The antigenic variability of HCV in viral HLA-Ag binding is related to the activation of the host immune response.

Our previous data show that hepatitis C virus (HCV) genotype 1 patients expressing the HLA-DQB1 * 0301 allele have a combined response probability of 69%, while the remaining 31% do not respond, probably because the HCV immunodominant epitope (IE) against the DQB1 * 0301 allele is mutated. HCV IE (region sequenced in NS3 is a region encoding aa 1253-1272) from 37 patients (21 Sustained Virological Response, SVR; 16 non-SVR) HLA-DQB1 * 0301+, were analysed by pyrosequencing. In vitro cultures were also determined by CD4+ proliferation, using non-mutated IE (wild-type synthetic peptide) and synthetic mutated peptide. The pyrosequencing study revealed 34 different haplotypes. The SVR patients had fewer haplotypes (P = 0.07), mutations/haplotypes (P = 0.01) and polymorphic sites (P = 0.02) than non-SVR. Three polymorphic sites were associated with the non-SVR patients: haplotype 7 (L5P); haplotype 11 (L7P); and haplotype 15, (L15S) (P = 0.02). The in vitro study (n = 7) showed that in 4/7 patients (Group 1) the CD4+ proliferation obtained with wild-type synthetic peptide was higher than that obtained with the negative control and with the synthetic mutated peptide (P = 0.039). However, in the remaining 3/7 patients (Group 2) this pattern was not observed (P = 0.7). Our findings suggest that HLA-DQB1 * 0301+ patients with high antigenic variability in HCV IE (NS31253-1272) have a lower SVR rate, due to reduced CD4+ proliferation as a result of incorrect viral HLA-Ag binding.

Influence of HLA class I, HLA class II and KIRs on vertical transmission and chronicity of hepatitis C virus in children.

BACKGROUND & AIM: There is evidence that maternal viral load of HCV during delivery influences the risk for Mother-to-child transmission (MTCT), but this does not explain all cases. We study the role of the immunogenetic profile (HLA, KIRs and KIR-ligand binding) of mothers and children in HCV-MTCT and in chronicity in the children. METHODOLOGY: 79 HCV-RNA (+) mothers and their 98 children were included. 24 children were infected, becoming chronic in 8 cases and clearing in 16. HLA-class-I and II and KIRs were determined by Luminex. RESULTS: MTCT study: The presence of HLA-C1-ligand in mothers and/or their children reduces the risk of transmission (mothers: Pc = 0.011, children: P = 0.033), whereas the presence of HLA-C2C2-ligand in mothers increases it (Pc = 0.011). In children KIR2DL3-HLA-C1 is a protector factor (Pc = 0.011). Chronicity in children study: Maternal DQA1*01 allele (Pc = 0.027), KIR2DS1 (Pc = 0.011) or KIR3DS1 (Pc = 0.011) favours chronicity in the child. The presence of the DQB1*03 allele (Pc = 0.027) and KIR2DS3 (P = 0.056) in the child and homozygosity for KIR3DL1/3DL1 (Pc = 0.011) and for the HLA-Bw4/Bw4 ligand (P = 0.027) is associated with viral clearance, whereas the presence of HLA-Bw6 ligand (P = 0.027), the binding of KIR3DS1-HLA-Bw4 (P = 0.037) and heterozygosity for KIR3DL1/3DS1 (Pc = 0.011) favour viral chronicity. Mother/child allele matching: In the joint HLA analysis, matching was greater between mothers and children with chronic infection vs those who had cleared the virus (67%±4.1 vs 57%±1.2, P = 0.003). CONCLUSIONS: The HLA-C1 ligand in the mother is related to MTCT, while several genetic factors of the mother or child are involved in the chronification or clearance of infection in the child. Matching allelic data is considered to be an indicator of HCV chronicity in the child and can be used as a potential prognostic test. This implies that NK cells may play a previously undocumented role in protecting against MTCT and that both NK cell immunity and adaptive T-cell responses may influence viral clearance in infected children.

