Correlation of antigen expression with epigenetic modifications after rAAV delivery of a human factor IX variant in mice and rhesus macaques.

We investigated long-term human coagulation factor IX (huFIX) expression of a novel variant when delivered into mice and rhesus macaques and compared transduction efficiencies using two different adeno-associated virus (AAV) capsids. In hemophilic mice injected with KP1-packaged recombinant AAV (rAAV) expressing the hyperactive FIX variant specific activity plasma levels were 10-fold or 2-fold enhanced when compared with wild-type or Padua huFIX injected mice, respectively. In rhesus macaques AAV-LK03 capsid outperformed AAV-KP1 in terms of antigen expression and liver transduction. Two animals from each group showed sustained low-level huFIX expression at 3 months after administration, while one animal from each group lost huFIX mRNA and protein expression over time, despite comparable vector copies. We investigated whether epigenetic differences in the vector episomes could explain this loss of transcription. Cut&Tag analysis revealed lower levels of activating histone marks in the two animals that lost expression. When comparing rAAV genome associated histone modifications in rhesus macaques with those in mice injected with the same vector, the activating histone marks were starkly decreased in macaque-derived episomes. Differential epigenetic marking of AAV genomes may explain different expression profiles in mice and rhesus macaques, as well as the wide dose response variation observed in primates in both preclinical and human clinical trials.

Mapping the literature on the qualitative approach to childhood asthma from 1996 to 2018: a bibliometric analysis / Mapeo de la literatura sobre el enfoque cualitativo del asma infantil desde 1996 hasta 2018: un análisis bibliométrico

Resumo Objectives: to describe the scientific production of qualitative studies in childhood asthma. Methods: bibliometric analysis. Articles were from Web of Science, Scopus, Cochrane, and PubMed (1996-2018), using the search terms asthma, children, qualitative research, qualitative study, qualitative analysis, ethnographic, phenomenology and narrative. Results: 258 articles were retrieved from 143 journals, representing 1.2% of scientific articles on childhood asthma. The growth rate was high. Authorship included 969 authors (85.3% occasional) from 279 institutions. 94.2% were co-authored and 3.5% were international collaborations. The greatest number of articles were from the United States (45.3%), United Kingdom (17.4%) and Canada (7.4%). The categories with the highest number of articles were Nursing & Public, Environmental & Occupational Health (18.2%), Respiratory System (10.1%) and Allergy (7.7%). 99.7% of the articles were in English. Conclusion: these results show a lack of consolidation of the literature based on qualitative studies on childhood asthma with a high percentage of occasional authors and limited international collaboration, indicating a need to strengthen this approach.

Resumen Objetivos: describir la producción científica de los estudios cualitativos sobre el asma infantil. Métodos: análisis bibliométrico. Los artículos procedían de Web of Science, Scopus, Cochrane y PubMed (1996-2018), utilizando los términos de búsqueda asthma, children, qualitative research, qualitative study, qualitative analysis, ethnographic, phenomenology y narrative. Resultados: se recuperaron 258 artículos de 143 revistas, lo que representa el 1,2% de los artículos científicos sobre asma infantil. La tasa de crecimiento fue elevada. La autoría incluyó 969 autores (85,3% ocasionales) de 279 instituciones. El 94,2% fueron coautores y el 3,5% colaboraciones internacionales. El mayor número de artículos procedió de Estados Unidos (45,3%), Reino Unido (17,4%) y Canadá (7,4%). Las categorías con mayor número de artículos fueron Enfermería y Salud Pública, Ambiental y Ocupacional (18,2%), Aparato Respiratorio (10,1%) y Alergia (7,7%). El 99,7% de los artículos estaban en inglés. Conclusión: estos resultados muestran una falta de consolidación de la literatura basada en estudios cualitativos sobre el asma infantil, con un alto porcentaje de autores ocasionales y una limitada colaboración internacional, lo que indica la necesidad de reforzar este enfoque.

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner.

