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Older individuals often face disabilities or diseases that lower their quality of life (QoL). While inpatient rehabilitation can initially enhance QoL, there is often a lack of continuation at home. Virtual coaches (VCs) as specific embodied conversational agents promise appropriate support for home rehabilitation. They emerge as complementary digital aids to ensure care continuity. This paper presents the results of implementing a full-featured VC for older patients' home rehabilitation in a multi-stage study, summarizing the main results regarding QoL outcomes and user experience tests. The study confirms the intervention as an engaging means for rehabilitation (mostly above user experience thresholds) and improvements of QoL (>10% between experimental and control groups).
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Serviços de Assistência Domiciliar , Tutoria , Qualidade de Vida , Humanos , Idoso , Masculino , Feminino , Interface Usuário-Computador , TelerreabilitaçãoRESUMO
Introducción. El cáncer colorrectal es uno de los tipos de cáncer más comunes y mortales a nivel mundial. Aunque los avances médicos han mejorado el manejo, la cirugía sigue siendo fundamental. La resección anterior baja (RAB) de recto ha ganado relevancia, a pesar de que puede llevar al síndrome de resección anterior baja de recto (LARS, por sus siglas en inglés), afectando la calidad de vida. Métodos. Estudio de corte transversal con intención analítica en un centro de referencia en Medellín, Colombia. Los pacientes con cáncer de recto sometidos a RAB entre enero de 2016 y diciembre de 2022 completaron el cuestionario LARS para evaluar disfunción intestinal. Se evaluaron factores relacionados con la presencia de LARS por medio de un análisis bivariado. Resultados. De 234 pacientes elegibles, 110 (47 %) respondieron la encuesta, predominantemente mujeres (58,2 %). La edad promedio fue 62 años. Dos tercios de los pacientes recibieron neoadyuvancia y el 69 % requirieron ileostomía. La prevalencia de LARS fue 47,3 %. El 80,9 % llevaban más de 12 meses desde la cirugía o el cierre del estoma. Factores estadísticamente significativos asociados a LARS fueron edad mayor de 65 años (p=0,03), estadío patológico avanzado (p=0,02) y requerimiento de estoma (p=0,03). Conclusiones. El LARS afecta a casi la mitad de los pacientes en diferentes etapas posquirúrgicas. El LARS scorees una herramienta práctica para evaluar la función intestinal en el seguimiento del paciente. La prevalencia y los factores de riesgo identificados contribuyen a la comprensión del impacto de la cirugía conservadora del esfínter en la calidad de vida de los pacientes.
Introduction. Colorectal cancer is one of the most common and deadly types of cancer worldwide, with a high incidence of rectal cancer. Although medical advances have improved management, surgery remains crucial. Low anterior resection of the rectum (LAR) has gained significance, despite its potential to lead to low anterior resection syndrome (LARS), affecting quality of life. Methods. A cross-sectional study with analytical intent was conducted at a referral center in Medellín, Colombia. Patients with rectal cancer who underwent LAR between January 2016 and December 2022 completed the LARS questionnaire to assess intestinal dysfunction. Factors related to the presence of LARS were analyzed using bivariate analysis. Results. Of 234 eligible patients, 110 (47%) responded, predominantly women (58.2%). The average age was 62 years. Two-thirds of patients received neoadjuvant therapy and 69% required ileostomy. The prevalence of LARS was 47.3%. 80.9% had been more than 12 months post-surgery or stoma closure. Statistically significant factors associated with LARS included age over 65 years (p=0.03), advanced pathological stage (p=0.02), and stoma requirement (p=0.03). Conclusions. LARS affects almost half of the patients in various post-surgical stages. The LARS score is a practical tool for assessing intestinal function in patient follow-up. The prevalence and risk factors identified contribute to the understanding of the impact of sphincter-conserving surgery on patients' quality of life.
