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Objectives. In diabetes accumulated advanced glycation end products (AGEs) are involved in the striking cardiovascular morbidity/mortality. We asked whether a hypovitaminosis D associates with an increased formation and toxicity of AGEs in diabetes.
Methods. In 276 diabetics (160M/116 F, age: 65.0 ± 13.4; 43 type 1,T1DM, and 233 type 2 patients, T2DM) and 121 nondiabetic controls (60 M/61 F; age: 58.6 ± 15.5 years) routine biochemistry, levels of 25-hydroxyvitamin D\(_{3}\) (25-(OH)D), skin autofluorescence (SAF), plasma AGE-associated fluorescence (AGE-FL), N\(^{ε}\) -(carboxymethyl) lysine (CML), soluble receptor for AGEs (sRAGE), soluble vascular adhesion protein-1 (sVAP-1), high sensitive C-reactive protein (hs-CRP), and renal function (eGFR) were determined.
Results. In the diabetics SAF and AGE-Fl were higher than those of the controls and correlated with age, duration of diabetes, and degree of renal impairment. In T2DM patients but not in T1DM the age-dependent rise of SAF directly correlated with hs-CRP and sVAP-1. 25-(OH)D levels in diabetics and nondiabetics were lowered to a similar degree averaging 22.5 ng/mL. No relationship between 25-(OH)D and studied markers except for sVAP-1 was observed in the diabetics. Conclusion. In diabetics hypovitaminosis D does not augment accumulation of AGEs and studied markers of microinflammation and oxidative stress except for sVAP-1.
Background and Objective
The aim of this single‐centre, two‐arm, parallel‐group, double‐blinded, randomised controlled trial was to investigate the disputed specific effectiveness of acupuncture by comparing acupuncture on specific and non‐specific points among patients with non‐chronic, painful TMDs.
Methods
Following predefined eligibility criteria, 49 consecutive patients of both sexes were recruited to the study. All subjects were diagnosed with a non‐chronic (Graded Chronic Pain Scale grade <3) painful TMD, as assessed using the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). Patients were randomly assigned to group A (acupuncture on specific points) or group B (acupuncture on non‐specific points) after the initial examination (T0). Both acupuncture treatment sessions were conducted by a trained dentist once a week for four weeks. The examination was repeated five weeks (T5) after T0 by one calibrated examiner who was unaware of the study groups. Characteristic pain intensity (CPI) was evaluated as the main outcome criterion and compared between times and treatment groups by means of non‐parametric tests (significance level set at P = .05). Secondary outcomes comprised the maximum corrected active mouth‐opening without pain (MAO); patients’ expectations regarding acupuncture treatment and pain development; depressivity; and oral health‐related quality of life (OHRQoL).
Results
A total of 41 patients (38 female) successfully completed the study (mean age: 40.17 ± 16.61). The two groups did not differ significantly at any time in terms of age and CPI. However, CPI was significantly (P < .05) lower at T5 than at T0 for both groups (29.66 and 30.35% lower in group A and group B, respectively). An increase in MAO was observed at T5 for both groups but was significant for group B only (P = .016). All patients had positive expectations of acupuncture therapy, and the two groups did not differ significantly at T5 with regard to the extent to which their expectations had been fulfilled by the treatment (P = .717). Comparison of T0 and T5 showed a statistically significant reduction of depressivity for group A (P = .0205), but no significant change for group B (P = .329). At T5, OHRQoL had improved significantly for both groups (group A, P = .018; group B, P < .001) compared with at T0.
Conclusions
Acupuncture on both specific and non‐specific points reduces the non‐dysfunctional pain of TMD patients. The effect of acupuncture on painful TMD cannot be attributed to the specific point selection.
Background
Differential RNA-sequencing (dRNA-seq) is indispensable for determination of primary transcriptomes. However, using dRNA-seq data to map transcriptional start sites (TSSs) and promoters genome-wide is a bioinformatics challenge. We performed dRNA-seq of Bradyrhizobium japonicum USDA 110, the nitrogen-fixing symbiont of soybean, and developed algorithms to map TSSs and promoters.
