Actitudes éticas de los pediatras de Cuidados Intensivos ante pacientes con atrofia muscular espinal tipo 1 / Ethical attitudes of intensive care paediatricians as regards patients with spinal muscular atrophy type 1

INTRODUCCIÓN: La atrofia muscular espinal tipo 1 (AME-1) es una enfermedad progresiva e incurable que plantea problemas éticos entre los profesionales de Pediatría. Nuestro objetivo ha sido conocer las opciones éticas de los pediatras de UCIP ante los pacientes con AME-1 y fracaso respiratorio. MATERIAL Y MÉTODOS: Estudio descriptivo transversal, mediante una encuesta anónima enviada a las UCIP de España y accesible en la web de la Sociedad Española de Cuidados Intensivos Pediátricos. RESULTADOS: Analizamos 124 respuestas (70% mujeres, 51% menores de 40 años, 54% de UCIP con más de 10 camas, 69% con experiencia previa con estos niños y 53% con creencias religiosas). En el último caso atendido, la mayoría de los pediatras optó por la ventilación no invasiva (VNI), realizando después limitación del esfuerzo terapéutico (LET). Ante un hipotético caso futuro, la mitad de los pediatras apoyarían la misma opción (VNI+LET) y el 74% apoyaría la decisión de la familia, aunque no coincidiera con la suya. No se observaron diferencias según la edad, la experiencia previa o el sexo. Los pediatras con creencias religiosas son menos partidarios de la LET inicial. El 63% considera que la calidad de vida de un niño con AME-1 y ventilación invasiva es muy mala. CONCLUSIONES: Ante un niño con AME-1 y fracaso respiratorio, la mayoría de los pediatras de UCIP están a favor de iniciar la VNI y realizar LET cuando dicho soporte no sea suficiente, pero apoyarían la decisión de la familia aunque no estuvieran de acuerdo con ella

INTRODUCTION: Spinal muscular atrophy type 1 (SMA-1) is a progressive and fatal disease that leads to ethical problems for Paediatric professionals. Our objective was to determine the ethical options of Paediatric Intensive Care Unit (PICU) paediatricians as regards a child with SMA-1 and respiratory failure. MATERIAL AND METHODS: A cross-sectional descriptive study was conducted using an anonymous questionnaire sent to PICUs in Spain (which can be accessed through the Spanish Society of Paediatric Critical Care web page). RESULTS: Of the 124 responses analysed, 70% were from women, 51% younger than 40 years, 54% from a PICU with more than 10 beds, 69% with prior experience in such cases, and 53% with religious beliefs. In the last patient cared for, most paediatricians opted for non-invasive mechanical ventilation (NIV) and limitation of therapeutic effort (LET) in case of NIV failure. Confronted with a future hypothetical case, half of paediatricians would opt for the same plan (NIV+LET), and 74% would support the family's decision, even in case of disagreement. Age, prior experience and sex were not related to the preferred options. Paediatricians with religious beliefs were less in favour of initial LET. Less than two-thirds (63%) scored the quality of life of a child with SMA-1 and invasive mechanical ventilation as very poor. CONCLUSIONS: Faced with child with SMA-1 and respiratory failure, most paediatricians are in favour of initiating NIV and LET when such support is insufficient, but they would accept the family's decision, even in case of disagreement

[Ethical attitudes of intensive care paediatricians as regards patients with spinal muscular atrophy type 1]. / Actitudes éticas de los pediatras de Cuidados Intensivos ante pacientes con atrofia muscular espinal tipo 1.

