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1.
J Scleroderma Relat Disord ; 8(3): 169-182, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37744047

RESUMEN

Introduction: Heart involvement is a common problem in systemic sclerosis. Recently, a definition of systemic sclerosis primary heart involvement had been proposed. Our aim was to establish consensus guidance on the screening, diagnosis and follow-up of systemic sclerosis primary heart involvement patients. Methods: A systematic literature review was performed to investigate the tests used to evaluate heart involvement in systemic sclerosis. The extracted data were categorized into relevant domains (conventional radiology, electrocardiography, echocardiography, cardiac magnetic resonance imaging, laboratory, and others) and presented to experts and one patient research partner, who discussed the data and added their opinion. This led to the formulation of overarching principles and guidance statements, then reviewed and voted on for agreement. Consensus was attained when the mean agreement was ⩾7/10 and of ⩾70% of voters. Results: Among 2650 publications, 168 met eligibility criteria; the data extracted were discussed over three meetings. Seven overarching principles and 10 guidance points were created, revised and voted on. The consensus highlighted the importance of patient counseling, differential diagnosis and multidisciplinary team management, as well as defining screening and diagnostic approaches. The initial core evaluation should integrate history, physical examination, rest electrocardiography, trans-thoracic echocardiography and standard serum cardiac biomarkers. Further investigations should be individually tailored and decided through a multidisciplinary management. The overall mean agreement was 9.1/10, with mean 93% of experts voting above 7/10. Conclusion: This consensus-based guidance on screening, diagnosis and follow-up of systemic sclerosis primary heart involvement provides a foundation for standard of care and future feasibility studies that are ongoing to support its application in clinical practice.

2.
ACR Open Rheumatol ; 5(2): 71-80, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36604819

RESUMEN

OBJECTIVE: Subclinical systemic sclerosis (SSc) primary heart involvement is commonly described. Whether these findings progress over time is not clear. The study aimed to investigate cardiovascular magnetic resonance (CMR) interval change of subclinical SSc primary heart involvement. METHODS: Patients with SSc with no cardiovascular disease underwent two CMR scans that included T1 mapping and quantitative stress perfusion. The CMR change (mean difference) and association between CMR measures and clinical phenotype were assessed. The study had a prospective design. RESULTS: Thirty-one patients with SSc participated, with a median (interquartile range) follow-up of 33 (17-37) months (10 [32%] in the diffuse subset, 16 [52%] with interstitial lung disease [ILD], and 11 [29%] who were Scl-70+). Four of thirty-one patients had focal late gadolinium enhancement (LGE) at visit 1; one of four had an increase in LGE scar mass between visits. Two patients showed new focal LGE at visit 2. No change in other CMR indices was noted. The three patients with SSc with increased or new LGE at visit 2 had diffuse cutaneous SSc with ILD, and two were Scl-70+. A reduction in forced vital capacity and total lung capacity was associated with a reduction in left ventricular ejection fraction (ρ = 0.413, P = 0.021; ρ = 0.335, P = 0.07) and myocardial perfusion reserve (MPR) (ρ = 0.543, P = 0.007; ρ = 0.627, P = 0.002). An increase in the N-terminal pro-brain natriuretic peptide level was associated with a reduction in MPR (ρ = -0.448, P = 0.042). Patients on disease-modifying antirheumatic drugs (DMARDs) had an increase in native T1 (mean [SD] 1208 [65] vs. 1265 [56] milliseconds, P = 0.008). No other clinically meaningful CMR change in patients receiving DMARDs or vasodilators was noted. CONCLUSION: Serial CMR detects interval subclinical SSc primary heart involvement progression; however, this study suggests abnormalities remain largely stable with follow-up.

