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BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.
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Esclerose Múltipla Recidivante-Remitente , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Fatores Imunológicos/uso terapêuticoRESUMO
BACKGROUND AND AIMS: In people with relapsing-remitting multiple sclerosis (pwRRMS), data from studies on non-pharmacological factors which may influence relapse risk, other than age, are inconsistent. There is a reduced risk of relapses with increasing age, but little is known about other trajectories in real-world MS care. METHODS: We studied longitudinal questionnaire data from 3885 pwRRMS, covering smoking, comorbidities, disease-modifying therapy (DMT), and patient-reported outcome measures, as well as relapses during the past year. We undertook Rasch analysis, group-based trajectory modelling, and multilevel negative binomial regression. RESULTS: The regression cohort of 6285 data sets from pwRRMS over time showed that being a current smoker was associated with 43.9% greater relapse risk; having 3 or more comorbidities increased risk and increasing age reduced risk. Those diagnosed within the last 2 years showed two distinct trajectories, both reducing in relapse frequency but 25.8% started with a higher rate and took 4 years to reduce to the rate of the second group. In the cohort with at least three data points completed, there were three groups: 73.7% followed a low stable relapse rate, 21.6% started from a higher rate and decreased, and 4.7% had an increasing then decreasing pattern. These different trajectory groups showed significant differences in fatigue, neuropathic pain, disability, health status, quality of life, self-efficacy, and DMT use. CONCLUSIONS: These results provide additional evidence for supporting pwRRMS to stop smoking and underline the importance of timely DMT decisions and treatment initiation soon after diagnosis with RRMS.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Qualidade de Vida , Recidiva , Nível de SaúdeRESUMO
INTRODUCTION: Reliable measurement of disability in multiple sclerosis (MS) using a comprehensive, patient self-reported scale, such as the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, would be of clinical and research benefit. METHODS: In the Trajectories of Outcome in Neurological Conditions-MS study, WHODAS 2.0 (WHODAS-36 items for working, WHODAS-32 items if not working, WHODAS-12 items short-form) was examined using Rasch analysis in 5809 people with MS. RESULTS: The 36- and 32-item parallel forms, and the cognitive and physical domains, showed reliability consistent with individual or group use. The 12-item short-form is valid for group use only. Interval level measurement for parametric statistics can be derived from all three scales which showed medium to strong effect sizes for discrimination across characteristics such as age, subtype, and disease duration. Smallest detectable difference for each scale was < 6 on the standardised metric of 0-100 so < 6% of the total range. There was no substantial differential item functioning (DIF) by age, gender, education, working full/part-time, or disease duration; the finding of no DIF for time or sample supports the use of WHODAS 2.0 for longitudinal studies, with the 36- and 32-item versions and the physical and cognitive domains valid for individual patient follow-up. CONCLUSIONS: Disability in MS can be comprehensively measured at interval level by the WHODAS 2.0, and validly monitored over time. Routine use of this self-reported measure in clinical and research practice would give valuable information on the trajectories of disability of individuals and groups.
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Pessoas com Deficiência , Esclerose Múltipla , Humanos , Reprodutibilidade dos Testes , Qualidade de Vida/psicologia , Pessoas com Deficiência/reabilitação , Avaliação da Deficiência , Psicometria , Organização Mundial da SaúdeRESUMO
BACKGROUND: Coping in multiple sclerosis (MS) refers to cognitive and behavioural efforts to manage stresses imposed by the illness. Existing generic and disease-specific coping scales do not meet modern guidelines for scale development and cannot produce interval-level metrics to allow for change scores. OBJECTIVE: The main aim of this study was to develop a brief patient-reported outcome measure for coping in MS, capable of interval-level measurement. METHODS: Qualitative work in 43 people with MS leads to a draft scale which was administered to 5747 participants, with longitudinal collection in 2290. A calibration sample of 1000 subjects split into development and validation sets was used to generate three scales consistent with Rasch model expectations. RESULTS: The total Coping Index-MS (CI-MS-T), CI-MS-Internal (CI-MS-I) and CI-MS-External (CI-MS-E) cover total, internal and externally focused coping. All three scales are capable of interval-level measurement. Trajectory analysis of 9000 questionnaires showed two trajectories in CI-MS-T: Group 1 showed a low level of coping with slight decline over 40 months, while Group 2 had a better and stable level of coping due to improving CI-MS-I which compensated for the deteriorating CI-MS-E over time. CI-MS-T < 30 identified group membership at baseline. CONCLUSION: The CI-MS-T, CI-MS-I and CI-MS-E, comprising 20 items, provide interval-level measurement and are free-for-use in not-for-profit settings.
