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Biomedical subjects

Tatsuya Kobayashi

Publications and source records attributed to Tatsuya Kobayashi.

At least 19 recordsLinked to original sources
PubMed2006

Stereotactic radiosurgery as a salvage treatment for recurrent epipharyngeal carcinoma.

Fourteen patients with recurrent epipharyngeal carcinoma (EPC) were treated by gamma knife stereotactic radiosurgery. The tumor volume ranged from 0.3 to 80 ml (median 18.9 ml). Treatment was done with a tumor margin dose of 10-27 Gy (median 15 Gy). The median follow-up period was 15 months (range 2-47 months). Ten patients were alive and 4 were dead at the end of the follow-up period. In 6 patients (43%), the tumor disappeared or decreased in size until the end of the follow-up period. In 2 (14%), the tumor remained unchanged in size. In 6 (43%), the tumor showed regression initially but was enlarged later. A second radiosurgery was performed in 4 of those 6 cases and the tumor decreased in size again in 3 of them. Thus, the overall control rate of local tumor was 79% (11/14). In selected patients with recurrent EPC, stereotactic radiosurgery can be considered as a salvage treatment producing local control.

Adult↗
PubMed2006

Stereotactic radiosurgery as a salvage treatment for recurrent skull base adenoid cystic carcinoma.

Twelve patients (15 lesions) with recurrent skull base adenoid cystic carcinoma (ACC) were treated by Gamma Knife stereotactic radiosurgery (SRS). The tumor volume ranged from 2 to 103 ml (median 15 ml). Treatment was prescribed at the 40-60% isodose line and ranged from 10 to 18 Gy (median: 13.0 Gy). The median follow-up period was 18 months (range 3-55). Six patients were alive and 6 dead at the end of the follow-up period. Only 1 patient died from local tumor recurrence. Ten among 15 tumors treated by SRS decreased in size until the end of the follow-up period or the patients' death. Three remained unchanged in size. Two tumors initially regressed but then increased in size. In selected patients with recurrent skull base ACC, SRS can be considered as a salvage treatment with good local control.

Adolescent↗
PubMed2006

Malignant lymphoma arising in the cerebral parenchyma adjacent to a parasagittal meningioma.

A 70-year-old woman with an asymptomatic parasagittal meningioma had been under observation with follow-up imaging for 2 years. She gradually developed motor weakness in the left hand. Magnetic resonance (MR) imaging disclosed a newly developed well-enhanced area in the cerebral parenchyma adjacent to the stable original meningioma. The new lesion was enhanced more intensely and less well demarcated. We suspected that the meningioma had enlarged into the brain parenchyma, although MR imaging suggested a border between the extra-axial and intra-axial portions. Craniotomy was performed. Two separate tumors were identified with quite different histological features. The extra-axial tumor was identified as benign transitional meningioma and the intra-axial tumor as diffuse large cell type malignant lymphoma. Immunostaining revealed the lymphoma had B cell origin. After surgical resection, stereotactic radiosurgery was performed for the residual lymphoma. The original site of the lymphoma remained free from relapse, but another lesion developed in the right frontal lobe 3 months later and chemotherapy was performed. The main concern for follow-up imaging of asymptomatic meningioma without surgical resection is growth of the meningioma. However, development of new different tumors is possible, although thought to be rare.

Aged↗
PubMed2005

BMP signaling stimulates cellular differentiation at multiple steps during cartilage development.

Bone morphogenetic proteins (BMPs) play important roles at multiple stages of endochondral bone formation. However, the roles of BMP signaling in chondrocytes in vivo are still contentious. In the present study, we overexpressed a constitutively active BMP receptor 1A (caBmpr1a) in chondrocytes by using two systems: caBmpr1a was directly driven by a rat type II collagen promoter in a conventional transgenic system and indirectly driven in a UAS-Gal4 binary system. CaBmpr1a expression caused shortening of the columnar layer of proliferating chondrocytes and up-regulation of maturation markers, suggesting acceleration of differentiation of proliferating chondrocytes toward hypertrophic chondrocytes. In addition to the acceleration of chondrocyte differentiation, conventional transgenic mice showed widening of cartilage elements and morphological alteration of perichondrial cells, possibly due to stimulation of differentiation of prechondrogenic cells. Moreover, bigenic expression of caBmpr1a rescued the differentiation defect of prechondrogenic cells in Bmpr1b-null phalanges. This finding indicates that BMP signaling is necessary for phalangeal prechondrogenic cells to differentiate into chondrocytes and that signaling of BMP receptor 1B in this context is replaceable by that of a constitutively active BMP receptor 1A. These results suggest that BMP signaling in prechondrogenic cells and in growth plate chondrocytes stimulates their chondrocytic differentiation and maturation toward hypertrophy, respectively.

