Biomedical subjects

D Inoue

Publications and source records attributed to D Inoue.

At least 73 records · Page 4Linked to original sources

PubMed1994

Effects of E-4031 on atrial fibrillation threshold in guinea pig atria: comparative study with class I antiarrhythmic drugs.

The effects of E-4031, a new class III antiarrhythmic agent, on atrial fibrillation threshold (AFT), atrial effective refractory period (ERP), and interatrial conduction time (ACT) were investigated in Langendorff-perfused guinea pig hearts; the results were then compared with those of the class I agents disopyramide, procainamide, lidocaine, and flecainide. Whole guinea pig hearts were perfused with Tyrode's solution containing acetylcholine (ACh 3 x 10(-7) M). The three indexes were measured before and after administration of the test drugs, using right atrial extrastimulus and 50-Hz continuous stimulation. Disopyramide, procainamide, and flecainide (> or = 10(-6) M) significantly increased AFT. Although E-4031 (> or = 3 x 10(-6) M) also increased AFT, this effect was less potent than that observed with the other drugs. E-4031 (> or = 10(-6) M) significantly prolonged ERP, and this prolongation was less pronounced than that observed with disopyramide but similar to that observed with procainamide or flecainide. E-4031 did not affect ACT, and the greatest prolongation of ACT was observed with flecainide. Lidocaine had no effect on any of the indexes. These findings suggest that in guinea pig hearts E-4031 exerts an antifibrillatory effect by prolonging atrial ERP alone, but this effect is less pronounced than that observed with class I drugs, because AFT measured by 50-Hz continuous stimulation is influenced by both ERP and ACT.

Acetylcholine↗

PubMed1994

Metastatic thyroid cancer presenting as thyrotoxicosis: report of three cases.

Three patients with metastatic thyroid follicular carcinoma developed thyrotoxicosis. Two had mild T3 toxicosis without detectable TSH binding inhibitor immunoglobulins (TBII) or thyroid stimulating antibodies (TSAb). Considerable concentration of 131I by tumours occurred, although serum TSH was undetectable. The third patient developed thyrotoxicosis several months after treatment with 131I had commenced and this was associated with concurrent increase in both TBII (90%; normal, less than 11%) and TSAb (2100%). We conclude that thyrotoxicosis in patients with metastatic thyroid carcinoma may result from a large bulk of tumour functioning either autonomously or after stimulation by TSH receptor antibodies.

Adenocarcinoma, Follicular↗

PubMed1994

Recent progress in TSH receptor studies with a new concept of "autoimmune TSH receptor disease".

Recent progress in the studies of epitope analysis of the TSH-R against TSH-R Ab was reviewed extensively. Using both site-directed mutagenesis and synthetic TSH-R peptide, binding and/or action sites of TSH-R Ab have been known to be multiple and discontinuous, but the significance of two unique and TSH-R specific regions has been implicated. Further, the possible existence of heterogeneity among stimulatory TSH-R Ab has also been indicated. As for immunogenetic factors related to autoimmune thyroid diseases, studies on HLA analysis, TSH-R specific T lymphocyte analysis and VH analysis of TSH-R Ab were discussed. Of note was the negative association of HLA-DP w2 antigen in Japanese patients with Graves' disease and hypothyroidism due to blocking TSH-R Ab, and we proposed a new concept of autoimmune TSH receptor disease within autoimmune thyroid disease and emphasized possible critical roles of HLA-DP. Recent evidence of restricted usage of the Ig VH gene in cloned B lymphocytes from Graves' patients producing TSH-R Ab has also been presented.

Autoimmune Diseases↗

PubMed1993

22-Oxacalcitriol, a noncalcemic analogue of calcitriol, suppresses both cell proliferation and parathyroid hormone-related peptide gene expression in human T cell lymphotrophic virus, type I-infected T cells.

