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1.
Arch Soc Esp Oftalmol (Engl Ed) ; 97(10): 543-548, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36038486

RESUMEN

GENERAL OBJECTIVE: To evaluate the accuracy and validity of images with smartphone compared to the RetCam® system for the diagnosis of retinopathy of prematurity (ROP). METHODOLOGY: Observational, longitudinal and masked study carried out at the Dr. Elías Santana hospital. Infants with birth weight ≤1500 g, gestational age ≤30 weeks and/or patients exposed to risk factors or complications linked to ROP were included. These subjects were screened using images with smartphone or RetCam®, both compared to conventional fundoscopy. The ICROP classification was used for staging. The main results analyzed were sensitivity, specificity, positive predictive values and kappa index. RESULTS: 915 images (n = 121) were obtained, distributed in smartphone group (50.4%) and RetCam® group (49.6%) between August 2020 and March 2021. Subjects with ROP had lower gestational age (30.2 sem ± 2.8), birth weight (1361 g ± 398), and greater exposure to oxygen therapy (12.8 days ± 11.3). The RetCam® group presented sensitivity = 80%, specificity = 78%, positive predictive value = 90% and kappa index = 0.70. The smartphone group presented sensitivity = 88%, specificity = 90%, positive predictive value = 93.75% and kappa index = 0.81. CONCLUSIONS: Both diagnostic methods were accurate to identify ROP. The smartphone group obtained superior results with excellent resolution, representing a cost-effective method to create a global impact on reducing preventable blindness in the pediatric population.


Asunto(s)
Retinopatía de la Prematuridad , Telemedicina , Peso al Nacer , Niño , Humanos , Lactante , Recién Nacido , Oftalmoscopía/métodos , Oxígeno , Retinopatía de la Prematuridad/diagnóstico
2.
PLoS One ; 16(8): e0255600, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34351991

RESUMEN

OBJECTIVE: Non-professional care provided in domestic settings by a family member or someone from the close environment and without a connection to a professional care service, is increasingly assumed by older people, mainly the spouses of those requiring care. The aim of this study was to describe the experience of older people providing care at home to older dependents. METHODS: A qualitative study was carried out to describe and explore the experience of older people, caregivers of dependent older people in the home. RESULTS: Four themes emerged as a result of the analysis: interpersonal relationships established in the caregivers' immediate environment; the need and request for public and private resources; consequences of providing care during old age; and adaptation to the circumstance of being a caregiver during old age. Older people who provide home-based care, experience their situation as stressful, feel that it limits their daily life, deprives them of their freedom, and affects their interpersonal relationships and social activities. DISCUSSION: Older caregivers learn quickly and can manage the skills issues. The volume of work is their challenge. Interpersonal relationships are altered depending on the length of time spent together and the demand for care. Public services and benefits are not adapted to the demands of caregivers or dependent persons.


Asunto(s)
Adaptación Psicológica/fisiología , Cuidadores/psicología , Emociones/fisiología , Familia/psicología , Servicios de Atención de Salud a Domicilio/estadística & datos numéricos , Aislamiento Social , Esposos/psicología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Investigación Cualitativa
3.
J Appl Stat ; 48(13-15): 2525-2541, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35707072

RESUMEN

We propose a new technique for the study of multivariate count data. The proposed model is applied to the study of the number of individuals several fossil species found in a set of geographical observation points. First, we are proposing a multivariate model based on the Poisson distributions, which allows positive and negative correlations between the components. We are extending the log-linear Poisson model in the multivariate case through the conditional distributions. For this model, we obtain the maximum likelihood estimates and compute several goodness of fit statistics. Finally we illustrate the application of the proposed method over data sets: various simulated data sets and a count data set of various fossil species.