Effects of manual therapy on treatment duration and motor development in infants with severe nonsynostotic plagiocephaly: a randomised controlled pilot study.

PURPOSE: Despite growing evidence regarding nonsynostotic plagiocephaly and their repercussions on motor development, there is little evidence to support the use of manual therapy as an adjuvant option. The aim of this study was to evaluate the effects of a therapeutic approach based on manual therapy as an adjuvant option on treatment duration and motor development in infants with severe nonsynostotic plagiocephaly. METHODS: This is a randomised controlled pilot study. The study was conducted at a university hospital. Forty-six infants with severe nonsynostotic plagiocephaly (types 4-5 of the Argenta scale) referred to the Early Care and Monitoring Unit were randomly allocated to a control group receiving standard treatment (repositioning and an orthotic helmet) or to an experimental group treated with manual therapy added to standard treatment. Infants were discharged when the correction of the asymmetry was optimal taken into account the previous clinical characteristics. The outcome measures were treatment duration and motor development assessed with the Alberta Infant Motor Scale (AIMS) at baseline and at discharge. RESULTS: Asymmetry after the treatment was minimal (type 0 or 1 according to the Argenta scale) in both groups. A comparative analysis showed that treatment duration was significantly shorter (p < 0.001) in the experimental group (109.84 ± 14.45 days) compared to the control group (148.65 ± 11.53 days). The motor behaviour was normal (scores above the 16th percentile of the AIMS) in all the infants after the treatment. CONCLUSIONS: Manual therapy added to standard treatment reduces the treatment duration in infants with severe nonsynostotic plagiocephaly.

Utilización de fármacos en niños en cuidados intensivos: estudio de las prescripciones off-label / Drug utilization pattern in children and off-label use of medicines in a pediatric intensive care unit

OBJETIVO: Evaluar los usos off-label (fuera de ficha técnica [FT]) y unlicensed (medicamentos no autorizados específicamente para niños) en cuidados intensivos neonatales y pediátricos. METODOLOGÍA: Se realizó un estudio transversal en la UCINP (Unidad de Cuidados Intensivos Neonatales y Pediátricos) de un hospital público de tercer nivel de Granada, incluyéndose a todos los niños en los que se indicara al menos un tratamiento farmacológico, mediante reclutamiento consecutivo, y durante un periodo de 5 meses (N = 81). Las variables recogidas fueron sociodemográficas, clínicas, y medicación. Todas las prescripciones fueron clasificadas a partir de la información contenida en FT sobre uso en niños. RESULTADOS: Hubo un total de 601 prescripciones, con una media de 7,4 ± 6 medicamentos por niño. Los fármacos más empleados pertenecían a los grupos J (antiinfecciosos), N (sistema nervioso) y C (cardiovascular). Algo más de la mitad de las prescripciones fueron off-label (52%), fundamentalmente por emplear una dosificación distinta de la recomendada en FT (79%), seguida de diferente indicación (13,5%), edad (5%) y vía de administración (2,5%). El uso de medicamentos no específicamente autorizados en niños solo supuso el 5% de las prescripciones. CONCLUSIONES: El presente estudio aporta datos sobre este tipo de prescripciones en una UCINP española. Pone de manifiesto que el 89% de los niños tiene al menos una prescripción fuera de FT y un 22,3% al menos un uso de fármaco no autorizado para niños. Cifras elevadas, pero justificables dentro del ámbito de unos cuidados intensivos que, además, incluyen neonatos. Pero aunque muchos de los tratamientos estén protocolizados, sería deseable mejorar la evidencia disponible, así como actualizar las FT

