T cell vaccination induces T cell receptor Vbeta-specific Qa-1-restricted regulatory CD8(+) T cells

Vaccination of mice with activated autoantigen-reactive CD4(+) T cells (T cell vaccination, TCV) has been shown to induce protection from the subsequent induction of a variety of experimental autoimmune diseases, including experimental allergic encephalomyelitis (EAE). Although the mechanisms involved in TCV-mediated protection are not completely known, there is some evidence that TCV induces CD8(+) regulatory T cells that are specific for pathogenic CD4(+) T cells. Previously, we demonstrated that, after superantigen administration in vivo, CD8(+) T cells emerge that preferentially lyse and regulate activated autologous CD4(+) T cells in a T cell receptor (TCR) Vbeta-specific manner. This TCR Vbeta-specific regulation is not observed in beta2-microglobulin-deficient mice and is inhibited, in vitro, by antibody to Qa-1. We now show that similar Vbeta8-specific Qa-1-restricted CD8(+) T cells are also induced by TCV with activated CD4(+) Vbeta8(+) T cells. These CD8(+) T cells specifically lyse murine or human transfectants coexpressing Qa-1 and murine TCR Vbeta8. Further, CD8(+) T cell hybridoma clones generated from B10.PL mice vaccinated with a myelin basic protein-specific CD4(+)Vbeta8(+) T cell clone specifically recognize other CD4(+) T cells and T cell tumors that express Vbeta8 and the syngeneic Qa-1(a) but not the allogeneic Qa-1(b) molecule. Thus, Vbeta-specific Qa-1-restricted CD8(+) T cells are induced by activated CD4(+) T cells. We suggest that these CD8(+) T cells may function to specifically regulate activated CD4(+) T cells during immune responses.     

Load relaxation and forces with activity in Hoffman external fixators: a clinical study in patients with Colles'' fractures

OBJECTIVE: To determine postoperative left ventricular mechanics following the arterial switch operation (ASO). DESIGN: Prospective, cohort study. SETTING: Pediatric cardiac recovery room. PATIENTS: Nine neonates with transposition of the great arteries undergoing the ASO within the first week of life. INTERVENTIONS: Noninvasive ejection phase indices: shortening fraction (% SF), corrected mean velocity of circumferential shortening (VCFc), and wall stress analysis were used to calculate indices of specific left ventricular systolic mechanics. The % SF and VCFc were respectively adjusted for left ventricular afterload (end-systolic wall stress) to derive an index for left ventricular performance (stress-shortening relation) and contractility (stress-velocity relation). Left ventricular preload was assessed as the variance between the performance and contractility indices. All indexed data are reported as mean Zscore (i.e., number of standard deviations from the mean of a normal age- and body surface area-adjusted population). A mean Zscore of < -2 or > 2 was regarded as a significant variance from normal. Transmitral Doppler flow patterns were recorded at each postoperative interval and analyzed for isovolumic relaxation time (IVRT) as an index of left ventricular compliance. MEASUREMENTS AND MAIN RESULTS: All nine patients did well clinically and completed the study. Noninvasive parameters were measured at mean intervals of 3 (early), 23 (intermediate), and 48 hrs (late postoperative) relative to the time of arrival in the cardiac recovery room. Postoperative left ventricular performance was decreased throughout the early (-4.0 +/- 1.5 SD), intermediate (-4.1 +/- 2.8), and late (-3.5 +/- 1.3) phases of recovery. In contrast, the overall left ventricular contractility remained normal throughout the three postoperative intervals (0.2 +/- 1.8, -1.2 +/- 1.9, and -1.0 +/- 1.6, respectively), although three of the nine patients had a diminished stress-velocity index during the study period. Left ventricular afterload was within normal range in the early (0.1 +/- 1.7) and intermediate (1.5 +/- 1.9) phases of recovery, but increased in the late postoperative period (2.5 +/- 2.9). Left ventricular preload was decreased significantly throughout the early (-4.2 +/- 1.3), intermediate (-2.8 +/- 2.0), and late (-2.5 +/- 1.0) postoperative phases. All nine patients demonstrated decreased preload during the recovery period. IVRT was decreased in the post-ASO patients at each phase of recovery compared with normal data (p < .001). CONCLUSIONS: Left ventricular performance is impaired in infants during the period immediately following the ASO. A persistent preload deficit closely matches the pattern of impaired ventricular performance. Decreased IVRT points to impaired ventricular compliance as the etiology of the altered preload. In contrast, left ventricular contractility remains normal in the majority of post-ASO patients. Decreased contractility may account for impaired ventricular performance in selected cases.     

