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OBJECTIVE: This study investigated the effectiveness of treatment with Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) assessed by ultrasonography (US) activity, and the influence of patient characteristics and previous treatments. METHOD: This prospective study assessed 60 treatment initiations among 53 Japanese patients diagnosed with RA who underwent treatment with JAK inhibitors during June 2013 to February 2020. Of the 53 patients, seven patients were enrolled in duplicate because they were treated with two different JAK inhibitors at different periods. For each case, the improvement rate on the power Doppler (PD) score was assessed at 6 month follow-up. Median improvement rate of PD score was used to classify cases as either US responders or non-responders, and patient characteristics were compared between the two groups. RESULTS: All indicators of clinical disease activity and US activity showed a significant improvement at 3 months compared with baseline. Although the JAK inhibitor-cycler group and the interleukin-6 (IL-6) inhibitor inadequate response (IR) group tended to show a later improvement for US activity, all indicators of clinical disease activity and US activity showed a significant improvement at 6 months compared with baseline for both groups. Multivariate analysis showed that concomitant methotrexate use and an IR to the previous biologic or targeted-synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) treatment were independently and significantly associated with US responders. CONCLUSION: Use of a JAK inhibitor in combination with methotrexate and an absence of IR to any previous b/tsDMARDs demonstrated superior effectiveness for patients with RA.
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Antirreumáticos , Artritis Reumatoide , Inhibidores de las Cinasas Janus , Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/tratamiento farmacológico , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Japón , Metotrexato/uso terapéutico , Estudios Prospectivos , Resultado del Tratamiento , UltrasonografíaRESUMEN
BACKGROUND: Polymyositis/dermatomyositis (PM/DM) is an autoimmune disease that is sometimes complicated with rapidly progressive interstitial lung disease (RPILD). However, serum and lung biomarkers that can predict RPILD development remain unclear. OBJECTIVES: To determine potential serum and lung biomarkers that can predict RPILD development in patients with PM/DM-ILD. METHODS: In total, 49 patients with PM/DM-ILD were enrolled. We measured the serum levels of 41 cytokines/chemokines, ferritin and anti-MDA5 antibody, compared them between the RPILD (n = 23) and non-RPILD (n = 26) groups, and ranked them by their importance through random forest analysis. To distinguish the two groups, we determined biomarker combinations by logistic regression analysis. We also measured the bronchoalveolar lavage fluid (BALF) levels of 41 cytokines/chemokines. Using immunohistochemistry, we examined IL-15 expression in lung tissues. The IL-15 production was also investigated using A549 and BEAS-2B cells. RESULTS: The RPILD group had significantly higher IL-15, IL-1RA, IL-6, CXCL10, VCAM-1, anti-MDA5 antibody and ferritin serum levels than the non-RPILD group, but it had a significantly low CCL22 level. Meanwhile, anti-MDA5 antibody, IL-15, CXCL8, CCL22, IL-1RA and ferritin were the best combination to distinguish the two groups. IL-15 and CCL22 were also predictive marker for RPILD development in anti-MDA5 antibody-positive patients. Additionally, the RPILD group had significantly high IL-15 levels in BALF. The lung tissues expressed IL-15, which increased after cytokine stimulation in the A549 cells. CONCLUSION: This study identified a combination of biomarkers predicting PM/DM-RPILD progression, and IL-15 is an important cytokine for predicting RPILD development and reflecting ILD severity.
