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1.
Brain ; 147(7): 2440-2448, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38366572

RESUMEN

We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at eight centres (seven US-based and one European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB and 23% to MSA). Faster phenoconversion from study enrolment to any diagnosis was associated with urinary and sexual dysfunction [hazard ratio (HR) 5.9, 95% confidence interval (CI): 1.6-22 and HR: 3.6, 95% CI: 1.1-12] followed by subtle motor signs (HR: 2.7, 95% CI: 1.2-6), trouble swallowing (HR 2.5, 95% CI: 1.4-4.5) and changes in speech (HR:2.4, 95% CI:1.1-4.8) at enrolment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95% CI: 1.1-5.9) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95% CI: 1.2-38). Patients with a younger age of PAF onset (HR: 11, 95% CI: 2.6-46), preserved olfaction (HR: 8.7, 95% CI: 1.7-45), anhidrosis (HR: 1.8, 95% CI: 1-3.1, P = 0.042) and severe urinary problems (HR 1.6, 95% CI: 1-2.5, P = 0.033) were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95% CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.


Asunto(s)
Enfermedad de Parkinson , Insuficiencia Autonómica Pura , Humanos , Masculino , Femenino , Anciano , Estudios Longitudinales , Persona de Mediana Edad , Insuficiencia Autonómica Pura/fisiopatología , Estudios Prospectivos , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/complicaciones , Progresión de la Enfermedad , Enfermedad por Cuerpos de Lewy/fisiopatología , Estudios de Cohortes , Atrofia de Múltiples Sistemas/fisiopatología , Atrofia de Múltiples Sistemas/epidemiología
2.
J Peripher Nerv Syst ; 29(2): 221-231, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38706223

RESUMEN

BACKGROUND: ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR. OBJECTIVES: To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients. METHODS: Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment. RESULTS: At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years. CONCLUSIONS: Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.


Asunto(s)
Neuropatías Amiloides Familiares , Benzoxazoles , Piel , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neuropatías Amiloides Familiares/tratamiento farmacológico , Benzoxazoles/farmacología , Benzoxazoles/administración & dosificación , Anciano , Piel/patología , Piel/inervación , Piel/efectos de los fármacos , Biomarcadores/metabolismo , Prealbúmina , Adulto , Resultado del Tratamiento , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/patología
3.
JAMA ; 331(15): 1298-1306, 2024 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-38506839

RESUMEN

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.


Asunto(s)
Piel , Sinucleinopatías , alfa-Sinucleína , Anciano , Femenino , Humanos , Masculino , alfa-Sinucleína/análisis , Biopsia , Estudios Transversales , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/patología , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/patología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/patología , Sinucleinopatías/diagnóstico , Sinucleinopatías/patología , Fosforilación , Piel/química , Piel/patología , Insuficiencia Autonómica Pura/diagnóstico , Insuficiencia Autonómica Pura/patología , Reproducibilidad de los Resultados , Adulto , Persona de Mediana Edad , Anciano de 80 o más Años , Método Simple Ciego , Estudios Prospectivos
4.
J Cell Physiol ; 238(7): 1478-1491, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37269472

RESUMEN

Osteohematology is an emerging research field that studies the crosstalk between hematopoietic and bone stromal cells, to elucidate the mechanisms of hematological and skeletal malignancies and diseases. The Notch is an evolutionary conserved developmental signaling pathway, with critical roles in embryonic development by controlling cell proliferation and differentiation. However, the Notch pathway is also critically involved in cancer initiation and progression, such as osteosarcoma, leukemia, and multiple myeloma. The Notch-mediated malignant cells dysregulate bone and bone marrow cells in the tumour microenvironment, resulting in disorders ranging from osteoporosis to bone marrow dysfunction. To date, the complex interplay of Notch signaling molecules in hematopoietic and bone stromal cells is still poorly understood. In this mini-review, we summarize the crosstalk between cells in bone and bone marrow and their influence under the Notch signaling pathway in physiological conditions and in tumour microenvironment.


