Biomedical subjects

Setsuro Komiya

Publications and source records attributed to Setsuro Komiya.

At least 37 records · Page 2Linked to original sources

PubMed2004

Treatment of spinal cord injury by transplantation of fetal neural precursor cells engineered to express BMP inhibitor.

Spontaneous recovery after spinal cord injury is limited. Transplantation of neural precursor cells (NPCs) into lesioned adult rat spinal cord results in only partial functional recovery, and most transplanted cells tend to differentiate predominantly into astrocytes. In order to improve functional recovery after transplantation, it is important that transplanted neural precursor cells appropriately differentiate into cell lineages required for spinal cord regeneration. In order to modulate the fate of transplanted cells, we advocate transplanting gene-modified neural precursor cells. We demonstrate that gene modification to inhibit bone morphogenetic protein (BMP) signaling by noggin expression promoted differentiation of neural precursor cells into neurons and oligodendrocytes, in addition to astrocytes after transplantation. Furthermore, functional recovery of the recipient mice with spinal cord injury was observed when noggin-expressing neural precursor cells were transplanted. These observations suggest that gene-modified neural precursor cells that express molecules involved in cell fate modulation could improve central nervous system (CNS) regeneration.

Animals↗

PubMed2004

Long-term result of combination of open reduction and femoral derotation varus osteotomy with shortening for developmental dislocation of the hip.

This study examined femoral derotation varus osteotomy with shortening performed on children with developmental dislocation of the hip. Each patient reached 14 years of age. Surgical outcomes were evaluated clinically and roentgenographically. We studied nine patients with 11 joints undergoing surgical repair. Age at the time of operation averaged 2 years and 1 month; the period of observation averaged 15 years and 7 months; and age at final investigation averaged 17 years and 8 months. Each patient underwent the study operation as an initial treatment. Salter pelvic osteotomy was reserved as a second treatment for those patients whose acetabular development proved inadequate during post-surgical observation. The evaluation method established by McKay was utilized to determine clinical results at the time of final investigation; 73% of the study group were established as having good results. Severin's evaluation method was used to assess roentgenographical results; 45% of the study group were determined to have good results. Kalamchi's evaluation method allowed six joints to be diagnosed with avascular necrosis of the femoral head; however, in all cases but one, necrosis had been present prior to surgery. Those six joints that did not have necrosis of the femoral head prior to surgery developed only one mild necrosis subsequent to surgery. Achieving a stable reduced position by femoral derotation varus osteotomy, as well as sufficient decompression of the femoral head by shortening osteotomy, are considered to have played very important roles in preventing the femoral head from developing necrosis.

Child, Preschool↗

PubMed2004

Endogenous cannabinoids are candidates for lipid mediators of bone cement implantation syndrome.

Acute hypotension, hypoxemia, cardiac arrhythmias, cardiac arrest, (or a combination of these), and sudden death are well-recognized complications of the cemented hip arthroplasty procedure. Collectively, these are known as the bone cement implantation syndrome (BCIS). The endogenous cannabinoids, anandamide (ANA) and 2-arachidonylglycerol (2-AG), are reported to be strong vasodilators and play a role in the hypotension associated with hemorrhagic and septic shock. In the present study, a potential role for the endogenous cannabinoids in influencing hemodynamic variables in BCIS was investigated. Thirty-five patients (35 hips) entered a prospective, randomized clinical trial. The patients were divided into two groups. Group 1 comprised 16 patients who had the component inserted using a conventional cementing technique, whereas group 2 consisted of 19 patients who had the femoral component inserted without cement. Blood samples were taken at six consecutive time points: before anesthesia, after reaming the femur, 2 min after insertion of stems with or without cement into the femur, and 10 min, 20, and 30 min after stem insertion. In group 1 (with cement), the mean levels of ANA and 2-AG significantly increased after stem insertion. In a comparison of each group after stem insertion, mean ANA and 2-AG levels in group 1 also significantly differed from those in group 2. By contrast, in group 2 (without cement) neither ANA nor 2-AG levels exhibited a significant increase or change at any point in time. In conclusion, we have shown for the first time that endogenous cannabinoids are candidates for lipid mediators of BCIS.

Aged↗

PubMed2004

Clinical course of patients with ossification of the posterior longitudinal ligament: a minimum 10-year cohort study.

OBJECT: Ossification of the posterior longitudinal ligament (OPLL) may produce quadriplegia. The course of future neurological deterioration in patients with radiographic evidence of OPLL, however, is not known. The authors conducted a long-term follow-up cohort study of more than 10 years to clarify the clinical course of this disease progression. METHODS: A total of 450 patients, including 304 managed conservatively and 146 treated by surgery, were enrolled in the study. All patients underwent neurological and radiographical follow-up examinations for a mean of 17.6 years. Myelopathy was graded using Nurick classification and the Japanese Orthopaedic Association scale. Fifty-five (17%) of 323 patients without myelopathy evident at the first examination developed myelopathy during the follow-up period. Risk factors associated with the evolution of myelopathy included greater than 60% OPLL-induced stenotic compromise of the cervical canal, and increased range of motion of the cervical spine. Using Kaplan-Meier analysis, the myelopathy-free rate in patients without first-visit myelopathy was 71% after 30 years. A significant difference in final functional outcome was not observed between nonsurgical and surgical cases in which preoperative Nurick grades were 1 or 2. In patients with Nurick Grade 3 or 4 myelopathy, however, only 12% who underwent surgery eventually became wheelchair bound or bedridden compared with 89% of those managed conservatively. Surgery proved ineffective in the management of patients with Grade 5 disease. CONCLUSIONS: Results of this long-term cohort study elucidated the clinical course of OPLL following conservative or surgical management. Surgery proved effective for the management of patients with Nurick Grades 3 and 4 myelopathy.

Aged↗

PubMed2004

Gene therapy eradicating distant disseminated micro-metastases by optimal cytokine expression in the primary lesion only: novel concepts for successful cytokine gene therapy.

The most serious problem in current gene therapy is that clinical applications have often led to unsatisfactory results. Here we show novel concepts and crucial factors that have been missing for successful cytokine gene therapy. A clinically-relevant mouse model of primary and micro-metastatic osteosarcoma was generated by subcutaneously and intravenously injecting murine osteosarcoma LM8 cells, in which adenoviral gene transduction efficiencies were extremely low; current therapies remain less effective for such disseminated micro-metastases. A single injection of adenoviral vector encoding interleukin-2 gene (Ad.IL-2) was given only into the established primary tumor. Notably, antitumoral immunity was successfully elicited by IL-2 secretion from connective tissues adjacent to the primary tumor, and this immunity not only suppressed primary tumor growth but also eradicated disseminated micro-metastases in distant organs. Most importantly, not only minimal side effects but also maximal therapeutic effects were exerted only in the case of injecting the optimal (i.e., not the highest) dose of Ad.IL-2, because spleen injuries caused by excessive levels of circulating IL-2 might diminish the therapeutic effect. Although the narrow range of the optimal therapeutic expression level of IL-2 may be crucial, it was feasibly determined by serum IL-2 levels. Thus, a crucial factor for successful cytokine gene therapy is not the high gene transduction efficiency in the tumor, which has been generally recommended, but the use of the optimal therapeutic expression level. In conclusion, just a single injection of Ad.IL-2 into a primary tumor lesion, which is feasible, not invasive and cost effective, is potently therapeutic for distant disseminated micro-metastases, as long as the optimal therapeutic level is monitored. These novel concepts, which contradict those of previous studies, warn researches about the possible problems with the ongoing clinical cytokine gene therapy.

Adenoviridae↗

PubMed2003

Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy.