Recombinant adeno-associated viral vectors (rAAVs) are among the most commonly used vehicles for in vivo based gene therapies. However, it is hard to predict which AAV capsid will provide the most robust expression in human subjects due to the observed discordance in vector-mediated transduction between species. In our study, we use a primate specific capsid, AAV-LK03, to demonstrate that the limitation of this capsid towards transduction of mouse cells is unrelated to cell entry and nuclear transport but rather due to depleted histone H3 chemical modifications related to active transcription, namely H3K4me3 and H3K27ac, on the vector DNA itself. A single-amino acid insertion into the AAV-LK03 capsid enables efficient transduction and the accumulation of active-related epigenetic marks on the vector chromatin in mouse without compromising transduction efficiency in human cells. Our study suggests that the capsid protein itself is involved in driving the epigenetic status of the vector genome, most likely during the process of uncoating. Programming viral chromatin states by capsid design may enable facile DNA transduction between vector and host species and ultimately lead to rational selection of AAV capsids for use in humans.

Medical specialist distributions in Ecuador: a geographical and temporal analysis of data from 2000 to 2017.

BACKGROUND: Knowledge of medical specialists' numbers and geographical distribution are essential for planning health services and health workforce supply. However, although the distribution of physicians is a significant concern for society and policymakers in Ecuador, no studies have evaluated the distribution of specialists in the country. This study aimed to explore the geographical and temporal distribution of medical specialists in Ecuador over 18 years from 2000 to 2017 and analyse its implications for health planning and medical training. METHODS: We conducted an ecological time-series study based on the National Statistical Register of Resources and Health Activities data. This register provides administrative information for health professionals working in public and private health institutions. Rates of medical specialists by year, geographical area, and speciality were estimated. We used joint-point analyses to identify time trends for medical specialists and physicians in training. RESULTS: From 2000 to 2017, medical specialists grew from 2737 to 10,929. The rate of medical specialists per 10,000 population increased from 4 in 2000 to 10.3 in 2017. Based on Joint point analysis, two temporal trends were identified. Between 2000 to 2015, specialists increased by 4.1% per year, and between 2015 and 2017, they increased by 20% per year. For the entire study period, three cities (Quito, Guayaquil, and Cuenca) accounted for more than 50% of the specialists in the country. However, medical specialists in other cities and rural areas increased from 37% in 2000 to 46% in 2017. The provinces of Esmeraldas, Carchi, Bolívar and Los Ríos presented rates of less than 6 specialists per 10,000 population by 2017. Of the 46 medical specialities identified by 2017, three represented more than 30% of the professionals (gynaecology 12%, paediatrics 11% and family and community health 8.4%). CONCLUSIONS: This study shows that the number of medical specialists in Ecuador has increased significantly over the last two decades, although with inequalities in the distribution of specialists between provinces and regions. The results of this study provide background for the Ecuadorian health system when introducing Human Resources of Health (HRH) policies.

Health workers' perspectives on asthma care coordination between primary and specialised healthcare in the COVID-19 pandemic: a protocol for a qualitative study in Ecuador and Brazil.

INTRODUCTION: Asthma is a common long-term disorder and strategies to improve asthma control are still a challenge. Integrated delivery of health systems is critical for effective asthma care: there is limited information on experiences of care coordination for asthma from Latin America, especially on perspectives of health personnel and in the context of the COVID-19 pandemic. METHODS AND ANALYSIS: This protocol details a qualitative approach to analyse health workers' perspectives of healthcare coordination for asthma control during COVID-19 pandemic in Ecuador and Brazil, at primary and specialised levels, through in-depth semistructured interviews using a video communications platform. The analysis will identify knowledge and perspectives based on coordination of clinical information, clinical management and administrative coordination. Theoretical sampling will be used to obtain approximately equal numbers of women and men within each level of healthcare; data saturation will be used to determine sample size. Transcripts will be analysed using content-coding procedures to mark quotations related to major topics and subthemes included in the interview guide, and narrative analysis will be based on a theoretical framework for healthcare coordination to identify new themes and subthemes. ETHICS AND DISSEMINATION: Ethical approval was obtained from the ethics committees of Hospital General Docente Calderón, Quito, Ecuador; and Universidade Federal da Bahia, Salvador, Brazil. The findings of this study will be disseminated through peer-reviewed articles, conference presentations and condensed summaries for key stakeholders and partners.