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Esclerose Múltipla , Humanos , Adaptação Psicológica , Benchmarking , Medicamentos Genéricos , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: The treatment landscape for relapsing multiple sclerosis (MS) has changed dramatically in recent decades, including an increasing number of high-efficacy disease-modifying therapies (DMTs) with varied administration and monitoring requirements. Coupled with greater focus on earlier treatment, these factors have resulted in stretching of the capacity of MS specialist services and allied healthcare professionals (HCPs). To assist with the effective planning of MS services in the UK NHS, this study quantified the administration and monitoring time burden associated with high-efficacy DMTs (alemtuzumab, cladribine tablets, fingolimod, natalizumab, and ocrelizumab) for relapsing MS. METHODS: A Time and Motion (T&M) study was conducted across four MS centres in the UK, over 3-4 months per centre (Aug 2019-Feb 2021). Time dedicated by HCPs (including but not limited to neurologists, MS specialist nurses, infusion nurses, and healthcare assistants) to pre-specified drug administration and monitoring activities, elicited during pre-study interviews at each centre, was assessed for each of the selected DMTs. Administration activities included: installing peripheral access; pre-medication administration (if needed); preparing drug for infusion; infusion initiation, monitoring, and disconnection; and patient monitoring post-infusion. Monitoring activities included: booking appointments for blood draws; blood draw; retrieval and review of blood results; maintaining blood records and follow-up with the patient; checking availability of MRI results and follow-up with the patient; booking appointments for neurologist or nurse consultations; and checking patient files prior to clinic visits. A T&M model was built using observational T&M study results, data obtained through pre-study interviews, as well as stipulated monitoring intervals from relevant Summaries of Product Characteristics for the selected DMTs, to estimate active HCP time with each DMT, extrapolated over a period of 4 years per-patient. RESULTS: For oral DMTs, projected total active HCP time (monitoring only) per-patient over 4 years was 14.7 h for cladribine tablets and 19.2 h for fingolimod. For infused DMTs, total time (administration and monitoring) for alemtuzumab was 37.7 h (6.0 and 31.6 h, respectively), 48.1 h for natalizumab (17.4 and 30.8 h, respectively), and 23.5 h for ocrelizumab (6.1 and 17.4 h, respectively). CONCLUSIONS: While active HCP time varied across centres, infused DMTs were projected to require the greatest amount of HCP time associated with administration and monitoring over 4 years versus oral DMTs. These findings may assist MS-specific HCPs in planning and delivering the equitable provision of DMT services for patients with relapsing MS.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Cladribina/uso terapêutico , Natalizumab/uso terapêutico , Alemtuzumab/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Estudos de Tempo e Movimento , Reino Unido , ComprimidosRESUMO
BACKGROUND: The prevalence of depression in Multiple Sclerosis (MS) is often assessed by administering patient reported outcome measures (PROMs) examining depressive symptomatology to population cohorts; a recent review summarised 12 such studies, eight of which used the Hospital Anxiety and Depression Scale-Depression (HADS-D). In clinical practice, depression is diagnosed by an individual structured clinical interview; diagnosis often leads to treatment options including antidepressant medication. It follows that an MS population will include those whose current depressive symptoms meet threshold for depression diagnosis, plus those who previously met diagnostic criteria for depression and have been treated such that depressive symptoms have improved below that threshold. We examined a large MS population to establish a multi-attribute estimate of depression, taking into account probable depression on HADS-D, as well as anti-depressant medication use and co-morbidity data reporting current treatment for depression. We then studied associations with demographic and health status measures and the trajectories of depressive symptoms over time. METHODS: Participants were recruited into the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study, with demographic and disease data from clinical records, PROMs collected at intervals of at least 9 months, as well as co-morbidities and medication. Interval level conversions of PROM data followed Rasch analysis. Logistic regression examined associations of demographic characteristics and symptoms with depression. Finally, a group-based trajectory model was applied to those with depression. RESULTS: Baseline data in 5633 participants showed the prevalence of depression to be 25.3 % (CI: 24.2-26.5). There were significant differences in prevalence by MS subtype: relapsing 23.2 % (CI: 21.8- 24.5), primary progressive 25.8 % (CI: 22.5-29.3), secondary