Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): a phase 2, randomised, open-label, standard-of-care controlled, multicentre trial.

BACKGROUND: Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke. METHODS: The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18-80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1-7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6-20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 106 BMMNCs/kg or 5 × 106 BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov, NCT02178657 and is completed. FINDINGS: Between April 1, 2015, and May 20, 2021, we assessed 114 patients for eligibility. We randomly assigned 77 (68%) patients: 38 (49%) to the control group, 20 (26%) to the low-dose BMMNC group, and 19 (25%) the high-dose BMMNC group. The mean age of participants was 62·4 years (SD 12·7), 46 (60%) were men, 31 (40%) were women, all were White, and 63 (82%) received thrombectomy. The median NIHSS score before randomisation was 12 (IQR 9-15), with intra-arterial BMMNC injection done a median of 6 days (4-7) after stroke onset. The primary efficacy outcome occurred in 14 (39%) patients in the control group versus ten (50%) in the low-dose group (adjusted odds ratio 2·08 [95% CI 0·55-7·85]; p=0·28), eight (44%) in the high-dose group (1·89 [0·52-6·96]; p=0·33), and 18 (47%) in the pooled BMMNC group (2·22 [0·72-6·85]; p=0·16). We found no differences in the proportion of patients who had adverse events or dose-related events, but two patients had a groin haematoma after cell injection in the low-dose BMMNC group. INTERPRETATION: Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints. FUNDING: Instituto de Salud Carlos III co-funded by the European Regional Development Fund/European Social Fund, Mutua Madrileña, and the Regional Ministry of Health of Andalusia.

Evaluation of the effectiveness of a new cryopreservation system based on a two-compartment vial for the cryopreservation of cell therapy products.

BACKGROUND AIMS: Successful cell cryopreservation and banking remain a major challenge for the manufacture of cell therapy products, particularly in relation to providing a hermetic, sterile cryovial that ensures optimal viability and stability post-thaw while minimizing exposure to toxic cryoprotective agents, typically dimethyl sulfoxide (Me2SO). METHODS: In the present study, the authors evaluated the effectiveness and functionality of Limbo technology (Cellulis S.L., Santoña, Spain). This system provides a hermetic vial with two compartments (one for adding cells with the cryoprotective agent solution and the other for the diluent solution) and an automated defrosting device. Limbo technology (Cellulis S.L.) allows reduction of the final amount of Me2SO, sidestepping washing and dilution steps and favoring standardization. The study was performed in several Good Manufacturing Practice laboratories manufacturing diverse cell therapy products (human mesenchymal stromal cells, hematopoietic progenitor cells, leukapheresis products, fibroblasts and induced pluripotent stem cells). Laboratories compared Limbo technology (Cellulis S.L.) with their standard cryopreservation procedure, analyzing cell recovery, viability, phenotype and functionality. RESULTS: Limbo technology (Cellulis S.L.) maintained the viability and functionality of most of the cell products and preserved sterility while reducing the final concentration of Me2SO. CONCLUSIONS: Results showed that use of Limbo technology (Cellulis S.L.) offers an overall safe alternative for cell banking and direct infusion of cryopreserved cell products into patients.

[Study protocol on Socioeconomic and Geographic Inequalities in Cancer Incidence, Mortality and Survival in Spain: Multilevel Population-Base Study: DESOCANES study]. / Protocolo del Estudio Poblacional Multinivel de las Desigualdades Socioeconómicas en la Distribución Geográfica de la Incidencia, la Mortalidad y la Supervivencia Neta del Cáncer en España: Estudio DESOCANES.

Incidence and mortality provide information on the burden of cancer morbidity and the potential years of life lost due to cancer. The Spanish Deprivation Index (SDI) has been developed as a standardized measure to study socioeconomic deprivation in Spain at the census tract level. In addition, SDI information can be combined with ecological variables at the population level and data from the High-Resolution European Studies in Cancer. The aim of this study is to characterize socioeconomic inequalities in incidence, excess mortality, premature mortality and net survival for three of the most incident cancers (lung, colon-rectum and breast) in Spain using the SDI. This national population-based study will assess the impact of socioeconomic inequalities using a multilevel modelling approach. Spatial analysis, multilevel modeling, net survival and economic impact assessment will be used. The results will be useful for supporting decision-making, planning, and management of public health interventions aimed at reducing the impact of socioeconomic inequalities in the diagnosis and prognosis of cancer patients in Spain.

