Type B insulin resistance syndrome with systemic lupus erythematosus.

Type B insulin resistance syndrome is a rare disease. Auto-antibodies to the insulin receptor frequently appear in the case of systemic lupus erythematosus (SLE). We report herein a case of a 56-year-old man who had presented discoid skin lesions since 1990. He was admitted to the hospital because of unconsciousness and severe hypoglycemia in 2006, and was diagnosed as having Type B insulin resistance syndrome with the presence of insulin receptor antibody. He had frequently repeated hypoglycemic and hyperglycemic episodes in spite of treatment with prednisolone (5 - 10 mg/day), and mild proteinuria of 1.5 g/day was observed. His laboratory findings on admission revealed pancytopenia and positive titer for antinuclear antibody (ANA). From these findings and his past history of skin lesions, we diagnosed him as SLE. We performed renal biopsy and his histological diagnosis was lupus nephritis Class 5 with the findings of podocytic shedding. Prednisolone dosage was increased from 10 to 60 mg/day. Thereafter, his glucose metabolism improved and proteinuria disappeared. The dose of prednisolone was tapered to 30 mg/day without recurrence of hypoglycemia and proteinuria. Early treatment with prednisolone might ameliorate proteinuria and insulin resistance. We experienced a rare case of Type B insulin resistance syndrome with increased activity of SLE, complicated with lupus nephritis. It appears that Type B insulin resistance syndrome should be suspected in differential diagnosis of hypoglycemia in SLE patients.

Association of endothelial nitric oxide synthase Glu298Asp polymorphism with end-stage renal disease.

BACKGROUND: Impairment of nitric oxide generation caused by gene polymorphism is considered as a major factor in the deterioration of progressive renal disease, including diabetic nephropathy and hypertension. The aim of the present study was to examine the Glu298Asp polymorphism of endothelial nitric oxide synthase (eNOS) in patients with end-stage renal disease (ESRD). METHODS: The Glu298Asp polymorphism in exon 7 was determined in 100 ESRD patients who were maintained on hemodialysis at Dr. Soetomo Hospital, Surabaya, Indonesia, and in a control group of 100 unrelated healthy individuals. In the patient group, 39 patients had Type 2 diabetes mellitus (DM), 44 hypertension (HT) and 17 miscellaneous conditions. The mean length of time from onset of ESRD to the start of this study was 24.37 +/- 32.37 months (Mean +/- SD). RESULTS: The positivity of Glu298Asp in the ESRD group was significantly higher than that in the control group (p < 0.0001). The odds ratio for this group was 4.57 (95% confidence interval 2.52 - 8.31). The positivity of 298Asp in Type 2 DM ESRD with subgroup was significantly higher than that in healthy controls (p < 0.0001). The positivity of 298Asp in the subgroup of patients with HT-derived ESRD was also significantly higher (males p < 0.036, females p < 0.005) than that in healthy control group. Homozygotes with glutamate to aspartate substitution at nucleotide position 7702 showed a single band at 457 bp. CONCLUSION: It appears that Glu298Asp may be a predisposing factor in DM-derived and HT-derived ESRD.

Improvement of peritoneal calcification after parathyroidectomy in a peritoneal dialysis patient.

Peritoneal calcification is one of the complications of peritoneal dialysis (PD). It can become serious, leading to severe abdominal pain and even death. Possible mediators of peritoneal calcification in PD patients are assumed to include acetate buffer, overdosage of vitamin D, repeated peritonitis, hypertonic dialysate, calciphylaxis and secondary hyperparathyroidism (SHPT). However, the mechanism and treatment of peritoneal calcification are controversial. Few reports have appeared on improvement of peritoneal calcification after parathyroidectomy (PTX) for SHPT of long duration. We report herein the case of a 48-year-old man on dialysis for 17 years including PD for 14 years. In 1989, he was admitted to hospital because of end-stage renal disease (ESRD), and started treatment with PD. Abdominal computed tomography (CT) first showed peritoneal calcification in August 2002. Peritoneal calcification did not improve despite conventional treatment including discontinuation of PD, control of calcium phosphate product to less than 55 mg2/dl2, removal of the peritoneal catheter and empirical prednisolone (PSL) usage. The intact parathyroid hormone (i-PTH) level was increased over 1,000 pg/ml and extra-osseous calcification occurred. Total PTX was performed in November 2004. Postoperatively, the i-PTH level decreased immediately and calcium phosphate product was maintained in the reference range. Abdominal CT after PTX showed improvement of peritoneal calcification in September 2005. It appeared that PTX could be used to treat patients with persistent peritoneal calcification not responding to conventional treatment. It was postulated that SHPT might play a crucial role in accelerating peritoneal calcification in PD patients.

