Search PubMed⌕ Search

Biomedical subjects

Kozo Nakamura

Publications and source records attributed to Kozo Nakamura.

At least 127 records · Page 7Linked to original sources
PubMed2003

Suppression of arthritic bone destruction by adenovirus-mediated dominant-negative Ras gene transfer to synoviocytes and osteoclasts.

OBJECTIVE: To determine the role of Ras-mediated signaling pathways in synovial cell activation and bone destruction in arthritic joints. METHODS: The E11 rheumatoid synovial cell line and primary synovial fibroblast-like cells (SFCs) from patients with rheumatoid arthritis (RA) were gene-transferred by replication-deficient adenovirus vector carrying the dominant-negative mutant of the ras gene (AxRasDN). The effects of RasDN overexpression on cellular proliferation, interleukin-1 (IL-1)-induced activation of mitogen-activated protein kinases (extracellular signal-regulated kinase [ERK], p38, c-Jun N-terminal kinase [JNK]), and IL-6 production by synovial cells were analyzed. The in vivo effects of Ras inhibition on synovial cell activation and arthritic bone destruction were analyzed by injection of AxRasDN into ankle joints of rats with adjuvant arthritis. RESULTS: AxRasDN markedly reduced the proliferation of RA SFCs. IL-1, a proinflammatory cytokine involved in RA pathology, induced activation of ERK, p38, and JNK in the cells. Adenovirus vector-mediated RasDN overexpression suppressed ERK activation, but not p38 or JNK activation, in SFCs. IL-6 is also an important proinflammatory cytokine, and RasDN inhibited IL-1-induced production of IL-6 by RA SFCs at both the transcriptional and protein levels. Injection of AxRasDN into ankle joints of rats with adjuvant arthritis ameliorated inflammation and suppressed bone destruction in the affected joints. CONCLUSION: Ras-mediated signaling pathways are involved in the activation of RA SFCs and the destruction of bone in arthritic joints, suggesting that inhibition of Ras signaling can be a novel approach for RA treatment that targets both synovial cell activation and bone destruction in the RA joint.

Adenoviridae↗
PubMed2003

Contribution of membrane-associated prostaglandin E2 synthase to bone resorption.

This study initially confirmed that, among prostaglandins (PGs) produced in bone, only PGE(2) has the potency to stimulate osteoclastogenesis and bone resorption in the mouse coculture system of osteoblasts and bone marrow cells. For the PGE(2) biosynthesis two isoforms of the terminal and specific enzymes, membrane-associated PGE(2) synthase (mPGES) and cytosolic PGES (cPGES) have recently been identified. In cultured mouse primary osteoblasts, both mPGES and cyclooxygenase-2 were induced by the bone resorptive cytokines interleukin-1, tumor necrosis factor-alpha, and fibroblast growth factor-2. Induction of mPGES was also seen in the mouse long bone and bone marrow in vivo by intraperitoneal injection of lipopolysaccharide. In contrast, cPGES was expressed constitutively both in vitro and in vivo without being affected by these stimuli. An antisense oligonucleotide blocking mPGES expression inhibited not only PGE(2) production, but also osteoclastogenesis and bone resorption stimulated by the cytokines, which was reversed by addition of exogenous PGE(2). We therefore conclude that mPGES, which is induced by and mediates the effects of bone resorptive stimuli, may make a target molecule for the treatment of bone resorptive disorders.

Animals↗
PubMed2003

Cervical myelopathy in an adult due to atlantoaxial subluxation associated with Down syndrome: a case study.

Atlantoaxial subluxation resulting in cervical myelopathy in patients with Down syndrome has been well documented. The risk of cervical myelopathy is reported to decrease with age, and reports of adult-onset cases are limited. We report an adult patient with Down syndrome who developed cervical myelopathy and was successfully treated by surgery. Because there is little information on this condition with adult onset, we report the features of the radiographic findings. Particular care over the long term should be taken in those who have atlantoaxial subluxation combined with odontoid hypoplasia or accessory ossicles, as they are at particular risk of cervical myelopathy even during adulthood.

Adult↗
PubMed2003

Correction of tibial deformity in adults.