Capacidad predictiva de la inteligencia emocional sobre el apoyo social percibido de adolescentes

Por medio del presente estudio se busca analizar la capacidad predictiva de la inteligencia emocional medida tanto desde el modelo de habilidad (atención, claridad y reparación emocional) como desde un modelo mixto (intrapersonal, interpersonal, manejo del estrés y adaptabilidad). Esto, sobre cada una de las fuentes del apoyo social percibido (familiares, amigos y personas significativas), teniendo en cuenta el sexo y la edad de los adolescentes. La muestra estuvo compuesta por 1030 estudiantes de educación secundaria con edades entre 11 y 19 años residentes en la República Dominicana. Los resultados señalan que la inteligencia emocional predice la percepción del apoyo social en las muestras de ambos sexos, aunque entre las chicas el efecto explicativo es mayor que entre los varones. Se observa también que la capacidad predictiva es mayor en la adolescencia media. Estos datos refuerzan la necesidad de desarrollar la inteligencia emocional.

Through this study we seek to analyze the predictive capacity of emotional intelligence measured, both from a model of skills (attention, clarity and emotional repair) and a mixed model (intrapersonal, interpersonal, stress management and adaptability), on each of the sources of perceived social support (family, friends and significant people), according to sex and age. The sample consisted of 1030 secondary school students aged between 11 and 19 years living in the Dominican Republic. The results indicate that emotional intelligence predicts the perception of social support in the samples of both sexes, even though in the female sample the explanatory effect is greater than in the males. It is also observed that the predictive capacity is greater in middle adolescence. These data reinforce the need to develop emotional intelligence.

Celia's encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. Clinical characterization, biochemistry, and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification, and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. One with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy, and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene and is responsible for a variant of Celia's encephalopathy, with variable phenotypic expression.

Rice Grain Quality Benchmarking Through Profiling of Volatiles and Metabolites in Grains Using Gas Chromatography Mass Spectrometry.

Gas chromatograph coupled with mass spectrometer is widely used to profile volatiles and metabolites from the homogenized rice flour obtained from mature grains. Rice grains consist of central endosperm which stores majorly starch and, in addition, accumulate various storage proteins as storage reserves. The outer nutritious aleurone layer stores lipids, sugar alcohols, volatiles, antioxidants, vitamins, and various micronutrients. Once paddy sample is dehulled, milled, and ground cryogenically, the brown rice flour is subjected to extraction of primary metabolites and volatiles using an appropriate extraction method. In metabolite profiling of the liquid extract obtained from the rice sample, mixture is initially subjected to methoxyamination then silylation before being subjected to untargeted metabolite profiling. Peaks obtained are processed for noise reduction and specific signal selection. Volatile compounds are initially extracted using a solid phase adsorbent prior to analysis. All these compounds, metabolites, and volatiles are detected in the mass selective detector by fragmentation at 70 eV ionization energy and the resultant mass spectrum compared with a built-in library of compounds. Data mined from the gas chromatography mass spectrometry analysis are then subjected to post-processing statistical analysis.

The Probiotic Lactobacillus fermentum Prevents Dysbiosis and Vascular Oxidative Stress in Rats with Hypertension Induced by Chronic Nitric Oxide Blockade.

SCOPE: Whether the probiotic Lactobacillus fermentum CECT5716 (LC40) ameliorates hypertension in rats with chronic nitric oxide (NO) synthase inhibition is tested. METHODS AND RESULTS: Rats are randomly divided into four different groups and treated for 4 weeks: a) vehicle (control), b) vehicle plus NG -nitro-l-arginine methyl ester (l-NAME; 50 mg 100 mL-1 in drinking water), c) LC40 (109 colony-forming units d-1 by gavage), and d) LC40 plus l-NAME. l-NAME induces gut dysbiosis, characterized mainly by an increased Fimicutes/Bacteroidetes (F/B) ratio and reduced Bifidobacterium content, increased Th17 cells and reduced Treg in mesenteric lymph nodes (MLN), increased aortic Th17 infiltration and reactive oxygen species, reduced aortic endothelium-dependent relaxant response to acetylcholine, and hypertension. LC40 prevents gut dysbiosis, alters the Th17/Treg balance in MLN, vascular oxidative stress, and inflammation, slightly improves endothelial dysfuncion but do not inhibit the development of l-NAME-induced hypertension. CONCLUSION: Chronic LC40 treatment, in this model of chronic inhibition of NO synthesis, reduces early events involved in atherosclerosis development, such as vascular oxidative stress and pro-inflammatory status, as a result of prevention of gut dysbiosis and immune changes in MLN, but not hypertension, confirming the critical role of NO in the antihypertensive effects of LC40 in genetic hypertension.

Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia's encephalopathy.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Skipped BSCL2 Transcript in Celia's Encephalopathy (PELD): New Insights on Fatty Acids Involvement, Senescence and Adipogenesis.

OBJECTIVE: PELD (Progressive Encephalopathy with or without Lipodystrophy or Celia's Encephalopathy) is a fatal and rare neurodegenerative syndrome associated with the BSCL2 mutation c.985C>T, that results in an aberrant transcript without the exon 7 (Celia seipin). The aim of this study was to evaluate both the process of cellular senescence and the effect of unsaturated fatty acids on preadipocytes from a homozygous c.985C>T patient. Also, the role of aberrant seipin isoform on adipogenesis was studied in adipose-derived human mesenchymal stem cells. MATERIAL AND METHODS: Cellular senescence was evaluated using ß-galactosidase staining of preadipocytes obtained from a homozygous c.985C>T patient. Moreover, these cells were cultured during 24 hours with Intralipid, a soybean oil-based commercial lipid emulsion. The expression of the different BSCL2 transcripts was measured by qPCR. Adipose-derived human mesenchymal stem cells were differentiated to a fat lineage using StemPRO adipogenesis kit, and the expression of BSCL2 transcripts and several adipogenesis-related genes was measured by qPCR. RESULTS: the treatment of preadipocytes with unsaturated fatty acids significantly reduced the expression of the BSCL2 transcript without exon 7 by 34 to 63%. On the other hand, at least in preadipocytes, this mutation does not disturb cellular senescence rate. Finally, during adipocyte differentiation of adipose-derived human mesenchymal stem cells, the expression of adipogenic genes (PPARG, LPIN1, and LPL) increased significantly over 14 days, and noteworthy is that the BSCL2 transcript without exon 7 was differentially expressed by 332 to 723% when compared to day 0, suggesting an underlying role in adipogenesis. CONCLUSIONS: our results suggest that Celia seipin is probably playing an underestimated role in adipocyte maturation, but not in senescence, and its expression can be modified by exogenous factors as fatty acids.

Role of UCP2 in the protective effects of PPARß/δ activation on lipopolysaccharide-induced endothelial dysfunction.

Bacterial endotoxin lipopolysaccharide (LPS) activates inflammatory pathways, induces cytokine expression in the endothelium, augments reactive oxygen species (ROS) production in the vascular wall, and induces endothelial dysfunction. The aim of the present study was to analyze the effects of peroxisome proliferator-activated receptor (PPAR)ß/δ activation on LPS-induced inflammation, oxidative stress and endothelial dysfunction and to determine whether uncoupling protein-2 (UCP2) plays a role in these effects. In vivo, the PPARß/δ agonist GW0742 treatment prevented the LPS-induced reduction in aortic relaxation, the increase in vascular ROS production, the upregulation of NOX1, NOX2, p47(phox), and p22(phox) mRNA levels, and the endoplasmic reticulum (ER) stress markers in mice. We show that in mouse aortic endothelial cells (MAECs), GW0742 prevented the decreased A23187-stimulated nitric oxide (NO) production, and the increased intracellular ROS levels caused by exposure to LPS in vitro. The PPARß/δ antagonist GSK0660 abolished all these in vivo and in vitro protective effects induced by GW0742. This agonist also restored the reduced expression of UCP2 and mitofusin-2 induced by LPS. The effects of GW0742 on NO and ROS production in MAEC exposed to LPS were abolished by the UCP2 inhibitor genipin or by siRNA targeting UCP-2. Genipin also suppressed the expressional changes on NADPH oxidase and ER stress markers induced by GW0742. In conclusion, PPARß/δ activation restored the LPS-induced endothelial dysfunction by upregulation of UCP2, with the subsequent alleviation of ER stress and NADPH oxidase activity, thus reducing intracellular ROS production and increasing NO bioavailability.

