Strongly correlated superconductivity in a copper-based metal-organic framework with a perfect kagome lattice.

Metal-organic frameworks (MOFs), which are self-assemblies of metal ions and organic ligands, provide a tunable platform to search a new state of matter. A two-dimensional (2D) perfect kagome lattice, whose geometrical frustration is a key to realizing quantum spin liquids, has been formed in the π - d conjugated 2D MOF [Cu3(C6S6)] n (Cu-BHT). The recent discovery of its superconductivity with a critical temperature T c of 0.25 kelvin raises fundamental questions about the nature of electron pairing. Here, we show that Cu-BHT is a strongly correlated unconventional superconductor with extremely low superfluid density. A nonexponential temperature dependence of superfluid density is observed, indicating the possible presence of superconducting gap nodes. The magnitude of superfluid density is much smaller than those in conventional superconductors and follows the Uemura's relation of strongly correlated superconductors. These results imply that the unconventional superconductivity in Cu-BHT originates from electron correlations related to spin fluctuations of kagome lattice.

Full-Gap Superconductivity Robust against Disorder in Heavy-Fermion CeCu_{2}Si_{2}.

A key aspect of unconventional pairing by the antiferromagnetic spin-fluctuation mechanism is that the superconducting energy gap must have the opposite sign on different parts of the Fermi surface. Recent observations of non-nodal gap structure in the heavy-fermion superconductor CeCu_{2}Si_{2} were then very surprising, given that this material has long been considered a prototypical example of a superconductor where the Cooper pairing is magnetically mediated. Here we present a study of the effect of controlled point defects, introduced by electron irradiation, on the temperature-dependent magnetic penetration depth λ(T) in CeCu_{2}Si_{2}. We find that the fully gapped state is robust against disorder, demonstrating that low-energy bound states, expected for sign-changing gap structures, are not induced by nonmagnetic impurities. This provides bulk evidence for s_{++}-wave superconductivity without sign reversal.

Evaluation of animal models for intestinal first-pass metabolism of drug candidates to be metabolized by CYP3A enzymes via in vivo and in vitro oxidation of midazolam and triazolam.

1. To search an appropriate evaluation methodology for the intestinal first-pass metabolism of new drug candidates, grapefruit juice (GFJ)- and vehicle (tap water)-pretreated mice or rats were orally administered midazolam (MDZ) or triazolam (TRZ), and blood levels of the parent compounds and their metabolites were measured by liquid chromatography/MS/MS. A significant effect of GFJ to elevate the blood levels was observed only for TRZ in mice. 2. In vitro experiments using mouse, rat and human intestinal and hepatic microsomal fractions demonstrated that GFJ suppressed the intestinal microsomal oxidation of MDZ and especially TRZ. Substrate inhibition by MDZ caused reduction in 1'-hydroxylation but not 4-hydroxylation in both intestinal and hepatic microsomal fractions. The kinetic profiles of MDZ oxidation and the substrate inhibition in mouse intestinal and hepatic microsomal fractions were very similar to those in human microsomes but were different from those in rat microsomes. Furthermore, MDZ caused mechanism-based inactivation of cytochrome P450 3A-dependent TRZ 1'-hydroxylation in mouse, rat and human intestinal microsomes with similar potencies. 3. These results are useful information in the analysis of data obtained in mouse and rat for the evaluation of first-pass effects of drug candidates to be metabolized by CYP3A enzymes.

Improvement of efficiency and temperature control of induction heating vapor source on electron cyclotron resonance ion source.

An electron cyclotron resonance ion source (ECRIS) is used to generate multicharged ions for many kinds of the fields. We have developed an evaporator by using induction heating method that can generate pure vapor from solid state materials in ECRIS. We develop the new matching and protecting circuit by which we can precisely control the temperature of the induction heating evaporator. We can control the temperature within ±15 °C around 1400 °C under the operation pressure about 10(-4) Pa. We are able to use this evaporator for experiment of synthesizing process to need pure vapor under enough low pressure, e.g., experiment of generation of endohedral Fe-fullerene at the ECRIS.

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes.