4.
Rev. psicol. polit ; 18(43): 524-542, set.-dez. 2018.
Artículo en Español | LILACS-Express | LILACS | ID: biblio-1004458

RESUMEN

Este artículo explora los actores y las estrategias del activismo católico laico en España, considerando cómo estos desafiadores se han vuelto voces representativas del discurso de la "ideología de género" que la iglesia católica promueve. A fin de esclarecer los factores que convierten al caso español en específico, en primer lugar se presentan algunos datos generales sobre el contexto histórico español. A continuación, analizamos quiénes son los activistas católicos, incluyendo organizaciones como Hazte Oír, Foro de la Familia), y teniendo en cuenta cuál es su estructura organizativa y sus conexiones con la iglesia católica o con partidos políticos. A continuación se analizará el repertorio de movilización presente en el activismo anti-género, prestando atención a la combinación estratégica de recursos tradicionales e innovadores en el marco del activismo conservador así como también se prestará atención a las reacciones y el impacto de las acciones en la opinión pública y en las decisiones políticas. Para concluir, exploramos por que razones estas estrategias han resultado poco exitosas (en términos de cambiar la opinión pública o dar un giro radical a las políticas de género) y en qué modo los actores anti-género se han convertido en una minoría radicalizada.


This chapter explores actors and strategies of Christian lay activism in Spain, considering how these actors have become representative voices of the discourse on "ideology of gender" that Catholic Church is promoting. Some general data about the historical context in Spain are presented in order to clarify the factors that make the Spanish case specific. We will then analyze who are these Christian lay activists (namely Hazte Oir, Foro de la Familia, and the new political party Vox) and what are their organizational structure and connections with the Catholic Church, advocacy groups or political parties. Thereon, the repertoire of mobilization will is considered, paying special attention to old and new actions: from demonstrations and crowded masses to active bloggerism, massive posting, Twitter and social media campaigns, complaints in court, signage and symbols or international conferences. The analysis includes reactions and impact of their strategies and activities on policies, public opinion and other social actors. To conclude, an explanation is presented of why these strategies have mostly been unsuccessful in recent years and why the most noticeable promoters of anti-gender discourses are becoming a radicalized minority in Spain.


O artigo explora os atores e estratégias de ativismo católico leigo na Espanha, considerando como esses ativistas tornaram-se vozes representativas do discurso sobre a "ideologia de gênero" que a Igreja Católica promove. A fim de esclarecer os fatores que tornam o caso espanhol específico, algumas informações gerais sobre o contexto histórico na Espanha são apresentadas em um primeiro momento. Em seguida, analisa-se quem são os ativistas católicos leigos (Hazte Oir, Fórum da Família e o novo partido político Vox), explorando quais são suas organizações e as suas conexões com a igreja católica, lobbies e partidos políticos formais. Nele, o repertório de mobilização será considerado, com atenção especial para antigas e novas ações de protesto: Manifestações nas estradas, campanhas de mídia social, reclamações aos tribunais, conferências internacionais e outros. A análise inclui a descrição das reações e impacto de suas estratégias e atividades políticas na opinião pública e em outros atores sociais. Para concluir, o artigo oferece uma explicação de por que essas estratégias foram apresentadas quase sempre sem sucesso nos últimos anos e por que os promotores mais notáveis do discurso anti-gênero na Espanha estão se tornando uma minoria radicalizada.


Ce chapitre explore les acteurs et les stratégies d'activisme des laïcs chrétiens en Espagne, en considérant comment ces acteurs sont devenus des voix représentatives du discours sur «l'idéologie du genre¼ promu par l'Église catholique. Quelques données générales sur le contexte historique en Espagne sont présentées afin de clarifier les facteurs qui rendent le cas espagnol spécifique. Nous analyserons ensuite qui sont ces militants laïcs chrétiens (à savoir Hazte Oir, le Forum de la famille et le nouveau parti politique Vox) et quelles sont leur structure organisationnelle et leurs liens avec l'Église catholique, des groupes de défense des droits ou des partis politiques. Ensuite, le répertoire de la volonté de mobilisation est pris en compte, en accordant une attention particulière aux actions anciennes et nouvelles: des manifestations et des foules nombreuses au blogging actif, en passant par les campagnes massives, les campagnes sur Twitter et les médias sociaux, les plaintes en cour, les panneaux et symboles ou les conférences internationales. L'analyse inclut les réactions et l'impact de leurs stratégies et activités sur les politiques, l'opinion publique et les autres acteurs sociaux. Pour conclure, une explication est présentée sur les raisons pour lesquelles ces stratégies ont été infructueuses ces dernières années et pourquoi les promoteurs les plus remarquables de discours anti-genre sont en train de devenir une minorité radicalisée en Espagne.

