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1.
The differences in amino acid residues of HLA-B27 subtypes are minor, but may play role in pathogenesis of ankylosing spondylitis (AS). Aim of this study was to investigate of frequency of B27 subtypes in Croatian AS patients and B27 positive healthy controls. Group of 50 AS patients and 38 B27 positive controls were typed for B27 subtypes by PCR-SSP method. In the group of AS patients we found four subtypes: B*2705 (83.0%), B*2702 (13.2%), while remaining two alleles B*2701 and B*2704 had one individual each. In the group of B27+ controls we also observed B*2705 (76.3%) as most frequent allele while frequency of B*2702 was 21.1%. No significant evidence for association between AS and a particular HLA-B27 subtype in the Croatian population were found.  相似文献   

2.
HLA-B27 polymorphism.   总被引:6,自引:0,他引:6  
HLA-B27 is a serologic specificity that encompasses 25 different alleles that encode 23 different products (proteins): HLA-B*2701 to B*2723. These alleles are also called subtypes of HLA-B27, and they may have evolved from the most widespread subtype, B*2705. These subtypes are distinguished from changes mostly in exons 2 and 3, which encode the alpha 1 and alpha 2 domains of the B27 molecule, respectively. Occurrence of ankylosing spondylitis (AS) or related spondyloarthropathy (SpA) has thus far been documented in subjects possessing any one of the first ten (B*2701 to B*2710) subtypes studied. However, B*2706 in Southeast Asian and B*2709 in the Italian island population of Sardinia seem not to be associated with AS. The 13 most recent subtypes have not yet been studied for disease association. It is important to investigate which of them are and are not associated with AS and related SpA, and whether certain subtypes show any preferential association with some of the clinical features or forms of these diseases among the various ethnic/racial populations and geographic regions of the world. This is expected to provide clues as to the mechanism of disease association, and one of the strongest reasons to study the B27 subtypes is to learn the effects of the sequence variations on the peptide-binding specificity of the molecule. Among these peptides may be the putative arthritogenic peptide(s).  相似文献   

3.
《Revue du Rhumatisme》2001,68(9):807-812
HLA-B27 is a serologic specificity that encompasses 25 different alleles that encode 23 different products (proteins) - HLA-B*2701 to B*2723. These alleles are also called subtypes of HLA-B27, and they may have evolved from the most widespread subtype, B*2705. These subtypes are distinguished from changes mostly in exons 2 and 3, which encode the alpha 1 and alpha 2 domains of the B27 molecule, respectively. Occurrence of ankylosing spondylitis (AS) or related spondyloarthropathy (SpA) has thus far been documented in subjects possessing any one of the first 10 (B*2701 to B*2710) subtypes, so studied. However, B*2706 in Southeast Asian and B*2709 in the Italian island population of Sardinia seem not to be associated with AS. The 13 most recent subtypes have not yet been studied for disease association. It is important to investigate which of them are and are not associated with AS and related SpA, and whether certain subtypes show any preferential association with some of the clinical features or forms of these diseases among the various ethnic/racial populations and geographic regions of the world. This is expected to provide clues as to the mechanism of disease association, and one of the strongest reasons to study the B27 subtypes is to learn the effects of the sequence variations on the peptide binding specificity of the molecule. Among these peptide may be the putative arthritogenic peptide(s).  相似文献   

4.
OBJECTIVE: To evaluate the relationship between the presence of different HLA-DRB1 genes and predisposition to develop a sporadic form of ankylosing spondylitis (AS) in a demographically well-defined population. METHODS: One hundred fifteen selected patients with sporadic (non-familial) forms of AS from six different cities and 748 bone marrow donors as control group. All individuals were typed for HLA-B27 by flow cytometry with monoclonal antibodies and PCR -SSP, as well as for HLA-DRB using the Dynal ELI SSO HLA-DRB Test (Dynal AS, Oslo, Norway). The Inno-Lipa DRB Decoder (Innogenetics NV Zwijndrecht, Belgium), was used for high-resolution HLA-DRB typing. RESULTS: The presence of the DRB1*01 antigen in the studied population is significantiy higher in B27 positive healthy individuals (bone marrow donors) than in B27 positive AS patients; also, DRB1*01 is higher in B27 negative AS patients than 827 negative controls. The frequency of DRB1*03 is higher in B27 negative controls than B27 negative AS patients. CONCLUSION: The results of this study suggest that DRB1*01 antigens might be involved in the development of sporadic forms of ankylosing spondylitis in HLA-B27 negative individuals in the studied area.  相似文献   