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Humanos , Doenças Retais , Protectomia , Complicações Pós-Operatórias , Neoplasias Retais , Cirurgia Colorretal , Estomas CirúrgicosRESUMO
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by heterogeneous symptoms, which lack specific biomarkers for its diagnosis. This study aimed to investigate plasma neurofilament light chain (NfL) levels as a potential biomarker for ME/CFS and explore associations with cognitive, autonomic, and neuropathic symptoms. Here, 67 ME/CFS patients and 43 healthy controls (HCs) underwent comprehensive assessments, including neuropsychological evaluation, autonomic nervous system (ANS) testing, and plasma NfL level analysis. ME/CFS patients exhibited significantly higher plasma NfL levels compared to HC (F = 4.30, p < 0.05). Correlations were observed between NfL levels and cognitive impairment, particularly in visuospatial perception (r = -0.42; p ≤ 0.001), verbal memory (r = -0.35, p ≤ 0.005), and visual memory (r = -0.26; p < 0.05) in ME/CFS. Additionally, higher NfL levels were associated with worsened autonomic dysfunction in these patients, specifically in parasympathetic function (F = 9.48, p ≤ 0.003). In ME/CFS patients, NfL levels explained up to 17.2% of the results in cognitive tests. Unlike ME/CFS, in HC, NfL levels did not predict cognitive performance. Elevated plasma NfL levels in ME/CFS patients reflect neuroaxonal damage, contributing to cognitive dysfunction and autonomic impairment. These findings support the potential role of NfL as a biomarker for neurological dysfunction in ME/CFS. Further research is warranted to elucidate underlying mechanisms and clinical implications.
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The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop inclusions neither reproducibly nor in a reasonable time frame. Here, we developed screenable iPSC "inclusionopathy" models utilizing piggyBac or targeted transgenes to rapidly induce CNS cells that express aggregation-prone proteins at brain-like levels. Inclusions and their effects on cell survival were trackable at single-inclusion resolution. Exemplar cortical neuron α-synuclein inclusionopathy models were engineered through transgenic expression of α-synuclein mutant forms or exogenous seeding with fibrils. We identified multiple inclusion classes, including neuroprotective p62-positive inclusions versus dynamic and neurotoxic lipid-rich inclusions, both identified in patient brains. Fusion events between these inclusion subtypes altered neuronal survival. Proteome-scale α-synuclein genetic- and physical-interaction screens pinpointed candidate RNA-processing and actin-cytoskeleton-modulator proteins like RhoA whose sequestration into inclusions could enhance toxicity. These tractable CNS models should prove useful in functional genomic analysis and drug development for proteinopathies.
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Introduction: Olfactory dysfunction (OD) is frequent after SARS-CoV-2 infection. The aim of this study was to examine if long-term OD is common in post-COVID condition, and the relationship between olfaction, cognition, neuropsychiatric symptoms, and disease duration in these patients. Methods: This study included 121 participants with post-COVID condition and 51 healthy controls (HC). A comprehensive neuropsychological and neuropsychiatric assessment was conducted, encompassing various domains, including general cognition, processing speed, verbal fluency, attention, verbal memory, visual memory, visuoconstructive ability, visuospatial ability, abstraction, executive functions, anxious-depressive symptoms, general health perception, fatigue level, sleep quality, and olfaction. Statistical analyses were carried out to understand the relationship of OD with cognition, and its role as moderator variable. Results: In total, 25% of the post-covid patients had a reduced smell capacity, while only 9.3% of HC presented OD. Post-COVID patients had statistically significantly worse cognitive performance and clinical status than HC. Verbal fluency (AUC = 0.85, p < 0.001), and attention (AUC = 0.82, p < 0.001) were the variables that best discriminate between groups. OD seemed to be a moderator between fatigue and cognition, and between disease duration and attention (ß = -0.04; p = 0.014). Discussion: The study highlights marked cognitive and neuropsychiatric sequelae in individuals post-COVID relative to HC. Olfactory impairment exhibits correlations with both cognitive performance and general health. Olfaction emerges as a potential prognostic marker owing to its moderating influence on disease severity indicators.
