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2.
J Neural Eng ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30524006

RESUMO

Deep Brain Stimulation (DBS) consists of delivering electrical stimuli to a brain target via an implanted lead to treat neurological and psychiatric conditions. Individualized stimulation is vital to ensure therapeutic results, since DBS may otherwise become ineffective or cause undesirable side effects. Since the DBS pulse generator is battery-driven, power consumption incurred by the stimulation is important. In this study, target coverage and power consumption are compared over a patient population for clinical and model-based patient-specific settings calculated by constrained optimization. APPROACH: Brain models for five patients undergoing bilateral DBS were built. Mathematical optimization of activated tissue volume was utilized to calculate stimuli amplitudes, with and without specifying the volumes, where stimulation was not allowed to avoid side effects. Power consumption was estimated using measured impedance values and battery life under both clinical and optimized settings. RESULTS: It was observed that clinical settings were generally less aggressive than the ones suggested by unconstrained model-based optimization, especially under asymmetrical stimulation. The DBS settings satisfying the constraints were close to the clinical values. SIGNIFICANCE: The use of mathematical models to suggest optimal patient-specific DBS settings that observe technological and safety constraints can save time in clinical practice. It appears though that the considered safety constraints based on brain anatomy depend on the patient and further research into it is needed. This work highlights the need of specifying the brain volumes to be avoided by stimulation while optimizing the DBS amplitude, in contrast to minimizing general stimuli overspill, and applies the technique to a cohort of patients. It also stresses the importance of considering power consumption in DBS optimization, since it increases with the square of the stimuli amplitude and also critically affects battery life through pulse frequency and duty cycle.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30281089

RESUMO

Objectives: Studies assessing relative mortality risks across the spectrum of systemic inflammatory rheumatic diseases are largely missing. In this study, we wanted to estimate standard mortality ratios (SMRs) and causes of death in an ethnically homogeneous cohort covering all major CTDs and primary systemic vasculitides (PSVs). Methods: We prospectively followed all incident CTD and PSV cases included in the Norwegian CTD and vasculitis registry (NOSVAR) between 1999 and 2015. Fifteen controls for each patient matched for sex and age were randomly drawn from the Norwegian National Population Registry. Causes of death were obtained from the National Cause of Death Register, death certificates and hospital charts. Results: The cohort included 2140 patients (1534 with CTD, 606 with PSV). During a mean follow-up time of 9 years, 279 of the patients (13%) died, compared with 2864 of 32 086 (9%) controls (P < 0.001). Ten years after diagnosis, the lowest survival was 60% in dcSSc, 73% in anti-synthetase syndrome (ASS) and 75% in lcSSc. In the CTD group, the highest SMRs were observed in dcSSc (SMR 5.8) and ASS (SMR 4.1). In the PSV group, Takayasu arteritis (SMR 2.5) and ANCA-associated vasculitis (SMR 1.5) had the highest SMRs. Major causes of death were cardiovascular disease (CTD 27%, PSV 28%), neoplasms (CTD 25%, PSV 27%), chronic respiratory disease (CTD 20%, PSV10%) and infections (CTD 9%, PSV 16%). Conclusion: We observed premature deaths across the spectrum of CTDs and PSVs, with highest SMRs in dcSSc and ASS. The overall mortality was highest in the CTD group.

5.
Clin Exp Rheumatol ; 36(1): 44-49, 2018 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28770709

RESUMO

OBJECTIVES: To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). METHODS: The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). RESULTS: 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). CONCLUSIONS: In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility.


Assuntos
Artrite/epidemiologia , Miosite/epidemiologia , Adulto , Artrite/diagnóstico , Artrite/imunologia , Autoanticorpos/sangue , Biomarcadores/sangue , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Miosite/diagnóstico , Miosite/imunologia , Fenótipo , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
6.
Ann Rheum Dis ; 77(1): 30-39, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28855174

