RESUMEN
OBJECTIVE: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1α and IL-1ß, in patients with knee osteoarthritis (OA). METHOD: This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate OA of the knee (NCT01668511). Three cohorts received ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week for a total of four SC injections, and one cohort received ABT-981 (3 mg/kg) or placebo every 4 weeks for a total of three SC injections. Assessment of safety and tolerability were the primary objectives. A panel of serum and urine biomarkers of inflammation and joint degradation were evaluated. RESULTS: A total of 36 patients were randomized (ABT-981, n = 28; placebo, n = 8); 31 (86%) completed the study. Adverse event (AE) rates were comparable between ABT-981 and placebo (54% vs 63%). The most common AE reported with ABT-981 vs placebo was injection site erythema (14% vs 0%). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1α/IL-1ß, high-sensitivity C-reactive protein, and matrix metalloproteinase (MMP)-derived type 1 collagen. Serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein demonstrated decreasing trends with ABT-981. Antidrug antibodies were found in 37% of patients but were not associated with the incidence or severity of AEs. CONCLUSION: ABT-981 was generally well tolerated in patients with knee OA and engaged relevant tissue targets, eliciting an anti-inflammatory response. Consequently, ABT-981 may provide clinical benefit to patients with inflammation-driven OA.
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Inmunoglobulinas/uso terapéutico , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1beta/antagonistas & inhibidores , Osteoartritis de la Rodilla/tratamiento farmacológico , Anciano , Agrecanos/efectos de los fármacos , Agrecanos/metabolismo , Proteína C-Reactiva/efectos de los fármacos , Proteína C-Reactiva/metabolismo , Proteína de la Matriz Oligomérica del Cartílago/efectos de los fármacos , Proteína de la Matriz Oligomérica del Cartílago/metabolismo , Citrulinación , Colágeno Tipo I/efectos de los fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo II/efectos de los fármacos , Colágeno Tipo II/metabolismo , Colágeno Tipo III/efectos de los fármacos , Colágeno Tipo III/metabolismo , Eritema , Femenino , Humanos , Inmunoglobulinas/farmacología , Reacción en el Punto de Inyección , Inyecciones Subcutáneas , Interleucina-1beta/efectos de los fármacos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Osteoartritis de la Rodilla/metabolismo , Péptidos/efectos de los fármacos , Péptidos/metabolismo , Índice de Severidad de la Enfermedad , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Vimentina/efectos de los fármacos , Vimentina/metabolismoRESUMEN
Infections occur frequently in chronic dialysis patients. An incidence study of 13 months' duration (December 2003-January 2004) on nosocomial bacterial infections was performed in a dialysis center (Rivoli Hospital) in the Piedmont region of northern Italy. Data were collected according to a modified CDC methodology (CDC Dialysis Surveillance Network). The total incidence of infections was 4.55/100 patients/month and was lower than that reported for other reference series (CDC 6.16/100 patients/month). The low incidence was associated with a greater use of low-risk vascular access (fistula) than in other countries such as the U.S. The infection rates were: vascular access 1.73% (1.55% local infections, 0.18% access-related bacteremia); 0.82% wound infections; 0.91% pneumonia; 1% urinary tract infections; 0.09% other bacteremias. The hospital utilization rate was 6.9/100 patients/month. Blood cultures were performed in only 28.4% of patients who had received a course of antibiotics. Antibiotics were widely used but the use of vancomycin was less than reported elsewhere (e.g., CDC surveillance). The prevalence of methicillin-resistant Staphylococcus aureus (28 strains isolated) was high (>50%), whereas no vancomycin-resistant enterococci were isolated. Preventing nosocomial bacterial infections in chronic dialysis patients is a top priority; therefore, a surveillance system along the lines of the CDC model should be adopted by all dialysis centers. The risk of nosocomial infection is strongly associated with the type of vascular access.
