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Malignant transformation of oral lichen planus (OLP) into oral squamous cell carcinoma is considered as one of the most serious complications of OLP. For the early detection of oral cancer in OLP follow-up, accurate localization of the OLP center is still difficult but often required for confirmatory biopsy with histopathological examination. Optical coherence tomography (OCT) offers the potential for more reliable biopsy sampling in the oral cavity as it is capable of non-invasively imaging the degenerated oral layer structure. In this case-series study with 15 patients, features of clinically classified forms of OLP in OCT cross-sections were registered and correlated with available histologic sections. Besides patients with reticular, atrophic, erosive and plaque-like OLP, two patients with leukoplakia were included for differentiation. The results show that OCT yields information about the epithelial surface, thickness and reflectivity, as well as the identifiability of the basement membrane and the vessel network, which could be used to complement the visual clinical appearance of OLP variants and allow a more accurate localization of the OLP center. This forms the basis for further studies on OCT-assisted non-invasive clinical classification of OLP, with the aim of enabling decision support for biopsy sampling in the future.

The risk of SARS-CoV-2 infection is particularly high for healthcare workers during the pandemic. Home care workers visit many different households per shift. Encounters with mostly elderly patients and their relatives increase the potential for the undetected spread of SARS-CoV-2. In order to gain insight into the seroprevalence of SARS-CoV-2 antibodies and possible transmission risks in outpatient care, this follow-up study was conducted with nursing services in Hamburg. The aim was to estimate the dynamics of seroprevalence in this occupational group over a 12-month period, to identify occupation-specific risk factors, and to collect information on the vaccination status of the surveyed nursing staff. Antibody testing for SARS-CoV-2 IgG against the S1 domain (EUROIMUN Analyser I ® Lübeck, Germany) was performed on participating healthcare workers with patient contact at a total of four time points within one year from July 2020 to October 2021 (baseline, follow-up after three, six and twelve months). The data were mostly analysed descriptively. Differences in IgG titres were analysed using variance analysis methods, particularly Tukey's range test. The seroprevalence was 1.2% (8/678) at baseline and 1.5% (9/581) at the three-month follow-up (T1). At the second follow-up (T2) after six months, vaccination against SARS-CoV-2 was available from January 2021 onwards. The prevalence rate of positive IgG antibodies relative to the S1 domain of the spike protein test among unvaccinated individuals was 6.5%. At (T3) after twelve months (July to October 2021), 482 participants were enrolled, and 85.7% of the workers were considered fully vaccinated at this time point, while 51 individuals were unvaccinated. The prevalence was 13.7% (7/51). In our study, a low seroprevalence was found among home care workers, which was lower than in our studies conducted in the clinical setting. Therefore, it can be assumed that the occupational risk of infection is rather low for both the nursing staff and the patients/clients cared for in the outpatient setting. The good provision of protective equipment and the high vaccination rate of the staff probably had a positive influence.

The in ovo sexing of chicken eggs is a current task and a prerequisite to overcome the mass killing of male day-old chicks from laying lines. Although various methods have been developed and tested in recent years, practicable methods for sex determination are still missing which can be applicated in poultry hatcheries before the chicken embryo is capable of nociception and pain sensation. Optical spectroscopic methods enable an early determination of the sex. In this study, a novel method based on two-wavelength in ovo fluorescence excitation is described. More than 1600 eggs were examined. In ovo fluorescence was sequentially excited at 532 nm and 785 nm. The fluorescence intensities of the spectral regions behave inversely with respect to sex. It is shown that the observed sex-related differences in the fluorescence intensities are based on the embryonic hemoglobin synthesis. The accuracy of sex determination is 96% for both sexes. The hatching rate is not reduced compared to an equivalent reference group., (© 2022. The Author(s).)

Background: Acute respiratory distress syndrome is a life-threatening condition with a hospital mortality rate of up to 40%. Biomarkers related to the pathophysiology of ARDS may not only identify patients at risk but may also serve as potential therapeutic targets. This study examined the association between the proteolytic C-terminal 42-peptide fragment of alpha-1 antitrypsin and ARDS severity., Methods: The 42-peptide fragment and interleukin-6 levels were measured in 21 patients with mild-to-moderate ARDS and 47 patients with moderate-to-severe ARDS on days 1, 3, and 5 after diagnosis/admission to the intensive care unit. To elucidate the association between both biomarkers and the PaO 2 /FiO 2 ratio, the concentrations of both biomarkers were compared between the two groups, and a multivariate regression analysis was performed., Results: The concentrations of both biomarkers were higher in patients with moderate-to-severe ARDS. While the PaO 2 /FiO 2 ratio increased from day 1 to day 3, the concentrations of both biomarkers decreased. Multivariate regression analysis revealed negative associations between the PaO 2 /FiO 2 ratio and both the C-terminal 42-peptide of alpha-1 antitrypsin and interleukin-6 on day 1 (beta: -0.138, p = 0.052; beta: -0.096, p = 0.004) and on day 3 (beta: -0.157, p = 0.045; beta: -0.106, p = 0.043)., Interpretation: The C-terminal 42-peptide of alpha-1 antitrypsin is a new biomarker associated with ARDS severity. Its predictive value in identifying patients at risk of developing moderate-to-severe ARDS must be investigated in additional, independent prospective studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

This study presents a highly miniaturized, handheld probe developed for rapid assessment of soft tissue using optical coherencetomography (OCT). OCT is a non-invasive optical technology capable of visualizing the sub-surface structural changes that occur in soft tissue disease such as oral lichen planus. However, usage of OCT in the oral cavity has been limited, as the requirements for high-quality optical scanning have often resulted in probes that are heavy, unwieldy and clinically impractical. In this paper, we present a novel probe that combines an all-fiber optical design with a light-weight magnetic scanning mechanism to provide easy access to the oral cavity. The resulting probe is approximately the size of a pen (10 mm × 140 mm) and weighs only 10 grams. To demonstrate the feasibility and high image quality achieved with the probe, imaging was performed on the buccal mucosa and alveolar mucosa during routine clinical assessment of six patients diagnosed with oral lichen planus. Results show the loss of normal tissue structure within the lesion, and contrast this with the clear delineation of tissue layers in adjacent inconspicuous regions. The results also demonstrate the ability of the probe to acquire a three-dimensional data volume by manually sweeping across the surface of the mucosa. The findings of this study show the feasibility of using a small, lightweight probe to identify pathological features in oral soft tissue.