OBJECTIVE: This study aims to assess the prescription profile and license status of drugs used in a neonatal and pediatric intensive care unit (NPICU). METHODS: A prospective observational study was conducted on a dynamic cohort of children admitted to an NPICU (N = 81) in a tertiary hospital (Granada, Spain). All prescriptions were classified asoff-label or unlicensed based on the summary of product characteristics (SPC). RESULTS: Of a total of 601 prescriptions, the patients received a mean of 7.4 ± 6 drugs each. The most commonly prescribed drugs corresponded to classes J (anti-infectious, systemic use) N (nervous system) and C (cardiovascular). A little over one-half of the prescriptions were off-label (52%), usually due to dosages differing from the SPC recommendations (79%), followed by different indications (13.5%), age (5%) and administration route (2.5%). In this NPICU, unlicensed usage represented only 5% of all prescriptions. CONCLUSIONS: This study contributes data on prescription of this kind in a Spanish NPICU, revealing at least one off-label prescription in 89% of the children and at least one unlicensed use in 22.3%. These are high figures, but are to be expected given the inclusion of newborn infants and the critical care setting. Even though such usage follows clinical protocols, we underscore the dual need to base treatment on the best available evidence, and to upgrade the SPC accordingly

Drug utilization pattern in children and off-label use of medicines in a pediatric intensive care unit.

OBJECTIVE: This study aims to assess the prescription profile and license status of drugs used in a neonatal and pediatric intensive care unit (NPICU). METHODS: A prospective observational study was conducted on a dynamic cohort of children admitted to an NPICU (N=81) in a tertiary hospital (Granada, Spain). All prescriptions were classified as off-label or unlicensed based on the summary of product characteristics (SPC). RESULTS: Of a total of 601 prescriptions, the patients received a mean of 7.4 ± 6 drugs each. The most commonly prescribed drugs corresponded to classes J (anti-infectious, systemic use) N (nervous system) and C (cardiovascular). A little over one-half of the prescriptions were off-label (52%), usually due to dosages differing from the SPC recommendations (79%), followed by different indications (13.5%), age (5%) and administration route (2.5%). In this NPICU, unlicensed usage represented only 5% of all prescriptions. CONCLUSIONS: This study contributes data on prescription of this kind in a Spanish NPICU, revealing at least one off-label prescription in 89% of the children and at least one unlicensed use in 22.3%. These are high figures, but are to be expected given the inclusion of newborn infants and the critical care setting. Even though such usage follows clinical protocols, we underscore the dual need to base treatment on the best available evidence, and to upgrade the SPC accordingly.

Functionalized magnetic nanoparticles as vehicles for the delivery of the antitumor drug gemcitabine to tumor cells. Physicochemical in vitro evaluation.

Gemcitabine is a chemotherapy drug used in different carcinomas, although because it displays a short biological half-life, its plasmatic levels can quickly drop below the effective threshold. Nanoparticle-based drug delivery systems can provide an alternative approach for regulating the bioavailability of this and most other anticancer drugs. In this work we describe a new model of composite nanoparticles consisting of a core of magnetite nanoparticles, coated with successive layers of high molecular weight poly(acrylic acid) and chitosan, and a final layer of folic acid. The possibility of using these self-assembled nanostructures for gemcitabine vehiculization is explored. First, the surface charge of the composite particles is studied by means of electrophoretic mobility measurements as a function of pH for poly(acrylic acid) (carbopol) of different molecular weights. The adsorption of folic acid, aimed at increasing the chances of the particles to pass the cell membrane, is followed up by optical absorbance measurements, which were also employed for drug adsorption determinations. As a main result, it is shown that gemcitabine adsorbs onto the surface of chitosan/carbopol-coated magnetite nanoparticles. In vitro experiments show that the functionalized magnetic nanoparticles are able to deliver the drug to the nuclei of liver, colon and breast tumor cells.

Nanoengineering of doxorubicin delivery systems with functionalized maghemite nanoparticles.

