Distinct serum metabolomic signatures of multiparous and primiparous dairy cows switched from a moderate to high-grain diet during early lactation.

INTRODUCTION: Feeding of high-grain diets is common in cows during early lactation, but increases the odds of metabolic derailments, which can likely be detected as undesirable shifts in the serum metabolome signature. OBJECTIVES: The present study aimed to identify the metabolic signatures of the serum metabolome of early lactation dairy cows switched from a moderate to a high-grain diet. METHODS: Targeted ESI-LC-MS/MS-based metabolomics was used to characterize metabolic alterations in the serum of early lactation multiparous (MP, n = 16) and primiparous (PP, n = 8) Simmental cows, according to parity and feeding phase. Data were analysed using different data mining approaches. RESULTS: Carnitine, acetylcarnitine, propionoylcarnitine, amino acid related compounds cis-4-hydroxyproline, trans-4-hydroxyproline, proline betaine, lysophosphatidylcholine PC a C16:1 and phosphatidylcholine PC ae C36:0 were identified as the key metabolites distinguishing MP from PP cows. A different serum metabolite composition during moderate and high-grain diet was also evident. Notably, cows fed high grain diet had higher serum concentrations of primary bile acids and triglycerides, but lower levels of conjugated bile acids and carboxylic acids during the first week in grain. Amino acids valine, cystine and taurine together with lysophosphatidylcholine PC a C26:0 and several phosphatidylcholines were classified as important features for cluster separation. CONCLUSIONS: Our study greatly expands earlier observations on dietary effects on serum metabolome composition of cows. The altered metabolomic fingerprints clearly distinguishable by diet and cow parity hold potential to be used as early diagnostic tools for cows experiencing grain-induced metabolic disturbances.

Serum-free light chains adjusted for renal function are a potential biomarker for post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disease (PTLD) is a serious complication of solid organ transplantation. As early diagnosis remains challenging, we investigated the utility of serum-free light chain (FLC) and heavy chain/light chain pairs (HLC) as diagnostic biomarkers. Pre-treatment serum FLC and HLC levels were measured in 20 patients at their first diagnosis of B cell PTLD and in 14/20 patients during follow-up. Results were compared to serum FLC/HLC levels of 90 matched PTLD-free transplanted controls. Renal dysfunction was common in both cohorts, and combined FLC levels were often elevated above the conventional upper limit of normal (45.7 mg/L). Combined FLC levels were higher in patients with PTLD than in transplant controls (p = 0.013), and levels above the conventional ULN were associated with PTLD (OR 3.2, p = 0.05). Following adjustment to cystatin C as a marker of renal function an even stronger association was found for a (dimensionless) threshold value of 37.8 (OR 8.9, p < 0.001). In addition, monoclonal proliferation (abnormal FLC ratio, using an established renal range cutoff) was more common in PTLD than in controls (3/20 vs. 2/90, p = 0.04). Following therapy, at the time of protocolised restaging, patients experiencing subsequent sustained complete remission displayed lower FLC levels than those not experiencing such remission (p = 0.053). No relationship with HLC results was seen. Elevated polyclonal FLC levels (especially when adjusted for renal function) and monoclonal proliferation are a potential biomarker for PTLD diagnosis and disease surveillance. However, prospective validation is necessary before FLC measurement should be incorporated in follow-up of transplant recipients and PTLD management.

Limit on Excitation and Stabilization of Atoms in Intense Optical Laser Fields.

Atomic excitation in strong optical laser fields has been found to take place even at intensities exceeding saturation. The concomitant acceleration of the atom in the focused laser field has been considered a strong link to, if not proof of, the existence of the so-called Kramers-Henneberger (KH) atom, a bound atomic system in an intense laser field. Recent findings have moved the importance of the KH atom from being purely of theoretical interest toward real world applications; for instance, in the context of laser filamentation. Considering this increasing importance, we explore the limits of strong-field excitation in optical fields, which are basically imposed by ionization through the spatial field envelope and the field propagation.

Unified Time and Frequency Picture of Ultrafast Atomic Excitation in Strong Laser Fields.

Excitation and ionization in strong laser fields lies at the heart of such diverse research directions as high-harmonic generation and spectroscopy, laser-induced diffraction imaging, emission of femtosecond electron bunches from nanotips, self-guiding, filamentation and mirrorless lasing during propagation of light in atmospheres. While extensive quantum mechanical and semiclassical calculations on strong-field ionization are well backed by sophisticated experiments, the existing scattered theoretical work aiming at a full quantitative understanding of strong-field excitation lacks experimental confirmation. Here we present experiments on strong-field excitation in both the tunneling and multiphoton regimes and their rigorous interpretation by time dependent Schrödinger equation calculations, which finally consolidates the seemingly opposing strong-field regimes with their complementary pictures. Most strikingly, we observe an unprecedented enhancement of excitation yields, which opens new possibilities in ultrafast strong-field control of Rydberg wave packet excitation and laser intensity characterization.

