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Biomedical subjects

Kazuo Chihara

Publications and source records attributed to Kazuo Chihara.

At least 55 records · Page 3Linked to original sources
PubMed2004

Thyroid hormone stimulates osteoclast differentiation by a mechanism independent of RANKL-RANK interaction.

It is well known that thyroid hormone excess causes bone loss. However, the precise mechanism of bone loss by thyroid hormone still remains unclear. When T(3) was added to unfractionated bone cells after degeneration of pre-existent osteoclasts, T(3) (1 pM-100 nM) dose-dependently stimulated osteoclast-like cell formation, irrespective of the presence of indomethacin and IL-6 Ab. T(3) increased the expression of osteoprotegerin (OPG) messenger RNA (mRNA), but not of receptor activator of nuclear factor kappaB ligand (RANKL) in unfractionated bone cells, suggesting that the stimulatory effect of T(3) on osteoclast formation was not mediated by the RANKL/OPG system. We next examined the direct effect of T(3) on osteoclast precursors in the absence of osteoblasts, using hemopoietic blast cells derived from spleen cells. T(3) (1 pM-100 nM) dose-dependently stimulated osteoclast-like cell formation from osteoclast precursors. OPG did not inhibit T(3)-induced osteoclast formation from osteoclast precursor cells. The polymerase chain reaction (PCR) product corresponding in size to the mouse T(3) receptor alpha1 cDNA was detected in osteoclast precursors from mouse hemopoietic blast cells as well as mouse heart and mouse osteoblastic cell line MC3T3-E1 cells, suggesting that T(3) directly stimulated osteoclast-like cell formation from osteoclast precursors in the absence of osteoblasts. Further, T(3) increased the expression of c-Fos mRNA at 15 min and 24 h and Fra-1 mRNA at 2 and 6 h in osteoclast precursors. Consistent with the increased expression of c-Fos mRNA observed by RT-PCR, the activation of c-Fos occurred in osteoclast precursor cells stimulated by T(3), while the activation of neither NF-kappaB nor MAPKs was observed by immunoblot analysis. Antisense oligodeoxynucleotides (as-ODN) complementary to c-Fos mRNA at 1 microM significantly inhibited T(3)-induced osteoclast-like cell formation from osteoclast precursors in the absence of stromal cells while sense-ODN did not affect T(3)-induced osteoclast-like cell formation. These results indicate that T(3) directly stimulates osteoclast differentiation at least in part by up-regulation of c-fos protein in osteoclast precursor cells.

Animals↗
PubMed2004

Pharmacological characteristics of KP-102 (GHRP-2), a potent growth hormone-releasing peptide.

KP-102 (D-alanyl-3-(2-naphthyl)-D-alanyl-L-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide dihydrochloride, growth hormone-releasing peptide-2, GHRP-2, pralmorelin, CAS 158861-67-7), is a potent synthetic growth hormone (GH) secretagogue. In the present study, the pharmacological characteristics of the GH-releasing property of KP-102 were investigated by means of in vivo and in vitro experiments. In conscious rats, the GH-releasing activity of KP-102 was more potent than that of exogenously injected GH-releasing hormone (GHRH). Under pentobarbital anesthesia in which endogenous somatostatin secretion is known to be decreased, KP-102 and GHRH, both showed an almost equivalent GH-releasing potency, which was also similar to that of KP-102 in conscious rats. Besides, KP-102 showed GH-releasing activity in conscious dogs as well, while GHRH failed to increase serum GH levels in conscious dogs. These findings suggest that the GH-releasing activity of KP-102 was less sensitive to GH suppression by endogenous somatostatin as compared with that of GHRH. The GH-releasing activity of KP-102 was completely absent in hypophysectomized rats, but present in median eminence-lesioned rats in which secreted GH amounts were significantly less than those normal rats, indicating necessity of the median eminence (endogenous GHRH) to exert the full activity of KP-102 in GH stimulation. KP-102 directly stimulated GH secretion from cultured rat anterior pituitary cells, although the GH-releasing potency of KP-102 was significantly weaker than that of GHRH in vitro. In conscious rats, KP-102 stimulated the secretion of both adrenocorticotrophic hormone (ACTH) and corticosterone, but not of prolactin. Three weeks administration of KP-102 showed growth-accelerating effect, a slight increase of body weight and wet weight of some organs in both normal and monosodium glutamate (MSG)-treated rats. These results suggest that KP-102 showed specific GH-releasing activity apart from slight ACTH secretion, and that the GH-releasing activity was stable in comparison with that of exogenously injected GHRH.