Asunto(s)
Receptores Notch , Transducción de Señal , Humanos , Médula Ósea/metabolismo , Leucemia/patología , Mieloma Múltiple/patología , Receptores Notch/genética , Receptores Notch/metabolismo , Microambiente Tumoral
5.
Muscle Nerve ; 67(5): 363-370, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36367813

RESUMEN

INTRODUCTION/AIMS: Small fiber neuropathies (SFN) have been associated with two autoantibodies, trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3), and intravenous immune globulin (IVIG) has been suggested as a potential therapy. The study objective is to determine the efficacy of IVIG on nerve density, pain and neurologic examinations in patients with SFN associated with TS-HDS and FGFR-3 autoantibodies. METHODS: This was a double-blind placebo-controlled pilot study. Subjects with SFN confirmed by history, examination, and skin biopsy with elevated autoantibodies to TS-HDS and/or FGFR-3 received IVIG (or blinded placebo) 2 grams/kg followed by 1 gram/kg every 3 wk for a total of 6 treatments. All subjects had Utah Early Neuropathy Scores (UENS), questionnaires and skin biopsies with quantitation of intra-epidermal nerve fiber density (IENFD) taken from adjacent sites at the distal leg at baseline and 6 mo later. The primary outcome was the change in IENFD over 6 mo. RESULTS: Twenty subjects were enrolled; 17 completed treatment (8 IVIG, 9 placebo). Three did not have final data due to coronavirus disease 2019 (COVID-19). Skin biopsy IENFD improved by 0.5 ± 0.8 fibers/mm in the placebo group and improved by 0.6 ± 0.6 fibers/mm in the IVIG-treated group (p = NS).Over 24 wk the change in pain scores (11 point pain scale) was -1.9 ± 2.6 in the placebo group, and - 1.7 ± 0.9 in the IVIG group (p = NS), the UENS improved by 3.0 ± 5.8 in the placebo group and improved by 1.8 ± 3.9 in the IVIG group (p = NS). DISCUSSION: This pilot study did not detect a benefit of treatment with IVIG in patients with SFN and autoantibodies to TS-HDS and FGFR-3.


Asunto(s)
COVID-19 , Enfermedades del Sistema Nervioso Periférico , Neuropatía de Fibras Pequeñas , Humanos , Neuropatía de Fibras Pequeñas/diagnóstico , Inmunoglobulinas Intravenosas/uso terapéutico , Proyectos Piloto , Autoanticuerpos , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Dolor/tratamiento farmacológico , Método Doble Ciego
6.
Eur J Neurol ; 30(5): 1281-1292, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36773001

RESUMEN

BACKGROUND AND PURPOSE: We characterized autonomic pilomotor and sudomotor skin function in early Parkinson's disease (PD) longitudinally. METHODS: We enrolled PD patients (Hoehn and Yahr 1-2) and healthy controls from movement disorder centers in Germany, Hungary, and the United States. We evaluated axon-reflex responses in adrenergic sympathetic pilomotor nerves and in cholinergic sudomotor nerves and assessed sympathetic skin response (SSR), predominantly parasympathetic neurocardiac function via heart rate variability, and disease-related symptoms at baseline, after 2 weeks, and after 1 and 2 years. CLINICALTRIALS: gov: NCT03043768. RESULTS: We included 38 participants: 26 PD (60% females, aged 62.4 ± 7.4 years, mean ± SD) and 12 controls (75% females, aged 59.5 ± 5.8 years). Pilomotor function was reduced in PD compared to controls at baseline when quantified via spatial axon-reflex spread (78 [43-143], median [interquartile range] mm2 vs. 175 [68-200] mm2 , p = 0.01) or erect hair follicle count in the axon-reflex region (8 [6-10] vs. 11 [6-16], p = 0.008) and showed reliability absent any changes from baseline to Week 2 (p = not significant [ns]). Between-group differences increased over the course of 2 years (p < 0.05), although no decline was observed within groups (p = ns). Pilomotor impairment in PD correlated with motor symptoms (rho = -0.59, p = 0.017) and was not lateralized (p = ns). Sudomotor axon-reflex and neurocardiac function did not differ between groups (p = ns), but SSR was reduced in PD (p = 0.0001). CONCLUSIONS: Impairment of adrenergic sympathetic pilomotor function and SSR in evolving PD is not paralleled by changes to cholinergic sudomotor function and parasympathetic neurocardiac function, suggesting a sympathetic pathophysiology. A pilomotor axon-reflex test might be useful to monitor PD-related pathology.


Asunto(s)
Enfermedades del Sistema Nervioso Autónomo , Enfermedad de Parkinson , Femenino , Humanos , Masculino , Enfermedad de Parkinson/diagnóstico , Reproducibilidad de los Resultados , Piel/patología , Sistema Nervioso Autónomo , Enfermedades del Sistema Nervioso Autónomo/etiología , Adrenérgicos
7.
Mov Disord ; 37(1): 130-136, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34582053

