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Objective. To determine the expression of interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), and oncostatin M (OSM) and their major cellular sources in the joints of rheumatoid arthritis (RA) patients, as well as the correlation of circulating levels of these IL-6-type cytokines and C-reactive protein (CRP). Methods. Messenger RNA (mRNA) and protein levels for IL-6, IL-11, LIF, and OSM were determined by using reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Results. Cells isolated from the synovium of RA patients expressed mRNA for IL-6, IL-11, LIF, and OSM at higher levels than did synovial cells from osteoarthritis (OA) patients, and spontaneously released greater quantities of these proteins in culture. Fibroblast cell lines derived from RA synovium were able to produce IL-6, IL-11, and LIF, but not OSM, when stimulated with IL-1 and tumor necrosis factor α. OSM was found to be produced spontaneously by synovial tissue macrophages. IL-6, IL-11, LIF, and OSM were present in synovial fluid from the RA patients; levels of IL-6, LIF, and OSM were present in significantly greater quantities in RA patients than in OA patients. However, only IL-6 was significantly elevated in the serum of RA patients and correlated with the serum CRP level, while other IL-6-type cytokines were not detected. Conclusion. IL-6, IL-11, LIF, and OSM are all produced in large amounts at the site of disease activity, but IL-6 derived from synovial fibroblasts may be the major hormone-like mediator that induces the hepatic synthesis of acute-phase proteins in RA.

To determine whether growth factors in the glomerulus are induced in the renin suppressed hypertensive model, we examined the mRNA expressions of platelet-derived growth factor (PDGF) B-chain, transforming growth factor (TGF)-beta 1 and angiotensin II type 1 (AT1) receptors in the glomeruli of deoxycorticosterone acetate (DOCA)-salt-treated hypertensive rats (DOCA-treated rats). We also examined the effects of treatment with cilazapril, an angiotensin I-converting enzyme inhibitor (ACEI), and L-158,809, an AT1 receptor antagonist, on these expressions in DOCA-treated rats. We administered oral 10 mg/kg of cilazapril (CILAZA group) and 1 mg/kg of L-158,809 (L158 group) to DOCA-treated rats daily. Systolic blood pressure in the two groups was not decreased compared with that in DOCA-treated rats given saline. The mRNA expressions were examined using reverse transcriptase polymerase chain reaction (RT-PCR) methods. The mRNA expressions of these genes were higher in DOCA-treated rats than in age-matched control rats. After treatment with these agents for 4 weeks, the mRNA expressions of growth factors were suppressed in both the CILAZA and L158 groups. Mesangial expansion and cell proliferation observed in DOCA-treated rats were suppressed in both the CILAZA and L158 groups. Decreases in the size of the glomerulus were observed only in the CILAZA group. These findings suggested that suppression of growth factors and glomerular proliferative changes of these agents are mediated by blocking tissue renin-angiotensin system (RAS) in the renin-suppressed model.

This study was intended to clarify the factors associated with the development and progression of diabetic retinopathy in patients with Type 2 diabetes. A total of 107 patients with Type 2 diabetes underwent fundoscopic examination by an ophthalmologist, and the factors that might be associated with the severity of retinopathy were investigated. Analysis of variance and the χ2 test were performed to determine whether 22 separate factors were associated with the severity of diabetic retinopathy. There were significant associations between retinopathy and duration of disease, systolic blood pressure, urinary albumin index, and blood urea nitrogen. Multiple regression analysis with retinopathy as the criterion variable and 20 other factors as explanatory variables revealed that, of those explanatory variables showing statistical significance, the strongest associations were with duration of disease and type of diabetic therapy, in that order. The χ2 test also revealed significant associations between retinopathy and both the type of diabetic therapy and the use of anti-hypertensive therapy. The results suggest that the duration of illness and the type of diabetic therapy are strongly related to the development and progression of retinopathy in patients with Type 2 diabetes. These findings suggest that insulin deficiency in patients with Type 2 diabetes should be corrected as early and as vigorously as possible, and that modification of daily activities to achieve a more nearly non-diabetic state should be instituted first, with supplementary drug therapy added as required.

