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BACKGROUND: Only 80% of children with idiopathic nephrotic syndrome respond well to glucocorticoid therapy. Multidrug-resistant nephrotic syndrome (MRNS) is associated with a poor kidney prognosis. Several retrospective studies have identified rituximab as an effective treatment for MRNS; however, prospective studies are required to assess its efficacy and safety. METHODS: We conducted a multicenter, non-blinded, single-arm trial to investigate the efficacy and safety of rituximab in patients with childhood-onset MRNS who were resistant to cyclosporine and more than three courses of steroid pulse therapy. The enrolled patients received four 375 mg/m2 doses of rituximab in combination with baseline cyclosporine and steroid pulse therapy. The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions were also evaluated. RESULTS: Six patients with childhood-onset MRNS were enrolled. All patients were negative for pathogenic variants of podocyte-related genes. On day 169, five patients (83.3%) showed a > 50% reduction in the urinary protein/creatinine ratio, two patients showed partial remission, and two patients showed complete remission. No deaths occurred and severe adverse events occurred in two patients (infection in one patient and acute kidney injury in one patient). Three patients needed treatment for moderate-to-severe infection. CONCLUSIONS: The study treatment effectively reduced the urinary protein/creatinine ratio in patients with childhood-onset MRNS. The adverse events in this study were within the expected range; however, attention should be paid to the occurrence of infections.
Assuntos
Ciclosporina , Síndrome Nefrótica , Criança , Humanos , Rituximab/efeitos adversos , Ciclosporina/efeitos adversos , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/induzido quimicamente , Imunossupressores/efeitos adversos , Estudos Retrospectivos , Creatinina , Indução de Remissão , Resultado do Tratamento , Esteroides/efeitos adversosRESUMO
BACKGROUND: Obstructive sleep apnea (OSA) is one of the major co-morbidities and aggravating factors of asthma. In OSA-complicated asthma, obesity, visceral fat, and systemic inflammation are associated with its severity, but the role of bronchial hyperresponsiveness (BHR) is unclear. We investigated the involvement of BHR and mediastinal fat width, as a measure of visceral fat, with OSA severity in patients with OSA and asthma-like symptoms. METHODS: Patients with OSA who underwent BHR test and chest computed tomography scan for asthma-like symptoms were retrospectively enrolled. We evaluated the relationship between apnea-hypopnea index (AHI) and PC20 or anterior mediastinal fat width, stratified by the presence or absence of BHR. RESULTS: OSA patients with BHR (n = 29) showed more obstructive airways and frequent low arousal threshold and lower mediastinal fat width, and tended to show fewer AHI than those without BHR (n = 25). In the overall analysis, mediastinal fat width was significantly positively correlated with AHI, which was significant even after adjustment with age and gender. This was especially significant in patients without BHR, while in OSA patients with BHR, there were significant negative associations between apnea index and airflow limitation, and hypopnea index and PC20. CONCLUSIONS: Risk factors for greater AHI differed depending on the presence or absence of BHR in OSA patients with asthma-like symptoms. In the presence of BHR, severity of asthma may determine the severity of concomitant OSA.
Assuntos
Asma , Hiper-Reatividade Brônquica , Apneia Obstrutiva do Sono , Humanos , Estudos Retrospectivos , Asma/complicações , Asma/diagnóstico , Asma/epidemiologia , Hiper-Reatividade Brônquica/epidemiologia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , ComorbidadeRESUMO
BACKGROUND: Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient). RESULTS: TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: P=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups. CONCLUSIONS: Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.