M-cadherin, a candidate gene for type 2 diabetes and related phenotypes in a KK/Ta mouse model.

The KK/Ta strain serves as a suitable polygenic mouse model for type 2 diabetes associated with fasting hyperglycaemia, glucose intolerance, hyperinsulinaemia, mild obesity and dyslipidaemia. Recently, we reported the susceptibility loci contributing to type 2 diabetes and related phenotypes in KK/Ta mice. In the present study, to identify susceptibility genes for type 2 diabetes and related disorders, GeneChip Expression Analysis was employed to survey the gene expression profile in the liver of KK/Ta and BALB/c mice. M-cadherin, a calciumdependent intercellular adhesion molecule, showed increased expression in the liver of KK/Ta mice, and sequence analysis revealed three missense mutations. The relationship between these polymorphisms and various phenotypes in 208 KK/Ta x (BALB/c x KK/Ta) F1 backcross mice was analysed. Statistical analysis revealed that M-cadherin exhibits linkage to levels of triglyceride and insulin in sera, glucose tolerance and body weight. Although it has been postulated that M-cadherin may be important for the regulation of morphogenesis of skeletal muscle cells, these results suggest that M-cadherin may influence hypertriglyceridaemia, glucose intolerance, hyperinsulinaemia and obesity in KK/Ta mice.

Minor gene effect of leptin receptor variant on the body weight in KK/Ta mice.

OBJECTIVE: Leptin is an adipocyte-derived hormone involved in body weight regulation that acts through the leptin receptor. Previous studies exploring potential association between the leptin receptor (Lepr) variant and obesity have reported conflicting results. The objectives of the present study are to evaluate (1) whether the Lepr variant contributes to type 2 diabetes and its related disorders such as obesity and (2) whether the gene interaction between Lepr and Zn-alpha(2) glycoprotein1 (Azgp1) genes is recognized using genetically homogeneous type 2 diabetic KK/Ta mice. METHODS: The levels of leptin (Lep) and Lepr mRNA in adipose tissues and brain were measured by relative quantitative RT-PCR. The levels of leptin protein in sera were measured by enzyme-linked immunosorbent assay. Genotyping of backcross mice was performed using a mismatch primer. RESULTS: Leptin protein and its mRNA levels were increased in KK/Ta mice. Lepr mRNA levels of KK/Ta mice did not differ from those of BALB/c mice. Sequence analysis revealed that the coding region of Lep in KK/Ta mice was identical to that in BALB/c mice. Six nucleotide polymorphisms were observed in the coding region of Lepr. In KK/Ta x (BALB/c x KK/Ta) F1 backcross mice, the Lepr variant of KK/Ta mice failed to alter any of the variables of obesity except for body weight at 20 weeks of age. However, it enhanced the effect of Azgp1 on body weight. CONCLUSION: It is concluded that the Lepr variant contributes to obesity to some degree in KK/Ta mice.

An (CA)n dinucleotide repeat polymorphism of the interleukin-6 (IL-6) gene is associated with metacarpal bone mineral density in hemodialysis patients.

