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BACKGROUND: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). METHODS: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. RESULTS: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, PWald<0.001); the expression correlated with pathological disease activity (R=0.59, Pt-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, Pt-statistic=0.031). CONCLUSIONS: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03660969.
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Cardiopatias/metabolismo , Doenças Musculares/metabolismo , Troponina I/metabolismo , Troponina T/metabolismo , Biomarcadores , Estudos de Casos e Controles , Feminino , Cardiopatias/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Estudos Prospectivos , RNA Mensageiro/análise , Reprodutibilidade dos Testes , Troponina I/genética , Troponina T/genéticaRESUMO
INTRODUCTION: In patients with ulnar neuropathy at the elbow (UNE) the precise determination of the site of lesion is important for subsequent differential diagnostic considerations and therapeutic management. Due to a paucity of comparable data, to better define the role of different diagnostic tests, we performed the first prospective study comparing the diagnostic accuracy of short segment nerve stimulation, nerve ultrasonography, MR neurography (MRN), and diffusion tensor imaging (DTI) in patients with UNE. METHODS: UNE was clinically diagnosed in 17 patients with 18 affected elbows. For all 18 affected elbows in patients and 20 elbows in 10 healthy volunteers, measurements of all different diagnostic tests were performed at six anatomical positions across the elbow with measuring points from distal (D4) to proximal (P6) in relation to the medial epicondyle (P0). Additional qualitative assessment regarding structural changes of surrounding nerve anatomy was conducted. RESULTS: The difference between affected arms of patients and healthy control arms were most frequently the largest at measure intervals D2 to P0 and P0 to P2 for electrophysiological testing, or measure points P0 and P2 for all other devices, respectively. At both levels P0 and at P2, T2 contrast-to-noise ratio (CNR) of MRN and mean diffusivity (MD) of DTI-based MRN showed best accuracies. DISCUSSION: This study revealed differences in diagnostic performance of tests concerning a specific location of UNE, with better results for T2 contrast to noise ratio (CNR) in MRN and mean diffusivity of DTI-based MRN. Additional testing with MRN and nerve ultrasonography is recommended to uncover anatomical changes.
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Cotovelo , Neuropatias Ulnares , Imagem de Tensor de Difusão , Cotovelo/diagnóstico por imagem , Eletrodiagnóstico , Humanos , Condução Nervosa , Estudos Prospectivos , Nervo Ulnar , Neuropatias Ulnares/diagnóstico por imagemRESUMO
Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neuromuscular signaling due to autoantibodies targeting the acetylcholine receptor. Although its auto-antigens and effector mechanisms are well defined, the cellular and molecular drivers underpinning MG remain elusive. Here, we employed high-dimensional single-cell mass and spectral cytometry of blood and thymus samples from MG patients in combination with supervised and unsupervised machine-learning tools to gain insight into the immune dysregulation underlying MG. By creating a comprehensive immune map, we identified two dysregulated subsets of inflammatory circulating memory T helper (Th) cells. These signature ThCD103 and ThGM cells populated the diseased thymus, were reduced in the blood of MG patients, and were inversely correlated with disease severity. Both signature Th subsets rebounded in the blood of MG patients after surgical thymus removal, indicative of their role as cellular markers of disease activity. Together, this in-depth analysis of the immune landscape of MG provides valuable insight into disease pathogenesis, suggests novel biomarkers and identifies new potential therapeutic targets for treatment.