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Resolution of inflammation is the cellular and molecular process that protects from widespread and uncontrolled inflammation and restores tissue function in the aftermath of acute immune events. This process is orchestrated by specialized pro-resolving mediators (SPM), a class of bioactive lipids able to reduce immune activation and promote removal of tissue debris and apoptotic cells by macrophages. Although SPMs are the lipid class that has been best studied for its role in facilitating the resolution of self-limited inflammation, a number of other lipid signals, including endocannabinoids, also exert protective immunomodulatory effects on immune cells, including macrophages. These observations suggest that endocannabinoids may also display pro-resolving actions. Interestingly, the endocannabinoid anandamide (AEA) is not only known to bind canonical type 1 and type 2 cannabinoid receptors (CB1 and CB2) but also to engage SPM-binding receptors such as GPR18. This suggests that AEA may also contribute to the governing of resolution processes. In order to interrogate this hypothesis, we investigated the ability of AEA to induce pro-resolving responses by classically-activated primary human monocyte-derived macrophages (MoDM). We found that AEA, at nanomolar concentration, enhances efferocytosis in MoDMs in a CB2- and GPR18-dependent manner. Using lipid mediator profiling, we also observed that AEA modulates SPM profiles in these cells, including levels of resolvin (Rv)D1, RvD6, maresin (MaR)2, and RvE1 in a CB2-dependent manner. AEA treatment also modulated the gene expression of SPM enzymes involved in both the formation and further metabolism of SPM such as 5-lipoxygenase and 15-Prostaglandin dehydrogenase. Our findings show, for the first time, a direct effect of AEA on the regulation of pro-resolving pathways in human macrophages. They also provide new insights into the complex interactions between different lipid pathways in activation of pro-resolving responses contributing to the reestablishment of homeostasis in the aftermath of acute inflammation.
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Ácidos Araquidônicos , Endocanabinoides , Macrófagos , Alcamidas Poli-Insaturadas , Receptor CB2 de Canabinoide , Receptores Acoplados a Proteínas G , Humanos , Endocanabinoides/metabolismo , Endocanabinoides/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Ácidos Araquidônicos/farmacologia , Ácidos Araquidônicos/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Inflamação/metabolismo , Células Cultivadas , Transdução de Sinais/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/metabolismo , Araquidonato 5-Lipoxigenase/metabolismoRESUMO
ABSTRACT: The leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) was recently identified as the cognate receptor for the proresolving mediator maresin 1 (MaR1). To address the biological role of LGR6 in humans, we investigated the functional impact of a genetic variant in the gene encoding for LGR6, which is predicted to lead to a frameshift mutation in one of the receptor isoforms, on both receptor expression and immune cell responses. In neutrophils, monocytes, and natural killer (NK) cells from volunteers homozygous for this variant, we found a significant downregulation in the expression of LGR6 when compared with controls without the variant; whereas the LGR6 expression was essentially similar in monocyte-derived macrophages and CD8+ T cells. Functionally, loss of LGR6 expression was linked with a decreased ability of neutrophils and monocytes to phagocytose bacteria. We observed an increase in neutrophil chemotaxis and leukotriene B4 production and increased expression of activation markers, including markers for platelet-leukocyte phagocyte heterotypic aggregates, such as CD41, in neutrophils and monocytes from the variant group. Using data from the UK Biobank, we found that at a population level the rs4266947 variant, which is in high linkage disequilibrium with rs74355478, was associated with a higher incidence of viral infections. Intriguingly, neutrophils, NK cells, and CD8+ T cells from volunteers with the LGR6 variant displayed altered viral responses when stimulated with Toll-like receptor 3 (TLR3), TLR7/TLR8, and TLR9 agonists. Together, these findings shed new light on the cell type-specific regulation of LGR6 expression and the role of this receptor in directing host immune responses.
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Mutação da Fase de Leitura , Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/genética , Viroses/imunologia , Viroses/genética , Masculino , Feminino , Fagocitose , Neutrófilos/metabolismo , Neutrófilos/imunologia , Leucócitos/metabolismo , Leucócitos/imunologia , Monócitos/metabolismo , Monócitos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Pessoa de Meia-Idade , Adulto , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismoRESUMO
Retinal thickness may serve as a biomarker in Parkinson's disease (PD). In this prospective longitudinal study, we aimed to determine if PD patients present accelerated thinning rate in the parafoveal ganglion cell-inner plexiform layer (pfGCIPL) and peripapillary retinal nerve fiber layer (pRNFL) compared to controls. Additionally, we evaluated the relationship between retinal neurodegeneration and clinical progression in PD. A cohort of 156 PD patients and 72 controls underwent retinal optical coherence tomography, visual, and cognitive assessments between February 2015 and December 2021 in two Spanish tertiary hospitals. The pfGCIPL thinning rate was twice as high in PD (ß [SE] = -0.58 [0.06]) than in controls (ß [SE] = -0.29 [0.06], p < 0.001). In PD, the progression pattern of pfGCIPL atrophy depended on baseline thickness, with slower thinning rates observed in PD patients with pfGCIPL below 89.8 µm. This result was validated with an external dataset from Moorfields Eye Hospital NHS Foundation Trust (AlzEye study). Slow pfGCIPL progressors, characterized by older at baseline, longer disease duration, and worse cognitive and disease stage scores, showed a threefold increase in the rate of cognitive decline (ß [SE] = -0.45 [0.19] points/year, p = 0.021) compared to faster progressors. Furthermore, temporal sector pRNFL thinning was accelerated in PD (ßtime x group [SE] = -0.67 [0.26] µm/year, p = 0.009), demonstrating a close association with cognitive score changes (ß [SE] = 0.11 [0.05], p = 0.052). This study suggests that a slower pattern of pfGCIPL tissue loss in PD is linked to more rapid cognitive decline, whereas changes in temporal pRNFL could track cognitive deterioration.