AIMS/HYPOTHESIS: We examined the link between altered gap junctional communication and renal haemodynamic abnormalities in diabetes in studies performed on Zucker lean (ZL) and the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes. METHODS: The abundance of connexin (Cx) 37, 40 and 43 was assessed by western blot and immunohistochemistry. Renal haemodynamics was characterised with GAP peptides, which are Cx mimetics, to inhibit gap junctions as a probe in both strains. RESULTS: ZDF rats exhibited higher plasma glucose, 8-epi-prostaglandin F2α excretion, renal plasma flow and GFR than ZL rats. In ZDF rat kidney phosphorylation of Cx43 was enhanced compared with that in ZL rats. Immunohistochemical study revealed that the density of abundance of Cx37 in renin-secreting cells was significantly reduced in ZDF rats. Although renal autoregulation was markedly impaired in ZDF rats, it was preserved in ZL rats. GAP27 for Cx37,43 and for Cx40 impaired renal autoregulation in ZL rats, but failed to induce further alterations in renal autoregulation in ZDF rats. CONCLUSIONS/INTERPRETATION: Our findings indicate that ZDF rats have glomerular hyperfiltration with impaired autoregulation. They also demonstrate enhanced phosphorylation of Cxs and reduced production of Cxs in ZDF rat kidney, especially of Cx37 in renin-secreting cells. Finally, our data suggest that an impairment of gap junctional communication in juxtaglomerular apparatus plays a role in altered renal autoregulation in diabetes.

Long-term survival of a patient with type A thymoma and Masaoka's stage IV b: case report.

Thymoma is the most common neoplasm in the anterior mediastinum. This report presents an extremely rare case of a type A thymoma with Masaoka's stage IV b due to lymph node metastasis. In 1997, a 59-year-old man underwent complete resection of a stage IV b type A thymoma with postoperative radiotherapy to the mediastinum. In 2006, small nodules were detected in the anterior mediastinum and above the right diaphragm and tumor resection was performed. The two lesions were both histologically diagnosed as recurrences of the type A thymoma. There has been no evidence of recurrence 15 months after the second surgery.

Separate evaluation of intestinal and hepatic metabolism of three benzodiazepines in rats with cannulated portal and jugular veins: comparison with the profile in non-cannulated mice.

Pharmacokinetic analyses of three kinds of benzodiazepines--midazolam (MDZ), triazolam (TRZ) and alprezolam (APZ)--were performed in rats with cannulated portal and jugular veins. Each drug was administered to the double-cannulated rats, and pharmacokinetic data for the parent drugs and their 1'- and 4-hydroxylated metabolites were compared with those obtained in non-cannulated mice. In bioavailability, the drugs ranked APZ >> TRZ = MDZ in rats, and APZ > TRZ >> MDZ in mice, with the values for MDZ remarkably different between rats and mice (19% in rats versus 2.3% in mice). In contrast, hepatic availability (Fh) was similar (APZ > TRZ > MDZ) in both species. Highly significant relationships were found between the ratio of the area under the plasma concentration-time curve (AUC) for the parent drugs in portal blood (AUC(por)) to that in systemic blood (AUC(sys)) and Fh in rats and mice. The double-cannulated rat is useful for estimating the hepatic availability of drug candidates by determining the AUC values for the parent drugs in portal and systemic blood samples.

Expression and role of connexins in the rat renal vasculature.

Gap junctions are present in the juxtaglomerular apparatus enabling intercellular communication. Our study determined the location of different connexin subtypes within the juxtaglomerular apparatus of the rat, and the role of these subtypes in renal hemodynamics through the use of specific mimetic peptides. Immunohistochemical analysis showed connexins 37 and 40 expression in the endothelial and renin-secreting cells of the afferent arteriole, while connexin 40 was also found in extra- and intraglomerular mesangial cells. In contrast, connexin 43 was weakly expressed in endothelial cells of the afferent arteriole and within the glomerulus. Intra-renal infusion of the peptides (GAP) reported to block specific gap junctions ((Cx37,43)GAP27 or (Cx40)GAP27), elevated blood pressure, plasma renin activity, and angiotensin II levels, while decreasing renal plasma flow without a significant change in the glomerular filtration rate. Subsequent restoration of blood pressure reduced both renal plasma flow and glomerular filtration rate. In contrast, (Cx43)GAP26 reduced glomerular filtration rate without alterations in blood pressure, renal plasma flow, plasma renin activity, or angiotensin II levels. Hence, connexins 37 and 40 are expressed in the rat juxtaglomerular apparatus and these proteins control, in part, the renin-angiotensin system and renal autoregulation.