[Optical coherence tomography in neuromyelitis optica spectrum disorders]. / Optische Kohärenztomographie bei Neuromyelitis optica-Spektrum-Erkrankungen.

Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing inflammatory conditions of the central nervous system (CNS). In 55% of the cases of NMOSD optic neuritis (ON) is the most frequent first manifestation and can cause severe damage to the afferent visual system and the retina with resultant severe visual impairment. In recent years, investigations of the retina as part of the CNS by optical coherence tomography (OCT) has been shown to be a valid and efficient method for diagnostics and evaluation of the disease course in NMOSD. In addition, OCT not only shows severe damage of the afferent visual system due to multiple bouts of ON but also reveals NMOSD-specific intraretinal pathologies. The latter could be just as important for future differential diagnostics as for the evaluation of potential therapeutic targets. This article briefly reviews the principles of the OCT technique and describes its relevance for the diagnostics and assessment of disease course in NMOSD.

Sensitive CH4 detection applying quantum cascade laser based optical feedback cavity-enhanced absorption spectroscopy.

We report on sensitive detection of atmospheric methane employing quantum cascade laser based optical feedback cavity-enhanced absorption spectroscopy (OF-CEAS). An instrument has been built utilizing a continuous-wave distributed feedback quantum cascade laser (cw-QCL) with a V-shaped cavity, a common arrangement that reduces feedback to the laser from non-resonant reflections. The spectrometer has a noise equivalent absorption coefficient of 3.6 × 10-9 cm-1 Hz-1/2 for a spectral scan of CH4 at 7.39 µm. From an Allan-Werle analysis a detection limit of 39 parts per trillion of CH4 at atmospheric pressure within 50 s acquisition time was found.

Brain parenchymal damage in neuromyelitis optica spectrum disorder - A multimodal MRI study.

OBJECTIVE: To investigate different brain regions for grey (GM) and white matter (WM) damage in a well-defined cohort of neuromyelitis optica spectrum disorder (NMOSD) patients and compare advanced MRI techniques (VBM, Subcortical and cortical analyses (Freesurfer), and DTI) for their ability to detect damage in NMOSD. METHODS: We analyzed 21 NMOSD patients and 21 age and gender matched control subjects. VBM (GW/WM) and DTI whole brain (TBSS) analyses were performed at different statistical thresholds to reflect different statistical approaches in previous studies. In an automated atlas-based approach, Freesurfer and DTI results were compared between NMOSD and controls. RESULTS: DTI TBSS and DTI atlas based analysis demonstrated microstructural impairment only within the optic radiation or in regions associated with the optic radiation (posterior thalamic radiation p < 0.001, 6.9 % reduction of fractional anisotropy). VBM demonstrated widespread brain GM and WM reduction, but only at exploratory statistical thresholds, with no differences remaining after correction for multiple comparisons. Freesurfer analysis demonstrated no group differences. CONCLUSION: NMOSD specific parenchymal brain damage is predominantly located in the optic radiation, likely due to a secondary degeneration caused by ON. In comparison, DTI appears to be the most reliable and sensitive technique for brain damage detection in NMOSD. KEY POINTS: • The hypothesis of a widespread brain damage in NMOSD is challenged. • The optic radiation (OR) is the most severely affected region. • OR-affection is likely due to secondary degeneration following optic neuritis. • DTI is currently the most sensitive technique for NMOSD-related brain-damage detection. • DTI is currently the most reliable technique for NMOSD-related brain-damage detection.

Speed optimized linear-mode high-voltage CMOS avalanche photodiodes with high responsivity.

Two different speed optimized avalanche photodiodes (APDs) fabricated in a 0.35 µm standard high-voltage (HV) complementary metal-oxide-semiconductor (CMOS) process with a high unamplified responsivity (avalanche gain M=1) of 0.41 A/W at 670 nm are presented. These APDs differ regarding the effective doping of the deep p well (90% and 75%), using lateral well modulation doping. Compared to the -3 dB bandwidth of the unmodulated APD with 100% doping (850 MHz), this optimization leads to an improved bandwidth of 1.02 and 1.25 GHz for the 75% APD and 90% APD, respectively, both at a gain of M=50.

Strong-field excitation of helium: bound state distribution and spin effects.

