RESUMO
OBJECTIVE: The optimal strategy for difficult-to-treat (D2T) rheumatoid arthritis (RA) has not been identified, and the ultrasound characteristics of D2T RA have not been reported. We investigated the clinical characteristics and factors contributing to the outcome in D2T RA in a multicentre RA ultrasound observational cohort. METHOD: We reviewed 307 Japanese patients diagnosed with RA who underwent treatment with biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). We compared the differences in patient characteristics between the D2T RA and non-D2T RA groups. We examined the factors contributing to a good response [defined as b/tsDMARD continuation and Clinical Disease Activity Index (CDAI) ≤ 10 at 12 months] in the D2T RA patient group. RESULTS: Forty-three patients (14%) were categorized as D2T RA and the remaining 264 (86%) as non-D2T RA at baseline. The grey-scale (GS) score, disease duration, and CDAI at the initiation of treatment were significantly higher in the D2T RA group than in the non-D2T RA group. In contrast, the power Doppler (PD) score was not significantly different between the two groups. Of the 43 D2T RA patients, 20 achieved a good response. The introduction of CTLA4-Ig (n = 5) was significantly associated with a good response in analysis based on inverse probability weighting with propensity score. GS and PD scores at baseline were not significantly associated with therapeutic response at 12 months in D2T RA patients. CONCLUSIONS: Patients with D2T RA had high clinical and ultrasound activity and poor responses to treatment with b/tsDMARDs. CTLA4-Ig was associated with a good response at 12 months in D2T RA patients.
Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/complicações , Estudos de Coortes , Ultrassonografia , Ultrassonografia DopplerRESUMO
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.
Assuntos
Antirreumáticos , Artrite Reumatoide , Inibidores de Janus Quinases , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Humanos , Inibidores de Janus Quinases/uso terapêutico , Japão , Metotrexato/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento , UltrassonografiaRESUMO
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.
Assuntos
Artrite Reumatoide , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Estudos de Coortes , Humanos , Japão , Indução de Remissão , Resultado do Tratamento , UltrassonografiaRESUMO
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.
Assuntos
Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Autoantígenos/imunologia , RNA Citoplasmático Pequeno/imunologia , Ribonucleoproteínas/imunologia , Idoso , Artrite Reumatoide/imunologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Abatacepte/administração & dosagem , Anticorpos Antiproteína Citrulinada/sangue , Artrite Reumatoide/imunologia , Idoso , Anticorpos Antiproteína Citrulinada/imunologia , Antirreumáticos/administração & dosagem , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Japão , Masculino , Estudos Prospectivos , Resultado do Tratamento , UltrassonografiaRESUMO
OBJECTIVES: An operations leader (OL) takes an important role in occupational health management for radiation decontamination workers in Japan, and candidates for the position must participate in a training session to acquire the necessary knowledge as required by law. However, it has not been clarified whether the candidates for the OL position actually possess accurate knowledge regarding occupational health management for such work after the training session. We, therefore, aimed at examining the current occupational health management knowledge among the candidates and investigating factors related to the knowledge, with hypothesis that possession of accurate knowledge is associated with prior experience of having worked in radiation decontamination. DESIGN: A cross-sectional study. SETTING: The training sessions held by Fukushima Prefecture Labor Standard Associations in Fukushima, Japan, in 2017. PARTICIPANTS: Eighty male candidates participated in the training sessions. OUTCOME: The number/proportion of correct answers to the questions regarding occupational health management, such as those on working environment management, control of operations and health management. RESULTS: The proportion of those who possessed accurate knowledge regarding working environment management, control of operations and health management was 68.8%, 55.0% and 51.2%, respectively. Experience of radiation decontamination work was associated with the possession of inaccurate knowledge regarding working environment management (OR 0.140 (95% CI 0.042 to 0.464)), and the uncertainty of future radiation decontamination work schedules in difficult-to-return zones was associated with the possession of accurate knowledge regarding health management (OR 4.344 (95% CI 1.509 to 12.50)). CONCLUSIONS: Previous experience in radiation decontamination work may hinder the ability to acquire accurate information regarding working environment management among candidates for an OL position. To promote adequate occupational health management for radiation decontamination workers, it is required to establish an effective instructional method for the OL candidate training sessions with consideration of previous relevant experience.
