Association of the -31C/T functional polymorphism in the interleukin-1beta gene with the intractability of Graves' disease and the proportion of T helper type 17 cells.

Interleukin (IL)-1beta is a proinflammatory cytokine and has been implicated in the pathogenesis of several autoimmune diseases. To evaluate the hypothesis that the functional -31C/T polymorphism (rs1143627) in the gene encoding IL-1beta is associated with the intractability and the severity of autoimmune thyroid diseases, we genotyped this polymorphism in 64 patients with intractable Graves' disease (GD), 28 GD patients in remission, 49 patients with Hashimoto's disease (HD) who developed hypothyroidism (severe HD), 28 untreated euthyroid HD patients (mild HD) and 59 healthy volunteers. The -31T allele, which is related to the high producibility of IL-1beta, was significantly more frequent in patients with intractable GD than in those with GD in remission (P = 0.0017; odds ratio 2.8; 95% confidence interval 1.5-5.3), although there was no difference in this frequency between two groups of HD patients. We showed additionally that the proportion of IL-17-producing T helper type 17 (Th17) cells, whose differentiation and proliferation are promoted by IL-1beta, was higher in autoimmune thyroid disease patients with the T allele than in those with CC genotypes. In conclusion, our data indicated that the T allele of -31C/T polymorphism in the IL1B gene was involved in the intractability of GD, and this involvement may arise through the differentiation and proliferation of Th17 cells.

Comparison of formation of thiolactones and active metabolites of prasugrel and clopidogrel in rats and dogs.

Prasugrel and clopidogrel are antiplatelet prodrugs that are converted to their respective active metabolites through thiolactone intermediates. Prasugrel is rapidly hydrolysed by esterases to its thiolactone intermediate, while clopidogrel is oxidized by cytochrome P450 (CYP) isoforms to its thiolactone. The conversion of both thiolactones to the active metabolites is CYP mediated. This study compared the efficiency, in vivo, of the formation of prasugrel and clopidogrel thiolactones and their active metabolites. The areas under the plasma concentration versus time curve (AUC) of the thiolactone intermediates in the portal vein plasma after an oral dose of prasugrel (1 mg kg(-1)) and clopidogrel (0.77 mg kg(-1)) were 15.8 +/- 15.9 ng h ml(-1) and 0.113 +/- 0.226 ng h ml(-1), respectively, in rats, and 454 +/- 104 ng h ml(-1) and 23.3 +/- 4.3 ng h ml(-1), respectively, in dogs, indicating efficient hydrolysis of prasugrel and little metabolism of clopidogrel to their thiolactones in the intestine. The relative bioavailability of the active metabolites of prasugrel and clopidogrel calculated by the ratio of active metabolite AUC (prodrug oral administration/active metabolite intravenous administration) were 25% and 7%, respectively, in rats, and 25% and 10%, respectively, in dogs. Single intraduodenal administration of prasugrel showed complete conversion of prasugrel, resulting in high concentrations of the thiolactone and active metabolite of prasugrel in rat portal vein plasma, which demonstrates that these products are generated in the intestine during the absorption process. In conclusion, the extent of in vivo formation of the thiolactone and the active metabolite of prasugrel was greater than for clopidogrel's thiolactone and active metabolite.

Involvement of functional polymorphisms in the TNFA gene in the pathogenesis of autoimmune thyroid diseases and production of anti-thyrotropin receptor antibody.

The severity of Hashimoto's disease (HD) and intractability of Graves' disease (GD) varies among patients. Severity of HD is associated with the functional +874A/T polymorphism for interferon-gamma, an inflammatory cytokine. To clarify the association between functional polymorphisms in two other inflammatory cytokine genes [tumour necrosis factor (TNF)-alpha and interleukin (IL)-2] and the severity of autoimmune thyroid disease (AITD), we examined the TNF-alpha-1031T/C, TNF-alpha-857C/T and IL-2 -330T/G polymorphisms in genomic DNA samples. We genotyped 41 patients with intractable GD, 34 patients with GD in remission, 41 patients with severe HD, 36 patients with mild HD and 70 healthy controls. The frequency of carriers of TNF-alpha-1031C (CT + CC), which correlates with higher TNF-alpha production, was significantly higher in HD and GD patients than in controls, but was not associated with the severity of HD. In GD patients, the levels of anti-thyrotropin receptor antibody (TRAb) at onset of the disease was higher in patients with the TNF-alpha-857T (CT + TT) genotype, which correlates with higher TNF-alpha production, than in those with the -857CC genotype. We found no differences in the IL-2 -330T/G polymorphism among groups of AITD patients. In conclusion, the functional -1031T/C polymorphism of the TNFA gene is associated with the development of AITD and the functional -857C/T polymorphism is associated with the levels of TRAb in active GD patients.