Animals↗
PubMed2005

Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP.

In the developing growth plate, periarticular chondrocytes proliferate, differentiate into columnar chondrocytes, and then further differentiate into postmitotic hypertrophic chondrocytes. Parathyroid hormone-related (PTH-related) protein (PTHrP), regulated by Indian hedgehog (Ihh), prevents premature hypertrophic differentiation, thereby maintaining the length of columns. Ihh regulates cartilage development through PTHrP-independent pathways as well. Here we show that Ihh stimulates differentiation of periarticular to columnar chondrocytes (periarticular chondrocyte differentiation) and thereby regulates the length of columns independently of PTHrP. Mosaic ablation of the PTH/PTHrP receptor in the growth plate caused upregulation of Ihh action, PTHrP upregulation, acceleration of periarticular chondrocyte differentiation, and elongation of the columnar region. Decreasing Ihh action in these mice reduced elongation of columns, whereas decreasing PTHrP showed only a modest effect on column length. Overexpression of Ihh caused PTHrP upregulation, elongation of columns, and acceleration of periarticular chondrocyte differentiation. PTHrP heterozygosity in this model had a minimal effect on the elongation of columns. Moreover, the elongation of columns and stimulation of periarticular chondrocyte differentiation in these models were still observed when PTHrP signaling was maintained so that it remained constant. These results demonstrate that Ihh acts on periarticular chondrocytes to stimulate their differentiation, thereby regulating the columnar cell mass independently of PTHrP.

Animals↗
PubMed2005

Reduced expression of the PTH/PTHrP receptor during development of the mammary gland influences the function of the nipple during lactation.

Signaling by the parathyroid hormone/parathyroid hormone-related protein receptor (Ppr) is necessary for mammary gland development beyond the early induction stage in mice. We used a series of murine models of reduced Ppr expression to determine how diminished receptor signaling influences mammary development. Reduction of Ppr expression to very low levels prevented mammary gland development. A less-severe reduction in Ppr expression permitted progression of mammary gland development beyond the induction stage, but the nipples of these mice were dramatically smaller than those of controls, with altered epidermis and connective tissue. Mothers with reduced expression of Ppr could not successfully nurse pups; however, the lactating glands did produce milk but could not efficiently deliver it. This finding was associated with reduced levels of matrix metalloproteinase-2 and an absence of pregnancy-associated remodeling of connective tissue matrix in the nipple. Reduced smooth muscle appears to underlie the majority of nipple deficiencies in mice with lower levels of the Ppr expression.

Animals↗
PubMed2005

Connective tissue growth factor mediates the profibrotic effects of transforming growth factor-beta produced by tubular epithelial cells in response to high glucose.

BACKGROUND: It was reported that connective tissue growth factor (CTGF) was expressed in the tubular epithelial cells of the diabetic kidney. CTGF has, among other factors, been implicated in mediating the downstream, profibrotic effects of transforming growth factor-beta (TGF-beta), though is precise role in interstitial fibrogenesis in the diabetic kidney has not yet been clarified. METHODS: We employed a coculture system involving cultured murine proximal tubular epithelial cells (mProx24) and renal fibroblasts (TFB), as a model of the subepithelial mesenchyme in the kidney in order to examine the profibrotic effects of CTGF derived from mProx24 cells in response to high glucose (30 mM). RESULTS: We showed that glucose stimulated CTGF expression in cultured mProx24 in both a dose- and a time-dependent manner, and that this effect was mediated by increased levels of TGF-beta. We also found that high glucose significantly stimulated TFB cells to produce profibrotic molecules, such as type I collagen, the EIIIA isoform of fibronectin, and plasminogen activator inhibitor-1. The induction of these molecules was both direct and indirect, the latter induction being mediated by mProx24 cell-derived CTGF, which, in turn, was induced by TGF-beta that was produced by the mProx24 cells. CONCLUSIONS: CTGF plays an important role in mediating renal interstitial fibrogenesis in response to high glucose and, as such, is a reasonable target for anti-fibrotic therapy.

Animals↗
PubMed2005

Radial augmentation index: a useful and easily obtainable parameter for vascular aging.

