Citations

Abstract Among all of the genetic factors associated with multiple sclerosis (MS) susceptibility, MHC class II molecules have the strongest association. Although a direct role of DR alleles in MS have been confirmed, it has been difficult to understand the role of DQ alleles in disease pathogenesis due to strong linkage disequilibrium with certain DR alleles. Population studies have indicated that DQ alleles may play a modulatory role in progression of MS. Using HLA class II transgenic (Tg) mice, we investigated gene complementation between DR and DQ genes in the disease process. Previously, using single Tg mice (expressing HLA-DR or DQ gene), we showed that PLP91–110 peptide induced experimental autoimmune encephalomyelitis (EAE) only in DR3.Aβ° mice, suggesting that DR3 (DRB1*0301) is a disease susceptibility gene in the context of PLP. We also showed that DQ6 protects development of EAE in DQ6/DR3 double Tg mice by production of anti-inflammatory IFN-γ. In this study, we investigated the ability of DQ8 to modulate disease in DR3/DQ8 double Tg mice. Introduction of DQ8 onto DR3 Tg mice led to higher disease incidence and increased disease severity on immunization with PLP91–110, indicating that DQ8 had an exacerbating effect on the development of EAE. Increased susceptibility in DR3/DQ8 Tg mice was due to increased production of proinflammatory cytokine IL-17 by DQ8-restricted T cells. HLA-DR3/DQ8 mice with EAE also demonstrated increased inflammation and demyelination in CNS as compared with single DR3 Tg mice. Thus double Tg mouse provides a novel model to study epistatic interactions between HLA class II molecules in inflammatory and demyelinating disease.

In this review, we have emphasized the importance of cholangiocytes in biology and pathology and highlighted recent advances in experimental approaches to study these increasingly important cells. It is anticipated that major advances will continue to be made in our understanding of how these cells funciton and the processes which result in their dysfunction. The techniques are now available to allow major inroads in our understanding of the pathobiology of cholangiocytes.

The authors evaluated existing and new criteria for defining the medical necessity for breast reduction surgery. Two cohorts of women (those requesting breast reduction surgery [N = 266] and a group of controls [N = 184]) completed a questionnaire including breast-specific symptom severity, the Short Form 36, the EuroQol, the McGill Pain Questionnaire, and the Multidimensional Body Self Relations Questionnaire. To evaluate prediction validity, the most widely accepted decision criteria and a new definition of medical necessity were applied to the data set to determine whether women meeting the definition had more favorable outcomes than those who did not as measured by validated self-report instruments. For existing criteria, women not meeting and meeting the criterion gained equal benefit from surgery. Women meeting the new definition (2 of 7 physical symptoms all or most of the time) had significantly greater improvement scores on 4 of the 5 health burden measures compared to women not meeting this definition. The authors conclude that medical necessity for breast reduction surgery is better defined by self-report of symptoms than by existing criteria.

Background. Patients’ values are fundamental to decision models, cost-effectiveness analyses, and pharmacoeconomic analyses. The standard methods used to assess how patients value different health states are inherently quantitative. People without strong quantitative skills (i.e., low numeracy) may not be able to complete these tasks in a meaningful way. Methods. To determine whether the validity of utility assessments depends on the respondent’s level of numeracy, the authors conducted in-person interviews and written surveys and assessed utility for the current health for 96 women volunteers. Numeracy was measured using a previously validated 3-item scale. The authors examined the correlation between self-reported health and utility for current health (assessed using the standard gamble, time trade-off, and visual analog techniques) across levels of numeracy. For half of the women, the authors also assessed standard gamble utility for 3 imagined health states (breast cancer, heart disease, and osteoporosis) and asked how much the women feared each disease. Results. Respondent ages ranged from 50 to 79 years (mean = 63), all were high school graduates, and 52% had a college or postgraduate degree. Twenty-six percent answered 0 or only 1 of the numeracy questions correctly, 37% answered 2 correctly, and 37% answered all 3 correctly. Among women with the lowest level of numeracy, the correlation between utility for current health and self-reported health was in the wrong direction (i.e., worse health valued higher than better health): for standard gamble, Spearman r = -0.16, P =0.44; for time trade-off, Spearman r = -0.13, P = 0.54. Among the most numerate women, the authors observed a fair to moderate positive correlation with both standard gamble (Spearman r = 0.22, P = 0.19) and time trade-off (Spearman r = 0.50, P = 0.002). In contrast, using the visual analog scale, the authors observed a substantial correlation in the expected direction at all levels of numeracy (Spearman r =0.82, 0.50, and 0.60 for women answering 0-1, 2, and 3 numeracy questions, respectively; all P s ≤ 0.003). With regard to the imagined health states, the most feared disease had the lowest utility for 35% of the women with the lowest numeracy compared to 76% of the women with the highest numeracy (P = 0.03). Conclusions. The validity of standard utility assessments is related to the subject’s facility with numbers. Limited numeracy may be an important barrier to meaningfully assessing patients’ values using the standard gamble and time trade-off techniques.