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BACKGROUND: Falls represent a critical concern in Parkinson's disease (PD), contributing to increased morbidity and reduced quality of life. PURPOSE: We conducted a systematic review to assess the prognostic factors associated with falls in PD, aiming to provide a comprehensive overview of relevant demographic and clinical parameters, and aid neurologists in identifying subsets of PD patients most susceptible to falls and associated injuries. METHODS: PubMed and Web of Science databases were searched for prospective studies assessing factors associated with falls in ambulatory PD patients across different settings, from inception to August 2023. Data extraction was conducted using CHARMS-PF checklist and risk of bias was assessed with QUIPS tool. PRISMA guidelines were followed. RESULTS: The initial search yielded 155 references. Thirty-four studies, involving a total of 3454 PD patients, were included in the final analysis. The mean pooled age was 67.6 years, and 45.1% were women. PD patients presented mild motor impairment (UPDRS III score 27.8) with mean pooled disease duration of 5.7 years. Gait and balance disorders and history of prior falls emerged as the most consistent predictors of falls across studies. Disease duration, disease severity, dysautonomic symptoms, freezing of gait, frontal cognitive functions, and PD medication dosages yielded inconsistent findings. Conversely, dyskinesias, age, sex, and depression were unrelated to future falls in PD. Logistic regression models were most commonly employed to identify factors significantly associated with falls in PD. Substantial heterogeneity prevailed in the inclusion of confounding factors. CONCLUSION: The evidence suggests that previous history of falls, gait disorders, and poor balance are robust prognostic markers for falls in PD.
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Transtornos Neurológicos da Marcha , Doença de Parkinson , Humanos , Feminino , Idoso , Masculino , Doença de Parkinson/complicações , Estudos Prospectivos , Prognóstico , Qualidade de VidaRESUMO
BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID condition can present similarities such as fatigue, brain fog, autonomic and neuropathic symptoms. METHODS: The study included 87 patients with post-COVID condition, 50 patients with ME/CFS, and 50 healthy controls (HC). The hemodynamic autonomic function was evaluated using the deep breathing technique, Valsalva maneuver, and Tilt test. The presence of autonomic and sensory small fiber neuropathy (SFN) was assessed with the Sudoscan and with heat and cold evoked potentials, respectively. Finally, a complete neuropsychological evaluation was performed. The objective of this study was to analyze and compare the autonomic and neuropathic symptoms in post-COVID condition with ME/CFS, and HC, as well as, analyze the relationship of these symptoms with cognition and fatigue. RESULTS: Statistically significant differences were found between groups in heart rate using the Kruskal-Wallis test (H), with ME/CFS group presenting the highest (H = 18.3; p ≤ .001). The Postural Orthostatic Tachycardia Syndrome (POTS), and pathological values in palms on the Sudoscan were found in 31% and 34% of ME/CFS, and 13.8% and 19.5% of post-COVID patients, respectively. Concerning evoked potentials, statistically significant differences were found in response latency to heat stimuli between groups (H = 23.6; p ≤ .01). Latency was highest in ME/CFS, and lowest in HC. Regarding cognition, lower parasympathetic activation was associated with worse cognitive performance. CONCLUSIONS: Both syndromes were characterized by inappropriate tachycardia at rest, with a high percentage of patients with POTS. The prolonged latencies for heat stimuli suggested damage to unmyelinated fibers. The higher proportion of patients with pathological results for upper extremities on the Sudoscan suggested a non-length-dependent SFN.
