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2.
Mol Cell ; 66(4): 447-457.e7, 2017 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-28506462

RESUMEN

The C-terminal transactivation domain (TAD) of BMAL1 (brain and muscle ARNT-like 1) is a regulatory hub for transcriptional coactivators and repressors that compete for binding and, consequently, contributes to period determination of the mammalian circadian clock. Here, we report the discovery of two distinct conformational states that slowly exchange within the dynamic TAD to control timing. This binary switch results from cis/trans isomerization about a highly conserved Trp-Pro imide bond in a region of the TAD that is required for normal circadian timekeeping. Both cis and trans isomers interact with transcriptional regulators, suggesting that isomerization could serve a role in assembling regulatory complexes in vivo. Toward this end, we show that locking the switch into the trans isomer leads to shortened circadian periods. Furthermore, isomerization is regulated by the cyclophilin family of peptidyl-prolyl isomerases, highlighting the potential for regulation of BMAL1 protein dynamics in period determination.


Asunto(s)
Factores de Transcripción ARNTL/metabolismo , Relojes Circadianos , Ritmo Circadiano , Factores de Transcripción ARNTL/química , Factores de Transcripción ARNTL/genética , Animales , Línea Celular Tumoral , Ciclofilinas/genética , Ciclofilinas/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Humanos , Isomerismo , Ratones , Mutación , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Filogenia , Prolina , Dominios Proteicos , Transducción de Señal , Relación Estructura-Actividad , Factores de Tiempo , Transfección , Triptófano
3.
Blood ; 140(1): 25-37, 2022 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-35507686

RESUMEN

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes, associated with higher rates of induction failure compared with those in B cell acute lymphoblastic leukemia. The potent immunotherapeutic approaches applied in B cell acute lymphoblastic leukemia, which have revolutionized the treatment paradigm, have proven more challenging in T-ALL, largely due to a lack of target antigens expressed on malignant but not healthy T cells. Unlike B cell depletion, T-cell aplasia is highly toxic. Here, we show that the chemokine receptor CCR9 is expressed in >70% of cases of T-ALL, including >85% of relapsed/refractory disease, and only on a small fraction (<5%) of normal T cells. Using cell line models and patient-derived xenografts, we found that chimeric antigen receptor (CAR) T-cells targeting CCR9 are resistant to fratricide and have potent antileukemic activity both in vitro and in vivo, even at low target antigen density. We propose that anti-CCR9 CAR-T cells could be a highly effective treatment strategy for T-ALL, avoiding T cell aplasia and the need for genome engineering that complicate other approaches.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores Quiméricos de Antígenos , Antígenos CD19 , Humanos , Inmunoterapia Adoptiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Receptores de Antígenos de Linfocitos T , Linfocitos T
4.
Haematologica ; 109(4): 1069-1081, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-37794795

RESUMEN

Advances in the clinical management of pediatric B-cell acute lymphoblastic leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is not directly dependent on MDM2 but correlates with degradation of MDM4. As such, STAT3 inhibition exhibits synergistic in vitro and in vivo anti-leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/ MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Niño , Humanos , Proteínas de Ciclo Celular/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Recurrencia , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
5.
BMC Neurol ; 23(1): 426, 2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-38036966

