Tolerogenic effect of fiber tract injury: reduced EAE severity following entorhinal cortex lesion

Despite transient, myelin-directed adaptive immune responses in regions of fiber tract degeneration, none of the current models of fiber tract injuries evokes disseminated demyelination, implying effective mechanisms maintaining or re-establishing immune tolerance. In fact, we have recently detected CD95L upregulation accompanied by apoptosis of leukocytes in zones of axonal degeneration induced by entorhinal cortex lesion (ECL), a model of layer-specific axonal degeneration. Moreover, infiltrating monocytes readily transformed into ramified microglia exhibiting a phenotype of immature (CD86+/CD80−) antigen-presenting cells. We now report the appearance of the axonal antigen neurofilament-light along with increased T cell apoptosis and enhanced expression of the pro-apoptotic gene Bad in cervical lymph nodes after ECL. In order to test the functional significance of such local and systemic depletory/regulatory mechanisms on subsequent immunity to central nervous system antigens, experimental autoimmune encephalomyelitis was induced by proteolipid protein immunization 30 days after ECL. In three independent experiments, we found significantly diminished disease scores and infiltrates in lesioned compared to sham-operated SJL mice. This is consistent with a previous meta-statistical analysis (Goodin et al. in Neurology 52:1737–1745, 1999) rejecting the O-hypothesis that brain trauma causes or exacerbates multiple sclerosis. Conversely, brain injuries may involve long-term tolerogenic effects towards brain antigens. Leman Mutlu, Christine Brandt, Jon D. Laman, and Ingo Bechmann have contributed equally.     

Subjektive Qualitätskonzepte im Vergleich zu objektiven Qualitätskriterien

Background

The need for quality management in prevention and health promotion continues to grow. The role of the participants’ and course instructors’ views on quality in prevention and health promotion has been insufficiently considered. The aim of the present study was to examine the participants’ and course instructors’ views on quality in movement-related prevention and health promotion.

Methods

Four participants and four course instructors were questioned using semistructured interviews. The data were analyzed according to the structured content analysis according to Kuckartz.

Results

The views on quality of participants and course instructors were comparable. Within the participants’ and course instructors’ views on quality in movement-related prevention and health promotion the “individual relationship between therapist and patient”, “personal atmosphere”, and “class structure” were identified as important quality dimensions, while proof of effectiveness seemed to be less important. Moreover, the understanding of proof of effectiveness turned out to be inconsistent.

Conclusions

Compared to the prevention guideline of the German statutory health insurers, participants’ and course instructors’ views on quality point out the importance of process quality. In contrast, proof of effectiveness and the qualification of the course instructor play a minor role in subjective quality concepts.

     

Evaluation von organisierten Programmen zur Krebsfrüherkennung: Allgemeine Aspekte und aktueller Stand in Deutschland

In the past decades, it has been increasingly recognized that cancer screening is not always or not exclusively beneficial and, in the case of some measures, the negative effects may even outweigh the benefits. This has fundamentally changed the significance and emphasis placed on the evaluation of cancer screening programs. Generally, there is a distinction between an endpoint evaluation, which assesses the effectiveness or risk/benefit ratio, and a process evaluation, which aims to ensure optimum implementation of the program.Prior to the nationwide introduction of a screening measure, proof of effectiveness should ideally be provided by a randomized controlled trial (RCT), in which persons without a screening offer form the control group. From a scientific point of view, this study design is by far the best method to evaluate the endpoint, as it avoids biases that may distort the results in observational studies. RCT evidence on cancer screening measures currently offered by statutory health insurance providers in Germany – if available at all – originates exclusively from other countries.When mammography screening was introduced as the first organized screening program in Germany, comprehensive measures for process evaluation were taken. In April 2013, the legal basis for the transfer of colorectal and cervical cancer screening into organized programs was created. According to the legal provisions, both a process and an endpoint evaluation are planned for the new programs. It remains to be seen how the necessary data flows will be conceptualized and later implemented in practice.     

Gesichtsästhetik Teil 1: Die Bedeutung der Symmetrieebene des Gesichts

When humans observe a face, the eyes, mouth and nose regions are the preferred targets of the centre of gaze, with the outlines of eye position recordings approximating a triangle with vertices located in the centre of the eyes and mouth [31]. We studied the significance of cutaneous asymmetries inside and outside the Yarbus triangle on the basis of the assessment of digitally-manipulated images by 201 independent judges. We show that certain facial variations (such as naevi) are more attractive when asymmetrical than symmetrical (p<?0,001). They appear more attractive when located laterally rather than medially, particularly so when located outside the Yarbus triangle as compared to inside it (p<?0,001). The significance of facial symmetry increases significantly when approaching the Yarbus triangle or the midline, respectively.     

