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1.
Br J Oral Maxillofac Surg ; 59(8): 941-946, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34456079

RESUMO

We investigated the value of the weighted lymph node ratio (WLNR), a new marker in pN0 patients that incorporates the number of metastatic lymph nodes with extranodal extension and the lymph node yield, for the prognosis and postsurgical management of oral squamous cell carcinoma (OSCC). We designed a retrospective study and enrolled patients with OSCC who were treated by neck dissection (ND). The predictor variable was WLNR, and the outcome variable was overall survival (OS). The Cox proportional-hazards model was used to identify independent prognostic factors. In 133 patients with OSCC, the WLNR cut-off value for predicting OS was 0.0363 (area under the curve 0.723, p<0.001). When stratified according to WLNR, there was a significant difference in OS (88.4% for low WLNR and 63.0% for high WLNR, p<0.001). Univariate analyses showed close associations between OS and age, dissection area, postoperative management, extranodal extension, number of positive lymph nodes, pN stage, WLNR, and nodal disease area. Cox multivariate analysis identified the WLNR as an independent predictive factor for OS (HR 3.273, 95% CI 1.227 to 8.731, p=0.018). As a predictive factor, a high WLNR (≥0.0363) in patients with pN0 disease, which included the addition of extranodal extension and lymph node yield to the LNR, was associated with diminished survival.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Extensão Extranodal , Humanos , Excisão de Linfonodo , Razão entre Linfonodos , Linfonodos/patologia , Neoplasias Bucais/patologia , Neoplasias Bucais/cirurgia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço
2.
Scand J Rheumatol ; 49(4): 301-311, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32286129

RESUMO

OBJECTIVE: The complement cascade, especially the alternative pathway of complement, has been shown in basic research to be associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). We aimed to elucidate relationships between serum complement components and clinical characteristics in AAV. METHOD: In a nationwide prospective cohort study (RemIT-JAV-RPGN), we measured the serum levels of C1q, C2, C3, C3b/iC3b, C4, C4b, C5, C5a, C9, factor B, factor D, factor H, factor I, mannose-binding lectin, and properdin in 52 patients with microscopic polyangiitis (MPA) and 39 patients with granulomatosis with polyangiitis (GPA). RESULTS: The properdin level of MPA and GPA was significantly lower than that of healthy donors. The properdin level was negatively correlated with the Birmingham Vasculitis Activity Score (BVAS) (ρ = -0.2148, p = 0.0409). The factor D level at 6 months was significantly positively correlated with the Vasculitis Damage Index (VDI) at 6, 12, and 24 months (ρ = 0.4207, 0.4132, and 0.3115, respectively). Patients with a higher ratio of C5a to C5 had higher neutrophil percentage and serum immunoglobulin G levels, and significantly lower creatinine levels. Cluster analysis divided the MPA and GPA patients into three subgroups. A principal component (PC) analysis aggregated 15 types of complements into alternative pathway-related PC 1 and complement classical pathway and common pathway-related PC 2. CONCLUSIONS: The serum levels of properdin and factor D were correlated with the BVAS and the VDI in MPA and GPA, respectively. Our analyses suggested the pathological heterogeneity of MPA and GPA from the aspect of complement components.


Assuntos
Proteínas do Sistema Complemento/metabolismo , Granulomatose com Poliangiite/sangue , Poliangiite Microscópica/sangue , Idoso , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/etiologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Poliangiite Microscópica/tratamento farmacológico , Poliangiite Microscópica/etiologia , Pessoa de Meia-Idade , Análise de Componente Principal , Estudos Prospectivos , Recidiva , Indução de Remissão
3.
Int J Oral Maxillofac Surg ; 49(9): 1143-1148, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32115310

RESUMO

The aim of this study was to perform a statistical evaluation of the risk factors for postoperative delirium after oral tumor resection and reconstructive surgery. The records of 69 consecutive patients who underwent major head and neck tumor resection and reconstructive surgery, and who received postoperative management in the high care unit (HCU) or intensive care unit (ICU) of Tsukuba University Hospital between January 2013 and December 2017, were analysed retrospectively. Delirium was diagnosed in 23 patients (33.3%) after surgery. There were significant differences in age, sex, history of diabetes mellitus and chronic obstructive pulmonary disease, recent hospitalization history, sedation period, duration of ventilator use, length of ICU/HCU stay, postoperative blood tests (haemoglobin and potassium), and postoperative medication with a major tranquilizer between those with and without delirium. Logistic regression analysis of selected independent variables revealed a hazard ratio (95% confidence interval) of 1.42 (1.09-1.86) for the sedation period. Delirium was hyperactive type in 15 cases, hypoactive type in five, and mixed type in three. There was no obvious difference in postoperative day of onset or delirium period according to subtype. In conclusion, a history of diabetes and the sedation period were found to be related to postoperative delirium. However, this study was small and retrospective, so further investigation is necessary.


