RESUMEN
BACKGROUND: Total knee arthroplasty (TKA) is a cost-effective procedure, but it is also associated with substantial postoperative pain. The present study aimed to compare pain relief and functional recovery after TKA among groups that received intravenous corticosteroids, periarticular corticosteroids, or a combination of both. METHODS: This randomized, double-blinded clinical trial in a local institution in Hong Kong recruited 178 patients who underwent primary unilateral TKA. Six of these patients were excluded because of changes in surgical technique; 4, because of their hepatitis B status; 2, because of a history of peptic ulcer; and 2, because they declined to participate in the study. Patients were randomized 1:1:1:1 to receive placebo (P), intravenous corticosteroids (IVS), periarticular corticosteroids (PAS), or a combination of intravenous and periarticular corticosteroids (IVSPAS). RESULTS: The pain scores at rest were significantly lower in the IVSPAS group than in the P group over the first 48 hours (p = 0.034) and 72 hours (p = 0.043) postoperatively. The pain scores during movement were also significantly lower in the IVS and IVSPAS groups than in the P group over the first 24, 48, and 72 hours (p ≤ 0.023 for all). The flexion range of the operatively treated knee was significantly better in the IVSPAS group than in the P group on postoperative day 3 (p = 0.027). Quadriceps power was also greater in the IVSPAS group than in the P group on postoperative days 2 (p = 0.005) and 3 (p = 0.007). Patients in the IVSPAS group were able to walk significantly further than patients in the P group in the first 3 postoperative days (p ≤ 0.003). Patients in the IVSPAS group also had a higher score on the Elderly Mobility Scale than those in the P group (p = 0.036). CONCLUSIONS: IVS and IVSPAS yielded similar pain relief, but IVSPAS yielded a larger number of rehabilitation parameters that were significantly better than those in the P group. This study provides new insights into pain management and postoperative rehabilitation following TKA. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.
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Artroplastia de Reemplazo de Rodilla , Manejo del Dolor , Humanos , Anciano , Manejo del Dolor/métodos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Resultado del Tratamiento , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Corticoesteroides , Anestésicos Locales , Método Doble CiegoRESUMEN
MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.
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Proteínas de Ciclo Celular/genética , Enfermedades Cerebelosas/genética , Proteínas del Citoesqueleto/genética , ADN Mitocondrial , Enfermedades Mitocondriales/genética , Distrofias Musculares/genética , Mutación , Adolescente , Adulto , Atrofia , Células Cultivadas , Enfermedades Cerebelosas/diagnóstico por imagen , Enfermedades Cerebelosas/patología , Enfermedades Cerebelosas/fisiopatología , Niño , Variaciones en el Número de Copia de ADN , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/patología , Enfermedades Mitocondriales/fisiopatología , Músculos/patología , Distrofias Musculares/diagnóstico por imagen , Distrofias Musculares/patología , Distrofias Musculares/fisiopatología , Fenotipo , Adulto JovenRESUMEN
Mitochondrial respiratory chain complex I consists of 44 different subunits and contains 3 functional modules: the Q-, the N- and the P-module. NDUFA9 is a Q-module subunit required for complex I assembly or stability. However, its role in complex I biogenesis has not been studied in patient fibroblasts. So far, a single patient carrying an NDUFA9 variant with a severe neonatally fatal phenotype has been reported. Via exome sequencing, we identified a novel homozygous NDUFA9 missense variant in another patient with a milder phenotype including childhood-onset progressive generalized dystonia and axonal peripheral neuropathy. We performed complex I assembly analysis using primary skin fibroblasts of both patients. Reduced complex I abundance and an accumulation of Q-module subassemblies were present in both patients but more pronounced in the severe clinical phenotype patient. The latter displayed additional accumulation of P-module subassemblies, which was not present in the milder-phenotype patient. Lentiviral complementation of both patient fibroblast cell lines with wild-type NDUFA9 rescued complex I deficiency and the assembly defects. Our report further characterizes the phenotypic spectrum of NDUFA9 deficiency and demonstrates that the severity of the clinical phenotype correlates with the severity of the effects of the different NDUFA9 variants on complex I assembly.
