RESUMEN
La neuromiotonía ocular es una patología poco frecuente caracterizada por episodios recurrentes de diplopía binocular ocasionada por una contracción paroxística mantenida de uno o más músculos extraoculares inervados por un mismo nervio craneal, espontáneamente o inducidos por una versión concreta mantenida en el tiempo, normalmente relacionado con un antecedente de radioterapia local intracraneal. Presentamos el caso de una mujer de 46 años que presenta episodios de diplopía binocular recurrentes, diagnosticada de neuromiotonía ocular del VI nervio craneal izquierdo a los 8 años de padecer un cáncer de cavum tratado mediante radioterapia local y en completa remisión. Aunque es poco frecuente, la radiación a nivel de cavum debe tenerse en cuenta como potencial causa de neuromiotonía ocular, por su proximidad a la base del cráneo y su estrecha relación con el trayecto de los nervios oculomotores, especialmente el VI par craneal, como el caso que se presenta en este artículo.(AU)
Ocular neuromyotonia is an infrequent disorder characterised by recurrent episodes of binocular diplopia caused by paroxysmal contraction of one or several extraocular muscles innervated by the same cranial nerve. It can be triggered spontaneously or caused by prolonged contraction of specific eye muscle(s) and is usually related to a local intracranial radiotherapy antecedent. We report the case of a 46-year-old woman who developed intermittent episodes of binocular diplopia 8 years after radiotherapy for a nasopharyngeal carcinoma. After a complete neuro-ophthalmic assessment we diagnosed the case as an abducens nerve neuromyotonia. Although it is infrequent, radiotherapy to the nasopharynx is a possible cause of ocular neuromyotonia, due to the proximity to the base of the skull and extraocular motor nerve pathways, especially that of the VI cranial nerve, as is the case presented in this article, about a patient whose history is a nasopharyngeal carcinoma treated with local radiotherapy.(AU)
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Humanos , Femenino , Persona de Mediana Edad , Síndrome de Isaacs , Carcinoma Nasofaríngeo , Diplopía , Radioterapia , Visión Ocular , Oftalmología , Oftalmopatías , Pacientes Internos , Examen FísicoRESUMEN
Ocular neuromyotonia (ONM) is an infrequent disorder characterised by recurrent episodes of binocular diplopia caused by paroxysmal contraction of one or several extraocular muscles innervated by the same cranial nerve. It can be triggered spontaneously or caused by prolonged contraction of specific eye muscle(s) and is usually related to a local intracranial radiotherapy antecedent. We report the case of a 46-year-old woman who developed intermittent episodes of binocular diplopia eight years after radiotherapy for a nasopharyngeal carcinoma. After a complete neuro-ophthalmic assessment we diagnosed the case as an abducens nerve neuromyotonia. Although it is infrequent, radiotherapy to the nasopharynx is a possible cause of ONM, due to the proximity to the base of the skull and extraocular motor nerve pathways, especially that of the VI cranial nerve, as is the case presented in this article, about a patient whose history is a nasopharyngeal carcinoma treated with local radiotherapy.
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Diplopía , Síndrome de Isaacs , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Femenino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/radioterapia , Síndrome de Isaacs/etiología , Síndrome de Isaacs/diagnóstico , Carcinoma Nasofaríngeo/radioterapia , Diplopía/etiología , Carcinoma/radioterapia , Enfermedades del Nervio Abducens/etiología , Traumatismos por Radiación/etiología , Traumatismos por Radiación/complicaciones , Radioterapia/efectos adversosRESUMEN
Topaz (Al2F1·44(OH)0·56SiO4)/corundum (Al2O3) composites were prepared by a facile and novel reversible process from the sintering of synthetic topaz and AlF3 powders, with corundum formed in situ into the topaz matrix. The corundum formation reaction occurs in the temperature range 875-975 °C, from 40 min sintering time, obtaining the topaz- Al2F1·44(OH)0·56SiO4/corundum- Al2O3 composites. Although sintering temperature and time increment lead to higher corundum formation in the topaz matrix (78.4 wt % Al2O3 at 975 °C for 60 min), longer residence times give place to corundum percentage decrease due to topaz reconversion. The composites' microstructure is characterized by a rectangular bar with stacked pyramidal ends and polycrystals of hexagonal plates for topaz and corundum, respectively. For the topaz/corundum composites, the maximum density was 3.05 g/cm3 (17 % porosity) for specimens sintered at 925 °C for 20 min. The glow curves of the topaz/in situ corundum composite sintered at 975 °C and 0 min dwell time show thermoluminescent peaks between 180 and 250 °C, useful for dosimetric applications. The most helpful peak (at 221 °C) in the topaz/corundum composite's glow curves determined by computational deconvolution is sharp and exhibits the highest thermoluminescent response. Dose-response analysis of the composite (sintered at 975 °C for 0 min) with the best thermoluminescent response revealed two ranges of linear behavior, the first from 2 to 200 mGy, with an adjustment of 99.9 % and the second in the range 5-300 Gy (99.8 % fitting). The thermoluminescent response improvement of the topaz/corundum composites is attributed to the corundum formed in situ during sintering. Fading rate studies of the composite with the best sintering treatment revealed a signal decrease of 4 % after 15 days, which remained constant for up to 30 days, and 8 % after 60 days. The kinetic parameters, kinetics order (b), activation energy (E), and frequency factor (s) determined using the glow peak shape method showed second-order kinetics. The topaz/corundum composite with the best TL response (975 °C, 0 min) presents an effective atomic number (Zeff) of 11.74. The detection of lower doses (mGy) and the linear response at higher doses (Gy) of beta 90Sr, together with the other thermoluminescent properties, suggest that the topaz/corundum composites sintered at 975° for 0 min dwell time may find application in radiotherapy, geological dating, and environmental dosimetry.
RESUMEN
The clubfoot is one of the most common conditions in Pediatric Orthopedics, may affect each part of the foot and ankle, equinus, varus, and internal rotation of the calcaneum, and true equinus of the ankle are common. The Ponseti method is an universally accepted treatment, consisting of three phases: manipulation and plaster, Achilles tendon tenotomy and maintenance phase. The highest percentage of relapses occurs in the maintenance phase and the deficient family member is associated in most cases. We present a clinical case of a patient with typical clubfoot treated with the Ponseti method on four occasions without the need of surgical treatment.
El pie equinovaro aducto congénito (PEVAC) es uno de los padecimientos más comunes en Ortopedia Pediátrica, el cual se compone del equino del retropié, el varo subastragalino, el aducto del antepié y el cavo del mediopié. El método de Ponseti es el tratamiento universalmente aceptado para el PEVAC; éste consta de tres fases: manipulación y enyesado, tenotomía del tendón de Aquiles y una fase de mantenimiento. El mayor porcentaje de las recaídas se presenta en la fase de mantenimiento; en la mayoría de los casos, está asociado el apego familiar deficiente. Presentamos el caso clínico de un paciente con PEVAC típico, tratado en cuatro ocasiones con el método de Ponseti y que no requirió tratamiento quirúrgico.
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Tendón Calcáneo , Pie Equinovaro , Tenotomía , Tendón Calcáneo/cirugía , Articulación del Tobillo , Moldes Quirúrgicos , Niño , Pie Equinovaro/cirugía , Humanos , Lactante , Resultado del TratamientoRESUMEN
Young people have incorporated information and communication technology (ICT) and its influence on socialization as a new instrument to exercise controlling behaviors in their relationships. The present research aims to analyse the influence of some variables that affect social perception of those controlling behaviors, such as the adopted role on the scene (i. e. , protagonist vs. observer) and means of control that is used (i. e. , face-to-face vs. WhatsApp) while considering the effect of attitudinal variables: acceptability of intimate partner violence against women (IPVAW), ambivalent sexism, and myths about romantic love. Two studies were implemented: Study 1 included women (n = 224) and Study 2 included men (n = 120), all of them college students. The main results revealed that both women and men perceive controlling behaviors amongst other peer couples; however, few of them recognize suffering or the exercise of these behaviors within their relationships. In addition, data pointed out the adopted role on the scene and the ideological variables (ambivalent sexism, acceptability of IPVAW, and myths about romantic love) that influenced social perception of dating violence; however, there was no influence of means of control. This research contributes to the previous literature, evidencing that controlling behaviors through technological means are accepted and normalized among young people. Additionally, it shows novel data about young people's social perception of controlling behaviors in their relationships, depending on whether they adopt the role of observer or the role of protagonist in a violent situation
