Mitochondrial DNA 3243 mutation is infrequent in Japanese diabetic patients with auditory disturbance.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
D Inoue
Publications and source records attributed to D Inoue.
The deletion of 14 amino acids in the seventh transmembrane domain of a naturally occurring calcitonin receptor isoform alters ligand binding and selectively abolishes coupling to phospholipase C.
The cDNA that encodes the rabbit calcitonin receptor was cloned by screening a rabbit osteoclast library. Reverse transcription-polymerase chain reaction amplification of calcitonin receptor sequences from rabbit osteoclast RNA yielded cDNAs that encode two isoforms of the calcitonin receptor. One isoform is homologous to the C1a isoform previously identified in multiple cell types and species, while the second, designated CTRDeltae13, is a previously unidentified isoform that is apparently generated by alternative splicing during mRNA processing that deletes exon 13, resulting in the absence of 14 amino acids in the predicted seventh transmembrane domain. Expression of mRNA transcripts encoding the two isoforms varies in a tissue-specific manner, with CTRDeltae13 accounting for less than 15% of the total calcitonin receptor mRNA in osteoclasts, kidney, and brain, but comprising at least 50% of the transcripts in skeletal muscle and lung. The two isoforms were expressed, and the ligand binding and signal transduction properties were characterized. Deletion of the residues in the seventh transmembrane domain in CTRDeltae13 reduced the binding affinity for salmon and human calcitonin by more than 10-fold and approximately 2-fold, respectively, resulting in a receptor that failed to discriminate between the two forms of calcitonin. Both isoforms activated adenylyl cyclase, with EC50 values consistent with the difference in ligand affinities. In contrast, only the C1a isoform, but not the CTRDeltae13 isoform, activated phospholipase C. Thus, while the CTRDeltae13 remains active despite the deletion of a significant portion of its seventh transmembrane domain, it has significantly altered ligand recognition and signal transduction properties.
Amino Acid Sequence↗
Effect of ischemic preconditioning on mitochondrial oxidative phosphorylation and high energy phosphates in rat hearts.
The ability of ischemic preconditioning (IP) to protect the myocardium against prolonged ischemia may derive from improved energy balance. We therefore examined myocardial energy metabolism and mitochondrial oxidative phosphorylation in isolated perfused rat hearts which were either subjected (IP group), or not subjected (control group), to preconditioning prior to 30 min sustained ischemia and 30 min reperfusion. Preconditioning was achieved with two cycles of 5 min ischemia followed by 5 min reperfusion. Recovery of myocardial function was significantly greater, and creatine kinase release was significantly lower, in the IP group. Although ATP hydrolysis during the sustained ischemia remained unchanged in both groups, greater preservation of high energy phosphate (eg. ATP and CP) was observed in the IP group after reperfusion. CP content immediately after preconditioning greatly exceeded pre-ischemic values. Lactate production during the sustained ischemia was significantly lower in the IP group, suggesting a decrease in anaerobic glycolysis and a probable attenuation of intracellular acidosis. Oligomycin-sensitive mitochondrial ATPase activity in the control group was significantly decreased both after the sustained ischemia and the reperfusion, but in the IP group it did not change after the preconditioning, sustained ischemia, or reperfusion. Although atractyloside-inhibitable adenine nucleotide translocase activity was markedly decreased during sustained ischemia in both groups, its activity was significantly higher after reperfusion in the IP group. These data suggest that (1) mitochondrial ATPase contributes only slightly to ATP depletion during sustained ischemia, (2) both the CP overshoot phenomenon and the decrease in anaerobic glycolysis can be attributable to cardioprotection during the sustained ischemia, and (3) the preservation of ATPase and adenine nucleotide translocase activities may be a possible explanation for the restoration of high energy phosphates after sustained ischemia-reperfusion injury in the preconditioned hearts of rats.
Adenosine Triphosphatases↗
Localization of insulinomas by selective intraarterial calcium injection.
Explore the source record for details and available documents.
Aged↗
Two cases of empty sella syndrome with variable dexamethasone-suppressibility of ACTH and cortisol.
We here describe two patients with empty sella syndrome who had variable and abnormal ACTH and cortisol secretory profiles. The patients are a 58-year old male and a 41-year old female, both of whom were neurotic. In both cases, low-dose dexamethasone suppression tests (1 mg, p.o., overnight) caused variable responses, such as a paradoxical increase, insufficient decrease or normal decrease in ACTH and cortisol depending on the period when they were performed. The circadian rhythm of ACTH and cortisol also showed variable patterns. Abdominal CT showed slight enlargement of both adrenal glands. Adrenal scintigraphy after dexamethasone suppression (3 mg, p.o., 7 days) revealed uptake into both adrenal glands. MRI of the brain indicated empty sella, but failed to show evidence of pituitary adenoma. It remains to be elucidated whether these secretory profiles of ACTH and cortisol in the two cases are only to be regarded as secondary changes associated with neurosis, as reported in depression or alcoholism, or the two cases share some pathogenetic mechanism with cyclic Cushing disease.