progressive 31.5 % (CI: 29.0-34.0); disability: EDSS 0-4 19.2 % (CI: 17.8-20.6), EDSS ≥4.5 31.9 % (CI: 30.2-33.6); and age: 42-57 years 27.7 % (CI: 26.0-29.3), above or below this range 23.1 % (CI: 21.6-24.7). Fatigue, disability, self-efficacy and self esteem correlated with depression with a large effect size (>0.8) whereas sleep, spasticity pain, vision and bladder had an effect size >0.5. The logistic regression model (N = 4938) correctly classified 80 % with 93 % specificity: risk of depression was increased with disability, fatigue, anxiety, more comorbidities or current smoking. Higher self-efficacy or self esteem and marriage reduced depression. Trajectory analysis of depressive symptoms over 40 months in those with depression (N = 1096) showed three groups: 19.1 % with low symptoms, 49.2 % with greater symptoms between the threshold of possible and probable depression, and 31.7 % with high depressive symptoms. 29.9 % (CI: 27.6-32.3) of depressed subjects were untreated, conversely of those treated, 26.1 % still had a symptom level consistent with a probable case (CI: 23.5-28.9). CONCLUSION: A multi-attribute estimate of depression in MS is essential because using only screening questionnaires, diagnoses or antidepressant medication all under-estimate the true prevalence. Depression affects 25.3 % of those with MS, almost half of those with depression were either untreated or still had symptoms indicating probable depression despite treatment. Services for depression in MS must be pro-active and flexible, recognising the heterogeneity of outcomes and reaching out to those with ongoing symptoms.
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Antidepressivos , Depressão , Esclerose Múltipla , Humanos , Feminino , Masculino , Prevalência , Pessoa de Meia-Idade , Adulto , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/complicações , Esclerose Múltipla/terapia , Depressão/epidemiologia , Depressão/etiologia , Antidepressivos/uso terapêutico , Comorbidade , Medidas de Resultados Relatados pelo Paciente , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: The role of CSF lymphocytic pleocytosis in predicting the clinical outcome of multiple sclerosis is unclear. We explored the impact of CSF pleocytosis at diagnosis on long-term disease progression in a large UK cohort. METHODS: We extracted demographic, clinical and CSF data of people with MS attending the MS clinics between 1996 and 2014 at two MS centres from the English Midlands. We compared EDSS at onset, follow up EDSS and progression indices Multiple Sclerosis Severity Score (MSSS), annualized change in EDSS and transition to secondary progression in the presence/absence of pleocytosis. Two-tailed student t-test, Mann-Whitney U test, Chi-Square or Fisher's exact tests were used for detecting the differences. RESULTS: A total of 247 patients with MS (178 females; mean age 42.4; 217 with relapsing onset) were followed up for an average of 13.56 years (median 12 years). Almost 18% had lymphocytic CSF ≥ 5 per microliter. CSF pleocytosis was not associated with higher EDSS at the time of LP or at follow up, and other progression indices like MSSS, annualized change in EDSS or transition to secondary progression. DISCUSSION: CSF pleocytosis at MS diagnosis does not predict higher long-term disability and has no long-term prognostic value in routine clinical circumstances. Differences between MS populations and potential differences in disease activity at the time of CSF analysis may account for differences between studies.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Feminino , Humanos , Adulto , Progressão da Doença , Esclerose Múltipla/diagnóstico , Prognóstico , LeucocitoseRESUMO
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a major challenge for clinicians. SARS-CoV-2 infection results in coronavirus disease 2019 (COVID-19), and it is best known for its respiratory symptoms. It can also result in several extrapulmonary manifestations such as neurological complications potentially experienced during the course of COVID-19. The association of dermatomyositis (DM) with COVID-19 pathogenesis has not been well-studied. This study aimed to present a previously healthy 37-year-old man, a soldier by profession, with symptoms of DM on the 4th day from the onset of COVID-19. The patient presented DM symptoms with both skin and muscle manifestations. The patient suffered from cough, fever, and fatigue to begin with, and reverse-transcription polymerase chain reaction (RT-PCR) reported positive for SARS-CoV-2 infection. The laboratory findings showed, intra alia, elevated muscle enzymes CK 8253 U/l (N: <145 U/l), a positive test for myositis-specific autoantibodies (anti-Mi-2), electrodiagnostic tests exhibited features of myopathy, with the presence of muscle and skin symptoms. The patient improved with corticosteroids and immunosuppressive agent therapy. In summary, the association between COVID-19 and the development of multi-system autoimmune disorders such as DM remains unclear. Nevertheless, viral infections such as SARS-CoV-2 may likely serve as a trigger.
