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Abstract Background Acute graft‐versus‐host disease (aGvHD) is a major cause of death for patients following allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification. Methods In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time‐dependent risk factors on the development of grades II–IV aGvHD within 100 days post‐HSCT. Results Using a dynamic longitudinal time‐to‐event model, we observed a non‐monotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11 days. Multivariable analysis revealed significant time‐dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades II–IV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo‐HSCT are associated with an increased incidence of grades II–IV aGvHD within 100 days indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for later grades II–IV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios. Conclusion Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time‐dependent risk factors for the prediction of aGvHD.

Even when guided by strong theories and sound methods, researchers must often choose a singular course of action from multiple viable alternatives. Regardless of the choice, it, along with all other choices made during the research process, individually and collectively affects study results, often in unpredictable ways. The inability to disentangle how much of an observed effect is attributable to the phenomenon of interest, and how much is attributable to what have come to be known as researcher degrees of freedom (RDF), slows theoretical progress and stymies practical implementation. However, if one could examine the results from a particular set of RDF (known as a universe) against a systematically and comprehensively determined background of alternative viable universes (known as a multiverse), then the effects of RDF can be directly examined to provide greater context and clarity to future researchers, and greater confidence in the recommendations to practitioners. This tutorial demonstrates a means to map result variability directly and efficiently, and empirically investigate RDF impact on conclusions via multiverse analysis. Using the R package multiverse, we outline best practices in planning, executing and interpreting of multiverse analyses., (© 2024 The Author(s). International Journal of Psychology published by John Wiley & Sons Ltd on behalf of International Union of Psychological Science.)

There are about 1500 genetic metabolic diseases. A small number of treatable diseases are diagnosed by newborn screening programs, which are continually being developed. However, most diseases can only be diagnosed based on clinical symptoms or metabolic findings. The main biological fluids used are urine, plasma and, in special situations, cerebrospinal fluid. In contrast to commonly used methods such as gas chromatography and high performance liquid chromatography mass spectrometry, ex vivo proton spectroscopy ( 1 H-NMR) is not yet used in routine clinical practice, although it has been recommended for more than 30 years. Automatic analysis and improved NMR technology have also expanded the applications used for the diagnosis of inborn errors of metabolism. We provide a mini-overview of typical applications, especially in urine but also in plasma, used to diagnose common but also rare genetic metabolic diseases with 1 H-NMR. The use of computer-assisted diagnostic suggestions can facilitate interpretation of the profiles. In a proof of principle, to date, 182 reports of 59 different diseases and 500 reports of healthy children are stored. The percentage of correct automatic diagnoses was 74%. Using the same 1 H-NMR profile-targeted analysis, it is possible to apply an untargeted approach that distinguishes profile differences from healthy individuals. Thus, additional conditions such as lysosomal storage diseases or drug interferences are detectable. Furthermore, because 1 H-NMR is highly reproducible and can detect a variety of different substance categories, the metabolomic approach is suitable for monitoring patient treatment and revealing additional factors such as nutrition and microbiome metabolism. Besides the progress in analytical techniques, a multiomics approach is most effective to combine metabolomics with, for example, whole exome sequencing, to also diagnose patients with nondetectable metabolic abnormalities in biological fluids. In this mini review we also provide our own data to demonstrate the role of NMR in a multiomics platform in the field of inborn errors of metabolism., (© 2022 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Nitrogen (N) loading and extreme drought strongly alter biomass production, species composition and carbon and water fluxes of temperate grasslands. Such changes at the community level are often attributed to species- and functional group-specific responses in phenology and/or physiology. In a multifactorial field experiment, we studied the responses of three abundant grassland species (forb Centaurea jacea, grasses Arrhenatherum elatius and Dactylis glomerata) to N loading and extreme drought, focusing on responses of carbon and water relations at the leaf level. We analysed (1) changes in bulk leaf N (uptake efficiency of additional N), (2) adaptation of plant water status (leaf water potential) and (3) impact on leaf carbon and water fluxes. We observed more efficient N utilization in the two grasses compared to C. jacea. Naturally occurring summer drought significantly impacted the plant water status of all species, while extreme drought treatment only further affected water status during and after summer drought. C. jacea was able to maintain much lower leaf water potentials compared to the grasses during drought. Despite these clear species-specific responses to N loading and drought, the species were able to maintain homeostasis of leaf carbon and water fluxes. Thus, strong declines in the (community) carbon sequestration observed at this site during the (natural) summer drought were not related to leaf physiological responses in assimilation, but were driven by phenological adaptions of the species community: the drought-sensitive grasses, even though exhibiting higher N uptake efficiency, responded with a shortened life cycle to severe summer drought., (© 2020 The Authors. Plant Biology published by John Wiley & Sons Ltd on behalf of German Society for Plant Sciences, Royal Botanical Society of the Netherlands.)

