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A 6-year-old girl had reduced fetal movements, numerous apneic spells, muscle hypotonia, and developmental motor delay. Her muscle biopsy tissue showed variation in myofiber diameters, small minicores by electron microscopy, and near-uniformity of type I fibers. Although no mutations were detected in RYR1 , SEPN1 , and DMPK genes, the RAPSN gene revealed one known mutation, p.Asn88Lys, from the mother, and one novel mutation, p.Cys366Gly, from the father. Life-saving pyridostigmine treatment suppressed her apneic spells and improved her motor development. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies revealed large differences in the transformation of pharmaceuticals in rivers with similar characteristics. The present work aimed at answering the question whether these differences are related to the transformation capacity of the specific river sediments. More generally, we also aimed at evaluating the overall diagnostic power of water/sediment tests. Incubation experiments with 9 pharmaceuticals were carried out with sediments sampled from three rivers. All compounds expect carbamazepine were removed at dissipation half-lives between 2.5 and 56 days; biotransformation was identified as the major removal process. Interestingly, sediment from river Roter Main was more efficient in removing pharmaceuticals than sediment from river Gründlach, while the opposite pattern was observed in previous field studies. Obviously, the physical boundary conditions are governing the actual elimination of pharmaceuticals and not the transformation potential of the specific sediments. In a separate experiment, an immediate onset of transformation was observed after introducing oxygen to an anoxic water/sediment system. Transformation rates in sediments sampled from several sites within one river varied up to a factor of 2.5. This considerable in-stream variability is a critical factor for environmental risk assessment where single cutoff values are being used for evaluating a compound's persistence. [Copyright &y& Elsevier]

Abstract: Pharmaceutical residues are commonly detected organic micropollutants in the aquatic environment. Their actual fate in rivers is still incompletely understood as their elimination is highly substance specific and studies often report contradictory results. To elucidate the ceiling of attenuation rates of pharmaceuticals in rivers we carried out a study at a river with favorable conditions for the elimination of organic micropollutants. Experiments were carried out at a small stream in Germany. Composite samples were taken at both ends of a 12.5 km long river stretch located downstream of a sewage treatment plant and analyzed for 10 pharmaceuticals. Moreover, pore water samples were taken and in situ photolysis experiments at several sites within the river stretch were performed to assess the importance of these individual elimination mechanisms. Pharmaceutical concentration in the surface water at the first sampling site ranged from 3.5 ng L−1 for propranolol to 1400 ng L−1 for diclofenac. In comparison to carbamazepine which was used as persistent tracer, all other pharmaceuticals were attenuated along the river stretch. Their elimination was higher in a sunny, dry weather period (period I) compared to a period with elevated discharge after a heavy rainfall (period II). Overall, the measured elimination rates ranged from 25% for sulfamethoxazole (period II) to 70% for propranolol (period I). Photolysis was only a relevant elimination process for diclofenac and potentially also for sotalol; for these compounds phototransformation half-life times of some hours were determined in the unshaded parts of the river. Biotransformation in the sediments was also an important attenuation process since the concentrations of the other pharmaceuticals in the sediments decreased relative to carbamazepine with depth. For the chiral betablocker metoprolol this biotransformation was also confirmed by a decrease in the enantiomer fractionation from 0.49 at site A to 0.43 at site B and to <0.40 in the deeper sediments. [Copyright &y& Elsevier]

We used XAD-resin based passive air samplers (PAS) to measure atmospheric levels of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) at five ombrotrophic bogs in Eastern Canada. The aims of our study were to investigate the influence of local roads on contaminant levels in the bogs, to derive the regional pattern of atmospheric concentrations, and to assess the uncertainties of the method. Expanded uncertainties based on the duplicate PAS deployed at 24 sites were good for the PAHs, while the deployment period of approx. 100 days was too short to yield acceptable uncertainties for PCBs. The regional PAH distribution was in good agreement with the calculated source proximity of the sampled bogs. We conclude that XAD-resin based PAS deployed for comparatively short periods are well suited for measuring atmospheric concentrations of volatile PAHs, while in remote regions longer deployment is necessary for less volatile PAHs and for PCBs. [Copyright &y& Elsevier]

Abstract: Concentrations of steroids and inorganic ions were measured in waste water of an aerated sand trap as well as in aerosol particles emitted from this tank at the waste water treatment plant (WWTP) of Bayreuth, Germany, in January and February 2003. The investigations comprised seven sterols, two estrogens, and several inorganic ions. Since an appropriate method for the determination of sterols in waste water was not available, a new method based on solid phase extraction was developed. The concentrations of the sterols coprostanol and cholesterol amounted to 30–180μgl−1 in waste water and to 400–5000pgm−3 in aerosol particles. All other sterols were present in markedly lower concentrations. The mean concentrations of the two estrogens estrone and 17β-estradiol were about 165pgm−3 in aerosol particles. The steroid concentrations in both waste water and aerosol particles varied greatly over time, however with the exception of coprostanol, no clear correlation was detected between concentrations in waste water and aerosol particles. [Copyright &y& Elsevier]

