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Purpose: Neural and peripheral effects of induced muscle pain on explosive force production were investigated., Methods: Nine participants performed two maximal, six explosive, and six electrical stimulations induced (twitches and octets) isometric knee extensions before and after (15 min of rest) receiving an intramuscular injection of hypertonic saline (pain inducer) or isotonic (placebo) infusions in two laboratory visits separated by 7 days., Results: It was observed a reduction of peak torque production in maximal voluntary contraction in both conditions (9.3 and 3.3% for pain and placebo, respectively) and in the rate of torque development in placebo (7%). There was an increase in the rate of torque development for twitch and octets (10.5 and 15.8%, respectively) in the pain condition and peak torque for twitch (12%) in both conditions (as did the total rate of torque development for octets)., Conclusion: Force production decreases and increases during voluntary and involuntary contractions, respectively, suggesting that acute pain impairs force production via central mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Our purpose was to characterize the oxygen uptake kinetics (VO 2 ), energy systems contributions and total energy expenditure during a CrossFit ® benchmark workout performed in the extreme intensity domain. Fourteen highly trained male CrossFitters, aged 28.3 ± 5.4 years, with height 177.8 ± 9.4 cm, body mass 87.9 ± 10.5 kg and 5.6 ± 1.8 years of training experience, performed the Isabel workout at maximal exertion. Cardiorespiratory variables were measured at baseline, during exercise and the recovery period, with blood lactate and glucose concentrations, including the ratings of perceived exertion, measured pre- and post-workout. The Isabel workout was 117 ± 10 s in duration and the VO 2 peak was 47.2 ± 4.7 mL·kg -1 ·min -1 , the primary component amplitude was 42.0 ± 6.0 mL·kg -1 ·min -1 , the time delay was 4.3 ± 2.2 s and the time constant was 14.2 ± 6.0 s. The accumulated VO 2 (0.6 ± 0.1 vs. 4.8 ± 1.0 L·min -1 ) value post-workout increased substantially when compared to baseline. Oxidative phosphorylation (40%), glycolytic (45%) and phosphagen (15%) pathways contributed to the 245 ± 25 kJ total energy expenditure. Despite the short ~2 min duration of the Isabel workout, the oxygen-dependent and oxygen-independent metabolism energy contributions to the total metabolic energy release were similar. The CrossFit ® Isabel requires maximal effort and the pattern of physiological demands identifies this as a highly intensive and effective workout for developing fitness and conditioning for sports.

Purpose: Fran is one of the most popular CrossFit benchmark workouts used to control CrossFitters' improvements. Detailed physiological characterization of Fran is needed for a more specific evaluation of CrossFitters' training performance improvements. The aim of the study was to analyze the oxygen uptake (V˙O2) kinetics and characterize the energy system contributions and the degree of postexercise fatigue of the unbroken Fran., Methods: Twenty trained CrossFitters performed Fran at maximal exertion. V˙O2 and heart-rate kinetics were assessed at baseline and during and post-Fran. Blood lactate and glucose concentrations and muscular fatigue were measured at baseline and in the recovery period., Results: A marked increase in V˙O2 kinetics was observed at the beginning of Fran, remaining elevated until the end (V˙O2peak: 49.2 [3.7] mL·kg-1·min-1, V˙O2 amplitude: 35.8 [5.2] mL·kg-1·min-1, time delay: 4.7 [2.5] s and time constant: 23.7 [11.1] s; mean [SD]). Aerobic, anaerobic lactic, and alactic pathways accounted for 62% (4%), 26% (4%), and 12% (2%) of energy contribution. Reduction in muscle function in jumping ability (jump height: 8% [6%], peak force: 6% [4%], and maximum velocity: 4% [2%]) and plank prone test (46% [20%]) was observed in the recovery period., Conclusions: The Fran unbroken workout is a high-intensity effort associated with an elevated metabolic response. This pattern of energy response highlights the primary contribution of aerobic energy metabolism, even during short and very intense CrossFit workouts, and that recovery can take >24 hours due to cumulative fatigue.

Low back pain is one of the main causes of motor disabilities and psychological stress, with the painful process encompassing sensory and affective components. Noxious stimuli originate on the periphery; however, the stimuli are recombined in the brain and therefore processed differently due to the emotional environment. To better understand this process, our objective was to develop a mathematical representation of the International Association for the Study of Pain (IASP) model of pain, covering the multidimensional representation of this phenomenon. Data from the Oswestry disability index; the short form of the depression, anxiety, and stress scale; and pain catastrophizing daily questionnaires were collected through online completion, available from 8 June 2022, to 8 April 2023 (1021 cases). Using the information collected, an artificial neural network structure was trained (based on anomaly detection methods) to identify the patterns that emerge from the relationship between the variables. The developed model proved to be robust and able to show the patterns and the relationship between the variables, and it allowed for differentiating the groups with altered patterns in the context of low back pain. The distinct groups all behave according to the main finding that psychological and pain events are directly associated. We conclude that our proposal is effective as it is able to test and confirm the definition of the IASP for the study of pain. Here we show that the fiscal and mental dimensions of pain are directly associated, meaning that mental illness can be an enhancer of pain episodes and functionality.

The accumulation of caries-preventive compounds on sound enamel is crucial in order to improve the inhibition of carious lesion initiation. The aim of this research was to investigate the initial accumulation of cerium, oligopeptide p11-4, and fluoride from NaF or amine fluoride (AmF) on sound enamel in vitro by means of energy dispersive X-ray spectroscopy (EDX). Polished bovine enamel specimens (n = 120 from 60 teeth) were fabricated. Out of these, 12 specimens each were treated with CeCl3 (cerium(III) chloride heptahydrate 25%), oligopeptide p11-4 (Curodont Repair, Credentis), NaF (10,000 ppm F−), AmF (amine fluoride, Elmex Fluid, CP-GABA GmbH, 10,000 ppm F−), or Aqua demin (control). After rinsing with water, the surface elemental composition (Ce, N, F, Ca, P, O, Na, Mg) was measured (EDX; EDAX Octane Elect detector, APEX v2.0), expressed in atomic percent (At%) and analyzed (non-parametric statistics, α = 0.05, error rates method). Another 12 specimens per treatment group were fabricated and used for analyzing accumulation in cross-sections with EDX linescans and two-dimensional EDX-mappings. The surface median atomic percent of cerium (At%Ce) was 0.8 for CeCl3, but no Ce was found for any other group. N, specifically for oligopeptide p11-4, could not be detected. Fluorine could only be detected on fluoridated surfaces. The median atomic percent of fluorine (At%F) was 15.2 for NaF and 17.0 for AmF. The Ca/P ratio increased significantly compared to the control following the application of NaF and AmF (p < 0.001), but decreased significantly for CeCl3 (p < 0.001). In cross-sectioned specimens of the CeCl3-group, 12.5% of the linescans revealed cerium at the enamel surface, whereas 83.3% of the NaF linescans and 95.8% of the AmF linescans revealed fluorine at the enamel surface. Following the application of oligopeptide p11-4, no traces of N were detectable. In the depth of the samples, no signal was detected for any of the corresponding elements exceeding the background noise. Cerium and fluorine (from both NaF and AmF), but not the oligopeptide p11-4, precipitated on sound enamel.