RESUMEN

BACKGROUND: X-linked dystonia parkinsonism (XDP) or "Lubag" is a genetic dystonia syndrome observed among Filipinos that can present with levodopa-responsive parkinsonism and abnormal dopamine transporter (DAT) imaging. OBJECTIVE: The aim of this study is to describe the results of skin biopsies for phosphorylated α-synuclein (P-SYN) in XDP. METHOD: This study used the retrospective chart review. RESULTS: We report 6 patients who carried the XDP gene mutation with DAT imaging and skin biopsies to detect P-SYN. Five had segmental or multifocal dystonia and parkinsonism: 4 were levodopa-responsive and 1 non-levodopa-responsive. One patient was asymptomatic but had mild bradykinesia. Cutaneous P-SYN and abnormal DAT scans were noted in the 4 levodopa-responsive patients and 1 asymptomatic patient. CONCLUSION: We report for the first time the presence of cutaneous P-SYN in XDP. Our findings suggest that XDP may be a hitherto-undescribed synucleinopathy or that some XDP patients may have concurrent Parkinson's disease.


Asunto(s)
Trastornos Distónicos , Enfermedades Genéticas Ligadas al Cromosoma X , Sinucleinopatías , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Estudios Retrospectivos
8.
Cerebellum ; 2022 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-36190676

RESUMEN

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

9.
Value Health ; 25(5): 824-834, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35500951

RESUMEN

OBJECTIVES: The Patient-Reported Outcome Measurement Information System (PROMIS) Preference score (PROPr) can be used to assess health state utility (HSU) and estimate quality-adjusted life-years in cost-effectiveness analyses. It is based on item response theory and promises to overcome limitations of existing HSU scores such as ceiling effects. The PROPr contains 7 PROMIS domains: cognitive abilities, depression, fatigue, pain, physical function, sleep disturbance, and ability to participate in social roles and activities. We aimed to compare the PROPr with the 5-level EQ-5D (EQ-5D-5L) in terms of psychometric properties using data from 3 countries. METHODS: We collected PROMIS-29 profile and EQ-5D-5L data from 3 general population samples (United Kingdom = 1509, France = 1501, Germany = 1502). Given that cognition is not assessed by the PROMIS-29, it was predicted by the recommended linear regression model. We compared the convergent validity, known-groups construct validity, and ceiling and floor effects of the PROPr and EQ-5D-5L. RESULTS: The mean PROPr (0.48, 0.53, 0.48; P<.01) and EQ-5D-5L scores (0.82, 0.85, 0.83; P<.01) showed significant differences of similar magnitudes (d = 0.34; d = 0.32; d = 0.35; P<.01) across all samples. The differences were invariant to sex, income, occupation, education, and most conditions but not for age. The Pearson correlation coefficients between both scores were r = 0.74, r = 0.69, and r = 0.72. PROPr's ceiling and floor effects both were minor to moderate. The EQ-5D-5L's ceiling (floor) effects were major (negligible). CONCLUSIONS: Both the EQ-5D-5L and the PROPr assessed by the PROMIS-29 show high validity. The PROPr yields considerably lower HSU values than the EQ-5D-5L. Consequences for quality-adjusted life-year measurements should be investigated in future research.


Asunto(s)
Medición de Resultados Informados por el Paciente , Calidad de Vida , Fatiga , Alemania , Humanos , Psicometría , Calidad de Vida/psicología
10.
Qual Life Res ; 31(2): 579-587, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34283380

RESUMEN

AIMS: Daily micro-surveys, or the high-frequency administration of patient-reported outcome measures (PROMs), may provide real-time, unbiased assessments of health-related quality of life (HRQoL). We evaluated the feasibility and accuracy of daily micro-surveys using a smartphone platform among patients recovering from cancer surgery. METHODS: In a prospective study (2017-2019), patients undergoing cancer surgery downloaded a smartphone application that administered daily micro-surveys comprising five randomly selected items from the Short Form-36 (SF-36). Micro-surveys were administered without replacement until the entire SF-36 was administered weekly. The full-length SF-36 was also administered preoperatively and 4, 12, and 24 weeks postoperatively. We assessed response and completion rates between the micro-surveys and full-length SF-36, as well as agreement of responses using Bland-Altman (B&A) analyses. RESULTS: Ninety-five patients downloaded the application and were followed for a mean of 131 days [SD ± 85]. Response rates for the full-length SF-36 and micro-surveys was 76% [95%CI 69, 83], and 34% [95%CI 26, 39]. Despite lower response rates, more SF-36 surveys were collected using the daily micro-surveys compared to the intermittent full-length SF-36 (9.9 [95%CI 8.4, 12.6] vs. 3.0 [95%CI 2.8, 3.3], respectively). B&A analyses demonstrated lack of agreement between micro-surveys and SF-36. However, agreement improved with higher micro-survey completion rate. Eighty-five percent of participants reported that daily micro-surveys were not burdensome. CONCLUSION: This study suggests that collection of daily micro-surveys among patients recovering from cancer surgery is feasible using smartphones in the early postoperative period. Future implementation of daily micro-surveys may more granularly describe momentary HRQoL changes through a greater volume of self-reported survey data.