This study examined factors contributing to the development of microalbuminuria in diabetic patients. A total of 236 patients with Type 2 diabetes were studied: 143 were normoalbuminuric and 86 were also normotensive. Multiple regression analysis was used to identify factors influencing the urinary albumin index (UAI), an index of proteinuria based on urinary albumin adjusted for urinary creatinine. Significant factors (retinopathy, systolic blood pressure, and glycosylated haemoglobin) were used to generate a formula for estimating the logeUAI. Target values for systolic blood pressure and glycosylated haemoglobin to maintain the urinary albumin index at or below 22 were determined for different degrees of retinopathy. Normoalbuminuric patients were followed for 3 years to evaluate their progression to microalbuminuria. Each month, blood pressure, urinary albumin and creatinine, and glycosylated haemoglobin were measured. In normotensive, normoalbuminuric patients, initial urinary albumin index and logeUAI were significantly higher in patients who subsequently developed microalbuminuria. Patients with initial logeUAI > 3.09 or initial glycosylated haemoglobin > 6.0% also showed greater progression to microalbuminuria. Hyperglycaemia was an independent factor for the development of microalbuminuria in Type 2 diabetes. The urinary albumin index was most significantly affected by retinopathy, systolic blood pressure, and glycosylated haemoglobin. The estimated logeUAI calculated from these factors is a useful predictor of progression to microalbuminuria.

The case of a 67-year-old women with non-insulin-dependent diabetes mellitus is described. Diabetes was first diagnosed when the woman was aged 55; a diet of 1440 kcal daily was recommended and 500 mg tolbutamide daily was prescribed. Hypoglycaemia was improved for a while but the blood-sugar concentration gradually increased until a tolbutamide dose of 2000 mg/day was needed. The patient eventually came to an out-patient clinic for diabetes control due to continuous hyperglycaemia. Her diabetes proved difficult to control, probably due, in part, to excessive eating and lack of exercise, despite appropriate education and glibenclamide treatment. After 15 months, an α-glycosidase inhibitor, at a dosage of 0.75 mg/day, was added to the treatment with glibenclamide at 7.5 mg/day and the glycosylated haemoglobin level was reduced to normal levels within 2 months. After a further 6 months the glibenclamide dose was reduced to 3.75 mg/day with no ill effects during the subsequent 4 weeks, up to the present day.

L-selectin and Mac-1 expressed on leukocytes are critical for leukocyte adhesion to inflamed endothelium. L-selectin is known to be rapidly shed from the cell surface of granulocytes after activation. In the present study the change of expressions of these adhesion molecules on granulocytes were analyzed by flow cytometry, and the serum concentration of shed L-selectin (soluble L-selectin; sL-selectin) was measured by enzyme-linked immunosorbent assay (ELISA) during hemodialysis in patients treated with regenerated cellulose membranes (RC group) versus polysulfone membranes (PS group). In the RC group, Mac-1 expression on granulocytes increased significantly at 30 min after the initiation of hemodialysis (p0.05) compared with predialysis values, coinciding with the nadir of dialysis-induced granulocytopenia. Granulocyte L-selectin expression decreased significantly at 15 min after the initiation of hemodialysis (p0.05) and remained decreased through the course of dialysis session, compared with predialysis values. Serum sL-selectin level significantly increased at 15 min after the initiation of hemodialysis (p0.05), compared with predialysis values. In the PS group, no significant variation in Mac-1 and L-selectin expression on granulocytes and serum sL-selectin level were detected. This reciprocal change of Mac-1 and L-selectin on granulocyte cell surface was attributed to development of granulocytopenia and subsequent reversal during dialysis with cellulose membranes. In this study, we confirmed the shedding of L-selectin during cellulosic dialysis by ELISA. The increase in sL-selectin, which has potential activity of inhibiting L-selectin-dependent adhesion of granulocyte to endothelium, might be involved in rebound granulocytosis during dialysis with cellulose membranes and impairment of the granulocyte function in patients on chronic hemodialysis.

The relationship between cardiac autonomic neuropathy and diabetic microangiopathies and macroangiopathy was investigated in 103 patients with non-insulin-dependent diabetes mellitus. Cardiac autonomic nerve function was assessed by determining the uptake of [123I]metaiodobenzyl-guanidine into the myocardium. Cardioparasympathetic nerve function was assessed by comparing electrocardiographically the expiratory and inspiratory respiratory rate (RR) interval ratios, during a period of deep breathing, and the coefficients of variation of the RR intervals. Nerve conduction velocity measurements were used to assess diabetic somatic neuropathy, and measurement of pulse-wave velocity provided an indication of the extent of aortic sclerosis. The only correlations between the parameters of cardiac autonomic neuropathy and parameters of diabetic microangiopathies and macroangiopathy were between the expiratory to inspiratory RR interval ratio and both the conduction velocity of the tibial nerve and pulse-wave velocity, and between the heart to lung ratio (cardiac autonomic nerve function) and nephropathy. These correlations may have occurred by chance; alternatively they may indicate a difference in the onset mechanisms of cardiac parasympathetic and sympathetic neuropathies in diabetics.