5.
Artículo en Inglés | MEDLINE | ID: mdl-27826442

RESUMEN

BACKGROUND: In order to improve ICSI, appropiate sperm selection and oocyte activation is necessary. The objective of the present study was to determine the efficiency of fertilization using ICSI with chemically activated ovine oocytes and sperm selected by swim up (SU) or swim up + zona pellucida (SU + ZP) binding. RESULTS: Experiment 1, 4-20 replicates with total 821 in vitro matured oocytes were chemically activated with ethanol, calcium ionophore or ionomycin, to determine oocyte activation (precense of one PN). Treatments showed similar results (54, 47, 42 %, respectively) but statistically differents (P < 0.05) than mechanical activated oocytes in sham, ICSI and sham injection (13, 25, 32 %, respectively) (10-17 replicates; n = 429). Experiment 2: Twelve ejaculates and 28 straws of semen were used (11-19 replicates). Sperm were selected by SU in BSA-TCM 199-H medium. A total of 2,294 fresh sperm and 2,760 from frozen-thawed semen were analyzed after SU or SU + ZP binding. Fresh sperm selected by SU showed acrosome reaction (AR) of 59 %, the sperm selected by SU + ZP binding increased AR to 91 %. In comparison, the AR of frozen-thawed sperm using SU or SU + ZP binding was 77 and 86 %, respectively (P < 0.05). Experiment 3: fertilization in 200 mechanical activativated oocytes (17 replicates) was 4 %, but fertilization increased in ethanol activated oocytes after ICSI (12-28 %) (5-6 replicates). When fresh sperm only selected by SU were injected to 123 oocytes, a fertilization rate (28 %) was achieved; in sperm selected by SU + ZP was 25 % (73 oocytes). In comparison, in frozen-thawed sperm selected by SU, fertilization was 13 % (70 oocytes), whereas sperm from SU + ZP binding displayed 12 % (51 oocytes) (P > 0.05). CONCLUSIONS: Chemical activation induces higher ovine oocyte activation than mechanical activation. Ethanol slightly displays higher oocyte activation than calcium ionophore and ionomicine. Sperm selection with SU + ZP increased AR/A and AR/D rates in comparison with SU in fresh and frozen-thawed sperm. According to this, in terms of fertilization rates, chemical activation after ICSI increased oocyte PN formation compared to mechanical activation. Also, fresh sperm treated with SU and SU + ZP were significantly different than frozen-thawed sperm, but between sperm treatments no significant differences were obtained.

6.
Antimicrob Agents Chemother ; 54(6): 2365-70, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20308381

RESUMEN

Small-molecule hepatitis C virus (HCV) NS3 protease inhibitors such as boceprevir (SCH 503034) have been shown to have antiviral activity when they are used as monotherapy and in combination with pegylated alpha interferon and ribavirin in clinical trials. Improvements in inhibitor potency and pharmacokinetic properties offer opportunities to increase drug exposure and to further increase the sustained virological response. Exploration of the structure-activity relationships of ketoamide inhibitors related to boceprevir has led to the discovery of SCH 900518, a novel ketoamide protease inhibitor which forms a reversible covalent bond with the active-site serine. It has an overall inhibition constant (K*(i)) of 7 nM and a dissociation half-life of 1 to 2 h. SCH 900518 inhibited replicon RNA at a 90% effective concentration (EC(90)) of 40 nM. In biochemical assays, SCH 900518 was active against proteases of genotypes 1 to 3. A 2-week treatment with 5x EC(90) of the inhibitor reduced the replicon RNA level by 3 log units. Selection of replicon cells with SCH 900518 resulted in the outgrowth of several resistant mutants (with the T54A/S and A156S/T/V mutations). Cross-resistance studies demonstrated that the majority of mutations for resistance to boceprevir and telaprevir caused similar fold losses of activity against all three inhibitors; however, SCH 900518 retained more activity against these mutants due to its higher intrinsic potency. Combination treatment with alpha interferon enhanced the inhibition of replicon RNA and suppressed the emergence of resistant replicon colonies, supporting the use of SCH 900518-pegylated alpha interferon combination therapy in the clinic. In summary, the results of the preclinical characterization of the antiviral activity of SCH 900518 support its evaluation in clinical studies.