4.
J Scleroderma Relat Disord ; 7(1): 24-32, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35386946

RESUMEN

Introduction: Primary heart involvement in systemic sclerosis may cause morpho-functional and electrical cardiac abnormalities and is a common cause of death. The absence of a clear definition of primary heart involvement in systemic sclerosis limits our understanding and ability to focus on clinical research. We aimed to create an expert consensus definition for primary heart involvement in systemic sclerosis. Methods: A systematic literature review of cardiac involvement and manifestations in systemic sclerosis was conducted to inform an international and multi-disciplinary task force. In addition, the nominal group technique was used to derive a definition that was then subject to voting. A total of 16 clinical cases were evaluated to test face validity, feasibility, reliability and criterion validity of the newly created definition. Results: In total, 171 publications met eligibility criteria. Using the nominal group technique, experts added their opinion, provided statements to consider and ranked them to create the consensus definition, which received 100% agreement on face validity. A median 60(5-300) seconds was taken for the feasibility on a single case. Inter-rater agreement was moderate (mKappa (95% CI) = 0.56 (0.46-1.00) for the first round and 0.55 (0.44-1.00) for the second round) and intra-rater agreement was good (mKappa (95% CI) = 0.77 (0.47-1.00)). Criterion validity showed a 78 (73-84)% correctness versus gold standard. Conclusion: A preliminary primary heart involvement in systemic sclerosis consensus-based definition was created and partially validated, for use in future clinical research.

5.
Rheumatology (Oxford) ; 61(4): 1651-1657, 2022 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-34273164

RESUMEN

OBJECTIVES: Peripheral muscle involvement in SSc may comprise myositis or a non-inflammatory myopathy. There is little understanding of the nature of SSc myopathy. This pilot study aimed to evaluate the presence of diffuse fibrosis in the peripheral muscle of patients with SSc by determining extracellular volume (ECV) MRI measurement. METHODS: SSc patients, with either suspected myopathy or no muscle involvement, and healthy controls (HCs) had native T1 and ECV MRI quantification of the thigh and creatine-kinase (CK) measured. Suspected myopathy was defined as current / history of minimally raised CK (>320; <600 IU/l) ± presence of clinical signs/symptoms (including proximal lower-limb muscle weakness and/or myalgia) ± a Manual Muscle Testing (MMT) 8 score of <5 in the thighs. RESULTS: Twelve SSc patients and 10 HCs were recruited. Of the 12 patients, 9 had limited cutaneous SSc, 4 had interstitial lung disease, and 7 had suspected myopathy. The higher skeletal muscle ECV was recorded for SSc patients compared with HCs [mean (s.d.) 23 (11)%, vs 11 (4)%, P = 0.04]. Peripheral muscle ECV was associated with CK (rho = 0.554, P = 0.061) and was higher in SSc patients with myopathy than in those with no myopathy [mean (s.d.) 28 (10) vs 15 (5), P = 0.023]. It was determined that an ECV of 22% best identified myopathy (with a sensitivity of 71% and a specificity of 80%). CONCLUSION: This hypothesis-generating study showed higher ECV in SSc patients compared with HCs, as well as association of ECV with suspected myopathy, suggesting the presence of diffuse fibrosis in the peripheral muscle of SSc patients. Further studies are needed to understand the nature of SSc myopathy.


Asunto(s)
Enfermedades Musculares , Miositis , Esclerodermia Sistémica , Creatina Quinasa , Fibrosis , Humanos , Imagen por Resonancia Magnética , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Enfermedades Musculares/complicaciones , Miositis/complicaciones , Proyectos Piloto , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico por imagen , Esclerodermia Sistémica/patología
6.
RMD Open ; 7(3)2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34663635