Results
A specialized machine learning procedure for TSS recognition allowed us to map 15,923 TSSs: 14,360 in free-living bacteria, 4329 in symbiosis with soybean and 2766 in both conditions. Further, we provide proteomic evidence for 4090 proteins, among them 107 proteins corresponding to new genes and 178 proteins with N-termini different from the existing annotation (72 and 109 of them with TSS support, respectively). Guided by proteomics evidence, previously identified TSSs and TSSs experimentally validated here, we assign a score threshold to flag 14 % of the mapped TSSs as a class of lower confidence. However, this class of lower confidence contains valid TSSs of low-abundant transcripts. Moreover, we developed a de novo algorithm to identify promoter motifs upstream of mapped TSSs, which is publicly available, and found motifs mainly used in symbiosis (similar to RpoN-dependent promoters) or under both conditions (similar to RpoD-dependent promoters). Mapped TSSs and putative promoters, proteomic evidence and updated gene annotation were combined into an annotation file.
Conclusions
The genome-wide TSS and promoter maps along with the extended genome annotation of B. japonicum represent a valuable resource for future systems biology studies and for detailed analyses of individual non-coding transcripts and ORFs. Our data will also provide new insights into bacterial gene regulation during the agriculturally important symbiosis between rhizobia and legumes.
Background
Postherpetic neuralgia (PHN) is the painful complication of a varicella zoster virus reactivation. We investigated the systemic and local gene expression of pro- and anti-inflammatory cytokine expression in patients with PHN.
Methods
Thirteen patients with PHN at the torso (Th4-S1) were recruited. Skin punch biopsies were obtained from the painful and the contralateral painless body area for intraepidermal nerve fiber density (IENFD) and cytokine profiling. Additionally, blood was withdrawn for systemic cytokine expression and compared to blood values of healthy controls. We analyzed the gene expression of selected pro- and anti-inflammatory cytokines (tumor necrosis factor-alpha [TNF] and interleukins [IL]-1β, IL-2, and IL-8).
Results
IENFD was lower in affected skin compared to unaffected skin (p<0.05), while local gene expression of pro- and anti-inflammatory cytokines did not differ except for two patients who had 7fold higher IL-6 and 10fold higher IL-10 gene expression in the affected skin compared to the contralateral unaffected skin sample. Also, the systemic expression of cytokines in patients with PHN and in healthy controls was similar.
Conclusion
While the systemic and local expression of the investigated pro- and anti-inflammatory cytokines was not different from controls, this may have been influenced by study limitations like the low number of patients and different disease durations. Furthermore, other cytokines or pain mediators need to be considered.
Interleukin-4 (IL-4) is an anti-inflammatory and analgesic cytokine that induces opioid receptor transcription. We investigated IL-4 knockout (ko) mice to characterize their pain behavior before and after chronic constriction injury (CCI) of the sciatic nerve as a model for neuropathic pain. We investigated opioid responsivity and measured cytokine and opioid receptor gene expression in the peripheral and central nervous system (PNS, CNS) of IL-4 ko mice in comparison with wildtype (wt) mice. Naïve IL-4 ko mice displayed tactile allodynia (wt: 0.45 g; ko: 0.18 g; p<0.001), while responses to heat and cold stimuli and to muscle pressure were not different. No compensatory changes in the gene expression of tumor necrosis factor-alpha (TNF), IL-1β, IL-10, and IL-13 were found in the PNS and CNS of naïve IL-4 ko mice. However, IL-1β gene expression was stronger in the sciatic nerve of IL-4 ko mice (p<0.001) 28 days after CCI and only IL-4 ko mice had elevated IL-10 gene expression (p = 0.014). Remarkably, CCI induced TNF (p<0.01), IL-1β (p<0.05), IL-10 (p<0.05), and IL-13 (p<0.001) gene expression exclusively in the ipsilateral spinal cord of IL-4 ko mice. The compensatory overexpression of the anti-inflammatory and analgesic cytokines IL-10 and IL-13 in the spinal cord of IL-4 ko mice may explain the lack of genotype differences for pain behavior after CCI. Additionally, CCI induced gene expression of μ, κ, and δ opioid receptors in the contralateral cortex and thalamus of IL-4 ko mice, paralleled by fast onset of morphine analgesia, but not in wt mice. We conclude that a lack of IL-4 leads to mechanical sensitivity; the compensatory hyperexpression of analgesic cytokines and opioid receptors after CCI, in turn, protects IL-4 ko mice from enhanced pain behavior after nerve lesion.
