Safety of tapering tacrolimus dose in patients with well-controlled anti-acetylcholine receptor antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS: We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction. RESULTS: Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, P = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, P = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cut-off values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction. CONCLUSION: Tapering of tacrolimus was possible in most patients with well-controlled anti-acetylcholine receptor antibody-positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease.

Highly sensitive nanoscale spin-torque diode.

Highly sensitive microwave devices that are operational at room temperature are important for high-speed multiplex telecommunications. Quantum devices such as superconducting bolometers possess high performance but work only at low temperature. On the other hand, semiconductor devices, although enabling high-speed operation at room temperature, have poor signal-to-noise ratios. In this regard, the demonstration of a diode based on spin-torque-induced ferromagnetic resonance between nanomagnets represented a promising development, even though the rectification output was too small for applications (1.4 mV mW(-1)). Here we show that by applying d.c. bias currents to nanomagnets while precisely controlling their magnetization-potential profiles, a much greater radiofrequency detection sensitivity of 12,000 mV mW(-1) is achievable at room temperature, exceeding that of semiconductor diode detectors (3,800 mV mW(-1)). Theoretical analysis reveals essential roles for nonlinear ferromagnetic resonance, which enhances the signal-to-noise ratio even at room temperature as the size of the magnets decreases.

Successful pregnancy outcomes in a patient with type A insulin resistance syndrome.

BACKGROUND: The management of severe insulin resistance during pregnancy is challenging because of the increased risk of perinatal complications for both mother and fetus. We describe two consecutive pregnancies in a patient with severe insulin resistance caused by a mutation in the ß subunit of the insulin receptor. CASE REPORT: A non-obese Japanese woman was diagnosed as having diabetes mellitus during her first pregnancy at age 31 years. She presented at 6 weeks' gestation with a fasting plasma glucose concentration of 15.1 mmol/l and an HbA(1c) level of 95 mmol/mol (10.8%). Fasting insulin concentration was high at 68.8 µU/ml, suggesting severe insulin resistance. Anti-insulin and insulin-receptor antibodies were both negative. Genetic analysis revealed an in-frame heterozygous deletion mutation (∆Leu(999)) in the insulin receptor gene. Despite large daily doses (up to 480 units per day) of insulin aspart and isophane, the patient's postprandial plasma glucose level exceeded 11.1 mmol/l. In the patient's second pregnancy, the addition of metformin at a dose of 2250 mg per day achieved tighter glycaemic control, with lower doses of insulin lispro and isophane (up to 174 units/day). Both newborns, who were found to carry the same mutation, were small for gestational age and developed transient hypoglycaemia after birth. CONCLUSION: Adding metformin to the conventional insulin regimen effectively achieved tight glycaemic control with a lower dose of insulin. The mutation of the insulin receptor gene might underlie the intrauterine growth retardation of the newborns. To our knowledge, this is the first report of successful management of diabetes mellitus in a pregnant woman with type A insulin resistance syndrome.

Spinal cord ring enhancement in patients with neuromyelitis optica.

OBJECTIVES: Clinical and pathological significance of gadolinium (Gd)-enhancing pattern on magnetic resonance imaging (MRI), including ring enhancement (RE), is well documented in multiple sclerosis but not in neuromyelitis optica (NMO), especially in the spinal cord. The purpose of this study is to examine the prevalence of spinal cord RE in NMO and to determine the association between clinical characteristics and spinal cord RE. MATERIALS AND METHODS: We retrospectively examined Gd-enhanced spinal cord MRI scans, during the acute phase, in patients with anti-aquaporin 4-positive NMO, including NMO spectrum disorder. We then analysed their clinical features and MRI imaging characteristics of spinal cord lesions. RESULTS: Of the 30 patients with NMO, we enrolled 12 patients with 16 Gd-enhanced spinal cord MRI scans in this study. Five scans revealed RE (31.2%). Male ratio, as well as myelin basic protein (MBP) levels, in the cerebrospinal fluid (CSF) of patients with RE was significantly higher than those of patients without RE (P = 0.018, P = 0.026, respectively). CONCLUSIONS: Spinal cord RE is common in patients with NMO. Higher MBP levels in the CSF of patients with RE can be associated with a higher degree of myelin damage.

