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The article Lower grip strength and dynamic body balance in women with distal radial fractures, written by. K. Fujita, H. Kaburagi, A. Nimura, T. Miyamoto, Y. Wakabayashi, Y. Seki, H. Aoyama, H. Shimura, R. Kato, A. Okawa was originally published electronically on the publisher's internet portal.
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In this case-control study, we concluded that women with distal radial fractures who were surgically treated showed lower grip strength and dynamic body balancing than those of controls. These results suggest that measurements of grip strength and dynamic body balance may be useful screening tools to assess future fracture risk. INTRODUCTION: Patients with distal radial fractures (DRFs) are at risk of future fragility fractures. However, their physical characteristics and tendencies for falls remain unclear. We aimed to compare the physical characteristics of women with and without distal radial fractures. METHODS: We included 128 women with a DRF as their first fragility fracture (fracture group) who underwent surgical treatment. Concurrently, 128 age- and sex-matched participants without a history of fragility fractures were selected as controls (control group). The participants underwent assessments of grip strength and the body balancing ability test. Measurements were taken twice in the fracture group, at 2 weeks and 6 months postoperatively, and once in the control group. The body balancing ability test included the Functional Reach Test, Timed Up and Go test (TUG), 2-Step test (2ST), and Timed Uni-pedal Stance test. The participants also completed questionnaires about their health. RESULTS: There were no significant differences (p > 0.05) in patient characteristics between the groups. The fracture group showed lower grip strength across all age groups. In the DRF group, prolonged TUG time was observed at 2 weeks postoperatively in all age groups and at 6 months in participants aged 55-74 years; the 2ST score was significantly lower in participants aged between 65 and 74 years. CONCLUSIONS: Women with DRF demonstrated lower grip strength and dynamic body balancing ability. Lower grip strength and dynamic body balancing ability were identified as significant risk factors in women with DRF, suggesting that these may be useful screening tools to assess fracture risk.
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Força da Mão/fisiologia , Fraturas por Osteoporose/fisiopatologia , Equilíbrio Postural/fisiologia , Fraturas do Rádio/fisiopatologia , Acidentes por Quedas , Adulto , Idoso , Densidade Óssea/fisiologia , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/etiologia , Período Pós-Operatório , Curva ROC , Fraturas do Rádio/etiologia , Fraturas do Rádio/cirurgia , Medição de Risco/métodos , Fatores de RiscoRESUMO
Heat shock protein 27 (HSP27) exerts cytoprotection against many cellular insults including cerebral ischemia. We previously indicated that intravenous injection of HSP27 purified from human lymphocytes (hHSP27) significantly reduced infarct volume following cerebral ischemia-reperfusion injury, while recombinant HSP27 (rHSP27) was less effective. Phosphorylation is important for HSP27 function, and hHSP27 was more highly phosphorylated than rHSP27. We hypothesized that MAPKAP kinase 2 in vitro-phosphorylated rHSP27 (prHSP27) might increase its brain protection. Mice underwent transient 1-h middle cerebral artery occlusion (MCAO), and then received tail-vein injections of one of the following 1h after reperfusion: hHSP27 as positive control, rHSP27, prHSP27, or bovine serum albumin (BSA) as control. We measured infarct volume, neurological deficits, neurological severity, physiological parameters, cell-death, oxidative stress, and inflammatory response. Compared with BSA controls (30.7±3.1mm(3), n=5), infarct volume was reduced by 67% in the hHSP27 positive-control group (10.1±4.6mm(3), P<0.001, n=5), 17% following rHSP27 (25.4±3.6mm(3), P<0.05, n=5), and 46% following prHSP27 (16.5±4.0mm(3), P<0.001, n=9). Compared to the rHSP27 and BSA-treated groups, prHSP27 also reduced functional deficits, and significantly suppressed apoptosis, oxidative stress, and inflammatory responses. Here, we showed the superior neuroprotective effects of phosphorylated HSP27 by administering prHSP27. prHSP27 may be a useful therapeutic agent to protect against acute cerebral ischemic stroke.