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Imunofenotipagem/métodos , Miastenia Gravis/imunologia , Miastenia Gravis/patologia , Análise de Célula Única , Linfócitos T/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos , Autoimunidade , Linfócitos B/imunologia , Biomarcadores , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Receptores Colinérgicos/imunologia , Linfócitos T/imunologia , Timectomia , TimoRESUMO
BACKGROUND: Migraine is a multifactorial neurovascular disorder, which affects about 12% of the general population. In episodic migraine, the visual cortex revealed abnormal processing, most likely due to decreased preactivation level. Transcranial direct current stimulation (tDCS) is able to modify cortical excitability and might result in an alleviation of migraine occurrence if used repetitively. OBJECTIVE: To test the hypothesis that self-administered anodal tDCS over the visual cortex significantly decreases the number of monthly migraine days in episodic migraine. MATERIALS AND METHODS: The study was single-blind, randomized, and sham-controlled. Inclusion criteria were age 18-80 years and an ICHD-3 diagnosis of episodic migraine. Exclusion criteria were pregnancy, presence of a neurodegenerative disorder, a contraindication against MRI examinations, and less than two migraine days during the 28-day baseline period. Patients in whom the baseline period suggested chronic migraine were excluded. After baseline, participants applied daily either verum (anodal-1 mA to 20 min) or sham tDCS (anodal-1 mA to 30 sec) at Oz (reference Cz electrode) for 28 days. Headache diaries were used to record the number of migraine days at baseline, during the stimulation period, and during four subsequent 28-day periods. RESULTS: Twenty-eight patients were included; two were excluded after the baseline period because less than two migraine days occurred; three were excluded because their headache diaries suggested the diagnosis of chronic migraine. Twenty-three datasets were taken for further analysis. Compared to sham tDCS (n = 12), verum tDCS (n = 11) resulted in a lower number of migraine days (p = 0.010) across all follow-up periods. We found no significant change in total headache days (p = 0.165), anxiety (p = 0.884), or depression scores (p = 0.535). No serious adverse events occurred; minor side effects were similar in both groups. CONCLUSIONS: This study provides Class II evidence that self-administered anodal tDCS over the visual cortex in episodic migraine results in a significantly lower number of monthly migraine days. However, it has neither an immediate nor a long-term effect.
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Transtornos de Enxaqueca , Estimulação Transcraniana por Corrente Contínua , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Eletrodos , Humanos , Pessoa de Meia-Idade , Transtornos de Enxaqueca/terapia , Método Simples-Cego , Adulto JovemRESUMO
Smarter Medicine in Headache Care - presentation and discussion of 5 recommendations Abstract. An unequivocal headache diagnosis cannot always be made. The lack of diagnostic tests able to prove primary headaches often prompts physicians to perform unnecessary examinations to reduce their uncertainty. When setting out the therapeutic strategy, again, insecurity often leads to mendable choices. In this Delphi study, members of the therapy commission of the Swiss Headache Society collected, rated, and re-rated doubtful and questionable procedures. Five recommendations that resulted from this survey are presented and reviewed in this article. The recommendations are: (A) no repeated cerebral imaging in headaches with unchanged phenotype; (B) no computed tomography in the work-up of non-acute headaches; (C) no tooth extraction to treat persistent idiopathic facial pain, (D) no migraine surgery; (E) no removal of amalgam fillings to treat headache disorders.
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Medicina , Transtornos de Enxaqueca , Médicos , Diagnóstico por Imagem , Cefaleia/diagnóstico , Cefaleia/terapia , Humanos , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/terapiaRESUMO
BACKGROUND: 1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids. They are formed during sphingolipid de novo synthesis by the enzyme serine palmitoyltransferase, due to the alternate use of alanine over its canonical substrate serine. Pathologically elevated 1-deoxySL are involved in several neurological and metabolic disorders. The objective of this study was to investigate the role of 1-deoxySL in glycogen storage disease type I (GSDI). METHODS: In this prospective, longitudinal observational study (median follow-up 1.8y), the plasma 1-deoxySL profile was analyzed in 15 adult GSDI patients (12 GSDIa, 3 GSDIb), and 31 healthy controls, along with standard parameters for monitoring GSDI. RESULTS: 1-Deoxysphinganine (1-deoxySA) concentrations were elevated in GSDI compared to controls (191⯱â¯129 vs 35⯱â¯14â¯nmol/l, pâ¯<â¯0.0001). Concordant with the mechanism of 1-deoxySL synthesis, plasma alanine was higher (625⯱â¯182 vs 398⯱â¯90⯵mol/l, pâ¯<â¯0.0001), while serine was lower in GSDI than in controls (88⯱â¯22 vs 110⯱â¯18⯵mol/l. pâ¯<â¯0.001). Accordingly, serine, alanine and triglycerides were determinants of 1-deoxySA in the longitudinal analysis of GSDIa. 1-deoxySA concentrations correlated with the occurrence of low blood glucose (area under the curve below 4â¯mmol/l) in continuous glucose monitoring. The 1-deoxySL profile in GSDIb was distinct from GSDIa, with a different ratio of saturated to unsaturated 1-deoxySL. CONCLUSION: In addition to the known abnormalities of lipoproteins, GSDI patients also have a disturbed sphingolipid metabolism with elevated plasma 1-deoxySL concentrations. 1-DeoxySA relates to the occurrence of low blood glucose, and may constitute a potential new biomarker for assessing metabolic control. GSDIa and Ib have distinct 1-deoxySL profiles indicating that both GSD subtypes have diverse phenotypes regarding lipid metabolism.