Con las tecnologías de la información y la comunicación (TIC) y su influencia en la socialización, los jóvenes han incorporado un instrumento más para ejercer comportamientos controladores en sus relaciones de pareja. Esta investigación pretende analizar la influencia de algunas variables que afectan a la percepción social de estos comportamientos controladores, como el rol del participante en el escenario (protagonista vs. observador u observadora) y el medio de control utilizado (cara a cara vs. WhatsApp), considerando el efecto de las variables ideológicas: aceptabilidad de la violencia, sexismo y mitos del amor romántico. Se llevaron a cabo dos estudios: un primer estudio con mujeres (n = 224) y uno segundo con hombres (n = 120), todos ellos estudiantes universitarios. Los principales resultados indicaron que tanto mujeres como hombres observan comportamientos controladores en otras parejas de su edad, aunque pocos reconocen sufrir o ejercer estos comportamientos en sus relaciones. Asimismo, se encuentra que el rol que se ocupa en el escenario y las variables ideológicas (sexismo ambivalente, aceptabilidad de la violencia y mitos sobre el amor romántico) influyen en la percepción social de la violencia en la pareja, si bien no se encontró influencia del medio de control. Estos hallazgos constituyen una aportación a la literatura existente, poniendo en evidencia que los comportamientos controladores ejercidos a través de los medios tecnológicos son aceptados y normalizados entre los jóvenes y las jóvenes. Asimismo, proporciona datos novedosos sobre la percepción social que esta población tiene de los comportamientos controladores en las relaciones en función de si se adopta el rol de observador o de protagonista de la situación violenta
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Humanos , Masculino , Femenino , Adolescente , Adulto Joven , Control de la Conducta , Violencia de Género/psicología , Sexismo/psicología , Relaciones Interpersonales , Internet , Terapia Conductista , Percepción Social , Estudiantes/psicologíaRESUMEN
INTRODUCTION: The pharmacokinetics (PK), safety and efficacy of BAY 81-8973, a full-length, unmodified, recombinant human factor VIII (FVIII), were evaluated in the LEOPOLD trials. AIM: The aim of this study was to develop a population PK model based on pooled data from the LEOPOLD trials and to investigate the importance of including samples with FVIII levels below the limit of quantitation (BLQ) to estimate half-life. METHODS: The analysis included 1535 PK observations (measured by the chromogenic assay) from 183 male patients with haemophilia A aged 1-61 years from the 3 LEOPOLD trials. The limit of quantitation was 1.5 IU dL-1 for the majority of samples. Population PK models that included or excluded BLQ samples were used for FVIII half-life estimations, and simulations were performed using both estimates to explore the influence on the time below a determined FVIII threshold. RESULTS: In the data set used, approximately 16.5% of samples were BLQ, which is not uncommon for FVIII PK data sets. The structural model to describe the PK of BAY 81-8973 was a two-compartment model similar to that seen for other FVIII products. If BLQ samples were excluded from the model, FVIII half-life estimations were longer compared with a model that included BLQ samples. CONCLUSIONS: It is essential to assess the importance of BLQ samples when performing population PK estimates of half-life for any FVIII product. Exclusion of BLQ data from half-life estimations based on population PK models may result in an overestimation of half-life and underestimation of time under a predetermined FVIII threshold, resulting in potential underdosing of patients.
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Factor VIII/farmacocinética , Límite de Detección , Proteínas Recombinantes/farmacocinética , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos como Asunto , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Distribución Tisular , Adulto JovenRESUMEN
INTRODUCTION: BAY 81-8973 (Kovaltry(®) ) is a full-length, unmodified recombinant human factor VIII (FVIII) with the same amino acid sequence as sucrose-formulated recombinant FVIII and is produced using additional advanced manufacturing technologies. AIM: To demonstrate efficacy and safety of BAY 81-8973 for treatment of bleeds and as prophylaxis based on two different potency assignments. METHODS: In LEOPOLD I (ClinicalTrials.gov identifier, NCT01029340), males aged 12-65 years with severe haemophilia A and ≥150 exposure days received BAY 81-8973 20-50 IU kg(-1) two or three times per week for 12 months. Potency was based on chromogenic substrate assay per European Pharmacopoeia and label adjusted to mimic one-stage assay potency. Patients were randomized for potency sequence and crossed over potency groups after 6 months, followed by an optional 12-month extension. Primary efficacy endpoint was annualized bleeding rate (ABR). Patients also received BAY 81-8973 during major surgeries. RESULTS: Sixty-two patients received BAY 81-8973 prophylaxis and were included in the analysis. Median ABR was 1.0 (quartile 1, 0; quartile 3, 5.1) without clinically relevant differences between potency periods. Median ABR was similar for twice-weekly vs. three times-weekly dosing (1.0 vs. 2.0). Haemostasis was maintained during 12 major surgeries. Treatment-related adverse event (AE) incidence was ≤7% overall; no patient developed inhibitors. One patient with risk factors for cardiovascular disease developed a myocardial infarction. CONCLUSIONS: BAY 81-8973 was efficacious in preventing and treating bleeding episodes, irrespective of the potency assignment method, with few treatment-related AEs. Caution should be used when treating older patients with cardiovascular risk factors.
