Citations

Abstract Purpose: The proteasome is a multisubunit cellular organelle that functions as a nonlysosomal threonine protease. Proteasomes play a critical role in the degradation of proteins, regulating a variety of cellular processes, and they are also the target for antineoplastic proteasome inhibitors. Genetic variation in proteasome subunits could influence both proteasome function and response to drug therapy. Experimental Design: We resequenced genes encoding the three active proteasome β subunits using 240 DNA samples from four ethnic groups and the β5 subunit gene in 79 DNA samples from multiple myeloma patients who had been treated with the proteasome inhibitor bortezomib. Resequencing was followed by functional studies of polymorphisms identified in the coding region and 3′-flanking region (3′-FR) of PSMB5, the gene encoding the target for clinically useful proteasome inhibitors. Results: Resequencing of 240 DNA samples identified a series of novel ethnic-specific polymorphisms that are not represented in public databases. The PSMB5 3′-FR 1042 G allele significantly increased transcription during reporter gene studies, observations confirmed by genotype-phenotype correlations between single nucleotide polymorphisms (SNP) in PSMB5 and mRNA expression in the 240 lymphoblastoid cell lines from which the resequenced DNA was obtained. Studies with patient DNA samples identified additional novel PSMB5 polymorphisms, including a SNP and an insertion in the 3′-FR. Reporter-gene studies indicated that these two novel polymorphisms might decrease transcription. Conclusions: These results show that nonsynonymous coding SNPs in the PSMB5 gene did not show significant effects on proteasome activity, but SNPs did influence transcription. Future studies might focus on regulatory region polymorphisms.

Phenylethanolamine N-methyltransferase (PNMT) catalyzes the synthesis of epinephrine from norepinephrine. We previously identified and functionally characterized common sequence variation in the PNMT gene. In the present study, we set out to determine whether common PNMT genetic polymorphisms might be associated with individual variation in circulating epinephrine levels during exercise in 74 Caucasian American subjects. Circulating epinephrine levels were measured in each subject at baseline and during two different levels of exercise, ∼40% and ∼75% of peak workload. The PNMT gene was resequenced with DNA from each study subject. Eight novel PNMT polymorphisms were identified, including a C319T (Arg107Cys) nonsynonymous single nucleotide polymorphism (SNP) and I1G(280)A, a SNP located in the first intron of the gene. The I1G(280)A SNP was significantly associated with decreased exercise-induced circulating epinephrine levels and with a decreased epinephrine-to-norepinephrine ratio. The Cys107 recombinant allozyme displayed significantly lower levels of both PNMT activity and immunoreactive protein than the wild-type allozyme after transfection into COS-1 cells, but it did not appear to be associated with level of epinephrine in these subjects. Electrophoretic mobility shift and reporter gene assays performed with the I1G(280)A SNP indicated that this polymorphism could bind nuclear proteins and might modulate gene transcription. Our studies suggest that functionally significant variant sequence in the human PNMT gene might contribute to individual variation in levels of circulating epinephrine during exercise.

Background Isolated meniscal tears in the skeletally immature patient are infrequent but well-recognized injuries. Although few studies have evaluated the pediatric and adolescent population, arthroscopic surgical repair remains the standard of care for Patients in this age group with unstable meniscal tears. Purpose To review our results of arthroscopic repair of isolated meniscal tears in pediatric and adolescent patients to further define future management of these injuries. Study Design Case series; Level of evidence, 4. Methods The records of all patients 18 years old or younger who underwent isolated meniscal repair between 1990 and 2005 were retrospectively reviewed. Forty-four patients (6 girls, 38 boys) with an average age of 15.8 years (range, 9.9-18.7 years) were included in this study, for a total of 45 isolated meniscal tears. Clinical examinations were performed, International Knee Documentation Committee forms were administered, and Tegner scores were determined at an average of 5.8 years (range, 2.5 months-13.8 years) postoperative follow-up. Three patients were lost to follow-up. Results The clinical success rate of arthroscopic meniscal repair was 80% for simple tears, 68% for displaced bucket-handle tears, and 13% for complex tears. Seventeen menisci (38% overall) failed initial repair at a mean of 17 months (range, 3-61 Months) postoperatively and underwent repeat arthroscopic surgery (15 partial meniscectomies, 2 rerepair). The average Tegner and International Knee Documentation Committee scores were 8 (range, 5-9) and 89.4 (range, 79-99), respectively, at the time of final follow-up. Risk factors for failure included complex tears and rim width greater than 3 mm. Conclusion Clinically successful repair of an isolated meniscal tear in patients 18 years or younger was variable depending on tear type, with complex tears and rim width 3 mm or greater being negative prognostic factors.