Asunto(s)
Neoplasias , Teléfono Inteligente , Estudios de Factibilidad , Humanos , Neoplasias/cirugía , Estudios Prospectivos , Calidad de Vida/psicología , Encuestas y Cuestionarios
11.
Anal Chem ; 93(10): 4449-4455, 2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33630567

RESUMEN

Absolute glycoproteomics quantification has drawn tremendous attention owing to its prospects in biomarker discovery and clinical implementation but is impeded by a general lack of suitable heavy isotope-labeled glycopeptide standards. In this study, we devised a facile chemoenzymatic strategy to synthesize a total of 36 human IgG glycopeptides attached with well-defined glycoforms, including 15 isotope-labeled ones with a mass increment of 6 Da to their native counterparts. Spiking of these standards into human sera enabled simplified, robust, and precise absolute quantification of IgG glycopeptides in a subclass-specific fashion. Additionally, the implementation of the absolute quantification approach revealed subclass-dependent alteration of serum IgG galactosylation and sialylation in colon cancer samples.


Asunto(s)
Glicopéptidos , Inmunoglobulina G , Glicosilación , Humanos , Isótopos
12.
J Peripher Nerv Syst ; 26(3): 276-289, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34169613

RESUMEN

Neuropathy is a major cause of morbidity and mortality in individuals with diabetes, with no effective therapy to alter the inevitable progression of nerve damage. We hypothesized that mesenchymal stroma cell-like populations, that are characterized as immune modulators also have the potential of inducing angiogenesis and neurite outgrowth, might be useful in treating diabetic peripheral neuropathy (DPN). The aims of this study were to investigate the efficacy and safety of mesenchymal stem cell-like product (PDA-002) in treating DPN. A phase-2 randomized placebo-controlled trial was conducted in 26 patients with DPN. Treatment consisted of three rounds of intramuscular injections in one lower limb using one of the three randomized treatment arms PDA-002 (low-dose 3 × 106 cells), PDA-002 (high-dose 30 × 106 cells), or placebo. Three treatments per patient occurred on days 1, 29, and 57. Study endpoints included efficacy and safety of PDA-002 in treating DPN in both lower extremities following unilateral local injection. Outcome measures included intra-epidermal nerve fiber density (IENFD) up to 1 year from the day of treatment with 6-month as the primary outcome measurement. In this phase 2 study of DPN, PDA-002 was well tolerated in both doses. No significant changes were noted in IENFD in both the treated and untreated leg in the NIS-LL, NTSS-6, or UENS. Mesenchymal stem cells represent a novel mechanism for treating diabetic neuropathy and are well tolerated. Preliminary results highlight the need of further investigation of PDA-001 as a disease modifying agent for treatment of DPN.


Asunto(s)
Neuropatías Diabéticas , Humanos , Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas/tratamiento farmacológico , Proyectos de Investigación
13.
Cochrane Database Syst Rev ; 5: CD012868, 2021 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-34000076

