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.

Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children.

OBJECTIVE: To establish a regression equation to properly estimate the unbound serum concentration of valproic acid (VPA) from its total serum concentration; the relationship between total and unbound serum VPA concentrations was retrospectively characterized. METHODS: Data were obtained from the clinical examination records that were routinely archived during therapeutic drug monitoring. The screening encompassed 342 records of 108 paediatric patients whose total and unbound VPA concentrations had been determined. The relationship between total and unbound VPA concentrations was characterized according to the Langmuir equation by taking account of inter-individual variability with the nonmem program. RESULTS: The total VPA concentration (C(t)) in the screened patients ranged from 5.5 to 179.8 microg/mL, and the unbound VPA concentration (C(f)) increased in a non-linear manner as the total VPA concentration increased. Taking account of the effects of antiepileptics concurrently administered, the VPA dissociation constant (K(d)) and maximum binding site concentration (B(m)) were 7.8 +/- 0.7 and 130 +/- 4.5 microg/mL respectively, for the regression equation, C(t) = C(f) + B(m) x C(f)/(K(d) + C(f)). An alteration in the unbound concentration was seen in patients who were treated with the combination of VPA and ethosuximide and in those who received two additional antiepileptics. CONCLUSIONS: A regression equation for estimation of the unbound VPA concentration, based on total VPA concentration collected during routine therapeutic drug monitoring was established. Use of two additional antiepileptics and ethosuximide treatment was considered as potential factors affecting unbound VPA concentration.

Comparison of relaxation responses to multiple vasodilators in TxA(2)-analog and endothelin-1-precontracted pulmonary arteries.

BACKGROUND: Peri-operative pulmonary hypertension can lead to right ventricular dysfunction and to an increase in morbidity and mortality. Altered function of the pulmonary vascular endothelium and vasoconstriction play a crucial role in the development of elevated pulmonary vascular resistance. Because pulmonary artery vasoreactivity is dependent on many factors including the constricting agent that precipitated the event therefore the aim of the current study was to investigate the effectiveness of different classes of vasodilator agents to reverse endothelin-1 (ET-1) or thromboxane A(2) (TxA(2))-induced vasoconstriction in porcine pulmonary artery (PA) in vitro. METHODS: Relaxation responses to vasodilatory drugs were studied in PA precontracted with ET-1 (1 x 10(-8) M) or TxA(2) analog (U46619, 1 x 10(-8) M). All vasodilating drugs were added in a cumulative fashion and isometric tension measurements were obtained using an organ chamber technique. RESULTS: In both groups relaxation responses to the vasodilators were dose dependent. When ET-1 was used as a constrictor nitroglycerin and milrinone caused nearly complete (80-100%) relaxation, whereas other agents were of limited effectiveness (40-50%). On the other hand, in the vessels constricted with U46619, olprinone, indomethacin, prostaglandin E(1) (PGE(1)), nitroglycerin, milrinone and clevidipine induced complete (90-110%) vasodilatation but brain natriuretic peptide (BNP), L-arginine, and isoproterenol relaxed the vessels maximally by 45-60%. CONCLUSIONS: Nitroglycerin and milrinone are very effective in reversing ET-1 and U46619-induced pulmonary vasoconstriction in vitro. The effectiveness of other drugs studied was dependent on the type of constrictor used. BNP, L-arginine and isoproterenol were shown to have minimal vasodilatory effects in porcine PA.

A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4.