Asunto(s)
Antivirales/farmacología , Dipéptidos/farmacología , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Inhibidores de Proteasas/farmacología , Sulfonas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/administración & dosificación , Antivirales/química , Ciclopropanos , Dipéptidos/administración & dosificación , Dipéptidos/química , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Farmacorresistencia Viral/genética , Genotipo , Hepacivirus/genética , Humanos , Técnicas In Vitro , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Cinética , Leucina/análogos & derivados , Mutación , Prolina/análogos & derivados , Prolina/farmacología , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/química , Proteínas Recombinantes , Replicón/efectos de los fármacos , Sulfonas/administración & dosificación , Sulfonas/química , Urea
7.
Stat Med ; 27(9): 1403-20, 2008 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-17680551

RESUMEN

Length of hospital stay (LOS) is an important indicator of the hospital activity and management of health care. The skewness exhibited by this variable poses problems in statistical modeling. The aim of this work is to model the variable LOS within diagnosis-related groups (DRG) through finite mixtures of distributions. A mixture of the union of Gamma, Weibull and Lognormal families is used in the model, instead of a mixture of a unique distribution family. Some theoretical questions regarding the model, such as the identifiability and study of asymptotic properties of ML estimators, are analyzed. The EM algorithm is proposed for performing these estimators. Finally, this new proposed model is illustrated by using data from different DRGs.


Asunto(s)
Tiempo de Internación/estadística & datos numéricos , Algoritmos , Biometría , Grupos Diagnósticos Relacionados/estadística & datos numéricos , Humanos , Funciones de Verosimilitud , Modelos Estadísticos
8.
J Nucl Med ; 47(11): 1875-83, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17079822

RESUMEN

UNLABELLED: The toxicity of red bone marrow is widely considered to be a key factor in restricting the activity administered in molecular radiotherapy to suboptimal levels. The assessment of marrow toxicity requires an assessment of the dose absorbed by red bone marrow which, in many cases, requires knowledge of the total red bone marrow mass in a given patient. Previous studies demonstrated, however, that a close surrogate-spongiosa volume (combined tissues of trabecular bone and marrow)-can be used to accurately scale reference patient red marrow dose estimates and that these dose estimates are predictive of marrow toxicity. Consequently, a predictive model of the total skeletal spongiosa volume (TSSV) would be a clinically useful tool for improving patient specificity in skeletal dosimetry. METHODS: In this study, 10 male and 10 female cadavers were subjected to whole-body CT scans. Manual image segmentation was used to estimate the TSSV in all 13 active marrow-containing skeletal sites within the adult skeleton. The age, total body height, and 14 CT-based skeletal measurements were obtained for each cadaver. Multiple regression was used with the dependent variables to develop a model to predict the TSSV. RESULTS: Os coxae height and width were the 2 skeletal measurements that proved to be the most important parameters for prediction of the TSSV. The multiple R(2) value for the statistical model with these 2 parameters was 0.87. The analysis revealed that these 2 parameters predicted the estimated the TSSV to within approximately +/-10% for 15 of the 20 cadavers and to within approximately +/-20% for all 20 cadavers in this study. CONCLUSION: Although the utility of spongiosa volume in estimating patient-specific active marrow mass has been shown, estimation of the TSSV in active marrow-containing skeletal sites via patient-specific image segmentation is not a simple endeavor. However, the alternate approach demonstrated in this study is fairly simple to implement in a clinical setting, as the 2 input measurements (os coxae height and width) can be made with either pelvic CT scanning or skeletal radiography.