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Complejo I de Transporte de Electrón/genética , Proteínas Mitocondriales/genética , Mutación Puntual , Células Cultivadas , Complejo I de Transporte de Electrón/metabolismo , Resultado Fatal , Células HEK293 , Humanos , Recién Nacido , Masculino , Proteínas Mitocondriales/metabolismo , Secuenciación del Exoma/métodosRESUMEN
Nasopharyngeal carcinoma (NPC) is a cancer that occurs in high frequency in Southern China. A previous functional complementation approach and the subsequent cDNA microarray analysis have identified that serum amyloid A1 (SAA1) is an NPC candidate tumor suppressor gene. SAA1 belongs to a family of acute-phase proteins that are encoded by five polymorphic coding alleles. The SAA1 genotyping results showed that only three SAA1 isoforms (SAA1.1, 1.3 and 1.5) were observed in both Hong Kong NPC patients and healthy individuals. This study aims to determine the functional role of SAA1 polymorphisms in tumor progression and to investigate the relationship between SAA1 polymorphisms and NPC risk. Indeed, we have shown that restoration of SAA1.1 and 1.3 in the SAA1-deficient NPC cell lines could suppress tumor formation and angiogenesis in vitro and in vivo. The secreted SAA1.1 and SAA1.3 proteins can block cell adhesion and induce apoptosis in the vascular endothelial cells. In contrast, the SAA1.5 cannot induce apoptosis or inhibit angiogenesis because of its weaker binding affinity to αVß3 integrin. This can explain why SAA1.5 has no tumor-suppressive effects. Furthermore, the NPC tumors with this particular SAA1.5/1.5 genotype showed higher levels of SAA1 gene expression, and SAA1.1 and 1.3 alleles were preferentially inactivated in tumor tissues that were examined. These findings further strengthen the conclusion for the defective function of SAA1.5 in suppression of tumor formation and angiogenesis. Interestingly, the frequency of the SAA1.5/1.5 genotype in NPC patients was ~2-fold higher than in the healthy individuals (P=0.00128, odds ratio=2.28), which indicates that this SAA1 genotype is significantly associated with a higher NPC risk. Collectively, this homozygous SAA1.5/1.5 genotype appears to be a recessive susceptibility gene, which has lost the antiangiogenic function, whereas SAA1.1 and SAA1.3 are the dominant alleles of the tumor suppressor phenotype.
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Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Neoplasias Nasofaríngeas , Neovascularización Patológica , Polimorfismo Genético , Proteína Amiloide A Sérica , Proteínas Supresoras de Tumor , Alelos , Apoptosis , Carcinoma , Adhesión Celular , Línea Celular Tumoral , Técnicas de Cocultivo , Células Endoteliales , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Proteína Amiloide A Sérica/biosíntesis , Proteína Amiloide A Sérica/genética , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/genéticaRESUMEN
Metastasis is the predominant cause of death in breast cancer patients. Several lines of evidence have shown that microRNAs (miRs) can have an important role in cancer metastasis. Using isogenic pairs of low and high metastatic lines derived from a human breast cancer line, we have identified miR-149 to be a suppressor of breast cancer cell invasion and metastasis. We also identified GIT1 (G-protein-coupled receptor kinase-interacting protein 1) as a direct target of miR-149. Knockdown of GIT1 reduced migration/invasion and metastasis of highly invasive cells. Re-expression of GIT1 significantly rescued miR-149-mediated inhibition of cell migration/invasion and metastasis. Expression of miR-149 impaired fibronectin-induced focal adhesion formation and reduced phosphorylation of focal adhesion kinase and paxillin, which could be restored by re-expression of GIT1. Inhibition of GIT1 led to enhanced protein degradation of paxillin and α5ß1 integrin via proteasome and lysosome pathways, respectively. Moreover, we found that GIT1 depletion in metastatic breast cancer cells greatly reduced α5ß1-integrin-mediated cell adhesion to fibronectin and collagen. Low level of miR-149 and high level of GIT1 was significantly associated with advanced stages of breast cancer, as well as with lymph node metastasis. We conclude that miR-149 suppresses breast cancer cell migration/invasion and metastasis by targeting GIT1, suggesting potential applications of the miR-149-GIT1 pathway in clinical diagnosis and therapeutics.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular/metabolismo , Integrinas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias de la Mama/metabolismo , Proteínas de Ciclo Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Integrinas/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia/patología , Transducción de Señal , Células Tumorales CultivadasRESUMEN