High-Dose Capsaicin for the Treatment of Neuropathic Pain: What We Know and What We Need to Know
(2014)
Neuropathic pain is a frequent and disabling condition with diverse underlying etiologies and is often difficult to treat. Systemic drug treatment is often limited in efficacy. Furthermore, adverse effects may be a limiting factor when trying to reach the necessary dose. Analgesics that can be applied topically have the potential to largely overcome this problem. They may be of particular advantage in localized neuropathic pain syndromes such as postherpetic neuralgia or small fiber neuropathy. Capsaicin, the pungent component of chili peppers, is a natural ligand of the transient receptor potential vanilloid 1 channel and has long been used as topically applicable cream with concentrations of 0.025 to 0.075%. In 2009, a high-concentration transdermal capsaicin 8% patch (Qutenza ; Acorda Therapeutics, Inc., Ardsley, NY, USA; Astellas Pharma Europe Ltd., Chertsey, Surrey, UK) was introduced for the treatment of peripheral neuropathic pain syndromes other than of diabetic origin in adults. It has since been widely used in diverse neuropathic pain disorders. In this review article, we summarize current knowledge on Qutenza, its advantages and problems, and expose unmet needs.
High-resolution ultrasonography (HRUS) is an emerging new tool in the investigation of peripheral nerves. We set out to assess the utility of HRUS performed at lower extremity nerves in peripheral neuropathies. Nerves of 26 patients with polyneuropathies of different etiologies and 26 controls were investigated using HRUS. Patients underwent clinical, laboratory, electrophysiological assessment, and a diagnostic sural nerve biopsy as part of the routine work-up. HRUS was performed at the sural, tibial, and the common, superficial, and deep peroneal nerves. The superficial peroneal nerve longitudinal diameter (LD) distinguished best between the groups: patients with immune-mediated neuropathies (n = 13, including six with histology-proven vasculitic neuropathy) had larger LD compared to patients with non-immune-mediated neuropathies (p < 0.05) and to controls (p < 0.001). Among all subgroups, patients with vasculitic neuropathy showed the largest superficial peroneal nerve LD (p < 0.001) and had a larger sural nerve cross-sectional area when compared with disease controls (p < 0.001). Enlargement of the superficial peroneal and sural nerves as detected by HRUS may be a useful additional finding in the differential diagnosis of vasculitic and other immune-mediated neuropathies.
Background
The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity.
Methods
At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data.
Results
We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy.
Conclusions
Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.
Objectives
The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS.
Methods
Sixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis.
Results
Quantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (p<0.05), but not different from that of patients with depression and accompanying physical pain. Pain and FMS symptom burden did not correlate with midbrain raphe echogenicity as well as the presence and severity of depressive symptoms.
Conclusion
We found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression.
Background
Fibromyalgia syndrome (FMS) is a chronic condition characterized by widespread pain and associated symptoms. We investigated cerebral activation in FMS patients by functional near-infrared spectroscopy (fNIRS).
Methods
Two stimulation paradigms were applied: a) painful pressure stimulation at the dorsal forearm; b) verbal fluency test (VFT). We prospectively recruited 25 FMS patients, ten patients with unipolar major depression (MD) without pain, and 35 healthy controls. All patients underwent neurological examination and all subjects were investigated with questionnaires (pain, depression, FMS, empathy).
Results
FMS patients had lower pressure pain thresholds than patients with MD and controls (p < 0.001) and reported higher pain intensity (p < 0.001). Upon unilateral pressure pain stimulation fNIRS recordings revealed increased bilateral cortical activation in FMS patients compared to controls (p < 0.05). FMS patients also displayed a stronger contralateral activity over the dorsolateral prefrontal cortex in direct comparison to patients with MD (p < 0.05). While all three groups performed equally well in the VFT, a frontal deficit in cortical activation was only found in patients with depression (p < 0.05). Performance and cortical activation correlated negatively in FMS patients (p < 0.05) and positively in patients with MD (p < 0.05).
Conclusion
Our data give further evidence for altered central nervous processing in patients with FMS and the distinction between FMS and MD.