Vascular compliance is secured under angiotensin inhibition in non-diabetic chronic kidney diseases.

Cardiovascular diseases constitute major cause of death in chronic kidney diseases (CKDs). We examined the effects of angiotensin inhibition either with angiotensin-converting enzyme inhibitor or with angiotensin receptor blocker on patient prognosis and heart-ankle pulse wave velocity (haPWV) in CKDs. Randomized controlled study was performed on 102 patients with non-diabetic CKDs. Patients were divided into two groups with or without angiotensin inhibition, and followed until death, creatinine clearance was halved or starting renal replacement therapy, whichever occurred first. For 4 years, haPWV was assessed repeatedly in the surviving patients. While both groups showed well blood pressure control throughout 4 years (129+/-1 to 131+/-2/71+/-1 to 73+/-2 mm Hg), renal prognosis was better in angiotensin inhibition group (P<0.05). In addition, angiotensin inhibition reduced cardiovascular and renal death (P<0.05). Age, sex, heart rate, systolic blood pressure and proteinuria were correlated to haPWV (R(2)=0.76, P<0.0001). Although haPWV was similar between two groups at the start of the study (1098+/-31 vs 1094+/-37 cm/s), it was higher in patients without angiotensin inhibition than that with angiotensin inhibition 4 years later (1034+/-38 cm/s (n=28) vs 1242+/-37 cm/s (n=23), P<0.01). The present results provided the evidence that angiotensin inhibition arrested a time-dependent elevation of haPWV in non-diabetic CKDs, conferring organ protection. Furthermore, our data indicated that angiotensin inhibition improved patient prognosis in non-diabetic chronic kidney diseases with mild-to-moderate renal dysfunction.

Attenuated radial augmentation index is associated with successful long-term antihypertensive treatment.

Pulse wave analysis was performed in apparently normal volunteers (n=164) and in essentially hypertensive patients without cardiovascular complications (n=171) using a newly developed non-invasive pulse wave measurement device (HEM-9010AI). Our results suggest that early wave reflections measured by radial augmentation index (AIr) are enhanced in volunteers with systolic blood pressure (SBP) >or= 160 mm Hg compared with the volunteers with their SBP<160 mmHg (98+/-18 vs 88+/-12, P<0.05). Furthermore, AIr is lower in hypertensive patients with long-term antihypertensive treatment than in those with short-term treatment (84+/-10 vs 89+/-13, P<0.01).

[Surgical management of papillary muscle rupture following acute myocardial infarction].

Papillary muscle rupture is a rare but severe complication of acute myocardial infarction. Two cases successfully underwent mitral valve replacement and concomitant coronary artery bypass grafting (CABG) for acute myocardial infarction with the anterior papillary muscle rupture in cardiogenic shock. Each of them needed preoperative massive inotropic infusion, respiratory support and intraaortic balloon pumping assist. The first case was a 76-year-old female. Double vessel disease (seg 7 : 90%, seg 11 : 100%) was revealed by coronary angiography and rupture of the papillary muscle was confirmed by transesophageal echocardiography. The second case was a 69-year-old female. Double vessel disease (seg 2 : 90%, seg 11 : 100%) was revealed and severe mitral regurgitation due to prolapse of the anterior leaflet was confirmed by transthoracic echocardiography. To assess the diagnosis of postinfarction papillary muscle rupture, transthoracic and/or transesophageal echocardiography is mandatory. Coronary angiography is also desirable because concomitant myocardial revascularization may improve the prognosis.

Interleukin-12 p40-homodimer production in sensory dorsal root ganglion neurons.