Human T cell lymphotrophic virus, type I (HTLV-I)-infected T cells overproduce parathyroid hormone-related peptide (PTHRP) and cause hypercalcemia in patients with adult T cell leukemia. The present study was undertaken to test whether 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and its noncalcemic analogue, 22-oxa-1,25-(OH)2D3 (OCT), could suppress cell proliferation and PTHRP gene expression in an HTLV-I-infected T cell line, MT-2. OCT as well as 1,25-(OH)2D3 inhibited the proliferation of MT-2 cells in a time- and dose-dependent manner. Cell cycle analysis revealed that OCT, like the parent compound, caused a transition delay of cells through the G1 phase. OCT and 1,25-(OH)2D3 decreased the steady state levels of PTHRP mRNA, and nuclear runoff assays demonstrated that the effect of OCT occurred at a transcription level. As a result, OCT caused a reduction in PTHRP concentrations in the conditioned medium by approximately 50%. OCT inhibited not only the basal secretion but also the stimulation of PTHRP secretion by interleukin-2 or cAMP, which we had identified as two important stimulators. Northern blot analysis and the specific uptake of [3H]1,25-(OH)2D3 revealed unexpectedly that the vitamin D receptor was abundantly expressed in MT-2 cells. These results suggest that OCT, as well as 1,25-(OH)2D3, has the potential to suppress both cell proliferation and PTHRP gene expression through binding to the vitamin D receptor overexpressed in HTLV-I-infected T cells.

Calcitriol↗

PubMed1993

Transcription of the gene for parathyroid hormone-related peptide from the human is activated through a cAMP-dependent pathway by prostaglandin E1 in HTLV-I-infected T cells.

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), and hypercalcemia frequently associated with ATL is mediated by parathyroid hormone-related peptide (PTHRP). The present study was undertaken to clarify the role of cAMP second messenger system in the regulation of human PTHRP gene expression in ATL cells, using an HTLV-I-infected T-cell line, MT-2. Forskolin and dibutyryl cAMP (Bt2cAMP) caused a marked and transient increase in the steady-state level of PTHRP mRNA. The effects of these agents were dose-dependent, and the maximal effects were observed at 3 h. Nuclear runoff transcription assay showed that forskolin and Bt2cAMP caused an increase in the transcription rate of the human PTHRP gene. In contrast, the stability of PTHRP mRNA was only modestly increased by these agents. Forskolin and Bt2cAMP also increased the secretion of PTHRP by MT-2 cells, as determined by both a newly established immunoradiometric assay using two antibodies against human PTHRP-(1-34) and PTHRP-(50-83) and a radioimmunoassay using an antibody against human PTHRP-(109-141). Prostaglandin E1 (PGE1) caused a marked stimulation of intracellular cAMP production in MT-2 cells, whereas PGE2 and PGF2 alpha had only modest effects. The ability of these PGs to stimulate cAMP production correlated well with their ability to increase PTHRP mRNA level and the secretion of PTHRP. Indomethacin did not affect the basal level of cAMP production or PTHRP mRNA, suggesting that endogenous PG was not involved in the basal production of cAMP or PTHRP. When PGE1 was given to MT-2 cells together with interleukin 2, which is another stimulator of PTHRP gene expression, PTHRP secretion was synergistically stimulated. These results suggest that the transcription of the human PTHRP gene is enhanced through a cAMP-dependent pathway by PGE1 and that PGE1, as well as interleukin 2, plays an important role in the overexpression of the human PTHRP gene in HTLV-I-infected T cells leading to the development of hypercalcemia in ATL patients.

Alprostadil↗

PubMed1993

Electrophysiological effects of flecainide acetate on stretched guinea pig left atrial muscle fibers.

