Susumu Yukawa

Effect of vitamin E on lipid metabolism and atherosclerosis in ESRD patients

BACKGROUND Oxidative stress is enhanced in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). Bioincompatibility represents an important source of reactive oxygen species. HD patients exhibit altered anti-oxidative defences and anti-oxidative vitamins such as vitamin E and C are altered in uremia. Frequently, HD patients also suffer from atherosclerotic cardiac disease. We have previously reported that low density lipoprotein (LDL) of HD patients is rich in malondialdehyde (MDA), an end product of lipid peroxidation. MDA rich LDL is thought to be an atherogenic lipoprotein due to its enhancement of macrophage foam cell formation. METHODS We conducted a controlled study for two years comparing the effects of a vitamin E coated cellulose membrane dialyzer and an ordinary cellulose membrane dialyzer on lipid metabolism and the progress of atherosclerosis. LDL-MDA and oxidized LDL (ox-LDL) were measured in HD patients using these two types of dialyzers. Plasma vitamin E and lipid concentrations were also evaluated. The aortic calcification index (ACI) was evaluated by CT scan to assess the progress of atherosclerosis before and for every year after treatment. RESULTS Use of a vitamin E coated cellulose membrane dialyzer for six months, one year and two years resulted in a significant reduction in LDL-MDA and ox-LDL compared to the ordinary cellulose membrane dialyzer. Treatment with a vitamin E-coated dialyzer significantly reduced the percentage increase in ACI after 24 months compared to the control. There were no significant changes in plasma vitamin E and lipid concentrations between the two groups. CONCLUSIONS These results suggest that the oxidative stress could be one of the stimulating factors of abnormal lipid metabolism and atherosclerosis in ESRD patients.

Abundant expression of thromboxane synthase in rat macrophages

The cloned cDNA for rat thromboxane (TX) synthase with a size of 1851 bp contained a 1599‐bp open reading frame which encoded a 533‐amino acid protein sharing 79.7% identity with human TX synthase. RNA blot analysis was carried out with rat cells and tissues. Rat peritoneal macrophages most abundantly expressed mRNA for TX synthase, and its level was not changed by in vivo stimulation of casein. Bone marrow, spleen, lung and thymus also expressed the TX synthase gene. These findings suggest the possibility that TXA2 plays a role in the immune system.

A Case of Pulmonary Intravascular Lymphomatosis Diagnosed by Thoracoscopic Lung Biopsy

Intravascular lymphomatosis with primary pulmonary lesion is an extremely rare disease. Although the major clinical symptoms include fever, cough, dyspnea and loss of body weight, these are not diagnostic. Chest radiograph findings are also nonspecific and include bilateral reticular shadow, reticulonodular shadow, ground-glass opacity or wedge-shaped subpleural opacities. Therefore, the antemortem diagnosis is relatively difficult. It is considered that intravascular lymphomatosis is a high-grade malignant lymphoma. However, it has been shown recently that a good response and long-term survival may possibly be obtained through systemic combination chemotherapy. We report a case of intravascular lymphomatosis with primary pulmonary lesion where an early diagnosis was obtained through thoracoscopic lung biopsy and subsequent systemic chemotherapy proved to be quite effective. Because the clinical symptoms or chest radiograph findings are usually nonspecific, it was thought that thoracoscopic lung biopsy could be a useful procedure for early and reliable diagnosis of primary pulmonary intravascular lymphomatosis and that it might contribute to an improved prognosis.