This report from five hospitals in Japan describes the results of correcting adult tibial deformities using external fixation. There were 49 patients with 59 lower limb deformities, with trauma being the most common cause of the deformity. Varus angulation was the most common deformity, and the most common magnitude was 11 degrees -30 degrees. Twenty-two patients had a leg-length discrepancy. The aim of the correction was to normalize both the mechanical axis and the inclination of the knee and ankle joints. In 63% of the patients corrections were performed gradually during bone lengthening or acutely after bone lengthening. Altogether, 71% of the patients were completely corrected, and no leg-length discrepancies remained after correction in 47%. Complications were encountered in 22 patients, about half of which were pin tract infections, 28% refractures, and the remainder delayed consolidation or fixator failure. There were no neurological or circulatory complications. The average fixation duration was 9 months. The average hospital charges were 3,740,000 yen in bilateral correction patients and 1,940,000 yen in unilateral correction patients. External fixation can correct not only the mechanical axis and joint inclination but also leg-length discrepancy simultaneously.

Adolescent↗
PubMed2003

Polyion complex micelles from plasmid DNA and poly(ethylene glycol)-poly(L-lysine) block copolymer as serum-tolerable polyplex system: physicochemical properties of micelles relevant to gene transfection efficiency.

Polyion complex (PIC) micelles composed of the poly(ethylene glycol)-poly(L-lysine) (PEG-PLL) block copolymer and plasmid DNA (pDNA) were investigated in this study from a physicochemical viewpoint to get insight into the structural feature of the PIC micellar vector system to show practical gene transfection efficacy particularly under serum-containing medium. The residual ratio (r) of the lysine units in PEG-PLL to the phosphate units of pDNA in the system significantly affects the size of the PIC micelles evaluated from dynamic light scattering, being decreased from approximately 120 to 80 nm with an increase in the r value for the region with r > or = 1.0. The zeta potential of the complexes slightly increased with r in the same region, yet maintained a very small absolute value and leveled off to a few mV at r approximately 2.0. These results suggest that the micelles are most likely to take the core-shell structure with dense PEG palisades surrounding the PIC core to compartmentalize the condensed pDNA. Furthermore, an increasing r value in the region of r > or = 1 induces a rearrangement of the stoichiometric complex formed at r=1.0 to the non-stoichiometric complex composed of the excess block copolymer. The association number of pDNA and the block copolymer in the micelle was estimated from the apparent micellar molecular weight determined by static light scattering measurements, indicating that a single pDNA molecule was incorporated in each of the micelles prepared from the PEG (Mw=12,000 g/mol)-PLL (polymerization degree of PLL segment: 48) (12-48) block copolymer at r=2.0. These 12-48/pDNA micelles showed a gene expression comparable to the lipofection toward cultured 293 cells, though 100 microM chloroquine was required in the transfection medium. Notably, even in the presence of serum, the PIC micelles achieved appreciable cellular association to attain a high gene expression, which is in sharp contrast with the drastic decrease in the gene expression for lipoplex system in the presence of serum. A virus-comparable size (approximately 100 nm) with a serum-tolerable property of the PIC micelles indeed suggests their promising feasibility as non-viral gene-vector systems used for clinical gene therapy.

Biocompatible Materials↗
PubMed2003

The use of stereolithography for an unusual patellofemoral disorder.

A patient with habitual patellar dislocation which was not treated successfully by the Elmslie-Trillat procedure is described. In the knee, a unique morphologic feature of the patellofemoral joint was suspected as a cause, and a stereolithographic model was produced from the patient's computed tomography data to determine the pathologic features. Because the solid model confirmed the speculation, additional surgery was done to modify the geometry of the joint. In the surgery, cancellous bone was removed below the cartilage, and the geometry of the cartilage was modified with the subchondral bone, taking advantage of the elasticity of the bone and cartilage. The second surgery eliminated maltracking of the patella and a satisfactory result was obtained. Therefore, stereolithography is useful for the treatment of atypical patellofemoral disorders, allowing an understanding of the pathologic features and dynamic simulation of the surgery. The surgical procedure could be a promising method to alter the joint geometry without impairing the cartilage.

Adult↗
PubMed2003

Image-guided resection for thoracic ossification of the ligamentum flavum.

