According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer's disease (AD) may lead to reduced activity of target neurons in ...cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r = 0.90, p < 0.0001; right: r = 0.597, p = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r = 0.551, p = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group.
This work addresses the strategies of concealment of the condition of forced displaced boys, girls and adolescents in Colombian schools. From the theoretical level, silence is conceived as a social ...practice. The general objective is to understand the silencing of the displaced condition by the victims themselves. To achieve the proposed goal, a qualitative methodological approach is adopted, as it is interesting to know how displaced girls and boys perceive the educational reality. A total of 26 interviews between open and semi-structured have been conducted. The sample has been composed of children, adolescents, parents, and professionals linked to the educational context. The technique of analysis followed is the theory based as an analysis technique. Specifically, we have followed an axial coding procedure defined by Strauss and Corbin. The conclusions show how meaningful each profile of respondents gives their action to silence the displaced person's condition. And how, these strategies paradoxically act as a mechanism of exclusion in the educational context.
The diagnosis of Mendelian disorders has notably advanced with integration of whole exome and genome sequencing (WES and WGS) in clinical practice. However, challenges in variant interpretation and ...uncovered variants by WES still leave a substantial percentage of patients undiagnosed. In this context, integrating RNA sequencing (RNA-seq) improves diagnostic workflows, particularly for WES inconclusive cases. Additionally, functional studies are often necessary to elucidate the impact of prioritized variants on gene expression and protein function.
Our study focused on three unrelated male patients (P1-P3) with ATP6AP1-CDG (congenital disorder of glycosylation), presenting with intellectual disability and varying degrees of hepatopathy, glycosylation defects, and an initially inconclusive diagnosis through WES. Subsequent RNA-seq was pivotal in identifying the underlying genetic causes in P1 and P2, detecting ATP6AP1 underexpression and aberrant splicing. Molecular studies in fibroblasts confirmed these findings and identified the rare intronic variants c.289-233C > T and c.289-289G > A in P1 and P2, respectively. Trio-WGS also revealed the variant c.289-289G > A in P3, which was a de novo change in both patients. Functional assays expressing the mutant alleles in HAP1 cells demonstrated the pathogenic impact of these variants by reproducing the splicing alterations observed in patients.
Our study underscores the role of RNA-seq and WGS in enhancing diagnostic rates for genetic diseases such as CDG, providing new insights into ATP6AP1-CDG molecular bases by identifying the first two deep intronic variants in this X-linked gene. Additionally, our study highlights the need to integrate RNA-seq and WGS, followed by functional validation, in routine diagnostics for a comprehensive evaluation of patients with an unidentified molecular etiology.
Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that activates the cellular response to hypoxia. The HIF1α subunit is constantly synthesized and degraded under normoxia, but ...degradation is rapidly inhibited when oxygen levels drop. Oxygen-dependent hydroxylation by prolyl-4-hydroxylases (PHD) mediates HIF1α proteasome degradation. Brain ischemia limits the availability not only of oxygen but also of glucose. We hypothesized that this circumstance could have a modulating effect on HIF. We assessed the separate involvement of oxygen and glucose in HIF1α regulation in differentiated neuroblastoma cells subjected to ischemia. We report higher transcriptional activity and HIF1α expression under oxygen deprivation in the presence of glucose (OD), than in its absence (oxygen and glucose deprivation, OGD). Unexpectedly, HIF1α was not degraded at reoxygenation after an episode of OGD. This was not due to impairment of proteasome function, but was associated with lower HIF1α hydroxylation. Krebs cycle metabolites fumarate and succinate are known inhibitors of PHD, while α-ketoglutarate is a co-substrate of the reaction. Lack of HIF1α degradation in the presence of oxygen was accompanied by a very low α-ketoglutarate/fumarate ratio. Furthermore, treatment with a fumarate analogue prevented HIF1α degradation under normoxia. In all, our data suggest that postischemic metabolic alterations in Krebs cycle metabolites impair HIF1α degradation in the presence of oxygen by decreasing its hydroxylation, and highlight the involvement of metabolic pathways in HIF1α regulation besides the well known effects of oxygen.
La pregunta principal de este artículo es la siguiente: ¿cómo estudiar la dimensión espacial de la ciudad y la vida urbana? Antes que presentar un estudio de caso, en estas páginas, se desarrolla un ...planteamiento teórico-metodológico para abordar el
caso de las grandes ciudades. El objetivo principales ofrecer una aproximación multidimensional y aterrizada de la construcción social de la ciudad movimiento. La primera parte revisa los diferentes aspectos de la perspectiva de la ciudad como espacio movimiento. La segunda parte analiza la componente de las prácticas y la subjetividad espacial integrada en esta concepción de la ciudad como espacio movimiento. El tercer apartado aborda las afectividades y la corporeidad de la ciudad movimiento. Posteriormente, se presenta la perspectiva situacional y las redes topológicas como formas de aprehender fragmentos densos de lo urbano que integren lo planteado en los apartados previos. Para cerrar con unas reflexiones finales que destacan tanto la potencialidad de tal aproximación como sus limitaciones.
Analysis of coenzyme Q(10) in lymphocytes by HPLC-MS/MS Arias, A; García-Villoria, J; Rojo, A ...
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences,
2012-Nov-01, 20121101, Letnik:
908
Journal Article
Recenzirano
Coenzyme Q(10) (CoQ(10)) deficiency syndromes are potentially treatable disorders. Skeletal muscle is the most widely accepted tissue for their study, but sampling is an invasive procedure. Cultured ...skin fibroblasts seem to improve the biochemical diagnosis, but their growth requires a certain period of time. Our aim was to set up a minimally invasive, fast and reliable analytical procedure to measure CoQ(10) in lymphocytes, to prevent any delay in diagnosing primary CoQ(10) deficiency. HPLC-MS/MS analysis of CoQ(10) showed high sensitivity and specificity. The reference range was established in apparently healthy volunteers (n=33); the mean of CoQ(10) in lymphocytes was 107nmol/g protein (95% confidence interval: 105-120) and 2.0nmol/UCS (95% confidence interval: 2.06-2.46). Therefore, the range was narrower when normalized to units of citrate synthase (UCS) than when normalized to grams of protein. The method was linear from 0.01 to 1μM with a good precision and sensitivity (limit of quantification 0.01μM). Intra-assay and inter-assay coefficients of variation were lower than 13%. Recovery was higher than 95%. In our hands, lymphocytes seem to be a reliable matrix as they reflect intracellular content of CoQ(10). In addition, they can be obtained by a minimally invasive procedure (venipuncture).
To describe the role of local anaesthetic blocks as a potential cause of paracentral acute middle maculopathy (PAMM) after uneventful ocular surgery.
Retrospective, observational, international, ...multicentre case series. Nine cases of PAMM with associated visual loss following uneventful ocular surgery with local anaesthetic blocks were observed in a 9-year period (2011-2020). Demographic, ocular and systemic data, anaesthetic data and surgical details were collected. Visual acuity (VA), fundus photography, fluorescein angiography, optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) images were reviewed.
All nine cases were associated with decreased VA at 24 h postoperative check (ranging from hand movement to 20/200). A hyperreflective band within the middle retinal layers was observed in the structural OCT in the acute phase, evolving to thinning and atrophy of the inner retinal layers in sequential follow-up scans performed. Fluorescein angiography showed delayed perfusion in early arterial phase with normal perfusion in late venous phases. OCTA showed decreased perfusion in the deep capillary plexus. Visual recovery was variable between cases during follow-up (ranging from count fingers to 20/20).
A combination of a vasoconstrictive effect of the anaesthetic agent, an intraocular pressure spike and a mechanical effect of the volume of anaesthetic injected may result in decreased retinal artery perfusion and be evidenced as PAMM in OCT scans. PAMM may present as a potential complication of local anaesthetic blocks in cases of unexpected visual loss after uneventful ocular surgery.
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