Arthroscopic Coracoclavicular Ligament Reconstruction of Chronic Acromioclavicular Dislocations Using Autogenous Semitendinosus Graft: A Two-Year Follow-up Study of 58 Patients.

PURPOSE: To determine the results of operatively treated chronic acromioclavicular (AC) joint dislocations after 2-year follow-up. METHODS: Fifty-eight patients with chronic acromioclavicular separations underwent arthroscopic coracoclavicular ligament reconstructions using semitendinosus autografts. Constant and Simple Shoulder Test scores were determined before and 2 years after surgery as a part of standard clinical practice. General patient satisfaction with the outcome (poor, fair, or excellent) also was assessed. In addition, for purposes of routine clinical follow-up, the coracoclavicular distance was measured from the inferior cortex of the clavicle to the superior cortex of the coracoid using anteroposterior radiographs taken 2 years after surgery. The results were compared with postoperative radiographs and changes in the distance were recorded. The clavicular drill hole was similarly measured 2 years after surgery to detect possible tunnel widening. RESULTS: The mean preoperative Constant score increased from a preoperative mean of 52.6 ± 16.5 to 94.7 ± 7.9 at 2 years postoperatively (P = .000). The Simple Shoulder Test score increased from a preoperative mean of 7.7 ± 1.64 to 11.8 ± 0.7 (P = .000). The mean coracoclavicular distance increased from 10.5 ± 3.4 to 12.4 ± 3.9 mm (P = .009). The diameter of the clavicular drill hole increased from 6.0 mm to a mean of 8.4 mm. Two coracoid fractures were observed, but no clavicular fractures. One patient experienced a deep infection, leading to total reconstruction failure, and 2 patients had superficial postoperative infections. Forty-five patients (85%) reported excellent subjective outcomes, and 8 (15%) reported a fair outcome. CONCLUSIONS: The outcomes of this series of coracoclavicular ligament reconstruction were favorable and the number of serious complications was small. However, clavicular wound issues were a significant problem. Coracoclavicular ligament reconstruction is a challenging procedure, but satisfactory results can be achieved with careful patient selection and good technique. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Genes involved in innate immunity associated with asbestos-related fibrotic changes.

OBJECTIVES: To determine whether genetic polymorphisms in several candidate genes related to innate immunity and protease-antiprotease balance modify individual susceptibility to develop asbestos-related fibrotic pleuropulmonary changes. METHODS: Sixteen polymorphisms from nine genes (NLRP3, CARD8, TNF, TGFB1, GC, MMP1, MMP9, MMP12 and TIMP2) were genotyped from 951 Finnish asbestos-exposed workers. The genotype/haplotype data were compared to signs of fibrosis and pleural thickenings using linear and logistic regression analysis adjusted for potential confounders. RESULTS: A functional polymorphism (Q705K; rs35829419) in the NLRP3 gene was associated with interstitial lung fibrosis (p=0.013), and the TGFB1 rs2241718 SNP with visceral pleural fibrosis (VPF) (p=0.044). In stratified analysis, the carriage of at least one NLRP3 variant allele conferred a 2.5-fold increased risk for pathological interstitial lung fibrosis (OR 2.44, 95% CI 0.97 to 6.14). Conversely, the carriage of at least one TGFB1 rs2241718 variant allele protected against VPF (OR 0.62, 95% CI 0.39 to 0.98). The TIMP2 rs2277698 SNP and a haplotype consisting of the TGFB1 rs1800469 and rs1800470 SNPs were associated with the degree of pleural thickening calcification (p=0.037 and p=0.035), and the CARD8 rs2043211 SNP with the greatest thickness of pleural plaques (p=0.015). CONCLUSIONS: Our results support the hypothesis that the NLRP3 inflammasome is important in the development of fibrotic lung disease by associating the NLRP3 rs35829419 variant allele with increased risk of asbestos-related interstitial lung fibrosis, and the TGFB1 rs2241718 variant allele with decreased risk of asbestos-related VPF. Polymorphisms in CARD8 and TIMP2 are proposed to modify the development and/or calcification of pleural thickenings.

Association of genes of protease-antiprotease balance pathway to lung function and emphysema subtypes.

BACKGROUND: The imbalance between proteases and antiproteases has been proposed to participate to the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. Gene level variation in different metalloproteinases, metalloproteinase inhibitors, and cytokines affecting them may contribute to this imbalance and destruction of the lung parenchyma. We investigated whether polymorphisms in selected protease-antiprotease balance pathway genes predispose to different emphysema subtypes (centrilobular, paraseptal, panlobular, and bullae) and airflow limitation among Finnish construction workers. METHODS: Eleven single nucleotide polymorphisms (SNPs) from seven genes (GC: rs7041 and rs4588; MMP1: rs1799750; MMP9: rs3918242; MMP12: rs652438; TIMP2: rs2277698; TNF: rs1799724 and rs1800629; TGFB1: rs1800469, rs1800470, and rs2241718) were analyzed from 951 clinically and radiologically characterized construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and maximal expiratory flow at 50% of FVC (MEF50) by using linear and logistic regression analyses, adjusted for potential confounders. RESULTS: The TIMP2 rs2277698 SNP was associated with overall (p = 0.022) and paraseptal (p = 0.010) emphysema, as well as with FEV1/FVC ratio (p = 0.035) and MEF50 (p = 0.008). The TGFB1 rs2241718 and MMP9 rs3918242 SNPs were associated with centrilobular emphysema (p = 0.022 and p = 0.008), and the TNF rs1800629 SNP with paraseptal emphysema (p = 0.017). In stratified analysis, individuals with at least one TIMP2 rs2277698 or TNF rs1800629 variant allele were found to be at around two-fold risk for pathological paraseptal changes (OR 1.94, 95% CI 1.14-3.30; OR 2.10, 95% CI 1.24-3.56). On the contrary, the risk for pathological centrilobular changes was halved for individuals with at least one MMP9 rs3918242 (OR 0.51, 95% CI 0.30-0.86) or TGFB1 rs2241718 (OR 0.53, 95% CI 0.30-0.90) variant allele, or TGFB1 rs1800469-rs1800470 AT-haplotype (OR 0.55, 95% CI 0.33-0.93). MEF50, in turn, was significantly reduced among individuals with at least one TIMP2 rs2277698 variant allele (p = 0.011). CONCLUSION: Our findings strengthen the hypothesis of the importance of protease-antiprotease balance in pathogenesis of emphysema and shed light on the aetiology of different emphysema subtypes by associating MMP9 and TGFB1 to centrilobular emphysema, and TIMP2 and TNF to paraseptal emphysema and/or airflow obstruction.

