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2.
Int J Mol Sci ; 24(10)2023 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-37240397

RESUMEN

Anti-PLA2R antibodies (Ab) are a diagnostic and prognostic biomarker in primary membranous nephropathy (PMN). We assessed the relationship between the levels of anti-PLA2R Ab at diagnosis and different variables related to disease activity and prognosis in a western population of PMN patients. Forty-one patients with positive anti-PLA2R Ab from three nephrology departments in Israel were enrolled. Clinical and laboratory data were collected at diagnosis and after one year of follow-up, including serum anti-PLA2R Ab levels (ELISA) and glomerular PLA2R deposits on biopsy. Univariable statistical analysis and permutation-based ANOVA and ANCOVA tests were performed. The median [(interquartile range (IQR)) age of the patients was 63 [50-71], with 28 (68%) males. At the time of diagnosis, 38 (93%) of the patients had nephrotic range proteinuria, and 19 (46%) had heavy proteinuria (≥8 gr/24 h). The median [IQR] level of anti-PLA2R at diagnosis was 78 [35-183] RU/mL. Anti-PLA2R levels at diagnosis were correlated with 24 h proteinuria, hypoalbuminemia and remission after one year (p = 0.017, p = 0.003 and p = 0.034, respectively). The correlations for 24 h proteinuria and hypoalbuminemia remained significant after adjustment for immunosuppressive treatment (p = 0.003 and p = 0.034, respectively). Higher levels of anti-PLA2R Ab at diagnosis in patients with active PMN from a western population are associated with higher proteinuria, lower serum albumin and remission one year after the diagnosis. This finding supports the prognostic value of anti-PLA2R Ab levels and their possible use in stratifying PMN patients.


Asunto(s)
Glomerulonefritis Membranosa , Hipoalbuminemia , Masculino , Humanos , Femenino , Glomerulonefritis Membranosa/diagnóstico , Pronóstico , Autoanticuerpos , Proteinuria/tratamiento farmacológico
3.
J Int Neuropsychol Soc ; 29(6): 605-614, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36239453

RESUMEN

OBJECTIVE: To evaluate the construct validity of the NIH Toolbox Cognitive Battery (NIH TB-CB) in the healthy oldest-old (85+ years old). METHOD: Our sample from the McKnight Brain Aging Registry consists of 179 individuals, 85 to 99 years of age, screened for memory, neurological, and psychiatric disorders. Using previous research methods on a sample of 85 + y/o adults, we conducted confirmatory factor analyses on models of NIH TB-CB and same domain standard neuropsychological measures. We hypothesized the five-factor model (Reading, Vocabulary, Memory, Working Memory, and Executive/Speed) would have the best fit, consistent with younger populations. We assessed confirmatory and discriminant validity. We also evaluated demographic and computer use predictors of NIH TB-CB composite scores. RESULTS: Findings suggest the six-factor model (Vocabulary, Reading, Memory, Working Memory, Executive, and Speed) had a better fit than alternative models. NIH TB-CB tests had good convergent and discriminant validity, though tests in the executive functioning domain had high inter-correlations with other cognitive domains. Computer use was strongly associated with higher NIH TB-CB overall and fluid cognition composite scores. CONCLUSION: The NIH TB-CB is a valid assessment for the oldest-old samples, with relatively weak validity in the domain of executive functioning. Computer use's impact on composite scores could be due to the executive demands of learning to use a tablet. Strong relationships of executive function with other cognitive domains could be due to cognitive dedifferentiation. Overall, the NIH TB-CB could be useful for testing cognition in the oldest-old and the impact of aging on cognition in older populations.