The cytokine erythropoietin (Epo) promotes erythropoietic progenitor cell proliferation and is required for erythropoietic differentiation. We have found that the Epo gene is a direct transcriptional target gene of retinoic acid signaling during early erythropoiesis (prior to embryonic day E12.5) in the fetal liver. Mouse embryos lacking the retinoic acid receptor gene RXR alpha have a morphological and histological phenotype that is comparable with embryos in which the Epo gene itself has been mutated, and flow cytometric analysis indicates that RXR alpha-deficient embryos are deficient in erythroid differentiation. Epo mRNA levels are reduced substantially in the fetal livers of RXR alpha(-/-) embryos at E10.25 and E11.25, and genetic analysis shows that the RXR alpha and Epo genes are coupled in the same pathway. We furthermore show that the Epo gene is retinoic acid inducible in embryos, and that the Epo gene enhancer contains a DR2 sequence that represents a retinoic acid receptor-binding site and a retinoic acid receptor transcriptional response element. However, unlike Epo-deficient embryos that die from anemia, the erythropoietic deficiency in RXR alpha(-/-) embryos is transient; Epo mRNA is expressed at normal levels by E12.5, and erythropoiesis and liver morphology are normal by E14.5. We show that HNF4, like RXR alpha a member of the nuclear receptor family, is abundantly expressed in fetal liver hepatocytes, and is competitive with retinoic acid receptors for occupancy of the Epo gene enhancer DR2 element. We propose that Epo expression is regulated during the E9.5--E11.5 phase of fetal liver erythropoiesis by RXR alpha and retinoic acid, and that expression then becomes dominated by HNF4 activity from E11.5 onward. This transition may be responsible for switching regulation of Epo expression from retinoic acid control to hypoxic control, as is found throughout the remainder of life.

Genetic changes in colorectal carcinoma tumors with liver metastases analyzed by comparative genomic hybridization and DNA ploidy.

BACKGROUND: Liver metastases are found in 10% of primary colorectal malignancies, and they affects the prognosis of patients with colorectal carcinoma. The authors investigated DNA copy number aberrations by using comparative genomic hybridization (CGH) and DNA ploidy alterations by using flow cytometry (FCM) in patients with primary colorectal carcinoma (primary tumors). To determine whether there are characteristic DNA copy number alterations that contribute to liver metastasis, cytogenetic aberrations were examined by CGH and FCM. METHODS: The authors analyzed 35 primary tumors, including 16 primary tumors with liver metastasis, by using CGH and FCM. RESULTS: Increases in DNA copy numbers were detected in 6q (5 of 16 tumors), 7q (6 of 16 tumors), 8q (7 of 16 tumors), 9p (5 of 16 tumors), 13q (8 of 16 tumors), 20p (9 of 16 tumors), and 20q (15 of 16 tumors) in primary tumors with liver metastases. Decreases in DNA copy numbers were found in 17p (5 of 16 tumors), 18p (6 of 19 tumors), 18q (8 of 16 tumors), and 22q (5 of 16 tumors). In contrast, primary tumors without liver metastasis showed gains in chromosome arms 8q (2 of 19 tumors), 13q (2 of 19 tumors), 20p (6 of 19 tumors), and 20q (5 of 19 tumors); however, they showed no gains in 6q or 7q and showed losses in chromosome arms 17p (2 of 19 tumors), 18p (4 of 19 tumors), 18q (6 of 19 tumors), and 22q (5 of 19 tumors). There was a significant difference in the frequency of DNA copy number gains and losses in 6q (P < 0.05), 7q (P < 0.01), 8q (P < 0.05), 13q (P < 0.05), and 20q (P < 0.01), respectively, between primary tumors with and without liver metastases. The differences in the DNA index were not significant between the two groups of primary tumors. CONCLUSIONS: In liver metastases of primary tumors from patients with colorectal carcinoma, a correlation between DNA copy number aberrations and gains of chromosome arms 6q, 7q, 8q, 13q, and 20q is suggested.

A dose-response study of anticholinesterase drugs on contractile and phosphatidylinositol responses of rat trachea.

