Espondiloencondrodisplasia con desregulación inmune relacionada a ACP5. Reporte de cuatro casos / Spondyloenchondrodysplasia with immune dysregulation related to ACP5. A report of 4 cases

La espondiloencondrodisplasia con desregulación inmune relacionada a ACP5 (SPENCDI #607944, por la sigla de spondyloenchondrodysplasia with immune dysregulation y el número que le corresponde en OMIM, Online Mendelian Inheritance in Man) es una displasia inmuno-ósea poco frecuente con manifestaciones heterogéneas y gravedad variable. Presenta lesiones espondilometafisarias, disfunción inmune y compromiso neurológico. Se reportan aspectos clínicos, radiológicos y genéticos de cuatro niñas con SPENCDI en un hospital pediátrico. Todas presentaron manifestaciones esqueléticas y tres de ellas enfermedad inmunológica grave. Se encontró en tres pacientes la variante probablemente patogénica c.791T>A; p.Met264Lys en homocigosis, y en una paciente las variantes c.791T>A; p.Met264Lys y c.632T>C; p.lle211Thr (variante de significado incierto con predicción patogénica según algoritmos bioinformáticos) en heterocigosis compuesta en ACP5. La presencia de la variante repetida c.791T>A sugiere la posibilidad de un ancestro en común en nuestra población. El reconocimiento y diagnóstico de esta entidad es importante para lograr un oportuno abordaje, que deberá ser multidisciplinario, orientado hacia la prevención de posibles complicaciones.

Spondyloenchondrodysplasia with immune dysregulation related to ACP5 (SPENCDI, OMIM number 607944) is an uncommon immune-skeletal dysplasia with heterogeneous manifestations and variable severity. It is characterized by spondylar and metaphyseal lesions, immune dysfunction, and neurological involvement. Here we report the clinical, radiological and genetic aspects of 4 girls with SPENCDI treated at a children's hospital. They all had skeletal manifestations and 3 developed severe immune disease. In 3 patients, the likely pathogenic variant c.791T>A; p.Met264Lys (homozygous mutation) was observed, while 1 patient had variants c.791T>A; p.Met264Lys and c.632T>C; p.lle211Thr (variant of uncertain significance with pathogenic prediction based on bioinformatics algorithms) caused by a compound heterozygous mutation in ACP5. The repeated presence of variant c.791T>A suggests the possibility of a common ancestor in our population. The recognition and diagnosis of this disorder is important to achieve a timely approach, which should be multidisciplinary and aimed at preventing possible complications.

Spondyloenchondrodysplasia with immune dysregulation related to ACP5. A report of 4 cases. / Espondiloencondrodisplasia con desregulación inmune relacionada a ACP5. Reporte de cuatro casos.

Spondyloenchondrodysplasia with immune dysregulation related to ACP5 (SPENCDI, OMIM number 607944) is an uncommon immune-skeletal dysplasia with heterogeneous manifestations and variable severity. It is characterized by spondylar and metaphyseal lesions, immune dysfunction, and neurological involvement. Here we report the clinical, radiological and genetic aspects of 4 girls with SPENCDI treated at a children's hospital. They all had skeletal manifestations and 3 developed severe immune disease. In 3 patients, the likely pathogenic variant c.791T>A; p.Met264Lys (homozygous mutation) was observed, while 1 patient had variants c.791T>A; p.Met264Lys and c.632T>C; p.lle211Thr (variant of uncertain significance with pathogenic prediction based on bioinformatics algorithms) caused by a compound heterozygous mutation in ACP5. The repeated presence of variant c.791T>A suggests the possibility of a common ancestor in our population. The recognition and diagnosis of this disorder is important to achieve a timely approach, which should be multidisciplinary and aimed at preventing possible complications.

La espondiloencondrodisplasia con desregulación inmune relacionada a ACP5 (SPENCDI #607944, por la sigla de spondyloenchondrodysplasia with immune dysregulation y el número que le corresponde en OMIM, Online Mendelian Inheritance in Man) es una displasia inmuno-ósea poco frecuente con manifestaciones heterogéneas y gravedad variable. Presenta lesiones espondilometafisarias, disfunción inmune y compromiso neurológico. Se reportan aspectos clínicos, radiológicos y genéticos de cuatro niñas con SPENCDI en un hospital pediátrico. Todas presentaron manifestaciones esqueléticas y tres de ellas enfermedad inmunológica grave. Se encontró en tres pacientes la variante probablemente patogénica c.791T>A; p.Met264Lys en homocigosis, y en una paciente las variantes c.791T>A; p.Met264Lys y c.632T>C; p.lle211Thr (variante de significado incierto con predicción patogénica según algoritmos bioinformáticos) en heterocigosis compuesta en ACP5. La presencia de la variante repetida c.791T>A sugiere la posibilidad de un ancestro en común en nuestra población. El reconocimiento y diagnóstico de esta entidad es importante para lograr un oportuno abordaje, que deberá ser multidisciplinario, orientado hacia la prevención de posibles complicaciones.