Genetic rearrangement by recombination is one of the major driving forces for genome evolution, and recombination is known to occur in non-random, discreet recombination sites within the genome. Mapping of recombination sites has proved to be difficult, particularly, in the human MHC region that is complicated by both population variation and highly polymorphic HLA genes. To overcome these problems, HLA-typed individuals from three representative populations: Asian, European and African were used to generate phased HLA haplotypes. Extended haplotype homozygosity (EHH) plots constructed from the phased haplotype data revealed discreet EHH drops corresponding to recombination events and these signatures were observed to be different for each population. Surprisingly, the majority of recombination sites detected are unique to each population, rather than being common. Unique recombination sites account for 56.8% (21/37 of total sites) in the Asian cohort, 50.0% (15/30 sites) in Europeans and 63.2% (24/38 sites) in Africans. Validation carried out at a known sperm typing recombination site of 45 kb (HLA-F-telomeric) showed that EHH was an efficient method to narrow the recombination region to 826 bp, and this was further refined to 660 bp by resequencing. This approach significantly enhanced mapping of the genomic architecture within the human MHC, and will be useful in studies to identify disease risk genes.
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Mapeo Cromosómico , Genoma Humano , Haplotipos , Complejo Mayor de Histocompatibilidad/genética , Recombinación Genética , Alelos , Pueblo Asiatico , Secuencia de Bases , Población Negra , Variación Genética , Prueba de Histocompatibilidad , Homocigoto , Humanos , Desequilibrio de Ligamiento , Masculino , Datos de Secuencia Molecular , Espermatozoides/metabolismo , Población BlancaRESUMEN
We report a novel HLA-B*13 allele, B*13:50, found using high-resolution sequence-based typing in a Chinese donor. B*13:50 differs from B*13:01:01 by a single-nucleotide substitution (AâT) at position 482, in exon 3.
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Alelos , Exones/genética , Antígenos HLA-B/genética , Mutación Missense , Pueblo Asiatico , Análisis Mutacional de ADN , Humanos , SingapurRESUMEN
BACKGROUND AND PURPOSE: Little information exists on the mechanisms that precipitate brain stem death, the legal definition of death in many developed countries. We investigated the role of tropomyocin receptor kinase B (TrkB) and its downstream signalling pathways in the rostral ventrolateral medulla (RVLM) during experimental brain stem death. EXPERIMENTAL APPROACH: An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos bilaterally into the RVLM of Sprague-Dawley rats was used, in conjunction with cardiovascular, pharmacological and biochemical evaluations. KEY RESULTS: A significant increase in TrkB protein, phosphorylation of TrkB at Tyr(516) (pTrkB(Y516) ), Shc at Tyr(317) (pShc(Y317) ) or ERK at Thr(202) /Tyr(204) , or Ras activity in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Microinjection bilaterally into RVLM of a specific TrkB inhibitor, K252a, antagonized those increases. Pretreatment with anti-pShc(Y317) antiserum, Src homology 3 binding peptide (Grb2/SOS inhibitor), farnesylthioacetic acid (Ras inhibitor), manumycin A (Ras inhibitor) or GW5074 (Raf-1 inhibitor) blunted the preferential augmentation of Ras activity or ERK phosphorylation in RVLM and blocked the up-regulated NOS I/protein kinase G (PKG) signalling, the pro-life cascade that sustains central cardiovascular regulation during experimental brain stem death. CONCLUSIONS AND IMPLICATIONS: Activation of TrkB, followed by recruitment of Shc/Grb2/SOS adaptor proteins, leading to activation of Ras/Raf-1/ERK signalling pathway plays a crucial role in ameliorating central cardiovascular regulatory dysfunction via up-regulation of NOS I/PKG signalling cascade in the RVLM in brain stem death. These findings provide novel information for developing therapeutic strategies against this fatal eventuality.