Assuntos
Descontaminação , Gestão do Conhecimento , Liderança , Doenças Profissionais/psicologia , Saúde Ocupacional/educação , Adulto , Ansiedade/psicologia , Estudos Transversais , Acidente Nuclear de Fukushima , Humanos , Japão , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Centrais Nucleares , Exposição Ocupacional , Exposição à Radiação , Inquéritos e Questionários , Local de TrabalhoRESUMO
This study was carried out to examine the changes in plasma concentrations of the Ca-binding antimicrobial proteins S100A7 and S100A8 during pregnancy in dairy cows. Holstein Friesian cows (n = 19) were inseminated with Holstein Friesian semen. Blood was collected at days 30, 60, 90, 120, 150, 180, 210, 240 and 270 after insemination. Plasma was used for measuring the concentrations of S100A7 and S100A8. Both S100A7 and S100A8 concentrations showed similar patterns during gestation; they increased during the midgestation, between days 90 and 180, and then declined before calving. The findings indicated that plasma concentrations of S100A7 and S100A8 did not change significantly during pregnancy in cows. Further studies are required to determine the roles of S100A7 and S100A8 in physiological function during pregnancy in dairy cows.
Assuntos
Calgranulina A/sangue , Bovinos/sangue , Regulação da Expressão Gênica/fisiologia , Prenhez , Proteína A7 Ligante de Cálcio S100/sangue , Animais , Feminino , Gravidez , Prenhez/sangueRESUMO
Mutations of calreticulin (CALR) are detected in 25-30% of patients with essential thrombocythemia (ET) or primary myelofibrosis and cause frameshifts that result in proteins with a novel C-terminal. We demonstrate that CALR mutations activated signal transducer and activator of transcription 5 (STAT5) in 293T cells in the presence of thrombopoietin receptor (MPL). Human megakaryocytic CMK11-5 cells and erythroleukemic F-36P-MPL cells with knocked-in CALR mutations showed increased growth and acquisition of cytokine-independent growth, respectively, accompanied by STAT5 phosphorylation. Transgenic mice expressing a human CALR mutation with a 52 bp deletion (CALRdel52-transgenic mice (TG)) developed ET, with an increase in platelet count, but not hemoglobin level or white blood cell count, in association with an increase in bone marrow (BM) mature megakaryocytes. CALRdel52 BM cells did not drive away wild-type (WT) BM cells in in vivo competitive serial transplantation assays, suggesting that the self-renewal capacity of CALRdel52 hematopoietic stem cells (HSCs) was comparable to that of WT HSCs. Therapy with the Janus kinase (JAK) inhibitor ruxolitinib ameliorated the thrombocytosis in TG mice and attenuated the increase in number of BM megakaryocytes and HSCs. Taken together, our study provides a model showing that the C-terminal of mutant CALR activated JAK-STAT signaling specifically downstream of MPL and may have a central role in CALR-induced myeloproliferative neoplasms.
Assuntos
Calreticulina/genética , Animais , Autorrenovação Celular , Células HEK293 , Células-Tronco Hematopoéticas , Humanos , Janus Quinases/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Transtornos Mieloproliferativos/induzido quimicamente , Transtornos Mieloproliferativos/etiologia , Nitrilas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas , Receptores de Trombopoetina , Fator de Transcrição STAT5/metabolismo , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genéticaRESUMO
BACKGROUND: Extramammary Paget disease (EMPD) is a skin adenocarcinoma of apocrine gland origin, in which Paget cells express receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) and matrix metalloproteinase (MMP)-7, and release soluble (s)RANKL into the tumour microenvironment. We previously reported that about 60% of the RANK+ cells among the stromal cells are M2 macrophages, but the identity of the remaining population of RANK+ cells is still unknown. OBJECTIVES: To investigate the unknown subpopulation of RANK-expressing cells in EMPD. METHODS: The main population of RANK-expressing cells in the epidermis was composed of epidermal Langerhans cells (LCs). To explore the effects of RANKL on LCs, we stimulated LCs generated from human CD34+ hematopoietic progenitor cells with graded concentrations of sRANKL. To further examine the correlation between LCs and regulatory T cells (Tregs) in EMPD, we employed immunohistochemical staining. RESULTS: sRANKL stimulation was shown to augment the production of C-C motif chemokine ligand 17 (CCL17) from LCs. We additionally demonstrated CCL17 expression by CD1a+ LCs in EMPD in an immunofluorescence study. Spearman's rank correlation test confirmed a correlation between the number of LCs and the number of Foxp3+ Tregs in the lesional skin of invasive EMPD. In addition, the numbers of Foxp3+ Tregs in the sentinel lymph nodes of metastatic EMPD were significantly higher than those of metastatic melanoma, which did not express RANKL. CONCLUSIONS: The findings suggest that the RANKL/RANK pathway in EMPD might contribute to the recruitment of Tregs and to maintenance of the tumour microenvironment.