Using field ionization combined with the direct detection of excited neutral atoms we measured the distribution of principal quantum number n of excited He Rydberg states after strong-field excitation at laser intensities well in the tunneling regime. Our results confirm theoretical predictions from semiclassical and quantum mechanical calculations and simultaneously underpin the validity of the semiclassical frustrated tunneling ionization model. Moreover, since our experimental detection scheme is spin sensitive in the case of He atoms, we show that strong-field excitation leads to strong population of triplet states. The origin of it lies in the fact that high angular momentum states are accessible in strong-field excitation. Thus, singlet-triplet transitions become possible due to the increased importance of spin-orbit interaction rather than due to direct laser induced spin-flip processes.

Neuromyelitis optica and multiple sclerosis: Seeing differences through optical coherence tomography.

Neuromyelitis optica (NMO) is an inflammatory autoimmune disease of the central nervous system that preferentially targets the optic nerves and spinal cord. The clinical presentation may suggest multiple sclerosis (MS), but a highly specific serum autoantibody against the astrocytic water channel aquaporin-4 present in up to 80% of NMO patients enables distinction from MS. Optic neuritis may occur in either condition resulting in neuro-anatomical retinal changes. Optical coherence tomography (OCT) has become a useful tool for analyzing retinal damage both in MS and NMO. Numerous studies showed that optic neuritis in NMO typically results in more severe retinal nerve fiber layer (RNFL) and ganglion cell layer thinning and more frequent development of microcystic macular edema than in MS. Furthermore, while patients' RNFL thinning also occurs in the absence of optic neuritis in MS, subclinical damage seems to be rare in NMO. Thus, OCT might be useful in differentiating NMO from MS and serve as an outcome parameter in clinical studies.

Towards the imaging of Weibel-Palade body biogenesis by serial block face-scanning electron microscopy.

Electron microscopy is used in biological research to study the ultrastructure at high resolution to obtain information on specific cellular processes. Serial block face-scanning electron microscopy is a relatively novel electron microscopy imaging technique that allows three-dimensional characterization of the ultrastructure in both tissues and cells by measuring volumes of thousands of cubic micrometres yet at nanometre-scale resolution. In the scanning electron microscope, repeatedly an image is acquired followed by the removal of a thin layer resin embedded biological material by either a microtome or a focused ion beam. In this way, each recorded image contains novel structural information which can be used for three-dimensional analysis. Here, we explore focused ion beam facilitated serial block face-scanning electron microscopy to study the endothelial cell-specific storage organelles, the Weibel-Palade bodies, during their biogenesis at the Golgi apparatus. Weibel-Palade bodies predominantly contain the coagulation protein Von Willebrand factor which is secreted by the cell upon vascular damage. Using focused ion beam facilitated serial block face-scanning electron microscopy we show that the technique has the sensitivity to clearly reveal subcellular details like mitochondrial cristae and small vesicles with a diameter of about 50 nm. Also, we reveal numerous associations between Weibel-Palade bodies and Golgi stacks which became conceivable in large-scale three-dimensional data. We demonstrate that serial block face-scanning electron microscopy is a promising tool that offers an alternative for electron tomography to study subcellular organelle interactions in the context of a complete cell.

[New Applications and Indications for Contrast-Enhanced Sonography in Endovascular Aortic Repair]. / Neue Applikationen und Indikationen der Kontrastmittelsonografie im Rahmen des Aortenstentings.

After edovascular repair of infrarenal aortic aneurysms (EVAR) endoleaks may occur necessitating further therapy. Therefore a reliable method for follow-up imaging after EVAR for detection and control of endoleaks is of high importance. Contrast-enhanced sonography (CEUS) does not require the application of nephrotoxid contrast media and does not stress the patient. CEUS is increasingly used and enables a quick, non-invasive follow-up examination for patient after EVAR. In addition, interventions as therapy for endoleaks may be executed using ultrasound. Initial experience with CEUS-guided aortic stenting shows that the amount of contrast media as well as X-ray time may be reduced.

[Growing old differently: Transdisciplinary perspective]. / Anders altern: Transdisziplinäre Perspektive.