19-Iodocholesterol↗
Severe alpha-2 agonist withdrawal syndrome in diabetes mellitus.
Explore the source record for details and available documents.
Adrenergic alpha-Agonists↗
Cardiomyopathy associated with Graves' disease.
Cardiovascular changes associated with Graves' disease are generally considered to be secondary to the increased levels of thyroid hormone. We describe a case of Graves' disease in a 25-year-old man, who developed cardiomyopathy with severe heart failure. Pathological examination of the myocardial biopsies showed fibroblast infiltration and degenerative changes. After the cardiomyopathy subsided the patient developed a goitre and signs of hyperthyroidism, followed by Graves' ophthalmopathy, which was treated successfully with a combination of high-dose corticosteroids and orbital radiotherapy. These findings suggested a common pathogenesis for the cardiomyopathy and ophthalmopathy, and prompted us to investigate the expression of TSH receptor (TSH-R) in human heart. TSH-R mRNA was identified in human heart using the reverse transcriptasepolymerase chain reaction (RT-PCR) and DNA sequencing. Taken together, these data suggest that autoimmunity against the TSH-R might contribute to both the cardiomyopathy and ophthalmopathy in similar cases of Graves' disease.
Adult↗
Effects of disopyramide on the atrial fibrillation threshold in the human atrium.
The effects of disopyramide on the atrial fibrillation threshold (AFT) in the human atrium were investigated. To evaluate atrial vulnerability, the following electrophysiologic parameters were measured before and after the administration of disopyramide (2 mg/kg) in 12 patients with paroxysmal atrial fibrillation: The right atrial effective refractory period (ERP) and percentage maximum atrial fragmentation (%MAF) were measured by atrial premature stimulation based on a cycle length of 500 ms. The inter-atrial conduction time (ACT) was measured by burst pacing (120/min) for 30 s. AFT was measured by applying a high-frequency (50 Hz) stimulation for 1 s given at the right atrial appendage. AFT was defined as the lowest intensity of electrical current that could induce atrial fibrillation lasting for more than 30 s. Disopyramide significantly reduced %MAF, and prolonged ERP and ACT. AFT was measured in all patients and the mean AFT was 3.1 +/- 1.7 mA. After the administration of disopyramide, AFT significantly increased to 6.1 +/- 3.6 mA. There was a positive correlation between ERP and AFT, and a negative correlation between %MAF and AFT. No correlation was detected between ACT and AFT. In conclusion, disopyramide increased AFT in the human atrium.
Adult↗
Parathyroid hormone-related peptide as a locally produced vasorelaxant: regulation of its mRNA by hypertension in rats.
The present study was undertaken to examine the effect of parathyroid hormone-related peptide (PTHrP) on the vascular tone as well as the expression of its mRNA in the cardiovascular system and its regulation in response to systemic hypertension in Sprague-Dawley rats. In aortic rings precontracted with 0.3 microM norepinephrine PTHrP(1-34) caused a dose-dependent relaxation with the maximal response of 33% being observed at 10(-6) M. PTHrP was nearly equipotent to PTH or CGRP in the vasodilatory action. Ribonuclease protection assay and Northern blot analysis demonstrated that PTHrP mRNA levels in the heart and aorta were increased as a result of systemic hypertension induced by constant infusion of angiotensin II and salt loading. The results of our in vivo studies suggest an autocrine/paracrine role for PTHrP as a local regulator of the vascular tone.
Angiotensin II↗
In vivo evidence for progressive activation of parathyroid hormone-related peptide gene transcription with tumor growth and stimulation of osteoblastic bone formation at an early stage of humoral hypercalcemia of cancer.
The present study was undertaken to clarify in vivo the temporal profile of parathyroid hormone-related peptide (PTHRP) gene expression as well as bone histomorphometric features as a function of tumor growth, using an athymic rat model associated with humoral hypercalcemia of malignancy (HHM). Tumor-bearing animals exhibited hypercalcemia, hypophosphatemia, and increased circulating levels of PTHRP, and died within 3 weeks. Steady-state PTHRP mRNA levels and the transcription rate of PTHRP gene in the tumors were markedly increased with tumor growth. RNAse mapping analysis revealed that both upstream and downstream promoters of the human PTHRP gene were utilized in the tumors and became progressively activated with time. Bone histomorphometric analysis showed that osteoclastic bone resorption was progressively increased throughout the course, whereas osteoblastic bone formation was stimulated more than 2-fold at a very early stage (day 6 after tumor implantation) and then markedly suppressed thereafter on day 12 and day 18 compared with age-matched control animals. These results provide in vivo evidence that PTHRP gene transcription is progressively activated with tumor growth and that activation of osteoblasts does occur at a very early phase of HHM syndrome in contrast to the marked suppression of bone formation at later stages.