RESUMEN

BACKGROUND: Orthostatic hypotension is an excessive fall in blood pressure (BP) while standing and is the result of a decrease in cardiac output or defective or inadequate vasoconstrictor mechanisms. Fludrocortisone is a mineralocorticoid that increases blood volume and blood pressure. Fludrocortisone is considered the first- or second-line pharmacological therapy for orthostatic hypotension alongside mechanical and positional measures such as increasing fluid and salt intake and venous compression methods. However, there has been no Cochrane Review of the benefits and harms of this drug for this condition. OBJECTIVES: To identify and evaluate the benefits and harms of fludrocortisone for orthostatic hypotension. SEARCH METHODS: We searched the following databases on 11 November 2019: Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL. We also searched trials registries. SELECTION CRITERIA: We included all studies evaluating the benefits and harms of fludrocortisone compared to placebo, another drug for orthostatic hypotension, or studies without comparators, including randomized controlled trials (RCTs), quasi-RCTs and observational studies. We included studies in people with orthostatic hypotension due to a chronic peripheral neuropathy, a central autonomic neuropathy, or autonomic failure from other causes, but not medication-induced orthostatic hypotension or orthostatic hypotension from acute volume depletion or blood loss. DATA COLLECTION AND ANALYSIS: We used Cochrane methodological procedures for most of the review. We developed and used a tool to prioritize observational studies that offered the best available evidence where there are gaps in the evidence from RCTs. We assessed the certainty of evidence for fludrocortisone versus placebo using GRADE. MAIN RESULTS: We included 13 studies of 513 participants, including three cross-over RCTs and 10 observational studies (three cohort studies, six case series and one case-control study). The included RCTs were small (total of 28 participants in RCTs), short term (two to three weeks), only examined fludrocortisone for orthostatic hypotension in people with two conditions (diabetes and Parkinson disease), and had variable risk of bias (two had unclear risk of bias and one had low risk of bias). Heterogeneity in participant populations, comparators and outcome assessment methods prevented meta-analyses of the RCTs. We found very low-certainty evidence about the effects of fludrocortisone versus placebo on drop in BP in people with diabetes (-26 mmHg versus -39 mmHg systolic; -7 mmHg versus -11 mmHg diastolic; 1 cross-over study, 6 participants). For people with Parkinson disease, we found very-low certainty evidence about the effects of fludrocortisone on drop in BP compared to pyridostigmine (-14 mmHg versus -22.1 mmHg diastolic; P = 0.036; 1 cross-over study, 9 participants) and domperidone (no change after treatment in either group; 1 cross-over study, 13 participants). For orthostatic symptoms, we found very low-certainty evidence for fludrocortisone versus placebo in people with diabetes (4 out of 5 analyzed participants had improvements in orthostatic symptoms, 1 cross-over study, 6 participants), for fludrocortisone versus pyridostigmine in people with Parkinson disease (orthostatic symptoms unchanged; 1 cross-over study, 9 participants) or fludrocortisone versus domperidone (improvement to 6 for both interventions on the Composite Autonomic Symptom Scale-Orthostatic Domain (COMPASS-OD); 1 cross-over study, 13 participants). Evidence on adverse events was also very low-certainty in both populations, but indicated side effects were minimal. Observational studies filled some gaps in evidence by examining the effects in larger groups of participants, with more diverse conditions, over longer periods of time. One cohort study (341 people studied retrospectively) found fludrocortisone may not be harmful in the long term for familial dysautonomia. However, it is unclear if this translates to long-term improvements in BP drop or a meaningful improvement in orthostatic symptoms. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effects of fludrocortisone on blood pressure, orthostatic symptoms or adverse events in people with orthostatic hypotension and diabetes or Parkinson disease. There is a lack of information on long-term treatment and treatment of orthostatic hypotension in other disease states. There is a need for standardized reporting of outcomes and for standardization of measurements of blood pressure in orthostatic hypotension.


Asunto(s)
Fludrocortisona/uso terapéutico , Hipotensión Ortostática/tratamiento farmacológico , Sesgo , Diabetes Mellitus , Domperidona/uso terapéutico , Disautonomía Familiar/complicaciones , Humanos , Estudios Observacionales como Asunto , Enfermedad de Parkinson/complicaciones , Bromuro de Piridostigmina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto
14.
Clin Orthop Relat Res ; 479(5): 1158-1166, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33196585

