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Site-specific suppressors of superoxide production (named S1QELs) in the quinone-reaction site in mitochondrial respiratory complex I during reverse electron transfer have been previously reported; however, their mechanism of action remains elusive. Using bovine heart submitochondrial particles, we herein investigated the effects of S1QELs on complex I functions. We found that the inhibitory effects of S1QELs on complex I are distinctly different from those of other known quinone-site inhibitors. For example, the inhibitory potencies of S1QELs significantly varied depending on the direction of electron transfer (forward or reverse). S1QELs marginally suppressed the specific chemical modification of Asp(160) in the 49-kDa subunit, located deep in the quinone-binding pocket, by the tosyl chemistry reagent AL1. S1QELs also failed to suppress the binding of a photoreactive quinazoline-type inhibitor ([(125)I]AzQ) to the 49-kDa subunit. Moreover, a photoaffinity labeling experiment with photoreactive S1QEL derivatives indicated that they bind to a segment in the ND1 subunit that is not considered to make up the binding pocket for quinone or inhibitors. These results indicate that unlike known quinone-site inhibitors, S1QELs do not occupy the quinone- or inhibitor-binding pocket; rather, they may indirectly modulate the quinone-redox reactions by inducing structural changes of the pocket through binding to ND1. We conclude that this indirect effect may be a prerequisite for S1QELs' direction-dependent modulation of electron transfer. This, in turn, may be responsible for the suppression of superoxide production during reverse electron transfer without significantly interfering with forward electron transfer.

NADH-quinone oxidoreductase (respiratory complex I) couples NADH-to-quinone electron transfer to the translocation of protons across the membrane. Even though the architecture of the quinone-access channel in the enzyme has been modeled by X-ray crystallography and cryo-EM, conflicting findings raise the question whether the models fully reflect physiologically relevant states present throughout the catalytic cycle. To gain further insights into the structural features of the binding pocket for quinone/inhibitor, we performed chemical biology experiments using bovine heart sub-mitochondrial particles. We synthesized ubiquinones that are oversized (SF-UQs) or lipid-like (PC-UQs) and are highly unlikely to enter and transit the predicted narrow channel. We found that SF-UQs and PC-UQs can be catalytically reduced by complex I, albeit only at moderate or low rates. Moreover, quinone-site inhibitors completely blocked the catalytic reduction and the membrane potential formation coupled to this reduction. Photoaffinity-labeling experiments revealed that amiloride-type inhibitors bind to the interfacial domain of multiple core subunits (49 kDa, ND1, and PSST) and the 39-kDa supernumerary subunit, although the latter does not make up the channel cavity in the current models. The binding of amilorides to the multiple target subunits was remarkably suppressed by other quinone-site inhibitors and SF-UQs. Taken together, the present results are difficult to reconcile with the current channel models. On the basis of comprehensive interpretations of the present results and of previous findings, we discuss the physiological relevance of these models.

Hypercholesterolemia is one of the most representative disorders of the common diseases. To evaluate the prevalence of hypothyroidism in the population of adult hypercholesterolemia, we prospectively examined the thyroid function in patients with untreated or treated hypercholesterolemia as a multi-center survey. Subjects were the patients who were treated with some antilipemic agents or the untreated patients whose total cholesterol (TC) was over 220 mg/dL and/or LDL-cholesterol (LDL-C) over 140 mg/dL. Among 737 cases recruited, 725 cases (300 males and 425 females) participated in the survey including the thyroid function test. The patient's backgrounds include hypertension (51%), diabetes mellitus (49%), fatty liver (17%), smoking (15%), and habitual drinking (10%). The 72% of the patients were treated with some antilipemic agents and the mean values of TC, LDL-C, triglyceride (TG), HDL-cholesterol (HDL-C), and LDL-C/HDL-C ratio (L/H) were 204.5 mg/dL, 119.6 mg/dL, 144.4 mg/dL, 60.7 mg/dL and 2.25, respectively. The primary hypothyroidism was seen in 27 cases (3.7%) (11 males, 16 females) with subclinical hypothyroidism in 17 cases (2.4%) and overt hypothyroidism in 10 cases (1.4%). The central hypothyroidism was seen in 4 cases (0.6%). The prevalence of hypothyroidism was 4.3% in patients with hypercholesterolemia. Taking account of the large number of patients with dyslipidemia and importance of avoiding unnecessary administration and associated adverse effects, evaluation of the thyroid function could be warranted in patients with dyslipidemia although cost-benefit issues waits further investigation.