Leisure-time physical activity is a significant predictor of stroke and total mortality in Japanese patients with type 2 diabetes: analysis from the Japan Diabetes Complications Study (JDCS).

AIMS/HYPOTHESIS: Our aim was to clarify the association between leisure-time physical activity (LTPA) and cardiovascular events and total mortality in a nationwide cohort of Japanese diabetic patients. METHODS: Eligible patients (1,702) with type 2 diabetes (mean age, 58.5 years; 47% women) from 59 institutes were followed for a median of 8.05 years. A comprehensive lifestyle survey including LTPA and occupation was performed using standardised questionnaires. Outcome was occurrence of coronary heart disease (CHD), stroke and total mortality. The adjusted HR and 95% CI were calculated by Cox regression analysis. RESULTS: A significant reduction in HR in patients in the top (≥ 15.4 metabolic equivalents [MET] h/week) vs the bottom tertile (≤ 3.7 MET h/week) of LTPA, adjusted by age, sex and diabetes duration, was observed in stroke (HR 0.55, 95% CI 0.32, 0.94) and total mortality (HR 0.49, 95% CI 0.26, 0.91) but not in CHD (HR 0.77, 95% CI 0.48, 1.25). The HR for stroke became borderline significant or nonsignificant after adjustment for lifestyle or clinical variables including diet or serum lipids. The significantly reduced total mortality by LTPA was independent of these variables and seemed not to be, at least mainly, attributed to reduced cardiovascular disease. CONCLUSIONS/INTERPRETATION: In Japanese persons with type 2 diabetes, LTPA of 15.4 MET h/week or more was associated with a significantly lower risk of stroke partly through ameliorating combinations of cardiovascular risk factors. It was also associated with significantly reduced total mortality but independently of cardiovascular risk factors or events. These findings, implying differences from Western diabetic populations, should be considered in the clinical management of East Asians with diabetes.

Resonant tunneling driven metal-insulator transition in double quantum-well structures of strongly correlated oxide.

The metal-insulator transition (MIT), a fascinating phenomenon occurring in some strongly correlated materials, is of central interest in modern condensed-matter physics. Controlling the MIT by external stimuli is a key technological goal for applications in future electronic devices. However, the standard control by means of the field effect, which works extremely well for semiconductor transistors, faces severe difficulties when applied to the MIT. Hence, a radically different approach is needed. Here, we report an MIT induced by resonant tunneling (RT) in double quantum well (QW) structures of strongly correlated oxides. In our structures, two layers of the strongly correlated conductive oxide SrVO3 (SVO) sandwich a barrier layer of the band insulator SrTiO3. The top QW is a marginal Mott-insulating SVO layer, while the bottom QW is a metallic SVO layer. Angle-resolved photoemission spectroscopy experiments reveal that the top QW layer becomes metallized when the thickness of the tunneling barrier layer is reduced. An analysis based on band structure calculations indicates that RT between the quantized states of the double QW induces the MIT. Our work opens avenues for realizing the Mott-transistor based on the wave-function engineering of strongly correlated electrons.

Long-term lifestyle intervention lowers the incidence of stroke in Japanese patients with type 2 diabetes: a nationwide multicentre randomised controlled trial (the Japan Diabetes Complications Study).