RESUMEN

OBJECTIVES: To explore the prognostic value of subclinical cardiovascular (CV) imaging measures and serum cardiac biomarkers in systemic sclerosis (SSc) for the development of CV outcomes of primary heart involvement (pHI). METHODS: Patients with SSc with no clinical SSc-pHI and no history of heart disease underwent cardiovascular magnetic resonance (CMR) imaging, and measurement of serum high-sensitivity-troponin I (hs-TnI) and N-terminal-pro-brain natriuretic peptide (NT-proBNP). Follow-up clinical and CV outcome data were recorded. CV outcomes were defined as myocarditis, arrhythmia and/or echocardiographic functional impairment including systolic dysfunction and/or diastolic dysfunction. RESULTS: Seventy-four patients with a median (IQR) age of 57 (49, 63) years, 32% diffuse cutaneous SSc, 39% interstitial lung disease, 30% Scl70+ were followed up for median (IQR) 22 (15, 54) months. Ten patients developed CV outcomes, comprising one patient with myocarditis and systolic dysfunction and nine arrhythmias: three non-sustained ventricular tachycardia and six supraventricular arrhythmias. The probability of CV outcomes was considerably higher in those with NT-proBNP >125 pg/mL versus normal NT-proBNP (X2=4.47, p=0.035). Trend for poorer time-to-event was noted in those with higher extracellular volume (ECV; indicating diffuse fibrosis) and hs-TnI levels versus those with normal values (X2=2.659, p=0.103; X2=2.530, p=0.112, respectively). In a predictive model, NT-proBNP >125 pg/mL associated with CV outcomes (OR=5.335, p=0.040), with a trend observed for ECV >29% (OR=4.347, p=0.073). CONCLUSION: These data indicate standard serum cardiac biomarkers (notably NT-proBNP) and CMR indices of myocardial fibrosis associate with adverse CV outcomes in SSc. This forms the basis to develop a prognostic model in larger, longitudinal studies.


Asunto(s)
Esclerodermia Sistémica , Biomarcadores , Fibrosis , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Estudios Prospectivos , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico por imagen
7.
Rheumatology (Oxford) ; 60(6): 2934-2945, 2021 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-34080001

RESUMEN

OBJECTIVES: SSc primary heart involvement (SSc-pHI) is a significant cause of mortality. We aimed to characterize and identify predictors of subclinical SSc-pHI using cardiovascular MRI. METHODS: A total of 83 SSc patients with no history of cardiovascular disease or pulmonary arterial hypertension and 44 healthy controls (HCs) underwent 3 Tesla contrast-enhanced cardiovascular MRI, including T1 mapping and quantitative stress perfusion. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide were also measured. RESULTS: Cardiovascular MRI revealed a lower myocardial perfusion reserve in the SSc patients compared with HCs {median (interquartile range (IQR)] 1.9 (1.6-2.4) vs 3 (2-3.6), P < 0.001}. Late gadolinium enhancement, indicating focal fibrosis, was observed in 17/83 patients but in none of the HCs, with significantly higher extracellular volume (ECV), suggestive of diffuse fibrosis, in SSc vs HC [mean (s.d.) 31 (4) vs 25 (2), P < 0.001]. Presence of late gadolinium enhancement and higher ECV was associated with skin score [odds ratio (OR) = 1.115, P = 0.048; R2 = 0.353, P = 0.004], and ECV and myocardial perfusion reserve was associated with the presence of digital ulcers at multivariate analysis (R2 = 0.353, P < 0.001; R2 = 0.238, P = 0.011). High-sensitivity troponin I was significantly higher in patients with late gadolinium enhancement, and N-terminal pro-brain natriuretic peptide was associated with ECV (P < 0.05). CONCLUSION: Subclinical SSc-pHI is characterized by myocardial microvasculopathy, diffuse and focal myocardial fibrosis but preserved myocardial contractile function. This subclinical phenotype of SSc-pHI was associated with high-sensitivity troponin I, N-terminal pro-brain natriuretic peptide, SSc disease severity and complicated peripheral vasculopathy. These data provide information regarding the underlying pathophysiological processes and provide a basis for identifying individuals at risk of SSc-pHI.