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Muerte Encefálica , Sistema Cardiovascular/efectos de los fármacos , Inhibidores de la Colinesterasa/toxicidad , Mevinfos/toxicidad , Receptor trkB/metabolismo , Animales , Western Blotting , Sistema Cardiovascular/fisiopatología , Activación Enzimática , Ensayo de Inmunoadsorción Enzimática , Masculino , Microinyecciones , Fosforilación , Ratas , Ratas Sprague-DawleyRESUMEN
HLA-C*03:85 differs from C*03:03:01 by a single nucleotide substitution at position 276, in exon 2.
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Pueblo Asiatico/genética , Antígenos HLA-C/genética , Sustitución de Aminoácidos , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , SingapurRESUMEN
PURPOSE: To analyze the effects of radiotherapy (RT) and chemotherapy in relation to sensorineural hearing loss (SNHL) after contemporary treatment of nasopharyngeal carcinoma. METHODS AND MATERIALS: A total of 87 nasopharyngeal carcinoma patients were treated with RT or chemoradiotherapy using either three-dimensional conformal RT or intensity-modulated RT between 2004 and 2005. Tympanometry and pure-tone audiogram assessments were performed before treatment and then serially at 6-month intervals. The dose-volume data of the cochlea were analyzed. The effects of cisplatin administered in concurrent and nonconcurrent phases was explored. RESULTS: Of the 170 eligible ears, RT (n = 30) and chemoradiotherapy (n = 140) resulted in 40% (n = 12) and 56.4% (n = 79) persistent SNHL (> or = 15 dB loss), respectively, after a median follow-up of 2 years. SNHL at a high frequency was more frequent statistically in the chemoradiotherapy group than in the RT-alone group (55% vs. 33.3%, p < 0.01), but not at a low frequency (7.9% vs. 16.7%, p = 0.14). Within the chemoradiotherapy group, the mean cochlea dose and concurrent cisplatin dose were important determinants of high-frequency SNHL, with an odds ratio of 1.07/Gy increase (p = 0.01) and an odds ratio of 1.008/mg/m(2) increase (p < 0.01), respectively. Age, gender, and nonconcurrent cisplatin dose were not statistically significant factors. A mean radiation dose to the cochlea of <47 Gy would result in <15% of patients developing severe (> or = 30 dB) high-frequency SNHL. CONCLUSION: The results of our study have shown that high-frequency SNHL is significantly related to the mean cochlea dose and the concurrent cisplatin dose. A mean dose constraint of 47 Gy to the cochlea is recommended to minimize SNHL after chemoradiotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/efectos adversos , Cóclea , Pérdida Auditiva Sensorineural/etiología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adulto , Anciano , Análisis de Varianza , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Cóclea/efectos de los fármacos , Cóclea/efectos de la radiación , Terapia Combinada/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Pérdida Auditiva Sensorineural/inducido químicamente , Humanos , Estudios Longitudinales , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Tolerancia a Radiación , Dosificación Radioterapéutica , Radioterapia Conformacional/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Carga Tumoral , Adulto JovenRESUMEN
The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 =*0401 =*0402 > *0404 > *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that meta-analyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels.