Costos de la enfermedad crónica no transmisible: la realidad colombiana / Chronic Disease Cost not Transferable: Colombian Reality / Crônica custo doença intransferível: realidade colombiana

Objetivo: Se pretende reflexionar sobre los costos sociales y económicos de la Enfermedad Crónica no Transmisible (ECNT) en Colombia para visualizar un indicador de carga de estas patologías. Materiales y métodos: Se hizo una revisión de cincuenta estudios, de los cuales se seleccionaron veintisiete, que cumplían con los criterios de inclusión; como el estudio del paciente crónico y los estudios realizados entre el 2002 y el 2011, relacionados con costos, patología crónica y ser colombiano. Resultados: Este es un estudio de revisión de enfermedades crónicas frente a sus costos, de estas, las enfermedades cardiovasculares hacen parte del llamado grupo de enfermedades de alto costo, y su mayor incidencia representa un gran riesgo para el equilibrio financiero de las empresas de salud. Existen pocos estudios que aborden los costos generados por el tratamiento de los pacientes con ECNT, que evidencien el impacto económico que sufren las instituciones prestadoras y promotoras de Salud, tanto públicas como privadas, se deja de lado el costo económico, familiar y social que debe asumir la población afectada. Conclusión: Las ECNT representan una carga para el sistema del servicio de salud por costos muy altos, intervención tardía y reducido beneficio significativo para esta población y sus familias.

Objective: The aim is to reflect on the social and economic costs of chronic non-communicable disease (NCD) in Colombia to display a charging indicator of these pathologies. Material and methods: In a review of 50 studies, 27 were selected since these met the inclusion criteria, like chronical disease, studies conducted between 2002 and 2011 related to costs, chronic disease, and being Colombian. Results: This is a review study of chronic diseases vs. their costs, being here cardiovascular diseases part of the group of high cost and higher incidence diseases, thus representing a great risk to the financial stability of healthcare companies. There are few studies that address the costs generated by the treatment of NCDS patients that show the economic impact experienced by public and private institutions providing and promoting health services. Most of them forget the economic, family and social costs the affected population must suffer. Conclusions: NCDS represent a burden to the health service system for their very high costs, untimely intervention and reduced significant benefit for this population and their families.

Objetivo: Refletir sobre os custos sociais e econômicos de doenças não transmissíveis na Colômbia para exibir um indicador de carga destas doenças. Materiais e métodos: Revisão de 50 estudos, dos quais 27 foram selecionados foi que preencheram os critérios de inclusão como eles são, sendo doentes crônicos, estudos realizados entre 2002 e 2011 custos relacionados e doenças crônicas, sendo colombiana. Resultados: Este é um estudo de revisão de doenças crônicas vs. custos, onde as doenças cardiovasculares são parte do grupo de doenças chamado de alto custo e maior incidência representa um grande risco para a estabilidade financeira das empresas de saúde. Existem poucos estudos que abordam os custos gerados pelo tratamento de pacientes com doenças não transmissíveis, que mostram o impacto econômico experimentado pelos prestadores e instituições que promovem a saúde pública e privada esquecendo os custos econômicos, familiares e sociais terão de sofrer a população afectada. Conclusões: as doenças não transmissíveis representam um fardo para o sistema de serviço de saúde para custos muito elevados, e reduziu tarde intervención benefício significativo para esta população e suas famílias.

Chronic peroxisome proliferator-activated receptorß/δ agonist GW0742 prevents hypertension, vascular inflammatory and oxidative status, and endothelial dysfunction in diet-induced obesity.

OBJECTIVE: Endothelial dysfunction plays a key role in obesity-induced risk of cardiovascular disease. The aim of the present study was to analyze the effect of chronic peroxisome proliferator-activated receptor (PPAR)ß/δ agonist GW0742 treatment on endothelial function in obese mice fed a high-fat diet (HFD). METHODS AND RESULTS: Five-week-old male mice were allocated to one of the following groups: control, control-treated (GW0742, 3 mg/kg per day, by oral gavage), HFD, HFD + GW0742, HFD + GSK0660 (1 mg/kg/day, intraperitoneal) or HFD-GW0742-GSK0660 and followed for 11 or 13 weeks. GW0742 administration to mice fed HFD prevented the gain of body weight, heart and kidney hypertrophy, and fat accumulation. The increase in plasma levels of fasting glucose, glucose tolerance test, homeostatic model assessment of insulin resistance, and triglyceride found in the HFD group was suppressed by GW0742. This agonist increased plasma HDL in HFD-fed mice and restored the levels of tumor necrosis factor-α and adiponectin in fat. GW0742 prevented the impaired nitric oxide-dependent vasodilatation induced by acetylcholine in aortic rings from mice fed HFD. Moreover, GW0742 increased both aortic Akt and endothelial nitric oxide synthase phosphorylation, and inhibited the increase in caveolin-1/endothelial nitric oxide synthase interaction, ethidium fluorescence, NOX-1, Toll-like receptor 4, tumor necrosis factor-α, and interleukin-6 expression, and IκBα phosphorylation found in aortae from the HFD group. GSK0660 prevented all changes induced by GW0742. CONCLUSION: PPARß/δ activation prevents obesity and exerts protective effects on hypertension and on the early manifestations of atherosclerosis, that is, endothelial dysfunction and the vascular pro-oxidant and pro-inflammatory status, in HFD-fed mice.