RESUMO

AIMS: The EuroMyositis Registry facilitates collaboration across the idiopathic inflammatory myopathy (IIM) research community. This inaugural report examines pooled Registry data. METHODS: Cross-sectional analysis of IIM cases from 11 countries was performed. Associations between clinical subtypes, extramuscular involvement, environmental exposures and medications were investigated. RESULTS: Of 3067 IIM cases, 69% were female. The most common IIM subtype was dermatomyositis (DM) (31%). Smoking was more frequent in connective tissue disease overlap cases (45%, OR 1.44, 95% CI 1.09 to 1.90, p=0.012). Smoking was associated with interstitial lung disease (ILD) (OR 1.32, 95% CI 1.06 to 1.65, p=0.013), dysphagia (OR 1.43, 95% CI 1.16 to 1.77, p=0.001), malignancy ever (OR 1.78, 95% CI 1.36 to 2.33, p<0.001) and cardiac involvement (OR 2.40, 95% CI 1.60 to 3.60, p<0.001).Dysphagia occurred in 39% and cardiac involvement in 9%; either occurrence was associated with higher Health Assessment Questionnaire (HAQ) scores (adjusted OR 1.79, 95% CI 1.43 to 2.23, p<0.001). HAQ scores were also higher in inclusion body myositis cases (adjusted OR 3.85, 95% CI 2.52 to 5.90, p<0.001). Malignancy (ever) occurred in 13%, most commonly in DM (20%, OR 2.06, 95% CI 1.65 to 2.57, p<0.001).ILD occurred in 30%, most frequently in antisynthetase syndrome (71%, OR 10.7, 95% CI 8.6 to 13.4, p<0.001). Rash characteristics differed between adult-onset and juvenile-onset DM cases ('V' sign: 56% DM vs 16% juvenile-DM, OR 0.16, 95% CI 0.07 to 0.36, p<0.001). Glucocorticoids were used in 98% of cases, methotrexate in 71% and azathioprine in 51%. CONCLUSION: This large multicentre cohort demonstrates the importance of extramuscular involvement in patients with IIM, its association with smoking and its influence on disease severity. Our findings emphasise that IIM is a multisystem inflammatory disease and will help inform prognosis and clinical management of patients.


Assuntos
Pesquisa Biomédica/métodos , Cooperação Internacional , Miosite/epidemiologia , Sistema de Registros/estatística & dados numéricos , Estudos de Coortes , Estudos Transversais , Feminino , Nível de Saúde , Humanos , Masculino , Miosite/etiologia , Miosite/patologia , Prognóstico , Índice de Gravidade de Doença , Fumar/efeitos adversos , Inquéritos e Questionários
7.
Arthritis Res Ther ; 19(1): 17, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28122635

RESUMO

BACKGROUND: Magnetic resonance imaging (MRI) of thigh muscles is increasingly used to assess disease activity and damage extent in chronic myositis, but the validity of the findings is not clear. Here, the primary aim was to compare thigh MRI findings in patients having chronic myositis associated with anti-synthetase syndrome (ASS) and in matched healthy controls. METHODS: Cross-sectional analyses of thigh muscle MRI, muscular function and creatinine kinase (CK) were performed in 68 ASS patients (median disease duration 71 months) and 67 controls matched for age and gender. MRI changes associated with disease activity (edema in muscles and fascia) and damage (fatty replacement and muscle volume reduction) were assessed semiquantitatively, giving a total MRI score of 0-78 (total edema 0-42 and total damage 0-36). RESULTS: ASS patients had higher total MRI score than the matched controls (14.1 versus 3.0; p < 0.001) and less muscle strength (p < 0.001). Muscle edema was more frequent in ASS patients than controls (38% versus 12%), as was fatty replacement (42% versus 4%). In ASS patients, we found that the total edema score correlated with CK, but 23% of the patients with normal CK had score > 18. Muscle compartment analyses in ASS patients showed that muscle edema was most pronounced anteriorly, while fatty replacement dominated posteriorly. CONCLUSIONS: This study showed, for the first time, the magnitude of difference in muscle MRI findings between chronic myositis cases and matched controls. In ASS patients, muscle MRI appeared to provide useful complementary information to muscle strength and CK levels in the assessment of myositis.


