Cancer may accelerate locomotive syndrome and deteriorate quality of life: a single-centre cross-sectional study of locomotive syndrome in cancer patients.

BACKGROUND: Thanks to recent advancement in cancer treatment, an increasing number of cancer patients are expected to live longer with cancer. The ambulatory ability is essential for cancer patients to spend their own independent lives, but locomotive syndrome (LS), a condition of reduced mobility due to impairment of locomotive organs, in cancer patients has been seldom examined. METHODS: This was a single-institutional cross-sectional study. Cancer patients receiving cancer therapy between April 2020 and March 2021 were asked to participate. LS was classified as stage 0-3, and compared with their performance status (PS). Physical component summary (PCS) and mental component summary (MCS) were calculated from the results of Short Form-8. Logistic regression analysis was performed to identify risk factors for LS stage 3. RESULTS: One hundred and seventy-six cancer patients were included. The rate of LS was 96.0%. That of LS stage 3 was 40.9% and as high as 29.7% even if limited to those with PS 0. The mean PCS and MCS were both inferior to the national averages. PCS decreased as the LS stage advanced. Old age and underweight were revealed as independent risk factors for LS stage 3. CONCLUSIONS: The ratio of LS in cancer patients was extremely high, and the LS stage correlated with physical QOL. Even those with PS 0 can have severe LS; thus, LS can be a sensitive detector of physical disability of cancer patients than PS. The improvement of LS can be a key to the preservation of their ADL and QOL.

Involvement of orthopaedic surgeons for cancer patients in orthopaedic training facilities certified by the Japanese Orthopaedic Association - A nationwide survey.

BACKGROUND: In order to improve cancer care in Japan further, it is now required for orthopaedic surgeons to get actively involved in managing locomotive organs such as bones, muscles and nerves in cancer patients. In 2018, the Japanese Orthopaedic Association (JOA) conducted a questionnaire survey to investigate the current status of cancer treatment at the orthopaedic training facilities certified by the JOA. We analyzed the results of that questionnaire survey, focusing on the data from the core hospitals for cancer care (designated cancer hospitals), to clarify the involvement of orthopaedic surgeons in cancer treatment. MATERIALS AND METHODS: A nationwide survey was conducted in the orthopaedic training facilities certified by the JOA using an online questionnaire from March 15th to 31st, 2018. To clarify the involvement of orthopaedic surgeons in cancer treatment, we analyzed the results of that questionnaire survey, focusing on the data from the designated cancer hospitals in Japan. RESULTS: From the questionnaire survey, it became clear that 24% of the orthopaedic training facilities certified by the JOA are designated cancer hospitals. There were significant differences concerning cancer treatment and the prospect of orthopaedic surgeons' involvement in the treatment for bone metastases between institutions classified according to number of both certified orthopaedic surgeons by the JOA and specialists for bone and soft tissue tumors. In addition, in 45% of the designated cancer hospitals, orthopaedic surgeons treated bone metastases that occur in cancer patients, but in the rest of the institutions, orthopaedic surgeons did not yet adequately respond. CONCLUSION: In order to further improve the locomotive function and quality of life (QOL) in cancer patients, it was seemed to be necessary that all medical professionals engaged in cancer treatment, including orthopaedic surgeons, recognize the importance of locomotive management for cancer patients. In addition, the results of this study suggested that the presence of more than six certified orthopaedic surgeons by the JOA, including one or more specialists for bone and soft tissue tumors, may be able to create an environment conducive to the involvement of orthopaedic surgeons in cancer treatment at the facility.

Accuracy and reliability of a smartphone application for measuring the knee joint angle.

[Purpose] Recently, a photo-based smartphone application for angle measurement-"Grid line imaging application Professional"-was developed to evaluate joint disease treatments. The aim of this study was to determine the accuracy and reliability of the application. [Participants and Methods] We measured the knee joint of a mannequin using an application and a universal goniometer. Twelve examiners measured eight knee joints of mannequins at different arbitrary angles using the application and a universal goniometer. Correlations between the application and universal goniometer measurements were examined using scatter plots and correlation coefficients. Systematic errors of the application were visually confirmed using the Bland-Altman method. Intra-class correlation coefficients were used to evaluate the inter-examiner reliability of the application. [Results] The application and universal goniometer measurements showed a good correlation (r=0.99) and no systematic error. The intra-class correlation coefficient for inter-examiner reliability was 0.999. Furthermore, to evaluate intra-examiner reliability, six examiners measured six different knee joints twice using the application on a 2-day interval. The intra-class correlation coefficient for intra-examiner reliability was 0.982. [Conclusion] The accuracy of the application was equivalent to that of a universal goniometer, and both the inter- and intra-examiner reliabilities of the application were almost perfect.