Assuntos
Delírio , Neoplasias Bucais , Procedimentos de Cirurgia Plástica , Humanos , Unidades de Terapia Intensiva , Complicações Pós-Operatórias , Estudos Retrospectivos , Fatores de Risco
4.
Transplant Proc ; 51(3): 761-767, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30979461

RESUMO

BACKGROUND: It has been reported that transplant recipients are exposed to physical and psychosocial stresses even after transplant surgery and exhibit psychological disorders such as depression. PURPOSE: In this study, we extracted trends concerning how recipients of kidney transplants cope with stress, and we also examined how they cope with depression and its countermeasures. METHOD: We administered questionnaire surveys to 109 kidney transplant recipients. These included items on personal attributes, medical information, depression, and stress-coping type scales. Statistical analysis was performed using factor analysis and multiple regression analysis. RESULTS: Fifteen out of 109 (13.8%) were found to be high-risk patients for depression based on responses to the questionnaire using the depression scale. We extracted 2 factors of stress-coping type, namely Factor 1, "Directly coping with the problem," of patients who try to directly resolve the problem in a positive manner and Factor 2, "Stress-release while avoiding the problem," for those who relieve their feelings in response to the stress without resolving the problem itself. When multiple regression analysis was conducted with the depression scale as the dependent variable and the stress-coping factor as the independent variable, Factor 1 tended to be associated with reduced depression and Factor 2 with increased depression. CONCLUSIONS: Results showed that to improve the mental health of those who receive kidney transplants, it is necessary to examine the depression and stress-coping types of such patients at an early stage and carry out education on stress-coping, focusing on resolving the actual problem.


Assuntos
Adaptação Psicológica , Depressão/psicologia , Transplante de Rim/psicologia , Transplantados/psicologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Psicológico/psicologia , Inquéritos e Questionários
5.
Leukemia ; 32(4): 855-864, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28951561

RESUMO

Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer originating from rare populations of leukemia stem cells (LSCs). AML relapse after conventional chemotherapy is caused by a remaining population of drug-resistant LSCs. Selective targeting of the chemoresistant population is a promising strategy for preventing and treating AML relapse. Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to maintain the stemness of LSCs. Here, we show that quiescent LSCs expressed the highest levels of enhancer of zeste (EZH) 1 and EZH2, the PRC2 catalytic subunits, in the AML hierarchy, and that dual inactivation of EZH1/2 eradicated quiescent LSCs to cure AML. Genetic deletion of Ezh1/2 in a mouse AML model induced cell cycle progression of quiescent LSCs and differentiation to LSCs, eventually eradicating AML LSCs. Quiescent LSCs showed PRC2-mediated suppression of Cyclin D, and Cyclin D-overexpressing AML was more sensitive to chemotherapy. We have developed a novel EZH1/2 dual inhibitor with potent inhibitory activity against both EZH1/2. In AML mouse models and patient-derived xenograft models, the inhibitor reduced the number of LSCs, impaired leukemia progression, and prolonged survival. Taken together, these results show that dual inhibition of EZH1/2 is an effective strategy for eliminating AML LSCs.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 2/antagonistas & inibidores , Animais , Histonas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL
6.
Osteoarthritis Cartilage ; 26(1): 108-117, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29074299

RESUMO

OBJECTIVE: Chondrocyte differentiation is crucial for long bone growth. Many cartilage extracellular matrix (ECM) proteins reportedly contribute to chondrocyte differentiation, indicating that mechanisms underlying chondrocyte differentiation are likely more complex than previously appreciated. Angiopoietin-like protein 2 (ANGPTL2) is a secreted factor normally abundantly produced in mesenchymal lineage cells such as adipocytes and fibroblasts, but its loss contributes to the pathogenesis of lifestyle- or aging-related diseases. However, the function of ANGPTL2 in chondrocytes, which are also differentiated from mesenchymal stem cells, remains unclear. Here, we investigate whether ANGPTL2 is expressed in or functions in chondrocytes. METHODS: First, we evaluated Angptl2 expression during chondrocyte differentiation using chondrogenic ATDC5 cells and wild-type epiphyseal cartilage of newborn mice. We next assessed ANGPTL2 function in chondrogenic differentiation and associated signaling using Angptl2 knockdown ATDC5 cells and Angptl2 knockout mice. RESULTS: ANGPTL2 is expressed in chondrocytes, particularly those located in resting and proliferative zones, and accumulates in ECM surrounding chondrocytes. Interestingly, long bone growth was retarded in Angptl2 knockout mice from neonatal to adult stages via attenuation of chondrocyte differentiation. Both in vivo and in vitro experiments show that changes in ANGPTL2 expression can also alter p38 mitogen-activated protein kinase (MAPK) activity mediated by integrin α5ß1. CONCLUSION: ANGPTL2 contributes to chondrocyte differentiation and subsequent endochondral ossification through α5ß1 integrin and p38 MAPK signaling during bone growth. Our findings provide insight into molecular mechanisms governing communication between chondrocytes and surrounding ECM components in bone growth activities.