Complete remission of a metastatic pancreatic carcinoma after modified G-FLIP therapy

This is a report about a patient who had a complete remission of a metastatic pancreatic adenocarcinoma after a modified G-FLIP therapy administered in an outpatient setting. The patient underwent surgery and the complete remission could be proven histologically. The administered chemotherapy was very effective and is even more attractive since it could be administered without admission to hospital.     

Discrimination of temporal information at the cerebellum: functional magnetic resonance imaging of nonverbal auditory memory

Until recently, the cerebellum was held to play its chief role in motor control. By contrast, Keele and Ivry (1990) proposed that it may subserve time estimation within the perceptual domain as well. In accordance with this suggestion, speech perception requiring minute differentiation of time intervals was found compromised by cerebellar pathology a subsequent functional magnetic resonance imaging (fMRI) study found hemodynamic activation of the right neocerebellum under these conditions. In the current fMRI investigation a non-speech task involving duration storage and comparison yielded significant hemodynamic responses within the lateral Crus I area of the right cerebellar hemisphere. Concomitantly, a left prefrontal cluster was observed. The present fMRI study employed single-shot double-echo echo-planar imaging (EPI) to reduce image distortion and acquisition time with whole-brain coverage (TE = 28 and 66 ms, TR = 5 s, 28 slices, TA = 2.8 s). Twelve healthy subjects performed two tasks: identifying pauses between tones as "short" or "long" (30-130 ms) and deciding which of two successive pauses was longer. The activation pattern in the discrimination task was analogous to that seen during speech perception and verbal working memory (WM) tasks. We suggest that the storage of precise temporal structures relies on a cerebellar-prefrontal loop. This network allows for temporal organization of verbal sequences and phoneme encoding based on durational operations in a linguistic context.     

Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization

Many current experimental results show the necessity of new conceptual approaches to understand hematopoietic stem cell organization. Recently, we proposed a novel theoretical concept and a corresponding quantitative model based on microenvironment-dependent stem cell plasticity. The objective of our present work is to subject this model to an experimental test for the situation of chimeric hematopoiesis. Investigating clonal competition processes in DBA/2-C57BL/6 mouse chimeras, we observed biphasic chimerism development with initially increasing but long-term declining DBA/2 contribution. These experimental results were used to select the parameters of the mathematical model. To validate the model beyond this specific situation, we fixed the obtained parameter configuration to simulate further experimental settings comprising variations of transplanted DBA/2-C57BL/6 proportions, secondary transplantations, and perturbation of stabilized chimeras by cytokine and cytotoxic treatment. We show that the proposed model is able to consistently describe the situation of chimeric hematopoiesis. Our results strongly support the view that the relative growth advantage of strain-specific stem cells is not a fixed cellular property but is sensitively dependent on the actual state of the entire system. We conclude that hematopoietic stem cell organization should be understood as a flexible, self-organized rather than a fixed, preprogrammed process.     

In situ activation of the type 2 ryanodine receptor in pancreatic beta cells requires cAMP-dependent phosphorylation

Molecular mechanisms that regulate in situ activation of ryanodine receptors (RY) in different cells are poorly understood. Here we demonstrate that caffeine (10 mM) released Ca²⁺ from the endoplasmic reticulum (ER) in the form of small spikes in only 14% of cultured fura-2 loaded beta cells from ob/ob mice. Surprisingly, when forskolin, an activator of adenylyl cyclase was present, caffeine induced larger Ca²⁺ spikes in as many as 60% of the cells. Forskolin or the phosphodiesterase-resistant PKA activator Sp-cAMPS alone did not release Ca²⁺ from ER. 4-Chloro-3-ethylphenol (4-CEP), an agent that activates RYs in other cell systems, released Ca²⁺ from ER, giving rise to a slow and small increase in [Ca²⁺]_i in beta cells. Prior exposure of cells to forskolin or caffeine (5 mM) qualitatively altered Ca²⁺ release by 4-CEP, giving rise to Ca²⁺ spikes. In glucose-stimulated beta cells forskolin induced Ca²⁺ spikes that were enhanced by 3,9-dimethylxanthine, an activator of RYs. Analysis of RNA from islets and insulin-secreting βTC-3-cells by RNase protection assay, using type-specific RY probes, revealed low-level expression of mRNA for the type 2 isoform of the receptor (RY₂). We conclude that in situ activation of RY₂ in beta cells requires cAMP-dependent phosphorylation, a process that recruits the receptor in a functionally operative form.