Background : Mechanical ventilation (MV) inflicts stress on the lungs, initiating or increasing lung inflammation, so-called ventilator-induced lung injury (VILI). Besides overdistention, cyclic opening-and-closing of alveoli (atelectrauma) is recognized as a potential mechanism of VILI. The dynamic stretch may be reduced by positive end-expiratory pressure (PEEP), which in turn increases the static stretch. We investigated whether static stretch modulates the inflammatory response of rat type 2 alveolar epithelial cells (AECs) at different levels of dynamic stretch and hypothesized that static stretch increases pro-inflammatory response of AECs at given dynamic stretch. Methods: AECs, stimulated and not stimulated with lipopolysaccharide (LPS), were subjected to combinations of static (10, 20, and 30%) and dynamic stretch (15, 20, and 30%), for 1 and 4 h. Non-stretched AECs served as control. The gene expression and secreted protein levels of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein 2 (MIP-2) were studied by real-time polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The effects of static and dynamic stretch were assessed by two-factorial ANOVA with planned effects post-hoc comparison according to Šidák. Statistical significance was considered for p < 0.05. Results: In LPS-stimulated, but not in non-stimulated rat type 2 AECs, compared to non-stretched cells: 1) dynamic stretch increased the expression of amphiregulin (AREG) ( p < 0.05), MCP-1 ( p < 0.001), and MIP-2 (<0.05), respectively, as well as the protein secretion of IL-6 ( p < 0.001) and MCP-1 ( p < 0.05); 2) static stretch increased the gene expression of MCP-1 ( p < 0.001) and MIP-2, but not AREG, and resulted in higher secretion of IL-6 ( p < 0.001), but not MCP-1, while MIP-2 was not detectable in the medium. Conclusion: In rat type 2 AECs stimulated with LPS, static stretch increased the pro-inflammatory response to dynamic stretch, suggesting a potential pro-inflammatory effect of PEEP during mechanical ventilation at the cellular level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ferreira, Huhle, Müller, Schnabel, Mehner, Koch and Gama de Abreu.)

C-terminal peptides (CAAPs) of the highly abundant serine protease alpha-1-antitrypsin (A1AT) have been identified at various lengths in several human materials and have been proposed to serve as putative biomarkers for a variety of diseases. CAAPs are enzymatically formed and these enzymatic activities are often associated with excessive immune responses (e.g. sepsis, allergies). However, most of those CAAPs have been either detected using in vitro incubation experiments or in human materials which are not easily accessible. To gain a comprehensive understanding about the occurrence and function of CAAPs in health and disease, a LC-MS/MS method for the simultaneous detection of nine CAAPs was developed and validated for human plasma (EDTA and lithium-heparin) and serum. Using this newly developed method, we were able to detect and quantify five CAAPs in healthy individuals thereby providing an initial proof for the presence of C36, C37, C40 and C44 in human blood. Concentrations of four CAAPs in a clinical test cohort of patients suffering from sepsis were significantly higher compared to healthy controls. These results reveal that in addition to C42 other fragments of A1AT seem to play a crucial role during systemic infections. The proposed workflow is simple, rapid and robust; thus this method could be used as diagnostic tool in routine clinical chemistry as well as for research applications for elucidating the diagnostic potential of CAAPs in numerous diseases. To this end, we also provide an overview about the current state of knowledge for CAAPs identified in vitro and in vivo., (© 2022. The Author(s).)

In comparison to mammals, zebrafish are able to regenerate many organs and tissues, including the central nervous system (CNS). Within the CNS-derived neural retina, light lesions result in a loss of photoreceptors and the subsequent activation of Müller glia, the retinal stem cells. Müller glia-derived progenitors differentiate and eventually restore the anatomical tissue architecture within 4 weeks. However, little is known about how light lesions impair vision functionally, as well as how and to what extent visual function is restored during the course of regeneration, in particular in adult animals. Here, we applied quantitative behavioral assays to assess restoration of visual function during homeostasis and regeneration in adult zebrafish. We developed a novel vision-dependent social preference test, and show that vision is massively impaired early after lesion, but is restored to pre-lesion levels within 7 days after lesion. Furthermore, we employed a quantitative optokinetic response assay with different degrees of difficulty, similar to vision tests in humans. We found that vision for easy conditions with high contrast and low level of detail, as well as color vision, was restored around 7-10 days post lesion. Vision under more demanding conditions, with low contrast and high level of detail, was regained only later from 14 days post lesion onwards. Taken together, we conclude that vision based on contrast sensitivity, spatial resolution and the perception of colors is restored after light lesion in adult zebrafish in a gradual manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hammer, Röppenack, Yousuf, Schnabel, Weber, Zöller, Koch, Hans and Brand.)

Employment relationships are embedded in a network of social norms that provide an implicit framework for desired behaviour, especially if contractual solutions are weak. The COVID-19 pandemic has brought about major changes that have led to situations, such as the scope of short-time work or home-based work in a firm. Against this backdrop, our study addresses three questions: first, are there social norms dealing with these changes; second, are there differences in attitudes between employees and supervisors (misalignment); and third, are there differences between respondents' average attitudes and the attitudes expected to exist in the population (pluralistic ignorance). We find that for the assignment of short-time work and of work at home, there are shared normative attitudes with only small differences between supervisors and nonsupervisors. Moreover, there is evidence for pluralistic ignorance; asked for the perceived opinion of others, respondents over- or underestimated the consensus in the (survey) population. Such pluralistic ignorance can contribute to the upholding of a norm even if individuals do not support the norm, with potentially far-reaching consequences for the quality of the employment relationship and the functioning of the organization. Our results show that, especially in times of change, social norms should be considered for the analysis of labour markets., Competing Interests: Competing interestsNo competing interests to declare., (© The Author(s) 2022.)

Aortic valve sclerosis is characterized as the thickening of the aortic valve without obstruction of the left ventricular outflow. It has a prevalence of 30% in people over 65 years old. Aortic valve sclerosis represents a cardiovascular risk marker because it may progress to moderate or severe aortic valve stenosis. Thus, the early recognition and management of aortic valve sclerosis are of cardinal importance. We examined the aortic valve geometry and structure from healthy C57Bl6 wild type and age-matched hyperlipidemic ApoE -/- mice with aortic valve sclerosis using optical coherence tomography (OCT) and multiphoton microscopy (MPM) and compared results with histological analyses. Early fibrotic thickening, especially in the tip region of the native aortic valve leaflets from the ApoE -/- mice, was detectable in a precise spatial resolution using OCT. Evaluation of the second harmonic generation signal using MPM demonstrated that collagen content decreased in all aortic valve leaflet regions in the ApoE -/- mice. Lipid droplets and cholesterol crystals were detected using coherent anti-Stokes Raman scattering in the tissue from the ApoE -/- mice. Here, we demonstrated that OCT and MPM, which are fast and precise contactless imaging approaches, are suitable for defining early morphological and structural alterations of sclerotic murine aortic valves.

To date, there is still a lack of reliable imaging modalities to improve the quality of consultation, diagnostic and medical examinations of the oral mucosa in dentistry. Even though, optical technologies have become an important element for the detection and treatment of different diseases of soft tissue, for the case of oral screenings the evidence of the benefit in comparison to conventional histopathology is mostly still pending. One promising optical technology for oral diagnostics is optical coherence tomography (OCT). To prove the potential of OCT, even the amount of freely accessible OCT data is not sufficient to describe the variance of healthy human oral soft tissue in vivo. In order to remedy this deficiency, the present study provides in vivo OCT cross sections of the human oral mucosa of the anterior and posterior oral cavity as well as the oropharynx of 47 adult volunteers. A collection of representative OCT cross sections forms the basis for a randomized blinded image analysis by means of seven criteria to assess the main features of the superficial layers of the human oral mucosa and to determine its correlation to regional features known from hematoxylin and eosin (HE) stained histology.