Assuntos
Proteínas Semelhantes a Angiopoietina/fisiologia , Desenvolvimento Ósseo/fisiologia , Proteína 2 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina/metabolismo , Animais , Animais Recém-Nascidos , Diferenciação Celular/fisiologia , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Condrogênese/fisiologia , Inibidores Enzimáticos/farmacocinética , Fêmur/crescimento & desenvolvimento , Imidazóis/farmacocinética , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Matrilinas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Piridinas/farmacocinética , Tíbia/crescimento & desenvolvimento
7.
Neuroscience ; 267: 277-85, 2014 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-24613720

RESUMO

In stroke-prone spontaneously hypertensive rats (SHRSP/Izm), ischemia induces swelling of astrocytes, a process that subsequently leads to neuronal death. Following ischemic insult, arginine vasopressin (AVP) can induce edema and l-serine released by astrocytes supports the survival of neuronal cells. The purpose of this study was to examine whether AVP contributed to the regulation of l-serine production following ischemic stroke. Here, we used cultured astrocytes from SHRSP/Izm rats and Wistar Kyoto rats (WKY/Izm) to examine whether AVP changed the production of l-serine and/or altered gene expression levels of the neural amino acid transporter (Slc1a4), 3-phosphoglycerate dehydrogenase (Phgdh) and serine racemase (SRR). Furthermore, using astrocytes from the congenic rat SHRpch1_18 strain having quantitative trait loci (QTL) of stroke, we examined expression of those genes under conditions of hypoxia and reoxygenation (H/R). The expression levels of ASCT1 protein, the genes described above and l-serine levels were determined by Western blotting (WB), RT-PCR, real-time quantitative RT-PCR and HPLC. AVP increased the production of l-serine and the expression of Slc1a4 in WKY/Izm and SHRSP/Izm astrocytes. The production of l-serine and the expression of Slc1a4 were lower in SHRSP/Izm than in WKY/Izm cells. This difference was not seen with Phgdh. In the SHRpch1_18 strain, the expression of Slc1a4 and Phgdh significantly decreased after H/R. AVP-mediated enhanced expression of ASCT1 was blocked by the addition of bumetanide. These results suggest that the AVP-mediated attenuated expression of ASCT1 in astrocytes is associated with reduced l-serine production in SHRSP/Izm astrocytes. We hypothesize that reduction of gene expression by AVP might be related to the induction of stroke in the SHRpch1_18 rat strain.


Assuntos
Sistema ASC de Transporte de Aminoácidos/metabolismo , Arginina Vasopressina/metabolismo , Astrócitos/metabolismo , Encéfalo/patologia , Regulação da Expressão Gênica/genética , Acidente Vascular Cerebral/patologia , Animais , Arginina Vasopressina/farmacologia , Astrócitos/efeitos dos fármacos , Bumetanida/farmacologia , Morte Celular , Células Cultivadas , Córtex Cerebral/citologia , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 18/genética , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipóxia/metabolismo , Hipóxia/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Acidente Vascular Cerebral/metabolismo
8.
Diabetologia ; 55(11): 2913-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22854890

