Stephen J. Huddleston

De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR

Although regulatory CD4+CD25+ forkhead box p3+ (Foxp3+) T cells (Tregs) are generally thought to arise in the thymus as a separate lineage of CD4 T cells, they can also be induced de novo in the periphery. Peripheral development of Tregs from naïve T cells is favored by low‐intensity activation and absence of inflammation. We show here that absence of CD28 costimulation results in a modest decrease in activation of naïve, antigen‐specific CD4 T cells under noninflammatory conditions and benefits their initial Foxp3 induction. However, expression of Foxp3 following T cell activation without CD28 costimulation remains sensitive to the antigen dose. Furthermore, basal CD28 costimulation is critical for survival of the induced Foxp3+ CD4 T cells, and their accumulation is abrogated in the absence of CD28. In contrast, pharmacologic blockade of mammalian target of rapamycin enhances lasting induction of Tregs, irrespective of the initial antigen dose used to activate the antigen‐specific T cells. This finding may have important practical, clinical implication in development of tolerance protocols.

Risk of Adverse Outcomes Associated With Blood Transfusion After Cardiac Surgery Depends on the Amount of Transfusion

BACKGROUND Blood product transfusion has been known for immunosuppressive effects, and over-transfusion is linked with adverse outcomes. In cardiac surgery, the risk of non-transfusion can be poor postoperative oxygen delivery and hemorrhage. We hypothesized that infectious complications, organ dysfunction, and mortality result after a given threshold of blood product transfusion is exceeded. METHODS Retrospectively, a prospectively maintained institutional database was analyzed from April 1, 2004 through December 31, 2006. All patients undergoing coronary artery bypass and/or valve operations were evaluated for bivariate and multivariate associations of blood-product transfusion with postoperative complications and mortality. Additionally, risk factors associated with transfusion were assessed. Receiver operator characteristic (ROC) curves analyses were employed to determine transfusion thresholds associated with complications. RESULTS During the study period, 741 patients met inclusion criteria. Fifty-four percent received postoperative blood-product transfusions. Previous cardiac intervention, renal dysfunction, stroke, and immunosuppression were some of the risks associated with transfusion (P < 0.05). Specific complications independently (P < 0.05) associated with total blood product transfusion identified from the multivariate analysis were infectious, neurologic, organ dysfunction, cardiac, and death. From ROC curve analyses, 5.5 units of total blood product transfusion was the inflection point for infectious complications (sensitivity 73%, specificity 64%) and organ dysfunction (sensitivity 73%, specificity 64%). For mortality, the inflection point was a transfusion of 7.5 units of total blood-products (sensitivity 73%, specificity 71%). CONCLUSION Bloodless cardiac surgery is associated with a decreased morbidity and mortality. Limiting transfusion is advisable. Transfusion of less than 5.5 units of total blood-products may not have deleterious effects on outcomes.

Role of the Cysteine-rich Domain of the t-SNARE Component, SYNDET, in Membrane Binding and Subcellular Localization

Wild-type syndet is efficiently recruited at the plasma membrane in transfected AtT-20 cells. A deletion at the cysteine-rich domain abolishes palmitoylation, membrane binding, and plasma membrane distribution of syndet. Syndet, SNAP-25A, and SNAP-25B share four cysteine residues, of which three, Cys2, Cys4, and Cys5, are absolutely conserved in all three homologs. Mutations at any pair of cysteines within cysteines 2, 4, and 5 shift syndet from the cell surface into the cytoplasm. Thus, at least two cysteines within the conserved triplet are necessary for plasma membrane localization. Syndet C1S/C3S, with substitutions at the pair Cys1 and Cys3, distributes to the plasma membrane, a Golgi-like compartment, and the cytosol. We conclude that Cys1 and Cys3 are not absolutely necessary for membrane binding or plasma membrane localization. Our results show that the cysteine-rich domain of syndet plays a major role in its subcellular distribution.

Anterograde Intussusception Following Laparoscopic Roux-en-Y Gastric Bypass: A Case Report and Review of the Literature

Intussusception is a rare but worrisome cause of bowel obstruction in patients following Roux-en-Y gastric bypass. When intussusceptions is discovered in the general adult population, most often there is a “lead-point”; however, following bariatric procedures, this may not be true. There appears to be an increased incidence of this condition in open compared to laparoscopic Roux-en-Y gastric bypass procedures. Intussusception is often difficult to diagnose, especially in this population. Symptoms and signs can be very vague, and even computed tomography may not be accurate in diagnosing this condition. A high index of suspicion is required to successfully diagnose intussusception, and treatment often requires exploration and bowel resection. Herein, we report a case that follows several of these trends and suggests other possible contributions to intussusception. We also review other cases of intussusception after laparoscopic gastric bypass reported in the literature.

CD154+ Graft Antigen‐Specific CD4+ T Cells are Sufficient for Chronic Rejection of Minor Antigen Incompatible Heart Grafts

We used a defined model system to address the role of minor histocompatibility antigen‐specific CD4+ T cells in chronic rejection. The coronary arteries of vascularized heart grafts expressing the model antigen ovalbumin developed intimal hyperplasia in normal recipients and those lacking CD8+ T cells but not in those lacking CD4+ T cells. Furthermore, purified ovalbumin‐specific CD4+ T cells from T‐cell antigen receptor transgenic mice caused intimal hyperplasia in ovalbumin‐expressing heart grafts in lymphocyte‐deficient mice. The graft antigen‐specific CD4+ T cells only caused intimal hyperplasia when expressing CD154 and were found in the intima of the affected coronary arteries along with CD40+ cells, CD11c+ dendritic cells and CD11b+, Gr‐1+ monocytes. These results show that minor histocompatibility antigen‐specific CD4+ T cells are required to cause the classical vascular changes of chronic rejection. They are capable of doing so without contributions from other lymphocytes, and may cause intimal hyperplasia by using CD154 to stimulate other non‐lymphoid cells in the intima.

Pulmonary embolism associated with a vacuum-induced arm compartment syndrome: a setting for increased vigilance.

Vacuum injuries, otherwise known as negative pressure injuries, are unique mechanisms of traumatic injury. There are few reports of this mechanism in the literature and, although rare, familiarity with the presentation and management is essential to be life and limb saving. In addition, because of the severe inflammatory process, the potential is increased for life-threatening thrombosis and embolism. This is a case of a circumferential vacuum injury to the arm requiring fasciotomy complicated by development of pulmonary embolism. We describe treatment, postoperative management and a review of the relevant literature.