Rheumatoid arthritis (RA) is one of the most critical articular diseases with synovial hyperplasia followed by impairment of quality of life. However, the mechanism(s) that regulates synovial cell outgrowth is not fully understood. To clarify its mechanism(s), we carried out immunoscreening by using antirheumatoid synovial cell antibody and identified and cloned "Synoviolin/Hrd1", an E3 ubiquitin ligase. Synoviolin/Hrd1 was highly expressed in the rheumatoid synovium, and mice overexpressing this enzyme developed spontaneous arthropathy. Conversely, synoviolin/hrd1(+/-) mice were resistant to collagen-induced arthritis by enhanced apoptosis of synovial cells. We conclude that Synoviolin/Hrd1 is a novel causative factor for arthropathy by triggering synovial cell outgrowth through its antiapoptotic effects. Our findings provide a new pathogenetic model of RA and suggest that Synoviolin/Hrd1 could be targeted as a therapeutic strategy for RA.

Amino Acid Sequence↗

PubMed2003

Occupational recovery after open-door type laminoplasty for patients with ossification of the posterior longitudinal ligament.

STUDY DESIGN: A cross-sectional survey of occupational recovery after surgery with patients who had ossification of the posterior longitudinal ligament. OBJECTIVES: To evaluate occupational recovery after open-door type laminoplasty for patients with ossification of the posterior longitudinal ligament. SUMMARY OF BACKGROUND DATA: The literature contains numerous reports on the surgical results of laminoplasty for ossification of the posterior longitudinal ligament, but very few reports are available on postoperative quality of life, and even fewer on occupational recovery after laminoplasty. METHODS: A cross-sectional survey was conducted of 301 patients with ossification of the posterior longitudinal ligament in the cervical spine who were employed before open-door type laminoplasty. Presurgical occupations were classified into three categories: light sedentary labor, light standing labor, and heavy labor. High-rise workers and professional drivers were analyzed separately. The subjects were rated by occupational category for determining the occupational recovery ratio. Factors analyzed for impact on recovery were pre- and postsurgery severity of myelopathy, duration of myelopathy, age at surgery, gender, and type of ossification of the posterior longitudinal ligament. RESULTS: Of the 301 patients studied, 160 (53%) returned to work. Poor recovery rates were observed for heavy labor, high-rise workers, and professional drivers. The period required for return to work did not significantly differ among occupational categories. Occupation, presurgery severity of myelopathy, and postsurgery severity of myelopathy were significantly correlated with occupational recovery. CONCLUSION: Patients' occupations should be carefully considered when designing postsurgery occupational rehabilitation programs, and patients should receive postoperative advice regarding the suitability of occupation.

Cross-Sectional Studies↗

PubMed2003

Prognosis of patients with upper cervical lesions caused by rheumatoid arthritis: comparison of occipitocervical fusion between c1 laminectomy and nonsurgical management.

STUDY DESIGN: A matched controlled comparative study of patients with upper cervical lesions caused by rheumatoid arthritis was performed at two different hospitals to evaluate occipitocervical fusion associated with C1 laminectomy and nonsurgical treatment. OBJECTIVES: To evaluate the long-term results and advantages of occipitocervical fusion associated with C1 laminectomy, and to compare these results with those of nonsurgical management of patients with myelopathy related to rheumatoid arthritis. SUMMARY OF BACKGROUND DATA: Few studies have reported the prognosis of patients with rheumatoid arthritis managed by occipitocervical fusion associated with C1 laminectomy. METHODS: In this study, 40 patients with rheumatoid arthritis and myelopathy caused by irreducible atlantoaxial dislocation with or without upward migration of the odontoid process were studied. Of these 40 patients, 19 were treated by occipitocervical fusion using a rectangular rod associated with C1 laminectomy at one hospital, whereas 21 matched patients were treated conservatively at another hospital. The patients were observed by the same protocol to assess the radiologic and clinical results, including functional recovery and survival rate. All the patients were followed until their death. RESULTS: The atlantodental interval was reduced immediately after surgery, and this result had been well maintained at the final follow-up assessment. Redlund-Johnell values did not vary significantly throughout the course of the study. As for neural assessment with the Ranawat classification system, improvement was found in 13 (68%) of the 19 patients who underwent surgery. The survival rate was 84% 5 years after surgery, and 37% in the first 10 years. In the patients who did not undergo surgical treatment, atlantodental interval and Redlund- Johnell values were aggravated. These patients showed no neural improvement, and aggravation was found in 16 (76%) of the 21 cases during the follow-up period. All the patients were bedridden within 3 years after the onset of myelopathy. The survival rate was 0% in the first 8 years. CONCLUSIONS: The findings lead to the conclusion that occipitocervical fusion associated with C1 laminectomy for patients with rheumatoid arthritis is useful for decreasing nuchal pain, reducing myelopathy, and improving prognosis.

