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Zika virus (ZIKV) is a flavivirus that is mainly transmitted by Aedes mosquitos and normally causes mild symptoms. During the outbreak in the Americas in 2015, it was associated with more severe implications, like microcephaly in newborns and the Guillain-Barré syndrome. The lack of specific vaccines and cures strengthens the need for a deeper understanding of the virus life cycle and virus-host interactions. The restriction factor tetherin (THN) is an interferon-inducible cellular protein with broad antiviral properties. It is known to inhibit the release of various enveloped viruses by tethering them to each other and the cell membrane, thereby preventing their further spread. On the other hand, different viruses have developed various escape strategies against THN. Analysis of the cross-talk between ZIKV and THN revealed that, despite a strong induction of THN mRNA expression in ZIKV-infected cells, this is not reflected by an elevated protein level of THN. Contrariwise, the THN protein level is decreased due to a reduced half-life. The increased degradation of THN in ZIKV infected cells involves the endo-lysosomal system but does not depend on the early steps of autophagy. Enrichment of THN by depletion of the ESCRT-0 protein HRS diminishes ZIKV release and spread, which points out the capacity of THN to restrict ZIKV and explains the enhanced THN degradation in infected cells as an effective viral escape strategy. IMPORTANCE Although tetherin expression is strongly induced by ZIKV infection there is a reduction in the amount of tetherin protein. This is due to enhanced lysosomal degradation. However, if the tetherin level is rescued then the release of ZIKV is impaired. This shows that tetherin is a restriction factor for ZIKV, and the induction of an efficient degradation represents a viral escape strategy. To our knowledge, this is the first study that describes and characterizes tetherin as a restriction factor for the ZIKV life cycle.

In genome-wide association studies, the CYP2C8 gene locus has been reported to be associated with bisphosphonate-related osteonecrosis of the jaw, a severe devastating side effect of antiresorptive bone treatment. The aim of this study was to elucidate the putative pathomechanism explaining the association between the genetic polymorphism with the alleles CYP2C8*2 and *3 causing low CYP2C8 activity, and disturbed periodontal remodelling in periodontal fibroblasts cultured from patients undergoing orthodontic treatment. CYP2C8 activity, enzyme expression and substrate metabolism were detected in human periodontal fibroblast cultures. Zoledronic acid caused enhanced reactive oxygen species (ROS) production in periodontal fibroblasts, which was enhanced by arachidonic acid as inflammatory signal. Enhanced bisphosphonate-induced uncoupling of the CYP2C8 enzyme was detected in the variant allele (CYP2C8*3) with the result of increased H 2 O 2 production and lowered substrate oxidation. Conversely, substrate (amodiaquine) addition led to decreased H 2 O 2 production in isolated CYP2C8 enzymes, but in CYP2C8*3 enzyme, increased H 2 O 2 was still detected, especially in presence of arachidonic acid. CYP2C8 variants leading to decreased enzyme activity in substrate oxidation may enhance ROS production by reaction uncoupling, and thus, contribute to difficulties in orthodontic treatment and the risk of side effects of antiresorptive drugs., (© 2021 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Adverse drug reactions (ADRs) in the pediatric population may differ in types and frequencies compared to other populations. Respective studies analyzing ADR reports referring to children have already been performed for certain countries. However, differences in drug prescriptions, among others, complicate the transferability of the results from other countries to Germany or were rarely considered. Hence, the first aim of our study was to analyze the drugs and ADRs reported most frequently in ADR reports from Germany referring to children contained in the European ADR database (EudraVigilance). The second aim was to set the number of ADR reports in relation to the number of drug prescriptions. These were provided by the Research Institute for Ambulatory Health Care in Germany., Methods: For patients aged 0-17 years 20,854 spontaneous ADR reports were received between 01/01/2000-28/2/2019. The drugs and ADRs reported most frequently were identified. Stratified analyses with regard to age, sex and drugs used "off-label" were performed. Reporting rates (number of ADR reports/number of drug prescriptions) were calculated., Results: Methylphenidate (5.5%), ibuprofen (2.3%), and palivizumab (2.0%) were most frequently reported as suspected. If related to the number of drug prescriptions, the ranking changed (palivizumab, methylphenidate, ibuprofen). Irrespective of the applied drugs, vomiting (5.4%), urticaria (4.6%) and dyspnea (4.2%) were the ADRs reported most frequently. For children aged 0-1 year, drugs for the treatment of nervous system disorders and foetal exposure during pregnancy were most commonly reported. In contrast, methylphenidate ranked first in children older than 6 years and referred 3.5 times more often to males compared to females. If age- and sex-specific exposure was considered, more ADR reports for methylphenidate referred to children 4-6 years and females 13-17 years. Drugs for the treatment of nervous system disorders ranked first among "off-label" ADR reports., Conclusions: Our analysis underlines the importance of putting the number of ADR reports of a drug in context with its prescriptions. Additionally, differences in age- and sex-stratified analysis were observed which may be associated with age- and sex-specific diseases and, thus, drug exposure. The drugs most frequently included in "off-label" ADR reports differed from those most often used according to literature., (© 2021. The Author(s).)

Background: Normal human breast tissues are a heterogeneous mix of epithelial and stromal subtypes in different cell states. Delineating the spectrum of cellular heterogeneity will provide new insights into normal cellular properties within the breast tissue that might become dysregulated in the initial stages of cancer. Investigation of surface marker expression provides a valuable approach to resolve complex cell populations. However, the majority of cell surface maker expression of primary breast cells have not been investigated., Methods: To determine the differences in expression of a range of uninvestigated cell surface markers between the normal breast cell subpopulations, primary human breast cells were analysed using high-throughput flow cytometry for the expression of 242 cell surface proteins in conjunction with EpCAM/CD49f staining., Results: We identified 35 surface marker proteins expressed on normal breast epithelial and/or stromal subpopulations that were previously unreported. We also show multiple markers were equally expressed in all cell populations (e.g. CD9, CD59, CD164) while other surface markers were confirmed to be enriched in different cell lineages: CD24, CD227 and CD340 in the luminal compartment, CD10 and CD90 in the basal population, and CD34 and CD140b on stromal cells., Conclusions: Our dataset of CD marker expression in the normal breast provides better definition for breast cellular heterogeneity.

We conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R- and S-PZQ in healthy male participants. This was toward evaluating the risk of drug-drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non-randomized, open-label, single-dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC-MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T 1/2 , C min , and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ (p < .05), reducing the AUC by 4-fold (1213.15 vs. 281.35 h·ng/ml for R-PZQ and 5669 vs. 871.84 h·ng/ml for S-PZQ). Ritonavir had no significant effect on R-PZQ but increased the AUC 2-fold for S-PZQ (p < .05) (4154.79 vs. 7291.05 h·ng/ml). Using PZQ in HIV patients needs investigation, as there is a risk of both treatment failure and adverse effects because of induction and inhibition, respectively., (© 2021 African Institute of Biomedical Science & technology (AIBST). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

The objective of this study was to analyse reports on adverse drug reactions (ADRs) from Germany in the particularly vulnerable patient group of children and adolescents. Reporting characteristics, demographic parameters and off-label use were examined among others. The ratio of ADR reports per number of German inhabitants and the ratio of ADR reports per number of German inhabitants exposed to drugs were calculated and compared. These parameters were examined to derive trends in reporting of ADRs. 20,854 spontaneous ADR reports for the age group 0-17 years were identified in the European ADR database EudraVigilance for the time period 01.01.2000-28.02.2019 and analysed with regard to the aforementioned criteria. 86.5% (18,036/20,854) of the ADR reports originated from Healthcare Professionals and 12.2% (2,546/20,854) from non-Healthcare Professionals. 74.4% (15,522/20,854) of the ADR reports were classified as serious. The proportion of ADR reports per age group was 11.8% (0-1 month), 11.0% (2 months-1 year), 7.4% (2-3 years), 9.3% (4-6 years), 25.8% (7-12 years), and 34.8% (13-17 years) years, respectively. Male sex slightly dominated (51.2% vs. 44.8% females). Only 3.5% of the ADR reports reported off-label use. The annual number of ADR reports increased since 2000, even if set in context with the number of inhabitants and assumed drug-exposed inhabitants. The pediatric population declined in the study period which argues against its prominent role for the increase in the total number of ADR reports. Instead, among others, changes in reporting obligations may apply. The high proportion of serious ADR reports underlines the importance of pediatric drug safety., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Sub-Saharan Africa and other low- and middle-income countries (LMICs) have the highest rates of antimicrobial resistance (AMR) driven by high rates of antimicrobial utilization. This is a concern as AMR appreciably increases morbidity, mortality and costs. Pharmacogenetics (PGx) and precision medicine are emerging approaches to combat AMR. Consequently, as a first step there is a need to assess AMR knowledge and attitudes, and knowledge of PGx, among healthcare professionals and use the findings to guide future interventions. Methodology: We conducted a cross-sectional study involving 304 healthcare professionals at tertiary hospitals in Lusaka, Zambia. Structural Equation Modeling (SEM) was used to analyze relationships among latent variables. Results: Overall correctness of answers concerning AMR among healthcare professionals was 60.4% (7/11). Knowledge of pharmacogenetics was low (38%). SEM showed that high AMR knowledge score correlated with a positive attitude toward combating AMR ( p < 0.001). Pharmacists had relatively higher AMR knowledge scores (mean = 7.67, SD = 1.1), whereas nurses had lower scores (mean = 5.57, SD = 1.9). A minority of respondents [31.5% ( n = 95)] indicated that poor access to local antibiogram data promoted AMR, with the majority [56.5% ( n = 190)] responding that poor adherence to prescribed antimicrobials can lead to AMR. Pharmacists had the highest scores for attitude (mean = 5.60, SD = 1.6) whereas nurses had the lowest scores (mean = 4.02, SD = 1.4). Conclusion: AMR knowledge and attitudes, as well as knowledge on PGx among healthcare professionals in Zambia, is sub-optimal and has the potential to affect the uptake of precision medicine approaches to reduce AMR rates. Educational and positive behavioral change interventions are required to address this and in future, we will be seeking to introduce these to improve the use of antimicrobials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mufwambi, Stingl, Masimirembwa, Manasa, Nhachi, Stadler, Mwila, Kalungia, Mukosha, Mutiti, Kamoto, Kaonga, Godman and Munkombwe.)

Zika virus (ZIKV) is a mosquito-borne virus, which can cause brain abnormalities in newborns, including microcephaly. MicroRNAs (miRNAs) are small non-coding RNAs, which post- transcriptionally regulate gene expression. They are involved in various processes including neurological development and host responses to viral infection, but their potential role in ZIKV pathogenesis remains poorly understood. MiRNAs can be incorporated into extracellular vesicles (EVs) and mediate cell-to-cell communication. While it is well known that in viral infections EVs carrying miRNAs can play a crucial role in disease pathogenesis, ZIKV effects on EV-delivered miRNAs and their contribution to ZIKV pathogenesis have not been elucidated. In the present study, we profiled intracellular and EV-derived miRNAs by next generation sequencing and analyzed the host mRNA transcriptome of neural stem cells during infection with ZIKV Uganda and French Polynesia strains. We identified numerous miRNAs, including miR-4792, which were dysregulated at the intracellular level and had altered levels in EVs during ZIKV infection. Integrated analyses of differentially expressed genes and miRNAs showed that ZIKV infection had an impact on processes associated with neurodevelopment and oxidative stress. Our results provide insights into the roles of intracellular and EV-associated host miRNAs in ZIKV pathogenesis.