A common symptom in neuromuscular diseases is pain, which changes human movement in many ways. Using the decomposed electromyographic signal, we investigate the strategy of the brain in recruiting different pools of motor units (MUs) to produce torque during induced muscle pain in terms of firing rate (FR), recruitment threshold (RT) and action potential amplitude (MUAP AMP ). These properties were used to define two groups (G1/G2) based on a K-means clusterization method. A 2.0 mL intramuscular hypertonic (6%) or isotonic (0.9%) saline solution was injected to induce pain or act as a placebo during isometric and isokinetic knee extension contractions. While isometric torque decreases after pain induction with hypertonic solution, this does not occur in isokinetic torque. This occurs because the MUs re-organized after the injection of both solutions. This is supported by an increase in RT, in both G1 and G2 MUs. However, when inducing pain with the hypertonic solution, RT increase is exacerbated. In this condition, FR also decreases, while MUAP AMP increases only for G1 MUs. Therefore, this study proposes that the strategy for maintaining force production during pain is to recruit MUs with higher RT and MUAP AMP .

The lateral septum (LS) has been implicated in the regulation of locomotion. Nevertheless, the neurons synchronizing LS activity with the brain's clock in the suprachiasmatic nucleus (SCN) remain unknown. By interrogating the molecular, anatomical and physiological heterogeneity of dopamine neurons of the periventricular nucleus (PeVN; A14 catecholaminergic group), we find that Th + /Dat1 + cells from its anterior subdivision innervate the LS in mice. These dopamine neurons receive dense neuropeptidergic innervation from the SCN. Reciprocal viral tracing in combination with optogenetic stimulation ex vivo identified somatostatin-containing neurons in the LS as preferred synaptic targets of extrahypothalamic A14 efferents. In vivo chemogenetic manipulation of anterior A14 neurons impacted locomotion. Moreover, chemogenetic inhibition of dopamine output from the anterior PeVN normalized amphetamine-induced hyperlocomotion, particularly during sedentary periods. Cumulatively, our findings identify a hypothalamic locus for the diurnal control of locomotion and pinpoint a midbrain-independent cellular target of psychostimulants., (© 2022. The Author(s).)

Lasers are fundamental tools in research and development. The shape of an incident laser beam directly affects the results, when it propagates through complex structured meso-aspheric optical elements. In conic-based systems utilizing elements such as axicons, the impact of secondary lobes is mostly overlooked, although the intensity distributions at the central spot and the side-lobes directly affect the beam properties. We investigate the interaction of two axicons (160° and 170°) with incident beams approximated by Gaussian, high-order Flattened-Gaussian, and low-order Flattened-Gaussian functions. We demonstrate that replacing an incident Gaussian beam with a low-order Flattened-Gaussian beam reduces the secondary lobes and significantly improves the uniformity of the intensity profile. We practically applied this effect in engineering a conic-aspheric-based static light-sheet microscope producing markedly improved results., (© 2022 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

Concepts about motor unit recruitment are important learning contents in exercise physiology and biomechanics classes that are usually taught theoretically. In the last few years, great advances have occurred in the decomposition of surface electromyography, allowing the learning of theoretical contents in an experimental way. In this tutorial paper, we have described the decomposition of surface electromyography methodological aspects and examples to teach motor unit recruitment concepts in exercise physiology and biomechanics practical lessons. This work has the aim to facilitate physiology and biomechanics academics to introduce this technique in practical classes.

We developed an open-source deconvolution software that stunningly increases the visibility of minute details, as for example, neurons or nerve fibers in light-sheet microscopy or confocal microscopy data by combining rolling ball background subtraction in three directions with deconvolution using a synthetic or measured point spread function. Via automatic block-wise processing image stacks of virtually unlimited size can be deconvolved even on small computers with 8 or 16 GB RAM. By parallelization and optional GPU-acceleration, the software works with high speed: On a PC equipped with a state-of-the-art NVidia graphic board a three dimensional (3D)-stack of about 1 billion voxels can be deconvolved within 5 to 10 minutes. The implemented variation of the Richardson-Lucy deconvolution algorithm preserves the photogrammetry of the image data by using flux-preserving regularization, an approach that to our knowledge has not been applied for deconvolving microscopy data before., (© 2021 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

Background:  Various life-prolonging therapy options are available for the treatment of metastatic castration-resistant prostate cancer (mCRPC)., Objective:  The optimal therapy sequence for mCRPC has been discussed for years. With the final results of the CARD study, important prospective data are available to enlighten the discussion about the therapy sequence., Material and Method:  CARD is a randomised phase IV trial in patients with mCRPC who were previously treated with docetaxel and an anti-androgen receptor (ARTA). The study showed significant efficacy benefits in favour of further treatment with cabazitaxel versus a second ARTA therapy. The study results are presented and discussed in the context of previous study data with regard to their importance for everyday clinical practice., Results:  The CARD study data confirm cabazitaxel as an effective therapy option for mCRPC patients previously treated with docetaxel and an ARTA. Cabazitaxel was safe to apply. The study results confirm the cross resistance between the two ARTAs Abiraterone and Enzalutamide., Conclusion: In mCRPC patients eligible for chemotherapy, the therapy sequence should be chosen so that the patients also receive cabazitaxel. A direct therapy sequence with two ARTAs should be avoided or, at least, only considered if other substances are contraindicated., Competing Interests: Axel Merseburger erhielt Honorare für Vorträge von Amgen, Astellas, Bayer, Ferring, Hexal, Ipsen, Janssen, Novartis, Roche, Sanofi, TEVA, für Beratertätigkeit von GBA, TEVA, UEG, Janssen, BMS, Novartis, Merck, Roche, Takeda sowie Unterstützung für die Durchführung klinischer Studien von Amgen, Astellas, Bayer, Ferring, Ipsen, Janssen, Roche, BMS und Merck. Firmenbeteiligungen: keine. Andreas Bannowsky erhielt Honorare von für Vorträge von Pfizer, Bayer, Lilly, Sanofi, Ferring, Coloplast und Janssen, für Beratertätigkeit von BMS, Bayer, Pfizer und Sanofi, Firmenbeteiligungen: keine. Klaus Becker erhielt Honorare in 2018 und 2019 Berater- und Referenten-Honorare der Firmen MSD, BMS, Eisai, Sanofi, Pfizer. Carsten Bokemeyer erhielt Honorare von für Vorträge, Beratungen, Gutachten und Advisory Boards von Sanofi-Aventis, Roche, Novartis, Merck Sharp and Dohme, Merck Serono, Bristol Myers Squibb, Bayer Healthcare, Astra Zeneca, Lilly Imclone, sowie von GSO, AOK und GBA.n. Im onkologischen Zentrum des UKE werden mehr als 70 Studien von pharmazeutischen Unternehmen unterstützt. Keine Firmenbeteiligungen. Rolf Eichenauer erhielt Honorare von Apogepha, Astellas, Bayer Health Care, Ferring, Hexal, Ipsen, Janssen-Cilag, me-dac, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi-Aventis, Takeda Jan Lehmann erhielt Honorare von für Vorträge von Ferring und Apogepha, für Beratertätigkeit von Ferring und Sanofi sowie Unterstützung für die Durchführung klinischer Studien von Amgen, Firmenbeteiligungen: keine. Gerald Mickisch erhielt Honorare/Thema PCA von Apogepha, Astellas, Astra Zeneca, Bayer, Ipsen, Janssen-Cilag, MSD, Novartis, Pfizer, Roche, Sanofi; keine Firmenbeteiligungen. Thomas Steuber Berater- und Referenten Honorare von den Firmen Astellas, Amgen, Bayer, Janssen, MSD, ProteoMedix, Sanofi. Gunhild von Amsberg erhielt Honorare von für Vorträge, Beratungen, Advisory Boards sowie Reiskosten und Kongressunterstützung von Janssen, Roche, BMS, Astellas, Sanofi, Ipsen, Eisai, Pierre Fabre, MSD, Pfizer, Astra Zeneca und Bayer. Finanzierung wissenschaftlicher Untersuchungen im Rahmen Industrie-gesponserter klinischer Studien erfolgte durch Roche, BMS, MSD, Astra Zeneca, Sanofi, Pfizer. Tobias von Kügelen erhielt Honorare von für Vorträge von Takeda, Apogepha, für Beratertätigkeit von Hexal, Sanofi-Aventis, für Übernachtung und Reisetätigkeiten von Roche, Bayer, Janssen, Pfleger Christian Wülfing erhielt Honorare von Astellas, Bayer, Ferring, Ipsen, Janssen, Medac, MSD, Roche, Sanofi, für Beratertätigkeit von Astellas, Direct Health Services, Janssen, BMS, Roche, Takeda sowie Unterstützung für die Durchführung klinischer Studien von Ipsen, Janssen, MSD und BMS., (Thieme. All rights reserved.)