Asunto(s)
Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/etiología , Esclerodermia Sistémica/complicaciones , Adulto , Biomarcadores/sangre , Femenino , Fibrosis , Humanos , Imagen por Resonancia Cinemagnética , Masculino , Persona de Mediana Edad , Factores de Riesgo
8.
Int J Cardiovasc Imaging ; 37(3): 1053-1062, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33057879

RESUMEN

The prevalence of undiagnosed cardiac involvement in granulomatosis with polyangiitis (GPA) is unknown. In this prospective study we investigated the utility of cardiovascular magnetic resonance (CMR) to identify myocardial abnormalities in GPA and their correlation with disease phenotype. Twenty-six patients with GPA and no cardiovascular disease or diabetes mellitus underwent contrast-enhanced CMR, including late gadolinium-enhancement (LGE), T1-mapping for native T1 and extra-cellular volume (ECV) quantification for assessment of myocardial fibrosis, cine imaging and tissue tagging for assessment of left ventricular (LV) function. Twenty-five healthy volunteers (HV) with comparable age, sex, BMI and arterial blood pressure served as controls. Patients with GPA had similar cardiovascular risk profile to HV. A focal, non-ischaemic LGE pattern of fibrosis was detected in 24% of patients and no controls (p = 0.010). Patients with myocardial LGE were less frequently PR3 ANCA (7% vs 93%, p = 0.007), and had involvement of the lower respiratory tract and skin. LGE scar mass was higher in patients presenting with renal involvement. Native T1 and ECV were higher in patients with GPA than HV; ECV was higher in those with relapsing disease, and native T1 was inversely associated with PR3 ANCA (ß = - 0.664, p = 0.001). Peak systolic strain was slightly reduced in GPA compared to controls; LV ejection function was inversely correlated with disease duration (ß = - 0.454, p = 0.026). Patients with GPA have significant myocardial abnormalities on CMR. ANCA, systemic involvement and disease severity were associated with myocardial fibrosis. CMR could be a useful tool for risk stratification of myocardial involvement in GPA.


Asunto(s)
Cardiomiopatías/diagnóstico por imagen , Granulomatosis con Poliangitis/diagnóstico por imagen , Imagen por Resonancia Cinemagnética , Miocardio/patología , Función Ventricular Izquierda , Remodelación Ventricular , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Medios de Contraste , Estudios Transversales , Femenino , Fibrosis , Granulomatosis con Poliangitis/patología , Granulomatosis con Poliangitis/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Volumen Sistólico
9.
Ann Rheum Dis ; 79(11): 1414-1422, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32859608

RESUMEN

OBJECTIVES: To determine whether patients with early rheumatoid arthritis (ERA) have cardiovascular disease (CVD) that is modifiable with disease-modifying antirheumatic drug (DMARD) therapy, comparing first-line etanercept (ETN) + methotrexate (MTX) with MTX strategy. METHODS: Patients from a phase IV ERA trial randomised to ETN+MTX or MTX strategy±month 6 escalation to ETN+MTX, and with no CVD and maximum one traditional risk factor underwent cardiovascular magnetic resonance (CMR) at baseline, years 1 and 2. Thirty matched controls underwent CMR. Primary outcome measure was aortic distensibility (AD) between controls and ERA, and baseline to year 1 AD change in ERA. Secondary analyses between and within ERA groups performed. Additional outcome measures included left ventricular (LV) mass and myocardial extracellular volume (ECV). RESULTS: Eighty-one patients recruited. In ERA versus controls, respectively, baseline (geometric mean, 95% CI) AD was significantly lower (3.0×10-3 mm Hg-1 (2.7-3.3) vs 4.4×10-3 mm Hg-1 (3.7-5.2), p<0.001); LV mass significantly lower (78.2 g (74.0-82.7), n=81 vs 92.9 g (84.8-101.7), n=30, p<0.01); and ECV increased (27.1% (26.4-27.9), n=78 vs 24.9% (23.8-26.1), n=30, p<0.01). Across all patients, AD improved significantly from baseline to year 1 (3.0×10-3 mm Hg-1 (2.7-3.4) to 3.6×10-3 mm Hg-1 (3.1-4.1), respectively, p<0.01), maintained at year 2. The improvement in AD did not differ between the two treatment arms and disease activity state (Disease Activity Score with 28 joint count)-erythrocyte sedimentation rate-defined responders versus non-responders. CONCLUSION: We report the first evidence of vascular and myocardial abnormalities in an ERA randomised controlled trial cohort and show improvement with DMARD therapy. The type of DMARD (first-line tumour necrosis factor-inhibitors or MTX) and clinical response to therapy did not affect CVD markers. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN89222125; ClinicalTrials.gov: NCT01295151.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Etanercept/uso terapéutico , Metotrexato/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Factores de Riesgo , Resultado del Tratamiento , Rigidez Vascular/efectos de los fármacos
10.
Materials (Basel) ; 13(9)2020 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-32365678

