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There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF.
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Insuficiencia Cardíaca , Infarto del Miocardio , Ratas , Ratones , Humanos , Animales , Porcinos , Infarto del Miocardio/patología , Infarto del Miocardio/terapia , Insuficiencia Cardíaca/metabolismo , Miocitos Cardíacos/metabolismo , Función Ventricular Izquierda , Macrófagos/metabolismoRESUMEN
BACKGROUND: Treatment for people with kidney disease is often associated with complicated combinations of medicines. Logistical challenges with traditiona paper-based prescribing means that these patients are particularly susceptible to medication-relation errors and harm. AIM: To improve the quality of care that people with kidney disease receive across Wales through a Value-Based digital transformation programme. SETTING: Renal units within the National Welsh Renal Clinical Network (WRCN). DEVELOPMENT: A novel Electronic Prescribing & Medicines Administration (EPMA) system, integrated into a patient care record and linked to a patient portal was developed in South West Wales (SWW) region of the WRCN, enabled by the Welsh Government (WG) Efficiency Through Technology Fund. National upscale was enabled through the WG Transformation Fund. IMPLEMENTATION: EPMA was designed and rolled out initially in SWW region of the WRCN (2018). A dedicated delivery team used the blueprint to finalise and implement a strategy for successful national roll-out eventually across all Wales (completed 2021). EVALUATION: A multi-factorial approach was employed, as both the technology itself and the healthcare system within which it would be introduced, were complex. Continuous cycles of action research involving informal and formal qualitative interviews with service-users ensured that EPMA was accessible and optimally engaging to all target stakeholders (patients and staff). Results confirmed that EPMA was successful in improving the quality of care that people with kidney disease receive across Wales, contributed to Value-Based outcomes, and put people who deliver and access care at the heart of transformation. CONCLUSION: Key findings of this study align directly with the national design principles to drive change and transformation, put forward by the WG in their plan for Health and Social Care: prevention and early intervention; safety; independence; voice; seamless care.
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Atención a la Salud , Humanos , GalesRESUMEN
We demonstrate magnetic confinement of an ultracold neutral plasma (UCNP) created at the null of a biconic cusp, or quadrupole magnetic field. Initially, the UCNP expands due to electron thermal pressure. As the plasma encounters stronger fields, expansion slows and the density distribution molds to the field. UCNP electrons are strongly magnetized over most of the plasma, while ion magnetization is only significant at the boundaries. Observations suggest that electrons and ions are predominantly trapped by magnetic mirroring and ambipolar electric fields, respectively. Confinement times approach 0.5 ms, while unmagnetized plasmas dissipate on a timescale of a few tens of microseconds.
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The profile and trajectory of cognitive impairment in mitochondrial disease are poorly defined. This systematic review sought to evaluate the current literature on cognition in mitochondrial disease, and to determine future research directions. A systematic review was conducted, employing PubMed, Medline, Psycinfo, Embase and Web of Science, and 360-degree citation methods. English language papers on adult patients were included. The literature search yielded 2421 articles, of which 167 met inclusion criteria. Case reports and reviews of medical reports of patients yielded broad diagnoses of dementia, cognitive impairment and cognitive decline. In contrast, systematic investigations of cognitive functioning using detailed cognitive batteries identified focal cognitive rather than global deficits. Results were variable, but included visuospatial functioning, memory, attention, processing speed and executive functions. Conclusions from studies have been hampered by small sample sizes, variation in genotype and the breadth and depth of assessments undertaken. Comprehensive cognitive research with concurrent functional neuroimaging and physical correlates of mitochondrial disease in larger samples of well-characterized patients may discern the aetiology and progression of cognitive deficits. These data provide insights into the pattern and trajectory of cognitive impairments, which are invaluable for clinical monitoring, health planning and clinical trial readiness.
