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Objective Obesity is associated with an increased risk of diabetes mellitus, hypertension, and renal dysfunction. Angiotensin 1–7 and alamandine are heptameric renin angiotensin system peptide hormones. Further, alamandine levels increase with renal dysfunction. In the cardiovascular system, angiotensin 1–7 and alamandine produce similar improvements and counterbalance angiotensin II in regulating vascular function. We aimed to determine whether the effect of alamandine on leptin expression and secretion in adipocytes was similar to that of angiotensin 1–7. Approach and results We studied isolated peri-renal visceral adipose tissue and peri-renal isolated visceral adipocytes from male Wistar rats. Angiotensin II from 0.01 to 10nM had no effect on leptin expression. Angiotensin 1–7 (1 nM) increased leptin secretion and expression, whereas alamandine (1 nM) decreased leptin secretion and expression in adipose tissue and isolated adipocytes and reduced blood leptin levels in vivo. These effects were mediated by Gq, c-Src, p38 mitogen-activated protein, and IκB activation. Additionally, alamandine induced nitric oxide expression via inducible nitric oxidase synthase and plasminogen activator inhibitor 1 expression in adipose tissue and isolated adipocytes. Conclusions Angiotensin 1–7 and alamandine produced opposing effects on leptin expression and secretion in adipose tissue. This result suggests that the action of Mas (angiotensin 1–7 receptor) and Mas-related G-protein coupled receptor D in adipocytes exhibited opposing actions similar to angiotensin II type 1 and type 2 receptors.

Weak pancreatic β-cell function is a cause of type 2 diabetes mellitus. Glucokinase regulates insulin secretion via phosphorylation of glucose. The present study focused on a system for the self-protection of pancreatic cell by expressing heat shock factor (HSF) and heat shock protein (HSP) to improve insulin secretion without inducing hypoglycemia. We previously generated a constitutively active form of human HSF1 (CA-hHSF1). An adenovirus expressing CA-hHSF1 using the cytomegalovirus promoter was generated to infect mouse insulinoma cells (MIN6 cells). An adenovirus expressing CA-hHSF1 using a human insulin promoter (Ins-CA-hHSF1) was also generated to infect rats. We investigated whether CA-hHSF1 induces insulin secretion in MIN6 cells and whether Ins-CA-hHSF1 can improve blood glucose and serum insulin levels in healthy Wister rats and type 2 diabetes mellitus model rats. CA-hHSF1 expression increased insulin secretion 1.27-fold compared with the overexpression of wild-type hHSF1 in MIN6 cells via induction of HSP90 expression and subsequent activation of glucokinase. This mechanism is associated with activation of both glucokinase and neuronal nitric oxide synthase. Ins-CA-hHSF1 improved blood glucose levels in neonatal streptozotocin-induced diabetic rats. Furthermore, Ins-CA-hHSF1 reduced oral glucose tolerance testing results in healthy Wister rats because of an insulin spike at 15 minutes; however, it did not induce hypoglycemia. CA-hHSF1 induced insulin secretion both in vitro and in vivo. These findings suggest that gene therapy with Ins-CA-hHSF1 will be able to be used to treat patients with type 2 diabetes mellitus and impaired glucose tolerance without causing hypoglycemia at fasting.

A prospective randomized open-labeled study was performed to compare the renoprotective effects of enarapril and losartan on the development of microalbuminuria in type 2 diabetic patients with hypertension. Diabetic patients who have hypertension and microalbuminuria at base line (n=19) were recruited. Enarapril (n=11) or losartan (n=8) was randomly chosen by envelope methods and was prescribed for one year. At the end of this study, the blood pressure of patients in these two groups decreased significantly. Urine albumin-creatinine ratio (U-ACR) also decreased in these two groups, however, U-ACR of enarapril group was not significantly different from that of losartan group at any time of this study. Body mass index, HbA1c, blood pressure, and serum lipid profiles were not significantly different between the two groups. From these results, we conclude that the effects of enarapril and losartan on the development of microalbuminuria in type 2 diabetic patients along with hypertension seem to be equivalent in terms of clinical renoprotection.