Asunto(s)
Médula Ósea/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Radiometría/métodos , Médula Ósea/patología , Huesos/efectos de la radiación , Cadáver , Femenino , Humanos , Modelos Lineales , Masculino , Modelos Químicos , Dosificación Radioterapéutica , Análisis de Regresión , Tomografía Computarizada por Rayos X/métodos , Imagen de Cuerpo Entero
9.
Phys Med Biol ; 51(18): 4447-67, 2006 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-16953037

RESUMEN

Recent advances in physical models of skeletal dosimetry utilize high-resolution 3-dimensional microscopic computed tomography images of trabecular spongiosa. These images are coupled to radiation transport codes to assess energy deposition within active bone marrow and trabecular endosteum. These transport codes rely primarily on the segmentation of the spongiosa images into bone and marrow voxels. Image thresholding has been the segmentation of choice for bone sample images because of its extreme simplicity. However, the ability of the segmentation to reproduce the physical boundary between bone and marrow depends on the selection of the threshold value. Statistical models, as well as visual inspection of the image, have been employed extensively to determine the correct threshold. Both techniques are affected by partial volume effect and can provide unexpected results if performed without care. In this study, we propose a new technique to threshold trabecular spongiosa images based on visual inspection of the image gradient magnitude. We first show that the gradient magnitude of the image reaches a maximum along a surface that remains almost independent of partial volume effect and that is a good representation of the physical boundary between bone and marrow. A computer program was then developed to allow a user to compare the position of the iso-surface produced by a threshold with the gradient magnitude. The threshold that produces the iso-surface that best coincides with the maximum gradient is chosen. The technique was finally tested with a set of images of a true bone sample with different resolutions, as well as with three images of a cube of Duocell aluminium foam of known mass and density. Both tests demonstrate the ability of the gradient magnitude technique to retrieve sample volumes or media volume fractions with 1% accuracy at 30 microm voxel size.


Asunto(s)
Médula Ósea/diagnóstico por imagen , Huesos/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/métodos , Tomografía Computarizada por Rayos X/métodos , Compuestos de Aluminio/farmacología , Médula Ósea/patología , Huesos/patología , Humanos , Microscopía Electrónica de Rastreo/métodos , Modelos Biológicos , Modelos Estadísticos
10.
Antimicrob Agents Chemother ; 50(3): 1013-20, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16495264

RESUMEN

Cleavage of the hepatitis C virus (HCV) polyprotein by the viral NS3 protease releases functional viral proteins essential for viral replication. Recent studies by Foy and coworkers strongly suggest that NS3-mediated cleavage of host factors may abrogate cellular response to alpha interferon (IFN-alpha) (E. Foy, K. Li, R. Sumpter, Jr., Y.-M. Loo, C. L. Johnson, C. Wang, P. M. Fish, M. Yoneyama, T. Fujita, S. M. Lemon, and M. Gale, Jr., Proc. Natl. Acad. Sci. USA 102:2986-2991, 2005, and E. Foy, K. Li, C. Wang, R. Sumpter, Jr., M. Ikeda, S. M. Lemon, and M. Gale, Jr., Science 300:1145-1148, 2003). Blockage of NS3 protease activity therefore is expected to inhibit HCV replication by both direct suppression of viral protein production as well as by restoring host responsiveness to IFN. Using structure-assisted design, a ketoamide inhibitor, SCH 503034, was generated which demonstrated potent (overall inhibition constant, 14 nM) time-dependent inhibition of the NS3 protease in cell-free enzyme assays as well as robust in vitro activity in the HCV replicon system, as monitored by immunofluorescence and real-time PCR analysis. Continuous exposure of replicon-bearing cell lines to six times the 90% effective concentration of SCH 503034 for 15 days resulted in a greater than 4-log reduction in replicon RNA. The combination of SCH 503034 with IFN was more effective in suppressing replicon synthesis than either compound alone, supporting the suggestion of Foy and coworkers that combinations of IFN with protease inhibitors would lead to enhanced therapeutic efficacy.


Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Interferón-alfa/farmacología , Inhibidores de Proteasas/uso terapéutico , Replicón/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sitios de Unión , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Células Clonales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Hepacivirus/enzimología , Hepatocitos/efectos de los fármacos , Hepatocitos/virología , Humanos , Hidrólisis , Neoplasias Hepáticas/patología , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Estructura Secundaria de Proteína
11.
Bioorg Med Chem Lett ; 15(20): 4515-9, 2005 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-16112862

RESUMEN

Modification of the P(2) and P(1) side chains of earlier P(3)-capped alpha-ketoamide inhibitor of HCV NS3 serine protease 1 resulted in the discovery of compound 24 with about 10-fold improvement in potency.


Asunto(s)
Alanina/química , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Difracción de Rayos X
12.
Bioorg Med Chem Lett ; 15(19): 4180-4, 2005 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-16087332

RESUMEN

We have discovered that introduction of appropriate amino acid derivatives at P'2 position improved the binding potency of P3-capped alpha-ketoamide inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.


Asunto(s)
Hepacivirus/química , Inhibidores de Serina Proteinasa/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sitios de Unión , Cristalografía por Rayos X , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad , Proteínas no Estructurales Virales/química
13.
Mol Cell Biochem ; 196(1-2): 51-7, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10448902

RESUMEN

The suggested role of oxidative stress in the pathogenesis of heart failure is largely based on utilizing left heart failure models. The present study on rats evaluated changes in antioxidants as well as oxidative stress in relation to hemodynamic function subsequent to the right heart failure induced by monocrotaline (50 mg/kg, i.p.). During the post-injection period, monocrotaline (MCT)-treated rats demonstrated a persistent growth depression. Two to three weeks after the injection, MCT-treated rats showed signs of fatigue, peripheral cyanosis and dyspnea. In these rats, right heart hypertrophy was confirmed by a significant increase in right ventricular weight as well as right ventricle to body weight ratio. In MCT-treated rats, there was also a significant increase in right ventricular systolic as well as end diastolic pressures. No change in lung and liver wet/dry weight ratios between MCT-treated and control animals was observed. Based on the hemodynamic data as well as other clinical observations, the functional stage achieved was compensated heart failure. Myocardial antioxidant enzymes, catalase, glutathione peroxidase and superoxide dismutase, in the MCT-treated rats were not different compared to control rats. Vitamin E levels were significantly depressed in the RV and there was no change in retinol levels. There was a significant increase in lipid hydroperoxide concentrations in MCT-treated rats as compared to the control group. These data provide evidence that right heart failure is associated with an increase in oxidative stress.


Asunto(s)
Gasto Cardíaco Bajo/fisiopatología , Corazón/fisiopatología , Estrés Oxidativo , Animales , Antioxidantes/metabolismo , Peso Corporal , Hemodinámica , Peroxidación de Lípido , Peróxidos Lipídicos/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo
14.
Bioorg Med Chem Lett ; 9(14): 1949-52, 1999 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-10450960

RESUMEN

A new hepatitis C virus (HCV) protease inhibitor designated as Sch 351633 (1) was isolated from the fungus, Penicillium griseofulvum. Structure elucidation of 1 was accomplished by analysis of spectroscopic data, which determined compound 1 to be a bicyclic hemiketal lactone. Compound 1 exhibited inhibitory activity in the HCV protease assay with an IC50 value of 3.8 microg/mL.


Asunto(s)
Lactonas/química , Lactonas/farmacología , Penicillium/química , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Antivirales/farmacología , Concentración 50 Inhibidora , Lactonas/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Peso Molecular , Inhibidores de Serina Proteinasa/aislamiento & purificación
15.
Virology ; 225(2): 328-38, 1996 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-8918919