Skin cytokine expression in patients with fibromyalgia syndrome is not different from controls
(2014)
Background
Fibromyalgia syndrome (FMS) is a chronic pain syndrome of unknown etiology. There is increasing evidence for small nerve fiber impairment in a subgroup of patients with FMS. We investigated whether skin cytokine and delta opioid receptor (DOR) gene expression in FMS patients differs from controls as one potential contributor to small nerve fiber sensitization.
Methods
We investigated skin punch biopsies of 25 FMS patients, ten patients with monopolar depression but no pain, and 35 healthy controls. Biopsies were obtained from the lateral upper thigh and lower calf. Gene expression of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF), interleukin (IL)-6, and IL-8 and of the anti-inflammatory cytokine IL-10 was analyzed using quantitative real-time PCR and normalizing data to 18sRNA as housekeeping gene. Additionally, we assessed DOR gene expression.
Results
All cytokines and DOR were detectable in skin samples of FMS patients, patients with depression, and healthy controls without intergroup difference. Also, gene expression was not different in skin of the upper and lower leg within and between the groups and in FMS patient subgroups.
Conclusions
Skin cytokine and DOR gene expression does not differ between patients with FMS and controls. Our results do not support a role of the investigated cytokines in sensitization of peripheral nerve fibers as a potential mechanism of small fiber pathology in FMS.
Background
Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP).
Methods
In this case–control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function.
Results
All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients.
Conclusion
Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction.
A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males – females; normal – impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13%) and 5/57 (9%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87%, specificity: 86%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.
Objective: We investigated cerebral opioid receptor binding potential in patients with fibromyalgia syndrome (FMS) using positron-emission-tomography (PET) and correlated our results with patients’ systemic interleukin-4 (IL-4) gene expression.
Methods: In this pilot study, seven FMS patients (1 man, 6 women) agreed to participate in experimental PET scans. All patients underwent neurological examination, were investigated with questionnaires for pain, depression, and FMS symptoms. Additionally, blood for IL-4 gene expression analysis was withdrawn at two time points with a median latency of 1.3 years. Patients were investigated in a PET scanner using the opioid receptor ligand F-18-fluoro-ethyl-diprenorphine ([18F]FEDPN) and results were compared with laboratory normative values.
Results: Neurological examination was normal in all FMS patients. Reduced opioid receptor binding was found in mid cingulate cortex compared to healthy controls (p < 0.005). Interestingly, three patients with high systemic IL-4 gene expression had increased opioid receptor binding in the fronto-basal cortex compared to those with low IL-4 gene expression (p < 0.005).
Conclusion: Our data give further evidence for a reduction in cortical opioid receptor availability in FMS patients as another potential central nervous system contributor to pain in FMS.
Fabry disease is an X-linked lysosomal storage disorder due to impaired activity of alpha-galactosidase A with intracellular accumulation of globotriaosylceramide. Associated small fiber pathology leads to characteristic pain in Fabry disease. We systematically assessed sensory system, physical activity, metabolic parameters, and morphology of male and female mice with alpha-galactosidase A deficiency (Fabry ko) from 2 to 27 months of age and compared results with those of age- and gender-matched wild-type littermates of C57Bl/6J background. Results From the age of two months, male and female Fabry mice showed mechanical hypersensitivity (p < 0.001 each) compared to wild-type littermates. Young Fabry ko mice of both genders were hypersensitive to heat stimulation (p < 0.01) and developed heat hyposensitivity with aging (p < 0.05), while cold hyposensitivity was present constantly in young (p < 0.01) and old (p < 0.05) Fabry ko mice compared to wild-type littermates. Stride angle increased only in male Fabry ko mice with aging (p < 0.01) in comparison to wild-type littermates. Except for young female mice, male (p < 0.05) and female (p < 0.01) Fabry ko mice had a higher body weight than wild-type littermates. Old male Fabry ko mice were physically less active than their wild-type littermates (p < 0.05), had lower chow intake (p < 0.001), and lost more weight (p < 0.001) in a one-week treadmill experiment than wild-type littermates. Also, Fabry ko mice showed spontaneous pain protective behavior and developed orofacial dysmorphism resembling patients with Fabry disease.
Conclusions. Mice with alpha-galactosidase A deficiency show age-dependent and distinct deficits of the sensory system. alpha-galactosidase A-deficient mice seem to model human Fabry disease and may be helpful when studying the pathophysiology of Fabry-associated pain.