We have been examining the role of heat shock factor 1 (HSF1) in the pleiotropic effects of statins. In parallel studies, we found that statin induces the nuclear translocation of HSF1 and that a decoy oligonucleotide encoding the heat shock element inhibits the statin-induced expression of heat shock protein 70, endothelial nitric oxide synthase (eNOS) and thrombomodulin. Also, in vascular endothelial cells, increases in the expression of human HSF1 corresponded with elevated steady-state levels of eNOS and thrombomodulin and reduced levels of endothelin-1 and plasminogen activator inhibitor-1. We also found that heat shock proteins induced eNOS and thrombomodulin expression and reduced PAI-1 and ET-1 expression. In particular, a combination of HSP70 and HSP90 strongly induced eNOS expression and reduced PAI-1 expression. In the current studies, we generated a constitutively active form of HSF1 and found that it is more effective than the wild-type HSF at inducing thrombomodulin and eNOS expression and decreasing endothelin-1 and plasminogen activator inhibitor-1 expression. These results show that the wild-type and constitutively active forms of HSF1 induce anticoagulation and relaxation factors in vascular endothelial cells and could therefore be used to treat cardiovascular disease.

Metabolic syndrome is characterized by visceral adiposity, insulin resistance, high triglyceride (TG)- and low high-density lipoprotein cholesterol-levels, hypertension, and diabetes-all of which often cause cardiovascular and cerebrovascular diseases. It remains unclear, however, why visceral adiposity but not subcutaneous adiposity causes insulin resistance and other pathological situations. Lipoprotein lipase (LPL) catalyzes hydrolysis of TG in plasma lipoproteins. In the present study, we investigated whether the effects of angiotensin II (AngII) on TG metabolism are mediated through an effect on LPL expression. Adipose tissues were divided into visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) for comparison. AngII accelerated LPL expression in SAT but, on the contrary, suppressed its expression in VAT. In both SAT and VAT, AngII signaled through the same type 1 receptor. In SAT, AngII increased LPL expression via c-Src and p38 MAPK signaling. In VAT, however, AngII reduced LPL expression via the Gq class of G proteins and the subsequent phospholipase C β4 (PLCβ4), protein kinase C β1, nuclear factor κB, and inducible nitric oxide synthase signaling pathways. PLCβ4 small interfering RNA experiments showed that PLCβ4 expression is important for the AngII-induced LPL reduction in VAT, in which PLCβ4 expression increases in the evening and falls at night. Interestingly, PLCβ4 expression in VAT decreased with fasting, while AngII did not decrease LPL expression in VAT in a fasting state. In conclusion, AngII reduces LPL expression through PLCβ4, the expression of which is regulated by feeding in VAT, whereas AngII increases LPL expression in SAT. The different effects of AngII on LPL expression and, hence, TG metabolism in VAT and SAT may partly explain their different contributions to the development of metabolic syndrome.

Statins not only reduce serum cholesterol but they also improve vascular endothelial function independent of their lipid-lowering effects. However, except for the mechanism of nitric oxide induction via calveolin, the physiologic basis for the pleiotropic effect of statins remains unknown. In the present study, we investigated the relationship between the effects of statins on vascular endothelial cell function and heat shock proteins. We found that, in vascular endothelial cells, simvastatin increased the steady-state levels of heat shock proteins 90 and 70, and heme oxygenase-1 and caused the nuclear translocation of heat shock factor 1. A decoy oligonucleotide encoding the heat shock element inhibited statin-induced expression of heat shock protein 70, endothelial nitric oxide synthase, and thrombomodulin. This decoy oligonucleotide also inhibited the ability of statin to reduce endothelin-1 and plasminogen activator inhibitor-1 expression. These results indicate that statins improve vascular endothelial function via heat shock factor 1, which may contribute to their ability to improve cardiovascular disease.

We report a 59-year-old woman with type 2 diabetes mellitus (DM) complicated with smoldering myeloma and non-alcoholic steatohepatitis. A diagnosis of smoldering myeloma was made on the basis of elevation of IgA, M-protein (type:IgA-lambda) and histological findings of bone marrow without bone lesion. As to liver dysfunction, anti-HBV, anti-HCV and a series of auto-immune antibody were negative. She had no alcohol drinking habit and histological findings showed pericellular fibrosis without fatty degeneration, suggesting liver cirrhosis due to non-alcoholic steatohepatitis (NASH). To date, there are no reports of cases with DM, NASH and myeloma. Particular attention may be necessary for these complications.