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Isquemia Encefálica/tratamento farmacológico , Proteínas de Choque Térmico HSP27/administração & dosagem , Proteínas de Choque Térmico HSP27/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/metabolismo , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/patologia , Morte Celular/efeitos dos fármacos , Encefalite/metabolismo , Humanos , Infarto da Artéria Cerebral Média , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Decline in research and development (R&D) productivity and changes in the business environment have led to pharmaceutical company management to strive to improve R&D productivity. This decline is widely considered to be a major cause of industry consolidation and has received increased scholarly attention. This study aims to construct an R&D productivity map to visualize the industry's R&D productivity and to identify similarity in corporate actions with a view to investigate whether there is a relationship between deterioration in R&D productivity and industry consolidation. METHODS: Research and development productivity is decomposed into two subprocesses to measure productivity: R&D efficiency and R&D effectiveness, and scores were calculated using a two-stage data envelopment analysis (DEA). The map is then constructed by projecting outputs. To identify any relationship between DEA scores and merger and acquisition transactions, a multiple regression model is employed. RESULTS AND DISCUSSION: Data on 21 global pharmaceutical companies, statistical results indicated that companies with lower R&D efficiency scores were more likely to engage in consolidation. Three US companies that were least successful in terms of R&D effectiveness, as measured by our indicators, were either acquired or changed their business model. CONCLUSION: The R&D productivity map is a useful means for visualizing productivity among companies. By grouping companies into four groups, behavioural commonalities can be observed. The R&D productivity map should be useful for monitor the industry's productivity and help to improve it.
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Indústria Farmacêutica/organização & administração , Eficiência Organizacional , Pesquisa/organização & administração , Indústria Farmacêutica/economia , Indústria Farmacêutica/tendências , Humanos , Análise de Regressão , Pesquisa/economia , Pesquisa/tendênciasRESUMO
AIM: Colonic diverticular hemorrhage often recurs. Several studies have identified risk factors for recurrence, but to our knowledge, none have focused on risk factors in the clinical situation. The present study aimed to identify risk factors for the recurrence of hemorrhage and to create a recurrence risk score. METHOD: Hospitalized patients diagnosed with diverticular bleeding from 2008 to 2013 (N = 151) were included in a retrospective cohort study. Risk factors predicting re-bleeding were identified using multivariate analysis, and a risk score was developed using receiver operator characteristic (ROC) analysis. RESULTS: Recurrence was identified in 52 patients (34.4%) at a median interval of 11.5 months. A history of hypertension and hyperlipidemia, a faster heart rate on admission, and longer hospitalization period were significant risk factors for re-bleeding. We developed a re-bleeding risk score by using these 4 factors; the area under the curve of ROC curve was 0.8. With this risk score, if the cut-off point is 7, then the sensitivity is very high (94%; specificity: 26%); if the cutoff point is 14, the specificity is very high (97%; sensitivity: 40%). This enables the division of patients into 3 groups: high risk, intermediate risk, and low risk. CONCLUSION: Colonic diverticular hemorrhage often recurs, and patients have high recurrence rates within short periods. Risk factors for re-bleeding include a history of hypertension and hyperlipidemia, faster heart rate, and longer hospitalization period, and the risk score may supply useful information for clinicians to aid management.
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Divertículo do Colo/diagnóstico , Divertículo do Colo/epidemiologia , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Recidiva , Estudos Retrospectivos , Fatores de RiscoRESUMO
Glutamate plays a central role in brain physiology and pathology. The involvement of excitatory amino acid transporters (EAATs) in neurodegenerative disorders including acute stroke has been widely studied, but little is known about the role of glial glutamate transporters in white matter injury after chronic cerebral hypoperfusion. The present study evaluated the expression of glial (EAAT1 and EAAT2) and neuronal (EAAT3) glutamate transporters in subcortical white matter and cortex, before and 3-28 days after the ligation of bilateral common carotid arteries (LBCCA) in rat brain. K-B staining showed a gradual increase of demyelination in white matter after ischemia, while there was no cortical involvement. Between 3 and 7 days after LBCCA, a significant increase in EAAT2 protein levels was observed in the ischemic brain and the number of EAAT2-positive cells also significantly increased both in the cortical and white matter lesions. EAAT2 was detected in glial-fibrillary acidic protein (GFAP)-positive astrocytes in both the cortex and white matter, but not in neuronal and oligodendroglial cells. EAAT1 was slightly elevated after ischemia only in the white matter, but EAAT3 was at almost similar levels both in the cortex and white matter after ischemia. A significant increase in EAAT2 expression level was also noted in the deep white matter of chronic human ischemic brain tissue compared to the control group. Our findings suggest important roles for up-regulated EAAT2 in chronic brain ischemia especially in the regulation of high-affinity of extracellular glutamate and minimization of white matter damage.