Background: Thermo-test devices are rarely used outside specialized pain centres because of high acquisition costs. Recently, a new, portable device ("Q-Sense") was introduced, which is less expensive but has reduced cooling capacity (20°C). We assessed the reliability/validity of the "Q-Sense" by comparing it with the Thermal Sensory Analyzer (TSA)., Methods: Using a phantom-skin model, the physical characteristics of both devices were compared. The clinical performance was assessed in a multicentre study by performing Quantitative Sensory Testing (QST) in 121 healthy volunteers and 83 diabetic patients (Eudra-Med-No. CIV-12-05-006501)., Results: Both device types showed ~40% slower temperature ramps for heating/cooling than nominal data. Cold/warm detection thresholds (CDT, WDT) and heat pain thresholds (HPT) of healthy subjects did not differ between device types. Cold pain thresholds (CPT) were biased for Q-Sense by a floor effect (p < .001). According to intraclass correlation coefficients (ICC), agreement between TSA and Q-Sense was good/excellent for CDT (ICC = 0.894) and WDT (ICC = 0.898), moderate for HPT (ICC = 0.525) and poor for CPT (ICC = 0.305). In diabetic patients, the sensitivity of Q-Sense to detect cold hypoesthesia was reduced in males >60 years. Moderate correlations between thermal detection thresholds and morphological data from skin biopsies (n = 51) were similar for both devices., Conclusions: Physical characteristics of both thermo-test devices are similarly limited by the poor temperature conduction of the skin. The Q-Sense is useful for thermal detection thresholds but of limited use for pain thresholds. For full clinical use, the lower cut-off temperature should be set to ≤18°C., Significance: High purchase costs prevent a widespread use of thermo-test devices for diagnosing small fibre neuropathy. The air-cooled "Q-Sense" could be a lower cost alternative, but its technical/clinical performance needs to be assessed because of its restricted cut-off for cooling (20°C). This study provides critical information on the physical characteristics and the clinical validity/reliability of the Q-Sense compared to the "Thermal Sensory Analyzer" (TSA). We recommend lowering the cut-off value of the Q-Sense to ≤18°C for its full clinical use., (© 2019 European Pain Federation - EFIC®.)