The aim of this study was to perform a pilot histological and quantitative analysis of the blood vessels accompanying the epicardial nerves (vasa nervorum) in the porcine hearts. Twenty healthy porcine hearts were used in this study. The blood vessels were analyzed by light microscopy using four different staining techniques in transverse sections taken from the upper, middle, and lower segments of the anterior part of the interventricular region and the adjacent parts of the right and left ventricles containing epicardial nerves and the endocardial peripheral parts of the Purkinje fibers. In total, 317 epicardial nerves were detected. The vasa nervorum were present in 75.7% of these nerves. The vasa nervorum resembled arterioles and postcapillary and collecting venules. One hundred and forty nine epicardial nerves were perivascular, located in the adventitia of the anterior interventricular artery and vein. The remaining 168 nerves ran freely through the epicardial interstitium. The presence of the vasa nervorum was not related to topographical location or nerve diameter. Additionally, from a total of 33 analyzed ventricular complexes of Purkinje fibers small blood vessels located in their proximity were identified in only two cases. It can be concluded that the majority of the anterior epicardial nerves of porcine heart possess well-developed vasa nervorum. In contrast, similar blood vessels are rarely present in the vicinity of the Purkinje fibers. The data obtained contribute to a better understanding of the nutrition of the cardiac nerves., (© 2020 Wiley Periodicals LLC.)

Objectives: Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design., Methods: An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses., Results: Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene-drug interaction in a gatekeeping analysis., Conclusion: Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene-drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine.

This review provides an overview of the basic knowledge of drug pain therapy in the palliative situation. Pain is one of the main symptoms in 60 to 90 % of cancer patients. Pain also develops with neurological and other diseases that occur in end-of-life situations. To address this symptom, a holistic strategy is required that encompasses all physical, psychological, social, and spiritual aspects of the multi-dimensional pain experience ("total pain" concept).Drug treatment for cancer pain has been based on a stepwise approach for many years, starting with non-opioid analgesics, followed by moderate and strong opioids. In contrast, today's pain management is determined more by the actual intensity of this aversive event.The pain assessment should be tailored to identify a nociceptive vs. neuropathic pain component that needs to be challenged by the most appropriate drug therapies. Non-opioid analgesics are ideal substances for relieving nociceptive pain. Antidepressants and anticonvulsants reduce the intensity of new neuropathic pain. Opioids are suitable for all types of pain, but are restricted to a second line choice. Among all opioids are tilidine and tramadol prodrugs, which only relieve pain after activation in the liver. Drug-drug interactions may also block this activation. Rapid release opioids should be used for cancer breakthrough pain. Transdermal opioid applications are recommended for swallowing disorders, but usually not to initiate pain control. An opioid switch can be performed if side effects such as hallucinations for the selected opioid are more pronounced than the pain reduction., Competing Interests: SW, JS, VPP, SH, IN: Keine Interessenkonflikte. AL: Vorträge für Grünenthal, Research agreement mit Roche. FE: Beratertätigkeit oder Vorträge für TEVA, Berlin Chemie, Menarini Group, Grünenthal. RR: Beratertätigkeit oder Vorträge für AOP Orphan, bionorica ethics, Grünenthal, Pfizer, Tilray Deutschland. Konsortialführer des G-BA Innovationsfonds-Projektes APVEL (Förderkennzeichen: 01VSF16007). Ko-Sprecher der Ärztinnen und Ärzte der Deutschen Gesellschaft für Palliativmedizin und Neuropalliativen Arbeitsgemeinschaft. RR und AL (Ko-Sprecherin) erhalten Forschungsförderung durch das BMBF-Projekt Bio2Treat (Förderkennzeichen: 13GW0334B)., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Pre-emptive testing of pharmacogenetically relevant single-nucleotide polymorphisms can be an effective tool in the prevention of adverse drug reactions and therapy resistance. However, most of the tests are not used as standard in routine care in Germany because of lacking evidence for the clinical and economical benefit and their impact on the usage of healthcare services. We address this issue by investigating the influence of pharmacogenetic profiles on the use of healthcare services over an extended period of several years using routine care data from a statutory health insurance company. The goal is to provide clinical evidence whether pre-emptive pharmacogenetic testing of metabolic profiles in routine care in Germany is beneficial and cost-effective., Methods and Analysis: The EMPAR (Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung) study is a non-interventional cohort study conducted to analyse pharmacogenetic risk factors that are important for drug therapy by means of endpoints relevant for healthcare. The analysis is based on pharmacogenetic profiles and statutory health insurance data. We perform pharmacogenetic, pharmacoepidemiological and pharmacoeconomic analyses using health care utilisation scores and machine learning techniques. Therefore, we aim to include about 10 000 patients (≥18 years) insured by the health insurance provider Techniker Krankenkasse. The study focuses on patients with prescriptions of anticoagulants and prescriptions of cholesterol-lowering drugs. Also, a screening for special pharmacogenetic characteristics will be performed in patients with at least one Y57.9! diagnosis (Complication of medical and surgical care: drug or medicament, unspecified). Outcomes include the utilisation of health insurance services, the incidence of incapacity for work and costs for drugs and treatment., Ethics and Dissemination: The protocol was approved by the Ethics Committee of the Medical Faculty, University of Bonn (Lfd. Nr. 339/17). The results of this research project will be published in scientific open access journals and at conferences., Trial Registration Number: German Clinical Trials Register, DRKS00013909., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The purpose of this study was to highlight the historical importance of the events of the year 1848 for Czech surgery and to provide a brief report on medical dissertations written in Prague between the years 1832 and 1846, focused on the surgical treatment of incarcerated hernias., Methods: The study was designed as a literary search using original materials of the Archive of Charles University, the National Library of the Czech Republic, and international sources., Results: In the year 1848 surgery became an official part of the university medical curriculum after a long process of integration. We identified and analysed ten medical dissertations on anatomy, diagnosis and treatment of incarcerated hernias, completed in the above mentioned period., Conclusion: Our results illustrate both the successful completion of implementation of surgery into the medical curriculum, as well as the ways and the quality of both conservative and surgical treatments of incarcerated hernias between 1832 and 1846.

Competing Interests: Die Autorin gibt an, dass kein Interessenkonflikt besteht.

