RESUMEN

OBJECTIVE: The Composite Index of Anthropometric Failure (CIAF) can only be applied to children under 5 years of age and does not contemplate obesity. The aim of this study was to propose an Extended CIAF (ECIAF) that combines the characterization of malnutrition due to undernutrition and excess weight, and apply it in six Argentine provinces. DESIGN: ECIAF excludes children not in anthropometric failure (group A) and was calculated from a percentage of children included in malnutrition categories B: wasting only; C: wasting and underweight; D: wasting, stunting and underweight; E: stunting and underweight; F: stunting only; Y: underweight only; G: only weight excess; and H: stunting and weight excess. SETTING: Cross-sectional study conducted in Buenos Aires, Catamarca, Chubut, Jujuy, Mendoza and Misiones (Argentina). PARTICIPANTS: 10 879 children of both sexes aged between 3 and 13·99. RESULTS: ECIAF in preschool children (3 to 4·99 years) was 15·1 %. The highest prevalence was registered in Mendoza (16·7 %) and the lowest in Misiones (12·0 %). In school children (5 to 13·99 years) ECIAF was 28·6 %. Mendoza also recorded the highest rate (30·7 %), while Catamarca and Chubut had the lowest values (27·0 %). In the whole sample, about 25 % of the malnutrition was caused by undernutrition and 75 % by excess weight. CONCLUSIONS: The ECIAF summarizes anthropometric failure by both deficiency and excess weight and it highlights that a quarter of the malnutrition in the Argentine population was caused by undernutrition, although there are differences between Provinces (P < 0·05). ECIAF estimates are higher than those of CIAF or under-nutrition.

Asunto(s)

Estado Nutricional/fisiología , Adolescente , Antropometría , Argentina/epidemiología , Niño , Trastornos de la Nutrición del Niño/diagnóstico , Trastornos de la Nutrición del Niño/epidemiología , Preescolar , Estudios Transversales , Femenino , Trastornos del Crecimiento/epidemiología , Humanos , Masculino

RESUMEN

Gene therapy using viral vectors that stably integrate into ex vivo cultured cells holds great promises for the treatment of monogenic diseases as well as cancer. However, carry-over of infectious vector particles has been described to occur upon ex vivo transduction of target cells. This, in turn, may lead to inadvertent spreading of viral particles to off-target cells in vivo, raising concerns for potential adverse effects, such as toxicity of ectopic transgene expression, immunogenicity from in vivo transduced antigen-presenting cells and, possibly, gene transfer to germline cells. Here, we have investigated factors influencing the extent of lentiviral vector (LV) shedding upon ex vivo transduction of human hematopoietic stem and progenitor cells. Our results indicate that, although vector carry-over is detectable when using laboratory-grade vector stocks, the use of clinical-grade vector stocks strongly decreases the extent of inadvertent transduction of secondary targets, likely because of the higher degree of purification. These data provide supportive evidence for the safe use of the LV platform in clinical settings.

Asunto(s)

Terapia Genética , Vectores Genéticos , Lentivirus/genética , Esparcimiento de Virus , Antígenos CD34/metabolismo , Humanos , Lentivirus/fisiología , Células Madre/metabolismo

RESUMEN

PURPOSE: The aim of the study was to analyze the effect of postnatal nutritional rehabilitation on the craniofacial growth in rats with intrauterine growth retardation (IUGR). MATERIALS AND METHODS: Wistar rats were assigned to one of the following groups: control, Sham-operated, and IUGR. The IUGR was produced by uterine vessels bending (day 14 of pregnancy). At days 1, 21, 42, 63, and 84 of postnatal life, each animal was X-rayed, and neural and facial length, width and height were measured. Volumetric and morphometric indices were calculated. RESULTS: The decreased maternal-fetal blood flow during the last-third of the gestation period modified cranial size and shape of both sexes at birth. DISCUSSION: Postnatal nutritional rehabilitation is not fully sufficient to reverse the prenatal growth retardation. There are specific responses depending on the sex and the age of the IUGR pups. Regardless of the changes in size, the shape is not modified during all the postnatal period.