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Dermatomiositis/complicaciones , Interleucina-15/inmunología , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/inmunología , Biomarcadores , Líquido del Lavado Bronquioalveolar/química , Quimiocinas/inmunología , Citocinas/inmunología , Progresión de la Enfermedad , Femenino , Ferritinas/inmunología , Humanos , Japón , MasculinoRESUMEN
Objectives: Using multicentre ultrasound (US) cohort data among patients with rheumatoid arthritis (RA), we aimed to identify baseline factors that permit differentiation between two patient cohorts achieving US remission and clinical remission, and to determine the factors contributing to the discrepancy.Method: We reviewed 248 Japanese patients diagnosed with RA who underwent treatment with biological disease-modifying anti-rheumatic drugs at 13 centres. We performed US assessments of the synovia of 22 joints. We assessed the percentages of patients with clinical remission and US remission, defined as total power Doppler scores of 0 at 12 months.Results: The 87 patients who achieved US remission were divided into a group that achieved both clinical and US remission (n = 53) and a group that achieved US remission only (n = 34). Baseline factors that were significantly and independently associated with clinical remission at 12 months among patients who also achieved US remission included short disease duration, the presence of concomitant methotrexate use, and low patient global assessment score (p < 0.05, p < 0.05, and p < 0.005, respectively).Conclusions: RA patients with baseline high patient global assessment scores and long disease duration at baseline were unlikely to achieve clinical remission even after achieving US remission. Objective joint assessments using US provide additional information of potential importance for the management of RA.
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Artritis Reumatoide , Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/tratamiento farmacológico , Estudios de Cohortes , Humanos , Japón , Inducción de Remisión , Resultado del Tratamiento , UltrasonografíaRESUMEN
Objective: To determine whether the positivity of baseline anti-Ro/Sjögren's syndrome antigen A (SSA) antibodies influences the response to abatacept, we compared therapeutic responses between anti-Ro/SSA antibody-negative and -positive patients with rheumatoid arthritis (RA) using a multicentre RA ultrasonography prospective cohort. Method: We reviewed Japanese patients with RA who started abatacept as the first biological disease-modifying anti-rheumatic drug between June 2013 and April 2018. We assessed 28-joint Disease Activity Score-erythrocyte sedimentation rate (DAS28-ESR) change between baseline and 6 or 12 months after treatment in RA patients treated with abatacept, and European League Against Rheumatism (EULAR) response at 6 and 12 months. The Global OMERACT-EULAR Synovitis Score (GLOESS) was calculated at baseline and at 6 and 12 months. Results: Overall, 51 patients were enrolled and divided into anti-Ro/SSA antibody-negative and -positive groups of 35 and 16, respectively. Median age at baseline was significantly higher in the anti-Ro/SSA antibody-negative group (p = 0.04). The retention rate and percentage of EULAR good responders at 12 months were significantly higher in the anti-Ro/SSA antibody-negative group (both p = 0.02). Anti-Ro/SSA antibody-negative patients exhibited larger decreases in both DAS28-ESR and DAS28-C-reactive protein at 12 months than anti-Ro/SSA antibody-positive patients (p = 0.02 and 0.04, respectively). GLOESS decreased significantly at 6 months in anti-Ro/SSA antibody-negative patients (p = 0.03). Multivariate analyses showed that anti-Ro/SSA antibody positivity was an independent factor associated with change in the DAS28-ESR at 6 months (p < 0.05). Conclusion: Anti-Ro/SSA antibody positivity predicts a poor response to abatacept and low retention rate.
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Abatacept/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Autoantígenos/inmunología , ARN Citoplasmático Pequeño/inmunología , Ribonucleoproteínas/inmunología , Anciano , Artritis Reumatoide/inmunología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment.Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation.Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months.Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.
