RESUMEN
PURPOSE: Fertility issues are of great concern for young women undergoing treatment for breast cancer (BC). Fertility preservation (FP) protocols using controlled ovarian stimulation (COS) with letrozole have been widely used with overall good results. However, letrozole cannot be used in every country in this context. This study aimed to assess the efficacy of tamoxifen for COS in women with early BC undergoing FP. METHODS: This multicentric prospective study included patients aged 18-40, diagnosed with stage I, II and III invasive BC, undergoing tamoxifen-COS before adjuvant or neoadjuvant chemotherapy (NAC). The primary endpoint was the efficacy of tamoxifen-COS protocol evaluated by the number of oocytes collected and vitrified. Secondary endpoints included the time interval before chemotherapy, breast cancer (BC) recurrence rates, and reproductive outcomes. RESULTS: Ninety-five patients were included between 2014 and 2017, aged 31.5 ± 4 years on average. 37.9 % received NAC and 62.1 % received adjuvant chemotherapy. FP procedure was successful in 89.5 % of the cycles. The mean number of collected and vitrified oocytes was 12.8 ± 7.9 and 9.8 ± 6.2, respectively. The mean duration of COS was 10.4 ± 1.9 days. Median time before chemotherapy initiation was 3.6 weeks (IQR 3.1; 4.1) for women receiving NAC. Five-year relapse-free and overall survival rates were in-line with those expected in this population. Twenty-one women had spontaneous full-term pregnancies, while 5 underwent IVF cycles with frozen-thawed oocytes, without pregnancy. CONCLUSION: Tamoxifen-COS protocols appear to be feasible before adjuvant or NAC treatment in young BC patients and efficient in terms of oocyte yield.
Asunto(s)
Neoplasias de la Mama , Preservación de la Fertilidad , Inducción de la Ovulación , Tamoxifeno , Humanos , Femenino , Preservación de la Fertilidad/métodos , Neoplasias de la Mama/tratamiento farmacológico , Tamoxifeno/administración & dosificación , Adulto , Estudios Prospectivos , Inducción de la Ovulación/métodos , Estudios de Seguimiento , Antineoplásicos Hormonales/administración & dosificación , Quimioterapia Adyuvante , Adulto Joven , Embarazo , Terapia Neoadyuvante/métodos , Letrozol/administración & dosificación , Letrozol/uso terapéutico , Índice de Embarazo , Adolescente , Recuperación del Oocito/métodos , Criopreservación/métodosRESUMEN
PURPOSE: GANEA2 study was designed to assess accuracy and safety of sentinel lymph node (SLN) after neo-adjuvant chemotherapy (NAC) in breast cancer patients. METHODS: Early breast cancer patients treated with NAC were included. Before NAC, patients with cytologically proven node involvement were allocated into the pN1 group, other patient were allocated into the cN0 group. After NAC, pN1 group patients underwent SLN and axillary lymph node dissection (ALND); cN0 group patients underwent SLN and ALND only in case of mapping failure or SLN involvement. The main endpoint was SLN false negative rate (FNR). Secondary endpoints were predictive factors for remaining positive ALND and survival of patients treated with SLN alone. RESULTS: From 2010 to 2014, 957 patients were included. Among the 419 patients from the cN0 group treated with SLN alone, one axillary relapse occurred during the follow-up. Among pN1 group patients, with successful mapping, 103 had a negative SLN. The FNR was 11.9% (95% CI 7.3-17.9%). Multivariate analysis showed that residual breast tumor size after NAC ≥ 5 mm and lympho-vascular invasion remained independent predictors for involved ALND. For patients with initially involved node, with negative SLN after NAC, no lympho-vascular invasion and a remaining breast tumor size 5 mm, the risk of a positive ALND is 3.7% regardless the number of SLN removed. CONCLUSION: In patients with no initial node involvement, negative SLN after NAC allows to safely avoid an ALND. Residual breast tumor and lympho-vascular invasion after NAC allow identifying patients with initially involved node with a low risk of ALND involvement.