RESUMEN

BACKGROUND: Stroke survivors rate longer-term (> 2 years) psychological recovery as their top priority, but data on how frequently psychological consequences occur is lacking. Prevalence of cognitive impairment, depression/anxiety, fatigue, apathy and related psychological outcomes, and whether rates are stable in long-term stroke, is unknown. METHODS: N = 105 long-term stroke survivors (M [SD] age = 72.92 [13.01]; M [SD] acute NIH Stroke Severity Score = 7.39 [6.25]; 59.0% Male; M [SD] years post-stroke = 4.57 [2.12]) were recruited (potential N = 208). Participants completed 3 remote assessments, including a comprehensive set of standardized cognitive neuropsychological tests comprising domains of memory, attention, language, and executive function, and questionnaires on emotional distress, fatigue, apathy and other psychological outcomes. Ninety participants were re-assessed one year later. Stability of outcomes was assessed by Cohen's d effect size estimates and percent Minimal Clinically Important Difference changes between time points. RESULTS: On the Montreal Cognitive Assessment 65.3% scored < 26. On the Oxford Cognitive Screen 45.9% had at least one cognitive impairment. Attention (27.1%) and executive function (40%) were most frequently impaired. 23.5% and 22.5% had elevated depression/anxiety respectively. Fatigue (51.4%) and apathy (40.5%) rates remained high, comparable to estimates in the first-year post-stroke. Attention (d = -0.12; 85.8% stable) and depression (d = 0.09, 77.1% stable) were the most stable outcomes. Following alpha-adjustments, only perceptuomotor abilities (d = 0.69; 40.4% decline) and fatigue (d = -0.33; 45.3% decline) worsened over one year. Cognitive impairment, depression/anxiety, fatigue and apathy all correlated with worse quality of life. CONCLUSION: Nearly half of participants > 2 years post-event exhibited psychological difficulties including domains of cognition, mood, and fatigue, which impact long-term quality of life. Stroke is a chronic condition with highly prevalent psychological needs, which require monitoring and intervention development.


Asunto(s)
Disfunción Cognitiva , Accidente Cerebrovascular , Anciano , Femenino , Humanos , Masculino , Depresión/epidemiología , Depresión/etiología , Depresión/psicología , Fatiga/epidemiología , Fatiga/etiología , Calidad de Vida , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/psicología , Persona de Mediana Edad , Anciano de 80 o más Años
6.
Ophthalmic Physiol Opt ; 43(4): 702-709, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36974523

RESUMEN

PURPOSE: Patient-Reported Experience Measures (PREMs) act to identify the patient's objective experience while receiving care. PREM data can provide feedback to professionals on patients' personal experience of care processes, quality of care and insight into patient expectations. This can support service improvements and person-centeredness of care. Despite this, PREMs are not currently routinely collected for any primary eye care services in Wales, inclusive of the National Low Vision Service Wales (LVSW). The primary aim of this project was to develop and pilot a community low-vision, service-specific, PREM (LVSWPREM). METHODS: The development of the LVSWPREMs was performed in partnership with LVSW service users. Fourteen people attended three successive, 1.5-h online focus groups, and informed the development of a draft of LVSWPREMs inclusive of item generation and face validity. Following several rounds of iterative improvements based on the feedback gathered during the focus groups, LVSWPREM V4.0 was agreed upon and piloted for a period of 3 months within Hywel Dda University Health Board. Reliability of the final LVSWPREM V4.0 was assessed using Cronbach α. RESULTS: The final LVSWPREMs consisted of two parts: (1) LVSW-specific items and (2) a generic PREM tool approved by the Welsh Government for use across National Health Service Wales. Reliability analyses with item deletion were conducted for each construct separately using Cronbach α and were 0.94 and 0.63 for parts 1 and 2, respectively. CONCLUSION: The LVSWPREM is a validated, reliable tool, which can be used to provide information regarding patients' experience of accessing a community-based, low-vision service. Developed in partnership with people with vision impairment, it has the potential to be useful as a means of patient engagement and improvement in the delivery of high-quality healthcare.


Asunto(s)
Medicina Estatal , Baja Visión , Humanos , Reproducibilidad de los Resultados , Medición de Resultados Informados por el Paciente
7.
Neuropsychol Rehabil ; 33(4): 680-702, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-35257640

RESUMEN

We investigated the relationships between cognitive change following stroke, awareness of cognitive impairments, and mood to further understanding of change processes influencing psychological outcomes post-stroke in line with the "Y-shaped" process model. Patients (n = 143; Mage = 73 years, SD = 13.73; 74 males) were assessed at 3-weeks (T1) and 6-months (T2) post-stroke and had completed the Oxford Cognitive Screen (T1 and T2), the Cognitive Failures Questionnaire (CFQ; T2), and the Hospital Anxiety and Depression Scale (HADS; T2). An ANCOVA controlling for disability relating to activities of daily living (ADL) revealed that awareness of cognitive impairment was significantly lower in participants with moderate-severe cognitive impairment. Regression analysis indicated that greater awareness of cognitive impairment and reduced independence in ADL were associated with greater emotional distress at T2. Cognitive improvement was associated with lower emotional distressat T2. Contrary to the awareness hypothesis, moderation analyses suggest that this effect was largest for those most cognitively impaired at T1. Findings emphasize the importance of monitoring stroke patients' capacity to be self-aware when assessing and formulating long-term post-stroke distress and have potential implications for improving long-term emotional status in those most cognitively impaired post-stroke, e.g., through psychoeducation, cognitive rehabilitation, and emotional support.