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Abatacept/administración & dosificación , Anticuerpos Antiproteína Citrulinada/sangre , Artritis Reumatoide/inmunología , Anciano , Anticuerpos Antiproteína Citrulinada/inmunología , Antirreumáticos/administración & dosificación , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Biomarcadores/sangre , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Japón , Masculino , Estudios Prospectivos , Resultado del Tratamiento , UltrasonografíaRESUMEN
Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease that is caused by heterozygous mutations in the TNFRSF1A gene. Although more than 150 TNFRSF1A mutations have been reported to be associated with TRAPS phenotypes only a few, such as p.Thr79Met (T79M) and cysteine mutations, have been functionally analyzed. We identified two TRAPS patients in one family harboring a novel p.Gly87Val (G87V) mutation in addition to a p.Thr90Ile (T90I) mutation in TNFRSF1A. In this study, we examined the functional features of this novel G87V mutation. In-vitro analyses using mutant TNF receptor 1 (TNF-R1)-over-expressing cells demonstrated that this mutation alters the expression and function of TNF-R1 similar to that with the previously identified pathogenic T79M mutation. Specifically, cell surface expression of the mutant TNF-R1 in transfected cells was inhibited with both G87V and T79M mutations, whereas the T90I mutation did not affect this. Moreover, peripheral blood mononuclear cells (PBMCs) from TRAPS patients harboring the G87V and T90I mutations showed increased mitochondrial reactive oxygen species (ROS). Furthermore, the effect of various Toll-like receptor (TLR) ligands on inflammatory responses was explored, revealing that PBMCs from TRAPS patients are hyper-responsive to TLR-2 and TLR-4 ligands and that interleukin (IL)-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) are likely to be involved in the pathogenesis of TRAPS. These findings suggest that the newly identified G87V mutation is one of the causative mutations of TRAPS. Our findings based on unique TRAPS-associated mutations provide novel insight for clearer understanding of inflammatory responses, which would be basic findings of developing a new therapeutic and prophylactic approach to TRAPS.
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Fiebre/genética , Predisposición Genética a la Enfermedad/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Mutación Missense , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Adulto , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Análisis Mutacional de ADN/métodos , Femenino , Fiebre/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Humanos , Masculino , Linaje , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in systemic lupus erythematosus (SLE). METHODS: We retrospectively analyzed cases of proliferative and membranous LN patients who underwent a renal biopsy at our hospital in 1993-2016. We analyzed the association between complete renal response (CR) rates at 12 months after induction therapy and predictive factors for CR and their association with renal flares. RESULTS: Of the 95 cases analyzed, we were able to track the therapeutic responses of 81 patients at 12 months after their induction therapy. The median follow-up duration after renal biopsy was 51 months (interquartile range: 16.5-154.5 months). The Cox proportional hazards model showed that, compared to not attaining CR at 12 months, the attainment of CR at 12 months was correlated with being free from renal flares. The multivariate logistic analysis revealed that the predictive factors for CR at 12 months were the anti-La/SSB antibodies (U/ml) (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.63, p = 0.0220), blood urea nitrogen (BUN) (OR 0.68, 95% CI 0.44-0.90, p = 0.00048) and serum ß2 microglobulin (MG) (OR 0.26, 95% CI 0.06-0.74, p = 0.00098) levels. CONCLUSIONS: Among LN patients, being free from renal flares was associated with attaining CR at 12 months after induction therapy. Anti-La/SSB antibodies were a positive predictive factor, and BUN and serum ß2MG levels were negative predictive factors of CR at 12 months.
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Hospitales Universitarios , Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/etiología , Adulto , Autoantígenos/sangre , Nitrógeno de la Urea Sanguínea , Femenino , Estudios de Seguimiento , Humanos , Japón , Estimación de Kaplan-Meier , Riñón/patología , Modelos Logísticos , Nefritis Lúpica/sangre , Nefritis Lúpica/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fragmentos de Péptidos/sangre , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Microglobulina beta-2/sangreRESUMEN
BACKGROUND: Mutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan. MATERIALS AND METHODS: From April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing. RESULTS: We identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy. CONCLUSION: We identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.