Genetic factors may play an important role in the pathogenesis of reduced bone mineral density (BMD). IL-6 is a multifunctional cytokine and a candidate gene for regulation of bone mineral density (BMD). The relationship between a microsatellite polymorphism of the IL-6 gene and metacarpal BMD in Japanese hemodialysis patients was examined. We selected 165 patients (96 males and 69 females) with a mean age of 62.0 +/- 13.7 years (mean +/- standard deviation (SD) in this study. They were dialyzed for an average of 75.8 +/- 60.8 months (mean +/- SD). The microsatellite polymorphism in the IL-6 gene was examined. According to the number of cytosine-adenine repeats, varying from 13 to 18, 6 alleles could be distinguished. Patients were categorized based on the presence or absence of the allele with 126 bp (i.e. 14 CA repeats) (allele A, all others allele O). The frequencies of IL-6 gene genotypes in hemodialysis patients were 16.4% for OO, 52.1% for AO and 31.5% for AA. The BMD score adjusted for age and body weight (Z score) in the AA genotype group (-0.93 +/- 1.17) was significantly lower than that in the OO (-0.09 +/- 1.42, mean +/- SD, p < 0.005) or AO group (-0.48 +/- 1.15, mean +/- SD, p < 0.01). Serum intact PTH in the OO genotype group (79.3 +/- 84.6) was lower than that in the AA (120.8 +/- 113.6, mean +/- SD, p 0.10) or AO group (132.1 +/- 106.5, mean +/- SD, p < 0.05). These results suggest that polymorphism of the IL-6 gene may be a useful marker for reduced BMD.

Effects of major histocompatibility complex matching on graft survival in allogeneic rat limb transplantation.

Differences in the major histocompatibility complex (MHC) between recipients and donors present a problem because of immunologic responses in graft rejection. The purpose of this study is to clarify the efficacy of MHC matching against acute graft rejection of allogeneic limb transplants in rats. Right hindlimb transplantations were performed using various MHC-mismatched pairs of inbred rats. The rats were classified into 5 groups according to the differences in subregions of the RT1 (rat MHC) between the recipient and the donor: group 1, RT1-A,B,D barrier (the differences of RT1-A,B,D subregions); group 2, RT1-A barrier; group 3, RT1-B,D barrier; group 4, RT1-B barrier; and group 5, RT1-D barrier. The mean survival time significantly decreased in group 1 and increased in group 4. The results suggest that MHC matching clearly improves survival of transplanted limbs. Specifically, both RT1-A and D matching is the most effective compatibility in prolonging survival time of allogeneic limb transplants in rats.

Dilazep hydrochloride, an antiplatelet drug, inhibits lipopolysaccharide-induced mouse mesangial cell IL-6 secretion and proliferation.

BACKGROUND: Antiplatelet agents have been widely used to reduce proteinuria and to prevent the progression of chronic glomerulonephritis or diabetic nephropathy to end-stage renal failure. Dipyridamole, one type of antiplatelet drug, inhibits the proliferation of glomerular mesangial cells (MCs). The effect of dilazep hydrochloride (dilazep) on these cells is still obscure. The effects of dilazep on cultured MC IL-6 secretion and proliferation were investigated in the present study. METHODS: IL-6 secretion from MC induced by bacterial lipopolysaccharide (LPS) were assessed using sandwich ELISA. LPS-induced MC proliferation was detected by 3H-thymidine incorporation and WST-1 assay (similar to MTT assay). RESULTS: Incubation of MCs with various dosages of LPS (0, 1, 10, 50 and 100 ng/ml) induced IL-6 secretion in a dose-dependent manner. However, dilazep significantly inhibited this LPS-induced IL-6 secretion from MCs in a dose- and time-dependent manner. Dilazep also significantly inhibited MC proliferation in a dose-dependent manner. CONCLUSION: It appears that these effects of dilazep may prevent progression of mesangial proliferative glomerulonephritis.

Serum cystatin C may predict the prognostic stages of patients with IgA nephropathy prior to renal biopsy.