Assuntos
Imunossupressores/administração & dosagem , Ácido Micofenólico/administração & dosagem , Síndrome Nefrótica/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Síndrome Nefrótica/imunologia , Recidiva , Esteroides/administração & dosagem , Fatores de Tempo , Falha de Tratamento , Resultado do TratamentoRESUMO
Demands for the elimination and replacement of animal experiments for cosmetic safety assessment have increased in recent years. Evaluation of skin sensitization, however, is a critical issue in cosmetic safety assessment. The SH test is an in vitro skin sensitization test method that evaluates protein binding of chemical substances, which is an important event in skin sensitization. We previously verified the technical transferability and between-laboratory reproducibility of the SH test, a domestic test method for which no scientific research has been conducted, and improved the protocol, but also noted some unresolved issues. Therefore, in the present study, we successfully improved the operational efficiency and clarity of the final judgment of the SH test by (i) developing a new decision-making system that can make a final judgment without statistical processing, (ii) changing the statistical method, and (iii) evaluating and determining the maximum number of repetitions necessary for optimal efficiency. The improved SH test was verified by comparing it with existing test methods already adopted by the Organization for Economic Cooperation and Development. The results of this study demonstrated excellent performance of the improved SH test, with high reproducibility, reliable predictability, and good operational efficiency. The predictive performance of the improved method does not differ significantly from that of the conventional method, although it is clearer and more efficient. Therefore, the results of the present improved method are consistent with those obtained using the conventional method, with higher efficiency.
Assuntos
Alternativas aos Testes com Animais , Cosméticos , Alternativas aos Testes com Animais/métodos , Animais , Árvores de Decisões , Reprodutibilidade dos Testes , Pele , Testes Cutâneos/métodosRESUMO
BACKGROUND: The impact of reduction in glycemic excursion on coronary plaques remains unknown. This study aimed to elucidate whether a dipeptidyl peptidase 4 inhibitor could reduce the glycemic excursion and stabilize the coronary plaques compared with conventional management in coronary artery disease (CAD) patients with impaired glucose tolerance (IGT). METHODS: This was a multicenter, randomized controlled trial including CAD patients with IGT under lipid-lowering therapy receiving either vildagliptin (50 mg once a day) or no medication (control group) regarding glycemic treatment. The primary endpoint was changes in the minimum fibrous cap thickness and lipid arc in non-significant native coronary plaques detected by optical coherence tomography at 6 months after intervention. Glycemic variability expressed as the mean amplitude of glycemic excursion (MAGE) measured with a continuous glucose monitoring system was evaluated before and 6 months after intervention. RESULTS: A total of 20 participants with 47 lesions were allocated to either the vildagliptin group (10 participants, 22 lesions) or the control group (10 participants, 25 lesions). The adjusted difference of mean changes between the groups was - 18.8 mg/dl (95% confidence interval, - 30.8 to - 6.8) (p = 0.0064) for the MAGE (vildagliptin, - 20.1 ± 18.0 mg/dl vs. control, 2.6 ± 12.7 mg/dl), - 22.8° (- 40.6° to - 5.1°) (p = 0.0012) for the mean lipid arc (vildagliptin, - 9.0° ± 25.5° vs. control, 15.8° ± 16.8°), and 42.7 µm (15.3 to 70.1 µm) (p = 0.0022) for the minimum fibrous cap thickness (vildagliptin, 35.7 ± 50.8 µm vs. control, - 15.1 ± 25.2 µm). CONCLUSIONS: Vildagliptin could reduce the MAGE at 6 months and may be associated with the decreased lipid arc and increased minimum FCT of the coronary plaques in CAD patients with IGT as compared with the control group. These findings may represent its potential stabilization effect on coronary plaques, which are characteristic in this patient subset. Trial registration Registered in the UMIN clinical trial registry (UMIN000008620), Name of the registry: VOGUE trial, Date of registration: Aug 6, 2012, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000010058.
Assuntos
Glicemia/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Intolerância à Glucose/tratamento farmacológico , Placa Aterosclerótica , Vildagliptina/uso terapêutico , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/diagnóstico , Humanos , Japão , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Ruptura Espontânea , Fatores de Tempo , Tomografia de Coerência Óptica , Resultado do Tratamento , Vildagliptina/efeitos adversosRESUMO
Optical frequency domain imaging (OFDI) is a high-resolution intracoronary imaging modality with fast automated longitudinal pullback. We aimed to evaluate the ability of performing OFDI from the superficial femoral artery (SFA) to the below-knee (BK) artery. This clinical trial was a multi-center, single-arm, open-label study. The primary endpoint was to obtain a clear image of the intra-vascular lumen from the SFA to the BK artery, specifically > 270° visualization of the blood vessel lumen with > 16/21 cross sections. The proportion of the clear image (≥ 85%) was regarded as confirmatory of the ability of OFDI to visualize the vessel lumen. Overall, 20 patients were enrolled. The proportion of the primary endpoint was 90% (18/20), and the pre-specified criterion was successfully attained. The proportion of the clear image assessed by the operator was 100% (20/20), and an additional statistical analysis for the proportion of the visualization, > 270°, of the blood vessel lumen revealed a significantly higher cut-off value than that for the pre-specified criterion, 85% (p = 0.0315). There were three adverse events not related to OFDI. OFDI achieved acceptable visualization of the vessel lumen without any adverse event related to it. After regulatory approval based on the present study, OFDI will be available as a new option of endovascular imaging for peripheral artery diseases in daily practiceTrial registration: This study was registered in the Japanese Registry of Clinical Trials (jRCT 2052190025, https://jrct.niph.go.jp/latest-detail/jRCT2052190025 ).