Assuntos
Células de Langerhans/fisiologia , NF-kappa B/metabolismo , Doença de Paget Extramamária/metabolismo , Ligante RANK/metabolismo , Neoplasias Cutâneas/metabolismo , Linfócitos T Reguladores/fisiologia , Quimiocina CCL17/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Metástase Linfática , Receptor Cross-Talk/fisiologia , Células Tumorais CultivadasRESUMO
The pH-induced conformational changes of proteins are systematically studied in the framework of a hydrophobic-polar (HP) model, in which proteins are dramatically simplified as chains of hydrophobic (H) and polar (P) beads on a lattice. We express the electrostatic interaction, the principal driving force of pH-induced unfolding that is not included in the conventional HP model, as the repulsive energy term between P monomers. As a result of the exact enumeration of all of the 14- to 18-mers, it is found that lowest-energy states in many sequences change from single "native" conformations to multiple sets of "denatured" conformations with an increase in the electrostatic repulsion. The switching of the lowest-energy states occurs in quite a similar way to real proteins: it is almost always between two states, while in a small fraction of ≥16-mers it is between three states. We also calculate the structural fluctuations for all of the denatured states and find that the denatured states contain a broad range of incompletely unfolded conformations, similar to "molten globule" states referred to in acid or alkaline denatured real proteins. These results show that the proposed model provides a simple physical picture of pH-induced protein denaturation.
Assuntos
Modelos Moleculares , Proteólise , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Conformação Proteica , Eletricidade EstáticaRESUMO
Dyskeratosis congenita (DC) is a rare inherited multisystem disorder caused by mutations in seven genes involved in telomere biology, with approximately 20% of cases having pulmonary complications. DKC1 mutations exhibit a severe disease phenotype of DC that develops in early childhood. Here, we report a unique case of DC with pulmonary fibrosis diagnosed at the age of 46. A novel missense mutation(p.Arg65Lys) of DKC1 was detected, and predicted to show a weak mutagenic effect. In spite of the steroid and immunosuppressive treatment, he died of an acute exacerbation seven months after the initial visit. This case suggests that mutation subtypes can cause heterogeneity in DC and pulmonary fibrosis.
Assuntos
Disceratose Congênita , Mutação de Sentido Incorreto , Humanos , Fenótipo , Fibrose Pulmonar , TelômeroRESUMO
Attached growth reactors were developed separately for solids retention time (SRT)-controlled partial nitrification and for anaerobic ammonia oxidation (Anammox) treatment, and a new nitrogen removal process is proposed for wastewater containing highly concentrated ammonia. For partial nitrification, an attached growth medium of polyurethane foam was used. Partial nitrification was achieved stably under a SRT of 4 days, and the abundance ratio of NO2(-)-N to the sum of NH4(+)-N, NO2(-)-N and NO3(-)-N was approximately 0.8 after 10 days. Under a SRT of4 days, the amoA gene concentrations of ammonia-oxidizing bacteria increased from 1 x 10(8) to 7 x 10(8) copies/l, whereas the 16S ribosomal RNA (16S rRNA) gene concentrations of nitrite-oxidizing bacteria did not increase. These results indicate that SRT-controlled operation is a promising technology for achieving partial nitrification. For the Anammox treatment, an attached growth medium of non-woven fabric was used. Inorganic nitrogen removal of approximately 80-90% was observed at an inorganic nitrogen loading rate of over 10 kgN/(m3-medium.d) and an influent nitrogen concentration of 400 mgN/l. Our non-woven fabric reactor showed similar or superior Anammox performance to that reported previously. By using a combination of these two rectors, we can develop a method that combines partial nitrification and Anammox treatment for effective and stable nitrogen removal.