Asunto(s)
Disfunción Cognitiva , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Masculino , Humanos , Anciano , Actividades Cotidianas/psicología , Accidente Cerebrovascular/complicaciones , Disfunción Cognitiva/complicaciones , Cognición
8.
J Exp Bot ; 73(12): 3978-3990, 2022 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-35383838

RESUMEN

Change in phenology has been an important component in crop evolution, and selection for earlier flowering through a reduction in environmental sensitivity has helped broaden adaptation in many species. Natural variation for flowering in domesticated pea (Pisum sativum L.) has been noted and studied for decades, but there has been no clear account of change relative to its wild progenitor. Here we examined the genetic control of differences in flowering time between wild P. sativum ssp. humile and a typical late-flowering photoperiodic P. s. sativum accession in a recombinant inbred population under long and short photoperiods. Our results confirm the importance of the major photoperiod sensitivity locus Hr/PsELF3a and identify two other loci on chromosomes 1 (DTF1) and 3 (DTF3) that contribute to earlier flowering in the domesticated line under both photoperiods. The domesticated allele at a fourth locus on chromosome 6 (DTF6) delays flowering under long days only. Map positions, inheritance patterns, and expression analyses in near-isogenic comparisons imply that DTF1, DTF3, and DTF6 represent gain-of-function alleles of the florigen/antiflorigen genes FTa3, FTa1, and TFL1c/LF, respectively. This echoes similar variation in chickpea and lentil, and suggests a conserved route to reduced photoperiod sensitivity and early phenology in temperate pulses.


Asunto(s)
Flores , Pisum sativum , Ritmo Circadiano , Florigena/metabolismo , Flores/genética , Pisum sativum/genética , Pisum sativum/metabolismo , Fotoperiodo
9.
Nat Immunol ; 10(10): 1118-24, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19749763

RESUMEN

Natural killer (NK) cells are a subset of lymphocytes crucial for innate immunity and modification of adaptive immune responses. In contrast to commitment to the T cell or B cell lineage, little is known about NK cell lineage commitment. Here we show that the basic leucine zipper (bZIP) transcription factor E4BP4 (also called NFIL3) is essential for generation of the NK cell lineage. E4BP4-deficient mice (Nfil3(-/-); called 'E4bp4(-/-)' here) had B cells, T cells and NKT cells but specifically lack NK cells and showed severely impaired NK cell-mediated cytotoxicity. Overexpression of E4bp4 was sufficient to increase NK cell production from hematopoietic progenitor cells. E4BP4 acted in a cell-intrinsic manner 'downstream' of the interleukin 15 receptor (IL-15R) and through the transcription factor Id2. E4bp4(-/-) mice may provide a model for definitive analysis of the contribution of NK cells to immune responses and pathologies.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Diferenciación Celular/inmunología , Citotoxicidad Inmunológica/inmunología , Células Asesinas Naturales/citología , Animales , Linfocitos B/inmunología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Diferenciación Celular/genética , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Citotoxicidad Inmunológica/genética , Citometría de Flujo , Expresión Génica/inmunología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Proteína 2 Inhibidora de la Diferenciación/genética , Proteína 2 Inhibidora de la Diferenciación/inmunología , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Células Asesinas Naturales/inmunología , Subgrupos Linfocitarios/inmunología , Ratones , Ratones Noqueados , Células T Asesinas Naturales/inmunología , Receptores de Interleucina-15/genética , Receptores de Interleucina-15/inmunología , Receptores de Interleucina-15/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/inmunología
10.
Neuroimage ; 223: 117289, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32835822

