An anti-CD103 immunotoxin promotes long-term survival of pancreatic islet allografts.

Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103+ cells from wild type hosts. To circumvent this problem, we conjugated the nondepleting anti-CD103 monoclonal antibody, M290, to the toxin, saporin, to produce an immunotoxin (M290-SAP) that efficiently depletes CD103+ cells in vivo. Herein, we show that M290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in the blood, spleen, mesenteric lymph nodes and intestinal epithelium of treated mice. We further demonstrate that M290-SAP promotes indefinite islet allograft survival in a fully MHC mismatched mouse model. The prolonged islet allograft survival resulting from M290-SAP treatment was associated with multiple effects in the host immune system including not only depletion of CD103-expressing leukocytes, but also an increase in CD4+CD25+FoxP3+ T regulatory cells and a predominance of effector-memory CD8 T cells. Regardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in allograft rejection.

Long-term performance of prostheses in mitral valve replacement.

The long-term performance of prostheses in mitral valve replacement (MVR) is now available with representatives of current generation prostheses to 15 years. Mechanical prostheses have been implanted for 33 years and bioprostheses for 22 years. The predominant complication of mechanical prostheses is hemorrhage from anticoagulation and reoperation for late structural valve deterioration of bioprostheses. Mitral valve (MV) reconstruction, over MVR, is recommended whenever possible, especially with the advancement of atrial fibrillation ablation techniques. The current indications for MVR are those valvular lesions that are unlikely to be repaired by most surgeons or which long-term results are suboptimal with reconstruction. Reconstruction is more common for degenerative disease, replacement for rheumatic disease and variable for advanced ischemic and infective disease. The recommendations for MVR for mitral stenosis (MS) are moderate to severe MS with advanced functional status and severe pulmonary hypertension when percutaneous balloon valvotomy or mitral reconstruction is not feasible. MVR is recommended in non-ischemic severe mitral regurgitation (MR) and for non-reparable acute symptomatic MR, advanced symptomatic status, systolic dysfunction and/or ventricular dysfunction. The recommendations for MV surgery in ischemic MR are acute post-infarction MR with cardiogenic shock, unstable angina with persistent moderate-severe and severe MR and chronic, dilated ischemic cardiomyopathy with moderate-severe and severe MR.

Choice of spectroscopic lineshape model affects metabolite peak areas and area ratios.

The use of Lorentzian model lineshapes leads to systematic errors in the quantification of in vivo (1)H NMR spectra. Experimental lineshapes are better modeled by the Voigt (mixed Lorentzian-Gaussian) function, leading to more accurate fits (reduced chi(2)). In this work, results from a group of 41 subjects are presented. It is shown that not only are the estimated metabolite peak areas affected by the choice of lineshape model, but so too are the metabolite ratios. For example, the NAA/choline ratio was 1.92 +/- 0.06 (mean +/- standard error) using the Lorentzian lineshape model and 1.85 +/- 0.05 using the Voigt lineshape model. The corresponding figures for NAA/creatine were 2.32 +/- 0.06 and 2. 10 +/- 0.05 respectively, which are significantly different for the two lineshape models. An explanation of this previously unreported effect is given. This finding clearly has serious implications for the methodology and reporting of spectroscopic studies.

An analytical derivation of a popular approximation of the Voigt function for quantification of NMR spectra.

The approximation of the Voigt line shape by the linear summation of Lorentzian and Gaussian line shapes of equal width is well documented and has proved to be a useful function for modeling in vivo (1)H NMR spectra. We show that the error in determining peak areas is less than 0.72% over a range of simulated Voigt line shapes. Previous work has concentrated on empirical analysis of the Voigt function, yielding accurate expressions for recovering the intrinsic Lorentzian component of simulated line shapes. In this work, an analytical approach to the approximation is presented which is valid for the range of Voigt line shapes in which either the Lorentzian or Gaussian component is dominant. With an empirical analysis of the approximation, the direct recovery of T(2) values from simulated line shapes is also discussed.