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Isquemia Encefálica/metabolismo , Corpo Caloso/metabolismo , Transportador 2 de Aminoácido Excitatório/biossíntese , Proteínas de Transporte de Glutamato da Membrana Plasmática/biossíntese , Fibras Nervosas Mielinizadas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Astrócitos/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Estudos de Casos e Controles , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Doença Crônica , Corpo Caloso/patologia , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/metabolismo , Transportador 1 de Aminoácido Excitatório/biossíntese , Transportador 3 de Aminoácido Excitatório/biossíntese , Feminino , Humanos , Masculino , Fibras Nervosas Mielinizadas/patologia , Neurônios/metabolismo , Oligodendroglia/metabolismo , Ratos , Regulação para CimaRESUMO
An extremely rare case of intractable ulcer caused by Mycobacterium shinshuense is described. A 59-year-old Japanese woman developed an ulcerated subcutaneous induration on the upper arm. Ziehl-Neelsen staining revealed positive bacilli. Tissue culture isolated Mycobacterium species, but standard identification techniques (including molecular biological approaches such as DNA-DNA hybridization) could not distinguish the precise causative pathogen, although it was narrowed down to three possibilities: Mycobacterium marinum, Mycobacterium ulcerans and M. shinshuense. Finally, a novel 16S rRNA sequencing method enabled the diagnosis of M. shinshuense infection. The epidemiology of the cutaneous infection caused by this mycobacterium has yet to be elucidated, but a review of reported cases indicated that ulcers having some resemblance to those caused by M. ulcerans infection were found in nonendemic areas and that M. shinshuense could be considered as the cause. The approach introduced in this report could provide a powerful tool for the identification of this organism.
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Infecções por Mycobacterium/microbiologia , Micobactérias não Tuberculosas/classificação , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Úlcera/microbiologia , Feminino , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Micobactérias não Tuberculosas/genéticaRESUMO
Various stimuli, such as ischemia/hypoxia enhance newborn cell survival in the subventricular zone and their migration tangentially in chains toward the olfactory bulb. The present study assessed the fate of newborn neurons from subventricular zone to olfactory bulb under conditions of chronic cerebral hypoperfusion, and examined the role of cAMP-responsive element binding protein signaling on the survival of these neurons by using cilostazol, a potent inhibitor of type III phosphodiesterase. Rats underwent bilateral common carotid artery ligation. They were divided into sham-operated (n=70), vehicle- (n=70), and type III phosphodiesterase inhibitor-treated (n=70) groups. Immunohistochemically-stained section for 5-bromodeoxyuridine and a series of neuronal and glial markers were analyzed at days 7, 14, 21 and 28 after hypoperfusion. The reduction of olfactory bulb size gradually progressed in the vehicle group (P<0.05), but not in the sham-operated and type III phosphodiesterase inhibitor-treated group. The subventricular zone of the vehicle-treated rats contained significantly larger numbers of newborn neuroblasts after hypoperfusion, compared with sham-operated rats (P<0.05), but significantly lower numbers in the rostral migratory stream and olfactory bulb (P<0.05). Treatment of rats with type III phosphodiesterase inhibitor increased the number of neuroblasts and enhanced the survival and differentiation of cells (P<0.05). Phosphorylated cAMP-responsive element binding protein within neuroblasts was markedly decreased in the subventricular zone, rostral migratory stream, and olfactory bulb of vehicle-treated rats (P<0.05), but treatment with type III phosphodiesterase inhibitor resulted in recovery of this expression throughout hypoperfusion, leading to enhanced neurogenesis (P<0.05). These effects were abrogated by protein kinase A and C inhibitor. Our results indicated that cAMP-responsive element binding protein signaling is a key mediator of neurogenesis after prolonged hypoperfusion and provide the basis for new regenerative therapies for ischemic brain injury.
