Mutations in the AAAS gene coding for the nuclear pore complex protein ALADIN lead to the autosomal recessive disorder triple A syndrome. Triple A patients present with a characteristic phenotype including alacrima, achalasia and adrenal insufficiency. Patient fibroblasts show increased levels of oxidative stress, and several in vitro studies have demonstrated that the nucleoporin ALADIN is involved in both the cellular oxidative stress response and adrenal steroidogenesis. It is known that ALADIN knock-out mice lack a phenotype resembling human triple A syndrome. The objective of this study was to determine whether the application of chronic oxidative stress by ingestion of paraquat would generate a triple A-like phenotype in ALADIN null mice. Adult male mice were fed either a paraquat (0.25 g/kg diet) or control diet for 11 days. After application of chronic oxidative stress, ALADIN knock-out mice presented with an unexpected compensated glutathione metabolism, but lacked a phenotype resembling human triple A syndrome. We did not observe increased levels of oxidative stress and alterations in adrenal steroidogenesis in mice depleted for ALADIN. This study stresses the species-specific role of the nucleoporin ALADIN, which in mice involves a novel compensatory mechanism for regulating the cellular glutathione redox response.

The monitoring of cognitive functions is central to the assessment and consecutive management of multiple sclerosis (MS). Though, especially cognitive processes that are central to everyday behavior like dual-tasking are often neglected. We examined dual-task performance using a psychological-refractory period (PRP) task in N = 21 patients and healthy controls and conducted standard neuropsychological tests. In dual-tasking, MS patients committed more erroneous responses when dual-tasking was difficult. In easier conditions, performance of MS patients did not differ to controls. Interestingly, the response times were generally not affected by the difficulty of the dual task, showing that the deficits observed do not reflect simple motor deficits or deficits in information processing speed but point out deficits in executive control functions and response selection in particular. Effect sizes were considerably large with d∼0.80 in mild affected patients and the achieved power was above 99%. There are cognitive control and dual tasking deficits in MS that are not attributable to simple motor speed deficits. Scaling of the difficulty of dual-tasking makes the test applied suitable for a wide variety of MS-patients and may complement neuropsychological assessments in clinical care and research setting.

In order to provide an alternative to day-old chick culling in the layer hatcheries, a noninvasive method for egg sexing is required at an early stage of incubation before onset of embryo sensitivity. Fluorescence and Raman spectroscopy of blood offers the potential for precise and contactless in ovo sex determination of the domestic chicken (Gallus gallus f. dom.) eggs already during the fourth incubation day. However, such kind of optical spectroscopy requires a window in the egg shell, is thus invasive to the embryo and leads to decreased hatching rates. Here, we show that near infrared Raman and fluorescence spectroscopy can be performed on perfused extraembryonic vessels while leaving the inner egg shell membrane intact. Sparing the shell membrane makes the measurement minimally invasive, so that the sexing procedure does not affect hatching rates. We analyze the effect of the membrane above the vessels on fluorescence signal intensity and on Raman spectrum of blood, and propose a correction method to compensate for it. After compensation, we attain a correct sexing rate above 90% by applying supervised classification of spectra. Therefore, this approach offers the best premises towards practical deployment in the hatcheries.

Background Demands placed on individuals in occupational and social settings, as well as imbalances in personal traits and resources, can lead to chronic stress. The Trier Inventory for Chronic Stress (TICS) measures chronic stress while incorporating domain-specific aspects, and has been found to be a highly reliable and valid research tool. The aims of the present study were to confirm the German version TICS factorial structure in an English translation of the instrument (TICS-E) and to report its psychometric properties. Methods A random route sample of healthy participants (N = 483) aged 18–30 years completed the TICS-E. The robust maximum likelihood estimation with a mean-adjusted chi-square test statistic was applied due to the sample’s significant deviation from the multivariate normal distribution. Goodness of fit, absolute model fit, and relative model fit were assessed by means of the root mean square error of approximation (RMSEA), the Comparative Fit Index (CFI) and the Tucker Lewis Index (TLI). Results Reliability estimates (Cronbach’s α and adjusted split-half reliability) ranged from .84 to .92. Item-scale correlations ranged from .50 to .85. Measures of fit showed values of .052 for RMSEA (Cl = 0.50–.054) and .067 for SRMR for absolute model fit, and values of .846 (TLI) and .855 (CFI) for relative model-fit. Factor loadings ranged from .55 to .91. Conclusion The psychometric properties and factor structure of the TICS-E are comparable to the German version of the TICS. The instrument therefore meets quality standards for an adequate measurement of chronic stress.