The electrophysiological effects of flecainide acetate (3 x 10(-6) M) on stretched atrial tissue were investigated using guinea-pig left atrial muscle fibers. Before stretching, the resting membrane potential was not affected by flecainide at 1 Hz, although the overshoot potential (Eov) and the action potential duration at 50% repolarization (APD50) were slightly but significantly decreased by 2 +/- 1 mV and 2 +/- 1 msec, respectively. The effective refractory period (ERP) was increased by 3 +/- 1 msec. The reduction of Vmax was 20.6 +/- 1.2%. The half-maximum potential (Vh) of the relationship between Vmax and the resting potential was shifted to become more negative by flecainide (from -60.6 +/- 2.1 mV to -63.2 +/- 1.7 mV). After 90-120 min of washout with drug-free Tyrode's solution, the tissue was mechanically stretched to 150% of its slack length. Stretching significantly decreased the Vmax by 16.9 +/- 3.1%, along with a slight but significant increase in ERP (3 +/- 1 msec) and shifted Vh to become more negative (from -60.6 +/- 2.1 to -63.1 +/- 1.8 mV). In the presence of flecainide, Vmax further decreased by 20.2 +/- 2.6%, and Vh shifted from -63.1 +/- 1.8 to -65.0 +/- 1.5 mV. Comparison with the control unstretched fibers showed that flecainide significantly decreased Vmax by 34.0 +/- 2.7%, reduced the resting membrane potential by 3 +/- 1 mV, decreased Eov by 4 +/- 1 mV, and shifted Vh from -60.6 +/- 2.1 to -65.0 +/- 1.5 mV, while the APD50 and ERP did not change. In conclusion, the reduction of Vmax in the presence of flecainide was much greater in the stretched atrial muscle fibers than in the unstretched fibers, because the Vmax-resting potential relationship was shifted towards more negative potentials by both flecainide and stretching. These results suggest that flecainide exerts a stronger antiarrhythmic action on stretched atrial muscle fibers than on normal fibers.

Animals↗

PubMed1993

Interleukin-2 increases production and secretion of parathyroid hormone-related peptide by human T cell leukemia virus type I-infected T cells: possible role in hypercalcemia associated with adult T cell leukemia.

Although parathyroid hormone-related peptide (PTHRP) is produced by adult T cell leukemia (ATL) cells and causes hypercalcemia in ATL patients, very little is known about the regulation of PTHRP gene expression in the leukemic cells. The present study was undertaken to clarify the role of T cell growth factor, interleukin-2 (IL-2), in the expression of PTHRP gene, using a human T cell leukemia virus type I (HTLV-I)-infected T cell line, MT-2. Recombinant human IL-2 caused a transient increase in the steady state level of PTHRP messenger RNA (mRNA) in MT-2 cells, and a maximal effect was observed at 3-6 h. The effect of IL-2 was dose dependent, with a maximal response being observed at 10(-10) M. A monoclonal antibody against IL-2 receptor (anti-Tac antibody) inhibited the IL-2-induced increase in PTHRP mRNA level. Recombinant human IL-1, IL-3, IL-4, and IL-6 failed to increase PTHRP mRNA level. Nuclear run-off transcription assay showed that the transcription rate of the PTHRP gene was modestly increased by IL-2. In addition, IL-2 caused a substantial increase in the stability of PTHRP mRNA, compared with control cells in which the apparent half-life of PTHRP mRNA was less than 30 min after RNA synthesis was inhibited by the RNA polymerase II inhibitor, dichlorobenzimidazole riboside. The secretion of PTHRP, as determined by both a newly established immunoradiometric assay using recombinant human PTHRP(1-87) as the standard and an RIA using an antibody against PTHRP(109-141), was increased by IL-2 but not by IL-1, IL-3, IL-4, or IL-6. The IL-2-induced increase in PTHRP secretion was completely inhibited by the addition of anti-Tac antibody. These results demonstrate that IL-2 stimulates the production and secretion of PTHRP by HTLV-I-infected T cells through specific binding to IL-2 receptor and that the effect of IL-2 is mediated by a posttranscriptional as well as a transcriptional mechanism. It is suggested that IL-2 may be involved in an auctocrine/paracrine fashion not only in the proliferation of HTLV-I-infected T cells but also in the enhanced production and secretion of PTHRP and thus the development of hypercalcemia in ATL patients.

Blotting, Northern↗

PubMed1993

Apparent genetic difference between hypothyroid patients with blocking-type thyrotropin receptor antibody and those without, as shown by restriction fragment length polymorphism analyses of HLA-DP loci.