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Isquemia Encefálica/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Neurônios/patologia , Serina/metabolismo , Células-Tronco/patologia , Animais , Apoptose , Isquemia Encefálica/etiologia , Isquemia Encefálica/fisiopatologia , Estenose das Carótidas/complicações , Ventrículos Cerebrais/patologia , Circulação Cerebrovascular , Doença Crônica , Cilostazol , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Masculino , Bulbo Olfatório/patologia , Inibidores da Fosfodiesterase 3 , Fosforilação , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Wistar , Transdução de Sinais , Tetrazóis/farmacologiaRESUMO
Friction occurs between solid surfaces, and even sometimes on lubricated surfaces. To understand tribological subjects, it is important to know the changes that occur in friction surfaces. In this study, a laser strobe technique is applied to a friction surface observation. The recorded surface images were analysed using pattern-matching methods and their correlations are discussed. A test using pin-on-plate methods with carbon steels was performed using a reciprocating motion speed of 10 Hz for 4.9 N. A pulsed laser light (Nd:YAG SHG=532 nm, 5 ns per pulse) was irradiated onto the friction surface. It was induced using an optical microscope that was located just to the side of the pin. The laser pulse was synchronized with the plate motion, which was a trigger of the laser pulse. The surface image was stored for every cycle. These sequences were calculated and their correlations were analysed as a function of the surface pattern and the friction track size and shape. Analysis revealed that some groups were distinguishable as parameters of the damage size and shape.
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In this study, we designed an in vitro azoxymethane (AOM)-induced carcinogenesis model and analyzed the effect of deoxycholic acid (DCA) on growth, apoptosis, genotoxicity, and transformation of IEC6 intestinal cells. CYP2E1 production was confirmed in IEC6 cells. The growth of IEC6 cells was enhanced by DCA (100 microg/ml). However, IEC6 cells treated with DCA (200 microg/ml) were inhibited and disappeared at 48 hrs after treatment. Apoptotic cells increased 11.2 times by treatment with DCA (200 microg/ml) as compared to cells with no treatment. DNA injury detected by comet assay was found in cells treated with AOM, but not in cells treated with DCA (100 microg/ml) and AOM. The number of colony formation in soft agar increased by AOM treatment. However, the number of foci treated with DCA (100 microg/ml) plus AOM was 69% that of cells treated with AOM alone. Two out of the 6 mice subcutaneously injected with AOM-treated IEC6 cells showed tumorigenesis, whereas IEC6 cells treated with DCA (100 microg/ml) plus AOM or DCA (100 microg/ml) alone did not form any tumor. Reduced protein expression of MLH1, Bcl-2 was detected in IEC6 cells treated with DCA (100 microg/ml). Production of Bax, pJNK, TGF-beta, TGFBRI, TGFBRII, and beta-catenin were higher in IEC6 cells treated with DCA (100 microg/ml) than that in cells with no treatment. These results suggest that high-dose DCA induced apoptosis and inhibited AOM-induced in vitro transformation of IEC6 cells.
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Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Ácido Desoxicólico/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Azoximetano/toxicidade , Carcinógenos/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Ensaio Cometa , Citocromo P-450 CYP2E1 , Técnicas In Vitro , Camundongos , Camundongos Nus , RatosRESUMO
PURPOSE: To present a novel method for analyzing the voltage waveform from high-frequency X-ray generators for radiographic systems. MATERIAL AND METHODS: The output signal of the actual voltage across the tube of a high-frequency generator was measured using the built-in voltage sense taps that are used for voltage regulation feedback in X-ray generators. The output signal was stored in an analyzing recorder, and the waveforms were analyzed using FFT analysis. The FFT analysis of high-frequency generators consisted of obtaining the power spectrum, comparing the major frequency components in the tube voltage waveforms, and examining the intensity of each frequency component. RESULTS: FFT analysis enables an objective comparison of the complex tube voltage waveforms in high-frequency X-ray generators. FFT analysis detected the change in the X-ray tube voltage waveform that occurred when there were problems with the high-frequency generator. CONCLUSION: High-frequency X-ray generators are becoming the universal choice for radiographic systems. The X-ray tube voltage and its waveform are important features of an X-ray generator, and quality assurance (QA) is important, too. As a tool for engineers involved in the design and development of X-ray generators, we can see that our methods (FFT analysis) might have some value as a means of describing generator performance under varying conditions. Furthermore, since the X-ray tube voltage waveform of a high-frequency generator is complex, FFT analysis may be useful for QA of the waveform.
