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Implementing complex clinical interventions is a key challenge in many global regions. Local communities play a necessary role in enhancing feasibility and strengthening adaptive issues in the design and implementation of stroke interventions in developing countries. Drawing on the knowledge of physicians, patients, and caregivers, the authors employed qualitative methods as a phase 1 strategy to explore the challenges of stroke management and improve the adaptability and efficient delivery of a multimodal preventive intervention for secondary stroke disease in Nigeria. A total of 22 individual interviews were conducted with healthcare professionals, as well as 12 focus groups with patients and caregivers. Findings revealed four operational domains to improve strategies for phase 2 implementation and intervention: (1) barriers influencing optimal adherence in stroke survivors, (2) patient health beliefs and perceptions of patient health beliefs by others, (3) adoption of the "patient report card," and (4) "medical action plan" and family management strategies.

ABSTRACT The objective was to evaluate the effects of cranberry on blood and urinary parameters of dogs (experiment I), digestibility of nutrients (experiment II), palatability of diet (experiment III) and the influence of cranberry on E. coli UPEC-MRHA fimbriae in vitro (experiment IV). For experiment I and II, ten dogs were fed with diets containing 0% or 0.4% cranberry for 30 days. Experiment III compared the diets containing 0% and 0.4% cranberry using 16 adult dogs. There were no statistical differences (P>0.05) in the blood parameters evaluated. Dogs consuming cranberry presented lighter color and appearance of urine, compared to the control group (P

Here, the authors employ Raman-Activated Cell Sorting (RACS) and metagenomics to identify organisms that can forage on O-glycan monosaccharides in the mouse gut, which they use to construct a bacterial consortium able to reduce Clostridioides difficile colonization based on competition for mucosal sugars.

Cancer cells frequently harbour genetic aberrations that protect them from programmed cell death. Here, the authors show in non-small cell lung cancer that the anti-apoptotic gene MCL-1 is subject to copy number gains and that deletion of MCL-1 reduces tumour formation.

Abstract Background Post-traumatic stress disorder is likely to affect clinical courses in the somatic hospital ward when appearing as comorbidity. Thus, this study aimed to assess the costs associated with comorbid post-traumatic stress disorder in a somatic hospital and to analyze if reimbursement appropriately compensated additional costs. Methods The study used data from a German university hospital between 2011 and 2014, analyzing 198,819 inpatient episodes. Inpatient’s episodes were included for analysis if they had a somatic primary diagnosis and a secondary diagnosis of post-traumatic stress disorder. Costs were calculated based on resource use and compared to reimbursement. Analyses were adjusted for sex, age and somatic comorbidities. Results N = 219 Inpatient’s episode were found with primary somatic disorder and a comorbid post-traumatic stress disorder. Inpatients episodes with comorbid post-traumatic stress disorder were compared to 34,229 control episodes, which were hospitalized with the same main diagnosis. Post-traumatic stress disorder was associated with additional hospital costs of €2311 [95%CI €1268 - €3355], while reimbursement rose by €1387 [€563 - €2212]. Results indicate that extra costs associated with post-traumatic stress disorder are not fully reimbursed. Male patients showed higher hospital costs associated with post-traumatic stress disorder. On average, post-traumatic stress disorder was associated with an extra length of stay of 3.4 days [2.1–4.6 days]. Conclusion Costs associated with post-traumatic stress disorder were substantial and exceeded reimbursement, indicating an inadequate reimbursement for somatic patients with comorbid post-traumatic stress disorder.

Altertoxin II is an epoxide-holding perylene quinone and secondary metabolite produced by Alternaria molds. Its genotoxic potential and the high concentrations determined in laboratory fungal cultures resulted in an increased scientific interest in this emerging contaminant. However, no natural occurrence in food has been reported to date to the best of our knowledge. Here, we unambiguously identified altertoxin II in a naturally infected, unprocessed apple. Applying a validated LC-MS/MS method, fruit peel spots (approx. 1 mm in diameter), typically associated with Alternaria infestation, were tested for 17 mycotoxins produced by this genus. Negligible concentrations of tentoxin were determined 24 h after harvest, and the dibenzopyrones alternariol, alternariol monomethyl ether (AME) and AME-3-sulfate after six months of storage. Overall, these contamination patterns can be considered unlikely to be of toxicological concern for consumers. However, an inconspicuous peel lesion (0.5 × 1 cm) separately sampled from a stored apple, exhibited considerably high concentrations of 14 Alternaria toxins, including dibenzopyrones, their barely studied modified forms (glucosides and sulfates), as well as genotoxic perylene quinones including altertoxin II. Considering the toxicological potential of this compound, contaminations in such infected fruit parts should not be underestimated, e.g. in the case of exposure through the consumption of fresh smoothies or fruit juices.