Superparamagnetic iron oxide nanoparticles are developing as promising candidates for biomedical applications such as targeted drug delivery. In particular, they represent an alternative to existing antitumor drug carriers, because of their ultra-fine size, low toxicity and magnetic characteristics. Nevertheless, there is a need to functionalize them in order to achieve good biocompatibility, efficient modification for further attachment of biomolecules, and improved stability. In this work we describe the functionalization of superparamagnetic maghemite nanoparticles encapsulated in a silica shell. After their chemical modification with positive (3-aminopropyl)trimethoxysilane, a gold layer was deposited in order to facilitate incorporation of the antitumor drug, doxorubicin (DOX), up to a maximum loading of 80 µmol/g. In vitro cell uptake of nanocomposites was performed with DLD-1 colon cancer cells and PLC-PRF-5 liver cancer cells. Confocal microscopy photos illustrate that doxorubicin-loaded nanoparticles accumulate in both the cytoplasm and the cell nuclei. Cell survival efficiency with maghemite nanocomposites was determined via the MTT assay, and the cytotoxicity study proved that they exhibited significant toxicity against both types of cancer cells, although the improvement over free DOX treatment is more evident in the case of DLD-1 cancer cells when the most dilute drug and particle solutions are compared.

Clinical profile and evolution of infants with deformational plagiocephaly included in a conservative treatment program.

PURPOSE: The aim of this study was to evaluate the results of a conservative intervention in infants with plagiocephaly according to their specific clinical profile. METHODS: Prospective clinical trial in which 104 infants with plagiocephaly accompanied or not by congenital or positional torticollis were referred to Early Care and Monitoring Unit (USAT) of San Cecilio Hospital in Granada, between 2009 and 2012. All the infants, grouped into three categories of severity, were included in the physiotherapy protocol until adequate craniofacial morphology and motor development were achieved. The study included an assessment of parents and infants. Parents were assessed with a questionnaire about the mother's medical history and birth-related issues. The assessment of infants included anthropometric measures, a positional assessment, the observation of the head, the assessment of severity, and motor development. RESULTS: Birth characteristics were similar in the total sample but showed different clinical profiles according to treatment aspects. More specifically, infants with severe plagiocephaly were referred to treatment later and spent more time in treatment; use of an orthotic helmet was also more prevalent in this category. There were also significant differences (P < 0.05) in the acquisition of specific gross motor skills depending on the severity of plagiocephaly. CONCLUSION: The findings suggest that the physiotherapy protocol presented is effective to correct plagiocephaly. Severity of plagiocephaly is a marker that should be taken into account when designing actions aimed at improving gross motor skill development.

Hepatotoxicidad por fármacos o productos naturales en ni˜nos / Hepatotoxicity due to drugs or natural products in children

Introducción: La incidencia de las reacciones adversas a medicamentos en pediatría se ha establecido recientemente en 15,1 reacciones por 1.000 niños. Representa un 2% de las admisiones de un hospital pediátrico, similares a las del paciente adulto, y de ellas solo un pequeño porcentaje (menos del 8%) cursan con afectación hepática, que puede ir desde un ligero aumento de las transaminasas hasta una hepatitis fulminante. El objetivo de este estudio ha sido determinar la importancia (frecuencia, formas de presentación, gravedad y cronificación) de la hepatotoxicidad por fármacos o remedios naturales en la población pediátrica. Pacientes y método: Se han incluido a todos los pacientes pediátricos, neonatos y niños en los que se ha sospechado una reacción hepatotóxica, remitidos de 8 hospitales españoles participantes. Para el análisis de la causalidad de cada caso se aplica la escala de Council for International Organizations of Medical. Sciences (CIOMS). Resultados y conclusiones: Se estudian un total de 36 reacciones hepatotóxicas en 33 niños. Los grupos farmacológicos involucrados con mayor frecuencia fueron los antitinfecciosos (71%). Amoxicilina-clavulánico fue el fármaco individual responsable del mayor número de casos (31,4%). Se concluye que el registro de hepatopatías asociadas a medicamentos ha demostrado ser un instrumento útil para la creación de una red activa de especialistas motivados en la detección y comunicación de incidencias de hepatopatía tóxica, aumentando las garantías de certeza diagnóstica(AU)