Background: The aim of this study was to assess the effect of day of the week and wearing a device (reactivity) on objectively measured physical activity (PA) in older people., Methods: Walking duration as a measure for PA was recorded from 1333 German community-dwelling older people (≥65 years, 43.8% women) over 5 days using accelerometers (activPAL). Least-square means of PA with 95%-confidence intervals (95%-CI) from multi-level analysis were calculated for each day of the week and each measurement day (days after sensor attachment)., Results: Walking duration on Sundays was significantly lower compared to working days (Sunday vs. Monday-Friday: - 12.8 min (95%-CI: - 14.7; - 10.9)). No statistically significant difference compared to working days was present for Saturdays. The linear slope for measurement day and walking duration was marginal and not statistically significant., Conclusions: Studies using PA sensors in older people should assess Sundays and working days to adequately determine the activity level of the participants., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

The aim of the study was to investigate the existence of valves in small peripheral coronary veins of porcine hearts. The study was performed on 20 porcine hearts using standard histological methods. The veins in the subepicardial and intramyocardial regions of the anterior and posterior parts of the interventricular septum and in the wall of the right atrium were studied. Valves were present in intramyocardial veins (diameter of 75-180 μm), in the veins located just beneath the external surface of the myocardium (diameter 120-170 μm) and in the terminal segments of the ventricular veins (diameter 250 μm) opening into the stems of the anterior interventricular vein and middle cardiac vein. Valves were also recorded in most veins of the subepicardial space. The described rich presence of valves in the small coronary veins may contribute to a better comprehension of their hemodynamic properties. These findings may also help to improve the understanding of the efficacy of retrograde application of medications, a novel technique in cardiology and cardiac surgery., (© 2019 Wiley Periodicals, Inc.)

Introduction: The vasa vasorum interna were described during the last decade as a special kind of vessels originating directly from the lumen of the paternal artery and participating in the nourishment of its wall, especially of the aorta and coronary arteries. At the same time, their existence was repeatedly denied/negated by many other authors., Aim: The purpose of the actual study was the anatomical verification of the existence of the vasa vasorum interna in porcine coronary arteries., Materials and Methods: The vascular supply was studied on the wall of the anterior interventricular branch of the left coronary artery on 36 hearts taken from healthy pigs. Light microscopy, vascular injections and scanning electron microscopy were used for the analysis of 141 samples., Results: In only two cases small arteries resembling vasa vasorum interna and originating directly from the lumen of the coronary artery were found. But, in both cases these vessels ran without branching, passed over the whole thickness of adventitia and branched in the wider periarterial space. In contrast to this all feeding arteries of the vasa vasorum arose from the larger branches of the paternal artery, branched entirely in its adventitia and did not enter the media., Conclusion: Due to the very low incidence of these small arteries originating from the lumen of the paternal artery and the absence of their participation on the nourishment of the arterial wall we came to the conclusion that it is not suitable to use the term "vasa vasorum interna" for their designation., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Purpose: The main objective of this study was to analyze validated cases of drug-induced anaphylactic reactions in children with regard to incriminated drugs, clinical characteristics, and associated factors. A further objective was to compare differences in incriminated drugs and characteristics between validated cases and a reference excluding anaphylactic reaction cases (basic dataset)., Methods: Spontaneous reports of anaphylactic reactions in children (0-17 years) registered between January 2000 to December 2016 were extracted from the adverse drug reaction database of the German Federal Institute for Drugs and Medical Devices. These reports were restricted to drugs for which at least four cases were found. After case validation, 159 reports remained (validated dataset) and were compared with the basic dataset (n = 12.168 reports) using inferential statistics., Results: Estimated yearly increase of reports (36.8 vs 0.1), most frequently incriminated drugs (antibiotics 30.2% vs 11%, analgesics/antipyretics 22.0% vs 5.6%; P values less than 0.001) and route of administration (38.4% vs 6.7%) differed between the validated dataset and the basic dataset. Validated cases differed in severity (higher with atracurium), reported symptoms (urticaria leading with analgesics), and associated factors (atopy/allergy rarely reported with antibiotics) depending on the incriminated drug class. In 13.8% (11.3% if excluding repeated readministration in one person) of the cases, the drug had not been tolerated before., Conclusions: A heterogeneous clinical phenotype with differences in associated factors was observed, suggesting different underlying mechanisms triggered by the different drug groups. Occurrence of serious drug-induced anaphylactic reactions in children could be reduced by carefully considering patient history., (© 2019 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.)