Short-latency somatosensory-evoked potentials (sSEPs) were recorded after median nerve stimulation in 91 patients with diabetes mellitus (DM). Patients were divided into three groups: (1) patients without neuropathy, (2) patients with mild neuropathy, and (3) patients with severe neuropathy. Discriminant analysis was carried out using the three groups as objective values and 26 variables; age, sex, DM type, DM duration, fasted blood sugar, HbA1C, sensory conduction velocity (SCV), N13–N20 interpeak latency, amplitude, latency, and shape of each of the six recorded waves as explanatory variables. Discrimination was statistically significant among the three groups (F-test, p

Objects: To investigate the effect of combined estrogen and progesterone therapy on insulin resistance (IR) and carbohydrate and lipid metabolism in postmenopausal women (PMW) with impaired (IGT) and normal glucose tolerance (NGT). Methods: Sixteen Japanese PMW with IGT and 33 with NGT received daily oral hormone replacement therapy (HRT; 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate) for 12 months. As controls, 13 Japanese PMW with IGT and 31 with NGT were enrolled and not treated by HRT. Fasting plasma glucose (FPG), fasting immunoreactive insulin (IRI), and IR were measured in each subject at study initiation and 12 months later. We used homeostasis model assessment (HOMA) to determine IR. Results: FPG and HOMA IR were decreased in both HRT groups, and fasting IRI was reduced in the HRT-NGT group. In controls, FPG, fasting IRI, and HOMA IR were unaltered. Total and low-density lipoprotein cholesterol were decreased and high-density lipoprotein cholesterol was increased in both HRT groups, but triglyceride was unchanged. In controls, lipid metabolism was unaltered. Conclusion: HRT decreased IR and improved carbohydrate and lipid metabolism in Japanese PMW with IGT and NGT. These beneficial effects argue for the use of HRT in PMW with IGT as well as NGT.

We investigated the therapeutic effect of branched chain amino acids (BCAA) on mice with glucose intolerance induced by encephalomyocarditis virus (EMCV). Male DBA/2 mice were divided into three groups: treated with BCAA, (such as valine, leucine, and isoleucine), untreated, and control. BCAA-treated and -untreated groups were inoculated intraperitoneally with the NDK25 variant of EMCV at 200 plaque-forming units per mouse. The BCAA-treated group was administered orally 0.9 g/kg/day of each BCAA from the day after viral inoculation. The control group neither received virus inoculation nor was treated with BCAA. One week after inoculation, oral glucose tolerance tests (OGTT) were performed. After the glucose loading at 1.5 g/kg of body weight, blood glucose levels in the untreated group were 92.0+/-10.0 mg/dl at baseline, 224.6+/-10.9 mg/dl at 30 min, and 169.4+/-21.4 mg/dl at 60 min, which were significantly (P

We investigated the therapeutic effects of OK432 (picibanil; CAS39325-1-4), an immunomodulator that is derived from the Su strain of Streptococcus pyogenes. This agent was administered alone or combined with human interferon-alpha in a murine model of insulin-dependent diabetes mellitus. Interferon-alpha inhibits viral replication, reducing the incidence of virus-induced IDDM. Groups of DBA/2 mice (N = 25 per group) received an intraperitoneal injection of OK432 and interferon-alpha daily for 16 d beginning 1 d after inoculation with 500 plaque-forming units of encephalomyocarditis virus (EMCV). The dose of OK432 was one clinical unit (corresponding to 0.1 mg dried cells) per mouse, and that of interferon-alpha was 1 x 10(4) u/g. The animals were killed at random at 3 or 7 d after inoculation with EMCV. The survival rate of mice treated with the combination of OK432 and with interferon-alpha was significantly greater than that of the non-treated infected control animals (P0.01). Fasting levels of blood glucose were significantly lower in the mice administered the combination, than in the controls, both on day 3 (68 +/- 21 mg/dl vs. 270 +/- 135 mg/dl, P0.01) and on day 7 (101 +/- 29 mg/dl vs. 219 +/- 112 mg/dl, P0.01). Serum levels of insulin were significantly higher in the treated mice than in the controls (65 +/- 5 vs. 55 +/- 1 microU/ml, P0.05). However, in the mice treated with OK432 or interferon-alpha alone, the survival rate and the blood level of glucose and insulin did not differ from those of infected controls. Natural killer (NK) cell activity was significantly higher in the mice treated with the drug combination than in the controls on both days evaluated: day 3, 65 +/- 5 vs. 55 +/- 1%, n = 3, P0.05; day 7, 44 +/- 3 vs. 22 +/- 8%, n = 3, P0.05). Serum levels of murine interferon in the treated mice exceeded those in controls on both days evaluated (day 3, 671 U/ml vs. 442 U/ml; day 7, 57 U/ml vs. 43 U/ml). There were no significant differences in NK cell activity or in the interferon level in mice treated with either OK432 or interferon-alpha alone as compared with the infected, non-treated controls. Results suggest that the combination of OK432 and interferon-alpha protects against virally induced IDDM by increasing the activity of NK cells as well as the plasma level of interferon.