RESUMO

AIMS/OBJECTIVE: Nephropathy, a major complication of diabetes, is the leading cause of end-stage renal disease. Recent studies have demonstrated that podocyte injury is involved in the onset of and progression to renal insufficiency. Here, we describe a novel, highly sensitive ELISA for detecting urinary podocalyxin, a glycoconjugate on the podocyte apical surface that indicates podocyte injury, particularly in the early phase of diabetic nephropathy. METHODS: Urine samples from patients with glomerular diseases (n = 142) and type 2 diabetes (n = 71) were used to quantify urinary podocalyxin by ELISA. Urine samples were obtained from 69 healthy controls for whom laboratory data were within normal values. Podocalyxin was detected in urine by immunofluorescence, immunoelectron microscopy and western blotting. RESULTS: Morphologically, urinary podocalyxin was present as a vesicular structure; western blotting showed it as a positive band at 165-170 kDa. Levels of urinary podocalyxin were elevated in patients with various glomerular diseases and patients with diabetes. In patients with diabetes, urinary podocalyxin was higher than the cut-off value in 53.8% patients at the normoalbuminuric stage, 64.7% at the microalbuminuric stage and 66.7% at the macroalbuminuric stage. Positive correlations were observed between urinary podocalyxin levels and HbA(1c), urinary ß(2) microglobulin, α(1) microglobulin and urinary N-acetyl-ß-D-glucosaminidase, although urinary podocalyxin levels were not correlated with other laboratory markers such as blood pressure, lipid level, serum creatinine, estimated GFR or proteinuria. CONCLUSIONS/INTERPRETATION: Urinary podocalyxin may be a useful biomarker for detecting early podocyte injury in patients with diabetes.


Assuntos
Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/urina , Ensaio de Imunoadsorção Enzimática/métodos , Podócitos/metabolismo , Sialoglicoproteínas/urina , Adulto , Idoso , Anticorpos Monoclonais , Especificidade de Anticorpos , Biomarcadores/urina , Western Blotting , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/urina , Diagnóstico Precoce , Feminino , Humanos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Masculino , Microscopia Imunoeletrônica , Pessoa de Meia-Idade , Podócitos/patologia , Podócitos/ultraestrutura , Proteinúria/diagnóstico , Proteinúria/urina , Sensibilidade e Especificidade , Sialoglicoproteínas/imunologia
9.
Bone Marrow Transplant ; 47(5): 725-30, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21874059

RESUMO

Oral mucositis (OM) is a frequent adverse effect of allogenic or autologous hematopoietic SCT. It results from direct toxic injury to the mucosal epithelial cells by the immunosuppressive regimen. Here, we compared the incidence and severity of OM between a group of 24 patients who received proper oral management during hematopoietic SCT and a group of 24 who did not. The oral management group received pre-hematopoietic SCT instruction on oral care and an oral examination in the clean room. Differences in the incidence and severity of OM between the two groups were examined statistically. OM was observed in 14 (58.3%) patients in the oral management group and 22 (91.6%) in the control group. The median of the OM score was 1 for the oral management group (range 0 to 3) and 2 for the control group (range 0 to 3). There was a significant difference in the OM score (P<0.05) and in the incidence of OM between the two groups (P<0.01). This study shows that oral management may decrease the occurrence of OM. Our results also suggest that it is important to include an oral management provider on the hematopoietic SCT team.


Assuntos
Assistência Odontológica , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estomatite/etiologia , Adulto , Idoso , Feminino , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estomatite/prevenção & controle
10.
Cent Nerv Syst Agents Med Chem ; 11(1): 45-59, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20812905

RESUMO

Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by various cellular stresses, as well as in response to inflammatory cytokines. In the central nervous systems (CNS), activation of the p38 MAPK pathway constitutes a key step in the development of several diseases, and the molecular mechanisms mediated by p38 MAPK signaling have been defined. Activation of this cascade releases pro-inflammatory cytokines that are known to be involved in cerebral ischemia, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), neuropathic pain and depression. In AD, stimulated p38 MAPK may trigger the hyperphosphorylation of a neural microtubule-associated protein, tau. In addition, we have recently revealed that activation of p38 MAPK signaling decreases dendritic spine number, which may be associated with memory impairment after epileptic seizures. Thus, p38 MAPK can serve as a target for novel drug development for neural diseases. p38 MAPK inhibitors have been studied extensively in both preclinical experiments and clinical trials for inflammatory diseases. New p38 MAPK inhibitors are now being tested in phase II clinical trials for neuropathic pain and depression. Here, we review current and possible future applications of p38 MAPK inhibitors as therapeutic agents in neural diseases.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Linhagem Celular , Ensaios Clínicos como Assunto , Humanos , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/uso terapêutico , Sistema de Sinalização das MAP Quinases/fisiologia , Modelos Moleculares , Estrutura Molecular , Plasticidade Neuronal , Estrutura Terciária de Proteína , Proteínas Quinases p38 Ativadas por Mitógeno/química
11.
Neuroscience ; 170(1): 1-7, 2010 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-20633610