Treatment with interferon (IFN) has been associated with depressive side effects. Previous neuroimaging studies have provided information about changes in brain activation patterns in patients under treatment with IFN-alpha, but the effect of other IFNs, or the role of the underlying disease, has yet to be clarified. In the present fMRI study, we looked at brain changes after 8 days of IFN-beta treatment in N = =17 healthy volunteers, thus avoiding the possible confound of the effects of underlying pathology in studies of IFN-treated patients with neurological or other medical disorders. We followed a symptom dimensional approach by simultaneously investigating two distinct symptom domains of depressiveness: negative affect (amygdala) and appetitive motivation (ventral striatum). In these early phases of IFN treatment we detected a selective change in neural substrates of appetitive motivation, consistent with the predominant symptomatic change recorded in psychopathology ratings. In contrast, the fMRI phenotype of negative affect, which is known to characterize disorders of affect involving anxiety and depressiveness as well as individual vulnerability to depression, was unchanged after treatment. These findings suggest that IFN may induce an affective syndrome through a mechanism involving down-regulation of appetitive motivation., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the impact of accelerated, single-shot 3D-GRASE acquisition on quantitative arterial spin labeling (ASL) with multiple and single post-labeling delay (PLD) in terms of perfusion-weighted SNR per unit scan time (TSNR PW ) and quantification accuracy., Methods: Five subjects were scanned on a 3T MRI scanner using the pseudo-continuous arterial spin labeling (PCASL) technique with a 3D-GRASE imaging sequence capable of parallel imaging acceleration. A 3-inversion pulse background suppression was simulated and implemented in the sequence. Three time-matched single PLD measurements, a segmented one without acceleration, 1 with conventional GRAPPA, and 1 with CAIPIRINHA sampling, were used to compare TSNR PW . Three time-matched multiple PLD measurements with the identical imaging parameters were additionally evaluated (no acceleration vs. CAIPIRINHA sampling vs. CAIPIRINHA sampling with doubled number of PLDs). Cerebral blood flow and arterial transit time fit uncertainties were compared and used as a quality measure., Results: The single PLD measurements show an 11% TSNR PW increase using CAIPIRINHA sampling instead of GRAPPA sampling, while the non-accelerated scan exhibits 35% higher TSNR PW compared to the GRAPPA scan. However, taking advantage of the increased number of averages for multiple PLD acquisitions, a 14%/16% (gray matter) and 34%/36% (white matter) reduction of CBF fit uncertainty is observed with CAIPIRINHA sampling (6 PLDs/12 PLDs) compared to no acceleration., Conclusion: Accelerated single-shot 3D-GRASE with PCASL allows for smaller quantification uncertainties than time-matched segmented acquisitions. Corresponding single-shot acquisitions with acceptable blurring and no intra-volume motion render state-of-the-art ASL methods in a clinically feasible time possible., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: The aim of the study was to describe the origin of the Latin anatomical term vasa vasorum and its role in current medical research and to present examples of grammatical errors in its use., Methods: Literary searches oriented on the term vasa vasorum were used to identify publications using it in the medical literature from the seventeenth century up to the present., Results: The Latin term vasa vasorum was introduced by Ludwig in 1739. The vasa vasorum became an important topic in clinical research around the middle of the twentieth century, with implications in angiology, cardiology and cardiosurgery. We report 18 grammatical errors concerning the use of the term vasa vasorum, starting from the year 1959. A similar decline in the correct use of Latin terminology is also evident in other medical research disciplines., Conclusions: The numerous errors found in the use of Latin terminology in recent medical literature have occurred as a consequence of decreased use of Latin in the medical community. The only way to improve this situation is by improving awareness of international standard anatomical terminology, which is available worldwide in both Latin and English.

Purpose: This study was designed to investigate the distribution of vasa vasorum in walls of failed aorto-coronary venous grafts., Methods: Fifty-one diseased venous grafts harvested from 39 patients underwent qualitative histological evaluation. The morphology of the grade of the pathological changes and the extent of the vascularisation were examined, and related to the length of the interval between the primary surgery and the explantation. The obtained results were placed into five groups, substantially differing one from the other in morphology and vascularisation., Results: The intervals between grafts implantation and explantation ranged from 1 day to 35 years. The onset of arterialization of the graft media was observed on average at 1 month after bypass implantation. During this same time period massive intimal hyperplasia and atherosclerosis occurred. Vasa vasorum proliferation from the adventitia to the outer layers of the media was first apparent between 7 and 24 months after implantation. Proliferation of the vasa vasorum throughout the entire atherosclerotic media and hyperplastic intima continued for a much longer time interval., Conclusion: No correlation between neoangiogenesis and age, sex or type of bypassed coronary branch was proven. Regarding the given findings, the authors believe that changes in hemodynamic conditions and endothelial trauma are primarily responsible for the development of graft disease and that vasa vasorum proliferation is only a secondary reaction to the structural changes of the graft wall. To what extent the frequently present pre-existing intimal hyperplasia of venous bypass grafts play in the development of graft disease remains questionable.

Background: The adverse drug reaction database of the German Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) contains reports of suspected adverse drug reactions (ADRs) that are spon- taneously submitted by physicians, pharmacists, or patients. The aim of the present study was a descriptive analysis of all of these spontaneous reports., Methods: 345 662 spontaneously submitted reports were analyzed with respect to the number of reports per year, the sources of the reports, demographic variables, the most commonly reported ADRs, and the drug classes most commonly suspected., Results: The number of reports submitted spontaneously each year has grown steadily since 1978. At the least detailed level of analysis, "drugs for the treatment of nervous system disorders" were the most common class of drugs under suspicion of causing the reported adverse drug reactions (23.1%). In a more detailed analysis by therapeutic subgroup, the three subgroups most commonly reported as suspected of causing side effects were antithrombotic agents, systemic antibiotics, and psycholeptics-causing thrombocytopenia, diarrhea, and drug dependency as the most frequently reported ADRs, respectively. The order of drug classes most commonly causing ADRs differed markedly between the physicians' reports (diazepines, fluoroquinolones, heparins) and the patients' reports (interferons, anti- thrombotic drugs, selective immunosuppressant drugs). Patients more commonly reported subjectively perceived ADRs, while physicians more commonly reported findings or diagnoses that require medical expertise., Conclusion: The increasing number of spontaneous reports is mainly due to reports forwarded from pharmaceutical companies to the BfArM. This, in turn, is probably a result of increasingly strict legal reporting requirements in Germany. The detected differences between physicians' and patients' ADR reports can be taken to indicate that patients should be more specifically informed and questioned about potential ADRs. By reporting adverse drug reactions, physicians may improve drug safety.