Assuntos
Imagem por Ressonância Magnética/métodos , Força Muscular , Músculo Esquelético/diagnóstico por imagem , Miosite/diagnóstico por imagem , Adulto , Creatina Quinase/sangue , Creatina Quinase/metabolismo , Creatinina/sangue , Creatinina/metabolismo , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/enzimologia , Músculo Esquelético/fisiopatologia , Miosite/enzimologia , Miosite/fisiopatologia
9.
J Rheumatol ; 43(6): 1107-13, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27036381

RESUMO

OBJECTIVE: Interstitial lung disease (ILD) is a major component of the antisynthetase syndrome, but quantitative data on longterm pulmonary outcome in antisynthetase syndrome are limited. In this study, the main aims were to compare pulmonary function tests (PFT) and the 6-min walking distance (6MWD) between patients with antisynthetase syndrome and healthy sex- and age-matched controls, to evaluate the extent of ILD by lung high-resolution computed tomography (HRCT), and to assess correlations between PFT measures and ILD extent. METHODS: Concurrent PFT and 6MWD were performed in 68 patients with antisynthetase syndrome and their individually matched controls. Additionally, in the patients, the extent of ILD was determined in 10 HRCT sections, expressed as percentage of total lung volumes. RESULTS: Median disease duration in the antisynthetase syndrome cohort was 71 months. Compared with the matched controls, the patients with antisynthetase syndrome had mean 28%, 27%, and 53% lower absolute values of forced vital capacity (FVC), forced expiratory volume in 1 s, and DLCO (p < 0.001). Mean difference in 6MWD between patients and controls was 116 m (p < 0.001). Median extent of ILD by HRCT was 20% (range 0-73) and correlated with FVC and DLCO. Pulmonary outcome did not differ between Jo1 and non-Jo1 subsets. CONCLUSION: To our knowledge, this study is the first to demonstrate a highly significant difference in PFT between patients with antisynthetase syndrome with 6 years of followup and healthy controls. DLCO displayed the highest difference with mean 53% lower value in the patients. FVC and DLCO correlated significantly with ILD extent, indicating these variables as appropriate outcome measures in antisynthetase syndrome-associated ILD.


Assuntos
Doenças Pulmonares Intersticiais/complicações , Pulmão/fisiopatologia , Miosite/complicações , Adulto , Estudos Transversais , Feminino , Humanos , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Miosite/diagnóstico por imagem , Miosite/fisiopatologia , Testes de Função Respiratória , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
10.
J Environ Qual ; 44(2): 512-23, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26023970

RESUMO

Transport of phosphorus (P) from agricultural fields to water bodies deteriorates water quality and causes eutrophication. To reduce P losses and optimize P use efficiency by crops, better knowledge is needed of P turnover in soil and the efficiency of best management practices (BMPs). In this review, we examined these issues using results from 10 Swedish long-term soil fertility trials and various studies on subsurface losses of P. The fertility trials are more than 50 years old and consist of two cropping systems with farmyard manure and mineral fertilizer. One major finding was that replacement of P removed by crops with fertilizer P was not sufficient to maintain soil P concentrations, determined with acid ammonium lactate extraction. The BMPs for reducing P leaching losses reviewed here included catch crops, constructed wetlands, structure liming of clay soils, and various manure application strategies. None of the eight catch crops tested reduced P leaching significantly, whereas total P loads were reduced by 36% by wetland installation, by 39 to 55% by structure liming (tested at two sites), and by 50% by incorporation of pig slurry into a clay soil instead of surface application. Trend analysis of P monitoring data since the 1980s for a number of small Swedish catchments in which various BMPs have been implemented showed no clear pattern, and both upward and downward trends were observed. However, other factors, such as weather conditions and soil type, have profound effects on P losses, which can mask the effects of BMPs.