Environmental exposure to xenoestrogens, i.e., chemicals that imitate the hormone 17β-estradiol, has the potential to influence hormone homeostasis and action. Detailed knowledge of xenobiotic biotransformation processes in cell models is key when transferring knowledge learned from in vitro models to in vivo relevance. This study elucidated the metabolism of two naturally-occurring phyto- and mycoestrogens; namely genistein and zearalenone, in an estrogen receptor positive breast cancer cell line (MCF-7) with the aid of stable isotope-assisted metabolomics and the bioinformatic tool MetExtract II. Metabolism was studied in a time course experiment after 2 h, 6 h and 24 h incubation. Twelve and six biotransformation products of zearalenone and genistein were detected, respectively, clearly demonstrating the abundant xenobiotic biotransformation capability of the cells. Zearalenone underwent extensive phase-I metabolism resulting in α-zearalenol (α-ZEL), a molecule known to possess a significantly higher estrogenicity, and several phase-II metabolites (sulfo- and glycoconjugates) of the native compound and the major phase I metabolite α-ZEL. Moreover, potential adducts of zearalenone with a vitamin and several hydroxylated metabolites were annotated. Genistein metabolism resulted in sulfation, combined sulfation and hydroxylation, acetylation, glucuronidation and unexpectedly adduct formation with pentose- and hexose sugars. Kinetics of metabolite formation and subsequent excretion into the extracellular medium revealed a time-dependent increase in most biotransformation products. The untargeted elucidation of biotransformation products formed during cell culture experiments enables an improved and more meaningful interpretation of toxicological assays and has the potential to identify unexpected or unknown metabolites.

A multi-specimen, multi-mycotoxin approach involving ultra-sensitive LC-MS/MS analysis of breast milk, complementary food and urine was applied to examine mycotoxin co-exposure in 65 infants, aged 1–18 months, in Ogun state, Nigeria. Aflatoxin M1 was detected in breast milk (4/22 (18%)), while six other classes of mycotoxins were quantified; including dihydrocitrinone (6/22 (27%); range: 14.0–59.7 ng/L) and sterigmatocystin (1/22 (5%); 1.2 ng/L) detected for the first time. Seven distinct classes of mycotoxins including aflatoxins (9/42 (21%); range: 1.0–16.2 µg/kg) and fumonisins (12/42 (29%); range: 7.9–194 µg/kg) contaminated complementary food. Mycotoxins covering seven distinct classes with diverse structures and modes of action were detected in 64/65 (99%) of the urine samples, demonstrating ubiquitous exposure. Two aflatoxin metabolites (AFM1 and AFQ1) and FB1 were detected in 6/65 (9%), 44/65 (68%) and 17/65 (26%) of urine samples, respectively. Mixtures of mycotoxin classes were common, including 22/22 (100%), 14/42 (33%) and 56/65 (86%) samples having 2–6, 2–4, or 2–6 mycotoxins present, for breast milk, complementary food and urine, respectively. Aflatoxin and/or fumonisin was detected in 4/22 (18%), 12/42 (29%) and 46/65 (71%) for breast milk, complimentary foods and urine, respectively. Furthermore, the detection frequency, median concentrations and occurrence of mixtures were typically greater in urine of non-exclusively breastfed compared to exclusively breastfed infants. The study provides novel insights into mycotoxin co-exposures in early-life. Albeit a small sample set, it highlights transition to higher levels of infant mycotoxin exposure as complementary foods are introduced, providing impetus to mitigate during this critical early-life period and encourage breastfeeding.

Abstract Background Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy. Methods In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer. Results We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival. Conclusions This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.

O ensaio teórico tem o propósito de pautar-se nos desafios encontrados pelos professores e instituições educacionais no processo de implementação das TICs no âmbito escolar e na prática pedagógica do professor de Educação Física. Considerando que entender como utilizá-las no contexto educacional e ter conhecimento de todo o suporte e materiais necessários para o bom aproveitamento nas aulas, é uma tarefa que deve ser encarada por toda a comunidade escolar. Com apoio na revisão de literatura, foi possível constatar e trazer ao debate as principais dificuldades da integração das TICs no ambiente escolar, assim como a necessidade de formação continuada para a comunidade escolar, além da importância da efetivação de políticas públicas voltadas para as aulas de Educação Física.

Peripheral induction of regulatory T (Treg) cells provides essential protection from inappropriate immune responses. CD4(+) T cells that lack endogenous miRNAs are impaired to differentiate into Treg cells, but the relevant miRNAs are unknown. We performed an overexpression screen with T-cell-expressed miRNAs in naive mouse CD4(+) T cells undergoing Treg differentiation. Among 130 candidates, the screen identified 29 miRNAs with a negative and 10 miRNAs with a positive effect. Testing reciprocal Th17 differentiation revealed specific functions for miR-100, miR-99a and miR-10b, since all of these promoted the Treg and inhibited the Th17 program without impacting on viability, proliferation and activation. miR-99a cooperated with miR-150 to repress the expression of the Th17-promoting factor mTOR. The comparably low expression of miR-99a was strongly increased by the Treg cell inducer "retinoic acid", and the abundantly expressed miR-150 could only repress Mtor in the presence of miR-99a. Our data suggest that induction of Treg cell differentiation is regulated by a miRNA network, which involves cooperation of constitutively expressed as well as inducible miRNAs.