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BACKGROUND: Visual dysfunction is common in people with Multiple Sclerosis (pwMS), associated with a variety of visual symptoms. Capturing the patient experience of these complex patterns of visual pathology is challenging. A valid and reliable patient reported measure, capable of detecting clinically significant change, would have considerable research and clinical benefits. We examined the properties of the MS Vision Questionnaire (MSVQ-7) in a large MS population. METHODS: Data were collected from participants in the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study: MS subtype and Expanded Disability Status Scale (EDSS) band from the clinical team, as well as serial packs including the MSVQ-7 and questionnaires on depression, anxiety and stigma. A calibration sample of 1000 pwMS contributing several years of follow-up were split into training and validation samples for a Confirmatory Factor Analysis and Rasch analysis. The Minimal Detectable Change (MDC) was computed as well as the Minimal Clinically Important Change (MIC), by an anchor-based method, for different MS subtypes. RESULTS: The MSVQ-7 is unidimensional and can be fit to the Rasch model with a solution discarding 3% of variance. Providing all 7 items are answered, the total can be converted to an interval-level metric for calculation of change scores and other parametric analyses. The % of missing values did not exceed 1.7%. Among 5478 pwMS, 80% reported visual problems. MSVQ-7 scores were categorised as mild for 36.1%, moderate for 33.6% and severe for 10.3%, and varied by MS subtype. In the follow-up sample of 2227 pwMS, 42.5% changed MSVQ-7 category between baseline and first follow-up (mean 22.6 months). The MIC exceeded the MDC so clinically significant change exceeds measurement error. While MDC was identical for relapsing and progressive MS, MIC varied by MS subtype, with smaller MIC in relapsing MS. Over one-quarter of the follow-up sample reported a clinically significant change in MSVQ-7: 12.2% improved and 13.5% deteriorated. For pwMS recruited within 2 years of diagnosis, 17.3% reported significant change on follow-up, all improving. MSVQ-7 scores showed strong associations with anxiety, depression and stigma (effect sizes>0.8). Duration, EDSS band and MS subtype all had effect sizes 0.2-0.49. A multinomial logistic regression exploring vision disturbance and depression, adjusted for age, gender, MS subtype, duration and disability, showed vision is the strongest significant predictor of depression. Each unit increase in interval MSVQ-7 increases risk by 10% of 'possible' and by 17% of 'probable' depression. CONCLUSIONS: The MSVQ-7 is a brief self-report measure of visual problems for pwMS. It can easily be converted to interval-level measurement for change scores or power calculations and has good precision and discrimination. Visual problems were reported by 80% of pwMS and changed over time, evidencing the need for regular monitoring. MIC varied by MS subtype, indicating that perception of impact changes over the disease course. Visual dysfunction significantly affects depression risk and perceived stigma, highlighting the importance of routine assessment of visual problems in comprehensive care. The MSVQ-7 has strong psychometric properties for adoption as a measure for vision in clinical and research settings.