Recently, the reports that sensory nerves contribute to induction and development of peripheral inflammation have been accumulating. Although neuropeptides have been thought to participate in modulation of inflammation, we supposed the involvement of cytokines. Interleukin-12 (IL-12) is a key regulator of cell-mediated immunity. IL-12 is heterodimer cytokine consisting of a p35 and a p40 subunit, but the results that some of immune cell types secrete p40-homodimer have been reported. In this study, we investigated the expression and secretion of IL-12 in mouse sensory neurons in order to evaluate the involvement of sensory neurons in cell-mediated immunity. Expression of IL-12 p40 mRNA was detected and enhanced by interferon-gamma (IFN-gamma), but another subunit of IL-12 p35 mRNA was not detected in sensory dorsal root ganglion (DRG) neurons in culture. IL-12 p40 molecule was detected in DRG neurons by immunocytochemistry. In addition, cultured DRG neurons secreted p40-homodimer that inhibited IL-12-induced STAT4 phosphorylation in T cells. p40 mRNA expression was accumulated in DRG after administration of IFN-gamma into mouse footpad, and this enhancement was eliminated by a cut of sciatic nerve. These results suggest the possibility that p40-homodimer derived from sensory nerves suppresses the excessive peripheral inflammation.

Morphological changes in the rat carotid body 1, 2, 4, and 8 weeks after the termination of chronically hypocapnic hypoxia.

Morphological changes in the rat carotid bodies 1, 2, 4, and 8 weeks after the termination of chronically hypocapnic hypoxia (10% O2 for 8 weeks) were examined by means of morphometry and immunohistochemistry. The rat carotid bodies after 8 weeks of hypoxic exposure were enlarged several fold with vascular expansion. The carotid bodies 1 and 2 weeks after the termination of 8 weeks of hypoxic exposure were diminished in size, although their diameter remained larger than the normoxic controls. The expanded vasculature in chronically hypoxic carotid bodies returned to the normoxic control state. In the carotid bodies 1 week after the termination of chronic hypoxia, the density of NPY fibers was remarkably increased and that of VIP fibers was dramatically decreased in comparison with the density in chronically hypoxic carotid bodies. In the carotid bodies 2 and 4 weeks after the termination of hypoxia, the density of SP and CGRP fibers was gradually increased. In the carotid bodies 8 weeks after the termination of hypoxia, the appearance of the carotid body returned to a nearly normoxic state, and the density of SP, CGRP, VIP, and NPY fibers also recovered to that of normoxic controls. These results suggest that the morphological changes in the recovering carotid bodies start at a relatively early period after the termination of chronic hypoxia, and a part of these processes may be under the control of peptidergic innervation.

Long-term administration of pravastatin reduces serum lipoprotein(a) levels.

BACKGROUND: The long-term effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum lipoprotein(a) (Lp(a)) levels has been poorly investigated. OBJECTIVE: This study sought to examine the effect of 24 months' administration of pravastatin on serum Lp(a) levels. SUBJECTS: 23 patients with coronary artery disease and serum low-density lipoprotein (LDL) cholesterol levels of 120 mg/dl or above were included. METHOD: Serum levels of lipids and Lp(a) were serially determined after the administration of pravastatin for 24 months. RESULTS: Serum LDL-cholesterol (LDL-C) levels significantly decreased from 1 month after the drug administration and the reduction persisted for 24 months, whereas Lp(a) levels did not decrease at 3 months after the administration but significantly decreased at 12 months or more. The reduction in the Lp(a) levels was not related to the dose of pravastatin. CONCLUSIONS: The results indicated that long-term administration of pravastatin for 12 months or more significantly reduced serum Lp(a) levels and the reduction of Lp(a) levels occurred much later than that of LDL-C levels. The delayed reduction in serum Lp(a) levels after the administration of pravastatin may be associated with a retarded inhibition of Lp(a) synthesis by the drug.

Peptidergic innervation in the rat carotid body after 2, 4, and 8 weeks of hypocapnic hypoxic exposure.