AIMS/HYPOTHESIS: The aim of the study was to clarify whether a therapeutic intervention focused on lifestyle modification affected the incidence of vascular complications in patients with established diabetes. METHODS: A total of 2,033 eligible Japanese men and women aged 40-70 years with type 2 diabetes from 59 institutes were randomised to a conventional treatment group (CON), which continued to receive the usual care, and a lifestyle intervention group (INT), which received education on lifestyle modification regarding dietary habits, physical activities and adherence to treatment by telephone counselling and at each outpatient clinic visit, in addition to the usual care. Randomisation and open-label allocation were done by a central computer system. Primary analysis regarding measurements of control status and occurrence of macro- and microvascular complications was based on 1,304 participants followed for an 8 year period. RESULTS: Although status of control of most classic cardiovascular risk factors, including body weight, glycaemia, serum lipids and BP, did not differ between groups during the study period, the incidence of stroke in the INT group (5.48/1,000 patient-years) was significantly lower than in the CON group (9.52/1,000 patient-years) by Kaplan- Meier analysis (p=0.02 by logrank test) and by multivariate Cox analysis (HR 0.62, 95% CI 0.39-0.98, p=0.04). The incidence of CHD, retinopathy and nephropathy did not differ significantly between groups. Lipoprotein(a) was another significant independent risk factor for stroke. CONCLUSIONS/INTERPRETATION: These findings suggest that lifestyle modification had limited effects on most typical control variables, but did have a significant effect on stroke incidence in patients with established type 2 diabetes. CLINICAL TRIAL REGISTRATION: UMIN-CTR C000000222 FUNDING: The Ministry of Health, Labour and Welfare, Japan

Large scale replication analysis of loci associated with lipid concentrations in a Japanese population.

BACKGROUND: Recent genome wide association studies discovered seven novel loci that influence plasma concentrations of triglycerides, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol in Europeans. To date, large scale replication studies using populations with known differences in genome-wide linkage disequilibrium (LD) pattern have not been undertaken. METHODS: To address this issue, we tested associations between single nucleotide polymorphisms (SNPs) within the seven novel loci and plasma lipid profiles in 21 010 Japanese individuals. RESULTS: Multiple linear regression analyses showed that the rs3812316 in MLXIPL was strongly associated with triglyceride concentrations (p approximately 3.0x10(-11), 7.1 mg/dl decrease per minor C allele) and that rs599839 in CELSR2/PSRC1/SORT1 was strongly associated with LDL cholesterol concentrations (p approximately 3.1x10(-11), 4.7 mg/dl decrease per minor G allele) in the Japanese population. SNPs near ANGPTL3, TRIB1 and GALNT2 showed evidence for associations with triglyceride concentrations (3.6x10(-6)

Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist.

The low density lipoprotein receptor-related protein (LRP) has been proposed to mediate in concert with the LDL receptor (LDLR) the uptake of dietary lipoproteins into the hepatocytes. This hypothesis was tested by transient inactivation of LRP in vivo. Receptor-associated protein (RAP), a dominant negative regulator of LRP function, was transferred by an adenoviral vector to the livers of mice lacking LDLR (LDLR-/-). The inactivation of LRP by RAP was associated with a marked accumulation of chylomicron remnants in LDLR-/- mice and to a lesser degree in normal mice, suggesting that both LDLR and LRP are involved in remnant clearance.

Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors.

The current studies were designed to determine whether chronic overexpression of low density lipoprotein (LDL) receptors in the liver would protect mice from the increase in plasma LDL-cholesterol that is induced by high-fat diets. A line of transgenic mice was studied that express the human LDL receptor gene in the liver under control of the transferrin promoter. When fed a diet containing cholesterol, saturated fat, and bile acids for 3 weeks, the transgenic mice, in contrast to normal mice, did not develop a detectable increase in plasma LDL. The current data indicate that unregulated overexpression of LDL receptors can protect against diet-induced hypercholesterolemia in mice.

Metformin, but not pioglitazone, decreases postchallenge plasma ghrelin levels in type 2 diabetic patients: a possible role in weight stability?

