Good outcome after liver transplantation for ALD without a 6 months abstinence rule prior to transplantation including post‐transplant CDT monitoring for alcohol relapse assessment – a retrospective study

Alcoholic liver disease (ALD) is the second most common indication for liver transplantation (LT). The utility of fixed intervals of abstinence prior to listing is still a matter of discussion. Furthermore, post‐LT long‐term observation is challenging, and biomarkers as carbohydrate‐deficient transferrin (CDT) may help to identify alcohol relapse. We retrospectively analyzed data from patients receiving LT for ALD from 1996 to 2012. A defined period of alcohol abstinence prior to listing was not a precondition, and abstinence was evaluated using structured psychological interviews. A total of 382 patients received LT for ALD as main (n = 290) or secondary (n = 92) indication; median follow‐up was 73 months (0–213). One‐ and five‐year patient survival and graft survival rates were 82% and 69%, and 80% and 67%, respectively. A total of 62 patients (16%) experienced alcohol relapse. Alcohol relapse did not have a statistically significant effect on patient survival (P = 0.10). Post‐transplant CDT measurements showed a sensitivity and specificity of 84% and 85%, respectively. In conclusion, this large single‐center analysis showed good post‐transplant long‐term results in patients with ALD when applying structured psychological interviews before listing. Relapse rates were lower than those reported in the literature despite using a strict definition of alcohol relapse. Furthermore, post‐LT CDT measurement proved to be a useful supplementary tool for detecting alcohol relapse.     

Reversible HLA multimers (Streptamers) for the isolation of human cytotoxic T lymphocytes functionally active against tumor- and virus-derived antigens

The development of MHC/peptide multimers has facilitated the visualization and purification of antigen-specific T cells. However, the persistence of multimers leads to prolonged T cell receptor signaling and subsequently to altered T-cell function. We have recently developed a new type of MHC/peptide multimers, which can be dissociated from the T cell. Herein, we have generated and tested for the first time reversible HLA/peptide multimers, termed Streptamers, for the isolation of human T cells. The Streptamer technique demonstrates the specificity and sensitivity of conventional HLA/peptide tetramers with regards to the sorting of human T lymphocytes. This is shown for T cells directed against immunogenic peptides derived from viral and tumor-associated antigens. We show that antigen-specific cytotoxic T cells remain functionally active following Streptamer dissociation, whereas lytic function and proliferation of the T cells is impaired in the presence of conventional tetramers. These novel HLA/peptide Streptamer reagents allow the isolation of antigen-specific T cells with preserved function and, therefore, facilitate the development of adoptive T cell transfer regimens for the treatment of patients with cancer or infectious diseases.     

Blood polymorphonuclear leukocyte migration as a predictive marker for infections in severe trauma: comparison with various inflammation parameters

Objective To assess in patients with multiple trauma the relevance of the following as predictive markers for infections: the inflammation parameters white blood count, body temperature, blood polymorphonuclear leukocyte (PMN) migration; blood levels of C-reactive protein, PMN elastase, procalcitonin, neopterin, interleukin 6, interleukin 8, malondialdehyde, total antioxidative status; the stress parameters cortisol and lactate.Design Prospective observational cohort study.Setting Intensive Care Unit of a university surgical department.Patients Twenty-six patients with multiple trauma of differing severity.Measurements and results Trauma severity was estimated by the ISS. PMN migration upon F-Met-Leu-Phe stimulation was determined in fresh whole blood in a ready-for-use, one-way membrane filter assay and evaluated by automated image analysis. The other parameters were measured with commercially available tests. During hospitalization, nine patients developed infections, and 17 patients were free of infection. PMN migration below a critical minimum preceded infections in eight of the infected, but occurred in only three of the non-infected patients (positive/negative predictive values 0.72/0.93; sensitivity/specificity 0.88/0.82; likelihood ratio 5.0). Fever (38.0 °C) had predictive values of 0.83/0.80 and a high likelihood ratio of 9.4, but a low sensitivity/specificity of 0.55/0.94. The other parameters were without significance. Procalcitonin, elastase, C-reactive protein, neopterin and lactate correlated positively with the injury severity score.Conclusion PMN migration proved to be a highly sensitive predictive marker for infections. The whole-blood PMN migration test may facilitate early aggressive antimicrobial therapy.Coauthors are listed in alphabetical order     

Biomechanical advantage of C1 pedicle screws over C1 lateral mass screws: a cadaveric study

Purpose

The established technique for posterior C1 screw placement is via the lateral mass. Use of C1 monocortical pedicle screws is an emerging technique which utilizes the bone of the posterior arch while avoiding the paravertebral venous plexus and the C2 nerve root. This study compared the relative biomechanical fixation strengths of C1 pedicle screws with C1 lateral mass screws.