First-line haploidentical stem cell transplantation in children and adolescents with severe aplastic anemia using mobilized peripheral blood as source of CD34+: Single-institutional experience in a transplant center from northeast Mexico.

INTRODUCTION: The only curative treatment for severe aplastic anemia in children is an allogeneic stem cell transplant; however, few patients have a matched related or unrelated donor. Haploidentical stem cell transplantation (haplo-SCT) using bone marrow (BM) and peripheral blood stem cells (PBSC) has been recently described as effective and safe. In this study, we retrospectively report the outcome of twelve pediatric patients who underwent haplo-SCT using only PBSC. METHODS: The conditioning regimen consisted on rabbit anti-thymocyte globulin (r-ATG) 2.5 mg/kg/d on days -7, -6,-5, and -4, and cyclophosphamide (Cy) 50 mg/kg/d on days -3 and -2. We used Cy 50 mg/kg/d on days +3 and +4, tacrolimus and mycophenolic acid as graft versus host disease (GVHD) prophylaxis. RESULTS: The median follow-up was 1,099 days (45-1258 days). The overall survival rate up-to-date is 83.3%. In 10 of the 12 patients, a sustained graft was achieved. None of the patients had acute or chronic GVHD. CONCLUSIONS: Haplo-SCT could be established as a first-line treatment when there is no matched related or unrelated donor. According to this short sample and previous reports, PBSC are a feasible option effectively used as the sole source of stem cells. Additionally, post-transplant cyclophosphamide remains a good strategy for GVHD prevention.

Loss of an H3K9me anchor rescues laminopathy-linked changes in nuclear organization and muscle function in an Emery-Dreifuss muscular dystrophy model.

Mutations in the nuclear structural protein lamin A produce rare, tissue-specific diseases called laminopathies. The introduction of a human Emery-Dreifuss muscular dystrophy (EDMD)-inducing mutation into the C. elegans lamin (LMN-Y59C), recapitulates many muscular dystrophy phenotypes, and correlates with hyper-sequestration of a heterochromatic array at the nuclear periphery in muscle cells. Using muscle-specific emerin Dam-ID in worms, we monitored the effects of the mutation on endogenous chromatin. An increased contact with the nuclear periphery along chromosome arms, and an enhanced release of chromosomal centers, coincided with the disease phenotypes of reduced locomotion and compromised sarcomere integrity. The coupling of the LMN-Y59C mutation with the ablation of CEC-4, a chromodomain protein that anchors H3K9-methylated chromatin at the nuclear envelope (NE), suppressed the muscle-associated disease phenotypes. Deletion of cec-4 also rescued LMN-Y59C-linked alterations in chromatin organization and some changes in transcription. Sequences that changed position in the LMN-Y59C mutant, are enriched for E2F (EFL-2)-binding sites, consistent with previous studies suggesting that altered Rb-E2F interaction with lamin A may contribute to muscle dysfunction. In summary, we were able to counteract the dominant muscle-specific defects provoked by LMNA mutation by the ablation of a lamin-associated H3K9me anchor, suggesting a novel therapeutic pathway for EDMD.

Mechanism of chromatin segregation to the nuclear periphery in C. elegans embryos.

In eukaryotic organisms, gene regulation occurs in the context of chromatin. In the interphase nucleus, euchromatin and heterochromatin occupy distinct space during cell differentiation, with heterochromatin becoming enriched at the nuclear and nucleolar peripheries. This organization is thought to fine-tune gene expression. To elucidate the mechanisms that govern this level of genome organization, screens were carried out in C. elegans which monitored the loss of heterochromatin sequestration at the nuclear periphery. This led to the identification of a novel chromodomain protein, CEC-4 (Caenorhabditis elegans chromodomain protein 4) that mediates the anchoring of H3K9 methylation-bearing chromatin at the nuclear periphery in early to mid-stage embryos. Surprisingly, the loss of CEC-4 does not derepress genes found in heterochromatic domains, nor does it affect differentiation under standard laboratory conditions. On the other hand, CEC-4 contributes to the efficiency with which muscle differentiation is induced following ectopic expression of the master regulator, HLH-1. This is one of the first phenotypes specifically attributed to the ablation of heterochromatin anchoring.