RESUMEN

The perovskite-type lanthanum ferrite, LaFeO3, has been prepared by thermal decomposition of in situ obtained lanthanum ferrioxalate compound precursor, LaFe(C2O4)3·3H2O. The oxalate precursor was synthesized through the redox reaction between 1,2-ethanediol and nitrate ion and characterized by chemical analysis, infrared spectroscopy, and thermal analysis. LaFeO3 obtained after the calcination of the precursor for at least 550-800 °C/1 h have been investigated by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), and high-resolution transmission electron microscopy (HRTEM). A boron-doped diamond electrode (BDD) modified with LaFeO3 ceramic powders at 550 °C (LaFeO3/BDD) by simple immersion was characterized by cyclic voltammetry and tested for the voltammetric and amperometric detection of capecitabine (CCB), which is a cytostatic drug considered as an emerging pollutant in water. The modified electrode exhibited a complex electrochemical behaviour by several redox systems in direct relation to the electrode potential range. The results obtained by cyclic voltammetry (CV), differential-pulsed voltammetry (DPV), and multiple-pulsed amperometry proved the electrocatalytic effect to capecitabine oxidation and reduction and allowed its electrochemical detection in alkaline aqueous solution.

11.
Br J Radiol ; 93(1111): 20190931, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32356494

RESUMEN

OBJECTIVE: This study aimed to assess the feasibility of extracellular volume-fraction (ECV) measurement, and time to achieve contrast equilibrium (CE), in healthy muscles, and to determine whether in-flow and partial-volume errors in the femoral artery affect measurements, and if there are differences in the partition coefficient (λ) between muscles. METHODS: T1 was measured in the biceps femoris, vastus intermedius, femoral artery and aorta of 10 healthy participants. This was repeated alternately between the thigh and aorta for ≥25 min following a bolus of gadoterate meglumine. λ was calculated for each muscle/blood measurement. Time to CE was assessed semi-quantitatively. RESULTS: 8/10 participants achieved CE. Time to CE = 19±2 min (mean ± 95% confidence interval). Measured λ: biceps femoris/aorta = 0.210±0.034, vastus intermedius/aorta = 0.165±0.015, biceps femoris/femoral artery = 0.265±0.054, vastus intermedius/femoral artery = 0.211±0.026. There were significant differences in λ between the muscles when using the same vessel (p < 0.05), and between λ calculated in the same muscle when using different vessels (p < 0.05). CONCLUSION: ECV measurements in the thigh are clinically feasible. The use of the femoral artery for the blood measurement is associated with small but significant differences in λ. ECV measurements are sensitive to differences between muscles within the healthy thigh. ADVANCES IN KNOWLEDGE: This paper determines the time to contrast equilibrium in the healthy thigh and describes a method for measuring accurately ECV in skeletal muscle. This can aid in the diagnosis and understanding of inflammatory auto-immune diseases.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Músculo Esquelético/anatomía & histología , Muslo/anatomía & histología , Adulto , Aorta/anatomía & histología , Medios de Contraste , Líquido Extracelular/fisiología , Estudios de Factibilidad , Femenino , Arteria Femoral/anatomía & histología , Músculos Isquiosurales/anatomía & histología , Humanos , Masculino , Músculo Cuádriceps/anatomía & histología , Adulto Joven
12.
J R Stat Soc Ser C Appl Stat ; 69(1): 25-46, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31929657