Background There are a few epidemiological studies that (1) link increased ambient air pollution (AP) with an increase in lung cancer incidence rates and (2) investigate whether residing in green spaces could be protective against cancer. However, it is completely unclear whether other forms of cancer are also affected by AP and if residential green spaces could lower cancer incidence rates in general. Therefore, the objective was to estimate whether AP and green space are associated with several cancer types. Methods The analysis was based on routine health care data from around 1.9 million people from Saxony who were free of cancer in 2008 and 2009. Incident cancer cases (2010–2014) of mouth and throat, skin (non-melanoma skin cancer - NMSC), prostate, breast, and colorectum were defined as: (1) one inpatient diagnosis, or (2) two outpatient diagnoses in two different quarters within one year and a specific treatment or death within two quarters after the diagnosis. Exposures, derived from freely available 3rd party data, included particulate matter with aerodynamic diameter of less than 10 μm (PM10) and nitrogen dioxide (N02) as well as green space (Normalized Difference Vegetation Index - NDVI). Associations between air pollutants, green space, and cancer incidence were assessed by multilevel Poisson models. Age, sex, physician contacts, short- and long-term unemployment, population density, and having an alcohol-related disorder were considered as potential confounders. Results Three thousand one hundred seven people developed mouth and throat cancer, 33,178 NMSC, 9611 prostate cancer, 9577 breast cancer, and 11,975 colorectal cancer during the follow-up period (2010–2014). An increase in PM10 of 10 μg/m3 was associated with a 53% increase in relative risk (RR) of mouth and throat cancer and a 52% increase in RR of NMSC. Prostate and breast cancer were modestly associated with PM10 with an increase in RR of 23 and 19%, respectively. The associations with N02 were in the same direction as PM10 but the effect estimates were much lower (7–24%). A 10% increase in NDVI was most protective of mouth and throat cancer (− 11% RR) and of NMSC (− 16% RR). Colorectal cancer was not affected by any of the exposures. Conclusions In addition to the studies carried out so far, this study was able to provide evidence that higher ambient AP levels increase the risk of mouth and throat cancer as well as of NMSC and that a higher residential green space level might have a protective effect for NMSC in areas with low to moderate UV intensity. Nevertheless, we cannot rule out residual confounding by socioeconomic or smoking status.

Background Over one million asylum seekers were registered in Germany in 2016, most from Syria and Afghanistan. The Refugee Convention guarantees access to healthcare, however delivery mechanisms remain heterogeneous. There is an urgent need for more data describing the health conditions of asylum seekers to guide best practices for healthcare delivery. In this study, we describe the state of health of asylum seekers presenting to a multi-specialty primary care refugee clinic. Methods Demographic and medical diagnosis data were extracted from the electronic medical records of patients seen at the ambulatory refugee clinic in Dresden, Germany between 15 September 2015 and 31 December 2016. Data were de-identified and analyzed using Stata version 14.0. Results Two-thousand-seven-hundred and fifty-three individual patients were seen in the clinic. Of these, 2232 (81.1%) were insured by the state indicating arrival within the last 3 months. The median age was 25, interquartile range 16–34. Only 786 (28.6%) were female, while 1967 (71.5%) were male. The most frequent diagnoses were respiratory (17.4%), followed by miscellaneous symptoms and otherwise not classified ailments (R series, 14.1%), infection (10.8%), musculoskeletal or connective tissue (9.3%), gastrointestinal (6.8%), injury (5.9%), and mental or behavioral (5.1%) categories. Conclusions This study illustrates the diverse medical conditions that affect the asylum seeker population. Asylum seekers in our study group did not have a high burden of communicable diseases, however several warranted additional screening and treatment, including for tuberculosis and scabies. Respiratory illnesses were more common amongst newly arrived refugees. Trauma-related mental health disorders comprised half of mental health diagnoses.

Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 α (HNF4α) in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4α binding site. Direct binding of HNF4α to Agxt2 promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of Hnf4a led to an almost 50% reduction in Agxt2 mRNA levels in Hepa 1–6 cells. Liver-specific Hnf4a knockout mice exhibited a 90% decrease in liver Agxt2 expression and activity, and elevated plasma levels of ADMA, SDMA and BAIB, compared to wild-type littermates. Thus we identified HNF4α as a major regulator of Agxt2 expression. Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4α deficiency might contribute to development of cardiovascular complications in diabetic patients.