Perfil de atención de pacientes con errores congénitos del metabolismo en un hospital pediátrico entre 2008 y 2018 / Profile of care of patients with inborn errors of metabolism in a pediatric hospital between 2008 and 2018 / Perfil do atendimento de pacientes com erros inatos do metabolismo em um hospital pediátrico entre 2008 e 2018

Resumen Los errores congénitos del metabolismo (ECM) son un grupo de enfermedades poco frecuentes que generan gran morbimortalidad. El objetivo de este trabajo fue describir el perfil de atención clínico y bioquímico de los ECM no incluidos en la pesquisa neonatal en menores de 15 años atendidos en un hospital pediátrico, entre enero de 2008 y diciembre de 2018. Se realizó un estudio descriptivo y retrospectivo en el que se evaluaron los registros hospitalarios: motivo de consulta, diagnóstico, evolución clínica, tiempos y costos diagnósticos de pacientes con sospecha y diagnóstico confirmado de ECM entre 2008 y 2018 en un hospital público pediátrico de Mendoza, Argentina. Se incluyeron 59 pacientes con ECM: enfermedades de depósito lisosomal (32,2%) y alteración metabólica de aminoácidos y acidurias orgánicas (27,1%), entre otros. La edad media fue de 2,6 años y la relación varón/mujer 1,5. La media de tiempo entre la primera consulta por sospecha de ECM y el diagnóstico fue de 11 meses. Hubo correspondencia entre el diagnóstico y el motivo de consulta (p=0,003). El 22% evolucionó al deterioro progresivo, 25,4% permanecieron estables, 28,8% con secuelas y 23,8% fallecieron. El costo directo total de los exámenes bioquímicos fue 61 560 UB=1 809 248 pesos argentinos=46 785 dólares estadounidenses (valor a finales de 2018). En conclusión, este trabajo refleja la variabilidad de los ECM, su evolución clínica, similar a lo publicado y el perfil bioquímico local.

Abstract Inborn errors of metabolism (IEM) are a group of rare diseases that cause high morbidity and mortality. The objective of the present study was to describe the clinical-biochemical profile of patients, under 15 years old, with IEM not included in newborn screening, in a pediatric hospital, from January 2008 to December 2018. A descriptive and retrospective study was carried out in which hospital records were evaluated: reason for consultation, diagnosis, clinical evolution, diagnostic times and costs of patients with suspected and confirmed diagnosis of IEM between 2008 and 2018 in a public pediatric hospital from Mendoza, Argentina. A total of 59 patients with IEM were evaluated: lysosomal storage diseases (32.2%) and metabolic alteration of amino acids and organic acidurias (27.1%), among others. The mean age was 2.6 years and the male/female ratio was 1.5. The mean time between the first consultation for suspected IEM and diagnosis was 11 months. There was correspondence between the diagnosis and the reason for consultation (p=0.003). Twenty-two percent evolved to progressive deterioration, 25.4% remained stable, 28.8% with sequelae and 23.8% died. The total direct cost of the biochemical tests was 61 560 UB=1 809 248 Argentine pesos=46 785 US dollars (value at the end of 2018). Concluding, this work reflects the variability of IEM and its clinical evolution, similar to what has been published, and the local biochemical profile.

Resumo Os erros inatos do metabolismo (EIM) são um grupo de doenças pouco frequentes que geram alta morbimortalidade. O objetivo deste trabalho foi descrever o perfil clínico e bioquímico de atendimento dos EIM não incluídos na triagem neonatal em menores de 15 anos atendidos em um hospital pediátrico, entre janeiro de 2008 e dezembro de 2018. Foi realizado um estudo descritivo e retrospectivo em que foram avaliados os registros hospitalares: motivo da consulta, diagnóstico, evolução clínica, tempos e custos diagnósticos de pacientes com diagnóstico suspeito e confirmado de EIM entre 2008 e 2018 em um hospital pediátrico público em Mendoza, Argentina. Foram avaliados 59 pacientes com EIM: doenças de depósito lisossômico (32,2%) e alteração metabólica de aminoácidos e acidúrias orgânicas (27,1%), entre outras. A média de idade foi de 2,6 anos e a relação homem/mulher foi de 1,5. O tempo médio entre a primeira consulta por suspeita de EIM e o diagnóstico foi de 11 meses. Houve correspondência entre o diagnóstico e o motivo da consulta (p=0,003). Evoluíram 22% para piora progressiva, 25,4% permaneceram estáveis , 28,8% com sequelas e 23,8% faleceram. O custo direto total dos testes bioquímicos foi de 61 560 UB=1 809 248 pesos argentinos=46 785 U$S (valor no final de 2018). Concluindo, este trabalho reflete a variabilidade da EIM e sua evolução clínica, semelhante ao que vem sendo publicado, e o perfil bioquímico local.