Asunto(s)
Neoplasias de la Mama/patología , Escisión del Ganglio Linfático/estadística & datos numéricos , Metástasis Linfática/diagnóstico , Biopsia del Ganglio Linfático Centinela/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Axila , Mama/patología , Mama/cirugía , Neoplasias de la Mama/terapia , Reacciones Falso Negativas , Femenino , Humanos , Escisión del Ganglio Linfático/efectos adversos , Metástasis Linfática/patología , Mastectomía , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Neoplasia Residual/patología , Selección de Paciente , Pronóstico , Estudios Prospectivos , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela/métodosRESUMEN
OBJECTIVE: The ENVOL study was designed to assess the psychosocial impact of disease and therapy in a French cohort of cryopyrin-associated periodic syndromes (CAPS) patients (and caregivers) treated with canakinumab. METHODS: The ENVOL study was a multicenter, observational study of CAPS patients given ≥1 canakinumab dose. Data were collected before treatment, at 6 and 12 months afterward, and at the last visit. Patients and caregivers completed questionnaires assessing changes from the 12 months of pretreatment to 12 months prior to interview. Data were analyzed retrospectively. RESULTS: The study included 10 physicians and 68 patients (53 adults, 15 children). Sixty-five patients (95.6%) were still receiving canakinumab at the last visit (median 5 years after starting therapy). The mean ± SD score for patient-reported general health increased from 7 ± 2.9 before canakinumab to 2.7 ± 2.7 after treatment (P < 0.001). Physical and emotional symptoms resolved or improved in a substantial proportion of patients, including bodily pain (38 of 46 patients), fever (32 of 39), skin disease (35 of 41), fatigue (31 of 47), self-confidence (29 of 46), and energy (34 of 47). Social activity, relationships, sexuality, and energy measures improved in >40% of respondents. Caregivers spent a median of 3 versus 0.5 hours/week on care in the 12 months of pretreatment versus 12 months prior to interview (P < 0.001). Following treatment, patients required fewer consultations with general practitioners (mean ± SD per patient per year: 5.2 ± 7.4 versus 8.5 ± 7.2 pretreatment), internists/rheumatologists/dermatologists (2.0 ± 2.1 versus 3.7 ± 3.9), and pediatricians (1.8 ± 1.5 versus 4.4 ± 4.2). CONCLUSION: Long-term treatment with canakinumab achieves a highly relevant improvement in the physical, emotional, and social lives of patients with CAPS, accompanied by a marked reduction in support required from caregivers and in health care consultations.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Síndromes Periódicos Asociados a Criopirina/diagnóstico , Síndromes Periódicos Asociados a Criopirina/tratamiento farmacológico , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados , Niño , Preescolar , Síndromes Periódicos Asociados a Criopirina/epidemiología , Esquema de Medicación , Femenino , Francia/epidemiología , Humanos , Masculino , Estudios RetrospectivosRESUMEN
INTRODUCTION: For nearly the past two decades, cytokines (CKs) have been the only systemic treatment option available for advanced renal cell carcinoma (RCC). In recent years, tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity on this tumour. Our purpose is to describe one centre's experience with the use of CKs and TKIs in the treatment of patients with advanced RCC. MATERIALS AND METHODS: This study was designed as a retrospective chart review of RCC patients who were treated with CKs and/or TKIs in our department between July 1996 and June 2008. Efficacy and toxicity were assessed using World Health Organization (WHO) criteria. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall (OS) survival. RESULTS: Ninety-four patients were classified into three groups depending on the modality of treatment administered: 46 were treated with CKs alone and/or chemotherapy (27 with immunotherapy, one with chemotherapy and 18 with both), 28 with TKIs alone (25 with sunitinib and 13 with sorafenib) and 20 with TKIs in second-line treatment following failure with CKs (17 with sunitinib, eight with sorafenib, four with bevacizumab and one with lapatinib). The median age was 60 years in the CK group and 65 and 62, respectively, in TKI in first and second-line treatment groups. Eighty-five percent of patients treated with CKs and 75% in the TKI group in first-line treatment and 80% in second-line treatment were men. Overall, 89% of patients had favourable risk, and 11% had intermediate risk. All patients were considered evaluable for toxicity. The main grade 3-4 (%) toxicity was asthenia for both groups, (ten in TKIs and 15 in CKs). Other grade 1-2 toxicities were mucositis (39), bleeding (8), hypertension (19), skin toxicity (33) and hypothyroidism (12.5) associated with TKIs; and anaemia (33), cough (29), asthenia (39) and emesis (14) associated with CKs. The objective response rate among 80 patients evaluable for activity was 10.6% with CKs and 46.5% and 35%, respectively, with TKIs in first- and second-line treatments. Disease stabilisation with CKs was recorded at 59% of patients and with TKIs 25% and 50% in first- and second-line treatment groups, respectively. The median progression-free survival (PFS) with CKs was 122 days [95% confidence interval (CI) 82-162] and with TKIs 201 days (65-337) in the first and 346 days (256-436) in second-line treatment groups. The median overall survival (OS) was 229 days (142-316) and 2,074 days (1,152-2,996) for patients treated with CKs and TKIs. CONCLUSIONS: Our results are in line with the activity and survival rates previously reported in the literature regarding the use of TKIs for patients with advanced RCC in first- and second-line treatment, which has demonstrated an acceptable toxicity level (AU)
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/uso terapéutico , Estudios RetrospectivosRESUMEN
La cirugía representa el tratamiento curativo de elección para los pacientes que son diagnosticadosde carcinoma no microcítico de pulmón en estadio local. Sin embargo, gran parte de ellos experimentanuna recurrencia de su enfermedad lo que ha llevado al empleo de opciones terapéuticas tanto localescomo sistémicas con el ánimo de mejorar las posibilidades de curación. Durante las últimas décadasdiversos estudios comparativos heterogéneos y varios meta-análisis publicados en los años 95 y 97no demostraron de forma significativa una ventaja al asociar la quimioterapia y/o radioterapia adyuvantea la cirugía. Desde entonces y hasta nuestros días otros trabajos realizados con un número mayorde pacientes y empleando una quimioterapia más eficaz basada en combinaciones de platino, coincidenen describir un beneficio con su utilización aunque no de forma unánime. Más recientemente, unnuevo meta-análisis recopilando la mayoría de los estudios antes mencionados ha confirmado de formasignificativa una mejoría absoluta del 4% en la supervivencia global de los pacientes sometidos aquimioterapia adyuvante, especialmente en los estadios patológicos II-III tras cirugía y tratados conregímenes que incluyen cisplatino y vinorelbina. Queda por ser determinado el papel que desempeñanotros agentes como el uracilo/tegafur así como la radioterapia en el contexto adyuvante
Surgery is the current treatment of choice in patients with early-stage non-small cell lung cancer.Based on the high rates of recurrence, additional local and systemic treatments have been developed,aimed at improving the cure rates. The comparative studies about the benefits of post-operativeadjuvant chemotherapy and/or radiotherapy, and the meta-analysis studies made during the lastdecades, reviewed in some articles appeared in 95 and 97, did not confirm a significant improvementof the overall survival. Since then, new comparative trials carried out with a higher number of patientsand with more active and standard chemotherapy seem to show a benefit of the administration ofplatinum-based chemotherapy, although it has not gained general acceptance. More recently, a newmeta-analysis, that included the previous studies, has confirmed an overall increase of 4 % in survivalof patients treated by surgery and adjuvant chemotherapy, especially in stages II-III patients receivingschedules of cisplatin and vinorelbine. Further studies are needed to determine the real therapeuticvalue of other agents, as uracil-tegafur and radiotherapy