5.
ObjectivesAnkylosing spondylitis is strongly associated with HLA-B27. However, the strength of the association with HLA-B27 and the clinical features may vary in different parts of the world. The aim of this study is to compare the clinical features of AS and the frequencies of HLA-B27 and its alleles in patients from Turkey with other series.MethodsOne hundred and twelve patients (72 male/40 female) fulfilling the modified New York criteria for the classification of AS and 55 (27 male/28 female) healthy controls were typed for HLA-B27 and allele frequencies by sequence specific primer (PCR/SSP) method and assessed for clinical manifestations.ResultsMale to female ratio was 1.8, mean age at disease onset was 23.5 and 24.1% of patients reported juvenile onset of symptoms. Peripheral arthritis was seen in 52.7% of patients. Family history (p = 0.01) and peripheral arthritis (p = 0.02) were more frequent in females and spinal involvement in males. HLA-B27 was found to be positive in 70% of patients and associated with younger mean age, uveitis and shorter time elapsed from symptom to diagnosis. The frequency of HLA-B27 alleles associated with SpA was not different between ankylosing spondylitis patients and healthy controls.ConclusionLow frequency of HLA-B27 and clinical variations in ankylosing spondylitis may be due to different genetic and/or environmental factors in Turkey.  相似文献   

6.
《Revue du Rhumatisme》2002,69(9):886-891
Objective. To evaluate the relationship between the presence of different HLA-DRB1 genes and predisposition to develop a sporadic form of ankylosing spondylitis (AS) in a demographically well-defined population. Methods. One hundred fifteen selected patients with sporadic (non-familial) forms of AS from six different cities and 748 bone marrow donors as control group. All individuals were typed for HLA-B27 by flow cytometry with monoclonal antibodies and PCR -SSP, as well as for HLA-DRB using the Dynal ELI™ SSO HLA-DRB Test (Dynal AS, Oslo, Norway). The Inno-Lipa DRB Decoder (Innogenetics NV Zwijndrecht, Belgium), was used for high-resolution HLA -DRB typing. Results. The presence of the DRB1*01 antigen in the studied population is significantly higher in B27 positive healthy individuals (bone marrow donors) than in B27 positive AS patients; also, DRB1*01 is higher in B27 negative AS patients than B27 negative controls. The frequency of DRB1*03 is higher in B27 negative controls than B27 negative AS patients. Conclusion. The results of this study suggest that DRB1*01 antigens might be involved in the development of sporadic forms of ankylosing spondylitis in HLA-B27 negative individuals in the studied area.  相似文献   

7.
In this study the immunogenetic relationships among 141 unrelated HLA-B27+ patients with ankylosing spondylitis (AS) and 792 members of their families were studied. Two control groups, with at least one B27+ parent were used (families undergoing transplantation program and triplet families undergoing paternity testing). All subjects were typed for HLA-A and -B antigens by microlyphocytotoxity test (MLCT) on local typing trays. The frequency of HLA-A and -B alleles was equal in the all tested groups. The segregation of all tested genes was regular regarding to the total number of positive and negative siblings, while regarding to the sex of sibs was irregular for HLA-B27 and -B5 gene. The statistical significance (p < 0.05) was found when ratio between B27+ and B27- sons in AS group was compared with the same ration in control families. In AS group was detected statistical significant (p < 0.01) high number of B5+ than B5- daughters and statistical significant (p < 0.05) less number of B5+ sons. HLA-B21 was shown to be decreased among B27+ AS patients. A synergistic effect between additional HLA-B alleles and B27 was not observed. The distribution of B27 haplotypes in AS and control families was similar except for haplotype HLA-A10, B27 which was significant (p < 0.001) less present in AS families.  相似文献   