Translation, cultural adaptation and evaluation of the psychometric properties of the Hamilton Anxiety Scale among a sample of Portuguese adult patients with mental health disorders.

BACKGROUND: Only a few anxiety assessment tools that nurses may administer are validated forthe Portuguese population exist in the literature. Thus, this study aimed to translate and culturally adapt the Hamilton Anxiety Scale for the Portuguese population and assess its psychometric properties in a sample of adult people with mental health disorders. METHODS: This psychometric study uses a convenience sample of adult patients with mental health disorders. RESULTS: The confirmatory factor analysis confirmed the two factors of the original version of the tool. The internal consistency (Cronbach's alpha) was high, at .92, as well as the inter-rater reliability (intraclass correlation coefficient) (.91). CONCLUSIONS: The validity and reliability of the instrument are supported. However, the Hamilton Anxiety Scale should be used cautiously in the Portuguese population because the correlation with the "Anxiety State" subscale of the State-Trait Anxiety Inventory is not statistically significant.

Tradução, adaptação cultural e avaliação das propriedades psicométricas da escala de ansiedade de Hamilton numa amostra de pessoas adultas com doença mental da população portuguesa / Translation, cultural adaptation and evaluation of the psychometric properties of the Hamilton anxiety scale among a sam ple of portuguese adult patients with mental disorders

Enquadramento: A temática da ansiedade está cada vez mais presente na sociedade atual, em consequência do ritmo de vida mais stressante e face às expetativas elevadas de cada um. Apesar de a ansiedade ser uma emoção que estimula a reação e funciona como alerta para que a pessoa possa lidar com a ameaça e estimule a capacidade de realizar as atividades exigidas no quotidiano, qua ndo esta se torna excessiva pode manifestar se de forma negativa e tornar se patológica, por isso, é um problema muito relevante a nível mundial e nacional. Existem várias escalas de avaliação de ansiedade validadas para Portugal, no entanto a Escala de An siedade de Hamilton, instrumento muito usado a nível internacional, não está validada, motivo pelo qual parece pertinente a realização deste estudo Objetivos: Traduzir e adaptar culturalmente a Escala de Ansiedade de Hamilton para a população portuguesa e avaliar as suas propriedades psicométricas. Métodos: Estudo psicométrico, com amostragem não probabilística por conveniência. Numa primeira fase foi realizado o processo de tradução e adaptação cultural do instrumento para a população portuguesa e numa se gunda fase a avaliação das propriedades psicométricas do mesmo. Resultados: Foi realizada a tradução e adaptação cultural do instrumento e avaliadas as propriedades psicométricas. Foi avaliada a validade de construto, por via da análise fatorial confirmató ria que confirmou a exist ên cia de duas dimensões, assim como na versão original. A análise da validade convergente, com recurso à correlação de Pearson, revelou validade convergente com o STAI Ansiedade Traço e ausência de validade convergente com o STAI Estado . No que concerne à fiabilidade, foi avaliada a consistência interna da escala global, por via do alfa de Cronbach ( α=0,92 ), e a concordância entre observadores, por via do coeficiente de correlação intraclasse (ICC=0,91). Conclusões: O estudo p ermitiu a tradução e adaptação cultural do instrumento e revelou que este apresenta boas propriedades psicométricas. Con tudo, n ão havendo validade convergente com um instrumento que, em teoria, avalia o mesmo constructo e se encontra já validado para a pop ulação portuguesa (STAI Estado), deve usar se a Hamilton com alguma prudência, até que novos estudos que permitam esta comparação venham a ser realizados.

Background: The theme of anxiety is increasingly present in today's society, as a result of the more stressful pace of life and given the high expectations of each person. Although anxiety is an emotion that stimulates the reacti on and works as an alert so that a person can deal with the threat and stimulate the ability to perform the activities required in daily life, when it becomes excessive it can manifest itself in a negative way and become pathological. Therefore, it is a ve ry relevant problem at a global and national level. There are several anxiety assessment scales validated for Portugal, however the Hamilton Anxiety Scale, an instrument widely used internationally, is not validated, which is why it seems important to carr y out this study. Objectives: To translate and culturally adapt the Hamilton Anxiety Scale for the Portuguese population and to assess its psychometric properties. Methods: Psychometric study, with non probabilistic convenience sample. In a first phase, th e process of translation and cultural adaptation of the instrument for the Portuguese population was carried out, and in a second phase, the evaluation of its psychometric properties. Results: The translation and cultural adaptation of the instrument was carried out and its psychometric properties were evaluated. Construct validity was assessed through confirmatory factor analysis, which confirmed the existence of two dimensions, as in the original version. The analysis of the convergent val idity, using Pearson's correlation, revealed a convergent validity with the STAI Trait Anxiety and an absence of convergent validity with the STAI State Anxiety. Regarding reliability, the internal consistency of the global scale was evaluated, via Cronbac h's alpha (α=0,92), and interobserver agreement, via the intraclass correlation coefficient (ICC=0,91). Conclusions: The study allowed the translation and cultural adaptation of the instrument and revealed that it has good psychometric properties. However, since there is no convergent validity with an instrument that, in theory, evaluates the same construct and is already validated for the Portuguese population (STAI State), Hamilton should be used with some caution, until further studies allow this compari son are to be carried out.