Vitamin D and its receptor may play a role in preventing tumor development and progression. As such antineoplastic effects are expected to be weak and to act over long periods, conditions with increased tumor incidence, such as the neurofibromatosis type 1 (NF1), provide suitable study models. We previously found an inverse correlation of serum 25(OH)D concentration with number of neurofibromas in NF1. Here we aim to further explore the role of the vitamin D receptor. A total of 141 adult NF1 patients were included in the study. For 101 of them, serum vitamin 25(OH)D data were available. From 87 patients, blood samples were obtained in PaxGene tubes containing a reagent to stabilize RNA immediately. mRNA of the vitamin D receptor (VDR) gene (coding for the vitamin D receptor) was measured by means of RT-PCR. Correlation of laboratory data with NF1-related tumors was statistically evaluated. Vitamin D receptor in NF1-tumors was examined by means of immunohistochemistry using an antibody against the vitamin D1 receptor. The number of dermal neurofibromas was significantly inversely correlated with VDR mRNA level and with serum 25(OH)D concentration in NF1 patients. In contrast, plexiform neurofibroma and malignant peripheral nerve sheath tumor did not correlate with these two parameters. Immunostaining did not detect vitamin D receptor in NF1-tumors. Both vitamin D and its receptor may play a role in suppressing the development of neurofibromas. Sustaining 25(OH)D at an adequate level may contribute to controlling neurofibromas and possibly also other tumors. This is especially important for individuals with lower expression of VDR.

An intraoperative imaging system facilitating the localisation and characterisation of functional areas, pathological tissue, or perfusion disorders, could enormously support medical decisions during neurosurgical interventions and, thus, reduce the risk for the patients. To provide both structural and functional information of the brain tissue to the surgeon, a novel multimodal approach based on the measurement of long-wave infrared radiation and visual-light imaging is very promising. In this contribution, we discuss various methods for the registration and fusion of thermographic and visual-light images. The methods are evaluated quantitatively and qualitatively regarding their practicability during surgery. Furthermore, we introduce appropriate architectures for a digital hardware implementation of the registration and fusion algorithms. The designs are implemented on our reconfigurable intraoperative imaging system, revealing real-time processing performance.

Cosmc is ubiquitously expressed and acts as a specific molecular chaperone assisting the folding and stability of core 1 synthase. Thus, it plays a crucial role in the biosynthesis of O-linked glycosylation of proteins. Here, we show that ablation of Cosmc in the exocrine pancreas of mice causes expression of truncated O-glycans (Tn antigen), resulting in exocrine pancreatic insufficiency with decreased activities of digestive enzymes and diabetes. To understand the molecular causes of the pleiotropic phenotype, we used Vicia villosa agglutinin to enrich Tn antigen-modified proteins from Cosmc-KO pancreatic lysates and performed a proteomic analysis. Interestingly, a variety of proteins were identified, of which bile salt-activated lipase (also denoted carboxyl-ester lipase, Cel) was the most abundant. In humans, frameshift mutations in CEL cause maturity-onset diabetes of the young type 8 (MODY8), a monogenic syndrome of diabetes and pancreatic exocrine dysfunction. Here, we provide data suggesting that differentially O-glycosylated Cel could negatively affect beta cell function. Taken together, our findings demonstrate the importance of correct O-glycan formation for normal exocrine and endocrine pancreatic function, implying that aberrant O-glycans might be relevant for pathogenic mechanisms of the pancreas.

Importance: Multiple molecular signatures are available for managing estrogen receptor (ER)-positive breast cancer but with little direct comparative information to guide the patient's choice., Objective: To conduct a within-patient comparison of the prognostic value of 6 multigene signatures in women with early ER-positive breast cancer who received endocrine therapy for 5 years., Design, Setting, and Participants: This retrospective biomarker analysis included 774 postmenopausal women with ER-positive ERBB2 (formerly HER2)-negative breast cancer. This analysis was performed as a preplanned secondary study of data from the Anastrozole or Tamoxifen Alone or Combined randomized clinical trial comparing 5-year treatment with anastrozole vs tamoxifen with 10-year follow-up data. The signatures included the Oncotype Dx recurrence score, PAM50-based Prosigna risk of recurrence (ROR), Breast Cancer Index (BCI), EndoPredict (EPclin), Clinical Treatment Score, and 4-marker immunohistochemical score. Data were collected from January 2009, through April 2015., Main Outcomes and Measures: The primary objective was to compare the prognostic value of these signatures in addition to the Clinical Treatment Score (nodal status, tumor size, grade, age, and endocrine treatment) for distant recurrence for 0 to 10 years and 5 to 10 years after diagnosis. Likelihood ratio (LR) statistics were used with the χ2 test and C indexes to assess the prognostic value of each signature., Results: In this study of 774 postmenopausal women with ER-positive, ERBB2-negative disease (mean [SD] age, 64.1 [8.1] years), 591 (mean [SD] age, 63.4 [7.9] years) had node-negative disease. The signatures providing the most prognostic information were the ROR (hazard ratio [HR], 2.56; 95% CI, 1.96-3.35), followed by the BCI (HR, 2.46; 95% CI, 1.88-3.23) and EPclin (HR, 2.14; 95% CI, 1.71-2.68). Each provided significantly more information than the Clinical Treatment Score (HR, 1.99; 95% CI, 1.58-2.50), the recurrence score (HR, 1.69; 95% CI, 1.40-2.03), and the 4-marker immunohistochemical score (HR, 1.95; 95% CI, 1.55-2.45). Substantially less information was provided by all 6 molecular tests for the 183 patients with 1 to 3 positive nodes, but the BCI (ΔLR χ2 = 9.2) and EPclin (ΔLR χ2 = 7.4) provided more additional prognostic information than the other signatures., Conclusions and Relevance: For women with node-negative disease, the ROR, BCI, and EPclin were significantly more prognostic for overall and late distant recurrence. For women with 1 to 3 positive nodes, limited independent information was available from any test. These data might help oncologists and patients to choose the most appropriate test when considering chemotherapy use and/or extended endocrine therapy., Trial Registration: isrctn.com Identifier: ISRCTN18233230.

The negative correlation between fattening and laying performance prevents breeding improvement in both laying performance and meat yield. Therefore, specialized chicken lines have been bred in order to achieve either an efficient production of high-quality eggs or high growth rates. As a result, day-old male chicks are culled in the layer hatchery, which poses animal welfare and ethical problems. Breeding companies, scientific groups, and hatcheries are attempting to resolve this issue, with a common aim to find feasible alternatives for the routine killing of male layer chicks. Some approaches aim to influence the sex ratio, while others target at the economically feasible use of the male layer offspring, such as the fattening of "laying hen brothers" or crossbreedings of layers and broilers to create "dual-purpose chickens." Another approach is the sex determination prior to hatch. One of the prerequisites of in ovo sex determination is a practicable method that can be used in industry. The analysis needs to be rapid, cost-efficient, and highly precise; in addition, negative impacts on hatching rate, animal health, and/or performance parameters should be limited. Furthermore, sex determination should be performed before the sensory nervous system's response of the chick embryo to certain or potentially harmful stimuli is developed, which according to current knowledge is before the d 7 of incubation.