Fluorescently labeled transgenic lines of Drosophila melanogaster are a powerful routine tool in fly laboratories. The possibility to fluorescently visualize individual cell populations or entire tissues and the constantly improving microscopy technologies such as two-photon or light-sheet applications, with deep tissue imaging, hold great potential to address central biological questions at an organismic level. However, strong pigmentation and the opaque nature of the D. melanogaster cuticle hinder the penetration of visible light into internal tissues, thereby limiting the application of fluorescent microscopes to analyses of the outermost surfaces of intact samples. In addition, tissue-induced light scattering and optical aberrations quickly blur the view and, hence, require tissue sectioning for further investigation. We have developed a tissue-clearing and depigmentation approach (FlyClear), which preserves endogenous fluorescent signals and is applicable to various developmental stages ranging from larvae to adult fruit flies (Pende et al. Nature communications 9:4731, 2018). In this chapter, we provide a detailed protocol of the experimental steps involved., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Primaquine (PQ) not only eliminates P. falciparum gametocytes but also kills liver dormant forms of P. vivax and P. ovale . Owing to these unique therapeutic properties, it is an essential drug. Although PQ has been used for over 70 years, its toxicological database has gaps such as the absence of studies on its reproductive and developmental toxicity and kinetics in pregnancy. This study investigated the transplacental transfer of PQ and the effects of intrauterine exposure on the postnatal growth, survival, and neurobehavioral development of the offspring. PQ kinetics and transplacental transfer were investigated in rats treated orally (40 mg.kg·bw -1 ) on gestation day (GD) 21. PQ was analyzed by high-performance liquid chromatography with diode array ultraviolet detection. To evaluate effects of intrauterine exposure on postnatal development, dams were treated orally with PQ (20 mg.kg·bw -1 ·d -1 ) or water (controls) on GD 0-21. Postnatal survival, body weight gain, somatic maturation, and reflex acquisition were evaluated. The open field test (OF) was conducted on PND 25. PQ concentration in the fetal plasma was nearly half that in maternal plasma. Except for increase in pregnancy loss, no effects of PQ were noted at term pregnancy and first days of life. Prenatal PQ did not affect postnatal weight gain nor did it impair somatic and neurologic development of the offspring. Pups born to PQ-treated dams showed reduced exploration and enhanced emotionality in the OF. PQ given in pregnancy, at doses greater than those recommended for malaria therapy, may affect pup postnatal survival and emotional behavior., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Klaus M. Becker et al.)

Here, we describe a novel approach that allows pathologists to three-dimensionally analyse malignant tissues, including the tumour-host tissue interface. Our visualization technique utilizes a combination of ultrafast chemical tissue clearing and light-sheet microscopy to obtain virtual slices and 3D reconstructions of up to multiple centimetre sized tumour resectates. For the clearing of tumours we propose a preparation technique comprising three steps: (a) Fixation and enhancement of tissue autofluorescence with formalin/5-sulfosalicylic acid. (b) Ultrafast active chemical dehydration with 2,2-dimethoxypropane and (c) refractive index matching with dibenzyl ether at up to 56 °C. After clearing, the tumour resectates are imaged. The images are computationally post-processed for contrast enhancement and artefact removal and then 3D reconstructed. Importantly, the sequence a-c is fully reversible, allowing the morphological correlation of one and the same histological structures, once visualized with our novel technique and once visualized by standard H&E- and IHC-staining. After reverting the clearing procedure followed by standard H&E processing, the hallmarks of ductal carcinoma in situ (DCIS) found in the cleared samples could be successfully correlated with the corresponding structures present in H&E and IHC staining. Since the imaging of several thousands of optical sections is a fast process, it is possible to analyse a larger part of the tumour than by mechanical slicing. As this also adds further information about the 3D structure of malignancies, we expect that our technology will become a valuable addition for histological diagnosis in clinical pathology.

Tissue clearing combined with deep imaging has emerged as a powerful alternative to classical histological techniques. Whereas current techniques have been optimized for imaging selected nonpigmented organs such as the mammalian brain, natural pigmentation remains challenging for most other biological specimens of larger volume. We have developed a fast DEpigmEntation-Plus-Clearing method (DEEP-Clear) that is easily incorporated in existing workflows and combines whole system labeling with a spectrum of detection techniques, ranging from immunohistochemistry to RNA in situ hybridization, labeling of proliferative cells (EdU labeling) and visualization of transgenic markers. With light-sheet imaging of whole animals and detailed confocal studies on pigmented organs, we provide unprecedented insight into eyes, whole nervous systems, and subcellular structures in animal models ranging from worms and squids to axolotls and zebrafish. DEEP-Clear thus paves the way for the exploration of species-rich clades and developmental stages that are largely inaccessible by regular imaging approaches., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The aim of this in vitro study was to investigate the change of erosive properties of apple and orange juice after dilution with tap water. Apple juice, orange juice and citric acid were assessed for pH and titratable acidity at different aqueous dilutions (100% – pure liquid, 60% – 3 : 2 mixing ratio, and 40% – 2 : 3 mixing ratio respectively). Thus, 72 bovine enamel specimens were distributed to 9 groups (n = 8 specimens per group), followed by 25 minutes of erosion by superfusion with the described test liquids according to group allocation. Erosive substance loss (µm) was determined profilometrically. The different substance losses within a dilution series were tested using the Wilcoxon rank sum test. The significance level was set to p ≤ 0.05. Erosive substance loss [µm] for 100% concentrations (median ± interquartile range) was highest for apple juice (5.7 ± 0.8), followed by citric acid (4.6 ± 0.4) and orange juice (1.5 ± 0.5). The dilution of apple juice (60%: 4.2 ± 0.7; 40%: 3.1 ± 0.5) and citric acid (60%: 3.7 ± 0.9; 40%: 2.8 ± 0.7) with tap water lead to a significant (p < 0.05) reduction of erosive potential in comparison to 100% concentrations. This effect was not consistent for orange juice, where significantly more substance loss was found for pure juice (100%) than for 60% diluted juice (60%: 1.1 ± 0.3, p < 0.05), but no significant difference was found between 100% and 40% (40%: 0.9 ± 0.6, p > 0.05), and 60% and 40%, respectively. In conclusion, dilution of apple juice with tap water led to a significant reduction of its erosive potential. For orange juice, the effect of dilution on the erosive substance loss was only limited.

