Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system

Recent research findings have provided convincing evidence indicating a role for Interleukin-33 (IL-33) signalling pathway in a number of central nervous system (CNS) diseases including multiple sclerosis (MS) and Alzheimer’s disease. However, the exact function of IL-33 molecule within the CNS under normal and pathological conditions is currently unknown. In this study, we have mapped cellular expression of IL-33 and its receptor ST2 by immunohistochemistry in the brain tissues of MS patients and appropriate controls; and investigated the functional significance of these findings in vitro using a myelinating culture system. Our results demonstrate that IL-33 is expressed by neurons, astrocytes and microglia as well as oligodendrocytes, while ST2 is expressed in the lesions by oligodendrocytes and within and around axons. Furthermore, the expression levels and patterns of IL-33 and ST2 in the lesions of acute and chronic MS patient brain samples are enhanced compared with the healthy brain tissues. Finally, our data using rat myelinating co-cultures suggest that IL-33 may play an important role in MS development by inhibiting CNS myelination

Microstructural Evolution During Hot Rolling of an AZ31 Mg Alloy

The microstructural evolution of a AZ31 Mg alloy during hot rolling has been investigated using optical microscopy and texture (macro and micro) analysis as the main characterization tools. In particular, the differences between the microstructure obtained by unidirectional rolling (UR) and cross rolling (CR) are studied. Significant twinning activity is observed in both cases. Additionally, after cross rolling, a rather heterogeneous microstructure develops, with scattered regions populated by very fine grains. The strong basal fiber texture of the as-received material remains present after both hot rolling schemes. The imposibility to obtain accurate EBSD measurements within the twinned regions suggests that significant localized deformation takes place in those areas. Thus, due to the increase in the local strain energy, these regions become preferential sites for nucleation of recrystallization.Peer reviewe

Line-field confocal optical coherence tomography: a new tool for the differentiation between nevi and melanomas?

SIMPLE SUMMARY: Typical benign nevi and advanced melanomas can be easily discriminated, but there are still some melanocytic lesions where even experts are not sure about the correct diagnosis and degree of malignity. The high penetration depth of optical coherence tomography (OCT) allows an assessment of tumor thickness of the lesion precisely, but without cellular resolution the differentiation of melanocytic lesions remains difficult. On the other hand, reflectance confocal microscopy (RCM) allows for very good morphological identification of either a nevus or a melanoma, but cannot show the infiltration depth of the lesion because of its low penetration depth. Since the new device of line-field confocal optical coherence tomography (LC-OCT) technically closes the gap between these other two devices, in this study, we wanted to examine if it is possible to differentiate between nevi and melanomas with LC-OCT, and which criteria are the most important for it. ABSTRACT: Until now, the clinical differentiation between a nevus and a melanoma is still challenging in some cases. Line-field confocal optical coherence tomography (LC-OCT) is a new tool with the aim to change that. The aim of the study was to evaluate LC-OCT for the discrimination between nevi and melanomas. A total of 84 melanocytic lesions were examined with LC-OCT and 36 were also imaged with RCM. The observers recorded the diagnoses, and the presence or absence of the 18 most common imaging parameters for melanocytic lesions, nevi, and melanomas in the LC-OCT images. Their confidence in diagnosis and the image quality of LC-OCT and RCM were evaluated. The most useful criteria, the sensitivity and specificity of LC-OCT vs. RCM vs. histology, to differentiate a (dysplastic) nevus from a melanoma were analyzed. Good image quality correlated with better diagnostic performance (Spearman correlation: 0.4). LC-OCT had a 93% sensitivity and 100% specificity compared to RCM (93% sensitivity, 95% specificity) for diagnosing a melanoma (vs. all types of nevi). No difference in performance between RCM and LC-OCT was observed (McNemar’s p value = 1). Both devices falsely diagnosed dysplastic nevi as non-dysplastic (43% sensitivity for dysplastic nevus diagnosis). The most significant criteria for diagnosing a melanoma with LC-OCT were irregular honeycombed patterns (92% occurrence rate; 31.7 odds ratio (OR)), the presence of pagetoid spread (89% occurrence rate; 23.6 OR) and the absence of dermal nests (23% occurrence rate, 0.02 OR). In conclusion LC-OCT is useful for the discrimination between melanomas and nevi

