Stellenwert der konfokalen In-vivo-Mikroskopie des subbasalen Nervenplexus der Hornhaut in der Diagnostik einer diabetischen Neuropathie

Die konfokale In-vivo-Laser-Scanning-Mikroskopie stellt eine Methode zur quantitativen Erfassung der Morphologie des Nervensystems der diabetischen Neuropathie (dN) dar. Die Nervenfaserdichte (NFD) ist am stärksten vom HbA1c und der Neuropathie abhängig. Die Korrelationen zwischen NFD und diabetischer Retinopathie (dR) sowie dN und dR waren nur gering ausgeprägt. Trotz des Bedarfs an Weiterentwicklungen besitzt diese Untersuchung ein erhebliches Potential als Surrogatparameter einer dN, objektiv und nicht-invasiv eine neuronale Beteiligung bei Diabetespatienten zu erfassen

Corneal Subbasal Nerve Plexus Changes in Severe Diabetic Charcot Foot Deformity: A Pilot Study in Search for a DNOAP Biomarker

Introduction. Diabetic neuroosteoarthropathy (DNOAP) early symptoms are unspecific, mimicking general infectious symptoms and rendering a diagnosis challenging. Consequently, unfavourable outcomes occur frequently, with recurrent foot ulceration, infectious complications, and eventually amputation. Corneal confocal microscopy (CCM) of the subbasal nerve plexus (SNP) is used to detect early peripheral neuropathy in diabetic patients without diabetic retinopathy. This pilot study was designed to determine if specific SNP changes manifest in severe DNOAP in comparison to a healthy control group. Methods. This pilot study utilized a matched-pair analysis to investigate SNP changes by in vivo CCM for 26 patients (mean patient age 63.7 years, range 27 to 78) with severe DNOAP defined by condition after the need for reconstructive foot surgery (n=13) and a healthy control group (n=13). Corneal nerve fibre length (CNFL), nerve fibre density (CNFD), nerve branch density (CNBD), average weighted corneal nerve fibre thickness (CNFTh), nerve connecting points (CNCP), and average weighted corneal nerve fibre tortuosity (CNFTo) were assessed as well as the general clinical status, diabetic status, and ophthalmologic basic criteria. Results. In vivo CCM revealed significantly reduced SNP parameters in the DNOAP group for CNFL (p=0.010), CNFD (p=0.037), CNBD (p=0.049), and CNCP (p=0.012) when compared to the healthy control group. Six patients (46%) of the DNOAP group suffered from diabetic retinopathy and none of the control group. Conclusions. This pilot study revealed a rarefication of SNP in all measured parameters in patients with severe DNOAP. We see a potential value of CCM providing a SNP-based biomarker for early stages of DNOAP prior to the development of any foot deformities that needs to be evaluated in further studies. This trial is registered with German Clinical Trials Register (DKRS) DRKS00007537

Numerical Investigations of Mixed Convection of Incompressible Viscous Fluid in LNG Storage with a Various Locations of Input and Output Mass

The article shows the results of mathematical simulation of mixed convection in the low-temperature storage of liquefied natural gas with a regenerative cooling. The regimes of mixed convection in a closed area with the different arrangement of the input and output sections of the masses are investigated. Two-dimensional nonstationary problem in the model of the Navier-Stokes in dimensionless variables "vorticity - stream function - temperature" was examined. Are obtained distributions of the hydrodynamic parameters and temperatures, characteristic basic laws governing the processes being investigated. Detailed circulating currents and carried out analysis of the mechanism of vortices formation and the temperature distribution in the solution for mixed convection mode with low Reynolds and Grashof numbers (Gr=10{6}, 100<Re<1000). Is established the significant influence of the geometrical arrangement of the input and output mass sections and input stream velocity on the structure of liquid flow and temperature in the low temperature LNG storage tanks

3D confocal laser-scanning microscopy for large-area imaging of the corneal subbasal nerve plexus