RESUMEN

The NS3 proteinase of hepatitis C virus utilizes NS4A as a cofactor for cleavages at four sites (3/4A, 4A/4B, 4B/5A, and 5A/5B) in the nonstructural region of the viral polyprotein. To characterize NS4A for its role in modulating the NS3 proteinase activity at various cleavage sites, synthetic peptides spanning various parts of NS4A were synthesized and tested in a cell-free trans-cleavage reaction using purified NS3 proteinase domain and polyprotein substrates. The NS3 proteinase domain was expressed in Escherichia coli, purified, denatured, and refolded to an enzymatically active form. We found that a 12-amino-acid peptide containing amino acid residues 22 to 33 in NS4A (CVVIVGRIVLSG) was sufficient for cofactor activity in NS3-mediated proteolysis. The peptide enhanced the cleavage at the NS5A/5B site and was necessary for NS3-mediated cleavage at NS4A/4B and NS4B/5A. Sequential amino acid substitution within the designated peptide identified residues I29 and I25 as critical for potential cofactor activity. We provide evidence that the NS4A peptide and the NS3 catalytic domain form an enzymatically active complex. These data suggest that the central 12-amino-acid peptide (aa 22-33) of NS4A is primarily important for the cofactor activity through complex formation with NS3, and the interaction may represent a new target for antiviral drug development.


Asunto(s)
Hepacivirus/metabolismo , Péptidos/metabolismo , Proteínas no Estructurales Virales/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Activación Enzimática , Humanos , Datos de Secuencia Molecular , Péptidos/química , Péptidos/genética , ARN Helicasas , Análisis de Secuencia , Serina Endopeptidasas , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/genética
16.
Artículo en Inglés | MEDLINE | ID: mdl-8983173

RESUMEN

This study shows that the nonsteroidal antiinflammatory drug, ketorolac, protects against myocardial damage induced by reperfusion. This effect was analyzed after 5 min of coronary occlusion in rat hearts. The results indicate that ketorolac, at a dose of 1 mg/kg, effectively protects the heart against reperfusion arrhythmias. Furthermore, it protects from the release of lactate dehydrogenase and creatine kinase to the plasma. We propose that the protective effect of the drug might be due to its chelating action on calcium ions, thus preventing the overload of such cation in myocardial cells.


Asunto(s)
Inhibidores de la Ciclooxigenasa/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Daño por Reperfusión Miocárdica/prevención & control , Tolmetina/análogos & derivados , Análisis de Varianza , Animales , Arritmias Cardíacas/prevención & control , Presión Sanguínea/efectos de los fármacos , Calcio/metabolismo , Creatina Quinasa/sangre , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacología , Modelos Animales de Enfermedad , Electrocardiografía/efectos de los fármacos , Depuradores de Radicales Libres/administración & dosificación , Depuradores de Radicales Libres/farmacología , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ketorolaco , L-Lactato Deshidrogenasa/sangre , Masculino , Miocardio/citología , Miocardio/metabolismo , Ratas , Ratas Wistar , Tolmetina/administración & dosificación , Tolmetina/farmacología , Tolmetina/uso terapéutico
17.
Nutr Hosp ; 11(1): 47-53, 1996.
Artículo en Español | MEDLINE | ID: mdl-8704017

RESUMEN

The nutritional support is essential in the treatment of the septic patient, but the optimal substrates, have not been well defined, although several studies advise the use of solutions with a high proportion of branched amino acids. The use of lipids in the Parenteral Nutrition (PN) of these patients is presently accepted by all authors, although there is no consensus of the composition of the mix to be used. We have done a prospective, randomized study in a group of critical septic patients who received PN. All cases were used a solution with a high proportion of branched amino acids and glucose. 40% of the non-protein calories were administered as lipids. Based on this, two groups were formed. Group 1 medium chain triglycerides and long chain triglycerides (MCT/LCT) in a ratio of 1:1, and Group II LCT. After ten days, both groups showed an increase in hepatic cholestasis enzymes and an improvement of the parameters of protein anabolism and catabolism. Group 1 showed a significantly higher increase in the retinol birdring protein and the improvement of the nitrogen balance. Besides this, the global analysis of all the parameters of protein anabolism and catabolism showed a more favorable evolution, with statistical significance, in those who received MCT/LCT. Therefore, the MCT/LCT in the PN of the septic patient who is given a solution rich in branched amino acids, achieves a greater protein saving and a faster recevesy of the markers of protein synthesis, than those with LCT. Both groups show an increase in cholestasis enzymes.