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COVID-19 , Síndrome de Fadiga Crônica , Síndrome da Taquicardia Postural Ortostática , Neuropatia de Pequenas Fibras , Humanos , Síndrome de Fadiga Crônica/diagnóstico , Síndrome de COVID-19 Pós-Aguda , COVID-19/complicações , Síndrome da Taquicardia Postural Ortostática/diagnósticoRESUMO
BACKGROUND AND OBJECTIVE: Multiple system atrophy is a rare and fatal neurodegenerative disorder, characterized by autonomic dysfunction in association with either parkinsonism or cerebellar signs. The pathologic hallmark is the presence of alpha-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Clinically, it may be difficult to distinguish form other parkinsonisms or ataxias, particularly in the early stages of the disease. In this case series we aim to describe in detail the features of MSA patients. MATERIAL AND METHODS: Unified MSA Rating Scale (UMSARS) score, structural and functional imaging and cardiovascular autonomic testing, are summarized since early stages of the disease. RESULTS: UMSARS proved to be useful to perform a follow-up being longitudinal examination essential to stratify risk of poor outcome. Neuropathological diagnosis showed an overlap between parkinsonian and cerebellar subtypes, with some peculiarities that could help to distinguish from other subtypes. CONCLUSION: A better description of MSA features with standardized test confirmed by means of neuropathological studies could help to increase sensitivity.
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Doenças do Sistema Nervoso Autônomo , Atrofia de Múltiplos Sistemas , Transtornos Parkinsonianos , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , AtaxiaRESUMO
INTRODUCTION: Parkinson's Disease (PD) is a progressive age-related neurodegenerative condition requiring new therapeutic alternatives. Safinamide, a novel levodopa add-on therapy, positively affects disease fluctuations by modulating both dopaminergic and glutamatergic systems. To further investigate the use of safinamide in European routine clinical practice, the present post-hoc analysis aimed to understand safinamide's safety profile within the Spanish study population. PATIENTS AND METHODS: Five hundred eleven Spanish patients with PD were evaluated at baseline, four (±1), eight (±1), and 12 (±1) months after initiating safinamide treatment. Unified Parkinson's Disease Rating Scale (UPDRS) total score and UPDRS part III score during on time were used to measure the overall severity of PD and motor complications, respectively, while the severity of adverse events was evaluated following the investigators' criteria. RESULTS: Safinamide showed a favourable safety profile within the Spanish study population, although prescription to patients with psychiatric conditions and off-label use were more frequent than in the European study population. In Spain, clinically meaningful improvements were observed in UPDRS scores when safinamide was used as the only add-on therapy to levodopa (57.4% and 53.7% of patients) and when switching from rasagiline (55.1% of patients). Motor complications were reduced from 83.2% to 63.3% after the study period. Increased safety concerns were undetected in any patient subgroup, although patients with cognitive impairment showed a slightly higher frequency of adverse events. CONCLUSIONS: This subanalysis further supports safinamide use as a safe and efficacious option for the management of motor fluctuations in different subgroups of levodopa-treated patients. However, safinamide should be used with caution in patients with cognitive impairment.
TITLE: SYNAPSES. Estudio observacional europeo para evaluar la seguridad y la efectividad de la safinamida en la práctica clínica habitual: análisis post hoc de la población española del estudio.Introducción. La enfermedad de Parkinson (EP) es una enfermedad neurodegenerativa progresiva relacionada con la edad que requiere nuevas alternativas terapéuticas. La safinamida, un nuevo tratamiento add-on a la levodopa, afecta positivamente a las fluctuaciones de esta enfermedad al modular los sistemas dopaminérgico y glutamatérgico. Para investigar más a fondo el uso de la safinamida en la práctica clínica rutinaria europea, el presente análisis post hoc tiene como objetivo comprender el perfil de seguridad de la safinamida dentro de la población española del estudio. Pacientes y métodos. Se evaluó a 511 pacientes españoles con EP al inicio, cuatro (±1), ocho (±1) y 12 (±1) meses después de iniciar el tratamiento con safinamida. Se utilizaron la puntuación total de la escala unificada de puntuación de la enfermedad de Parkinson (UPDRS) y la puntuación de la UPDRS III, durante el tiempo en on para medir la gravedad general de la EP y las complicaciones motoras, respectivamente, mientras que la gravedad de los acontecimientos adversos se evaluó siguiendo los criterios de los investigadores. Resultados. La safinamida mostró un perfil de seguridad favorable en la población española del estudio, aunque la prescripción a pacientes con enfermedades psiquiátricas y el uso para indicaciones no autorizadas fueron más frecuentes que en la población europea del estudio. En España se observaron mejoras clínicamente significativas en las puntuaciones de la UPDRS cuando se utilizó la safinamida como único tratamiento add-on a la levodopa (el 57,4 y el 53,7% de los pacientes) y cuando se venía de administrar rasagilina (el 55,1% de los pacientes). Las complicaciones motoras se redujeron del 83,2 al 63,3% tras el período de estudio. No se detectaron mayores problemas de seguridad en ningún subgrupo de pacientes, aunque los pacientes con deterioro cognitivo mostraron una frecuencia algo superior de acontecimientos adversos. Conclusiones. Este subanálisis respalda el uso de la safinamida como opción segura y eficaz para el tratamiento de las fluctuaciones motoras en diferentes subgrupos de pacientes tratados con levodopa. Sin embargo, la safinamida debe utilizarse con precaución en pacientes con deterioro cognitivo.