INTRODUCTION: Spinal muscular atrophy type 1 (SMA-1) is a progressive and fatal disease that leads to ethical problems for Paediatric professionals. Our objective was to determine the ethical options of Paediatric Intensive Care Unit (PICU) paediatricians as regards a child with SMA-1 and respiratory failure. MATERIAL AND METHODS: A cross-sectional descriptive study was conducted using an anonymous questionnaire sent to PICUs in Spain (which can be accessed through the Spanish Society of Paediatric Critical Care web page). RESULTS: Of the 124 responses analysed, 70% were from women, 51% younger than 40 years, 54% from a PICU with more than 10 beds, 69% with prior experience in such cases, and 53% with religious beliefs. In the last patient cared for, most paediatricians opted for non-invasive mechanical ventilation (NIV) and limitation of therapeutic effort (LET) in case of NIV failure. Confronted with a future hypothetical case, half of paediatricians would opt for the same plan (NIV+LET), and 74% would support the family's decision, even in case of disagreement. Age, prior experience and sex were not related to the preferred options. Paediatricians with religious beliefs were less in favour of initial LET. Less than two-thirds (63%) scored the quality of life of a child with SMA-1 and invasive mechanical ventilation as very poor. CONCLUSIONS: Faced with child with SMA-1 and respiratory failure, most paediatricians are in favour of initiating NIV and LET when such support is insufficient, but they would accept the family's decision, even in case of disagreement.

Analysis of Immunogenetic Factors in Idiosyncratic Drug-induced Liver Injury in the Pediatric Population.

OBJECTIVES: Idiosyncratic drug-induced liver injury is a multifactorial complex disease, in which the toxic potential of the drug, together with genetic and acquired factors and deficiencies in adaptive processes, which limit the extent of damage, can determine susceptibility, and make individuals unique in their development of hepatotoxicity. The aim of the present study is to analyse the genetic factors (human leukocyte antigen [HLA], cytokine polymorphisms, and killer cell immunoglobulin-like receptor [KIR] genotype) of children who experience an episode of drug-induced liver injury. PATIENTS AND METHODS: Prospective multicentre case-control study. The subjects included in the study were 30 paediatric patients-infants and children ages between 0 and 15 years and who presented possible liver disease associated with the intake of medicines, herbal products, drugs, or toxins. As a control group, 62 subjects were selected. RESULTS: Although HLAC0401 and HLADQB0603 may provide a hepatoprotective mechanism in the paediatric population, HLADQA0102 and HLA-DR12 are more commonly found in sick children and their presence may be related to liver damage. The KIR inhibitor KIR3DL1 was not present in any child in the control group. CONCLUSIONS: Polymorphisms that are low producers of interleukin-10 occur more frequently in children who have experienced hepatotoxicity.

[HEPATOTOXICITY FROM THE CONSUMPTION OF HERBALIST PRODUCTS BY A PAEDIATRIC POPULATION]. / HEPATOTOXICIDAD Y CONSUMO DE PRODUCTOS DE HERBORISTERÍA EN LA POBLACIÓN PEDIÁTRICA.

The consumption of herbal products is mainly due to the perception that being "natural" can only be beneficial and without risk to health. However the properties thereof are poorly studied and proven. Four episodes are presented of hepatotoxicity from the consumption of herbal products, by three children. We analyse the epidemiological and clinical characteristics of these products, and stress the importance of proper anamnesis for accurate diagnosis.

El consumo de productos de herboristería es debido principalmente a la percepción de que al ser "naturales", solo pueden ser beneficiosos y carecen de riesgos para la salud. Sin embargo, las propiedades de los mismos están escasamente estudiadas y contrastadas. Se presentan cuatro episodios de hepatotoxicidad por productos naturales en tres niños, analizándose sus características epidemiológicas y clínicas. Se hace especial hincapié en la importancia de una correcta anamnesis para la sospecha diagnóstica.

Hepatotoxicidad y consumo de productos de herboristería en la población pediátrica / Hepatotoxicity from the consumption of herbalist products by a paediatric population

El consumo de productos de herboristería es debido principalmente a la percepción de que al ser «naturales», solo pueden ser beneficiosos y carecen de riesgos para la salud. Sin embargo, las propiedades de los mismos están escasamente estudiadas y contrastadas. Se presentan cuatro episodios de hepatotoxicidad por productos naturales en tres niños, analizándose sus características epidemiológicas y clínicas. Se hace especial hincapié en la importancia de una correcta anamnesis para la sospecha diagnóstica (AU)

The consumption of herbal products is mainly due to the perception that being «natural» can only be beneficial and without risk to health. However the properties thereof are poorly studied and proven. Four episodes are presented of hepatotoxicity from the consumption of herbal products, by three children. We analyse the epidemiological and clinical characteristics of these products, and stress the importance of proper anamnesis for accurate diagnosis (AU)

High-resolution hepatitis C virus subtyping using NS5B deep sequencing and phylogeny, an alternative to current methods.