Entrevista Percepción de Carga del Cuidado de Zarit: pruebas psicométricas para Colombia / Zarit Burden Interview: Psychometric Tests for Colombia / Entrevista de Percepção de Carga do Cuidado de Zarit: provas psicométricas para a Colômbia

Objetivo: determinar la validez y confiabilidad de la Entrevista de Percepción de Carga del Cuidado de Zarit, versión de 22 ítems en español, con cuidadores familiares de personas con enfermedades crónicas en Colombia. Materiales y métodos: estudio metodológico de corte transversal, con 652 cuidadores familiares de personas con enfermedades crónicas, residentes en las cinco regiones de Colombia, con el fin de establecer la validez de constructo, con un análisis factorial y la confiabilidad a través de la consistencia interna determinando el alfa de Cronbach. Resultado: respecto a la validez de constructo, el estudio reporta a partir de la asociación libre de la rotación Varimax la carga total, y en sus dimensiones que incluyen carga interpersonal, impacto del cuidado, y las competencias y expectativas sobre el cuidado. Las cargas factoriales corresponden a los ítems planteados para medir cada una de las dimensiones propuestas. Conclusión: el instrumento Entrevista de Percepción de Carga del Cuidado de Zarit, versión de 22 ítems en español, es una herramienta de fácil aplicación y comprensión en población colombiana de diferente nivel educativo, socioeconómico y cultural; además, mostró ser válido y confiable para evaluar la carga del cuidado en cuidadores familiares de personas con enfermedad crónica.

Objective: This research was designed to determine the validity and reliability of the Zarit Burden Interview, specifically the 22-item Spanish version, as an instrument to measure the burden of care perceived by family caregivers of patients in Colombia with chronic diseases. Materials and Methods: A cross-sectional study of 652 family caregivers of patients with chronic diseases who reside in five regions of Colombia was conducted to establish construct validity, with a factor analysis and internal consistency reliability measured by determining the Cronbach's alpha value. Result: In terms of construct validity, the study reports the total loading, based on free association of a varimax rotation, and in the dimensions that include interpersonal burden, impact of care, and skills and expectations about care. The factor loadings pertain to the items introduced to measure each of the proposed dimensions. Conclusion: The results showed the 22-item Spanish version of the Zarit Burden Interview is an instrument that can be applied and understood easily in a Colombian population with different educational, socio-economic and cultural levels. It also proved to be valid and reliable for assessing the burden of care perceived by family caregivers of patients with chronic diseases.

Objetivo: determinar a validade e confiabilidade da Entrevista de Percepção de Carga do Cuidado de Zarit, versão de 22 itens em espanhol, com cuidadores familiares de pessoas com doenças crônicas na Colômbia. Materiais e métodos: estudo metodológico de corte transversal, com 652 cuidadores familiares de pessoas com doenças crônicas, residentes nas cinco regiões da Colômbia, para estabelecer a validade de constructo, com uma análise fatorial, e a confiabilidade por meio da consistência interna que determina o alfa de Cronbach. Resultado: a respeito da validade de constructo, o estudo relata, a partir da associação livre da rotação Varimax, a carga total, e em suas dimensões que incluem carga interpessoal, impacto do cuidado, bem como as competências e expectativas sobre o cuidado. As cargas fatoriais correspondem aos itens apresentados para mediar cada uma das dimensões propostas. Conclusão: o instrumento Entrevista de Percepção de Carga do Cuidado de Zarit, versão de 22 itens em espanhol, é uma ferramenta de fácil aplicação e compreensão em população colombiana de diferente nível educativo, socioeconômico e cultural; além disso, mostrou ser válido e confiável para avaliar a carga do cuidado em cuidadores familiares de pessoas com doença crônica.

[Hirayama disease in paediatrics: a clinical case report and review of the literature]. / Enfermedad de Hirayama en pediatría: aportación de un caso clínico y revisión de la bibliografía.