UNLABELLED: We investigated whether anticholinesterase drugs in large doses inhibit muscarinic receptors of airway smooth muscle. In vitro measurements of isometric tension and [(3)H]inositol monophosphate (IP(1)) that formed were conducted by using rat tracheal rings or slices. Neostigmine and pyridostigmine caused muscular contraction and IP(1) accumulation in small doses (10 microM and < or = 100 microM, respectively), but they attenuated muscular contraction and IP(1) accumulation in larger doses (1000 microM). Edrophonium did not affect the smooth muscle tone and IP(1) levels. Neostigmine, pyridostigmine, and edrophonium attenuated the carbachol (5.5 microM)-induced smooth muscle contraction and IP(1) accumulation, when administered in large doses (1000 microM). The attenuation of contraction by neostigmine at large doses was not affected by methoctramine, an M(2) muscarinic receptor antagonist, but was reversed by washing with fresh Krebs-Henseleit solution. The results suggest that anticholinesterase drugs have dual effects on the tension and phosphatidylinositol responses of rat trachea. Large doses of anticholinesterase drugs cause airway smooth muscle relaxation, which may be seen in patients with myasthenia gravis who have received excessive anticholinesterase therapy. IMPLICATIONS: Neostigmine and pyridostigmine, but not edrophonium, have dual effects on the tension and phosphatidylinositol responses of rat trachea. Large doses of anticholinesterase drugs cause airway smooth muscle relaxation, which may be seen in patients with myasthenia gravis who have received excessive anticholinesterase therapy.

Remnant-like particle cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients.

OBJECTIVE: The aim of the study was to investigate the relationships between remnant-like particle (RLP) cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 86 nonobese Japanese type 2 diabetic patients (72 men and 14 women, aged 40-83 years, BMI 20.1-26.6 kg/m2) were studied. BMI, HbA1c levels, and fasting concentrations of plasma glucose, serum lipids (RLP cholesterol, total cholesterol, HDL cholesterol, and triglycerides), and serum insulin were measured. Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). The subjects were divided into two groups according to the value of HOMA-IR. Values >2.5 were indicative of the insulin-resistant state, and values <2.5 were indicative of the insulin-sensitive state. RESULTS: The insulin-resistant group had significantly higher RLP cholesterol and triglyceride levels and lower HDL cholesterol levels compared with the insulin-sensitive group. Univariate regression analysis showed that insulin resistance was positively correlated with BMI (r = 0.254, P = 0.019), HbA1c levels (r = 0.278, P = 0.011), RLP cholesterol levels (r = 0.315, P = 0.004), and triglyceride levels (r = 0.332, P = 0.002) and was negatively correlated with HDL cholesterol levels (r = -0.301, P = 0.006) in our diabetic patients. Multiple regression analysis showed that insulin resistance was independently associated with serum triglyceride levels, which explained 13.5% of the variability of insulin resistance in our nonobese Japanese type 2 diabetic patients. CONCLUSIONS: These results indicate that 1) nonobese Japanese type 2 diabetic patients with insulin resistance are characterized by high RLP cholesterol and triglyceride levels, and low HDL cholesterol levels; and 2) the level of serum triglycerides is an independent predictor of insulin resistance in these patients.

Two new isoflavonoids from Erythrina variegata.

Two new isoflavonoids, eryvarin A (1) and eryvarin B (2) were isolated from the wood of Erythrina variegata and their structures were elucidated on the basis of spectroscopic evidence.

Adaptation of the muscles of mastication to the flat skull feature in the polar bear (Ursus maritimus).

The muscles of mastication of the polar bear (Ursus maritimus) and those of the brown bear (U. arctos) were examined by anatomical approach. In addition, the examination of the skull was carried out in the polar bear, brown bear and giant panda (Ailuropoda melanoleuca). In the polar bear, the rostro-ventral part of the superficial layer of the M. masseter possessed the abundant fleshy portion folded in the rostral and lateral directions like an accordion. Moreover, the rostro-medial area of the superficial layer became hollow in the nuchal direction when the mouth was closed. The M. temporalis of the polar bear covered up the anterior border of the coronoid process of the mandible and occupied the almost entire area of the cranial surface. The M. pterygoideus medialis of the polar bear was inserted on the ventral border of the mandible and on the ventral part of the temporal bone more widely than that of the brown bear. As results of our measurements of the mandible, an effect of the leverage in the polar bear was the smallest in three species. In the polar bear, the skull was flat, and the space between zygomatic arch and ventral border of the mandible, occupied by the M. masseter was the narrowest. It is suggested that the muscles of mastication of the polar bear is adapted to the flat skull feature for supplementing the functions.