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Trastornos del Conocimiento/etiología , Disfunción Cognitiva/etiología , Enfermedades Mitocondriales/complicaciones , Adulto , Cognición/fisiología , Trastornos del Conocimiento/psicología , Disfunción Cognitiva/psicología , Progresión de la Enfermedad , Función Ejecutiva/fisiología , Humanos , Memoria/fisiología , Enfermedades Mitocondriales/psicologíaRESUMEN
OBJECTIVE: Mitochondrial disease is a disorder of energy metabolism that affects 1 in 4300 adults in the UK. Pregnancy is associated with physiological demands that have implications for energy metabolism. We were interested to know how pregnancy was affected in women with mitochondrial disease, particularly those with the most common pathogenic mutation m.3243A>G. DESIGN: Retrospective case-comparison study. POPULATION/SETTING: Sixty-seven women with genetically confirmed mitochondrial disease from the UK Mitochondrial Diseases Cohort and 69 unaffected women participated. METHODS: Participants answered questionnaires regarding each of their pregnancies. Patients were divided into two groups according to genetic mutation, with those harbouring m.3243A>G comprising a single group. MAIN OUTCOME MEASURES: Pregnancy-related complications, mode of delivery, gestational age and birthweight of newborns. RESULTS: Of 139 live births in the comparison group, 62 were in the m.3243A>G group and 87 were in the 'all other mutations' group. Pregnancies of women with the m.3243A>G mutation had significantly more gestational diabetes (odds ratio [OR] = 8.2, 95% CI 1.3-50.1), breathing difficulties (OR = 7.8, 95% CI 1.0-59.1) and hypertension (OR = 8.2, 95% CI 3.1-21.5) than the comparison group. Only half of the pregnancies in the m.3243A>G group had normal vaginal delivery, with emergency caesarean section accounting for 24.2% of deliveries. Babies were born significantly earlier to mothers harbouring m.3243A>G with 53.3% of them preterm (<37 weeks). These babies were also more likely to require resuscitation and admission. CONCLUSION: Women who carried the m.3243A>G mutation appeared to be at higher risk of complications during pregnancies, caesarean section and preterm delivery than the unaffected women or those with other forms of mitochondrial disease. TWEETABLE ABSTRACT: Pregnant women with mitochondrial disease - m.3243A>G mutation - are at greatly increased risk of complications and preterm delivery.
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Enfermedades Mitocondriales/genética , Mutación Puntual/genética , Complicaciones del Embarazo/genética , Adolescente , Adulto , Estudios de Casos y Controles , ADN Mitocondrial/genética , Femenino , Humanos , Recién Nacido , Persona de Mediana Edad , Enfermedades Mitocondriales/epidemiología , Embarazo , Complicaciones del Embarazo/epidemiología , Resultado del Embarazo , Estudios Retrospectivos , Reino Unido/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: The loss of mitochondrial function and content have been implicated in sarcopenia although they have been little studied in the very old, the group in which sarcopenia is most common. In this pilot study, our aim was to determine if mitochondrial respiratory chain function and content are preserved among healthy 85-year-olds. METHODS: We recruited 19 participants (11 female) through their general practitioner and assessed their medical history, functional status and self-reported physical activity. We identified sarcopenia using grip strength, Timed Up-and-Go and bioimpedance analysis. We assessed mitochondrial respiratory chain function using phosphorous magnetic resonance spectroscopy, estimating τ1/2 PCr, the recovery half-time of phosphocreatine in the calf muscles following a bout of aerobic exercise. We performed a biopsy of the vastus lateralis muscle and assessed mitochondrial respiratory chain content by measuring levels of subunits of complex I and IV of the respiratory chain, expressed as Z-scores relative to that in young controls. RESULTS: Participants had a median (IQR) of 2 (1,3) long-term conditions, reported regular aerobic physical activity, and one participant (5.3%) had sarcopenia. Sixteen participants completed the magnetic resonance protocol and the mean (SD) τ1/2 PCr of 35.6 (11.3) seconds was in keeping with preserved mitochondrial function. Seven participants underwent muscle biopsy and the mean fibre Z-scores were -0.7 (0.7) and -0.2 (0.4) for complexes I and IV, respectively, suggesting preserved content of mitochondrial respiratory chain enzymes. CONCLUSION: Muscle mitochondrial respiratory chain function and content are preserved in a sample of active, well-functioning 85-year-olds, among whom sarcopenia was uncommon. The results from this study will help inform future work examining the association between muscle mitochondrial deficiency and sarcopenia.
