Frecuencia elevada del alelo ε4 del gen de apolipoproteína E en una muestra de pacientes con síndrome Down

La enfermedad de Alzheimer es la entidad más frecuente enpacientes con síndrome Down (SD) y a su vez uno de losfactores de riesgo para el desarrollo de esta entidad es lapresencia del alelo ε4 de apolipoproteína E. En el presenteestudio se evaluó el genotipo de apolipoproteína E en ungrupo de pacientes de ambos sexos con síndrome Down.Los resultados muestran que hay una frecuencia aumentadapara el alelo ε4 en esta población cuando se hizo la comparacióncon los valores previamente encontrados para unamuestra de la población del Departamento de Risaralda queno presentaban SD la cual se tomó como control

Frecuencia elevada del alelo ε4 del gen de apolipoproteína E en una muestra de pacientes con síndrome Down

La enfermedad de Alzheimer es la entidad más frecuente enpacientes con síndrome Down (SD) y a su vez uno de losfactores de riesgo para el desarrollo de esta entidad es lapresencia del alelo ε4 de apolipoproteína E. En el presenteestudio se evaluó el genotipo de apolipoproteína E en ungrupo de pacientes de ambos sexos con síndrome Down.Los resultados muestran que hay una frecuencia aumentadapara el alelo ε4 en esta población cuando se hizo la comparacióncon los valores previamente encontrados para unamuestra de la población del Departamento de Risaralda queno presentaban SD la cual se tomó como control

Frecuencia elevada del alelo ε4 del gen de apolipoproteína E en una muestra de pacientes con síndrome Down

La enfermedad de Alzheimer es la entidad más frecuente enpacientes con síndrome Down (SD) y a su vez uno de losfactores de riesgo para el desarrollo de esta entidad es lapresencia del alelo ε4 de apolipoproteína E. En el presenteestudio se evaluó el genotipo de apolipoproteína E en ungrupo de pacientes de ambos sexos con síndrome Down.Los resultados muestran que hay una frecuencia aumentadapara el alelo ε4 en esta población cuando se hizo la comparacióncon los valores previamente encontrados para unamuestra de la población del Departamento de Risaralda queno presentaban SD la cual se tomó como control

Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

Background: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E 04), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E 02). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons

International Neurotrauma Training Based on North-South Collaborations: Results of an Inter-institutional Program in the Era of Global Neurosurgery.

Objective: Shortage of general neurosurgery and specialized neurotrauma care in low resource settings is a critical setback in the national surgical plans of low and middle-income countries (LMIC). Neurotrauma fellowship programs typically exist in high-income countries (HIC), where surgeons who fulfill the requirements for positions regularly stay to practice. Due to this issue, neurosurgery residents and medical students from LMICs do not have regular access to this kind of specialized training and knowledge-hubs. The objective of this paper is to present the results of a recently established neurotrauma fellowship program for neurosurgeons of LMICs in the framework of global neurosurgery collaborations, including the involvement of specialized parallel education for neurosurgery residents and medical students. Methods: The Global Neurotrauma Fellowship (GNTF) program was inaugurated in 2015 by a multi-institutional collaboration between a HIC and an LMIC. The course organizers designed it to be a 12-month program based on adapted neurotrauma international competencies with the academic support of the Barrow Neurological Institute at Phoenix Children's Hospital and Meditech Foundation in Colombia. Since 2018, additional support from the UK, National Institute of Health Research (NIHR) Global Health Research in Neurotrauma Project from the University of Cambridge enhanced the infrastructure of the program, adding a research component in global neurosurgery and system science. Results: Eight fellows from Brazil, Venezuela, Cuba, Pakistan, and Colombia have been trained and certified via the fellowship program. The integration of international competencies and exposure to different systems of care in high-income and low-income environments creates a unique environment for training within a global neurosurgery framework. Additionally, 18 residents (Venezuela, Colombia, Ecuador, Peru, Cuba, Germany, Spain, and the USA), and ten medical students (the United Kingdom, USA, Australia, and Colombia) have also participated in elective rotations of neurotrauma and critical care during the time of the fellowship program, as well as in research projects as part of an established global surgery initiative. Conclusion: We have shown that it is possible to establish a neurotrauma fellowship program in an LMIC based on the structure of HIC formal training programs. Adaptation of the international competencies focusing on neurotrauma care in low resource settings and maintaining international mentoring and academic support will allow the participants to return to practice in their home-based countries