OBJECT: The purpose of this study was to evaluate the advantages of using an image guidance system to aid in the resection of ossified of the ligamentum flavum (OLF) in the thoracic spine. The procedure and surgery-related outcome are discussed. METHODS: Ten patients with myelopathy underwent laminotomy with medial facetectomy and an image guidance system was used to remove the OLF. No neurological deterioration occurred, and postoperative computerized tomography scanning demonstrated successful decompression and good preservation of the lateral parts of the facet joints. CONCLUSIONS: The image guidance system allows accurate resection of the OLF while preserving as much as possible the facet joints and posterior elements of the thoracic spine.

Adult↗
PubMed2002

Chondrosarcoma of the hand secondary to multiple enchondromatosis; report of two cases.

Although malignant transformation to chondrosarcoma may occur in some patients with multiple enchondromatosis, this event rarely occurs in the hand. We encountered two patients with chondrosarcoma of the hand secondary to multiple enchondromatosis. One patient was a 27-year-old man and the other, a 76-year-old man. Both patients manifested multiple osteolytic lesions in the hand on the plain radiographs. Severe bone destruction associated with a large soft-tissue swelling of the proximal and middle phalanges of the little finger was seen in case 1. In case 2, tremendous expansion and bone destruction of the middle phalanx of the ring finger was seen. Magnetic resonance images of the tumour in both patients showed low signal intensity on T1-weighted and high signal intensity on T2-weighted images. Amputation was performed in each patient. Histological examination revealed that the tumour was a grade 2 chondrosarcoma in case 1 and a grade 1 chondrosarcoma in case 2 accompanied by enchondromata. From these findings, the diagnosis of chondrosarcoma secondary to multiple enchondromatosis was made. Because quite a few patients with multiple enchondromatosis develop secondary chondrosarcoma, although rarely in the hand, the enchondromata should be curetted, unless impractical, before malignant transformation occurs.

Adult↗
PubMed2002

Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia.

Mutations in the gene encoding cartilage oligomeric matrix protein ( COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). More than 40 mutations have been identified; however, genotype-phenotype relationships are not well delineated. Further, mutations other than in-frame insertion/deletions and substitutions have not been found, and currently known mutations are clustered within relatively small regions. Here we report the identification of nine novel and three recurrent COMP mutations in PSACH and MED patients. These include two novel types of mutations; the first, a gross deletion spanning an exon-intron junction, causes an exon deletion. The second, a frameshift mutation that results in a truncation of the C-terminal domain, is the first known truncating mutation in the COMP gene. The remaining mutations, other than a novel exon 18 mutation, affected highly conserved aspartate or cysteine residues in the calmodulin-like repeat (CLR) region. Genotype-phenotype analysis revealed a correlation between the position and type of mutations and the severity of short stature. Mutations in the seventh CLR produced more severe short stature compared with mutations elsewhere in the CLRs ( P=0.0003) and elsewhere in the COMP gene ( P=0.0007). Patients carrying mutations within the five-aspartates repeat (aa 469-473) in the seventh CLR were extremely short (below -6 SD). Patients with deletion mutations were significantly shorter than those with substitution mutations ( P=0.0024). These findings expand the mutation spectrum of the COMP gene and highlight genotype-phenotype relationships, facilitating improved genetic diagnosis and analysis of COMP function in humans.

Achondroplasia↗
PubMed2002

Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts.

Insulin receptor substrates (IRS-1 and IRS-2) are essential for intracellular signaling by insulin and insulin-like growth factor-I (IGF-I), anabolic regulators of bone metabolism. Although mice lacking the IRS-2 gene (IRS-2-/- mice) developed normally, they exhibited osteopenia with decreased bone formation and increased bone resorption. Cultured IRS-2-/- osteoblasts showed reduced differentiation and matrix synthesis compared with wild-type osteoblasts. However, they showed increased receptor activator of nuclear factor kappaB ligand (RANKL) expression and osteoclastogenesis in the coculture with bone marrow cells, which were restored by reintroduction of IRS-2 using an adenovirus vector. Although IRS-2 was expressed and phosphorylated by insulin and IGF-I in both osteoblasts and osteoclastic cells, cultures in the absence of osteoblasts revealed that intrinsic IRS-2 signaling in osteoclastic cells was not important for their differentiation, function, or survival. It is concluded that IRS-2 deficiency in osteoblasts causes osteopenia through impaired anabolic function and enhanced supporting ability of osteoclastogenesis. We propose that IRS-2 is needed to maintain the predominance of bone formation over bone resorption, whereas IRS-1 maintains bone turnover, as we previously reported; the integration of these two signalings causes a potent bone anabolic action by insulin and IGF-I.