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Derivación Arteriovenosa Quirúrgica/efectos adversos , Bacteriemia/epidemiología , Bacteriemia/prevención & control , Infección Hospitalaria/epidemiología , Vigilancia de la Población , Diálisis Renal/estadística & datos numéricos , Derivación Arteriovenosa Quirúrgica/instrumentación , Bacteriemia/etiología , Catéteres de Permanencia/efectos adversos , Infección Hospitalaria/microbiología , Humanos , Incidencia , Italia/epidemiología , Fallo Renal Crónico/terapia , Registros Médicos , Diálisis Renal/efectos adversos , Diálisis Renal/instrumentación , Estudios Retrospectivos , Servicio de Urología en HospitalRESUMEN
BACKGROUND: The aim of the study is to examine the situation of chronic uremia substitutive treatment by means of peritoneal dialysis in Piedmont on December 31, 1997 using data from the Piedmont regional dialysis and transplant register. METHODS: Starting from the year 1981, data are reported (absolute, per million population, and according to different patient's anagraphic ages) about peritoneal dialysis prevalence and incidence; about basic nephropathies; drop-out from treatment; patient's rehabilitation; complications incidence, particularly peritonitis; patient's survival compared with survival of patients treated, during the same years with extracorporeal techniques. RESULTS: The data demonstrate, during these years, an increase of peritoneal dialysis incidence and prevalence; patients' survival curves, compared with those of patients treated with extracorporeal techniques, are very similar during the first years of treatment and worse afterwards, but never reaching statistical significance. CONCLUSIONS: They support Peritoneal Dialysis as a very good kind of substitutive treatment for some years, but this opinion deserves further examination and investigation on a longer period of time.
Asunto(s)
Diálisis Peritoneal/tendencias , Humanos , ItaliaRESUMEN
Recent evidence suggests that HIV-1 Vpr exists in soluble form in the serum and cerebrospinal fluid (CSF). Further, its abundance in the bloodstream, and the CSF, and its activity on other cell types suggest that it could have an effect on brain activity. Using mixed embryonic rat brain cultures as a model to examine the effects of physiological concentrations of extracellular Vpr protein, Vpr-induced cell death was observed. We also observed similar Vpr-induced effects in enriched primary cortical rat astrocytes, as well as in the C6 glioma cell line. Vpr-induced cell death observed in the astrocytic cells appeared to be caused primarily by a necrotic mechanism, although a few apoptotic nuclei were also present. We did not observe Vpr-induced effects on any primary cortical neurons, although we did observe Vpr-induced cell death in hippocampal neurons and astrocytes. Finally, we observed no cell cycle effects due to extracellular Vpr protein. This data points out that different cell types are affected by the toxic effects of extracellular Vpr protein, and that differential toxic effects of extracellular Vpr protein are observed in similar cell types.
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Corteza Cerebral/efectos de los fármacos , Productos del Gen vpr/farmacología , VIH-1 , Animales , Apoptosis , Astrocitos/efectos de los fármacos , Astrocitos/patología , Células Cultivadas , Colorantes , Fragmentación del ADN , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Hipocampo/efectos de los fármacos , Humanos , Etiquetado Corte-Fin in Situ , Necrosis , Neuronas/efectos de los fármacos , Neuronas/patología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Productos del Gen vpr del Virus de la Inmunodeficiencia HumanaRESUMEN
BACKGROUND: Patients starting dialysis in old age (age > 70 and > 80) in Piedmont are widely increasing: the survival curves of this group of patients can give very important information to evaluate the quality of both the delivered therapy and our very wide criteria of acceptance to the treatment. To this end, using data from the Piedmont Dialysis and Transplant Register, the survival curves of patients with age over 70 and 80, beginning dialysis in all Piedmont Dialysis Units between 1981 and 1996, have been examined. METHODS: These curves have been considered both in a general way and according to the presence or absence of further high risk conditions; they show results better than expected and improving from 1981 to 1995. RESULTS: If the survival curves of these patients are considered according to the kind of dialytic treatment performed, they do not show any significative difference. CONCLUSIONS: The conclusion is drawn that these data strongly support first, the fitness of criteria of very wide acceptance to the treatment and modulated choice of the kind of dialytic treatment at present followed in Piedmont; and second, that dialysis treatment can give very good results also in elderly patients. So, it is suggested that the economic and structural difficulties of dialysis Units must not influence the nephrologist's choice towards elderly patients.
