Direct to Implant Reconstruction.

Implant-based breast reconstruction remains the most commonly performed type of restorative surgery after mastectomy for breast cancer. Placement of a tissue expander at the time of mastectomy allows gradual skin envelope expansion but requires additional surgery and time to completion of a patient's reconstruction. Direct-to-implant reconstruction provides a one-stage, final implant insertion, thereby bypassing the need for serial tissue expansion. With proper patient selection, successful preservation of the breast skin envelope, and accurate implant size and placement, direct-to-implant reconstruction has a very high rate of success and patient satisfaction.

Ear lobule reconstruction using nasal septal cartilage.

Surgical reconstruction of an earlobe requires adequate support without sacrificing the delicacy necessary for an attractive result. A two-stage ear lobule reconstruction using a mastoid skin pocket and cartilage from the nasal septum was performed in six patients. The earlobe aesthetics were acceptable and allowed ear piercing. There were no major complications, including no loss of flap, graft extrusion, septal perforation, or infection. Range of follow-up was 1 to 6 years, with an average of 3 years. No revisions have been performed. A two-stage technique for ear lobule reconstruction is described using septal cartilage to preserve shape and definition that has the additional advantage of minimal morbidity.

Best face forward: Virtual modeling and custom device fabrication to optimize craniofacial vascularized composite allotransplantation.

Craniofacial vascularized composite allotransplantation is especially challenging when bony components are required. Matching the complex three-dimensional anatomy of the donor and recipient craniofacial skeletons to optimize bony contact and dental occlusion is a time-consuming step in the operating room. Currently, few tools exist to facilitate this process. The authors describe the development of a virtual planning protocol and patient-specific device design to efficiently match the donor and recipient skeletal elements in craniofacial vascularized composite allotransplantation. The protocol was validated in a cadaveric transplant. This innovative planning method allows a "snap-fit" reconstruction using custom surgical guides while maintaining facial height and width and functional occlusion. Postoperative overlay technology in the virtual environment provides an objective outcome analysis.

The adapter protein SLP-76 mediates "outside-in" integrin signaling and function in T cells.

The adapter protein SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) is an essential mediator of signaling from the T-cell antigen receptor (TCR). We report here that SLP-76 also mediates signaling downstream of integrins in T cells and that SLP-76-deficient T cells fail to support adhesion to integrin ligands. In response to both TCR and integrin stimulation, SLP-76 relocalizes to surface microclusters that colocalize with phosphorylated signaling proteins. Disruption of SLP-76 recruitment to the protein named LAT (linker for activation of T cells) inhibits SLP-76 clustering downstream of the TCR but not downstream of integrins. Conversely, an SLP-76 mutant unable to bind ADAP (adhesion and degranulation-promoting adapter protein) forms clusters following TCR but not integrin engagement and fails to support T-cell adhesion to integrin ligands. These findings demonstrate that SLP-76 relocalizes to integrin-initiated signaling complexes by a mechanism different from that employed during TCR signaling and that SLP-76 relocalization corresponds to SLP-76-dependent integrin function in T cells.

Selection of CD4+CD25+ regulatory T cells by self-peptides.

Regulatory T cells have been shown to prevent the development of autoimmune disease, and can modulate immune responses during infections or following tissue transplantation. Recently, the processes by which CD4+CD25+ regulatory T cells are produced during immune repertoire formation have begun to be elucidated. This review focuses on the role of self-peptides in mediating CD4+CD25+ regulatory T cell selection in the thymus. How self-peptides continue to have an important influence on the accumulation of CD4+CD25+ regulatory T cells in the periphery is also discussed.

Coupling of the TCR to integrin activation by Slap-130/Fyb.