Asunto(s)

Huesos Faciales/crecimiento & desarrollo , Retardo del Crecimiento Fetal/rehabilitación , Apoyo Nutricional/métodos , Preñez , Cráneo/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Femenino , Retardo del Crecimiento Fetal/diagnóstico por imagen , Masculino , Embarazo , Radiografía , Ratas , Ratas Wistar

RESUMEN

The aim of this study was to analyze growth in relation to menarche in girls from two Argentinean urban populations. We performed a comparative-descriptive cross sectional study in 2474 schoolchildren between 8.0 and 16.9 years old from Santa Rosa (SR) and La Plata (LP) cities. We registered the presence of menarche and anthropometrics variables of body weight, total and sitting heights, arm circumference, triceps and subscapular skinfolds. Body mass index, subscapular/triceps index and muscle and fat arm areas were calculated. The study group was divided into 4 groups according to the city and menarche. The socio-environmental structured survey indicated significant differences between cities with these variables: tenure status, building materials and services, health care coverage, cash assistance, educational level and parents' occupation, therefore establishing a higher welfare in youngsters of SR. Menarche at a mean age of 12.7 years old was more prevalent in SR (40.6%) than in LP (33.7%) (c2 = 12.9; p < 0.01). The ANOVA indicated significant differences between cities in total and sitting heights and muscle area (p < 0.01), body weight and arm circumference (p < 0.05) which were generally held in the post hoc comparison by age in pre-menarche and post-menarche groups. The presence of a small body size at the expense of lowering in: total height, muscle area and leg length in LP youngsters, associated with a lower prevalence of menarche in this city, it would represents the adaptive cost of a lower welfare environment.

Asunto(s)

Composición Corporal , Crecimiento/fisiología , Menarquia/fisiología , Maduración Sexual/fisiología , Adolescente , Argentina , Niño , Estudios Transversales , Femenino , Humanos , Factores Socioeconómicos , Población Urbana

RESUMEN

OBJECTIVE: To report 4 cases of autosomal recessive hereditary neuropathy associated with novel mutations in the periaxin gene (PRX) with a review of the literature. Periaxin protein is required for the maintenance of peripheral nerve myelin. Patients with PRX mutations have early-onset autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4F) or Déjèrine-Sottas neuropathy (DSN). Only 12 different mutations have been described thus far. METHODS: Case reports and literature review. RESULTS: Four patients from 3 unrelated families (2 siblings and 2 unrelated patients) were affected by an early-onset, slowly progressive demyelinating neuropathy with relevant sensory involvement. All carried novel frameshift or nonsense mutations in the PRX gene. The 2 siblings were compound heterozygotes for 2 PRX null mutations (p.Q547X and p.K808SfsX2), the third patient harbored a homozygous nonsense mutation (p.E682X), and the last patient had a homozygous 2-nt insertion predicting a premature protein truncation (p.S259PfsX55). Electrophysiologic analysis showed a severe slowing of motor nerve conduction velocities (MNCVs, between 3 and 15.3 m/s) with undetectable sensory nerve action potentials (SNAPs). Sural nerve biopsy, performed in 2 patients, demonstrated a severe demyelinating neuropathy and onion bulb formations. Interestingly, we observed some variability of disease severity within the same family. CONCLUSIONS: These cases and review of the literature indicate that PRX-related neuropathies have early onset but overall slow progression. Typical features are prominent sensory involvement, often with sensory ataxia; a moderate-to-dramatic reduction of MNCVs and almost invariable absence of SNAPs; and pathologic demyelination with classic onion bulbs, and less commonly myelin folding and basal lamina onion bulbs.