Adult↗

PubMed2003

Percutaneous CT-guided puncture and steroid injection for the treatment of lumbar discal cyst: a case report.

STUDY DESIGN: A case report of discal cyst treated by percutaneous CT-guided puncture and steroid injection. OBJECTIVES: To present the efficacy of percutaneous CT-guided puncture and steroid injection for the treatment of this disorder. SUMMARY OF THE BACKGROUND DATA: Surgical removal of the cyst is usually performed for the treatment of this disorder. However, it was recently reported that direct CT-guided puncture and steroid injection was useful for the treatment of intraspinal synovial cyst. METHODS: A 37-year-old man experienced low back pain and right lower extremity pain with sensory abnormality over the right leg and foot. MRI revealed an extradural spherical mass with low signal intensity on T1-weighted imaging and high signal intensity on T2-weighted imaging behind the L5 vertebral body. On discography, contrast medium rapidly flowed into the cyst through a thin channel from the neighboring disc cavity. Based on these findings, a diagnosis of discal cyst was made. Percutaneous CT-guided puncture and steroid injection were performed. RESULTS: Low back pain, right extremity pain, and numbness disappeared immediately after the procedure. On MRI examination, the cyst gradually diminished in size after the procedure. CONCLUSION: CT-guided percutaneous puncture and steroid injection may be a useful procedure for the treatment of discal cyst.

Adult↗

PubMed2003

High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine.

OBJECTIVE: High mobility group box chromosomal protein 1 (HMGB-1), a nuclear DNA binding protein, was recently rediscovered as a new proinflammatory cytokine. The purpose of this study was to demonstrate HMGB-1 expression in vivo and to identify the role of HMGB-1 in the pathogenesis of rheumatoid arthritis (RA). METHODS: HMGB-1 concentrations in synovial fluid (SF) and serum from RA and osteoarthritis (OA) patients were measured by immunoblot analysis. The protein's specific receptor, receptor for advanced glycation end products (RAGE), was examined in SF macrophages (SFMs). We measured levels of proinflammatory cytokines released by SFMs treated with HMGB-1 via enzyme-linked immunosorbent assay and used soluble RAGE (sRAGE) to block the release of tumor necrosis factor alpha (TNFalpha). Immunohistochemical analysis and immunofluorescence assay were employed to examine localization of HMGB-1 in RA synovium and its translocation in SFMs after TNFalpha stimulation. RESULTS: HMGB-1 concentrations were significantly higher in SF of RA patients than in that of OA patients. SFMs expressed RAGE and released TNFalpha, interleukin-1beta (IL-1beta), and IL-6 upon stimulation with HMGB-1. HMGB-1 was found in CD68-positive cells of RA synovium, and TNFalpha stimulation translocated HMGB-1 from the nucleus to the cytosol in SFMs. Blockade by sRAGE inhibited the release of TNFalpha from SFMs. CONCLUSION: HMGB-1 was more strongly expressed in SF of RA patients than in that of OA patients, inducing the release of proinflammatory cytokines from SFMs. HMGB-1 plays a pivotal role in the pathogenesis of RA and may be an original target of therapy as a novel cytokine.

Aged↗

PubMed2003

An optimal therapeutic expression level is crucial for suicide gene therapy for hepatic metastatic cancer in mice.