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Doença de Depósito de Glicogênio Tipo I/sangue , Metabolismo dos Lipídeos/genética , Esfingolipídeos/sangue , Adolescente , Adulto , Alanina/sangue , Feminino , Glucose/metabolismo , Doença de Depósito de Glicogênio Tipo I/genética , Doença de Depósito de Glicogênio Tipo I/patologia , Humanos , Masculino , Serina/sangue , Serina C-Palmitoiltransferase/genética , Esfingolipídeos/genética , Adulto JovemRESUMO
BACKGROUND: Mitochondrial disease can present as a movement disorder. Data on this entity's epidemiology, genetics, and underlying pathophysiology, however, is scarce. OBJECTIVE: The objective of this study was to describe the clinical, genetic, and volumetric imaging data from patients with mitochondrial disease who presented with movement disorders. METHODS: In this retrospective analysis of all genetically confirmed mitochondrial disease cases from three centers (n = 50), the prevalence and clinical presentation of video-documented movement disorders was assessed. Voxel-based morphometry from high-resolution MRI was employed to compare cerebral and cerebellar gray matter volume between mitochondrial disease patients with and without movement disorders and healthy controls. RESULTS: Of the 50 (30%) patients with genetically confirmed mitochondrial disease, 15 presented with hypokinesia (parkinsonism 3/15), hyperkinesia (dystonia 5/15, myoclonus 3/15, chorea 2/15), and ataxia (3/15). In 3 patients, mitochondrial disease presented as adult-onset isolated dystonia. In comparison to healthy controls and mitochondrial disease patients without movement disorders, patients with hypo- and hyperkinetic movement disorders had significantly more cerebellar atrophy and an atrophy pattern predominantly involving cerebellar lobules VI and VII. CONCLUSION: This series provides clinical, genetic, volumetric imaging, and histologic data that indicate major involvement of the cerebellum in mitochondrial disease when it presents with hyper- and hypokinetic movement disorders. As a working hypothesis addressing the particular vulnerability of the cerebellum to energy deficiency, this adds substantially to the pathophysiological understanding of movement disorders in mitochondrial disease. Furthermore, it provides evidence that mitochondrial disease can present as adult-onset isolated dystonia. © 2017 International Parkinson and Movement Disorder Society.
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Cerebelo/patologia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/genética , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/patologia , Translocador 1 do Nucleotídeo Adenina/genética , Adulto , Idoso , Cerebelo/diagnóstico por imagem , DNA Polimerase gama/genética , Feminino , Substância Cinzenta/patologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/diagnóstico por imagem , Mutação/genética , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: McLeod syndrome (MLS) is hematologically defined by the absence of the red blood cell (RBC) antigen Kx on the transmembrane RBC protein, XK, representing a highly specific diagnostic marker. Direct molecular assessment of XK therefore represents a desirable diagnostic tool. Whereas pathogenic point mutations may be simply identified, partial and complete deletions of XK on Xp21.1, eventually covering adjacent genes and causing multifaceted "continuous gene syndromes," are difficult to localize. STUDY DESIGN AND METHODS: Three different McLeod patient samples were tested using 16 initial positional polymerase chain reaction (PCR) procedures distributed over an approximately 2.8-Mbp Xp-chromosomal region, ranging telomeric from MAGEB16 to OTC, centromeric of XK. The molecular breakpoint of one sample with an apparent large Xp deletion was iteratively narrowed down by stepwise positioning further PCR procedures and sequenced. Two mutant XK genes, one previously published and serving as a positive control, were also sequenced. RESULTS: We confirmed the positive control as previously published and listed as XK*N.20 by the International Society of Blood Transfusion (ISBT). The other XK showed a novel four-nucleotide deletion in Exon 1, 195-198delCCGC (newly listed as XK*N.39 by the ISBT). The third sample had an approximately 151-kbp X-chromosomal deletion, reaching from Exon 2 of LANCL3, across XK to Exon 3 of CYBB (newly listed as XK*N.01.016 by the ISBT). Carrier status of the patients' sister was diagnosed using a diagnostic "gap-PCR." CONCLUSIONS: The stepwise partitioning of Xp21.1 is pragmatic and cost-efficient in comparison to other diagnostic techniques such as "massive parallel sequencing" given the rarity of MLS. All males with suspected MLS should be considered for molecular XK profiling.