Methamphetamine pollution elicits addiction in wild fish.

Illicit drug abuse presents pervasive adverse consequences for human societies around the world. Illicit drug consumption also plays an unexpected role in contamination of aquatic ecosystems that receive wastewater discharges. Here, we show that methamphetamine, considered as one of the most important global health threats, causes addiction and behavior alteration of brown trout Salmo trutta at environmentally relevant concentrations (1 µg l-1). Altered movement behavior and preference for methamphetamine during withdrawal were linked to drug residues in fish brain tissues and accompanied by brain metabolome changes. Our results suggest that emission of illicit drugs into freshwater ecosystems causes addiction in fish and modifies habitat preferences with unexpected adverse consequences of relevance at the individual and population levels. As such, our study identifies transmission of human societal problems to aquatic ecosystems.

Julbernardia paniculata and Pterocarpus angolensis: From Ethnobotanical Surveys to Phytochemical Characterization and Bioactivities Evaluation.

Julbernardia paniculata and Pterocarpus angolensis are two plant species with important application in African traditional medicine, particularly in Angola, in the treatment of several diseases. However, scientific studies concerning these species are scarce. The goal of this work was to know better which medicinal approaches are used by the Huíla population in Angola by means of ethnobotanical surveys. Furthermore, extracts of both plants were phytochemically characterized. Antioxidant, anti-inflammatory, wound-healing activities, and potential cytotoxicity were also studied. With this study it was possible to verify that 67% of the individuals that use medicinal plants are women, and their main therapeutic uses are the treatment of problems of the digestive system and skin disorders. Barks of J. paniculata and leaves of P. angolensis are the most often used plant parts. Through high-performance liquid chromatography coupled to diode-array detector (HPLC-DAD) and GC-MS it was possible to characterize the chemical composition of the two species, which are rich in phenolic compounds, terpenes, terpenoids, sesquiterpenoids and fatty acids. Both plants showed to possess antioxidant, anti-inflammatory proprieties, and wound-healing activity. To the best of our knowledge, this is the most comprehensive study of these two species and the first ethnobotanical and ethnopharmacological study of medicinal plants from this region of Angola.

The Loop of the TPR1 Subdomain of Phi29 DNA Polymerase Plays a Pivotal Role in Primer-Terminus Stabilization at the Polymerization Active Site.

Bacteriophage Phi29 DNA polymerase belongs to the protein-primed subgroup of family B DNA polymerases that use a terminal protein (TP) as a primer to initiate genome replication. The resolution of the crystallographic structure showed that it consists of an N-terminal domain with the exonuclease activity and a C-terminal polymerization domain. It also has two subdomains specific of the protein-primed DNA polymerases; the TP Regions 1 (TPR1) that interacts with TP and DNA, and 2 (TPR2), that couples both processivity and strand displacement to the enzyme. The superimposition of the structures of the apo polymerase and the polymerase in the polymerase/TP heterodimer shows that the structural changes are restricted almost to the TPR1 loop (residues 304-314). In order to study the role of this loop in binding the DNA and the TP, we changed the residues Arg306, Arg308, Phe309, Tyr310, and Lys311 into alanine, and also made the deletion mutant Δ6 lacking residues Arg306-Lys311. The results show a defective TP binding capacity in mutants R306A, F309A, Y310A, and Δ6. The additional impaired primer-terminus stabilization at the polymerization active site in mutants Y310A and Δ6 allows us to propose a role for the Phi29 DNA polymerase TPR1 loop in the proper positioning of the DNA and TP-priming 3'-OH termini at the preinsertion site of the polymerase to enable efficient initiation and further elongation steps during Phi29 TP-DNA replication.

Equivalence class formation via class-specific consequences in children diagnosed with autism spectrum disorder / Formação de classes de equivalência via consequências específicas das classes em crianças diagnosticadas com transtorno do espectro do autismo / Formación de clases equivalentes a través de consecuencias específicas de clase en niños diagnosticados con trastorno del espectro autista

Previous equivalence-class formation studies, with class-specific consequences, found inter-subject variability, probably due to loss of efficacy of the consequences as reinforcers. This study evaluated (a) the efficacy of introducing variations of events (within a category) as class-specific consequences and (b) the inclusion of these consequences into the equivalence classes. Two children diagnosed with Autism Spectrum Disorder (ASD), and with intellectual disabilities, were given identity matchingto-sample training (Set A - Sample A1, S+A1/S-A2 and Sample A2, S+A2/S-A1) and simple discrimination reversal training (Set B - S+B1/S-B2 and reversals). Two sets of assorted videos on the same theme plus two sets of assorted food items within the same category were used as class-specific consequences. The data show that the variety of elements was efficient to maintain reinforcement efficacy and encourage the use of similar procedures in the applied context. Both participants showed strong evidence of equivalence class formation, confirming the theoretical prediction regarding the inclusion of the class-specific consequences in the classes. The data confirm that equivalence relations can be found in three-term contingencies.