Adrenocorticotropic Hormone↗
PubMed2004

Marked and sustained increase in bone mineral density after parathyroidectomy in patients with primary hyperparathyroidism; a six-year longitudinal study with or without parathyroidectomy in a Japanese population.

OBJECTIVE: Although many reports have demonstrated the sustained increase in bone mineral density (BMD) at trabecular sites in primary hyperparathyroidism (pHPT) after parathyroidectomy (PTX), there have been no data available on BMD changes over the long-term in pHPT patients with and without PTX in Japanese population. The present study was designed to investigate long-term BMD changes at both trabecular and cortical sites in Japanese pHPT patients with or without PTX. METHODS: The subjects were 97 patients who had been followed up in Kobe University Hospital for at least 1 year up to 6 years with or without PTX. PTX was recommended to all patients whose pathological parathyroid gland(s) could be determined by image diagnosis. BMD was measured at the lumbar spine (L2-L4) and at distal one-third of the radius (R1/3) by dual energy X-ray absorptiometry (QDR2000). Serum levels of calcium, alkaline phosphatase and parathyroid hormone (PTH) were determined at the time of the BMD measurement. RESULTS: Significant increases in any of the indices of BMD from the baseline values were observed within three months after PTX, followed by sustained increases over 6 years at L2-L4 even in postmenopausal women. Radial BMD also showed a marked increase six years after PTX. L2-L4 eventually reached the normal BMD but R1/3 did not. The percentage changes in L2-L4 were positively and significantly correlated with the preoperative PTH levels over the study period. However, the percentage changes in R1/3 showed a significant correlation with the preoperative PTH levels only 5 and 6 years after PTX. In the patients without PTX, no obvious changes in biochemical indices and BMD were observed over the six years. CONCLUSION: We demonstrated that PTX led to marked and sustained increases in BMD not only at L2-L4 but also at R1/3 in Japanese pHPT patients, including postmenopausal women. The preoperative PTH level could be a clinically useful index for predicting long-term BMD changes after PTX.

Bone Density↗
PubMed2004

Long-term improvement of quality of life during growth hormone (GH) replacement therapy in adults with GH deficiency, as measured by questions on life satisfaction-hypopituitarism (QLS-H).

Questions on Life Satisfaction-Hypopituitarism (QLS-H) is a new quality-of-life (QoL) questionnaire developed for adults with hypopituitarism. To determine the effects of long-term GH treatment on QoL, we evaluated QLS-H Z-scores in 576 adult patients with GH deficiency (GHD) enrolled in HypoCCS, an international observational study, using data from five countries in which comparative QLS-H data from the general population were available. Baseline QLS-H Z-scores were significantly lower in GH-deficient patients than in the general population of the same age, gender, and nationality. Z-scores were also significantly lower in female patients vs. males (P = 0.006) and in adult-onset vs. childhood-onset GHD (P = 0.002). Multivariate analysis associated female gender, multiple pituitary hormone deficiencies, low serum IGF-I values (<75 micro g/liter), and concomitant antidepressant medication with low baseline Z-scores. QLS-H Z-scores increased from -1.02 +/- 1.43 (SD) at baseline to -0.25 +/- 1.34 (SD) after 1 yr of GH treatment (P < 0.001) and were no longer significantly different from the general population after 4 yr of treatment. There was no correlation between change in Z-score and GH dose or changes in IGF-I and IGF binding protein-3 during treatment. This study demonstrates that 1) improvements in QoL, as measured by the QLS-H, are maintained during long-term GH replacement therapy of adults with GHD, and 2) the QLS-H is a useful tool for evaluating QoL in hypopituitary patients treated in clinical practice. The authors suggest that evaluation of QoL should be a part of the routine clinical management of adult GH-deficient patients, complementing the measurement of surrogate biological markers or other clinical end points.

Adult↗
PubMed2004

Metabolic effects of 20-kilodalton human growth hormone (20K-hGH) for adults with growth hormone deficiency: results of an exploratory uncontrolled multicenter clinical trial of 20K-hGH.