BACKGROUND: It has been shown that the systolic augmentation index (AI) in the central arteries, including the aorta and carotid arteries, changes with age. The AI can also be obtained from the peripheral arteries. The possible usefulness of AI obtained from the radial artery as an index for vascular aging was investigated. METHODS: Radial arterial waveforms were obtained from 632 subjects with no cardiovascular disease, using radial tonometry. Radial AI was calculated as follows: (Second peak systolic blood pressure [SBP2] - diastolic blood pressure [DBP]) / (first peak SBP - DBP) x100 (%). RESULTS: Radial AI was significantly higher in women than in men (81.1% +/- 16.1% compared with 69.5% +/- 16.3%, P < .001). Radial AI was positively related to age in healthy men and women (r = 0.619, P < .001, and r = 0.644, P < .001, respectively). When comparing subjects in their 20s to those in their 70s, radial AI increased 1.56 times (from 53.2% to 83.0%) in men and 1.49 times (from 64.6% to 96.4%) in women. Multiple regression analysis showed that age is a potent predictor of radial AI in addition to gender, DBP and pulse rate. CONCLUSIONS: These findings indicate that simple and easily-obtainable radial AI is age-dependent and could be a useful index of vascular aging.

Aging↗
PubMed2005

Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34.

Mice heterozygous for targeted disruption of Pthrp exhibit, by 3 months of age, diminished bone volume and skeletal microarchitectural changes indicative of advanced osteoporosis. Impaired bone formation arising from decreased BM precursor cell recruitment and increased apoptotic death of osteoblastic cells was identified as the underlying mechanism for low bone mass. The osteoporotic phenotype was recapitulated in mice with osteoblast-specific targeted disruption of Pthrp, generated using Cre-LoxP technology, and defective bone formation was reaffirmed as the underlying etiology. Daily administration of the 1-34 amino-terminal fragment of parathyroid hormone (PTH 1-34) to Pthrp+/- mice resulted in profound improvement in all parameters of skeletal microarchitecture, surpassing the improvement observed in treated WT littermates. These findings establish a pivotal role for osteoblast-derived PTH-related protein (PTHrP) as a potent endogenous bone anabolic factor that potentiates bone formation by altering osteoblast recruitment and survival and whose level of expression in the bone microenvironment influences the therapeutic efficacy of exogenous PTH 1-34.

Animals↗
PubMed2005

Long-term outcomes in patients with vestibular schwannomas treated using gamma knife surgery: 10-year follow up.

OBJECT: Gamma knife surgery (GKS) has been a safe and effective treatment for vestibular schwannomas in both the short and long term, although less is known about long-term outcomes in the past 10 years. The aim of this study was to clarify long-term outcomes in patients with vestibular schwannomas treated using GKS based on techniques in place in the early 1990s. METHODS: Eighty patients harboring a vestibular schwannoma (excluding neurofibromatosis Type 2) were treated using GKS between May 1991 and December 1993. Among these, 73 patients were assessed; seven were lost to follow up. The median duration of follow up was 135 months. The mean patient age at the time of GKS was 56 years old. The mean tumor volume was 6.3 cm3, and the mean maximal and marginal radiation doses applied to the tumor were 28.4 and 14.6 Gy, respectively. Follow-up magnetic resonance images were obtained in 71 patients. Forty-eight patients demonstrated partial tumor remission, 14 had tumors that remained stable, and nine demonstrated tumor enlargement or radiation-induced edema requiring resection. Patients with larger tumors did not fare as well as those with smaller lesions. The actuarial 10-year progression-free survival rate was 87% overall, and 93% in patients with tumor volumes less than 10 cm3. No patient experienced malignant transformation. CONCLUSIONS: Gamma knife surgery remained an effective treatment for vestibular schwannomas for longer than 10 years. Although treatment failures usually occurred within 3 years after GKS, it is necessary to continue follow up in patients to reveal delayed tumor recurrence.

Adolescent↗
PubMed2005

Long-term results of gamma knife surgery for growth hormone-producing pituitary adenoma: is the disease difficult to cure?