Point of care tests (POCTs) might be used to identify patients with undiagnosed celiac disease who require further evaluation. We performed a large multicenter study to determine the performance of a POCT for celiac disease and assessed celiac disease prevalence in endoscopy centers. We performed a prospective study of 1055 patients (888 adults; median age, 48 yrs and 167 children; median age, 10 yrs) referred to 8 endoscopy centers in Germany, for various indications, from January 2016 through June 2017. Patients were tested for celiac disease using Simtomax, which detects immunoglobulin (Ig)A and IgG antibodies against deamidated gliadin peptides (DGP). Results were compared with findings from histologic analyses of duodenal biopsies (reference standard). The primary aim was to determine the accuracy of this POCT for the detection of celiac disease, to identify candidates for duodenal biopsy. A secondary aim was to determine the prevalence of celiac disease in adult and pediatric populations referred for outpatient endoscopic evaluation. The overall prevalence of celiac disease was 4.1%. The POCT identified individuals with celiac disease with 79% sensitivity (95% CI, 64%–89%) and 94% specificity (95% CI, 93%–96%). Positive and negative predictive values were 37% and 99%. When we analyzed the adult and pediatric populations separately, we found the test to identify adults with celiac disease (prevalence 1.2%) with 100% sensitivity and 95% specificity. In the pediatric population (celiac disease prevalence 19.6%), the test produced false-negative results for 9 cases; the test therefore identified children with celiac disease with 72% sensitivity (95% CI 53%–86%). Analyses of serologic data revealed significantly lower DGP titers in the false-negative vs the true-positive group. In a study of more than 1000 adults and children, we found the Simtomax POCT to detect celiac disease with lower overall levels of sensitivity than expected. Although the test identifies adults with celiac disease with high levels of sensitivity and specificity, the prevalence of celiac disease was as low as 1.2% among adults. The test's lack of sensitivity might be due to the low intensity of the POCT bands and was associated with low serum DGP titers. Study ID no: DRKS00012499. [ABSTRACT FROM AUTHOR]

Abstract: Ombrotrophic peat bogs are natural archives of atmospheric pollution, their depth profiles can be used to study the deposition chronology of harmful contaminants. Prerequisites for deriving historical deposition rates from the peat archive are that contaminants are persistent and immobile in the peat and that the applied dating technique is accurate. To examine these requirements and the accuracy of peat archives for polycyclic aromatic hydrocarbons (PAHs) 12 peat profiles were sampled in 4 bogs in Ontario, Canada, as well as surface peat in one bog. Additionally we carried out laboratory incubations; no degradation occurred over a 3-year period in these experiments. The standard deviations of PAH concentrations in surface samples and of PAH inventories in whole cores was approximately 30%, and concentrations in surface peat were on average 50% higher in hollows than in hummocks. No indications for mobility of PAHs were observed in peat. Temporal deposition trends inferred from peat cores were generally in agreement with trends derived from a sediment core sampled close by but deposition rates to the sediment were substantially higher. A major source of uncertainty was the rather coarse vertical sampling resolution of 5cm which introduced substantial uncertainty in the dating of the individual segments. This caused variations of the deposition rates up to 70% per PAH between three replicate cores, and it also impedes the identification of deposition peaks. Overall, we conclude that peat cores are suitable archives for inferring atmospheric deposition trends, but due to their relatively low temporal resolution short-term events may not be identified and the development of sampling methods that allow a higher vertical resolution would greatly improve the performance of the method. The analysis of more than one core per site is suggested to provide a realistic estimate of the historic deposition and total inventories. [Copyright &y& Elsevier]