INTRODUCTION: Hirayama disease is a rare children's muscular atrophy that affects young Asian males, with muscular atrophy usually in one of the upper limbs that progresses slowly and later stabilises. It is diagnosed by means of electromyographic/electroneurographic with conduction speed studies (EMG/ENG-CS) and by magnetic resonance imaging (MRI) of the spinal cord in a neutral position and with cervical flexion. Treatment is based on the cervical collar and surgery (severe cases). Very few studies have been conducted on patients at the paediatric age. CASE REPORT: We report the case of a 7-year-old girl with atrophy of the muscles of the left hand and forearm, and a disease history of two years. The EMG/ENG-CS scans presented signs of very severe chronic denervation in the myotomes of C7, C8 and T1 on the left side, with conservation of the amplitudes of sensory evoked potentials, consistent with cervical myelopathy. Results of an MRI scan of the cervical spinal cord in a neutral position were normal at that level. Later, owing to suspicions pointing towards Hirayama disease, a new MRI scan of the cervical spinal cord was performed in a neutral position and in flexion. This second scan showed asymmetry in the size and morphology of the anterior funiculi of the spinal cord at C6/C7, hypersignal in the homolateral anterior horn and ingurgitation of the posterior epidural venous plexus. With a diagnosis of Hirayama disease, treatment is started with a cervical collar in order to prevent the damage from getting worse. CONCLUSIONS: This case of Hirayama disease is peculiar due to its epidemiological characteristics and is presented here with the aim of making this entity more widely known in our milieu. If diagnosed at an early stage, treatment is effective, and the studies conducted on children at the paediatric age are reviewed.

TITLE: Enfermedad de Hirayama en pediatria: aportacion de un caso clinico y revision de la bibliografia.Introduccion. La enfermedad de Hirayama es una rara atrofia muscular juvenil que afecta a varones jovenes de origen asiatico, con atrofia muscular habitualmente de una de las extremidades superiores de progresion lenta con estabilizacion posterior. Se diagnostica por estudios electromiograficos/electroneurograficos con velocidad de conduccion (EMG/ENG-VC), y por resonancia magnetica (RM) medular en posicion neutra y en flexion cervical. El tratamiento se basa en el collarin cervical y cirugia (casos graves). Son muy pocos los estudios realizados en edad pediatrica. Caso clinico. Niña de 7 años, con atrofia de la musculatura de la mano y el antebrazo izquierdos, de dos años de evolucion. En EMG/ENG-VC presenta signos de denervacion cronica muy grave en los miotomos correspondientes a C7, C8 y D1 izquierdos, con conservacion de amplitudes de potenciales sensitivos evocados, congruentes con mielopatia cervical. La RM medular cervical en posicion neutra muestra un resultado normal en ese nivel. Posteriormente, por la sospecha dirigida de enfermedad de Hirayama, se realiza una nueva RM medular cervical en posicion neutra y en flexion, que muestra asimetria en el tamaño y morfologia de los cordones anteriores medulares en C6/C7, hiperseñal en el asta anterior homolateral e ingurgitacion del plexo venoso epidural posterior. Con el diagnostico de enfermedad de Hirayama se inicia tratamiento con collarin cervical para evitar la progresion del daño. Conclusiones. Se presenta un caso de enfermedad de Hirayama peculiar por las caracteristicas epidemiologicas, con la finalidad de difundir esta entidad en nuestro medio, cuyo diagnostico precoz permite un tratamiento eficaz, y se revisan los estudios realizados en edad pediatrica.

Kv7 channels critically determine coronary artery reactivity: left-right differences and down-regulation by hyperglycaemia.

AIMS: Voltage-gated potassium channels encoded by KCNQ genes (Kv7 channels) are emerging as important regulators of vascular tone. In this study, we analysed the contribution of Kv7 channels to the vasodilation induced by hypoxia and the cyclic AMP pathway in the coronary circulation. We also assessed their regional distribution and possible impairment by diabetes. METHODS AND RESULTS: We examined the effects of Kv7 channel modulators on K+ currents and vascular reactivity in rat left and right coronary arteries (LCAs and RCAs, respectively). Currents from LCA were more sensitive to Kv7 channel inhibitors (XE991, linopirdine) and activators (flupirtine, retigabine) than those from RCA. Accordingly, LCAs were more sensitive than RCAs to the relaxation induced by Kv7 channel enhancers. Likewise, relaxation induced by the adenylyl cyclase activator forskolin and hypoxia, which were mediated through Kv7 channel activation, were greater in LCA than in RCA. KCNQ1 and KCNQ5 expression was markedly higher in LCA than in RCA. After incubation with high glucose (HG, 30 mmol/L), myocytes from LCA, but not from RCA, were more depolarized and showed reduced Kv7 currents. In HG-incubated LCA, the effects of Kv7 channel modulators and forskolin were diminished, and the expression of KCNQ1 and KCNQ5 was reduced. Finally, vascular responses induced by Kv7 channel modulators were impaired in LCA, but not in RCA, from type 1 diabetic rats. CONCLUSION: Our results reveal that the high expression and function of Kv7 channels in the LCA and their down-regulation by diabetes critically determine the sensitivity to key regulators of coronary tone.