The investigation of the Earth system and interplays between its components is of utmost importance to enhance the understanding of the impacts of global climate change on the Earth's land surface. In this context, Earth observation (EO) provides valuable long-term records covering an abundance of land surface variables and, thus, allowing for large-scale analyses to quantify and analyze land surface dynamics across various Earth system components. In view of this, the geographical entity of river basins was identified as particularly suitable for multivariate time series analyses of the land surface, as they naturally cover diverse spheres of the Earth. Many remote sensing missions with different characteristics are available to monitor and characterize the land surface. Yet, only a few spaceborne remote sensing missions enable the generation of spatio-temporally consistent time series with equidistant observations over large areas, such as the MODIS instrument.
In order to summarize available remote sensing-based analyses of land surface dynamics in large river basins, a detailed literature review of 287 studies was performed and several research gaps were identified. In this regard, it was found that studies rarely analyzed an entire river basin, but rather focused on study areas at subbasin or regional scale. In addition, it was found that transboundary river basins remained understudied and that studies largely focused on selected riparian countries. Moreover, the analysis of environmental change was generally conducted using a single EO-based land surface variable, whereas a joint exploration of multivariate land surface variables across spheres was found to be rarely performed.
To address these research gaps, a methodological framework enabling (1) the preprocessing and harmonization of multi-source time series as well as (2) the statistical analysis of a multivariate feature space was required. For development and testing of a methodological framework that is transferable in space and time, the transboundary river basins Indus, Ganges, Brahmaputra, and Meghna (IGBM) in South Asia were selected as study area, having a size equivalent to around eight times the size of Germany. These basins largely depend on water resources from monsoon rainfall and High Mountain Asia which holds the largest ice mass outside the polar regions. In total, over 1.1 billion people live in this region and in parts largely depend on these water resources which are indispensable for the world's largest connected irrigated croplands and further domestic needs as well. With highly heterogeneous geographical settings, these river basins allow for a detailed analysis of the interplays between multiple spheres, including the anthroposphere, biosphere, cryosphere, hydrosphere, lithosphere, and atmosphere.
In this thesis, land surface dynamics over the last two decades (December 2002 - November 2020) were analyzed using EO time series on vegetation condition, surface water area, and snow cover area being based on MODIS imagery, the DLR Global WaterPack and JRC Global Surface Water Layer, as well as the DLR Global SnowPack, respectively. These data were evaluated in combination with further climatic, hydrological, and anthropogenic variables to estimate their influence on the three EO land surface variables. The preprocessing and harmonization of the time series was conducted using the implemented framework. The resulting harmonized feature space was used to quantify and analyze land surface dynamics by means of several statistical time series analysis techniques which were integrated into the framework. In detail, these methods involved (1) the calculation of trends using the Mann-Kendall test in association with the Theil-Sen slope estimator, (2) the estimation of changes in phenological metrics using the Timesat tool, (3) the evaluation of driving variables using the causal discovery approach Peter and Clark Momentary Conditional Independence (PCMCI), and (4) additional correlation tests to analyze the human influence on vegetation condition and surface water area.
These analyses were performed at annual and seasonal temporal scale and for diverse spatial units, including grids, river basins and subbasins, land cover and land use classes, as well as elevation-dependent zones. The trend analyses of vegetation condition mostly revealed significant positive trends. Irrigated and rainfed croplands were found to contribute most to these trends. The trend magnitudes were particularly high in arid and semi-arid regions. Considering surface water area, significant positive trends were obtained at annual scale. At grid scale, regional and seasonal clusters with significant negative trends were found as well. Trends for snow cover area mostly remained stable at annual scale, but significant negative trends were observed in parts of the river basins during distinct seasons. Negative trends were also found for the elevation-dependent zones, particularly at high altitudes. Also, retreats in the seasonal duration of snow cover area were found in parts of the river basins. Furthermore, for the first time, the application of the causal discovery algorithm on a multivariate feature space at seasonal temporal scale revealed direct and indirect links between EO land surface variables and respective drivers. In general, vegetation was constrained by water availability, surface water area was largely influenced by river discharge and indirectly by precipitation, and snow cover area was largely controlled by precipitation and temperature with spatial and temporal variations. Additional analyses pointed towards positive human influences on increasing trends in vegetation greenness. The investigation of trends and interplays across spheres provided new and valuable insights into the past state and the evolution of the land surface as well as on relevant climatic and hydrological driving variables. Besides the investigated river basins in South Asia, these findings are of great value also for other river basins and geographical regions.