Assuntos
Artéria Femoral/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Doença Arterial Periférica/diagnóstico , Tomografia de Coerência Óptica/métodos , Ultrassonografia de Intervenção/métodos , Idoso , Feminino , Humanos , Masculino , Método Simples-CegoRESUMO
BACKGROUND: Area-level deprivation is well known to have an adverse impact on mortality, morbidity, or other specific health outcomes. This study examined how area-level deprivation may affect self-rated health (SRH) and life satisfaction (LS), an issue that is largely understudied. METHODS: We used individual-level data obtained from a nationwide population-based internet survey conducted between 2019 and 2020, as well as municipality-level data obtained from a Japanese government database (N = 12,461 living in 366 municipalities). We developed multilevel regression models to explain an individual's SRH and LS scores using four alternative measures of municipality-level deprivation, controlling for individual-level deprivation and covariates. We also examined how health behavior and interactions with others mediated the impact of area-level deprivation on SRH and LS. RESULTS: Participants in highly deprived municipalities tended to report poorer SRH and lower LS. For example, when living in municipalities falling in the highest tertile of municipality-level deprivation as measured by the z-scoring method, SRH and LS scores worsened by a standard deviation of 0.05 (p < 0.05) when compared with those living in municipalities falling in the lowest tertile of deprivation. In addition, health behavior mediated between 17.6 and 33.1% of the impact of municipality-level deprivation on SRH and LS, depending on model specifications. CONCLUSION: Results showed that area-level deprivation modestly decreased an individual's general health conditions and subjective well-being, underscoring the need for public health policies to improve area-level socioeconomic conditions.
Assuntos
Nível de Saúde , Satisfação Pessoal , Cidades , Humanos , Japão/epidemiologia , AutorrelatoRESUMO
Early kidney failure in the hereditary type IV collagen disease, Alport syndrome, can be delayed by renin-angiotensin inhibitors. However, whether all patients and all different genotypes respond equally well to this kidney-protective therapy remains unclear. Here, we performed a retrospective study on 430 patients with male X-linked Alport syndrome to examine the relationships among kidney prognosis, genotype, and treatment effect in a large cohort of Japanese patients. We analyzed the clinical features, genotype-phenotype correlation, and kidney survival period for patients treated with or without renin-angiotensin inhibitors. As a result, the median kidney survival period of patients in this cohort was found to be at 35 years with a strong genotype-phenotype correlation. The median age at the onset of end stage kidney disease (ESKD) significantly differed between patients treated with and without renin-angiotensin inhibitors (over 50 years versus 28 years, respectively). Moreover, these drugs delayed the onset of ESKD in patients with truncating variants for 12 years, extending the median age from 16 years to 28 years. Thus, our results confirmed a strong genotype-phenotype correlation in patients with male X-linked Alport syndrome. Additionally, it was suggested that renin-angiotensin inhibitors could significantly delay ESKD progression. Despite these therapies, patients with truncating variants developed ESKD at the median age of 28 years.