RESUMEN

Investigation of relationships between age-related changes in regional brain volumes and changes in domain-specific cognition could provide insights into the neural underpinnings of individual differences in cognitive aging. Domain-specific cognition (memory, verbal fluency, visuospatial ability) and tests of executive function and attention (Trail-Making Test Part A and B) and 47 brain volumes of interest (VOIs) were assessed in 836 Baltimore Longitudinal Study of Aging participants with mean follow-up of 4.1 years (maximum 23.1 years). To examine the correlation between changes in domain-specific cognition and changes in brain volumes, we used bivariate linear mixed effects models with unstructured variance-covariance structure to estimate longitudinal trajectories for each variable of interest and correlations among the random effects of these measures. Higher annual rates of memory decline were associated with greater volume loss in 14 VOIs primarily within the temporal and occipital lobes. Verbal fluency decline was associated with greater ventricular enlargement and volume loss in 24 VOIs within the frontal, temporal, and parietal lobes. Decline in visuospatial ability was associated with volume loss in 3 temporal and parietal VOIs. Declines on the attentional test were associated with volume loss in 4 VOIs located within temporal and parietal lobes. Greater declines on the executive function test were associated with greater ventricular enlargement and volume loss in 10 frontal, parietal, and temporal VOIs. Our findings highlight domain-specific patterns of regional brain atrophy that may contribute to individual differences in cognitive aging.


Asunto(s)
Envejecimiento/fisiología , Envejecimiento/psicología , Encéfalo/anatomía & histología , Envejecimiento Cognitivo/fisiología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tamaño de los Órganos
11.
Neuroimage ; 221: 117182, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32702483

RESUMEN

Studies suggest that concussions may be related to increased risk of neurodegenerative diseases, such as Chronic Traumatic Encephalopathy and Alzheimer's Disease. Most neuroimaging studies show effects of concussions in frontal and temporal lobes of the brain, yet the long-term impacts of concussions on the aging brain have not been well studied. We examined neuroimaging data from 51 participants (mean age at first imaging visit=65.1 ± 11.23) in the Baltimore Longitudinal Study of Aging (BLSA) who reported a concussion in their medical history an average of 23 years prior to the first imaging visit, and compared them to 150 participants (mean age at first imaging visit=66.6 ± 10.97) with no history of concussion. Participants underwent serial structural MRI over a mean of 5.17±6.14 years and DTI over a mean of 2.92±2.22 years to measure brain structure, as well as 15O-water PET over a mean of 5.33±2.19 years to measure brain function. A battery of neuropsychological tests was also administered over a mean of 11.62±7.41 years. Analyses of frontal and temporal lobe regions were performed to examine differences in these measures between the concussion and control groups at first imaging visit and in change over time. Compared to those without concussion, participants with a prior concussion had greater brain atrophy in temporal lobe white matter and hippocampus at first imaging visit, which remained stable throughout the follow-up visits. Those with prior concussion also showed differences in white matter microstructure using DTI, including increased radial and axial diffusivity in the fornix/stria terminalis, anterior corona radiata, and superior longitudinal fasciculus at first imaging visit. In 15O-water PET, higher resting cerebral blood flow was seen at first imaging visit in orbitofrontal and lateral temporal regions, and both increases and decreases were seen in prefrontal, cingulate, insular, hippocampal, and ventral temporal regions with longitudinal follow-up. There were no significant differences in neuropsychological performance between groups. Most of the differences observed between the concussed and non-concussed groups were seen at the first imaging visit, suggesting that concussions can produce long-lasting structural and functional alterations in temporal and frontal regions of the brain in older individuals. These results also suggest that many of the reported short-term effects of concussion may still be apparent later in life.


Asunto(s)
Envejecimiento , Conmoción Encefálica , Corteza Cerebral , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Sustancia Blanca , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Envejecimiento/fisiología , Baltimore , Conmoción Encefálica/diagnóstico por imagen , Conmoción Encefálica/patología , Conmoción Encefálica/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Imagen de Difusión Tensora , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Sustancia Blanca/fisiopatología
12.
Emerg Med J ; 37(9): 586-587, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32873548

RESUMEN

A short cut review was carried out to whether the FAST screening tool is more accurate than the ROSIER tool at correctly identifying those with stroke in the prehospital setting. 9 papers presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. It is concluded that FAST and ROSIER have similar sensitivities in the recognition of stroke, with ROSIER demonstrating a higher specificity in the prehospital setting.