Hepatitis C virus (HCV) is classified into seven major genotypes and 67 subtypes. Recent studies have shown that in HCV genotype 1-infected patients, response rates to regimens containing direct-acting antivirals (DAAs) are subtype dependent. Currently available genotyping methods have limited subtyping accuracy. We have evaluated the performance of a deep-sequencing-based HCV subtyping assay, developed for the 454/GS-Junior platform, in comparison with those of two commercial assays (Versant HCV genotype 2.0 and Abbott Real-time HCV Genotype II) and using direct NS5B sequencing as a gold standard (direct sequencing), in 114 clinical specimens previously tested by first-generation hybridization assay (82 genotype 1 and 32 with uninterpretable results). Phylogenetic analysis of deep-sequencing reads matched subtype 1 calling by population Sanger sequencing (69% 1b, 31% 1a) in 81 specimens and identified a mixed-subtype infection (1b/3a/1a) in one sample. Similarly, among the 32 previously indeterminate specimens, identical genotype and subtype results were obtained by direct and deep sequencing in all but four samples with dual infection. In contrast, both Versant HCV Genotype 2.0 and Abbott Real-time HCV Genotype II failed subtype 1 calling in 13 (16%) samples each and were unable to identify the HCV genotype and/or subtype in more than half of the non-genotype 1 samples. We concluded that deep sequencing is more efficient for HCV subtyping than currently available methods and allows qualitative identification of mixed infections and may be more helpful with respect to informing treatment strategies with new DAA-containing regimens across all HCV subtypes.

Melatonin reduces endothelin-1 expression and secretion in colon cancer cells through the inactivation of FoxO-1 and NF-κß.

Melatonin is an indoleamine that is synthesised from tryptophan under the control of the enzymes arylalkylamine N-acetyltransferase (AA-NAT) and acetylserotonin methyltransferase (ASMT). Melatonin inhibits colon cancer growth in both in vivo and in vitro models; however, a precise mechanism responsible for inhibiting tumour growth has not been clearly described. Endothelin-1 (ET-1) is a peptide that acts as a survival factor in colon cancer, inducing cell proliferation, protecting carcinoma cells from apoptosis and promoting angiogenesis. The data presented show that melatonin inhibits edn-1 mRNA expression (the first step in ET-1 synthesis), ECE-1 protein expression and the release of ET-1 from colorectal cancer cells in vitro. ET-1 levels in cultured media present a similar inhibition pattern to that of edn-1 mRNA expression despite the inhibition of ECE-1 protein after melatonin treatment, which suggests that an endopeptidase other than ECE-1 could be mainly responsible for ET-1 synthesis. The inhibition of edn-1 expression is due to an inactivation of FoxO1 and NF-κß transcription factors. FoxO1 inactivation is associated with an increased Src phosphorylation, due to elevated cAMP content and PKA activity, whereas NF-κß inactivation is associated with the blockade of Akt and ERK phosphorylation due to the inhibition of PKC activity after melatonin treatment. Melatonin also inhibits edn-1 promoter activity regulated by FoxO1 and NF-κß. Finally, a significant correlation was observed between AA-NAT and edn-1 expression downregulation in human colorectal cancer tissues. In conclusion, melatonin may be useful in treating colon carcinoma in which the activation of ET-1 plays a role in tumour growth and progression.

Amoxicillin-clavulanic acid hepatotoxicity in children.