On a pathophysiological level, angioedema can be differentiated into histamine- and bradykinin-mediated types. The prototype drug-associated, bradykinin-mediated form of angioedema is angiotensin-converting enzyme (ACE) inhibitor-induced angioedema. The hypothesized cause is a decrease in bradykinin degradation via ACE inhibition. In this scenario, other bradykinin-degrading enzymes assume major importance. When the effect of these enzymes is also diminished, e. g., due to genetic variants or external factors, compensation for the inhibition of ACE may be insufficient. An increased risk of angioedema has also been reported for other drugs, particularly when prescribed in combination with ACE inhibitors. Here, the suspected cause also relates to the degradation of bradykinin. When angioedema arises within the context of concomitant ACE inhibitor use, additive bradykinin degradation effects may be implicated.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Epidermal growth factor receptor overexpression in human cancer can be effectively targeted by drugs acting as specific inhibitors of the receptor, like erlotinib, gefitinib, cetuximab and panitumumab. A common adverse effect is a typical papulopustular acneiform rash, whose occurrence and severity are positively correlated with overall survival in several cancer types. We studied molecules involved in epidermal growth factor receptor signaling which are quantifiable in plasma, with the aim of identifying biomarkers for the severity of rash. With a predictive value for the rash these biomarkers may also have a prognostic value for survival and disease outcome.The concentrations of amphiregulin, hepatocyte growth factor (HGF) and calcidiol were determined by specific enzyme-linked immunosorbent assays in plasma samples from 211 patients.We observed a significant inverse correlation between the plasma concentration of HGF and overall survival in patients with an inhibitor-induced rash (p-value = 0.0075; mean overall survival low HGF: 299 days, high HGF: 240 days) but not in patients without rash. The concentration of HGF was also significantly inversely correlated with severity of rash (p-value = 0.00124).High levels of HGF lead to increased signaling via its receptor MET, which can activate numerous pathways which are normally also activated by epidermal growth factor receptor. Increased HGF/MET signaling might compensate the inhibitory effect of epidermal growth factor receptor inhibitors in skin as well as tumor cells, leading to less severe skin rash and decreased efficacy of the anti-tumor therapy, rendering the plasma concentration of HGF a candidate for predictive biomarkers.

The neurotrophic hypothesis of depression suggests an association between effects on neuroplasticity and clinical response to antidepressant drug therapy. We studied individual variability in antidepressant drug effects on cell proliferation in lymphoblastoid cell lines (LCLs) from n=25 therapy-resistant patients versus n=25 first-line therapy responders from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Furthermore, the variability in gene expression of genes associated with cell proliferation was analyzed for tentative candidate genes for prediction of individual LCL donor's treatment response. Cell proliferation was quantified by EdU (5-ethynyl-2'-deoxyuridine) assays after 21-day incubation of LCLs with fluoxetine (0.5 ng μl -1 ) and citalopram (0.3 ng μl -1 ) as developed and described earlier. Gene expression of a panel of candidate genes derived from genome-wide expression analyses of antidepressant effects on cell proliferation of LCLs from the Munich Antidepressant Response Signature (MARS) study was analyzed by real-time PCR. Significant differences in in vitro cell proliferation effects were detected between the group of LCLs from first-line therapy responders and LCLs from treatment-resistant patients. Gene expression analysis of the candidate gene panel revealed and confirmed influence of the candidate genes ABCB1, FZD7 and WNT2B on antidepressant drug resistance. The potential of these genes as tentative biomarkers for antidepressant drug resistance was confirmed. In vitro cell proliferation testing may serve as functional biomarker for individual neuroplasticity effects of antidepressants.

Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach., (© 2016 American Society for Clinical Pharmacology and Therapeutics.)

The mammary epithelium is composed of a variety of specialized cell types that function in a coordinated fashion to produce and eject milk through multiple cycles of pregnancy. The ability to identify and purify these subsets of cells in order to interrogate their growth and differentiation capacities, as well as to characterize the molecular mechanisms that regulate their behavior, is essential in identifying the processes associated with breast cancer initiation and progression. This methods chapter outlines the step-by-step methods for dissociating human breast reduction specimens to a single cell suspension of viable cells. As well, strategies for purifying four distinct subsets of epithelial cells by using fluorescence-activated cell sorting and protocols for interrogating the growth and differentiation properties of these purified cells at clonal densities in adherent culture are also described.

The current therapy success of depressive disorders remains in need of improvement due to low response rates and a delay in symptomatic improvement. Reliable functional biomarkers would be necessary to predict the individual treatment outcome. On the basis of the neurotrophic hypothesis of antidepressant's action, effects of antidepressant drugs on proliferation may serve as tentative individual markers for treatment efficacy. We studied individual differences in antidepressant drug effects on cell proliferation and gene expression in lymphoblastoid cell lines (LCLs) derived from patients treated for depression with documented clinical treatment outcome. Cell proliferation was characterized by EdU (5-ethynyl-2'-deoxyuridine) incorporation assays following a 3-week incubation with therapeutic concentrations of fluoxetine. Genome-wide expression profiling was conducted by microarrays, and candidate genes such as betacellulin-a gene involved in neuronal stem cell regeneration-were validated by quantitative real-time PCR. Ex vivo assessment of proliferation revealed large differences in fluoxetine-induced proliferation inhibition between donor LCLs, but no association with clinical response was observed. Genome-wide expression analyses followed by pathway and gene ontology analyses identified genes with different expression before vs after 21-day incubation with fluoxetine. Significant correlations between proliferation and gene expression of WNT2B, FZD7, TCF7L2, SULT4A1 and ABCB1 (all involved in neurogenesis or brain protection) were also found. Basal gene expression of SULT4A1 (P=0.029), and gene expression fold changes of WNT2B by ex vivo fluoxetine (P=0.025) correlated with clinical response and clinical remission, respectively. Thus, we identified potential gene expression biomarkers eventually being useful as baseline predictors or as longitudinal targets in antidepressant therapy.