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Diálisis Renal/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Italia/epidemiología , Esperanza de Vida , Tablas de Vida , Masculino , Mortalidad , Diálisis Renal/clasificación , Estudios Retrospectivos , Análisis de Supervivencia , Tasa de SupervivenciaRESUMEN
The parameters used at present by the Piedmont Dialysis and Transplant Register to evaluate rehabilitation and quality of life of the dialyzed patients have been useful in the past, but they will no longer be so in the future, as the typology of the dialyzed patient is changing: the mean age is increasing, patients with high-risk conditions as vasculopathy and diabetes are widely accepted to the treatment. Thus, rehabilitation has to be evaluated not only from a social and professional viewpoint, but also as "illness situation" and "quality of life" and this can be done using the Karnofsky scale and the test of Spitzer: our Register needs to be implemented in the future by such evaluations, to go on giving us useful information about rehabilitation of the dialyzed patients.
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Fallo Renal Crónico/terapia , Calidad de Vida , Diálisis Renal , Femenino , Humanos , Fallo Renal Crónico/rehabilitación , Masculino , Índice de Severidad de la Enfermedad , Tasa de SupervivenciaRESUMEN
The parameters used at present by the Dialysis and Transplant Registries of various countries to evaluate dialyzed patients' comorbidity show great differences, mostly owing to the different epidemiological, social and racial characteristics of the studied populations. Moreover, the typology of the dialyzed patient is changing: the mean age is increasing, patients with high-risk conditions as vasculopathy and diabetes are widely accepted to the treatment. Thus the Piedmont Registry will be implemented as follows: new fields about comorbidity for clinical (blindness, cachexy and dementia), social (smoking, alcohol and drugs addiction) and diagnostic (type of diabetes, of neoplasm, of cardiovascular problem) parameters, and questions needing dichotomic response (vasculopathy yes or no) will be added. The exact time of appearance of any risk factor will be requested, and a field for "others" risk factors will be added as well, trying to deeply identify the dialytic population not affected by any comorbidity factor. Finally, a new improved control system of the collected data will be used: our registry needs to be implemented in the future by such evaluations, to go on giving useful informations about epidemiology of the dialyzed patients.
Asunto(s)
Comorbilidad , Sistema de Registros/estadística & datos numéricos , Diálisis Renal/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Anciano , Enfermedades Cardiovasculares/epidemiología , Niño , Preescolar , Diabetes Mellitus/epidemiología , Grupos Diagnósticos Relacionados , Etnicidad , Femenino , Humanos , Lactante , Infecciones/epidemiología , Italia/epidemiología , Fallo Renal Crónico/epidemiología , Masculino , Trastornos Mentales/epidemiología , Persona de Mediana Edad , Morbilidad/tendencias , Neoplasias/epidemiología , Factores de Riesgo , Factores Socioeconómicos , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
The HIV-1 encoded regulatory Rev protein acts to selectively increase the cytoplasmic concentration of incompletely spliced viral mRNAs through interaction with the Rev responsive element (RRE). In addition, the Rev activation domain, believed to be a nuclear export sequence, has been shown to modulate the export of non-RRE containing RNAs (e.g. 5S rRNA, splicesomal U snRNAs). Recent evidence suggests Rev activity depends on interactions with cellular cofactors, leading to speculation that Rev utilizes a cellular RNA and/or a protein export pathway. Rev interactions with cellular cofactors could lead to sequestration of those cofactors from normal cellular activities, suggesting potential Rev effects on cellular gene products and their resultant activity. We have examined the role of Rev in modulating the expression of cellular gene products. Through transient cotransfection assays, we observed a consistent and significant decrease in the levels of luciferase and B-galactosidase activity in the presence of a Rev expressing construct. Cell fractionation studies demonstrated the nuclear retention of the luciferase gene transcripts. Surprisingly, similar effects were observed on constitutively expressed RNAs such as gamma-actin transcripts, and the 18S and 28S rRNAs. These results suggest Rev can disrupt the nuclear export of multiple classes of RNAs.