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Complejo I de Transporte de Electrón/metabolismo , Mitocondrias/metabolismo , Músculo Esquelético/fisiología , Sarcopenia/fisiopatología , Anciano de 80 o más Años , Ejercicio Físico , Femenino , Fuerza de la Mano , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Músculo Esquelético/patología , Proyectos PilotoRESUMEN
Mitochondrial respiratory chain defects are an important cause of inherited disorders affecting approximately 1 in 5000 people in the UK population. Collectively these disorders are termed 'mitochondrial diseases' and they result from either mitochondrial DNA mutations or defects in nuclear DNA. Although they are frequently multisystem disorders, neurological deficits are particularly common, wide-ranging and disabling for patients. This review details the manifold neurological impairments associated with mitochondrial disease, and describes the efforts to understand how they arise and progressively worsen in patients with mitochondrial disease. We describe advances in our understanding of disease pathogenesis through detailed neuropathological studies and how this has spurred the development of cellular and animal models of disease. We underscore the importance of continued clinical, molecular genetic, neuropathological and animal model studies to fully characterize mitochondrial diseases and understand mechanisms of neurodegeneration. These studies are instrumental for the next phase of mitochondrial research that has a particular emphasis on finding novel ways to treat mitochondrial disease to improve patient care and quality of life.
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Enfermedades del Sistema Nervioso Central/etiología , Enfermedades Mitocondriales/complicaciones , Animales , HumanosRESUMEN
Neuroferritinopathy is an autosomal dominant adult-onset movement disorder which occurs due to mutations in the ferritin light chain gene (FTL). Extensive iron deposition and cavitation are observed post-mortem in the basal ganglia, but whether more widespread pathological changes occur, and whether they correlate with disease severity is unknown. 3D-T1w and quantitative T2 whole brain MRI scans were performed in 10 clinically symptomatic patients with the 460InsA FTL mutation and 10 age-matched controls. Voxel-based morphometry (VBM) and voxel-based relaxometry (VBR) were subsequently performed. Clinical assessment using the Unified Dystonia Rating Scale (UDRS) and Unified Huntington's Disease Rating Scale (UHDRS) was undertaken in all patients. VBM detected significant tissue changes within the substantia nigra, midbrain and dentate together with significant cerebellar atrophy in patients (FWE, p < 0.05). Iron deposition in the caudate head and cavitation in the lateral globus pallidus correlated with UDRS score (p < 0.001). There were no differences between groups with VBR. Our data show that progressive iron accumulation in the caudate nucleus, and cavitation of the globus pallidus correlate with disease severity in neuroferritinopathy. We also confirm sub-clinical cerebellar atrophy as a feature of the disease. We suggest that VBM is an effective technique to detect regions of iron deposition and cavitation, with potential wider utility to determine radiological markers of disease severity for all NBIA disorders.