To clarify the relationship between early diabetic nephropathy and the glycemic control in non-insulin-dependent diabetes mellitus (NIDDM) without hypertension, excretion of urinary albumin was studied retrospectively for 8 years. The patients with early diabetic nephropathy were divided into two groups according to the initial urinary albumin index (UAI: mg/g.creatinine), namely, a normoalbuminuric (less than 15 mg/g.creatinine) and a microalbuminuric group (15 or = 200 mg/g.creatinine), although only one case worsened of five patients with good glycemic control (p < 0.05). In conclusion, the development or progression of early diabetic nephropathy in NIDDM was significantly inhibited by good glycemic control (FPG < 140 mg/100 mL and HbA1 < 9.0%), independent of hypertension, and probably irrespective of the mode of therapeutic intervention.

In 197 patients with coronary artery disease (CAD) who underwent coronary angiography, 75 g oral glucose tolerance test (OGTT) was performed, measuring plasma glucose(PG) and plasma insulin (IRI) at 4 time points (0, 30, 60 and 120 min). Subjects were separated into two groups by their insulinogenic index (I.I. = delta IRI/delta PG from 0 up to 30 min), 99 cases with good insulin response (I.I. > or = 0.4) and 98 cases with poor insulin response (I.I. < 0.4). Only two subjects were diabetic in good insulin response, while 37 were diabetic in poor insulin response. The severity of coronary atherosclerosis was expressed as a coronary index (CI), calculated according to Balcon's method. Fasting PG and the sum of PG were significantly higher in the latter group, while the sum of IRI was significantly lower. CI was not significantly different, however. In the group with good insulin response, the severity of CAD was significantly correlated to fasting IRI (n = 99, r = -0.387, P < 0.02), but, there was no such relationship in the other group. We conclude that hyperinsulinemia might be a risk factor for ischemic heart disease, but in diabetics it is difficult to link the relationship between fasting IRI and CI.

Glycyrrhetinic acid (GA), the main metabolic product of glycyrrhizin (GLY), could be detected in formalin-fixed tissue from a man who died 6 hours after therapeutic administration of a GLY-containing agent. GA was extracted from homogenized formalin-fixed liver tissue and 3 ng GA/g could be detected by HPLC. The extraction from formalin-fixed liver tissue gave the same retention time peak as the GLY control. GA could also be detected by mass spectrometry in the blood sample. This confirms that the man had received a GLY-containing agent for therapeutic use prior to his death and that GA can be determined from formalin-fixed tissue.

虚血性心疾患151例を対象として, 負荷201TI心筋シンチグラフ (SPECT) , ECG, VOGの心筋虚血領域の判定の差異について検討した.虚血と判定したのは, SPECTで142件, ECGで140件であった.両法の判定が一致したのは117件で, 両法とも虚血と判定したうちの84%であり, 虚血についての感度は両法ほぼ同程度であった.しかし, 負荷ECGでST低下のみられた誘導部位はSPECTによる心筋虚血部位とは対応せず, ECGでは部位診断は不可能であった.左室造影をgoldstandardとした心筋梗塞数は73例で, SPECTの梗塞診断率はECGに比較して優れていた (P

LDL-apheresis is introduced in many cases all over Japan. Among them, evaluation of long-term effect on ischemic heart disease (IHD) has made on 10 cases with homozygous familial hypercholesterolemia (FH) and 49 cases with heterozygous FH.As to homozygous FH, 3 patients had angina pectoris. Mean duration of treatment was 26 months (52 treatments). The changes in total cholesterol (TC) in each treatment was from 426 mg/dl to 151 mg/dl. Improvement in IHD was observed in 5 out of 10 cases.As to heterozygous FH, 17 cases had history of myocardial infarction and 12 had angina pectoris. Mean duration of treatment was 13 months (19 treatments). Mean TC was decreased from 271 mg/dl to 126 mg/dl by each treatment. Regression in Achilles tendon thickenting or skin and palpebral xanthomas was observed. Frequency of anginal attacks decreased in 8 out of 17 cases. Ischemic change in ECG were improved in 3 out of 26 cases. Coronary angiography performed with 2 to 3 years of interval in some cases revealed regression o...