8.
The aim of the present study was to analyze the distribution of HLA-A, -B, -Cw, and -DRB1 alleles among patients with psoriatic arthritis (PsA) in Croatia. DNA was isolated from peripheral blood of 58 PsA patients (28 male and 30 female) and tested by PCR-SSP (Polymerase Chain Reaction - Sequence Specific Primers) method for polymorphism of the above mentioned HLA loci. The strongest association between psoriatic arthritis and HLA in the Croatian population was observed for alleles at HLA-B locus (B*39 and B*57), while the association of B*27 and B* 13 alleles with PsA reached significance only before correction of p value with the number of tested alleles. Higher frequency of Cw*02 and DRB1*16 alleles is a result of linkage disequilibrium between these alleles and HLA-B alleles associated with PsA in Croatia. We also observed lower frequency of B*0702, B*18 and B*38 alleles in our group of patients.  相似文献   

9.
ObjectiveThe aim of the present study was to investigate the prevalence of MEFV gene mutations in patients with ankylosing spondylitis (AS) and to assess the clinical significance of the MEFV gene mutations in AS.MethodsEighty AS patients and 85 healthy controls were examined for 12 common MEFV mutations via strip-assay technique. Bath ankylosing spondylitis disease activity index (BASDAI), bath ankylosing spondylitis functional index (BASFI), visual analogue scale (VAS) for pain, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Schober test, chest expansion measurements, hip involvement, ocular involvement, articular pain, and presence of syndesmophytes were used to assess the disease severity in patients.ResultsTwenty-four of the AS patients (30%) and 17 of the healthy controls (20%) were found to carry a single MEFV mutation. There was no significant difference between the AS patients and controls in terms of MEFV gene mutation frequency (p = 0.13, OR: 1.71, 95% CI: 0.83–3.50). When the patients were divided into two groups as MEFV mutation carriers and noncarriers, there was significant difference between the groups regarding BASFI and BASDAI whereas there was no significant difference in VAS score for pain. No association was found with the clinical findings and MEFV mutation except hip involvement. While there was no significant difference in CRP levels, individuals with MEFV mutation had a higher ESR than the noncarriers.ConclusionMEFV gene mutation carriage rate was not found to be significantly higher in AS patients when compared with healthy controls. However having an MEFV mutation seems to aggravate the disease course in AS.  相似文献   

10.
ObjectivesTo evaluate the influence of homozygosity for HLA-B27 on the radiographic damage in ankylosing spondylitis (AS).MethodsA total of 368 AS patients with positive HLA-B27 status from the Observation Study of Korean spondyloArthropathy Registry (OSKAR) cohort were recruited for this study. HLA-B27 positive patients out of all AS patients were assessed for whether they had homozygosity or heterozygosity for HLA-B27. First, all data were stratified in relation to the carrier state of positive HLA-B27 for cross-sectional survey. Then we compared the radiographic damage score between groups. Second, we evaluated collected clinical and radiographic parameters at two different time points. Then we compared radiographic progression between groups. To use the mSASSS, cervical and lumbar spinal radiographs were examined by two experienced bone and joint radiologists (S. Lee, K.B. Joo).ResultsThe agreement between the two readers regarding mSASSS was very good: ICC coefficient 0.70 (95% CI 0.60–0.81). The mean age (SD) of the AS patients was 37.0 (9.2) years, and the mean disease duration (SD) was 15.6 (9.1) years. Of these patients, 34.5% (127 patients) had HLA-B27 homozygosity. The mean mSASSS unit (SEM) was not significantly different between groups (homozygosity 28.57 ± 4.12 vs heterozygosity 23.34 ± 3.44, P = 0.344) on cross-sectional survey. When it comes to radiographic progression between groups over 5 years, there was no significant difference in spite of adjusting for confounding variable (homozygosity 4.98 ± 0.98 vs heterozygosity 4.21 ± 0.82, P = 0.562).ConclusionThe carrier state of positive HLA-B27 plays no role in determining the radiographic progression in AS.  相似文献   