Breaking inversion symmetry in crystalline solids enables the formation of spin-polarized electronic states by spin-orbit coupling without the need for magnetism. A variety of interesting physical phenomena related to this effect have been intensively investigated in recent years, including the Rashba effect, topological insulators and Weyl semimetals. In this work, the interplay of inversion symmetry breaking and spin-orbit coupling and, in particular their general influence on the character of electronic states, i.e., on the spin and orbital degrees of freedom, is investigated experimentally. Two different types of suitable model systems are studied: two-dimensional surface states for which the Rashba effect arises from the inherently broken inversion symmetry at the surface, and a Weyl semimetal, for which inversion symmetry is broken in the three-dimensional crystal structure. Angle-resolved photoelectron spectroscopy provides momentum-resolved access to the spin polarization and the orbital composition of electronic states by means of photoelectron spin detection and dichroism with polarized light. The experimental results shown in this work are also complemented and supported by ab-initio density functional theory calculations and simple model considerations.
Altogether, it is shown that the breaking of inversion symmetry has a decisive influence on the Bloch wave function, namely, the formation of an orbital angular momentum. This mechanism is, in turn, of fundamental importance both for the physics of the surface Rashba effect and the topology of the Weyl semimetal TaAs.
Since the early days of Dirac flux quantization, magnetic monopoles have been sought after as a potential corollary of quantized electric charge. As opposed to magnetic monopoles embedded into the theory of electromagnetism, Weyl semimetals (WSM) exhibit Berry flux monopoles in reciprocal parameter space. As a function of crystal momentum, such monopoles locate at the crossing point of spin-polarized bands forming the Weyl cone. Here, we report momentum-resolved spectroscopic signatures of Berry flux monopoles in TaAs as a paradigmatic WSM. We carried out angle-resolved photoelectron spectroscopy at bulk-sensitive soft X-ray energies (SX-ARPES) combined with photoelectron spin detection and circular dichroism. The experiments reveal large spin- and orbital-angular-momentum (SAM and OAM) polarizations of the Weyl-fermion states, resulting from the broken crystalline inversion symmetry in TaAs. Supported by first-principles calculations, our measurements image signatures of a topologically non-trivial winding of the OAM at the Weyl nodes and unveil a chirality-dependent SAM of the Weyl bands. Our results provide directly bulk-sensitive spectroscopic support for the non-trivial band topology in the WSM TaAs, promising to have profound implications for the study of quantum-geometric effects in solids. Weyl semimetals exhibit Berry flux monopoles in momentum-space, but direct experimental evidence has remained elusive. Here, the authors reveal topologically non-trivial winding of the orbital-angular-momentum at the Weyl nodes and a chirality-dependent spin-angular-momentum of the Weyl bands, as a direct signature of the Berry flux monopoles in TaAs.
Background: To perform a systematic review and meta-analysis on cytokine levels in patients with fibromyalgia syndrome (FMS). Methods: Through December 2010 we systematically reviewed the databases PubMed, MEDLINE, and PsycINFO and screened the reference lists of 22 review articles for suitable original articles. Original articles investigating cytokines in patients with FMS were included. Data were extracted by two independent authors. Differences of the cytokine levels of FMS patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed applying methodological scores: modified Center of Evidence Based Medicine, Newcastle-Ottawa-Scale, and Würzburg Methodological Quality Score. Results: Twenty-five articles were included investigating 1255 FMS patients and 800 healthy controls. Data of 13/25 studies entered meta-analysis. The overall methodological quality of studies was low. The results of the majority of studies were not comparable because methods, investigated material, and investigated target cytokines differed. Systematic review of the selected 25 articles revealed that FMS patients had higher serum levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8, and higher plasma levels of IL-8. Meta-analysis of eligible studies showed that FMS patients had higher plasma IL-6 levels compared to controls (SMD = -0.34 [-0.64, -0.03] 95% CI; p = 0.03). The majority of investigated cytokines were not different between patients and controls. Conclusions: The pathophysiological role of cytokines in FMS is still unclear. Studies of higher quality and with higher numbers of subjects are needed.