OBJECTIVES: The objectives of the present study were to determine the importance of amoxicillin-clavulanic acid (AC) hepatotoxicity in the paediatric population and to characterise the episodes identified and potential host-specific factors. This was addressed via a prospective observational study in which 8 Spanish hospitals participated. METHODS: A total of 11 cases were examined. For each patient included in the study, a structured and codified data-collection protocol was complied with, taking note of patient demographics, characteristics of the treatment assumed to provoke the reaction, concomitant medication, course and outcome of the episode, and laboratory variables during the reaction. The latter were determined every 6 months from the outset to the eventual resolution of the case. RESULTS: A total of 11 cases of AC hepatotoxicity were detected, affecting 9 boys and 2 girls, ages 1 to 11 years. Causality criteria were assessed using the Council for International Organizations of Medical Sciences scale. CONCLUSIONS: We conclude that the introduction of hepatotoxicity record systems in paediatric care, together with the continuing study and development of existing systems, would contribute to improving our epidemiological knowledge about the harmful effects of drugs on the liver.

Gender-related invasion differences associated with mRNA expression levels of melatonin membrane receptors in colorectal cancer.

Melatonin inhibits growth and invasive capacity of colon cancer cells in vitro through its membrane (MT1 and MT2) and/or nuclear receptors (RORα). Previous studies showed that this indoleamine is present in both the normal and colon cancer at similar levels. Therefore, we analyzed MT1, MT2, and RORα expression in tumor samples versus normal mucosa (NM) from patients suffering from colorectal cancer (CRC). Given the existence of sex differences in the incidence and pathology of CRC and the involvement of steroid receptors in the oncostatic actions of melatonin in some types of cancer, we also analyzed the expression of androgen (AR) and estrogen receptor (ER) α and ERß. Finally, we conducted some experiments in colon cancer cell lines to corroborate the experiments carried out in human tumors. We found a decreased expression of MT1, MT2, AR, ERα, and ERß in tumor samples versus NM, but no changes in RORα expression in the whole cohort of patients. Classifying tumors by stage and gender, MT1, MT2, AR, ERα, and ERß expression decreased in both early stage and advanced tumors, but only in male patients. On the other hand, MT1 and MT2 expression correlated positively with AR, ERα, and ERß expression in male patients and with ERα or ERß in female patients. In vitro, the invasive capacity was higher in cells with the least expression of MT1, MT2, and AR, and nonselective MT1/MT2 agonists inhibited cell growth and invasion. These results could indicate a possible interaction of these pathways.

Quasispecies as predictive response factors for antiviral treatment in patients with chronic hepatitis C.

The object of this study was to evaluate the viral factor, especially the quasispecies, as predictive of sustained virologic response. We studied the quasispecies, genotype, viral load, and hepatitis C (HCV) cAg in 41 patients with chronic hepatitis C treated with interferon and in 84 with interferon and ribavirin. In the interferon group, responders presented a lower viral load. From logistic regression analysis of patients treated with interferon plus ribavirin, independent predictors for sustained virologic response were genotype 3a, a low baseline viral load and

Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients.

BACKGROUND & AIMS: We evaluated the effect of insulin resistance and viral factors on sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin. METHODS: Patients (n=159; 94 men; age, 41.7 +/- 11.1 years) with chronic hepatitis C (genotype 1, n=113; non-1 genotype, n=46) received treatment with interferon plus ribavirin. Serum levels of leptin and insulin were measured, and the insulin resistance index (HOMA-IR: homeostasis model of assessment) and body mass index were calculated. RESULTS: A sustained virological response was associated with lower age, insulin resistance index, body mass index, and gamma-glutamyltranspeptidase and serum leptin levels. There was no association with viral load, sex, type of interferon, or cholesterol levels. A sustained virological response was achieved in 43.4% (46/113) of genotype 1 and 89% (32/36) of genotype 2 and 3 (P=.0001) patients. Necroinflammatory activity and steatosis were not associated with the sustained virological response rate. Multivariate regression analysis indicated that the independent variables related to sustained virological response were genotype (odds ratio, 3.57; 95% confidence interval, 1.49-8.3; P=.001), insulin resistance index (odds ratio, 1.82; 95% confidence interval, 1.08-3.06; P=.012), and fibrosis (odds ratio, 1.36; 95% confidence interval, 1.01-1.84; P=.029). A sustained virological response in patients with genotype 1 and insulin resistance (HOMA-IR > 2) occurred in 23 of 70 (32.8%; 95% confidence interval, 21.9%-43.9%) patients, vs. 26 of 43 (60.5%; 95% confidence interval, 45.9%-75.1%) genotype 1 patients without insulin resistance (P=.007; odds ratio, 3.12, 95% confidence interval, 1.42-6.89). CONCLUSIONS: Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin.