Pressure tuning of an ionic insulator into a heavy electron metal: an infrared study of YbS.

Optical conductivity [sigma(omega)] of YbS has been measured under pressure up to 20 GPa. Below 8 GPa, sigma(omega) is low since YbS is an insulator with an energy gap between a fully occupied 4f state and an unoccupied conduction (c) band. Above 8 GPa, however, sigma(omega) increases dramatically, developing a Drude component due to heavy carriers and characteristic infrared peaks. It is shown that increasing pressure has caused an energy overlap and hybridization between the c band and 4f state, thus driving the initially ionic and insulating YbS into a correlated metal with heavy carriers.

The +869T/C polymorphism in the transforming growth factor-beta1 gene is associated with the severity and intractability of autoimmune thyroid disease.

The severity of Hashimoto's disease (HD) and the intractability of Graves' disease (GD) vary among patients. To clarify whether the +869T/C polymorphism in the transforming growth factor-beta1 (TGF-beta1) gene, which is associated with TGF-beta1 expression, is involved in the intractability of GD and severity of HD, we genotyped the TGF-beta1 +869T/C polymorphism by polymerase chain reaction-restriction fragment length polymorphism method in genomic DNA samples from 33 patients with HD who developed hypothyroidism before they were 50 years old (severe HD) and 30 untreated, euthyroid patients with HD who were older than 50 years (mild HD). We also examined 48 euthyroid patients with GD who had been under treatment and were still positive for anti-thyrotropin receptor antibodies (intractable GD), 20 euthyroid patients with GD in remission and 45 healthy controls. The frequency of the T allele and the TT genotype were higher in patients with severe HD than in those with in mild HD. In contrast, the frequency of the CC genotype was higher in patients with intractable GD than in patients with GD in remission. In conclusion, the +869T/C polymorphism in the TGF-beta1 gene is associated with the severity and intractability of autoimmune thyroid disease.

Fulminant myocarditis in polymyositis.

Cardiac involvement in patients with polymyositis is usually asymptomatic and associated with a mild clinical course. A female patient with muscle weakness and cardiogenic shock, who was diagnosed with polymyositis and fulminant myocarditis, is described. A large amount of methylprednisolone, in addition to intra-aortic balloon pumping and percutaneous cardiopulmonary support, led to the recovery of her cardiac function. However, a massive cerebral embolism occurred and she died. Postmortem histopathological examination showed necroses of muscles and diffuse invasion of mononuclear cells in both the myocardium and the biceps muscle of her arm. Although the mechanism of cardiac dysfunction is not clear, immunosuppressive therapy was effective for fulminant myocarditis in the present case.

Pseudogap formation in the intermetallic compounds (Fe1-xVx)3Al

Optical conductivity data of the intermetallic compounds (Fe1-xVx)3Al ( 0

[Coronary artery bypass grafting for a patient with bronchial asthma seceeded from cardiopulmonary bypass by additional bypass for spasm of radial artery graft: a case report].

A 78-year-old male who had a bronchial asthma underwent coronary artery bypass grafting (CABG) using the left internal thoracic artery and the radial artery. The patient could not be weaned from the cardiopulmonary bypass because the radial artery which anastomosed to the obtuse marginal artery (OM) had a spasm after CABG. An additional bypass using a long saphenous vein to OM was carried out immediately. It brought a weaning from cardiopulmonary bypass. If the cardiac function after CABG is insufficient in patients with bronchial asthma, CABG must be re-done immediately, considering that they cause the arterial spasm more than patients without bronchial asthma.

Clinical characteristics of aged Becker muscular dystrophy patients with onset after 30 years.

To elucidate the clinical characteristics of aged patients with Becker muscular dystrophy (BMD), 4 patients with this disease who were over 50 years were examined. The ages at onset in all patients were later than 30 years. All were proven to have a deletion around exons 45-55 of the Duchenne muscular dystrophy (DMD) gene. Two patients became wheelchair bound in their 40s or beyond, while the other 2 (aged 73 and 69, respectively) were still able to walk at the time of examination. Three of 4 patients had no obvious hypertrophy in their calves, which is known to be one of the characteristic clinical features in the juvenile BMD patients. Serum creatine kinase levels were elevated in all patients, but not markedly (mean 444.8 +/- 230.3 U/l; normal value < 180 U/l). Dilated cardiomyopathy was clinically apparent in 2 patients. We emphasize that some BMD patients are free of muscular symptoms until their 50s and are still self-supporting in their 60s or 70s.