11.
J Environ Qual ; 44(2): 535-44, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26023972

RESUMO

The importance of subsoil features for phosphorus (P) leaching is frequently mentioned, but subsoil effects are still poorly documented. This study examined whether the subsoil of four agricultural Swedish soils (two sand and two clay) functioned as a source or sink for P leaching by measuring P leaching from intact soil columns with topsoil (1.05 m deep) and without topsoil (0.77 m deep) over 3 yr. One sandy soil with high topsoil P content (Olsen P, 84 mg kg) and high subsoil sorption capacity (P sorption index [PSI], 3.7 mmol kg) had low leaching of dissolved reactive P (DRP) from full-length and subsoil lysimeters (0.12 and 0.08 kg ha yr, respectively). The other sandy soil, with high Olsen P content in the topsoil and subsoil (27 and 19 mg kg, respectively) and low PSI in the subsoil (1.4 mmol kg), had high DRP leaching from full-length and subsoil lysimeters (3.33 and 3.29 kg ha yr, respectively). High P content at depth (Olsen P, 21 mg kg) in one clay soil resulted in relatively higher subsoil DRP contribution (89%) to total leaching than observed in the other clay soil (71%). These results indicate that the subsoil can act as source or sink for P leaching, depending on P content, degree of P saturation, and P sorption capacity, and therefore subsoil properties should be considered when selecting mitigation measures to reduce P leaching.

12.
Rheumatology (Oxford) ; 54(8): 1420-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25740830

RESUMO

OBJECTIVE: To retrospectively evaluate the efficacy and safety of rituximab (Rtx) treatment in patients with anti-synthetase syndrome (ASS) and severe interstitial lung disease (ILD). METHODS: Patients with severe ILD and >12 months follow-up post-Rtx were identified from the Oslo University Hospital ASS cohort (n = 112). Clinical data, including pulmonary function tests (PFTs), were retrospectively collected from medical reports. Extent of ILD pre-, and post-Rtx was scored on thin-section high-resolution CT (HRCT) images and expressed as a percentage of total lung volume. Muscle strength was evaluated by manual muscle testing of eight muscle groups (MMT8). RESULTS: Altogether, 34/112 ASS patients had received Rtx; 24/34 had severe ILD and >12 months follow-up post-Rtx (median 52 months). In these 24 patients, the median percentage of predicted forced vital capacity, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) increased by 24%, 22% and 17%, respectively, post-Rtx. Seven patients (all with disease duration <12 months and/or acute onset/exacerbation of ILD) had >30% improvement in all three PFTs. HRCT analysis showed a median 34% reduction in ILD extent post-Rtx. MMT8 score increased post-Rtx. During follow-up, 7/34 (21%) Rtx-treated ASS patients died; 6/7 deaths were related to infections. The mortality rate in the Rtx-treated group was comparable to that of the remaining ASS cohort (25/78 deceased; 32%). CONCLUSION: This study, which included 24 Rtx-treated ASS patients with severe ILD, reports improved PFTs after a median 52 months follow-up post-Rtx. The best outcome was observed in patients with a disease duration <12 months and/or acute onset/exacerbation of ILD. The study indicates that Rtx could be a treatment option for selected ASS patients, but infections should be given attention.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antirreumáticos/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Miosite/complicações , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Miosite/fisiopatologia , Testes de Função Respiratória , Estudos Retrospectivos , Rituximab , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Resultado do Tratamento
13.
Sports Med ; 44(9): 1225-40, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24803162

RESUMO

The popularity and professionalism of female soccer has increased markedly in recent years, with elite players now employed on either a professional or semi-professional basis. The previous review of the physiological demands of female soccer was undertaken two decades ago when the sport was in its relative infancy. Increased research coupled with greater training and competition demands warrants an updated review to consider the effect on physical performance and injury patterns. The physical demands of match-play along with the influence of factors such as the standard of competition, playing position and fatigue have been explored. Total distance covered for elite female players is approximately 10 km, with 1.7 km completed at high speed (>15 kmh(-1)) [corrected].Elite players complete 28% more high-speed running and 24 % more sprinting than moderate-level players. Decrements in high-speed running distance have been reported between and within halves, which may indicate an inability to maintain high-intensity activity. Although the physical capacity of female players is the most thoroughly researched area, comparisons are difficult due to differing protocols. Elite players exhibit maximal oxygen uptake (VO2max) values of 49.4-57.6 mL·kg(-1)·min(-1), Yo Yo Intermittent Endurance test level 2 (YYIE2) scores of 1,774 ± 532 m [mean ± standard deviation (SD)] and 20 m sprint times of 3.17 ± 0.03 s (mean ± SD). Reasons for the increased prevalence of anterior cruciate ligament injuries in females (2-6 times greater than males) are discussed, with anatomical, biomechanical loading and neuromuscular activation differences being cited in the literature. This review presents an in-depth contemporary examination of the applied physiology of the female soccer player.