SLAP-130/Fyb (SLP-76-associated phosphoprotein or Fyn-binding protein; also known as Fyb/Slap) is a hematopoietic-specific adapter, which associates with and modulates function of SH2-containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76). T cells from mice lacking SLAP-130/Fyb show markedly impaired proliferation following CD3 engagement. In addition, the T cell receptor (TCR) in SLAP-130/Fyb mutant cells fails to enhance integrin-dependent adhesion. Although TCR-induced actin polymerization is normal, TCR-stimulated clustering of the integrin LFA-1 is defective in SLAP-130/Fyb-deficient cells. These data indicate that SLAP-130/Fyb is important for coupling TCR-mediated actin cytoskeletal rearrangement with activation of integrin function, and for T cells to respond fully to activating signals.

Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells.

CD4(+)25(+) T cells are a unique population of immunoregulatory T cells which are critical for the prevention of autoimmunity. To address the thymic selection of these cells we have used two models of attenuated thymic deletion. In K14-A(beta)(b) mice, major histocompatibility complex (MHC) class II I-A(b) expression is limited to thymic cortical epithelium and deletion by hematopoietic antigen-presenting cells does not occur. In H2-DMalpha-deficient mice, MHC class II molecules contain a limited array of self-peptides resulting in inefficient clonal deletion. We find that CD4(+)25(+) T cells are present in the thymus and periphery of K14-A(beta)(b) and H2-DMalpha-deficient mice and, like their wild-type counterparts, suppress the proliferation of cocultured CD4(+)25(-) effector T cells. In contrast, CD4(+)25(+) T cells from MHC class II-deficient mice do not suppress responder CD4(+) T cells in vitro or in vivo. Thus, development of regulatory CD4(+)25(+) T cells is dependent on MHC class II-positive thymic cortical epithelium. Furthermore, analysis of the specificities of CD4(+)25(+) T cells in K14-A(beta)(b) and H2-DMalpha-deficient mice suggests that a subset of CD4(+)25(+) T cells is subject to negative selection on hematopoietic antigen-presenting cells.

CD4+ T cells that evade deletion by a self peptide display Th1-biased differentiation.

We have examined factors governing the differentiation of autoreactive CD4+ T cells that have evaded deletion by a self peptide. Two lineages of transgenic mice (HA12 and HA104) expressing the influenza virus hemagglutinin (HA) were mated with TS1 mice that express a clonotypic T cell receptor (TCR) specific for the I-Ed-restricted determinant site 1 (S1) of HA. Thymocytes expressing high levels of the clonotypic TCR were deleted in both TS1xHA transgenic lineages. However, through allelic inclusion, thymocytes expressing low levels of the clonotypic TCR and high levels of endogenous TCR alpha-chains evaded deletion in TS1xHA12 and TS1xHA104 mice to graded degrees. When stimulated with S1 peptide in vitro, the non-autoreactive TS1 T cells were biased toward differentiation into Th2 effectors. By contrast, CD4+ T cells that evaded deletion in TS1xHA12 and TS1xHA104 mice were progressively biased toward Th1-like differentiation. Moreover, the effector cells from TS1xHA12 and TS1xHA104 mice secreted higher levels of IFN-gamma , on a per cell basis, than were secreted by their non-autoreactive counterparts. Thus, CD4+ T cells that evade deletion by a self peptide can exhibit an intrinsic bias toward differentiation into Th1 effector cells.

Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.

Despite accumulating evidence that regulatory T cells play a crucial role in preventing autoimmunity, the processes underlying their generation during immune repertoire formation are unknown. We show here that interactions with a single self-peptide can induce thymocytes that bear an autoreactive T cell receptor (TCR) to undergo selection to become CD4+CD25+ regulatory T cells. Selection of CD4+CD25+ thymocytes appears to require a TCR with high affinity for a self peptide because thymocytes that bear TCRs with low affinity do not undergo selection into this pathway. Our findings indicate that specificity for self-peptides directs the selection of CD4+CD25+ regulatory thymocytes by a process that is distinct from positive selection and deletion.

Differential requirement for SLP-76 domains in T cell development and function.