The relationship between the levels of serum cystatin C and the prognostic stages of IgA nephropathy was determined in a multicenter trial in Japan. The levels of serum cystatin C in patients with IgA nephropathy were measured using the Dade Behring N Latex Cystain C assay. In 1995, the Joint Committee of the Special Study Group on Progressive Glomerular Diseases, Ministry of Health and Welfare of Japan, and the Japanese Society of Nephropathy reported four prognostic stages. These are: good prognosis group (Group I), relatively good prognosis group (Group II), relatively poor prognosis group (Group III), and poor prognosis group (Group IV), for this disease. Three-hundred and six patients with IgA nephropathy and other glomerular diseases were examined. There were no significant changes in the levels of serum creatinine (Cr) or creatinine clearance (CCr) between Group I and Group II. The mean levels of serum cystatin C in Group II were significantly higher than those in Group I (P < 0.05). The mean levels of serum cystatin C in Group III or IV were significantly higher than those in Group I (P < 0.001, P < 0.005, respectively). These suggest that the measurement of serum cystatin C may predict the prognostic stages of patients with IgA nephropathy prior to renal biopsy.

Association of the DD genotype and development of Japanese type 2 diabetic nephropathy.

We determined the insertion/deletion (I/D) polymorphism of the angiotensin-coverting enzyme (ACE) gene in a multicenter trial of ethnically homogeneous Japanese type 2 diabetes mellitus (DM) patients. All patients (n = 748) were divided into 5 groups as follows: group I (normoalbuminuric patients), group II (microalbuminuric patients), group III (overt albuminuric patients with serum creatinine (s-Cr) levels of less than 1.2 mg/dl), group IV (overt albuminuric patients with s-Cr levels of more than 1.3 mg/dl but excluding hemodialysis patients), and group V (hemodialysis patients). We selected patients with a diabetic duration of more than 15 years in the mild stage (groups I and II), but placed no limits on those in the advanced and end-stages (groups III, IV and V). The frequency of the DD genotype was slightly higher in the advanced and end stages. The frequency of the DD genotype in the mild stage differed from that in the end stage (II/ID/DD 47.8%/41.0%/11.2% vs. 37.0 %/43.3%/19.7% p = 0.07, II + ID/DD 88.8%/11.2% vs. 80.3%/19.7%, p < 0.05). D allele frequency in the mild stage also differed from that in the end stage (I/D 68.3%/31.7% vs. 58.7%/41.3%, p < 0.02). The presence of the DD genotype increased the risk of end-stage renal disease (ESRD) more than that of the other genotypes (odds ratio ID/II = 1.37, 95% CI 0.82-2.27; DD/II = 2.27, 95% CI 1.12-4.61). It appears that the DD genotype is associated with progression of Japanese type 2 diabetic nephropathy.

Effect of calcium channel blockers, nifedipine and benidipine, on death of cultured mouse mesangi al cells.

We examined the effects of the short-acting calcium channel blocker (CCB) nifedipine and the long-acting CCB benidipine on the death of mouse cultured mesangial cells induced by tumor necrosis factor alpha (TNF-alpha) and/or cycloheximide (CHX). Cell death was evaluated by a morphological study using semithin sections. The dead cells were divided into three types, i.e., apoptotic cells (type 1), necrotic cells (type 3) and other types of dead cells, the so-called 'secondary necrotic cells' or 'postapoptotic necrotic cells' (type 2). In the morphological study with semithin sections, cells in the presence of TNF-alpha or CHX and nifedipine or benidipine showed low percentages of all dead cell types with 24 h incubation. Both nifedipine and benidipine have protective effects against TNF-alpha or CHX. It is postulated that CCB might inhibit the apoptotic or necrotic processes by TNF-alpha or CHX with 24 h incubation. With 36 h incubation, CCB increased the percentages of all types of dead cells except for treatment with 1x10(-5) M benidipine and CHX. It appears that these cell-protective effects might be decreased after treatment with TNF-alpha or CHX and CCB for 36 h. In conclusion, the short-acting CCB nifedipine and the long-acting CCB benidipine have protective effects on mouse cultured mesangial cells against TNF-alpha or CHX. However, nifedipine and benidipine did not inhibit specific types of cell death using semithin sections in this study.