11.
ObjectivesThe aim of this study was to determine the clinical profile of ankylosing spondylitis (AS) in Korea.MethodsA total of 732 men and 98 women with AS were recruited for the cross-sectional component of the Hanyang University ankylosing spondylitis (HYAS) Study. All participants completed extensive questionnaires about their medical and personal histories, and two rheumatologists concomitantly performed clinical evaluation and previous medical record reviews for all participants.ResultsThe mean age of onset (SD) was 20.9 (8.1) years. Three hundred and ninety-one patients (47.1%) were found to have a history of peripheral arthritis. Six hundred and four patients (73.9%) were found to have a history of hip joint involvement. Two hundred and thirty-six patients (28.7%) were found to be juvenile-onset AS (JoAS) patients. The frequency of uveitis differed between the sexes (28.2% of men vs 40.8% of women; p = 0.03; OR: 1.63; 95% CI: 1.05–2.53). Peripheral arthritis (p < 0.001; OR: 4.19; 95% CI: 2.98–5.88) and hip joint involvement (p < 0.001; OR: 2.76; 95% CI; 1.77–4.29) were more frequent in JoAS group. HLA-B27 positive cases had a significantly younger age of symptom onset (by 5.3 years), more uveitis, and a higher frequency of hip joint involvement than HLA-B27 negative patients.ConclusionsThe clinical features of our patients are largely similar to those in other studies, with a few noticeable differences: 1) AS patients in Korea have a higher prevalence of peripheral arthritis and hip joint involvement; 2) female patients have more uveitis, and; 3) JoAS is common in our group.  相似文献   

12.
ObjectivesHLA-B27 positivity strongly influences Ankylosing spondylitis (AS) disease susceptibility and phenotype. The aim of this study was to analyse an AS cohort with respect to quality of life (ASQoL), extra-articular disease, markers of disease activity (BASDAI), functional capacity (BASFI), biologic requirement, and the influence of HLA-B27 on these parameters.MethodsData recorded in 82 patients included demographics (age, sex), extra-articular disease (GI, ocular, dermatological, GU), cardiac and pulmonary diagnoses. BASDAI, BASFI, ASQoL, joint counts, disease duration and past/present treatment (NSAID, DMARD, steroid and biologic use) were also recorded.Results90.2% of the cohort was B27 positive with significantly longer disease duration (17.6 v 6.9 years, p < 0.05). BASFI (42.2 v 5.9), BASDAI (3.22 v 1.3), ASQoL (10 v 4), physician assessment of biologic need (24 v 5), steroid (15.7% v 12.5%) and NSAID use (98.6% v 75%) were higher in the B27 positive group, as were ocular (38.9% v 12.5%), pulmonary (4.2% v 0%) and cardiac (4.3% v 0%) features. Negative patients displayed more GI (37.5% v 19.4%), dermatological (25% v 19.7%) and GU (25% v 4.2%) features. Patients satisfying ASAS (AS assessment study group) criteria and receiving biologic therapy were 18.9% (B27 positive group) and 0% (B27 negative group).ConclusionsAS patients have significantly longer disease duration if B27 positive, higher markers of disease activity, poorer functional status, poorer quality of life, and more extra-articular manifestations. These findings were reflected in the percentage of patients needing biologic therapies.  相似文献   

13.
强直性脊柱炎合并颈胸段脊柱骨折脱位的诊治   总被引:1,自引:1,他引:1  
尹国栋  倪斌  杨军  郭翔  周风金  杨建  刘军 《中国骨伤》2009,22(8):577-579
目的:探讨强直性脊柱炎(AS)合并颈胸段脊柱骨折脱位的病理临床特点、治疗方法及围手术期注意事项。方法:回顾分析2001年1月至2009年3月收治手术的13例AS合并颈胸段脊柱骨折脱位病例,男11例,年龄33-60岁,平均46岁;女2例,年龄36-59岁,平均47.5岁。AS病程12—27年,平均14.5年。主要临床表现为颈肩部疼痛,可伴有四肢肌力减弱、上肢感觉麻木等,X线片示颈胸段脊柱连续性中断,HIA—B27阳性。观察术后骨折愈合及脊髓神经功能改善情况(ASIA评分)。结果:13例中,6例行颈前路单间隙减压内固定术,4例行颈前路椎体次全切减压内固定术,1例行颈后路全椎板减压侧块螺钉内固定术,2例行前后联合入路复位减压内固定术。术后随访12~43个月,平均35.6个月,骨折脱位复位良好,均获得骨性融合。术后神经功能除1例A级无明显改善外,其余均有不同程度恢复。围手术期并发症5例。结论:AS合并颈胸段脊柱骨折多为不稳定的三柱骨折,常需手术治疗,术前合理选择手术适应证及术式,可减少并发症,获得较好的神经功能恢复。  相似文献   