SERPINE2 haplotype as a risk factor for panlobular type of emphysema.

BACKGROUND: SERPINE2 (serpin peptidase inhibitor, clade E, member 2) has previously been identified as a positional candidate gene for chronic obstructive pulmonary disease (COPD) and has subsequently been associated to COPD and emphysema in several populations. We aimed to further examine the role of SERPINE2 polymorphisms in the development of pulmonary emphysema and different emphysema subtypes. METHODS: Four single nucleotide polymorphisms (SNPs) in SERPINE2 were analyzed from 951 clinically and radiologically examined Finnish construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high-resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusing capacity (DLCO), and specific diffusing capacity (DLCO/VA). RESULTS: Three of the studied SERPINE2 SNPs (rs729631, rs975278, and rs6748795) were found to be in tight linkage disequilibrium. Therefore, only one of these SNPs (rs729631) was included in the subsequent analyses, in addition to the rs840088 SNP which was in moderate linkage with the other three studied SNPs. The rs729631 SNP showed a significant association with panlobular emphysema (p = 0.003). In further analysis, the variant allele of the rs729631 SNP was found to pose over two-fold risk (OR 2.22, 95% CI 1.05-4.72) for overall panlobular changes and over four-fold risk (OR 4.37, 95% CI 1.61-11.86) for pathological panlobular changes. A haplotype consisting of variant alleles of both rs729631 and rs840088 SNPs was found to pose an almost four-fold risk for overall panlobular (OR 3.72, 95% CI 1.56-8.90) and subnormal (OR 3.98, 95% CI 1.55-10.20) emphysema. CONCLUSIONS: Our results support the previously found association between SERPINE2 polymorphisms and pulmonary emphysema. As a novel finding, our study suggests that the SERPINE2 gene may in particular be involved in the development of panlobular changes, i.e., the same type of changes that are involved in alpha-1-antitrypsin (AAT) -deficiency.

Genetic polymorphisms of xenobiotic-metabolizing enzymes influence the risk of pulmonary emphysema.

BACKGROUND: Pulmonary emphysema is a smoking-induced condition of the lung. Genetically determined differences in the activities of enzymes that metabolize oxidative agents are suspected to modify individual susceptibility to emphysema, as well as other smoking-related pulmonary disorders. OBJECTIVES: We investigated whether polymorphisms in selected xenobiotic-metabolizing enzyme genes predispose to emphysematous changes and airflow limitation among Finnish Caucasian construction workers. METHODS: PCR-based methods were used to analyze nine common polymorphisms in EPHX1, GSTM1, GSTM3, GSTP1, GSTT1, and NAT2 genes among 988 Finnish construction workers. The genotype data were compared with different emphysematous signs confirmed with high-resolution computed tomography and with forced vital capacity and forced expiratory volume in 1 s. For this, linear and logistic regression analyses, adjusted for the potential confounders, were used. RESULTS: The EPHX1 Tyr113His polymorphism was associated with emphysematous changes (P=0.007), including paraceptal (P=0.039), panlobular (P=0.013), and bullae (P=0.003) type changes. The GSTM3 promoter polymorphism was associated with forced expiratory volume in 1 s/forced vital capacity ratio (P=0.010), and the GSTT1 genotype with emphysematous signs (P=0.008), including paraceptal (P=0.015), panlobular (P=0.031), and bullae-type (P=0.045) changes. In further analysis, the GSTT1 deletion was found to pose a two-fold overall risk for having emphysematous changes (odds ratio: 2.01; 95% confidence interval: 1.33-3.03), and almost a four-fold risk for having severe emphysematous changes (odds ratio: 3.70; 95% confidence interval: 2.15-6.36). CONCLUSION: The results indicate a significant modifying role for GSTT1 gene polymorphism in the individual risk and severity of emphysematous changes.

Alternative mRNA splicing of SAP30L regulates its transcriptional repression activity.

Covalent modification of histones regulates chromatin structure and gene expression. Sin3A mediates the association of histone deacetylase enzymes with a large number of sequence-specific transcriptional repressors. In this study we characterized three novel transcripts of SAP30L, a recently identified Sin3A-associated protein. These splice variants show significant differences in transcriptional repression capabilities and associating histone deacetylase activities. Furthermore, they differ in binding to Sin3A and in subcellular localization when transiently transfected. These data suggest that the transcriptional repression of a Sin3A corepressor complex can be regulated not only by sequence-specific transcriptional repressors, but also by modification of associated proteins, such as SAP30L.