 as well as rifampicin could increase bone markers such as alkaline phosphatase in human osteoblastic cells. Thus, the SXR could mediate vitamin K2 signaling pathway in bone cells. Therefore, we analyzed expression of the SXR mRNA in human primary osteoblasts and chondrocytes. We also studied association of a single nucleotide polymorphism (SNP) in the SXR gene with bone mineral density (BMD). Expression levels of the SXR mRNA were analyzed during the culture course of human primary osteoblasts and chondrocytes. Association of a SNP in the SXR gene in intron 1 (IVS1-579A>G) with BMD was examined in 294 healthy postmenopausal Japanese women. The SXR mRNA increased at day 5 and then decreased at day 10 in human primary osteoblasts. Its mRNA gradually increased in human primary chondrocytes until day 10. As an association study of a SNP in the SXR gene (IVS1-579A/G), the subjects without the A allele (GG; n  = 47) had significantly higher total BMD than the subjects bearing at least one A allele (AA + AG; n  = 247) (Z score ± SD; 0.635 ± 1.031 versus 0.268 ± 1.061; P  = 0.0298). The SXR mRNA was expressed and regulated in primary human osteoblasts and chondrocytes. A genetic variation at the SXR gene locus is associated with BMD, suggesting an involvement of the SXR gene in human bone metabolism.     

Tumor size dependent changes in a murine fibrosarcoma: use of in vivo 31P NMR for non-invasive evaluation of tumor metabolic status

Tumor tissue contains viable hypoxic regions that are radioresistant and often chemoresistant and may therefore be responsible for some treatment failures. A subject of general interest has been the development of non-invasive means of monitoring tissue oxygen. Pulse Fourier transform 31P NMR spectroscopy can be used to estimate intracellular nucleotide triphosphates (NTP), phosphocreatinine (PCr), inorganic phosphate (Pi) and pH. We have obtained 31P NMR spectra as an indirect estimate of tissue oxygen and metabolic status in a C3H mouse fibrosarcoma FSaII. Sequential spectra were studied during tumor growth in a cohort of animals and peak area ratios for several metabolites were computed digitally by computer. During growth, tumors showed a progressive loss of PCr with increasing Pi, and most tumors greater than 250 mm3 in volume had little or no measurable PCr. The smallest tumors (38 mm3 average volume) had PCr/Pi ratios of 1.03 +/- .24, whereas tumors 250 mm3 or more had an average PCr/Pi ratio of 0.15 +/- .04. Similarly derived NTP/Pi ratios decreased with tumor size, but this change was not significant (p = .17). Radiobiologic hypoxic cell fractions were estimated using the radiation dose required to control tumor in 50% of animals (TCD50) or by the lung colony technique. Tumors less than 100 mm3 had a hypoxic cell fraction of 4% (TCD50) while tumors 250 mm3 had a 40% hypoxic cell fraction (lung colony assay). These hypoxic fraction determinations correlated well with the depletion of PCr and decline in NTP/Pi ratios seen at 250 mm3 tumor volumes. Tumor spectral changes with acute ischemia were studied after ligation of the tumor bearing limb and were similar to changes seen with tumor growth. PCr was lost within 7 minutes, with concurrent increase in Pi and loss of NTP. Complete loss of all high energy phosphates occurred by 40 minutes of occlusion. In vivo tumor 31P NMR spectroscopy can be used to estimate tissue metabolic status and may be useful in non-invasive prediction of hypoxic cell fraction, reoxygenation, and radiation treatment response.     