Apoptosis in glomerular sclerosis. Glomerulosclerosis is characterized by progressive extracellular matrix accumulation and glomerular cell loss. The role of glomerular cell apoptosis in glomerulosclerosis was investigated in the rat remnant kidney model and in human glomerular diseases. We identified apoptotic cells in the glomeruli, tubules and interstitium in the remnant kidney by electron microscopy. DNA fragmentation, which is a biochemical characteristic of apoptosis, was detected by in situ nick end-labeling of fragmented DNA with terminal deoxynucleotidyl transferase and biotinylated deoxyuridine triphosphate. Fragmented DNA in the glomeruli and tubules increased with the progression of glomerulosclerosis in the remnant kidney model. This finding was also demonstrated in other glomerular sclerotic lesions such as IgA and lupus nephritis. The number of cells positive for nick end-labeling in the glomerulus significantly correlated with the degree of glomerulosclerosis and the deterioration of renal function. These results indicate that apoptosis is, at least in part, involved in the cell deletion of various glomerular diseases leading to sclerosis.

Intercellular adhesion molecule-1 (ICAM-1, CD54), an adhesion molecule of the immunoglobulin superfamily, is an endothelial cell surface ligand for such leukocyte integrins as lymphocyte-function-associated molecule 1 (LFA-1, CD11a/CD18), Mac-1 (CD11b/CD18) and CD43. These molecules mediate adhesive interactions between leukocytes and endothelial cells and are critically involved in infiltration of leukocytes into inflammatory lesions. We examined the expression of ICAM-1 in renal tissues of Masugi nephritis rats and directly examined the role of ICAM-1 by administration of neutralizing monoclonal antibodies (MAbs) to rat ICAM-1, LFA-1 alpha-subunit (LFA-1 alpha), beta-subunit (LFA-1 beta) and Mac-1 alpha-subunit (Mac-1 alpha). Within 3 h after injection of nephrotoxic serum, increased expression of ICAM-1 was detected in the glomeruli by in situ hybridization and an immunofluorescence study. Proteinuria was significantly suppressed by the MAbs against ICAM-1, Mac-1 alpha and LFA-1 beta. Neutrophil infiltration into the glomeruli was significantly prevented by injection of the MAbs against ICAM-1, LFA-1 alpha and LFA-1 beta. These results indicate that both ICAM-1/LFA-1 and ICAM-1/Mac-1 pathways are involved in neutrophil infiltration into the glomeruli. On the other hand, monocytic infiltration was prevented by the MAbs against ICAM-1, LFA-1 alpha and LFA-1 beta but not by anti-Mac-1 alpha MAb. Due to these results, ICAM-1 is considered to be a critical molecule involved in the pathogenesis of the leukocyte infiltration into the glomeruli in the heterologous phase of Masugi nephritis. Anti-ICAM-1 antibody may be beneficial in the treatment of leukocyte-mediated glomerular diseases.

Type IV collagen is a major component of the renal glomerular extracellular matrix. A recently characterized monoclonal antibody, JK132, which was originally produced by immunization with human placental type IV collagen, recognizes a new epitope which is different from alpha 1-alpha 6 chains of type IV collagen. Using immunofluorescence and immunogold electron microscopy, the distribution of the epitope of JK132 has been compared with the distribution of alpha 1, alpha 2, alpha 3 and alpha 4 chains of type IV collagen in normal human kidney and in the renal tissues of patients with various types of glomerulonephritis. In normal human kidney, JK132 reacted with mesangial matrix, Bowman's capsular basement membrane (BCBM), tubular basement membrane, and vessel walls, but did not react with glomerular basement membrane (GBM). This distribution is different from the distribution of alpha 1-alpha 4(IV) chains. In IgA nephropathy and membranoproliferative glomerulonephritis, the staining intensity for JK132 was increased in expanded mesangial matrix. In glomeruli with severe mesangial proliferation, the epitope of JK132 extended to the endothelial side of the GBM. In membranous nephropathy, staining for JK132 was virtually unchanged from normal. This study suggests that the epitope of JK132 increases in amount during the process of mesangial proliferation and could serve as a marker for mesangial matrix expansion in glomerulonephritis.

For 10 patients (three women and seven men) with non-insulin-dependent diabetes mellitus, who had been given insulin (22.6 ± 19.6 U/day) and had frequently shown hypo-glycaemia, the insulin dose was slightly reduced and the administration of an α-glucosidase inhibitor was simultaneously started. Hypoglycaemic symptoms disappeared immediately and completely, and sugar metabolism immediately before the withdrawal of treatment was not aggravated: the glycosylated haemoglobin level was unchanged and the post-prandial blood glucose level was increased though not significantly. The results of the present study indicate that the combined use of an α-glucosidase inhibitor with a reduced insulin dose improves the quality of life of patients and may improve hyperinsulinaemia.