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Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Predisposición Genética a la Enfermedad , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Haplotipos , Europa (Continente) , Genotipo , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , HumanosRESUMEN
Status epilepticus results in preferential neuronal cell loss in the hippocampus. We evaluated the hypothesis that the repertoire of intracellular events in the vulnerable hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus entails upregulation of nitric oxide synthase II (NOS II), followed by the release of mitochondrial cytochrome c that triggers the cytosolic caspase-3 cascade, leading to apoptotic cell death. In Sprague-Dawley rats, significant and temporally correlated upregulation of NOS II (3-24h), but not NOS I or II expression, enhanced cytosolic translocation of cytochrome c (days 1 and 3), augmented activated caspase-3 in cytosol (days 1, 3 and 7) and DNA fragmentation (days 1, 3 and 7) was detected bilaterally in the hippocampal CA3 subfield after elicitation of sustained seizure activity by microinjection of kainic acid into the unilateral CA3 subfield. Application bilaterally into the hippocampal CA3 subfield of a selective NOS II inhibitor, S-methylisothiourea, significantly blunted these apoptotic events; a selective NOS I inhibitor, N(omega)-propyl-l-arginine or a potent NOS III inhibitor, N(5)-(1-iminoethyl)-l-ornithine was ineffective. We conclude that upregulation of NOS II contributes to apoptotic cell death in the hippocampal CA3 subfield via a cytochrome c/caspase-3 signaling cascade following the induction of experimental temporal lobe status epilepticus.
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Apoptosis/fisiología , Caspasa 3/fisiología , Citocromos c/fisiología , Epilepsia del Lóbulo Temporal/fisiopatología , Hipocampo/fisiología , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Transducción de Señal/fisiología , Estado Epiléptico/fisiopatología , Regulación hacia Arriba/efectos de los fármacos , Animales , Western Blotting , Citosol/enzimología , Fragmentación del ADN/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Técnica del Anticuerpo Fluorescente , Lateralidad Funcional/fisiología , Hipocampo/citología , Etiquetado Corte-Fin in Situ , Masculino , Microscopía Confocal , Óxido Nítrico/biosíntesis , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Ratas , Ratas Sprague-DawleyRESUMEN
Our current understanding of the nature of cell death that is associated with fatal organophosphate poisoning and the underlying cellular mechanisms is surprisingly limited. Taking advantage of the absence in an in vitro system of acetylcholinesterase, the pharmacological target of organophosphate compounds, the present study evaluated the hypothesis that the repertoire of cholinergic receptor-independent cellular events that underlie fatal organophosphate poisoning entails induction of mitochondrial dysfunction, followed by bioenergetic failure that leads to necrotic cell death because of ATP depletion. Pheochromocytoma PC12 cells incubated with the organophosphate pesticide mevinphos (0.4 or 4mumol) for 1 or 3h underwent a dose-related and time-dependent loss of cell viability that was not reversed by muscarinic (atropine) or nicotinic (mecamylamine) blockade. This was accompanied by depressed NADH cytochrome c reductase, succinate cytochrome c reductase or cytochrome c oxidase activity in the mitochondrial respiratory chain, reduced mitochondrial transmembrane potential, decreased ATP concentration, elevated ADP/ATP ratio, increased lactate dehydrogenase release and necrotic cell death. We conclude that Mev induces cholinergic receptor-independent necrotic cell death by depressing the activity of Complexes I to IV in the mitochondrial respiratory chain, eliciting reduction in mitochondrial transmembrane potential, depleting intracellular ATP contents and damaging cell membrane integrity.