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Esclerose Múltipla , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Reprodutibilidade dos Testes , Inquéritos e Questionários , Autorrelato , AnsiedadeRESUMO
BACKGROUND: Longitudinal studies among people with Multiple Sclerosis (pwMS) have shown that self-efficacy is linked to physical, cognitive and psychological functioning. OBJECTIVES: To determine the distribution of self-efficacy in a large sample of pwMS, examining whether there are distinct groups which show different self-efficacy trajectories over time, and the health status characteristics of any groups identified. METHODS: Participants completed serial questionnaire packs, including Unidimensional Self-efficacy-MS (USE-MS) scale, for the Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study over an average 46-month period. The resulting longitudinal data were analysed by a group-based trajectory model. RESULTS: 5887 pwMS were studied: mean age 50.2 years (SD 12.0); 73.6% female; Relapsing Remitting MS (61.8%), Secondary Progressive (22.9%), Primary Progressive (11.1%), Rapidly Evolving Relapsing Remitting MS (4.2%). Four distinct self-efficacy trajectories emerged, with declining, slightly declining, stable or improving self-efficacy, each showing different patterns of health status indicators such as EQ-5D-5L, disability and depression. USE-MS ≤ 18 at baseline detected all participants in the two declining groups. CONCLUSION: Future trials on interventions for self-efficacy should assume a priori that those with low levels of self-efficacy (USE-MS ≤ 18 at baseline) are likely to be on a declining trajectory and may need different interventions from those with stable self-efficacy.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla Recidivante-Remitente/complicações , Autoeficácia , Inquéritos e QuestionáriosRESUMO
BACKGROUND AND OBJECTIVE: Quality of life in multiple sclerosis (MS) reflects complex relationships between symptoms (fatigue, spasticity pain, and bladder or vision dysfunction), disability, health perceptions, and self-efficacy. METHODS: In this cross-sectional study, a self-report questionnaire pack of patient reported outcome measures was collected from 5695 people with MS (pwMS) alongside clinical data from their neurologists. Each patient reported outcome measure was converted to interval-scaled estimates following fit to the Rasch model. The patient reported outcome measures, as well as perceived health, age, disease subtype and gender, were then subject to path analysis to analyse their relationships with quality of life (QoL), guided by the Wilson and Clearly conceptual framework. RESULTS: The final model explains 81.2% of the variance of QoL. Fatigue is clearly dominant, suggesting a means to intervene and improve QoL. The next most influential factors were disability and self-efficacy, which have similar effect levels. The model can be replicated for pwMS on disease modifying therapy and is largely invariant for gender and disease subtype. Age had an insignificant effect. CONCLUSIONS: In order to promote better QoL, MS care should include management of fatigue, interventions to ameliorate disability, and support to enhance self-efficacy. The range of skills needed for these treatments will require input from medical, nursing, therapy and psychology staff, so these findings provide evidence substantiating the need for pwMS to be provided with care by comprehensive multidisciplinary teams.
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Esclerose Múltipla , Qualidade de Vida , Estudos Transversais , Avaliação da Deficiência , Fadiga/etiologia , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/terapia , AutoeficáciaRESUMO
Vascular parkinsonism (VP) remains a loose constellation of various clinical features. We systematically reviewed studies comparing clinical, neuroimaging and other investigations that might distinguish VP from idiopathic Parkinson's disease (PD). Medline, Embase, Cinahl (R), and PsycINFO were searched by querying appropriate key words. Reports were included if the study population contained comparative findings between patients with VP and PD. Twenty-five articles fulfilled the selection criteria. Patients with VP were older, with a shorter duration of illness, presented with symmetrical gait difficulties, were less responsive to levodopa, and were more prone to postural instability, falls, and dementia. Pyramidal signs, pseudobulbar palsy, and incontinence were more common in VP. Tremor was not a main feature of VP. Structural neuroimaging was more likely to be abnormal in VP (90-100% of cases) than in PD (12-43% of cases), but there was no specific abnormal structural imaging pattern for VP. Two studies of presynaptic striatal dopamine transporters (using single photon emission computed tomography) showed a significant reduction in striatal uptake ratios in PD but not in VP, whereas another study found that only the mean asymmetry index was significantly lower in VP. Various other investigations, including alternative imaging techniques, electrophysiological, and neuropsychological studies, are reported, but the diverse diagnostic criteria used makes it difficult to reach any firm conclusions. The development of accepted international diagnostic criteria for VP is urgently needed to facilitate further studies.