Introduction: The incidence of adverse drug reactions in children has recently been established at 15.1 reactions per 1000 children. This represents 2% of admissions to a paediatric hospital, and is similar to adult patients. Only a small percentage (less than 8%) may have liver involvement, which can range from a slight increase in transaminases to fulminant hepatitis. The aim of this study was to determine the importance (frequency, types of presentation, severity and chronicity) of hepatotoxicity by drugs or natural remedies in the paediatric population. Patients and method: All paediatric patients, neonates and children who had suspected hepatotoxic reactions notified by the eight participating Spanish hospitals. The Council for International Organizations of Medical Sciences (CIOMS) scale was used for the analysis of causality in each case. Results and conclusions: We studied a total of 36 hepatotoxic reactions in 33 children. The drug classes most frequently involved were antimicrobials (71%). Amoxicillin-clavulanate was the individual drug responsible for the greatest number of cases (31.4%). We conclude that the registration of drugs associated with liver disease has proved a useful tool for creating an active network of motivated specialists in detecting and reporting incidents of toxic liver disease, ensuring increasing diagnostic accuracy(AU)

[Hepatotoxicity due to drugs or natural products in children]. / Hepatotoxicidad por fármacos o productos naturales en niños.

INTRODUCTION: The incidence of adverse drug reactions in children has recently been established at 15.1 reactions per 1000 children. This represents 2% of admissions to a paediatric hospital, and is similar to adult patients. Only a small percentage (less than 8%) may have liver involvement, which can range from a slight increase in transaminases to fulminant hepatitis. The aim of this study was to determine the importance (frequency, types of presentation, severity and chronicity) of hepatotoxicity by drugs or natural remedies in the paediatric population. PATIENTS AND METHOD: All paediatric patients, neonates and children who had suspected hepatotoxic reactions notified by the eight participating Spanish hospitals. The Council for International Organizations of Medical Sciences (CIOMS) scale was used for the analysis of causality in each case. RESULTS AND CONCLUSIONS: We studied a total of 36 hepatotoxic reactions in 33 children. The drug classes most frequently involved were antimicrobials (71%). Amoxicillin-clavulanate was the individual drug responsible for the greatest number of cases (31.4%). We conclude that the registration of drugs associated with liver disease has proved a useful tool for creating an active network of motivated specialists in detecting and reporting incidents of toxic liver disease, ensuring increasing diagnostic accuracy.

Análisis del conocimiento y manejo de la fiebre por parte de pediatras y residentes en relación a un proceso asistencial establecido / Analysis of pediatricians' and residents' knowledge of fever management in relation to established guidelines

Objetivo: evaluar el consejo dado a padres sobre la fiebre y conocer la incidencia estimada de fiebre sin foco (FSF) en consulta, la accesibilidad a exámenes complementarios (EC) y la aplicación de un protocolo (PF). Métodos: cuestionario sobre un total de 151 pediatras de Atención Primaria (PAP), pediatras de hospital (PH) y residentes de Pediatría (R). Se utiliza el paquete estadístico SPSS® 15.0. Para variables cualitativas el test de la χ2, siendo el valor significativo p < 0,05. Resultados: se han evaluado 109 cuestionarios: mujeres 65,4% y hombres 34,6%. El 44,9% definió como fiebre 37,5 °C en axila y 38 °C en recto. El 78,9% aconseja termómetro electrónico; el 93,6%, medidas físicas; el 79,8%, paracetamol, y el 76,1% alterna antitérmicos en casos seleccionados. El 56,2% diagnostica un 10% de FSF a la semana, el 19,3% codifica siempre; el 31,2% algunas veces, y el 45,9% no lo hace. En menores de seis meses, el 91,7% solicita tira de orina, y el 41,3%, urocultivo; En pacientes de 6-12 meses, el 96,3% solicita tira de orina, y el 11,9%, urocultivo. Los PAP reciben resultados el mismo día: hemograma (3%) y radiografía (68,6%), en menos de 72 horas: urocultivo (38,7%). Los PH y R reciben el mismo día: hemograma (88,3%) y radografía (85,7%); en menos de 72 horas: urocultivo (85,7%). El 74,6% de los PAP deriva al hospital a los menores de tres meses con FSF, el 64,7% de los PH y el 83,3% de los R hacen EC. Conoce el PF el 78,9%, de los cuales, el 69,8% cree que es aplicable y, a su vez, lo aplica un 65,4%. Conclusiones: consejo mayoritario de termómetro electrónico, uso de medidas físicas y paracetamol. Alternancia seleccionada de antitérmicos. Bajo diagnóstico y codificación de FSF. Limitado acceso a exámenes complementarios para PAP. Alto conocimiento del PF pero baja aplicación (AU)