Asunto(s)
Humanos , Quimioterapia Adyuvante/métodos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Medicina Basada en la Evidencia , Tasa de Supervivencia , Uracilo/uso terapéutico , Tegafur/uso terapéutico , Cisplatino/uso terapéutico , Terapia NeoadyuvanteRESUMEN
Hyperphosphatemic tumoral calcinosis (HTC) is an inherited metabolic disorder characterized by calcified soft tissue masses and hyperphosphatemia. Besides these typical features, a number of less common manifestations have been reported, all of them related to pathologic calcification of various tissues. We have investigated the case of a woman with hyperphosphatemia, recurrent episodes of lumbar pain, and a positive familial history of HTC. A bone scan showed markedly increased uptake in the lower lumbar spine. Magnetic resonance imaging showed pathological changes in L5 compatible with an inflammatory reaction and not suggestive of neoplastic process. There was no evidence of infection, trauma, malignancy, or other disease that could cause the lesion. We treated the patient with analgesics and NSAIDs and the pain remitted over a period of 1 week. In a follow-up magnetic resonance imaging 7 months later, the L5 lesion had disappeared completely. A computed tomography scan analysis with a bone window showed a sclerotic area at the L5 vertebral body. We believe that this patient was affected by the syndrome of HTC and that the inflammatory phenomena found in L5 are a manifestation of this disease.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Calcinosis/tratamiento farmacológico , Vértebras Lumbares/patología , Errores Innatos del Metabolismo/tratamiento farmacológico , Fosfatos/sangre , Adulto , Calcinosis/patología , Femenino , Humanos , Vértebras Lumbares/virología , Imagen por Resonancia Magnética , Errores Innatos del Metabolismo/patologíaAsunto(s)
Enfermedades Cerebelosas/diagnóstico , Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/secundario , Ataxia Cerebelosa/diagnóstico , Diagnóstico Diferencial , Errores Diagnósticos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/secundarioRESUMEN
No disponible
Asunto(s)
Humanos , Síndromes Paraneoplásicos del Sistema Nervioso , Enfermedades Cerebelosas , Ataxia Cerebelosa , Diagnóstico Diferencial , Errores Diagnósticos , Adenocarcinoma , Neoplasias PulmonaresRESUMEN
Two human cDNAs encoding proteins similar to yeast enzymes involved in proteolytic processing of farnesylated proteins like a-factor mating pheromone and Ras2p have been cloned from an ovary cDNA library. These proteins have been tentatively called Face-1 and Face-2 (farnesylated protein-converting enzymes 1 and 2), respectively, and are integral membrane proteins, belonging to distinct families of metalloproteinases. Northern blot analysis of poly(A)+ RNAs isolated from a wide variety of human tissues demonstrated that both genes are expressed in all examined tissues, which suggests that these enzymes play housekeeping roles in normal processes. Fluorescence in situ hybridization experiments showed that the human FACE-1 gene maps to 1p34, whereas FACE-2 is located at 11q13, a region frequently amplified in human carcinomas and lymphomas. On the basis of these results, we suggest that inhibition of Face-1 and/or Face-2 could be part of strategies directed to block the functioning of prenylated proteins activated in oncogenic processes, including Ras proteins.