Inhibition of macrophage migration inhibitory factor secretion from macrophages by vitamin E

Macrophage migration inhibitory factor (MIF) was identified in rat peritoneal macrophages by Western blot analysis and its secretion into culture medium by enzyme-linked immunosorbent assay. We investigated the effect of vitamin E on MIF production in macrophages in response to phorbol 12-myristate-13-acetate (PMA), calcium ionophore A23187, and lipopolysaccharide (LPS). Intraperitoneal injections of vitamin E (5 mg per rat) for 6 successive days resulted in a significant increase of alpha-tocopherol content in peritoneal macrophages (478.3+/-90.7 ng/106 cells) compared with the control (1.5+/-0.5 ng/10(6) cells). For the control macrophages, MIF content of the medium (2.5x10(6) cells/18 ml) without stimulation was 2.27+/-0.20 ng/ml after 14 h culture, whereas stimulation with calcium ionophore A23187 (400 nM) and LPS (5.0 microg/ml) induced the elevation of MIF content to 3. 66+/-0.41 and 4.12+/-0.58 ng/ml, respectively. On the other hand, vitamin E-enriched macrophages without stimulation showed less MIF content (0.77+/-0.23 ng/ml) than the control. Similarly, the increase of MIF of vitamin E-treated macrophages was significantly suppressed after stimulation with calcium ionophore A23187 or LPS, compared with the control macrophages. From analysis of intracellular MIF content by Western blot, we found no alteration of intracellular MIF content of vitamin E-macrophages, in contrast to the decreased content of control stimulated-macrophages. Taken together, these results indicate that vitamin E may contribute to the regulation of immune responses through regulation of MIF secretion.

Effect of environmental changes on oxidative deoxyribonucleic acid (DNA) damage in systemic lupus erythematosus

Abstract In a study conducted in Japan, the authors used urinary 8-hydroxydeoxyguanosine (8-OHdG) to study the effects of high-intensity and low-intensity sunlight on oxidative damage to deoxyribonucleic acid (DNA) in patients who had systemic lupus erythematosus (SLE). During late May through early September (i.e., a period of high-intensity sunlight), the mean urinary 8-OHdG level in SLE patients was significantly higher than in controls (31.0 ± 20.6 [standard deviation] ng/mg vs. 15.4 ± 7.2 ng/mg, respectively [p < .05]). During late November through early March (i.e., low-intensity sunlight season), however, no significant differences were noted (15.4 ± 5.5 ng/mg vs. 16.3 ± 4.6 ng/mg, respectively). The mean urinary 8-OHdG level in SLE patients during the period of high-intensity sunlight was significantly higher than during the period of low-intensity sunlight (21.3 ± 20.6 ng/mg vs. 12.6 ± 6.7 ng/mg, respectively; p < .01), although no such seasonal changes were observed among controls (16.2 ± 8.0 ng/mg vs. 15.7 ± 5.1 ng/mg, respectively). The effect of sunlight intensity (i.e., season) may require consideration when oxidative DNA damage occurs in individuals who have SLE.

Massive gastrointestinal hemorrhage in a case of amyloidosis secondary to rheumatoid arthritis.

A case of a 60-year-old woman with secondary gastrointestinal amyloidosis to rheumatoid arthritis is reported. Biopsy findings in the mucosa of the stomach and lower gastrointestinal tract revealed amyloidosis. Endoscopic examination of the lower gastrointestinal tract revealed multiple nodular elevations. The patient showed massive melena. Emergency angiography was performed and an extravasation was found at branches of the jejunal artery. Embolization was performed and this lead to a good prognosis. Patients with massive hemorrhages following gastrointestinal amyloidosis generally have a poorer prognosis. Embolotherapy performed for the present case might represent an effective therapeutic method for gastrointestinal hemorrhage in gastrointestinal amyloidosis.

Tonsillectomy with steroid pulse therapy has more effect on the relapse rate than steroid pulse monotherapy in IgA nephropathy patients.