Malnutrition is a significant factor in the development of pressure ulcers and many nutritional guidelines for preventing pressure ulcers have been published. However, few clinical investigations have examined the energy required to heal pressure ulcers. The aim of the present study was to investigate the relationship between nutritional intake and improvement of pressure ulcers. Total calories, which were supplied by mouth through a feeding tube and via venous alimentation were examined for 40 hospitalized bedridden inpatients who had pressure ulcers. Of these patients, 21 whose wounds improved or healed and 19 whose wounds became worse or did not improve were eligible for this retrospective study. Pressure ulcers in patients who received more than 30 kcal/kg per day improved or healed, while those of patients who received less than 20 kcal/kg per day worsened or failed to improve. Furthermore, intake of 30 kcal/kg per day enabled serum albumin levels to improve. Energy intake of 30 kcal/kg per day is comparable to the predicted total energy expenditure and is thought to be essential for improving pressure ulcers in bedridden patients .

本稿の課題は、寝屋川市の教師殺傷事件に関する諸報道の分析を通じて、それらの言説が孕む諸問題を明らかにするとともに、現代の少年事件をどうみるか、このような悲劇を繰り返さないために私たち大人に何が求められているのか、といった課題について、メディア論ならびに知識論の視点から考察を加えることにある。そして同時にそれは、別様の社会や教育への想像力を枯渇させた現代社会において、私たち自身の社会的構想力を取り戻すための一つの試みでもある。

本稿では、学生の学習観・授業観に揺さぶりをかけ、あらためて大学教育とは何か、どうあるべきかを学生とともに探求することを課題として行った2003年度前期専門科目「教育人間学」の授業実践を紹介する。さらにそこから、学生の真の教育ニーズとは何かを考察したい。

The accumulation of activated CD4+ T cells and antigen (Ag)-dependent cellular interactions between thyrocytes and CD4+ T cells have been determined in thyroid gland from patients with Graves' disease. The Fas/Fas ligand (FasL) interaction between antigen-presenting cells and T cells regulates the apoptosis of the former cells triggered by the latter cells. The inhibition of Fas-mediated apoptosis in thyrocytes could be a underlying mechanism of hyperplasia of thyrocytes in patients with Graves' disease. We investigated the potential role of Fas/FasL interaction between thyrocytes and CD4+ T cells in the induction of Fas-mediated apoptosis of the former cells induced by the latter cells. The presence of only a few specific T cells responsive to a putative autoantigen has hampered the investigation of specific T cell activation toward antigen-presenting cells (APCs). Therefore, we used a superantigen, staphylococcal enterotoxin B (SEB), to examine specific T cell activation toward thyrocytes in vitro since it stimulates a large proportion of T cells with particular Vbeta elements. Spontaneous apoptosis of thyrocytes in culture was not found even in the presence of various kinds of cytokines. In contrast, a clear induction of Fas-mediated apoptosis by anti-Fas IgM was determined in interferon-gamma (IFN-gamma)-stimulated thyrocytes. In addition, a significant cytotoxicity of purified CD4+ T cells toward IFN-gamma-stimulated thyrocytes in the presence of SEB was induced, and the addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or blockade of the Fas/FasL interaction reduced this cytotoxicity. FasL expression of CD4+ T cells cocultured with IFN-gamma-stimulated thyrocytes in the presence of SEB was clearly induced. Furthermore, the addition of mAbs against CD54 and CD58 inhibited both cytotoxicity and FasL expression of CD4+ T cells. The cytotoxicity of CD4+ T cells toward IFN-gamma-stimulated, SEB-pulsed thyrocytes was markedly inhibited when we used thyrocytes cultured with IFN-gamma in the presence of thyroid-stimulating hormone (TSH) as target cells. Our results suggest that 1) CD4+ T cells were activated by thyrocytes expressing MHC class II molecules in an SEB-dependent manner and then expressed FasL. 2) These activated FasL+ CD4+ T cells killed thyrocytes by interacting with Fas on thyrocytes and FasL on activated CD4+ T cells. The presence of costimulating molecules such as CD54 and CD58 on thyrocytes was also necessary to generate activated FasL+ CD4+ T cells. 3) Since the actions of thyroid stimulating antibody (TSAb) toward thyrocytes are similar to those of TSH, one goitrogenic activity of TSAb may, in part, be due to the inhibitory effect on Fas-mediated apoptosis of thyrocytes triggered by activated CD4+ T cells.