The common way to diagnose hard and soft tissue irregularities in the oral cavity is initially the visual inspection by an experienced dentist followed by further medical examinations, such as radiological imaging and/or histopathological investigation. For the diagnosis of oral hard and soft tissues, the detection of early transformations is mostly hampered by poor visual access, low specificity of the diagnosis techniques, and/or limited feasibility of frequent screenings. Therefore, optical noninvasive diagnosis of oral tissue is promising to improve the accuracy of oral screening. Considering this demand, a rigid handheld endoscopic scanner was developed for optical coherence tomography (OCT). The novelty is the usage of a commercially near-infrared endoscope with fitting optics in combination with an established spectral-domain OCT system of our workgroup. By reaching a high spatial resolution, in vivo images of anterior and especially posterior dental and mucosal tissues were obtained from the oral cavity of two volunteers. The convincing image quality of the endoscopic OCT device is particularly obvious for the imaging of different regions of the human soft palate with highly scattering fibrous layer and capillary network within the lamina propria., ((2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).)

Objectives: To determine predictive/prognostic factors for patients with metastatic breast cancer (MBC) receiving first-line monochemotherapy using biomarker analysis and geriatric assessment (GA)., Materials and Methods: Karnofsky Performance Status (KPS) and GA as clinical parameters, and prognostic inflammatory and nutritional index (PINI), and Glasgow prognostic score (GPS) as biomarkers were analyzed for association with clinical outcome within the randomized phase III PEg-LIposomal Doxorubicin vs. CApecitabin iN MBC (PELICAN) trial of first-line pegylated liposomal doxorubicin (PLD) or capecitabine., Results: Of 210 patients, 38% were >65years old. GA (n=152) classified 74% as fit, 10% as compromised, and 16% as frail. Biomarkers showed no age dependency. In multivariate analysis (n=70) KPS, GA, cumulative illness rating scale-geriatrics (CIRS-G), and GPS were significantly associated with time to progression, and KPS, CIRS-G, and instrumental activities of daily living (IADL) from GA, and PINI showed a significant correlation with overall survival., Conclusion: GA evaluation was feasible. KPS significantly correlated with efficacy outcomes. Items of a GA and biomarkers of inflammation and nutrition may have prognostic significance in patients with MBC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In order to provide an alternative to day-old chick culling in the layer hatcheries, a noninvasive method for egg sexing is required at an early stage of incubation before onset of embryo sensitivity. Fluorescence and Raman spectroscopy of blood offers the potential for precise and contactless in ovo sex determination of the domestic chicken (Gallus gallus f. dom.) eggs already during the fourth incubation day. However, such kind of optical spectroscopy requires a window in the egg shell, is thus invasive to the embryo and leads to decreased hatching rates. Here, we show that near infrared Raman and fluorescence spectroscopy can be performed on perfused extraembryonic vessels while leaving the inner egg shell membrane intact. Sparing the shell membrane makes the measurement minimally invasive, so that the sexing procedure does not affect hatching rates. We analyze the effect of the membrane above the vessels on fluorescence signal intensity and on Raman spectrum of blood, and propose a correction method to compensate for it. After compensation, we attain a correct sexing rate above 90% by applying supervised classification of spectra. Therefore, this approach offers the best premises towards practical deployment in the hatcheries.

Recent developments in the prediction of local aerosol deposition in human lungs are driven by the fast development of computational simulations. Although such simulations provide results in unbeatable resolution, significant differences among distinct methods of calculation emphasize the need for highly precise experimental data in order to specify boundary conditions and for validation purposes. This paper reviews and critically evaluates available methods for the measurement of single and disperse two-phase flows for the study of respiratory airflow and deposition of inhaled particles, performed both in vivo and in replicas of airways. Limitations and possibilities associated with the experimental methods are discussed and aspects of the computational calculations that can be validated are indicated. The review classifies the methods into following categories: 1) point-wise and planar methods for velocimetry in the airways, 2) classic methods for the measurement of the regional distribution of inhaled particles, 3) standard medical imaging methods applicable to the measurement of the regional aerosol distribution and 4) emerging and nonconventional methods. All methods are described, applications in human airways studies are illustrated, and recommendations for the most useful applications of each method are given., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.

The 138 La- 138 Ce decay system (half-life 1.02 × 10 11 years) is a potentially highly useful tool to unravel information about the timing of geological processes and about the interaction of geological reservoirs on earth, complementing information from the more popular 147 Sm- 143 Nd and 176 Lu- 176 Hf isotope systems. Previously published analytical protocols were limited to TIMS. Here we present for the first time an analytical protocol that employs MC-ICPMS, with an improved precision and sensitivity. To perform sufficiently accurate La-Ce measurements, an efficient ion-chromatographic procedure is required to separate Ce from the other rare earth elements (REE) and Ba quantitatively. This study presents an improved ion-chromatographic procedure that separates La and Ce from rock samples using a three-step column separation. After REE separation by cation exchange, Ce is separated employing an Ln Spec column and selective oxidation. In the last step, a cation clean-up chemistry is performed to remove all remaining interferences. Our MC-ICPMS measurement protocol includes all stable Ce isotopes ( 136 Ce, 138 Ce, 140 Ce and 142 Ce), by employing a 10 10 ohm amplifier for the most abundant isotope 140 Ce. An external reproducibility of ±0.25 ε -units (2 r.s.d) has been routinely achieved for 138 Ce measurements for as little as 150-600 ng Ce, depending on the sample-skimmer cone combinations being used. Because the traditionally used JMC-304 Ce reference material is not commercially available anymore, a new reference material was prepared from AMES laboratory Ce metal (Cologne-AMES). In order to compare the new material with the previously reported isotopic composition of AMES material prepared at Mainz (Mainz-AMES), Cologne-AMES and JMC-304 were measured relative to each other in the same analytical session, demonstrating isotope heterogeneity between the two AMES and different JMC-304 batches used in the literature. To enable sufficiently precise age correction of radiogenic 138 Ce and to perform isochron dating, a protocol was developed where La and Ce concentrations are determined by isotope dilution (ID), using an isotope tracer enriched in 138 La and 142 Ce. The new protocols were applied to determine the variations of Ce isotope compositions and La-Ce concentrations of certified geochemical reference materials (CRMs): BCR-2, BCR-1, BHVO-2, JR-1, JA-2, JB-3, JG-1, JR-1, JB-1b, AGV-1 and one in-house La Palma standard.

Multimodal medical image fusion combines information of one or more images in order to improve the diagnostic value. While previous applications mainly focus on merging images from computed tomography, magnetic resonance imaging (MRI), ultrasonic and single-photon emission computed tomography, we propose a novel approach for the registration and fusion of preoperative 3D MRI with intraoperative 2D infrared thermography. Image-guided neurosurgeries are based on neuronavigation systems, which further allow us track the position and orientation of arbitrary cameras. Hereby, we are able to relate the 2D coordinate system of the infrared camera with the 3D MRI coordinate system. The registered image data are now combined by calibration-based image fusion in order to map our intraoperative 2D thermographic images onto the respective brain surface recovered from preoperative MRI. In extensive accuracy measurements, we found that the proposed framework achieves a mean accuracy of 2.46 mm.