Asunto(s)
Endopeptidasas , Lipoproteínas , Proteínas de la Membrana/genética , Metaloendopeptidasas/genética , Metaloproteasas , Precursores de Proteínas/metabolismo , Proteínas de Saccharomyces cerevisiae , Secuencia de Aminoácidos , Secuencia de Bases , Northern Blotting , Mapeo Cromosómico , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 11/genética , ADN Complementario/química , ADN Complementario/genética , Femenino , Expresión Génica , Humanos , Células Híbridas , Hibridación Fluorescente in Situ , Masculino , Metaloendopeptidasas/metabolismo , Datos de Secuencia Molecular , Proproteína Convertasas , Prenilación de Proteína , ARN Mensajero/genética , ARN Mensajero/metabolismo , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Alineación de Secuencia , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Distribución Tisular , Transcripción Genética , Proteínas ras/metabolismoRESUMEN
We previously compared the structure and motility suppressive capacity of nm23-H1 by transfection of wild type and site-directed mutant forms into breast carcinoma cells. Wild type nm23-H1 and an nm23-H1(S44A) (serine 44 to alanine) mutant suppressed motility, whereas the nm23-H1(P96S), nm23-H1(S120G), and to a lesser extent, nm23-H1(S120A) mutant forms failed to do so. In the present study wild type and mutant recombinant Nm23-H1 proteins have been produced, purified, and assayed for phosphorylation and phosphotransfer activities. We report the first association of Nm23-H1 mutations lacking motility suppressive capacity with decreased in vitro activity in histidine-dependent protein phosphotransferase assays. Nm23-H1(P96S), a Drosophila developmental mutation homolog, exhibited normal autophosphorylation and nucleoside-diphosphate kinase (NDPK) characteristics but deficient phosphotransfer activity in three histidine protein kinase assays, using succinic thiokinase, Nm23-H2, and GST-Nm23-H1 as substrates. Nm23-H1(S120G), found in advanced human neuroblastomas, exhibited deficient activity in several histidine-dependent protein phosphotransfer reactions, including histidine autophosphorylation, downstream phosphorylation on serines, and slightly decreased histidine protein kinase activity; significant NDPK activity was observed. The Nm23-H1(S120A) mutant was deficient in only histidine-dependent serine autophosphorylation. Nm23-H1 and Nm23-H1(S44A) exhibited normal activity in all assays conducted. Based on this correlation, we hypothesize that a histidine-dependent protein phosphotransfer activity of Nm23-H1 may be responsible for its biological suppressive effects.
Asunto(s)
Proteínas de Unión al GTP Monoméricas , Nucleósido-Difosfato Quinasa/metabolismo , Sistema de Fosfotransferasa de Azúcar del Fosfoenolpiruvato/metabolismo , Factores de Transcripción/genética , Relación Dosis-Respuesta a Droga , Glutatión Transferasa/metabolismo , Histidina , Histidina Quinasa , Humanos , Modelos Biológicos , Mutagénesis Sitio-Dirigida , Nucleósido Difosfato Quinasas NM23 , Fosforilación , Proteínas Quinasas/metabolismo , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Serina , TransfecciónRESUMEN
Using PCR with degenerate primers and screening of a human B-cell lymphoblast cDNA library, a full-length cDNA encoding a 375-amino-acid protein was isolated. It contains seven regions of hydrophobic amino acids probably representing membrane-spanning domains of a novel heptahelix receptor, tentatively named CMKRL2. It shows nearly 30% overall identity with the high-affinity IL8 receptor and similar degree of homology with other chemoattractant receptors, including the "fusin" coreceptors for HIV1. Measurements of various transduction pathways following application of a panel of chemokines to transfected cells failed to evoke any reproducible response. Although the natural ligand for CMKRL2 could, thus, not be identified, receptor expression in spleen and lymph nodes as well as in Burkitt's lymphoma (irrespective of EBV status) supports a functional role in activated B-cells. Receptor message was ubiquitously distributed in normal peripheral tissues and CNS, suggesting that CMKRL2 is expressed in widespread cell populations, such as macrophages and neuroglia.