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Levodopa , Doença de Parkinson , Humanos , Levodopa/efeitos adversos , Sinapses , Doença de Parkinson/tratamento farmacológico , Benzilaminas/efeitos adversosRESUMO
Considering pure quantum states, entanglement concentration is the procedure where, from N copies of a partially entangled state, a single state with higher entanglement can be obtained. Obtaining a maximally entangled state is possible for N=1. However, the associated success probability can be extremely low when increasing the system's dimensionality. In this work, we study two methods to achieve a probabilistic entanglement concentration for bipartite quantum systems with a large dimensionality for N=1, regarding a reasonably good probability of success at the expense of having a non-maximal entanglement. Firstly, we define an efficiency function Q considering a tradeoff between the amount of entanglement (quantified by the I-Concurrence) of the final state after the concentration procedure and its success probability, which leads to solving a quadratic optimization problem. We found an analytical solution, ensuring that an optimal scheme for entanglement concentration can always be found in terms of Q. Finally, a second method was explored, which is based on fixing the success probability and searching for the maximum amount of entanglement attainable. Both ways resemble the Procrustean method applied to a subset of the most significant Schmidt coefficients but obtaining non-maximally entangled states.
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INTRODUCTION: We propose a protocol for study of complex regional pain syndrome (CRPS) based on a battery of quantitative measures (skin thermography, electrochemical skin conductance and sensory thresholds) and apply such protocol to 5 representative cases of CRPS. PATIENTS AND METHODS: 5 CPRS cases (2 women/3 men) that met the Budapest criteria for the diagnosis of CRPS. RESULTS: All patients showed spontaneous pain and allodynia. Two cases correspond to a stage I, in both the resting basal temperature was increased in the affected limb. Three cases reflect more advanced stages with a decrease in resting temperature and a delay in the recovery of the temperature when compared to contralateral limb. DISCUSSION: These non-invasive quantitative functional tests not only improve the diagnostic accuracy of CRPS but also, they help us to stratify and understand the pathological processes of the disease.
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Síndromes da Dor Regional Complexa , Termografia , Masculino , Humanos , Feminino , Termografia/métodos , Síndromes da Dor Regional Complexa/diagnósticoRESUMO
BACKGROUND: Cognitive decline has been reported in premanifest and manifest Huntington's disease but reliable biomarkers are lacking. Inner retinal layer thickness seems to be a good biomarker of cognition in other neurodegenerative diseases. OBJECTIVE: To explore the relationship between optical coherence tomography-derived metrics and global cognition in Huntington's Disease. METHODS: Thirty-six patients with Huntington's disease (16 premanifest and 20 manifest) and 36 controls matched by age, sex, smoking status, and hypertension status underwent macular volumetric and peripapillary optical coherence tomography scans. Disease duration, motor status, global cognition and CAG repeats were recorded in patients. Group differences in imaging parameters and their association with clinical outcomes were analyzed using linear mixed-effect models. RESULTS: Premanifest and manifest Huntington's disease patients presented thinner retinal external limiting membrane-Bruch's membrane complex, and manifest patients had thinner temporal peripapillary retinal nerve fiber layer compared to controls. In manifest Huntington's disease, macular thickness was significantly associated with MoCA scores, inner nuclear layer showing the largest regression coefficients. This relationship was consistent after adjusting for age, sex, and education and p-value correction with False Discovery Rate. None of the retinal variables were related to Unified Huntington's Disease Rating Scale score, disease duration, or disease burden. Premanifest patients did not show a significant association between OCT-derived parameters and clinical outcomes in corrected models. CONCLUSIONS: In line with other neurodegenerative diseases, OCT is a potential biomarker of cognitive status in manifest HD. Future prospective studies are needed to evaluate OCT as a potential surrogate marker of cognitive decline in HD.