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Eletricidade , Análise de Fourier , Radiografia/instrumentação , Radiometria/métodos , Algoritmos , Humanos , Garantia da Qualidade dos Cuidados de Saúde/métodos , Reprodutibilidade dos TestesRESUMO
A 66-year-old woman underwent coronary artery bypass grafting (CABG). Postoperative angiography on postoperative day (POD) 11 revealed that right internal thoracic artery (RITA) anastomosed to left anterior descending artery (LAD) had a kinking. The angiography performed 30 months after operation revealed no specific changes in the kinking of RITA and in the left ventricular function. Another case was a 74-year-old man with chronic renal failure under hemodialysis. He underwent CABG with left internal thoracic artery (LITA) to LAD. Post-operatively he had chest pain during hemodialysis. On POD 10, angiography revealed that LITA had a kinking with moderate stenosis and normal left ventricular function. The angiography performed 10 months after operation revealed no specific changes in the kinking of LITA. However, left ventriculography revealed akinesis in the antero-apical region. It suggested that the viability was lost due to the graft kinking of LITA and steal phenomenon on hemodialysis.
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Ponte de Artéria Coronária/métodos , Doença das Coronárias/cirurgia , Artéria Torácica Interna/diagnóstico por imagem , Artéria Torácica Interna/transplante , Complicações Pós-Operatórias/diagnóstico por imagem , Idoso , Doença das Coronárias/diagnóstico por imagem , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Radiografia , Diálise RenalRESUMO
BACKGROUND: The risk of port site metastasis in laparoscopic surgery for cancer patients is a problem that has yet to be resolved. We examined the protective effect of a sodium hyaluronate-based bioresorbable membrane (Seprafilm) on tumor cell implantation at laparoscopic trocar sites. METHODS: Four 2-mm trocar sites were created in nude mice, and the peritoneal wounds were covered with different-sized pieces of Seprafilm. The protective effect of Seprafilm on the implantation of GB-d1 (a human gallbladder cancer cell line) at the trocar sites was assessed after 7 days. In addition, the effects of sodium hyaluronate and Seprafilm on the growth and motility of GB-d1 were examined in vitro. RESULTS: Seprafilm significantly decreased the incidence of implantation compared with the control group. Histologically, Seprafilm was observed on days 1 and 3, as a sheet of gel that covered the injured peritoneum and muscle layer. In an invasion assay using Seprafilm, no cells were found to infiltrate through the gel sheet. CONCLUSION: Seprafilm protects peritoneal wounds by physically covering the injured peritoneum. Therefore, if Seprafilm were attached to the injured peritoneum after laparoscopic surgery for cancer patients, it might reduce port site metastasis.
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Adenocarcinoma/prevenção & controle , Materiais Biocompatíveis/uso terapêutico , Carboximetilcelulose Sódica/uso terapêutico , Colecistectomia Laparoscópica/efeitos adversos , Neoplasias da Vesícula Biliar/cirurgia , Ácido Hialurônico/uso terapêutico , Implantes Experimentais , Membranas Artificiais , Inoculação de Neoplasia , Neoplasias Peritoneais/prevenção & controle , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Animais , Materiais Biocompatíveis/administração & dosagem , Carboximetilcelulose Sódica/administração & dosagem , Linhagem Celular Tumoral , Colecistectomia Laparoscópica/métodos , Neoplasias da Vesícula Biliar/patologia , Géis , Humanos , Ácido Hialurônico/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Peritoneais/etiologia , Instrumentos Cirúrgicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We analyzed 44 patients undergoing coronary artery bypass grafting (CABG) from November 2001 to March 2003. Of 44 patients, 40 patients (29 men and 11 women; mean age 68.1 +/- 9.2 years) underwent off-pump CABG (OPCAB) [90.9%]. The mean number of bypass grafts was 2.53 +/- 0.78. In-hospital mortality was none and major complications except for one case of reexploration for bleeding were not seen. The early patency rate of over-all grafts was 94.6%. The quality of OPCAB was considered to be equivalent to conventional CABG.