HLA types in Japanese patients with primary hypothyroidism were analyzed to see whether those with blocking-type TSH receptor antibody (TSH-R BAb M) differed genetically from those with idiopathic myxedema (IM). HLA typings of -A, -B, -C, -DR, and -DQ (73 antigens) were performed serologically, and those of -D and -DP (29 antigens) were analyzed by the restriction fragment length polymorphism method. Thirty patients were studied with TSH-R BAb M, and 28 with IM. The data were analyzed and compared with our previous results from 88 Graves' patients, 46 Hashimoto patients, and 186 control subjects. Overall, 192 patients with 4 autoimmune thyroid disorders showed a decrease in -Aw19 and an increase in -DQw4 (corrected P < 0.05) and significant associations of -Aw33, -Bw46, -Cw3, -DRw8, -DR9, and -DQw3. In TSH-R BAb M patients, increases in -B35, -Bw60, and -Dw8 and decreases in -DR4 and -DPw2 were seen, whereas IM patients showed increased -DPw2, -Bw61, and -Dw23. In comparisons between TSH-R BAb M and IM, the difference in -DPw2 was highly significant. HLA-B35 differed significantly in these 2 types of hypothyroidism. In conclusion, TSH-R BAb M patients have decreased frequency of -DPw2 and are genetically similar to Graves' disease, whereas IM patients are characterized by high frequency of -DPw2 and are genetically similar to Hashimoto's thyroiditis.

Adult↗

PubMed1993

Chimeric studies of the extracellular domain of the rat thyrotropin (TSH) receptor: amino acids (268-304) in the TSH receptor are involved in ligand high affinity binding, but not in TSH receptor-specific signal transduction.

A series of chimeric TSH-LH/CG receptors were constructed by substituting homologous segments of the extracellular domain of the rat TSH receptor with corresponding segments of rat LH/CG receptor: C1 (amino acids 37-123 substituted), C2 (91-112), C3 (173-234), C4 (233-266), C5 (268-304), C6 (112-305) and C7 (36-404). After transfection in Cos-7 cell, TSH- and LH/CG-receptor activities of these chimeras were evaluated and compared with those of deletion mutants involving the same residues [Kosugi et al. Thyroid 1:321 (1991)]. Western blot analyses revealed that most of the chimeric receptor proteins were normally synthesized and integrated in the membrane of transfected Cos-7 cells: an antibody to a TSH receptor specific synthetic peptide (residues 352-366) identified 170-190kDa and 90-100kDa TSH receptor structures in the plasma membrane fractions of Cos-7 cells transfected with wild-type TSH receptor cDNA and the C1 to C6 chimeras, but not C7 or wild LH/CG receptor cDNA. Despite this, no receptor except C5 exhibited any significant TSH receptor activities either in [12I]TSH binding or in cAMP responses to TSH and thyroid-stimulating antibodies (TSAbs) from Graves' patients. The chimeric receptor C5 exhibited only low affinity TSH binding (Kd = 3.5 x 10(-8) M), as did its counterpart the M2C mutant with residues 268-304 deleted. However, unlike M2C, C5 demonstrated a significant cAMP response to TSH as well as to TSAbs. The cAMP increase in response to TSH in the wild type receptor was observed at 10(-11) M TSH. In C5 the response was first evident at 10(-10) M TSH, but the maximum cAMP stimulation by TSH and TSAbs in C5 (EC50 = 6.7 x 10(-10) M) was approximately the same as the wild type receptor (EC50 = 1.5 x 10(-10) M). Inhibition of either TSH- or TSAb- stimulated cAMP increase by thyroid-stimulating blocking antibodies (TSBAbs) was also preserved in C5. These results suggest that amino acids 268-304 do not include an important determinant required for signal transduction, since a significant cAMP response to TSH and TSAbs was observed in the C5 receptor with these residues substituted. Additionally, these residues appear to be involved in ligand high affinity binding because high affinity TSH binding was lost in the chimeric receptor C5.

Amino Acid Sequence↗

PubMed1993

Effects of pilsicainide on the atrial fibrillation threshold in guinea pig atria. A comparative study with disopyramide, lidocaine and flecainide.