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Sistemas de Transporte de Aminoácidos Neutros/genética , Cromossomos Humanos X/genética , Neuroacantocitose/genética , Deleção de Genes , Humanos , Masculino , Reação em Cadeia da Polimerase , Deleção de SequênciaRESUMO
NEW FINDINGS: What is the central question of this study? Acute skeletal muscle satellite cell (SC) activation is associated with skeletal muscle hypertrophy. Although the quantity of SCs has been reported to increase following a single bout of resistance exercise, data on muscle fibre type-specific SC quantity and/or activation status after a single bout of vibration is presently lacking. What is the main finding and its importance? By determining SCs from muscle biopsies of the vastus lateralis using immunohistochemistry, we conclude that modification of vibration exercise by superimposition of occlusion induced activation and differentiation of SCs in young men, which had not been observed with whole-body vibration or blood flow restriction alone. We tested the hypothesis that whole-body vibration (WBV) is insufficient to expand satellite cell numbers 24 h postexercise, whereas WBV in combination with blood flow restriction (BFR) is sufficient. Twenty-five young men were randomly assigned to one of the following three groups: WBV, BFR exercise or WBVBFR. Satellite cell numbers were determined from muscle biopsies of the vastus lateralis muscle using immunohistochemistry. Satellite cell quantity and frequency (+99.4%, P = 0.012 and +77.1%, P = 0.010, respectively) increased only in the WBVBFR group. Similar results were obtained for the quantity and frequency of myogenin-positive myonuclei (+139.0%, P < 0.001 and +148.4%, P < 0.001, respectively). We conclude that modification of WBV by superimposition of BFR induced activation and differentiation of satellite cells in young men, which had not been observed with WBV or BFR alone. These data suggest that WBVBFR might represent a novel viable anabolic stimulus.
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Exercício Físico/fisiologia , Células Satélites de Músculo Esquelético/fisiologia , Adulto , Biópsia/métodos , Diferenciação Celular/fisiologia , Humanos , Masculino , Músculo Esquelético/fisiologia , Miogenina/metabolismo , Músculo Quadríceps/fisiologia , VibraçãoRESUMO
BACKGROUND: Dysferlin is reduced in patients with limb girdle muscular dystrophy type 2B, Miyoshi myopathy, distal anterior compartment myopathy, and in certain Ethnic clusters. METHODS: We evaluated clinical and genetic patient data from three different Swiss Neuromuscular Centers. RESULTS: Thirteen patients from 6 non-related families were included. Age of onset was 18.8 ± 4.3 years. In all patients, diallelic disease-causing mutations were identified in the DYSF gene. Nine patients from 3 non-related families from Central Switzerland carried the identical homozygous mutation, c.3031 + 2 T>C. A possible founder effect was confirmed by haplotype analysis. Three patients from two different families carried the heterozygous mutation, c.1064_1065delAA. Two novel mutations were identified (c.2869 C>T (p.Gln957Stop), c.5928 G>A (p.Trp1976Stop)). CONCLUSIONS: Our study confirms the phenotypic heterogeneity associated with DYSF mutations. Two mutations (c.3031 + 2 T>C, c.1064_1065delAA) appear common in Switzerland. Haplotype analysis performed on one case (c. 3031 + 2 T>C) suggested a possible founder effect.