OBJECT: The authors conducted a study to determine the long-term results of gamma knife surgery for residual or recurrent growth hormine (GH)-producing pituitary adenomas and to compare the results with those after treatment of other pituitary adenomas. METHODS: The series consisted of 67 patients. The mean tumor diameter was 19.2 mm and volume was 5.4 cm3. The mean maximum dose was 35.3 Gy and the mean margin dose was 18.9 Gy. The mean follow-up duration was 63.3 months (range 13-142 months). The tumor resolution rate was 2%, the response rate 68.3%, and the control rate 100%. Growth hormone normalization (GH < 1.0 ng/ml) was found in 4.8%, nearly normal (< 2.0 ng/ml) in 11.9%, significantly decreased (< 5.0 ng/ml) in 23.8%, decreased in 21.4%, unchanged in 21.4%, and increased in 16.7%. Serum insulin-like growth factor (IGF)-1 was significantly decreased (IGF-1 < 400 ng/ml) in 40.7%, decreased in 29.6%, unchanged in 18.5%, and increased in 11.1%, which was almost parallel to the GH changes. CONCLUSIONS: Gamma knife surgery was effective and safe for the control of tumors; however, normalization of GH and IGF-1 secretion was difficult to achieve in cases with large tumors and low-dose radiation. Gamma knife radiosurgery is thus indicated for small tumors after surgery or medication therapy when a relatively high-dose radiation is required.

Adenoma↗
PubMed2005

Long-term results of gamma knife surgery for the treatment of craniopharyngioma in 98 consecutive cases.

OBJECT: The authors analyzed the long-term outcomes of gamma knife surgery (GKS) for residual or recurrent craniopharyngiomas after microsurgery and the effects of dose reduction. METHODS: A total of 107 patients with craniopharyngiomas were treated with GKS at Komaki City Hospital during the past 12 years, and 98 patients were followed up for 6 to 148 months (mean 65.5 months). The mean tumor diameter and volume were 18.8 mm and 3.5 ml, respectively. These tumors were treated with a maximal dose of 21.8 Gy and a tumor margin dose of 11.5 Gy by using a mean of 4.5 isocenters. Final overall response rates were as follows: complete response 19.4%, partial response 67.4%, tumor control 79.6%, and tumor progression 20.4%. Reducing the tumor margin dose resulted in decreased therapeutic response and increased tumor progression, although the rate of visual and pituitary function loss also decreased. Among the factors examined, age (for adults) and the nature of the tumor (cystic or mixed) were statistically significant favorable and unfavorable prognostic factors, respectively. The actuarial 5- and 10-year survival rates were 94.1 and 91%, respectively. The progression-free survival rates were 60.8 and 53.8%, respectively. Patient outcomes were reportedly excellent in 45 cases, good in 23, fair in four, and poor in three; 16 patients died. Deterioration both in vision and endocrinological functions were documented as side effects in six patients (6.1%). CONCLUSIONS: Stereotactic GKS is safe and effective, in the long term, as an adjuvant or boost therapy for residual or recurrent craniopharyngiomas after surgical removal and has minimal side effects. New treatment strategies must be devised to manage these tumors.

Adolescent↗
PubMed2004

Minireview: transcriptional regulation in development of bone.

Regulation of gene expression by transcription factors is one of the major mechanisms for controlling cellular functions. Recent advances in genetic manipulation of model animals has allowed the study of the roles of various genes and their products in physiological settings and has demonstrated the importance of specific transcription factors in bone development. Three lineages of bone cells, chondrocytes, osteoblasts, and osteoclasts, develop and differentiate according to their distinct developmental programs. These cells go through multiple differentiation stages, which are often regulated by specific transcription factors. In this minireview, we will discuss selected transcription factors that have been demonstrated to critically affect bone cell development. Further study of these molecules will lead to deeper understanding in mechanisms that govern development of bone.

Amino Acid Motifs↗
PubMed2004

Chondrocyte-specific knockout of the G protein G(s)alpha leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation.

UNLABELLED: G(s)alpha is a ubiquitously expressed G protein alpha-subunit that couples receptors to adenylyl cyclase. Mice with chondrocyte-specific ablation of the G(s)alpha gene had severe epiphyseal and growth plate abnormalities and ectopic cartilage formation within the metaphyseal region of the tibia. These results show that G(s)alpha negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTH-rP receptor in growth plate chondrocytes. INTRODUCTION: G(s)alpha is a ubiquitously expressed G protein alpha-subunit that mediates signaling through G protein-coupled receptors to activate the cAMP/protein kinase A signaling pathway. Although studies suggest an important role for G(s)alpha in regulating growth plate development, direct in vivo results examining this role are lacking. MATERIALS AND METHODS: The G(s)alpha gene was ablated in murine cartilage by mating mice with loxP sites surrounding the G(s)alpha promoter and first exon with collagen 2a1 promoter-Cre recombinase transgenic mice. Skeletal tissues were studied by gross and microscopic pathology, and gene expression was determined by in situ hybridization. RESULTS AND CONCLUSIONS: Mice with complete chondrocyte-specific G(s)alpha deficiency (homozygotes) died within minutes after birth and had severe epiphyseal and growth plate defects with shortening of the proliferative zone and accelerated hypertrophic differentiation of growth plate chondrocytes, a phenotype similar to that of PTH/PTH-related peptide (PTHrP) receptor knockout mice. Indian hedgehog and PTH/PTHrP receptor expression in prehypertrophic chondrocytes was unaffected in mutant mice. PTHrP expression in periarticular cartilage was increased in the mutant mice, probably because of the closer proximity of Ihh-secreting chondrocytes to the periarticular zone. In addition, these mice developed ectopic cartilage at the anterior side of the metaphyseal region in the tibia. Mice with partial G(s)alpha deficiency (heterozygotes) exhibited no phenotype. These results show that G(s)alpha negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTHrP receptor in epiphyseal and growth plate chondrocytes.