RESUMEN

The paper develops a parsimonious modelling framework to study the time-varying association between scalar outcomes and functional predictors observed at many instances, in longitudinal studies. The methods enable us to reconstruct the full trajectory of the response and are applicable to Gaussian and non-Gaussian responses. The idea is to model the time-varying functional predictors by using orthogonal basis functions and to expand the time-varying regression coefficient by using the same basis. Numerical investigation through simulation studies and data analysis show excellent performance in terms of accurate prediction and efficient computations, when compared with existing alternatives. The methods are inspired and applied to an animal science application, where of interest is to study the association between the feed intake of lactating sows and the minute-by-minute temperature throughout the 21 days of their lactation period. R code and an R illustration are provided.

13.
Ann Rheum Dis ; 79(4): 464-471, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31996367

RESUMEN

OBJECTIVES: We sought to confirm in very early rheumatoid arthritis (ERA) a much greater superiority (30%) of first-line etanercept+methotrexate (ETN+MTX) over treat-to-target MTX (MTX-TT) than previously reported in ERA (14%); and explore whether ETN following initial MTX secures a comparable response to first-line ETN+MTX. METHODS: Pragmatic, open-label, randomised controlled trial of treatment-naïve ERA (≤12 months symptom), Disease Activity Score 28 joint (DAS28)-erythrocyte sedimentation rate (ESR) ≥3.2, rheumatoid factor (RF)+/-anticitrullinated peptide antibody (ACPA) positive or ultrasound power Doppler (PD) if RF and ACPA negative. Subjects were randomised 1:1 to ETN+MTX; or MTX-TT, escalated to ETN if week 24 DAS28-ESR ≥2.6 and intramuscular corticosteroid at protocolised time points. Primary endpoint of week 48 DAS28ESR remission with clinical and imaging secondary endpoints. RESULTS: We randomised 120 patients, 60 to each arm (71% female, 73% RF/84% ACPA positive, median (IQR) symptom duration 20.3 (13.1, 30.8) weeks; mean (SD) DAS28 5.1 (1.1)). Remission rates with ETN+MTX and MTX-TT, respectively, were 38% vs 33% at week 24; 52% vs 38% at week 48 (ORs 1.6, 95% CI 0.8 to 3.5, p=0.211). Greater, sustained DAS28-ESR remission observed with ETN+MTX versus MTX-TT (42% and 27%, respectively; p=0.035). PD was fully suppressed by week 48 in over 90% in each arm. Planned exploratory analysis revealed OR 2.84, 95% CI 0.8 to 9.6) of achieving remission after 24 weeks of ETN administered first line compared with administered post-MTX. CONCLUSIONS: Compared with remission rates typically reported with first-line tumour necrosis factor inhabitor+MTX versus MTX-TT, we did not demonstrate a larger effect in very ERA. Neither strategy conferred remission in the majority of patients although ultrasound confirmed local inflammation suppression. Poorer ETN response following failure of MTX-TT is also suggested. Trial registration number NCT02433184.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Etanercept/uso terapéutico , Metotrexato/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adulto , Artritis Reumatoide/fisiopatología , Quimioterapia Combinada , Intervención Médica Temprana , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento
15.
Elife ; 82019 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-31682229