AIMS Both steroid pulse (SP) monotherapy and the combination of tonsillectomy and SP therapy (TSP) are effective for achieving clinical remission (CR), defined as negative hematuria and proteinuria, in patients with IgA nephropathy (IgAN). The role of tonsillectomy in the treatment of IgAN has been analyzed only from the aspect of CR or renal survival after TSP treatment, so there is no evidence of its effect on the relapse after CR. METHODS We retrospectively investigated relapse (re-appearance of urinary abnormalities) from CR after TSP or SP monotherapy in 62 IgAN patients (mean follow-up, 70.1 ± 35.3 months). The SP therapy comprised 0.5 g methylprednisolone administered intravenously on 3 consecutive days followed by oral prednisolone (30 mg/day) on 4 consecutive days, with the course repeated 3 times. Oral prednisolone (30 mg/day) was then given on alternative days and gradually tapered and finished over 1 year. Tonsillectomy was performed either before or within 6 months of starting SP therapy. RESULTS At baseline, the mean age was 34.6 years, the mean serum creatinine (Cr) level was 0.9 mg/dl, and the mean level of proteinuria was 876 mg/day. There were no differences between the TSP group (41 patients) and SP monotherapy group (21 patients). In total, 24 of the TSP and 10 of the SP patients achieved CR. Of the 34 patients who achieved CR, 13 relapsed after TSP or SP monotherapy. Using Kaplan-Meier analysis, tonsillectomy was associated with a lower incidence of relapse from CR after treatment (p = 0.045). Multivariate Cox regression analysis revealed that tonsillectomy reduced the rate of from CR after SP therapy. CONCLUSION Tonsillectomy was associated with a reduction in the relapse rate from CR after SP therapy in IgAN patients.

Effects of antioxidants on kidney disease.

Kidney mesangial cells (MCs) and vascular smooth muscle cells (VSMCs) are closely related in terms of origin, microscopic anatomy, histochemistry, and contractility. This relationship suggests a similarity between kidney glomerular sclerosis and atherosclerosis. Vitamin E appears beneficial in the prevention and treatment of coronary disease and also inhibits the proliferation of VSMCs in vitro. We used vitamin E and probucol to treat glomerular sclerosis and MC-proliferative glomerulonephritis (GN) in two animal models of glomerular disease. Using rats, a remnant kidney model accelerated with hyperlipidemia was employed to reflect progressive glomerular sclerosis leading to chronic renal failure, and an anti-thymocyte serum treatment was used to model acute MC-proliferative GN. Supplemental dietary antioxidants suppress MC proliferation and glomerular sclerosis in models of glomerular disease in rats. These results suggest that treatment with antioxidants may be a promising intervention to prevent progression of kidney disease.

Successful pregnancy and delivery in a case of systemic lupus erythematosus treated with immunoadsorption therapy and cyclosporin A.

A 32-year-old woman diagnosed as systemic lupus erythematosus (SLE) became pregnant. During pregnancy she was treated with a daily dosage of prednisolone 15 mg. However, because the exanthema became worse, she was hospitalized on January 14, 1997 in order to receive immunoadsorption therapy. Before delivery we implemented the immunoadsorption therapy twice and cyclosporin A (CsA) was administered simultaneously. She gave birth in her 37th week. The baby weighed 2260 g at the time of delivery and had no deformities. The mother also had no side effects. The success of pregnancy and childbirth in our case, without any side effects, shows the possibility that the combination of CsA and immunoadsorption therapy may be considered safe to control a pregnancy complicated by SLE.

Successful immunochemotherapy for patients with malignant mesothelioma: report of two cases.

Malignant mesothelioma is a clinically aggressive tumor and has a poor prognosis; therefore, the selection of therapeutic strategies is important to improve the prognosis. Two patients with intraperitoneal malignant mesothelioma received combination therapy as follows: (1) case-oriented chemotherapy according to the results of a chemosensitivity test, and (2) adoptive immunotherapy using cytotoxic T lymphocytes (CTL). The chemosensitivity test was assessed by an MTT colorimetric assay. CTL was generated by a mixed culture with autologous tumor cells, and activated by immobilized anti-CD3 monoclonal antibody and interleukin-2. The MTT assay indicated that cisplatin and adriamycin were sensitive drugs in both patients, and they thus received the caseoriented chemotherapy according to the MTT assay. The activated CTL exhibited a high cytotoxicity against autologous malignant mesothelioma cells, and were transferred intraperitoneally. The patients were controllable for ascites, and the tumor masses gradually vanished (partial response). Chemoimmunotherapy is thus considered to be an effective treatment for intraperitoneal malignant mesothelioma, especially to improve the quality of life.