Estudos anteriores sobre a formação de classes de equivalência, com consequências específicas para as classes, apontaram variabilidade intersujeitos provavelmente devida a perda de eficácia das consequências como reforçadores. O presente estudo avaliou (a) a eficácia da introdução de variações de eventos (dentro de uma categoria) como consequências específicas das classes e (b) a inclusão de tais consequências nas classes. Duas crianças diagnosticadas com Transtorno do Espectro do Autismo (TEA), e com deficiência intelectual, foram submetidas a treino de emparelhamento ao modelo (Conjunto A - Modelo A1, S+A1/S-A2 e Modelo A2, S+A2/S-A1) e treino de reversões de discriminações simples (Conjunto B - S+B1/S-B2 e reversões). Dois conjuntos de vídeos variados de um mesmo tema e dois conjuntos de alimentos variados dentro de uma mesma categoria foram usados como consequências específicas. Os dados mostram que a variedade de elementos foi eficiente para manter a eficácia do reforçamento e encoraja o uso de procedimentos similares em contexto aplicado. Ambos os participantes mostraram forte evidência de formação de classes de equivalência, confirmando a predição teórica sobre a inclusão de consequências específicas nas classes. Os dados confirmam que relações de equivalência podem ser encontradas em contingências de três termos.

Estudios previos de formación de clases de equivalencia, con consecuencia específica de clase, encontraron variabilidad interindividual probablemente debido a la pérdida de eficacia de las consecuencias como reforzadores. Este estudio evaluó (a) la eficacia de la introducción de variaciones de eventos (dentro de una categoría) como consecuencias específicas de clase y (b) la inclusión de tales consecuencias en las clases de equivalencia. Dos niños diagnosticados con Trastorno del Espectro Autista y con discapacidad intelectual, recibieran entrenamiento de igualación de identidad a la muestra (Conjunto A - Muestra A1, S+A1/S-A1 y Muestra A2, S+A2/S-A1) y entrenamiento de inversión de la discriminación simple (Conjunto B - S+B1/S-B2 y inversiones). Se utilizaron dos conjuntos de vídeos diversos de un mismo tema, más dos conjuntos de alimentos diversos dentro de la misma categoría como consecuencias específicas de clase. Los datos muestran que la variedad de elementos fue eficiente para mantener la eficacia del refuerzo y fomentan el uso de procedimientos similares en contexto aplicado. Ambos los participantes mostraron una fuerte evidencia de la formación de clases de equivalencia, lo que confirma la predicción teórica sobre la inclusión de las consecuencias específicas de clase en las clases de equivalencia. Los datos confirman que las relaciones de equivalencia pueden ser encontradas en las contingencias de tres términos.

Equivalence class formation via class-specific consequences in children diagnosed with autism spectrum disorder / Formação de classes de equivalência via consequências específicas das classes em crianças diagnosticadas com transtorno do espectro do autismo / Formación de clases equivalentes a través de consecuencias específicas de clase en niños diagnosticados con trastorno del espectro autista

Previous equivalence-class formation studies, with class-specific consequences, found inter-subject variability, probably due to loss of efficacy of the consequences as reinforcers. This study evaluated (a) the effi cacy of introducing variations of events (within a category) as class-specific consequences and (b) the inclusion of these consequences into the equivalence classes. Two children diagnosed with Autism Spectrum Disorder (ASD), and with intellectual disabilities, were given identity matchingto-sample training (Set A – Sample A1, S+A1/S-A2 and Sample A2, S+A2/S-A1) and simple discrimination reversal training (Set B – S+B1/S-B2 and reversals). Two sets of assorted videos on the same theme plus two sets of assorted food items within the same category were used as class-specific consequences. The data show that the variety of elements was efficient to maintain reinforcement efficacy and encourage the use of similar procedures in the applied context. Both participants showed strong evidence of equivalence class formation, confirming the theoretical prediction regarding the inclusion of the class-specific consequences in the classes. The data confirm that equivalence relations can be found in three-term contingencies.(AU)