Three-dimensional motion analysis of lumbopelvic rhythm during lateral trunk bending.

[Purpose] To examine the variations in the lumbopelvic rhythm and lumbar-hip ratio in the frontal plane. [Subjects and Methods] Markers were placed on the T10 and T12 spinous processes, bilateral paravertebral muscles at the T11 level, the pelvis, and the femur. Lumbar spine and hip angles were measured during lateral trunk bending using three-dimensional motion analysis. Data from the trunk lateral bending movement were categorized into descending (start of hip movement to when the hip angle reached its maximum value) and ascending (from the maximum hip angle to the end of movement) phases. The lumbar-hip ratio was calculated as the ratio of the lumbar spine angle to the hip angle. [Results] The lumbar-hip ratio decreased from 5.9 to 3.6 in the descending phase, indicating lumbar spinal movement was less than hip movement. In the ascending phase, the lumbar-hip ratio was reversed. The lumbopelvic rhythm was better expressed by a cubic or quadratic function rather than a linear function. These functions indicate that when the hip inclines by 1° that the lumbar spine bends laterally by 2.4°. [Conclusion] The lumbopelvic rhythm and lumbar-hip ratio indicate lumbar lateral bending instead of a limitation of hip inclination.

Neck range of motion measurements using a new three-dimensional motion analysis system: validity and repeatability.

PURPOSE: Neck movement is important for many activities of daily living (ADL). Neck disorders, such as cervical spondylosis and whiplash can limit neck movement and ADL. The cervical range of motion (CROM) device has been recently used to measure neck range of motion (ROM); however, this measurement includes trunk motion, and therefore does not represent a pure neck ROM measurement. The authors aimed to develop a new method to establish pure neck ROM measurements during flexion, extension, lateral bending, and rotation using a three-dimensional motion analysis system, VICON. METHODS: Twelve healthy participants were recruited and neck ROMs during flexion, extension, lateral bending, and rotation were measured using VICON and the CROM device. Test-retest repeatability was assessed using interclass correlation coefficients (ICCs), standard error of measurement (SEM), and minimal detectable change (MDC). Validity between two measurements was evaluated using a determination coefficient and Pearson's correlation coefficient. RESULTS: ICCs of neck ROM measured using VICON and the CROM device were all at substantial or almost perfect levels [VICON: ICC(1,2) = 0.786-0.962, the CROM device: ICC(1,2) = 0.736-0.950]. Both SEMs and MDCs were low in all measurement directions (VICON: SEM = 1.3°-4.5°, MDC = 3.6°-12.5°; the CROM device: SEM = 2.2°-3.9°, MDC = 6.1°-10.7°). Determination coefficients (R(2)s) and Pearson's correlation coefficients (rs) between the two measurement methods were high (R(2) = 0.607-0.745, r = 0.779-0.863). CONCLUSIONS: VICON is a useful system to measure neck ROMs and evaluate the efficacy of interventions, such as surgery or physiotherapeutic exercise.

ß-catenin regulates parathyroid hormone/parathyroid hormone-related protein receptor signals and chondrocyte hypertrophy through binding to the intracellular C-terminal region of the receptor.