Mechanical ventilation has the potential to increase inflammation in both healthy and injured lungs. Several animal studies have shown that variable ventilation recruits the lungs and reduces inflammation. However, it is unclear which cellular mechanisms are involved in those findings. We hypothesized that variable stretch of LPS-stimulated alveolar epithelial cells (AECs) reduces the production of pro-inflammatory cytokines compared to non-variable stretch. AECs were subjected to non-variable or variable cyclic stretch (sinusoidal pattern), with and without LPS stimulation. The expression and release of interleukin-6, CXCL-2 and CCL-2 mRNA were analyzed after 4 hours. The phosphorylation of the MAPKs ERK1/2 and SAPK/JNK was determined by Western Blot analysis at 0, 15, 30, 45 and 60 min of cyclic stretch. In LPS-stimulated AECs, variable cyclic cell stretching led to reduced cytokine expression and release compared to non-variable cell stretching. Furthermore, the phosphorylation of the MAPK ERK1/2 was increased after 30 minutes in non-variable stretched AECs, whereas variable stretched cells demonstrated only the non-stretched level of phosphorylation. After the 4h period of cyclic cell stretch and inhibition of the ERK1/2, but not the SAPK/JNK, signaling pathway, the gene expression of investigated cytokines increased in variable stretched, and decreased in non-variable stretched AECs. We conclude that in LPS-stimulated AECs, variable stretch reduced the pro-inflammatory response compared to non-variable stretch. This effect was mediated by the ERK1/2 signaling pathway, and might partly explain the findings of reduced lung inflammation during mechanical ventilation modes that enhance breath-by-breath variability of the respiratory pattern.

The structure of domain walls (DW) in ferroelectric media is of great interest as this material is used for frequency doublers and other applications. We show that the structure of the DWs can nicely be visualized by high resolution optical coherence tomography (OCT). While the high group refractive index of lithium niobate allows a resolution much better than 1 µm, the large dispersion can blur the image and has to be compensated. Therefore, we developed an adaptive dispersion compensation algorithm based on maximizing the intensity of the DWs. By measuring a group of DWs, the mean period of the DWs could be measured with an accuracy of less than 10 nm differentiating samples with only 30 nm distinct periods. By analyzing the peak position, amplitude and phase shift within a DW, we were able to determine steps in the DW of only 50 nm. Furthermore, the inclined course of the DWs in a fan-shaped frequency doubler could be displayed. Therefore, we conclude that OCT is able to provide valuable information about the structure of domain walls in periodically poled lithium niobate (PPLN).

Extended adjuvant endocrine therapy (10 vs. 5 years) trials have demonstrated improved outcomes in early-stage estrogen receptor (ER)-positive breast cancer; however, the absolute benefit is modest, and toxicity and tolerability challenges remain. Predictive and prognostic information from genomic analysis may help inform this clinical decision. The purpose of this study was to assess the impact of the Breast Cancer Index (BCI) on physician recommendations for extended endocrine therapy and on patient anxiety and decision conflict. Patients with stage I-III, ER-positive breast cancer who completed at least 3.5 years of adjuvant endocrine therapy were offered participation. Genomic classification with BCI was performed on archived tumor tissues and the results were reported to the treating physician who discussed results with the patient. Patients and physicians completed pre- and post-test questionnaires regarding preferences for extended endocrine therapy. Patients also completed the validated traditional Decisional Conflict Scale (DCS) and State Trait Anxiety Inventory forms (STAI-Y1) pre- and post-test. 96 patients were enrolled at the Yale Cancer Center [median age 60.5 years (range 45-87), 79% postmenopausal, 60% stage I). BCI predicted a low risk of late recurrence in 59% of patients versus intermediate/high in 24 and 17%, respectively. Physician recommendations for extended endocrine therapy changed for 26% of patients after considering BCI results, with a net decrease in recommendations for extended endocrine therapy from 74 to 54%. After testing, fewer patients wanted to continue extended therapy and decision conflict and anxiety also decreased. Mean STAI and DCS scores were 31.3 versus 29.1 (p = 0.031) and 20.9 versus 10.8 (p < 0.001) pre- and post-test, respectively. Incorporation of BCI into risk/benefit discussions regarding extended endocrine therapy resulted in changes in treatment recommendations and improved patient satisfaction.

Intravital microscopy (IVM) is a well-established imaging technique for real-time monitoring of microscale lung tissue dynamics. Although accepted as a gold standard in respiratory research, its characteristic image features are scarcely understood, especially when trying to determine the actual position of alveolar walls. To allow correct interpretation of these images with respect to the true geometry of the lung parenchyma, we analyzed IVM data of alveoli in a mouse model in comparison with simultaneously acquired optical coherence tomography images. Several IVM characteristics, such as double ring structures or disappearing alveoli in regions of liquid filling, could be identified and related to the position of alveoli relative to each other. Utilizing a ray tracing approach based on an idealized geometry of the mouse lung parenchyma, two major reflection processes could be attributed to the IVM image formation: partial reflection and total internal reflection between adjacent alveoli. Considering the origin of the reflexes, a model was developed to determine the true position of alveolar walls within IVM images. These results allow thorough understanding of IVM data and may serve as a basis for the correction of alveolar sizes for more accurate quantitative analysis within future studies of lung tissue dynamics.

Leukocytes and their functional capacities are used extensively as biomarkers in immunological research. Commonly employed indicators concerning leukocytes are as follows: number, composition in blood, response to discrete stimuli, cytokine release, and morphometric characteristics. In order to employ leukocytes as biomarkers for disease and therapeutic monitoring, physiological variations and influencing factors on the parameters measured have to be considered. The aim of this report was to describe the ranges of selected leukocyte parameters in a sample of healthy horses and to analyse whether age, sex, breed, and sampling time point (time of day) influence peripheral blood leukocyte composition, cell morphology and release of cytokines ex vivo. Flow cytometric comparative characterisation of cell size and complexity in 24 healthy horses revealed significant variance. Similarly, basal release of selected cytokines by blood mononuclear cells also showed high variability [TNFα (65-16,624pg/ml), IFNγ (4-80U/ml), IL-4 (0-5069pg/ml), IL-10 (49-1862pg/ml), and IL-17 (4-1244U/ml)]. Each animal's age influenced leukocyte composition, cell morphology and cytokine release (TNFα, IL-4, IL-10) ex vivo. Geldings showed smaller monocytes and higher spontaneous production of IL-10 when compared to the mares included. The stimulation to spontaneous release ratios of TNFα, IL-4 and IL-17 differed in Warmblood and Thoroughbred types. Sampling time influenced leukocyte composition and cell morphology. In summary, many animal factors - age being the dominant one - should be considered for studies involving the analysis of equine leukocytes. In addition, high inter-individual variances argue for individual baseline measurements., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The management of patients with acquired factor V inhibitors is challenging, because their bleeding risk is highly variable and only poorly correlated with routine coagulation tests. Furthermore, there is no standardized treatment for bleeding control or inhibitor eradication. An 84-year-old white man underwent uneventful surgery for a ruptured intracerebral haemangioma. There were no perioperative coagulation abnormalities. Eight weeks after surgery, however, the prothrombin and the activated partial thromboplastin times were found to be maximally prolonged without signs of acute haemorrhage. A factor V inhibitor of 212 Bethesda units was diagnosed. We used a fluorogenic real-time thrombin generation assay with low concentrations of tissue factor (TF) to analyse the factor V inhibitor for interference with coagulation in platelet-poor plasma. Compared with three bleeding patients with acquired haemophilia A and severely deficient thrombin generation, total thrombin generation capacity was similar in the patient and healthy controls. However, the lag phase was significantly prolonged, suggesting a defect in the initiation/amplification, but not in the propagation phase of TF-triggered thrombin generation. This defect could be fully reproduced by purified patient IgG and largely corrected by ex-vivo addition of activated prothrombin complex concentrate, but not recombinant human FVIIa. Addition of normal platelets to the patient's plasma resulted in a pronounced shortening of the lag phase, suggesting that platelet-derived factor V can escape the inhibitor. Our findings offer an explanation for the absence of spontaneous bleeding in this patient and support the concept of platelet transfusions for the management of acute haemorrhages in patients with acquired factor V inhibitors.