Stress was assessed using State-Trait Anxiety Inventory scores in 40 non-insulin-dependent diabetes mellitus (NIDDM) patients, and the results were compared with those for 40 sex- and age-matched healthy controls. Fludiazepam was administered to the patients for 12 weeks and stress was reassessed. The Manifest Anxiety Scale score correlated with Trait ( r = 0.548, P 2= 0.3224, P < 0.0022). The results indicate that stress is detected at a higher frequency in patients withNIDDM than in healthy controls, and that blood glucose and lipid metabolic factors are significant explanatory variables for this stress. This stress is correlated with glucose metabolism and blood pressure and, moreover, these factors could all be proved concomitantly by the administration of an anxiolytic.

Twenty patients with non-insulin-dependent diabetes mellitus whose glucose metabolism was unsatisfactory, even though they were receiving appropriate dietary therapy, were treated with an alpha-glucosidase inhibitor (0.6 mg/day) for 12 weeks. The connecting peptide immunoreactivity value (selected as the evaluation criterion of post-prandial endogenous insulin secretion) was compared in patients with and without improved glycosylated haemoglobin levels. A significant difference was found between the connecting peptide immunoreactivity value of the group with improved glycosylated haemoglobin levels (5.0 +/- 1.0 ng/ml) and that in the group without the improvement (2.7 +/- 0.9 ng/ml).

The pathologic feature of acute interstitial nephritis is the infiltration of mononuclear cells, predominantly lymphocytes and monocytes, into the interstitium. We present an unusual case of a 49-year-old man with drug-induced acute interstitial nephritis whose renal biopsy specimen showed a massive infiltration of eosinophils into the interstitium and eosinophils infiltrating into the glomerulus through a gap in Bowman's capsule and the juxtaglomerular zone. The patient initially was referred to us with a recurrence of the nephrotic syndrome. Deterioration of renal function and an increase in proteinuria was noted at that time. Triazolam, a sleep inducer, was the suspected cause of the acute interstitial nephritis. Renal biopsy revealed sclerotic glomeruli containing eosinophils among massive infiltrated eosinophils and a loss of endothelial cells and mesangial cells in contrast to a preservation of epithelial cells. Infiltrating eosinophils were directly attached to the glomerular basement membrane, and free granules from the eosinophils were observed in the capillary lumen. In addition to chronic sclerotic change, eosinophils may have further damaged the glomerular capillary wall, leading to an increased severity of proteinuria in this case.

Ten patients with non-insulin-dependent diabetes mellitus who were being treated with a sulphonylureal compound but whose glucose metabolism needed further improvement were given a combination of their usual sulphonylurea treatment and an α-glucosidase inhibitor. Treatment with the α-glucosidase inhibitor (0.6 mg/day), in addition to glibenclamide (7.5 mg/day in two patients; 5.0 mg/day in four; 2.5 mg/day in one) or tolbutamide (500 mg/day in three patients) for 4 weeks, improved hyperglycaemia after meals from 237 – 247 mg/dl to 192 mg/dl, and reduced glycosylated haemoglobin levels from 8.5 – 8.6% to 7.9% without causing hypoglycaemia.

The possibility of a relationship between diabetic somatic neuropathy and cardiosympathetic neuropathy was investigated in 103 patients with non-insulin-dependent diabetes mellitus. Cardiosympathetic nerve function was assessed by myocardial scintigraphy. The severity of diabetic somatic neuropathy was determined by measuring the motor conduction velocities of the peroneal and tibial nerves and the sensory conduction velocity of the sural nerve. Analysis of the results did not show any correlations between the measures of cardiosympathetic nerve function and the measures of diabetic somatic neuropathy. The results indicate that diabetic somatic neuropathy and cardiomyosympathetic neuropathy develop independently in patients with non-insulin-dependent diabetes mellitus.

The effects of a combined α- and β-adrenoceptor blocking agent on glucose and lipid metabolism were examined in 27 out-patients with both non-insulin-dependent diabetes mellitus and hypertension. Systolic blood pressure was significantly reduced ( P < 0.02), compared with the baseline value, after 1, 2, 3 and 12 months of treatment, and diastolic blood pressure was reduced after 6 and 12 months while the reductions in blood pressure at the other times were not statistically significant. Total cholesterol, and low-density and high-density lipoprotein cholesterol, decreased or showed decreasing trends during treatment, while triglycerides and very low-density lipoprotein cholesterol did not change in response to treatment. The glycosylated haemoglobin level, an indicator of glucose metabolism, did not change throughout treatment compared with its baseline value. The results suggest that a combined α- and β-adrenoceptor blocking agent is less harmful to lipid metabolism and insulin sensitivity than a β-adrenoceptor blocker would be. Such combined agents may be useful for treating hypertension accompanying diabetes mellitus.