Assuntos
Futebol/fisiologia , Antropometria , Comportamento Competitivo/fisiologia , Feminino , Humanos , Força Muscular , Educação Física e Treinamento , Resistência Física/fisiologia , Corrida/fisiologia , Fatores Sexuais , Futebol/lesões
14.
Blood ; 123(25): 3979-87, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24740810

RESUMO

Protein S is a cofactor for tissue factor pathway inhibitor (TFPI), accelerating the inhibition of activated factor X (FXa). TFPI Kunitz domain 3 residue Glu226 is essential for enhancement of TFPI by protein S. To investigate the complementary functional interaction site on protein S, we screened 44 protein S point, composite or domain swap variants spanning the whole protein S molecule for their TFPI cofactor function using a thrombin generation assay. Of these variants, two protein S/growth arrest-specific 6 chimeras, with either the whole sex hormone-binding globulin (SHBG)-like domain (Val243-Ser635; chimera III) or the SHBG laminin G-type 1 subunit (Ser283-Val459; chimera I), respectively, substituted by the corresponding domain in growth arrest-specific 6, were unable to enhance TFPI. The importance of the protein S SHBG-like domain (and its laminin G-type 1 subunit) for binding and enhancement of TFPI was confirmed in FXa inhibition assays and using surface plasmon resonance. In addition, protein S bound to C4b binding protein showed greatly reduced enhancement of TFPI-mediated inhibition of FXa compared with free protein S. We show that binding of TFPI to the protein S SHBG-like domain enables TFPI to interact optimally with FXa on a phospholipid membrane.


Assuntos
Lipoproteínas/metabolismo , Proteína S/metabolismo , Sítios de Ligação/genética , Western Blotting , Proteína de Ligação ao Complemento C4b/metabolismo , Fator Xa/metabolismo , Células HEK293 , Humanos , Lipoproteínas/genética , Mutação , Fosfolipídeos/metabolismo , Proteína C/metabolismo , Proteína S/genética , Globulina de Ligação a Hormônio Sexual/metabolismo , Ressonância de Plasmônio de Superfície , Trombina/metabolismo , Tromboplastina/metabolismo
16.
J Environ Qual ; 42(2): 455-63, 2013 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23673838

RESUMO

Eutrophication, a major problem in many fresh and brackish waters, is largely caused by nonpoint-source pollution by P from agricultural soils. This lysimeter study examined the influence of P content, physical properties, and sorption characteristics in topsoil and subsoil on P leaching measured during 21 mo in 1-m-long, undisturbed soil columns of two clay and two sandy soils. Total P losses during the period varied between 0.65 and 7.40 kg ha. Dissolved reactive P was the dominant form in leachate from the sandy soils and one clay soil, varying from 48 to 76%. Particulate P dominated in leachate from the other clay soil, where low pH (5.2) in the subsoil decreased aggregate stability and thereby probably increased the dispersion of clay particles. Phosphorus leaching was small from soils with high P sorption index (PSI) and low P saturation (<10% of PSI) in the subsoil, even though extractable P (Olsen P) in the topsoil was high, and large from a soil with low sorption capacity and high P saturation (>35% of PSI) in the profile. High sorption capacity in the subsoil was more important for P leaching in sandy soils than in clay soils with macropore flow, where the effect of high sorption capacity was reduced due to less interaction between percolating water and the soil matrix. The results suggest that P leaching is greatly affected by subsoil properties and that topsoil studies, which dominate current research, are insufficient for assessing P leaching in many soils.