14.
目的观察强直性脊柱炎(AS)患者外周血白介素(IL)-17A、IL-23水平及Th17/Treg比例,探讨骨髓间充质干细胞(BMSCs)与Th17/Treg体外相互作用,为研究AS发生机制提供理论依据。方法研究对象为48例活动期AS患者[实验组,男43例、女5例,年龄(26.2±5.2)岁,均为HLA-B27~+]和49例健康志愿者[对照组,男44例、女5例,年龄(25.9±4.8)岁,HLA-B27~+43例、HLA-B27~-6例]。ELISA检测外周血清中IL-17A及IL-23水平,流式细胞术检测外周血单个核细胞(PBMCs)中的CCR4~+CCR6~+Th细胞(Th17)及Treg细胞数量。分离健康志愿者的PBMCs,将PBMCs分别与AS患者及健康志愿者的BMSCs体外共培养72 h,收集PBMCs行流式细胞术检测,评价BMSCs与Th17/Treg体外的相互作用。结果实验组与对照组血清IL-17A及IL-23的表达水平相近(P0.05);实验组Th17细胞明显高于对照组(P0.05),而Treg细胞明显低于对照组(P0.05)。与健康志愿者BMSCs共培养72 h后的PBMCs中Th17较培养前轻度下降,Treg轻度上升,差异无统计学意义(P0.05);而与AS患者BMSCs共培养72 h的PBMCs中Th17较培养前及对照组均明显上升,Treg均明显下降,差异均有统计学意义(P0.05)。结论 AS患者PBMCs中Th17/Treg细胞亚群失衡。免疫抑制能力明显下降的BMSCs极可能通过诱导Th17/Treg失衡而在AS免疫发生机制中发挥重要作用。  相似文献   

15.
Hip involvement is uncommon in familial Mediterranean fever (FMF) and can result either from a process specific to this disease or from a coexisting chronic inflammatory joint disease, usually suggestive of ankylosing spondylitis (AS). We report ten cases of FMF with radiologically-documented inflammatory hip disease. Five patients had AS and one had juvenile idiopathic arthritis. There were six men and four women, with a mean age of 34.4 years +/- 17.6 (range, 15-70 years). Onset of the inflammatory hip disease occurred after bouts of acute hip symptoms in one of the patients with isolated FMF and after protracted hip arthritis in another; the two other patients had no history of hip symptoms. The HLA-B27 antigen was looked for in two of the five patients with FMF and AS, with negative results in both; another patient in this subgroup had severe ulcerative colitis. Total hip replacement or replacement of the acetabulum was required in six patients, including two with isolated FMF. Chronic joint disease has been estimated to contribute fewer than 5% of the joint manifestations in FMF. In previous studies, the hips and knees were affected in 75% of patients with chronic joint disease related to FMF. The association of FMF and AS (usually without the HLA-B27 antigen) has been well documented, although the pathogenic mechanisms that link these two conditions remain unknown.  相似文献   

16.
It has long been known that the major histocompatibility complex (MHC) is essentially involved in genetic susceptibility to ankylosing spondylitis (AS). The HLA-B27 antigen has been accounted for 20 to 50% of the total genetic risk for this disease. However, susceptibility to AS cannot be fully explained by associations with the MHC. Recent studies including linkage analyses as well as candidate gene and, most recently, genome-wide association studies indicate significant associations of the interleukin-1 gene cluster, interleukin-23 receptor and ARTS1 genes as well as other possible loci with AS. In the murine model of proteoglycan-induced spondylitis, two susceptibility loci termed Pgis1 and Pgis2 were identified. Thus, AS is not a single-gene disease and the involvement of multiple non-MHC genes may account for the individual as well as geographical differences seen in AS.  相似文献   

17.
《Revue du Rhumatisme》2002,69(12):1195-1200
Hip involvement is uncommon in familial Mediterranean fever (FMF) and can result either from a process specific to this disease or from a coexisting chronic inflammatory joint disease, usually suggestive of ankylosing spondylitis (AS). We report ten cases of FMF with radiologically-documented inflammatory hip disease. Five patients had AS and one had juvenile idiopathic arthritis. There were six men and four women, with a mean age of 34.4 years ± 17.6 (range, 15-70 years). Onset of the inflammatory hip disease occurred after bouts of acute hip symptoms in one of the patients with isolated FMF and after protracted hip arthritis in another; the two other patients had no history of hip symptoms. The HLA-B27 antigen was looked for in two of the five patients with FMF and AS, with negative results in both; another patient in this subgroup had severe ulcerative colitis. Total hip replacement or replacement of the acetabulum was required in six patients, including two with isolated FMF. Chronic joint disease has been estimated to contribute fewer than 5% of the joint manifestations in FMF. In previous studies, the hips and knees were affected in 75% of patients with chronic joint disease related to FMF. The association of FMF and AS (usually without the HLA-B27 antigen) has been well documented, although the pathogenic mechanisms that link these two conditions remain unknown.  相似文献   