The most serious problem in current gene therapy is discrepancies between experimental data and actual clinical outcomes, which may be due to insufficient analyses and/or inappropriate animal models. We have explored suicide gene therapy by using various clinically relevant animal models and doubt the clinical use of maximal suicide gene expression, which has been generally recommended. To explore this subject further, we studied what expression level of suicide gene and what promoter led to the maximal clinical benefit in the case of hepatic metastatic cancer in mice. Therapeutic and adverse side effects of 4 adenoviral vectors that express herpes simplex virus thymidine kinase (HSV-tk) under different promoters were scrupulously investigated in 2 mouse models of hepatic metastasis of gastric cancer that possess clinical characteristics. Surprisingly, increases in HSV-tk expression beyond a certain point, achieved by the Rous sarcoma virus long terminal repeat promoter, not only enhanced the adverse side effects of lethal hepatotoxicity and ganciclovir-independent cytotoxicity but also failed to further increase therapeutic potential. Moreover, the carcinoembryonic antigen (CEA) tumor-specific promoter, the therapeutic potential of which had been underestimated, was much more useful-even in the case of low CEA-producing cancer-than had been previously reported. In conclusion, the optimal therapeutic expression level of a suicide gene is a novel concept and a crucial factor for successful cancer gene therapy. The present results, which contradict those of previous studies, alert researchers about possible problems with ongoing and future clinical trials that lack this concept.

Adenoviridae↗

PubMed2003

Age-related changes in expression of transforming growth factor-beta and receptors in cells of intervertebral discs.

OBJECT: The authors conducted a study to determine age-related changes in expression of transforming growth factor (TGF)-beta1, -beta2, -beta3, and Type I and Type II receptors in various cells in the nucleus pulposus and anulus fibrosus. Immunolocalization of TGFbetas and Type I and II receptors was examined during the aging process of cervical intervertebral discs in senescence-accelerated mice (SAM). The TGFbeta family has important roles for cellular function of various tissues. Its role in disc aging, however, is unknown. Detailed information on the temporal and spatial localization of TGFbetas and their receptors in discs is required before discussing introduction of them clinically into the intervertebral disc. METHODS: Three groups of five SAM each were used. The groups of SAM were age 8, 24, and 50 weeks, respectively. Hematoxylin and eosin staining and immunohistochemical study involving specific antibodies for TGFbeta1, -beta2, -beta3, and Types I and II TGF receptors were performed. Intervertebral discs exhibited degenerative change with advancing age. The TGFbetas and their receptors were present in the fibrocartilaginous cells within the anulus fibrosus and notochord-like cells within the nucleus pulposus of young mice. Expression of TGFbetas and Type I and Type II receptors changed markedly in the cells within the anulus fibrosus during the aging process. CONCLUSIONS: The TGFbetas and their receptors were present in cells within the nucleus pulposus and the anulus fibrosus of young mice, and their expression decreased with age.

Aging↗

PubMed2002

Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage.

Osteoarthritis is a degenerative joint disorder characterized by breakdown of articular cartilage. Degradation of aggrecan, which together with type II collagen provides cartilage with its unique characteristics of compressibility and elasticity, is an early and sustained feature of osteoarthritis. The present work was set up to identify the enzyme(s) responsible for aggrecan breakdown in osteoarthritis. We found that the two cartilage aggrecanases, ADAM-TS4 and ADAM-TS5, are present in osteoarthritic cartilage and that they are responsible for aggrecan degradation without the participation of matrix metalloproteinases. This is based on 1) neoepitopes found on aggrecan fragments in osteoarthritis (OA) cartilage explants in vitro, 2) aggrecan fragments detected in synovial fluid of OA patients, 3) the observation that an aggrecanase inhibitor, BB-16, blocked aggrecan degradation in OA cartilage in vitro, whereas the matrix metalloproteinase inhibitor XS309 did not, and 4) the presence of mRNA and protein for ADAM-TS4 and ADAM-TS5 in OA cartilage. These results suggest that ADAM-TS4 and ADAM-TS5 represent a potential target for the treatment of osteoarthritis.