Clonidine attenuates the carbachol-induced contractile and phosphatidylinositol responses of rat trachea.

Although clonidine is known to affect vascular smooth muscle, its effects on airway smooth muscle are not fully understood. This study was designed to examine the effects of clonidine on carbachol-induced contractile and phosphatidylinositol responses of rat trachea. Clonidine, at a dose of 100 microM or greater, attenuated carbachol-induced contraction and the accumulation of carbachol-induced inositol monophosphate (IP1). Clonidine also attenuated the accumulation of aluminium fluoride-induced IP1. The concentration-effect relationship of IP1 accumulation was similar to that of carbachol-induced contraction; r = 0.797, P < 0.001. These results suggest that clonidine attenuates contractile responses, at least in part, through the inhibition of phospholipase C (coupled with G-proteins) in phosphatidylinositol responses.

Agonist-independent modulation of L-type Ca currents by basal Gs protein activities in single guinea pig ventricular myocytes.

The modulation of L-type Ca2+ currents (I(Ca,L)) by the basal activities of G proteins was studied in adult guinea pig ventricular myocytes by whole-cell patch-clamp techniques. With intrapipette guanosine triphosphate (GTP) (100 microM), a specific inhibition of G1 proteins by pertussis toxin (PTX) produced an increase in the basal density of I(Ca,L) (from 11.0+/-0.8, n = 13, to 25.0+/-2.0 pA/pF, n = 11, at OmV test potential). In addition, PTX shifted the forskolin (Fsk) concentration-I(Ca,L) response relation significantly leftward (EC50, = 63.7+/-12.5 vs 625+/-75 nM). With intrapipette guanosine diphosphate (GDP)betaS (1 mM), the Fsk-I(Ca,L) relation was also shifted leftward (EC50 = 197+/-18.3 vs 781+/-82.5 nM). However, chronic GDPbetaS dialysis accelerated the rundown of I(Ca,L) significantly, suggesting a potential contribution of Gs proteins in maintaining basal I(Ca,L). In contrast, intra-pipette GTPgammaS (100 microM) produced a transient rise in I(Ca,L) from 11.0+/-3.0 to 22.8+/-7.0 pA/pF (in 3.4 min after whole-cell formation at 0 mV, n = 9), presumably through the activation of Gs proteins. It was followed by a gradual decline in I(Ca,L) (to 15.5+/-3.5 pA/pF), which was still enhanced by Fsk (EC50 = 1450+/-98 nM), indicating that the current decay was not solely due to rundown but to activation of Gi proteins. Gs, in addition to Gi proteins, show sufficient basal activity to modulate I(Ca,L) in an agonist-independent manner.

Comparative anatomy of the radial sesamoid bone in the polar bear (Ursus maritimus), the brown bear (Ursus arctos) and the giant panda (Ailuropoda melanoleuca).