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Núcleo Caudado/metabolismo , Cerebelo/patología , Globo Pálido/patología , Trastornos del Metabolismo del Hierro/diagnóstico , Hierro/metabolismo , Imagen por Resonancia Magnética/métodos , Distrofias Neuroaxonales/diagnóstico , Adulto , Atrofia/patología , Femenino , Humanos , Trastornos del Metabolismo del Hierro/patología , Trastornos del Metabolismo del Hierro/fisiopatología , Masculino , Persona de Mediana Edad , Distrofias Neuroaxonales/patología , Distrofias Neuroaxonales/fisiopatología , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
Mitochondrial diseases are a clinically diverse group of genetic disorders that often present to neurologists. Health related quality of life (HRQOL) is increasingly recognised as a fundamental patient based outcome measure in both clinical intervention and research. Generic outcome measures have been extensively validated to assess HRQOL across populations and different disease states. However, due to their inclusive construct, it is acknowledged that not all relevant aspects of a specific illness may be captured. Hence there is a need to develop disease specific HRQOL measures that centre on symptoms characteristic of a specific disease or condition and their impact. This study presents the initial conceptualisation, development and preliminary psychometric assessment (validity and reliability) of a mitochondrial disease specific HRQOL measure (Newcastle Mitochondrial Quality of life measure (NMQ)). NMQ is a valuable assessment tool and consists of 63 items within 16 unidimensional domains, each demonstrating good internal reliability (Cronbach's α≥0.83) and construct validity.
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Enfermedades Mitocondriales/psicología , Calidad de Vida , Adulto , Análisis Factorial , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Psicometría/instrumentación , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Neuroferritinopathy is an autosomal dominant extrapyramidal movement disorder, caused by FTL gene mutations. Iron decreases the MR T2* decay time, therefore increasing the R2* (R2* = 1 /T2*), which correlates with brain tissue iron content. 3T structural and quantitative MR imaging assessment of R2* in 10 patients with neuroferritinopathy demonstrated a unique pattern of basal ganglia cavitation involving the substantia nigra in older patients and increasing thalamic R2* signal intensity detectable during 6 months. Increasing R2* signal intensity in the thalamus correlated with progression on a clinical rating scale measuring dystonia severity. Thalamic R2* signal intensity is a clinically useful method of objectively tracking disease progression in this form of neurodegeneration with brain iron accumulation.
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Interpretación de Imagen Asistida por Computador/métodos , Trastornos del Metabolismo del Hierro/metabolismo , Sobrecarga de Hierro/metabolismo , Hierro/metabolismo , Distrofias Neuroaxonales/metabolismo , Tálamo/metabolismo , Adulto , Femenino , Humanos , Trastornos del Metabolismo del Hierro/complicaciones , Trastornos del Metabolismo del Hierro/patología , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/patología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Distrofias Neuroaxonales/complicaciones , Distrofias Neuroaxonales/patología , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tálamo/patologíaAsunto(s)
CADASIL/epidemiología , CADASIL/genética , Receptores Notch/genética , Adulto , Estudios de Cohortes , Inglaterra/epidemiología , Exones/genética , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Linaje , Prevalencia , Receptor Notch3RESUMEN
Regulation of expression of the class I major histocompatability complex (MHC class I) at the maternal fetal interface may play a critical role in embryo survival and the establishment of pregnancy in cattle. However, information concerning immunoregulation of implantation in cattle remains quite limited. Therefore, our current research is concerned with characterizing the expression and regulatory effect of a number of immune factors in the developing bovine embryo. We have analysed the effect of embryo culture in vitro (IVC) in medium supplemented with progesterone (P4): leukemia inhibitory factor (LIF), interferon gamma (IFNG), interleukin (IL)-1B, IL3, IL4, IL10 and granulocyte-colony stimulating factor (G-CSF) on in vitro embryo development and expression of the bovine non-classical MHC class I genes NC2, NC3 and N4 in blastocysts. Cytokine supplementation during IVC did not affect cleavage rate or blastocyst development. However, embryo mRNA expression of NC2, NC3 and NC4 was significantly (p≤0.05) modified in a gene- and cytokine-specific manner. Sequence analysis of the promoter regions of these genes confirmed the presence of appropriate binding sites through which the cytokine signalling could be mediated. In contrast to the lack of effect on in vitro blastocyst development, the non-classical MHC-I expression data suggests a preferential immunomodulatory role of these cytokines during preimplantation embryo development.