The heart and its mechanical components, especially the heart valves and leaflets, are under enormous strain and undergo fatigue, which impinge upon cardiac output. The knowledge about changes of the dynamic behavior and the possibility of early stage diagnosis could lead to the development of new treatment strategies. Animal models are suited for the development and evaluation of new experimental approaches and therefor innovative imaging techniques are necessary. In this study, we present the time resolved visualization of healthy and calcified aortic valves in an ex vivo artificially stimulated heart model with 4D optical coherence tomography and high-speed video microscopy.

Objectives: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, frequently associated with reduced bone mineral density. Serum 25-hydroxyvitamin D3 concentrations in NF1 adults are lower than in healthy controls in autumn respectively winter and are inversely correlated with the number of dermal neurofibromas. We investigated 25-hydroxyvitamin D3 levels in children and adults with neurofibromatosis type 1 in winter and summer and compared them to healthy controls to get more pathogenic insights in vitamin D3 metabolism in NF1 patients., Design and Methods: NF1 patients were clinically examined and serum 25-hydroxyvitamin D3 concentrations were measured in 58 NF1 adults and 46 children in winter as well as in summer and compared to sex-, age- and month-matched controls., Results: 52 adults suffered from 10 to 5000 dermal neurofibromas, whereas none of the children presented neurofibromas. 25-Hydroxyvitamin D3 increased from winter to summer (mean: 21.0 to 46.5nmol/l) in NF1 adults. This increase was even larger (p=0.0001) than in healthy controls (mean: 50.5 to 60.5nmol/l). However, there were no differences of 25-hydroxyvitamin D3 concentrations in NF1 children and healthy controls both in winter and in summer., Conclusions: Only adults with NF1 showed lower 25-hydroxyvitamin D3 levels in winter and summer, which are unlikely due to impaired UV-dependent dermal synthesis, but rather might be caused by an accelerated catabolism., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Degenerative heart valve disease is a life-threatening disease affecting about 3% of the population over 65 years. Up to date, cardiac surgery with heart valve replacement is the only available therapy. The disease is characterized by degenerative disorganization of the heart valve structure and alterations in the residing cell populations. Causes and mechanisms of disease genesis are still not fully understood and until now pharmacological therapies are not available. Thus there is enormous interest in new technologies that enable a better characterization of structure and composition of diseased valves. Currently most research techniques demand for extensive processing of extracted valve material. We present a novel approach combining coherent anti-Stokes Raman scattering, endogenous two-photon excited fluorescence and second harmonic generation. Cusp constituents can be examined simultaneously, three-dimensionally and without extensive manipulation of the sample enabling impressive insights into a complex disease.

Neurofibromatosis type 1 is a tumor suppressor gene disorder which predisposes patients to cutaneous neurofibromas, plexiform neurofibromas (PNFs) and malignant peripheral nerve sheath tumors (MPNSTs) among other neoplasias and manifestation. In this study, we examined the efficiency of nilotinib on PNF-derived Schwann cells and on cells of established MPNST lines in vitro. Nilotinib treatment for 10 days led to decreased proliferation, viability and vitality of the cells with 50 % inhibitory concentration (IC50) for proliferation varying from 3.1 to 9.0 μM. We further addressed selectivity of the drug for tumor cells by simultaneously examining its efficacy on tumor cells (Schwann cells) and non-tumor cells (fibroblasts) from the same tumor. For four out of the six PNFs studied, IC50 was lower in Schwann cells than in fibroblasts for all parameters measured (proliferation, vitality and viability), indicating good drug selectivity. In addition, nilotinib induced apoptosis and suppressed collagenase activity. Our results suggest that nilotinib may provide a treatment option for some PNFs and MPNSTs and our in vitro model of comparative treatment on tumor and non-tumor cells may provide a prototype of preclinical drug screening system toward personalized treatment.

Little is known about mechanical processes of alveolar tissue during mechanical ventilation. Optical coherence tomography (OCT) as a three-dimensional and high-resolution imaging modality can be used to visualize subpleural alveoli during artificial ventilation. The quality of OCT images can be increased by matching the refractive index inside the alveoli to the one of tissue via liquid-filling. Thereby, scattering loss can be decreased and higher penetration depth and tissue contrast can be achieved. We show the liquid-filling of alveolar structures verified by optical coherence tomography and intravital microscopy (IVM) and the advantages of index matching for OCT imaging of subpleural alveoli in a mouse model using a custom-made liquid ventilator.

Research on equine cytokines is often performed by analyses of mRNA. For many equine cytokines an analysis on the actual protein level is limited by the availability of antibodies against the targeted cytokines. Generation of new antibodies is ongoing but time consuming. Thus, testing the reactivity of commercially available antibodies for cross-reactivity with equine cytokines is of particular interest. Fifteen monoclonal antibodies against IL-1β, IL-6, IL-8, IL-12, IL-18 and Granulocyte Macrophage Colony stimulating factor (GM-CSF) of different species were evaluated for reactivity with their corresponding equine cytokines. Dot Blot (DB) and Western Blot (WB) analyses were performed using recombinant equine cytokines as positive controls. Immunohistochemistry (IHC) was carried out on equine tissue and flow cytometry on equine PBMC as positive controls. As expected, three equine IL-1β antibodies detected equine IL-1β in DB, WB and IHC. For these, reactivity in IHC has not been described before. One of them was also found to be suitable for intracellular staining of equine PBMC and flow cytometric analysis. Two antibodies raised against ovine GM-CSF cross-reacted with equine GM-CSF in DB, WB and IHC. For these anti-GM-CSF mAbs this is the first experimental description of cross-reactivity with equine GM-CSF (one mAb was predicted to be cross-reactive in WB in the respective data sheet). The other clone additionally proved to be appropriate in flow cytometric analysis. Two mAbs targeting porcine IL-18 cross-reacted in IHC, but did not show specificity in the other applications. No reactivity was shown for the remaining five antibodies in DB, although cross-reactivity of two of the antibodies was described previously. The results obtained in this study can provide beneficial information for choosing of antibodies for immunological tests on equine cytokines., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objectives: We have previously demonstrated reduced bone density and an increased incidence of 25-hydroxy vitamin D3 (25-OH D3) deficiency in adults with neurofibromatosis 1 (NF1) compared to healthy controls. Vitamin D3 is a cheap, safe, and effective supplement in the general population, but its value in NF1 patients has not been demonstrated. This study investigates the therapeutic potential of oral vitamin D3 on bone mineral density (BMD) in NF1 patients with vitamin D3 deficiency., Methods: We measured serum 25-OH D3, parathyroid hormone, calcium, and bone alkaline phosphatase concentrations, urinary deoxypyridinoline concentrations, and BMD in 35 adults with NF1. Nineteen patients received vitamin D3 supplementation for 2 years, six patients received supplementation for 1 year and 10 patients received no supplementation. Supplementation was administered in a dose that maintained the serum 25-OH D3 level above 30 μg/l. BMD was measured again at 1 and 2 years, and biochemical assessments of bone metabolism were measured at least every half year during therapy., Results: Treated subjects had significantly reduced loss of BMD, as measured by T score at the hip (p=0.011) and lumbar spine (p=0.022). The effect on hip BMD was apparent at 1 year in comparison to baseline (p=0.02) and was greater at 2 years in comparison to measurements at 1 year (p=0.02)., Conclusions: Vitamin D3 supplementation improves BMD in adult NF1 patients. Further studies are needed to elucidate the mechanisms responsible for reduced BMD in NF1 patients., (Copyright © 2012 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

