Parkinson's disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration.

A deeper understanding of early disease mechanisms occurring in Parkinson's disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients' networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases.

Allergic rhinoconjunctivitis due to pediculus humanus capitis

No disponible

[Analysis of clinical safety in the units of Allergy of the Valencian Community]. / Análisis de la seguridad clínica en las unidades de Alergología de la Comunidad Valenciana.

The introduction of new diagnostic and therapeutic procedures involving allergen exposure may increase the risk of allergic reactions. We designed and distributed an anonymous questionnaire among the allergy units of the Valencian Community in order to collect information on measures to ensure clinical safety. Twelve hospital outpatient clinics and 8 ambulatory care centres reported similar patterns of activities, including the use of critical care units, emergency rooms or day hospitals for higher risk techniques. The provision of security-related instruments is broader in hospital outpatient clinics and included: oxygen (91.7%), pulse oximeter (75.0%) or vital signs monitor (8.3%), resuscitation material (91.7%) and defibrillator (83.3%). The response time for emergencies is set in 50% of clinics. The resuscitation material is systematically reviewed and informed consent signed. Security is more limited in ambulatory care centres. It is necessary to set down the conditions for clinical safety in allergology. Key words. Allergy. Ambulatory care. Clinical safety. Health services. Hospital outpatient clinic.

Analytical strategy based on the combination of gas chromatography coupled to time-of-flight and hybrid quadrupole time-of-flight mass analyzers for non-target analysis in food packaging.

The potential of an advanced analytical strategy based on the use of gas chromatography (GC) coupled to high resolution mass spectrometry (HRMS) with two different analyzers and ionization sources has been investigated and applied to the non-target analysis of food packaging contaminants. Initially, the approach based on GC-time-of-flight (TOF) MS with electron ionization (EI) source allowed performing a library search and mass accurate measurements of selected ions. Then, a second analysis was performed using hybrid quadrupole (Q) TOF MS with an atmospheric pressure chemical ionization (APCI) source in order to search for the molecular ion or the protonated molecule and study the fragmentation behavior. This analytical strategy was applied to the analysis of four polypropylene/ethylene vinyl alcohol/polypropylene (PP/EVOH/PP) multilayer trays and one PP/Al foil/PP film, each one subjected to migration assays with the food simulants isooctane and Tenax®, in order to investigate its potential on the determination of migrant substances.

Safety and efficacy profile and immunological changes associated with oral immunotherapy for IgE-mediated cow's milk allergy in children: systematic review and meta-analysis.

BACKGROUND: Cow's milk allergy (CMA), one of the main types of childhood allergy, considerably impairs patient quality of life. Allergen avoidance is difficult, and mistakes are common. Therefore, new treatment strategies such as oral immunotherapy (OIT) have been sought for patients with CMA. Our objective was to review current evidence on immunological changes, efficacy, and safety when using OIT as an alternative to an avoidance diet in the treatment of children with IgE-mediated CMA. METHODS: We performed a systematic review and subsequent meta-analysis of all randomized controlled studies published to date in which OIT is used to treat CMA in children.We evaluated immunological effects, acquisition of desensitization, and adverse events. Immunological changes were examined by means of a meta-analysis of individual patient data. RESULTS: Desensitization using OIT to cow's milk is 10.2 times more likely than in non-0IT-treated patients. The decrease in cow's milk-specific IgE levels was found to differ by 8.1 kUA/L between OIT-treated patients and those on an avoidance diet. This difference was not statistically significant (P=.318). Although side effects are common, they usually involve mild reactions that are easy to manage without parenteral epinephrine. CONCLUSION: OIT can be considered safe and effective (in terms of acquiring desensitization) and reasonably safe (mild-to-moderate adverse events, little need for parenteral epinephrine) in patients with CMA. Although OIT leads to changes in cow's milk-specific IgE levels, the differences between OIT-treated and non-0IT-treated patients are not significant. More studies are needed to evaluate other immunological changes that may occur, such as the increase in IgG4 levels.