Estudos anteriores sobre a formação de classes de equivalência, com consequências específicas para as classes, apontaram variabilidade intersujeitos provavelmente devida a perda de eficácia das consequências como reforçadores. O presente estudo avaliou (a) a eficácia da introdução de variações de eventos (dentro de uma categoria) como consequências específicas das classes e (b) a inclusão de tais consequências nas classes. Duas crianças diagnosticadas com Transtorno do Espectro do Autismo (TEA), e com deficiência intelectual, foram submetidas a treino de emparelhamento ao modelo (Conjunto A – Modelo A1, S+A1/S-A2 e Modelo A2, S+A2/S-A1) e treino de reversões de discriminações simples (Conjunto B – S+B1/S-B2 e reversões). Dois conjuntos de vídeos variados de um mesmo tema e dois conjuntos de alimentos variados dentro de uma mesma categoria foram usados como consequências específicas. Os dados mostram que a variedade de elementos foi eficiente para manter a eficácia do reforçamento e encoraja o uso de procedimentos similares em contexto aplicado. Ambos os participantes mostraram forte evidência de formação de classes de equivalência, confirmando a predição teórica sobre a inclusão de consequências específicas nas classes. Os dados confirmam que relações de equivalência podem ser encontradas em contingências de três termos.(AU)

Estudios previos de formación de clases de equivalencia, con consecuencia específi ca de clase, encontraron variabilidad interindividual probablemente debido a la pérdida de efi cacia de las consecuencias como reforzadores. Este estudio evaluó (a) la efi cacia de la introducción de variaciones de eventos (dentro de una categoría) como consecuencias específi cas de clase y (b) la inclusión de tales consecuencias en las clases de equivalencia. Dos niños diagnosticados con Trastorno del Espectro Autista y con discapacidad intelectual, recibieran entrenamiento de igualación de identidad a la muestra (Conjunto A – Muestra A1, S+A1/S-A1 y Muestra A2, S+A2/S-A1) y entrenamiento de inversión de la discriminación simple (Conjunto B – S+B1/S-B2 y inversiones). Se utilizaron dos conjuntos de vídeos diversos de un mismo tema, más dos conjuntos de alimentos diversos dentro de la misma categoría como consecuencias específi cas de clase. Los datos muestran que la variedad de elementos fue efi ciente para mantener la efi cacia del refuerzo y fomentan el uso de procedimientos similares en contexto aplicado. Ambos los participantes mostraron una fuerte evidencia de la formación de clases de equivalencia, lo que confi rma la predicción teórica sobre la inclusión de las consecuencias específi cas de clase en las clases de equivalencia. Los datos confi rman que las relaciones de equivalencia pueden ser encontradas en las contingencias de tres términos.(AU)

Role of the LEXE motif of protein-primed DNA polymerases in the interaction with the incoming nucleotide.

The LEXE motif, conserved in eukaryotic type DNA polymerases, is placed close to the polymerization active site. Previous studies suggested that the second Glu was involved in binding a third noncatalytic ion in bacteriophage RB69 DNA polymerase. In the protein-primed DNA polymerase subgroup, the LEXE motif lacks the first Glu in most cases, but it has a conserved Phe/Trp and a Gly preceding that position. To ascertain the role of those residues, we have analyzed the behavior of mutants at the corresponding ϕ29 DNA polymerase residues Gly-481, Trp-483, Ala-484, and Glu-486. We show that mutations at Gly-481 and Trp-483 hamper insertion of the incoming dNTP in the presence of Mg(2+) ions, a reaction highly improved when Mn(2+) was used as metal activator. These results, together with previous crystallographic resolution of ϕ29 DNA polymerase ternary complex, allow us to infer that Gly-481 and Trp-483 could form a pocket that orients Val-250 to interact with the dNTP. Mutants at Glu-486 are also defective in polymerization and, as mutants at Gly-481 and Trp-483, in the pyrophosphorolytic activity with Mg(2+). Recovery of both reactions with Mn(2+) supports a role for Glu-486 in the interaction with the pyrophosphate moiety of the dNTP.

Compensatory T-cell regulation in unaffected relatives of SLE patients, and opposite IL-2/CD25-mediated effects suggested by coreferentiality modeling.

In human systemic lupus erythematosus (SLE), diverse autoantibodies accumulate over years before disease manifestation. Unaffected relatives of SLE patients frequently share a sustained production of autoantibodies with indiscriminable specificity, usually without ever acquiring the disease. We studied relations of IgG autoantibody profiles and peripheral blood activated regulatory T-cells (aTregs), represented by CD4(+)CD25(bright) T-cells that were regularly 70-90% Foxp3(+). We found consistent positive correlations of broad-range as well as specific SLE-associated IgG with aTreg frequencies within unaffected relatives, but not patients or unrelated controls. Our interpretation: unaffected relatives with shared genetic factors compensated pathogenic effects by aTregs engaged in parallel with the individual autoantibody production. To study this further, we applied a novel analytic approach named coreferentiality that tests the indirect relatedness of parameters in respect to multivariate phenotype data. Results show that independently of their direct correlation, aTreg frequencies and specific SLE-associated IgG were likely functionally related in unaffected relatives: they significantly parallelled each other in their relations to broad-range immunoblot autoantibody profiles. In unaffected relatives, we also found coreferential effects of genetic variation in the loci encoding IL-2 and CD25. A model of CD25 functional genetic effects constructed by coreferentiality maximization suggests that IL-2-CD25 interaction, likely stimulating aTregs in unaffected relatives, had an opposed effect in SLE patients, presumably triggering primarily T-effector cells in this group. Coreferentiality modeling as we do it here could also be useful in other contexts, particularly to explore combined functional genetic effects.

