The Disabled Anesthesiologist.

A significant number of anesthesiologists will experience a disabling illness or injury during their careers. In addition to ethical obligations to patients, physicians have ethical obligations to their colleagues: both to recognize and intervene when disabilities have the potential of interfering with patient care and to try, whenever it is possible and safe, to support colleagues with disabilities in pursuing a successful career. Encouraging and accommodating physicians with disabilities in their practice of medicine benefits patients, by including physicians who may better understand the challenges of the disabled, and also the profession, by promoting acceptance of diversity in practice.

Long-term Tolerance to Islet Transplantation via Targeted Reduction of beta cell-specific T cells.

Unlabelled: Type 1 diabetes (T1D) results from insulin insufficiency due to the loss or dysfunction of pancreatic beta cells following T cell-mediated autoimmune attack. Currently the only long-term therapy is daily exogenous insulin replacement. The ideal curative approach is the durable restoration of functional islets via transplantation.

Alloreactive memory CD4 T cells promote transplant rejection by engaging DCs to induce innate inflammation and CD8 T cell priming.

Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL-6, IL-1β, and IL-12, are also associated with rejection of organ transplants. However, the pathways of innate immune activation in allogeneic transplantation are unclear.

Prior viral infection primes cross-reactive CD8+ T cells that respond to mouse heart allografts.

Introduction: Significant evidence suggests a connection between transplant rejection and the presence of high levels of pre-existing memory T cells. Viral infection can elicit viral-specific memory T cells that cross-react with allo-MHC capable of driving allograft rejection in mice. Despite these advances, and despite their critical role in transplant rejection, a systematic study of allo-reactive memory T cells, their specificities, and the role of cross-reactivity with viral antigens has not been performed.

Subset-specific and temporal control of effector and memory CD4+ T cell survival.

Following their proliferative expansion and differentiation into effector cells like Th1, Tfh, and T central memory precursors (Tcmp), most effector CD4+ T cells die, while some survive and become memory cells. Here, we explored how Bcl-2 family members controlled the survival of CD4+ T cells during distinct phases of mouse acute LCMV infection. During expansion, we found that Th1 cells dominated the response, downregulated expression of Bcl-2, and did not require Bcl-2 for survival.

Pro-Inflammatory Alterations of Circulating Monocytes in Latent Tuberculosis Infection.

Background: Latent tuberculosis infection (LTBI) has been associated with increased cardiovascular risk. We investigated the activation and pro-inflammatory profile of monocytes in individuals with LTBI and their association with coronary artery disease (CAD).

Methods: Individuals 40-70 years old in Lima, Peru, underwent QuantiFERON-TB testing to define LTBI, completed a coronary computed tomography angiography to evaluate CAD, and provided blood for monocyte profiling using flow cytometry.

Restoring tolerance to β-cells in Type 1 diabetes: Current and emerging strategies.

Type 1 diabetes (T1D) results from insulin insufficiency due to islet death and dysfunction following T cell-mediated autoimmune attack. The technical feasibility of durable, functional autologous islet restoration is progressing such that it presents the most likely long-term cure for T1D but cannot succeed without the necessary counterpart of clinically effective therapeutic strategies that prevent grafted islets' destruction by pre-existing anti-islet T cells. While advances have been made in broad immunosuppression to lower off-target effects, the risk of opportunistic infections and cancers remains a concern, especially for well-managed T1D patients.

T cells instruct myeloid cells to produce inflammasome-independent IL-1β and cause autoimmunity.

The cytokine interleukin (IL)-1β is a key mediator of antimicrobial immunity as well as autoimmune inflammation. Production of IL-1β requires transcription by innate immune receptor signaling and maturational cleavage by inflammasomes. Whether this mechanism applies to IL-1β production seen in T cell-driven autoimmune diseases remains unclear.

Extending Remission and Reversing New-Onset Type 1 Diabetes by Targeted Ablation of Autoreactive T Cells.

Preserving endogenous insulin production is clinically advantageous and remains a vital unmet challenge in the treatment and reversal of type 1 diabetes. Although broad immunosuppression has had limited success in prolonging the so-called remission period, it comes at the cost of compromising beneficial immunity. Here, we used a novel strategy to specifically deplete the activated diabetogenic T cells that drive pathogenesis while preserving not only endogenous insulin production but also protective immunity.

Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases.