Background Although the use of rotator interval closure is frequently advocated as a useful supplement to shoulder instability repairs, the addition of a rotator interval closure after arthroscopic instability repair has not been fully investigated. Purpose The objective of this study was to investigate whether a rotator interval closure improves glenohumeral stability in an anterior and posterior instability shoulder model. Study Design Controlled laboratory study. Methods Fourteen fresh-frozen cadaveric shoulder specimens were dissected free of soft tissues, leaving the rotator cuff intact with simulated cuff loading. All specimens were mounted in a custom testing apparatus using infrared sensors to document glenohumeral translation and rotation. The specimens were then tested for stability in the following order: vented/subluxated state, after arthroscopic anterior (Group 1; 7 specimens) or posterior (Group 2; 7 specimens) instability repair with suture anchors, and then after rotator interval closure. For each of the 3 testing conditions, the following were measured: (1) external and internal rotation at neutral, (2) external and internal rotation at 90° of abduction, (3) posterior and anterior translation at neutral rotation (15 N and 25 N), (4) anterior translation at 90° of abduction and external rotation (Group 1; 15 N and 25 N), (5) posterior translation at 90° of flexion and internal rotation (Group 2; 15 N and 25 N), and (6) sulcus testing in neutral (7.5 N). Results Posterior stability was only improved after anchor capsulolabral repair (8.0 to 5.0 mm; P = .017, 25 N), but there was no improvement after rotator interval closure (5.0 to 4.6 mm; P = .453). However, anterior stability was improved after capsulolabral repair (8.6 to 4.0 mm; P = .016, 25 N) and also improved further by rotator interval closure (4.0 to 2.4 mm; P = .007). The mean loss of external rotation was significantly increased by the addition of the rotator interval closure in both neutral and abducted glenohumeral positions, with a mean external rotation loss of 28° in neutral ( P = .013). The addition of a rotator interval closure did not improve sulcus stability ( P = .4). Conclusion The addition of an arthroscopic rotator interval closure after posterior capsulolabral repair did not improve posterior stability; however, anterior stability was improved further after a rotator interval closure. Inferior stability was not improved. Arthroscopic rotator interval closure significantly decreased external rotation at both neutral and abducted arm positions. Clinical Relevance Arthroscopic closure may be beneficial in certain cases of anterior shoulder instability; however, posterior instability was not improved. Predictable losses of external rotation after rotator interval closure are of concern.

Abstract Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.

Abstract Rationale Adenotonsillectomy, the first line of treatment of sleep-disordered breathing (SDB), is the most commonly performed pediatric surgery. Predictors of the recurrence of SDB after adenotonsillectomy and its impact on cardiovascular risk factors have not been identified. Objectives Demonstrate that gain velocity in body mass index (BMI) defined as unit increase in BMI/year confers an independent risk for the recurrence of SDB 1 year after adenotonsillectomy. Methods Children with SDB and hypertrophy of the tonsils and a comparison group of healthy children were followed prospectively for 1 year. Measurements and Main Results Serial polysomnographies, BMI, and blood pressure were obtained before adenotonsillectomy and 6 weeks, 6 months, and 1 year postoperatively. Gain velocity in BMI, BMI and being African American (odds ratios, 4–6/unit change/yr; 1.4/unit and 15, respectively) provided equal amounts of predictive power to the risk of recurrence of SDB. In the group that experienced recurrence, systolic blood pressure at 1 year was higher than at baseline and higher than in children who did not experience recurrence. Conclusions Three clinical parameters confer independent increased risk for high recurrence of SDB after adenotonsillectomy: gain velocity in BMI, obesity, and being African American. A long-term follow-up of children with SDB and monitoring of gain velocity in BMI are essential to identifying children at risk for recurrence of SDB and in turn at risk for hypertension.