The goals of this German guideline are the improvement of diagnosis and therapy of scabies, the implementation of a coordinated action in outbreaks of scabies, and the control of this infestation in large migration or refugee flows.Sarcoptes scabiei var. hominis is transmitted by direct skin-to-skin contact of sufficient duration. The infectivity of female mites when removed from patients does not exceed 48 hours at room temperature (21°C) and relative humidity of 40-80%. The risk of infection rises proportionally to the number of mites on the skin and is particularly high in crusted scabies. As elderly persons tend to develop crusted scabies due to disease- or medication-related immunosuppression, there is an increased risk for outbreaks of scabies at nursing homes and extended-care facilities. The guideline contains detailed recommendations for management of such outbreaks. In refugees the prevalence of scabies is higher than in the general population in Germany, but the risk for outbreaks is not high. Scabies infestation should be considered when a recent onset of itching is associated with eczema and presence of burrows or comma-like papules at predilection sites. It is confirmed by dermatoscopic detection of mites or by microscopic identification of mites, mite eggs or fecal matter (scybala) from skin scrapings.The treatment of choice for common scabies is topical permethrin 5% cream applied for 8-12 hours. Permethrin can be considered for off-label use also in infants of less than 3 months of age and pregnant women. For this group crotamiton is another option, which, besides benzyl benzoate, presents a good second line therapy for the other indications. Indications for oral ivermectin, which has just been licensed in Germany, include patients with immunosuppression, severe dermatitis, and low adherence.Crusted scabies is preferentially treated by a combination of topical permethrin and oral ivermectin. Affected patients should be isolated, and all contact persons should be treated. The guideline contains lists for additional measures, including possible treatment of contact persons, clothes, linen and other possibly infested articles., (© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Aim: The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors., Methods: From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis., Results: Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10(-4)) and OS (p = 5.8 × 10(-5))., Conclusion: The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Pharmacogenetics are an important component in the individualization of treatment; however, pharmacogenetic diagnostics have so far not been used to any great extent in clinical practice. A consistent consideration of individual patient factors, such as pharmacogenetics may help to improve drug therapy and increase individual safety and efficacy aspects., Objective: A brief summary of structures and effects of genetic variations on drug efficacy is presented. Some frequently prescribed pharmaceuticals are specified. Furthermore, the feasibility of pharmacogenetic diagnostics and dose recommendations in the clinical practice are described., Current Data: The European Medicines Agency (EMA) as the European approval authority has already extended the drug labels of more than 70 pharmaceuticals by information on pharmacogenetic biomarkers and the U.S. Food and Drug Administration (FDA) more than 150. This is a crucial step towards targeted medicine. Guidelines on dose and therapy adjustments are provided by the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network., Conclusion: It is fundamental to consider individual patient factors for successful drug therapy. Dose and therapy recommendations based on pharmacogenetic diagnostics are highly important for individualization as well as improvement of safety and efficiency of drug therapy.

Aims: Dementia and type 2 diabetes (T2D) are two major phenomena in older people. To compare anti-hyperglycemic therapy and diabetes-related comorbidities between elderly T2D patients with or without comorbid dementia., Methods: 215,932 type 2 diabetes patients aged ≥ 40 years (median [Q1;Q3]: 70.4 [61.2;77.7] years) from the standardized, multicenter German/Austrian diabetes patient registry, DPV, were studied. To identify patients with comorbid dementia, the registry was searched by ICD-10 codes, DSM-IV/-5 codes, respective search terms and/or disease-specific medication. For group comparisons, multiple hierarchic regression modeling with adjustments for age, sex, and duration of diabetes was applied., Results: 3.1% (n=6770; 57% females) of the eligible T2D patients had clinically recognized comorbid dementia. After adjustment for demographics, severe hypoglycemia (insulin group: 14.8 ± 0.6 vs. 10.4 ± 0.2 events per 100 patient-years, p<0.001), hypoglycemia with coma (insulin group: 7.6 ± 0.4 vs. 3.9 ± 0.1 events per 100 patient-years, p<0.001), depression (9.9 vs. 4.7%, p<0.001), hypertension (74.7 vs. 72.2%, p<0.001), stroke (25.3 vs. 6.5%, p<0.001), diabetic foot syndrome (6.0 vs. 5.2%, p=0.004), and microalbuminuria (34.7 vs. 32.2%, p<0.001) were more common in dementia patients compared to T2D without dementia. Moreover, patients with dementia received insulin therapy more frequently (59.3 vs. 54.7%, p<0.001), but metabolic control (7.7 ± 0.1 vs. 7.7 ± 0.1%) was comparable to T2D without dementia., Conclusions: In T2D with dementia, higher rates of hypoglycemia and other diabetes-related comorbidities were observed. Hence, the risks of a glucocentric and intense diabetes management with insulin and a focus on tight glycemic control without considering other factors may outweigh the benefits in elderly T2D patients with comorbid dementia., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Despite strong pharmacological support, association studies using genotype-predicted phenotype as a variable have yielded conflicting or inconclusive evidence to promote personalized pharmacotherapy. Unless the patient is a genotypic poor metabolizer, imputation of patient's metabolic capacity (or metabolic phenotype), a major factor in drug exposure-related clinical response, is a complex and highly challenging task because of limited number of alleles interrogated, population-specific differences in allele frequencies, allele-specific substrate-selectivity and importantly, phenoconversion mediated by co-medications and inflammatory co-morbidities that modulate the functional activity of drug metabolizing enzymes. Furthermore, metabolic phenotype and clinical outcomes are not binary functions; there is large intragenotypic and intraindividual variability. Therefore, the ability of association studies to identify relationships between genotype and clinical outcomes can be greatly enhanced by determining phenotype measures of study participants and/or by therapeutic drug monitoring to correlate drug concentrations with genotype and actual metabolic phenotype. To facilitate improved analysis and reporting of association studies, we propose acronyms with the prefixes 'g' (genotype-predicted phenotype) and 'm' (measured metabolic phenotype) to better describe this important variable of the study subjects. Inclusion of actually measured metabolic phenotype, and when appropriate therapeutic drug monitoring, promises to reveal relationships that may not be detected by using genotype alone as the variable.

Objective: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome., Methods: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10)., Results: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46; p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52; p=0.01)., Conclusions: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment., (© The Author(s) 2015.)

Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.

The cycling properties of mammary stem and progenitor cells is not well understood. To determine the division properties of these cells, we administered synthetic nucleosides for varying periods of time to mice at different stages of postnatal development and monitored the rate of uptake of these nucleosides in the different mammary cell compartments. Here we show that most cell division in the adult virgin gland is restricted to the oestrogen receptor-expressing luminal cell lineage. Our data also demonstrate that the oestrogen receptor-expressing, milk and basal cell subpopulations have telomere lengths and cell division kinetics that are not compatible with these cells being hierarchically organized; instead, our data indicate that in the adult homeostatic gland, each cell type is largely maintained by its own restricted progenitors. We also observe that transplantable stem cells are largely quiescent during oestrus, but are cycling during dioestrus when progesterone levels are high.