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Expresión Génica/efectos de los fármacos , Productos del Gen rev/farmacología , Genes Reporteros/efectos de los fármacos , VIH-1/genética , Linfocitos T/virología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Expresión Génica/genética , Regulación Viral de la Expresión Génica , Genes Reporteros/genética , Células HeLa , Humanos , Células Jurkat , Luciferasas/metabolismo , Procesamiento Postranscripcional del ARN , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Transfección , Productos del Gen rev del Virus de la Inmunodeficiencia HumanaRESUMEN
HIV-1 produces more than 20 mRNAs encoding the viral proteins. We have used a sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) approach to determine HIV-1 transcriptional patterns during the course of viral infection in unstimulated peripheral blood mononuclear cells (PBMCs) from different patients. Several sets of PCR primers, used in parallel reactions, allowed the amplification and specific detection of almost all individual HIV-1 transcripts. We investigated the transcriptional profile in two individuals during primary acute and early chronic infection. In these individuals, HIV-1 mRNA expression was elevated at the first time points examined and declined over time. In addition, we performed a detailed study of HIV-1 expression in several individuals over a minimum of 7 years following seroconversion. We found that long-term asymptomatic individuals had undetectable or low levels of the three classes of HIV-1 transcripts (unspliced, singly spliced, and multiply spliced). Individuals who demonstrated disease progression showed either a general increase in the amount of expression of all transcripts or elevated levels of unspliced transcripts in late-stage disease. The splicing pattern in each patient was conserved over the years and differed among the different individuals. No evidence of major changes in the splicing pattern was found during disease progression within the same individual. Thus, HIV-1 transcriptional patterns are viral strain specific rather than disease stage specific. These results indicate that high-level expression of any class of HIV-1 transcripts is associated with clinical progression. Our analysis also demonstrates the importance of using more than one set of primers to evaluate HIV-1 RNA expression, since virus in patient PBMCs showed sequence heterogeneity in conserved regions.
Asunto(s)
VIH-1/genética , Leucocitos Mononucleares/virología , Empalme del ARN , ARN Mensajero/química , ARN Viral/química , Recuento de Linfocito CD4 , Progresión de la Enfermedad , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
At the end of December, 1993, 389 patients treated by means of dialysis for more than 15 years were registered in the Piedmont Dialysis and Transplantation Register; among them, 183 were alive. Characteristics of these patients as age at the beginning of dialytic treatment, casual nephropathies, causes of death, high risk conditions, dialytic schedules, vascular access, hospitalization requirements, rehabilitation, dialysis efficacy, gross mortality, were compared with those of patients treated for a shorter time, concluding that a very long dialytic survival can be achieved with a good clinical and social rehabilitation.
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Diálisis Renal , Sobrevivientes , Causas de Muerte , Humanos , Enfermedades Renales/mortalidad , Enfermedades Renales/terapia , Factores de TiempoRESUMEN
Using degenerate oligonucleotide probes encoding conserved regions of the gamma-aminobutyric acid/norepinephrine transporter gene family, we have cloned a rat brain cDNA encoding a creatine transporter (rCREAT). rCREAT encodes a highly hydrophobic, 635-amino-acid protein possessing 12 potential transmembrane domains and canonical sites for N-linked glycosylation and protein phosphorylation. Transfection of rCREAT cDNA into mammalian cells results in the expression of [14C]creatine uptake, which is blocked by low micromolar concentrations of recognized creatine uptake inhibitors. Two rCREAT mRNAs are expressed in the rat brain, retina, kidney and heart. Whole-brain rCREAT mRNAs demonstrate a marked postnatal rise to steady-state adult levels. In situ hybridization studies indicate a widespread, differential rCREAT mRNA expression in adult rat brain, with high expression noted over myelinated fiber tracts, cerebellar granule cells, hippocampal pyramidal cells, brainstem nuclei and endothelial cells of the choroid plexus. These studies will allow the development of new molecular probes useful for defining the creatine transporter's cellular expression pattern, function in ATP homeostasis and association with disorders of cellular energy metabolism.