Das kolorektale Karzinom ist in der westlichen Welt die zweithäufigste Todesursache bei Männer und Frauen. Wichtige Pathomechanismen der kolorektalen Karzinome konnten in den letzten Jahren aufgedeckt werden. Die Anhäufung von genetischen Alterationen spielen sowohl bei sporadischen, als auch bei den hereditären Formen eine wichtige Rolle. Zwei molekulargenetische Hauptwege sind bei der kolorektalen Karzinogenese identifiziert worden: erstens der Tumorsuppressor-Pathway, bei dem es zu Alterationen in Tumorsuppresor- und Onkogenen kommt und zweitens der Mutatior-Pathway, der auf genetischen Alterationen in DNA-mismatch-Reparatur-Genen beruht, die zu einer genetischen Instabilität führen mit einer hohen Mutationsrate in repetitiven DNA-Sequenzen (sog. Mikrosatelliten). Es konnte gezeigt werden, dass oxidativer Stress, der durch die Bildung von H2O2 und anderen reaktiven Sauerstoffspezies (ROS) hervorgerufen wird, zur Entstehung von zellulären und DNA-Schäden wie z.B. oxidative Basenschäden, die ihrerseits u.a. die Entstehung von fixen Punktmutationen, Fragmentation der Desoxiribose und DNA-Strangbrüche initiieren, führen kann. Diese Veränderungen und auch die Mismatch-Reparatur-Defizienz begünstigen die Tumorprogression im Kolon. Es wird geschätzt, dass durch ROS täglich ca.20 000 hits pro Zelle verursacht werden. Es existieren sowohl extrazelluläre, als auch zelluläre antioxidative Abwhrsysteme, die Biomoleküle wie u.a. die DNA vor dem oxidativen Stress schützen. Unter diesen protektiven Enzymen gibt es neben der Superoxidismutase und der Katalase auch zahlreiche Selenoproteine, die Selenocystein in ihrem aktiven Zentrum tragen. Zu diesen Enzymen, die antioxidative Funktionen wahrnehmen gehören u.a. die Glutathionperoxidase, die Thioredoxinreduktase und das Selenoprotein P. Die Glutathionperoxidase-Familie besteht aus der cytosolischen Glutathioperoxidase (cGPx), der plasmatischen Glutathionperoxidase (pGPx), der gastrointestinalen Glutathionperoxidase (GI-GPx) und der Phospholipid-Hydroperoxid-Glutathionperoxidase (PH-GPx). Diese Enzymfamilie ist an der Reduktion von Hydroperoxiden beteiligt, wobei sie Glutathion als Cofaktor benutzt. Die Thioredoxinreduktase-Familie (TrxR-alpha und Trxr-beta) regeneriert oxidiertes Thioresoxin, das in die DNA-Synthese involviert ist und auch in zelluläre Redox-Regulationssysteme eingreift und Transkriptionsfaktoren beeinflusst. Das Selenoprotein P, das bis zu 10 Seleocysteinreste pro Molekül enthält, baut Peroxinitrit ab, das seinerseits ein starkes Agens bei der Nitrosylation von Biomolekülen ist. Zusätzlich reduziert Selenoprotein P auch Phospholipid-Hydroperoxide, wenn auch weniger effektiv als PH-GPx. Es konnte in Vorarbeiten gezeigt werden, dass Selenoproteine im Gastrointestinaltrakt eine differentielle Expression aufweisen. Kürzlich konnte in unserer Arbeitsgruppe die inverse mRNA-Expression selnocysteinhaltigen Proteine GI-GPx und Selenoprotein P in kolorektalen Adenomen im Vergleich zur Normalmukosa charakterisiert werden. Dabei zeigte sich eine dramatische Abnahme der Selenoprotein P-Expression, während die Expression der GI-GPx signifikant erhöht war. Im Rahmen der vorliegenden Arbeit untersuchten wir die Expression der GI-GPx in kolorektalen Karzinomen und Kolonkarzinom-Zelllinien, um auf Ebene der Selenoprotein-kodierenden Gene nach Alterationen zu suchen, die die veränderte Expression mit verursachen könnten.