T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via TLRs. In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations against the cancer/testis Ag NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod preconditioned sites followed by additional topical applications of imiquimod. The regimen was very well tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod’s in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs, NK cells, and, to a lesser extent, plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist used as a vaccine adjuvant in cancer patients. Imiquimod’s adjuvant effects require further evaluation and likely need optimization of parameters such as formulation, dose, and timing relative to Ag exposure for maximal immunogenicity.

Prior exposure to social disruption stress (SDR) exacerbates both the acute and chronic phase of Theiler's murine encephalomyelitis virus infection (TMEV; [Johnson, R.R., Storts, R., Welsh, T.H., Jr., Welsh, C.J., Meagher, M.W., 2004. Social stress alters the severity of acute Theiler's virus infection. J. Neuroimmunol. 148, 74--85; Johnson, R.R., Prentice, T.W., Bridegam, P., Young, C.R., Steelman, A.J., Welsh, T.H., Welsh, C.J.R., Meagher, M.W., 2006. Social stress alters the severity and onset of the chronic phase of Theiler's virus infection. J. Neuroimmunol. 175, 39--51]). However, the neuroimmune mechanism(s) mediating this effect have not been determined. The present study examined whether stress-induced increases in the proinflammatory cytokine interleukin-6 (IL-6) contributes to the adverse effects of SDR on acute TMEV infection. Experiment 1 demonstrated that SDR increases central and peripheral levels of IL-6 and that this effect is reversed by intracerebral ventricular infusion of neutralizing antibody to IL-6 prior to each of six SDR sessions. Although SDR reduced the sensitivity of spleen cells to the anti-inflammatory effects of corticosterone, the neutralizing antibody to IL-6 did not alter this effect. To investigate whether stress-induced increases in IL-6 contribute to the exacerbation of acute TMEV infection, Experiment 2 examined whether intracerebral administration of neutralizing antibody to IL-6 during SDR would prevent the subsequent exacerbation of acute TMEV infection. Experiment 3 then replaced the social stress with intracerebral infusion of IL-6 to assess sufficiency. As expected, prior exposure to SDR subsequently increased infection-related sickness behaviors, motor impairment, CNS viral titers, and CNS inflammation. These deleterious effects of SDR were either prevented or significantly attenuated by intracerebral infusion of neutralizing antibody to IL-6 during the stress exposure period. However, infusion of IL-6 alone did not mimic the adverse effects of SDR. We conclude that IL-6 is necessary but not sufficient to exacerbate acute TMEV infection.

Abstract. Objective: Fractures around the wrist are common in pediatric patients presenting to the emergency department (ED). This pilot study was aimed at identifying clinical variables that are most likely to be associated with a fracture. Methods: This was a prospective blinded case series of patients 3-18 years of age presenting with an acute (<3 days) wrist injury, without obvious deformity. A team of five investigators blinded to the eventual radiographic findings evaluated patients. Physical examination variables included range of motion (ROM), site of maximal tenderness, and functional deficit. The latter was determined objectively, by recording any difference in grip strength between the injured and noninjured hands. Diagnostic radiographs were obtained for all patients. Univariate analysis using Wilks' log likelihood ratio test was performed to identify clinical variables associated with confirmed wrist fractures. Sample size was determined based on the ability to detect a difference of 15 degrees in the ROM variables, 20% point differences in grip strength, and 30% proportion differences in categorical variables using a power of 0.8 and a two-tailed ␣ of 0.05. Results: The ROMs were not significantly different between the fracture (Fx) and nonfracture (NFx) group. There was significant change in the grip strength between the Fx and NFx groups (t = 3.3, p = 0.0019). Tenderness over the distal radius was also associated with a greater likelihood of a fracture (G 2 = 5.0, p = 0.02). Sensitivity of clinical prediction was found to be 79%, and specificity was 63%. The false-negative rate was 0.21 and the false-positive rate was 0.37, while the positive predictive value was found to be 0.68 and negative predictive value 0.75. Conclusions: Distal radius point tenderness and a 20% or more decrease in grip strength were predictive of fractures.

Background Accurate assessment of cardiac output is critical to the diagnosis and management of various cardiac disease states; however, clinical standards of direct Fick and thermodilution are invasive. Noninvasive alternatives, such as closed‐circuit acetylene (C 2 H 2 ) rebreathing, warrant validation. Methods and Results We analyzed 10 clinical studies and all available cardiopulmonary stress tests performed in our laboratory that included a rebreathing method and direct Fick or thermodilution. Studies included healthy individuals and patients with clinical disease. Simultaneous cardiac output measurements were obtained under normovolemic, hypovolemic, and hypervolemic conditions, along with submaximal and maximal exercise. A total of 3198 measurements in 519 patients were analyzed (mean age, 59 years; 48% women). The C 2 H 2 method was more precise than thermodilution in healthy individuals with half the typical error (TE; 0.34 L/min [ r =0.92] and coefficient of variation, 7.2%) versus thermodilution (TE=0.67 [ r =0.70] and coefficient of variation, 13.2%). In healthy individuals during supine rest and upright exercise, C 2 H 2 correlated well with thermodilution (supine: r =0.84, TE=1.02; exercise: r =0.82, TE=2.36). In patients with clinical disease during supine rest, C 2 H 2 correlated with thermodilution ( r =0.85, TE=1.43). C 2 H 2 was similar to thermodilution and nitrous oxide (N 2 O) rebreathing technique compared with Fick in healthy adults (C 2 H 2 rest: r =0.85, TE=0.84; C 2 H 2 exercise: r =0.87, TE=2.39; thermodilution rest: r =0.72, TE=1.11; thermodilution exercise: r =0.73, TE=2.87; N 2 O rest: r =0.82, TE=0.94; N 2 O exercise: r =0.84, TE=2.18). The accuracy of the C 2 H 2 and N 2 O methods was excellent ( r =0.99, TE=0.58). Conclusions The C 2 H 2 rebreathing method is more precise than, and as accurate as, the thermodilution method in a variety of patients, with accuracy similar to an N 2 O rebreathing method approved by the US Food and Drug Administration.