The biological effects of 20-kDa human GH (20K-hGH), which is produced in the pituitary by alternative splicing of GH mRNA and comprises approximately 6% of all GH in serum, have not been reported. We have investigated the metabolic effects of recombinant 20K-hGH in adult patients with GH deficiency in an exploratory study. Three doses of 20K-hGH (0.006, 0.012, and 0.024 mg/kg.d), were administered for 16 wk to three groups (consisting of 18 or 19 subjects), respectively. The 20K-hGH dose-dependently increased serum IGF-I and IGFBP-3 levels, and the lowest dose (0.006 mg/kg) was enough to normalize both hormones by wk 4. Serum osteocalcin levels and urinary deoxypyridinoline excretion were also dose-dependently increased. There was a significant decrease in body fat mass with an increase of lean body mass at the lowest dose of 0.006 mg/kg.d. Blood glucose and serum insulin were increased significantly at 4 wk only in the high-dose group (0.024 mg/kg). Glucose tolerance was slightly impaired in 26-39% of patients in all treatment groups as judged by oral glucose tolerance tests, but there was no development of overt diabetes. The major adverse event in the 20K-hGH treatment was peripheral edema, similar to the incidence reported for 22K-hGH. The data demonstrated that 20K-hGH had metabolic effects comparable to those of 22K-hGH in humans. The results suggest that 20K-hGH could be used to treat GH-deficient patients, although further studies may be required to investigate the optimum dose and superiority of 20K-hGH over 22K-hGH in a comparative study.

Abdomen↗
PubMed2004

Direct causes of death in Japanese patients with hypopituitarism as analyzed from a nation-wide autopsy database.

OBJECTIVES: The direct causes of death in Japanese patients with hypopituitarism remain unclear. In this study, the direct causes of death were investigated and compared between Japanese patients with hypopituitarism from a nation-wide autopsy database and an age- and gender-matched control population from national reports. SUBJECTS: Three hundred and ninety-one subjects with hypopituitarism who had died were selected from a nation-wide autopsy database (1984-1993). The ratios of each cause of death among the age- and gender-matched control population were derived from national reports. RESULTS: In subjects with hypopituitarism, an increased relative frequency of death from cerebrovascular diseases (male; 2.02 (95% confidence interval (CI) 1.45-2.82), female; 1.73 (95% CI 1.18-2.52)) was found. In particular, the relative frequency of death from cerebral hemorrhage was 4.60 (95% CI 2.95-7.17) in male and 4.80 (95% CI 2.90-7.94) in female subjects with hypopituitarism. Unexpectedly, a decreased relative frequency of death from all heart diseases (male; 0.439 (95% CI 0.277-0.696), female; 0.267 (95% CI 0.149-0.478)) was found in subjects with hypopituitarism, although there was no difference between subjects with hypopituitarism and controls in the frequency of death from ischemic heart disease. CONCLUSIONS: These results provide useful information for the long-term care of Japanese patients with hypopituitarism.

Adolescent↗
PubMed2004

Adult GH deficiency in Japanese patients: effects of GH treatment in a randomised, placebo-controlled trial.

OBJECTIVE: To evaluate the influence of factors intrinsic to the Japanese population on consequences of growth hormone deficiency (GHD) and effects of GH treatment in adult Japanese hypopituitary patients with GHD. STUDY DESIGN: A 24-week, randomised, placebo-controlled, double-blind study in 64 patients in Japan, with GHD onset during adulthood (AO; n=27) or childhood (CO; n=37). Body composition measured by dual-energy X-ray absorptiometry (DXA) was evaluated centrally. Serum IGF-I, IGF binding protein-3 (IGFBP-3) and lipid levels were determined centrally. RESULTS: In contrast to Caucasian patients, there were no significant differences before treatment between AO and CO patients for body mass index (BMI), lean body mass (LBM) and fat mass (FM). Baseline BMI was >/=25 kg/m(2) for 32.8% of patients. For all patients combined, a significant increase in LBM and decrease in FM (P<0.001 for each) was seen with GH treatment. Serum IGF-I and IGFBP-3 were significantly lower at baseline in CO compared with AO patients, similar to Caucasian patients, and were increased in both onsets following GH treatment. Serum total and low-density lipoprotein (LDL)-cholesterol concentrations did not differ between AO and CO patients at baseline and were elevated compared with normal ranges. GH-induced decreases were significant compared with placebo for both total (P=0.036) and LDL-cholesterol (P=0.040). Glycosylated haemoglobin was increased with GH compared with placebo treatment (P=0.016) but remained within the upper limit of normal for all patients at endpoint. CONCLUSIONS: Adult Japanese hypopituitary patients with GHD demonstrated obesity relative to healthy Japanese subjects but the clinical presentation differed from that of Caucasian patients. GH treatment improved body composition and serum cholesterol profiles of adult Japanese hypopituitary patients with GHD.