The distribution and abundance of neuropeptide-containing nerve fibers were examined in the carotid bodies of rats exposed to hypocapnic hypoxia (10% O2 in N2) for 2, 4, and 8 weeks. The carotid bodies after 2, 4, and 8 weeks of hypoxic exposure were enlarged by 1.2-1.5 times in the short axis, and 1.3-1.7 times in the long axis in comparison with the normoxic control ones. The enlarged carotid bodies contained a number of expanded blood vessels. Mean density per unit area (10(4) microm2) of substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactive fibers was transiently high in the carotid bodies after 4 weeks of hypoxic exposure, and decreased significantly to nearly or under 50% after 8 weeks of hypoxic exposure. Density of vasoactive intestinal polypeptide (VIP) immunoreactive fibers increased significantly in all periods of hypoxic exposure observed, and was especially high in the carotid bodies after 4 weeks of hypoxic exposure. Density of neuropeptide Y immunoreactive fibers was unchanged in the carotid bodies during hypoxic exposure. These characteristic changes in the density of SP, CGRP, and VIP fibers in the carotid bodies after 4 weeks of hypoxic exposure suggest that the role of these neuropeptide-containing fibers may be different in the carotid bodies after each of three periods of hypoxic exposure, and that the peptidergic innervation after 8 weeks of hypoxic exposure may show an acclimatizing state.

Oxidized low density lipoprotein (Ox-LDL) as a marker of atherosclerosis in hemodialysis (HD) patients.

AIM: To characterize the relationship between oxidative stress and atherosclerosis in HD patients. METHODS: Seventy-five HD patients were entered into the study. Ox-LDL was measured as a probe for peroxidation and compared to clinical atherosclerotic parameters. Prospective studies were also performed to assess the effects of vitamin E-bonded membrane on oxidative stress. RESULTS: Elderly patients tended to show elevated Ox-LDL (alpha = 0.060+/-0.021 ng/microg LDL protein/year, r = 0.35, p < 0.05). Levels of Ox-LDL in the patients with positive history for atherosclerotic diseases (3.1+/-0.4 ng/microg LDL protein, n = 36) were higher than those with a negative history (1.6+/-0.2, n = 39, p < 0.01). Further-more, ankle/brachial pressure index was negatively correlated to Ox-LDL (alpha = -0.052+/-0.012/ng/microg LDL protein, r = 0.42, p < 0.01). Application of vitamin E-bonded membrane for 10 months (-38+/-11%, n = 14, p < 0.05), but not synthetic membrane, ameliorated Ox-LDL. CONCLUSIONS: Our results indicate that Ox-LDL is elevated in aged HD patients. In addition, the present data provide evidence that vitamin E-bonded dialyzers attenuate oxidative stress. Finally, our findings suggest that Ox-LDL correlates to the magnitude of peripheral arterial diseases in HD patients.

Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.

BACKGROUND: Although studies have suggested that "late-onset" hypertrophic cardiomyopathy (HCM) may be caused by sarcomeric protein gene mutations, the cause of HCM in the majority of patients is unknown. This study determined the prevalence of a potentially treatable cause of hypertrophy, Anderson-Fabry disease, in a HCM referral population. METHODS AND RESULTS: Plasma alpha-galactosidase A (alpha-Gal) was measured in 79 men with HCM who were diagnosed at > or =40 years of age (52.9+/-7.7 years; range, 40-71 years) and in 74 men who were diagnosed at <40 years (25.9+/-9.2 years; range, 8-39 years). Five patients (6.3%) with late-onset disease and 1 patient (1.4%) diagnosed at <40 years had low alpha-Gal activity. Of these 6 patients, 3 had angina, 4 were in New York Heart Association class 2, 5 had palpitations, and 2 had a history of syncope. Hypertrophy was concentric in 5 patients and asymmetric in 1 patient. One patient had left ventricular outflow tract obstruction. All patients with low alpha-Gal activity had alpha-Gal gene mutations. CONCLUSION: Anderson-Fabry disease should be considered in all cases of unexplained hypertrophy. Its recognition is important given the advent of specific replacement enzyme therapy.