• Neither vaccination certificate nor history of chicken pox predicts VZV immunity. • Insufficient VZV vaccination catch-up in birth cohorts born prior 2005. • Better realization of vaccination catch-up by paediatrician than general practitioner. • Serologic investigations demonstrate occult immunization of non-immunized patients. Immunosuppressed patients are at risk of severe infections with vaccination preventable diseases. We evaluated vaccination rate and immunity of children and adolescents with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). Immunization rate of 329 children with IBD (n = 300) and AIH (n = 29) was assessed in seven German centres using vaccination certificates, history of chicken pox and by determining anti-varicella zoster virus (VZV) and anti-measles IgG antibodies. Of the total cohort 86% received long-term immunosuppression. Four doses of a hexavalent vaccine were documented in 89%, at least one dose of measles, mumps, and rubella (MMR) vaccination was documented in 325 (99%), with 300 (92%) receiving two doses. Anti-measles IgG concentrations were insufficient in 11% of the immunized patients. VZV vaccination was officially recommended in Germany since 2004, and implemented in 88% born from 2005 onwards. In patients born earlier VZV catch up vaccination only reached 25% (n = 67). Of 118 patients with documented VZV vaccination 25 (21%) did not display sufficient anti-VZV IgG. Of 198 patients with a history of chicken pox, six had undetectable anti-VZV IgG. Of 29 patients having neither had chicken pox nor VZV vaccination, 20 were found to have sufficient anti-VZV IgG. In our cohort vaccination coverage for hexavalent and MMR vaccinations was good, but insufficient for VZV vaccination in patients born before 2005. Neither the vaccination certificate nor the history of chicken pox is reliable to predict VZV immunity indicating a need for serologic investigations and if needed vaccination before initiating immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Occurrence of the antibiotic sulfamethoxazole (SMX) in the aquatic environment is of concern due to its potential to induce antibiotic resistance in pathogenic bacteria. While degradation of SMX can occur by numerous processes, the environmental fate of its transformation products (TPs) remains poorly understood. In the present work, biodegradation of SMX photo-TPs was investigated in a water/sediment system. Photo-TPs were produced by exposing SMX to artificial sunlight for 48 h. The resulting mixture of 8 photo-TPs was characterized using a combination of ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry and tandem mass spectrometry, and then used in biodegradation experiments. Significant differences in transformation among SMX photo-TPs were observed in the water/sediment system, with four photo-TPs displaying evidence of biodegradation (dissipation half-lives [DT 50 ] of 39.7 d for 3-amino-5-methylisoxazole, 12.7 d for 4-nitro-sulfamethxoazole, 7.6 d for an SMX isomer and 2.4 d for [C 10 H 13 N 3 O 4 S]), two displaying primarily abiotic degradation (DT 50 of 31 d for sulfanilic acid and 74.9 d for 5-methylisoxazol-3-yl-sulfamate), and two photo-TPs behaving largely recalcitrantly. Remarkably, TPs previously reported to be photo-stable also were persistent in biodegradation experiments. The most surprising observation was an increase in SMX concentrations when the irradiated solution was incubated, which we attribute to back-transformation of certain photo-TPs by sediment bacteria (85% from 4-nitro-sulfamethoxazole). This process could contribute to exposure to SMX in the aquatic environment that is higher than one would expect based on the fate of SMX alone. The results highlight the importance of considering TPs along with their parent compounds when characterizing environmental risks of emerging contaminants. [ABSTRACT FROM AUTHOR]

Src homology and collagen A (ShcA) is an adaptor protein that binds to tyrosine kinase receptors. Its germ line deletion is embryonic lethal with abnormal cardiovascular system formation, and its role in cardiovascular development is unknown. To investigate its functional role in cardiovascular development in mice, ShcA was deleted in cardiomyocytes and vascular smooth muscle cells by crossing ShcA flox mice with SM22a-Cre trans-genic mice. Conditional mutant mice developed signs of severe dilated cardiomyopathy, myocardial infarctions, and premature death. No evidence of a vascular contribution to the phenotype was observed. Histological analysis of the heart revealed aberrant sarcomeric Z-disk and M-band structures, and misalignments of T-tubules with Z-disks. We find that not only the ErbB3/Neuregulin signaling pathway but also the baroreceptor reflex response, which have been functionally associated, are altered in the mutant mice. We further demonstrate that ShcA interacts with Caveolin-1 and the costameric protein plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA), and that its deletion leads to abnormal dystrophin signaling. Collectively, these results demonstrate that ShcA interacts with crucial proteins and pathways that link Z-disk and costamere. [ABSTRACT FROM AUTHOR]

Abstract: Quantitative information regarding the capacity of rivers to self-purify pharmaceutical residues is limited. To bridge this knowledge gap, we present a methodology for quantifying the governing processes affecting the fate of pharmaceuticals in streaming waters and, especially, to evaluate their relative significance for tracer observations. A tracer test in Säva Brook, Sweden was evaluated using a coupled physical–biogeochemical model framework containing surface water transport together with a representation of transient storage in slow/immobile zones of the stream, which are presumably important for the retention and attenuation of pharmaceuticals. To assess the key processes affecting the environmental fate of the compounds, we linked the uncertainty estimates of the reaction rate coefficients to the relative influence of transformation and sorption that occurred in different stream environments. The hydrological and biogeochemical contributions to the fate of the pharmaceuticals were decoupled, and the results indicate a moderate hydrological retention in the hyporheic zone as well as in the densely vegetated parts of the stream. Biogeochemical reactions in these transient storage zones further affected the fate of the pharmaceuticals, and we found that sorption was the key process for bezafibrate, metoprolol, and naproxen, while primary transformation was the most important process for clofibric acid and ibuprofen. Conversely, diclofenac was not affected by sorption or transformation. [Copyright &y& Elsevier]