Thermochemotherapy (combined cyclophosphamide and hyperthermia) with or without hyperglycemia as an adjuvant to radiotherapy

Our previous study demonstrated the presence of a thermochemotherapy-resistant cell fraction in a tumor. The present study investigated whether thermochemotherapy-resistant cells are radioresistant and whether thermochemotherapy changes the size of hypoxic cell fraction in the tumor. Early generation isotransplants of a spontaneous fibrosarcoma, FSa-II tumors, were used. A radiation dose that yields 50% tumor control rate in 150 days after local irradiation, TCD50, was determined. Cyclophosphamide (CY) was the test agent. TCD50 values of the 4 mm tumor following gamma-ray alone given under hypoxic conditions or in air were 80.9 or 65.8 Gy, respectively. Thermochemotherapy reduced TCD50 values congruent to 20 Gy, suggesting that thermochemotherapy resistant cells are not identical to the radioresistant cells. Glucose administered 60 min before thermochemotherapy further reduced TCD50 values. Foot-reaction scored in the tumor-controlled animals was significantly less severe following combined thermochemo- and radiotherapy compared to that following radiotherapy alone. Acute foot reaction studies also supported this observation. These results indicated that thermochemotherapy could be an excellent adjuvant to radiotherapy. Further studies using a 6 mm tumor indicated that thermochemotherapy was less effective on the large tumor than on the small tumor. Indirect analysis showed no significant changes in the size of hypoxic cell fraction following thermochemotherapy.     

Influence of baseline values on lipids, lipoproteins and fibrinolytic parameters during treatment of hypertension with cilnidipine.

Sixteen adult hypertensive patients of both sexes, classified as having 'medium' (total lipid profile 240-300 mg dl(-1)), and 'high' (total lipid profile >300 mg dl(-1)) baseline values, underwent serum lipids, lipoproteins and plasma fibrinolytic parameters evaluations after 3 months of cilnidipine treatment. Patients with 'medium baseline values' did not have any change in lipids, lipoproteins and fibrinolytic parameters while patients with 'high baseline values' had beneficial lipid and lipoprotein changes [decreases in total cholesterol (TC), triglycerides (TG), very low density lipoprotein-cholesterol (VLDLC) and increases in high density lipoprotein-cholesterol (HDLC), and HDLC/TC ratio] after cilnidipine treatment. Changes in lipids were negatively associated with fibrinolysis for the patients with 'medium baseline values' and positively associated in patients with 'high baseline values' after cilnidipine treatment. Reduction in blood pressure was related to fibrinolysis and reduced risk of coronary heart disease in the patients with 'high baseline values' after cilnidipine therapy. These results show that during cilnidipine treatment, the baseline lipid profile levels of the patients may influence the lipid altering actions as well as the interaction between lipids and fibrinolysis.     

The quantitative and qualitative defect of CD4+ CD45RO+ memory-type T cells are involved in the abnormality of TH1 immunity in atopic dermatitis patients.

Peripheral blood mononuclear cells (PBMCs) obtained from atopic dermatitis (AD) patients produced low levels of IFN-gamma in response to Dermatophagoides farinae antigen (Der f Ag) plus IL-2 or OKT3 MoAb in contrast with PBMCs obtained from healthy donors. The reduced IFN-gamma production in AD patients' T cells appeared to be derived from the defect of CD4+ T cells but not CD8+ T cells. Indeed, from the cytoplasmic staining analysis of cytokines, it was demonstrated that the frequency of IFN-gamma producing CD4+ T cells (TH1 cells) in AD patients was markedly lower than that of healthy donors. From the phenotypic analysis using flow cytometry, it was also found that the number of CD4+ CD45RO+ memory type T cells was significantly reduced in AD patients compared with that of healthy donors. In addition to quantitative defect of memory type CD4+ T cells, functional defect of CD4+ CD45RO+ memory type T cells was also demonstrated in AD patients. Enriched CD4+ CD45RO+ T cells obtained from AD patients, who exhibited greatly reduced delayed-type hypersensitivity (DTH) response in tuberculin test, showed no significant TH1 immunity in terms of IFN-gamma production by stimulation with OKT3 MoAb or purified protein derivative (PPD). Thus, the immunological abnormality of TH1 immunity in AD patients appeared to be induced in concomitant with both the quantitative and qualitative defect of memory type CD4+ T cells.