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Ponte Cardiopulmonar , Ponte de Artéria Coronária/métodos , Doença das Coronárias/cirurgia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Garantia da Qualidade dos Cuidados de Saúde , Estudos Retrospectivos , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
Prior selective cerebral perfusion is the method whereby selective cerebral perfusion and systemic perfusion start almost simultaneously, and the arch vessels are clamped. Cerebral circulation is isolated from systemic circulation to avoid cerebral embolization owing to detachment of atherosclerotic material from the aorta, caused by the "sandblasting" effect of high-velocity jets of blood exiting the aortic canula. Twenty-seven consecutive patients underwent total arch replacement for degenerative aortic arch aneurysm using prior selective cerebral perfusion from 1992 to 2001. Surgical death (within 1 month after operation) was 2 cases (7.4%), in-hospital death was 5 cases (18.5%). Systemic circulatory arrest time is almost equal to the time which distal anastomosis takes. The time was 81.4 +/- 24.3 minutes. Selective cerebral perfusion time was 194.9 +/- 30.9 minutes. Extracorporeal circulation time was 280.6 +/- 55.3 minutes. The time for emergence from anesthesia was 6.0 +/- 2.7 hours. Permanent neurologic dysfunction which was thought to occurred within 48 hours after surgery was noted in 1 case (3.7%). Postoperative survival at 8 years was 73.3%. There was 1 arch aneurismal related accident. Prior selective cerebral perfusion may be useful for avoiding cerebral embolization.
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Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular , Perfusão/métodos , Cuidados Pré-Operatórios , Idoso , Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/mortalidade , Implante de Prótese Vascular/mortalidade , Circulação Cerebrovascular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Autosomal recessive juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease. AR-JP is characterized by selective and massive loss of dopaminergic neurons in the substantia nigra of the midbrain and absence of Lewy bodies, the pathological hallmark of idiopathic Parkinson's disease. Parkin, the causative gene of AR-JP, encodes a 52-kDa protein that is a RING-type ubiquitin (Ub) protein ligase (E3) collaborating with a Ub-conjugating enzyme (E2) belonging to a cognate class of UbcH7 or UbcH8. Analysis of parkin mutations in AP-JP patients reveals that the functional loss of parkin as an E3 enzyme is the molecular basis of AR-JP. Thus it is now clear that AR-JP is due to failure of proteolysis mediated by the Ub-proteasome system and accumulation of as yet unidentified protein(s) causes nigral neuronal death without formation of Lewy bodies. These findings should shed new light on the mechanisms underlying neurodegeneration in sporadic Parkinson's disease as well as AR-JP.
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Encéfalo/metabolismo , Ligases/fisiologia , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/metabolismo , Ubiquitina-Proteína Ligases , Ubiquitina/fisiologia , Animais , Humanos , Ligases/genética , Modelos Biológicos , Doença de Parkinson/genética , Transtornos Parkinsonianos/genética , Substância Negra/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismoRESUMO
BACKGROUND: In spite of many reports focusing on prognostic factors after hepatectomy in patients with colorectal liver metastases, few studies have investigated pathological factors, eg, fibrous pseudocapsulation, growth pattern at the tumor margin, and proliferation activity of cancer cells, other than histological type and surgical margin. The aim of the present study was to investigate whether absence of pseudocapsulation, infiltrative growth pattern of metastases, and higher proliferation of cancer cells shown by Ki-67 immunohistochemical reactivity were associated with poorer survival after hepatectomy among patients with colorectal liver metastases. METHODS: Between 1988 and 1998, 221 patients underwent hepatic resection of colorectal metastases with curative intent in our institution. Pathology analyses were focused on pseudocapsulation of liver metastases, growth pattern at the tumor edge, and Ki-67 labelling index (Ki-67 LI) of cancer cell nuclei. Univariate analyses of survival and of disease-free survival were performed for several clinicopathological factors, and multivariate analyses of survival and disease-free survival were also performed. RESULTS: The univariate survival analyses showed that pseudocapsulation, growth pattern, and Ki-67 LI were significant prognostic factors, besides synchronous versus metachronous occurrence of metastases, carcinoembryonic antigen level before hepatectomy, and number of metastases. A multivariate analysis showed that Ki-67 labeling index was the most reliable prognostic factor of survival. In addition, Ki-67 LI and microscopic growth pattern were multivariately predictive factors of disease-free survival. CONCLUSIONS: This large single-institution study showed that investigation of cancer cell proliferation and pathologic characteristics of the tumor margin are major prognostic factors.