Growing old differently: the phrase is intended to call something other to mind than merely the fact that images and forms of old age and aging have multiplied and diversified to an enormous extent. The suggestion put forward here is that otherness (as opposed to mere differences) should be positively reinforced. In other words, it is not just a matter of noting different forms of old age and aging but more than this, of seeking out opportunities for aging differently. In order to explore this, the article follows an older strand of theory, which has recently come to be frequently quoted in gerontology: the phenomenology of difference as reasoned analytically by Lévinas and Sartre and applied to gerontology by Améry and de Beauvoir. Here, opportunities for aging crucially depend on the way we look at it, how we observe and describe it and not least, how gerontology frames it. A distinction is made between two perspectives and their associated consequences for old age: alienation and alterity. Alienation means looking at old age above all as a disconcerting "other", as a perplexing, problematic deviation from the norm of vitality. Alterity, by contrast, refers to different options for living life in old age: options to be explored and opened up in contradistinction to cultural or academic alienation. Not least, the article appeals for diversity in scholarly approaches and for cross-disciplinary perspectives.

Effects of Respiratory Therapy (bagging) on Respiratory Function, Swallowing Frequency and Vigilance in Tracheotomized Patients in Early Neurorehabilitation.

OBJECTIVE: Tracheotomized patients often suffer from impairments in mucociliary clearance and limited capacities for active expectoration of secretions. We investigated the effects of a specific respiratory intervention method (bagging) for tracheotomized patients on respiratory parameters (pO2, pCO2, SpO2, respiratory rates), swallowing frequency, vigilance and secretion viscosity. METHODS: The bagging method supports enforced mobilization and expectoration of secretions by application of a series of manual hyperinflations with a resuscitation bag during active inspiration and manual cough support on the chest. 30 tracheotomized neurological patients participated in a multiple-baseline study including a three-weeks intervention period and a follow-up measurement three weeks after termination of the treatment. RESULTS: Most outcome parameters improved significantly during the intervention period: pO2 (p < .01), SpO2 (p < .01), respiratory rates (p < .01), swallowing rates (p < .01), and vigilance scores (p < .01). The quality of bronchial secretions improved in all participants. All effects were sustained up to the follow-up measurements. CONCLUSION: This preliminary data indicates positive effects for a respiratory intervention method (bagging) on respiratory function and additional respiration-related functions in tracheotomized neurological patients. This easy-to-learn and inexpensive method might expand the range of treatment options for tracheotomized and non-responsive patients.

Human cardiac telocytes: 3D imaging by FIB-SEM tomography.

Telocyte (TC) is a newly identified type of cell in the cardiac interstitium (www.telocytes.com). TCs are described by classical transmission electron microscopy as cells with very thin and long telopodes (Tps; cellular prolongations) having podoms (dilations) and podomers (very thin segments). TCs' three-dimensional (3D) morphology is still unknown. Cardiac TCs seem to be particularly involved in long and short distance intercellular signalling and, therefore, their 3D architecture is important for understanding their spatial connections. Using focused ion beam scanning electron microscopy (FIB-SEM) we show, for the first time, the whole ultrastructural anatomy of cardiac TCs. 3D reconstruction of cardiac TCs by FIB-SEM tomography confirms that they have long, narrow but flattened (ribbon-like) telopodes, with humps generated by the podoms. FIB-SEM tomography also confirms the network made by TCs in the cardiac interstitium through adherens junctions. This study provides the first FIB-SEM tomography of a human cell type.

Strong-field Kapitza-Dirac scattering of neutral atoms.

Laser induced strong-field phenomena in atoms and molecules on the femtosecond (fs) time scale have been almost exclusively investigated with traveling wave fields. In almost all cases, approximation of the strong electromagnetic field by an electric field purely oscillating in time suffices to describe experimental observations. Spatially dependent electromagnetic fields, as they occur in a standing light wave, allow for strong energy and momentum transfer and are expected to extend strong-field dynamics profoundly. Here we report a strong-field version of the Kapitza-Dirac effect for neutral atoms where we scatter neutral He atoms in an intense short pulse standing light wave with fs duration and intensities well in the strong-field tunneling regime. We observe substantial longitudinal momentum transfer concomitant with an unprecedented atomic photon scattering rate greater than 10(16)s(-1).

Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short-term mortality.