Objective: to evaluate the advice given to parents about fever, determine the incidence of Fever Without Source (FWS) in the pediatrician’s office, availability of complementary examinations (CE) and the implementation of fever guidelines (FG). Methods: questionnaires distributed to 151 Primary Attention Pediatricians (PAP), Hospital Pediatricians (HP) and Residents (R). Statistical analysis SPSS 15.0. For qualitative variables the 2 test was used. Significant value was p < 0.05. Results: 109 questionnaires analyzed: women 65.4% and men 34.6%. 44.9% defined fever 37.5 °C axilar temperature and 38 °C rectal temperature. 78.9% advise the use of electronic thermometer, 93.6% advice taking non-drug measures, 79.8% choose paracetamol and 76.1% alternate antipyretics in selected cases. 56.2% diagnosed 10% of FWS per week, 19.3% always encode it, 31.2% sometimes and 45.9% never. For infants < 6 m are required: 91.7% urine strips, 41.3% urine culture; from 6-12 months: 96.3% urine strips and 11.9% urine culture. PAP receive results the same day: CBC count 3%, radiology 68.6% and urine culture in less than 72h, 38.7%. HP and R the same day, CBC (AU)

Histological and immunohistochemical assessment of liver biopsies in morbidly obese patients.

AIMS: To study liver lesions in morbidly obese patients who underwent liver biopsy at the time of bariatric surgery to define histological lesions, especially inflammatory infiltrate, diagnostic categories and the possible influence of gender in this respect. METHODS AND RESULTS: 110 biopsies (36 males-M- and 76 females -F-) were evaluated and categorised, according to the NAS (NAFLD -non alcoholic fatty liver disease- Activity Score) system and other criteria, as non-NAFLD (15.5%, F predominance), non-alcoholic steatohepatitis (NASH) (16.5%, M predominance), non-alcoholic hepatosteatosis (NAHS) (21%, F predominance) and, the most numerous group, NASH-borderline (NASH-BORD) (47%), with three subgroups, characterised by centrozonal lesions, portal area preferential involvement or affecting both areas. The predominant form of hepatocytesteatosis was mixed with a multivesicular component that was present in most cases with fibroinflammatory portal involvement. Nuclear glycogenosomes were found in greater number of biopsies in patients in the third and sixth decades. Portal inflammation was present in a large number of cases (M predominance); the application of immunohistochemical techniques (myeloperoxidase and CD68 antibodies) to evaluate lobular inflammation revealed "surgical hepatitis" in one third of the cases, and the presence of microgranulomas (CD68+) (M predominance), which were more abundant with increasing lesion severity. CONCLUSIONS: Portal inflammation and multivesicular hepatocytesteatosis are highly prevalent in morbidly obese patients. This study identifies a new subtype of NASH-BORD characterized by centrizonal and porto-periportal area involvement and the existence of liver biopsies without steatosis. CD68+ microgranulomas constitute an unequivocal marker of lobular inflammation in surgical biopsies and of lesion severity, which is gender-related.