Asunto(s)
Servicios Médicos de Urgencia , Accidente Cerebrovascular/diagnóstico , Medicina de Emergencia Basada en la Evidencia , Humanos , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad
13.
Emerg Med J ; 37(11): 725-728, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33097554

RESUMEN

A short cut review was carried out to establish whether intra-articular injection of local anaesthetic is an effective alternative to intravenous analgesia with or without sedation to facilitate reduction of acute shoulder dislocations. Eleven studies were considered relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these studies are tabulated. The clinical bottom line is that intra-articular injection of local anaesthetic is a safe and effective method of providing procedural analgesia for the reduction of acute shoulder dislocations.


Asunto(s)
Anestesia Local/métodos , Anestésicos Locales/administración & dosificación , Sedación Consciente , Manejo del Dolor/métodos , Luxación del Hombro/terapia , Medicina de Emergencia Basada en la Evidencia , Humanos , Inyecciones Intraarticulares
14.
Stroke ; 50(10): 2775-2782, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31510902

RESUMEN

Background and Purpose- Cerebral small vessel disease (SVD) is the most common cause of vascular cognitive impairment, with a significant proportion of cases going on to develop dementia. We explore the extent to which diffusion tensor image segmentation technique (DSEG; which characterizes microstructural damage across the cerebrum) predicts both degree of cognitive decline and conversion to dementia, and hence may provide a useful prognostic procedure. Methods- Ninety-nine SVD patients (aged 43-89 years) underwent annual magnetic resonance imaging scanning (for 3 years) and cognitive assessment (for 5 years). DSEG-θ was used as a whole-cerebrum measure of SVD severity. Dementia diagnosis was based Diagnostic and Statistical Manual of Mental Disorders V criteria. Cox regression identified which DSEG measures and vascular risk factors were related to increased risk of dementia. Linear discriminant analysis was used to classify groups of stable versus subsequent dementia diagnosis individuals. Results- DSEG-θ was significantly related to decline in executive function and global cognition (P<0.001). Eighteen (18.2%) patients converted to dementia. Baseline DSEG-θ predicted dementia with a balanced classification rate=75.95% and area under the receiver operating characteristic curve=0.839. The best classification model included baseline DSEG-θ, change in DSEG-θ, age, sex, and premorbid intelligence quotient (balanced classification rate of 79.65%; area under the receiver operating characteristic curve=0.903). Conclusions- DSEG is a fully automatic technique that provides an accurate method for assessing brain microstructural damage in SVD from a single imaging modality (diffusion tensor imaging). DSEG-θ is an important tool in identifying SVD patients at increased risk of developing dementia and has potential as a clinical marker of SVD severity.


Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Demencia/diagnóstico por imagen , Demencia/etiología , Interpretación de Imagen Asistida por Computador/métodos , Adulto , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Imagen de Difusión Tensora/métodos , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad
15.
Neuroimage ; 188: 572-583, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30557663

RESUMEN

White matter microstructure can be measured with diffusion tensor imaging (DTI). While increasing age is a predictor of white matter (WM) microstructure changes, roles of other possible modifiers, such as cardiovascular risk factors, APOE ε4 allele status and biological sex have not been clarified. We investigated 665 cognitively normal participants from the Baltimore Longitudinal Study of Aging (age 50-95, 56.7% female) with a total of 1384 DTI scans. WM microstructure was assessed by fractional anisotropy (FA) and mean diffusivity (MD). A vascular burden score was defined as the sum of five risk factors (hypertension, obesity, elevated cholesterol, diabetes and smoking status). Linear mixed effects models assessed the association of baseline vascular burden on baseline and on rates of change of FA and MD over a mean follow-up of 3.6 years, while controlling for age, race, and scanner type. We also compared DTI trajectories in APOE ε4 carriers vs. non-carriers and men vs. women. At baseline, higher vascular burden was associated with lower FA and higher MD in many WM structures including association, commissural, and projection fibers. Higher baseline vascular burden was also associated with greater longitudinal decline in FA in the hippocampal part of the cingulum and the fornix (crus)/stria terminalis and splenium of the corpus callosum, and with greater increases in MD in the splenium of the corpus callosum. APOE ε4 carriers did not differ from non-carriers in baseline DTI metrics but had greater decline in FA in the genu and splenium of the corpus callosum. Men had higher FA and lower MD in multiple WM regions at baseline but showed greater increase in MD in the genu of the corpus callosum. Women showed greater decreases over time in FA in the gyrus part of the cingulum, compared to men. Our findings show that modifiable vascular risk factors (1) have a negative impact on white matter microstructure and (2) are associated with faster microstructural deterioration of temporal WM regions and the splenium of the corpus callosum in cognitively normal adults. Reducing vascular burden in aging could modify the rate of WM deterioration and could decrease age-related cognitive decline and impairment.