Background: The innate immune receptor RIG-I detects viral RNA within the cytosol of infected cells. Activation of RIG-I leads to the induction of antiviral cytokines, in particular type I interferon, the inhibition of a T(H)17 response as well as to the suppression of tumor growth. Therefore, RIG-I is a promising drug target for the treatment of cancer as well as multiple sclerosis. A specific ligand for RIG-I is currently in preclinical testing. The first-in-human trial will need to be carefully designed to avoid an overshooting cytokine response. Therefore, the ResI study was set up to analyze the human immune response to standard treatment with recombinant interferon-beta to establish biomarkers for safety and efficacy of the upcoming first-in-human trial investigating the RIG-I ligand., Methods/design: ResI is a single center, prospective, open label, non-randomized phase I clinical trial. Three different cohorts (20 healthy volunteers, 20 patients with RRMS and ongoing interferon-beta treatment and 10 patients starting on interferon-beta) will receive standard interferon-beta-1a therapy for nine days. The study will be conducted according to the principles of the german medicinal products act, ICH-GCP, and the Declaration of Helsinki on the phase I unit of the Institute of Clinical Chemistry and Clinical Pharmacology and in the Department of Neurology, both University Hospital Bonn. Interferon-beta-induced cytokine levels, surface marker on immune cells, mRNA- and miRNA-expression as well as psychometric response will be investigated as target variables., Discussion: The ResI study will assess biomarkers in response to interferon-β treatment to guide the dose steps within the first-in-human trial with a newly developed RIG-I ligand. Thus, ResI is a biomarker study to enhance the safety of the clinical development of a first-in-class compound. The data can additionally be used for the development of other therapies based on type I interferon induction such as TLR ligands. Moreover, it will help to understand the interferon-beta induced immune response in a controlled in vivo setting in the human system., Trial Registration: clinicaltrials.gov ID NCT02364986.

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org)., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)

Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

Heterogeneity within the self-renewal durability of adult hematopoietic stem cells (HSCs) challenges our understanding of the molecular framework underlying HSC function. Gene expression studies have been hampered by the presence of multiple HSC subtypes and contaminating non-HSCs in bulk HSC populations. To gain deeper insight into the gene expression program of murine HSCs, we combined single-cell functional assays with flow cytometric index sorting and single-cell gene expression assays. Through bioinformatic integration of these datasets, we designed an unbiased sorting strategy that separates non-HSCs away from HSCs, and single-cell transplantation experiments using the enriched population were combined with RNA-seq data to identify key molecules that associate with long-term durable self-renewal, producing a single-cell molecular dataset that is linked to functional stem cell activity. Finally, we demonstrated the broader applicability of this approach for linking key molecules with defined cellular functions in another stem cell system., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. The top association result in the meta-analysis of response represents SNPs 5′ upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

Numerous studies in the field of psychopharmacological treatment have investigated the possible contribution of genetic variability between individuals to differences in drug efficacy and safety, motivated by the wide individual variation in treatment response. Genomewide analyses have been conducted in several large-scale studies on antidepressant drug response. However, no consistent findings have emerged from these studies. In a recent meta-analysis of genomewide data from the three studies capturing common variation for association with symptomatic improvement and remission revealed the absence of any strong genetic association and failed to replicate results of individual studies in the pooled data. However, there are good reasons to consider the possible importance of pharmacogenetic variants separately. These variants explain a large portion of the manifold variability in individual drug metabolism. More than 20 psychotropic drugs have now been relabelled by the FDA adding information on polymorphic drug metabolism and therapeutic recommendations. Furthermore, dose recommendations for polymorphisms in drug metabolizing enzymes, first and foremost CYP2D6 and CYP2C19, have been issued with the advice to reduce the dosage in poor metabolizers to 50% or less (in eight cases), or to choose an alternative treatment. Beside the well-described role in hepatic drug metabolism, these enzymes are also expressed in the brain and play a role in biotransformation of endogenous substrates. These polymorphisms may therefore modulate brain metabolism and affect the function of the neural substrates of cognition and emotion., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

Triple-negative breast cancer (TNBC) has poor prognostic outcome compared with other types of breast cancer. The molecular and cellular mechanisms underlying TNBC pathology are not fully understood. Here, we report that the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumours. Exogenous BCL11A overexpression promotes tumour formation, whereas its knockdown in TNBC cell lines suppresses their tumourigenic potential in xenograft models. In the DMBA-induced tumour model, Bcl11a deletion substantially decreases tumour formation, even in p53-null cells and inactivation of Bcl11a in established tumours causes their regression. At the cellular level, Bcl11a deletion causes a reduction in the number of mammary epithelial stem and progenitor cells. Thus, BCL11A has an important role in TNBC and normal mammary epithelial cells. This study highlights the importance of further investigation of BCL11A in TNBC-targeted therapies.

Purpose: The aim of this literary search was to chart the etymology of 32 selected human skeletal muscles, representative of all body regions., Methods: In researching this study, analysis of 15 influential Latin and German anatomical textbooks, dating from the sixteenth to the nineteenth century, was undertaken, as well as reference to four versions of the official Latin anatomical terminologies. Particular emphasis has been placed on the historical development of muscular nomenclature, and the subsequent division of these data into groups, defined by similarities in the evolution of their names into the modern form., Results: The first group represents examples of muscles whose names have not changed since their introduction by Vesalius (1543). The second group comprises muscles which earned their definitive names during the seventeenth and eighteenth century. The third group is defined by acceptance into common anatomical vernacular by the late nineteenth century, including those outlined in the first official Latin terminology (B.N.A.) of 1895. The final group is reserved for six extra-ocular muscles with a particularly poetic history, favoured and popularised by the anatomical giants of late Renaissance and 1,700 s., Conclusions: As this study will demonstrate, it is evident that up until introduction of the B.N.A. there was an extremely liberal approach to naming muscles, deserving great respect in the retrospective terminological studies if complete and relevant results are to be achieved. Without this knowledge of the vernacular of the ages past, modern researchers can find themselves 'reinventing the wheel' in looking for their answers.