Topological-chiral magnetic interactions driven by emergent orbital magnetism.

Two hundred years ago, Ampère discovered that electric loops in which currents of electrons are generated by a penetrating magnetic field can mutually interact. Here we show that Ampère's observation can be transferred to the quantum realm of interactions between triangular plaquettes of spins on a lattice, where the electrical currents at the atomic scale are associated with the orbital motion of electrons in response to the non-coplanarity of neighbouring spins playing the role of a magnetic field. The resulting topological orbital moment underlies the relation of the orbital dynamics with the topology of the spin structure. We demonstrate that the interactions of the topological orbital moments with each other and with the spins form a new class of magnetic interactions [Formula: see text] topological-chiral interactions [Formula: see text] which can dominate over the Dzyaloshinskii-Moriya interaction, thus opening a path for realizing new classes of chiral magnetic materials with three-dimensional magnetization textures such as hopfions.

Differential effect of drought regimes on the seedling performance of six floodplain grassland species.

The performance of seedlings is crucial for the survival and persistence of plant populations. Although drought frequently occurs in floodplains and can cause seedling mortality, studies on the effects of drought on seedlings of floodplain grasslands are scarce. We tested the hypotheses that drought reduces aboveground biomass, total biomass, plant height, number of leaves, leaf area and specific leaf area (SLA), and increases root biomass and root-mass fraction (RMF) and that seedlings from species of wet floodplain grasslands are more affected by drought than species of dry grasslands. In a greenhouse study, we exposed seedlings of three confamilial pairs of species (Pimpinella saxifraga, Selinum carvifolia, Veronica teucrium, Veronica maritima, Sanguisorba minor, Sanguisorba officinalis) to increasing drought treatments. Within each plant family, one species is characteristic of wet and one of dry floodplain grasslands, confamilial in order to avoid phylogenetic bias of the results. In accordance with our hypotheses, drought conditions reduced aboveground biomass, total biomass, plant height, number of leaves and leaf area. Contrary to our hypotheses, drought conditions increased SLA and decreased root biomass and RMF of seedlings. Beyond the effects of the families, the results were species-specific (V. maritima being the most sensitive species) and habitat-specific. Species indicative of wet floodplain grasslands appear to be more sensitive to drought than species indicative of dry grasslands. Because of species- and habitat-specific responses to reduced water availability, future drought periods due to climate change may severely affect some species from dry and wet habitats, while others may be unaffected.

Significantly enhanced lung metastasis and reduced organ NK cell functions in diet-induced obese rats.

BACKGROUND: Obesity was identified as a major risk factor for malignant diseases, but underlying mechanisms remain unclear. Natural killer (NK) cells, a pivotal aspect of innate immunity, are capable of identifying and killing virally infected and tumor cells. Previous studies have shown altered NK cell functions in obesity, and the current study aimed to investigate the relationship between altered NK cell functions and increased cancer risk in obesity. METHODS: To induce obesity male F344-rats received a high-fat diet (34% fat) or a control diet (4% fat). Thereafter, syngeneic mammary adenocarcinoma cells (MADB106) or a vehicle were intravenously (i.v.) injected. 15 min after injection, half of each group of rats were killed, lungs removed and immunohistochemically stained. Numbers of NK cells, MADB106 cells and NK cell-tumor cell interactions were quantified. Twenty-one days after tumor-cell injection the other half group of rats was killed and lung metastases were counted and relative mRNA concentrations of different NK cell receptors were determined. RESULTS: After short-term MADB106-challenge, DIO fed animals showed significantly decreased NK cell numbers in the blood and NK cell-tumor cell interactions in the lung as compared to their control littermates. Twenty-one days after MADB106 injection, the lungs of the DIO fed rats showed significantly more lung metastases compared to control animals, accompanied by reduced relative mRNA concentrations of the activating NK cell receptor NKG2D. CONCLUSIONS: We conclude that induction of obesity in F344-rats leads to reduced lung NK cell function against tumor cells and results in significantly enhanced lung metastasis as compared to lean animals. It can be hypothesized that obesity-induced altered NK cell functions play an important role in cancer growth and metastasis.

Arterial and portal venous liver perfusion using selective spin labelling MRI.