On TADs and LADs: Spatial Control Over Gene Expression.

The combinatorial action of transcription factors drives cell-type-specific gene expression patterns. However, transcription factor binding and gene regulation occur in the context of chromatin, which modulates DNA accessibility. High-resolution chromatin interaction maps have defined units of chromatin that are in spatial proximity, called topologically associated domains (TADs). TADs can be further classified based on expression activity, replication timing, or the histone marks or non-histone proteins associated with them. Independently, other chromatin domains have been defined by their likelihood to interact with non-DNA structures, such as the nuclear lamina. Lamina-associated domains (LADs) correlate with low gene expression and late replication timing. TADs and LADs have recently been evaluated with respect to cell-type-specific gene expression. The results shed light on the relevance of these forms of chromatin organization for transcriptional regulation, and address specifically how chromatin sequestration influences cell fate decisions during organismal development.

Histones and histone modifications in perinuclear chromatin anchoring: from yeast to man.

It is striking that within a eukaryotic nucleus, the genome can assume specific spatiotemporal distributions that correlate with the cell's functional states. Cell identity itself is determined by distinct sets of genes that are expressed at a given time. On the level of the individual gene, there is a strong correlation between transcriptional activity and associated histone modifications. Histone modifications act by influencing the recruitment of non-histone proteins and by determining the level of chromatin compaction, transcription factor binding, and transcription elongation. Accumulating evidence also shows that the subnuclear position of a gene or domain correlates with its expression status. Thus, the question arises whether this spatial organization results from or determines a gene's chromatin status. Although the association of a promoter with the inner nuclear membrane (INM) is neither necessary nor sufficient for repression, the perinuclear sequestration of heterochromatin is nonetheless conserved from yeast to man. How does subnuclear localization influence gene expression? Recent work argues that the common denominator between genome organization and gene expression is the modification of histones and in some cases of histone variants. This provides an important link between local chromatin structure and long-range genome organization in interphase cells. In this review, we will evaluate how histones contribute to the latter, and discuss how this might help to regulate genes crucial for cell differentiation.

Perinuclear Anchoring of H3K9-Methylated Chromatin Stabilizes Induced Cell Fate in C. elegans Embryos.

Interphase chromatin is organized in distinct nuclear sub-compartments, reflecting its degree of compaction and transcriptional status. In Caenorhabditis elegans embryos, H3K9 methylation is necessary to silence and to anchor repeat-rich heterochromatin at the nuclear periphery. In a screen for perinuclear anchors of heterochromatin, we identified a previously uncharacterized C. elegans chromodomain protein, CEC-4. CEC-4 binds preferentially mono-, di-, or tri-methylated H3K9 and localizes at the nuclear envelope independently of H3K9 methylation and nuclear lamin. CEC-4 is necessary for endogenous heterochromatin anchoring, but not for transcriptional repression, in contrast to other known H3K9 methyl-binders in worms, which mediate gene repression but not perinuclear anchoring. When we ectopically induce a muscle differentiation program in embryos, cec-4 mutants fail to commit fully to muscle cell fate. This suggests that perinuclear sequestration of chromatin during development helps restrict cell differentiation programs by stabilizing commitment to a specific cell fate. PAPERCLIP.

Matched sibling donors versus alternative donors in allogeneic hematopoietic stem cell transplantation for pediatric severe aplastic anemia in México.

Objectives Hematopoietic stem cell transplantation (HSCT) from a matched sibling donor (MSD) is the preferred initial treatment for children with severe aplastic anemia (SAA). Unfortunately, only about 30% of patients have a suitable human leukocyte antigen-matched sibling. Methods We have analyzed the outcome of 42 patients who received HSCT (22 MSD and 20 alternative donors (AD)) for SAA at the seven major pediatric HSCT centers in Mexico between 2001 and 2013. Results With a median follow-up of 30 months (range, 0.4-144), the 5-year overall survival in children transplanted from MSD was 86.4 + 7.3 vs. 49.5 + 11% for children after AD-HSCT (P = 0.013). The cumulative incidence of treatment-related mortality (TRM) was in the MSD-HSCT 9.1 + 3.9% vs. 47.6 + 9.1% in the AD-HSCT context (P = 0.007). Infectious complications contributed to death (91%) of most patients who received AD-HSCT. Discussion Even when the results of patients given MSD-HSCT are adequate, there is still much room for improvement particularly in children allografted with AD and in the supportive care. The development of an economicwise designed prospective project with MSD or matched unrelated donor HSCTs as a first line of treatment of children with SAA as a unified national trial could address these issues.