OBJECTIVE: To investigate the underlying mechanisms of action and functional relevance of ß-catenin in chondrocytes, by examining the role of ß-catenin as a novel protein that interacts with the intracellular C-terminal portion of the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor type 1 (PTHR-1). METHODS: The ß-catenin-PTHR-1 binding region was determined with deletion and mutagenesis analyses of the PTHR1 C-terminus, using a mammalian two-hybrid assay. Physical interactions between these 2 molecules were examined with an in situ proximity ligation assay and immunostaining. To assess the effects of gain- and loss-of-function of ß-catenin, transfection experiments were performed to induce overexpression of the constitutively active form of ß-catenin (ca-ß-catenin) and to block ß-catenin activity with small interfering RNA, in cells cotransfected with either wild-type PTHR1 or mutant forms (lacking binding to ß-catenin). Activation of the G protein α subunits G(αs) and G(αq) in the cells was determined by measurement of the intracellular cAMP accumulation and intracellular Ca(2+) concentration, while activation of canonical Wnt pathways was assessed using a TOPflash reporter assay. RESULTS: In differentiated chondrocytes, ß-catenin physically interacted and colocalized with the cell membrane-specific region of PTHR-1 (584-589). Binding of ß-catenin to PTHR-1 caused suppression of the G(αs)/cAMP pathway and enhancement of the G(αq)/Ca(2+) pathway, without affecting the canonical Wnt pathway. Inhibition of Col10a1 messenger RNA (mRNA) expression by PTH was restored by overexpression of ca-ß-catenin, even after blockade of the canonical Wnt pathway, and Col10a1 mRNA expression was further decreased by knockout of ß-catenin (via the Cre recombinase) in chondrocytes from ß-catenin-floxed mice. Mutagenesis analyses to block the binding of ß-catenin to PTHR1 caused an inhibition of chondrocyte hypertrophy markers. CONCLUSION: ß-catenin binds to the PTHR-1 C-tail and switches the downstream signaling pathway from G(αs)/cAMP to G(αq)/Ca(2+), which is a possible mechanism by which chondrocyte hypertrophy may be regulated through the PTH/PTHrP signal independent of the canonical Wnt pathway.

A genome-wide sib-pair linkage analysis of ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common musculoskeletal disease among people after middle age. The OPLL presents with serious neurological abnormalities due to compression of the spinal cord and nerve roots. The OPLL is caused by genetic and environment factors; however, its etiology and pathogenesis still remain to be elucidated. To determine the susceptibility loci for OPLL, we performed a genome-wide linkage study using 214 affected sib-pairs of Japanese. In stratification analyses for definite cervical OPLL, we found loci with suggestive linkage on 1p21, 2p22-2p24, 7q22, 16q24 and 20p12. Fine mapping using additional markers detected the highest non-parametric linkage score (3.43, P = 0.00027) at D20S894 on chromosome 20p12 in a subgroup that had no complication of diabetes mellitus. Our result would shed a new light on genetic aspects of OPLL.

A Case of Fibula Regeneration after Below-the-knee Amputation in an Adult.

We report the case of an adult with fibula regeneration after below-the-knee amputation. Fibula regeneration conventionally occurs at the donor site of children after autogenous fibula transplantation when the periosteum is preserved. However, the patient was an adult, and the regenerated fibula was 7-cm long and grew directly from the stump. A 47-year-old man was referred to the plastic surgery department owing to stump pain. He had an open comminuted fracture of the right fibula and tibia due to a traffic accident when he was 44 years old and underwent below-the-knee amputation and negative pressure wound therapy for skin defects. The patient recovered and was able to walk using a prosthetic limb. Upon radiography, the fibula was found to have regenerated 7 cm directly from the stump. Pathological examination revealed that the regenerated fibula contained normal bone tissue and neurovascular bundles in the cortex. The periosteum, mechanical stimuli with limb proteases, and negative pressure wound therapy were suspected to have accelerated bone regeneration. He had no inhibitory factors for bone regeneration, including diabetes mellitus, peripheral arterial disease, or active smoking status. After the resection of the regenerated fibula, the patient was ambulatory without further bone regeneration or pain. This case report suggests that bone regeneration may occur even in adults. The surgeon should not leave any part of the periosteum behind in patients undergoing amputation. In adult amputees complaining of stump pain, the possibility of bone regeneration may be considered.

G alpha(q) signal in osteoblasts is inhibitory to the osteoanabolic action of parathyroid hormone.

This study examined the role of the Gα(q) signal constituted by Gα(q) and Gα(11) (encoded by Gnα(q) and Gnα(11), respectively), a major intracellular pathway of parathyroid hormone (PTH), in the PTH osteoanabolic action by the gain- and loss-of-function analyses. Transgenic mice with osteoblast-specific overexpression of the constitutively active Gnα(q) gene under the control of 2.3-kb type I collagen α1 chain (Col1a1) promoter exhibited osteopenia with decreased bone formation parameters and did not respond to the daily PTH treatment. We then established osteoblast-specific Gnα(q) and Gnα(11) double-knock-out (cDKO) mice by crossing the 2.3-kb Col1a1 promoter-Cre recombinase transgenic mice and those with Gnα(q) gene flanked with loxP and global ablation of Gnα(11) (Col1a1-Cre(+/-);Gna(q)(fl/fl);Gna(11)(-/-)) and found that the cDKO and single knock-out littermates of Gnα(q) or Gnα(11) exhibited normal bone volume and turnover under physiological conditions. With a daily injection of PTH, however, the cDKO mice, but not the single knock-out mice, showed higher bone volume and turnover than the wild-type littermates. Cultures of primary osteoblasts derived from cDKO and wild-type littermates confirmed enhancement of the PTH osteoanabolic action by the Gα(q) signal deficiency in a cell-autonomous mechanism, in association with the membrane translocation of protein kinase Cδ. This enhancement was reproduced by overexpression of regulator of G protein signaling-2, a Gα(q) signal inhibitor, in osteoblastic MC3T3-E1 cells. Hence, the Gα(q) signal plays an inhibitory role in the PTH osteoanabolic action, suggesting that its suppression may lead to a novel treatment in combination with PTH against osteoporosis.

Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.

cGMP-dependent protein kinase II (cGKII; encoded by PRKG2) is a serine/threonine kinase that is critical for skeletal growth in mammals; in mice, cGKII deficiency results in dwarfism. Using radiographic analysis, we determined that this growth defect was a consequence of an elongated growth plate and impaired chondrocyte hypertrophy. To investigate the mechanism of cGKII-mediated chondrocyte hypertrophy, we performed a kinase substrate array and identified glycogen synthase kinase-3beta (GSK-3beta; encoded by Gsk3b) as a principal phosphorylation target of cGKII. In cultured mouse chondrocytes, phosphorylation-mediated inhibition of GSK-3beta was associated with enhanced hypertrophic differentiation. Furthermore, cGKII induction of chondrocyte hypertrophy was suppressed by cotransfection with a phosphorylation-deficient mutant of GSK-3beta. Analyses of mice with compound deficiencies in both protein kinases (Prkg2(-/-)Gsk3b(+/-)) demonstrated that the growth retardation and elongated growth plate associated with cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b. We found that beta-catenin levels decreased in Prkg2(-/-) mice, while overexpression of cGKII increased the accumulation and transactivation function of beta-catenin in mouse chondroprogenitor ATDC5 cells. This effect was blocked by coexpression of phosphorylation-deficient GSK-3beta. These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII.

Akt1 in murine chondrocytes controls cartilage calcification during endochondral ossification under physiologic and pathologic conditions.

OBJECTIVE: To examine the role of the phosphoinositide-dependent serine/threonine protein kinase Akt1 in chondrocytes during endochondral ossification. METHODS: Skeletal phenotypes of homozygous Akt1-deficient (Akt1(-/-)) mice and their wild-type littermates were compared in radiologic and histologic analyses. An experimental osteoarthritis (OA) model was created by surgically inducing instability in the knee joints of mice. For functional analyses, we used primary costal and articular chondrocytes from neonatal mice and mouse chondrogenic ATDC5 cells with retroviral overexpression of constitutively active Akt1 or small interfering RNA (siRNA) for Akt1. RESULTS: Among the Akt isoforms (Akt1, Akt2, and Akt3), Akt1 was the most highly expressed in chondrocytes, and the total level of Akt protein was decreased in Akt1(-/-) chondrocytes, indicating a dominant role of Akt1. Akt1(-/-) mice exhibited dwarfism with normal proliferative and hypertrophic zones but suppressed cartilage calcification in the growth plate compared with their wild-type littermates. In mice with surgically induced OA, calcified osteophyte formation, but not cartilage degradation, was prevented in the Akt1(-/-) joints. Calcification was significantly suppressed in cultures of Akt1(-/-) chondrocytes or ATDC5 cells overexpressing siRNA for Akt1 and was enhanced in ATDC5 cells overexpressing constitutively active Akt1. Neither proliferation nor hypertrophic differentiation was affected by the gain or loss of function of Akt1. The expression of ANK and nucleotide pyrophosphatase/phosphodiesterase 1, which accumulate pyrophosphate, a crucial calcification inhibitor, was enhanced by Akt1 deficiency or siRNA for Akt1 and was suppressed by constitutively active Akt1. CONCLUSION: Our findings indicate that Akt1 in chondrocytes controls cartilage calcification by inhibiting pyrophosphate during endochondral ossification in skeletal growth and during osteophyte formation in OA.

Mechanisms underlying catabolic and anabolic functions of parathyroid hormone on bone by combination of culture systems of mouse cells.