OBJECTIVE: Patients with decompensated cirrhosis are susceptible to bacterial infections, which are associated with organ failure and a high mortality rate. Reliable biomarkers are needed to identify patients who require intensified treatment. Our objective was to study the regulation and prognostic relevance of elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) in patients with advanced cirrhosis. DESIGN, SETTING AND PARTICIPANTS: We examined the associations between serum and ascitic fluid (AF) suPAR and liver function, bacterial infection, and short-term mortality in 162 consecutive patients with decompensated cirrhosis undergoing diagnostic paracentesis in a tertiary health care centre in Germany. MAIN OUTCOME MEASURE: Twenty-eight-day mortality. RESULTS: Circulating suPAR levels were increased in patients with decompensated cirrhosis and correlated with the severity of liver dysfunction and systemic inflammation but were not indicative of bacterial infection. Circulating suPAR levels >14.4 ng mL(-1) predicted 28-day mortality, even after adjustment for liver function and confounders [HR = 3.05 (1.35-6.90); P = 0.0076] equal to the MELD score (AUC = 0.71; 95% CI = 0.61-0.81; P < 0.001). Cut-off levels derived from cohorts without liver disease were not applicable due to the low specificity. AF suPAR levels were elevated during spontaneous bacterial peritonitis (SBP), but not during episodes in which bacteria or bacterial DNA was translocated into the ascites. AF suPAR levels correlated poorly with systemic suPAR but were associated with a more severe course of SBP and a worse outcome. In vitro experiments revealed that monocytes, and to a lesser extent neutrophils, secrete suPAR after Toll-like-receptor ligation, which led to rapid urokinase plasminogen activator receptor cleavage followed by increased synthesis. CONCLUSION: Blood and ascitic suPAR levels provide distinct, but relevant prognostic information on the severity of complications in patients with end-stage liver disease.

Optical coherence tomography does not support optic nerve involvement in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In recent years a possible non-motor involvement of the nervous system in amyotrophic lateral sclerosis (ALS) has come into the focus of research and has been investigated by numerous techniques. Optical coherence tomography (OCT) - with its potential to reveal neuroaxonal retinal damage - may be an appropriate tool to investigate whether the anterior visual pathway is involved. Our aim was to determine whether OCT-based measures of retinal nerve fiber layer, ganglion cell layer, inner nuclear layer and outer nuclear layer thickness are abnormal in ALS, or correlated with disease severity. METHODS: Seventy-six ALS patients (144 eyes) and 54 healthy controls (108 eyes; HCs) were examined with OCT, including automated intraretinal macular segmentation. ALS disease severity was determined with the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised. RESULTS: There was no significant difference between ALS patients and HCs in any of the examined OCT measures. Moreover, OCT parameters showed no correlation with clinical measures of disease severity. CONCLUSIONS: These findings indicate that involvement of the anterior visual pathway is not one of the non-motor manifestations of ALS.

Primary and secondary relaxation process in plastically crystalline cyanocyclohexane studied by 2H nuclear magnetic resonance. I.

We study the main (α-) and secondary (ß-) relaxation in the plastically crystalline (PC) phase of cyanocyclohexane by various 2H nuclear magnetic resonance (NMR) methods (line-shape, spin-lattice relaxation, stimulated echo, and two-dimensional spectra) above and below the glass transition temperature T(g) = 134 K. Our results regarding the α-process demonstrate that molecular motion is not governed by the symmetry of the lattice. Rather it is similar to the one reported for structural glass formers and can be modeled by a reorientation proceeding via a distribution of small and large angular jumps. A solid-echo line-shape analysis regarding the ß-process below T(g) yields again very similar results when compared to those of the structural glass formers ethanol and toluene. Hence we cannot confirm an intramolecular origin for the ß-process in cyanocyclohexane. The fast ß-process in the PC phase allows for the first time a detailed 2H NMR study of the process also at T > T(g): an additional minimum in the spin-lattice relaxation time reflecting the ß-process is found. Furthermore the solid-echo spectra show a distinct deviation from the rigid limit Pake pattern, which allows a direct determination of the temperature dependent spatial restriction of the process. In Part II of this work, a quantitative analysis is carried out, where we demonstrate that within the model of a "wobbling in a cone" the mean cone angle increases above T(g) and the corresponding relaxation strength is compared to dielectric results.

Cryopreservation with a twist - towards a sterile, serum-free surface-based vitrification of hESCs.

Human embryonic stem cells (hESCs) play an important role in the fields of regenerative medicine, basic scientific research, tissue engineering and toxicology. Their unique morphology however makes them very sensitive to cryopreservation procedures. We recently introduced a surface dependent, enzyme- and serum-free method for the effective cryopreservation of bulk quantities of hESC colonies using direct immersion into liquid nitrogen (Beier et al., 2011 [5]). However, direct contact with liquid nitrogen risks contamination and cell infection and severely limits clinical application. This work introduces a modified method and a new combined cultivation and cryopreservation device to facilitate the surface dependent vitrification without contact with (possibly unsterile) liquid nitrogen. The technique allows the culture, cryopreservation, storage and post-thawing cultivation in the same device without detaching cell samples from the cultivation surface. Successful vitrification of bulk quantities of hESCs without direct liquid nitrogen contact is an important step towards automated cryopreservation processes for clinical applications of stem cells and other colony forming cell types.