Methods

Nine human C1 vertebrae were instrumented with one lateral mass screw and one pedicle screw. The specimens were subjected to sinusoidal, cyclic (0.5 Hz) fatigue loading. Peak compressive and tensile forces started from ±25 N and constantly increased by 0.05 N every cycle. Testing was stopped at 5 mm displacement. Cycles to failure, displacement, and initial and end stiffness were measured. Finally, CT scans were taken and the removal torque measured.

Results

The pedicle screw technique consistently and significantly outperformed the lateral mass technique in cycles to failure (1,083 ± 166 vs. 689 ± 240 cycles), initial stiffness (24.6 ± 3.9 vs. 19.9 ± 3.2 N/mm), end stiffness (16.6 ± 2.7 vs. 11.6 ± 3.6 N/mm) and removal torque (0.70 ± 0.78 vs. 0.13 ± 0.09 N m). Only 33 % of pedicle screws were loose after testing compared to 100 % of lateral mass screws.

Conclusions

C1 pedicle screws were able to withstand higher toggle forces than lateral mass screws while maintaining a higher stiffness throughout and after testing. From a biomechanical point of view, the clinical use of pedicle screws in C1 is a promising alternative to lateral mass screws.     

Behandlung von Knorpeldefekten

Trauma und Berufskrankheit -     

Impact of Resting and Ischemic Blood Flow on Infarct Probability in Ischemic Preconditioning-a New Approach to Infarct Size-Blood Flow Data by Logistic Regression

The linear regression analysis of infarct size (IS)vischemic myocardial blood flow (MBF) does not account for the heterogeneity of MBF and infarcted tissue; moreover, it cannot assess a blood flow threshold for infarction (MBFT) accurately, as with ischemic preconditioning (IP) the close relationship between ischemic MBF and IS otherwise observed is lost. Finally, the impact of resting blood flow on myocardial infarction cannot be considered in such analysis. Therefore, in a retrospective data analysis of 32 enflurane-anaesthetized swine undergoing 90 min severe ischemia and 120 min reperfusion without (CON,n=12) or with IP induced by either 3 (IP3,n=8) or 10 min ischemia (IP10,n=12) and 15 min reperfusion, a MBFT was assessed by logistic regression (LR) in individual tissue pieces. MBFT was arbitrarily defined as that ischemic MBF (microspheres) at which infarct probability was 0.2, derived from the ratio of infarcted (n=141, TTC) to all tissue samples (n=684). The duration of the preconditioning ischemia and MBF both at rest and during the sustained ischemia were significant predictors of infarct probability. Ischemic MBFT at an infarct probability of 0.2, was 0.089±0.023 ml/min/g in CON. MBFT was decreased to 0.051±0.03 ml/min/g with IP3 (P<0.05vCON) and further to 0.004±0.037 ml/min/g with IP10 (P<0.05vCON, IP3). Corresponding to the leftward shift of MBFT, the relationships between infarct probability and MBF were shifted in parallel by IP with no change in their slopes.     

A Molecular Model of High Density Lipoproteins

Based on the analysis of recombined lipidapoprotein complexes by C-13 and P-31 nuclear magnetic resonance spectroscopy and circular dichroism [Assmann, G., Sokoloski, E. A. & Brewer, H. B., Jr. (1974) Proc. Nat. Acad. Sci. USA 71, 549-553; Assmann, G., Highet, R. J., Sokoloski, E. A. & Brewer, H. B., Jr. (1974) Proc. Nat. Acad. Sci. USA 71, in press; Assmann, G. & Brewer, H. B., Jr. (1974) Proc. Nat. Acad. Sci. USA 71, 989-993] and the identification of conformational amphipathic regions in apoproteins, a new model for human high density lipoproteins is proposed. This model is analogous to membrane models proposed by Singer, in that protein "icebergs" are embedded in a "sea" of lipid.     

Methods for the analysis of multiple endpoints in small populations: A review

While current guidelines generally recommend single endpoints for primary analyses of confirmatory clinical trials, it is recognized that certain settings require inference on multiple endpoints for comprehensive conclusions on treatment effects. Furthermore, combining treatment effect estimates from several outcome measures can increase the statistical power of tests. Such an efficient use of resources is of special relevance for trials in small populations. This paper reviews approaches based on a combination of test statistics or measurements across endpoints as well as multiple testing procedures that allow for confirmatory conclusions on individual endpoints. We especially focus on feasibility in trials with small sample sizes and do not solely rely on asymptotic considerations. A systematic literature search in the Scopus database, supplemented by a manual search, was performed to identify research papers on analysis methods for multiple endpoints with relevance to small populations. The identified methods were grouped into approaches that combine endpoints into a single measure to increase the power of statistical tests and methods to investigate differential treatment effects in several individual endpoints by multiple testing.