Assuntos
Angiotensinas , Nefrite Hereditária , Preparações Farmacêuticas , Colágeno Tipo IV/genética , Estudos de Associação Genética , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/genética , Estudos RetrospectivosRESUMO
A polychromatic simultaneous wavelength-dispersive X-ray fluorescence (PS-WDXRF) spectrometer can measure the valence changes of 3d transition metals with high precision in the laboratory. Adjustment and maintenance of the drive mechanism are unnecessary, and high-precision measurements are possible in a short time because the optical system has no moving parts and is compact. We have developed a PS-WDXRF spectrometer with improved analytical precision that can measure simultaneously the valence changes of three main elements, Mn, Co, and Ni, which are used as cathode materials in Li-ion batteries (LIBs). In this study, the analytical precision of the spectrometer is evaluated, and its precision is confirmed with actual battery cathodes. The identification precision of the fluorescent X-ray peak energy is <0.015 eV, and the valence identification precision is obtained to be <0.06. LiNi0.5Co0.2Mn0.3O2 (NCM523)-based LIB cathodes are analyzed under conditions maintaining this precision, and the valence changes of the 3d transition metals in NCM523 during charging and discharging are found to be 0.68 for Ni, 0.19 for Co, and 0.08 for Mn. These results indicate that Ni contributes the most to the redox process in NCM523-based LIBs, Co contributes slightly, and Mn does not contribute.
RESUMO
Recent improvements of balloon aortic valvuloplasty (BAV) devices and procedures have provided improved outcomes, but it is not clear whether the multiple-inflation BAV technique is effective in patients with symptomatic severe aortic valve stenosis (AS). We conducted an analysis of the impact of multiple-inflation BAV (at least 6 times inflation) on the mean aortic valve area (AVA) and mean aortic valve pressure gradient (AV-PG) in patients with symptomatic severe aortic stenosis as compared with conventional BAV (from single to three times inflation). We identified two studies of multiple-inflation BAV with antegrade approach using Inoue-balloon catheter (425 patients) and four studies of conventional BAV (170 patients) with retrograde approach. Using a random intercept model, we found that multiple-inflation BAV significantly increased mean AVA (mean difference (MD) [95% indicates confidence interval (CI)] = 0.25 [0.16-0.34], P < 0.001) and significantly decreased mean AV-PG (MD [95% CI] = - 20.2 [- 27.8, - 12.70], P < 0.001) as compared with the conventional BAV. Furthermore, despite an extremely high Society of Thoracic Surgeons (STS) score (9.2-14.5), the all-cause mortality rate at one year of multiple-inflation BAV was 16-17%. The results of our analyses indicate that the multiple-inflation BAV technique seem to be effective for patients with symptomatic severe AS as compared with conventional BAV.
Assuntos
Estenose da Valva Aórtica/terapia , Valva Aórtica/fisiopatologia , Valvuloplastia com Balão , Hemodinâmica , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/fisiopatologia , Valvuloplastia com Balão/efeitos adversos , Feminino , Humanos , Masculino , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Eighty percent of children with idiopathic nephrotic syndrome respond well to steroid therapy, but up to 50% of patients with steroid-sensitive nephrotic syndrome exhibit frequently relapsing (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Several studies identified the chimeric anti-CD20 monoclonal antibody rituximab as an effective treatment for patients with complicated FRNS/SDNS. Recent studies suggested that rituximab could also be a first-line treatment for early-stage uncomplicated FRNS/SDNS, although further studies are required to confirm its efficacy and safety. METHODS/DESIGN: We are conducting a multicenter, double-blind, randomized placebo controlled trial to investigate the efficacy and safety of rituximab for the treatment of childhood-onset early-stage uncomplicated FRNS/SDNS. Patients will be allocated to receive two 375 mg/m2 doses (maximum dose: 500 mg) of either rituximab or placebo. Investigators are permitted to request the disclosure of a subject's allocation code if he or she exhibits treatment failure. Additionally, if placebo-treated subjects display early relapse (a sign of treatment failure), they have the option to receive rituximab in an unblinded phase. The primary endpoint is relapse-free survival during the observation period. DISCUSSION: The results will provide important data on the use of rituximab for patients with uncomplicated FRNS/SDNS. In the future, rituximab treatment will enable most patients with uncomplicated FRNS/SDNS to discontinue or reduce steroid therapy without relapse, and it is possible that rituximab could represent an immunosuppressive therapy for these diseases. TRIAL REGISTRATION: This trial was prospectively registered to the JMACCT Clinical Trials Registry on September 6, 2018 (Trial ID: JMA-IIA00380 ).