Electro-Optical Diagnostics at KARA and FLUTE – Results and Prospects

Electro-optical (EO) methods are nowadays well-proven diagnostic tools, which are utilized to detect THz fields in countless experiments. The world’s first near-field EO sampling monitor at an electron storage ring was developed and installed at the KIT storage ring KARA (Karlsruhe Research Accelerator) and optimized to detect longitudinal bunch profiles. This experiment with other diagnostic techniques builds a distributed, synchronized sensor network to gain comprehensive data about the phase-space of electron bunches as well as the produced coherent synchrotron radiation (CSR). These measurements facilitate studies of physical conditions to provide, at the end, intense and stable CSR in the THz range. At KIT, we also operate FLUTE (Ferninfrarot Linac- und Test-Experiment), a new compact versatile linear accelerator as a test facility for novel techniques and diagnostics. There, EO diagnostics will be implemented to open up possibilities to evaluate and compare new techniques for longitudinal bunch diagnostics. In this contribution, we will give an overview of results achieved, the current status of the EO diagnostic setups at KARA and FLUTE and discuss future prospects

Line‐field confocal optical coherence tomography, a novel non‐invasive tool for the diagnosis of onychomycosis

Background and objectives Onychomycosis is common and important to distinguish from other nail diseases. Rapid and accurate diagnosis is necessary for optimal patient treatment and outcome. Non-invasive diagnostic tools have increasing potential for nail diseases including onychomycosis. This study evaluated line-field confocal optical coherence tomography (LC-OCT) as a rapid non-invasive tool for diagnosing onychomycosis as compared to confocal laser scanning microscopy (CLSM), optical coherence tomography (OCT), and conventional methods. Patients and Methods In this prospective study 86 patients with clinically suspected onychomycosis and 14 controls were examined using LC-OCT, OCT, and CLSM. KOH-preparation, fungal culture, PCR, and histopathology were used as comparative conventional methods. Results LC-OCT had the highest sensitivity and negative predictive value of all methods used, closely followed by PCR and OCT. Specificity and positive predictive value of LC-OCT were as high as with CLSM, while OCT scored much lower. The gold standard technique, fungal culture, showed the lowest sensitivity and negative predictive value. Only PCR and culture allowed species differentiation. Conclusions LC-OCT enables quick and non-invasive detection of onychomycosis, with advantages over CLSM and OCT, and similar diagnostic accuracy to PCR but lacking species differentiation. For accurate nail examination, LC-OCT requires well-trained and experienced operators

Dynamic optical coherence tomography of blood vessels in cutaneous melanoma — correlation with histology, immunohistochemistry and dermoscopy

Dermoscopy adds important information to the assessment of cutaneous melanoma, but the risk of progression is predicted by histologic parameters and therefore requires surgery and histopathologic preparation. Neo-vascularization is crucial for tumor progression and worsens prognosis. The aim of this study was the in vivo evaluation of blood vessel patterns in melanoma with dynamic optical coherence tomography (D-OCT) and the correlation with dermoscopic and histologic malignancy parameters for the risk assessment of melanoma. In D-OCT vessel patterns, shape, distribution and presence/type of branching of 49 melanomas were evaluated in vivo at three depths and correlated with the same patterns in dermoscopy and with histologic parameters after excision. In D-OCT, blood vessel density and atypical shapes (coils and serpiginous vessels) increased with higher tumor stage. The histologic parameters ulceration and Hmb45- and Ki67-positivity increased, whereas regression, inflammation and PD-L1-positivity decreased with risk. CD31, VEGF and Podoplanin correlated with D-OCT vasculature findings. B-RAF mutation status had no influence. Due to pigment overlay and the summation effect, the vessel evaluation in dermoscopy and D-OCT did not correlate well. In summary, atypical vessel patterns in melanoma correlate with histologic parameters for risk for metastases. Tumor vasculature can be noninvasively assessed using D-OCT before surgery