RESUMO

Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) develop severe hypertension, and more than 95% of them die of cerebral stroke. Hypoxic stimulation followed by oxygen reperfusion induces neuronal damage in both normotensive Wistar Kyoto/Izm (WKY/Izm) and SHRSP/Izm rats, and the percentage of neurons that undergo apoptosis during hypoxia-reperfusion is markedly higher in SHRSP/Izm rats than in WKY/Izm rats. The biochemical characteristics of the SHRSP/Izm rats, unlike those of WKY/Izm rats, might act as a factor in the stroke proneness of SHRSP/Izm rats. In the hippocampus, the formation of hydroxyl radicals and the cerebral blood flow-independent formation of nitric oxide (NO) were strongly increased after reperfusion in SHRSP/Izm rats, and the neuronal expression of the thioredoxin and Bcl-2 genes was significantly decreased in the SHRSP/Izm rats compared with the WKY/Izm rats. On the other hand, the effects of antioxidants against neuronal death associated with cerebral ischemia-reperfusion were stronger in the SHRSP/Izm rats, in which the addition of vitamin E or ebselen almost completely inhibited neuronal death. Namely, the addition of 100 microg/ml of vitamin E under hypoxia/reoxygenation (H/R) conditions completely inhibited WKY and SHRSP/Izm neuronal death. Vitamin E exerts a marked inhibitory effect against neuronal damage via its incorporation into mitochondrial membranes, where it captures reactive oxygen and free radicals. The susceptibility of neurons to apoptosis in SHRSP/Izm rats is partly due to an insufficiency of mitochondrial redox regulation and apoptosis-inhibitory proteins. In this review, we describe the neuronal vulnerability of SHRSP/Izm rats induced by cerebral ischemia and the effects of antioxidants such as vitamin E.


Assuntos
Antioxidantes/uso terapêutico , Isquemia Encefálica/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Vitamina E/uso terapêutico , Animais , Antioxidantes/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Humanos , Fármacos Neuroprotetores/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Espécies Reativas de Oxigênio/metabolismo , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Vitamina E/metabolismo
12.
Clin Exp Immunol ; 159(1): 1-10, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19807734

RESUMO

To determine the cytokine balance in patients with lupus nephritis (LN), we analysed kidney-infiltrating T cells. Renal biopsy samples from 15 systemic lupus erythematosus (SLE) patients were used. In accordance with the classification of International Society of Nephrology/Renal Pathology Society, they were categorized into Class III, Class III+V (Class III-predominant group, n = 4), Class IV, Class IV+V (Class IV-predominant group, n = 7) and Class V (n = 4) groups. The single-cell samples of both the glomelular and interstitial infiltrating cells were captured by laser-microdissection. The glomerular and interstitial infiltrating T cells produced interleukin (IL)-2, IL-4, IL-10, IL-13 and IL-17 cytokines in the Class III-predominant, Class IV-predominant and Class V groups. Interferon-gamma was detected only in the glomeruli of the Class III-predominant and Class V group samples. The expression level of IL-17 was correlated closely with clinical parameters such as haematuria, blood urea nitrogen level, SLE Disease Activity Index scores in both glomeruli and interstitium, urine protein level in glomeruli and serum creatinine and creatinine clearance levels in interstitium. This suggests that the glomerular infiltrating T cells might act as T helper type 1 (Th1), Th2 and Th17 cells while the interstitial infiltrating T cells, act as Th2 and Th17 cells in the Class III-predominant and Class V groups. In contrast, both the glomerular and interstitial infiltrating T cells might act as Th2 and Th17 cells in the Class IV-predominant group. The cytokine balances may be dependent upon the classification of renal pathology, and IL-17 might play a critical role in SLE development.


Assuntos
Citocinas/metabolismo , Rim/metabolismo , Terapia a Laser , Nefrite Lúpica/metabolismo , Microdissecção/métodos , Linfócitos T/metabolismo , Actinas/genética , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Biópsia , Citocinas/genética , Feminino , Expressão Gênica/genética , Humanos , Interferon gama/metabolismo , Interleucina-17/genética , Interleucinas/metabolismo , Rim/patologia , Rim/cirurgia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Nefrite Lúpica/cirurgia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Células Th1/metabolismo , Células Th2/metabolismo , Adulto Jovem
13.
Neuroscience ; 153(2): 428-35, 2008 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-18384965