Antigen-activated lymphocytes undergo extraordinarily rapid cell division in the course of immune responses. We hypothesized that this unique aspect of lymphocyte biology leads to unusual genomic stress in recently antigen-activated lymphocytes and that targeted manipulation of DNA damage-response (DDR) signaling pathways would allow for selective therapeutic targeting of pathological T cells in disease contexts. Consistent with these hypotheses, we found that activated mouse and human T cells display a pronounced DDR in vitro and in vivo.

Dying to protect: cell death and the control of T-cell homeostasis.

T cells play a critical role in immune responses as they specifically recognize peptide/MHC complexes with their T-cell receptors and initiate adaptive immune responses. While T cells are critical for performing appropriate effector functions and maintaining immune memory, they also can cause autoimmunity or neoplasia if misdirected or dysregulated. Thus, T cells must be tightly regulated from their development onward.

The impaired and/or disabled anesthesiologist.

Purpose Of Review: Impairment and/or disability resulting from any of a number of etiologies will afflict a significant number of anesthesiologists at some point during their career. The impaired anesthesiologist can be difficult to identify and challenging to manage. Questions will arise as to if, how, and when colleagues, family members, or friends should intercede if significant impairment is suspected.

Control of the Environment in the Operating Room.

There is a direct relationship between the quality of the environment of a workplace and the productivity and efficiency of the work accomplished. Components such as temperature, humidity, ventilation, drafts, lighting, and noise each contribute to the quality of the overall environment and the sense of well-being of those who work there.The modern operating room is a unique workplace with specific, and frequently conflicting, environmental requirements for each of the inhabitants.

The aging anesthesiologist.

Purpose Of Review: The average age of anesthesiologists in the USA is increasing. Advancing age is accompanied by challenges and opportunities to the individual anesthesiologist and his/her colleagues. This article will discuss the science behind policies to assure continued competence among these aging physicians and safety for their patients.

Reversal of New-Onset Type 1 Diabetes With an Agonistic TLR4/MD-2 Monoclonal Antibody.

Type 1 diabetes (T1D) is currently an incurable disease, characterized by a silent prodromal phase followed by an acute clinical phase, reflecting progressive autoimmune destruction of insulin-producing pancreatic β-cells. Autoreactive T cells play a major role in β-cell destruction, but innate immune cell cytokines and costimulatory molecules critically affect T-cell functional status. We show that an agonistic monoclonal antibody to TLR4/MD-2 (TLR4-Ab) reverses new-onset diabetes in a high percentage of NOD mice.

Eliminating encephalitogenic T cells without undermining protective immunity.

The current clinical approach for treating autoimmune diseases is to broadly blunt immune responses as a means of preventing autoimmune pathology. Among the major side effects of this strategy are depressed beneficial immunity and increased rates of infections and tumors. Using the experimental autoimmune encephalomyelitis model for human multiple sclerosis, we report a novel alternative approach for purging autoreactive T cells that spares beneficial immunity.

Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is an inborn disorder of immune regulation caused by mutations affecting perforin-dependent cytotoxicity. Defects in this pathway impair negative feedback between cytotoxic lymphocytes and APCs, leading to prolonged and pathologic activation of T cells. Etoposide, a widely used chemotherapeutic drug that inhibits topoisomerase II, is the mainstay of treatment for HLH, although its therapeutic mechanism remains unknown.

United States anesthesiologists over 50: retirement decision making and workforce implications.

Background: Anesthesiology is among the medical specialties expected to have physician shortage. With little known about older anesthesiologists' work effort and retirement decision making, the American Society of Anesthesiologists participated in a 2006 national survey of physicians aged 50-79 yr.

Methods: Samples of anesthesiologists and other specialists completed a survey of work activities, professional satisfaction, self-defined health and financial status, retirement plans and perspectives, and demographics.

IFN-γ receptor deficiency prevents diabetes induction by diabetogenic CD4+, but not CD8+, T cells.

IFN-γ is generally believed to be important in the autoimmune pathogenesis of type 1 diabetes (T1D). However, the development of spontaneous β-cell autoimmunity is unaffected in NOD mice lacking expression of IFN-γ or the IFN-γ receptor (IFNγR), bringing into question the role IFN-γ has in T1D. In the current study, an adoptive transfer model was employed to define the contribution of IFN-γ in CD4(+) versus CD8(+) T cell-mediated β-cell autoimmunity.