ADAM Proteins↗

PubMed2002

Treatment of craniocervical spine lesion with osteogenesis imperfecta: a case report.

STUDY DESIGN: A case report of craniocervical spine lesions including basilar impression, atlantoaxial dislocation, and syringomyelia, with osteogenesis imperfecta is presented, and the literature is reviewed. OBJECTIVE: To discuss the problems involved in the surgical management of craniocervical spine lesion with osteogenesis imperfecta. SUMMARY OF BACKGROUND DATA: Osteogenesis imperfecta is known to have various spine lesions as complications. However, few reports have described craniocervical lesions associated with osteogenesis imperfecta. METHODS: A 14-year-old girl with osteogenesis imperfecta, Silence classification IVB, experienced difficulty walking, with marked motor disturbance and muscle weakness in the extremities. Deep tendon reflexes were exaggerated bilaterally in the upper and lower extremities, and positive Babinski reflex and ankle clonus were observed bilaterally. Basilar impression, atlantoaxial dislocation, and syringomyelia were shown by plain radiography, tomography, three-dimensional computed tomography, and magnetic resonance imaging. RESULTS: In the reported patient, posterior fossa decompression and atlantoaxial posterior fusion could not be performed because the foramen magnum and upper cervical spine invaginated to the base of the skull. Therefore, occipitocervical spine fusion using titanium loop and wires was performed at the reduced position of the atlantoaxial dislocation, resulting in improvement of neurologic deficits. CONCLUSIONS: For patients with atlantoaxial dislocation, syringomyelia, and basilar impression without clinical symptoms or signs of brain stem compression, occipitocervical spine fusion alone at the reduction of the atlantoaxial dislocation may be indicated because these procedures improve neurologic deficits and prevent postoperative development of basilar impression and enlargement of syringomyelia.

Adolescent↗

PubMed2002

Primary epidural hemangiopericytoma in the lumbar spine: a case report.

STUDY DESIGN: A case report of primary epidural hemangiopericytoma in the lumbar spine and a review of the literature are presented. OBJECTIVE: To present the result of pathologic diagnosis using immunohistochemical staining and the treatment of spinal hemangiopericytoma. SUMMARY OF BACKGROUND DATA: Spinal hemangiopericytoma is a very rare soft tissue tumor with specific pathologic features and a clinical course featuring high rates of recurrence and metastasis. METHODS: A 39-year-old woman reported numbness in both legs. Neither sensory abnormalities nor muscle weakness was present in her lower extremities. Magnetic resonance imaging showed a tumor dorsal to the thecal sac at L1-L2. After L1 and L2 laminectomy, the tumor with its dural base was resected en bloc. RESULTS: The patient's clinical and neurologic symptoms disappeared after surgery. Microscopic examination showed oval- or spindle-shaped cells with slightly acidic cytoplasm and oval nuclei. Silver staining emphasized fibers around tumor cells. The test results for the tumor cells were positive for vimentin staining, but negative for alpha-TM staining using thrombomodulin, a marker for endothelial cells. On the basis of these pathologic findings, the tumor was diagnosed as a hemangiopericytoma, a type of tumor composed of mesenchymal hemangiopericytes. Neither recurrence nor metastasis of the tumor was found during the 2-year follow-up period after surgery. CONCLUSIONS: Soft tissue hemangiopericytoma is a well-recognized entity considered to be an aggressive neoplasm with a high rate of recurrence and a propensity to metastasize. Immunohistochemical investigation was essential for the diagnosis of this tumor. Although hemangiopericytoma very rarely occurs in the spine, surgeons treating patients with this tumor should be aware of its metastatic potential.

Adult↗

PubMed2002

Mechanism of destructive pathologic changes in the spinal cord under chronic mechanical compression.