X-ray study of deformation density and spontaneous polarization in ferroelectric NaNO2

The deformation electron density of ferroelectric sodium nitrite has been determined from X-ray diffraction data at 30 K, using Hirshfeld deformation functions. Owing to the strong correlation between odd terms of the deformation coefficients, constraints were imposed in the refinement. The net charges for Na, N and O atoms were estimated to be 0.27, 0.20 and -0.24 e, respectively. The calculated spontaneous polarization using these net charges and atomic dipole terms, 7.8 microC cm(-2), is much closer to the recently measured value, 12 microC cm-2, as compared with the value calculated from the formal point charges (74 microC cm(-2)).

Relationship between polymorphism in the angiotensinogen, angiotensin-converting enzyme or angiotensin II receptor and renal progression in Japanese NIDDM patients.

We determined the relationship between the gene polymorphism of angiotensinogen (AGT), angiotensin-converting enzyme (ACE), or angiotensin II receptor (AT1R) and the progression of diabetic nephropathy in a multicenter trial of ethnically homogeneous Japanese patients with non-insulin-dependent diabetes (NIDDM). Gene polymorphism of ACE I/D, AGT M235T and AT1R A1166C was determined by polymerase chain reaction amplification using allele-specific primers. Japanese NIDDM patients (n = 1,152) were selected from several diabetic clinics. All patients were divided into three groups as follows: (1) group I (n = 407): normoalbuminuric patients; (2) group II (n = 327): microalbuminuric patients, and (3) group III (n = 418): overt albuminuric patients. Clinical factors for investigation in all patients were the date of birth, gender, levels of urinary albumin excretion, findings of the ocular fundus, duration of diabetes, hemoglobin A1c and blood pressure. It appears that genetic polymorphisms in the renin-angiotensin systems, i.e. ACE or AT1R, may affect the progression to renal failure of patients (especially females) with NIDDM.

[A case of leukemic lymphoma complicated by M-proteinemia: effectiveness of long-term daily administration of oral low-dose etoposide in continuing remission].

A 51-year-old man was admitted with systemic lymph node adenopathy. Hematological examination on admission revealed leukocytosis, and 35% of leukocytes were classified as pathologically abnormal. Moreover, increases in serum IgM (kappa type) and plasma viscosity were recognized. Following biopsy of the lymph node, a diagnosis of non-Hodgkin's lymphoma (diffuse, mixed type) was made. After the implementation of combination chemotherapy, the results of hematological and physical examinations improved. As the nadir receded, serum IgM increased once more, and nine courses of chemotherapy were necessary. In order to promote steady progress toward discharge, etoposide therapy was instituted. Subsequent low-dose etoposide therapy at 50 mg/day rarely resulted in an increase in serum IgM, subjective or objective adverse effects, except for mild lekopenia. After discharge the patient was placed on intermittent etoposide therapy and remained in a state of remission for approximately 11 months. Fortunately, his rehabilitation was successful, and he returned temporarily to his former position. The 2nd remission has continued for approximately seven months. Consequently, long-term low-dose etoposide therapy is speculated to be a significantly useful therapeutic technique for intractable malignant lymphoma.

[Clinical results of selective cerebral perfusion during reconstruction of the transverse aortic arch].

Selective cerebral perfusion (SPC) has become a reliable method for brain protection during reconstruction of the transverse aortic arch. However, arterial cannulation technique for the branches of the aortic arch varies among groups, and the necessity of perfusion for the left subclavian artery is controversial. To avoid atheroembolism to the brain and malperfusion of the vertebral arterial system, we carefully selected the arterial cannulation technique according to the result of preoperative ultrasonographic and angiographic evaluation of the branches of the aortic arch, and decided the necessity of perfusion for the left subclavian artery according to the dominance of the two vertebral arteries and the result of pressure monitoring of all three branches. In this report, we analyzed our clinical results of selective cerebral perfusion on 22 consecutive patients, which was performed between April 1992 and December 1993. There were 14 atherosclerotic aneurysms and 8 aortic dissections. The flow rate for SCP was controlled by a single blood pump separate from that for systemic perfusion, with the mean value being 13.1 ml/kg/min. Mean of minimum left superficial temporal arterial pressure was 51 mmHg, mean duration of SCP was 134 minutes, and mean of the lowest esophageal temperature was 17.9 degrees C. Blood pH was regulated with alpha-stat strategy. Arterial cannula for SCP was inserted directly into the vessels through a stab wound in most cases. In three of four patients in whom dissection extended to the branches, a balloon catheter was introduced through the lumen of the aortic arch.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical application of evoked spinal cord potentials elicited by direct stimulation of the cord during temporary occlusion of the thoracic aorta.

Evoked spinal cord potentials elicited by direct stimulation of the cord were used to monitor spinal cord ischemia in 68 patients undergoing temporary occlusion of the thoracic aorta (29 thoracic nondissecting aortic aneurysms, 9 nondissecting thoracoabdominal aneurysms, and 30 dissecting aneurysms). "Immediate" postoperative paraplegia developed in three patients and "immediate" paraparesis developed in one, whereas "delayed" paraplegia developed in two others. During aortic crossclamping, four response patterns of the spinal cord potentials were obtained: (1) no change (n = 53), (2) change with return (n = 10), (3) change with inconsistent return (n = 2), and (4) change without return (n = 3). Neurologic complications occurred in 2%, 0%, 100% of these groups, respectively. Delayed paraplegia developed on the second postoperative day in only one patient with a false-negative result, and the potentials correlated well with this patient's clinical neurologic recovery. The aortic crossclamp time was significantly longer in the patients with "change with inconsistent return" and "change without return" than in the other two groups (p < 0.01). Femoral artery pressure and the cardiopulmonary bypass flow rate were also significantly lower in these groups than in the other two groups (p < 0.02 and p < 0.01, respectively). We conclude that intraoperative monitoring of direct spinal cord responses is useful for the early detection of spinal cord ischemia for assessing the efficacy of surgical countermeasures.

[Correlation of myocardial temperature, intramyocardial pH, and myocardial electrical activity during hyperkalemic hypothermic cardioplegic arrest to functional recovery after reperfusion].

We estimated the correlation of myocardial temperature, intramyocardial pH, and myocardial electrical activity (MEA) during hyperkalemic hypothermic cardioplegic arrest to functional recovery after reperfusion to assess those parameters as intra-operative on-line assessment of myocardial preservation during cardiac operation. Twenty dogs underwent cardiopulmonary bypass at 30 degrees C. Cardiac function was evaluated before and after two hours ascending aortic cross-clamping. The dogs were divided into four groups according to cardiac preservation methods employed. Group I (n = 6): 4 degrees C hyperkalemic crystalloid cardioplegic solution was delivered antegradely through the aorta every 30 minutes without topical cooling. Group II (n = 4): total volume of cardioplegic solution same as Group I was delivered only once without topical cooling. Group III (n = 5): cardioplegic solution same as Group I with lidocaine (100 mg/l) was delivered every 30 minutes without topical cooling. Group IV (n = 5): cardioplegic solution same as Group I was delivered every 30 minutes with topical cooling. Hearts at less than 8 degrees C during aortic cross-clamping (Group I) revealed better functional recovery (72 +/- 21%) than those over 15 degrees C (Group II-IV, 28 +/- 30%). There was no significant correlation between intramyocardial pH changes during aortic cross-clamping and functional recovery after reperfusion (R = -.2257). During aortic cross-clamping, the occurrence of MEA which was obtained directly from the electrode inserted into left ventricular anterior free wall (direct MEA) was observed in all cases. However the myocardial activities which were identified by direct MEA were not necessarily observed visually or by routine electrocardiogram.(ABSTRACT TRUNCATED AT 250 WORDS)