Asunto(s)
Envejecimiento/patología , Apolipoproteína E4 , Cuerpo Calloso/patología , Enfermedades Vasculares , Sustancia Blanca/patología , Anciano , Anciano de 80 o más Años , Cuerpo Calloso/diagnóstico por imagen , Imagen de Difusión Tensora , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores Sexuales , Enfermedades Vasculares/epidemiología , Sustancia Blanca/diagnóstico por imagen
16.
Euro Surveill ; 24(13)2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30940316

RESUMEN

BACKGROUND: In 2015, Bristol (South West England) experienced a large increase in cases of meticillin-resistant Staphylococcus aureus (MRSA) infection in people who inject drugs (PWID). AIM: We aimed to characterise and estimate the prevalence of MRSA colonisation among PWID in Bristol and test evidence of a clonal outbreak. METHODS: PWID recruited through an unlinked-anonymous community survey during 2016 completed behavioural questionnaires and were screened for MRSA. Univariable logistic regression examined associations with MRSA colonisation. Whole-genome sequencing used lineage-matched MRSA isolates, comparing PWID (screening and retrospective bacteraemia samples from 2012-2017) with non-PWID (Bristol screening) in Bristol and national reference laboratory database samples. RESULTS: The MRSA colonisation prevalence was 8.7% (13/149) and was associated with frequently injecting in public places (odds ratio (OR): 5.5; 95% confidence interval (CI):1.34-22.70), recent healthcare contact (OR: 4.3; 95% CI: 1.34-13.80) and injecting in groups of three or more (OR: 15.8; 95% CI: 2.51-99.28). People reporting any one of: injecting in public places, injection site skin and soft tissue infection or hospital contact accounted for 12/13 MRSA positive cases (sensitivity 92.3%; specificity 51.5%). Phylogenetic analysis identified a dominant clade associated with infection and colonisation among PWID in Bristol belonging to ST5-SCCmecIVg. CONCLUSIONS: MRSA colonisation in Bristol PWID is substantially elevated compared with general population estimates and there is evidence of clonal expansion, community-based transmission and increased infection risk related to the colonising strain. Targeted interventions, including community screening and suppression therapy, education and basic infection control are needed to reduce MRSA infections in PWID.


Asunto(s)
Bacteriemia/epidemiología , Infecciones Comunitarias Adquiridas/epidemiología , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Infecciones Estafilocócicas/epidemiología , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto , Infecciones Comunitarias Adquiridas/microbiología , Infecciones Comunitarias Adquiridas/transmisión , Estudios Transversales , Femenino , Humanos , Masculino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/genética , Epidemiología Molecular , Tipificación Molecular , Filogenia , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Abuso de Sustancias por Vía Intravenosa/epidemiología , Encuestas y Cuestionarios , Reino Unido/epidemiología , Secuenciación Completa del Genoma
17.
Alzheimers Dement ; 15(12): 1558-1567, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31561966

RESUMEN

INTRODUCTION: Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. METHODS: In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). RESULTS: In men, older baseline age was associated with greater effects of APOE-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability, or processing speed. DISCUSSION: Results highlight the importance of considering sex and age when assessing APOE-ε4-associated vulnerability to cognitive decline.