Conocimiento y actuación de los padres sobre la fiebre / Knowledge and management of fever by parents

Objetivos: evaluar los conocimientos y actitudes que tienen los padres sobre la fiebre, así como la influencia de los aspectos familiares. Material y métodos: cuestionario distribuido a padres de dos áreas asistenciales con hijos de 1-5 años. Para variables cualitativas se aplicaron pruebas de asociación mediante el test X2; para las variables cuantitativas se aplicó la diferencia de medias mediante la t de Student o análisis de la varianza (ANOVA). Se consideró como valor estadísticamente significativo p < 0,05. Resultados: se analizaron 288 cuestionarios. El 50% de los encuestados tiene dos hijos. Trabaja el 64,5%. En el área urbana son de mayor edad y nivel de estudios (p < 0,001). Un 50,3% considera la fiebre mala, menos los de edad media superior (p < 0,05). El 67,7% utiliza termómetro electrónico. Consideran fiebre una temperatura de 37,7 ºC en axila. Ante la fiebre, el 58,3% utiliza en primer lugar un antitérmico. El 98,2% usa medidas físicas y el 49,3% de ellos piensa que mejoran la fiebre; las usan menos los que trabajan (p < 0,05). Los de estudios superiores quitan ropa y dan líquidos más que los de estudios primarios (p = 0,035). Los antitérmicos más empleados fueron paracetamol e ibuprofeno. Un 64,6% de los encuestados percibe diferencias en cuanto a eficacia. El 85,4% utiliza la dosis indicada por su pediatra y el 21,5%, la que indica la ficha técnica, sobre todo los de estudios superiores frente a los de estudios primarios (p < 0,05). El 67,4% alterna antitérmicos, siempre aconsejados por el pediatra. Conclusiones: globalmente, en la población estudiada existe un buen conocimiento y una actitud adecuada ante la fiebre (AU)

Objective: To assess parental knowledge and attitudes about fever and the influence of social and family aspects. Methods: Questionnaires distributed to parents of children 1-5 years old in two health districts. For qualitative variables association tests with X2 test were applied, and mean differences by Student’s t-distribution or analysis of variance (ANOVA) were used for quantitative variables. It was considered statistically significant the value of p < 0.05. Results: There were 288 questionnaires analyzed. Fifty percent of respondents have 2 children, and 64.5% work. Older age and higher education levels were found in urban areas (p < 0.001). Fever was considered to be a bad thing by 50.3%, less so those with higher mean age (p < 0.05). Electronic thermometers was used in 67.7%, and 86.2% took armpit temperature considering 37.7 ºC as fever. When faced with fever, 58.3% of parents first use antipyretics. Physical measures are used in the first term by 98.2% and 49.3% think these measures lower the fever; they are used less by those parents who work (p < 0.05). Parents with higher education levels remove the clothing and give liquids more than those with primary education (p = 0.035). Most commonly used antipyretics are acetaminophen and ibuprofen; 64.6% perceived differences in efficiency; 65.4% think that ibuprofen is more effective than acetaminophen. Most parents use the dosage prescribed by the pediatrician (85.4%), and 21.5% use the dosage specified in the leaflet, especially those with higher education levels, compared to parents with primary education (p < 0.05). They sometimes alternate antipyretics (67.4%), always following the advice of their pediatrician. Conclusions: There is an overall good knowledge and attitudes about fever (AU)

Inhibition of poly (ADP-ribose) polymerase-1 enhances doxorubicin activity against liver cancer cells.