PURPOSE: To investigate the feasibility of selective arterial and portal venous liver perfusion imaging with spin labelling (SL) MRI, allowing separate labelling of each blood supply. METHODS: The portal venous perfusion was assessed with a pulsed EPISTAR technique and the arterial perfusion with a pseudo-continuous sequence. To explore precision and reproducibility, portal venous and arterial perfusion were separately quantified in 12 healthy volunteers pre- and postprandially (before and after meal intake). In a subgroup of 6 volunteers, the accuracy of the absolute portal perfusion and its relative postprandial change were compared with MRI flow measurements of the portal vein. RESULTS: The portal venous perfusion significantly increased from 63 ± 22 ml/100g/min preprandially to 132 ± 42 ml/100g/min postprandially. The arterial perfusion was lower with 35 ± 22 preprandially and 22 ± 30 ml/100g/min postprandially. The pre- and postprandial portal perfusion using SL correlated well with flow-based perfusion (r(2) = 0.71). Moreover, postprandial perfusion change correlated well between SL- and flow-based quantification (r(2) = 0.77). The SL results are in range with literature values. CONCLUSION: Selective spin labelling MRI of the portal venous and arterial blood supply successfully quantified liver perfusion. This non-invasive technique provides specific arterial and portal venous perfusion imaging and could benefit clinical settings where contrast agents are contraindicated. KEY POINTS: • Perfusion imaging of the liver by Spin Labelling MRI is feasible • Selective Spin Labelling MRI assessed portal venous and arterial liver perfusion separately • Spin Labelling based portal venous liver perfusion showed significant postprandial increase • Spin Labelling based portal perfusion correlated well with phase-contrast based portal perfusion • This non-invasive technique could benefit settings where contrast agents are contraindicated.

A new era of ventricular assist device surgery: less invasive procedures.

As the number of patients suffering of congestive heart failure is rising worldwide, the use of mechanical circulatory support to treat these patients has also grown enormously, surpassing the number of annual heart transplants. Moreover latest generation of left ventricular assist devices (LVADs) is characterized by improved technologies. Moreover the size of new LVAD systems is considerably reduced when compared to older generation devices. Therefore, less invasive surgery is now possible for the implantation, explantation, and exchange of LVADs. Although experience with these new techniques is still limited, minimally invasive procedures are thought to improve surgical outcomes by declining the rates of operative complications such as bleeding or wound infection. The miniaturization of LVADs will continue, so that minimally invasive techniques will be used for most LVAD-related procedures in the future. In this article, we summarize and describe minimally invasive surgical techniques, with a focus on the most common LVAD systems in adults.

Liver perfusion in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI): comparison of enhancement in Gd-BT-DO3A and Gd-EOB-DTPA in normal liver parenchyma.

PURPOSE: Within-patient comparison of the enhancement patterns of normal liver parenchyma after gadobutrol and gadoxetate disodium, with emphasis on the start of hepatocytic uptake of gadoxetate disodium. MATERIALS AND METHODS: Twenty-one patients (12 female, 9 male) without chronic liver disease underwent 1.5-T contrast-enhanced MRI twice, once with an extracellular contrast agent (gadobutrol) and once with a hepatospecific agent (gadoxetate disodium), using a T1-weighted keyhole sequence. Fifteen whole-liver datasets were acquired up to 5 min for both contrast agents and two additional datasets, up to 20 min, for gadoxetate. Signal intensities (SI) of the parenchyma, aorta and portal vein were measured and analysed relative to pre-contrast parenchymal SI. RESULTS: After gadoxetate, in 29% of the patients the parenchymal SI decreased by ≥5% after the initial vascular-phase-induced peak, while in the other 71% the parenchymal SI remained stable or gradually increased until up to 20 min after the initial peak. The hepatocytic gadoxetate uptake started at a mean of 37.8 s (SD 14.7 s) and not later than 76 s after left ventricle enhancement. CONCLUSION: Parenchymal enhancement due to hepatocytic uptake of gadoxetate can start as early as in the late arterial phase. This may confound the assessment of lesion appearance as compared to extracellular contrast such as gadobutrol. KEY POINTS: Gadoxetate-enhanced liver MRI results in early enhancement of normal parenchyma in patients The start of the hepatobiliary phase coincides with the late arterial phase. This may confound the assessment of lesion appearance compared to extracellular contrast. Different parenchymal enhancement patterns after gadoxetate were found for normal parenchyma.

The distribution of nociceptive innervation in the painful hip: a histological investigation.