Asunto(s)
Alelos , Apolipoproteína E4/genética , Trastornos del Conocimiento/genética , Factores de Edad , Anciano , Función Ejecutiva , Femenino , Humanos , Estudios Longitudinales , Masculino , Memoria , Pruebas Neuropsicológicas/estadística & datos numéricos , Factores Sexuales , Población Blanca
18.
Stroke ; 49(3): 586-593, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29438074

RESUMEN

BACKGROUND AND PURPOSE: Cerebral small-vessel disease is a major cause of cognitive impairment. Perivascular spaces (PvS) occur in small-vessel disease, but their relationship to cognitive impairment remains uncertain. One reason may be difficulty in distinguishing between lacunes and PvS. We determined the relationship between baseline PvS score and PvS volume with change in cognition over a 5-year follow-up. We compared this to the relationship between baseline lacune count and total lacune volume with cognition. In addition, we examined change in PvS volume over time. METHODS: Data from the prospective SCANS study (St Georges Cognition and Neuroimaging in Stroke) of patients with symptomatic lacunar stroke and confluent leukoaraiosis were used (n=121). Multimodal magnetic resonance imaging was performed annually for 3 years and neuropsychological testing annually for 5 years. Lacunes were manually identified and distinguished from PvS. PvS were rated using a validated visual rating scale, and PvS volumes calculated using T1-weighted images. Linear mixed-effect models were used to determine the impact of PvS and lacunes on cognition. RESULTS: Baseline PvS scores or volumes showed no association with cognitive indices. No change was detectable in PvS volumes over the 3 years. In contrast, baseline lacunes associated with all cognitive indices and predicted cognitive decline over the 5-year follow-up. CONCLUSIONS: Although a feature of small-vessel disease, PvS are not a predictor of cognitive decline, in contrast to lacunes. This study highlights the importance of carefully differentiating between lacunes and PvS in studies investigating vascular cognitive impairment.


Asunto(s)
Disfunción Cognitiva , Imagen por Resonancia Magnética , Imagen Multimodal , Accidente Vascular Cerebral Lacunar , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Accidente Vascular Cerebral Lacunar/complicaciones , Accidente Vascular Cerebral Lacunar/diagnóstico por imagen , Accidente Vascular Cerebral Lacunar/fisiopatología
19.
Adv Exp Med Biol ; 962: 201-216, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28299659

RESUMEN

The t(12;21)(p13;q22) translocation is the most frequently occurring single genetic abnormality in pediatric leukemia. This translocation results in the fusion of the ETV6 and RUNX1 genes. Since its discovery in the 1990s, the function of the ETV6-RUNX1 fusion gene has attracted intense interest. In this chapter, we will summarize current knowledge on the clinical significance of ETV6-RUNX1, the experimental models used to unravel its function in leukemogenesis, the identification of co-operating mutations and the mechanisms responsible for their acquisition, the function of the encoded transcription factor and finally, the future therapeutic approaches available to mitigate the associated disease.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Carcinogénesis/genética , Carcinogénesis/patología , Humanos , Leucemia/patología , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción/genética , Proteína ETS de Variante de Translocación 6
20.
Br J Haematol ; 171(2): 263-272, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26115422

RESUMEN

Here, we report a high incidence of PAX5 abnormalities observed in 32/68 (47%) of patients with genetically unclassified childhood precursor B-cell acute lymphoblastic leukaemia (pre-B ALL). Various deletions, gains, mutations and rearrangements of PAX5 comprised 45%, 12%, 29% and 14%, respectively, of the abnormalities found. 28% of patients showed more than one abnormality of the gene, implying bi-allelic impairment of PAX5. Novel PAX5-RHOXF2, PAX5-ELK3 and PAX5-CBFA2T2 rearrangements, which lead to aberrant expression of PAX5, were also identified. PAX5 rearrangements demonstrated a complex mechanism of formation including concurrent duplications/deletions of PAX5 and its partner genes. Finally, the splice variant c.1013-2A>G, seen in two patients with loss of one PAX5 allele, was confirmed to be germ-line in one patient and somatic in the other. PAX5 alterations were also found to be clinically associated with a higher white blood cell count (P = 0·015). These findings contribute to the knowledge of PAX5 alterations and their role in the pathogenesis of pre-B ALL.

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