Since bone resorption and formation by continuous and intermittent parathyroid hormone (PTH) treatments involve various types of cells in bone, this study examined the underlying mechanism by combining culture systems using mouse primary calvarial osteoblasts and bone marrow cells. The PTH/PTHrP receptor (PTH1R) expression and the cAMP accumulation in response to PTH were increased in accordance with the differentiation of osteoblasts. Osteoclast formation was strongly induced by continuous PTH treatment in the monolayer co-culture of osteoblasts and bone marrow cells, which was associated with RANKL expression in differentiated osteoblasts. Bone formation determined by ALP activity and the type I collagen mRNA expression was stimulated by intermittent PTH treatment in the monolayer co-culture and in the bone marrow cell layer of the separated co-culture in a double chamber dish, but not in the culture of bone marrow cells alone. The stimulation in the separated co-culture, accompanied by IGF-I production by osteoblasts, was abolished when bone marrow cells were derived from knockout mice of insulin-receptor substrate-1 (IRS-1-/-) or when osteoblasts were from PTH1R-/- mice. We conclude that differentiated osteoblasts are most likely the direct target of both continuous and intermittent PTH, while bone marrow cells are likely the effector cells. The osteoblasts stimulated by continuous PTH express RANKL which causes osteoclastogenesis from the precursors in bone marrow via cell-to-cell contact, leading to bone resorption; while the osteoblasts stimulated by intermittent PTH secrete IGF-I which activates IRS-1 in osteoblast precursors in bone marrow via a paracrine mechanism, leading to bone formation.

[Cytokines in bone diseases. Genetic defects of PTH/PTHrP receptor in chondrodysplasia].

Parathyroid hormone-related protein (PTHrP) signaling plays important roles in regulating the differentiation of chondrocytes in endochondral bone development. PTHrP signaling functions as an inhibitory effect on chondrocyte hypertrophy which is a terminal stage of differentiation at a growth plate. Mutations of the PTH÷PTHrP receptor have been identified in Jansen metaphyseal chondrodysplasia, Blomstrand's lethal chondrodysplasia, and enchondromatosis. Furthermore, genetic manipulations of the PTHrP and its receptor genes in mice have demonstrated the critical roles of these proteins in regulating both the switch between proliferation and differentiation of chondrocytes.

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.

[Involvement of insulin and IGF-1 signaling molecules in bone metabolism].

Insulin and IGF-1 signaling is the most important factors in diabetes, but is also important regulators in bone metabolism. Insulin and IGF-1 have anabolic effects on osteoblasts in vitro and an association of diabetes with abnormal bone metabolism has been reported. Insulin receptor substrates (IRS), which is a main target molecule of insulin/IGF-1 receptor signaling, have been shown to play important roles in maintaining normal bone turn-over by skeletal analysis of IRS-1 and -2 knock-out mice. Skeletal analysis of disruptive AKT, a downstream molecule of IRS, in mice also revealed that AKT was established as a crucial regulator of osteoblasts and osteoclasts by promoting their differentiation and survival to maintain bone mass and turnover. Further analysis of molecular network in diabetes and bone metabolism will provide a basis for rational therapeutic targets for bone disorders.

[Optimization of signaling pathways for bone regeneration].

We have developed an ES cell-based monitoring system for osteogenic differentiation and identified a potent combination of osteogenic genes. ES cells were isolated from mice carrying a transgene expressing GFP driven by the 2.3 kb fragment of rat type I collagen alpha1 promoter. We have screened cDNA libraries and combinations of major osteogenesis-related genes and identified that the combination of constitutively active activin receptor-like kinase 6 (caALK6) and runt-related transcription factor 2 (Runx2) was the minimal unit that induced GFP. These combinations of genes would be a potent and ideal tool for bone regeneration.

[Parathyroid and bone. The mechanism of anabolic function of parathyroid hormone on bone].

Parathyroid hormone (PTH) has been applied to postmenopausal women and several studies revealed that intermittent PTH treatment significantly increases lumbar bone mineral density and reduces fracture risk. However, the mechanism of PTH anabolic function on bone is not fully understood yet. PTH receptors (PPR) are expressed in osteoblasts and PPR stimulates multiple intracellular signal pathways, including those mediated by cAMP-PKA signaling pathway and PLC-PKC signaling pathway. Several studies demonstrate that the PKA signaling through G-proteins in osteoblasts play important roles in regulating gene expression and osteogenesis by PTH.

Three-Dimensional Motion Analysis of Lumbopelvic Rhythm During Trunk Extension.