RESUMO

Cerebral ischemia followed by oxygen reperfusion induced apoptosis in hippocampal neurons in the stroke-prone spontaneously hypertensive rat (SHRSP) but not in Wistar Kyoto rats (WKY). We investigated whether 2-phenyl-1,2-benzisoselenazol-3(2H)-one, also called PZ51 (ebselen), useful for treating ischemic damage or antihypertension in the brain, can protect against ischemic neuronal damage in SHRSP. In this study, we compared the effects of ebselen, carvedilol, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) as well as vitamin E, added to cultures of neurons after reoxygenation (20% O(2)) following hypoxia (1% O(2)). SHRSP neurons died rapidly during reoxygenation following hypoxia but were rescued in large measure by 10 muM ebselen (neuronal death; 2.7+/-1.4%). In order of neuroprotective potency, the agents ranked as follows: ebselen>carvedilol>MCI-186>vitamin E. In vivo, strong neuroprotection by ebselen was observed in the hippocampal CA1 region of SHRSP (32.9+/-9.5 apoptotic neuron/1000 neurons, 30 mg/kg/day). Ebselen prevented apoptosis as confirmed by morphological observations in vivo. Its effect was associated with the expression of Bcl-2 and Bax. These findings suggest that ebselen has a marked inhibitory effect on neuronal damage during stroke. Ebselen may be effective in the prevention and/or treatment of neurodegenerative diseases associated with excessive apoptosis in patients with stroke.


Assuntos
Antioxidantes/farmacologia , Azóis/farmacologia , Hipóxia/tratamento farmacológico , Degeneração Neural/prevenção & controle , Compostos Organosselênicos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Acidente Vascular Cerebral/genética , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , DNA Complementar/biossíntese , DNA Complementar/genética , Relação Dose-Resposta a Droga , Hipóxia/complicações , Isoindóis , L-Lactato Desidrogenase/metabolismo , Microscopia Eletrônica , Degeneração Neural/etiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/ultraestrutura , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , RNA/biossíntese , RNA/genética , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Traumatismo por Reperfusão/complicações , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína X Associada a bcl-2/biossíntese
14.
Diabetes Obes Metab ; 9 Suppl 2: 40-5, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17919177

RESUMO

Maturity-onset diabetes of the young (MODY) is a monogenic form of type 2 diabetes mellitus that is characterized by impairment of glucose-stimulated insulin secretion from pancreatic beta-cells. We previously reported that heterozygous mutations of the hepatocyte nuclear factor (HNF)-1alpha gene cause a form of MODY (MODY3). We have subsequently found that collectrin, a recently cloned kidney-specific gene of unknown function, is a novel target of HNF-1alpha in pancreatic beta-cells. In addition, we have demonstrated that collectrin forms a complex with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex by direct interaction with snapin, a protein that is thought to be involved in neurotransmission by binding to synaptosomal-associated protein, 25 KD (SNAP25). Collectrin favours the formation of SNARE complexes and controls insulin exocytosis.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Células Secretoras de Insulina/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas SNARE/metabolismo , Animais , Modelos Animais de Doenças , Exocitose/fisiologia , Humanos , Insulina/metabolismo , Secreção de Insulina , Camundongos , Mutação
15.
J Exp Clin Cancer Res ; 26(2): 215-20, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17725101

RESUMO

Cytokeratin (CK) 13 is an intermediate filament protein that is expressed in a cell-type-specific manner, in the tongue and occasionally in tongue squamous cell carcinoma (SCC). Correlations between the clinical features of patients with SCC and CK13 expression in the tumor are here investigated along with CK13's utility as a marker for tongue cancer status. Samples from 121 patients with SCC of the tongue were examined by immunohistochemistry with antibodies against CK13. Correlations between the expression level of CK13 in the tumor and the patients' clinical features were statistically analyzed by univariate and multivariate methods. Univariate analysis showed a more relevant number of local recurrence (P = 0.04) in CK13-negative staining patients. In addition, CK13-negative cases were associated with local recurrence by multiple logistic regression analysis (OR: 3.36; 95% CI: 1.044-10.78; P = 0.04). Our results suggest that the loss of CK13 expression indicates tumors with a high potential for recurrence, and thus CK13 could be useful for determining the best course of treatment.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/diagnóstico , Queratina-13/análise , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Língua/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imuno-Histoquímica , Queratina-13/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Língua/patologia
16.
Diabetologia ; 50(9): 1900-1909, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17632702