In order to verify whether angiotensin II (Ang II) induced in vivo protooncogene, c-fos, expression in the rat renal cortex and medulla, we administered various concentrations of Ang II to Wistar rats and measured the c-fos expression from the renal cortex and medulla using the method of Northern hybridization c-fos expression induced by 1 µg (1.6×10-6 M) of atrial natriuretic peptide (ANP) was also examined. The result was that the peak expression of c-fos mRNA was observed at approximately 10 min after Ang II administration in both rat renal cortex and medulla. This expression was reduced to the control level at 30 min. The measurement of the concentration of injected-Ang II and c-fos mRNA expression revealed that the peak expression of c-fos mRNA in the renal cortex and medulla was detected at the concentration of 1.0x10-6 M and 1.0 × 10-6M Ang II, respectively. Nevertheless, ANP had no significant effect on the increase in c-fos mRNA expression. These data revealed that Ang II transiently increases the in vivo c-fos expression in both rat renal cortex and medulla but ANP does not. This protooncogene expression may induce vascular and mesangial proliferation in the kidney.

A 10-year-old boy presented in 1989 with repeated episodes of vomiting, abdominal distension and severe growth retardation. Endocrinologic examination indicated growth hormone (GH) secretory dysfunction. Administration of recombinant human GH (rhGH) led to growth, but the patient discontinued treatment. He was readmitted to our hospital in 1993, at the age of 16. His stature was very short. Laboratory findings suggested malnutrition. Radiologic examination revealed regional stenosis and a cobblestone appearance of the intestine. The histologic diagnosis was compatible with Crohn's disease. Administration of prednisolone alleviated gastrointestinal symptoms with the improvement of GH secretory function.

Recent studies demonstrate that apoptosis is an important process in physiological and pathological cell death. We examined the apoptotic phenomena in thyroid tissues by two methods: immunohistological and in situ end-labeling of fragmented DNA (ISEL). In thyroid tissues from patients with Hashimoto's thyroiditis and thyroid cancer, fragmented nuclear DNA and LeY (apoptosis associated antigen) were observed. In tissues from patients with Graves' disease, LeY and bcl-2 oncoprotein were expressed, but no ISEL positive cells were observed. In contrast, thyrocytes in normal thyroid tissues were not stained with ISEL or anti-LeY antibodies (Abs). Fas antigen (Ag) was expressed in various thyroid tissues, including normal subjects. The clinical meaning of this was not determined. These results suggest that the apoptotic process takes place in Hashimoto's thyroiditis and thyroid cancer, and is overcome in Graves' disease by bcl-2 expression.

To clarify the ultrastructure in situ of the normal human glomerular basement membrane and ultrastructural changes of the glomerular basement membrane in patients with nephrotic syndrome, specimens of normal renal tissue and specimens from patients with membranous nephropathy, lupus nephritis, minimal change nephrotic syndrome, diabetic nephropathy, and Alport's syndrome were obtained. Specimens were examined by transmission electron microscopy by the newly devised "tissue negative staining method." Normal glomerular basement membrane showed a three-dimensional lattice-like meshwork of fibrils measuring 1.9 +/- 0.4 nm in diameter that formed numerous uniform, round, oval, or polygonal pores 2.5 +/- 0.4 nm in short diameter and 2.8 +/- 0.5 nm in long dimension. The nephrotic glomerular basement membrane revealed varying degrees of ultrastructural defects, the most prominent being tunnels and cavities. Tortuous tunnels measuring approximately 15 to 50 nm in diameter penetrated the entire glomerular basement membrane. Cavities of various shapes measuring 15 to 200 nm in diameter were diffusely scattered in the glomerular basement membrane and occasionally aggregated to form a honeycomb structure that occupied the whole thickness of the glomerular basement membrane. These defects appeared to be the pathway for protein leakage.

The mesangium is centrally located in the glomerulus and plays an important role in the microcirculation within the glomerulus. In order to reveal the role of the mesangial matrix in the microcirculat

20～80歳代の日本の健康成人について,モノクローナル抗体によるELISA法を用いてIgGサブクラスの正常値を調べた. 20歳以降のIgGサブクラス濃度において, IgG 1は加齢とともに直線的な漸増傾向がみられたが, IgG 2, IgG 3およびIgG 4は有意な変動はみられなかった.また, IgGサブクラス構成比率においては, IgG 3だけがわずかながら加齢に伴う増加傾向を示した. さらに,日本の健康成人と米国の健康成人におけるIgGサブクラス構成比率の違いについて考察した.その結果,日本の健康成人のIgGサブクラス平均構成比率は,米国健康成人に比較してIgG 1が約8%, IgG 3が約2%低い比率を示す反面, IgG 2が約10%高い比率を示した. IgG 4については有意な差はみられなかった.