Purpose The purpose of this systematic review was to address the treatment of multiligament knee injuries, specifically ( 1 ) surgical versus nonoperative treatment, ( 2 ) repair versus reconstruction of injured ligamentous structures, and ( 3 ) early versus late surgery of damaged ligaments. Methods Two independent reviewers performed a search on PubMed from 1966 to August 2007 using the terms “knee dislocation,” “multiple ligament–injured knee,” and “multiligament knee reconstruction.” Study inclusion criteria were ( 1 ) levels I to IV evidence, ( 2 ) “multiligament” defined as disruption of at least 2 of the 4 major knee ligaments, ( 3 ) measures of functional and clinical outcome, and ( 4 ) minimum of 12 months' follow‐up, with a mean of at least 24 months. Results Four studies compared surgical treatment with nonoperative treatment. There was a higher percentage of excellent/good International Knee Documentation Committee (IKDC) scores (58% v 20%) in surgically treated patients, as well as higher rates for return to work (72% v 52%) and return to full sport (29% v 10%). Two studies compared repair with reconstruction of damaged structures, with similar mean Lysholm scores (88 v 87) and excellent/good IKDC scores (51% v 48%). However, repair of the posterolateral corner had a higher failure rate (37% v 9%). Similarly, repair of the cruciates yielded decreased stability and range of motion and a lower return to preinjury activity levels (0% v 33%). There were 5 studies comparing early surgery (≤3 weeks) with late surgery. Early treatment resulted in higher mean Lysholm scores (90 v 82) and a higher percentage of excellent/good IKDC scores (47% v 31%), as well as higher sports activity scores (89 v 69) on the Knee Outcome Survey. Conclusions Our review suggests that early operative treatment of the multiligament‐injured knee yields improved functional and clinical outcomes compared with nonoperative management or delayed surgery. Repair of the posterolateral corner may yield higher revision rates compared with reconstruction.

Toxic shock syndrome (TSS) is an acute, serious systemic illness caused by bacterial superantigens. Nonavailability of a suitable animal model until recently has hampered an in-depth understanding of the pathogenesis of TSS. In the current study, we characterized the early molecular events underlying TSS using our HLA-DR3 transgenic mouse model. Gene expression profiling using DNA microarrays identified a rapid and significant upregulation of several pro- as well as anti-inflammatory mediators, many of which have never been previously described in TSS. In vivo administration of staphylococcal enterotoxin B (SEB) led to an increase in the expression of Th0- (IL-2, 240-fold); Th1- (IFN-γ, 360-fold; IL-12, 8-fold); Th2- (IL-4, 53-fold; IL-5, 4-fold) as well as Th17-type cytokines (IL-21, 19-fold; IL-17, 5-fold). The immunoregulatory cytokines (IL-6, 700-fold; IL-10, 18-fold); CC chemokines (such as CCL 2, 11, 3, 24, 17, 12, 7), CXC chemokines (such as CXCL 1, 2, 5, 11, 10, 19); and several proteases (matrix metalloproteinases 13, 8, 3, and 9) were also upregulated. Serum levels of several of these cytokines/chemokines were also significantly elevated. Pathway analyses revealed significant modulation in a variety of biochemical and cellular functions, providing molecular insights into the pathogenesis of TSS. Administration of bortezomib, a clinically approved proteasome inhibitor capable of blocking NF-κB pathway, was able to significantly modulate the expression of a variety of genes induced by SEB. Thus, our study showed that TSS is a complex process and emphasized the potential of use of bortezomib in the therapy of superantigen-induced TSS.