Adult↗
PubMed2004

Intravenous administration of ghrelin stimulates growth hormone secretion in vagotomized patients as well as normal subjects.

OBJECTIVE: Ghrelin is a potent peptide stimulating GH secretion. Besides its direct action on the pituitary, ghrelin has been reported to stimulate GH release via the vagal afferent nerve in rats. To examine the involvement of vagal nerve in ghrelin-induced GH secretion in humans, GH responses to ghrelin were compared between vagotomized patients with gastrectomy and normal subjects. METHODS: Ghrelin (0.2 microg/kg) or GHRH (1 microg/kg) was administered intravenously in vagotomized patients and normal subjects on separate days, and plasma GH responses to the stimuli were examined. RESULTS: Ghrelin caused a significant plasma GH rise in both vagotomized patients and normal subjects. Peak GH levels in vagotomized patients (37.5+/-16.9 ng/ml) were not different from those in normal subjects (29.9+/-23.1 ng/ml). The areas under the curve of GH response to ghrelin did not differ between the two groups. GHRH also increased GH levels, and peak GH levels and areas under the curve after GHRH stimulation were also comparable between vagotomized patients and normal subjects. CONCLUSIONS: In the present study, the involvement of the afferent vagal nerve in ghrelin-induced GH secretion was not confirmed in humans.

Adult↗
PubMed2004

Focal myositis in monozygotic twins.

Focal myositis is a rare disease with unknown etiology and a broad spectrum. Here, we present two cases in monozygotic twins who complained of recurrent pain of their calves and showed histological signs of inflammation and MRI image compatible with the diagnosis of focal myositis. The occurrence of twin cases not living in the same household suggests a genetic susceptibility to the disease.

Adult↗
PubMed2004

Subacute bulbar palsy as the initial sign of follicular thyroid cancer.

We report a 64-year-old woman with follicular thyroid cancer found by subacute bulbar palsy. Progressive bulbar palsy (PBP) was considered the most likely diagnosis, because no abnormal finding was detected on brain CT and blood test except for the decrease of free T4. An echogram of the thyroid revealed a small nodule which was shown to be class IIb by fine needle biopsy. However, 201Tl scintillation examination showed skull base metastasis. Follicular thyroid cancer sometimes seems to manifest as a distant metastasis with no clinically evident thyroid lesion. This case suggested the importance of a detailed survey for malignancy, when subacute bulbar palsy is seen.

Acute Disease↗
PubMed2004

A variety of phenotype with R161Q germline mutation of the von Hippel-Lindau tumor suppressor gene in Japanese kindred.

Von Hippel-Lindau (VHL) syndrome is an autosomal dominant neoplastic disorder characterized by hemangioblastomas of the central nervous system and retina, renal cell carcinomas, pheochromocytoma, and islet cell tumors. This syndrome is closely related with the VHL, a tumor suppressor gene, implying that loss of function or inactivating mutations of both alleles or copies of this gene cause tumor formation. The product of the VHL gene, pVHL, is known to be a component of ubiquitin ligase which targets the transcription factor such as hypoxia-inducible factor (HIF) for degradation in the presence of oxygen. Different VHL mutations confer different site-specific risks of cancer. However, the precise role of pVHL to develop only some specified tumors, especially pheochromocytoma, is not fully understood. We identified a missense mutation of VHL gene, 695 G --> A (R161Q), in a Japanese kindred with type 2A VHL syndrome. We analysed 16 members of this family and detected the same mutation in 8 individuals. All 5 members with tumors possessed the same mutation. Interestingly, one of the identical twins, who had the same R161Q germline mutation, did not show any visible tumors throughout the body, while another of the twins developed a huge pheochromocytoma and retinal angioma. Moreover, one of the affected members in the kindred developed pancreatic neuro-endocrine tumors without pheochromocytoma in spite of possessing the identical germline mutation of the VHL gene. These findings suggest that there are some other additional factors including environmental exposures to initiate and develop tumor formation in the VHL syndrome although abnormalities of VHL gene might be involved.

Base Sequence↗
PubMed2004

Direct effects of tumor necrosis factor alpha (TNF-alpha) on L6 myotubes.