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Blastocisto/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Antígenos de Histocompatibilidad Clase I/biosíntesis , ARN Mensajero/biosíntesis , Animales , Blastocisto/citología , Blastocisto/inmunología , Bovinos , Citocinas/inmunología , Citocinas/metabolismo , Citocinas/farmacología , Técnicas de Cultivo de Embriones , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Antígenos de Histocompatibilidad Clase I/inmunología , Embarazo , ARN Mensajero/inmunología , Elementos de Respuesta/fisiologíaAsunto(s)
Proteínas de Ciclo Celular/genética , ADN Mitocondrial/genética , Eliminación de Gen , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Oftalmoplejía Externa Progresiva Crónica/genética , Ribonucleótido Reductasas/deficiencia , Ribonucleótido Reductasas/genética , Adulto , Factores de Edad , Estudios de Cohortes , Femenino , Humanos , Masculino , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Oftalmoplejía Externa Progresiva Crónica/diagnóstico , Oftalmoplejía Externa Progresiva Crónica/metabolismoRESUMEN
A 39-year-old woman presented to the neurology clinic with an abnormal gait. Subsequent investigations confirmed a rare neurodegenerative disease. This case highlights the key clinical features and diagnostic approach to neuroferritinopathy, and describes the discovery of the disease in a family from Cumbria in the north west of England.
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Enfermedades de los Ganglios Basales/diagnóstico , Distonía/etiología , Trastornos Neurológicos de la Marcha/etiología , Trastornos del Metabolismo del Hierro/diagnóstico , Adulto , Enfermedades de los Ganglios Basales/complicaciones , Enfermedades de los Ganglios Basales/genética , Enfermedades de los Ganglios Basales/patología , Distonía/genética , Distonía/patología , Femenino , Trastornos Neurológicos de la Marcha/genética , Trastornos Neurológicos de la Marcha/patología , Humanos , Trastornos del Metabolismo del Hierro/complicaciones , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/patología , Distrofias Neuroaxonales/complicaciones , Distrofias Neuroaxonales/diagnóstico , Distrofias Neuroaxonales/genética , Distrofias Neuroaxonales/patologíaRESUMEN
Glucagon-like peptide-1 (GLP-1) is an incretin that has glucoregulatory effects as well as protective effects in a variety of tissues, including the heart. We hypothesized that GLP-1 may have a direct effect on neutrophils (PMNs) after myocardial ischemia, to ameliorate reperfusion injury. Deeply anesthetized Sprague-Dawley rats underwent 30 min of left coronary artery occlusion followed by 120 min of reperfusion. Immediately prior to reperfusion, rats were treated with either GLP-1 (human rGLP-1, 30 pM/kg/min) or PBS as placebo. GLP-1 significantly decreased myocardial infarct size [73.2±11.7% INF/AAR in PBS (n=4) vs. 15.7 ±5.52% INF/AAR in GLP-1-treated animals (n=5), p<0.05], PMN activation in blood in vivo (fMLP-stimulated CD11b surface expression: PBS 2.78±1.14 vs. GLP-1 1.7±0.21, TFI, p<0.05), and accumulation in myocardium (PBS: 6.52±0.31 vs. GLP-1: 4.78±0.90, n=4-6 animals/group, p<0.05). In addition, we found that GLP-1 mitigated PMN CD11b surface expression in whole rat blood in vitro, an effect that was abolished by GLP-1 receptor blockade (PBS 6.52±0.31 vs. GLP-1 4.78±0.90, TFI, p<0.05). These findings suggest that one mechanism by which GLP-1 decreases reperfusion injury may be the attenuation of PMN-mediated reperfusion injury.