We developed a deconvolution software for light sheet microscopy that uses a theoretical point spread function, which we derived from a model of image formation in a light sheet microscope. We show that this approach provides excellent blur reduction and enhancement of fine image details for image stacks recorded with low magnification objectives of relatively high NA and high field numbers as e.g. 2x NA 0.14 FN 22, or 4x NA 0.28 FN 22. For these objectives, which are widely used in light sheet microscopy, sufficiently resolved point spread functions that are suitable for deconvolution are difficult to measure and the results obtained by common deconvolution software developed for confocal microscopy are usually poor. We demonstrate that the deconvolutions computed using our point spread function model are equivalent to those obtained using a measured point spread function for a 10x objective with NA 0.3 and for a 20x objective with NA 0.45.

Objective: Autoantibodies against CD74 (anti-CD74) are associated with ankylosing spondylitis (AS). The present multicenter study, the International Spondyloarthritis Autoantibody (InterSpA) trial, was undertaken to compare the sensitivity and specificity of anti-CD74 and HLA-B27 in identifying patients with nonradiographic axial spondyloarthritis (axSpA)., Methods: Patients ages 18-45 years with inflammatory back pain of ≤2 years' duration and a clinical suspicion of axSpA were recruited. HLA-B27 genotyping and magnetic resonance imaging of sacroiliac joints were performed in all patients. One hundred forty-nine patients with chronic inflammatory back pain (IBP) not caused by axSpA served as controls, and additional controls included 50 AS patients and 100 blood donors whose specimens were analyzed., Results: One hundred patients with inflammatory back pain received a diagnosis of nonradiographic axSpA from the investigators and fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria. The mean age was 29 years, and the mean symptom duration was 12.5 months. The sensitivity of IgA anti-CD74 and IgG anti-CD74 for identifying the 100 axSpA patients was 47% and 17%, respectively. The specificity of both IgA anti-CD74 and IgG anti-CD74 was 95.3%. The sensitivity of HLA-B27 was 81%. The positive likelihood ratios were 10.0 (IgA anti-CD74), 3.6 (IgG anti-CD74), and 8.1 (HLA-B27). Assuming a 5% pretest probability of axSpA in chronic back pain patients, the posttest probability, after consideration of the respective positive test results, was 33.3% for IgA anti-CD74, 15.3% for IgG anti-CD74, and 28.8% for HLA-B27. A combination of IgA anti-CD74 and HLA-B27 results in a posttest probability of 80.2%., Conclusion: IgA anti-CD74 may be a useful tool for identifying axSpA. The diagnostic value of the test in daily practice requires further confirmation., (© 2018, American College of Rheumatology.)

Objectives: The study evaluated the suitability of pure crystalline hydroxyapatite (HA) as a substitute for human (H) and bovine (B) enamel in erosion experiments., Methods: Human and bovine enamel and hydroxyapatite specimens (n = 18 each) were submitted to demineralisation by HCl at pH values of 3.0, 2.6 and 2.0 (1.0, 2.5, and 10 mmol/l concentration). Specimens were eroded in a superfusion chamber for 7 min (flow rate: 1 μl/s). Multiple fluid samples were taken per specimen throughout the exposure period. The dissolved calcium content was measured using a colorimetric assay with Arsenazo III reagent, to serve as surrogate for erosive substance loss. Additionally, erosive tissue loss was quantified by profilometry. Differences in erosive substance loss were assessed by the Kruskal-Wallis and Conover's posthoc test., Results: Good agreement in erosive substance loss between HA and human specimens was found at pH 2.6, as no statistically significant difference and considerable overlap of their respective interquartile ranges was observed. At pH 2.0 and 3.0, a statistically significant difference between HA and human and bovine enamel was determined. HA consistently tended to have lower mean dissolution rates, with a maximum deviation from human enamel of -16% at pH 3. It displayed lower specimen variability with an average coefficient of variation of 17%, compared to 25% (H) and 25% (B), respectively., Conclusions: Crystalline hydroxyapatite may not be suitable for full substitution of biologic enamel in erosion experiments focusing on absolute measurement values, but is useful for establishing consistent relative trends between erosive agents due to biosimilar erosion behavior and lower experimental variability. This is especially true for preliminary studies where approval for use of biological samples is restricted., Clinical Significance: Crystalline hydroxyapatite is a useful substitute of human or bovine enamel in experiments studying chemical aspects of dental erosion., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The aim of this in vitro study was to investigate the impact of saliva on the abrasion of eroded enamel using two measuring methods. A total of 80 bovine enamel specimens from 20 bovine incisors were allocated to four experimental groups (n = 20 specimens per group). After baseline surface microhardness (SMH) measurements and profilometry all specimens were subjected to erosion (2 min, 1% citric acid, pH: 3.6, 37°C). SMH was determined again, and the depths of the Knoop indentations were calculated. Thereafter, specimens were incubated in human saliva (group 1 - no incubation/control, group 2 - 0.5 h, group 3 - 1 h, group 4 - 2 h) before toothbrush abrasion was performed. After final SMH measurements and profilometry, indentations were remeasured, and surface loss was calculated. SMH did not return to baseline values regardless of the length of saliva incubation. Further, an irreversible substance loss was observed for all specimens. With the indentation method, significantly (p < 0.05) more substance loss was found for controls (least square means ± standard error of 198 ± 19 nm) than for groups 2-4 (110 ± 10, 114 ± 11, and 105 ± 14 nm). Profilometric assessment showed significantly more substance loss for controls (122 ± 8 nm) than for group 4 (106 ± 5 nm). Intraclass correlation for interrater reliability between measurement methods was low (0.21, CI: 0.1-0.3), indicating poor agreement. Exposure of eroded enamel to saliva for up to 2 h could not re-establish the original SMH. The amount of measured substance loss depended on the measurement method applied., (© 2018 S. Karger AG, Basel.)

The fruit fly, Drosophila melanogaster, is an important experimental model to address central questions in neuroscience at an organismic level. However, imaging of neural circuits in intact fruit flies is limited due to structural properties of the cuticle. Here we present a novel approach combining tissue clearing, ultramicroscopy, and data analysis that enables the visualisation of neuronal networks with single-cell resolution from the larval stage up to the adult Drosophila. FlyClear, the signal preserving clearing technique we developed, stabilises tissue integrity and fluorescence signal intensity for over a month and efficiently removes the overall pigmentation. An aspheric ultramicroscope set-up utilising an improved light-sheet generator allows us to visualise long-range connections of peripheral sensory and central neurons in the visual and olfactory system. High-resolution 3D reconstructions with isotropic resolution from entire GFP-expressing flies are obtained by applying image fusion from orthogonal directions. This methodological integration of novel chemical, optical, and computational techniques allows a major advance in the analysis of global neural circuit organisation.

Here, we present an optically optimized system for static ultramicroscopy imaging technique. The unit for generating an ultra-thin light sheet employs aspheric and meso-optical elements (meso-aspheric system). An analytical as well as an experimental comparison between the light sheet produced by the standard system (using a rectangular slit aperture and one cylindrical lens) and the one produced by our latest optimized system, which converts a symmetrical Gaussian beam into an ultra-thin light sheet is presented. Using the new light sheet in combination with our objective equipped with a modulator unit to compensate the refractive index mismatch between air and mediums with indices of 1.45-1.56, we present high resolution images of various biological samples that were chemically cleared using different methods. They demonstrate a marked improvement in quality, contrast and resolution., (© 2016 Wiley Periodicals, Inc.)