General overview of the Seventh International Symposium on Stem Cell Therapy and Cardiovascular Innovations.

The Seventh International Symposium on Stem Cell Therapy and Cardiovascular Innovations was held in Madrid on the 6th and 7th of May 2010. Gathering for the seventh consecutive year the most relevant researchers and opinion leaders on cardiovascular cell therapy, it has become the most important worldwide event on this field. A comprehensive review of the last developments on cell therapy, surgery for heart failure and tissue engineering was made, and the results of three clinical trials were reported. The Symposium was dedicated to the memory of Professor Helmut Drexler.

Early translation of adipose-derived cell therapy for cardiovascular disease.

Over the past decade, cell therapy has emerged as a new approach to reversing myocardial ischemia. Several types of adult stem cells have been studied in both preclinical and clinical conditions for this purpose: bone marrow cells, circulating cells, and myoblasts. Nevertheless, the quest for the ideal "anti-ischemic" cell is still ongoing. Recently, the existence of a population of stem cells located in adipose tissue (adipose-derived stem cells) has been observed. These are able to differentiate into multiple cell lineages including cardiomyocytic differentiation. In this review we discuss the basic principles of adipose-derived stem cells (types and characteristics, harvesting, and expansion), the initial experimental studies, and the currently ongoing clinical trials.

Low frequency of CD4+CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFbeta gene variants.

BACKGROUND: CD4+CD25+ regulatory T cells play an essential role in maintaining immune homeostasis and preventing autoimmunity. Therefore, defects in Treg development, maintenance or function have been associated with several human autoimmune diseases including Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease characterized by loss of tolerance to nuclear components and significantly more frequent in females. RESULTS: To investigate the involvement of Treg in SLE pathogenesis, we determined the frequency of CD4+CD25+CD45RO+ T cells, which encompass the majority of Treg activity, in the PBMC of 148 SLE patients (76 patients were part of 54 families), 166 relatives and 117 controls. SLE patients and their relatives were recruited in several Portuguese hospitals and through the Portuguese Lupus Association. Control individuals were blood donors recruited from several regional blood donor centers. Treg frequency was significantly lower in SLE patients than healthy controls (z = -6.161, P < 0.00001) and intermediate in the relatives' group. Remarkably, this T cell subset was also lower in females, most strikingly in the control population (z = 4.121, P < 0.001). We further ascertained that the decreased frequency of Treg in SLE patients resulted from the specific reduction of bona fide FOXP3+CD4+CD25+ Treg. Treg frequency was negatively correlated with SLE activity index (SLEDAI) and titers of serum anti-dsDNA antibodies. Both Treg frequency and disease activity were modulated by IVIg treatment in a documented SLE case. The segregation of Treg frequency within the SLE families was indicative of a genetic trait. Candidate gene analysis revealed that specific variants of CTLA4 and TGFbeta were associated with the decreased frequency of Treg in PBMC, while FOXP3 gene variants were associated with affection status, but not with Treg frequency. CONCLUSION: SLE patients have impaired Treg production or maintenance, a trait strongly associated with SLE disease activity and autoantibody titers, and possibly resulting from the inability to convert FOXP3+CD25- into FOXP3+CD25+ T cells. Treg frequency is highly heritable within SLE families, with specific variants of the CTLA4 and TGFbeta genes contributing to this trait, while FOXP3 contributes to SLE through mechanisms not involving a modulation of Treg frequency. These findings establish that the genetic components in SLE pathogenesis include genes related to Treg generation or maintenance.

Heritable factors shape natural human IgM reactivity to Ro60/SS-A and may predispose for SLE-associated IgG anti-Ro and anti-La autoantibody production.

Systemic lupus erythematosus (SLE) is characterized by various IgG autoreactivities, among which anti-Ro/SS-A is particularly pathology-associated and early detectable. SLE also shows significant familial aggregation, but genetic factors are not well understood and remain controversial for disease-associated IgG. Here we report that IgM anti-Ro showed a uniquely high degree of heritability in a study of SLE-affected families. Unlike IgM anti-La or anti-dsDNA, IgM anti-Ro was also significantly correlated to IgG anti-Ro among SLE patients, as well as to IgG anti-La and anti-dsDNA. We conclude that largely genetically determined, thus natural IgM anti-Ro-bearing precursor B-cells, may be an important factor for class switching and determinant spreading in early phases of SLE pathogenesis. Furthermore, we found unexpected sex differences in isotype/specificity correlations among SLE-unaffected relatives and control subjects, which could help understand the strong gender bias associated with SLE. We propose that the study of such correlation structures may reveal characteristic spreading pathways relevant for human SLE.

Lymphadenopathy after BCG vaccination in a child with chronic granulomatous disease.