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Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Células HeLa/metabolismo , Proteínas de Transporte de Membrana , Ratas/metabolismo , Transfección , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos/metabolismo , Secuencia de Bases , Proteínas Portadoras/genética , Expresión Génica , Humanos , Datos de Secuencia Molecular , ARN/metabolismo , Especificidad por Sustrato , Distribución TisularRESUMEN
Basaloid squamous cell carcinoma (BSCC) is an unusual but well-established entity, primarily in the upper aerodigestive tract, composed of basaloid cells associated with dysplastic to neoplastic squamous cells, and characterized by an aggressive and rapidly fatal course. To date, BSCC originating in the trachea has not been reported. In this article, the authors describe the clinical, gross, and microscopic pathologic, histochemical, and immunohistochemical features of two cases of BSCC arising in the trachea. Features distinguishing this entity from other, more common tumors of the trachea, including metastases and direct extension from other sites of origin, are also discussed.
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Carcinoma Basoescamoso/patología , Neoplasias de la Tráquea/patología , Anciano , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana EdadRESUMEN
Ehlers-Danlos syndrome (EDS) is an inherited disorder of connective tissue with multiple thoracic manifestations. We present an unusual thoracic manifestation of EDS consisting of parenchymal cysts and fibrous and fibroosseous nodules. These manifestations may be related to an abnormal attempt at repair of parenchymal or vascular tears.
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Síndrome de Ehlers-Danlos/diagnóstico por imagen , Enfermedades Pulmonares/diagnóstico por imagen , Adolescente , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/patología , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/patología , Tomografía Computarizada por Rayos XRESUMEN
Forty-nine haemodialyzed patients have been submitted consecutively, under informed consent, to endoscopy with multiple antral gastric mucosa biopsies for Helicobacter pylori (HP) identification, performed by urease, microscopic and cultural tests, as well as histologic examination. Patients have been considered HP negative when negative for all tests; positivity for HP has been correlated with gastritis histologically evaluated according to Whitehead; at endoscopy, blood samples for HP specific IgG, IgA, IgM have been collected; patient's life style concerning smoke, alcohol and drugs as FANS has been investigated as well. HP prevalence in our haemodialyzed patients is 38.8 per cent, similar to general population submitted to endoscopy; a statistically significant correlation between HP and gastritis and specific IgG, but no correlation between HP and age, dialysis duration, IgA, IgM, smoking, alcohol or drugs consumption has been found.
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Helicobacter pylori/aislamiento & purificación , Diálisis Renal , Estómago/virología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A quantitative RNA-polymerase chain reaction (PCR) method able to detect the majority of mRNAs produced by human immunodeficiency virus type 1 (HIV-1) was developed and used to study expression of different HIV-1 clones in human cells. Amplified mRNAs were compared to known cDNA standards. This comparison permitted the optimization of PCR conditions and eliminated the generation of artifactual PCR bands. The use of RNA and cDNA standards demonstrated that the RNA amplification is linear within the tested range and suggested that it can be used to quantitate individual mRNAs. The results demonstrate the overall conservation of splicing in different HIV-1 clones. Although, in general, splicing was conserved, extensive qualitative and quantitative variability was observed in different HIV-1 clones. This variability is likely one determinant of the biological characteristics of the different HIV-1 clones, and demonstrates a great plasticity of the HIV-1 genome. The described RNA-PCR methodology was used for the study of HIV-1 expression in unstimulated peripheral blood mononuclear cells (PBMCs) of infected individuals. In general, the same mRNAs were identified in HIV-infected cultured cell lines and in unstimulated PBMCs. Analysis of a variant band found after amplification of PBMC RNA from an HIV-infected individual revealed a new splice site for the generation of Rev/Nef-encoding mRNAs. The availability of a sensitive, rapid, and essentially quantitative method to examine the major HIV-1 mRNAs will facilitate the detailed analysis of HIV-1 expression in human cells.