Asunto(s)

Enfermedad de Charcot-Marie-Tooth/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Proteínas de la Membrana/fisiología , Adulto , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/fisiopatología , Progresión de la Enfermedad , Femenino , Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Mutación , Vaina de Mielina/metabolismo , Estudios Retrospectivos , Nervio Sural/patología

RESUMEN

Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder resulting from the inherited deficiency of the arylsulfatase A (ARSA) enzyme. Currently, no valid therapeutic options are available for affected patients. A thorough knowledge of disease progression in its diverse clinical variants, together with the identification of reliable prognostic factors, could be instrumental in accurate patient selection for new upcoming therapeutic opportunities, such as enzyme replacement and gene therapy. The described correlation between genotype and clinical presentation proved helpful in predicting patient's prognosis, only in the minority of MLD patients harboring common mutations. Molecular characterization of a cohort of 26 MLD patients allowed us to identify 18 mutations, excluding the common 0 and R alleles, 10 of which are rare and 8 are novel. By categorizing the rare mutations, we were able to confirm a correlation between ARSA gene mutations, age at onset and patterns of disease progression, not only in those patients bearing common mutations, but also in those carrying rare mutant alleles. Moreover, in the case of absent or delayed molecular diagnosis, or of newly identified mutations, the involvement of peripheral nervous system from disease onset proved to be a sensitive prognostic marker predicting a severe progression.

Asunto(s)

Genotipo , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/genética , Mutación/genética , Alelos , Encéfalo/patología , Cerebrósido Sulfatasa/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Familia , Femenino , Humanos , Leucodistrofia Metacromática/enzimología , Masculino , Fenotipo

RESUMEN

Successful gene therapy approaches for metachromatic leukodystrophy (MLD), based either on hematopoietic stem/progenitor cells (HSPCs) or direct central nervous system (CNS) gene transfer, highlighted a requirement for high levels of arylsulfatase A (ARSA) expression to achieve correction of disease manifestations in the mouse model. Full assessment of the safety of ARSA expression above physiological levels thus represents a prerequisite for clinical translation of these approaches. Here, using lentiviral vectors (LVs), we generated two relevant models for the stringent evaluation of the consequences of ARSA overexpression in transduced cells. We first demonstrated that ARSA overexpression in human HSPCs does not affect their clonogenic and multilineage differentiation capacities in clonogenic assays and in a neonatal hematochimeric mouse model. Further, we studied ARSA overexpression in all body tissues by generating transgenic mice overexpressing the ARSA enzyme by LV up to 15-fold above the normal range and carrying multiple copies of LV in their genome. Characterization of these mice demonstrated the safety of ARSA overexpression in two main gene therapy targets, HSPCs and neurons, with maintenance of the complex functions of the hematopoietic and nervous system in the presence of supraphysiological enzyme levels. The activity of other sulfatases dependent on the same common activator, sulfatase-modifying factor-1 (SUMF1), was tested in ARSA-overexpressing HSPCs and in transgenic mice, excluding the occurrence of saturation phenomena. Overall, these data indicate that from the perspective of clinical translation, therapeutic levels of ARSA overexpression can be safely achieved. Further, they demonstrate an experimental platform for the preclinical assessment of the safety of new gene therapy approaches.

Asunto(s)

Cerebrósido Sulfatasa/metabolismo , Terapia Genética , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/terapia , Animales , Animales Recién Nacidos , Antígenos CD34/inmunología , Antígenos CD34/metabolismo , Southern Blotting , Diferenciación Celular , Linaje de la Célula , Proliferación Celular , Cerebrósido Sulfatasa/efectos adversos , Cerebrósido Sulfatasa/análisis , Ensayo de Unidades Formadoras de Colonias , Estudios de Factibilidad , Vectores Genéticos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Lentivirus/genética , Leucodistrofia Metacromática/metabolismo , Leucodistrofia Metacromática/patología , Ratones , Ratones Transgénicos , Modelos Animales , Neuronas/citología , Neuronas/metabolismo , Reacción en Cadena de la Polimerasa , Bazo/citología , Transducción Genética