Our understanding of the origin of hip pain in degenerative disorders of the hip, including primary osteoarthritis, avascular necrosis and femoroacetabular impingement (FAI), is limited. We undertook a histological investigation of the nociceptive innervation of the acetabular labrum, ligamentum teres and capsule of the hip, in order to prove pain- and proprioceptive-associated marker expression. These structures were isolated from 57 patients who had undergone elective hip surgery (44 labral samples, 33 ligamentum teres specimens, 34 capsular samples; in 19 patients all three structures were harvested). A total of 15,000 histological sections were prepared that were investigated immunohistochemically for the presence of protein S-100, 68 kDa neurofilament, neuropeptide Y, nociceptin and substance P. The tissues were evaluated in six representative areas. Within the labrum, pain-associated free nerve ending expression was located predominantly at its base, decreasing in the periphery. In contrast, the distribution within the ligamentum teres showed a high local concentration in the centre. The hip capsule had an almost homogeneous marker expression in all investigated areas. This study showed characteristic distribution profiles of nociceptive and pain-related nerve fibres, which may help in understanding the origin of hip pain.

Pregnancy rates, prenatal and postnatal survival of offspring, and litter sizes after reciprocal embryo transfer in DBA/2JHd, C3H/HeNCrl and NMRI mice.

Success of embryo transfer is often a limiting factor in transgenic procedures and rederivation efforts, and depends on the genetic background of the donor and recipient strains used. Here we show that embryo transfer to DBA/2J females is possible, and present data on pre- and postnatal success rates after reciprocal embryo transfer using the inbred DBA/2J and C3H/HeN, and outbred NMRI strains. The highest embryo yield was achieved in outbred NMRI females, but embryo yields were similar in DBA/2J and C3H/HeN mice following superovulation despite poor estrus cycle synchronization in DBA/2J females. In-strain transfer of DBA/2J blastocysts (transfer of embryos to recipients from the same strain) resulted in pregnancy rates (57.1%) similar to those obtained following in-strain transfer of C3H/HeN (60.0%) and NMRI mice (83.3%), although the prenatal survival rate of blastocysts was low. Moreover, from the pups born only half survived the postnatal period after transfer of DBA/2J and C3H/HeN blastocysts to DBA/2J recipients. These problems were not observed when transferring NMRI-blastocysts to C3H/HeN and DBA/2J mothers. The number of blastocysts transferred also had a positive effect on the success of embryo transfer. In conclusion, C3H/HeN and DBA/2J females can be used as recipients for embryo transfer procedures for certain donor strains like NMRI, as one major determinant seems to be the genetic background of the embryos transferred. We also recommend to increase the number of DBA/2J blastocysts transferred, and to foster the DBA/2J pups to other DBA/2J mothers postnatally for in-strain transfer of DBA/2J mice.

Protein biomarkers and drug design for cancer treatments.

The development of new cancer treatments is quickly evolving away from traditional practices of the last 25 years. This change is occurring not only at the technical level, but also conceptually as the human genome is unravelled and decades of research contribute to our understanding of the molecular complexity of this disease. It is anticipated that disease initiation and progression is dictated by an understandable set of acquired capabilities. Knowledge of the molecular events associated with these acquired capabilities will allow the development of targeted agents coupled with new biomarkers for the prevention of cancer progression. This will have a profound influence on how drugs are developed, approved, and used by the medical community. The Food and Drug Administration (FDA) has over 400 Investigational New Drug (IND) applications for cancer in its portfolio, which increasingly involve molecular targets and genomic applications. However, only one-fifth of IND agents succeed in New Drug Application (NDA) and there is more expense and uncertainty around successful drug development than ever before. Biomarkers should help the success rate of INDs by enhancing the link between target and disease as well as in improving patient selection and monitoring response. In this review, we discuss how biomarkers can be used for target validation and pharmacodynamic modeling in preclinical drug discovery. We then explore the use of biomarkers in clinical development from proof of mechanism to proof of concept studies, as well as their use in the prevention setting.

L-type calcium channel antagonist nifedipine reduces neurofilament restitution following traumatic optic nerve injury.