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VIH-1/genética , Empalme del ARN/genética , Secuencia de Bases , Línea Celular , Cartilla de ADN/genética , ADN Complementario/genética , ADN Viral/genética , Variación Genética , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , VIH-1/metabolismo , Células HeLa , Humanos , Técnicas In Vitro , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Viral/genética , ARN Viral/metabolismo , Transcripción GenéticaRESUMEN
Caprine arthritis encephalitis virus (CAEV) is a lentivirus that is closely related to visna virus and more distantly related to the human lentivirus human immunodeficiency virus 1 (HIV-1). Like other lentiviruses, the genome of CAEV contains multiple small ORFs that encode viral regulatory proteins. Sequence analysis of the CAEV genome and cDNAs generated from mRNA in infected cells has suggested that one of these ORFs encodes a protein (Rev-C) that is analogous to Rev of visna virus and HIV. Antibodies generated to a carboxy-terminal peptide of the rev ORF immunoprecipitate an 18-kDa protein from cells transfected with the Rev cDNA clone. Immunoprecipitation and immunofluorescence analysis of CAEV-infected ovine primary cells show that the product of the rev ORF is expressed during infection and localizes to the nucleolus of infected cells. Also, sera from CAEV-infected goats specifically immunoprecipitates an in vitro-translated product from the full-length Rev cDNA clone as well as that from the unique second open reading frame of Rev-C which shows that the Rev-C protein is expressed during natural CAEV infection of animals. Insertion of either a mutation that creates two stop codons in the unique second open reading frame of Rev-C or a mutation in the basic domain of Rev-C into the CAEV infectious molecular clone renders the virus unable to replicate in primary goat synovial membrane cells. Analysis of the RNA and proteins produced from both Rev-deficient clones indicates that they are defective in the accumulation of structural gene mRNAs in the cytoplasm as well as in synthesis of structural proteins compared to the wild-type CAEV clone. These data indicate that CAEV encodes a Rev protein that is required for efficient viral replication in culture.
Asunto(s)
Virus de la Artritis-Encefalitis Caprina/fisiología , Productos del Gen rev/biosíntesis , Replicación Viral/genética , Secuencia de Aminoácidos , Animales , Virus de la Artritis-Encefalitis Caprina/genética , Virus de la Artritis-Encefalitis Caprina/metabolismo , Células Cultivadas , Clonación Molecular , ADN Complementario , Técnica del Anticuerpo Fluorescente , Productos del Gen rev/genética , Cabras , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Pruebas de Precipitina , Homología de Secuencia de Aminoácido , TransfecciónRESUMEN
Nineteen patients with clinical stage I malignant pleural mesothelioma were treated with aggressive multimodality therapy. Nine patients underwent pleurectomy and decortication followed by immediate intrapleural chemotherapy with cisplatin and mitomycin C. Ten patients required pleuropneumonectomy followed within 1 week to 2 weeks by intrapleural administration of cisplatin (100 mg). Four to 8 weeks after operation, 15 patients underwent postoperative adjuvant cisplatin-based systemic chemotherapy. There were three postoperative complications (16%) requiring reoperation and one postoperative death (5%). Intrapleural chemotherapy was well tolerated with no complications. Systemic chemotherapy was poorly tolerated, and there was one chemotherapy-related death. Sixteen patients (84%) experienced good to excellent palliation. Three patients are currently alive with no evidence of recurrent disease at 10, 35, and 43 months. The median overall survival was 13 months and the median disease-free survival, 11 months. Overall and disease-free 3-year survivals were 17% and 22%, respectively. Patients with epithelial malignant pleural mesothelioma had significantly better overall survival (p = 0.037) and disease-free survival (p = 0.02) than patients with sarcomatous or biphasic malignant pleural mesothelioma. We conclude that despite major toxicity, in select patients with clinical stage I malignant pleural mesothelioma, aggressive multimodality therapy offers effective palliation and occasional long-term disease-free survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mesotelioma/terapia , Neoplasias Pleurales/terapia , Cisplatino/administración & dosificación , Terapia Combinada , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Mesotelioma/mortalidad , Persona de Mediana Edad , Mitomicina/administración & dosificación , Cuidados Paliativos/métodos , Pleura/cirugía , Neoplasias Pleurales/mortalidad , Reoperación , Análisis de Supervivencia , Tasa de Supervivencia , Factores de TiempoAsunto(s)