Assuntos
Fatores Imunológicos/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab/uso terapêutico , Adolescente , Criança , Método Duplo-Cego , Humanos , Fatores Imunológicos/administração & dosagem , Japão , Estudos Multicêntricos como Assunto , Placebos/uso terapêutico , Recidiva , Rituximab/administração & dosagem , Tamanho da Amostra , Esteroides/farmacologiaRESUMO
BACKGROUND: Clinicians have very limited options to improve fracture repair. Therefore, it is critical to develop a new clinically available therapeutic option to assist fracture repair biologically. We previously reported that the topical cutaneous application of carbon dioxide (CO2) via a CO2 absorption-enhancing hydrogel accelerates fracture repair in rats by increasing blood flow and angiogenesis and promoting endochondral ossification. The aim of this study was to assess the safety and efficacy of CO2 therapy in patients with fractures. METHODS: Patients with fractures of the femur and tibia were prospectively enrolled into this study with ethical approval and informed consent. The CO2 absorption-enhancing hydrogel was applied to the fractured lower limbs of patients, and then 100% CO2 was administered daily into a sealed space for 20 min over 4 weeks postoperatively. Safety was assessed based on vital signs, blood parameters, adverse events, and arterial and expired gas analyses. As the efficacy outcome, blood flow at the level of the fracture site and at a site 5 cm from the fracture in the affected limb was measured using a laser Doppler blood flow meter. RESULTS: Nineteen patients were subjected to complete analysis. No adverse events were observed. Arterial and expired gas analyses revealed no adverse systemic effects including hypercapnia. The mean ratio of blood flow 20 min after CO2 therapy compared with the pre-treatment level increased by approximately 2-fold in a time-dependent manner. CONCLUSIONS: The findings of the present study revealed that CO2 therapy is safe to apply to human patients and that it can enhance blood flow in the fractured limbs. TRIAL REGISTRATION: This study has been registered in the UMIN Clinical Trials Registry (Registration number: UMIN000013641, Date of registration: July 1, 2014).
Assuntos
Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Dióxido de Carbono/administração & dosagem , Fraturas do Colo Femoral/tratamento farmacológico , Hidrogéis/administração & dosagem , Fraturas da Tíbia/tratamento farmacológico , Administração Tópica , Adulto , Idoso , Velocidade do Fluxo Sanguíneo/fisiologia , Dióxido de Carbono/metabolismo , Feminino , Fraturas do Colo Femoral/diagnóstico por imagem , Fraturas do Colo Femoral/fisiopatologia , Seguimentos , Humanos , Hidrogéis/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fraturas da Tíbia/diagnóstico por imagem , Fraturas da Tíbia/fisiopatologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Thanatophoric dysplasia (TD) is a rare congenital disease of the skeletal system, with an incidence of 1.68-8.3 per 100 000 births, but statistical data on the estimated number of TD patients across Japan are not available. The aim of this study was therefore to investigate the prevalence and prognosis of TD in Japan. METHODS: A nationwide primary questionnaire survey was conducted. RESULTS: A total of 127 obstetric, 186 pediatric, and 115 orthopedic facilities provided responses. Excluding duplications, we identified 73 patients with TD. Of the 73 cases, 15 were abortions, four were stillbirths, 51 were live births, and three had unknown details. Of the 51 live newborns, 27 died ≤7 days after birth, with an early neonatal mortality rate of 56%. Of the 24 newborns who survived the early neonatal period, 16 survived for ≥1 year. All of the 24 newborns received respiratory management and survived during the early neonatal period. Of the 51 live newborns, 25 did not receive respiratory management and died ≤2 days after birth. CONCLUSIONS: The prevalence of TD in Japan is estimated to be at 1.1 (95%CI: 0.84-1.37) per 100 000 births, but the actual incidence is expected to be higher. To our knowledge, we have confirmed for the first time that newborns with TD may not always die during the early neonatal period but can survive the early neonatal period with appropriate respiratory management. Therefore, the term "thanatophoric dysplasia" does not accurately reflect the nature of the disease.
Assuntos
Displasia Tanatofórica/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Inquéritos Epidemiológicos , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Japão/epidemiologia , Masculino , Prevalência , Prognóstico , Estudos Retrospectivos , Displasia Tanatofórica/diagnóstico , Displasia Tanatofórica/terapia , Adulto JovemRESUMO
BACKGROUND: X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS. METHODS: We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level. RESULTS: We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001). CONCLUSIONS: We report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.