The case of 41 year-old man with non-insulin dependent diabetes mellitus and severe type V hyperlipidemia is reported. On admission, the fasting plasma glucose was 157 mg/dl and Hb A1c 9.8%. The serum total cholesterol was 638 mg/dl, triglyceride 2, 779 mg/dl, apoprotein (apo) A-I 174 mg/dl, apo A-II 86.9 mg/dl, apo B 475 mg/dl and apo E 28.2 mg/dl. Agar gel electrophoresis revealed increased chylomicron and beta lipoprotein. The serum apoproteins were normalized by diet therapy. However, the oral administration of 75 g of olive oil induced a marked increase in the serum triglyceride even with good control of the diabetes by appropriate diet. We postulate that insufficient chylomicron receptor may be responsible for the abnormalities of serum lipids in this patient.

We reviewed the histories and laboratory data of 67 young patients with ischemic heart disease under the age of 40 years. Twenty-three cases were associated with hypercholesterolemia. Of these. 10 were of the familial type. Twenty patients had hypertension, while 14 were diabetics and 13 were heavy smokers. It is noteworthy that 13 of 17 patients with multi-vessel disease had hypercholesterolemia. Significant atherosclerotic coronary stenosis was demonstrated in 51 cases. The incidences of hypercholesterolemia, hypertension and diabetes mellitus in these 51 patients were not only significantly higher than those in age-matched normal healthy subjects and young patients with non-ischemic heart disease, but also higher than those in patients with ischemic heart disease over the age of 40 years. The results indicated that hypercholesterolemia is the most important risk factor for ischemic heart disease in young patients. although the three previously accepted risk factors (hypertension, diabetes mellitus and cigarette smoking) were all associated with the development of the disease. We could not find any obvious risk factor in 18 young patients with ischemic heart disease, including 12 cases of myocardial infarction. Myocardial infarction in the absence of any obvious risk factor occurred during strenuous physical exercise in 5 patients and following excessive alcohol consumption in 4.

脳血管障害とリポ蛋白代謝異常の関係を検討する目的で, 発症後3ヵ月以上を経過しリハビリテーションの目的で入院中の脳梗塞103例, 脳出血88例と対照としての非脳血管障害43例について, 血清脂質, アポ蛋白, lecithin cholesterol acyltransferase (LCAT) 活性を比較検討した.血清総コレステロール, LDL-cholesterol (LDL-ch) は, 対照に比べ脳梗塞群で有意に高値 (p

UNLABELLED Although neutrophils are essential components of the natural immune system, they have also been implicated in the pathogenesis of tissue injuries. We assessed the clinical significance of neutrophil apoptosis in the peripheral blood of patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS The study included 52 patients with T2DM (30 men, 22 women). Control subjects were 16 healthy volunteers without diabetes (7 men, 9 women). Neutrophil apoptosis levels were measured active caspase-3 positive rate by flow cytometry. RESULTS The mean rate of neutrophil apoptosis in patients with T2DM was 15.0% (95% confidence interval [CI]: 9.5% approximately 20.5%), while that in the control group was 5.8% (95% CI: 1.6% approximately 10.0%). There were significant negative correlations between neutrophil apoptosis rate and hemoglobin (Hb) A1c levels (r = -0.352, P < .01). The mean rate of neutrophil apoptosis in the patient group with the 3 major complications (diabetic retinopathy, nephropathy, and neuropathy) was 11.1% (95% CI: 5.5%-16.7%, n = 36) and that of another group without complications was 23.8% (95% CI: 11.4%-36.2%, n = 16). There was a significant difference between these 2 groups (P < .05). CONCLUSIONS The neutrophil apoptosis rate in patients with T2DM was significantly correlated with HbA1C levels. The mean rate of neutrophil apoptosis in the patient group with 3 major diabetic complications remained lower than that in another patient group without complications. The inhibition of neutrophil apoptosis by chronic hyperglycemia is thought to promote tissue injury and to enhance the risk of microangiopathy.