Background Pancreatic heterotopia (PH) is defined as ectopic pancreatic tissue outside the normal pancreas and its vasculature and duct system. Most frequently, PH is detected incidentally by histopathological examination. The aim of the present study was to analyze a large single-center series of duodenal PH with respect to the clinical presentation. Methods A prospective pancreatic database was retrospectively analyzed for cases of PH of the duodenum. All pancreatic and duodenal resections performed between January 2000 and October 2015 were included and screened for histopathologically proven duodenal PH. PH was classified according to Heinrich’s classification (Type I acini, ducts, and islet cells; Type II acini and ducts; Type III only ducts). Results A total of 1274 pancreatic and duodenal resections were performed within the study period, and 67 cases of PH (5.3%) were identified. The respective patients were predominantly male (72%) and either underwent pancreatoduodenectomy (n = 60); a limited pancreas resection with partial duodenal resection (n = 4); distal pancreatectomy with partial duodenal resection (n = 1); total pancreatectomy (n = 1); or enucleation (n = 1). Whereas 65 patients (83.5%) were asymptomatic, 11 patients (18.4%) presented with symptoms related to PH (most frequently with abdominal pain [72%] and duodenal obstruction [55%]). Of those, seven patients (63.6%) had chronic pancreatitis in the heterotopic pancreas. The risk of malignant transformation into adenocarcinoma was 2.9%. Conclusions PH is found in approximately 5% of pancreatic or duodenal resections and is generally asymptomatic. Chronic pancreatitis is not uncommon in heterotopic pancreatic tissue, and even there is a risk of malignant transformation. PH should be considered for the differential diagnosis of duodenal lesions and surgery should be considered, especially in symptomatic cases.

Unmyelinated low threshold C-tactile fibers moderate pleasant aspects of touch. These fibers respond optimally to stroking stimulation of the skin with slow velocities (1–10 cm/s). Low threshold mechanoreceptors are arranged around hair follicles in rodent skin. If valid also in humans, hair follicle density (HFD) may relate to the perceived pleasantness of stroking tactile stimulation. We conducted two studies that examined the relation between HFD and affective touch perception in humans. In total, 138 healthy volunteers were stroked on the forearm and rated the pleasantness and intensity. Stimulation was performed by a robotic tactile stimulator delivering C-tactile optimal (1, 3, 10 cm/s) and non-optimal (0.1, 0.3, 30 cm/s) stroking velocities. Additionally, a measure of discriminative touch was applied in study 2. HFD of the same forearm was determined using the Cyanoacrylate Skin Stripping Method (CSSM), which we validated in a pretest. Women had higher HFD than men, which was explained by body size and weight. Furthermore, women rated affective touch stimuli as more pleasant and had higher tactile acuity. Depilation did not affect touch perception. A weak relationship was found between the C-tactile specific aspects of affective touch perception and HFD, and the hypothesis of HFD relating to pleasant aspects of stroking only received weak support.

Glycosaminoglycans are known to bind biological mediators thereby modulating their biological activity. Sulfated hyaluronans (sHA) were reported to strongly interact with transforming growth factor (TGF)-β1 leading to impaired bioactivity in fibroblasts. The underlying mechanism is not fully elucidated yet. Examining the interaction of all components of the TGF-β1:receptor complex with sHA by surface plasmon resonance, we could show that highly sulfated HA (sHA3) blocks binding of TGF-β1 to its TGF-β receptor-I (TβR-I) and -II (TβR-II). However, sequential addition of sHA3 to the TβR-II/TGF-β1 complex led to a significantly stronger recruitment of TβR-I compared to a complex lacking sHA3, indicating that the order of binding events is very important. Molecular modeling suggested a possible molecular mechanism in which sHA3 could potentially favor the association of TβR-I when added sequentially. For the first time bioactivity of TGF-β1 in conjunction with sHA was investigated at the receptor level. TβR-I and, furthermore, Smad2 phosphorylation were decreased in the presence of sHA3 indicating the formation of an inactive signaling complex. The results contribute to an improved understanding of the interference of sHA3 with TGF-β1:receptor complex formation and will help to further improve the design of functional biomaterials that interfere with TGF-β1-driven skin fibrosis.