Abstract: Many rivers and streams worldwide are impacted by pharmaceuticals originating from sewage. The hyporheic zone underlying streams is often regarded as reactive bioreactor with the potential for eliminating such sewage-born micropollutants. The present study aims at checking the elimination potential and analyzing the coupling of hydrodynamics, biogeochemistry and micropollutant processing. To this end, two sites at the lowland stream Erpe, which receives a high sewage burden, were equipped and sampled with nested piezometers. From temperature depth profiles we determined that at one of the sites infiltration of surface water into the aquifer occurs while exfiltration dominates at the other site. Biogeochemical data reveal intense mineralization processes and strictly anoxic conditions in the streambed sediments at both sites. Concentrations of the pharmaceuticals indomethacin, diclofenac, ibuprofen, bezafibrate, ketoprofen, naproxen and clofibric acid were high in the surface water and also in the subsurface at the infiltrating site. The evaluation of the depth profiles indicates some attenuation but due to varying surface water composition the evaluation of subsurface processes is quite complex. Borate and non-geogenic gadolinium were measured as conservative wastewater indicators. To eliminate the influence of fluctuating sewage proportions in the surface water, micropollutant concentrations are related to these indicators. The indicators can cope with different dilutions of the sewage but not with temporally varying sewage composition. [Copyright &y& Elsevier]

Objectives: We investigated the role of the Coxsackievirus-adenovirus receptor (CAR) in viral myocarditis. Background: CAR is involved in virus uptake into various cell types. It has therefore been suggested as a therapeutic target to prevent or treat Coxsackievirus B3 (CVB3)-induced diseases such as myocarditis and cardiomyopathy. Recent work in CAR-deficient animals has indicated a role in embryonic development and remodeling with cardiac malformation and lethality. Methods: We generated a tamoxifen-inducible knockout (KO) mouse to study CAR in the adult heart after CVB3 infection. Histomorphology, virus distribution, and cardiac function were compared in CAR-KO versus noninduced littermate control animals expressing wild-type CAR (WT). Results: We have demonstrated that eliminating CAR prevents signs of inflammatory cardiomyopathy, with essentially no pathology in KO hearts. Unlike CVB3-infected WT control animals, the cardiac inducible KO mice did not exhibit structural changes such as monocyte infiltration or fibrosis after CVB3 infection or increased production of markers of inflammation such as interleukin-6 and -10. Whereas CVB3 infection resulted in severe contractile dysfunction in the hearts of animals that express WT, the CAR-deficient hearts appeared normal. Conclusions: Elimination of CAR in adult hearts can efficiently block virus entry and the associated pathology including contractile dysfunction. The lack of infiltration or other morphological changes in CVB3-infected KO hearts emphasizes the contribution of direct virus-mediated pathology in enteroviral myocarditis. [Copyright &y& Elsevier]

Abstract: Studies that document historic and recent polycyclic aromatic hydrocarbons (PAH) deposition rates over large regions are rare. To address this knowledge gap, peat cores of 15 ombrotrophic bogs along a transect across Eastern Canada were dated with 210Pb for the period of about 1850–2000, extracted using accelerated solvent extraction (ASE) and analysed for 14 PAH by GC-MS/MS. Additional parameters, such as sulphur contents, were also determined. In the more populated regions along the St. Lawrence River, deposition rates in individual bogs peaked at 300–1430μgm−2 yr−1 in the mid-20th century, whereas in the remote regions of northern Québec, northern Ontario, and Nova Scotia deposition rates remained below 150μgm−2 yr−1. Total deposition rates were moderately but significantly correlated to sulphur deposition rates (, ), suggesting coal combustion as an important source of PAH depositions. Phenanthrene, benzo[b+k]fluoranthene, fluoranthene and pyrene were the most abundant PAH. In the remote regions phenanthrene dominated (40–60% of total), whereas along the St. Lawrence River benzo[b+k]fluoranthene were most abundant (25–40%) and indeno[1,2,3-c,d]pyrene and benzo[g,h,i]perylene occurred in larger quantities. This pattern only emerged in the 20th century, whereas before, deposition rates and composition were more uniform. The study documents that within Eastern Canada regions of particular PAH deposition patterns exist and suggests that both local and regional emission and transport played a role in the formation of these patterns. [Copyright &y& Elsevier]