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Efeito Fundador , Proteínas de Membrana/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Adolescente , Adulto , Disferlina , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Suíça , Adulto JovemRESUMO
PURPOSE: It is a widely accepted premise in the scientific community and by athletes alike, that adding resistance exercise to a regular regimen of endurance training increases endurance performance in endurance-trained men. However, critical power (CP), capillarization, and myofiber size remain unaffected by this addition. Therefore, we tested whether the superimposition of resistance exercise with whole-body vibration and vascular occlusion (vibroX) would improve these variables in endurance-trained males relative to resistance exercise alone. METHODS: Twenty-one young, endurance-trained males were randomly assigned either to a vibroX (n = 11) or resistance (n = 10) training group. Both groups trained in a progressive mode twice a week for 8 weeks. Pre and post training, histochemical muscle characteristics, thigh muscle size, endurance and strength parameters were determined. RESULTS: vibroX increased CP (P = 0.001), overall capillary-to-fiber ratio (P = 0.001) and thigh lean mass (P < 0.001), while these parameters were unaffected by resistance training. The gain in CP by vibroX was positively correlated with the gain in capillarization (R(2) = 0.605, P = 0.008), and the gain in thigh lean mass was paralleled by increases in MyHC-1 and MyHC-2 fiber cross-sectional areas and strength. Maximum voluntary torque and the finite work capacity above CP (W') increased significantly only following resistance training. CONCLUSIONS: We achieved a proof of concept by demonstrating that modification of resistance exercise by superimposing side-alternating whole-body vibration and sustained vascular occlusion induced further improvements in CP, capillarization and hypertrophy, all of which were not observed with resistance training alone.
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Neovascularização Fisiológica , Músculo Quadríceps/fisiologia , Treinamento Resistido , Vibração , Adulto , Capilares/fisiologia , Glicerolfosfato Desidrogenase/metabolismo , Humanos , Masculino , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/fisiologia , Miosinas/metabolismo , Músculo Quadríceps/irrigação sanguínea , Músculo Quadríceps/metabolismo , Fluxo Sanguíneo Regional , Succinato Desidrogenase/metabolismoRESUMO
STUDY OBJECTIVES: Wearable devices that monitor sleep stages and heart rate offer the potential for longitudinal sleep monitoring in patients with neurodegenerative diseases. Sleep quality reduces with disease progression in Huntington's disease (HD). However, the involuntary movements characteristic of HD may affect the accuracy of wrist-worn devices. This study compares sleep stage and heart rate data from the Fitbit Charge 4 (FB) against polysomnography (PSG) in participants with HD. METHODS: Ten participants with manifest HD wore an FB during overnight hospital-based PSG, and 9 of these participants continued to wear the FB for 7 nights at home. Sleep stages (30-second epochs) and minute-by-minute heart rate were extracted and compared against PSG data. RESULTS: FB-estimated total sleep and wake times and sleep stage times were in good agreement with PSG, with intraclass correlations of 0.79-0.96. However, poor agreement was observed for wake after sleep onset and the number of awakenings. FB detected waking with 68.6 ± 15.5% sensitivity and 93.7 ± 2.5% specificity, rapid eye movement sleep with high sensitivity and specificity (78.7 ± 31.9%, 95.6 ± 2.3%), and deep sleep with lower sensitivity but high specificity (56.4 ± 28.8%, 95.0 ± 4.8%). FB heart rate was strongly correlated with PSG, and the mean absolute error between FB and PSG heart rate data was 1.16 ± 0.42 beats/min. At home, longer sleep and shorter wake times were observed compared with hospital data, whereas percentage sleep stage times were consistent with hospital data. CONCLUSIONS: Results suggest the potential for long-term monitoring of sleep patterns using wrist-worn wearable devices as part of symptom management in HD. CITATION: Doheny EP, Renerts K, Braun A, et al. Assessment of Fitbit Charge 4 for sleep stage and heart rate monitoring against polysomnography and during home monitoring in Huntington's disease. J Clin Sleep Med. 2024;20(7):1163-1171.
