Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis.

CD8+ T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8+ T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8+ T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8+ T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8+ T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramer-positive myelin-specific CD8+ T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8+ T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8+ T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20+ CD8+ T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8+ T cells in MS, indicates these cells may be attractive targets in MS therapy

Clinical aspects of Mayer-Rokitansky-Kuester-Hauser syndrome: recommendations for clinical diagnosis and staging

BACKGROUND: The Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome is a malformation of the female genitals (occurring in one in 4000 female live births) as a result of interrupted embryonic development of the Müllerian (paramesonephric) ducts. This retrospective study examined the issue of associated malformations, subtyping, and the frequency distribution of subtypes in MRKH syndrome. METHODS: Fifty-three MRKH patients were investigated using a newly developed standardized questionnaire. Together with the results of clinical and diagnostic examinations, the patients were classified into the three recognized subtypes [typical, atypical and MURCS (Müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia)]. RESULTS: The typical form was diagnosed in 25 patients (47%), the atypical form in 11 patients (21%), and the most marked form—the MURCS type—in 17 patients (32%). Associated malformations were notably frequent among the patients. Malformations of the renal system were the most frequent type of accompanying malformation, with 23 different malformations in 19 patients, followed by 18 different skeletal changes in 15 patients. CONCLUSIONS: In accordance with the literature, this study shows that associated malformations are present in more than a third of cases. Therefore, new basic guidelines for standard diagnostic classification involving patients with suspected MRKH are presente

Evaluation of Madurahydroxylactone as a Slow Release Antibacterial Implant Coating

Madurahydroxylactone (MHL), a secondary metabolite with antibacterial activity was evaluated for its suitability to generate controlled drug release coatings on medical implant materials. A smooth and firmly attached layer could be produced from a precursor solution on various metallic implant materials. In physiological salt solutions these coatings dissolved within a time period up to one week. A combination of MHL with a broad spectrum fluoroquinolone antibiotic was used to create a coating that was active against all bacterial strains tested. The time period during which the coating remained active against Pseudomonas aeruginosa was investigated. The results indicated a delayed drug release from single layer coatings in the course of seven days. MHL was biocompatible in cell culture assays and could after a delay even serve as a cell adhesion substrate for human or murine cells. The findings indicate a potential for MHL for the generation of delayed release antimicrobial implant coatings

Evaluating a Novel Class of Biomaterials: Magnesium-Containing Layered Double Hydroxides

Metallic magnesium and compounds such as magnesium hydroxide Mg(OH)2 have been shown to have osteoconductive properties under experimental conditions and are gaining an increasing interest in the field of degradable biomaterials. The application of the compounds as implant coatings could support implant incorporation, resulting in an increased period of use of the implants. A variety of Mg-containing Layered Double Hydroxides (Mg-LDHs) has been synthesized and examined. These materials have been tested in various in vitro and in vivo studies; the latter took place in different sites like in the middle ear or in the condyle of New Zealand White Rabbits. In the latest study newly formed bone could be found around the Mg-Al-CO3-LDH pellets, making it a promising compound for bone-healing applications.DFG/SFB/59

Hippocampal-midbrain circuit enhances the pleasure of anticipation in the prefrontal cortex

Having something to look forward to is a keystone of well-being. Anticipation of a future reward, like an upcoming vacation, can be more gratifying than the experience of reward itself. Theories of anticipation have described how it causes behaviors ranging from beneficial information-seeking to harmful addiction. Here, we investigated how the brain generates and enhances anticipatory pleasure, by analyzing brain activity of human participants who received information predictive of future pleasant outcomes in a decision-making task. Using a computational model of anticipation, we show that three regions orchestrate anticipatory pleasure. We show ventromedial prefrontal cortex (vmPFC) tracks the value of anticipation; dopaminergic midbrain responds to information that enhances anticipation, while the sustained activity in hippocampus provides for functional coupling between these regions. This coordinating role for hippocampus is consistent with its known role in the vivid imagination of future outcomes. Our findings throw new light on the neural underpinnings of how anticipation influences decision-making, while also unifying a range of phenomena associated with risk and time-delay preference

Active adaptive conservation of threatened species in the face of uncertainty

Adaptive management has a long history in the natural resource management literature, but despite this, few practitioners have developed adaptive strategies to conserve threatened species. Active adaptive management provides a framework for valuing learning by measuring the degree to which it improves long-run management outcomes. The challenge of an active adaptive approach is to find the correct balance between gaining knowledge to improve management in the future and achieving the best short-term outcome based on current knowledge. We develop and analyze a framework for active adaptive management of a threatened species. Our case study concerns a novel facial tumor disease affecting the Australian threatened species Sarcophilus harrisii: the Tasmanian devil. We use stochastic dynamic programming with Bayesian updating to identify the management strategy that maximizes the Tasmanian devil population growth rate, taking into account improvements to management through learning to better understand disease latency and the relative effectiveness of three competing management options. Exactly which management action we choose each year is driven by the credibility of competing hypotheses about disease latency and by the population growth rate predicted by each hypothesis under the competing management actions. We discover that the optimal combination of management actions depends on the number of sites available and the time remaining to implement management. Our approach to active adaptive management provides a framework to identify the optimal amount of effort to invest in learning to achieve long-run conservation objectives

Fermi-liquid instabilities at magnetic quantum phase transitions

This review discusses instabilities of the Fermi-liquid state of conduction electrons in metals with particular emphasis on magnetic quantum critical points. Both the existing theoretical concepts and experimental data on selected materials are presented; with the aim of assessing the validity of presently available theory. After briefly recalling the fundamentals of Fermi-liquid theory, the local Fermi-liquid state in quantum impurity models and their lattice versions is described. Next, the scaling concepts applicable to quantum phase transitions are presented. The Hertz-Millis-Moriya theory of quantum phase transitions is described in detail. The breakdown of the latter is analyzed in several examples. In the final part experimental data on heavy-fermion materials and transition-metal alloys are reviewed and confronted with existing theory.Comment: 62 pages, 29 figs, review article for Rev. Mod. Phys; (v2) discussion extended, refs added; (v3) shortened; final version as publishe