RESUMEN

BACKGROUND: Delivering uninterrupted cancer treatment to patients with musculoskeletal tumors has been essential during the rapidly evolving coronavirus 2019 (COVID-19) pandemic, as delays in management can be detrimental. Currently, the risk of contracting COVID-19 in hospitals when admitted for surgery and the susceptibility due to adjuvant therapies and associated mortality due to COVID-19 is unknown, but knowledge of these potential risks would help treating clinicians provide appropriate cancer care. QUESTIONS/PURPOSES: (1) What is the risk of hospital-acquired COVID-19 in patients with musculoskeletal tumors admitted for surgery during the initial period of the pandemic? (2) What is the associated mortality in patients with musculoskeletal tumors who have contracted COVID-19? (3) Are patients with musculoskeletal tumors who have had neoadjuvant therapy (chemotherapy or radiation) preoperatively at an increased risk of contracting COVID-19? (4) Is a higher American Society of Anesthesiologists (ASA) grade in patients with musculoskeletal tumors associated with an increased risk of contracting COVID-19 when admitted to the hospital for surgery? METHODS: This retrospective, observational study analyzed patients with musculoskeletal tumors who underwent surgery in one of eight specialist centers in the United Kingdom, which included the five designated cancer centers in England, one specialist soft tissue sarcoma center, and two centers from Scotland between March 12, 2020 and May 20, 2020. A total of 347 patients were included, with a median (range) age of 53 years (10 to 94); 60% (207 of 347) were men, and the median ASA grade was II (I to IV). These patients had a median hospital stay of 8 days (0 to 53). Eighteen percent (61 of 347) of patients had received neoadjuvant therapy (8% [27] chemotherapy, 8% [28] radiation, 2% [6] chemotherapy and radiation) preoperatively. The decision to undergo surgery was made in adherence with United Kingdom National Health Service and national orthopaedic oncology guidelines, but specific data with regard to the number of patients within each category are not known. Fifty-nine percent (204 of 347) were negative in PCR testing done 48 hours before the surgical procedure; the remaining 41% (143 of 347) were treated before preoperative PCR testing was made mandatory, but these patients were asymptomatic. All patients were followed for 30 days postoperatively, and none were lost to follow-up during that period. The primary outcome of the study was contracting COVID-19 in the hospital after admission. The secondary outcome was associated mortality after contracting COVID-19 within 30 days of the surgical procedure. In addition, we assessed whether there is any association between ASA grade or neoadjuvant treatment and the chances of contracting COVID-19 in the hospital. Electronic patient record system and simple descriptive statistics were used to analyze both outcomes. RESULTS: Four percent (12 of 347) of patients contracted COVID-19 in the hospital, and 1% (4 of 347) of patients died because of COVID-19-related complications. Patients with musculoskeletal tumors who contracted COVID-19 had increased mortality compared with patients who were asymptomatic or tested negative (odds ratio 55.33 [95% CI 10.60 to 289.01]; p < 0.001).With the numbers we had, we could not show that adjuvant therapy had any association with contracting COVID-19 while in the hospital (OR 0.94 [95% CI 0.20 to 4.38]; p = 0.93). Increased ASA grade was associated with an increased likelihood of contracting COVID-19 (OR 58 [95% CI 5 to 626]; p < 0.001). CONCLUSION: Our results show that surgeons must be mindful and inform patients that those with musculoskeletal tumors are at risk of contracting COVID-19 while admitted to the hospital and some may succumb to it. Hospital administrators and governmental agencies should be aware that operations on patients with lower ASA grade appear to have lower risk and should consider restructuring service delivery to ensure that procedures are performed in designated COVID-19-restricted sites. These measures may reduce the likelihood of patients contracting the virus in the hospital, although we cannot confirm a benefit from this study. Future studies should seek to identify factors influencing these outcomes and also compare surgical complications in those patients with and without COVID-19. LEVEL OF EVIDENCE: Level III, therapeutic study.


Asunto(s)
Neoplasias Óseas/terapia , COVID-19/complicaciones , Infección Hospitalaria/complicaciones , Neoplasias de los Tejidos Blandos/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/mortalidad , COVID-19/mortalidad , Niño , Infección Hospitalaria/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Pandemias , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Neoplasias de los Tejidos Blandos/mortalidad , Reino Unido/epidemiología , Adulto Joven
15.
BMC Musculoskelet Disord ; 22(1): 18, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33402136

RESUMEN

BACKGROUND: Like with all cancers, multidisciplinary team (MDT) meetings are the norm in bone and soft tissue tumour (BST) management too. Problem in attendance of specialists due to geographical location is the one of the key barriers to effective functioning of MDTs. To overcome this problem, virtual MDTs involving videoconferencing or telemedicine have been proposed, but however this has been seldom used and tested. The COVID-19 pandemic forced the implementation of virtual MDTs in the Oxford sarcoma service in order to maintain normal service provision. We conducted a survey among the participants to evaluate its efficacy. METHODS: An online questionnaire comprising of 24 questions organised into 4 sections was circulated among all participants of the MDT after completion of 8 virtual MDTs. Opinions were sought comparing virtual MDTs to the conventional face-to-face MDTs on various aspects. A total of 36 responses were received and were evaluated. RESULTS: 72.8% were satisfied with the depth of discussion in virtual MDTs and 83.3% felt that the decision-making in diagnosis had not changed following the switch from face-to-face MDTs. About 86% reported to have all essential patient data was available to make decisions and 88.9% were satisfied with the time for discussion of patient issues over virtual platform. Three-fourths of the participants were satisfied (36.1% - highly satisfied; 38.9% - moderately satisfied) with virtual MDTs and 55.6% of them were happy to attend MDTs only by the virtual platform in the future. Regarding future, 77.8% of the participants opined that virtual MDTs would be the future of cancer care and an overwhelming majority (91.7%) felt that the present exercise would serve as a precursor to global MDTs involving specialists from abroad in the future. CONCLUSION: Our study shows that the forced switch to virtual MDTs in sarcoma care following the unprecedented COVID-19 pandemic to be a viable and effective alternative to conventional face-to-face MDTs. With effective and efficient software in place, virtual MDTs would also facilitate in forming extended MDTs in seeking opinions on complex cases from specialists abroad and can expand cancer care globally.