We report a 15-month-old boy who developed an ulcer in the left axillary fold following bacillus Calmette-Guerin vaccination. Subsequent immunologic and genetic studies led to the diagnosis of chronic granulomatous disease. His mother had "lupus-like" lesions, described in some carriers of this disease, that were thus related to her son's diagnosis. Although in healthy subjects this vaccination is usually harmless, in instances of impaired immunity it may cause adverse reactions. When a vaccine-related complication occurs, an underlying immunodeficiency should be sought.

Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus.

Several lines of evidence implicate the Cytotoxic T Lymphocyte Antigen 4 (CTLA4) gene in susceptibility to autoimmune disease. We have examined the association of systemic lupus erythematosus (SLE) with polymorhisms within the CTLA4 gene that were previously proposed to regulate CTLA-4 function: a single nucleotide polymorphism (SNP) in position +49 of exon 1 and a dinucleotide repeat in the 3' untranslated region (3'UTR). The 3'UTR repeat showed a significant association with SLE, with one allele conferring susceptibility and another conferring protection to the disease. The associated alleles do not support previous suggestions of an allele size-dependent effect of the 3' UTR polymorphism in autoimmunity development and instead suggest that it is in linkage disequilibrium with a true causative locus. No association of the exon 1 SNP with SLE was found in our population. Given the conflicting results obtained in different studies on the association of SLE with this polymorphism, we performed a meta-analysis including seven previously published studies and the present one. Significantly increased and decreased risks for SLE were found for carriers of the G allele and the A allele, respectively. The functional characterization of disease-associated CTLA4 gene variants is now required to elucidate their role in the pathogenesis of SLE and other autoimmune diseases.

Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients.

To describe the clinical and immunologic characteristics of patients with adrenal involvement and antiphospholipid syndrome (APS), we conducted a computer-assisted (PubMed) search of the literature to identify all cases of primary adrenal insufficiency associated with antiphospholipid antibodies published in English, French, and Spanish from 1983 (when APS was first defined) through March 2002. We reviewed 86 patients (80 from the literature plus 6 from our cohort); 55% were male, and the mean age at presentation was 43 +/- 16 years. Sixty-one (71%) patients had primary APS, and 14 (16%) had systemic lupus erythematosus. In 31 (36%) patients, adrenal insufficiency was the first clinical manifestation of APS. Abdominal pain was present in 55% of patients, followed by hypotension (54%), fever (40%), nausea or vomiting (31%), weakness or fatigue (31%), and lethargy or altered mental status (19%). The main finding in imaging techniques was compatible with adrenal hemorrhage (59%) and in histopathologic study was a hemorrhagic infarction with vessel thrombosis (55%). Lupus anticoagulant was detected in 97% of patients and the anticardiolipin antibodies titer was positive in 93% of patients. Most patients (95%) were positive for the IgG isotype of anticardiolipin antibodies, whereas 40% were positive for the IgM isotype. Baseline cortisol levels were decreased in 98% of patients, ACTH hormone levels were increased in 96% of patients, and the cosyntropin stimulation test was positive in 100% of patients tested. Steroid replacement therapy was the most frequent treatment (84%), followed by anticoagulation (52%) and aspirin (6%). Thirty-two of 35 (91%) patients with prolonged anticoagulant therapy were in good health with a mean follow-up of 25 months, whereas 25 of the 69 (36%) patients with outcome data available had died. The results of the present review stress the clinical importance of systematic screening for lupus anticoagulant and anticardiolipin antibodies in all cases of adrenal hemorrhage or infarction. An initial screening for hypoadrenalism is mandatory in any antiphospholipid antibody-positive patient who complains of abdominal pain and undue weakness or asthenia.

A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus.

UNLABELLED: Males with X-linked agammaglobulinaemia (XLA) due to mutations in the Bruton tyrosine kinase gene constitute the major group of congenital hypogammaglobulinaemia with absence of peripheral B cells. In these cases, blockages between the pro-B and pre-B cell stage in the bone marrow are found. The remaining male and female cases clinically similar to XLA represent a genotypically heterogeneous group of diseases. In these patients, various autosomal recessive disorders have been identified such as mutations affecting IGHM, CD79A, IGLL1 genes involved in the composition of the pre-B cell receptor (pre-BCR) or the BLNK gene implicated in pre-BCR signal transduction. In this paper, we report on a young female patient characterised by a severe non-XLA agammaglobulinaemia that represents a new case of Igmu defect. We show that the B cell blockage at the pro-B to pre-B cell transition is due to a large homologous deletion in the IGH locus encompassing the IGHM gene leading to the inability to form a functional pre-BCR. The deletion extends from the beginning of the diversity (D) region to the IGHG2 gene, with all JH segments and IGHM, IGHD, IGHG3 and IGHG1 genes missing. CONCLUSION: alteration in Igmu expression seems to be relatively frequent and could account for most of the reported cases of autosomal recessive agammaglobulinaemia.