The purpose of this study was to investigate whether PARP-1 inhibition sensitizes human liver cancer cell lines to doxorubicin treatment. Both the addition of PARP-1 inhibitor (ANI) and depletion by means of stable siRNA significantly enhanced the growth inhibition induced by the DNA damage agents used. This effect was associated with an accumulation of unrepaired DNA, with a reduction in EGFR and Bcl-xL gene expression as well as with positive annexin-V staining. These results provide novel evidence of the direct role of PARP-1 in tumour chemoresistance in relation to its effects on the transcription of key genes involved in tumour survival.

Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of hepatitis C virus genotype 1 and their relationships to pegylated interferon-ribavirin treatment responses.

Mutations in several subgenomic regions of hepatitis C virus (HCV) have been implicated in influencing the response to interferon (IFN) therapy. Sequences within HCV NS5A (PKR binding domain [PKRBD], IFN sensitivity-determining region [ISDR], and variable region 3 [V3]) were analyzed for the pretreatment serum samples of 60 HCV genotype 1-infected patients treated with pegylated IFN plus ribavirin (1b, n = 47; 1a, n = 13) but with different treatment outcomes, those with sustained virologic responses (SVR; n = 36) or nonresponders (NR; n = 24). Additionally, the sequence of the PKR/eIF-2alpha phosphorylation homology domain (E2-PePHD) region was determined for 23 patients (11 SVR and 12 NR). The presence of > 4 mutations in the PKRBD region was associated with SVR (P = 0.001) and early virologic responses (EVR; 12 weeks) (P = 0.037) but not rapid virologic responses (4 weeks). In the ISDR, the difference was almost statistically significant (68% of SVR patients with mutations versus 45% without mutations; P = 0.07). The V3 region had a very high genetic variability, but this was not related to SVR. Finally, the E2-PePHD (n = 23) region was well conserved. The presence of > 4 mutations in the PKRBD region (odds ratio [OR] = 9.9; P = 0.006) and an age of < or = 40 years (OR = 3.2; P = 0.056) were selected in a multivariate analysis as predictive factors of SVR. NS5A sequences from serum samples taken after 1 month of treatment and posttreatment were examined for 3 SVR and 15 NR patients to select treatment-resistant viral subpopulations, and it was found that in the V3 and flanking regions, the mutations increased significantly in posttreatment sera (P = 0.05). The genetic variability in the PKRBD (> 4 mutations) is a predictive factor of SVR and EVR in HCV genotype 1 patients treated with pegylated IFN and ribavirin.

Hipertensión arterial y manchas café con leche / Hypertension and white coffee stains

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Modulation of transcription by PARP-1: consequences in carcinogenesis and inflammation.

Post-translational modification of proteins by poly(ADP-ribosyl)ation is involved in the regulation of a number of biological functions. While an 18 member superfamily of poly(ADP-ribose) polymerases (PARP)s has been described PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 act as a DNA nick sensor and is activated by DNA breaks to cleave NAD(+) into nicotinamide and ADP-ribose to synthesize long branching poly(ADP-ribose) polymers (PAR) covalently attached to nuclear acceptor proteins. Whereas activation of PARP-1 by mild genotoxic stimuli facilitate DNA repair and cell survival, severe DNA damage triggers different pathways of cell death including PARP-mediated cell death through the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. PAR and PARP-1 have also been described as having a function in transcriptional regulation through their ability to modify chromatin-associated proteins and as a cofactor of different transcription factors, most notably NF-kappaB and AP-1. Pharmacological inhibition or genetic ablation of PARP-1 not only provided remarkable protection from tissue injury in various oxidative stress-related disease models but it result in a clear benefit in the treatment of cancer by different mechanisms including selective killing of homologous recombination-deficient tumor cells, down regulation of tumor-related gene expression and decrease in the apoptotic threshold in the co-treatment with chemo and radiotherapy. We will summarize in this review the current findings and concepts for the role of PARP-1 and poly(ADP-ribosyl)ation in the regulation of transcription, oxidative stress and carcinogenesis.

¿Cómo se comporta la hepatitis autoinmune en los niños? / How does autoimmune hepatitis behave in children?

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