Safety and efficacy profile and immunological changes associated with oral immunotherapy for IgE-mediated cow's milk allergy in children: systematic review and meta-analysis

Background: Cow's milk allergy (CMA), one of the main types of childhood allergy, considerably impairs patient quality of life. Allergen avoidance is difficult, and mistakes are common. Therefore, new treatment strategies such as oral immunotherapy (OIT) have been sought for patients with CMA. Our objective was to review current evidence on immunological changes, efficacy, and safety when using OIT as an alternative to an avoidance diet in the treatment of children with IgE-mediated CMA. Methods: We performed a systematic review and subsequent meta-analysis of all randomized controlled studies published to date in which OIT is used to treat CMA in children. We evaluated immunological effects, acquisition of desensitization, and adverse events. Immunological changes were examined by means of a meta-analysis of individual patient data. Results: Desensitization using OIT to cow's milk is 10.2 times more likely than in non-OIT-treated patients. The decrease in cow's milk-specific IgE levels was found to differ by 8.1 kUA/L between OIT-treated patients and those on an avoidance diet. This difference was not statistically significant (P=.318). Although side effects are common, they usually involve mild reactions that are easy to manage without parenteral epinephrine. Conclusion: OIT can be considered safe and effective (in terms of acquiring desensitization) and reasonably safe (mild-to-moderate adverse events, little need for parenteral epinephrine) in patients with CMA. Although OIT leads to changes in cow's milk-specific IgE levels, the differences between OIT-treated and non-OIT-treated patients are not significant. More studies are needed to evaluate other immunological changes that may occur, such as the increase in IgG4 levels (AU)

Antecedentes: La alergia a la leche de vaca (LV) es una de las principales causas de alergia en la infancia, que altera la calidad de vida de los pacientes y su familia. La evitación del alérgeno es difícil y pueden producirse reacciones adversas graves por ingesta accidental. Esto ha impulsado a la investigación de nuevas estrategias terapéuticas como es la inmunoterapia oral (ITO) para la alergia a LV. Objetivo: Determinar la evidencia actual acerca de los cambios inmunológicos, la eficacia y seguridad de la ITO como alternativa a la dieta de exclusión en el tratamiento del niño con alergia IgE-mediada a LV. Métodos: Revisión sistemática y posterior meta-análisis de todos los estudios controlados aleatorizados publicados hasta el momento actual en los que se emplea la ITO para el tratamiento de la alergia a la LV en niños, evaluando los cambios inmunológicos, la adquisición de desensibilización y los efectos adversos. Los cambios inmunológicos se evaluaron realizando un meta-análisis de los datos individuales de cada paciente. Resultados: La adquisición de desensibilización empleando la ITO con LV es 10.2 veces más frecuente que en los pacientes no tratados. Se observa una diferencia en el descenso de los niveles de IgE específica frente a LV en los pacientes tratados con ITO y los que llevan a cabo una dieta de evitación de 8.1, que no es estadísticamente significativa (p=0.318). Aunque los efectos secundarios son frecuentes, se trata en la mayoría de las ocasiones de reacciones leves de fácil manejo que no requieren el uso de adrenalina parenteral. Conclusión: Existe evidencia suficiente para poder considerar que la ITO es efectiva (en términos de adquisición de desensibilización) y razonablemente segura (efectos adversos leves-moderados, con escasos requerimientos de adrenalina parenteral) para el tratamiento de la alergia a LV. Produce modificaciones inmunológicas en cuanto a los niveles de IgE específica frente a LV, sin embargo, las diferencias no resultan significativas a corto plazo. Hacen falta más estudios para valorar otras cambios inmunológicos que pueden producirse, como es el incremento de los niveles de IgG4 (AU)

Spatio-temporal dynamics of genetic diversity in Sorghum bicolor in Niger.

The dynamics of crop genetic diversity need to be assessed to draw up monitoring and conservation priorities. However, few surveys have been conducted in centres of diversity. Sub-Saharan Africa is the centre of origin of sorghum. Most Sahel countries have been faced with major human, environmental and social changes in recent decades, which are suspected to cause genetic erosion. Sorghum is the second staple cereal in Niger, a centre of diversity for this crop. Niger was submitted to recurrent drought period and to major social changes during these last decades. We report here on a spatio-temporal analysis of sorghum genetic diversity, conducted in 71 villages covering the rainfall gradient and range of agro-ecological conditions in Niger's agricultural areas. We used 28 microsatellite markers and applied spatial and genetic clustering methods to investigate change in genetic diversity over a 26-year period (1976-2003). Global genetic differentiation between the two collections was very low (F (st) = 0.0025). Most of the spatial clusters presented no major differentiation, as measured by F (st), and showed stability or an increase in allelic richness, except for two of them located in eastern Niger. The genetic clusters identified by Bayesian analysis did not show a major change between the two collections in the distribution of accessions between them or in their spatial location. These results suggest that farmers' management has globally preserved sorghum genetic diversity in Niger.

Partial inhibition of the proteasome enhances the activity of the myelin basic protein promoter.