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Antiparkinsonianos/uso terapêutico , Encéfalo/diagnóstico por imagem , Transtornos Cerebrovasculares/complicações , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Levodopa/uso terapêutico , Doença de Parkinson Secundária/diagnóstico , Doença de Parkinson/diagnóstico , Fatores Etários , Encéfalo/fisiopatologia , Transtornos Cerebrovasculares/fisiopatologia , Diagnóstico Diferencial , Marcha , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/fisiopatologia , Índice de Gravidade de Doença , Tomografia Computadorizada de Emissão de Fóton Único , Tremor/fisiopatologiaRESUMO
Cubilin, a 456 kDa multipurpose receptor lacking in both transmembrane and cytoplasmic domains is expressed in the apical BBMs (brush border membranes) of polarized epithelia. Cubilin interacts with two transmembrane proteins, AMN, a 45-50 kDa protein product of the amnionless gene, and megalin, a 600 kDa giant endocytic receptor. In vitro, three fragments of cubilin, the 113-residue N-terminus and CUB domains 12-17 and 22-27, demonstrated Ca2+-dependent binding to megalin. Immunoprecipitation and immunoblotting studies using detergent extracts of rat kidney BBMs revealed that cubilin interacts with both megalin and AMN. Ligand (intrinsic factor-cobalamin)-affinity chromatography showed that in renal BBMs, functional cubilin exists as a complex with both AMN and megalin. Cubilin and AMN levels were reduced by 80% and 55-60% respectively in total membranes and BBMs obtained from kidney of megalin antibody-producing rabbits. Immunohistochemical analysis and turnover studies for cubilin in megalin or AMN gene-silenced opossum kidney cells showed a significant reduction (85-90%) in cubilin staining and a 2-fold decrease in its half-life. Taken together, these results indicate that three distinct regions of cubilin bind to megalin and its interactions with both megalin and AMN are essential for its intracellular stability.
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Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteínas/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Rim/metabolismo , Microvilosidades/metabolismo , Proteínas/química , Proteínas/genética , RatosAssuntos
Anticonvulsivantes , Inibidores da Aromatase/uso terapêutico , Convulsões/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/complicações , Eletroencefalografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Tamoxifeno/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
Consumption of dietary oil, viz., corn, fish, coconut, or olive, induced the secretion of surfactant-like particles (SLP) in rat intestine. These lipoprotein particles differ in (i) levels of alkaline phosphatase activity, (ii) lipid composition, and (iii) FA composition in response to feeding of different oils. The secreted particles had similar buoyancy (1.07-1.08 g/mL) and cholesterol/phospholipid molar ratios (0.61-0.72) except that feeding coconut oil to rats produced SLP with a low (0.18) cholesterol/phospholipid molar ratio compared to control animals. It is concluded from these observations that feeding different oils induces the secretion of lipoprotein particles in rat intestine with different chemical compositions.
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Gorduras na Dieta/farmacologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Tensoativos/química , Tensoativos/metabolismo , Fosfatase Alcalina/sangue , Fosfatase Alcalina/metabolismo , Animais , Colesterol/análise , Ácidos Graxos/análise , Masculino , Óleos/farmacologia , Fosfolipídeos/análise , Fosfolipídeos/sangue , Ratos , Ratos Wistar , Triglicerídeos/sangueRESUMO
BACKGROUND: While many factors have been examined, male gender and older age at multiple sclerosis onset are among few variables consistently associated with increased disability. Interestingly, the association between onset age and disability may not be linear with some data suggesting a faster rate of accumulation of disability in patients aged more than 30 years at onset. OBJECTIVE: Explore the relationship between onset age and disability. METHODS: We studied 500 MS patients grouped by cut-offs in onset age. Disability was assessed using Multiple Sclerosis Severity Scale (MSSS) and, a model based on time to reach an Extended Disability Severity Score (EDSS) (progression model). Data were analyzed using linear and logistic regression. RESULTS: The association between disability (assessed by both MSSS and the progression model) and onset age was different in patients whose MS onset occurred after an age band of 30-35 years. Before this age range, changing age was not associated with changes in disability while during and after this age range, disability was increased. CONCLUSION: We found a significant change in the relationship between disability and onset age after about 31 years supporting the idea that while onset age does not define a sharp cut-off, it can help define subgroups of patients with differing rates of accumulation of disability.