Assuntos
Colágeno Tipo IV/genética , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/epidemiologia , Nefrite Hereditária/genética , Mutação Puntual/genética , Adulto , Estudos de Coortes , Análise Mutacional de DNA , Humanos , Japão , Masculino , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/epidemiologia , Linhagem , Estudos RetrospectivosRESUMO
Recently UN GHS has introduced the sub-categorization of skin sensitizers for which ECt (concentration estimated to induce stimulation index above threshold) of the murine local lymph node assay (LLNA) is used as criteria. Non-radioisotopic variants of LLNA, LLNA: DA, LLNA: BrdU-ELISA, LNCC and LLNA: BrdU-FCM were developed yet their utilities for potency sub-categorization are not established. Here we assessed the agreement of LLNA variants with LLNA or human data in potency sub-categorization for 22 reference substances of OECD TG429. Concordance of sub-categorization with LLNA was highest for LLNA: BrdU-FCM(91%, κ = 0.833, weighted kappa) followed by LLNA: BrdU-ELISA (82%, κ = 0.744) and LLNA: DA (73%, κ = 0.656) whereas LNCC only showed a modest association (64%, κ = 0.441). With human data, LLNA agreed best (77%) followed by LLNA: DA and LLNA: BrdU-FCM(73%), LLNA: BrdU-ELISA (68%) and LNCC(55%). Bland-Altman plot revealed that ECt's of LLNA variants largely agreed with LLNA where most values fell within 95% limit of agreement. Correlation between ECt's of LLNA and LLNA variants were high except for LNCC(pair-wise with LLNA, LLNA: DA, r = 0.848, LLNA: BrdU-ELISA, r = 0.744, LLNA: BrdU-FCM, r=0.786, and LNCC, r = 0.561 by Pearson). Collectively, these results demonstrated that LLNA variants exhibit performance comparable to LLNA in the potency sub-categorization although additional substances shall be analyzed in the future.
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Dermatite Alérgica de Contato , Ensaio Local de Linfonodo , Alérgenos/classificação , Alérgenos/toxicidade , Animais , Haptenos/classificação , Haptenos/toxicidade , Humanos , Camundongos , Radioisótopos , Reprodutibilidade dos Testes , Nações UnidasRESUMO
OBJECTIVE: This study clarified sensitization patterns to house dust mite (HDM) and Japanese cedar pollen (JCP) in Japanese lower-grade schoolchildren. We also explored factors associated with allergic sensitization. METHODS: This cross-sectional study used a database from the Study on Respiratory Disease and Automobile Exhaust (SORA), a Japanese health study project. The subjects comprised 8,815 pupils aged 6-9 years. We obtained the distribution of HDM- and JCP-specific IgE, respectively, as a marker of sensitization. To determine factors associated with sensitization, we used logistic regression and calculated adjusted odds ratios (AORs) for the relative prevalence of sensitization. The cut-off point for specific IgE levels was 0.35 kU/l. RESULTS: Sensitization to HDM and JCP was detected in 51 and 39% of subjects, respectively, occurring more often in boys and at older ages. In addition, AORs of sensitization to HDM/JCP were higher in subjects with a history of bronchitis, parental asthma, parental atopic eczema and parental pollinosis. In contrast, AORs for sensitization were lower in those subjected to maternal passive smoking as well as among boys with pets. AORs of sensitization to JCP alone were lower in those with a history of otitis media, those who had been bottle milk fed, and those who were not the firstborn and who lived near a busy road. CONCLUSION: Sensitization to HDM and JCP was detected in 51 and 39% of lower-grade schoolchildren, respectively.
Assuntos
Hipersensibilidade/etiologia , Rinite Alérgica Sazonal/etiologia , Alérgenos/imunologia , Animais , Especificidade de Anticorpos , Povo Asiático , Criança , Estudos Transversais , Cryptomeria/efeitos adversos , Cryptomeria/imunologia , Dermatophagoides pteronyssinus/imunologia , Feminino , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/imunologia , Imunoglobulina E/sangue , Japão/epidemiologia , Masculino , Razão de Chances , Pólen/efeitos adversos , Pólen/imunologia , Prevalência , Rinite Alérgica Sazonal/epidemiologia , Rinite Alérgica Sazonal/imunologia , Fatores de RiscoRESUMO
Potential genotoxicity is one of the essential considerations in the safety assessment of chemicals to which humans may be exposed. Several endpoints are used to evaluate genotoxicity, but, in each case, a binary assessment (negative/positive) is demanded by regulators. The use of binary assessment has rarely been questioned, although we have pointed out some questions and difficulties with regard to the statistical methods used and the evaluation of biological significance, both of which inform the calls of negative/ positive. Here, we discuss these issues further, focusing on ambiguity and uncertainty in the binary paradigm, and we seek a new direction for genotoxicity assessment. To this end, we need to understand, acknowledge, and accept these ambiguities and study-related uncertainties and then to consider new strategies for safety assessment. We also discuss the communication of ambiguity and uncertainty in risk communication.