Spatiotemporal Differences in Gene Expression Between Motor and Sensory Autografts and Their Effect on Femoral Nerve Regeneration in the Rat

To improve the outcome after autologous nerve grafting in the clinic, it is important to understand the limiting variables such as distinct phenotypes of motor and sensory Schwann cells. This study investigated the properties of phenotypically different autografts in a 6 mm femoral nerve defect model in the rat, where the respective femoral branches distally of the inguinal bifurcation served as homotopic, or heterotopic autografts. Axonal regeneration and target reinnervation was analyzed by gait analysis, electrophysiology, and wet muscle mass analysis. We evaluated regeneration-associated gene expression between 5 days and 10 weeks after repair, in the autografts as well as the proximal, and distal segments of the femoral nerve using qRT-PCR. Furthermore we investigated expression patterns of phenotypically pure ventral and dorsal roots. We identified highly significant differences in gene expression of a variety of regeneration-associated genes along the central – peripheral axis in healthy femoral nerves. Phenotypically mismatched grafting resulted in altered spatiotemporal expression of neurotrophic factor BDNF, GDNF receptor GFRα1, cell adhesion molecules Cadm3, Cadm4, L1CAM, and proliferation associated Ki67. Although significantly higher quadriceps muscle mass following homotopic nerve grafting was measured, we did not observe differences in gait analysis, and electrophysiological parameters between treatment paradigms. Our study provides evidence for phenotypic commitment of autologous nerve grafts after injury and gives a conclusive overview of temporal expression of several important regeneration-associated genes after repair with sensory or motor graft

Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9

The failure of remyelination in multiple sclerosis is largely unexplained. Lindner et al. report that glial cells in demyelinating lesions show increased expression of fibroblast growth factor 9 (FGF9). This induces astrocyte-dependent responses that inhibit remyelination and stimulate expression of pro-inflammatory chemokines, supporting a feedback loop that amplifies disease activit

Fibroblast growth factor signalling in multiple sclerosis:inhibition of myelination and induction of pro-inflammatory environment by FGF9

Remyelination failure plays an important role in the pathophysiology of multiple sclerosis, but the underlying cellular and molecular mechanisms remain poorly understood. We now report actively demyelinating lesions in patients with multiple sclerosis are associated with increased glial expression of fibroblast growth factor 9 (FGF9), which we demonstrate inhibits myelination and remyelination in vitro. This inhibitory activity is associated with the appearance of multi-branched ‘pre-myelinating’ MBP+/PLP+ oligodendrocytes that interact with axons but fail to assemble myelin sheaths; an oligodendrocyte phenotype described previously in chronically demyelinated multiple sclerosis lesions. This inhibitory activity is not due to a direct effect of FGF9 on cells of the oligodendrocyte lineage but is mediated by factors secreted by astrocytes. Transcriptional profiling and functional validation studies demonstrate that these include effects dependent on increased expression of tissue inhibitor of metalloproteinase-sensitive proteases, enzymes more commonly associated with extracellular matrix remodelling. Further, we found that FGF9 induces expression of Ccl2 and Ccl7, two pro-inflammatory chemokines that contribute to recruitment of microglia and macrophages into multiple sclerosis lesions. These data indicate glial expression of FGF9 can initiate a complex astrocyte-dependent response that contributes to two distinct pathogenic pathways involved in the development of multiple sclerosis lesions. Namely, induction of a pro-inflammatory environment and failure of remyelination; a combination of effects predicted to exacerbate axonal injury and loss in patients