[Toxicity study of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na) (4). 6-month repeated dose intravenous toxicity study in rats with 1-month recovery test].

A 6-month repeated dose toxicity study with 1-month recovery test of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na), a novel neutrophil elastase inhibitor, was conducted in Sprague-Dawley (SD) rats. The rats of both sexes were administered ONO-5046.Na intravenously at a daily dose of 0 (vehicle control), 18.75, 37.5 or 75 mg/kg. ONO-5046.Na did not affect clinical signs, body weight, food consumption, opthalmology, urinalysis, hematology, blood chemistry, organ weight, necropsy or histopathology at any dose. These results indicate that the NOAEL of ONO-5046.Na in rats is 75 mg/kg/day for both sexes in this study.

Upgraded IR beamline at UVSOR.

BL6A1, a far-infrared (FIR) beamline at UVSOR, originally built in 1986, has been recently upgraded. The upgrade included the introduction of a second FT-IR spectrometer, making it possible to cover the entire FIR-IR range (3-10000 cm(-1)) in one sequence of measurements, without having to open the sample chamber; the beamline has become a more convenient and powerful experimental station than before. The upgrade is also expected to enable such experiments as IR studies of molecules adsorbed on solid surfaces, and time-resolved IR spectroscopies. This paper describes the characteristics of the upgraded BL6A1.

Reconstruction of BL7B for UV, VIS and IR spectroscopy with a 3 m normal-incidence monochromator.

The beamline BL7B at the UVSOR facility for solid-state spectroscopy is currently under reconstruction. This reconstruction mainly involves the replacement of the 1 m Seya-Namioka-type monochromator (50-600 nm) with a 3 m NIM (modified version of McPherson model 2253), which covers the 50-1000 nm range with three gratings. The deviation angle of the gratings is 15 degrees. For linear and circular polarization experiments, the beamline optics consist of a two-grazing-incidence (87.5 degrees ) pre-mirror system and a normal-incidence (15 degrees ) post-mirror.

Phase transitions of CdS microcrystals under high pressure.

The experiment under high pressure using a diamond anvil cell (DAC) requires the utilization of synchrotron radiation. High-pressure experiments were performed using a DAC on CdS microcrystals, both in the far-IR and in the X-ray regions, in order to study the lattice dynamics and lattice stability concerned with the phase transitions. From these experiments, experimental evidence is presented indicating that a CdS microcrystal of smaller diameter shows a higher transition pressure for lattice transformation under pressure. The origin of such an increase in the transition pressure in the microcrystals is discussed in relation to the surface tension.

[Dynamic MR hepatocholangiography with the SIP Fast GRE (saturation inversion projection fast gradient echo) method].

The purpose of this study was to assess the utility of dynamic MR hepatocholangiography with the Gd-EOB-DTPA enhanced SIP Fast GRE sequence in the hepatobiliary system. The SIP Fast GRE sequence was used for sequential imaging of the hepatobiliary system with a frame rate of 3 sec in a 256 x 192 matrix. Dynamic sequential acquisition was performed for 51 min before and after the injection of 30 mu mol/kg of Gd-EOB-DTPA in a rabbit. Dynamic images of the hepatobiliary system were obtained in the rabbit study. Dynamic MR hepatocholangiography provides better functional information than conventional MR cholangiography.

Assessment of breast cancer with dynamic gadolinium-enhanced MR imaging combined with magnetization transfer contrast using a newly developed breast surface coil for the supine position.

To assess the value of dynamic gadolinium-enhanced MR imaging combined with magnetization transfer contrast (MTC) of breast cancer by SPGR sequence, 15 patients with breast cancer were imaged in the supine position with the newly developed breast coil in a 1.5 Tesla imager. Dynamic gadolinium-enhanced MR imaging combined with MTC (10 cases) and conventional dynamic gadolinium-enhanced MR imaging (5 cases) were performed after the administration of Gd-DTPA (0.2 ml/kg). Sagittal images were obtained every 22 seconds during the first 264 seconds. Thus, a total of 15 images were obtained in each lesion. The signal intensity ratio (SIR) of lesion to mammary glarid was calculated for each image as follows: (SI lesion/SI mammary gland)/(SI (pre)lesion/SI (pre)mammary gland). Dynamic gadolinium-enhanced MR imaging with MTC always allowed better SIR at 88 seconds than conventional dynamic gadolinium-enhanced MR imaging after bolus injection (p < 0.01). Dynamic gadolinium-enhanced MR imaging with MTC improved detection of the boundary of the lesion and mammary gland.