RESUMEN

Alexander disease (AxD) is a fatal neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), which supports the structural integrity of astrocytes. Over 70 GFAP missense mutations cause AxD, but the mechanism linking different mutations to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes to investigate the hypothesis that AxD-causing mutations perturb key post-translational modifications (PTMs) on GFAP. Our findings reveal selective phosphorylation of GFAP-Ser13 in patients who died young, independently of the mutation they carried. AxD iPSC-astrocytes accumulated pSer13-GFAP in cytoplasmic aggregates within deep nuclear invaginations, resembling the hallmark Rosenthal fibers observed in vivo. Ser13 phosphorylation facilitated GFAP aggregation and was associated with increased GFAP proteolysis by caspase-6. Furthermore, caspase-6 was selectively expressed in young AxD patients, and correlated with the presence of cleaved GFAP. We reveal a novel PTM signature linking different GFAP mutations in infantile AxD.


Asunto(s)
Enfermedad de Alexander/metabolismo , Biomarcadores/metabolismo , Caspasas/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Adulto , Enfermedad de Alexander/diagnóstico , Enfermedad de Alexander/genética , Astrocitos/metabolismo , Sitios de Unión/genética , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Proteína Ácida Fibrilar de la Glía/genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Lactante , Filamentos Intermedios/metabolismo , Mutación , Fosforilación , Proteolisis , Índice de Severidad de la Enfermedad
17.
J Colloid Interface Sci ; 552: 258-270, 2019 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-31129297

RESUMEN

Single ZnO crystallites assembled into porous hierarchical structures have been prepared by topotactic thermal decomposition of in situ obtained zinc oxalate precursors, whose synthesis involves a redox reaction between 1,2-ethanediol and nitrate ion. For the first time it was demonstrated that post-synthesis protocols of the precursors (e.g. ultrasound irradiation, hydrolytic decomposition) master the hydrogen bonds formed between oxalate chains, allowing that way the adjustment of materials properties (morphology, porosity and optical) and a rational introduction of different dopants (Eu3+/Er3+). The ZnO surface reactivity is confirmed by the significant biocidal activity of the obtained materials against Gram-positive and Gram-negative planktonic and biofilm-embedded cells, superior to those reported in the literature for other ZnO-based materials or antibiotics, associated also with a good biocompatibility.


Asunto(s)
Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Oxalatos/farmacología , Compuestos de Zinc/farmacología , Óxido de Zinc/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Biopelículas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxalatos/química , Tamaño de la Partícula , Propiedades de Superficie , Compuestos de Zinc/química , Óxido de Zinc/síntesis química , Óxido de Zinc/química
18.
Rheumatology (Oxford) ; 58(7): 1221-1226, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-30690570

RESUMEN

OBJECTIVES: To screen for significant arrhythmias with an implantable loop recorder (ILR) in patients with SSc and no known cardiovascular disease, and identify associated disease phenotype, blood and cardiovascular magnetic resonance (CMR) biomarkers. METHODS: Twenty patients with SSc with no history of primary SSc heart disease, traditional cardiovascular disease, diabetes or maximum one traditional cardiovascular risk factor underwent clinical assessment, contrast-enhanced CMR and ILR insertion. RESULTS: ILR data were available for 19 patients: 63% female, mean (s.d.) age of 53 (12) years, 32% diffuse SSc. Eight patients had significant arrhythmias over 3 years: one complete heart block, two non-sustained ventricular tachycardia [all three dcSSc, two anti-topoisomerase antibodies (Scl70) positive, three interstitial lung disease and two previous digital ulceration] and five atrial arrhythmias of which four were with limited SSc. These required interventions with one permanent pacemaker implantation, four anti-arrhythmic pharmacotherapy, one anticoagulation.Patients with significant arrhythmia had higher baseline high-sensitivity troponin I and N-terminal pro-brain natriuretic peptide [mean difference (95% CI) 117 (-11, 245) and 92 (-30, 215) ng/l, respectively], and CMR-extracellular volume [mean (s.d.) 32 (2) vs 29 (4)%]. Late gadolinium enhancement was observed in five patients, only one with significant arrhythmia. CONCLUSION: This first ILR study identified potentially life-threatening arrhythmias in asymptomatic SSc patients attributable to a primary SSc heart disease. Disease phenotype, CMR-extracellular volume (indicating diffuse fibrosis) and cardiac biomarkers may identify at-risk patients that would benefit from ILR screening. Future studies can inform a risk model and provide insights into SSc-associated arrhythmia pathogenesis.