Fallo Renal Crónico/epidemiología , Diálisis Renal/estadística & datos numéricos , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Demografía , Femenino , Humanos , Lactante , Italia/epidemiología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Diálisis Renal/tendenciasRESUMEN
Caprine Arthritis Encephalitis Virus (CAEV) is a lentivirus closely related to visna virus of sheep and more distantly related to the human lentivirus HIV-1. The genomes of lentiviruses contain additional genes that regulate the lentivirus gene expression; one of these is Rev, a protein that regulates the expression of viral proteins via post-transcriptional mechanisms. A cDNA clone was isolated from CAEV infected cells and shown to encode the 18-kDa Rev protein of CAEV. Antibodies against CAEV Rev (Rev-C) demonstrated that the CAEV Rev protein accumulated in the nucleus and in particular in the nucleolus of transiently transfected cells. Mutation of a basic region in the CAEV Rev protein resulted in loss of nucleolar localization. A highly structured RNA element has been identified in the env gene of CAEV (nt 7850-8150); its structure and location suggested that it was analogous to the Rev-responsive element (RRE) of HIV-1 and visna virus. A 300-bp fragment (nt 7850-8150) spanning this region was substituted for the HIV-1 RRE in an HIV-1 Gag expression vector. Expression of the Gag protein was dramatically increased when Rev-C was added in trans, indicating that this fragment contained the cis-acting CAEV Rev Responsive Element. Cross-activation by the Rev/Rex proteins of other lentiviruses and members of the HTLV-I family indicated that this RRE could interact with Rev or Rex proteins of other viruses. This suggests that the highly divergent lentiviruses share similar mechanisms and cofactors regulating post-transcriptional viral gene expression. The Rev/RRE mechanism is thus the most conserved regulatory mechanism in lentiviruses and other complex retroviruses.
Asunto(s)
Virus de la Artritis-Encefalitis Caprina/genética , Productos del Gen rev/genética , Secuencias Reguladoras de Ácidos Nucleicos , Secuencia de Aminoácidos , Animales , Clonación Molecular , ADN Viral , Técnica del Anticuerpo Fluorescente , Humanos , Datos de Secuencia MolecularRESUMEN
Caprine arthritis-encephalitis virus (CAEV) is a lentivirus which is closely related by nucleotide sequence and biological properties to visna virus. Sequence analysis of the CAEV genome revealed the presence of a small open reading frame (ORF) which shares amino acid identity with the visna virus tat gene. Using an infectious molecular clone of CAEV the role of the tat ORF in viral replication was examined. Mutations were made in the tat ORF that introduced two in frame stop codons six amino acids downstream of the tat AUG; in addition, a deletion mutant was made that removed most of the tat ORF. Both of these mutants had greatly reduced virus titers (> 1000-fold less than the wild type infectious clone). Co-transfection of a tat expressing plasmid with these viruses containing the tat ORF mutations resulted in higher levels of virus production demonstrating that the effects of both mutants are tat specific. These mutants provide data that the CAEV tat gene is necessary for efficient virus replication. Analysis of the RNA in these transfected cells showed that complementation of the tat gene was in trans and not the result of recombination. Analysis of the gag and rev proteins in the transfected cells demonstrated that these proteins were not detectable in cells transfected with the tat mutants but could be readily detected when the mutations were complemented in trans with a tat expression vector. To test for tat mediated trans-activation a plasmid expressing the CAEV tat ORF was co-transfected with plasmids containing either the CAEV or visna virus LTR driving transcription of the bacterial chloramphenicol acetyltransferase gene (CAT). These experiments indicate that one function of the CAEV tat protein is to trans-activate gene expression from the viral promoter. RNase protection analysis of CAT mRNA from co-transfected cells demonstrated that CAEV Tat trans-activates gene expression by increasing steady-state levels of mRNA.