The effects of pilsicainide, a new class Ic antiarrhythmic agent, on the atrial fibrillation threshold (AFT), the atrial effective refractory period (ERP), and the interatrial conduction time (ACT) in Langendorff-perfused guinea pig hearts were investigated. These effects were compared with those of disopyramide, lidocaine and flecainide. Whole guinea pig heart was perfused with Tyrode's solution containing acetylcholine (3 x 10(-7) M). Three indices were measured before and after the administration of the test drugs using right atrial extrastimulus and high frequency stimulation. Pilsicainide, disopyramide and flecainide (> or = 10(-6) M) all significantly increased the AFT. Both pilsicainide and flecainide (> or = 3 x 10(-6) M) significantly prolonged the ERP, but this prolongation was less pronounced than that observed with disopyramide. The ACT was significantly prolonged with pilsicainide (> or = 10(-6) M), and this prolongation was greater than that observed with disopyramide but less than that with flecainide. Lidocaine had no effects on any of the indices measured. In conclusion, pilsicainide had a preventive effect on the atrial fibrillation induced by a combination of acetylcholine and high frequency stimulation in guinea pig hearts, by increasing the atrial ERP and slowing the interatrial conduction. These effects may explain, in part, the clinical effectiveness of this drug on paroxysmal atrial fibrillation.

Animals↗

PubMed1993

Effects of caffeine on ischemia-reperfusion injury in isolated rat hearts.

Cardiac sarcoplasmic reticulum (SR) plays an important role in regulation of the intracellular Ca2+ concentration. It is well known that intracellular Ca2+ overload is one cause of reperfusion injury. Thus, it is predicted that reperfusion injury of myocardium can be prevented by eliminating the Ca2+ overload. This study examined the effects of caffeine, a SR blocker, on reperfusion injury in isolated perfused rat hearts. Working hearts were reperfused for 25 min after 30 or 50 min of ischemia. Caffeine (10(-4) M) was administered during the period of ischemia or the initial 5 min of reperfusion. The left ventricular pressure and the electrocardiogram were recorded. Rate-pressure products were calculated as an index of cardiac function. Adenine nucleotides were measured by high-performance liquid chromatography to assess energy charge. The administration of caffeine for a short period during the initial reperfusion significantly improved cardiac function in the hearts. Caffeine pretreatment during 50 min of ischemia, though, resulted in deterioration of both energy charge and cardiac function. Caffeine did not affect the incidence of either ventricular fibrillation or reversion to sinus rhythm. The energy charges were lower in the preparations with sustained ventricular fibrillation.

Animals↗

PubMed1993

[Frequency dependent prolongation of inter-atrial conduction time by mexiletine in human atrium].

To investigate frequency dependent conduction slowing by mexiletine in the human atrium, we examined inter-atrial conduction time (IACT) at different stimulation frequencies (100/min to 220/min) in 13 patients with paroxysmal atrial fibrillation (Paf) and 7 patients without Paf. IACT was prolonged as the stimulation frequency was increased, and either before or after mexiletine administration IACT was longer in the Paf group (max 114 +/- 9 msec, p < 0.01, mean +/- SD) at any stimulation frequency than in the non-Paf group (max 100 +/- 8 msec). The change in IACT induced by mexiletine administration (% delta IACT) was larger in the Paf group (max 14.8 +/- 5.4%, p < 0.05) than in the non-Paf group (max 5.5 +/- 2.2%) at stimulation frequency over 140/min. Effective refractory period measured at the high right atrium was slightly decreased due to mexiletine in both the non-Paf and the Paf group. In conclusion, mexiletine showed frequency dependent suppression of conduction in the human atrial myocardium especially in patients with Paf.

Adolescent↗

PubMed1993

[Effects of propafenone on the parameters of body surface electrocardiogram in comparison with those of disopyramide].