RESUMO

AIMS/HYPOTHESIS: We examined the effect of glucagon-like peptide-1 (GLP-1) on the development of diabetes and islet morphology in NOD mice by administering GLP-1 to prediabetic mice. METHODS: Eight-week-old female NOD mice were infused subcutaneously with human GLP-1 via a mini-osmotic pump for 4 or 8 weeks. In mice treated with GLP-1 for 4 weeks, blood glucose levels and body weight were measured. An intraperitoneal glucose tolerance test (IPGTT) and evaluation of insulitis score were also performed. Beta cell area, proliferation, apoptosis, neogenesis from ducts and subcellular localisation of forkhead box O1 (FOXO1) were examined by histomorphometrical, BrdU-labelling, TUNEL, insulin/cytokeratin and FOXO1/insulin double-immunostaining methods, respectively. RESULTS: Mice treated with human GLP-1 for 4 weeks had lower blood glucose levels until 2 weeks after completion of treatment, showing improved IPGTT data and insulitis score. This effect continued even after cessation of the treatment. In addition to the increase of beta cell neogenesis, BrdU labelling index was elevated (0.24 vs 0.13%, p < 0.001), while apoptosis was suppressed by 54.2% (p < 0.001) in beta cells. Beta cell area was increased in parallel with the translocation of FOXO1 from the nucleus to the cytoplasm. The onset of diabetes was delayed in mice treated with GLP-1 for 4 weeks, while mice treated with GLP-1 for 8 weeks did not develop diabetes by age 21 weeks compared with a 60% diabetes incidence in control mice at this age. CONCLUSIONS/INTERPRETATION: Continuous infusion of human GLP-1 to prediabetic NOD mice not only induces beta cell proliferation and neogenesis, but also suppresses beta cell apoptosis and delays the onset of type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Fragmentos de Peptídeos/fisiologia , Animais , Glicemia/metabolismo , Divisão Celular , Diabetes Mellitus Tipo 1/patologia , Feminino , Teste de Tolerância a Glucose , Humanos , Imuno-Histoquímica , Células Secretoras de Insulina/citologia , Camundongos , Camundongos Endogâmicos NOD , Pâncreas/patologia
17.
Diabetologia ; 50(3): 596-601, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17221211

RESUMO

AIMS/HYPOTHESIS: Type 1A diabetes results from autoimmune destruction of pancreatic beta cells. We examined the involvement of TNF-alpha and IL-1beta, as well as of T cells, macrophages and dendritic cells, in the destruction of beta cells in patients with recent-onset type 1 diabetes. MATERIALS AND METHODS: We obtained pancreatic biopsy specimens from six patients with recent-onset type 1 diabetes and analysed these by immunohistochemistry. RESULTS: T cell infiltration was less common in islets without beta cells (12.5 [0-33.3]%) than in those with beta cells (46.0 [17.4-83.3]%), while macrophages and dendritic cells showed a similar extent of infiltration into islets both with or without beta cells. TNF-alpha was detected in 25.0 (4.3-46.9)% of macrophages and 11.8 (0-40.0)% of dendritic cells infiltrating the islets in samples from each patient, but not at all in T cells. IL-1beta was detected in 1.8 (0-11.3)% of T cells infiltrating the islets with beta cells, while it was found in 19.2 (0-35.3)% of macrophages or 10.7 (0-31.3)% of dendritic cells infiltrating the islets in samples from each patient (all values median [range]). CONCLUSIONS/INTERPRETATION: Macrophages and dendritic cells infiltrate the islets and produce inflammatory cytokines (TNF-alpha and IL-1beta) during the development of type 1A diabetes.


Assuntos
Células Dendríticas/patologia , Diabetes Mellitus Tipo 1/genética , Ilhotas Pancreáticas/fisiopatologia , Macrófagos/patologia , Fator de Necrose Tumoral alfa/biossíntese , Adolescente , Adulto , Antígenos CD/análise , Feminino , Humanos , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/patologia , Masculino , Fator de Necrose Tumoral alfa/sangue
18.
Kidney Int ; 71(2): 159-66, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17136030

RESUMO

The purpose of this study was to explore risk factors affecting the incidence of chronic kidney disease (CKD) in general population. We conducted a 10-year follow-up study with 123 764 (male: 41 012, female: 82 752) adults aged 40 years and over who received community-based annual examinations. The primary outcome for the analysis was the development of CKD during the follow-up period. Predictors for the development of CKD were obtained by the significant hazard ratios (HR) in Cox regression model by sex. During the follow-up period, 4307 subjects (male: 2048, female: 2259) developed CKD stage I or II, and 19 411 subjects (male: 4257, female: 15 154) developed CKD stage III or higher. The baseline-adjusted predictor of developing CKD included age, glomerular filtration rate, hematuria, hypertension, diabetes, serum lipids, obesity, smoking status, and consumption of alcohol. Treated diabetes in male subjects, and treated hypertension, systolic blood pressure >160 mm Hg and/or diastolic blood pressure >100 mm Hg, diabetes, and treated diabetes in female subjects were associated with more than a doubling of the HR. For the development of CKD stage III or higher, proteinuria of >or= + +, and proteinuria and hematuria were associated with more than a doubling of the HR in male subjects. The prevalence of newly developed CKD over 10 years was 23 718 subjects (19.2%) in adults. This study suggested that not only hypertension and diabetes but also several metabolic abnormalities were independent risk factors for developing CKD.