Asunto(s)
Encéfalo/metabolismo , Linfoma de Burkitt/metabolismo , Cromosomas Humanos Par 7 , Estructura Secundaria de Proteína , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/química , Receptores Acoplados a Proteínas G , Adenilil Ciclasas/metabolismo , Secuencia de Aminoácidos , Antígenos CD/química , Linfocitos B/metabolismo , Secuencia de Bases , Linfoma de Burkitt/genética , Calcio/metabolismo , Línea Celular , Células Cultivadas , Mapeo Cromosómico , Clonación Molecular , Cartilla de ADN , ADN Complementario , Humanos , Ganglios Linfáticos/metabolismo , Datos de Secuencia Molecular , Especificidad de Órganos , Reacción en Cadena de la Polimerasa , Receptores de Superficie Celular/genética , Receptores de Estrógenos , Receptores de Interleucina/química , Receptores de Interleucina-8A , Proteínas Recombinantes/biosíntesis , Homología de Secuencia de Aminoácido , Bazo/metabolismo , Transfección , Células Tumorales CultivadasRESUMEN
Electrospray mass spectrometry was used to accurately measure the molecular masses of single chain lectins from legume seeds and also of three recombinant lectins, expressed in Escherichia coli. The five single chain lectins, Erythrina corallodendron lectin, soybean and peanut agglutinins, Dolichos biflorus lectin, and Phaseolus vulgaris hemagglutinin E, all showed evidence of C-terminal proteolytic processing, in some cases to "ragged" ends, when their masses were compared to those expected from their cDNA sequences and their known carbohydrate chains. Recombinant forms of the lectins from E. corallodendron, soybean, and peanut also showed C-terminal trimming, but not to the same points as the natural forms. Discrepancies between the protein and cDNA sequences of the E. corallodendron lectin were resolved by combined liquid chromatography-mass spectrometry peptide mapping and protein sequencing experiments, and the presence of a second glycosylation site was demonstrated. Our data show that all of these lectins undergo C-terminal proteolytic processing of a readily attacked peptide segment. This trimming is frequently imprecise, and the resulting heterogeneity may be a major contributor to the appearance of isolectin forms of these proteins.
Asunto(s)
Escherichia coli/genética , Lectinas/metabolismo , Plantas/metabolismo , Procesamiento Proteico-Postraduccional , Secuencia de Aminoácidos , Secuencia de Carbohidratos , Clonación Molecular , Hidrólisis , Lectinas/genética , Espectrometría de Masas/métodos , Datos de Secuencia Molecular , Lectinas de Plantas , Plantas/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
Brain expression of transferrin (Tf) and transthyretin (TTR) mRNA has been demonstrated in different species, TTR being found only in the choroid plexus. We report here that both these mRNAs are also expressed in the meninges. In vitro studies have shown that Tf secretion by the rat choroid plexus is stimulated by 5-hydroxytryptamine (5-HT) while sympathetic nerves regulate different transport functions in the same tissue. We have used various in vivo models to study the neuroendocrine regulation of Tf and TTR mRNA expression in the choroid plexus and meninges. Destruction of the serotonergic nerves in the brain by either raphe nuclei lesion or intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT), which both decreased brain 5-HT levels significantly, did not affect Tf or TTR mRNA levels in choroid plexus and meninges, but increased TTR mRNA in liver. Intraventricular injection of 10 or 100 pmol 5-HT did not change the expression of these proteins in any of the tissues studied. Removal of the sympathetic innervation to the choroid plexus by cervical sympathectomy did not affect Tf or TTR mRNA levels in choroid plexus and liver, nor the incorporation of radioactive leucine into protein in various parts of the brain. In conclusion, our results do not support a regulatory role in vivo for neuronally derived 5-HT or sympathetic nerve activity on Tf and TTR mRNA expression in rat choroid plexus and meninges.