Informal entrepreneurship in developing economies: the impacts of starting-up unregistered on firm performance

To advance understanding of the entrepreneurship process in developing economies, this paper evaluates whether registered enterprises that initially avoid the cost of registration, and focus their resources on overcoming other liabilities of newness, lay a stronger foundation for subsequent growth. Analyzing World Bank Enterprise Survey data across 127 countries, and controlling for other firm performance determinants, registered enterprises that started-up unregistered and spent longer operating unregistered are revealed to have significantly higher subsequent annual sales, employment and productivity growth rates compared with those that registered from the outset. The theoretical and policy implications are then discussed

Critical Dynamics in Genetic Regulatory Networks: Examples from Four Kingdoms

The coordinated expression of the different genes in an organism is essential to sustain functionality under the random external perturbations to which the organism might be subjected. To cope with such external variability, the global dynamics of the genetic network must possess two central properties. (a) It must be robust enough as to guarantee stability under a broad range of external conditions, and (b) it must be flexible enough to recognize and integrate specific external signals that may help the organism to change and adapt to different environments. This compromise between robustness and adaptability has been observed in dynamical systems operating at the brink of a phase transition between order and chaos. Such systems are termed critical. Thus, criticality, a precise, measurable, and well characterized property of dynamical systems, makes it possible for robustness and adaptability to coexist in living organisms. In this work we investigate the dynamical properties of the gene transcription networks reported for S. cerevisiae, E. coli, and B. subtilis, as well as the network of segment polarity genes of D. melanogaster, and the network of flower development of A. thaliana. We use hundreds of microarray experiments to infer the nature of the regulatory interactions among genes, and implement these data into the Boolean models of the genetic networks. Our results show that, to the best of the current experimental data available, the five networks under study indeed operate close to criticality. The generality of this result suggests that criticality at the genetic level might constitute a fundamental evolutionary mechanism that generates the great diversity of dynamically robust living forms that we observe around us

The Smallest Known Genomes of Multicellular and Toxic Cyanobacteria: Comparison, Minimal Gene Sets for Linked Traits and the Evolutionary Implications

Cyanobacterial morphology is diverse, ranging from unicellular spheres or rods to multicellular structures such as colonies and filaments. Multicellular species represent an evolutionary strategy to differentiate and compartmentalize certain metabolic functions for reproduction and nitrogen (N2) fixation into specialized cell types (e.g. akinetes, heterocysts and diazocytes). Only a few filamentous, differentiated cyanobacterial species, with genome sizes over 5 Mb, have been sequenced. We sequenced the genomes of two strains of closely related filamentous cyanobacterial species to yield further insights into the molecular basis of the traits of N2 fixation, filament formation and cell differentiation. Cylindrospermopsis raciborskii CS-505 is a cylindrospermopsin-producing strain from Australia, whereas Raphidiopsis brookii D9 from Brazil synthesizes neurotoxins associated with paralytic shellfish poisoning (PSP). Despite their different morphology, toxin composition and disjunct geographical distribution, these strains form a monophyletic group. With genome sizes of approximately 3.9 (CS-505) and 3.2 (D9) Mb, these are the smallest genomes described for free-living filamentous cyanobacteria. We observed remarkable gene order conservation (synteny) between these genomes despite the difference in repetitive element content, which accounts for most of the genome size difference between them. We show here that the strains share a specific set of 2539 genes with >90% average nucleotide identity. The fact that the CS-505 and D9 genomes are small and streamlined compared to those of other filamentous cyanobacterial species and the lack of the ability for heterocyst formation in strain D9 allowed us to define a core set of genes responsible for each trait in filamentous species. We presume that in strain D9 the ability to form proper heterocysts was secondarily lost together with N2 fixation capacity. Further comparisons to all available cyanobacterial genomes covering almost the entire evolutionary branch revealed a common minimal gene set for each of these cyanobacterial traits

Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence