RESUMEN

Tissues are active materials where epithelial turnover, immune surveillance, and remodeling of stromal cells such as macrophages all regulate form and function. Scattering modalities such as Brillouin microscopy (BM) can non-invasively access mechanical signatures at GHz. However, our traditional understanding of tissue material properties is derived mainly from modalities which probe mechanical properties at different frequencies. Thus, reconciling measurements amongst these modalities remains an active area. Here, we compare optical tweezer active microrheology (OT-AMR) and Brillouin microscopy (BM) to longitudinally map brain development in the larval zebrafish. We determine that each measurement is able to detect a mechanical signature linked to functional units of the brain. We demonstrate that the corrected BM-Longitudinal modulus using a density factor correlates well with OT-AMR storage modulus at lower frequencies. We also show that the brain tissue mechanical properties are dependent on both the neuronal architecture and the presence of macrophages. Moreover, the BM technique is able to delineate the contributions to mechanical properties of the macrophage from that due to colony stimulating factor 1 receptor (CSF1R) mediated stromal remodeling. Here, our data suggest that macrophage remodeling is instrumental in the maintenance of tissue mechanical homeostasis during development. Moreover, the strong agreement between the OT-AM and BM further demonstrates that scattering-based technique is sensitive to both large and minute structural modification in vivo.

RESUMEN

Biophysical profiling of primary tumors has revealed that individual tumor cells fall along a highly heterogeneous continuum of mechanical phenotypes. One idea is that a subset of tumor cells is "softer" to facilitate detachment and escape from the primary site, a step required to initiate metastasis. However, it has also been postulated that cells must be able to deform and generate sufficient force to exit into distant sites. Here, we aimed to dissect the mechanical changes that occur during extravasation and organ colonization. Using multiplexed methods of intravital microscopy and optical tweezer based active microrheology, we obtained longitudinal images and mechanical profiles of cells during organ colonization in vivo. We determined that cells were softer, more liquid like upon exit of the vasculature but stiffened and became more solid like once in the new organ microenvironment. We also determined that a YAP mediated mechanogenotype influenced the global dissemination in our in vivo and in vitro models and that reducing mechanical heterogeneity could reduce extravasation. Moreover, our high throughput analysis of mechanical phenotypes of patient samples revealed that this mechanics was in part regulated by the external hydrodynamic forces that the cancer cells experienced within capillary mimetics. Our findings indicate that disseminated cancer cells can keep mutating with a continuum landscape of mechano-phenotypes, governed by the YAP-mediated mechanosensing of hydrodynamic flow.

RESUMEN

Professional or governmental agencies and organizations have developed guidelines to define the problem and evaluate and manage patients with Post-Acute Sequelae of SARS CoV-2 (PASC). Multidisciplinary models largely exist in academic centers and larger cities; however, most care for PASC patients is provided by the primary care providers. The American Academy of Physical Medicine and Rehabilitation has been in the forefront in releasing consensus statements as a part of the long COVID collaborative.

Asunto(s)

COVID-19 , Prestación Integrada de Atención de Salud , Medicina Física y Rehabilitación , Humanos , Síndrome Post Agudo de COVID-19 , Consenso , SARS-CoV-2 , Progresión de la Enfermedad

RESUMEN

The microenvironment is an important regulator of intertumoral trafficking and activity of immune cells. Understanding how the immune system can be tailored to maintain anti-tumor killing responses in metastatic disease remains an important goal. Thus, immune mediated eradication of metastasis requires the consideration of organ specific microenvironmental cues. Using a xenograft model of melanoma metastasis in adult zebrafish, we perturbed the dynamic balance between the infiltrating immune cells in the metastatic setting using a suite of different transgenic zebrafish. We employed intravital imaging coupled with metabolism imaging (FLIM) to visualize and map the organ specific metabolism with near simultaneity in multiple metastatic lesions. Of all the MHC complexes examined for brain and skeletal metastases, we determined that there is an organ specific expression of mhc1uba (human ortholog, MR1) for both the melanoma cells and the resident and infiltrating immune cells. Specifically, immune clusters did not express mhc1uba in brain metastatic lesions in immune competent fish. Finally, the differential immune response drove organ specific metabolism where tumor glycolysis was increased in brain metastases compared to skeletal and parental lines as measured using fluorescence lifetime imaging microscopy (FLIM). As MR1 belongs to the MHC class I molecules and is a target of immunotherapeutic drugs, we believe that our data presents an opportunity to understand the relationship between organ specific tumor metabolism and drug efficacy in the metastatic setting.

RESUMEN

Loss of SFPQ is a hallmark of motor degeneration in ALS and prevents maturation of motor neurons when occurring during embryogenesis. Here, we show that in zebrafish, developing motor neurons lacking SFPQ exhibit axon extension, branching and synaptogenesis defects, prior to degeneration. Subcellular transcriptomics reveals that loss of SFPQ in neurons produces a complex set of aberrant intron-retaining (IR) transcripts coding for neuron-specific proteins that accumulate in neurites. Some of these local IR mRNAs are prematurely terminated within the retained intron (PreT-IR). PreT-IR mRNAs undergo intronic polyadenylation, nuclear export, and localise to neurites in vitro and in vivo. We find these IR and PreT-IR mRNAs enriched in RNAseq datasets of tissue from patients with familial and sporadic ALS. This shared signature, between SFPQ-depleted neurons and ALS, functionally implicates SFPQ with the disease and suggests that neurite-centred perturbation of alternatively spliced isoforms drives the neurodegenerative process.

Asunto(s)

Esclerosis Amiotrófica Lateral , Animales , Intrones/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Axones/metabolismo , Neuronas Motoras/metabolismo

RESUMEN

Regulation of pre-mRNA splicing and polyadenylation plays a profound role in neurons by diversifying the proteome and modulating gene expression in response to physiological cues. Although most of the pre-mRNA processing is thought to occur in the nucleus, numerous splicing regulators are also found in neurites. Here, we show that U1-70K/SNRNP70, a component of the major spliceosome, localizes in RNA-associated granules in zebrafish axons. We identify the extra-nuclear SNRNP70 as an important regulator of motor axonal growth, nerve-dependent acetylcholine receptor (AChR) clustering, and neuromuscular synaptogenesis. This cytoplasmic pool has a protective role for a limited number of transcripts regulating their abundance and trafficking inside axons. Moreover, non-nuclear SNRNP70 regulates splice variants of transcripts such as agrin, thereby controlling synapse formation. Our results point to an unexpected, yet essential, function of non-nuclear SNRNP70 in axonal development, indicating a role of spliceosome proteins in cytoplasmic RNA metabolism during neuronal connectivity.

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Precursores del ARN , Pez Cebra , Animales , Pez Cebra/genética

RESUMEN

ABSTRACT: Histoplasmosis is a dimorphic fungal infection, which is rare outside endemic pockets in North, Central, and South America, Asia, and Africa. Herein, we describe a woman in her 80s living in the Scottish Borders region of the United Kingdom with a recent diagnosis of granulomatous rosacea, who on receiving escalating immunosuppression for suspected sarcoidosis, and long-standing rheumatoid arthritis developed a striking eruption involving her eyelids along with painful ulceration of the oral and nasal mucosa. Histopathologic examination of the skin and mucosal lesions demonstrated granulomatous inflammation with numerous yeast forms of fungal organisms with morphological characteristics of Histoplasma species. This was confirmed to be H. capsulatum on fungal culture and direct panfungal polymerase chain reaction assay. Although the patient had not left the United Kingdom for more than 20 years, she gave a travel history involving multiple trips to countries where histoplasmosis is known to occur, before that. This case exemplifies the challenges involved in making a diagnosis of histoplasmosis in nonendemic regions for both clinicians and pathologists alike. In this particular patient, the diagnostic difficulties were compounded by the clinicopathological overlap with other cutaneous and systemic granulomatous disorders like granulomatous rosacea and suspected sarcoidosis and also the exceptionally long latency period between the purported historical primary infection and recent recrudescence. We highlight this unusual case to increase an awareness of histoplasmosis, which is very rare in nonendemic regions like the United Kingdom and involves cases acquired during residence in or travel to endemic areas, to ensure its prompt recognition and treatment.

Asunto(s)

Histoplasmosis , Rosácea , Sarcoidosis , Humanos , Femenino , Histoplasmosis/diagnóstico , Histoplasmosis/tratamiento farmacológico , Sarcoidosis/diagnóstico , Reino Unido , Inmunosupresores/efectos adversos , Recurrencia

RESUMEN

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. CONCLUSION: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.

Asunto(s)

Trastornos del Neurodesarrollo , Miosina Tipo IIB no Muscular , Actinas , Cilios/genética , Proteínas Hedgehog/genética , Humanos , Cadenas Pesadas de Miosina/genética , Trastornos del Neurodesarrollo/genética , Miosina Tipo IIB no Muscular/genética

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Introducción. En este artículo se presenta una reflexión sobre la necesidad de tener una visión holística en la problemática de la prematurez, para que los equipos del área de salud puedan tener una comprensión de la multiplicidad de factores presentes en el parto prematuro, y sus consecuencias para el menor, la madre, los familiares y el personal de salud involucrado. Tema de reflexión. El tema se sustenta en dos investigaciones realizadas con las madres, los padres y los niños beneficiarios del Programa Madre Canguro en un hospital del Estado, en dos momentos, 2012 y 2014, con algunos de los autores del presente artículo. Conclusiones. Además de la revisión de la literatura científica relacionada con el tema y la problemática, se concluye que, bajo una mirada holística, se comprende de manera integral la problemática y se propicia una mejor comunicación con los padres; con el equipo de la atención en salud, se logra un manejo transdisciplinario, superando los objetos de estudios aislados. Se da así un abordaje integrador y significativo en la cotidianidad de cada actor, desde la piel, con el Programa Madre Canguro, hasta la racionalidad de la ciencia.

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Introduction. This article presents a reflection on the need for a holistic view of the problem of premature births, so that healthcare teams can understand the multiplicity of factors present in premature births, and its consequences for the minor, the mother, the family members, and the healthcare staff involved. Topic of reflection. The topic is based on two investigations carried out with mothers, fathers, and children's beneficiaries of the Mother Kangaroo Program in a State hospital, at two moments, 2012 and 2014, with some of the authors of this article. Conclusions. In addition to the review of the scientific literature related to the topic and the problem, it is concluded that, under a holistic view, the problem is understood in a comprehensive way and better communication with the parents is encouraged. With the healthcare team, cross-disciplinary handling is achieved, overcoming the objects of isolated studies. As such, there is an integrative and significant approach in the daily life of each actor, from the skin, with the Mother Kangaroo Program, to the rationality of science.

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Introdução. Este artigo apresenta uma reflexão sobre a necessidade de se ter uma visão holística da problemática da prematuridade, para que as equipes da área da saúde possam ter uma compreensão da multiplicidade de fatores presentes no parto prematuro, e suas consequências para a criança, a mãe, os familiares e o pessoal de saúde envolvido. Tópico de reflexão. O tema é baseado em duas pesquisas realizadas com mães, pais e filhos beneficiários do Programa Mãe Canguru em um hospital estadual, em dois momentos, 2012 e 2014, com alguns dos autores deste artigo. Conclusões. Além da revisão da literatura científica relacionada ao tópico e ao problema, conclui-se que, sob uma visão holística, o problema é plenamente compreendido e incentiva-se uma melhor comunicação com os pais; com a equipe de saúde, consegue-se uma gestão transdisciplinar, superando os objetos de estudos isolados. Isto proporciona uma abordagem integradora e significativa no cotidiano de cada ator, desde a pele, com o Programa Mãe Canguru, até a racionalidade da ciência.

Asunto(s)

Recien Nacido Prematuro , Desarrollo Infantil , Grupo de Atención al Paciente , Antropometría , Atención Integral de Salud , Signos Vitales , Método Madre-Canguro

RESUMEN

INTRODUCTION: Mechanical thrombectomy (MT) can improve outcomes following ischaemic stroke. Patient selection for MT is predominantly based on physiological and imaging parameters. We assessed whether people living with pre-stroke frailty had differing outcomes following MT. METHODS: We included consecutive patients undergoing MT at a UK comprehensive stroke centre. We calculated a cumulative deficits frailty index to identify pre-stroke frailty in those patients presenting directly to the centre. Frailty was defined as an index score ≥ 0.24. We assessed univariable and multivariable association between pre-stroke frailty and stroke outcomes. Our primary outcomes were modified Rankin Scale (mRS) and mortality at 90 days. RESULTS: Of 175 patients who underwent MT (2014-2018), we identified frailty in 49 (28%). Frail and non-frail patients had similar rates of thrombolysis administration, successful recanalization and onset to recanalization times. Those with pre-stroke frailty had higher 24 hour National Institutes of Health Stroke Scale (12(IQR: 8-17) versus 3(IQR: 2-13); P = 0.001); were less likely to be independent (mRS 0-2: 18% versus 61%; P < 0.001) and more likely to die (47% versus 14%; P < 0.001) within 90 days. Adjusting for age, baseline NIHSS and thrombolysis, frailty remained a strong, independent predictor of poor clinical outcome at 90 days (Death OR: 3.12 (95% CI: 1.32-7.4); dependency OR: 3.04 (95%CI: 1.10-8.44). Age was no longer a predictor of outcome when adjusted for frailty. CONCLUSION: Pre-stroke frailty is prevalent in real-world patients eligible for MT and is an important predictor of poor outcomes. Routine assessment of pre-stroke frailty could help decision-making around patient selection for MT.

Asunto(s)

Isquemia Encefálica , Fragilidad , Accidente Cerebrovascular , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/terapia , Estudios de Cohortes , Fragilidad/complicaciones , Fragilidad/diagnóstico , Humanos , Estudios Retrospectivos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/terapia , Trombectomía/efectos adversos , Trombectomía/métodos , Resultado del Tratamiento

RESUMEN

The RNA-binding protein SFPQ plays an important role in neuronal development and has been associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. Here, we report that loss of sfpq leads to premature termination of multiple transcripts due to widespread activation of previously unannotated cryptic last exons (CLEs). These SFPQ-inhibited CLEs appear preferentially in long introns of genes with neuronal functions and can dampen gene expression outputs and/or give rise to short peptides interfering with the normal gene functions. We show that one such peptide encoded by the CLE-containing epha4b mRNA isoform is responsible for neurodevelopmental defects in the sfpq mutant. The uncovered CLE-repressive activity of SFPQ is conserved in mouse and human, and SFPQ-inhibited CLEs are found expressed across ALS iPSC-derived neurons. These results greatly expand our understanding of SFPQ function and uncover a gene regulation mechanism with wide relevance to human neuropathologies.

Asunto(s)

Esclerosis Amiotrófica Lateral/genética , Codón sin Sentido , Exones/genética , Factor de Empalme Asociado a PTB/genética , Animales , Secuencia de Bases , Embrión no Mamífero/embriología , Embrión no Mamífero/metabolismo , Regulación del Desarrollo de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Hibridación in Situ/métodos , Intrones/genética , Ratones , Neuronas/metabolismo , Pez Cebra/embriología , Pez Cebra/genética

RESUMEN

Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase (GAA) enzyme activity is measured by flow-injection tandem mass spectrometry (FIA/MS/MS) and full sequencing of the GAA gene is performed as a second-tier test in all newborns with low GAA enzyme activity [<2.10 micromole/L/h]. A total of 115 newborns had low GAA enzyme activity and abnormal genetic testing and were referred to metabolic centers. Two newborns were diagnosed with Infantile Onset Pompe Disease (IOPD), and 31 newborns were confirmed to have Late Onset Pompe Disease (LOPD). The incidence of IOPD + LOPD was 1:16,095. A total of 30 patients were compound heterozygous for one pathogenic and one variant of unknown significance (VUS) mutation or two VUS mutations and were defined as suspected LOPD. The incidence of IOPD + LOPD + suspected LOPD was 1: 8431 in PA. We also found 35 carriers, 15 pseudodeficiency carriers, and 2 false positive newborns.

RESUMEN

Hydrofluoric acid elicits cell cycle arrest through a mechanism that has long been presumed to be linked with the high affinity of fluoride to metals. However, we have recently found that the acid stress from fluoride exposure is sufficient to elicit many of the hallmark phenotypes of fluoride toxicity. Here we report the systematic screening of genes involved in fluoride resistance and general acid resistance using a genome deletion library in Saccharomyces cerevisiae. We compare these to a variety of acids - 2,4-dinitrophenol, FCCP, hydrochloric acid, and sulfuric acid - none of which has a high metal affinity. Pathways involved in endocytosis, vesicle trafficking, pH maintenance, and vacuolar function are of particular importance to fluoride tolerance. The majority of genes conferring resistance to fluoride stress also enhanced resistance to general acid toxicity. Genes whose expression regulate Golgi-mediated vesicle transport were specific to fluoride resistance, and may be linked with fluoride-metal interactions. These results support the notion that acidity is an important and underappreciated principle underlying the mechanisms of fluoride toxicity.

RESUMEN

Age-dependent changes in metabolism can manifest as cellular lipid accumulation, but how this accumulation is regulated or impacts longevity is poorly understood. We find that Saccharomyces cerevisiae accumulate lipid droplets (LDs) during aging. We also find that over-expressing BNA2, the first Biosynthesis of NAD+ (kynurenine) pathway gene, reduces LD accumulation during aging and extends lifespan. Mechanistically, this LD accumulation during aging is not linked to NAD+ levels, but is anti-correlated with metabolites of the shikimate and aromatic amino acid biosynthesis (SA) pathways (upstream of BNA2), which produce tryptophan (the Bna2p substrate). We provide evidence that over-expressed BNA2 skews glycolytic flux from LDs towards the SA-BNA pathways, effectively reducing LDs. Importantly, we find that accumulation of LDs does not shorten lifespan, but does protect aged cells against stress. Our findings reveal how lipid accumulation impacts longevity, and how aging cell metabolism can be rewired to modulate lipid accumulation independently from longevity.

Asunto(s)

Metabolismo de los Lípidos , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismo , Vías Biosintéticas , Frío , Gotas Lipídicas/metabolismo , Metaboloma , NAD/metabolismo , Saccharomyces cerevisiae/citología , Proteínas de Saccharomyces cerevisiae/metabolismo , Ácido Shikímico/metabolismo , Estrés Fisiológico

RESUMEN

BACKGROUND: Phenylketonuria (PKU) is a rare autosomal recessive disorder caused by mutations in the gene encoding phenylalanine hydroxylase, an enzyme that converts phenylalanine to tyrosine. Untreated, PKU is characterized by a range of neuropsychological and neurocognitive impairments. Due to ubiquitous newborn genetic screening programs, treatment for PKU can be commenced shortly after birth and can prevent many of the severe manifestations of the disease. However, lifelong management is critical for patients with PKU as high levels of phenylalanine are neurotoxic. As for all chronic diseases, long-term management can be challenging and most adult patients with PKU become lost to follow-up (LTFU). A survey of PKU clinics across the United States and a multidisciplinary Expert Meeting were conducted to develop best practices to engage LTFU patients with PKU. RESULTS: We defined LTFU patients with PKU as "patients with no contact with the clinic for at least 2 consecutive years." Combining the results from our survey and our discussion at the Expert Meeting, we have prepared six best practice recommendations to engage LTFU patients with PKU: 1) Ensure patients are aware of the current treatment guidelines for PKU; 2) Communicate to patients any new treatment and diet options as they become available for PKU; 3) Consider the neuropsychological and neurocognitive aspects of PKU; 4) Prioritize motivated LTFU patients; 5) Explore new approaches of outreach to LTFU patients; and 6) Formalize approaches to track and/or identify PKU patients. CONCLUSION: We strongly advocate the importance of engaging LTFU patients with PKU and encourage implementation of our best practice recommendations. Although it takes time and effort to engage LTFU patients, we believe that clinics are capable of supporting this significant patient group.

RESUMEN

Activated factor X is a key component of the coagulation cascade, but whether it directly regulates pathological cardiac remodeling is unclear. In mice subjected to pressure overload stress, cardiac factor X mRNA expression and activity increased concurrently with cardiac hypertrophy, fibrosis, inflammation and diastolic dysfunction, and responses blocked with a low coagulation-independent dose of rivaroxaban. In vitro, neurohormone stressors increased activated factor X expression in both cardiac myocytes and fibroblasts, resulting in activated factor X-mediated activation of protease-activated receptors and pro-hypertrophic and -fibrotic responses, respectively. Thus, inhibition of cardiac-expressed activated factor X could provide an effective therapy for the prevention of adverse cardiac remodeling in hypertensive patients.

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More women die from heart disease than any other illness. This article focuses on risk factors and their prevalence in women along with strategies for preventing this disease. Armed with this information, the NP can play a major role in preventing cardiovascular deaths in women.

Asunto(s)

Cardiopatías/prevención & control , Enfermeras Practicantes , Rol de la Enfermera , Femenino , Humanos , Evaluación en Enfermería , Factores de Riesgo

RESUMEN

BACKGROUND: Mechanical thrombectomy has revolutionised the treatment of acute ischaemic stroke due to large vessel occlusion. It is well recognised that patients are more likely to benefit when reperfusion happens quickly, however, there is uncertainty as to how best to deliver this service. OBJECTIVES: To compare outcomes of patients in Northern -Ireland who underwent thrombectomy via direct admission to the single endovascular centre (mothership [MS]) with those transferred from primary stroke centres (drip-and-ship [DS]). METHODS: Analysis was conducted on the records of all patients who underwent thrombectomy from January 2014 to December 2017 inclusive. The primary outcome measure was 3 months functional independence (modified Rankin Score [mRS] 0-2). Secondary outcome measures were full recovery (mRS 0) at 3 months, symptomatic intracranial haemorrhage (sICH) rates and mortality rates. RESULTS: Two hundred fourteen patients underwent thrombectomy (MS 124, DS 90). Patients in the MS group were older (median 73 vs. 70 years, p = 0.026), but there was no significant difference in baseline National Institutes of Health Stroke Scale (median 15 MS vs. 16.5 DS, p = 0.162) or thrombolysis rates (41.9% MS vs. 54.4% DS, p = 0.070) between the groups. Time from stroke onset to arrival at thrombectomy centre was shorter in the MS group (median 71 vs. 218 min, p < 0.001) but door to groin puncture time was shorter in the DS group (median 30 vs. 60 min, p < 0.001). There was no significant difference in 3 months functional independence (51.6% MS vs. 62.2% DS, p = 0.123), or in the secondary outcome measures of full recovery (21.8% MS vs. 12.2% DS, p = 0.071), sICH (MS 0.8%, DS 4.4%, p = 0.082) and mortality (MS 24.2%, DS 20.0%, p = 0.468). CONCLUSIONS: Our analysis showed similar outcomes after thrombectomy in the MS and DS groups. For patients potentially eligible for thrombectomy, rapid access to the endovascular centre is essential to optimise both the number of patients treated and the outcomes achieved.

Asunto(s)

Isquemia Encefálica/terapia , Procedimientos Endovasculares , Admisión del Paciente , Transferencia de Pacientes , Accidente Cerebrovascular/terapia , Trombectomía , Terapia Trombolítica , Tiempo de Tratamiento , Adulto , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/mortalidad , Isquemia Encefálica/fisiopatología , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Irlanda del Norte , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/fisiopatología , Trombectomía/efectos adversos , Trombectomía/mortalidad , Terapia Trombolítica/efectos adversos , Terapia Trombolítica/mortalidad , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

Type 2 Diabetes Mellitus (T2DM) is the most prevalent form of diabetes in the USA, thus, the identification of biomarkers that could be used to predict the progression from prediabetes to T2DM would be greatly beneficial. Recently, circulating RNA including microRNAs (miRNAs) present in various body fluids have emerged as potential biomarkers for various health conditions, including T2DM. Whereas studies that examine the changes of miRNA spectra between healthy controls and T2DM individuals have been reported, the goal of this study is to conduct a baseline comparison of prediabetic individuals who either progress to T2DM, or remain prediabetic. Using an advanced small RNA sequencing library construction method that improves the detection of miRNA species, we identified 57 miRNAs that showed significant concentration differences between progressors (progress from prediabetes to T2DM) and non-progressors. Among them, 26 have been previously reported to be associated with T2DM in either body fluids or tissue samples. Some of the miRNAs identified were also affected by obesity. Furthermore, we identified miRNA panels that are able to discriminate progressors from non-progressors. These results suggest that upon further validation these miRNAs may be useful to predict the risk of conversion to T2DM from prediabetes.

Asunto(s)

Biomarcadores/sangre , Ácidos Nucleicos Libres de Células/sangre , Diabetes Mellitus Tipo 2/diagnóstico , MicroARNs/sangre , Anciano , Estudios de Casos y Controles , Ácidos Nucleicos Libres de Células/genética , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Pronóstico

RESUMEN

Resumen El objetivo de este estudio es valuar las evidencias de validez de una aproximación unidimensional al WHOQOL-BREF en adultos mayores. Se aplicó el instrumento a una muestra probabilística de 510 adultos mayores de Bucaramanga y Manizales adscritos a centros día o centros vida. Se realizaron análisis Rasch de ajuste de categorías de respuesta, ajuste de los ítems y de las personas, funcionamiento diferencial de los ítems, unidimensionalidad y confiabilidad. Fue necesario colapsar las categorías de respuesta de cinco a cuatro opciones. Todos los ítems se ajustaron de forma adecuada al modelo de Rasch, al igual que una alta proporción de adultos mayores. Se identificó funcionamiento diferencial tipo C en cinco ítems, aunque se pudo establecer que este tiene un bajo impacto en la medida. La consistencia interna fue de 0,92, y la confiabilidad de los ítems de 0,98. Se presenta el mapa de Wright. A partir del WHOQOL-BREF se puede obtener una medida unidimensional a nivel de intervalo de calidad de vida en adultos mayores.

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Abstract This research aimed to evaluate the validity evidences of a unidimensional approach to WHOQOL-BEF in older adults. The instrument was applied to a probabilistic sample of 510 older adults from Bucaramanga and Manizales beneficiaries of day care institutions. Rasch analyses of category function, item and person fit, differential item functioning, unidimensionality and reliability analyses were performed. The category structure had to be collapsed from five to four choices. All items and a high proportion of older adults showed adequate adjustment to the Rasch model. Differential item functioning was identified in five items, although their impact on overall measure was low. Internal consistency was 0.92 and item reliability 0.98. Wright's map is presented. A unidimensional, interval-scale measure of quality of life can be obtained from the WHOQOL-BREF for older adults.