Animals↗
PubMed2002

Intracortical chondromyxoid fibroma of humerus.

The clinicoradiologic and pathologic aspects of an intracortical, diaphyseal chondromyxoid fibroma of the humerus are reported. Because of the location of the lesion, the possibility of chondromyxoid fibroma was not considered radiologically. The diagnosis was made only after histologic examination of tissue obtained via an open biopsy, which led to the appropriate treatment, surgical curettage.

Adult↗
PubMed2002

Identification and characterization of the human long form of Sox5 (L-SOX5) gene.

The Sox (Sry-type HMG box) group of transcription factors, which is defined by a high-mobility group (HMG) DNA-binding domain, is categorized into six subfamilies. Sox5 and Sox6 belong to the group D subfamily, which is characterized by conserved N-terminal domains including a leucine-zipper, a coiled-coil domain and a Q-box. Group D Sox genes are expressed as long and short transcripts that exhibit differential expression patterns. In mouse, the long form of Sox5, L-Sox5, is co-expressed and interacts with Sox6; together, these two proteins appear to play a key role in chondrogenesis and myogenesis. In humans, however, only the short form of Sox5 has previously been identified. To gain insight into Sox5 function, we have identified and characterized human L-SOX5. The human L-SOX5 cDNA encodes a 763-amino-acid protein that is 416 residues longer than the short form and contains all of the characteristic motifs of group D Sox proteins. The predicted L-SOX5 protein shares 97% amino acid identity with its mouse counterpart and 59% identity with human SOX6. The L-SOX5 gene contains 18 exons and shows similar genomic structure to SOX6. We have identified two transcription start sites in L-SOX5 and multiple alternatively spliced mRNA variants that are distinct from the short form. Unlike the short form, which shows testis-specific expression, L-SOX5 is expressed in multiple tissues. Like SOX6, L-SOX5 shows strong expression in chondrocytes and striated muscles, indicating a likely role in human cartilage and muscle development.

Alternative Splicing↗
PubMed2002

Association of bone metabolism regulatory factor gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity.

STUDY DESIGN: A case-control association study and a stratified study investigating the genetic etiology for ossification of the posterior longitudinal ligament of the spine. OBJECTIVE: To determine the association of restriction fragment length polymorphisms of estrogen receptor, vitamin D receptor, parathyroid hormone, and interleukin-1alpha and -1beta with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity. SUMMARY OF BACKGROUND DATA: Contribution of genetic backgrounds to the etiology for ossification of the posterior longitudinal ligament of the spine has been suggested by epidemiologic studies. METHODS: Genomic deoxyribonucleic acid samples obtained from 120 patients (77 men and 43 women) with ossification of the posterior longitudinal ligament of the spine and 306 control subjects without the disorder (166 men and 140 women) were amplified by polymerase chain reaction, and polymorphism genotypes were determined by restriction endonuclease digestion. The distribution of genotypes was compared between patients with the disorder and control subjects. In addition, the severity of ossification was determined by the number of ossified vertebrae in patients with the disorder, and associations of the severity with age, gender, and genotypes were examined. RESULTS: Estrogen receptor (P = 0.007) and interleukin-1beta (P = 0.001) polymorphisms exhibited different distributions between patients with ossification of the posterior longitudinal ligament of the spine and control subjects in women, but not in men. In patients with the disorder, the severity of ossification was negatively correlated with age in women (P = 0.013), but not in men. Estrogen receptor polymorphism was associated with the severity only in women (P = 0.001). CONCLUSIONS: The contribution of genetic backgrounds is likely to be stronger in women than in men with ossification of the posterior longitudinal ligament of the spine. Estrogen receptor polymorphism was associated with both initiation and promotion of the disorder, but interleukin-1beta polymorphism was associated only with its initiation in women.