Since we have clarified the manipulation mechanism using the radial sesamoid (RS) in the giant panda (Ailuropoda melanoleuca), our aim in this study is to examine the position, shape and function of the RS morphologically, and to observe the attachment to the RS of the M. abductor pollicis longus and the M. opponens pollicis in the other Ursidae species. So, we focused on the carpus and manus of the polar bear (Ursus maritimus) and the brown bear (Ursus arctos) in this study. The RS was tightly articulated to the radial carpal, and could not adduct-abduct independently of the radial carpal. The M. abductor pollicis longus tendon and the M. opponens pollicis belly were attached to the RS, independently. In the polar bear, the deep concave and the flat surface were confirmed in attachment area for these two muscles. The morphological relationship between the RS and the M. abductor pollicis longus and the M. opponens pollicis in the two species of bears were essentially consistent with that in the giant panda. It also demonstrated that the manipulation mechanism of the giant panda has been completely based on the functional relationship between the small RS, and the M. abductor pollicis longus and the M. opponens pollicis in Ursidae species.

[Monitored anesthesia care for a patient with malignant pheochromocytoma].

Monitored anesthesia care (MAC) is being increasingly used in the 1990s for a wide variety of diagnostic and therapeutic procedures. The primary objective in providing MAC is to ensure patients' comfort and safety, whether in the operating room or in other places. We experienced MAC for a patient with pheochromocytoma. A 63-year-old man with hepatic metastasis of malignant pheochromocytoma, received transcatheter arterial embolization (TAE) in the angiographic room. Hypertension and ventricular arrhythmia occurred during the hepatic arterial embolization. However, we successfully controlled the hemodynamic changes using phentolamine and propranolol under the close monitoring. He showed an uneventful recovery during postoperative period except for mild hypotension on the third day which needed temporary norepinephrine infusion.

Importance of glycation in the acceleration of low density lipoprotein (LDL) uptake into macrophages in patients with diabetes mellitus.

BACKGROUND: Two studies were conducted to determine the importance of glycation in the acceleration of low density lipoprotein (LDL) uptake by macrophages in patients with diabetes mellitus. METHODS: Healthy individuals (n=6) and non-insulin-dependent diabetic patients (n=6) were studied. LDL was separated by sequential ultracentrifugation. Macrophages were collected from the abdominal cavity of ICR-mice and incubated in a medium containing [14C] oleate. In Study 1, LDL from diabetic patients (DM-LDL) and control LDL were then incubated with this medium. The uptake of DM-LDL by macrophages was compared with that of control LDL by measuring the [14C] content of the synthesized cholesteryl ester. In Study 2, glycated LDL was prepared by glycating LDL from 6 healthy individuals in vitro. The uptake of native LDL by macrophages was compared with that of glycated LDL using the same method as in Study 1. RESULTS: In Study 1, the uptake of DM-LDL (median: 1,405; range: 985-2269 dpm) was significantly higher than that of control LDL (median: 1,095; range: 990-1104 dpm, p<0.05). In Study 2, the uptake of glycated LDL (median: 1,556; range: 889-2837 dpm) was significantly higher than that of native LDL (median: 1,176; range: 789-2098 dpm, p<0.05). CONCLUSIONS: The results indicate that the greater uptake of DM-LDL than that of control LDL may be attributed to glycation of LDL caused by hyperglycemia in diabetic patients. Glycation of LDL by hyperglycemia may be one cause of the accelerated atherogenesis in diabetic patients.

Effects of maternal acetazolamide treatment on body weights and incisor development of the fetal rat.

The incisor development of fetal rats on gestation day 19 was well correlated with their fetal weights. The number of odontoblasts in the mandibular incisors, an index of incisor development, increased more than that of the maxillary incisors with increase in fetal body weights. Maternal acetazolamide treatments were observed to suppress the mean fetal weight and to retard incisor development. A smaller incisor size, a thinner predentin layer, and fewer odontoblasts were characteristic of the acetazolamide group. There was also a good correlation between the fetal weights and the number of odontoblasts in the acetazolamide group. From these results, we postulated that the retarded incisor development of the fetal rats caused by the maternal acetazolamide treatment was related to their suppressed fetal weights. However, the regression coefficient of the fetal weights and the number of odontoblasts in the acetazolamide group was smaller than that of the vehicle control group. It may indicate that retarded incisor development in response to maternal acetazolamide treatment is to some extent independent of suppressed fetal weight.