Based on the modal analysis method, we developed a model that describes the output beam of a diode-pumped solid state (DPSS) laser emitting a multimode beam. Measuring the output beam profile in the near field and at the constructed far field the individual modes, their respective contributions, and their optical parameters are determined. Using this information, the beam is optically reshaped into a quasi-Gaussian beam by the interference and superposition of the various modes. This process is controlled by a mode modulator unit that includes different meso-aspheric elements and a soft-aperture. The converted beam is guided into a second optical unit comprising achromatic-aspheric elements to produce a thin light sheet for ultramicroscopy. We found that this light sheet is markedly thinner and exhibits less side shoulders compared with a light sheet directly generated from the output of a DPSS multimode laser., (© 2018 The Authors. Journal of Biophotonics published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: Aim of this investigation was to study the temperature-dependent in vitro enamel erosion of five acidic drinks and citric acid under controlled conditions in an artificial mouth., Methods: The erosive potential of Orange juice, Coca-Cola Zero, Sprite Zero, two fruit teas and citric acid (control) was investigated on bovine enamel specimens at temperatures between 5 °C and 55 °C. The pH values and total calcium content of all test drinks were determined. Specimens were immersed into an artificial mouth to imitate physiological oral conditions for 60 h. Cyclic de- and re-mineralization was performed, imitating the intake of six drinks in six h followed by a six-hour remineralization phase, where only artificial saliva ran over the specimens. Total erosive enamel loss was determined by contact profilometry. Differences in substance loss at different temperatures were tested for statistical significance (p-values ≤ 0.05) by means of ANOVA., Results: Rising liquid temperature did not result in a considerable change of pH. Highest substance loss was observed for citric acid (33.6 ± 6 μm to 38.7 ± 6 μm), while only little erosion was induced by fruit tea (0.8 ± 1 μm to 5.9 ± 1 μm). Rising liquid temperature did not result in significantly increased substance loss for citric acid, orange juice and Coca-Cola Zero. Sprite Zero and both fruit teas, however, caused significantly (p < 0.001) more enamel loss at elevated temperature., Conclusions: Not all investigated drinks showed a temperature-induced change in erosivity., Clinical Significance: For some erosive beverages it can be recommended to keep the consummation temperature as low as possible to decrease the risk of erosive tooth substance loss., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Jatropha seed cake (JSC) is an excellent source of protein but does contain some antinutritional factors (ANF) that can act as toxins and thus negatively affect the growth and health status of fish. While this can limit the use of JSC, detoxified Jatropha protein isolate (DJPI) may be a better option. An 8-week study was performed to evaluate dietary DJPI to common carp Cyprinus carpio. Five iso-nitrogenous diets (crude protein of 38%) were formulated that consisted of a C ontrol (fish meal (FM) based protein), J 50 or J 75 (50 and 75% of FM protein replaced by DJPI), and S 50 or S 75 (50 and 75% of FM protein replaced by soy protein isolate, SPI) and fed to triplicate groups of 75 carp fingerlings (75; av. wt. ± SD; 11.4 ± 0.25 g). The growth, feeding efficiencies, digestibility, plasma biochemistry, and intestinal enzymes were measured. Results showed that growth performance of fish fed the S 75 - or DJPI-based diets were not significantly different from those fed the C ontrol diet, while carp fed the S 50 had significantly better growth than the J 75 diet. Fish fed the J 75 diet had significantly lower protein and lipid digestibility as well as significantly lower intestinal amylase and protease activities than all other groups. However, all plant protein-based diets led to significantly higher crude protein, crude lipid, and gross energy in the body of common carp compared to the control treatment. Plasma cholesterol and creatinine significantly decreased in the plant protein fed groups, although plasma triglyceride as well as the red blood cells count, hematocrit, albumin, globulin, total plasma protein, and lysozyme activity were higher in plant protein fed groups compared to FM fed group. White blood cells, hemoglobulin concentration, alkaline phosphatase and alanine transaminase activities, and glucose level in blood did not differ significantly among treatments. The results suggest that the DJPI is non-toxic to carp and can be used to replace FM in the diets of common carp up to 75%, but further research to potentially reduce some inherent ANF within this protein source, such as non-starch polysaccharides, may improve nutrient utilization.

This study was to analyse the abrasive wear of differently composed diamond dentifrices loaded with 2.4 μm diamond particles on dentine and enamel surfaces in vitro. Bovine specimens were brushed with a diamond-loaded dentifrice (DD2; 2 g particles/kg), a diamond-loaded dentifrice (1.5 g/kg) containing 20% hydrated silica as extra abrasive (DD1.5+S), or a diamond-loaded dentifrice (3 g/kg) containing 20% hydrated silica abrasive (DD3+S). Values were compared to those obtained with Colgate Total (CT) and Elmex Sensitive plus (ES). Brushing was performed using a cross brushing machine (F = 2.5 N; 120 brushing strokes/min). Abrasive wear [μm] of specimens (n = 12) was measured profilometrically and adjusted to 10,000 brushing strokes (10 kBS). Data were compared between groups using one-way ANOVA and post-hoc pairwise tests with Tukey correction, alpha = 0.05. Diamond dentifrices and ES showed no difference on dentine specimens: DD2 7.7 ± 2.6 μm/10 kBS; DD1.5+S 10.1 ± 2.3 μm/ 10 kBS; DD3+S 10.1 ± 2.6 μm/10 kBS; ES 7.4 ± 1.1 μm/10 kBS, while CT–brushed specimens exhibited significantly higher dentinal abrasion compared to all other groups: CT 31.0 ± 7.7 μm/ 10 kBS. Diamond loading significantly influenced enamel wear (mean ± SD μm/10 kBS): DD2 1.8 ± 0.5 μm/10 kBS. Conversely, addition of the silica abrasive reduced these values: DD1.5+S 1.1 ± 0.3 μm/10 kBS; DD3+S 1.6 ± 0.3 μm/10 kBS. CT and ES revealed similarly low values: CT 0.3 ± 0.1 μm/10 kBS; ES 0.2 ± 0.1 μm/10 kBS. These data suggest that abrasion caused by diamond particles in experimental toothpastes is differentially affected by diamond particle load, additional abrasives, and the type of hard tissue.

Aim: This study evaluated the efficacy of self-etching adhesive systems associated or not associated with the neodymium-doped yttrium aluminum garnet (Nd:YAG) laser on the protection against enamel erosive/abrasive wear., Materials and Methods: Bovine enamel specimens were demineralized with 0.3% citric acid (5 minutes). The samples were randomly assigned to eight groups (n = 20): SB - Single Bond Universal (3M/ESPE); SB+L - Single Bond Universal + laser (80 mJ/10 Hz); FB - Futurabond U (Voco); FB+L -Futurabond U + laser; GEN - G-aenial bond (GC); GEN+L -G-aenial bond + laser; L - laser irradiation; and C - no treatment. The laser was applied before light curing. The samples were subjected to erosive/abrasive challenges (0.3% citric acid - 2 minutes and tooth brushing four times daily for 5 days). Enamel surface loss was recovered profilometrically by comparison of baseline and final profiles. The adhesive layer thickness, retention percentage of the protective layer, and microhardness of cured adhesive were measured. Data were analyzed using one-way analysis of variance and Tukey's test (5%)., Results: There were significant differences for all parameters (p = 0.0001). Mean values ± SD and results of the Tukey's test were: Surface wear: GEN - 4.88 (±1.09)a, L - 5.04 ± 0.99)a, FB - 5.32 (±0.93)ab, GEN + L - 5.46 (±1.27)abc, SB + L - 5.78 (±1.12)abc, FB + L - 6.23 (±1.25)bc, SB - 6.35 (±1.11)c, and C - 6.46 (±0.61)c; layer thickness: GEN - 15.2 (±8.63)c, FB - 5.06 (±1.96)a, GEN + L - 13.96 (±7.07)bc, SB + L - 4.24 (±2.68)a, FB + L - 9.03 (±13.02)abc, and SB - 7.49 (±2.80)ab; retention: GEN - 68.89 (±20.62)c, FB - 54.53 (±24.80)abc, GEN + L - 59.90 (±19.79)abc, SB + L - 63.37 (±19.30)bc, FB + L - 42.23 (±17.68) a, and SB - 47.78 (±18.29)ab; microhardness: GEN - 9.27 (±1.75)c; FB - 6.99 (±0.89)b; GEN + L - 6.22 (±0.87)ab; SB + L - 15.48 (±2.51)d; FB + L - 10.67 (±1.58)c; SB - 5.00 (±1.60)a., Conclusion: The application of Futurabond U and G-aenial bond on enamel surface, as well as the Nd:YAG laser irradiation alone, was able to reduce the enamel wear. The use of laser after the adhesive systems did not improve their efficacy., Clinical Significance: Erosive/abrasive wear is a prevalent condition in clinical practice affecting many patients. The association of adhesive systems and Nd:YAG laser is of considerable clinical interest because it assesses new treatments to reduce the erosive/abrasive wear that would help dentists in clinical treatment decisions to reduce enamel wear and achieve a successful treatment.