Tumor necrosis factor (TNF)-alpha is a pleiotropic cytokine responsible for a diverse range of signaling events within cells. We studied direct effects of TNF-alpha on skeletal muscle protein content. Incubation of the L6 myotubes with 1 to 10 U/ml of TNF-alpha resulted in a significant increase of total and myofibrillar protein contents as compared with the control. However, incubation with lower (0.001-0.1 U/ ml) or higher (100-300 U/ml) doses of TNF-alpha resulted in a decrease of protein content. These findings suggest that TNF-alpha may elicit both anabolic and catabolic effects on L6 myotubes in a dose dependent manner. The anabolic effect of TNF-alpha was mediated at least in part by mitogen activated protein kinase (MAPK), especially by an extracellular-regulated kinases (ERK). This divergent effect of TNF-alpha may be crucial to elucidate the complexity of TNF-alpha action on the skeletal muscle.

Anabolic Agents↗
PubMed2003

Two types of VIP neuronal components in rat suprachiasmatic nucleus.

Vasoactive intestinal peptide (VIP) neurons constitute a large group in the suprachiasmatic nucleus (SCN) and it is thought that they are involved in the generation and entrainment of circadian rhythm. We have characterized these VIP-expressing neurons in rat SCN by their ability to induce the mammalian Period1 (Per1) gene in response to light exposure, innervation of retinal afferents, day-night variations in VIP mRNA, and coexpression of gastrin releasing peptide (GRP). VIP neurons in the ventrolateral SCN (SCNVL) were subdivided into two groups, light-evoked Per1-inducible main SCNVL (SCNVLmain) and non-Per1-inducible medially located SCNVL (SCNVLmed). Retinal innervation was abundant in the SCNVLmain but nearly absent in the SCNVLmed. Day-night variation in VIP mRNA expression level was observed in the SCNVLmain but not in the SCNVLmed. GRP mRNA was seen in rarely SCNVLmed but abundant in SCNVLmain, where some neurons coexpressed VIP mRNA. These findings indicate that VIP neurons in the SCN can be divided into two topographically and functionally distinct groups.

Animals↗
PubMed2003

Diverse regulation of full-length and truncated growth hormone receptor expression in 3T3-L1 adipocytes.

Two truncated forms of growth hormone (GH) receptor (GHR), 1-277 and 1-279, were reported to be normally produced in human tissues by alternative splicing in exon 9 and its boundary. We found previously that GHR-277 exerts a dominant-negative effect on full-length GHR (GHR-fl)-mediated GH signaling causing short stature. The existence of truncated GHRs (hGHR-tr) in normal tissues suggests that hGHR-tr may play a physiological role in regulation of GH action at the cellular level. To clarify the physiological significance of GHR-tr and the regulation mechanism of GHR-tr expression, we examined the expression of mouse GHR-tr (mGHR-tr) mRNA in mouse adipocyte 3T3-L1 cells, comparing with that of mouse GHR-fl (mGHR-fl). The mRNAs of two mGHR-tr, mGHR-282 and mGHR-280, were detected by RT-PCR methods using specific primers. Although the mGHR-282 and mGHR-280 mRNA levels were approximately 100 times lower than that of mGHR-fl in mature 3T3-L1 cells, quantitative analysis by competitive RT-PCR methods revealed that the mRNA levels of mGHR-280 in 3T3-L1 cells were transiently reduced and thereafter increased during differentiation from preadipocyte to adipocyte. In contrast, the mRNA levels of mGHR-fl were increased in parallel with the progress of differentiation. Stimulation by GH of differentiated 3T3-L1 mature adipocytes resulted in dose-dependent increases of the mRNA of both mGHR-fl and mGHR-282, whereas it caused a paradoxical decrease of the mRNA of mGHR-280 stimulated by high concentration of GH. These findings suggest that the expressions of truncated mGHRs were regulated in a different manner from that of mGHR-fl, thereby modulating GH action in murine adipocytes.

3T3 Cells↗
PubMed2003

Cloning of a protein binding to the most proximal Pit-1 binding element of prolactin gene from human pituitary cDNA library.

A human pituitary cDNA library was screened using a yeast one-hybrid system to find a factor binding Pit-1 binding elements in the PRL gene other than Pit-1. Beside colonies containing Pit-1 or Oct-1 cDNA, three colonies contained mPOU cDNA, a member of the POU protein family. Immunohistochemical analysis showed mPOU-like immunoreactivity was present in human PRL-producing pituitary tumors but not in non-functioning pituitary tumors. Mobility shift analysis revealed that mPOU bound to Pit-1 binding elements of the PRL gene, 1P and 3P. mPOU activated the expression of 0.6 k PRL and 7x1P reporter genes in the presence of Pit-1 and cAMP, although it did not enhance Pit-1-induced expression of 7x3P reporter gene. These findings suggest that mPOU is involved in the activation of the PRL gene by cAMP through 1P in the presence of Pit-1.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