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Adenosina Trifosfato/metabolismo , Transporte de Electrón/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Mevinfos/toxicidad , Mitocondrias/efectos de los fármacos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Células PC12/efectos de los fármacos , Animales , Atropina/farmacología , Sustancias para la Guerra Química/farmacología , Sustancias para la Guerra Química/toxicidad , Colesterol/análogos & derivados , Colesterol/farmacología , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/toxicidad , Complejo IV de Transporte de Electrones/antagonistas & inhibidores , Insecticidas/farmacología , Insecticidas/toxicidad , L-Lactato Deshidrogenasa/análisis , Mecamilamina/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Mevinfos/antagonistas & inhibidores , Mevinfos/farmacología , Mitocondrias/enzimología , Mitocondrias/fisiología , Antagonistas Muscarínicos/farmacología , NADH Deshidrogenasa/antagonistas & inhibidores , Necrosis , Antagonistas Nicotínicos/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Células PC12/fisiología , Polietilenglicoles/farmacología , Ratas , Receptores Colinérgicos/fisiología , Ubiquinona/farmacologíaRESUMEN
OBJECTIVES: To assess the prevalence of macroalbuminuria and microalbuminuria, and the level of blood pressure control in patients with type 2 diabetes and hypertension in Hong Kong. DESIGN: Cross-sectional clinic-based epidemiological study. SETTING: Six medical centres (including two public hospital diabetes centres) in Hong Kong. PATIENTS: Recruited from the medical centres from April to November 2002, after excluding those with bacteriuria and haematuria. MAIN OUTCOME MEASURES: Body mass index; blood pressure; levels of blood glucose, macroalbuminuria, and microalbuminuria; treatments for hypertension and diabetes. RESULTS: The as per-protocol recruited population of 437 hypertensive type 2 diabetic patients had a mean age of 61.7 (standard error, 0.5) years. Overall, the prevalence of diabetic nephropathy in this population was high; 18.3% had macroalbuminuria (95% confidence interval, 16.5-20.2%) and 24.9% had microalbuminuria (95% confidence interval, 22.9-27.0%). Predictive factors were advanced age, male sex, poor blood pressure control, and existing cardiovascular complications. Whilst almost all patients (96.1%) were receiving treatment for hypertension, only 25.6% had systolic/diastolic blood pressures below the 130/85 mm Hg target. CONCLUSIONS: In Hong Kong, the prevalence of microalbuminuria and macroalbuminuria is high in type 2 diabetic patients with hypertension, particularly in males and those with poorly controlled systolic blood pressure. Tight glycaemic control, antihypertensive therapy, and use of renin-angiotensin system inhibitors/blockers are necessary to retard the progression of nephropathy to advanced renal disease.
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Albuminuria/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/epidemiología , Hipertensión/complicaciones , Anciano , Albuminuria/etiología , Antihipertensivos/uso terapéutico , Estudios Transversales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Hong Kong/epidemiología , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , PrevalenciaRESUMEN
INTRODUCTION: Older children and adults, susceptible to pertussis because of waning immunity, may serve as a reservoir of infection, leading to severe disease among young unvaccinated infants. Booster diphtheria-tetanus-acellular pertussis (dTpa) vaccination in older age groups is rare in Singapore, one reason being the increase in reactogenicity with each successive dose. The aim of this study was to assess the immunogenicity, safety and reactogenicity of a reduced antigen, combined dTpa vaccine as a single booster dose in healthy adults aged 18 years or older. METHODS: A total of 150 healthy adults, 18 to 60 years of age, received a single dose of GlaxoSmithKline Biologicals' dTpa vaccine with reduced content for diphtheria and pertussis, with measurement of pre- and post-vaccination antibody titres. RESULTS: Prior to vaccination, 71.6 percent and 92.6 percent of the subjects had anti-diphtheria and anti-tetanus antibody levels greater than or equal to 0.1 IU/mL, respectively. 46.7 percent, 98.5 percent and 44.4 percent of subjects were seropositive for pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) antibodies, respectively. One month after vaccination, there was an increase in geometric mean titres from pre-vaccination to post-vaccination blood samples for anti-diphtheria (greater than seven-fold), anti-tetanus (greater than five-fold), anti-PT (greater than 11-fold), anti- FHA (greater than 25-fold) and anti-PRN (greater than 31-fold) antibodies. Solicited grade three local symptoms (pain, redness and swelling) were reported in 14.1 percent, 8.1 percent and 10.4 percent of subjects, respectively. No serious adverse events were reported. CONCLUSION: In summary, the dTpa vaccine is immunogenic, safe and well-tolerated in Singaporean adults.