Radial glia-like cells (RGCs) are the hypothesized source of adult hippocampal neurogenesis. However, the current model of hippocampal neurogenesis does not fully incorporate the in vivo heterogeneity of RGCs. In order to better understand the contribution of different RGC subtypes to adult hippocampal neurogenesis, we employed widely used transgenic lines (Nestin-CreER(T2) and GLAST::CreER(T2) mice) to explore how RGCs contribute to neurogenesis under basal conditions and after stimulation and depletion of neural progenitor cells. We first used these inducible fate-tracking transgenic lines to define the similarities and differences in the contribution of nestin- and GLAST-lineage cells to basal long-term hippocampal neurogenesis. We then explored the ability of nestin- and GLAST-lineage RGCs to contribute to neurogenesis after experimental manipulations that either ablate neurogenesis (i.c.v. application of the anti-mitotic AraC, cytosine-β-D-arabinofuranoside) or stimulate neurogenesis (wheel running). Interestingly, in both ablation and stimulation experiments, labeled RGCs in GLAST::CreER(T2) mice appear to contribute to neurogenesis, whereas RGCs in Nestin-CreER(T2) mice do not. Finally, using NestinGFP reporter mice, we expanded on previous research by showing that not all RGCs in the adult dentate gyrus subgranular zone express nestin, and therefore RGCs are antigenically heterogeneous. These findings are important for the field, as they allow appropriately conservative interpretation of existing and future data that emerge from these inducible transgenic lines. These findings also raise important questions about the differences between transgenic driver lines, the heterogeneity of RGCs, and the potential differences in progenitor cell behavior between transgenic lines. As these findings highlight the possible differences in the contribution of cells to long-term neurogenesis in vivo, they indicate that the current models of hippocampal neurogenesis should be modified to include RGC lineage heterogeneity., (Copyright © 2013 Wiley Periodicals, Inc.)

In the adult mammalian brain, neurogenesis is restricted to few regions, while gliogenesis continues in a wide-spread manner. Here we discuss our knowledge of extrinsic and intrinsic factors regulating neuro- and gliogenesis in the adult brain and propose a model of fate specification identifying the states of easiest transition between glio- and neurogenesis, highlighting the unique mechanisms stabilising the neural stem cell state. The model also encompasses the fate alterations achieved by direct reprogramming, and hence addresses a novel avenue for repair, namely eliciting neurogenesis from glial cells outside the neurogenic niches., (Copyright © 2013 WILEY Periodicals, Inc.)

Background: Gastric cancer is one of the most frequent malignant tumors worldwide. Despite improvements in diagnostic procedures, as well as the introduction of multimodal treatment strategies, the overall prognosis remains poor. The role of gastric resection in elderly patients with gastric cancer has not been clearly defined as yet. The goal of the present study was to assess whether specific pathohistological features result in different outcomes for younger patients and elderly patients., Methods: A total of 272 patients with advanced gastric cancer treated surgically in our hospital between 1998 and 2009 were included in the study. Data were analyzed from a prospectively maintained database., Results: Median overall survival was 84 months in the younger subgroup and 37 months in the elderly subgroup (P = 0.038), whereas local recurrence occurred more frequently in younger patients (33% vs. 23%). We identified positive lymph nodes at the contralateral curvature, perilymphonodular tumor cells, and positive lymph node conglomerates as strong negative prognostic factors. There were few pathohistological characteristics that affected survival and the incidence of tumor recurrence differently in elderly and younger patients. Although only a few elderly patients underwent chemotherapy plus gastric resection (7% vs. 28% of the younger patients), there was a trend toward longer survival for those who received multimodal treatment., Conclusions: Our results suggest that there is no tumor-related prognostic difference between young and elderly patients that would preclude radical surgery in elderly patients, as long as they are generally fit for surgery.

Transgenic Phytophthora ramorum strains that produce green fluorescent protein (GFP) constitutively were obtained after stable DNA integration using a polyethylene glycol and CaCl₂-based transformation protocol. Green fluorescent protein production was studied in developing colonies and in different propagules of the pathogen to evaluate its use in molecular and physiological studies. About 12% of the GFP transformants produced GFP to a level detectable by a confocal laser scanning microscope. Green fluorescent protein could be visualized in structures with vital protoplasm, such as hyphal tips and germinating cysts. In infection studies with Rhododendron, one of the GFP expressing strains showed aggressiveness equal to that of the corresponding non-labelled isolate. Thus, GFP could be used as a reporter gene in P. ramorum. Limitations of the technology are discussed.