Remnant-like particles (RLP) were studied in 139 diabetic patients. RLP were those lipoproteins that did not bind to an immunoaffinity gel mixture using anti-apo B-100 and apo A-1 monoclonal antibodies, and were shown to provide a useful index for atherogenic chylomicron and very low density lipoprotein remnants. RLP-positive findings (RLP≥ 5 mg/dl) in diabetics (42%) were significantly higher in prevalence than those in controls (12%) (p

The association between the lack of adrenergic symptoms during hypoglycemia and myocardial 123I-metaiodobenzylguanidine (MIBG) accumulation was investigated in 12 insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) patients who had no evidence of heart disease. These patients were divided into 2 groups according to the presence (group A) or absence (group B) of adrenergic symptoms during hypoglycemia. Autonomic function tests revealed significantly severe autonomic dysfunction in group B compared to that in group A. Insulin infusion test indicated no significant difference in the catecholamine response between the two groups. 123I-MIBG scintigraphy showed that the heart/mediastinum ratio of MIBG uptake was significantly lower, and scintigraphic defect was greater in group B than in group A. There were no significant differences in the washout rate between the two groups. These results suggested that the lack of adrenergic symptoms during hypoglycemia may be associated with cardiac sympathetic nervous dysfunction in insulin-treated NIDDM patients, and this dysfunction is mainly due to cardiac sympathetic denervation.(Internal Medicine 35: 94-99, 1996)

To investigate predictive genetic markers for diabetic nephropathy, we studied the genetic polymorphisms of angiotensin-converting enzyme (ACE) and angiotensinogen (AGN) in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM) with and without nephropathy. Genotype distributions were studied in 132 unrelated NIDDM patients of three groups with normoalbuminuria ([Normo] n = 53), microalbuminuria ([Micro] n = 54), and macroalbuminuria ([Macro] n = 25). The ACE insertion/deletion (I/D) polymorphism of intron 16 was identified by polymerase chain reaction, and the AGN M235T polymorphism was identified by restriction fragment length polymorphism analysis. There were no significant associations between AGN 235 allele or genotype and diabetic nephropathy. The D allele of ACE was significantly more frequent in the Micro (P = .003) and Macro (P = .009) group than in the Normo group. Overall frequencies of the ACE genotype did not differ significantly between the Micro and Macro groups. There were significant relationships between I/D polymorphism and plasma ACE activity; the DD genotype had the highest activity. A multiple logistic regression analysis revealed that the D allele is a strong and independent risk factor for abnormal albuminuria in NIDDM patients. These results suggested that ACE I/D polymorphism, but not AGN M235T polymorphism, is a possible genetic risk factor for diabetic nephropathy in Japanese NIDDM patients.

To investigate whether the remnant like particles (RLP), separated from serum by an immunoaffinity gel mixture of anti-apo B-100 and apo A-I monoclonal antibodies, are relevant to the initiation or progression of atherosclerosis, the incorporation of RLP into mouse macrophages was studied using histochemical and biochemical techniques. Remnant lipoproteins such as RLP are reported to contain a large quantity of chyloniron and very low density lipoprotein (VLDL) remnants, especially in diabetic patients. The RLP separated from the sera of 32 diabetic patients were found to be predominantly taken up into macrophages harvested from mouse abdominal cavities by the staining method applying oil red O. Furthermore, using 14C-oleate to prove the uptake of lipoproteins by macrophages, the uptake of RLP-VLDL, a VLDL fraction of RLP by ultracentrifugation, was the next highest to that of the oxidized LDL, which suggests that RLP-VLDL is also aggressively taken up by macrophages. The degree of uptake of RLP-VLDL by macrophages was positively correlated with HbA1c of these diabetic patients (r = 0.556, p < 0.01), irrespective of the ways of the treatment of diabetes. In conclusion, RLP can contribute to the foaming of macrophages, which in turn may explain the acceleration of atherosclerosis in diabetic patients.

Remission of diabetes, i.e. significant amelioration from absolute insulin-dependency, has been sometimes observed in diabetic BB/Wor//Tky rats which were treated with insulin. In remission BB/Wor//Tky rats, plasma glucose levels improved to near normal level and insulin content was also preserved as much as that between diabetic and non-diabetic rats. In this process, we hypothesized that autoimmune insulitis was suppressed and remaining islet B-cells was restored from severe destruction by recovering in number and/or function. While, recently, a novel regenerating (reg) gene, identified in the regenerating pancreatic islets of surgical models, is reported to be related to the replication of pancreatic B-cells in vitro. Based on these findings, we histologically investigated whether the reg protein could be actually expressed or not in the islets from remission BB/Wor//Tky rats. As expected, reg protein was observed in the islets from remission BB/Wor//Tky rats mainly in accordance with pancreatic B-cells. Thus, the present findings suggested that the regeneration of pancreatic B-cells represented by the expression of reg protein might be, at least in part, relevant to remission induced by insulin therapy in spontaneously occurring Type 1 diabetes in BB/Wor//Tky rats.