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Antígenos Bacterianos/sangre , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Difteria/prevención & control , Inmunización Secundaria , Tétanos/prevención & control , Vacunación/métodos , Tos Ferina/prevención & control , Adolescente , Adulto , Vacuna contra Difteria, Tétanos y Tos Ferina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , SingapurAsunto(s)
Alelos , Antígenos HLA-C/genética , Pueblo Asiatico/etnología , Secuencia de Bases , Variación Genética , Antígenos HLA/genética , Antígenos HLA-DR/genética , Haplotipos , Humanos , Masculino , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Homología de Secuencia , Singapur/epidemiologíaRESUMEN
HLA Class I-restricted CD8(+) T-cell responses are believed to play an important role in controlling Epstein-Barr virus (EBV) infection, which has been consistently associated with nasopharyngeal carcinoma (NPC). Immediate early transactivator Rta of EBV has been shown to be associated with the reactivation of EBV from latency and drive the lytic cascade of EBV and comprise an important target for EBV-specific cellular cytotoxicity. Furthermore, BRLF1 is specifically expressed in NPC tumor cells. The protein product of BRLF1, Rta, could then be considered as a NPC tumor antigen. Therefore, cellular immunity against Rta represents a very important part of the immunity against NPC, as they should prevent the replication of EBV. In the present study, Rta-specific CD8(+) T-cell responses in healthy virus carriers were characterized by using A1101 tetramer containing the known Rta epitope ATIGTAMYK (134-142). We clearly showed A1101/ATIGTAMYK tetramer-reactive CD8(+) T cells in the circulation of healthy virus carriers, ranging from 2.13 to 9.03%. We then studied the expression of perforin and interferon-gamma (IFN-gamma) secretion in these Rta-specific T cells. Our study demonstrated that Rta-specific T cells are capable of IFN-gamma production and nearly 90% of the Rta-specific CD8(+) T cells expressed perforin. Presumably, these are the cells that play an important role in determining the initiation of the lytic cycle or the clearance of EBV.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Portador Sano/inmunología , Antígenos HLA-A/inmunología , Herpesvirus Humano 4/metabolismo , Proteínas Inmediatas-Precoces/fisiología , Transactivadores/fisiología , Proteínas Virales/genética , Antígenos de Neoplasias/química , Antígenos CD8/biosíntesis , Linfocitos T CD8-positivos/virología , Proliferación Celular , Ensayo de Inmunoadsorción Enzimática , Epítopos/química , Infecciones por Virus de Epstein-Barr/inmunología , Antígenos HLA/química , Antígeno HLA-A11 , Humanos , Proteínas Inmediatas-Precoces/metabolismo , Interferón gamma/metabolismo , Leucocitos Mononucleares/citología , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Péptidos/química , Perforina , Proteínas Citotóxicas Formadoras de Poros , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/virología , Transactivadores/metabolismo , Activación TranscripcionalRESUMEN
The organophosphate insecticide mevinphos (Mev) acts on the rostral ventrolateral medulla (RVLM), where sympathetic vasomotor tone originates, to elicit phasic cardiovascular responses via nitric oxide (NO) generated by NO synthase (NOS) I and II. We evaluated the contribution of soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) cascade and peroxynitrite in this process. PKG expression in ventrolateral medulla of Sprague-Dawley rats manifested an increase during the sympathoexcitatory phase (Phase I) of cardiovascular responses induced by microinjection of Mev bilaterally into the RVLM that was antagonized by co-administration of 7-nitroindazole or Nomega-propyl-L-arginine, two selective NOS I inhibitors or 1-H-[1,2,4]oxadiaolo[4,3-a]quinoxalin-1-one (ODQ), a selective sGC antagonist. Co-microinjection of ODQ or two PKG inhibitors, KT5823 or Rp-8-Br-cGMPS, also blunted the Mev-elicited sympathoexcitatory effects. However, the increase in nitrotyrosine, a marker for peroxynitrite, and the sympathoinhibitory circulatory actions during Phase II Mev intoxication were antagonized by co-administration of S-methylisothiourea, a selective NOS II inhibitor, Mn(III)-tetrakis-(4-benzoic acid) porphyrin, a superoxide dismutase mimetic, 5,10,15,20-tetrakis-N-methyl-4'-pyridyl)-porphyrinato iron (III), a peroxynitrite decomposition catalyst, or L-cysteine, a peroxynitrite scavenger. We conclude that sGC/cGMP/PKG cascade and peroxynitrite formation may participate in Mev-induced phasic cardiovascular responses as signals downstream to NO generated respectively by NOS I and II in the RVLM.