Superoxide production, risk factors, and endothelium-dependent relaxations in human internal mammary arteries.

BACKGROUND: In a variety of disease states, endothelium-dependent vasodilation is abnormal. Reduced nitric oxide (NO) production, increased destruction of NO by superoxide, diminished cellular levels of L-arginine or tetrahydrobiopterin, and alterations in membrane signaling have been implicated. We examined these potential mechanisms in human vessels. METHODS AND RESULTS: Relaxations to acetylcholine, the calcium ionophore A23187, and nitroglycerin, as well as superoxide production and NO synthase expression, were examined in vascular segments from patients with identified cardiovascular risk factors. Endothelium-dependent relaxations were also studied after incubation with L-arginine, L-sepiapterin, and liposome-entrapped superoxide dismutase (SOD) and after organoid culture with cis-vaccenic acid. Relaxations to acetylcholine and to a lesser extent the calcium ionophore A23187 were highly variable and correlated with the number of risk factors present among the subjects studied. Treatment of vessels with L-arginine, L-sepiapterin, liposome-entrapped SOD, or cis-vaccenic acid did not augment endothelium-dependent relaxations. Hypercholesterolemia was the only risk factor associated with high levels of superoxide; however, there was no correlation between superoxide production and the response to either endothelium-dependent vasodilator used. CONCLUSIONS: In human internal mammary arteries, depressed endothelium-dependent relaxations could not be attributed to increases in vascular superoxide production, deficiencies in either L-arginine or tetrahydrobiopterin, or reduced membrane fluidity. Variability in signaling mechanisms may contribute to the differences in responses to acetylcholine and the calcium ionophore A23187.

Effect of glycated low density lipoprotein on smooth muscle cell proliferation.

BACKGROUND: We investigated the effect of glycated low density lipoprotein (LDL) on smooth muscle cell proliferation. METHODS: Blood was drawn from 6 healthy subjects after overnight fasting. Native LDL was obtained by separating LDL from the samples with sequential ultracentrifugation. Glycated LDL was prepared by glycating the native LDL in vitro. Native and glycated LDL were added to a medium containing cultured porcine coronary artery smooth muscle cells, and the change in cell proliferation was examined after 24, 48, 72, and 96 hs. The cells were counted using a cell counting kit (Dojin Chemical Co., Ltd.). RESULTS: There was no significant difference in the cell count between the control group, in which only PBS was added, and the native LDL group. However, cell proliferation was appreciably higher in the glycated LDL group than in the native LDL group. The mean total cell count at 24, 48, 72 and 96 hs was significantly higher (p<0.01) in the glycated LDL group (median: 0.843; range: 0.576-1.060) than in the native LDL group (median: 0.541; range: 0.282-0.683). CONCLUSIONS: These findings suggest that glycated LDL induces significantly greater acceleration of smooth muscle cell proliferation than does native LDL. Therefore, the acceleration of smooth muscle cell proliferation requires modification of LDL.

Hepatic histopathology of a vitamin A overdose in mouse liver.

The effect of vitamin A on peroxisomal catalase in liver of male ICR mice was studied electron microscopically after a single subcutaneous injection of retinyl acetate. A significant proliferation of peroxisomes in hepatocytes was observed up to 3 days after a single injection of 80,000 IU of retinyl acetate. This was followed by a significant decrease up to 21 days and increase above control levels at 60 days after the injection. Histopathological alterations, such as focal necrosis of hepatocytes in the peripheral zone of hepatic lobules, release of their membrane-bound bodies from Disse's space and the appearance of large vacuoles around the nucleus, were observed from early stages onwards. These findings indicated that alterations on lipid metabolism in the liver were induced when a subacute dose of retinyl acetate was administered. Histopathological alterations were probably attributable either to accumulation of retinyl esters or effect of mediators released from activated leucocytes at an early stage.