The significance of necrosis (karyorrhexis), among the most characteristic findings in lupus nephritis, was evaluated by studying the correlation between the existence of necrosis in renal biopsy specimens and laboratory findings. The subjects were 54 patients with diffuse proliferative lupus nephritis and 6 patients with focal proliferative lupus nephritis selected from 143 patients with lupus nephritis. We also compared the clinical course of oral prednisolone and intravenous methylprednisolone pulse therapies after steroid administration. Compared with the non-necrosis group, the necrosis group had significantly lower CH50 levels and more proteinuria. Patients with necrosis were effectively treated with repeated pulse therapy judging by immunological activity and the decrease in proteinuria at an early stage, but responded poorly to oral steroid therapy. As the presence of necrosis in cases of lupus nephritis means high immunological activity of the lesion and there is responsiveness to a large dose of steroids, extensive immunosuppressive therapy including methylprednisolone pulse therapy should be applied to these patients.

維持透析導入半年後に胸腺癌を発症した非常に稀な1例を経験した. 患者は80歳男性で, 78歳時に胃癌の摘出術を施行された. 糖尿病の治療を17年間続けていたが, 腎機能が悪化したため1992年7月に血液透析へ導入した. 同年10月から前縦隔の腫瘤を認め悪性腫瘍を強く疑ったが, 患者と家族の希望により経過を観察していた. 食欲低下や咳嗽, 胸水の貯留などが出現したため, 1993年4月に当科へ入院したが入院第22日目に死亡した. Necropsyを施行したところ病理組織検査で胸腺癌と診断した. 我々が検索した限りでは, 透析導入後に胸腺癌が発生した報告はなく, わずかに胸腺癌の摘出後7か月目に悪性高血圧のため急激に腎機能が悪化し, 最終的に維持血液透析を施行された全身性進行性硬化症の1例が報告されているだけである. しかも, 本症例では透析導入2年前に胃癌の摘出術を受けており, 透析患者の悪性腫瘍の発生要因や発生時期を考えるうえで興味深い症例と思われたため報告した.

The effect of prostaglandin E1 (PGE1) on the renin–aldosterone system was investigated in hospitalized patients with non-insulin-dependent diabetes mellitus presenting with continuous proteinuria but without nephrotic syndrome. Of the 20 patients studied, 10 had continuous positive proteinuria ≥ 200 mg/day and 10 had continuous positive proteinuria < 200 mg/day. Prostaglandin El (40 μg in 100 ml normal saline) was infused intravenously over 2 h twice daily for 4 weeks. Plasma renin activity (PRA) and the plasma aldosterone concentration (PAC) were determined by radioimmunoassay at 0 and 120 min after a frusemide injection given before the start of PGE1 treatment and during administration of PGE1 in week 4. The patients who had proteinuria < 200 mg/day showed significant decreases in the PRA0 and the ratio of PRA120:PRA0 and a decrease in the PAC120 during prostaglandin PGE1 administration. When the results for the two patient groups were combined, both the PAC120 and the PRA120 were found to be significantly lowered during administration of PGE1. The results indicate that PGE1 may be valuable in the treatment of diabetic nephropathy, since the compound inhibited the increased reactivity of the renin–aldosterone system in patients with non-insulin-dependent diabetes mellitus.

Hydroxymethylglutaryl–coenzyme A (HMG–CoA) reductase inhibitor (pravastatin sodium) can selectively inhibit cholesterol biosynthesis in the liver and may lower serum cholesterol concentrations even where there are no particular dietary restrictions. A 72-year old housewife with non-insulin-dependent diabetes mellitus complicated by hyperlipaemia type IIb, who did not follow directions for diet therapy or kinesitherapy, was administered HMG–CoA reductase inhibitor. The initial dose of 10 mg/day HMG–CoA reductase inhibitor was increased by 10 mg/day every 4 weeks to 30 mg/day, maintained at 30 mg/day for 8 weeks and then reduced gradually until discontinuation after a further 27 weeks. Test results showed the changes in low-density lipoprotein cholesterol and apoprotein B to be dose-dependent. The findings represent the first clinical evidence that hypercholesterolaemia can be adequately managed by the use of HMG–CoA reductase inhibitor, even when no specific dietary restrictions are imposed, and may contribute to improvements in the quality of daily life for many patients suffering from hyperlipaemia type IIb.