Mechanisms of heterochromatin subnuclear localization.

Transcriptionally repressed heterochromatin becomes the dominant form of chromatin in most terminally differentiated cells. Moreover, in most cells, at least one class of heterochromatin is positioned adjacent to the nuclear lamina. Recent approaches have addressed the mechanism of heterochromatin localization, in order to determine whether spatial segregation contributes to gene repression. Findings in worms and human cells confirm a role for histone H3K9 methylation in heterochromatin positioning, identifying a modification that is also necessary for gene repression of worm transgenic arrays. These pathways appear to be conserved, although mutations in mammalian cells have weaker effects, possibly due to redundancy in positioning mechanisms. We propose a general model in which perinuclear anchoring is linked to an epigenetic propagation of the heterochromatic state, through histone modification.

Validación de un instrumento para la detección oportuna de problemas de desarrollo en menores de 5 años en México / Validation of an instrument for early detection of developmental problems in children under 5 years in Mexico

Introducción. En México, no se contaba con una prueba de evaluación del desarrollo infantil con propiedades psicométricas. La prueba de evaluación del desarrollo infantil (EDI) se desarrolló con este fin. El objetivo de este trabajo fue determinar las propiedades psicométricas de la EDI como prueba de tamizaje para los problemas de desarrollo infantil en menores de 5 años. Métodos. Se realizó un estudio transversal que incluyó pacientes menores de 5 años en tres entidades de la República Mexicana: Chihuahua, Yucatán y Distrito Federal. El espectro de la población incluyó niños con factores de riesgo biológico, ambiental y sin riesgo para retraso en el desarrollo. Se excluyeron los pacientes con alteraciones neurológicas evidentes. Se consideró, como prueba diagnóstica, el Inventario de Desarrollo de Battelle-2 en las tres entidades. En el Distrito Federal, adicionalmente, se aplicó Bayley-III. A cada participante se le aplicaron la prueba de tamizaje en dos versiones y la prueba diagnóstica, el mismo día o en un lapso no mayor a una semana. La persona que aplicó la prueba diagnóstica no conocía el resultado de la prueba de tamizaje. Se definió retraso cuando el cociente total de desarrollo resultó menor a 90. Resultados. Se incluyeron, en total, 438 niños menores de 5 años provenientes del Distrito Federal (n =152, 34.7%), Yucatán (n =151, 34.5%) y Chihuahua (n =135, 30.8%). Del total, 43.4% fueron del sexo femenino (n =190). La clasificación por tipo de riesgo fue biológico (n =197, 45%), ambiental (n =137, 31.3%) y sin riesgo (n =104, 23.7%). Se encontró una sensibilidad de 0.81 (IC 95%: 0.75-0.86), especificidad de 0.61 (IC 95%: 0.54-0.67), concordancia 0.70 (IC 95%: 0.66-0.74). La correlación parcial de las áreas del desarrollo entre la prueba de tamizaje y la prueba Bayley III (n =87) ajustada por grupo de edad del tamizaje fue la siguiente: área motor fino 0.468, motor grueso 0.441, lenguaje 0.508, social 0.336 y adaptativo 0.355 (p ≤0.001). Conclusiones. La prueba EDI posee propiedades adecuadas y similares a las pruebas más utilizadas en América.