Adult↗
PubMed2002

IL-1 regulates cytoskeletal organization in osteoclasts via TNF receptor-associated factor 6/c-Src complex.

Targeted disruption of either c-Src or TNFR-associated factor 6 (TRAF6) in mice causes osteoclast dysfunction and an osteopetrotic phenotype, suggesting that both molecules play important roles in osteoclastic bone resorption. We previously demonstrated that IL-1 induces actin ring formation and osteoclast activation. In this study, we examined the relationship between IL-1/TRAF6-dependent and c-Src-mediated pathways in the activation of osteoclast-like cells (prefusion cells (pOCs); multinucleated cells) formed in the murine coculture system. In normal pOCs, IL-1 induces actin ring formation and tyrosine phosphorylation of p130(Cas), a known substrate of c-Src. However, in Src-deficient pOCs, p130(Cas) was not tyrosine phosphorylated following IL-1 treatment. In normal pOCs treated with IL-1, anti-TRAF6 Abs coprecipitate p130(Cas), protein tyrosine kinase 2, and c-Src. In Src-deficient pOCs, this molecular complex was not detected, suggesting that c-Src is required for formation of the TRAF6, p130(Cas), and protein tyrosine kinase 2 complex. Moreover, an immunocytochemical analysis revealed that in osteoclast-like multinucleated cells, IL-1 induced redistribution of TRAF6 to actin ring structures formed at the cell periphery, where TRAF6 also colocalized with c-Src. Taken together, these data suggest that IL-1 signals feed into the tyrosine kinase pathways through a TRAF6-Src molecular complex, which regulates the cytoskeletal reorganization essential for osteoclast activation.

Actins↗
PubMed2002

p53AIP1 regulates the mitochondrial apoptotic pathway.

We identified recently the p53AIP1 gene, a novel p53 target that mediates p53-dependent apoptosis. In the experiments reported here, ectopic expression of p53AIP1 induced down-regulation of mitochondrial DeltaPsim and release of cytochrome c from mitochondria in human cells. Immunoprecipitation and immunostaining experiments indicated interaction between p53AIP1 and bcl-2 proteins at mitochondria. Overexpression of bcl-2 blocked the down-regulation of mitochondrial DeltaPsim and the proapoptotic activity of p53AIP1. Our results implicate p53AIP1 as a pivotal mediator of the p53-dependent mitochondrial apoptotic pathway.

Animals↗
PubMed2002

Long-term results of operative treatment for cervical spondylotic myelopathy in patients with athetoid cerebral palsy: an over 10-year follow-up study.

STUDY DESIGN: A retrospective radiographic and medical record analysis of patients followed for more than 10 years after operative treatment for cervical spondylotic myelopathy complicating athetoid cerebral palsy. OBJECTIVE: To describe the incidence of late neurologic deterioration and spinal deformity after operative treatment for cervical spondylotic myelopathy in athetoid cerebral palsy. SUMMARY OF BACKGROUND DATA: The possibility of recurrence of symptoms after operative treatment for cervical spondylotic myelopathy seems greater in patients with athetoid cerebral palsy because of their involuntary neck movements. Although there are several reports of surgical results, long-term follow-up studies are very rare. METHODS: Ten patients with athetoid cerebral palsy were evaluated over an average of 15 years after anterior decompression (corpectomy) and fusion (three patients), laminectomy (one patient), and laminoplasty (six patients, four with accompanying posterior fusion). They averaged 45 years of age at surgery. Surgical results were assessed using Kurokawa's method. Late neurologic deterioration was based on decrement in the JOA score, and the evolution of kyphosis or instability of the cervical spine was observed radiographically. RESULTS: Surgical results at the most improved period were good or excellent in all 10 patients. Eight showed late neurologic deterioration, however, and six of them deteriorated from 8 to 13 years after surgery, largely because of progressive deformity. CONCLUSIONS: Long-term follow-up evaluation is essential in any type of operation, particularly with patients with athetoid cerebral palsy who often undergo this operation in their 30s or 40s.

Adult↗