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Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Coagulantes/efectos adversos , Coagulantes/farmacocinética , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Factor VIII/efectos adversos , Factor VIII/farmacocinética , Semivida , Hemofilia A/patología , Hemorragia/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Ortopedia , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: BAY 81-8973 is a full-length, unmodified, recombinant human factor VIII (FVIII) with the same primary amino acid sequence as sucrose-formulated recombinant FVIII but produced with certain more advanced manufacturing technologies. AIM: This global laboratory study evaluated variability in measurement of BAY 81-8973 using one-stage and chromogenic assays compared with antihaemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM; Advate(®) ) under assay conditions routinely used in clinical laboratories. METHODS: BAY 81-8973 or rAHF-PFM was spiked into FVIII-deficient plasma at 0.043 (low), 0.375 (medium) and 0.865 (normal) IU mL(-1) . Participating laboratories analysed blinded samples and normal plasma in triplicate using their routine assay, reagents and standards. Results were analysed for intra- and interlaboratory variability. RESULTS: Forty-one laboratories in 11 countries participated in the study. One-stage assay and chromogenic assays were used by 40 and 10 laboratories, respectively; 9 laboratories used both assays. Intralaboratory variability was <11% for both assays and both products at all concentrations. Interlaboratory variability was highest at the low concentration in the chromogenic and one-stage assay for BAY 81-8973 (60.0% and 33.7%, respectively) and rAHF-PFM (51.0% and 30.8%) and was lowest at the normal concentration (BAY 81-8973, 5.4% and 14.0%; rAHF-PFM, 5.8% and 12.4%), which was similar to the plasma control (6.6% and 10.3%). The chromogenic:one-stage assay ratio ranged from 0.95 (low concentration) to 1.10 (normal concentration) for BAY 81-8973 and 0.96-1.18 for rAHF-PFM. CONCLUSIONS: BAY 81-8973 can be accurately measured in plasma using the one-stage and chromogenic assays routinely used in clinical laboratories without a product-specific standard.
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Factor VIII/análisis , Preparaciones Farmacéuticas/análisis , Plasma/química , Proteínas Recombinantes/análisis , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Humanos , Cooperación Internacional , Laboratorios , Variaciones Dependientes del Observador , Proteínas Recombinantes/uso terapéuticoRESUMEN
INTRODUCTION: BAY 81-8973 is a recombinant factor VIII (rFVIII) with the same amino acid sequence as Bayer's sucrose-formulated rFVIII (rFVIII-FS) but manufactured with certain more advanced technologies. AIM: To describe surgery outcomes with BAY 81-8973 in the LEOPOLD trials. METHODS: Male patients with severe haemophilia A and no inhibitors aged 12-65 years with ≥150 exposure days (EDs) to FVIII (LEOPOLD I and II), or aged ≤12 years with ≥50 EDs to FVIII (LEOPOLD Kids), received BAY 81-8973 based on dosing recommendations for rFVIII-FS according to surgical requirements. Haemostasis-related complications, investigator/surgeon assessment of haemostasis, blood loss, need for transfusion and use of BAY 81-8973 were determined. RESULTS: In LEOPOLD I and II, 11 patients (mean age, 35.3 years) underwent 13 major surgeries. In LEOPOLD Kids, one patient (aged 6 years) underwent one major surgery. Thirty-two adult and paediatric patients underwent 46 minor surgeries. Haemostasis was rated good or excellent in all major and minor surgeries. Blood loss during surgery did not exceed expected amounts; blood transfusions were required in three of the 14 major surgeries. For major surgeries in LEOPOLD I and II, patients received a presurgical 50-IU kg(-1) dose of BAY 81-8973; median nominal dose on day of surgery was 7000 IU (107.5 IU kg(-1) ). Total BAY 81-8973 dose was 2500 IU (108.7 IU kg(-1) ) on the day of the only major surgery in LEOPOLD Kids. No haemostasis-related complications were reported. CONCLUSIONS: Haemostatic control with BAY 81-8973 during all surgeries in the LEOPOLD trials was good or excellent, with no haemostasis-related complications.