[Neurological complications in the population of children with leukaemia]. / Complicaciones neurológicas en población infantil con leucemia.

INTRODUCTION: Leukaemia is the most frequent type of cancer at the paediatric age. The cure rate is 80% with intensive chemotherapy, which improves survival but also often increases the frequency of adverse side effects, including those of a neurological nature. AIMS: To describe the frequency and characteristics of the neurological complications (NC) in patients with acute lymphoid leukaemia (ALL) and acute myeloid leukaemia (AML), as well as to identify factors associated to their presence, neurological morbidity and survival rate. PATIENTS AND METHODS: A retrospective study was conducted of the NC present in patients with ALL and AML between 1997 and 2012 treated and followed up by the child onco-haematology unit. The following variables were analysed: demographic data, oncological diagnosis, treatment and NC. RESULTS: Altogether 157 patients were included, 145 without infiltration of the central nervous system at diagnosis and eight with infiltration (rate of NC of 14% and 12%, respectively). The most frequent NC were: neuropathies (31%), altered levels of consciousness (27%), convulsions (22%) and headache (12%). Forty per cent of the patients with NC presented sequelae but none of them died as a consequence of the NC. More NC were detected in the age group of children aged under 6 years with high-degree ALL, at higher levels of severity and in patients who had received a haematopoietic stem-cell transplant, all of them with statistically significant differences. CONCLUSIONS: Neurological complications are common in patients with acute leukaemia, especially in those at a high-risk stage (above all if they are under the age of 6 years) and with haematopoietic stem-cell transplant. The associated mortality rate is low.

TITLE: Complicaciones neurologicas en poblacion infantil con leucemia.Introduccion. La leucemia es el cancer mas frecuente en edad pediatrica. Su tasa de curacion es del 80% con quimioterapia intensiva, que mejora la supervivencia, pero que tambien aumenta la frecuencia de efectos adversos, incluyendo los neurologicos. Objetivos. Describir la frecuencia y caracteristicas de las complicaciones neurologicas (CN) en pacientes con leucemia aguda linfoide (LAL) y leucemia aguda mieloide (LAM), e identificar los factores asociados a su presencia, la tasa de morbilidad neurologica y la supervivencia. Pacientes y metodos. Estudio retrospectivo de las CN presentes durante el tratamiento y seguimiento de los pacientes con LAL y LAM entre 1997 y 2012 por la unidad de oncohematologia infantil. Variables analizadas: datos demograficos, diagnostico oncologico, tratamiento y CN. Resultados. Se incluyo un total de 157 pacientes, 145 sin infiltracion de sistema nervioso central al diagnostico y ocho con infiltracion (tasa de CN del 14 y 12%, respectivamente). Las CN mas frecuentes fueron: neuropatias (31%), alteracion del nivel de conciencia (27%), convulsiones (22%) y cefalea (12%). Un 40% de los pacientes con CN ha presentado secuelas, pero ninguno ha fallecido como consecuencia de la CN. Se han detectado mas CN en el grupo de edad menor de 6 años con LAL de alto grado, en niveles de gravedad mas altos y en pacientes que habian recibido trasplante de precursores hematopoyeticos, todas ellas con diferencias estadisticamente significativas. Conclusiones. Las complicaciones neurologicas son frecuentes en los pacientes con leucemia aguda, en especial en aquellos con estadio de riesgo alto (sobre todo si son menores de 6 años) y trasplante de precursores hematopoyeticos. La mortalidad asociada es baja.

Recombinant human leptin treatment in genetic lipodystrophic syndromes: the long-term Spanish experience.