Asunto(s)
Plexo Coroideo/metabolismo , Meninges/metabolismo , Prealbúmina/biosíntesis , ARN Mensajero/biosíntesis , Serotonina/fisiología , Sistema Nervioso Simpático/fisiología , Transferrina/biosíntesis , 5,7-Dihidroxitriptamina/farmacología , Animales , Northern Blotting , Plexo Coroideo/efectos de los fármacos , Densitometría , Expresión Génica/efectos de los fármacos , Leucina/metabolismo , Masculino , Meninges/efectos de los fármacos , ARN Mensajero/aislamiento & purificación , Núcleos del Rafe/fisiología , Ratas , Ratas Sprague-Dawley , Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Ganglio Cervical Superior/fisiologíaRESUMEN
Rats were made hypo- or hyperthyroid to study the role of thyroid hormones on cerebral transthyretin (TTR) mRNA expression. TTR mRNA was detected by Northern blot in rat liver, choroid plexus and meninges but not in cultured astrocytes or cultured cerebral endothelial cells. No changes were found in the levels of TTR mRNA in liver, choroid plexus or meninges in hypo- or hyperthyroid rats compared with the controls. In order to investigate the main route of thyroxine transport from blood to brain, the distribution of [125I]thyroxine in the brain was studied after intravenous (i.v.) and intraventricular (i.v.c.) injection by both direct counting and autoradiography. While distribution of [125I]thyroxine could be seen throughout the brain parenchyma after i.v. injection, the labelling was confined to the CSF spaces after i.v.c. administration. When protein synthesis was inhibited by cycloheximide treatment and [125I]thyroxine was injected intravenously, the uptake of [125I]thyroxine in the choroid plexus decreased while the uptake in the cerebral cortex increased. This indicates that thyroxine is transported into the brain primarily through the blood-brain barrier and not via the choroid plexus and CSF. We discuss the possibility that TTR has a role in the distribution of thyroxine throughout the brain.
Asunto(s)
Encéfalo/metabolismo , Expresión Génica , Hipertiroidismo/metabolismo , Hipotiroidismo/metabolismo , Prealbúmina/biosíntesis , Glándula Tiroides/fisiología , Tiroxina/metabolismo , Animales , Autorradiografía , Northern Blotting , Plexo Coroideo/metabolismo , Radioisótopos de Yodo , Hígado/metabolismo , Masculino , Meninges/metabolismo , Especificidad de Órganos , ARN Mensajero/biosíntesis , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Tiroxina/sangre , Tiroxina/farmacocinéticaRESUMEN
To elucidate the function of insulin-like growth factor-II (IGF-II) in the choroid plexus, the gene expression and receptor binding of IGF-II were studied in isolated epithelial cells from the porcine choroid plexus. The choroid plexus expressed multiple IGF-II transcripts of 1.2, 1.6, 2.4, and 4.4 kb, at levels higher than those found in porcine liver and kidney. These data suggest that IGF-II is synthesized by the choroid plexus. Choroid plexus epithelial cells contained high levels of IGF-I receptors on the cell surface whereas very low levels of receptor binding were found for 125I-IGF-II and 125I-insulin. Solubilization of epithelial cells showed that a large proportion of the IGF-I receptors were present in the detergent-insoluble fraction whereas IGF-II receptors and insulin receptors were concentrated in the detergent-soluble fraction. These results suggest that IGF-I receptors are located in clathrin-coated pits of the plasma membrane whereas IGF-II receptors and insulin receptors are present in endosomal vesicles. The tyrosine kinase activity of the IGF-I receptor beta-subunit was stimulated by IGF-I, IGF-II, and insulin, in order of potency, suggesting that these peptides exert a regulatory function in the choroid plexus epithelium. In conclusion, we propose that the IGF-I receptor tyrosine kinase on the surface of the epithelial cells in the pig choroid plexus mediates effects of IGF-I and IGF-II, whereas IGF-II receptors are down-regulated due to the synthesis and secretion of IGF-II in these cells.