The investigation of lung dynamics on alveolar scale is crucial for the understanding and treatment of lung diseases, such as acute lung injury and ventilator induced lung injury, and to promote the development of protective ventilation strategies. One approach to this is the establishment of numerical simulations of lung tissue mechanics where detailed knowledge about three-dimensional alveolar structure changes during the ventilation cycle is required. We suggest four-dimensional optical coherence tomography (OCT) imaging as a promising modality for visualizing the structural dynamics of single alveoli in subpleural lung tissue with high temporal resolution using a mouse model. A high-speed OCT setup based on Fourier domain mode locked laser technology facilitated the acquisition of alveolar structures without noticeable motion artifacts at a rate of 17 three-dimensional stacks per ventilation cycle. The four-dimensional information, acquired in one single ventilation cycle, allowed calculating the volume-pressure curve and the alveolar compliance for single alveoli., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Acquired factor XIII (FXIII) deficiency is associated with reduced clot firmness and increased bleeding in patients undergoing major surgery. In contrast, only limited information is available on the haemostatic relevance of acquired FXIII deficiency in non-surgical patients., Case Report: An 81-year-old patient, who had experienced acute type-A dissection of the aorta eight years earlier, presented with a 3-year history of progressive mucocutaneous and soft-tissue bleeding. Diagnostic work-up was unremarkable for global coagulation tests, but FXIII and alpha2-antiplasmin were decreased to 33% and 27%, respectively, while plasma D-dimer was elevated to > 35 mg/l. A FXIII inhibitor was excluded by mixing studies. CT scanning revealed a massively elongated and progressively dilated aorta with a false lumen reaching from the left carotid artery to the iliac bifurcation. Bleeding control was achieved by single doses of FXIII at 20-30 IU/kg body weight and tailored oral tranexamic acid., Conclusion: Acquired FXIII deficiency with activity levels of 30-35% may confer a severe bleeding tendency in non-surgical patients, especially in the context of increased thrombin an fibrin generation.

Here we present the first reconstruction of vertical ice-sheet profile changes from any of the Southern Hemisphere's mid-latitude Pleistocene ice sheets. We use cosmogenic radio-nuclide (CRN) exposure analysis to record the decay of the former Patagonian Ice Sheet (PIS) from the Last Glacial Maximum (LGM) and into the late glacial. Our samples, from mountains along an east-west transect to the east of the present North Patagonian Icefield (NPI), serve as 'dipsticks' that allow us to reconstruct past changes in ice-sheet thickness, and demonstrates that the former PIS remained extensive and close to its LGM extent in this region until ~19.0 ka. After this time rapid ice-sheet thinning, initiated at ~18.1 ka, saw ice at or near its present dimension by 15.5 ka. We argue this rapid thinning was triggered by a combination of the rapid southward migration of the precipitation bearing Southern Hemisphere (SH) westerlies and regional warming.

Background: The aim of neoadjuvant chemotherapy is to increase the likelihood of successful breast conservation surgery (BCS). Accurate identification of BCS candidates is a diagnostic challenge. Breast Cancer Index (BCI) predicts recurrence risk in estrogen receptor+lymph node-breast cancer. Performance of BCI to predict chemosensitivity based on pathological complete response (pCR) and BCS was assessed., Methods: Real-time RT-PCR BCI assay was conducted using tumor samples from 150 breast cancer patients treated with neoadjuvant chemotherapy. Logistical regression and c-index were used to assess predictive strength and additive accuracy of BCI beyond clinicopathologic factors., Results: BCI classified 42% of patients as low, 35% as intermediate and 23% as high risk. Low BCI risk group had 98.4% negative predictive value (NPV) for pCR and 86% NPV for BCS. High versus low BCI group had a 34 and 5.8 greater likelihood of achieving pCR and BCS, respectively (P=0.0055; P=0.0022). BCI increased c-index for pCR (0.875-0.924; P=0.017) and BCS prediction (0.788-0.843; P=0.027) beyond clinicopathologic factors., Conclusions: BCI significantly predicted pCR and BCS beyond clinicopathologic factors. High NPVs indicate that BCI could be a useful tool to identify breast cancer patients who are not eligible for neoadjuvant chemotherapy. These results suggest that BCI could be used to assess both chemosensitivity and eligibility for BCS.

The tumor suppressor disorder neurofibromatosis type 1 (NF1) is associated with development of multiple neurofibromas which may grow intraneurally as plexiform neurofibromas (PNF) or intracutaneously (CNF). Upon surgery neurofibromas may show prominent swelling hindering skin-edge approximation. To assess whether the water binding glycosaminoglycan hyaluronan is involved in intra-operative swelling, 51 neurofibromas from 33 NF1-patients were investigated. Hyaluronan was histologically demonstrated and was quantified by ELISA. Molecular weight of hyaluronan was determined by gel filtration. Further, hyaluronan content was measured in cultivated Schwann cells and fibroblasts. Clinically, 67% of PNF were associated with moderate or severe intra-operative swelling, whereas only 36% of CNF showed this feature. Significantly higher levels of hyaluronan content were found in PNF compared to CNF (P < 0.05). Mast cell density did not correlate with any of the parameters. Molecular weight of hyaluronan in PNF and CNF ranged from higher than 10⁶ Da to approximately 10⁵ Da. Fibroblasts produced less hyaluronan than Schwann cells. The findings support the view that hyaluronan plays an important role in intra-operative swelling in neurofibroma surgery., (© 2011 Japanese Society of Neuropathology.)