The capability of corneal confocal microscopy (CCM) to acquire high-resolution in vivo images of the densely innervated human cornea has gained considerable interest in using this non-invasive technique as an objective diagnostic tool for staging peripheral neuropathies. Morphological alterations of the corneal subbasal nerve plexus (SNP) assessed by CCM have been shown to correlate well with the progression of neuropathic diseases and even predict future-incident neuropathy. Since the field of view of single CCM images is insufficient for reliable characterisation of nerve morphology, several image mosaicking techniques have been developed to facilitate the assessment of the SNP in large-area visualisations. Due to the limited depth of field of confocal microscopy, these approaches are highly sensitive to small deviations of the focus plane from the SNP layer. Our contribution proposes a new automated solution, combining guided eye movements for rapid expansion of the acquired SNP area and axial focus plane oscillations to guarantee complete imaging of the SNP. We present results of a feasibility study using the proposed setup to evaluate different oscillation settings. By comparing different image selection approaches, we show that automatic tissue classification algorithms are essential to create high-quality mosaic images from the acquired 3D dataset

Desainer Grafis yang Menciptakan dan Menjual Produk Berupa Barang

Graphic designers in their economic activities are more widely known simply as seller of the product in the form of services. Whereas in reality it is not so since the days of Art and Craft movement spearheaded by William Morris at the end of the 19th century. William Morris, a graphic designer, had created products with good design for sale. Many reasons are behind it, starting from desires to break free from pressures of the clients, expanding spaces to express creativity to economic motives. Discussion of graphic designers crossing border of disciplines by creating products is very interesting. They do not just perform the profession on the basis of orders (client-based), but they are able to read the market that will absorb the products they created. Even, they create market trend (as a trendsetter). At this level, a designer does not just make value-added work, but already at the level of creating new value (value creation)

Isolation of human MHC class II-restricted T cell receptors from the autologous T-cell repertoire with potent anti-leukaemic reactivity

Summary Adoptive transfer of T cells genetically modified with tumour-specific T-cell receptors (TCR) is a promising novel approach in the treatment of cancer. We have previously isolated an allorestricted MHC class I-restricted TCR with specificity for Formin-like protein 1 (FMNL1) with potent activity against chronic lymphocytic leukaemia cells. CD4 + T cells have been described to be highly important for tumour elimination although TCR derived from CD4 + T cells with anti-tumour reactivity have been only rarely described. In this study we aimed to isolate MHC class-II-restricted CD4 + T cells and TCR with specificity for leukaemia antigens. We used professional antigen-presenting cells pulsed with the leukaemiaassociated and tumour-associated antigen FMNL1 for stimulation of autologous T cells in vitro. We isolated two CD4 + HLA-DR-restricted T-cell clones and T-cell-derived TCR with so far unknown specificity but high reactivity against lymphoma cells and native malignant cells derived from HLA-matched patients with diverse leukaemias. Moreover, characterization of the TCR after TCR gene transfer revealed that specific characteristics of isolated TCR as reactivity in response to Toll-like receptors were transferable on effector cells. Our results have a major impact on the development of novel immunotherapies. They demonstrate that TCR with potent HLA-DR-restricted anti-leukaemic reactivity against so far undefined self-restricted antigens can be isolated from the healthy autorestricted CD4 + T-cell repertoire and these TCR are highly interesting candidate tools for novel immunotherapies

The corneal subbasal nerve plexus and thickness of the retinal layers in pediatric type 1 diabetes and matched controls