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Disfunção Cognitiva , Doença de Huntington , Humanos , Doença de Huntington/complicações , Doença de Huntington/diagnóstico por imagem , Retina/diagnóstico por imagem , Biomarcadores , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/complicações , Tomografia de Coerência Óptica/métodosRESUMO
BACKGROUND: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD). OBJECTIVE: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity. METHODS: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort fromJanuary 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL:1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8). RESULTS: Four hundred and thirty-nine PD patients (62.05±7.84 years old; 59% males) were included. MNCD stage was:stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advancedMNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p< 0.0001) and EUROHIS-QOL8 (p< 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages. CONCLUSION: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.
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Doença de Parkinson , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Doença de Parkinson/diagnóstico , Doença de Parkinson/complicações , Qualidade de Vida , Atividades Cotidianas , Índice de Gravidade de Doença , Gravidade do PacienteRESUMO
BACKGROUND: We aimed to characterize subtypes of synucleinopathies using a clustering approach based on cognitive and other nonmotor data and to explore structural and functional magnetic resonance imaging (MRI) brain differences between identified clusters. METHODS: Sixty-two patients (n = 6 E46K-SNCA, n = 8 dementia with Lewy bodies (DLB) and n = 48 idiopathic Parkinson's disease (PD)) and 37 normal controls underwent nonmotor evaluation with extensive cognitive assessment. Hierarchical cluster analysis (HCA) was performed on patients' samples based on nonmotor variables. T1, diffusion-weighted, and resting-state functional MRI data were acquired. Whole-brain comparisons were performed. RESULTS: HCA revealed two subtypes, the mild subtype (n = 29) and the severe subtype (n = 33). The mild subtype patients were slightly impaired in some nonmotor domains (fatigue, depression, olfaction, and orthostatic hypotension) with no detectable cognitive impairment; the severe subtype patients (PD patients, all DLB, and the symptomatic E46K-SNCA carriers) were severely impaired in motor and nonmotor domains with marked cognitive, visual and bradykinesia alterations. Multimodal MRI analyses suggested that the severe subtype exhibits widespread brain alterations in both structure and function, whereas the mild subtype shows relatively mild disruptions in occipital brain structure and function. CONCLUSIONS: These findings support the potential value of incorporating an extensive nonmotor evaluation to characterize specific clinical patterns and brain degeneration patterns of synucleinopathies.
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BACKGROUND: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).
Assuntos
Fator IX , Terapia Genética , Hemofilia B , Humanos , Masculino , Fator IX/genética , Fator IX/uso terapêutico , Terapia Genética/métodos , Hemofilia B/complicações , Hemofilia B/genética , Hemofilia B/terapia , Hemorragia/etiologia , Hemorragia/terapia , Vetores Genéticos/administração & dosagemRESUMO
Etranacogene dezaparvovec (AMT-061) is a recombinant adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) transgene with a liver-specific promoter. Here, we report 3-year outcomes from a phase 2b, open-label, single-dose, single-arm, multicenter trial conducted among adults with severe or moderately severe hemophilia B (FIX ≤2%). All participants (n = 3) received a single intravenous dose (2 × 1013 gene copies per kg) and will be followed up for 5 years. The primary end point of FIX activity ≥5% at 6 weeks was met. Secondary end points included bleed frequency, FIX concentrate use, joint health, and adverse events (AEs). All participants required routine FIX prophylaxis and had neutralizing antibodies to AAV5 before etranacogene dezaparvovec treatment. After administration, FIX activity rose to a mean of 40.8% in year 1 and was sustained in year 3 at 36.9%. All participants discontinued FIX prophylaxis. Bleeding was completely eliminated in 2 out of 3 participants. One participant required on-demand FIX replacement therapy per protocol because of elective surgical procedures, for 2 reported bleeding episodes, and twice for a single self-administered infusion because of an unreported reason. One participant experienced 2 mild, self-limiting AEs shortly after dosing. During the 3-year study period, there were no clinically significant elevations in liver enzymes, no requirement for steroids, no FIX inhibitor development, and no late-emergent safety events in any participant. Etranacogene dezaparvovec was safe and effective in adults with hemophilia B over 3 years after administration. This trial was registered at www.clinicaltrials.gov as #NCT03489291.