The epigenetics and molecular biology of human embryonic stem cells (hES cells) have received much more attention than their architecture. We present a more complete look at hES cells by electron microscopy, with a special emphasis on the architecture of the nucleus. We propose that there is an ultrastructural signature of pluripotent human cells. hES cell nuclei lack heterochromatin, including the peripheral heterochromatin, that is common in most somatic cell types. The absence of peripheral heterochromatin may be related to the absence of lamins A and C, proteins important for linking chromatin to the nuclear lamina and envelope. Lamins A and C expression and the development of peripheral heterochromatin were early steps in the development of embryoid bodies. While hES cell nuclei had abundant nuclear pores, they also had an abundance of nuclear pores in the cytoplasm in the form of annulate lamellae. These were not a residue of annulate lamellae from germ cells or the early embryos from which hES cells were derived. Subnuclear structures including nucleoli, interchromatin granule clusters, and Cajal bodies were observed in the nuclear interior. The architectural organization of human ES cell nuclei has important implications for cell structure-gene expression relationships and for the maintenance of pluripotency. J. Cell. Biochem. 118: 764-774, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

This study analyzed the anti-erosive effect of a self-assembling peptide fibre gel. One hundred and twelve bovine enamel samples were ground flat and subjected to a three times de- and re-mineralization cycle: erosion (5 min, HCl, pH 2.6) alternated with storage in artificial saliva under agitation. Then, samples were covered with different anti-erosive compounds (2 min): Duraphat toothpaste (DT), Elmex Erosion Protection Toothpaste (EET) or Elmex Gelée (EG) – all mixed with saliva (1:3) –, Elmex Erosion Protection Mouthwash (EEM), Curodont Protect (CP; self-assembling peptide gel) or MI Paste Plus (MIP). Untreated, water stored samples served as control. In experiment 1, half of the samples of each group were continuously superfused with HCl (pH 2.6, 60 μl/min, 8 min). In experiment 2, the second half of samples were subjected to eight cycles, each consisting of application of the respective anti-erosive compound followed by an erosion (60 s, HCl, pH 2.6), followed by remineralization in artificial saliva (45 min). Enamel loss was profilometrically determined. In experiment 1, EEM and EET performed significantly better compared to all other compounds. Substance loss of all other compounds did not differ significantly from control. In experiment 2, significantly better performance was achieved by EEM and EET. EG showed significantly lower protection than the control. All other applied compounds yielded no significant difference compared to control. Under the chosen conditions, the self-assembling peptide-containing compound showed no anti-erosive effect.

Light-sheet microscopy is an effective technique in neuroscience, developmental biology, and cancer research for visualizing and analyzing cellular networks and whole organs in three dimensions. Because this technique requires specimens to be translucent they commonly have to be cleared before microscopy inspection. Here, we provide 3DISCO based protocols for preparing cleared samples of immuno-stained neural networks, lectin-labeled vascular networks, and Methoxy-X04 labeled beta-amyloid plaques in mice. 3DISCO utilizes the lipophilic solvents tetrahydrofuran (THF) and dibenzylether (DBE) for dehydration and successive clearing. Crucial steps for obtaining transparent tissues and preserving the fragile endogenous GFP are the transcardial perfusion, as well as the proper implementation of the 3DISCO clearing process using peroxide free chemicals. We further provide a protocol for resin embedding of 3DISCO cleared specimens that allows long term archiving of samples for years with virtually no loss in signal quality.

OBJECTIVE To determine the prevalence of multidrug-resistant organisms (MDROs) colonizing in pediatric refugees admitted to a University Children Hospital in Germany. DESIGN Retrospective observational study. SETTING General pediatric and pediatric surgery units. PATIENTS In Germany, recommendations for MDRO screening of pediatric refugees were recently published. According to these and institutional recommendations, all hospitalized pediatric refugees were screened for MDROs between October 2015 and March 2016. METHODS Using electronic surveillance data, we performed a chart review to identify the prevalence of MDROs among and the clinical diagnoses of pediatric refugees. RESULTS Among 325 patients hospitalized for various causes, most frequently gastroenteritis (30.9%), MDROs were detected in 33.8%. Most of these patients were colonized with multidrug-resistant Gram-negative (MRGN) bacteria (113 isolates), mostly 2MRGN/ESBL (87 isolates); some patients were colonized with methicillin-resistant Staphylococcus aureus (MRSA, 22 isolates); and 1 patient was colonized with vancomycin-resistant enterococci (VRE). Among 110 refugee patients, we detected single colonization with an MDRO in 84 patients (76.4%), co-colonization with 2 pathogens in 23 patients (20.9%), and triple colonization in 3 patients (2.7%). However, infections with MDROs occurred in only 3.6% of pediatric refugees. The peak of positive MDRO screening results in 2015 correlated with an increased hospitalization rate. CONCLUSION Implementation of infection control measures among pediatric refugees is challenging. Due to the high frequency of MDROs in these patients, current screening, isolation, and treatment strategies may have to be adapted. Infect Control Hosp Epidemiol 2016;1-5.

Aim: Citric acid (CA) is a component in beverages responsible for dental erosion. The aim of this study was to examine the influence of CA with different pH, titratable acid and buffer capacity (ß), and the impact of the chelating effect of CA on development of enamel erosions., Material and Methods: In a superfusion model, hydroxy apatite (HAp) dissolution of bovine enamel was measured in four experiments (EXP 1-4) with 27 experimental groups (n = 8 per group). The samples were superfused with different CA variations and respective controls. EXP-1: Dilution series of HCl (pH 2.15-3.02). EXP-2: Dilution series of natural CA (56-1.75 mmol l(-1); pH 2.15-3.02). EXP-3: CA solutions (56 and 14 mmol l(-1), ß: 39.7 and 10.2 mmol l(-1) pH(-1), respectively) with different titratable acidity at equal pH values. EXP-4: CA concentrations (56-1.75 mmol l(-1)) neutralized to pH 7., Results: CA led to higher HAp-dissolution than HCl. With higher pH, the difference in HAp-dissolution rate between the two acids became increasingly smaller. At equal pH, HAp-dissolution was higher for the CA with the higher amount of titratable acid. However, no clear correlation between erosion and titratable acid or ß could be found. Only minimal amounts of HAp were dissolved by neutralized CA compared to CA with natural pH., Conclusion: Under the chosen conditions chelating effects of CA do not have a relevant influence of HAp-dissolution of enamel. Moreover, amount of HAp-dissolution by CA is not attributed to a single factor alone. The interplay between the different parameters of CA seems to be responsible for its erosive potential., Clinical Relevance: The erosive potential of solutions containing citric acid with unknown concentrations could not be predicted using a single parameter alone, and should at best determined in experimental set-ups.