Patología orofacial en niños nacidos en condiciones de alto riesgo. Estudio piloto / Orofacial pathology in children born under high-risk conditions. A pilot study

Introducción: los niños nacidos en condiciones de alto riesgo presentan mayor riesgo de padecer enfermedades. A nivel oral observamos en estudios previos hipoplasias de esmalte, caries y alteraciones en paladar, fundamentalmente. Nuestro objetivo fue conocer la patología orofacial y su relación con el bajo peso al nacimiento en una población de niños nacidos en condiciones de alto riesgo de Granada. Pacientes y método: la muestra fue de 60 niños de 46 años nacidos en condiciones de alto riesgo y que necesitaron cuidados intensivos neonatales. Se realizó un estudio descriptivo para determinar la patología en estos niños y un análisis estadístico univariante para analizar las variables según el peso en el nacimiento. Resultados: observamos una relación estadísticamente significativa entre el peso al nacimiento menor de 1550 gramos y las variables perinatales. El porcentaje de anomalías estructurales dentarias, caries, hábitos orofaciales y traumatismos observado en nuestra muestra fue elevado, existiendo relación estadísticamente significativa con el peso al nacer. Los hábitos higiénicos y asistencia dental previa fueron escasos, no estando relacionados con el peso en el nacimiento. Conclusiones: es importante considerar los datos neonatales ya que aportan información sobre la presencia de secuelas en el paciente infantil nacido en condiciones de riesgo y permitirá al odontopediatra establecer protocolos preventivos y de atención al niño (AU)

Estudio de la coinfección por el virus de la hepatitis G en la hepatitis crónica C. Respuesta al tratamiento con interferón alfa / Study of co-infection of hepatitis G virus in chronic hepatitis C. Response to alpha interferon

Fundamento: Se cree que el poder citopático del virus de la hepatitis G (VHG) es escaso; no obstante, su efecto sobre el hígado es menos conocido en los casos de coinfección con el VHC. Los objetivos de este trabajo fueron estudiar la prevalencia de la coinfección en pacientes con hepatitis crónica C (HCC) y analizar los aspectos clínicos, epidemiológicos e histológicos y la respuesta al interferón (IFN). Pacientes y métodos: Se incluyeron 180 pacientes con HCC y se determinó el ARN-VHG. Resultados: La prevalencia de la coinfección fue del 12,2 por ciento (n = 22). No se observaron diferencias estadísticamente significativas entre el grupo no coinfectado y coinfectado al estudiar la edad, el sexo, los mecanismos de transmisión y la ingesta de alcohol. Tampoco había diferencias en la bioquímica hepática, los autoanticuerpos no organoespecíficos, la lesión histológica y el índice de Knodell. La respuesta bioquímica (RB) y virológica (RV) del VHC a los 6 meses post-IFN fue similar en los dos grupos (VHG negativo: RB = 29 por ciento, RV = 12 por ciento; VHG positivo: RB = 22 por ciento, RV = 18 por ciento). El ARN-VHG se determinó también a los 6 meses postratamiento en el grupo de coinfectados (primer ciclo de IFN: n = 22; segundo ciclo de IFN: n = 9): 12 (55 por ciento) negativizaron el ARN-VHG y 5 (23 por ciento) el ARN-VHC (p = 0,021). Al comparar la RB con la RV en este grupo, había 12 que negativizaron el ARN-VHG pero sólo 2 tenían RB (diferencias no significativas). Por el contrario, la RB sí se relacionó con la negativización del ARN-VHC (p = 0,023). Conclusión: La prevalencia de coinfección por VHG en pacientes con hepatitis crónica C es elevada (12,8 por ciento). El VHG no aumenta la patogenicidad del VHC ni modifica la respuesta al IFN, aunque el VHG es más sensible al IFN que el VHC. La determinación del VHG no es necesaria en los pacientes con HCC. (AU)