Asunto(s)
Neoplasias Óseas/terapia , COVID-19 , Comunicación Interdisciplinaria , Oncología Médica/organización & administración , Neoplasias de los Músculos/terapia , Grupo de Atención al Paciente/organización & administración , Sarcoma/terapia , Telemedicina/organización & administración , Comunicación por Videoconferencia/organización & administración , Actitud del Personal de Salud , Actitud hacia los Computadores , Neoplasias Óseas/diagnóstico , Toma de Decisiones Clínicas , Prestación Integrada de Atención de Salud/organización & administración , Conocimientos, Actitudes y Práctica en Salud , Humanos , Neoplasias de los Músculos/diagnóstico , Sarcoma/diagnóstico , Centros de Atención Terciaria
16.
Ann Surg ; 271(3): 475-483, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-30188401

RESUMEN

OBJECTIVE: The aim of the study was to determine the association of patient-reported experiences (PREs) and risk-adjusted surgical outcomes among group practices. BACKGROUND: The Centers for Medicare and Medicaid Services required large group practices to submit PREs data for successful participation in the Physician Quality Reporting System (PQRS) using the Consumer Assessment of Healthcare Providers and Systems for PQRS survey. Whether these PREs data correlate with perioperative outcomes remains ill defined. METHODS: Operations between January 1, 2014 and December 31, 2016 in the American College of Surgeons' National Surgical Quality Improvement Program registry were merged with 2015 Consumer Assessment of Healthcare Providers and Systems for PQRS survey data. Hierarchical logistic models were constructed to estimate associations between 7 subscales and 1 composite score of PREs and 30-day morbidity, unplanned readmission, and unplanned reoperation, separately, while adjusting for patient- and procedure mix. RESULTS: Among 328 group practices identified, patients reported their experiences with clinician communication the highest (mean ±â€Šstandard deviation, 82.66 ±â€Š3.10), and with attention to medication cost the lowest (25.96 ±â€Š5.14). The mean composite score was 61.08 (±6.66). On multivariable analyses, better PREs scores regarding medication cost, between-visit communication, and the composite score of experience were each associated with 4% decreased odds of morbidity [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.92-0.99], readmission (OR 0.96, 95% CI 0.93-0.99), and reoperation (OR 0.96, 95% CI 0.93-0.99), respectively. In sensitivity analyses, better between-visit communication remained significantly associated with fewer readmissions. CONCLUSIONS: In these data, patients' report of better between-visit communication was associated with fewer readmissions. More sensitive, surgery-specific PRE assessments may reveal additional unique insights for improving the quality of surgical care.


Asunto(s)
Práctica de Grupo , Medición de Resultados Informados por el Paciente , Procedimientos Quirúrgicos Operativos , Centers for Medicare and Medicaid Services, U.S. , Honorarios Farmacéuticos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Readmisión del Paciente/estadística & datos numéricos , Relaciones Médico-Paciente , Complicaciones Posoperatorias/epidemiología , Mejoramiento de la Calidad , Sistema de Registros , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , Ajuste de Riesgo , Estados Unidos/epidemiología
17.
Oncologist ; 25(5): 384-390, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31848315

RESUMEN

Value in health care is defined as the health outcome achieved per unit of cost. For health care systems, improving value means achieving better outcomes at lower costs. Improving outcomes, including patient-reported outcomes (PROs), as well as more established metrics such as mortality and complication rates, ensures high-quality care. This is particularly true in breast cancer surgery, where survival and recurrence rates are comparable across different surgical approaches. Outcomes reflecting survivorship quality may therefore better inform decision making regarding surgical approaches. PROs can be assessed using validated instruments known as patient-reported outcome measures (PROMs). They are obtained directly from patients reflecting their health-related quality of life (HRQOL). Ongoing initiatives strive to define PROMs that accurately reflect HRQOL and demonstrate value, with the goal of establishing benchmarks for quality of care. Clinicians caring for patients with breast cancer are well positioned to be involved in defining meaningful measures of value-based breast cancer care. This article reviews value-based breast cancer care in the context of locoregional therapy, with attention paid to the work done by the International Consortium of Health Outcome Measures in which a "standard set" of value-based patient-centered outcomes for breast cancer for international use is defined. In addition, an overview is provided of relevant PROMs and previously reported scores. Recommendations and future challenges for implementation of routine collection of PROs are also discussed. IMPLICATIONS FOR PRACTICE: Opportunity exists to act as early adopters of the routine collection of longitudinal patient-reported outcome data for breast cancer, allowing transition of current care to value-based cancer care.


