Experience in the Adaptive Immunity Impacts Bone Homeostasis, Remodeling, and Healing

Bone formation as well as bone healing capacity is known to be impaired in the elderly. Although bone formation is outpaced by bone resorption in aged individuals, we hereby present a novel path that considerably impacts bone formation and architecture: Bone formation is substantially reduced in aged individual owing to the experience of the adaptive immunity. Thus, immune-aging in addition to chronological aging is a potential risk factor, with an experienced immune system being recognized as more pro-inflammatory. The role of the aging immune system on bone homeostasis and on the bone healing cascade has so far not been considered. Within this study mice at different age and immunological experience were analyzed toward bone properties. Healing was assessed by introducing an osteotomy, immune cells were adoptively transferred to disclose the difference in biological vs. chronological aging. In vitro studies were employed to test the interaction of immune cell products (cytokines) on cells of the musculoskeletal system. In metaphyseal bone, immune-aging affects bone homeostasis by impacting bone formation capacity and thereby influencing mass and microstructure of bone trabeculae leading to an overall reduced mechanical competence as found in bone torsional testing. Furthermore, bone formation is also impacted during bone regeneration in terms of a diminished healing capacity observed in young animals who have an experienced human immune system. We show the impact of an experienced immune system compared to a naive immune system, demonstrating the substantial differences in the healing capacity and bone homeostasis due to the immune composition. We further showed that in vivo mechanical stimulation changed the immune system phenotype in young mice toward a more naive composition. While this rescue was found to be significant in young individuals, aged mice only showed a trend toward the reconstitution of a more naive immune phenotype. Considering the immune system's experience level in an individual, will likely allow one to differentiate (stratify) and treat (immune-modulate) patients more effectively. This work illustrates the relevance of including immune diagnostics when discussing immunomodulatory therapeutic strategies for the progressively aging population of the industrial countries

Experience in the Adaptive Immunity Impacts Bone Homeostasis, Remodeling, and Healing

Bone formation as well as bone healing capacity is known to be impaired in the elderly. Although bone formation is outpaced by bone resorption in aged individuals, we hereby present a novel path that considerably impacts bone formation and architecture: Bone formation is substantially reduced in aged individual owing to the experience of the adaptive immunity. Thus, immune-aging in addition to chronological aging is a potential risk factor, with an experienced immune system being recognized as more pro-inflammatory. The role of the aging immune system on bone homeostasis and on the bone healing cascade has so far not been considered. Within this study mice at different age and immunological experience were analyzed toward bone properties. Healing was assessed by introducing an osteotomy, immune cells were adoptively transferred to disclose the difference in biological vs. chronological aging. In vitro studies were employed to test the interaction of immune cell products (cytokines) on cells of the musculoskeletal system. In metaphyseal bone, immune-aging affects bone homeostasis by impacting bone formation capacity and thereby influencing mass and microstructure of bone trabeculae leading to an overall reduced mechanical competence as found in bone torsional testing. Furthermore, bone formation is also impacted during bone regeneration in terms of a diminished healing capacity observed in young animals who have an experienced human immune system. We show the impact of an experienced immune system compared to a naïve immune system, demonstrating the substantial differences in the healing capacity and bone homeostasis due to the immune composition. We further showed that in vivo mechanical stimulation changed the immune system phenotype in young mice toward a more naïve composition. While this rescue was found to be significant in young individuals, aged mice only showed a trend toward the reconstitution of a more naïve immune phenotype. Considering the immune system's experience level in an individual, will likely allow one to differentiate (stratify) and treat (immune-modulate) patients more effectively. This work illustrates the relevance of including immune diagnostics when discussing immunomodulatory therapeutic strategies for the progressively aging population of the industrial countries

Mutational Characterization of the Bile Acid Receptor TGR5 in Primary Sclerosing Cholangitis

TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants. Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11-1.27, p = 8.5 x 10(-7)), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases

Deeply virtual Compton scattering at small x_B and the access to the GPD H

We give a partonic interpretation for the deeply virtual Compton scattering (DVCS) measurements of the H1 and ZEUS collaborations in the small-x_B region in terms of generalized parton distributions. Thereby we have a closer look at the skewness effect, parameterization of the t-dependence, revealing the chromomagnetic pomeron, and at a model dependent access to the anomalous gravitomagnetic moment of nucleon. We also quantify the reparameterization of generalized parton distributions resulting from the inclusion of radiative corrections up to next-to-next-to-leading order. Beyond the leading order approximation, our findings are compatible with a `holographic' principle that would arise from a (broken) SO(2,1) symmetry. Utilizing our leading-order findings, we also perform a first model dependent dispersion relation fit of HERMES and JLAB DVCS measurements. From that we extract the generalized parton distribution H on its cross-over line and predict the beam charge-spin asymmetry, measurable at COMPASS.Comment: LaTeX, 71 page, 15 figures, Sect. 5 improved, matches published versio

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndrome

Modellversuch Weniger Verkehrszeichen : Bericht der Projektgruppe Modellversuch "Weniger Verkehrszeichen" der Bundesanstalt für Straßenwesen

