Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells

Lysine ?-acetylation is a post-translational modification that alters the biochemical properties of many proteins. The reaction is catalyzed by histone/protein acetyltransferases (HATs), and is reversed by histone/protein deacetylases (HDACs). As a result, HATs and HDACs constitute an important, though little recognized, set of proteins that control the functions of T-regulatory (Treg) cells. Targeting certain HDACs, especially HDAC6, HDAC9, and Sirtuin-1 (Sirt1), can augment Treg suppressive potency by several distinct and potentially additive mechanisms. These involve promoting Forkhead box p3 (Foxp3) gene expression and preserving Foxp3 lysine ?-acetylation, which infers resistance to ubiquitination and proteasomal degradation, and increases DNA binding. Moreover, depleting certain HDAC can enhance the heat shock response, which increases the tenacity of Treg to survive under stress, and helps preserve a suppressive phenotype. As a result, HDAC inhibitor therapy can be used to enhance Treg functions in vivo and have beneficial effects on allograft survival and autoimmune diseases.     

Humoral immune responses in humanized BLT mice immunized with West Nile virus and HIV-1 envelope proteins are largely mediated via human CD5+ B cells

BLT mice, constructed by surgical implantation of human fetal thymus-liver tissues and intravenous delivery of autologous CD34+ haematopoietic stem cells into adult non-obese diabetic/severe combined immunodeficiency mice, were evaluated for vaccine-induced humoral immune responses. Following engraftment, these mice developed a human lymphoid system; however, the majority of the peripheral human B lymphocytes displayed an immature phenotype as evidenced by surface CD10 expression. Over 50% of the human B cells in the periphery but not in the bone marrow also expressed the CD5 antigen, which is found only infrequently on mature follicular B cells in humans. A single intramuscular immunization with recombinant viral envelope antigens, e.g., HIVgp140 and West Nile Virus envelope proteins, together with the immune stimulatory KLK/ODN1a composition) [corrected] adjuvant resulted in seroconversion characterized by antigen-specific human antibodies predominantly of the IgM isotype. However, repeated booster immunizations did not induce secondary immune responses as evidenced by the lack of class switching and specific IgM levels remaining relatively unchanged. Interestingly, the peripheral CD19+ CD5+ but not the CD19+ CD5- human B lymphocytes displayed a late developing CD27+ IgM+ memory phenotype, suggesting that the CD5+ B-cell subset, previously implicated in 'natural antibody' production, may play a role in the vaccine-induced antibody response. Furthermore, human T lymphocytes from these mice demonstrated suboptimal proliferative responses and loss of co-stimulatory surface proteins ex vivo that could be partially reversed with human interleukin-2 and interleukin-7. Therefore, vaccine-induced immune responses in BLT mice resemble a T-cell-independent pathway that can potentially be modulated in vivo by the exogenous delivery of human cytokines/growth factors.     

Development and Validation of a Computational Model for Investigation of Wrist Biomechanics

In this study, a computational model of the wrist joint complex was developed and validated for investigating the biomechanical function of the joint in clinically representative scenarios. Joint behavior and kinematics were dictated only by osteoarticular contact, ligamentous constraints, and muscle loading. Three-dimensional articular surfaces of each bone were generated from CT images, while ligaments and muscles were modeled as linear springs and constant-magnitude force vectors, respectively. Commercially available rigid body dynamics software was to both build the model and simulate joint function. Range of motion model predictions were compared to a cadaveric study analyzing the effects of scaphoid distal pole excision and triquetral excision after radioscapholunate (RSL) fusion for validation. The computational model was able to accurately predict flexion, extension, radial deviation, and ulnar deviation motions in four states: normal (intact), RSL fusion, RSL fusion with the scaphoid distal pole excised, and RSL fusion with both the scaphoid distal pole and triquetrum excised. The model was also able to calculate other parameters of interest that are not easily obtainable experimentally, such as midcarpal forces. This model and modeling approach are anticipated to have value as a predictive clinical tool including effect of injuries or anatomical variations and initial outcome of surgical procedures for patient specific planning and custom implant design.     

Microarrayed recombinant allergens for diagnostic testing

The development of protein microarray-based immunoassays and the availability of recombinant allergens have, to a significant extent, emerged together over the past decade. Their long-anticipated wider application to allergy diagnosis has recently begun to accelerate. This review discusses some of the strengths and weaknesses of molecularly defined allergy testing and the microarray platform. Several recent applications of microarray assays to allergy testing are also summarized. Promising findings, particularly in the context of food and latex allergy, point to the potential for greater resolution between clinical reactivity and asymptomatic sensitization with this platform.     

Bilateral Total Joint Arthroplasty : The Early Results from the New Zealand National Joint Registry

This study evaluated the mortality rate, major complications, and early outcomes of single anesthetic bilateral total hip and knee arthroplasty compared with unilateral and staged procedures. A total of 37 828 total hip and knee arthroplasties were evaluated with 6-month Oxford 12 scores. Major complications and mortality rates were recorded. Analysis of variance tables were used for statistical analysis. The single anesthetic bilateral group were significantly younger (P < .001), with their age-adjusted postoperative Oxford 12 scores significantly better (P < .001) than the other 2 groups. The surgeons involved, in general, performed more than 25 total knee and hip arthroplasties per year. There was 1 death within the first 6 months occurring in the staged bilateral group and was unrelated to the surgery. The complication rate as reported by patients was low in all groups, and there was no significant difference. The results show that, in selected patients, single anesthetic bilateral total knee or hip arthroplasty is a safe, low-risk procedure with very good patient-generated outcome scores at 6 months when performed by an experienced surgeon.