Background. The ''Evaluación del Desarrollo Infantil'' (EDI) test was developed as an screening tool for the developmental evaluation of Mexican children younger than 5 years old. The objective of this study was to evaluate the psychometric properties of EDI as a screening tool for children with developmental problems. Methods. We carried out a cross-sectional study including patients from urban and rural areas in three locations: Mexico City, Yucatan and Chihuahua. The disease spectrum was defined according to biological risk, environmental risk or without risk for developmental problems. Patients with obvious neurological disabilities or genetic syndromes were excluded. The gold standards were the Battelle Developmental Inventory 2 (in Spanish) and Bayley-III. Each participant had two complete applications of the EDI test (all interrogated and all observed) and the gold standard (Bayley-III only in Mexico City). Developmental delay was defined as a total development quotient <90. Results. The study included 438 children <5 years old. Distribution by site includes Mexico City (n =152, 34.7%), Yucatan (n =151, 34.5%), Chihuahua (n =135, 30.8%); female gender (n =190, 43.4%). Classification by risk includes biological (n =197, 45%), environmental (n =137, 31.3%), without risk (n =104, 23.7%). With BDI-II as the gold standard, the modified version of EDI (interrogated plus observation) has a sensitivity of 0.81 (95% CI: 0.75-0.86), specificity 0.61 (95% CI: 0.54-0.67), and concordance 0.70 (95% CI: 0.66-0.74). The partial correlation between EDI areas and Bayley-III areas (n =87) was adjusted by test group: fine motor 0.468, gross motor 0.441, language 0.508, social 0.336 and adaptive 0.355 (p ≤0.001). Conclusions. The modified version of EDI has similar properties as the various developmental screening tools available in the U.S. or Latin America and could be a good screening tool in Spanish.

The formation and sequestration of heterochromatin during development: delivered on 7 September 2012 at the 37th FEBS Congress in Sevilla, Spain.

Chromatin is not randomly positioned in the nucleus, but is distributed in subdomains based on its degree of compaction and transcriptional status. Recent studies have shed light on the logic of chromatin distribution, showing that tissue-specific promoters drive distinct patterns of gene positioning during cell-type differentiation. In addition, the sequestration of heterochromatin at the nuclear envelope has been found to depend on lamin and lamin-associated proteins. On the chromatin side, H3K9 monomethylation, dimethylation and trimethylation were shown to be the critical signals for perinuclear anchoring in worm embryonic nuclei. Downregulation of an equivalent histone methyltransferase, G9a, in human cells has a similar effect. In worms, the sequestration of the terminal methyltransferase by repressed chromatin may facilitate the propagation of a heterochromatin compartment, much as the sequestration of the silent information regulatory complex does at telomeric foci in budding yeast. These results argue for conserved logic in eukaryotic nuclear organization.

An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity.

BACKGROUND: In worms, as in other organisms, many tissue-specific promoters are sequestered at the nuclear periphery when repressed and shift inward when activated. It has remained unresolved, however, whether the association of facultative heterochromatin with the nuclear periphery, or its release, has functional relevance for cell or tissue integrity. RESULTS: Using ablation of the unique lamin gene in C. elegans, we show that lamin is necessary for the perinuclear positioning of heterochromatin. We then express at low levels in otherwise wild-type worms a lamin carrying a point mutation, Y59C, which in humans is linked to an autosomal-dominant form of Emery-Dreifuss muscular dystrophy. Using embryos and differentiated tissues, we track the subnuclear position of integrated heterochromatic arrays and their expression. In LMN-1 Y59C-expressing worms, we see abnormal retention at the nuclear envelope of a gene array bearing a muscle-specific promoter. This correlates with impaired activation of the array-borne myo-3 promoter and altered expression of a number of muscle-specific genes. However, an equivalent array carrying the intestine-specific pha-4 promoter is expressed normally and shifts inward when activated in gut cells of LMN-1 Y59C worms. Remarkably, adult LMN-1 Y59C animals have selectively perturbed body muscle ultrastructure and reduced muscle function. CONCLUSION: Lamin helps sequester heterochromatin at the nuclear envelope, and wild-type lamin permits promoter release following tissue-specific activation. A disease-linked point mutation in lamin impairs muscle-specific reorganization of a heterochromatic array during tissue-specific promoter activation in a dominant manner. This dominance and the correlated muscle dysfunction in LMN-1 Y59C worms phenocopies Emery-Dreifuss muscular dystrophy.

Dynamics of expression of ARID1A and ARID1B subunits in mouse embryos and in cells during the cell cycle.