The large abundance of bioactive single- and multiple-stranded cystine-rich peptides in nature has fostered the development of orthogonal thiol-protection schemes and of efficient chemistries for regioselective disulfide formation in synthetic replica for decades. In parallel to these entirely synthetic strategies, an increased knowledge of oxidative refolding mechanisms of proteins has been accumulated, and the collective experience with air oxidation of cysteine-rich peptides into their native disulfide frameworks have largely confirmed Anfinsen's principle of the self-assembly of polypeptide chains. In fact, a continuously growing number of cysteine-rich bioactive peptides from the most diverse sources and with differing cysteine patterns were found to retain the critical sequence-encoded structural information for correct oxidative folding into the native structures as dominant isomers, although in the biosynthetic pathways the mature peptide forms are mostly generated by posttranslational processing of folded precursors. Such self-assembly processes can be optimized by opportune manipulation of the experimental conditions or by induction of productive intermediates. But there are also numerous cases where folding and disulfide formation are thermodynamically not coupled and where the application of a defined succession of regioselective cysteine pairings still represents the method of choice to install the desired native or non-native cystine frameworks. Among our contributions to the state of the art in the synthesis of cystine-rich peptides, we have mainly addressed the induction of correct oxidative refolding of single-stranded cysteine-rich peptides into their native structures by the use of selenocysteine and suitable strategies for disulfide-mediated assembly of monomers into defined oligomers as mimics of homo- and heterotrimeric collagens as a synthetic approach for the development of new biomaterials., (Copyright 2005 Wiley Periodicals, Inc)

Patch testing was done on 2776 consecutive patients (76.5% female) with a locally revised standard series of 34 contact allergens and the results analyzed for age- and gender-specific differences. At least one positive epicutaneous test reaction occurred in 48.9% of patients. Nickel (20.9%), ethylmercuric chloride (13.2%), thimerosal (11.8%), fragrance mix (9.3%), metallic mercury (8.9%), palladium (5.8%), balsam of Peru (3.8%), copper (3.7%), cobalt (3.3%), and chromium (2.3%) were the 10 most important sensitizers. The following tested allergens with sensitization rates of more than 1% were not part of the usual standard series: ethylmercuric chloride, metallic mercury, copper, propolis (1.3%), propylene glycol (1.0%). Reactions to nickel, cobalt, and palladium, but not to chromium, were significantly more abundant in females (p < 0.002, chi-squared test). The overall sensitization rate was highest in children less than 10 years old (62%) and decreased steadily, to be lowest among patients more than 70 years old (34.9%). The rate of positive reactions to nickel and thimerosal decreased with age, while fragrance mix and metallic mercury stayed at the same level through all age groups.

Chelating agents in protective barrier creams have often been used in the prevention of allergic contact dermatitis to nickel. In a pilot study, we demonstrated the preventive effect of 10% diethylenetriaminepentaacetic acid (DTPA) in an oil-in-water emulsion in nickel-sensitized patients. Now we reproduced these results in a randomized, double-blind study. Additionally, we investigated the efficacy of the barrier cream in other clinically relevant metal allergies. Individuals sensitized to various metals had a significant decrease in positive patch test reactions after pre-treatment with the DTPA-cream: 2.5% nickel sulfate (24/28 positive without pre-treatment versus 1/28 with pre-treatment; p<0.0001), 5% nickel sulfate (30/32 versus 15/32; p=0.0003), 1% cobalt chloride (19/20 versus 6/20; p=0.001) and 5% copper sulfate (13/14 versus 5/14; p=0.02). However, the cream had no protective effect with 1% palladium chloride (17/23 versus 16/23) and with 0.5% potassium dichromate (9/13 versus 7/13). We conclude that the DTPA-cream clearly abrogates positive patch test reactions in nickel-, cobalt- and copper-sensitized subjects and that it may therefore be helpful in the management of allergic contact dermatitis.