Renal basement membranes by ultrahigh resolution scanning electron microscopy. Three-dimensional ultrastructures of basement membranes of the rat kidney were investigated with an ultrahigh resolution scanning electron microscope (HSEM) equipped with a resolving power of 0.5nm. All cellular components were extracted from renal cortical tissues by sequential-detergent treatment. Four types of acellular basement membranes were observed after tannin-osmium conductive staining: the glomerular basement membrane (GBM) associated with the mesangial matrix, the tubular basement membrane (TBM), the Bowman's capsule basement membrane (BCBM), and the peritubular capillary basement membrane (PTCBM). We could demonstrate the polygonal meshwork structures composed of strands in the respective basement membranes. The strands averaged 6 to 7 nm wide, whereas the pore sizes within the meshworks were variable and differed according to the basement membrane type. Moreover, we confirmed the presence of the heterogeneity of the GBM suggested by several approaches. Present data support the proposition that a polygonal meshwork structure may represent the basic structure of basement membrane. Some of the observed architectural dissimilarities in basement membrane types may reflect their different functional properties, which in turn may reflect the heterogeneous distribution of major basement membrane components as demonstrated by immunohistochemical and biochemical studies.

A 27-year-old womandeveloped proteinuria, hypertension, and peripheral edema during the ninth monthof her first pregnancy. The clinical and serological features were compatible with a diagnosis of toxemia of pregnancy, except for the presence of hypocomplementemia. The patient had glomerulonephritis characterized by large electron-dense deposits, predominantly in the mesangium. Immunofluorescence studies revealed striking accumulations of Clq and C3, and the presence of small amounts of IgG and IgM in the mesangium. Serum and plasma levels of complement components were normal, except for the C9 component. Family studies demonstrated that the C9 deficiency was inherited.(Internal Medicine 32: 806-809, 1993)

The glomerular basement membrane (GBM) is considered to regulate glomerular permselectivity for proteins by acting as both size barrier and charge barrier. Since heparan sulfate-proteoglycan (HS-PG), which forms the charge barrier of GBM, contains a sulfonic acid, we made membranes with various degrees of negative charge models of GBM by addition of sulfonic acid to ethylene vinyl alcohol (EVAL) membranes. A high-resolution scanning electron-microscopic study revealed no ultrastructural alterations after adding sulfonic acid to EVAL membranes. Both neutrally and negatively charged membranes had porous structures in the inner surface of the membranes. The interrelation between the two actions of size and charge of GBM was studied using special dialyzers with various degrees of negative charge and different pore sizes. The negatively charged membranes adsorbed proteins with positive charge and repulsed proteins with negative charge. The degrees of adsorption and repulsion were weaker in membranes with larger pores and were stronger for proteins with larger molecular weights. The permselectivity for proteins of a charged membrane depends largely upon the interrelation between the pore size of the membrane and the size of the proteins. It is, therefore, suggested that the presence of a size barrier in GBM is necessary for the charge barrier to effectively exert glomerular permselectivity for proteins. Our study may lead to the development of a dialyzer with higher permselectivity by adding sulfonic acid rather than conventional dialyzers.

慢性透析患者の合併症の一つである皮膚掻痒症は, いまだに原因は十分に解明されておらず, そのため治療法も確立していない.そこで, 今回我々は, 脂肪乳剤の投与条件を設定し, その条件を満たす難治性の皮膚掻痒症を有する慢性血液透析患者7名に対し, 脂肪乳剤の投与を行った. その結果, 皮膚乾燥に対しても, 掻痒感に対しても, 同じ5名 (71.4%) の有効性を認めた. また脂肪乳剤投与前後における検査値で有意差を認めた検査項目はなく, 副作用は認めなかった. しかし投与終了4週後には, 脂肪乳剤の有効性を認めた5名のうち4名が増悪し, 再投与により, 再び改善を認めた.このように, 適応を十分に考慮すれば, 脂肪乳剤が慢性透析患者の難治性皮膚掻痒症に対して有効かつ安全な薬剤であることが確認された. 今後, この脂肪乳剤の皮膚掻痒に対する有効性の機序が明らかにされれば, より有効で安全な薬剤の開発や, あるいは新たな透析方法の開発が期待できるものと考えられる.

血漿vetronectin (VN) 値は, 血液透析患者では低値を示すが, 透析歴が長くなるほど, より低値を示すことが知られている. そこで, 今回我々は, 同一患者に対し, regenerated cellulose (RC膜), cellulose triacetate膜 (CTA膜), polysulfone膜 (PS膜) の3種類の透析膜を順次変えて血液透析を施行し, その際の血漿VN値の変動を測定することにより, これらの透析膜で血漿VN値の変動に有意な変化があるか否かを検討した. また, 抗凝固剤としてのheparinの影響の有無を検討するため, 抗凝固剤として, heparinを使用した時とnafamostat mesilate (NM) を使用した時の, 血漿VN値の変動を比較検討した.その結果, すべての膜において, 透析開始前の血漿VN値は, 正常値より低値を示した. 血漿VN値の変動では, RC膜のみ有意な変化を認め, 透析開始後15分の血漿VN値が, 開始前に比べ有意に低値を示したが, CTA膜, PS膜には, 有意な変動を認めなかった. 従って, 使用している透析膜の種類により補体活性化の程度が異なり, VNの消費の程度が異なってくることが示唆された. また, 抗凝固剤による検討では, すべての膜において, heparin使用時とNM使用時とでは, 血漿VN値の変動に関し有意差を認めなかったため, VNがheparinと結合することによりVNが消費されるという説を支持する結果は得られなかった.