The mammalian SWI/SNF chromatin remodeling complexes play essential roles in cell cycle control through the transcriptional regulation of cell-cycle-specific genes. These complexes depend on the energy of ATP hydrolysis provided by the BRG1 or BRM catalytic subunit. They contain seven or more noncatalytic subunits, some being constitutive components, with others having paralogs that assemble in a combinatory manner producing different SWI/SNF-related complexes with specific functions. ARID1A and ARID1B are mutually exclusive subunits of the BAF complex. The specific presence of these subunits in the complex has been demonstrated to determine whether SWI/SNF functions as a corepressor (ARID1A) or as a coactivator (ARID1B) of the cell cycle genes. Our aim has been to analyze the relevance of the ARID1 subunits in development. We have compared the patterns of expression of these two genes through various mouse embryonic stages. Arid1a is expressed widely and intensively, whereas Arid1b is poorly transcribed and expressed in selected regions. Moreover, ARID1A and ARID1B present different kinetics of expression in the cell cycle. ARID1A accumulates in G0 and is downregulated throughout the cell cycle phases but is completely eliminated during mitosis, whereas ARID1B is expressed at comparable levels at all phases, even during mitosis. These kinetics probably affect the incorporation patterns of the ARID1 proteins to the complex and hence modulate SWI/SNF activity during proliferation and arrest.

Toxocariasis en adulto manifestada como síndrome hipereosinofílico con compromiso neurológico predominante: caso clínico / Toxocariasis manifesting as an hypereosinophilic syndrome with predominant neurological involvement: report of adult case

Hypereosinophilic syndrome is characterized by persistent hypereosinophilia and signs or symptoms due to organ involvement, specially nervous system, heart and skin. It can be primary or secondary to allergies, parasites or cancer. Toxocariasis is an uncommon parasitic disease in adults. There is a variant, called visceral larva migrans, that can involve different organs, and among those, the central nervous system. We report a 61 years old male, with a cerebrovascular disease. There were focalizing symptoms, the CAT scan showed multiple ischemic lesions and a peripheral eosinophilia of 12152 cells/mm3 was present. Anti toxocara IgG antibody titers were 1/1000. The patient was treated with albendazole for 14 days. After a 2 years follow up the patients is in good conditions and, for the first time, his eosinophil count is within normal limits

Ictericia neonatal: II tratamiento de la hiperbilirrubinemia no conjugada. Consideraciones fetales y neonatales / Neonatal jaundice: II treatment of unconjugated hyperbilirubinemia

En la segunda parte de esta serie se describen algunas consideraciones con respecto al mecanismo de acción de las principales medidas terapéuticas de la hiperbilirrubinemia neonatal, así como el abordaje del feto con anemia hemolítica y recomendaciones actuales para el manejo del recién nacido sano o enfermo con hiperbilirrubinemia.

Anticuerpos anti LKM-1 y crioglobulinemia en hepatitis crónica autoinmune y por virus C de la hepatitis / Anti LKM-1 and cryoglobulinemia in autoimmune and virus C associated chronic hepatitis

Background: Anti liver kidney microsome antibodies (LKM-1) have been recently incorporated to the study and classification of chronic autoimmune hepatitis (HC-A1). The presence of anti LKM-1 antibodies and essential cryoglobulinemia is frequent in virus C associated chronic hepatitis (HC-VC). Aim: To study the frequency of anti LKM-1 antibodies and cryoglobulin levels in patients with HC-AI, HC-VC and cryptogenic cirrhosis. Patients and methods: Forty two patients were studied. Nineteen adult women with classic HC-AI with positive antinuclear or anti smooth muscle antibodies. Five patients of less than 20 years old with HC-AI and negative antinuclear and anti smooth muscle antibodies. Ten adult women with cryptogenic cirrhosis, 4 women and 4 men with HC-VC. Serum samples were obtained at 37­C. Antinuclear, anti smooth muscle and anti LKM-1 antibodies were measured by indirect immunofluorescence using Hep-2 cells and rat tissue slices as substrates. Cryoglobulins were determined by the traditional method and cryocrit. Results: All studied patients were anti LKM-1 negative. All had significant circulating cryoglobulin levels. Conclusions: In this sample of patients with HC-AI or HC-VC, anti LKM-1 antibodies were not detected but all had cryoglobulinemia