18.
BackgroundLong-term outcome of Total Hip arthroplasty (THA) in Ankylosing Spondylitis (AS) remains unreported. Literature suggests a higher overall failure rate in ankylosing spondylitis as compared to osteoarthritis. Concern has been expressed regarding joint survival, given that recipients are generally young. The results of cemented THA in patients with ankylosing spondylitis were studied to determine the utility of THA for these patients.MethodsConsecutive series of 96 patients (77 males (80%) and 19 females (20%)) with ankylosing spondylitis who underwent 154 cemented THAs at a tertiary referral orthopaedic centre between January 1990–September 2015 were retrospectively analyzed for clinical and radiological outcomes; 58 patients (60.4%) underwent bilateral surgery.ResultsMean age at surgery was 48 years. Average follow up was 12.8 (2.1–24.8) years. 95% of the patients had a good or excellent post-operative outcome.Out of the total 154 hips operated on, 11% (17 hips) developed post-operative complications. Overall, 15 hips (9.7%) required a revision of the procedure, with the most common indication being aseptic loosening of the acetabulum. Average time to revision was 8.5 years (2–15). Survivorship analysis revealed probability of survival of both components at the end of 10 years, with revision due to any reason as the end point to be 92% (with 95% confidence intervals).21 hips (14%) developed heterotopic ossification post-operatively, of which 4 patients (2%) had clinically significant ossification (Brooker III or IV).ConclusionThis is one of the largest series of patients with ankylosing spondylitis with long term follow up available. Cemented THA in patients with ankylosing spondylitis provided consistently good and predictable long term results, with low rate of complications and revisions.  相似文献   

19.
目的:探讨血管内皮生长因子(vascular endothelial growth factor,VEGF)在强直性脊柱炎(ankylosing spondylitis,AS)活动期骶髂关节滑膜的病理性表达及意义。方法:通过原位杂交技术检测活动期AS患者与对照组(骨盆骨折患者)骶髂关节滑膜组织中VEGF的表达,用图像分析系统比较它们的表达差异。结果:在活动期AS患者骶髂关节滑膜组织中VEGF阳性表达,而对照组骶髂关节滑膜组织中VEGF阴性表达,阳性细胞计数及平均灰度值比较差异有统计学意义(P﹤0.01)。结论:VEGF为强直性脊柱炎发病机制中的重要因子,与强直性脊柱炎骶髂关节骨与软骨的破坏及成骨硬化过程密切相关,控制VEGF的表达可能阻断AS的骨质破坏及病理性成骨硬化,为治疗强直性脊柱炎提供新的思路。  相似文献   

20.
Objectives. To estimate the prevalence of aortic regurgitation (AR) in the Sámi population and its association with ankylosing spondylitis and HLA-B27. Design. A random sample from two Norwegian Sámi communities was invited to participate in a health survey. Echocardiography was carried out for 84% of the 416 invited. Logistic regression analysis was used to estimate the odds ratios (OR). The AR persons entered a clinical follow-up programme. Results. Altogether 28 subjects had AR. Weighted overall prevalence of AI was 8.8%. OR of AR for ankylosing spondylitis, age and HLA-B27 were 7.4 (95% CI: 1, 1-49, 0), 1.08 (95% CI, 1, 03-2, 14) and 1.8 (95% CI: 0, 6-5, 4), respectively. Conclusions. The prevalence of AR was 8.8% in the Sámi populations in Northern Norway, which is comparable to that reported in other populations; however, data from other populations are sparse. AR was strongly associated with ankylosing spondylitis, but not with HLA-B27 antigen. The progress rate of AR seems to be low; no clinically significant hemodynamic changes were noted during the 14-to-17-year follow-up programme.  相似文献   

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