Background: Pneumatic tube systems (PTSs) for the transport of blood samples are regaining popularity in medical centers after earlier reports that their use could introduce preanalytical distortions such as hemolysis and changes in blood gases., Methods: We drew duplicate blood samples from 30 volunteers. One sample was hand transported, and the other sample was transported through a PTS together with a mini-data logger that provided continuous measurements of temperature, humidity, pressure, and acceleration. After transport the samples were analyzed at the same time. We looked for possible relationships of the transport method and the parameters measured by the data loggers with differences in hematological parameters, standard clinical chemistry analyses, blood coagulation, erythrocyte sedimentation rate, and blood gas analysis., Results: There were no significant differences in temperature, humidity, and pressure between the methods of transport, but we observed significant differences in 3-axis accelerations. The combined effect of these forces could be described by the right-tailed area under the vector sum acceleration distribution. Our data show that this area correlated with PTS speed and that PTS speed and the area under the curve exhibited a direct relation to the degree of hemolysis., Conclusions: Assessment of 3-axis acceleration by use of data loggers can be used to identify preanalytical deviations that result from the transportation of blood samples in PTSs. Our approach could be used for the evaluation and regular control of PTSs without the need for repeated blood drawing and laboratory analyses.

We report the details of the total synthesis of natural and non-natural jatropha-5,12-dienes. The successful tactic for the assembly of the strained trans-bicyclo[10.3.0]pentadecane scaffold employed a B-alkyl Suzuki-Miyaura cross-coupling for the formation of the C5/C6 double bond and a ring-closing metathesis for the construction of the C12/C13 double bond. The key step of the synthesis of the cyclopentane fragment, an uncatalyzed intramolecular carbonyl-ene reaction, was studied computationally by DFT calculations. The members of the ensemble of synthetic natural and non-natural jatrophanes were subsequently examined as modulators for the ABCB1, ABCG2, and ABCC1 efflux proteins, which are associated with multidrug resistance in cancer chemotherapy.

Protein biomarker discovery in the low concentration range of human body fluids requires the enrichment of the proteins of interest. Here we report on a tandem affinity strategy: In the first step, we isolated a human plasma glyco-subproteome of healthy individuals by wheat germ agglutinin (WGA) lectin affinity chromatography. In the second step, the proteins of this subproteome were used to raise antibodies in llama (Lama glama). The heavy-chain fraction of the llama antibodies was used to deplete from the WGA lectin binding fraction all proteins normally found in human plasma. In this way, we selectively enriched the glycoprotein, CEA, a known cancer marker which had been spiked into normal plasma. As a proof of concept, we applied this method to the analysis of plasma sample from colon cancer patients. We could demonstrate the selective enrichment of CEA by a factor of 600-800.

In vivo determination of 3-D and dynamic geometries of alveolar structures with adequate resolution is essential for developing numerical models of the lung. A thorax window is prepared in anesthetized rabbits by removal of muscle tissue between the third and fourth rib without harming the parietal pleura. The transparent parietal pleura allows contact-free imaging by intravital microscopy (IVM) and 3-D optical coherence tomography (3-D OCT). We demonstrate that dislocation of the lung surface is small enough to observe identical regions in the expiratory and inspiratory plateau phase, and that OCT in this animal model is suitable for generating 3-D geometry of in vivo lung parenchyma. To our knowledge, we present a novel thorax window preparation technique for 3-D imaging of alveolar dynamics for the first time. The 3-D datasets of the fine structure of the lung beneath the pleura could provide a basis for the development of 3-D numerical models of the lung.

Unlabelled: Although it is known that neurofibromatosis 1 (NF1) patients suffer from vitamin D deficiency and display decreased bone mineral density (BMD), a systematic clinical and histomorphometrical analysis is absent. Our data demonstrate that NF1 patients display high bone turnover and accumulation of osteoid and that supplementation of vitamin D has a beneficial effect on their BMD., Introduction: Neurofibromatosis 1 results in a wide range of clinical manifestations, including decreased BMD. Although it has been reported that NF1 patients have decreased vitamin D serum levels, the manifestation of the disease at the bone tissue level has rarely been analyzed., Methods: Thus, we performed a clinical evaluation of 14 NF1 patients in comparison to age- and sex-matched control individuals. The analysis included dual X-ray absorptiometry osteodensitometry, laboratory parameters, histomorphometric and quantitative backscattered electron imaging (qBEI) analyses of undecalcified bone biopsies., Results: NF1 patients display significantly lower 25-(OH)-cholecalciferol serum levels and decreased BMD compared to control individuals. Histomorphometric analysis did not only reveal a reduced trabecular bone volume in biopsies from NF1 patients, but also a significantly increased osteoid volume and increased numbers of osteoblasts and osteoclasts. Moreover, qBEI analysis revealed a significant decrease of the calcium content in biopsies from NF1 patients. To address the question whether a normalization of calcium homeostasis improves BMD in NF1 patients, we treated four patients with cholecalciferol for 1 year, which resulted in a significant increase of BMD., Conclusion: Taken together, our data provide the first complete histomorphometric analysis from NF1 patients. Moreover, they suggest that low vitamin D levels significantly contribute to the skeletal defects associated with the disease.

The enantioselective total synthesis of the jatrophane diterpene (-)-15-O-acetyl-3-O-propionylcharaciol is described. Starting from an advanced cyclopentane building block, a B-alkyl Suzuki-Miyaura cross-coupling and carbonyl addition were utilized to assemble a fully functionalized triene, and a ring-closing metathesis was then employed to construct the rigid 12-membered ring. Twenty-five years after the original report on the isolation of the natural product, our total synthesis unambiguously corroborates the original tentative structural assignment.

Background: Patients with neurofibromatosis 1 (NF1) are shorter than expected and often have low bone mineral density (BMD), but the pathogenesis of these bony problems is poorly understood., Methods: We performed an exploratory study of BMD, 18 laboratory measures of bone metabolism, and fracture history in 72 adult NF1 patients., Results: Eight of the 18 clinical biochemical measures of bone health had at least 10% of NF1 patients outside the standard reference range. Serum 25-hydroxy-vitamin D concentrations were low in 56% of the NF1 patients, serum parathyroid hormone (PTH) concentrations were high in 34%, and urine deoxypyridinoline cross-link concentrations were high in 50%. Mean serum 25-hydroxy-vitamin D concentrations were significantly lower in people with NF1 than in season matched controls in both summer (p = 0.008) and winter (p<0.001). 36 (50%) of the 72 people with NF1 studied had BMD consistent with osteopenia, and 14 (19%) had BMD consistent with osteoporosis. High serum PTH concentration, high serum bone tartrate resistant acid phosphatase concentration, and high serum calcium concentration were associated with lower BMD among the NF1 patients. Males were more likely than females to have low BMD. The reported frequency of fractures in individuals with NF1 was much higher than in their unaffected siblings and spouses (p<0.001), and pathological fractures were reported only in NF1 patients., Conclusion: People with NF1 often have a generalised abnormality of bone metabolism. Further studies are needed to determine the biochemical and molecular basis of this abnormality.

Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma (PCNSL). Clinically, the disease typically presents with a rapidly progressive dementia and unsteadiness of gait. Its presentation on cerebral MRI, which is characterised by diffuse leukoencephalopathy without contrast enhancement, often causes diagnostic confusion1 with suspected diagnoses ranging from Binswanger's disease to leukoencephalopathy or encephalomyelitis. Here we report a patient with subacute dementia and diffuse bilateral white matter changes in the cerebral hemispheres and additional involvement of the brainstem, basal ganglia and thalamus on MRI. Initially, she was considered to suffer from an autoimmune encephalitis, transiently responded to immunosuppression but then developed multiple solid appearing cerebral lymphomas.