Asunto(s)
Aminoácidos de Cadena Ramificada/administración & dosificación , Infecciones/terapia , Nutrición Parenteral , Triglicéridos/administración & dosificación , Adolescente , Adulto , Anciano , Femenino , Humanos , Infecciones/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos
18.
J Bioenerg Biomembr ; 26(4): 457-62, 1994 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7844120

RESUMEN

The effect of triphenyltin on mitochondrial Ca2+ content was studied. It was found that this trialkyltin compound induces an increase in membrane permeability that leads to Ca2+ release, drop of the transmembrane potential, and efflux of matrix proteins. Interestingly, cyclosporin A was unable to inhibit triphenyltin-induced Ca2+ release. Based on these results it is proposed that the hyperpermeable state is produced by modification of 2.25 nmol of membrane thiol groups.


Asunto(s)
Membranas Intracelulares/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Compuestos Orgánicos de Estaño/farmacología , Animales , Calcio/metabolismo , Ciclosporina/farmacología , Cisteína/metabolismo , Ditiotreitol/farmacología , Membranas Intracelulares/metabolismo , Riñón , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Permeabilidad/efectos de los fármacos , Ratas
19.
Arch Inst Cardiol Mex ; 64(4): 325-30, 1994.
Artículo en Español | MEDLINE | ID: mdl-7840715

RESUMEN

This study shows that the nonsteroidal anti-inflammatory drug. Ketorolac, has an ionophore-like action for calcium, such a drug may transfer calcium through an hydrophobic phase. This property does not affect the respiratory rate of mitochondria. These results indicate that the ionophoretic effect is not due to an uncoupling action of Ketorolac. The effect of this compound was tested in a reperfusion model where it was observed that Ketorolac (1 mg/Kg weight) administered 30 min before an ischemic period was induced, reverts the arrhythmic effect of reperfusion. These results are in agreement with the analysis of the plasmatic concentrations of the enzymes creatine kinase and lactic dehydrogenase. It was found that the levels of such enzymes were lower in Ketorolac treated group, than in the untreated one. The results clearly indicate that Ketorolac prevents from the myocardial damage induced by reperfusion, probably by avoiding calcium overload in myocytes.


Asunto(s)
Ionóforos/uso terapéutico , Isquemia Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Tolmetina/análogos & derivados , Animales , Transporte Biológico/efectos de los fármacos , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ionóforos/farmacología , Ketorolaco , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratas , Ratas Wistar , Tolmetina/farmacología , Tolmetina/uso terapéutico
20.
Gac Med Mex ; 130(3): 134-8, 1994.
Artículo en Español | MEDLINE | ID: mdl-7657076

RESUMEN

The experiments referred to in this article point to the fact that relatively low concentrations of Hg2+ (5-10 mM) produce damage to the internal mitochondrial membrane. This damage results in the formation of ionic channels that allow the spontaneous effusion of Ca+2 from the matrix. Together with this, the formation of channels produce the balance of the chemo-osmotic gradient, resulting in the overcoming of the transmembrane potential and the uncoupling of oxidative phosphorylation. The experiments carried out in vivo, point to the fact mercury produces acute tubular necrosis of kidney tissue. These toxic effects produced by Hg2+ in vitro with the addition of 15 microM of the inhibition of the angiotensin converting enzyme, captopril. In vivo experiments show that intraperitoneal infection of captopril (40 mg/kg) completely protects from mitochondrial dysfunction produced by mercurial intoxication.


Asunto(s)
Captopril/farmacología , Mercurio/toxicidad , Mitocondrias/efectos de los fármacos , Animales , Calcio/metabolismo , Captopril/uso terapéutico , Cisteína/farmacología , Relación Dosis-Respuesta a Droga , Riñón/efectos de los fármacos , Riñón/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Mitocondrias/metabolismo , Ratas , Ratas Wistar
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