Thyroid peroxidase (TPO) is an essential enzyme involved in thyroid hormone synthesis and is closely related to the microsomal antigen which is the target of thyroid microsomal antibody. There have been several reports on direct inhibition of peroxidase activity by thyroid microsomal antibody. We prepared a mini organ culture of thyroid glands obtained at operation, and investigated the localization of thyroid peroxidase activity in follicular cells proliferated around the thyroid tissue blocks by electron microscopy. The development of microvilli containing TPO activity on the cell surface facing the culture medium was observed when normal thyroid tissue or Graves' thyroid tissue was incubated with TSH but in the TSH-free group the development of microvilli was poor and TPO activity was very much decreased. After the addition of serum positive for thyroid microsomal antibody, the TPO activity of the microvilli was retained in 4/6 tissue samples, but it disappeared in 2 cases. Our findings suggested that thyroid peroxidase activity is regulated by thyroid stimulating substances such as TSH and by TPO in tissue.

The effectiveness and safety of MCI-028, a synthetic human corticotropin-releasing hormone (hCRH), as a diagnostic drug were examined in 65 healthy male and 24 healthy female adult volunteers. Mean maximum concentrations of plasma ACTH and cortisol after intraveneous administration of 100 μg of MCI-028 were 3.0 and 2.0 times their basal concentrations, respectively, and there were no significant age or sex differences in the responses. Good reproducibility was observed in the responses in 59 male subjects who received a second administration after 1 to 2 weeks. Although slight adverse reactions such as mild and transient hot flushing were observed, these were not serious.

We previously reported that food deprivation significantly decreased arginine-vasopressin (AVP) mRNA levels in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus and also greatly stimulated the pituitary-adrenocortical system in rats. In this study, we deprived adrenalectomized rats with subcutaneously implanted low-dose corticosterone pellets (ADX + B) of food for 3 days to investigate the involvement of corticosteroid feedback regulation in the food deprivation-induced decrease in AVP mRNA in both the SON and the PVN. The plasma corticosterone levels in these animals were maintained at low levels constantly over 24 h. The ACTH concentration in the morning plasma was markedly increased in the food-deprived ADX + B rats as compared to the fed ADX + B rats. Food deprivation significantly decreased the corticotropin-releasing hormone (CRH) content in the median eminence and increased the CRH and AVP content in the neurointermediate lobe of the pituitary. Semiquantitative in situ hybridization histochemistry revealed that AVP mRNA levels were decreased in the SON but, inversely, increased in magnocellular as well as parvocellular subdivisions of the PVN following food deprivation. These results suggest that: (1) AVP mRNA responds differently to food deprivation between the SON and the PVN; (2) the glucocorticoid feedback can exert on AVP mRNA in the PVN but not in the SON in the food-deprived rats; and (3) food deprivation affects the neurohypophysial levels of CRH and AVP.

In an investigation into the effect of prostaglandin E1on proteinuria in nephrotic diabetic nephropathy, five patients were treated with 40 μg prostaglandin E1administered intravenously over 2 h twice daily for 4 weeks. The following parameters were compared before and after treatment: protein excretion in urine; total serum protein concentration; serum albumin concentration; creatinine clearance; blood urea nitrogen; and serum creatinine content. A further five patients with nephropathy resulting from non-insulin-dependent diabetes mellitus were selected as controls. Analysis of the results using Student's t-test showed no significant change in any of the parameters before and after treatment.

A simple method that can be performed at the bedside using a spring balance was developed in order to quantify spasticity. The effects of tizanidine on spasticity were evaluated in 30 patients with sequelae of cerebrovascular disease using this method. Treatment with tizanidine was effective in 60% of the patients; there were high correlations between spasticity before and after tizanidine administration and the severity of symptoms and also between the degree of improvement in spasticity and in that of the symptoms. Atonic seizures, due to overdose of tizanidine, were observed in only one patient. The simple spasticity quantification method developed was useful for monitoring tizanidine administration in order to prevent drug overdose. The method appears to be very useful for evaluating the degree of spasticity at the bedside and in measuring the effects of antispastic drugs.