Thalidomide-induced Teratogenesis : History and Mechanisms

Peer reviewedPublisher PD

Population Pharmacokinetics of Telapristone (CDB-4124) and its Active Monodemethylated Metabolite CDB-4453, with a Mixture Model for Total Clearance

Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h−1. Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmetest) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5

Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing

The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown. Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127+ ILCs across four human tissues. Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs, and signatures of tissue-residency, activation and modified metabolism in colon and lung ILCs. Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident na\uefve ILCs to a spectrum of mature ILC subsets. In the lung we identified both CRTH2+ and CRTH2− ILC2 with lung-specific signatures, which could be recapitulated by alarmin-exposure of circulating ILC2. Finally, we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells, revealing a subset of potentially immature ILCs with TCR-δ rearrangement. Our study provides a useful resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease

Health status in the ambulance services: a systematic review

BACKGROUND: Researchers have become increasingly aware that ambulance personnel may be at risk of developing work-related health problems. This article systematically explores the literature on health problems and work-related and individual health predictors in the ambulance services. METHODS: We identified the relevant empirical literature by searching several electronic databases including Medline, EMBASE, PsychINFO, CINAHL, and ISI Web of Science. Other relevant sources were identified through reference lists and other relevant studies known by the research group. RESULTS: Forty-nine studies are included in this review. Our analysis shows that ambulance workers have a higher standardized mortality rate, higher level of fatal accidents, higher level of accident injuries and a higher standardized early retirement on medical grounds than the general working population and workers in other health occupations. Ambulance workers also seem to have more musculoskeletal problems than the general population. These conclusions are preliminary at present because each is based on a single study. More studies have addressed mental health problems. The prevalence of post-traumatic stress symptom caseness was > 20% in five of seven studies, and similarly high prevalence rates were reported for anxiety and general psychopathology in four of five studies. However, it is unclear whether ambulance personnel suffer from more mental health problems than the general working population. CONCLUSION: Several indicators suggest that workers in the ambulance services experience more health problems than the general working population and workers in other health occupations. Several methodological challenges, such as small sample sizes, non-representative samples, and lack of comparisons with normative data limit the interpretation of many studies. More coordinated research and replication are needed to compare data across studies. We discuss some strategies for future research

The role of population PK-PD modelling in paediatric clinical research

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child

Diagnostic properties of metabolic perturbations in rheumatoid arthritis

Introduction: The aim of this study was to assess the feasibility of diagnosing early rheumatoid arthritis (RA) by measuring selected metabolic biomarkers. Methods: We compared the metabolic profile of patients with RA with that of healthy controls and patients with psoriatic arthritis (PsoA). The metabolites were measured using two different chromatography-mass spectrometry platforms, thereby giving a broad overview of serum metabolites. The metabolic profiles of patient and control groups were compared using multivariate statistical analysis. The findings were validated in a follow-up study of RA patients and healthy volunteers. Results: RA patients were diagnosed with a sensitivity of 93% and a specificity of 70% in a validation study using detection of 52 metabolites. Patients with RA or PsoA could be distinguished with a sensitivity of 90% and a specificity of 94%. Glyceric acid, D-ribofuranose and hypoxanthine were increased in RA patients, whereas histidine, threonic acid, methionine, cholesterol, asparagine and threonine were all decreased compared with healthy controls. Conclusions: Metabolite profiling (metabolomics) is a potentially useful technique for diagnosing RA. The predictive value was without regard to the presence of antibodies against cyclic citrullinated peptides

Intraspecific Diversity Regulates Fungal Productivity and Respiration

Individuals and not just species are key components of biodiversity, yet the relationship between intraspecific diversity and ecosystem functioning in microbial systems remains largely untested. This limits our ability to understand and predict the effects of altered genetic diversity in regulating key ecosystem processes and functions. Here, we use a model fungal system to test the hypothesis that intraspecific genotypic richness of Paxillus obscurosporus stimulates biomass and CO2 efflux, but that this is dependent on nitrogen supply. Using controlled experimental microcosms, we show that populations containing several genotypes (maximum 8) of the fungus had greater productivity and produced significantly more CO2 than those with fewer genotypes. Moreover, intraspecific diversity had a much stronger effect than a four-fold manipulation of the carbon:nitrogen ratio of the growth medium. The effects of intraspecific diversity were underpinned by strong roles of individuals, but overall intraspecific diversity increased the propensity of populations to over-yield, indicating that both complementarity and selection effects can operate within species. Our data demonstrate the importance of intraspecific diversity over a range of nitrogen concentrations, and the need to consider fine scale phylogenetic information of microbial communities in understanding their contribution to ecosystem processes