A Mathematical Model of the Vagus-Heart Period System in the Cat

The dynamic relation between changes in heart period and changes in the frequency of stimulation applied to the nerves involved in slowing the heart (vagus nerves) in chloralosed vagotomized cats pretreated with propranolol was investigated in ten cats using time-domain techniques. The strength of the stimuli was such that a sinus rhythm was always maintained. The typical response of heart period to step changes in the frequency of stimulation (range 4-50 Hz) was found to be an increase in heart period to a steady value preceded by an overshoot, and followed, after the stimulus was removed, by an undershoot (postvagal tachycardia). The observed response was accurately described by a dynamic model consisting of a third-order nonlinear system with time delay. The postvagal tachycardia was accounted for by including in the model a negative feedback loop; a portion of the overshoot was accounted for by the feedback loop and the remainder by including in the model a negative coefficient that varied as a negative exponential function of frequency. For small variations in the frequency of stimulation, it was shown in agreement with previous results, that the model could be approximated by a first-order system with time delay. In addition, it was found that provided a sinus rhythm was maintained, the steady-state value of heart period during vagal stimulation was neither a hyperbolic nor a logarithmic function of frequency of stimulation as suggested by previous investigators, but rather exhibited a maximum in the neighborhood of the middle of the frequency range studied.     

Kappa chain monoallelic demethylation and the establishment of allelic exclusion

Allelic exclusion in kappa light-chain synthesis is thought to result from a feedback mechanism by which the expression of a functional kappa light chain on the surface of the B cell leads to an intracellular signal that down-regulates the V(D)J recombinase, thus precluding rearrangement of the other allele. Whereas such a feedback mechanism clearly plays a role in the maintenance of allelic exclusion, here we provide evidence suggesting that the initial establishment of allelic exclusion involves differential availability of the two kappa alleles for rearrangement. Analysis of kappa+ B-cell populations and of individual kappa+ B cells that have rearranged only one allele demonstrates that in these cells, critical sites on the rearranged allele are unmethylated, whereas the nonrearranged allele remains methylated. This pattern is apparently generated by demethylation that is initiated at the small pre-B cell stage, on a single allele, in a process that occurs prior to rearrangement and requires the presence in cis of both the intronic and 3' kappa enhancers. Taken together with data demonstrating that undermethylation is required for rearrangement, these results indicate that demethylation may actually underly the process of allelic exclusion by directing the initial choice of a single kappa allele for rearrangement.     

Speaking with One Voice: Risk Communication Lessons from the US Anthrax Attacks1

It is often said that in times of crises experts, officials, and organizations should speak with one voice. But this homily has not been subjected to either conceptual or empirical scrutiny. We begin those tasks in this paper. To pursue our analysis, we use statements from the popular and scholarly presses; we also use our interviews with local officials in New Jersey, USA, who had to respond to the anthrax attacks in the fall of 2001. We outline some of the meanings of the admonition to “speak with one voice” and discuss the rhetorical significance of the advice. Our argument is that it may be wise to speak with one voice, but this can not be taken for granted. Difference audiences may well need different messages or different kinds of messages. Speaking with multiple voices is often the most effective way to advance meaningful communication.     

Three-dimensional motion tracking for high-resolution optical microscopy, in vivo

When conducting optical imaging experiments, in vivo, the signal to noise ratio and effective spatial and temporal resolution is fundamentally limited by physiological motion of the tissue. A three-dimensional (3D) motion tracking scheme, using a multiphoton excitation microscope with a resonant galvanometer, (512 × 512 pixels at 33 frames s(-1)) is described to overcome physiological motion, in vivo. The use of commercially available graphical processing units permitted the rapid 3D cross-correlation of sequential volumes to detect displacements and adjust tissue position to track motions in near real-time. Motion phantom tests maintained micron resolution with displacement velocities of up to 200 μm min(-1), well within the drift observed in many biological tissues under physiologically relevant conditions. In vivo experiments on mouse skeletal muscle using the capillary vasculature with luminal dye as a displacement reference revealed an effective and robust method of tracking tissue motion to enable (1) signal averaging over time without compromising resolution, and (2) tracking of cellular regions during a physiological perturbation.     

Security for the Rest of Us: An Industry Perspective on the Secure-Software Challenge

While security was once a specialty of interest to only a few programmers, it's now a critical topic for almost all software engineers, project managers, and decision makers. Getting security right is hard because an attacker—having virtually unlimited time—needs to find only one vulnerability in a system to succeed, whereas the defender—constrained in time—must ensure that the system has no weak points. This article provides an introduction into the special issue, which focuses on creating and maintaining secure software by the wide range of developers who constitute the software industry—many who work in domains where cost (both production and maintenance) and time-to-market are the main driving factors. This article is part of a special issue on Security for the Rest of Us.