Assuntos
Fósforo , Solo , Agricultura , Eutrofização , Fósforo/química , Solo/química , Poluentes do Solo/química , Poluentes Químicos da Água/química
17.
Phys Chem Chem Phys ; 15(17): 6456-66, 2013 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-23525209

RESUMO

Poly(methyl methacrylate) microspheres have been prepared by the internal phase separation method using either of the three conventional dispersants poly(vinyl alcohol) (PVA), poly(methacrylic acid) (PMAA), or the amphiphilic block copolymer poly(methyl methacrylate)-block-poly(sodium methacrylate). The block copolymer based microsphere, which has a polyelectrolyte brush on the surface, was surface modified with up to two poly(diallyldimethylammonium chloride)-poly(sodium methacrylate) bilayers. The microspheres were loaded with the hydrophobic dye 2-(4-(2-chloro-4-nitrophenylazo)-N-ethylphenylamino)ethanol (Disperse Red 13) and its release from aqueous dispersions of microspheres with the different surface compositions was measured by spectrophotometry. The burst fraction, burst rate and the diffusion constant were determined from a model combining burst and diffusive release. Out of the three dispersants, the block copolymer gave the slowest release of the dye, with respect to both burst release and diffusive release. A very pronounced further reduction of the diffusion constant was obtained by applying polyelectrolyte multilayers on top of the microspheres. However, the diffusion constant was very weakly dependent on further polyelectrolyte adsorption and one polyelectrolyte bilayer appeared to suffice.


Assuntos
Microesferas , Polímeros/química , Eletrólitos/síntese química , Eletrólitos/química , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Polímeros/síntese química , Água/química
18.
Blood ; 120(25): 5059-62, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-23074276

RESUMO

Protein S is a cofactor for tissue factor pathway inhibitor (TFPI) that critically reduces the inhibition constant for FXa to below the plasma concentration of TFPI. TFPI Kunitz domain 3 is required for this enhancement to occur. To delineate the molecular mechanism underlying enhancement of TFPI function, in the present study, we produced a panel of Kunitz domain 3 variants of TFPI encompassing all 12 surface-exposed charged residues. Thrombin-generation assays in TFPI-depleted plasma identified a novel variant, TFPI E226Q, which exhibited minimal enhancement by protein S. This was confirmed in purified FXa inhibition assays in which no protein S enhancement of TFPI E226Q was detected. Surface plasmon resonance demonstrated concentration-dependent binding of protein S to wild-type TFPI, but almost no binding to TFPI E226Q. We conclude that the TFPI Kunitz domain 3 residue Glu226 is essential for TFPI enhancement by protein S.


Assuntos
Lipoproteínas/genética , Lipoproteínas/metabolismo , Mutação Puntual , Proteína S/metabolismo , Fator Xa/metabolismo , Inibidores do Fator Xa , Humanos , Lipoproteínas/química , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ressonância de Plasmônio de Superfície , Trombina/metabolismo
20.
Blood ; 119(6): 1555-60, 2012 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-22110247

RESUMO

VWF and ADAMTS13 are major determinants of platelet adhesion after vessel injury. In the present study, we aimed to determine whether VWF or ADAMTS13 plasma antigen levels influence the risks of ischemic stroke (IS) or myocardial infarction (MI) in young women and how these risks are affected by oral contraceptive (OC) use. VWF and ADAMTS13 plasma antigen levels were measured in a frequency-matched case-control study of 1018 young (18-49 years) women including 175 IS patients and 205 MI patients. Increasing levels of VWF and decreasing levels of ADAMTS13 were associated with the risk of IS and MI in a dose-dependent manner. Having both high VWF and low ADAMTS13 resulted in an odds ratio (OR) of 6.9 (95% confidence interval [95% CI], 2.0-23.0) for IS and 11.3 (95% CI, 3.6-35.2) for MI. Use of OCs increased the risk of IS and MI associated with high VWF (OR = 12; 95% CI, 5.5-26.2 and OR = 7.5, 95% CI, 3.6-15.7, respectively) and the risk of IS associated with low ADAMTS13 (OR = 5.8, 95% CI, 2.7-12.4). We conclude that high VWF and low ADAMTS13 plasma levels both increase the risk of IS and MI. The risks associated with high VWF or low ADAMTS13 levels are further increased by the use of OCs.


Assuntos
Proteínas ADAM/sangue , Anticoncepcionais Orais/efeitos adversos , Infarto do Miocárdio/sangue , Acidente Vascular Cerebral/sangue , Fator de von Willebrand/metabolismo , Proteína ADAMTS13 , Adolescente , Adulto , Isquemia Encefálica/complicações , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Razão de Chances , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Adulto Jovem
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