Assuntos
Amônia/isolamento & purificação , Reatores Biológicos , Eliminação de Resíduos Líquidos/métodos , Bactérias/genética , Bactérias/metabolismo , Reatores Biológicos/microbiologia , Desenho de Equipamento , Nitratos/metabolismo , Nitrificação , Nitrogênio , Poliuretanos , RNA Ribossômico 16S , Eliminação de Resíduos Líquidos/instrumentaçãoRESUMO
Ten-Eleven-Translocation 2 (TET2) is an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) and thereby alters the epigenetic state of DNA; somatic loss-of-function mutations of TET2 are frequently observed in patients with diverse myeloid malignancies. To study the function of TET2 in vivo, we analyzed Ayu17-449 (TET2(trap)) mice, in which a gene trap insertion in intron 2 of TET2 reduces TET2 mRNA levels to about 20% of that found in wild-type (WT) mice. TET2(trap/trap) mice were born at Mendelian frequency but died at a high rate by postnatal day 3, indicating the essential role of TET2 for survival. Loss of TET2 results in an increase in the number of hematopoietic stem cells (HSCs)/progenitors in the fetal liver, and TET2(trap/trap) HSCs exhibit an increased self-renewal ability in vivo. In competitive transplantation assays, TET2(trap/trap) HSCs possess a competitive growth advantage over WT HSCs. These data indicate that TET2 has a critical role in survival and HSC homeostasis.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Homeostase , Proteínas Proto-Oncogênicas/fisiologia , Animais , Sobrevivência Celular , Dioxigenases , Hematopoese , Células-Tronco Hematopoéticas/citologia , Janus Quinase 2/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/análiseAssuntos
Medula Óssea/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Regulação Leucêmica da Expressão Gênica , Células HL-60 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células K562 , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Camundongos , Neoplasia Residual/etiologia , Neoplasia Residual/genética , Neoplasia Residual/metabolismo , Células-Tronco Neoplásicas/patologia , Células U937 , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cell adhesion molecule 1 (CADM1/TSLC1) was recently identified as a novel cell surface marker for adult T-cell leukemia/lymphoma (ATLL). In this study, we developed various antibodies as diagnostic tools to identify CADM1-positive ATLL leukemia cells. In flow cytometric analysis, the percentages of CD4(+)CADM1(+) double-positive cells correlated well with both the percentages of CD4(+)CD25(+) cells and with abnormal lymphocytes in the peripheral blood of patients with various types of ATLL. Moreover, the degree of CD4(+)CADM1(+) cells over 1% significantly correlated with the copy number of the human T-lymphotropic virus type 1 (HTLV-1) provirus in the peripheral blood of HTLV-1 carriers and ATLL patients. We also identified a soluble form of CADM1 in the peripheral blood of ATLL patients, and the expression levels of this form were correlated with the levels of soluble interleukin 2 receptor alpha. Moreover, lymphomas derived from ATLL were strongly and specifically stained with a CADM1 antibody. Thus, detection of CD4(+)CADM1(+) cells in the peripheral blood, measurement of serum levels of soluble CADM1 and immunohistochemical detection of CADM1 in lymphomas would be a useful set of markers for disease progression in ATLL and may aid in both the early diagnosis and measurement of treatment efficacy for ATLL.
Assuntos
Moléculas de Adesão Celular/metabolismo , Infecções por HTLV-I/diagnóstico , Imunoglobulinas/metabolismo , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Estudos de Casos e Controles , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular/imunologia , DNA Viral/genética , Progressão da Doença , Citometria de Fluxo , Infecções por HTLV-I/genética , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Técnicas Imunoenzimáticas , Imunoglobulinas/imunologia , Leucemia-Linfoma de Células T do Adulto/virologia , Linfócitos/citologia , Linfócitos/metabolismo , Provírus/genética , Reação em Cadeia da Polimerase em Tempo Real , Carga ViralRESUMO
Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs). The purpose of this study was to evaluate the effects of the selective mineralocorticoid receptor blocker, eplerenone, on endothelial function and ROCK activity in patients with hypertension. The study was carried out over 48 weeks in 60 untreated patients with hypertension who were randomly assigned to eplerenone, nifedipine, and losartan groups. We evaluated the effects of each treatment on flow-mediated vasodilation (FMD) and ROCK activity in peripheral leukocytes. Eplerenone increased FMD and decreased leukocyte ROCK activity. Nifedipine decreased ROCK activity but did not alter FMD. Losartan increased FMD but did not alter ROCK activity. Hypotensive effects were similar in the three groups, as was nitroglycerin-induced vasodilation during the follow-up period. There were no significant differences between the groups with respect to other parameters. The study results show that eplerenone improves endothelial function and inhibits ROCK activity in patients with essential hypertension.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Espironolactona/análogos & derivados , Quinases Associadas a rho/antagonistas & inibidores , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Movimento Celular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Eplerenona , Feminino , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Leucócitos/enzimologia , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nifedipino/farmacologia , Nifedipino/uso terapêutico , Nitroglicerina/farmacologia , Espironolactona/farmacologia , Espironolactona/uso terapêutico , Células-Tronco/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/agonistas , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
To test whether hyperthermophilic treatment promotes polylactide (PLA) dissolution and methane conversion under anaerobic digestion conditions, a single thermophilic control reactor (55 °C) and a two-phase system consisting of a hyperthermophilic reactor (80 °C) and a thermophilic reactor (55 °C) were continuously fed with a mixture of PLA and artificial kitchen garbage. In Runs 1 and 2, the PLA dissolution ratios in the two-phase system were 79.2 ± 6.5% and 85.2 ± 7.0%, respectively, higher than those of the control. Batch experimental results indicated that hyperthermophilic treatment could promote PLA dissolution to a greater degree as compared with single thermophilic treatment and that ammonia addition also had a promotional effect on PLA dissolution. In the two-phase system, after hyperthermophilic treatment, dissolved PLA was converted to methane gas under the subsequent thermophilic condition.