Optical coherence tomography (OCT) of the retina and corneal confocal laser scanning microscopy (CLSM) of the subbasal nerve plexus (SBP) are noninvasive techniques for quantification of the ocular neurodegenerative changes in individuals with type 1 diabetes mellitus (T1DM). In adult T1DM patients these changes are hardly related to T1DM only. Instead, ageing and/or lifestyle associated comorbidities have to be considered as putative confounding variables. Therefore, we investigated pediatric T1DM patients (n = 28; 14.2 ± 2.51 y; duration of disease: 5.39 ± 4.16 y) without clinical signs of diabetic retina disease, neuropathy, vasculopathy or nephropathy and compared our findings with those obtained in healthy controls (n = 46; 14.8 ± 1.89 y). The SBP was characterized by the averaged length, thickness, and tortuosity of nerve fibers as well as the number of branching and connecting points. OCT was used to determine the total thickness of the retina (ALL) and the thickness of each retinal layer. Both methods revealed signs of early neurodegenerative changes, e.g. thinning of distinct retinal layers at the pericentral ring and shortening of corneal nerve fibers that are already present in pediatric T1DM patients. Standardization of instruments and algorithms are urgently required to enable uniform comparison between different groups and define normative values to introduce in the clinical setting

Spatial analysis improves the detection of early corneal nerve fiber loss in patients with recently diagnosed type 2 diabetes

Corneal confocal microscopy (CCM) has revealed reduced corneal nerve fiber (CNF) length and density (CNFL, CNFD) in patients with diabetes, but the spatial pattern of CNF loss has not been studied. We aimed to determine whether spatial analysis of the distribution of corneal nerve branching points (CNBPs) may contribute to improving the detection of early CNF loss. We hypothesized that early CNF decline follows a clustered rather than random distribution pattern of CNBPs. CCM, nerve conduction studies (NCS), and quantitative sensory testing (QST) were performed in a cross-sectional study including 86 patients recently diagnosed with type 2 diabetes and 47 control subjects. In addition to CNFL, CNFD, and branch density (CNBD), CNBPs were analyzed using spatial point pattern analysis (SPPA) including 10 indices and functional statistics. Compared to controls, patients with diabetes showed lower CNBP density and higher nearest neighbor distances, and all SPPA parameters indicated increased clustering of CNBPs (all P97.5th percentile of controls in up to 23.5% of patients. When combining an individual SPPA parameter with CNFL, ≥1 of 2 indices were >99th or <1st percentile of controls in 28.6% of patients compared to 2.1% of controls, while for the conventional CNFL/CNFD/CNBD combination the corresponding rates were 16.3% vs 2.1%. SPPA parameters correlated with CNFL and several NCS and QST indices in the controls (all P<0.001), whereas in patients with diabetes these correlations were markedly weaker or lost. In conclusion, SPPA reveals increased clustering of early CNF loss and substantially improves its detection when combined with a conventional CCM measure in patients with recently diagnosed type 2 diabetes

APC/CCdh1-Mediated Degradation of the F-Box Protein NIPA Is Regulated by Its Association with Skp1

NIPA (Nuclear Interaction Partner of Alk kinase) is an F-box like protein that targets nuclear Cyclin B1 for degradation. Integrity and therefore activity of the SCFNIPA E3 ligase is regulated by cell-cycle-dependent phosphorylation of NIPA, restricting substrate ubiquitination to interphase. Here we show that phosphorylated NIPA is degraded in late mitosis in an APC/CCdh1-dependent manner. Binding of the unphosphorylated form of NIPA to Skp1 interferes with binding to the APC/C-adaptor protein Cdh1 and therefore protects unphosphorylated NIPA from degradation in interphase. Our data thus define a novel mode of regulating APC/C-mediated ubiquitination

Resonant metamaterials for contrast enhancement in optical lithography

The transmission through ultra-thin metal films is noticeable and thus limits their potential for the formation of lithographic masks. By sub-wavelength patterning of a metal film with a post structure, a resonant metamaterial is formed, which can effectively suppress the transmission. Measurements as well as calculations identify the width of the metal islands as a critical geometrical feature. Hence, the extraordinarily low transmission effect can be explained by the resonant response of single scatterers known as Localized Surface Plasmon Resonances (LSPR). A potential application of this suppressed transmission effect to thin metal masks in optical lithography is experimentally investigated