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Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Mutación , Proteínas del Tejido Nervioso/genética , Fenotipo , Adolescente , Adulto , Alelos , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Efecto Fundador , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Japón , Masculino , Persona de Mediana Edad , Proteínas de la Mielina/genética , Linaje , Reproducibilidad de los Resultados , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of Charcot-Marie-Tooth disease (CMT) type 2Z in 2016. We aimed to describe the clinical and mutational spectrum of patients with CMT harboring MORC2 mutations in Japan. METHODS: We analyzed samples from 781 unrelated patients clinically diagnosed with CMT using deoxyribonucleic acid microarray or targeted resequencing by next-generation sequencing, and samples from 434 mutation-negative patients were subjected to whole-exome sequencing. We extracted MORC2 variants from these whole-exome sequencing data and classified them according to American College of Medical Genetics standards and guidelines. RESULTS: We identified MORC2 variants in 13 patients. As the second most common causative gene of CMT type 2 after MFN2, MORC2 variants were detected in 2.7% of patients with CMT type 2. The mean age of onset was 10.3 ± 8.7 years, and the inheritance pattern was mostly sporadic (11/13 patients, 84.6%). The clinical phenotype was typically length-dependent polyneuropathy, and electrophysiological studies revealed sensory-dominant axonal neuropathy. Mental retardation was identified in 4/13 patients (30.8%). p.Arg190Trp, as a mutational hotspot, was observed in eight unrelated families. We also identified two novel probably pathogenic variants, p.Cys345Tyr and p.Ala369Val, and one novel uncertain significance variant, p.Tyr332Cys. CONCLUSIONS: Our study is the largest report of patients harboring MORC2 variants. We revealed a clinical and mutational spectrum of Japanese patients with MORC2 variants. More attention should be paid to cognitive impairment, and the responsible mechanism requires further research for elucidation.
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Enfermedad de Charcot-Marie-Tooth/genética , Mutación , Factores de Transcripción/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Japón , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
PURPOSE OF INVESTIGATION: Pericardial effusion with cardiac tamponade is an uncommon metastatic manifestation of ovarian tumors, with only one previously reported case involving a borderline ovarian tumor (BOT). CASE: A 50-year-old woman was diagnosed and treated for a primary Stage IIc BOT. The disease recurred as an emergency pericardiocentesis eight years later, which was resected following pericardial effusion with a cardiac tamponade. This occurred two more times, and on the last occasion, drainage failed to relieve her symptoms. However, her symptoms resolved after the creation of a pericardium pleural window together with a pericardiectomy. CONCLUSION: For patients with a metastatic BOT, the creation of a pericardium pleural window and pericardiectomy is effective for recurrent pericardial tamponade, if the pericardial space is posteriorly located and/or segmented.
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Taponamiento Cardíaco/cirugía , Neoplasias Ováricas/complicaciones , Pericardiectomía/métodos , Pericardio/cirugía , Femenino , Humanos , Persona de Mediana Edad , RecurrenciaRESUMEN
A 27-year-old woman with complete placenta previa was referred at 22 weeks of gestation because of vaginal bleeding and fetal growth restriction. At 24 weeks, sudden fetal death occurred, but bleeding continued and transvaginal sonography revealed abundant periplacental blood flow in the uterine wall. To avoid cesarean section, the authors performed uterine artery embolization (UAE) be- fore vaginal delivery of the fetus. Subsequently, there was little bleeding when laminaria was inserted for cervical ripening and the fetus was delivered vaginally by using vaginal gemeprost. Total blood loss was only 149 ml. The present case suggests that UAE may be an option for patients with placenta previa who desire vaginal delivery after intrauterine fetal death (IUFD) in a second-trimester pregnancy.
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Placenta Previa/terapia , Embolización de la Arteria Uterina , Adulto , Maduración Cervical , Cesárea , Femenino , Muerte Fetal , Humanos , Embarazo , Segundo Trimestre del Embarazo , MortinatoRESUMEN
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers in Japan. Anticancer chemotherapy has been useful for ESCC treatment. However, therapeutic options are limited. Recently, bisphosphonates (BPs), which are osteoporosis drugs, have shown anticancer effects in several cancer cell lines, but the effects against ESCC cell lines are unknown. In this study, we examined the cytotoxic effects of BPs and their mechanisms of cytotoxicity in human ESCC cell lines. A first-generation BP (etidronate), two second-generation BPs (alendronate and pamidronate), and two third-generation BPs (risedronate and zoledronate) were used in this study. All BPs, except etidronate, were cytotoxic, as indicated by increased caspase-3/7 activity and numbers of Annexin-fluorescein isothiocyanate positive cells in ESCC cell lines. From cell cycle analysis, G0/G1-phase arrest was observed upon treatment with second- and third-generation BPs. In addition, Cyclin D1 protein expression levels were decreased by second- and third-generation BP treatment. Although squalene and trans, trans-farnesol minimally affected BP cytotoxicity, treatment with geranylgeraniol inhibited BP cytotoxicity almost completely. We concluded that second- and third-generation BPs are cytotoxic to ESCC cell lines as they induce apoptosis and inhibit the cell cycle through mevalonate pathway inhibition. Therefore, BP treatment may be a beneficial therapy in ESCC patients.