Apoptosis, a physiological process of cell death, may modulate the mass of the thyroid gland. We investigated the role of apoptosis and the possible involvement of Fas/Fas ligand (FasL) system in apoptosis during goiter formation and involution in a rat model of goiter. Rats were fed a low iodine diet and a goitrogen, 6-propyl-2-thiouracil, to induce goiter. Rats with goiter were then fed a high iodine diet to study the phase of involution. We examined the presence of apoptosis by electron microscopy (EM) and terminal deoxy-UTP nick end labeling (TUNEL). We also investigated the association between Fas and FasL expression and thyrocyte apoptosis using immunohistochemistry and Western blotting. To evaluate the proliferation of thyrocytes, proliferating cell nuclear antigen was examined immunohistochemically. The number of apoptotic cells increased during goiter formation and the early stage of involution, which were also associated with increased number of Fas-positive thyrocytes, and some of these cells c...

In the present studies, the long term effects of IFNα on thyroid function and thyroid autoantibodies were evaluated in 42 patients with chronic viral hepatitis type C treated with IFNα for at least 4 months. Before IFN treatment, 41 patients tested were all euthyroid. Five (12%) out of 24 patients tested had positive tests for thyroid autoantibodies. MCHA/TPOAb was detected in all 5 and TGHA/TGAb in 3 out of these 5 patients. Six to 10×106 units (U) of recombinant or natural IFNα were given intramuscularly daily for the first 2 to 4 weeks, followed by 3 to 10×106 U thrice weekly for the subsequent 14 to 22 weeks. Thyroid dysfunction and/or rises in titers of thyroid autoantibodies were observed in 6 patients during IFNα treatment; clinically overt thyroid dysfunctions, destructive thyroiditis and thyrotoxicosis of unidentified etiology, developed in 2 patients 4 to 5 months after start of IFN treatment, subclinical hypothyroidism with a slight increase in serum TSH concentrations but no serum thyroid hormone alternations was observed in 2 patients, and increases in titers of thyroid autoantibodies without thyroid dysfunction were found in 2 patients. Thus, IFNα exacerbated thyroid autoimmunity exclusively in all patients with positive tests for thyroid autoantibodies prior to treatment, but did not induce thyroid autoimmunity in thyroid autoantibody-negative patients. These data suggest that the prolonged IFNα therapy can lead to exacerbation of thyroid autoimmunity in susceptible (thyroid autoantibody-positive) patients.

Corrosion fatigue crack propagation of ship structural steel plates such as KA36 (TMCP) has been investigated from a viewpoint of hydrogen embrittlement. Hydrogen permeation coefficient was measured to be about 0.11 μA/cm in sour crude oil with H2S and H2O. It was simulated by cathodic hydrogen charging in some electrolytic solution.In this condition, the crack propagation rate of KA36 (TMCP) steel was accelerated as well as in sour crude oil. It increased with an increase in hydrogen permeation coefficient. It was well coincident with the spacing per cycle of brittle striation, which was observed in the accelerated crack propagation area in both conditions. The crack propagation rate, da/dN, increased with a decrease in the cycle of stress.Hydrogen content near the crack tip in the, ΔK of 37 MPa√m might be about one order of magnitude more than that in base material, which was estimated by both the observation of dislocation density in the plastic deformation region and the measurement of hydrogen diffusion coefficient of cold rolled steels. As the result, the hydrogen content in steel near the crack tip in high ΔK region might be approximately 0.1 mass ppm.Considering these results, it was concluded that the environmental enhancement of the crack propagation rate in sour crude oil was due to hydrogen embrittlement.

The paper presents a numerical method for solving an initial-boundary value problem of heat equations. The boundary matrix method, which is a kind of boundary element method, is formulated for the one-dimensional problem. The solution procedure is applied to two-and three-dimensional problems with the local one-dimensional method. Although the present method is a kind of implicit method, it is easy to describe it with an explicit form. It means that it is unnecessary to solve a large linear system to proceed the numerical time integration. The present algorithm suits a vector computer since two-and three-dimensional problems are reduced to one-dimensional problems. We show some numerical examples to verify the method, numerically and discuss the ratio of vectorization on the supercomputer VP30E. Consequently, we develop the program whichi has 99.6% vectorization.