The purpose of this study is to investigate the clinical effects of propafenone on the QT(QTc), QRS, PQ and RR interval of body surface electrocardiogram (ECG) in comparison with the effects of disopyramide. In 10 patients (5 with paroxysmal atrial fibrillation and 5 with ventricular premature complex: ages 48-77), after 4 days' observation without any cardioactive drugs, disopyramide (300mg/day) was administered orally for 7 days. After discontinuing the administration of disopyramide, 4 more days were allowed to wash out the drug, and propafenone (450mg/day) was administered orally for 7 days. 12-lead ECG was taken twice before the administration of disopyramide (Pre-1 and -2), on the 1st, 3rd, 5th and 7th days after the administration of disopyramide. Then it was also taken on the day before the beginning of propafenone administration and on the 1st, 3rd, 5th and 7th days after the administration of propafenone. The corrected QT (QTc = QT/square root of RR), QRS, PQ and RR intervals in lead II or V2 of each ECG were measured as the mean value of 5 consecutive sinus beats. The control values of QTc, QRS, PQ and RR intervals were calculated as the mean values of Pre-1 and -2, and the other values were expressed as the % ratio to the control values. Propafenone hardly altered the QTc interval but prolonged QRS interval after the 5th day of administration (110 +/- 12%, p < 0.05), while disopyramide significantly prolonged the QTc interval after the 3rd day of administration (109 +/- 5%, p < 0.001) without affecting the QRS interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1993

[Effect of pilsicainide hydrochloride on atrial fibrillation threshold].

To inventigate the electrophysiologic effects of pilsicainide hydrochloride on atrial fibrillation, we compared atrial fibrillation threshold (AFT), right atrial effective refractory period (RAERP), and inter-atrial conduction time (Inter-ACT) before and after the administration of pilsicainide in 12 patients with lone paroxysmal atrial fibrillation. The following electrophysiologic study was performed before and after the administration of the drug as the paced cycle length of 500msec. First, RAERP was measured. Secondly, Inter-ACT from the stimulating artifact to the initial deflection in the elecrocardiograms of the coronary sinus was measured. Thirdly, high-frequency (50Hz) stimulation was given at right atrial appendage continuously for one second just after the eighth basic paced beat. The stimulation current was increased by 1mA in a stepwise fashion from 2mA until atrial fibrillation ensued. AFT was defined as the lowest intensity of the current that induced atrial fibrillation or flutter of more than 30 seconds. Pilsicanide significantly increased AFT and Inter-ACT, but did not change RAERP. In conclusion, it is suggested that pilsicainide might decrease atrial vulnerability mainly by its effect on inter-atrial conduction delay and by the resulting increase in AFT.

Adult↗

PubMed1992

[Metastatic carcinoma of the sigmoid colon to the thyroid gland].

A case of metastatic thyroid cancer from sigmoid colon cancer is presented. A 52-year-old woman had a sigmoidectomy due to adenocarcinoma of the sigmoid colon in April 1988. Serum carcinoembryonic antigen (CEA) levels gradually rose from July 1990 along with multiple metastatic lesions which appeared in the lung. They were resected in January 1991. Two months later the subject noticed a painless and firm lump on the left anterior neck. She was found to have a solitary mass in the left thyroid lobe. Thyroid function remained within normal range. Cytological findings obtained by fine-needle aspiration biopsy showed tall columnar carcinoma cells with an acinar pattern. Subtotal thyroidectomy was performed, and histological examination revealed metastatic adenocarcinoma from colon cancer. Immunohistochemical staining by anti-CEA was positive but anti-thyroglobulin was negative.

Adenocarcinoma↗

PubMed1992

Acute effects of doxorubicin on skinned cardiac muscle fibres of guinea pigs.

OBJECTIVE: The aim was to examine the effect of doxorubicin on spontaneous cyclic Ca2+ release from the sarcoplasmic reticulum of skinned fibres, as measured by isometric tension development in EGTA free, Ca2+ free solution. METHODS: Experiments were done on fragments of papillary muscles from the right ventricles of guinea pigs. Skinned fibres were prepared by treatment with saponin. The effects of doxorubicin in concentrations of 2 x 10(-9) to 2 x 10(-5) M on cyclic contractions were evaluated in 20 muscles. The effects of doxorubicin in concentrations of 2 x 10(-7) and 2 x 10(-5) M on pCa-tension relation were examined in 14 muscles treated with Brij-58. RESULTS: Doxorubicin (2 x 10(-9) to 2 x 10(-5) M) increased the frequency of cyclic contractions and induced an incomplete muscle relaxation in a dose dependent manner. Doxorubicin 2 x 10(-7) M had no effect on pCa-tension relation. Doxorubicin 2 x 10(-5) M shifted the pCa-tension curve slightly to the left. CONCLUSIONS: An incomplete muscle relaxation is considered to be due to an increase in Ca2+ release from the sarcoplasmic reticulum and a slight increase in the sensitivity of the contractile proteins to Ca2+. These observations suggest that one cause of the intracellular Ca2+ overload induced by doxorubicin, a putative mechanism of the doxorubicin induced cardiomyopathy, is attributable to the direct effects of doxorubicin on the sarcoplasmic reticulum, impairing its ability to sequester Ca2+.