Der Bundesminister für Verkehr hat im Verkehrssicherheitsprogramm 1984 erklärt, in einem Modellversuch Bemühungen um weniger Verkehrszeichen zu unterstützen. Die Durchführung des Modellversuches wurde der Bundesanstalt für Straßenwesen übertragen und für die wissenschaftliche Begleitung eine Projektgruppe gebildet. Zur Vorbereitung des Modellversuches entwickelte die Projektgruppe einen Leitfaden, in dem Maßnahmen für weniger Verkehrszeichen und eine bessere Beschilderung anschaulich dargestellt wurden. Von 1985 bis 1990 wurde in den Städten Husum, Kassel und Straubing in ausgewählten Stadtbereichen der Schilderbestand überprüft, überflüssige Schilder abgebaut und die Beschilderung in Konzeption und Aufstellung verbessert. Diese Maßnahmen wurden durch gezielte verkehrliche Untersuchungen und Unfallanalysen begleitet. Weitere Erkenntnisse ergaben sich in Städten und Gemeinden, die durch den Leitfaden des Bundesministers für Verkehr angeregt wurden, im gleichen Zeitraum "ihren Schilderwald" zu lichten. Aus den Ergebnissen werden Ursachen für zuviele Verkehrszeichen abgeleitet und Maßnahmen zur Verringerung und Verbesserung der Beschilderung gegliedert nach Verantwortungsbereichen entwickelt. Zusammenfassend lässt sich feststellen, dass bei einem systematischen Vorgehen ohne Beeinträchtigung von Verkehrssicherheit und Verkehrsablauf etwa 20 Prozent der Verkehrszeichen entfernt werden können. Zu einem systematischen Vorgehen gehört: - Konsequente Anwendung der Straßenverkehrsordnung und der zugehörigen Verwaltungsvorschriften; - Periodische Kontrolle des Bestandes; - Vereinfachung der Wegweisung; - Nutzung von Zonenregelungen; - Abbau nichtamtlicher Schilder. Am Schluss des Berichtes werden Empfehlungen für die Fortschreibung von StVO und Verwaltungsvorschriften sowie für die Anwendung dieser Vorschriften zusammengestellt.In the 1984 Road Safety Programme of the Federal Republic, the Federal Ministry of Transport offered its assistance in furthering the model project "Fewer Traffic Signs" and commissioned the Federal Highway Research Institute (BASt) to undertake the project and establish a project group for monitoring the project. In order to lay the groundwork for the model project, guidelines were drawn up by the project group describing measures to reduce traffic signs and illustrating a better signposting scheme. Between 1985 and 1990, the signposting was checked, redundant signs removed and the signposting scheme improved in selected areas of the cities of Husum, Kassel and Straubing. Targeted traffic studies and accident analyses were undertaken at the same time. Further knowledge was acquired in cities and municipalities which moved by these guidelines had begun to clear their own "signposting forest". Based on the research findings, the causes for excess signposting were derived and measures to reduce and improve signposting schemes developed, classified by areas of jurisdiction. The following conclusions were drawn: by handling the process in a systematic manner about 20 per cent of all traffic signs can be removed without compromising road safety and traffic flow conditions. A systematic procedure includes the following steps: - consistent application of the German highway code (StVO) and its administrative provisions - periodic checks of the signs placed - simplification of signposting zoning and the corresponding signs - removal of unofficial signs. The report ends with recommendations for updating StVO and its administrative provisions as well as for the application of these regulations

Weniger Verkehrszeichen

Im Verkehrssicherheitsprogramm der Bundesregierung hat der Bundesminister für Verkehr seine Bereitschaft erklärt, Städte und Gemeinden bei den Bemühungen um "Weniger Verkehrszeichen" zu unterstützen. Diesem Ziel dient ein Modellversuch, bei dem in einer ganzen Stadt oder in einem Stadtviertel jedes Verkehrszeichen daraufhin überprüft wird, ob der Grund für die Aufstellung noch gegeben ist oder ob es ohne Beeinträchtigung der Ordnung und der Sicherheit im Verkehr abgebaut werden kann. Der Versuch läuft 1985 und 1986 in drei Städten. Vorgestellt wird der Leitfaden für den Modellversuch. Er bietet keine neuen Konzepte für die Beschilderung an, sondern soll helfen die Beschilderung zu vereinfachen und die Auswirkungen auf die Verkehrssicherheit zu überprüfen. Er will dafür Anregungen geben und die dargestellten Beispiele sollen die Anregungen verdeutlichen

Autonotfunk - nichttechnische Begleitforschung : Schlussbericht

Es wird über die nichttechnische Begleitforschung zum Autonotfunk berichtet. Die Wirkung des Autonotfunks im Rettungswesen wird abgeschätzt und eine zusammenfassende Beurteilung des Systems vorgenommen. Aus den Wirkungen wird abgeleitet, dass durch die Verkürzung der Rettungszeit um eine Minute zwischen 0,26 und 0,66 Prozent der Unfalltoten vermieden werden können. Bei einer Ausstattungsquote von 10 Prozent aller Kraftfahrzeuge werden Investitionskosten von 700 Millionen DM berechnet, für die Relaisstellen bei etwa 4.000 Anlagen ca. 1,1 Milliarde DM. Hinsichtlich der Wirtschaftlichkeit wird bei einer 5- bis 10 prozentigen Ausstattung mit Mobilgeräten ein in etwa ausgeglichenes Nutzen/Kostenverhältnis erwartet. Die Projektgruppe empfiehlt mehrheitlich die bundesweite Einführung des Autonotfunks

Predicting Humoral Alloimmunity from Differences in Donor and Recipient HLA Surface Electrostatic Potential.

In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure, but our ability to assess the immunological risk associated with a potential donor-recipient HLA combination is limited. We hypothesized that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared with recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level [three-dimensional electrostatic mismatch score (EMS-3D)]. We then examined humoral alloimmune responses in healthy females subjected to a standardized injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation.NIH