We study the competition between unconventional superconducting pairing and charge density wave (CDW) formation for the two-dimensional Edwards Hamiltonian at half filling, a very general two-dimensional transport model in which fermionic charge carriers couple to a correlated background medium. Using the projective renormalization method we find that a strong renormalization of the original fermionic band causes a new hole-like Fermi surface to emerge near the center of the Brillouin zone, before it eventually gives rise to the formation of a charge density wave. On the new, disconnected parts of the Fermi surface superconductivity is induced with a sign-changing order parameter. We discuss these findings in the light of recent experiments on iron-based oxypnictide superconductors.

We present an overview of the ultramicroscopy technique we developed. Starting from developments 100 years ago, we designed a light sheet microscope and a chemical clearing to image complete mouse brains. Fluorescence of green fluorescent protein (GFP)-labeled neurons in mouse brains could be preserved with our 3DISCO clearing and high-resolution three-dimensional (3-D) recordings were obtained. Ultramicroscopy was also used to image whole mouse embryos and flies. We improved the optical sectioning of our light sheet microscope by generating longer and thinner light sheets with aspheric optics. To obtain high-resolution images, we corrected available air microscope objectives for clearing solutions with high refractive index. We discuss how eventually super resolution could be realized in light sheet microscopy by applying stimulated emission depletion technology. Also the imaging of brain function by recording of mouse brains expressing cfos-GFP is discussed. Finally, we show the first 3-D recordings of human breast cancer with light sheet microscopy as application in medical diagnostics.

Background: The purpose of this in-vitro study was to investigate the potential of biofilm removal in interproximal tooth regions using intervallic cleaning with an oral irrigator or a sonic toothbrush., Methods: Three-species biofilms (Streptococcus mutans (OMZ 918), Streptococcus oralis SK 248 (OMZ 60), Actinomyces naeslundii (OMZ 745)) were grown on hydroxyapatite discs for 3 days in culture media. Every 24 h, specimens were incubated for 15 min in resazurin solution (i.e., culture medium and 10 % v/v alamarBlue®) to measure the metabolic activity with a fluorescence spectrophotometer in relative fluorescence units (rfu) at baseline. Then, specimens were fixed in interproximal holding devices and underwent treatment with an oral irrigator (WF; Waterpik® Sensonic WP-100E), an active sonic toothbrush (WPa), or an inactive sonic toothbrush (WPi; Waterpik® Sensonic SR-3000E) for 10 s (n = 18/group). Untreated biofilms served as controls (CO). After treatment, bacterial activity was re-measured, and specimens were re-grown in fresh medium for 24 h until next cleaning procedure. Altogether, cleaning was repeated in intervals of three treatment days (d1, d2, d3). After d3, SEM images were taken (n = 8) and CFU was measured (n = 3). Metabolic activity was analyzed for each disc separately, rfu values were averaged for d1 to compare initial biofilm stability, and ratios of baseline and post-treatment values were compared. Results were analyzed using ANOVA with the post-hoc Scheffé test, or Kruskal-Wallis with post-hoc Mann-Whitney test., Results: Median baseline rfu-values of d1 resulted in 7821.8 rfu (interquartile range = 5114.5). Highest reduction in metabolic activity was recorded significantly for the oral irrigator used for 10 s (residual activity per day d1: WF 17.9 %, WPa 58.8 %, WPi 82.5 %, CO 89.6 %; d2: WF 36.8 %, WPa 85.2 %, WPi 82.5 %, CO 90.0 %; d3: WF 17.2.%, WPa 79.6 %, WPi 96.3 %, CO 116.3 %). SEM images of untreated specimens (CO) and specimens treated with the sonic toothbrush (WPa and WPi) showed huge amounts of biofilm, while oral irrigator-treated specimens (WF) revealed barely any bacteria. CFU data confirmed the graduations between the groups., Conclusions: Cleaning of interproximal regions achieved better success with an oral irrigator as compared to the use of a sonic toothbrush. (350/350 words).

Alzheimer´s disease (AD) is the most common neurodegenerative disorder. AD neuropathology is characterized by intracellular neurofibrillary tangles and extracellular β-amyloid deposits in the brain. To elucidate the complexity of AD pathogenesis a variety of transgenic mouse models have been generated. An ideal imaging system for monitoring β-amyloid plaque deposition in the brain of these animals should allow 3D-reconstructions of β-amyloid plaques via a single scan of an uncropped brain. Ultramicroscopy makes this possible by replacing mechanical slicing in standard histology by optical sectioning. It allows a time efficient analysis of the amyloid plaque distribution in the entire mouse brain with 3D cellular resolution. We herein labeled β-amyloid deposits in a transgenic mouse model of cerebral β-amyloidosis (APPPS1 transgenic mice) with two intraperitoneal injections of the amyloid-binding fluorescent dye methoxy-X04. Upon postmortem analysis the total number of β-amyloid plaques, the β-amyloid load (volume percent) and the amyloid plaque size distributions were measured in the frontal cortex of two age groups (2.5 versus 7-8.5 month old mice). Applying ultramicroscopy we found in a proof-of-principle study that the number of β-amyloid plaques increases with age. In our experiments we further observed an increase of large plaques in the older age group of mice. We demonstrate that ultramicroscopy is a fast, and accurate analysis technique for studying β-amyloid lesions in transgenic mice allowing the 3D staging of β-amyloid plaque development. This in turn is the basis to study neural network degeneration upon cerebral β-amyloidosis and to assess Aβ-targeting therapeutics.

Introduction: Human epidermal growth factor receptor 2 (HER2) amplification is present in a subgroup of gastroo-esophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-epidermal growth factor receptor (EGFR) and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC., Materials and Methods: Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250mg per day 1-21 plus capecitabine (CAP) 2000mg/m(2) on days 1-14 of a 21-day cycle or LAP 1500mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary end-point was the objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). We aimed to include 38 pts per arm to show an interesting response rate of ⩾20% in either of the two arms., Results: 37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% confidence interval (CI): 1.37-34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38-61) days in the LAP group and 83 (95% CI: 42-86) days in the LAP+CAP group. Other secondary efficacy end-points (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhoea were higher with LAP+CAP (61%; 95% CI: 35-83) compared to 26% (95% CI 9-51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] versus 17 [90%])., Discussion: Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. (ClinicalTrials.gov Identifier, NCT01145404)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Tissue clearing allows microscopy of large specimens as whole mouse brains or embryos. However, lipophilic tissue clearing agents as dibenzyl ether limit storage time of GFP-expressing samples to several days and do not prevent them from photobleaching during microscopy. To preserve GFP fluorescence, we developed a transparent solid resin formulation, which maintains the specimens' transparency and provides a constant signal to noise ratio even after hours of continuous laser irradiation. If required, high-power illumination or long exposure times can be applied with virtually no loss in signal quality and samples can be archived for years.