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Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Anciano , Transfusión Sanguínea , Niño , Coagulantes/efectos adversos , Coagulantes/farmacocinética , Estudios Cruzados , Factor VIII/efectos adversos , Factor VIII/farmacocinética , Hemofilia A/patología , Hemorragia/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Operativos , Resultado del Tratamiento , Adulto JovenRESUMEN
UNLABELLED: Essentials Discrepancies can exist in factor VIII activity measured by the one-stage or chromogenic assays. LEOPOLD trial data were used to assess clinical impact of BAY 81-8973 potency assignment assay. Efficacy was not affected by the assay used for potency assignment and dosing of BAY 81-8973. Either assay may be used to measure factor VIII activity after BAY 81-8973 infusion. SUMMARY: Background Product-specific discrepancies have been reported for factor VIII (FVIII) activity determined with one-stage or chromogenic assays. Objective To assess the clinical impact of potency assignment of BAY 81-8973, a full-length, unmodified, recombinant human FVIII, by use of the chromogenic assay or chromogenic assay adjusted to mimic results obtained with the one-stage assay Patients/methods Patients aged 12-65 years with severe hemophilia A received BAY 81-8973 in LEOPOLD I (20-50 IU kg(-1) two or three times weekly [investigator decision]) and LEOPOLD II (randomized to 20-30 IU kg(-1) twice weekly, 30-40 IU kg(-1) three times weekly, or on-demand treatment). Both trials included two 6-month crossover periods in which potency labeling was determined with the chromogenic substrate assay as per the European Pharmacopoeia (CS/EP) or the chromogenic substrate assay adjusted to mimic results obtained with the one-stage assay (CS/ADJ). The annualized bleeding rate (ABR) and FVIII incremental recovery were assessed by the use of pooled data. Results The analysis was perfomed on 121 patients. Median (quartile [Q] 1; Q3) ABRs during the CS/EP and CS/ADJ periods were 1.98 (0; 5.92) and 1.98 (0; 7.34), respectively. The mean incremental recovery was > 2 IU dL(-1) per IU kg(-1) in both periods with the use of either assay for postinfusion FVIII measurements. The median (Q1; Q3) chromogenic/one-stage assay recovery ratio was 1.054 (0.892; 1.150) for the CS/EP period when a plasma standard was used for calibration. Conclusions No impact on the ABR was observed with chromogenic-based as compared with one-stage assay-based potency and dosing. Either assay may be used to determine FVIII plasma activity after infusion of BAY 81-8973 without the need for a product-specific standard.
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Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Anciano , Pruebas de Coagulación Sanguínea , Niño , Compuestos Cromogénicos/química , Ensayos Clínicos como Asunto , Estudios Cruzados , Europa (Continente) , Hemorragia , Humanos , Persona de Mediana Edad , Plasma/química , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: BAY 81-8973, a full-length, unmodified, recombinant factor VIII (FVIII) in development for treatment of haemophilia A, has the same primary amino acid sequence as Bayer's sucrose-formulated recombinant FVIII but is produced with more advanced manufacturing technologies. AIM: To demonstrate safety and efficacy of BAY 81-8973 for prophylaxis and treatment of bleeds in previously treated children. METHODS: In this phase III, multicentre, open-label, nonrandomized study, boys aged ≤12 years with severe haemophilia A and ≥50 exposure days (EDs) to FVIII products received prophylaxis with BAY 81-8973 25-50 IU kg(-1) ≥2 times weekly for ≥50 EDs. The efficacy endpoint was annualized number of total bleeds. Adverse events (AEs) and immunogenicity were assessed. RESULTS: Fifty-one patients were treated (age: <6 years, n = 25; 6-<12 years, n = 26) with a 2× per week (43%) or >2× per week (57%) regimen at study start. Median [quartile 1; quartile 3 (Q1; Q3)] annualized number of bleeds for the combined age groups was 1.90 (0; 6.02) for total bleeds, 0 (0; 2.01) for joint bleeds and 0 (0; 0) for spontaneous bleeds. Median (Q1; Q3) annualized number of total bleeds within 48 h of previous prophylaxis infusion was 1.88 (0; 3.97) for children aged <6 years and 0 (0; 1.96) for children aged 6-<12 years. No drug-related serious AEs or inhibitors were reported. CONCLUSIONS: Prophylaxis with BAY 81-8973 using individualized prophylaxis regimens of 2× per week, 3× per week and every-other-day infusions was efficacious in prevention and treatment of bleeds in children with severe haemophilia A. Treatment with BAY 81-8973 was well tolerated.