[Toxicity studies of landiolol hydrochloride (ONO-1101) (1). Single intravenous toxicity study in rats and dogs].

Single dose toxicity studies of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, were conducted in Sprague-Dawley (SD) rats and beagle dogs. ONO-1101 was administered intravenously at a dose level of 37.5, 75, 150 or 300 mg/kg to rats of both sexes and 25, 50 or 100 mg/kg to male dogs. In the rat study, 5/6 males in the 150 mg/kg group and all animals in the 300 mg/kg group died during or right after administration. Survivors in the 150 mg/kg group showed temporal hypoactivity, bradypnea, dyspnea, tremor, loss of righting reflex and reddish lacrimation up to 5 min after injection. One male in the 150 mg/kg group had a tendency of suppression on body weight gain. No effects on clinical signs and body weight gain were seen in the 75 mg/kg group or lower. Necropsy findings showed only red tear in the majority of the decedents. In the dog study, all animals died within 6 min after administration in the 100 mg/kg group, showed ataxic gait, rolling and tachypnea followed by bradypnea and gasping/apnea. Incontinence of urine, defecation and vocalization were also seen in each one of two animals before death. Temporal hypoactivity was seen 1 min after administration in the 50 mg/kg group. No clinical signs were seen in the 25 mg/kg group. ONO-1101 did not affect bodyweight or food consumption. Necropsy findings of the decedents showed no abnormalities. It is indicated that the minimum lethal doses are 150 mg/kg in rats and 100 mg/kg in dogs.

Dynamic MRI with slow injection of contrast material for the diagnosis of pituitary adenoma.

Magnetic resonance (MR) imaging of pituitary adenoma is usually carried out in dynamic studies with bolus contrast material injections, with the result that few strong images are obtained. Dynamic studies using a slowly injected contrast material were carried out in 14 cases of pituitary adenomas. The examinations were performed with a 1.5 Tesla superconducting MR imaging system using the spin-echo technique. Gd-DTPA (0.1 mmol/kg) was slowly injected (within 90 sec) by hand, providing seven to nine dynamic images during 350 sec from the start of injection. The average time to reach the maximum signal intensity was 170.6 sec in adenoma and 156.2 sec in normal gland tissue. The maximum contrast signal intensity ratio of adenoma to normal gland was 0.527 in the fifth image. The contrast of adenoma to normal gland tissue was calculated by the following formula: ASII (adenoma signal intensity index) = (adenoma signal intensity-tissue signal intensity)/tissue signal intensity. The most remarkable contrast between adenoma and normal tissue was obtained from the fourth to eighth images. In other words, we could obtain the strongest contrast at 144.8 sec to 299.6 sec from the start of contrast injection. Our results with slow injection suggest that stronger images can be obtained a longer period after contrast injection.

Apical hypertrophy associated with rapid T wave inversion on the electrocardiogram.

A 53-year-old man who had no chest pain and no family history of heart disease demonstrated a rapid T wave change on an electrocardiogram, from a positive T wave to a giant negative T wave, within 1 year. Echocardiography showed no left ventricular hypertrophy before or after the T wave change. Cine-magnetic resonance imaging revealed focal apical hypertrophy after the appearance of the giant negative T wave. Although T wave inversions sometimes develop within a short period in patients with hypertrophic cardiomyopathy, they are rare in a patient without hypertension or chest pain.

Cystic radio-lucency of carpal bones in haemodialysis patients. An early indicator of the onset of carpal tunnel syndrome.

Patients receiving haemodialysis for more than 10 years were selected for this study in order to clarify an apparent sequential association of cystic lesions of carpal bones and carpal tunnel syndrome. X-rays and computed tomographs of 138 hands of 69 patients revealed cystic radiolucency of carpal bones in 35% of the hands. Radiographs were classified into three groups: Group A--cyst growing, Group B--cyst not growing, and Group C--cyst absent. The prevalence of carpal tunnel syndrome was 100% (27/27) in Group A, 5.6% (1/18) in Group B, and 6.5% (6/93) in Group C. Growth of the cyst precedes the development of carpal tunnel syndrome by about 2 or 3 years. Growth of the bone cyst indicates that inflammation had already extended to the tenosynovium and median nerve. Cystic radio-lucency of the carpal bones appears to be a useful indicator of the onset of carpal tunnel syndrome.