Objective: The objective of this in vitro study was to investigate the effect of viscosity-modified soft acidic drinks on enamel erosion., Materials and Methods: A total of 108 bovine enamel samples (∅ = 3 mm) were embedded in acrylic resin and allocated into six groups (n = 18). Soft acidic drinks (orange juice, Coca-Cola, Sprite) were used both in their regular forms and at a kinetic viscositiy of 5 mm(2)/s, which was adjusted by adding hydroxypropyl cellulose. All solutions were pumped over the enamel surface from a reservoir with a drop rate of 3 ml/min. Each specimen was eroded for 10 min at 20 °C. Erosion of enamel surfaces was measured using profilometry. Data were analyzed using independent t tests and one-way ANOVAs (p < 0.05)., Results: Enamel loss was significantly higher for the regular (Coca-Cola, 5.60 ± 1.04 μm; Sprite, 5.49 ± 0.94 μm; orange juice, 1.35 ± 0.4 μm) than for the viscosity-modified drinks (Coca-Cola, 4.90 ± 0.34 μm; Sprite, 4.46 ± 0.39 μm; orange juice, 1.10 ± 0.22 μm)., Conclusion: For both regular and viscosity-modified forms, Coca-Cola and Sprite caused higher enamel loss than orange juice. Increasing the viscosity of acidic soft drinks to 5 mm(2)/s reduced enamel erosion by 12.6-18.7 %., Clinical Relevance: The erosive potential of soft acidic drinks is not only dependent on various chemical properties but also on the viscosity of the acidic solution and can be reduced by viscosity modification.

Several genotoxicity endpoints have been evaluated to define nonlinear dose-responses for SN 1 and SN 2 alkylating genotoxicants. Dose-response studies acknowledging the process of multistage tumorigenesis are important; however, data pertaining nonlinearity are not yet available. In this communication, the role of DNA repair in the dose-response relationship for benign papillomas was examined using the two-stage skin carcinogenesis protocol. The data obtained with O(6) -methylguanine-DNA methyltransferase (MGMT) overexpressing mice in which papillomas were induced by a single topical treatment with N-methyl-N-nitrosourea (MNU) followed by promotion with 12-O-tetradecanoylphorbol-13-acetate are reported. As MGMT efficiently protects cells from mutations by repairing O(6) -methylguanine, a miscoding lesion induced by MNU, the question whether MGMT is able to nullify carcinogenic lesions to an extent where they would be considered nonhazardous has been addressed. It is shown here that MGMT overexpression significantly protects against, but does not completely nullify, the effect of MNU in tumor initiation. The possible mechanisms involved have also been discussed., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Splenic abscesses in children are rare. In recent years aseptic abscesses have been recognized as a new disease entity, especially in adults., Case Presentation: We present a rare case of a 15 year old girl with aseptic abscesses, in whom antibiotic therapy comprising metronidazole and meropenem was partly beneficial in improving the patient's clinical condition and inflammatory parameters. Eventually corticosteroid therapy led to complete and long lasting resolution of symptoms. Further diagnostic work-up revealed autoimmune thyroiditis, but no signs of inflammatory bowel disease., Conclusion: Aseptic splenic abscesses should always prompt clinicians to initiate further diagnostics to determine a potential underlying condition and a regular follow-up. Anaerobic bacteria may play a role in the pathogenesis of the disease and besides corticosteroid treatment antibiotics covering anaerobes may be beneficial.

Using a combination of achromatic aspheric optical elements and achromatic cylindrical lenses, we developed an improved laser light sheet generator for two-side illumination ultramicroscopy. This light sheet generator has a much longer Rayleigh range, a more uniform spatial intensity distribution along x -, y - and z-axis, and reduced aberrations than the standard system consisting of a slit aperture and a single cylindrical lens, which is commonly used in light sheet microscopy. As there is no truncation of the beam by a slit aperture in our design the laser energy is used more efficiently. Applying this light sheet generator to ultramicroscopy of chemically cleared biological samples, such as Drosophila, dissected mouse hippocampi, and entire mouse brains, we achieved a markedly improved resolution of fine details., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Here we describe methods for imaging neurons and neuronal excitation in brain slices with infrared video microscopy. Patch clamping in conjunction with a gradient-contrast system allows electrical recording from fine neuronal processes. Imaging with an infrared (IR)-darkfield system allows visualization of the intrinsic optical signal (IOS).

A new series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a-m) and their precursor 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a-m) were synthesized and evaluated as antileishmanials against Leishmania braziliensis and Leishmania amazonensis promastigotes in vitro. In parallel, the cytotoxicity of these compounds was evaluated on the RAW 264.7 cell line. The results showed that among the assayed compounds the substituted 3-chlorophenyl (4a) (IC50/24h=15±0.14 μM) and 3,4-dichlorophenyl tetrazoles (4d) (IC50/24h=26±0.09 μM) were the most potent against L. braziliensis promastigotes, as compared the reference drug pentamidine, which presented IC50=13±0.04 μM. In addition, 4a and 4d derivatives were less cytotoxic than pentamidine. However, these tetrazole derivatives (4) and pyrazole-4-carbonitriles precursors (3) differ against each of the tested species and were more effective against L.braziliensis than on L. amazonensis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Technological and scientific challenges coupled with environmental considerations have prompted a search for simple and energy-efficient syntheses and processing routes of materials. This tutorial review provides an overview of recent research efforts in non-conventional reactions and syntheses of oxides induced by mechanical action. It starts with a brief account of the history of mechanochemistry. Ensuing discussions will review the progress in homogeneous and heterogeneous mechanochemical reactions in oxides of various structures. The review demonstrates that the event of mechanically induced reactions provides novel opportunities for the non-thermal manipulation of materials and for the tailoring of their properties.

Jatropha curcas seeds are a promising feedstock for biodiesel production. However, Jatropha seed oil and other plant parts are toxic due to the presence of phorbol esters (PEs). The ever-increasing cultivation of toxic genotype of J. curcas runs the risk of increased human exposure to Jatropha products. In the present study, effects of J. curcas oil (from both toxic and nontoxic genotypes), purified PEs-rich extract and purified PEs (factors C1, C2, C(3mixture), (C4+C5)) on reconstituted human epithelium (RHE) and human corneal epithelium (HCE) were evaluated in vitro. The PEs were purified from toxic Jatropha oil. In both RHE and HCE, the topical application of PEs containing samples produced severe cellular alterations such as marked oedema, presence of less viable cell layers, necrosis and/or partial tissue disintegration in epithelium and increased inflammatory response (interleukin-1α and prostaglandin E2). When compared to toxic oil, histological alterations and inflammatory response were less evident (P<0.05) in nontoxic oil indicating the severity of toxicity was due to PEs. Conclusively, topical applications of Jatropha PEs are toxic towards RHE and HCE models, which represents dermal and occular toxicity respectively. Data obtained from this study would aid in the development of safety procedures for Jatropha biodiesel industries. It is advised to use protective gloves and glasses when handling PEs containing Jatropha products., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Ultramicroscopy (UM) is a powerful imaging technique that achieves precise and accurate three-dimensional (3D) reconstructions of intact macroscopic specimens with micrometer resolution. It was developed for specimens in the size range of ∼1-15 mm, such as whole mouse brains, mouse embryos, mouse organs, and Drosophila melanogaster. In UM, the specimen is illuminated perpendicular to the observation pathway by two thin counterpropagating sheets of laser light. UM is closely related to a growing family of comparable microscopy approaches based on light sheet illumination developed in recent years. This article presents an overview of light-sheet-based microscopy and describes the underlying physics of light sheet generation. The assembly of an "ultramicroscope" for investigating fixed chemically cleared tissue is described in detail, and the functions of the essential components, such as mechanics, camera, and objectives, are discussed. Finally, practical applications of UM for studying mouse organs, mouse embryos, and Drosophila adults are described.