55 research outputs found
Influencia de los ligandos auxiliares en la reacciĂłn de activaciĂłn de enlaces CH promovida por Pd
EL trabajo desarrollado se basa en determinar el papel de los ligandos auxiliares en los procesos de funcionalizaciĂłn C-H catalizados por paladio. La sĂntesis orgĂĄnica a travĂ©s de procesos de funcionalizaciĂłn CH es una de las ĂĄreas que mĂĄs expansiĂłn ha sufrido en la quĂmica los Ășltimos 15 años. Esta metodologĂa permite la formaciĂłn de enlaces C-C, C-N, C-O y C-S (entre otros), y por tanto la creaciĂłn de nuevos esqueletos orgĂĄnicos, mediante la modificaciĂłn de enlaces C-H en precursores no modificados. En general, estos procesos estĂĄn catalizados por metales de transiciĂłn. Su ventaja fundamental es el ahorro de energĂa, etapas de reacciĂłn y tiempo, a la vez que se generan muchos menos residuos, y el control de la selectividad (quimio-, regio-, estĂ©reo-). Por todo ello, es probablemente la metodologĂa mĂĄs empleada ahora en sĂntesis orgĂĄnica avanzada.El presente TFG se ha centrado en la quĂmica de paladio, como metal mĂĄs representado en las funcionalizaciones CH, y en concreto en el papel de los ligandos auxiliares, verdaderos moduladores de la reactividad, en determinados tipos particulares de acoplamientos C-C. Este TFG abarca, , procesos de sĂntesis de orgĂĄnica de determinados compuestos, procesos de sĂntesis organometĂĄlica, y como se trasladan a reacciones catalĂticas. AdemĂĄs se ha de hacer especial hincapiĂ© en la relaciĂłn estructura- actividad (quĂ© ligandos producen quĂ© cambios). <br /
Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.
OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age
Next-generation sequencing improves precision medicine in hearing loss
Background: An early etiological diagnosis of hearing loss positively impacts childrenâs quality of life including language and cognitive development. Even though hearing loss associates with extremely high genetic and allelic heterogeneity, several studies have proven that Next-Generation Sequencing (NGS)-based gene panel testing significantly reduces the time between onset and diagnosis.Methods: In order to assess the clinical utility of our custom NGS GHELP panel, the prevalence of pathogenic single nucleotide variants, indels or copy number variants was assessed by sequencing 171 nuclear and 8 mitochondrial genes in 155 Spanish individuals with hearing loss.Results: A genetic diagnosis of hearing loss was achieved in 34% (52/155) of the individuals (5 out of 52 were syndromic). Among the diagnosed cases, 87% (45/52) and 12% (6/52) associated with autosomal recessive and dominant inheritance patterns respectively; remarkably, 2% (1/52) associated with mitochondrial inheritance pattern. Although the most frequently mutated genes in this cohort were consistent with those described in the literature (GJB2, OTOF or MYO7A), causative variants in less frequent genes such as TMC1, FGF3 or mitCOX1 were also identified. Moreover, 5% of the diagnosed cases (3/52) were associated with pathogenic copy number variants.Conclusion: The clinical utility of NGS panels that allows identification of different types of pathogenic variantsânot only single nucleotide variants/indels in both nuclear and mitochondrial genes but also copy number variantsâhas been demonstrated to reduce the clinical diagnostic odyssey in hearing loss. Thus, clinical implementation of genomic strategies within the regular clinical practice, and, more significantly, within the newborn screening protocols, is warranted
Prognostic factors of a lower CD4/CD8 ratio in long term viral suppression HIV infected children
Background
Combination antiretroviral therapy (cART) is associated with marked immune reconstitution. Although a long term viral suppression is achievable, not all children however, attain complete immunological recovery due to persistent immune activation. We use CD4/CD8 ratio like a marker of immune reconstitution.
Methods
Perinatal HIV-infected children who underwent a first-line cART, achieved viral suppression in the first year and maintained it for more than 5 years, with no viral rebound were included. Logistic models were applied to estimate the prognostic factors, clinical characteristics at cART start, of a lower CD4/CD8 ratio at the last visit.
Results
146 HIV-infected children were included: 77% Caucasian, 45% male and 28% CDC C. Median age at cART initiation was 2.3 years (IQR: 0.5-6.2). 42 (30%) children received mono-dual therapy previously to cART. Time of undetectable viral load was 9.5 years (IQR: 7.8, 12.5). 33% of the children not achieved CD4/CD8 ratio >1. Univariate analysis showed an association between CD4/CD8 <1 with lower CD4 nadir and baseline CD4; older age at diagnosis and at cART initiation; and a previous exposure to mono-dual therapy. Multivariate analysis also revealed relationship between CD4/CD8 <1 and lower CD4 nadir (OR: 1.002, CI 95% 1.000-1.004) as well as previous exposure to mono-dual therapy (OR: 0.16, CI 95% 0.003-0.720).
Conclusions
CD4/CD8 > 1 was not achieved in 33% of the children. Lower CD4 nadir and previous exposure to suboptimal therapy, before initiating cART, are factors showing independently association with a worse immune recovery (CD4/CD8 < 1)
Malignancies among children and young people with HIV in Western and Eastern Europe and Thailand
Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand
Objective: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV.
Design: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand.
Methods: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters.
Results: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean.
Conclusion: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age
Functional and regulatory profiling of energy metabolism in fission yeast
Background: The control of energy metabolism is fundamental for cell growth and function and anomalies in it
are implicated in complex diseases and ageing. Metabolism in yeast cells can be manipulated by supplying
different carbon sources: yeast grown on glucose rapidly proliferates by fermentation, analogous to tumour cells
growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration.
Results: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth.
Growth media and auxotrophic mutants strongly influenced respiratory metabolism. Most genes uncovered in the
mutant screens have not been implicated in respiration in budding yeast. We applied gene-expression profiling
approaches to compare steady-state fermentative and respiratory growth and to analyse the dynamic adaptation to
respiratory growth. The transcript levels of most genes functioning in energy metabolism pathways are coherently
tuned, reflecting anticipated differences in metabolic flows between fermenting and respiring cells. We show that
acetyl-CoA synthase, rather than citrate lyase, is essential for acetyl-CoA synthesis in fission yeast. We also investigated
the transcriptional response to mitochondrial damage by genetic or chemical perturbations, defining a retrograde
response that involves the concerted regulation of distinct groups of nuclear genes that may avert harm from
mitochondrial malfunction.
Conclusions: This study provides a rich framework of the genetic and regulatory basis of energy metabolism in fission
yeast and beyond, and it pinpoints weaknesses of commonly used auxotroph mutants for investigating metabolism. As
a model for cellular energy regulation, fission yeast provides an attractive and complementary system to budding yeast
Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.
Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (â„2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of â„1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch
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