AIM: Effects of metformin and pioglitazone on body weight are clearly different. Recently, the role of ghrelin, an orexigenic peptide derived from stomach, has been appreciated. Plasma ghrelin levels display a preprandial peak and postprandial suppression, suggesting its physiological role. We hypothesized that metformin or pioglitazone may modulate circulating ghrelin levels and this modulation may be related to differential effects on body weight with these agents. METHODS: Thirty-five Japanese type 2 diabetic patients [21 men and 14 women, age 62 +/- 2 years, body mass index (BMI) 26.6 +/- 0.5 kg/m(2) and haemoglobin A1c (HbA1c) 8.2 +/- 0.1%, mean +/- s.e.] were randomly assigned to groups for the addition of metformin or pioglitazone. At baseline and 4 months later, a 75-g oral glucose tolerance test (OGTT) was performed to measure plasma ghrelin levels. RESULTS: In 33 subjects who completed the study, the overall decrease in HbA1c ( approximately 1%) was comparable between the two groups. As expected, BMI increased in the pioglitazone group but not in the metformin group. After the treatment, plasma ghrelin levels at each point of OGTT remained unchanged in the pioglitazone group. In the metformin group, fasting ghrelin levels were unaltered, whereas the absolute levels at 30, 60 and 120 min decreased significantly. The area under the curve for the 2-h ghrelin profile also decreased significantly. CONCLUSIONS: Metformin, but not pioglitazone, decreased plasma ghrelin levels after the glucose load. This decrease may in part account for weight stability in type 2 diabetic patients treated with metformin.

Influence of IOP measurement through the wrong eyepiece of the slit lamp on Goldmann applanation tonometry.

PURPOSE: This study examined whether intraocular pressure (IOP) measurements through the wrong eyepiece of the slit lamp may be a source of error. METHODS: Seven skilled observers measured the IOP from seven healthy subjects. The observers used a Haag-Streit Goldmann applanation tonometer with two types of slit lamps (Haag-Streit and Rodenstock). In the Haag-Streit slit lamp the prism of the tonometer is aligned with the right part of the slit lamp optics. Conversely, in the Rodenstock slit lamp, the prism is aligned with the left. Each observer measured the IOP of each subject through the right eyepiece, through the left eyepiece, and under binocular vision. RESULTS: The IOP measured with the left eyepiece of the Haag-Streit slit lamp was significantly higher than that measured with the right eyepiece and binocular vision. The IOP measured with the right eyepiece of the Rodenstock slit lamp was significantly higher than that measured with the left eyepiece and binocular vision. CONCLUSIONS: IOP measurement through the wrong eyepiece of the slit lamp may be a source of error.

Strong polarization switching with low-energy loss in hydrogen-bonded organic antiferroelectrics.

The electric-field-induced phase transition from antipolar to polar structures is at the heart of antiferroelectricity. We demonstrate direct evidence of antiferroelectricity by applying a strong electric field to two antipolar crystals of squaric acid (SQA) and 5,5'-dimethyl-2,2'-bipyridinium chloranilate. The field-induced polarization of SQA is quite large and reasonably explained by the theoretically calculated polarization on the hydrogen-bonded sheet sublattice. The pseudo-tetragonal lattice of SQA permits unique switching topologies that produce two different ferroelectric phases of low and high polarizations. By tilting the applied field direction, the electrical switching mechanism can be attributed to a 90° rotation of the sheet polarization. From the viewpoint of applications, the strong polarization, high switching field, and quite slim hysteresis observed in the polarization versus electric field curve for SQA are advantageous for excellent-efficiency energy storage devices.

Weaning stage hyperglycemia induces glucose-insensitivity in arcuate POMC neurons and hyperphagia in type 2 diabetic GK rats.

Hyperphagia triggers and accelerates diabetes, and prevents proper dietary control of glycemia. Inversely, the impact of hyperglycemia on hyperphagia and possible mechanistic cause common for these two metabolic disorders in type 2 diabetes are less defined. The present study examined the precise developmental process of hyperglycemia and hyperphagia and explored the alterations in the hypothalamic arcuate nucleus (ARC), the primary feeding and metabolic center, in Goto-Kakizaki (GK) rats with type 2 diabetes and nearly normal body weight. At mid 3 to 4 weeks of age, GK rats first exhibited hyperglycemia, and then hyperphagia and reduced mRNA expressions for anorexigenic pro-opiomelanocortin (POMC) and glucokinase in ARC. Furthermore, [Ca2+]i responses to high glucose in ARC POMC neurons were impaired in GK rats at 4 weeks. Treating GK rats from early 3 to mid 6 weeks of age with an anti-diabetic medicine miglitol not only suppressed hyperglycemia but ameliorated hyperphagia and restored POMC mRNA expression in ARC. These results suggest that the early hyperglycemia occurring in weaning period may lead to impaired glucose sensing and neuronal activity of POMC neurons, and thereby induce hyperphagia in GK rats. Correction of hyperglycemia in the early period may prevent and/or ameliorate the progression of hyperphagia in type 2 diabetes.

Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice.

Mice that are homozygous for a targeted disruption of the LDL receptor gene (LDLR-/- mice) were fed a diet that contained 1.25% cholesterol, 7.5% cocoa butter, 7.5% casein, and 0.5% cholic acid. The total plasma cholesterol rose from 246 to > 1,500 mg/dl, associated with a marked increase in VLDL, intermediate density lipoproteins (IDL), and LDL cholesterol, and a decrease in HDL cholesterol. In wild type littermates fed the same diet, the total plasma cholesterol remained < 160 mg/dl. After 7 mo, the LDLR-/- mice developed massive xanthomatous infiltration of the skin and subcutaneous tissue. The aorta and coronary ostia exhibited gross atheromata, and the aortic valve leaflets were thickened by cholesterol-laden macrophages. No such changes were seen in the LDLR-/- mice on a normal chow diet, nor in wild type mice that were fed either a chow diet or the high-fat diet. We conclude that LDL receptors are largely responsible for the resistance of wild type mice to atherosclerosis. The cholesterol-fed LDLR-/- mice offer a new model for the study of environmental and genetic factors that modify the processes of atherosclerosis and xanthomatosis.

Induction of sustained expression of proto-oncogene c-fms by platelet-derived growth factor, epidermal growth factor, and basic fibroblast growth factor, and its suppression by interferon-gamma and macrophage colony-stimulating factor in human aortic medial smooth muscle cells.

Vascular medial smooth muscle cells migrate, proliferate and transform to foam cells in the process of atherosclerosis. We have reported that the intimal smooth muscle cells express proto-oncogene c-fms, a characteristic gene of monocyte-macrophages, which is not normally expressed in medial smooth muscle cells. In the present study, we demonstrated that combinations of platelet-derived growth factor (PDGF)-BB and either epidermal growth factor (EGF) or fibroblast growth factor (FGF) induced high expression of c-fms in normal human medial smooth muscle cells to the level of intimal smooth muscle cells or monocyte-derived macrophages, whereas c-fms expression by PDGF-BB alone was 1/10 and both EGF and FGF had no independent effect on c-fms expression. By contrast, interferon (IFN)-gamma and macrophage colony-stimulating factor (M-CSF) suppressed the induction of c-fms expression. These results indicate that multiple growth factors and cytokines may play a role in the phenotypic transformation of medial smooth muscle cells to intimal smooth muscle cells in atherosclerotic lesions by altering c-fms expression.

Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.

We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-/- mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type litter-mates, owing to a seven- to ninefold increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for intravenously administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of 125I-HDL was normal in the LDLR-/- mice. Unlike wild-type mice, LDLR-/- mice responded to moderate amounts of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR-/- mice was reduced to normal 4 d after the intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. We conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.

Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1.

Insulin resistance is often associated with atherosclerotic diseases in subjects with obesity and impaired glucose tolerance. This study examined the effects of insulin resistance on coronary risk factors in IRS-1 deficient mice, a nonobese animal model of insulin resistance. Blood pressure and plasma triglyceride levels were significantly higher in IRS-1 deficient mice than in normal mice. Impaired endothelium-dependent vascular relaxation was also observed in IRS-1 deficient mice. Furthermore, lipoprotein lipase activity was lower than in normal mice, suggesting impaired lipolysis to be involved in the increase in plasma triglyceride levels under insulin-resistant conditions. Thus, insulin resistance plays an important role in the clustering of coronary risk factors which may accelerate the progression of atherosclerosis in subjects with insulin resistance.