Serum levels of type IV collagen (7S-IV) and laminin P1 in 185 non-insulin-dependent diabetes mellitus patients were significantly higher than those in normal subjects. Furthermore, they were significantly elevated in relation to the excretion of urinary albumin, showing their increases even at the stage of microalbuminuria, although they were not correlated with HbA1c or age in diabetic patients. Thus, the determination of serum levels of basement membrane components, 7S-IV and laminin, could be beneficial as the early indices of diabetic microangiopathy, including diabetic nephropathy.

2年以内の間隔で,くり返し胸部と腰椎のX線検査を行ない,観察期間中に大動脈弓部およびその近辺(以下大動脈弓部と略)または腹部大動脈に新たに石灰化の出現した66例(男45例,女21例)につきその初発した年令,部位,形態について検討した.なお, 66例中4例では,大動脈弓部と腹部大動脈とに,ほぼ同時に石灰化像が初発した. (1)大動脈弓部に石灰化が初発したものは39例(男24例,女15例)であり,初発時平均年令は61才,腹部大動脈においては31例(男23例,女8例)に初発し,その初発時平均年令は63才であつた. (2)大動脈弓部における石灰化像の初発部位は,弓部左側壁と,上行大動脈左側壁に多かつた.腹部大動脈においては,第3腰椎から第4腰椎の高さが最も多く,前壁と後壁による頻度の差はみられなかつた. (1)石灰化の初発像は,大動脈弓部では細く淡い線状ないし,弧状の陰影であり,腹部大動脈では点状あるいは斑状であつた.

Developmental patterns of taurine biosynthesizing system were investigated using primary cultured neurons prepared from the neopallium of 15-day-old fetal mice by a trypsin treatment in comparison with those in cerebral cortices obtained from age-matched fetal and neonatal mice. The morphological observations by phase contrast and scanning electron micrographies indicated that the cells in primary culture used in the present study possessed typical features of neurons. In addition, the immunohistochemical studies using the antibody to glial fibrillary acidic protein (GFAP), a specific marker for astroglia, revealed that the contamination of astroglias was negligible. The contents of taurine and metabolic intermediates in taurine biosynthesis, cysteine sulfinic acid and cysteic acid, in primary cultured neurons showed decreases during their development, especially during the first week after the inoculation. Similar developmental patterns of these amino acids were observed in cerebral cortices in vivo during perinatal stage which corresponded to the first week of neuronal growth in vitro. On the other hand, the activities of cysteine sulfinic acid decarboxylase and cysteine dioxygenase, both of which are involved in the biosynthesis of taurine, were found to be increased progressively both in primary cultured neurons and in cerebral cortices in vivo during their growth. The immunohistochemical study using antitaurine antibody obtained from rabbit clearly demonstrated that immunoreactive materials were localized in cell bodies and the processes of neurons, and the intensity of the immunoreactivity in primary cultured neurons also showed a reduction with time of culture. These results indicate that primary cultured neurons used in this study possess a similar capacity to synthesize taurine from cysteine as developing brains in vivo. The present results also strongly suggest the well known decrease in cerebral taurine content in vivo during neonatal stages may be predominantly due to the decrease of taurine in neuronal cells.

A 52-year-old male was found to have fever and complained of myalgia and joint pain.On physical examination by admission, his blood pressure was 128/68 mmHg, pulse 66 per minute, regular, temperature 38.5°C. The patient was pale and appeared chronically ill. Bilateral temporal arteries were extended and moderately tender by percussion. Cardiac dulness was normal and heart sound was clear. Liver and spleen were not palpable. Muscles of extremities were slightly atrophic. Raynaud's phenomen negative. Purpuras on backs of feet were noticed. ECG showed normal sinus rhythm, no axis deviation, ST, T waves normal. X-ray of chest normal.At 2 weeks after admission, he had been noticed his blood pressure was elevated (BP 210/100 mmHg) and abdominal bruit audible. Following comfirming of polyarteritis nodosa by muscle biopsy of right quadriceps, steroid therapy bigan. On the 26th hospital day, suddenly he experienced severe pain in left hypochondrium which radiated into the back. He was explored surgically because the pain was persistent and anemia revealed progressively.Retroperitoneal hematoma was found along abdominal aorta and left kidney with subcapular bleeding enlarged as child's head sized but could not be removed because his general condition got worse. Peripheral plasma renin activity (PRA) on restricted salt intake (5g/day) while the patient kept in supine position was 11.9 ng/ml/h, renal vein renin analysis was as follows; r-renal vein 12.1 ng/ml/h, 1-renal vein 14.2 ng/ml/h, upper IVC 12.1 ng/ml/h, lower IVC 8.3 ng/ml/h. Angiotensin II analogue test was carried out using in-fusion of 1-Sarcosine 8-Isoleucine Angiotensin II. Blood pressure before test was 180/130 mmHg and reduced to 130/100 mmHg at 20 minutes after the biginning of infusion at the rate 300 ng/kg/min.. The blood pressure rose gradually to control level over subsequent one hour after the cessation of angiotensin II analogue. PRA level was 8.4 ng/ml/h before administration of angiotensin II analogue and similar value during infusion, then 8.7 ng/ml/h at 110 minutes after cessation of the infusion.