Animals↗

PubMed1992

Correlation of HLA types and clinical findings in Japanese patients with hyperthyroid Graves' disease: evidence indicating the existence of four subpopulations.

OBJECTIVES: To re-evaluate the associations of HLA types with Japanese patients having hyperthyroid Graves' disease, HLA types and clinical findings were correlated. DESIGN: Four independent clinical findings (ophthalmopathy, family history, age at onset and size of goitre) and two autoantibody titres, thyrotrophin binding inhibitor immunoglobulin (TBII) and anti-thyroid microsmall antibody (anti-M), were analysed. PATIENTS: Eighty-eight Japanese patients with hyperthyroid Graves' disease and 186 control subjects were assessed. MEASUREMENT: Serological HLA typing was performed on 73 antigens in HLA-A, -B, -C, -DR and -DQ loci. HLA-D and -DP (29 antigens) were determined by the restricted fragment length polymorphism (RFLP) methods. TBII and anti-M were measured by commercially available kits. RESULTS: Patients with potent antibody titres had HLA antigens commonly seen among all the patients with Graves' disease. Interestingly, however, HLA-B35 and -Cw11 were found to relate with negative and/or weak TBII, and HLA-B7 and absence of HLA-Aw19 with negative anti-M. Significant associations were observed between HLA-DRw8 and large goitre and absence of ophthalmopathy, and between HLA-DQw4 and a negative family history of diffuse goitre (corrected P less than 0.05). Several other antigens were also found to be significant. Among these antigens, four pairs of MHC classes I and II were found to relate to the clinical findings independently. HLA-DQw4 and negative -A31 pair was closely related to ophthalmopathy, negative family history and late onset of disease. The HLA-B5 and -Dw12 pair was associated with ophthalmopathy, positive family history and early onset of disease. The HLA-A11 and negative -DPw2 pair was associated with ophthalmopathy, negative family history and early onset of disease. The HLA-Bw46 and -DRw8 pair did not increase in frequency above that seen with HLA-DRw8 alone. These four antigen groups (HLA-DRw8, HLA-DQw4 and negative-A31, HLA-B5 and -Dw12, and HLA-A11 and negative -DPw2) were observed in the majority (68%) of patients with Graves' disease and at a significantly higher incidence than in the control group (P less than 0.05). CONCLUSION: There are four subpopulations of Japanese patients with hyperthyroid Graves' disease. This is one of the reasons why the association of HLA types in Japanese patients is rather weak when they are studied as one group.

Adolescent↗

PubMed1992

Slow kinetic property of mexiletine in guinea pig atrium.

We studied the onset and offset of use-dependent block (UDB) of maximum rate of rise of action potential (Vmax) with 3 x 10(-5)M mexilietine in guinea pig left atrium. A large decrease of Vmax was observed between the first and the second excitation when the preparations were stimulated at 4Hz after two minutes of rest period. UDB after the second excitation developed slowly to reach steady state within 30 sec. These two onset rates were 1.016 +/- 0.055 and 0.070 +/- 0.009/action potential. Recovery process was also fitted with two exponential equations. The time constant of the fast recovery was 528 +/- 23 msec. and the slow one was 3099 +/- 435 msec. The relative contribution of the slow component was 38.3 +/- 2.6% in the onset and 29.7 +/- 3.1% in the recovery. In spite of elevated maximum diastolic potential at 4 Hz stimulation, the relationship between resting membrane potential and Vmax disclosed voltage-dependent block of Vmax was no more than 5%. It is concluded that mexiletine has a slow kinetic component as well as a fast one. When atrial muscle is depolarized, Vmax decreases further. Therefore, mexiletine may be more effective against the atrial arrhythmias than predicted previously.

Action Potentials↗