Emerging evidence suggests that Complex Regional Pain Syndrome (CRPS) is in part a post-traumatic autoimmune disease mediated by an adaptive immune response after limb injuries. We previously observed in a murine tibial fracture model of CRPS that pain-related behaviors were dependent upon adaptive immune mechanisms including the neuropeptide-dependent production of IgM for 5 months after injury. However, the time course of induction of this immune response and the demonstration of germinal center formation in lymphoid organs has not been evaluated. Using the murine fracture model, we employed behavioral tests of nociceptive sensitization and limb dysfunction, serum passive transfer techniques, western blot analysis of IgM accumulation, fluorescence-activated cell sorting (FACS) of lymphoid tissues and immunohistochemistry to follow the temporal activation of the adaptive immune response over the first 3 weeks after fracture. We observed that: 1) IgM protein levels in the skin of the fractured mice were elevated at 3 weeks post fracture, but not at earlier time points, 2) serum from fracture mice at 3 weeks, but not 1 and 2 weeks post fracture, had pro-nociceptive effects when passively transferred to fractured muMT mice lacking B cells, 3) fracture induced popliteal lymphadenopathy occurred ipsilateral to fracture beginning at 1 week and peaking at 3 weeks post fracture, 4) a germinal center reaction was detected by FACS analysis in the popliteal lymph nodes from injured limbs by 3 weeks post fracture but not in other lymphoid tissues, 5) germinal center formation was characterized by the induction of T follicular helper cells (Tfh) and germinal center B cells in the popliteal lymph nodes of the injured but not contralateral limbs, and 6) fracture mice treated with the Tfh signaling inhibitor FK506 had impaired germinal center reactions, reduced IgM levels, reduced nociceptive sensitization, and no pronociceptive serum effects after administration to fractured muMT mice. Collectively these data demonstrate that tibia fracture induces an adaptive autoimmune response characterized by popliteal lymph node germinal center formation and Tfh cell dependent B cell activation, resulting in nociceptive sensitization within 3 weeks.

Micro RNAs (miRs) are involved in many biological processes. The challenge of identifying genes influenced by miRs is evidenced by the relatively few validated miR–target interactions. In this work, we used the Mus spretus SPRET/Ei strain as an in vivo system to identify new miR–target relations. Mus spretus diverged from Mus musculus over one million years ago, making it genetically and phenotypically divergent. SPRET/Ei mice are resistant to inflammation and several cancers, making them attractive for different research fields. Their phenotype is unique and is considerably different from that of almost all other laboratory mouse strains. We exploited the characteristics of SPRET/Ei mice as a tool to identify miR–target relationships. Hepatic genes and miRs differentially expressed between C57BL/6 and SPRET/Ei mice at basal levels were identified with an Affymetrix microarray and a multiplex qPCR, respectively. A total of 955 genes and 38 miRs were identified as differentially expressed. Increased miR expression might result in downregulation of its target mRNA and vice versa. Subsequently, we used our miR and mRNA data to identify possible in vivo miR–target interactions. Ingenuity pathway analysis (IPA) analysis revealed 380 possible miR–target interactions. Five miRs were selected for experimental validation by in vivo overexpression of the miRs. This resulted in the confirmation of six previously unknown miR–target interactions: miR-146a, Zdhhc2; miR-150, Elovl3, Kcnk5, and Nrd1d2; miR-155, Camta1; and miR-592, Steap2. In conclusion, we show that SPRET/Ei mice can be used as a platform for miR–target identification in vivo, and we used this platform to identify and experimentally confirm miR–target interactions.

Under the condition that the propagation constant k in dispersive media should be larger than zero, a simple method is proposed to eliminate the spatial singularity of ultrashort pulsed beams propagating in dispersive media. Taking the pulsed Gaussian beam (PGB) as a typical example, the analytical propagation equation in the space–time domain is derived and the spatiotemporal propagation properties of PGBs in normal and anomalous dispersive media are discussed both analytically and numerically. The physical explanation of the results is presented.

The prevalence of age-related diseases is increased in individuals with post-traumatic stress disorder (PTSD). However, the underlying biological mechanisms are still unclear. N-glycosylation is an age-dependent process, identified as a biomarker for physiological aging (GlycoAge Test). To investigate whether traumatic stress accelerates the aging process, we analyzed the N-glycosylation profile in n=13 individuals with PTSD, n=9 trauma-exposed individuals and in n=10 low-stress control subjects. Individuals with PTSD and trauma-exposed individuals presented an upward shift in the GlycoAge Test, equivalent to an advancement of the aging process by 15 additional years. Trauma-exposed individuals presented an intermediate N-glycosylation profile positioned between severely traumatized individuals with PTSD and low-stress control subjects. In conclusion, our data suggest that cumulative exposure to traumatic stressors accelerates the process of physiological aging.

Background and Aims: Cancer of the liver is currently the fifth most common cancer worldwide.Primary liver cancers comprise hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) with HCC representing the majority of cases.For ICC high incidence rates are found in Asia.Since first reports of a rising incidence came from the UK in the 1990s, similar observations have been reported for several geographic regions while Denmark has reported falling incidence.For Germany, the most population rich country in central Europe, detailed analyses of the incidence of and mortality from hepatobiliary malignancies have not been reported.Aim of this study was to analyze trends in the epidemiology of liver-related mortality and hepato-biliary malignancies with a focus on ICC in Germany.Methods: Mortality data were obtained from Federal Statistics Office where all death certificate data from the German national territory are collected.Causes of death were coded according to the German version of The International Statistical Classification of Diseases and Related Health Problems 9 th and 10 th revision for the year 1979-1997 and 1998-2008, respectively.Incidence data were obtained from the cancer registries of the federal states of Hamburg and Saarland.Data for 1970Data for -2006Data for and 1990Data for -2006 were retrieved for Saarland and Hamburg, respectively.Results: We made the following observations: 1. Mortality attributed to hepato-biliary cancers has largely been constant over past years while overall liver disease mortality has slightly declined.2. However, there have been opposing trends with regard to individual entities with ICC showing a striking increase, HCC largely constant; extrahepatic cholangiocarcinoma (ECC) modestly declining and gall bladder cancer declining strongly.3. The rapid increase in ICC is also observable in incidence data from states where sufficiently long-reaching data from cancer registries are available.However, long-term incidence data is currently only available for few smaller German states.It will be important to confirm these findings as more data from more population-rich states become available.Conclusions: Epidemiological studies are important to detect changes of disease activity in a population so that causes can be identified and countermeasures taken.Cleary, the rise in ICC needs to be further monitored and its causes identified.