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Frequência Cardíaca , Doença de Huntington , Polissonografia , Fases do Sono , Dispositivos Eletrônicos Vestíveis , Humanos , Polissonografia/métodos , Polissonografia/instrumentação , Masculino , Doença de Huntington/fisiopatologia , Doença de Huntington/complicações , Feminino , Frequência Cardíaca/fisiologia , Pessoa de Meia-Idade , Fases do Sono/fisiologia , Adulto , Monitorização Ambulatorial/instrumentação , Monitorização Ambulatorial/métodosRESUMO
AIMS OF THE STUDY: Systemic amyloidoses are rare protein-folding diseases with heterogeneous, often nonspecific clinical presentations. To better understand systemic amyloidoses and to apply state-of-the-art diagnostic pathways and treatment, the interdisciplinary Amyloidosis Network was founded in 2013 at University Hospital Zurich. In this respect, a registry was implemented to study the characteristics and life expectancy of patients with amyloidosis within the area covered by the network. Patient data were collected retrospectively for the period 2005-2014 and prospectively from 2015 onwards. METHODS: Patients aged 18 years or older diagnosed with any subtype of systemic amyloidosis were eligible for inclusion if they were treated in one of the four referring centres (Zurich, Chur, St Gallen, Bellinzona). Baseline data were captured at the time of diagnosis. Follow-up data were assessed half-yearly for the first two years, then annually. RESULTS: Between January 2005 and March 2020, 247 patients were screened, and 155 patients with confirmed systemic amyloidosis were included in the present analysis. The most common amyloidosis type was light-chain (49.7%, n = 77), followed by transthyretin amyloidosis (40%, n = 62) and amyloid A amyloidosis (5.2%, n = 8). Most patients (61.9%, n = 96) presented with multiorgan involvement. Nevertheless, single organ involvement was seen in all types of amyloidosis, most commonly in amyloid A amyloidosis (75%, n = 6). The median observation time of the surviving patients was calculated by the reverse Kaplan-Meier method and was 3.29 years (95% confidence interval [CI] 2.33-4.87); it was 4.87 years (95% CI 3.14-7.22) in light-chain amyloidosis patients and 1.85 years (95% CI 1.48-3.66) in transthyretin amyloidosis patients, respectively. The 1-, 3- and 5-year survival rates were 87.0% (95% CI 79.4-95.3%), 68.5% (95% CI 57.4-81.7%) and 66.0% (95% CI 54.6-79.9%) respectively for light-chain amyloidosis patients and 91.2% (95% CI 83.2-99.8%), 77.0% (95% CI 63.4-93.7%) and 50.6% (95% CI 31.8-80.3%) respectively for transthyretin amyloidosis patients. There was no significant difference between the two groups (p = 0.81). CONCLUSION: During registry set-up, a more comprehensive work-up of our patients suffering mainly from light-chain amyloidosis and transthyretin amyloidosis was implemented. Survival rates were remarkably high and similar between light-chain amyloidosis and transthyretin amyloidosis, a finding which was noted in similar historic registries of international centres. However, further studies are needed to depict morbidity and mortality as the amyloidosis landscape is changing rapidly.
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Neuropatias Amiloides Familiares , Amiloidose , Humanos , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/metabolismo , Neuropatias Amiloides Familiares/terapia , Sistema de Registros , Estudos Retrospectivos , Proteína Amiloide A Sérica , Suíça/epidemiologia , AdultoRESUMO
Acanthocytic RBCs are a peculiar diagnostic feature of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder. Although recent years have witnessed some progress in the molecular characterization of ChAc, the mechanism(s) responsible for generation of acanthocytes in ChAc is largely unknown. As the membrane protein composition of ChAc RBCs is similar to that of normal RBCs, we evaluated the tyrosine (Tyr)-phosphorylation profile of RBCs using comparative proteomics. Increased Tyr phosphorylation state of several membrane proteins, including band 3, ß-spectrin, and adducin, was noted in ChAc RBCs. In particular, band 3 was highly phosphorylated on the Tyr-904 residue, a functional target of Lyn, but not on Tyr-8, a functional target of Syk. In ChAc RBCs, band 3 Tyr phosphorylation by Lyn was independent of the canonical Syk-mediated pathway. The ChAc-associated alterations in RBC membrane protein organization appear to be the result of increased Tyr phosphorylation leading to altered linkage of band 3 to the junctional complexes involved in anchoring the membrane to the cytoskeleton as supported by coimmunoprecipitation of ß-adducin with band 3 only in ChAc RBC-membrane treated with the Lyn-inhibitor PP2. We propose this altered association between membrane skeleton and membrane proteins as novel mechanism in the generation of acanthocytes in ChAc.