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Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Área Bajo la Curva , Niño , Preescolar , Coagulantes/efectos adversos , Coagulantes/farmacocinética , Factor VIII/efectos adversos , Factor VIII/farmacocinética , Semivida , Hemofilia A/patología , Hemorragia/prevención & control , Humanos , Lactante , Masculino , Curva ROC , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: The immunotherapy using dendritic cells (DCs) against different varieties of cancer is an approach that has been previously explored which induces a specific immune response. This work presents a mathematical model of DCs immunotherapy for melanoma in mice based on work by Experimental Immunotherapy Laboratory of the Medicine Faculty in the Universidad Autonoma de Mexico (UNAM). METHOD: The model is a five delay differential equation (DDEs) which represents a simplified view of the immunotherapy mechanisms. The mathematical model takes into account the interactions between tumor cells, dendritic cells, naive cytotoxic T lymphocytes cells (inactivated cytotoxic cells), effector cells (cytotoxic T activated cytotoxic cells) and transforming growth factor ß cytokine (T G F-ß). The model is validated comparing the computer simulation results with biological trial results of the immunotherapy developed by the research group of UNAM. RESULTS: The results of the growth of tumor cells obtained by the control immunotherapy simulation show a similar amount of tumor cell population than the biological data of the control immunotherapy. Moreover, comparing the increase of tumor cells obtained from the immunotherapy simulation and the biological data of the immunotherapy applied by the UNAM researchers obtained errors of approximately 10 %. This allowed us to use the model as a framework to test hypothetical treatments. The numerical simulations suggest that by using more doses of DCs and changing the infusion time, the tumor growth decays compared with the current immunotherapy. In addition, a local sensitivity analysis is performed; the results show that the delay in time " τ", the maximal growth rate of tumor "r" and the maximal efficiency of tumor cytotoxic cells rate "aT" are the most sensitive model parameters. CONCLUSION: By using this mathematical model it is possible to simulate the growth of the tumor cells with or without immunotherapy using the infusion protocol of the UNAM researchers, to obtain a good approximation of the biological trials data. It is worth mentioning that by manipulating the different parameters of the model the effectiveness of the immunotherapy may increase. This last suggests that different protocols could be implemented by the Immunotherapy Laboratory of UNAM in order to improve their results.
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Células Dendríticas , Inmunoterapia , Melanoma/terapia , Modelos Biológicos , Animales , Simulación por Computador , RatonesRESUMEN
OBJECTIVE: This systematic review applied meta-analytic procedures to synthesise medication adherence (also termed compliance) interventions that focus on healthcare providers. DESIGN: Comprehensive searching located studies testing interventions that targeted healthcare providers and reported patient medication adherence behaviour outcomes. Search strategies included 13 computerised databases, hand searches of 57 journals, and both author and ancestry searches. Study sample, intervention characteristics, design and outcomes were reliably coded. Standardised mean difference effect sizes were calculated using random-effects models. Heterogeneity was examined with Q and I(2) statistics. Exploratory moderator analyses used meta-analytic analogue of ANOVA and regression. RESULTS: Codable data were extracted from 218 reports of 151,182 subjects. The mean difference effect size was 0.233. Effect sizes for individual interventions varied from 0.088 to 0.301. Interventions were more effective when they included multiple strategies. Risk of bias assessment documented larger effect sizes in studies with larger samples, studies that used true control groups (as compared with attention control), and studies without intention-to-treat analyses. CONCLUSION: Overall, this meta-analysis documented that interventions targeted to healthcare providers significantly improved patient medication adherence. The modest overall effect size suggests that interventions addressing multiple levels of influence on medication adherence may be necessary to achieve therapeutic outcomes.
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Prestación Integrada de Atención de Salud , Cumplimiento de la Medicación , Comunicación , Prestación Integrada de Atención de Salud/métodos , Prestación Integrada de Atención de Salud/organización & administración , Prestación Integrada de Atención de Salud/normas , Humanos , Evaluación de Procesos y Resultados en Atención de Salud , Relaciones Profesional-Paciente , Sistemas RecordatoriosRESUMEN
BACKGROUND: BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. OBJECTIVES: To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. PATIENTS/METHODS: In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 1265 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. RESULTS: Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. CONCLUSIONS: Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.