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Avaliação da Deficiência , Modelos Estatísticos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/mortalidade , Índice de Gravidade de Doença , Adolescente , Adulto , Distribuição por Idade , Idade de Início , Simulação por Computador , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade , Distribuição por Sexo , Estatística como Assunto , Taxa de Sobrevida , Suécia/epidemiologia , Adulto JovemRESUMO
Neuro-Behçet's disease (NBD) is one of the more serious manifestations of Behçet's disease (BD), which is a relapsing inflammatory multisystem disease with an interesting epidemiology. Though NBD is relatively uncommon, being potentially treatable, neurologists need to consider it in the differential diagnosis of inflammatory, infective, or demyelinating CNS disorders. Evidence-based information on key issues of NBD diagnosis and management is scarce, and planning for such studies is challenging. We therefore initiated this project to develop expert consensus recommendations that might be helpful to neurologists and other clinicians, created through an extensive literature review and wide consultations with an international advisory panel, followed by a Delphi exercise. We agreed on consensus criteria for the diagnosis of NBD with two levels of certainty in addition to recommendations on when to consider NBD in a neurological patient, and on the use of various paraclinical tests. The management recommendations included treatment of the parenchymal NBD and cerebral venous thrombosis, the use of disease modifying therapies, prognostic factors, outcome measures, and headache in BD. Future studies are needed to validate the proposed criteria and provide evidence-based treatments.
Assuntos
Síndrome de Behçet/diagnóstico , Síndrome de Behçet/terapia , Consenso , Síndrome de Behçet/complicações , Diagnóstico Diferencial , Prática Clínica Baseada em Evidências/tendências , Humanos , Trombose Intracraniana/etiologia , Trombose Intracraniana/terapia , Trombose Venosa/etiologia , Trombose Venosa/terapiaRESUMO
BACKGROUND: The extended disability severity scale (EDSS) is clinically useful in assessing disability in multiple sclerosis (MS) patients. It is also being used in studies to determine how genes and environment influence disability. However, since it has a complex relationship with functional scores and mobility and is strongly determined by disease duration its use can be limiting. OBJECTIVE: Study associations of variables with progression described by time from disease onset until EDSS. METHODS: We used a variable based on below/above median time from MS onset to reach a single EDSS value to define slow or fast progression. We compared patient categorization using this variable and MSSS, and in 533 patients (EDSS 1-8) and 242 of these patients with EDSS1-4, studied associations with skin type, gender, ultraviolet radiation and MC1R Asp294His. RESULTS: Classifying patients into quartiles of slow/fast progression showed mean MSSS increased with faster progression (p<0.001). For EDSS 1-8: MSSS, late onset age and childhood sunburning were associated with fast and MC1R CG/GG(294) with slow progression. Combinations of skin type (1/2 or 3/4) with childhood weekend exposure (< or ≥median) or sunburning (yes/no) were not associated with progression. However, in patients with EDSS1-4, relative to other combinations, those with no sunburning history and types 1/2 demonstrated slow progression (odds ratio=0.15, 95% CI=0.04, 0.57). CONCLUSION: This method, though a pilot, allows study of associations of variables with EDSS. It is based on local patients and could substitute for MSSS. In patients with EDSS1-4 but not 1-8, skin type 1/2 with no history of childhood sunburning was associated with slow progression. This is compatible with the view that disability develops through a first stage dependent on inflammation.
RESUMO
Arrhythmias in pregnancy are common and may cause concern for the well-being of both mother and fetus. Generally, no previous history of heart disease is elicited and majority of the arrhythmias are benign. Bradycardia is commonly seen following subarachnoid block for cesarean section. However, the incidence of subsequent heart block is low. This case report highlights the occurrence of perioperative arrhythmias following sympathetic blockade in pregnant patients and their early detection by vigilant monitoring.