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Apoptosis/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacología , Carcinoma de Células Escamosas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Difosfonatos/farmacología , Neoplasias Esofágicas/patología , Anexinas/efectos de los fármacos , Anexinas/metabolismo , Caspasa 3/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 7/efectos de los fármacos , Caspasa 7/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclina D1/efectos de los fármacos , Ciclina D1/metabolismo , Diterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Carcinoma de Células Escamosas de Esófago , Farnesol/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Escualeno/farmacologíaRESUMEN
OBJECTIVE: Interferon alpha (IFN-α) is a key cytokine associated with systemic lupus erythematosus (SLE). IFN-α induces the expression of CD64 on monocytes (mCD64). Although enhanced mCD64 expression has been reported in patients with SLE, it has never been assessed quantitatively. The aim of this study was to investigate whether or not mCD64 expression correlates with SLE disease activity. METHODS: The mCD64 expression levels were assessed quantitatively in 40 patients with active or inactive SLE by using flow cytometry. The mCD64 expression levels were subsequently compared with the SLE disease activity index (SLEDAI) and levels of existing SLE activity biomarkers, such as anti-DNA antibody, complements, and so on. RESULTS: The mCD64 expression was significantly higher in active disease than in inactive disease SLE (median molecules/cell, interquartile range: 34,648, 8174-24,932 and 20,865, 6357-21,503, respectively; p < 0.001). The levels of mCD64 expression strongly correlated with SLEDAI (r = 0.68, p < 0.001). CONCLUSION: The mCD64 expression is a simple and useful biomarker for evaluating disease activity in patients with SLE.
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Lupus Eritematoso Sistémico/inmunología , Monocitos/inmunología , Receptores de IgG/biosíntesis , Adulto , Anticuerpos Antinucleares/sangre , Anticuerpos Antinucleares/inmunología , Biomarcadores/sangre , Citocinas/sangre , Citocinas/inmunología , Femenino , Citometría de Flujo/métodos , Humanos , Interferón-alfa/sangre , Interferón-alfa/inmunología , Lupus Eritematoso Sistémico/sangre , Masculino , Persona de Mediana Edad , Receptores de IgG/sangre , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: To compare the discriminative capabilities for the manifestation of sarcopenia or physical frailty between serum creatinine- and cystatin C-derived indices among community-dwelling older adults. DESIGN: Cross-sectional study. SETTING: Primary Care and Community. PARTICIPANTS: We utilized a subset of data from the Frail Elderly in the Sasayama-Tamba Area (FESTA) study, which was initiated in 2015 to gather comprehensive information on various health-related parameters among community-dwelling older individuals (age ≥65 years). MEASUREMENTS: Five serum creatinine-cystatin C based indices including the Sarcopenia Index, the serum creatinine/cystatin C ratio, the disparity between serum cystatin-C-based and creatinine-based estimated GFR, the total body muscle mass index (TBMM), and the prediction equation for skeletal muscle mass index (pSMI) were employed. Sarcopenia and physical frailty were identified based on the Asian Working Group for Sarcopenia criteria and the revised Japanese version of the Cardiovascular Health Study criteria, respectively. The receiver operating characteristic (ROC) and logistic regression analyses were performed to assess the discriminative abilities of these tools. RESULTS: In the analysis of 954 participants, 52 (5.5%) were identified with sarcopenia and 35 (3.7%) with physical frailty. Regarding sarcopenia discrimination, TBMM and pSMI both exhibited area under the curve (AUC) values exceeding 0.8 for both men and women. Concerning the identification of physical frailty, AUC values ranged from 0.61 to 0.77 for males and 0.50 to 0.69 for females. In the multivariate logistic regression analyses, only TBMM and pSMI consistently displayed associations with sarcopenia, irrespective of sex (P<0.001, respectively). On the other hand, no consistent associations were observed between the indices and physical frailty. CONCLUSIONS: This study provides a robust association of a serum creatinine- and cystatin C-derived indices, especially TBMM and pSMI, with sarcopenia among community-dwelling older adults. Conversely, the application of these indices for the screening of physical frailty has its constraints, necessitating further investigation.