Analysis of Variance↗
Thyroid hemiagenesis with subacute thyroiditis.
A 58-year-old woman with thyroid hemiagenesis associated with subacute thyroiditis is described. Physical examinations revealed a firm nodule with spontaneous pain and tenderness in the left thyroid lobe. A serum thyroid hormone levels were elevated and thyroid scintiscan with 99mTc pertechnetate showed an extremely low uptake, we made a diagnosis of subacute thyroiditis. A 201Tl thyroid scan demonstrated an enlarged left lobe and absence of the right lobe. Ultrasonography of the thyroid gland revealed an enlarged left lobe occupied mostly with a hypoechoic region. An incidental finding was absence of the right lobe. Two months later thyroid function returned to normal. A follow-up thyroid scintiscan revealed a normal left lobe but absent right lobe. The diagnosis of hemiagenesis was confirmed by CT scan. This appears to be the first case report of thyroid hemiagenesis associated with subacute thyroiditis.
Blood Cell Count↗
Kinetics of frequency-dependent conduction delay by class I antiarrhythmic drugs in human atrium.
We investigated use-dependent prolongation of interatrial conduction time (IACT) by class I antiarrhythmic drugs in 16 patients. Changes in IACT at the initiation of atrial pacing were used to evaluate the onset kinetics. We examined recovery kinetics by giving a single extra stimulus with a varying coupling interval after discontinuing train stimulation. Time constants of the onset kinetics were 1.52 +/- 0.15/n(fast) and 0.087 +/- 0.031/n(slow) for mexiletine, 0.075 +/- 0.015/n for aprindine, 0.078 +/- 0.019/n for disopyramide, and 0.050 +/- 0.006/n for pilsicainide. The recovery time constants were 203 +/- 66 ms for mexiletine, 1,021 +/- 162 ms for aprindine, 993 +/- 101 ms for disopyramide, and 2,930 +/- 569 ms for pilsicainide. Class I antiarrhythmic drugs produced use-dependent IACT prolongation in humans, with characteristic kinetics for each agent similar to that of depression of the maximum upstroke velocity of cardiac action potential (Vmax) reported in in vitro studies.
Anti-Arrhythmia Agents↗
Effect of doxorubicin on postrest contraction in isolated rat hearts.
Clinical use of doxorubicin is limited by its cardiotoxicity. In doxorubicin-induced cardiomyopathy, vacuolization of the sarcoplasmic reticulum (SR) has been reported. We investigated whether doxorubicin had a direct action on the sarcoplasmic reticulum (SR) in isolated perfused rat hearts. The left and right atria were trimmed to maintain heart rate (HR) <200 beats/min. Postrest contractions, which are believed to be due primarily to Ca2+ release from the SR, were evoked with a programmable stimulator after variable rest intervals. The amplitude of the postrest contractions increased markedly as the rest interval increased. Doxorubicin (0.1 mM) significantly suppressed this potentiation of the postrest contractions. Furthermore, doxorubicin slowly induced aftercontractions and an increase in left ventricular diastolic pressure (LVDP), phenomena that are usually associated with ouabain intoxication. We conclude that doxorubicin-induced cardiomyopathy may be due to SR dysfunction, leading to intracellular Ca2+ overload.
Animals↗
Effect of nicorandil on cardiac dysfunction during reperfusion in normotensive and spontaneously hypertensive rats.
The cardioprotective effect of nicorandil, an opener of ATP-sensitive potassium channels, was studied in the isolated perfused hearts of the spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY) rat. The hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion. Controls received no drug. In the nicorandil group, the hearts were treated with 0.03 to 0.3 mmol/L nicorandil for 15 min before ischemia. Left ventricular developed pressure (LVDP) and end diastolic pressure (LVEDP) at 30 min of reperfusion were significantly lower and larger, respectively, in SHR than in WKY rats. Nicorandil improved LVDP and decreased LVEDP at 30 min of reperfusion in both SHR and WKY rats dose-dependently. The hypertensive heart in the early stage is already susceptible to reperfusion-cardiac dysfunction. Nicorandil has a beneficial effect on the post-ischemic dysfunction in both SHR and WKY rats.