Assuntos
Falência Renal Crônica/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus/diagnóstico , Feminino , Seguimentos , Humanos , Hipertensão/diagnóstico , Incidência , Japão/epidemiologia , Masculino , Doenças Metabólicas/diagnóstico , Pessoa de Meia-Idade , População , Prevalência , Características de Residência , Fatores de Risco
19.
Neuroscience ; 143(3): 729-37, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17027164

RESUMO

In the CNS, l-serine (l-Ser) plays an essential role in neuronal survival by evoking a variety of biological responses in glial cells. Initially, we examined whether glutamate, hydrogen peroxide (H(2)O(2)), interleukin-1 (IL-1) beta, and sodium nitroprusside (SNP) induce the secretion of l-Ser in astrocytes isolated from Wistar Kyoto rats (WKY). The secretion of l-Ser was significantly induced with glutamate and SNP in cultured astrocytes. Next, to gain insight into the involvement of l-Ser in glutamate-induced neuroprotection, we compared the secretion of l-Ser in astrocytes isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive rats, WKY. We also examined the mRNA expression of the enzyme that produces l-Ser, 3-phosphoglycerate dehydrogenase (PHGDH), and a neural amino acid transporter, ASCT1, in the cultured astrocytes. A dose-dependent study of glutamate in astrocytes of SHRSP indicated differences in the secretion of l-Ser, and gene expression of PHGDH and ASCT1, compared with levels in the WKY astrocytes. We demonstrated that both the secretion and the gene expression were significantly attenuated in glutamate-treated astrocytes from SHRSP. Cerebral ischemia in SHRSP induced a massive efflux of glutamate, causing delayed neuronal death in region CA1 of the hippocampus. The results suggest that the attenuated secretion of l-Ser in astrocytes is involved in neuronal vulnerability and survival in SHRSP during the production of glutamate, as the secretion of l-Ser, which is stimulated by glutamate, is closely related to the protective effect against glutamate-mediated neurotoxicity. We conclude that glutamate and SNP up-regulate the secretion of l-Ser in primary astrocytes. Secretion of l-Ser is regulated in astrocytes in response to glutamate and nitric oxide and may correspond to the level of l-Ser needed for neuronal survival during brain insults such as ischemic stroke in SHRSP.


Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Ácido Glutâmico/farmacologia , Serina/metabolismo , Análise de Variância , Animais , Células Cultivadas , Córtex Cerebral/citologia , Cromatografia Líquida de Alta Pressão/métodos , Meios de Cultivo Condicionados/química , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/farmacologia , Peróxido de Hidrogênio/farmacologia , Interleucina-1/farmacologia , Fragmentos de Peptídeos/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Especificidade da Espécie , Fatores de Tempo
20.
Bone Marrow Transplant ; 38(3): 237-42, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16850033

RESUMO

Pre-hematopoietic stem cell transplantation (HSCT) dental treatment is essential to prevent serious infections from oral sources during immunosuppression, in patients who undergo HSCT therapy. This study was planned to establish a dental management protocol for such patients. Forty-one patients scheduled for HSCT to treat hematological malignancies were consecutively enrolled in the prospective trial. The dental status of all patients was evaluated by clinical and radiographic examination at a median of 47 days before the commencement of HSCT therapy. Thirty-six patients had one or more dental diseases; the remaining five had none. Caries was found in 26 patients, apical periodontitis in 19, marginal periodontitis in 24 and a partially erupted third molar in 11. Our policy is to preserve patients' teeth whenever possible, and therefore minimal dental intervention was planned. Treatment was completed for all 36 patients with dental pathologies, before the conditioning regimen began. All patients received the scheduled HSCT therapy without alteration, interruption or delay, and did not show any signs or symptoms associated with odontogenic infection while they were immunosuppressed. This protocol, therefore, appears to be appropriate for the pre-HSCT dental treatment of patients with hematological diseases.


Assuntos
Protocolos Clínicos , Assistência Odontológica/métodos , Transplante de Células-Tronco Hematopoéticas , Doenças Periodontais/terapia , Doenças Dentárias/terapia , Adolescente , Adulto , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
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