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Acantócitos/enzimologia , Membrana Eritrocítica/enzimologia , Neuroacantocitose/metabolismo , Quinases da Família src/metabolismo , Acantócitos/patologia , Adulto , Proteína 1 de Troca de Ânion do Eritrócito/metabolismo , Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/metabolismo , Ativação Enzimática/fisiologia , Membrana Eritrocítica/patologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Neuroacantocitose/patologia , Fosforilação/fisiologia , Proteínas Tirosina Quinases/metabolismo , Proteômica , Quinase Syk , Tirosina/metabolismoRESUMO
Background: The COVID-19 pandemic had a significant impact on the Swiss health care system, affecting especially vulnerable people, such as patients suffering from dementia. The purpose of this study was to investigate the challenges experienced by dementia patients, their carers, and clinicians during the pandemic in Switzerland. Methods: An online survey was sent to all memory clinics in the German speaking part of Switzerland. Patients diagnosed with dementia and their carers were recruited for semi-structured telephone interviews at the memory clinic of the University Hospital Zurich. Results: A total of 28 clinicians, 17 carers, and seven patients participated in this study. According to the clinicians, all aspects of clinical work were affected by the pandemic. Carers did not perceive a significant role of the pandemic in the disease progression of the patients, despite many challenges faced. Patients described a high level of conscientiousness during the pandemic. Recommendations for future scenarios were provided from all groups. Conclusion: In order to increase the systemic resilience of the Swiss health care system, it is important to consider the experiences and recommendations of vulnerable groups and health care professionals for future public health measures and policies.
RESUMO
The two very rare neurodegenerative diseases historically known as the "neuroacanthocytosis syndromes" are due to mutations of either VPS13A or XK. These are phenotypically similar disorders that affect primarily the basal ganglia and hence result in involuntary abnormal movements as well as neuropsychiatric and cognitive alterations. There are other shared features such as abnormalities of red cell membranes which result in acanthocytes, whose relationship to neurodegeneration is not yet known. Recent insights into the functions of these two proteins suggest dysfunction of lipid processing and trafficking at the subcellular level and may provide a mechanism for neuronal dysfunction and death, and potentially a target for therapeutic interventions.
Assuntos
Doença de Huntington/patologia , Complexos Multienzimáticos/metabolismo , Músculo Esquelético/enzimologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Doença de Huntington/fisiopatologia , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mitocôndrias/enzimologia , Mitocôndrias/patologiaRESUMO
Neurodegenerative tauopathies may be inherited as autosomal-dominant disorders with variable clinicopathological phenotypes, and causative mutations in the microtubule-associated protein tau (MAPT) gene are not regularly seen. Herein, we describe a patient with clinically typical and autopsy-proven corticobasal degeneration (CBD). Her mother was diagnosed to have Parkinson's disease, but autopsy showed CBD pathology as in the index patient. The sister of the index patient had the clinical symptoms of primary progressive aphasia (PPA), but no pathology was available to date. Molecular analysis did not reveal any mutation in the MAPT or progranulin (GRN) genes. Our findings illustrate that CBD, progressive supranuclear palsy and PPA may be overlapping diseases with a common pathological basis rather than distinct entities. Clinical presentation and course might be determined by additional, yet unknown, genetic modifying factors.
Assuntos
Doenças dos Gânglios da Base/patologia , Encéfalo/patologia , Degeneração Neural/patologia , Tauopatias/patologia , Afasia Primária Progressiva/genética , Afasia Primária Progressiva/patologia , Afasia Primária Progressiva/psicologia , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/psicologia , Feminino , Humanos , Pessoa de Meia-Idade , Degeneração Neural/genética , Degeneração Neural/psicologia , Exame Neurológico , Testes Neuropsicológicos , Linhagem , Fenótipo , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/psicologia , Tauopatias/genética , Tauopatias/psicologiaRESUMO
Cobalt intoxication is a rare complication of joint arthroplasty with a metal-on-metal prothesis or metal implants after broken ceramic implants. Patients with metal components should be monitored closely for complications. The awareness for the wide range of clinical pictures of this cobalt intoxication should be increased. We here describe the clinical presentation, diagnostic and therapeutic work-up of a 70-year-old patient with a cobalt metallosis. The patient presented with a progressive deterioration of vision and hearing, axonal sensorimotor polyneuropathy and cataract. The extensive work-up resulted in the diagnosis of a cobalt metallosis as a complication of a metal hip prosthesis. Cobalt intoxication, especially after metal-on-metal total joint arthroplasty, is a rare complication; however, there have been several reports of similar cases. It is therefore recommended to avoid the implantation of a metal-on-metal prothesis or metal implants after broken ceramic implants as in this case whenever possible. Patients with exclusively metal components should be monitored closely for complications.