BACKGROUND: The aim of the present study was to observe if the use of the L-type calcium channel antagonist nifedipine would offer advantages for the retinal ganglion cells and the restitution of the axonal cytoskeleton after optic nerve crush. METHODS: Retinal ganglion cells were retrogradely labeled with a fluorescent calcium marker. With the in vivo confocal neuroimaging (ICON) method we observed the fluorescent cell metabolism marker Oregon Green BAPTA in the same retinal ganglion cells over 3 weeks after optic nerve crush. 2 micromol nifedipine were injected intraocularly 30 minutes following optic nerve crush. FINDINGS: Investigation of the optic nerve immunostained for NF-H presented decreased restitution of the neurofilaments in the axonal cytoskeleton after 3 weeks in the optic nerve crush group treated with nifedipine as compared to the optic nerve crush only group. INTERPRETATION: These results show that a single injection of the calcium L-type antagonist nifedipine shortly after optic nerve injury has long-lasting negative effects on the recovery of the retinal ganglion cells.

Neonatal thyroxine treatment: changes in the number of corticotropin-releasing-factor (CRF) and neuropeptide Y (NPY) containing neurons and density of tyrosine hydroxylase positive fibers (TH) in the amygdala correlate with anxiety-related behavior of wistar rats.

Neonatal hyperthyroidism induces persisting alterations in the adult brain, e.g. in spatial learning and hippocampal morphology. In the present study, the relationship between anxiety-related behavior and amygdala morphology was investigated in the adult rat after transient neonatal hyperthyroidism (daily s.c. injections of 7.5 microg L-thyroxine in 0.5 ml 0.9% NaCl solution from postnatal day p1 to p12). The behavioral tests used to study anxiety-related behavior were the motility test, elevated plus-maze and fear-sensitized acoustic startle response. In the amygdala, the number of neurons containing the anxiogenic peptide corticotropin releasing factor (CRF-ir and CRF mRNA) and anxiolytic neuropeptide Y (NPY-ir), the total number of neurons and the density of tyrosine hydroxylase immunoreactive (TH-ir) fibers were quantified. Thyroxine-treated pups presented an accelerated development including opening of eyes and snout elongation as typical signs of hyperthyroidism. Thyroxine-treated adult animals displayed a reduced anxiety in the motility box and elevated plus maze, a reduction in the number of CRF-ir neurons in the central nucleus of the amygdala, as well as an increase in the number of NPY-ir neurons and density of TH-ir fibers in nuclei of the basolateral complex of the amygdala. Moreover, there was a reduction in the total number of neurons in all nuclei of the basolateral complex (despite the higher number of NPY-ir neurons), but not central nucleus of the amygdala. The number of CRF-ir neurons in the central nucleus correlated positively with anxiety-related behavior, and the number of NPY-ir neurons and the density of TH-ir fibers in the basolateral complex correlated inversely with anxiety-related behavior. The findings suggested a shift toward an anxiolytic rather than anxiogenic distribution of peptidergic neurons and fibers in the amygdala at adult age following transient neonatal hyperthyroidism.

Anatomical correlations of intrinsic axon repair after partial optic nerve crush in rats.

About 15% of retinal ganglion cells survive diffuse axonal injury of the optic nerve in adult rats. Following initial blindness, discrimination of visual stimuli in behavioral tests recovers within three weeks. To investigate the mechanisms promoting this functional recovery the axonal transport and the neurofilaments were studied. Intraocularly applied MiniRuby is transported until the place of crush and accumulated in enlarged axon terminals. Three weeks after lesion the anterograde transport of MiniRuby recovers distal to the place of crush. At the same point in time the retrograde transport of surviving retinal ganglion cells is restored which was visualized by horseradish peroxidase injected into the superior colliculus. The heavy neurofilament was stained immunohistochemically and analyzed statistically up to three weeks after optic nerve crush. The stained filaments in the axon fibers of retinal ganglion cells appear wavelike and/or fragmented up to day 8, but first signs of heavy neurofilament restitution in the fibers of the optic nerve are seen at day 12 after axonal injury. Because these results cannot be explained by longlasting axon regeneration, the present results provide convincing evidence for intrinsic axon repair soon after diffuse axonal injury that correlates in time with recovery of vision.

Apoptosis in cultured rat islets of langerhans and occurrence of Bcl-2, Bak, Bax, Fas and Fas ligand.