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Coagulantes/administración & dosificación , Factor VIII/administración & dosificación , Hemofilia A/tratamiento farmacológico , Proteínas Recombinantes/administración & dosificación , Adolescente , Adulto , Anciano , Asia , Niño , Coagulantes/efectos adversos , Estudios Cruzados , Esquema de Medicación , Monitoreo de Drogas/métodos , Europa (Continente) , Factor VIII/efectos adversos , Hemofilia A/sangre , Hemofilia A/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , América del Norte , Proteínas Recombinantes/efectos adversos , Índice de Severidad de la Enfermedad , Sudáfrica , América del Sur , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
The post-translational palmitoylation of WNT morphogens is critical for proper signaling during embryogenesis and adult homeostasis. The addition of palmitoyl groups to WNT proteins is catalyzed by Porcupine (PORCN). However, the Wnt amino acid residues required for recognition and palmitoylation by PORCN have not been fully characterized. We show that WNT1 residues 214-234 are sufficient for PORCN-dependent palmitoylation of Ser224. Substitution of Ser224 with Thr, but not Cys, is tolerated in palmitoylation and biological assays. Our data highlight the importance of palmitoylation for WNT1 activity and establish PORCN as an O-acyl transferase for WNT1.
Asunto(s)
Proteínas de la Membrana/metabolismo , Ácido Palmítico/metabolismo , Procesamiento Proteico-Postraduccional , Proteína Wnt1/química , Proteína Wnt1/metabolismo , Aciltransferasas/metabolismo , Secuencia de Aminoácidos , Animales , Embrión de Pollo , Pollos , Células HEK293 , Humanos , Ratones , Datos de Secuencia Molecular , Especificidad por SustratoRESUMEN
Foliar tissue samples of cultivated daylilies (Hemerocallis hybrids) showing the symptoms of a newly emergent foliar disease known as 'spring sickness' were investigated for associated fungi. The cause(s) of this disease remain obscure. We isolated repeatedly a fungal species which proved to be member of the genus Botrytis, based on immunological tests. DNA sequence analysis of these isolates, using several different phyogenetically informative genes, indicated that they represent a new Botrytis species, most closely related to B. elliptica (lily blight, fire blight) which is a major pathogen of cultivated Lilium. The distinction of the isolates was confirmed by morphological analysis of asexual sporulating cultures. Pathogenicity tests on Hemerocallis tissues in vitro demonstrated that this new species was able to induce lesions and rapid tissue necrosis. Based on this data, we infer that this new species, described here as B. deweyae, is likely to be an important contributor to the development of 'spring sickness' symptoms. Pathogenesis may be promoted by developmental and environmental factors that favour assault by this necrotrophic pathogen. The emergence of this disease is suggested to have been triggered by breeding-related changes in cultivated hybrids, particularly the erosion of genetic diversity. Our investigation confirms that emergent plant diseases are important and deserve close monitoring, especially in intensively in-bred plants.
Asunto(s)
Botrytis/fisiología , Hemerocallis/crecimiento & desarrollo , Hemerocallis/microbiología , Enfermedades de las Plantas/microbiología , Hojas de la Planta/microbiología , Secuencia de Bases , Botrytis/citología , Botrytis/genética , Botrytis/patogenicidad , ADN Intergénico/genética , Genes del Tipo Sexual de los Hongos , Datos de Secuencia Molecular , Filogenia , Alineación de Secuencia , Análisis de Secuencia de ADN , Esporas Fúngicas/citología , Esporas Fúngicas/crecimiento & desarrollo , Esporas Fúngicas/ultraestructura , EsterilizaciónRESUMEN
Prospective data on the efficacy of secondary prophylaxis in adults with haemophilia A are limited. To analyse bleeding outcomes in the sucrose-formulated recombinant factor VIII [rFVIII-FS (control)] arm of the LIPLONG study, a randomized, double-blind, 52-week trial was conducted in patients with severe haemophilia A receiving prophylaxis with the investigational product BAY 79-4980 or rFVIII-FS. The per-protocol population of previously treated patients with severe haemophilia A without a history of inhibitors (n = 68 males; mean age, 34.4 years) received 25 IU kg−1 rFVIII-FS three times per week for a median of 50.7 weeks. Annualized bleeding rates were assessed and analysed according to predefined target joint status at study start, prestudy treatment type (prophylaxis vs. on demand), age (<30 or ≥30 years), geographical region, bleeding frequency during the previous 6 months and physical activity status during the study using the Student t-test. The annualized median (range) number of bleeds was 2.2 (0.023) bleeds per year. The median (range) number of bleeds per year was significantly lower in patient subgroups without vs. with target joints [0.5 (0.017.1) vs. 4.2 (0.022.8); P = 0.02] and in those with ≤9 vs. >9 bleeds during the previous 6 months [1.1 (0.019.2) vs. 5.3 (0.022.8); P = 0.01]. Following randomization to prophylaxis with rFVIII-FS, bleeding frequency was effectively reduced. Absence of target joints and prestudy bleeding frequency were predictors of a low bleeding frequency during prophylaxis treatment.