Asunto(s)
Cognición , Función Ejecutiva , Adulto , Humanos , Anciano de 80 o más Años , Anciano , Estados Unidos , Reproducibilidad de los Resultados , Envejecimiento , Memoria a Corto Plazo , Pruebas Neuropsicológicas , National Institutes of Health (U.S.)
9.
J Clin Exp Neuropsychol ; 40(10): 963-970, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29569517

RESUMEN

OBJECTIVE: Age differences have been noted in the discrepancies between crystallized and fluid ability (Gc-Gf). Larger Gc-Gf discrepancies have also been shown to be associated with Alzheimer's disease biomarkers and clinical severity. However, little is known regarding the relationship between Gc-Gf discrepancies in normal aging and functional outcomes. The aim of the present study was to examine this. METHOD: Data from 104 adults (Mage = 71.70 years, SD = 9.016) were included in the present study. Measures from the NIH toolbox were used to form the discrepancy scores. Physical, cognitive, and social activities were identified using the Community Healthy Activities Model Program for Seniors activity questionnaire. Linear regression analyses, controlling for age, education, gender, health, and depressive symptoms, were used to examine the association between social, cognitive, and physical activities on Gc-Gf discrepancies. RESULTS: Results showed that social and physical activity were significantly associated with greater discrepancies between crystallized and fluid ability, independent of covariates. There was no association between cognitive activity and Gc-Gf discrepancies. CONCLUSIONS: Larger discrepancies between crystallized and fluid ability are related to frequency of social and physical activity. The findings support previous research that discrepancy scores may serve as a marker of cognitive decline. In more highly educated older individuals, Gc-Gf discrepancies may be a more accurate indicator of actual cognitive status.


Asunto(s)
Ejercicio Físico/fisiología , Conducta Social , Anciano , Anciano de 80 o más Años , Envejecimiento/psicología , Disfunción Cognitiva/psicología , Depresión/psicología , Escolaridad , Femenino , Estado de Salud , Humanos , Vida Independiente , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Características de la Residencia , Factores Sexuales , Encuestas y Cuestionarios
10.
J Gerontol A Biol Sci Med Sci ; 73(12): 1695-1700, 2018 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-29244089

RESUMEN

Background: Decrements in instrumental activities (IADL) have been observed in the prodromal phase of dementia. Given the long predementia stage in neurodegenerative diseases, it has been proposed that subtle functional changes may precede clinical IADL impairment. Incorporating more challenging advanced ADLs (eg, volunteer work) into the assessment process may increase the sensitivity of functional measures, thus expanding the window for monitoring or interventions. Methods: Longitudinal cohort study was used (follow-ups, 18-24 month), with subjects aged 60 and older (n = 3,635). To elucidate the relationship between cognitive ability and functional status we employed an IADL scale with an extended range (ADL-extended; includes IADL but also more challenging advanced ADLs) that meets item response theory properties of dimensionality, monotonicity, and item hierarchy. Procedures involved (a) a dynamic change model employed to inspect the temporal relationship between ADL-extended and cognitive status and (b) Cox proportional hazards to assess the risk of incident dementia based on ADL-extended scores. Results: Growth curve modeling: baseline ADL-extended was significantly associated with all four cognitive domains investigated. Worse baseline ADL-extended was associated with more rapid declines in speed/executive function, and worse baseline memory was associated with more rapid declines in ADL-extended; a concurrent association was found for language and ADL-extended. Cox model: the risk of dementia was decreased for each additional ADL-extended item endorsed (hazard ratio [HR], 0.85; 95% confidence interval = 0.81-0.90). Conclusions: An increased risk of dementia could be observed in the ADL-extended items, which reflects an area of the functional continuum beyond IADL competencies.


Asunto(s)
Actividades Cotidianas/psicología , Disfunción Cognitiva/fisiopatología , Demencia/fisiopatología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Factores de Edad , Anciano , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Estudios de Cohortes , Demencia/epidemiología , Demencia/psicología , Femenino , Evaluación Geriátrica/métodos , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores Sexuales
13.
JAMA ; 314(8): 781-90, 2015 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-26305648