Animals↗
Parathyroid hormone-related peptide in hypercalcemia associated with adult T cell leukemia/lymphoma: molecular and cellular mechanism of parathyroid hormone-related peptide overexpression in HTLV-I-infected T cells.
Explore the source record for details and available documents.
Humans↗
[A case report of primary triple cancers in the thyroid, stomach and rectum with evidence of variable oncoprotein expressions].
A case with primary triple cancers including thyroid cancer is reported. A 57-year old woman complaining of laryngeal discomfort was found to have an firm elastic lump on the right anterior neck. On 123I scan, the nodule in the right thyroid lobe accumulated considerable amounts of radioiodine as a warm nodule, while the remainder of the gland showed decreased uptake. Thyroid hormone levels remained within normal ranges. Cytological findings obtained by fine-needle aspiration biopsy showed papillary carcinoma. Right lobectomy was performed. The histological examinations revealed papillary carcinoma embedded within adenomatous thyroid tissue. It is probable that the surrounding adenomatous tissue accumulated radioiodine, since the warm nodule on 123I scan was larger than the size of the carcinoma. Examinations of the gastrointestinal tract revealed the presence of poorly differentiated adenocarcinoma in the stomach and well differentiated adenocarcinoma (carcinoma in adenoma) in the rectum. Expressions of ras p21 and p53 were examined immunohistochemically in these carcinoma tissues. The ras p21 product was clearly detected in not only the thyroid carcinoma but in a part of the surrounding adenomatous regions as well. Both ras p21 and p53 proteins were observed in the rectal cancer tissue. In contrast, these oncoproteins were not found in the gastric cancer tissue. In this case ras oncogene activation may be an early event in the tumorigenic process of the thyroid and rectum. However, different genetic alterations seem to occur during the development of these three carcinomas.
Adenocarcinoma↗
Effects of repeated ischemia on release kinetics of troponin T, creatine kinase, and lactate dehydrogenase in coronary effluent from isolated rat hearts.
We studied the release kinetics of cardiac troponin T (TnT) from coronary effluent in a re-stenosis model of 13 isolated rat hearts. After a 20-min period of global ischemia, we reperfused the hearts for 60 min according to the method of Langendorff. A second period of global ischemia was then induced for 5 min (protocol A) or 20 min (protocol B), followed by a second 60-min period of reperfusion. Coronary flow was measured by a timed collection of the coronary effluent. Levels of TnT in the effluent were compared to those of creatine kinase (CK) and lactate dehydrogenase (LD). Levels of TnT increased after the second global ischemia, but no differences were found in the released levels of TnT between protocols A and B. However, the amounts of CK and LD released in protocol B were much greater than those released in protocol A. These studies indicate that the release kinetics of TnT are different from that of CK and LD during reperfusion. It appears that after the initial ischemic damage to TnT, subsequent ischemia causes damage to TnT regardless of the duration of the insult, whereas the damage to sarcolemma is dependent on the duration of the ischemia.
Animals↗
Further studies of amino acids (268-304) in thyrotropin (TSH)--lutropin/chorionic gonadotropin (LH/CG) receptor chimeras: cysteine-301 is important in TSH binding and receptor tertiary structure.
Our previous study of chimeric TSH-LH/CG receptors showed that substituting amino acid residues 268-304 of the TSH receptor with homologous residues from the LH/CG receptor markedly decreased high affinity TSH binding as evidenced by ligand displacement assays [Akamizu et al. Endocr J 40:363-372, 1993]. Despite this change in TSH binding, there was a minimal change in TSH-stimulated activity in cAMP assays. To explain this dissociation of TSH binding and function, further characterization of individual residues within the 268-304 segment was performed. Five additional chimeric TSH-LH/CG receptors within this region were constructed by substituting corresponding residues of rat LH/CG receptor. After transfection in Cos-7 cells, TSH receptor activities of these chimeras were evaluated. A single point mutation of cysteine-301 to glutamate resulted in a mutant receptor that exhibited the same receptor bioactivity as the chimeric receptor with amino acids 268-304 substituted by LH/CG receptor residues: apparent low affinity TSH binding in ligand displacement assays but significant retention of the cAMP response to TSH. The four other chimeric substitutions yielded cDNAs coding for receptors that behaved like wild-type receptors. Western blot analyses using a TSH receptor-specific antibody showed that all five of the new mutants were synthesized and integrated in the membrane. These results suggest that cysteine-301 is the critical residue whose mutation accounts for the original chimeric results and the dissociation of binding and functional activity. The possibility must be considered that cysteine-301 is involved in disulfide bond formation and is important in tertiary structure and that conformational changes in the receptor result from its mutation.
Amino Acid Sequence↗