Isolated Langerhans islets are widely used for diabetic transplantation experiments and investigations of the mechanisms leading to the death or survival of insulin-producing cells in cultured islets. The present study was aimed at investigating programmed cell death and the role of apoptosis-associated peptides in insulin and glucagon cells of islets isolated from untreated rats and held in cultured suspension. Islets were removed from medium on days 0, 7, 14, 21 and 29, embedded in Epon, and semi-thin serial sections were prepared. At designated intervals, histologic sections were treated with the direct fluorescein-labelled TUNEL method and immunostained for pancreatic hormones (glucagon, insulin) and apoptotic peptides [Bak, Bax, Fas, Fas ligand (FasL)], as well as for the anti-apoptotic peptide Bcl-2. All tissue sections were investigated using confocal laser scanning microscopy under identical setting for semiquantitative estimation of staining intensity. The percentage of apoptotic cells was between 1.6 and 2.1% and most apoptotic cells were beta-cells. Corresponding cells often contained Bak and Bax. Fas and FasL were mostly detected in islet cells within the first week after preparing the cultured suspension. The insulin content was low (1.1 +/- 0.22 ng per islet) directly after isolation. It then increased progressively up to day 14, after which it began to decrease. Glucagon expression, on the other hand, remained high for the entire duration of the investigation. In conclusion, the islet beta-cells may recover after the isolation procedure, but after 4 weeks in culture, both the insulin content and Bcl-2 staining decrease. Moreover, apoptosis is mediated by different mechanisms after the isolation procedure and after culturing the islets for 1 month. The present data may be important for further studies on isolated, cultivated or transplanted islets.

[Effectiveness of an improved antiseptic in treatment of contaminated soft tissue wounds]. / Wirksamkeit eines neuartigen Antisepticum in der Behandlung kontaminierter Weichteilwunden.

A novel antiseptic biguanide has been shown to be more bactericidal and tissue compatible in vitro than other antiseptics. In our controlled, prospective and randomized double-blind study on patients with bacteria-contaminated wound types 2-4, one group (n = 45) was treated with humid cotton swab dressings of 0.2% Lavasept solution compared with Ringer solution (n = 35). No deterioration of wound healing was observed in either group. Lavasept treatment resulted in faster and significant reduction of gram-positive germs. The tissue compatibility of Lavasept was evaluated as significantly better than Ringer solution.

Apoptosis and occurrence of Bcl-2, Bak, Bax, Fas and FasL in the developing and adult rat endocrine pancreas.

Apoptotic cell death is thought to play a crucial role in the manifestation of insulin- and non-insulin dependent diabetes mellitus. Therefore, apoptosis and apoptotic markers were studied in the rat endocrine pancreas to get insight into the possible life cycle of Langerhans islets. The islets were investigated at 13 time points between day E19 and 18 months. At each time point, histologic sections were treated with the direct fluorescein-labelled TUNEL method and immunostained for pancreatic hormones (glucagon, insulin), apoptotic promoters (Bak, Bax, Fas, Fas Ligand) as well as for the anti-apoptotic peptide Bcl-2. All tissue sections were investigated using confocal laser scanning microscopy under identical settings for semiquantitative estimation of staining intensity. TUNEL-positive cells occurred in all pre- or postnatal stages. The findings indicated a biphasic apoptotic activity in the endocrine pancreas during the lifetime of rats. The first phase began at E19 and peaked at P5 accompanied by a considerable increase in Bak fluorescence staining intensity, while the second phase began at P30 and peaked at 18 months with increasing amounts of Fas and FasL staining intensities in the islet cells. The presented in situ data may be important for understanding the increased age-related vulnerability of islet cells and for studies of isolated and cultivated rat islets.

EST comparison indicates 38% of human mRNAs contain possible alternative splice forms.

Expressed sequence tag (EST) databases represent a large volume of information on expressed genes including tissue type, expression profile and exon structure. In this study we create an extensive data set of human alternative splicing. We report the analysis of 7867 non-redundant mRNAs, 3011 of which contained alternative splice forms (38% of all mRNAs analysed). From a total of 12572 ESTs 4560 different possible alternative splice forms were detected. Interestingly, 70% of the alternative splice forms correspond to exon deletion events with only 30% exonic insertions. We experimentally verified 19 different splice forms from 16 genes in a total subset of 20 studied; all of the respective genes are of medical relevance.

Genomics and new technologies as catalysts for change in the drug discovery paradigm.

The pharmaceutical industry is faced with unprecedented opportunities emerging from genomic sequencing. In parallel, many new technologies in the areas of informatics, molecular biology, combinatorial chemistry, and high throughput screening offer new strategies to deal with this mass of information and translate it into tangible treatments for human diseases. Increasing pressures to control prices counterbalances these opportunities. This paradox will require a rethinking of how the industry approaches drug discovery and development, and new paradigms will need to be explored to ensure these opportunities can realized for human health care in a timely and cost-effective manner.