STUDY DESIGN: A histologic and histochemical study was performed both in the autopsy of a human patient with cervical spinal cord compression caused by ossification of the posterior longitudinal ligament and in a tiptoe-walking Yoshimura mouse model of progressive cervical cord compression. OBJECTIVES: To clarify the mechanism of destructive pathologic changes in the spinal cord under chronic mechanical compression. SUMMARY OF BACKGROUND DATA: Under chronic compression, the spinal cord exhibits destructive changes considered to be causes of profound and irreversible motor paresis. Recently, some investigators have found that apoptosis in acute spinal cord injury induces both secondary degeneration at the site of injury and chronic demyelination of tracts away from the site of injury. However, the mechanism responsible for these destructive spinal cord changes under chronic compression remains unclear. METHODS: The spinal cord was examined histologically, and an attempt was made to detect apoptotic cells using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling in both the autopsy of a human patient and tiptoe-walking mice exhibiting spinal cord compression. RESULTS: Apoptotic cells were observed in the chronically compressed spinal cord in both the autopsy of a human patient and model mice. In tiptoe-walking mice exhibiting spinal cord compression, descending degeneration in the anterior and lateral columns and ascending degeneration in the posterior column were observed. The distribution of oligodendrocytes with positive results from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling was similar to that for degeneration of the long tracts. CONCLUSIONS: Spinal cord cell apoptosis may produce destructive changes in the spinal cord under chronic compression, with a resulting irreversible neurologic deficit.

Aged↗

PubMed2002

Sortilin is upregulated during osteoblastic differentiation of mesenchymal stem cells and promotes extracellular matrix mineralization.

Osteoblasts and adipocytes are derived from a common precursor in bone marrow, the mesenchymal stem cell (MSC). Factors driving human MSCs (hMSCs) to differentiate down the two lineages play important roles in determining bone density because it has been shown that bone volume loss associated with osteoporosis and aging is accompanied by reduced osteoblastic bone formation and increased marrow adipose tissue. The genes upregulated in hMSCs during osteogenic differentiation were screened using cDNA microarrays and were semi-quantitated by real-time RT-PCR. One of the genes identified was sortilin, which was upregulated one day after osteogenic induction and remained upregulated for a week. The overexpression of sortilin in hMSCs using an adenovirus vector resulted in the acceleration of mineralization during osteogenic differentiation without affecting alkaline phosphatase activity. Lipoprotein lipase (LPL), produced by adipocytes, is bound by sortilin, which may mediate its endocytosis. By adding LPL to osteogenic induction medium, osteoblastic mineralization was inhibited in a dose-dependent manner. Interestingly, sortilin overexpression abolished the LPL-mediated suppression of osteogenic differentiation. hMSCs exist in marrow where LPL-producing adipose cells are abundant and where osteogenesis is negatively regulated by LPL. Sortilin has a counter effect of promoting osteogenesis by acting as a scavenger of LPL.

Adaptor Proteins, Vesicular Transport↗

PubMed2002

Akaike's information criterion for a measure of linkage disequilibrium.

The extent and distribution of linkage disequilibrium ( LD) in humans is a current topic especially for gene mapping of complex diseases. Akaike's information criterion ( AIC) was applied to estimate LD and compared with other standard LD measures, D' and r(2). By comparison of an independent model (IM; linkage equilibrium) and a dependent model (DM; linkage disequilibrium), the parsimonious model is the one with the smaller AIC score. Therefore, the extent of LD by AIC is expressed as AIC( IM) -- AIC( DM)( AIC( LD)). A total of 39 single-nucleotide polymorphisms on a 1.6-Mb region of chromosome 21 q22 were identified, and genotyped in 192 Japanese individuals. All possible pairs were analyzed to estimate LD and the analyses were compared. AIC( LD) became highly positive as the D' value increased and was negative at D' values of around 0.2. Because a negative value of AIC( LD) implies linkage equilibrium, D' values below 0.2 should be regarded as linkage equilibrium. The LD estimate by AIC yielded results similar to those obtained by r(2), indicating that AIC( LD) would be useful for fine gene mapping.

Algorithms↗