Asunto(s)
Factor VIII/administración & dosificación , Hemofilia A/tratamiento farmacológico , Sacarosa/administración & dosificación , Adolescente , Adulto , Anciano , Niño , Método Doble Ciego , Esquema de Medicación , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor (VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen (VWF:Ag) levels are correlated with FVIII pharmacokinetic (PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non-inhibitor patients in a multinational, randomized, double-blind, Ph II study received prophylaxis with once-weekly BAY 79-4980 (35 IU kg(-1)) or thrice-weekly recombinant sucrose-formulated FVIII (rFVIII-FS; 25 IU kg(-1)). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13-64 years; BAY 79-4980, n = 63; rFVIII-FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age (P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUC(norm) and T1/2 significantly increased with increased VWF:Ag (P < 0.001); clearance significantly decreased with increased VWF:Ag (P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII-FS significantly correlated with VWF:Ag and age (P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK.
Asunto(s)
Factor VIII/uso terapéutico , Hemofilia A/sangre , Hemofilia A/tratamiento farmacológico , Hemorragia/metabolismo , Premedicación , Sacarosa/uso terapéutico , Factor de von Willebrand/metabolismo , Adolescente , Adulto , Factores de Edad , Anciano , Pruebas de Coagulación Sanguínea , Esquema de Medicación , Ensayo de Inmunoadsorción Enzimática , Factor VIII/administración & dosificación , Hemorragia/sangre , Hemorragia/etiología , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Sacarosa/administración & dosificación , Resultado del Tratamiento , Adulto Joven , Factor de von Willebrand/inmunologíaRESUMEN
Genetic model organisms have revolutionized science, and today, with the rapid advances in technology, there is significant potential to launch many more plant species towards model status. However, these new model organisms will have to be carefully selected. Here, we argue that Hemerocallis (daylily) satisfies multiple criteria for selection and deserves serious consideration as a subject of intensive biological investigation. Several attributes of the genus are of great biological interest. These include the strict control of flower opening and, within a short period, the precisely regulated floral death by a programmed cell death system. The self-incompatibility system in Hemerocallis is also noteworthy and deserves more attention. Importantly, the genus is widely cultivated for food, medicinal value and ornamental interest. Hemerocallis has considerable potential as a 'nutraceutical' food plant and the source of new compounds with biomedical activity. The genus has also been embraced by ornamental plant breeders and the extraordinary morphological diversity of hybrid cultivars, produced within a relatively short time by amateur enthusiasts, is an exceptional resource for botanical and genetic studies. We explore these points in detail, explaining the reasons why this genus has considerable value-both academic and socio-economic-and deserves new resources devoted to its exploration as a model. Its impact as a future model will be enhanced by its amenability to cultivation in laboratory and field conditions. In addition, established methods for various tissue and cell culture systems as well as transformation will permit maximum exploitation of this genus by science.
RESUMEN
Studies performed on human trisomic 21 oocytes have revealed that during meiosis, the three homologues 21 synapse and, in some cases, achieve what looks like a trivalent. This implies that meiotic recombination takes place among the three homologous chromosomes 21, and to some extent, crossovers form between them. To see how meiotic recombination is in the presence of an extra chromosome 21, we analyzed the distribution of three recombination markers (γH2AX, RPA, and MLH1) on trisomic 21 oocytes at pachynema and, in particular, on chromosomes 21. Results clearly show how the presence of an extra chromosome 21 alters meiotic recombination progression, leading to the presence of a higher number of early recombination markers at pachynema. Moreover, the distribution on these chromosomes 21 of some of these markers is different in aneuploid oocytes. Finally, there is a substantial increase in the number of MLH1 foci, a marker of most crossovers in mammals, which is related to the number of synapsed chromosomes in pachynema. Thus, bivalents 21 had fewer MLH1 foci than partial or total trivalents, suggesting a close relationship between synapsis and crossover designation. All of the data presented suggest that the presence of an extra chromosome alters meiotic recombination globally in aneuploid human oocytes.