Assuntos
Temperatura Alta , Poliésteres/química , Poliésteres/metabolismo , Poluentes Químicos da Água/química , Anaerobiose , Biodegradação Ambiental , Reatores Biológicos , Fermentação , Metano/química , Metano/metabolismo , Eliminação de Resíduos/métodos , Poluentes Químicos da Água/metabolismoRESUMO
Janus kinase 1 (JAK1) and JAK3 plays a critical role in lymphocyte proliferation and differentiation. Somatic JAK1 mutations are found in 18% of adult precursor T acute lymphoblastic leukemias and somatic JAK3 mutations are found in 3.3% of cutaneous T cell lymphomas. Some of the mutations are confirmed as a gain-of-function mutation and are assumed to be involved in leukemogenesis. Adult T cell leukemia/lymphoma (ATLL) is a type of T cell neoplasm, and activation of JAK/STAT pathways is sometimes observed in them. We investigated JAK1 and JAK3 mutations in 20 ATLL patients. No JAK1 mutations were found, and five types of single nucleotide polymorphisms were observed in 12 cases, whose frequencies almost match those in Asian populations. As for JAK3, a synonymous mutation was found in one case. JAK1 and JAK3 mutations are unlikely involved in the leukemogenesis of ATLL.
Assuntos
Janus Quinase 1/genética , Janus Quinase 3/genética , Leucemia-Linfoma de Células T do Adulto/genética , Adulto , Diferenciação Celular , Proliferação de Células , Análise Mutacional de DNA , Humanos , Japão , Leucemia-Linfoma de Células T do Adulto/etiologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A simple L-lactate fermentation of organic wastes at pH 5.5 and 55 degrees C under nonsterile conditions using Bacillus coagulans can be suitable for L-lactate fermentation of garbage. A mathematical model that simulated the lactate fermentation characteristics of B. coagulans was developed by focusing on the inhibitory effects of substrate, lactate (product) and NaCl, and bacterial growth. Basic fermentation experiments were performed using simple substrates to derive fundamental parameters of growth rate and inhibition effects. The model was then applied to fermentations using simple substrates and artificial kitchen garbage in order to verify its applicability. Microbial concentration, a key state variable of the model was measured using both real-time polymerase chain reaction (PCR) and traditional methods. The results of these methods were compared for experimental cases in which only soluble substrates were used. B. coagulans concentrations were suitably measured using real-time PCR, even when traditional measurement methods for microbial concentrations cannot be used. The results indicate that the developed model and biomass measurement can be used to evaluate lactate fermentations using both simple and complex substrates. These proposed methods would be useful for developing a new bacterial function-based mathematical model for more complex acid fermentations.
Assuntos
Bacteriocinas/metabolismo , Ácido Láctico/metabolismo , Eliminação de Resíduos , Bacteriocinas/genética , Fermentação , Modelos Teóricos , Reação em Cadeia da Polimerase , TemperaturaRESUMO
Licorice flavonoid oil (LFO) is a new functional food ingredient consisting of licorice hydrophobic polyphenols in medium-chain triglycerides (MCT). As part of a safety evaluation, a 90-day oral toxicity study in rats was conducted using an LFO concentrate solution (2.90% glabridin). Male and female animals were assigned to one of 12 groups (10 males or females per group) and received corn oil (negative control), MCT (vehicle control), or 400, 600, 800 or 1600 mg/kg of the LFO concentrate solution. In conclusion, LFO concentrate solution induced an anticoagulation effect in both sexes, although there was a clear sex difference. Based on these findings, it is concluded that the no-observed-adverse-effect level (NOAEL) for the LFO concentrate solution is estimated to be 800 mg/kg/day for female rats, and approximately 400 mg/kg/day for male rats.