Asunto(s)
Arritmias Cardíacas/etiología , Miocardio/patología , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Esclerodermia Difusa/complicaciones , Troponina I/sangre , Adulto , Anciano , Arritmias Cardíacas/diagnóstico , Biomarcadores/sangre , Electrocardiografía Ambulatoria/métodos , Femenino , Fibrosis , Corazón/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Esclerodermia Difusa/sangre
19.
Clin Oral Investig ; 23(1): 141-151, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29589156

RESUMEN

OBJECTIVES: To compare the effect of non-surgical periodontal therapy on clinical and inflammatory parameters in patients with moderate to severe chronic periodontitis (CP) and rheumatoid arthritis (RA) (RA-CP) with that in CP patients without RA. MATERIAL AND METHODS: Eighteen patients with RA-CP and 18 systemically healthy patients with CP were treated with scaling and root planing (SRP) within 24 h. At baseline, and at 3 and 6 months after SRP, clinical periodontal parameters, inflammatory markers, and microorganisms in subgingival biofilm were assessed. In addition, disease activity markers of RA (DAS28, CRP, ESR) and specific antibodies (RF) were monitored in the RA-CP group. RESULTS: In both groups, non-surgical therapy yielded to statistically significant improvements in all investigated clinical periodontal variables; in RA patients, a statistically significant decrease in serum-CRP was seen at 3 months. At all time-points, levels of inflammatory markers in GCF were higher in RA-CP than in CP patients. Counts of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola decreased statistically significantly in CP but not in the RA-CP group. Changes of DAS28 correlated positively with those of P. gingivalis and negatively with the plaque index. CONCLUSIONS: Within their limits, the present data suggest that (a) non-surgical periodontal therapy improves periodontal conditions in CP patients with and without RA and (b) in patients with RA, eradication of P. gingivalis in conjunction with a high level oral hygiene may transiently decrease disease activity of RA. CLINICAL RELEVANCE: In patients with RA and CP, non-surgical periodontal therapy is a relevant modality not only to improve the periodontal condition but also to decrease RA activity.


Asunto(s)
Artritis Reumatoide/complicaciones , Artritis Reumatoide/terapia , Periodontitis Crónica/complicaciones , Periodontitis Crónica/terapia , Adulto , Biomarcadores/análisis , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Periodontitis Crónica/microbiología , Raspado Dental , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice Periodontal , Estudios Prospectivos , Aplanamiento de la Raíz , Resultado del Tratamiento
20.
Rheumatology (Oxford) ; 58(2): 254-259, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30239834

RESUMEN

Objectives: To validate enhanced liver fibrosis (ELF) test and its components-amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA-as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort. Methods: Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software. Results: Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = -0.21, P = 0.0012; PIIINP, r = -0.26, P = 0.0001), TLC% (ELF score, r = -0.20, P = 0.0036; TIMP-1, r = -0.32, P < 0.0001; PIIINP, r = -0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score. Conclusion: Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression.


Asunto(s)
Cirrosis Hepática/etiología , Esclerodermia Sistémica/complicaciones , Adulto , Anciano , Bancos de Muestras Biológicas , Biomarcadores/sangre , Femenino , Fibrosis , Humanos , Ácido Hialurónico/sangre , Cirrosis Hepática/diagnóstico , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Fibrosis Pulmonar/diagnóstico , Fibrosis Pulmonar/etiología , Esclerodermia Sistémica/diagnóstico , Índice de Severidad de la Enfermedad , Piel/patología , Inhibidor Tisular de Metaloproteinasa-1/sangre
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