RESUMEN

IMPORTANCE: Epidemiological evidence suggests that physical activity benefits cognition, but results from randomized trials are limited and mixed. OBJECTIVE: To determine whether a 24-month physical activity program results in better cognitive function, lower risk of mild cognitive impairment (MCI) or dementia, or both, compared with a health education program. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial, the Lifestyle Interventions and Independence for Elders (LIFE) study, enrolled 1635 community-living participants at 8 US centers from February 2010 until December 2011. Participants were sedentary adults aged 70 to 89 years who were at risk for mobility disability but able to walk 400 m. INTERVENTIONS: A structured, moderate-intensity physical activity program (n = 818) that included walking, resistance training, and flexibility exercises or a health education program (n = 817) of educational workshops and upper-extremity stretching. MAIN OUTCOMES AND MEASURES: Prespecified secondary outcomes of the LIFE study included cognitive function measured by the Digit Symbol Coding (DSC) task subtest of the Wechsler Adult Intelligence Scale (score range: 0-133; higher scores indicate better function) and the revised Hopkins Verbal Learning Test (HVLT-R; 12-item word list recall task) assessed in 1476 participants (90.3%). Tertiary outcomes included global and executive cognitive function and incident MCI or dementia at 24 months. RESULTS: At 24 months, DSC task and HVLT-R scores (adjusted for clinic site, sex, and baseline values) were not different between groups. The mean DSC task scores were 46.26 points for the physical activity group vs 46.28 for the health education group (mean difference, -0.01 points [95% CI, -0.80 to 0.77 points], P = .97). The mean HVLT-R delayed recall scores were 7.22 for the physical activity group vs 7.25 for the health education group (mean difference, -0.03 words [95% CI, -0.29 to 0.24 words], P = .84). No differences for any other cognitive or composite measures were observed. Participants in the physical activity group who were 80 years or older (n = 307) and those with poorer baseline physical performance (n = 328) had better changes in executive function composite scores compared with the health education group (P = .01 for interaction for both comparisons). Incident MCI or dementia occurred in 98 participants (13.2%) in the physical activity group and 91 participants (12.1%) in the health education group (odds ratio, 1.08 [95% CI, 0.80 to 1.46]). CONCLUSIONS AND RELEVANCE: Among sedentary older adults, a 24-month moderate-intensity physical activity program compared with a health education program did not result in improvements in global or domain-specific cognitive function. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01072500.


Asunto(s)
Disfunción Cognitiva/prevención & control , Demencia/prevención & control , Función Ejecutiva , Terapia por Ejercicio/métodos , Promoción de la Salud , Conducta Sedentaria , Factores de Edad , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/epidemiología , Demencia/epidemiología , Femenino , Educación en Salud , Humanos , Masculino , Ejercicios de Estiramiento Muscular , Entrenamiento de Fuerza , Resultado del Tratamiento , Extremidad Superior , Caminata
15.
Mult Scler ; 21(10): 1322-31, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25583832

RESUMEN

BACKGROUND: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). OBJECTIVES: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). METHODS: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. RESULTS: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. CONCLUSIONS: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.


Asunto(s)
4-Aminopiridina/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Bloqueadores de los Canales de Potasio/uso terapéutico , Caminata/fisiología , 4-Aminopiridina/administración & dosificación , Adulto , Anciano , Método Doble Ciego , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
16.
J Pathol ; 235(5): 745-59, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25421310

RESUMEN

Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the most frequently occurring histological subtypes of breast cancer, accounting for 80-90% and 10-15% of the total cases, respectively. At the time of diagnosis and surgical resection of the primary tumour, most patients do not have clinical signs of metastases, but bone micrometastases may already be present. Our aim was to develop a novel preclinical ILC model of spontaneous bone micrometastasis. We used murine invasive lobular breast carcinoma cells (KEP) that were generated by targeted deletion of E-cadherin and p53 in a conditional K14cre;Cdh1((F/F));Trp53((F/F)) mouse model of de novo mammary tumour formation. After surgical resection of the growing orthotopically implanted KEP cells, distant metastases were formed. In contrast to other orthotopic breast cancer models, KEP cells readily formed skeletal metastases with minimal lung involvement. Continuous treatment with SD-208 (60 mg/kg per day), an orally available TGFß receptor I kinase inhibitor, increased the tumour growth at the primary site and increased the number of distant metastases. Furthermore, when SD-208 treatment was started after surgical resection of the orthotopic tumour, increased bone colonisation was also observed (versus vehicle). Both our in vitro and in vivo data show that SD-208 treatment reduced TGFß signalling, inhibited apoptosis, and increased proliferation. In conclusion, we have demonstrated that orthotopic implantation of murine ILC cells represent a new breast cancer model of minimal residual disease in vivo, which comprises key steps of the metastatic cascade. The cancer cells are sensitive to the anti-tumour effects of TGFß. Our in vivo model is ideally suited for functional studies and evaluation of new pharmacological intervention strategies that may target one or more steps along the metastatic cascade of events.


Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Carcinoma Lobular/secundario , Neoplasias Mamarias Experimentales/patología , Inhibidores de Proteínas Quinasas/toxicidad , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pteridinas/toxicidad , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Neoplasias Óseas/enzimología , Neoplasias Óseas/genética , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Carcinoma Lobular/inducido químicamente , Carcinoma Lobular/enzimología , Carcinoma Lobular/genética , Proteínas Cdh1/deficiencia , Proteínas Cdh1/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/genética , Ratones Noqueados , Micrometástasis de Neoplasia , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transfección , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética
17.
Int J MS Care ; 16(3): 153-60, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25337058

RESUMEN

BACKGROUND: Two phase 3 clinical trials demonstrated that dalfampridine extended-release 10-mg tablets (D-ER), twice daily, significantly improved walking relative to placebo in patients with multiple sclerosis (MS). The objective of this study was to evaluate the efficacy and safety of D-ER in patients with MS using pooled data from the two phase 3 trials. METHODS: Data were pooled from the two trials, and D-ER was compared with placebo for timed-walk responder rate, changes in walking speed, and the 12-item Multiple Sclerosis Walking Scale (MSWS-12). Response rates were evaluated with respect to demographic and clinical characteristics. RESULTS: D-ER had a significantly higher proportion of timed-walk responders relative to placebo (37.6% vs. 8.9%; P < .0001). The responder rate was independent of age, gender, race, body-mass index, type of MS, duration of MS, baseline Expanded Disability Status Scale score, baseline walking speed, and concomitant use of immunomodulatory therapies. Significant improvements were observed in walking speed and in MSWS-12 score for the pooled D-ER group compared with placebo. The safety profile was consistent with the individual studies; no new safety or tolerability concerns were identified. CONCLUSIONS: D-ER demonstrated efficacy for the improvement of walking in patients with MS; response was independent of demographic and clinical characteristics.

18.
Lancet ; 384(9942): 492-3, 2014 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-25103174

Asunto(s)
Guerra , Humanos
19.
Ann N Y Acad Sci ; 1329: 33-44, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25154911

RESUMEN

Walking impairment is a clinical hallmark of multiple sclerosis (MS). Dalfampridine-ER, an extended-release formulation of dalfampridine (also known by its chemical name, 4-aminopyridine, and its international nonproprietary name, fampridine), was developed to maintain drug plasma levels within a narrow therapeutic window, and assessed for its ability to improve walking in MS. The putative mechanism of action of dalfampridine-ER is restoration of axonal conduction via blockade of the potassium channels that become exposed during axonal demyelination. Two pivotal phase III clinical trials demonstrated that dalfampridine-ER 10-mg tablets administered twice daily improved walking speed and patient-reported perceptions of walking in some patients. Dalfampridine-ER was generally well tolerated, and, at the approved dose, risk of seizure was neither elevated relative to placebo nor higher than the rate in the MS population. Dalfampridine-ER (AMPYRA®) was approved in the United States for the treatment of walking in patients with MS as demonstrated by an increase in walking speed. The use of the dalfampridine-ER is contraindicated in patients with a history of seizure. It is the first pharmacologic therapy for this indication and has been incorporated into clinical management of MS.


Asunto(s)
4-Aminopiridina/uso terapéutico , Descubrimiento de Drogas/tendencias , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/fisiopatología , Bloqueadores de los Canales de Potasio/uso terapéutico , Caminata/fisiología , Ensayos Clínicos como Asunto/tendencias , Humanos , Esclerosis Múltiple/diagnóstico , Resultado del Tratamiento
20.
Neuroimage Clin ; 3: 132-42, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24179857

RESUMEN

Cognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV + patients scanned with whole-brain MRI at 1.5 T (mean age: 48.6 ± 8.4 years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4 + count, with a 1-2% white matter volume reduction for each 25-point reduction in nadir CD4 +. Even so, brain volume measured by TBM showed no detectable association with current CD4 + count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex - were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage.

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