Asunto(s)
Plexo Coroideo/fisiología , Expresión Génica , Factor I del Crecimiento Similar a la Insulina/genética , Receptores de Superficie Celular/metabolismo , Marcadores de Afinidad , Animales , Plexo Coroideo/citología , Plexo Coroideo/metabolismo , Células Epiteliales , Epitelio/metabolismo , Epitelio/fisiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Receptores de Somatomedina , PorcinosRESUMEN
Ion-spray mass spectrometry was investigated for the analysis of 21 antibacterial sulfonamide drugs. All of the sulfonamides analyzed gave positive ion mass spectra with abundant protonated molecules and no fragmentation. Tandem mass spectrometry (MS-MS) using collision-induced dissociation provided structural information, allowing the identification of common fragmentation pathways and the differentiation of isomeric and isobaric sulfonamides. A reversed-phase high-performance liquid chromatographic method was developed, using gradient elution and ultraviolet diode-array detection (DAD), enabling the separation of 16 of the sulfonamides. Combined liquid chromatography (LC)-MS was accomplished using the ion-spray interface. Analyses of a mixture of sulfonamide standards were performed with gradient elution and the mass spectrometer configured for full-scan acquisition, selected-ion monitoring, or selected-reaction monitoring. Procedures for the analysis of sulfadimethoxine (SDM), a representative sulfonamide used in the aquaculture industry, are described. The presence of SDM in cultured salmon flesh was confirmed at levels as low as 25 ng/g by a combination of LC-DAD and LC-MS-MS.
Asunto(s)
Cromatografía Líquida de Alta Presión , Productos Pesqueros/análisis , Análisis de los Alimentos/métodos , Espectrometría de Masas , Salmón , Sulfonamidas/análisis , Animales , Estructura Molecular , Sulfadimetoxina/análisis , Sulfonamidas/químicaRESUMEN
Acivicin inhibits gamma-glutamyl transpeptidase activity in human keratinocytes in culture. Treatment of these cells with acivicin produces a decrease in the uptake of L-[U-14C]alanine, 2-amino-[1-14C]-isobutyrate, L-[U-14C]leucine and 1-aminocyclopentane-1-[14C]carboxylate. D-[U-14C]glucose uptake is not affected by the presence of acivicin. These results support, for the first time in vitro, the hypothesis that the gamma-glutamyl cycle may be involved in amino acid uptake by human cells.
Asunto(s)
Aminoácidos/metabolismo , Queratinocitos/enzimología , gamma-Glutamiltransferasa/antagonistas & inhibidores , Transporte Biológico/efectos de los fármacos , Células Cultivadas , Glucosa/metabolismo , Glutatión/metabolismo , Humanos , Técnicas In Vitro , Isoxazoles/farmacología , Queratinocitos/metabolismoRESUMEN
Several studies conducted during the past few years have shown that the pharmacokinetics of a variety of drugs may be altered following viral infection or vaccination. The elimination of drugs which are extensively metabolized, such as theophylline, may be prolonged, especially following exposure to RNA viruses such as Type A influenza or similar orthomyxoviruses. The purpose of this study was to determine whether vaccination of horses with equine influenza virus affected pharmacokinetic parameters describing the distribution and elimination of intravenously administered theophylline. Three thoroughbred horses and three ponies were vaccinated with a trivalent vaccine containing inactivated strains of A/Equi 1 (Prague), A/Equi 2 (Miami) and A/Equi 2 (Kentucky 81). Antibody titre, serum interferon concentrations, and the pharmacokinetic parameters t1/2 beta, Vc, Vd(ss), Vd(area) and ClB were measured at various intervals after vaccination. Antibody titre increased substantially in only two animals, while plasma interferon was detectable in low concentrations in four subjects. There was no significant change in any parameter describing the pharmacokinetics of theophylline when measured 2, 6, or 12 days after vaccination. It is suggested that the failure of vaccination to substantially increase plasma interferon concentrations, and thereby alter theophylline elimination, was related to the use of an inactivated viral vaccine, the only type available for vaccination of horses against infection with equine influenza. Regular use of such vaccines, as is required by most Racing Authorities, is therefore unlikely to affect drug withdrawal times.