Hip-spine coordination, known as the lumbopelvic rhythm, can be expressed as the lumbar-hip ratio. The lumbopelvic rhythm and lumbar-hip ratio can be used to assess lower limb function. We clarified the lumbopelvic rhythm and lumbar-hip ratio during trunk extension. We established a novel set of marker positions for three-dimensional motion analysis to assess the lumbar spinal angle. The original markers were placed on both paravertebral muscle groups at the 11th thoracic spinous process level, the 10th and 12th thoracic spinous processes, and the pelvis. We measured angle data during trunk extension using three-dimensional motion analysis, and the data for eight healthy male subjects were categorized into backward and forward phases. The lumbar-hip ratio increased significantly from 1.2 to 1.9 (mean, 1.6) in the backward phase, indicating considerable movement of the lumbar spine compared with hip movement in the latter phase. In the forward phase, the ratio decreased significantly from 1.9 to 0.5 (mean, 1.5). After completion of 80% of the forward phase, the lumbar-hip ratio decreased to <1.0. The lumbopelvic rhythm for trunk extension was better expressed by a cubic or quadratic function than a linear function. According to a linear function, when the hip extends by 1°, lumbar spine extends by 1.9°. Therefore, lumbar spinal movement was greater than hip movement in the sagittal plane. The implication of the curved line would indicate lumbar extension instead of the limitation of hip extension.

Mortality-Reducing Effect of Rehabilitation for COPD: Observational Propensity-Matched Cohort Study Using a Nationwide Database.

BACKGROUND: In the course of therapy of patients with COPD, non-pharmacologic treatment, such as rehabilitation, plays an important role. Although some studies have provided concrete evidence of the effectiveness of rehabilitation in improving functional outcomes in subjects with COPD, evidence of its mortality-reducing effect has been insufficient. In the present study, we examined whether rehabilitation had positive effects on in-hospital mortality of subjects with COPD. METHODS: We used the Japanese Diagnosis Procedure Combination nationwide administrative claims database. This was a retrospective cohort study, and there were 18,037 eligible subjects with COPD from 1,055 hospitals. The main outcome was in-hospital mortality rates. A one-to-one propensity score matching method was used to compare hospital mortality rates after admission between rehabilitation and non-rehabilitation groups. RESULTS: A total of 3,356 pairs of subjects were selected from the rehabilitation and non-rehabilitation groups (n = 6,712). Subjects in the rehabilitation program showed a reduction in the odds of mortality (odds ratio = 0.80, 95% CI 0.65-1.00, P = .045). In the subgroup analyses, the rehabilitation group had a lower in-hospital mortality in the pre-obese subgroup (body mass index 25.0-29.9) than the non-rehabilitation group (P = .02). Although not significant, the rehabilitation group showed a relatively low in-hospital mortality in the Hugh-Jones dyspnea scale class 5 subgroup (P = .066). CONCLUSIONS: This large nationwide cohort study showed that rehabilitation indeed contributed to a reduction of in-hospital mortality. These findings underscore the importance of adopting rehabilitation as part of the treatment of COPD.

Insulin receptor substrate-1 is required for bone anabolic function of parathyroid hormone in mice.

Bone anabolic action of PTH has been suggested to be mediated by induction of IGF-I in osteoblasts; however, little is known about the molecular mechanism by which IGF-I leads to bone formation under the PTH stimulation. This study initially confirmed in mouse osteoblast cultures that PTH treatment increased IGF-I mRNA and protein levels and alkaline phosphatase activity, which were accompanied by phosphorylations of IGF-I receptor, insulin receptor substrate (IRS)-1 and IRS-2, essential adaptor molecules for the IGF-I signaling. To learn the involvement of IRS-1 and IRS-2 in the bone anabolic action of PTH in vivo, IRS-1-/- and IRS-2-/- mice and their respective wild-type littermates were given daily injections of PTH (80 mug/kg) or vehicle for 4 wk. In the wild-type mice, the PTH injection increased bone mineral densities of the femur, tibia, and vertebrae by 10-20% without altering the serum IGF-I level. These stimulations were similarly seen in IRS-2-/- mice; however, they were markedly suppressed in IRS-1-/- mice. Although the PTH anabolic effects were stronger on trabecular bones than on cortical bones, the stimulations on both bones were blocked in IRS-1-/- mice but not in IRS-2-/- mice. Histomorphometric and biochemical analyses showed an increased bone turnover by PTH, which was also blunted by the IRS-1 deficiency, though not by the IRS-2 deficiency. These results indicate that the PTH bone anabolic action is mediated by the activation of IRS-1, but not IRS-2, as a downstream signaling of IGF-I that acts locally as an autocrine/paracrine factor.