Assuntos
Dano ao DNA , Humanos , Testes de Mutagenicidade/métodos , Medição de RiscoRESUMO
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease that can affect multiple generations and cause complications with long-term prednisolone treatment. This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) in preventing NMOSD relapse while reducing prednisolone dosage. The trial involved nine patients with NMOSD who received MMF along with prednisolone dose reduction. MMF was effective in achieving prednisolone dose reduction without relapse in 77.8% of patients, with a significant decrease in mean annualized relapse rate. All adverse events were mild. The findings suggest that MMF could be a viable treatment option for middle-aged and older patients who require steroid reduction.Clinical trial registration number: jRCT, jRCTs051180080. Registered February 27th, 2019-retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs051180080.
Assuntos
Ácido Micofenólico , Neuromielite Óptica , Prednisolona , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imunossupressores/efeitos adversos , Imunossupressores/administração & dosagem , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/administração & dosagem , Neuromielite Óptica/tratamento farmacológico , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Estudos Prospectivos , Recidiva , Resultado do TratamentoRESUMO
INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type 2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes. METHODS: The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10 mg of empagliflozin daily. If the hemoglobin A1c (HbA1c) level was ≥ 7.0% (52 mmol/mol) after 12 weeks, the dose was adjusted to 25 mg. The study duration was 24 weeks, and the primary outcome was the change in HbA1c level by the end of the treatment period. Safety evaluations were performed for all participants. RESULTS: By the end of the 24-week treatment period, the mean HbA1c level for all eight patients had decreased by 0.99 percentage points (10.8 mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9 mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9 mg/dL (3.55 mmol/L) (95% CI 25.5 to 102.3 mg/dL, 1.42 to 5.68 mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6 mg/dL (9.13 ± 4.23 to 7.65 ± 2.59 mmol/L) as well as an increase in the time in range (70-180 mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment. CONCLUSION: Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes. TRIAL REGISTRATION: jRCTs2051190029 and NCT04018365.
RESUMO
AIMS/INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are rare conditions characterized by the development of treatment-refractory diabetes with severe insulin resistance. We recently conducted a 24 week, multicenter, single-arm trial (EMPIRE-01) that demonstrated a certain level of effectiveness and safety of empagliflozin for these conditions. To evaluate treatment safety over a longer period, we have now performed an additional 28 week trial (EMPIRE-02) that followed on from EMPIRE-01. MATERIALS AND METHODS: The primary and secondary outcomes were safety and efficacy evaluations, respectively. All eight subjects of the EMPIRE-01 trial participated in EMPIRE-02. RESULTS: Twenty adverse events (AEs) were recorded among five individuals during the combined 52 week treatment period of both trials. Whereas one case of chronic hepatitis B was moderate in severity, all other AEs were mild. There were thus no serious AEs or events necessitating discontinuation or suspension of treatment or a reduction in drug dose. Whereas ketoacidosis or marked increases in serum ketone body levels were not observed, the mean body mass of the subjects was decreased slightly after completion of EMPIRE-02. The improvement in mean values of glycemic parameters observed in EMPIRE-01 was not sustained in EMPIRE-02, mostly because of one individual whose parameters deteriorated markedly, likely as a result of nonadherence to diet therapy. The improvement in glycemic parameters was sustained during EMPIRE-02 after exclusion of this subject from analysis. CONCLUSIONS: Empagliflozin demonstrated a certain level of safety and efficacy for the treatment of insulin resistance syndrome and lipoatrophic diabetes over 52 weeks, confirming its potential as a therapeutic option.