Asunto(s)
Calidad de Vida , Oncología Quirúrgica , Humanos , Mastectomía , Recurrencia Local de Neoplasia , Medición de Resultados Informados por el Paciente
18.
Muscle Nerve ; 62(4): 492-501, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32270499

RESUMEN

INTRODUCTION: To develop a new method to quantify the density of nerves, vessels, and the neurovascular contacts, we studied skin biopsies in diabetes and control subjects. METHODS: Skin biopsies with dual immunofluorescent staining were used to visualize nerves and blood vessels. The density of nerves, vessels, and their neurovascular contacts were quantified with unbiased stereology. Results were compared with examination findings, validated questionnaires, and autonomic function. RESULTS: In tissue from 19 controls and 20 patients with diabetes, inter-rater and intra-rater intraclass correlation coefficients were high (>0.85; P < .001) for all quantitative methods. In diabetes, the nerve densities (P < .05), vessel densities (P < .01), and the neurovascular densities (P < .01) were lower compared with 20 controls. Results correlated with autonomic function, examination and symptom scores. DISCUSSION: We report an unbiased, stereological method to quantify the cutaneous nerve, vessel and neurovascular density and offer new avenues of investigation into cutaneous neurovascular innervation in health and disease.


Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/patología , Neuropatías Diabéticas/patología , Microvasos/patología , Nervios Periféricos/patología , Piel/patología , Neuropatía de Fibras Pequeñas/patología , Adulto , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Capilares/inervación , Capilares/patología , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/fisiopatología , Femenino , Humanos , Masculino , Microscopía Confocal , Microscopía Fluorescente , Microvasos/inervación , Persona de Mediana Edad , Piel/irrigación sanguínea , Piel/inervación , Neuropatía de Fibras Pequeñas/fisiopatología
19.
Chem Rev ; 118(17): 8151-8187, 2018 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-30011195

RESUMEN

Oligosaccharides together with oligonucleotides and oligopeptides comprise the three major classes of natural biopolymers. Automated systems for oligonucleotide and oligopeptide synthesis have significantly advanced developments in biological science by allowing nonspecialists to rapidly and easily access these biopolymers. Researchers have endeavored for decades to develop a comparable general automated system to synthesize oligosaccharides. Such a system would have a revolutionary impact on the understanding of the roles of glycans in biological systems. The main challenge to achieving automated synthesis is the lack of general synthetic methods for routine synthesis of glycans. Currently, the two main methods to access homogeneous glycans and glycoconjugates are chemical synthesis and enzymatic synthesis. Enzymatic glycosylation can proceed stereo- and regiospecifically without protecting group manipulations. Moreover, the reaction conditions of enzyme-catalyzed glycosylations are extremely mild when compared to chemical glycosylations. Over the past few years methodology toward the automated chemical synthesis of oligosaccharides has been developed. Conversely, while automated enzymatic synthesis is conceptually possible, it is not as well developed. The goal of this survey is to provide a foundation on which continued technological advancements can be made to promote the automated enzymatic synthesis of oligosaccharides.


Asunto(s)
Automatización , Técnicas de Química Sintética/métodos , Glicoconjugados/síntesis química , Glicosiltransferasas/química , Oligosacáridos/síntesis química , Secuencia de Carbohidratos , Catálisis , Glicoconjugados/química , Glicosilación , Oligosacáridos/química , Estereoisomerismo
20.
Pain Med ; 21(10): 2336-2347, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32895703

RESUMEN

OBJECTIVE: Recent studies suggest that sensory phenotyping may provide critical information for the diagnosis and management of patients with chronic neuropathic pain (NP). However, many formal quantitative sensory testing (QST) paradigms require expensive equipment, a dedicated location, and substantial time commitments on the part of patient and examiner, highlighting the need for a convenient and portable "bedside" QST battery. We developed and tested a bedside QST battery in a sample of patients with chronic NP. METHODS: Participants (N = 51) attended two in-person visits over approximately two weeks, during which they underwent QST using both laboratory-based equipment and simple, easily accessible bedside tools. Participants also completed questionnaires about their daily pain and NP symptoms. RESULTS: Test-retest reliability estimates were highly statistically significant and did not differ between bedside (mean r = 0.60) and laboratory-based (mean r = 0.72) QST. Bedside QST variables and corresponding laboratory-based QST variables were highly correlated, suggesting adequate criterion validity for the bedside tests. CONCLUSIONS: Results from the present study may have important implications for the sensory phenotyping and subsequent management of patients with chronic NP. Implementation of a protocol that uses inexpensive, portable, and convenient tools may allow for the application of QST in variety of clinical settings and advance NP research.


Asunto(s)
Neuralgia , Umbral del Dolor , Boston , Humanos , Neuralgia/diagnóstico , Dimensión del Dolor , Reproducibilidad de los Resultados
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