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Péptido 1 Similar al Glucagón/uso terapéutico , Infarto del Miocardio/complicaciones , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/inmunología , Activación Neutrófila/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Péptido 1 Similar al Glucagón/inmunología , Humanos , Masculino , Infarto del Miocardio/inmunología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome c oxidase (COX)-deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease. METHODS: We reviewed the clinical, histochemical, and molecular genetics analysis of 33 unreported patients from 26 families together with all previous cases described in the literature to define the clinical phenotype associated with PEO1 mutations. RESULTS: Ptosis and ophthalmoparesis were almost universal clinical features among this cohort, with 52% (17/33) reporting fatigue and 33% (11/33) having mild proximal myopathy. Features consistent with CNS involvement were rarely described; however, in 24% (8/33) of the patients, cardiac abnormalities were reported. Mitochondrial histochemical changes observed in muscle showed remarkable variability, as did the secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Moreover, we report 7 novel PEO1 variants. CONCLUSIONS: Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of adPEO may well be underestimated. Direct sequencing of the PEO1 gene should be considered in adPEO patients prior to muscle biopsy.
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ADN Helicasas/genética , ADN Mitocondrial/genética , Mitocondrias Musculares/genética , Músculo Esquelético/patología , Oftalmoplejía Externa Progresiva Crónica/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/patología , Proteínas Mitocondriales , Mutación/genética , Músculos Oculomotores/patología , Oftalmoplejía Externa Progresiva Crónica/patología , FenotipoRESUMEN
Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.
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Enfermedades del Sistema Nervioso Central/complicaciones , GTP Fosfohidrolasas/genética , Atrofia Óptica Autosómica Dominante/complicaciones , Adolescente , Adulto , Anciano , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/metabolismo , Enfermedades del Sistema Nervioso Central/patología , Niño , Estudios de Cohortes , ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Familia , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mutación , Atrofia Óptica Autosómica Dominante/genética , Atrofia Óptica Autosómica Dominante/metabolismo , Atrofia Óptica Autosómica Dominante/patología , Fenotipo , Adulto JovenRESUMEN
Research into the use of unstructured mesh methods in oceanography has been growing steadily over the past decade. The advantages of this approach for domain representation and non-uniform resolution are clear. However, a number of issues remain, in particular those related to the computational cost of models produced using unstructured mesh methods compared with their structured mesh counterparts. Mesh adaptivity represents an important means to improve the competitiveness of unstructured mesh models, where high resolution is only used when and where necessary. In this paper, an optimization-based approach to mesh adaptivity is described where emphasis is placed on capturing anisotropic solution characteristics. Comparisons are made between the results obtained with uniform isotropic resolution, isotropic adaptive resolution and fully anisotropic adaptive resolution.
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BACKGROUND: Cognitive impairment and dementia has been reported in autosomal dominant hereditary spastic paraparesis (HSP) linked to the SPG4 locus. There has only been one postmortem examination described; not all accept that progressive cognitive decline is a feature of this disorder. OBJECTIVE: A family with SPG4-HSP known to have a deletion of exon 17 in the spastin gene (SPG4delEx17) was cognitively assessed over a 7-year period. The index family member died and a postmortem examination was performed. METHODS: Thirteen family members older than 40 years were clinically and cognitively assessed using the Cambridge Cognitive Assessment over a 7-year period. The presence of SPG4delEx17 was assessed; a neuropathologic examination of the brain of the index family member was performed. RESULTS: Cognitive decline occurred in 6 of the 13 family members and in all 4 older than 60 years. Two genetic deletions were identified: SPG4delEx17 in 12 of the 13 family members and a deletion of SPG6 (SPG6del) in 5. Eight individuals had the SPG4delEx17 deletion only; 4 had evidence of progressive cognitive impairment. Four family members had both SPG4delEx17 and SPG6del; 2 of these had cognitive impairment. One family member with the SPG6del alone had neither HSP nor cognitive impairment. The index case with both deletions died with dementia; the brain showed widespread ubiquitin positivity within the neocortex and white matter. CONCLUSION: Cognitive decline and dementia is a feature of SPG4-HSP due to a deletion of exon 17 of the spastin gene.