A 35-year-old male was admitted to the hospital because of massive pleural effusion. Aleukocytosis with marked eosinophilia was present and the pleural effusion contained numerous eosinophils. The diagnosis of paragonimiasis Miyazakii was established by immunological studies. This is the third case of this infection in Gunma prefecture.

Sodium balance studies were performed in chronic Goldblatt type renovascular hypertensive rabbits in order to clarify the mechanism for maintaining the chronic hypertensive states in renovascular hypertension. In two kidney renovascular hypertension, the blood pressure was correlated positively with plasma renin activity and negatively with serum K and faecal Na excretion. Significant correlations were also demonstrated between the latter 3 parameters each other. On the other hand, there was no obvious relationship between the blood pressure and the above parameters in one kidney renovascular hypertension. When the clipped kidney was removed in two kidney type rabbits, a significant fall of blood pressure and significant decreases in hematocrit and Na retention were observed. The fall of blood pressure following the removal of the clipped kidney correlated significantly with the decrease in plasma renin activity, the decrease in hematocrit, the increase in serum K and the increase in faecal Na excretion.The above observations were interpreted as suggesting a possibility that the increase in plasma renin activity might play an important role in maintaining hypertension in two kidney renovascular hypertension, especially in those with marked elevation of the blood pressure. However, the evidences were not obtained that either renin-angiotensin system or one kidney renovascular hypertension.

Observations of the routine chest X -ray films of the patients between the age of 40 and 59 years revealed a high incidence of calcification of aortic arch in the presence of significant coronary stenosis as compared with those without significant coronary lesions and those without arteriosclerotic disease. The incidence of aortic arch calcification of zero, one and multivessel coronary disease was 15%, 29% and 38%, respectively. The difference was not obvious in the patients above the age of 60 years.

During the last 11 years, 259 diabetics who visited our outpatient diabetic clinic were treated for at least for six months. Of these, 111 are still regularly visiting our outpatient clinic and 58 are cared for at other medical insitutions, while 40 died and 21 are without any medical supervdsion at present. Twenty-nine cases were lost to follow-up. All the living patients initially treated by insulin are under proper medical care now.The mortality rate was significantly higher in insulin-treated patients than in those given diet therapy alone or those treated by oral hypoglycemic agents. The mortality rate was also high in patients over the age of 60 years and in relatively young patients under the age of 40 years. The leading causes of death were cerebrovascular accidents (11 cases) and heart failure (11cases).

One hundred and four patients with congenital heart disease and over the age of 40 years have been visited the Second Department of Internal Medicine, Gunma University Hospital during the last 11 years. The most frequent lesion was the atrial septal defect of secundum type (72 cases) which was followed by ventricular septal defect (12 cases) and patent ductus arteriosus (7 cases). Forty eight of the above cases were first pointed out the cardiac abnormalities at the age of 40 years or later, while a correct diagnosis of congenital heart disease had been made only in 14 cases before.The numbers of the disabled patients increased with the advancing age. Three fourths of the elderly patients over the age of 60 years were classified as being NYHA function class III or IV. Significant positive correlations were demonstrated between the age and the cardio-thoracic ratio and between the age and the right ventricular systolic pressure in atrial septal defect.The clinical course of 68 cases followed for 2 years or longer were rather favorable under proper medical care. Only 3 died, while 9 cases without any medical supervisions were deteorirated. The course of 17 operated cases were good. Although an appropriate medical care is effective to relieve the symptoms, we thought that the surgical interventions should not be hesitated in middle-aged and even in elderly patients with congenital heart disease if indicated.