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Fragilidad , Sarcopenia , Anciano , Masculino , Humanos , Femenino , Cistatina C , Creatinina , Estudios Transversales , Fragilidad/diagnóstico , Fragilidad/epidemiología , Vida Independiente , Sarcopenia/diagnóstico , Sarcopenia/epidemiologíaRESUMEN
BACKGROUND: In end-stage arthritis indicated for total ankle arthroplasty (TAA), full-thickness cartilage damage, subchondral bone defect/shaving, and fluttering of the talar dome occur, shortening the distance between the tibial and talar insertions of ligaments and leading to laxity of ligaments surrounding the ankle joint. Under such conditions, medial ligaments (including the deltoid ligament) would not be expected to function properly. To stabilize the ankle joint during the stance phase, medial ligament function under tension is important. This study therefore examined whether TAA contributes to lengthening of the medial tibio-talar joint as evaluated radiographically, as a preferable method for achieving tensile effects on medial ligaments. MATERIALS AND METHODS: Twenty-four feet with end-stage varus deformity of the ankle joint that underwent TAA were retrospectively investigated, excluding cases with any malleolar osteotomy or fracture. Distance between proximal and distal insertions of medial ligaments, lateralization of the talus, and talar tilt angle under valgus/varus stress condition were evaluated pre- and postoperatively. RESULTS: Distance between proximal and distal insertions of medial ligaments was significantly elongated after TAA. At the same time, the talus showed significant lateralization. Furthermore, talar tilt under valgus/varus stress conditions was also significantly reduced after TAA. CONCLUSION: TAA affects distal translation and lateralization of the talus in cases of varus ankle deformity. These effects might contribute to re-providing tensile force on lax medial ligaments, improving ligament function.
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Articulación del Tobillo , Artroplastia de Reemplazo de Tobillo , Astrágalo , Humanos , Astrágalo/cirugía , Astrágalo/diagnóstico por imagen , Masculino , Femenino , Artroplastia de Reemplazo de Tobillo/métodos , Estudios Retrospectivos , Articulación del Tobillo/cirugía , Articulación del Tobillo/diagnóstico por imagen , Articulación del Tobillo/fisiopatología , Persona de Mediana Edad , Anciano , Inestabilidad de la Articulación/cirugía , Inestabilidad de la Articulación/etiología , Inestabilidad de la Articulación/fisiopatología , Radiografía , Osteoartritis/cirugía , Osteoartritis/diagnóstico por imagen , Deformidades Adquiridas de la Articulación/cirugía , Deformidades Adquiridas de la Articulación/etiología , Deformidades Adquiridas de la Articulación/diagnóstico por imagen , Deformidades Adquiridas de la Articulación/fisiopatología , Ligamentos Articulares/cirugía , Resultado del TratamientoRESUMEN
Hereditary progressive dystonia with marked diurnal fluctuation (HPD) (also known as dopa responsive dystonia) is a dystonia with onset in childhood that shows a marked response without any side effects to levodopa. Recently the gene for dopa responsive dystonia (DRD) was mapped to chromosome 14q. Here we report that GTP cyclohydrolase I is mapped to 14q22.1-q22.2. The identification of four independent mutations of the gene for GTP cyclohydrolase I in patients with HPD, as well as a marked decrease in the enzyme's activity in mononuclear blood cells, confirms that the GTP cyclohydrolase I gene is a causative gene for HPD/DRD. This is the first report of a causative gene for the inherited dystonias.