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Neoplasias Colorretais/patologia , Hepatectomia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Análise de Variância , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica/patologia , Valor Preditivo dos Testes , Prognóstico , Taxa de SobrevidaRESUMO
We have reviewed recent progress in establishing the function of alpha-synuclein and parkin in relation to nigral degeneration in autosomal dominant and autosomal recessive PD. Mutations of alpha-synuclein (Ala53Thr and Ala30Pro) cause a form of autosomal dominant PD with early onset. Parkin is a novel protein expressed in the cytoplasm, including the terminal regions and Golgi apparatus. Mutations of parkin cause a form of autosomal recessive young-onset PD (ARJP). Both proteins appear to be associated with fast axonal transport. In addition, in sporadic PD, normal alpha-synuclein shows an increased tendency to self-aggregate. Thus, altered axonal transport of presynaptic proteins appears to play a crucial role in neurodegeneration in PD.
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Ligases/genética , Proteínas do Tecido Nervoso/genética , Transtornos Parkinsonianos/genética , Ubiquitina-Proteína Ligases , Humanos , Degeneração Neural/genética , Degeneração Neural/patologia , Transtornos Parkinsonianos/patologia , Sinucleínas , alfa-SinucleínaRESUMO
We recently identified a novel gene, parkin, as a pathogenic gene for autosomal recessive juvenile parkinsonism. Parkin encodes a 52-kDa protein with a ubiquitin-like domain and two RING-finger motifs. To provide a insight into the function of parkin, we have examined its intracellular distribution in cultured cells. We found that parkin was localized in the trans-Golgi network and the secretory vesicles in U-373MG or SH-SY5Y cells by immunocytochemical analyses. In the subsequent subcellular fractionation studies of rat brain, we showed that parkin was copurified with the synaptic vesicles (SVs) when we used low ionic conditions throughout the procedure. An immunoelectromicroscopic analysis indicated that parkin was present on the SV membrane. Parkin was readily released from SVs into the soluble phase by increasing ionic strength at neutral pH, but not by a non-ionic detergent. To elucidate its responsible region for membrane association, we transfected with green fluorescent protein-tagged deletion mutants of parkin into COS-1 cells followed by subcellular fractionation. We demonstrated the ability of parkin to bind to the membranes through a broad region except for the ubiquitin-like domain. The significance of SV localization of parkin is discussed.
Assuntos
Ligases/metabolismo , Vesículas Secretórias/metabolismo , Ubiquitina-Proteína Ligases , Animais , Fusão Gênica Artificial , Encéfalo/metabolismo , Células COS , Complexo de Golgi/metabolismo , Proteínas de Fluorescência Verde , Humanos , Membranas Intracelulares/metabolismo , Ligases/genética , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Mutação/fisiologia , Ratos , Frações Subcelulares/metabolismo , Distribuição Tecidual , Transfecção , Células Tumorais CultivadasRESUMO
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive accumulation in selected neurons of protein inclusions containing alpha-synuclein and ubiquitin. Rare inherited forms of PD are caused by autosomal dominant mutations in alpha-synuclein or by autosomal recessive mutations in parkin, an E3 ubiquitin ligase. We hypothesized that these two gene products interact functionally, namely, that parkin ubiquitinates alpha-synuclein normally and that this process is altered in autosomal recessive PD. We have now identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UbcH7 as its associated E2 ubiquitin conjugating enzyme, and a new 22-kilodalton glycosylated form of alpha-synuclein (alphaSp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive PD failed to bind alphaSp22. In an in vitro ubiquitination assay, alphaSp22 was modified by normal but not mutant parkin into polyubiquitinated, high molecular weight species. Accordingly, alphaSp22 accumulated in a non-ubiquitinated form in parkin-deficient PD brains. We conclude that alphaSp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathological alphaSp22 accumulation. These findings demonstrate a critical biochemical reaction between the two PD-linked gene products and suggest that this reaction underlies the accumulation of ubiquitinated alpha-synuclein in conventional PD.