The age- and sex-related distribution of positive patch test reactions was investigated in 234 children (0-7 years, n = 72 and 8-14 years, n = 162), 1200 adults (20 to 50 years) and 295 elderly patients (> or = 70 years) with suspected allergic contact dermatitis using a European standard series. In girls from 0 to 7 years, the most frequent contact allergens were thimerosal (37.5%) and nickel (27.5%), in girls from 8 to 14 years, nickel (28.7%) and thimerosal (26.6%), in women, thimerosal (25.3%) and nickel (25.2%), and in elderly women, nickel (12.6%) and balsam of Peru (9.7%). The most frequent contact allergens in boys from 0 to 7 years were ethylmercuric chloride (28.1%) and thimerosal (25.0%), in boys from 8 to 14 years, thimerosal (30.9%) and ethylmercuric chloride (14.7%), in men, thimerosal (21.1%) and ethylmercuric chloride (13.7%) and in elderly men, nickel (11.2%) and balsam of Peru (6.7%). Females showed more positive reactions than males. Whilst 0 to 7 year-old girls and boys showed relatively more frequent reactions, the elderly of both sexes were clearly less affected. Nickel is the most frequent contact allergen in females of 8 years and more. In men, thimerosal is most frequent and reactions to balsam of Peru show a peak incidence in the elderly. Results indicate that patch testing should be considered in children and elderly patients with appropriate indications.

We have used retroviral vectors to study cell lineage in the embryonic rat cerebral cortex both in vivo and in dissociated cell culture. We provide evidence that during the late phase of corticogenesis, most precursor cells of the ventricular zone are specified for the production of a single cell type, either neurons or one of the glial cell types. Although specified, the precursor cells that generate neurons can apparently generate both pyramidal and non-pyramidal cells. Earlier stages of development are dominated by a different type of precursor cell with a number of properties that lead us to believe that it is the founding, multipotential precursor cell of the cerebral cortex. We discuss a possible model of cell lineage which unifies these various observations.

Epilepsy is a well-documented consequence of about 150 rare genetic syndromes and malformations of the central nervous system. These syndromes are generally associated with fairly gross defects within the central nervous system and they were thought to be responsible for a small minority of cases. However, improved methods of neuropathological investigations and extensive magnetic resonance imaging studies have revealed a range of disturbances in cortical cytoarchitecture in patients with epileptic seizures previously considered as idiopathic (up to 70% of epilepsy). Structural abnormalities have also been demonstrated in the brain in schizophrenia. These consist of disturbed cortical cytoarchitecture (best described in the temporal lobe) and a diffuse loss of grey matter. The absence of the pathological stigma characteristic of degenerative processes indicates that these structural changes are the result of an abnormal pattern of brain development. The relationship between the type and location of developmental abnormality and the subsequent clinical syndrome (e.g. generalized or localized epilepsy) and the effects of aberrant cortical development on the functional integrity of the adult brain require definition.

The morphological changes in the region of the reticulum were examined ultrasonographically in 26 cows with traumatic reticuloperitonitis, and a radiograph of the reticulum was also taken. The ultrasonographic examination included observations of reticular motility during a three minute period, of reticular contours and of adjacent structures such as the diaphragm, the anterior dorsal blind sac of the rumen, the ventral sac of the rumen, the spleen, omasum, abomasum and liver. In cows with disturbed reticular motility, biphasic contractions were slower than normal or indistinct, and the number of contractions was reduced. Fibrinous changes appeared as echogenic deposits, sometimes accompanied by hypoechogenic fluid. Abscesses had an echogenic capsule with a hypoechogenic centre. In seven cows, there was an effusion in the region of the reticulum in addition to the morphological changes. The spleen was involved in the adhesions in four cows, the omasum in three cows, the liver in one cow and the abomasum in one cow. Radiography revealed foreign bodies penetrating the reticulum of 12 cows and magnets in the reticulum of seven cows. None of these foreign bodies or magnets could be visualised by ultrasonography.