Animals↗
PubMed2004

Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis.

Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-beta. However, its precise role in renal interstitial fibrogenesis has not yet been clarified. It was demonstrated previously that CTGF was expressed in tubular epithelial cells that had been engulfed by interstitial fibrosis in the remnant kidney of the subtotal nephrectomy (SNx) model. In the present study, co-cultures of tubular epithelial cells (mProx24) and tubulointerstitial fibroblasts (TFB) that mimic the subepithelial mesenchyme in the kidney were used to study the profibrotic effects of TGF-beta1-induced CTGF. In these co-cultures, TGF-beta1 treatment resulted in significantly increased mRNA levels of type I collagen and fibronectin in the TFB. These effects were both direct and indirect, with the latter being mediated by CTGF derived from the co-cultured mProx24. Then TGF-beta1 transgenic mice were subtotally nephrectomized and treated with CTGF antisense oligodeoxynucleotide, and their kidneys were analyzed for fibrosis. Intravenous administration of CTGF antisense oligodeoxynucleotide significantly blocked CTGF expression in the proximal tubular epithelial cells in the remnant kidney of these animals despite the sustained level of TGF-beta1 mRNA. This reduction in CTGF mRNA level paralleled a reduction in mRNA levels of matrix molecules as well as proteinase inhibitors plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase-1, suppressing renal interstitial fibrogenesis. In conclusion, tubular CTGF acts as a downstream mediator of the profibrotic effects of TGF-beta1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-beta1-dependent interstitial fibrosis.

Animals↗
PubMed2004

Angiotensin II type 1 and type 2 receptors reciprocally modulate pro-inflammatory/ pro-fibrotic reactions in activated splenic lymphocytes.

Angiotensin II (Ang II) type 1 receptor (AT1R) has been confirmed to confer renoprotection in the progressive, immune-mediated nephritis in animal models as well as in humans. However, the relative contributions of direct AT1R blockade, indirect counteractivation of Ang II type 2 receptor (AT2R), or both, to renoprotection through AT1R antagonism remains to be clarified. Immunohistochemical studies in the nephritic kidney revealed that tubular epithelial cells and infiltrating immune cells were positive for AT1R and AT2R. In the present study, we investigated the action of Ang II on both receptors on immune cells. A subpopulation of lipopolysaccharide-activated splenic lymphocytes (mixed lymphocyte populations) was positive for AT1R and AT2R. Ang II alone could not induce gene expression of a pro-inflammatory chemokine JE or a pro-fibrotic cytokine transforming growth factor-beta1 in those cells. However, Ang II could significantly suppress the expression of both genes in those cells under AT1R blockade, and this action was mediated through AT2R. Conversely, the pro-inflammatory/pro-fibrotic gene expression could be enhanced by AT2R blockade, and this was mediated through AT1R. AT1R and AT2R expressed in activated immune cells can modulate pro-inflammatory and pro-fibrotic reactions reciprocally. In advanced immune-mediated nephritic kidneys, AT1R antagonism likely confers renoprotection via activation of AT2R.

Animals↗
PubMed2004

Enantioselective total synthesis of (+)-tricycloclavulone.

The first total synthesis of (+)-tricycloclavulone having a unique tricyclo[5,3,0,01,4]decane skeleton and six chiral centers was achieved in a highly stereoselective manner. It includes a catalytic enantioselective [2+2]-cycloaddition reaction using novel chiral copper catalyst, extremely effecting an intramolecular ester transfer reaction, and asymmetric reduction of the carbonyl group on the alpha-chain using Noyori's chiral ruthenium catalyst.

Prostaglandins↗