Asunto(s)
Mapeo Cromosómico , Distonía/genética , GTP Ciclohidrolasa/genética , Mutación , Edad de Inicio , Biopterinas/biosíntesis , Encéfalo/enzimología , Cromosomas Humanos Par 14 , Ritmo Circadiano , Clonación Molecular , Análisis Mutacional de ADN , Dopamina/biosíntesis , Distonía/clasificación , Distonía/tratamiento farmacológico , Distonía/epidemiología , Escherichia coli , Femenino , GTP Ciclohidrolasa/sangre , Heterocigoto , Humanos , Células Híbridas , Levodopa/uso terapéutico , Masculino , Mutagénesis Sitio-Dirigida , Proteínas del Tejido Nervioso/metabolismo , Linaje , Reacción en Cadena de la Polimerasa , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
A specific isoform of apolipoprotein E has been associated with the accelerated rate of disease expression of sporadic Alzheimer's disease (AD) and late-onset familial AD (FAD). An earlier age at onset has also been demonstrated in familial AD patients with mutations in the amyloid precursor protein (APP) gene (APP717 and APP670/671)13 carrying the APOE epsilon-4 allele compared to those who do not, but not in familial AD patients with APP692 or 693 mutations, or in chromosome 14-linked familial AD patients. Hypothesizing that receptors for apoE-containing lipoproteins act as a potential risk factor for AD, we performed an association study using a polymorphic triplet (CGG) repeat in the gene for the VLDL receptor (VLDL-R), a receptor for apoE-containing lipoproteins. The frequency of the 5-repeat allele was significantly higher in all of the Japanese sporadic AD patients (P < 0.02) than in the Japanese controls. Moreover, the odds ratio was significantly increased in the AD patients homozygous for the 5-repeat allele (OR = 2.1, 95% CI = [1.1-4.2]). Multiple logistic regression analysis reveals that the relative risk conferred by the presence of two copies of the 5-repeat allele and at least one copy of the APOE epsilon-4 allele is 8.7 (95% CI = [2.9-25.8]). Our results suggest that the VLDL-R gene is a susceptibility gene for AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 14 , Receptores de LDL/genética , Secuencias Repetitivas de Ácidos Nucleicos , Alelos , Enfermedad de Alzheimer/epidemiología , Apolipoproteínas E/genética , Secuencia de Bases , Corteza Cerebral/metabolismo , Cartilla de ADN , Humanos , Japón , Datos de Secuencia Molecular , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Valores de Referencia , Análisis de Regresión , Factores de RiesgoRESUMEN
Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs. We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus. We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.
Asunto(s)
Apraxias/genética , Ataxia/genética , Proteínas de Unión al ADN/genética , Mutación , Proteínas Nucleares/genética , Músculos Oculomotores/fisiopatología , Albúmina Sérica/metabolismo , Secuencia de Aminoácidos , Animales , Apraxias/complicaciones , Ataxia/complicaciones , Mapeo Cromosómico , Cromosomas Humanos Par 9 , Proteínas de Unión al ADN/química , Femenino , Ligamiento Genético , Humanos , Masculino , Datos de Secuencia Molecular , Proteínas Nucleares/química , Linaje , Filogenia , Homología de Secuencia de AminoácidoRESUMEN
To elucidate the molecular mechanisms whereby expanded polyglutamine stretches elicit a gain of toxic function, we expressed full-length and truncated DRPLA (dentatorubral-pallidoluysian atrophy) cDNAs with or without expanded CAG repeats in COS-7 cells. We found that truncated DRPLA proteins containing an expanded polyglutamine stretch form filamentous peri- and intranuclear aggregates and undergo apoptosis. The apoptotic cell death was partially suppressed by the transglutaminase inhibitors cystamine and monodansyl cadaverine (but not putrescine), suggesting involvement of a transglutaminase reaction and providing a potential basis for the development of therapeutic measures for CAG-repeat expansion diseases.