We have previously shown that low concentrations of a specific proteasome inhibitor accelerate exit from the cell cycle and enhance oligodendroglial cell (OLGc) differentiation. To elucidate the mechanisms involved in this process, OLGcs of the N20.1 cell line, transfected with a reporter gene driven by the MBP promoter, were treated with proteasome inhibitors and/or inhibitors of different signaling pathways. Partial proteasome inhibition resulted in enhanced activation of the MBP promoter which involved the tyrosine kinase, PI3-Akt and PKC pathways, accompanied by an increase in the levels of p21(Cip1), p27(Kip1) and Sp1 and by a decrease in Nkx2.2. Binding of Sp1 to DNA was also increased. These results were not observed when the Sp1 binding site was mutated. We conclude that the enhanced activation of the MBP promoter induced by partial inhibition of the proteasome could be due, at least in part, to the stabilization of p27(Kip1) and Sp1.

Phylogeographic evidence of crop neodiversity in sorghum.

Sorghum has shown the adaptability necessary to sustain its improvement during time and geographical extension despite a genetic foundation constricted by domestication bottlenecks. Initially domesticated in the northeastern part of sub-Saharan Africa several millenia ago, sorghum quickly spread throughout Africa, and to Asia. We performed phylogeographic analysis of sequence diversity for six candidate genes for grain quality (Shrunken2, Brittle2, Soluble starch synthaseI, Waxy, Amylose extender1, and Opaque2) in a representative sample of sorghum cultivars. Haplotypes along 1-kb segments appeared little affected by recombination. Sequence similarity enabled clustering of closely related alleles and discrimination of two or three distantly related groups depending on the gene. This scheme indicated that sorghum domestication involved structured founder populations, while confirming a specific status for the guinea margaritiferum subrace. Allele rooted genealogy revealed derivation relationships by mutation or, less frequently, by recombination. Comparison of germplasm compartments revealed contrasts between genes. Sh2, Bt2, and SssI displayed a loss of diversity outside the area of origin of sorghum, whereas O2 and, to some extent, Wx and Ae1 displayed novel variation, derived from postdomestication mutations. These are likely to have been conserved under the effect of human selection, thus releasing valuable neodiversity whose extent will influence germplasm management strategies.

Niger-wide assessment of in situ sorghum genetic diversity with microsatellite markers.

Understanding the geographical, environmental and social patterns of genetic diversity on different spatial scales is key to the sustainable in situ management of genetic resources. However, few surveys have been conducted on crop genetic diversity using exhaustive in situ germplasm collections on a country scale and such data are missing for sorghum in sub-Saharan Africa, its centre of origin. We report here a genetic analysis of 484 sorghum varieties collected in 79 villages evenly distributed across Niger, using 28 microsatellite markers. We found a high level of SSR diversity in Niger. Diversity varied between eastern and western Niger, and allelic richness was lower in the eastern part of the country. Genetic differentiation between botanical races was the first structuring factor (Fst = 0.19), but the geographical distribution and the ethnic group to which farmers belonged were also significantly associated with genetic diversity partitioning. Gene pools are poorly differentiated among climatic zones. The geographical situation of Niger, where typical western African (guinea), central African (caudatum) and eastern Sahelian African (durra) sorghum races converge, explained the high observed genetic diversity and was responsible for the interactions among the ethnic, geographical and botanical structure revealed in our study. After correcting for the structure of botanical races, spatial correlation of genetic diversity was still detected within 100 km, which may hint at limited seed exchanges between farmers. Sorghum domestication history, in relation to the spatial organisation of human societies, is therefore key information for sorghum in situ conservation programs in sub-Saharan Africa.

The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia.

In order to further characterize the still unknown mechanism of cuprizone-induced demyelination, we investigated its effect on rat primary oligodendroglial cell cultures. Cell viability was not significantly affected by this treatment. However, when concentrations of IFNgamma and/or TNFalpha having no deleterious effects per se on cell viability were added together with cuprizone, cell viability decreased significantly. In mitochondria isolated from cuprizone-treated glial cells, we observed a marked decrease in the activities of the various complexes of the respiratory chain, indicating a disruption of mitochondrial function. An enhancement in oxidant production was also observed in cuprizone and/or TNFalpha-treated oligodendroglial cells. In in vivo experiments, inhibition of microglial activation with minocycline prevented cuprizone-induced demyelination. Based on the above-mentioned results we suggest that these microglial cells appear to have a very active role in cuprizone-induced oligodendroglial cell death and demyelination, through the production and secretion of pro-inflammatory cytokines.