The hematopoietic cell-specific adaptor protein, SLP-76, is critical for T cell development and mature T cell receptor (TCR) signaling; however, the structural requirements of SLP-76 for mediating thymopoiesis and mature T cell function remain largely unknown. In this study, transgenic mice were generated to examine the requirements for specific domains of SLP-76 in thymocytes and peripheral T cells in vivo. Examination of mice expressing various mutants of SLP-76 on the null background demonstrates a differential requirement for specific domains of SLP-76 in thymocytes and T cells and provides new insight into the molecular mechanisms underlying SLP-76 function.

Graded deletion and virus-induced activation of autoreactive CD4+ T cells.

We have examined factors governing the negative selection of autoreactive CD4(+) T cells in transgenic mice expressing low (HA12 mice) vs. high (HA104 mice) amounts of the influenza virus hemagglutinin (HA). When mated with TS1 mice that express a transgenic TCR specific for the I-Ed-restricted determinant site 1 (S1) of HA, thymocytes expressing high levels of the clonotypic TCR were deleted in both HA-transgenic lineages. However, through allelic inclusion, thymocytes with lower levels of the clonotypic TCR evaded deletion in TS1 x HA12 and TS1 x HA104 mice to graded degrees. Moreover, in both lineages, peripheral CD4(+) T cells could be activated by the S1 peptide in vitro, and by influenza virus in vivo. These findings indicate that allelic inclusion can allow autoreactive CD4(+) thymocytes to evade thymic deletion to varying extents reflecting variation in the expression of the self peptide, and can provide a basis for the activation of autoreactive peripheral T cells by viruses bearing homologues of self peptides ("molecular mimicry").

Anergy and suppression regulate CD4(+) T cell responses to a self peptide.

To examine the role of cognate peptide in establishing CD4(+) T cell tolerance, we have mated transgenic mice that express the major I-E(d)-restricted determinant (S1) from the influenza virus PR8 hemagglutinin (HA28 mice) with mice expressing a S1-specific T cell receptor (TS1 mice). Surprisingly, S1-specific CD4(+) T cells were not substantially deleted in TS1xHA28 mice; indeed, lymph node cells expressing the S1-specific TCR were as abundant in TS1xHA28 mice as in TS1 mice. The S1-specific T cells in TS1xHA28 mice were, however, impaired in their ability to respond to S1 peptide both in vitro and in vivo, and contained two distinct populations. Approximately half expressed a unique cell surface phenotype (CD25(hi)/CD45RB(int)) and had been anergized by the neo-self S1 peptide. The remainder responded normally to the S1 peptide if purified away from the anergic T cells, but their proliferation was suppressed when the anergic T cells were also present in unfractionated lymphnode cells or in mixed cultures. These findings establish that anergy and suppression are coordinated mechanisms by which autoreactive CD4(+) T cells are regulated and that anergic/suppressor CD4(+) T cells can develop in response to self peptides.

The relationships of cognitive coping and pain control beliefs to pain and adjustment among African-American and Caucasian women with rheumatoid arthritis.

OBJECTIVE: Ethnic groups may experience or report pain differently; thus, we compared ethnic differences on pain coping strategies and control beliefs, and the relationships of these variables to health status, among women with rheumatoid arthritis (RA). METHODS: Using a sample of 100 women (48 African-American, 52 Caucasian), we related pain coping strategies and control beliefs to pain severity, activity levels, and affective state, controlling for socioeconomics, behavioral impairment, and disease activity. RESULTS: Ethnic groups did not differ in pain severity or negative affect, but African-Americans were less physically active. African-Americans used more coping techniques involving diverting attention and praying/hoping; Caucasians used more coping techniques involving ignoring pain. The relationships of praying/hoping and reinterpreting pain to RA adjustment differed by ethnic group. In contrast, ignoring pain, coping statements, and stronger control beliefs predicted better health status, and diverting attention predicted more pain for all patients. CONCLUSION: There are ethnic differences in the use of coping strategies that should be acknowledged when helping RA patients cope with their disease, but control beliefs and several coping strategies predict pain and adjustment, regardless of ethnicity.