Lipodystrophies are a group of diseases mainly characterized by a loss of adipose tissue and frequently associated with insulin resistance, hypertriglyceridemia, and hepatic steatosis. In uncommon lipodystrophies, these complications frequently are difficult to control with conventional therapeutic approaches. This retrospective study addressed the effectiveness of recombinant methionyl leptin (metreleptin) for improving glucose metabolism, lipid profile, and hepatic steatosis in patients with genetic lipodystrophic syndromes. We studied nine patients (five females and four males) with genetic lipodystrophies [seven with Berardinelli-Seip syndrome, one with atypical progeroid syndrome, and one with type 2 familial partial lipodystrophy (FPLD)]. Six patients were children under age 9 years, and all patients had baseline triglycerides levels >2.26 mmol/L and hepatic steatosis; six had poorly controlled diabetes mellitus. Metreleptin was self-administered subcutaneously daily at a final dose that ranged between 0.05 and 0.24 mg/(kg day) [median: 0.08 mg/(kg day)] according to the body weight. The duration of treatment ranged from 9 months to 5 years, 9 months (median: 3 years). Plasma glucose, hemoglobin A1c (Hb A1c), lipid profile, plasma insulin and leptin, and hepatic enzymes were evaluated at baseline and at least every 6 months. Except for the patient with FPLD, metreleptin replacement significantly improved metabolic control (Hb A1c: from 10.4 to 7.1 %, p < 0.05). Plasma triglycerides were reduced 76 % on average, and hepatic enzymes decreased more than 65 %. This study extends knowledge about metreleptin replacement in genetic lipodystrophies, bearing out its effectiveness for long periods of time.

The flavonoid quercetin induces acute vasodilator effects in healthy volunteers: correlation with beta-glucuronidase activity.

UNLABELLED: Quercetin exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in hypertensive humans and animal models. We hypothesized that oral quercetin might induce vasodilator effects in humans and that they might be related to the deconjugation of quercetin-3-O-glucuronide (Q3GA). DESIGN: double blind, randomized, placebo-controlled trial. Fifteen healthy volunteers (26±5 years, 6 female) were given a capsule containing placebo, 200 or 400mg of quercetin in random order in three consecutive weeks. At 2h a dose-dependent increase in Q3GA was observed in plasma (∼0.4 and 1µM for 200 and 400mg, respectively) with minor levels of quercetin and isorhamnetin. No changes were observed in blood pressure. At 5h quercetin induced and increase in brachial arterial diameter that correlated with the product of the levels of Q3GA by the plasma glucuronidase activity. There was an increase in urinary levels of glutathione but there was no increase in nitrites plus nitrates. Quercetin and isorhamnetin also relaxed human umbilical arteries in vitro while Q3GA was without effect. In conclusions, quercetin exerts acute vasodilator effects in vivo in normotensive, normocholesterolemic human subjects. These results are consistent with the effects being due to the deconjugation of the metabolite Q3GA.

The probiotic Lactobacillus coryniformis CECT5711 reduces the vascular pro-oxidant and pro-inflammatory status in obese mice.

Obesity is associated with intestine dysbiosis and is characterized by a low-grade inflammatory status, which affects vascular function. In the present study, we evaluated the effects of a probiotic with immunomodulatory properties, Lactobacillus coryniformis CECT5711, in obese mice fed on an HFD (high-fat diet). The probiotic treatment was given for 12 weeks, and it did not affect the weight evolution, although it reduced basal glycaemia and insulin resistance. L. coryniformis administration to HFD-induced obese mice induced marked changes in microbiota composition and reduced the metabolic endotoxaemia as it decreased the LPS (lipopolysaccharide) plasma level, which was associated with a significant improvement in gut barrier disruption. Furthermore, it lowered TNFα (tumour necrosis factor α) expression in liver, improving the inflammatory status, and thus the glucose metabolism. Additionally, the probiotic reversed the endothelial dysfunction observed in obese mice when endothelium- and NO (nitric oxide)-dependent vasodilatation induced by acetylcholine in aortic rings was studied. It also restored the increased vessel superoxide levels observed in obese mice, by reducing NADPH oxidase activity and increasing antioxidant enzymes. Moreover, chronic probiotic administration for 2 weeks also improved endothelial dysfunction and vascular oxidative stress induced by in vivo administration of LPS in control mice fed on a standard chow diet. The results of the present study demonstrate an endothelial-protective effect of L. coryniformis CECT5711 in obese mice by increasing NO bioavailability, suggesting the therapeutic potential of this gut microbiota manipulation to prevent vasculopathy in obesity.