We have previously demonstrated that thyrocytes from patients with Graves' disease induce autologous peripheral blood T cell proliferation in response to soluble antigens, and a synergistic augmentation of T cell response by adding suboptimal numbers of monocytes. In the present study, we examined the role of costimulatory molecules, expressed on the surface of thyrocytes and intrathyroidal mononuclear cells, in antigen-specific T cell proliferation. Intercellular associated molecule (ICAM)-1 and lymphocyte function associated antigen-3 were constitutively expressed on the surface of both normal and Graves' thyrocytes. However, ICAM-2, vascular cell adhesion molecule-1, B7-1, and B7-2 were not detected and induced by cytokines. B7-1, was expressed on intrathyroidal monocytes only, while B7-2 was present on intrathyroidal lymphocytes, peripheral blood monocytes, and intrathyroidal monocytes. Furthermore, the density of B7-2 was higher on intrathyroidal monocytes than on peripheral blood monocytes. The intensity of CD28 expression on intrathyroidal CD8bright+ cells was less than that on peripheral blood CD8bright+ cells. The antigen-specific T cell response induced by thyrocytes was blocked completely by anti-human leukocyte antigen-DR monoclonal antibody (mAb) and partially by anti-ICAM-1 mAb and anti-lymphocyte function associated antigen-3 mAb. Furthermore, the synergistic augmentation of T cell response, induced by the addition of suboptimal number of monocytes, was suppressed completely by combining anti-B7-1 mAb and anti-B7-2 mAb, to a level equivalent to that observed when thyrocytes were used alone as antigen-presenting cells. Our results suggest that T cell proliferation was induced by cooperation of thyrocytes and infiltrating professional antigen-presenting cells.

We report a 50-year-old female who suffered from reversible hypothyroidism accompanied by isolated ACTH deficiency. There were no findings indicating a complication of autoimmune thyroiditis. Replacement of maintenance dose of glucocorticoid not only led to improvement of thyroid function, but also caused a transient decrease in T 3 and an increase in reverse T 3 , suggesting that chronic cortisol deficiency may impair thyroid function, and that the maintenance dose, as well as pharmacological doses of glucocorticoids may influence T 4 deiodination. The findings of this case suggest that thyroid function should be re-evaluated to avoid unnecessary replacement of thyroid hormone, a few months after glucocorticoid replacement.

We report a 42-year-old Japanese woman with Recklinghausen's neurofibromatosis 1 (NF1) who developed mixed connective tissue disease (MCTD). Previously experiencing good health without an increase in subcutaneous nodules, she presented with Raynaud's phenomenon, swollen hands and polyarthralgia Clinical examination revealed a high titer of anti-RNP antibody, and she was thus diagnosed as having MCTD. She was treated with oral prednisolone (10 mg/day) and her symptoms improved rapidly. Since the association of MCTD and NF1 has not been reported previously, we concluded that this association is rare. We also discussed the association of NF1 and autoimmune diseases including MCTD.

A 65-year-old Japanese man who suffered from secondary hypopituitarism due to Rathke's cleft cyst is reported. Although computed tomography failed to detect any pituitary abnormality, magnetic resonance imaging demonstrated the presence of a cystic intrasellar mass, initially suggesting craniopharyngioma or abscess. Operative findings revealed Rathke's cleft cysts within the pituitary fossa which resulted in secondary hypopituitarism. Among cases of secondary hypopituitarism with abnormal findings in the pituitary, symptomatic Rathke's cleft cysts should be included in the differential diagnosis of adrenal insufficiency.

PTC gene, which is derived from the rearranged form of the ret proto-oncogene, was originally discovered in human thyroid papillary carcinomas. This gene has been thought to act as a tumorigenetic factor in thyroid carcinoma, although the action of PTC oncogene products is still unknown. To study the frequency of the PTC gene present in human thyroid carcinomas, we investigated four cell lines derived from thyroid carcinoma and 22 thyroid tumor tissue specimens. The reverse transcriptase-polymerase chain reaction (RT-PCR) method was performed to detect putative PTC mRNA. The presence of the PTC gene in genomic DNA was analyzed by Southern blot hybridization. PTC mRNA was detected by the RT-PCR method in only one papillary carcinoma cell line (TPC-1 cell). Southern gel analysis confirmed the rearrangement of the ret proto-oncogene in this cell line. In the other three cell lines and 22 tumor tissue specimens, however, neither the PTC gene or mRNA was detected. These results demonstrate that the prevalence of the PTC gene in thyroid tumor is low and may not be essential for human thyroid tumorigenesis. That our present results conflict with previous reports may be due to general differences in genetic background among races.

A 40-year-old woman with adrenal insufficiency was clinically diagnosed and examined with human corticotropin releasing hormone (CRH). This patient with secondary hypo-adrenalism has shown a normal serum cortisol response to exogenous ACTH administration and has been examined with CRH, lysine-vasopressin (LVP) and insulin tolerance test (ITT), respectively. Success in secreting ACTH in response to both CRH and LVP tests, but not ITT, suggests that this disorder was possibly due to a hypothalamic CRH deficiency rather than pituitary corticotroph dysfunction. A combination of the CRH test and ITT has come to play an increasingly significant role in the diagnosis and differential diagnosis of isolated ACTH deficiency syndrome.