Biological variability hampers the use of skeletal staining methods in zebrafish embryo developmental toxicity assays.

Zebrafish embryo assays are used by pharmaceutical and chemical companies as new approach methodologies (NAMs) in developmental toxicity screening. Despite an overall high concordance of zebrafish embryo assays with in vivo mammalian studies, false negative and false positive results have been reported. False negative results in risk assessment models are of particular concern for human safety, as developmental anomalies may be missed.

Modeling Ovo-vegetarian, Lacto-vegetarian, Pescatarian, and Vegan USDA Food Patterns and Assessing Nutrient Adequacy for Lactation among Adult Females.

Background: Among its recommended dietary patterns for Americans, including lactating mothers, the 2020 Dietary Guidelines for Americans (DGA) includes a Healthy Vegetarian Dietary Pattern (HVDP). However, the DGA does not provide guidance for adapting the HVDP for vegetarians who avoid dairy (ovo-vegetarian) or eggs (lacto-vegetarian), eat fish (pescatarians), or avoid all animal foods (vegan).

Objective: To determine whether models of the HVDP for different vegetarian diets could provide sufficient nutrition during lactation, a life stage with unique nutrient needs.

Advancing the use of new approach methodologies for assessing teratogenicity: Building a tiered approach.

Many New Approach Methodologies (NAMs) have been developed for the safety assessment of new ingredients. Research into reproductive toxicity and teratogenicity is a particularly high priority, especially given their mechanistic complexity. Forty-six non-teratogenic and 39 teratogenic chemicals were screened for teratogenic potential using the in silico DART model from the OECD QSAR Toolbox; the devTox quickPredict™ (devTox assay) test and the Zebrafish Embryotoxicity Test (ZET).

Evaluation of Clinical Trials in Onco-haematology: A New Method Based on Risk Analysis and Multidisciplinarity.

Background: European member states are increasingly vying with one another to recruit patients for clinical trials (CTs). The French national agency for medicines (ANSM) now receives an ever-growing number of CTs, extending response times. The aim of the new methodology presented herein is to reduce assessment times below the national mandatory timeframe of 60 days and to improve patient safety.

From the Cover: MechanisticInsights in Cytotoxic and Cholestatic Potential of the Endothelial Receptor Antagonists Using HepaRG Cells.

Several endothelin receptor antagonists (ERAs) have been developed for the treatment of pulmonary arterial hypertension (PAH). Some of them have been related to clinical cases of hepatocellular injury (sitaxentan [SIT]) and/or cholestasis (bosentan [BOS]). We aimed to determine if ambrisentan (AMB) and macitentan (MAC), in addition to BOS and SIT, could potentially cause liver damage in man by use of human HepaRG cells.

Early Alterations of Bile Canaliculi Dynamics and the Rho Kinase/Myosin Light Chain Kinase Pathway Are Characteristics of Drug-Induced Intrahepatic Cholestasis.

Intrahepatic cholestasis represents 20%-40% of drug-induced injuries from which a large proportion remains unpredictable. We aimed to investigate mechanisms underlying drug-induced cholestasis and improve its early detection using human HepaRG cells and a set of 12 cholestatic drugs and six noncholestatic drugs. In this study, we analyzed bile canaliculi dynamics, Rho kinase (ROCK)/myosin light chain kinase (MLCK) pathway implication, efflux inhibition of taurocholate [a predominant bile salt export pump (BSEP) substrate], and expression of the major canalicular and basolateral bile acid transporters.

Differential sensitivity of metabolically competent and non-competent HepaRG cells to apoptosis induced by diclofenac combined or not with TNF-α.

The role of reactive metabolites and inflammatory stress has been largely evoked in idiosyncratic hepatotoxicity of diclofenac (DCF); however mechanisms remain poorly understood. We aimed to evaluate the influence of liver cell phenotype on the hepatotoxicity of DCF combined or not with TNF-α using differentiated and undifferentiated HepaRG cells, and for comparison, HepG2 cells. Our results demonstrate that after a 24h-treatment metabolizing HepaRG cells were less sensitive to DCF than their undifferentiated non-metabolizing counterparts as shown by lower oxidative and endoplasmic reticulum stress responses and lower activation of caspase 9.

Rho-kinase/myosin light chain kinase pathway plays a key role in the impairment of bile canaliculi dynamics induced by cholestatic drugs.

Intrahepatic cholestasis represents a frequent manifestation of drug-induced liver injury; however, the mechanisms underlying such injuries are poorly understood. In this study of human HepaRG and primary hepatocytes, we found that bile canaliculi (BC) underwent spontaneous contractions, which are essential for bile acid (BA) efflux and require alternations in myosin light chain (MLC2) phosphorylation/dephosphorylation. Short exposure to 6 cholestatic compounds revealed that BC constriction and dilation were associated with disruptions in the ROCK/MLCK/myosin pathway.

Bacillus and other spore-forming genera: variations in responses and mechanisms for survival.

The ubiquity of Bacilli endospores in soils facilitates their easy transfer routes to other environments, including cleanrooms and low-biomass sites required by many industries such as food production and processing. A bacterial endospore is a metabolically dormant form of life that is much more resistant to heat, desiccation, lack of nutrients, exposure to UV and gamma radiation, organic chemicals, and oxidizing agents than is a vegetative cell. For example, the heat tolerance of endospores depends on multiple factors such as sporulation temperature, core dehydration, and the presence of minerals and small, acid-soluble proteins (SASPs) in the core.

Protection of Bacillus pumilus spores by catalases.

Bacillus pumilus SAFR-032, isolated at spacecraft assembly facilities of the National Aeronautics and Space Administration Jet Propulsion Laboratory, is difficult to kill by the sterilization method of choice, which uses liquid or vapor hydrogen peroxide. We identified two manganese catalases, YjqC and BPUM_1305, in spore protein extracts of several B. pumilus strains by using PAGE and mass spectrometric analyses.

Assessing public attitudes on the retention and use of residual newborn screening blood samples: a focus group study.

This paper discusses attitudes and opinions of a diverse group of participants toward the retention and use of residual newborn blood samples for research. Data were drawn from focus groups based in six states in the USA, and results provide support for the retention and use of residual newborn blood samples for research when parental permission is asked beforehand. However, there were a number of concerns that also warrant attention for the development of policy and maintaining trust with the public, such as timing of permission, use of samples already stored, level of personal control of sample use and education.

Public attitudes regarding the use of residual newborn screening specimens for research.

Background And Objectives: Many state newborn screening (NBS) programs retain residual NBS bloodspots after the completion of screening. Potential uses for residual specimens include laboratory quality assurance, biomedical research, and, rarely, forensic applications. Our objective was to evaluate public opinion about the policies and practices relevant to the retention and use of residual bloodspots for biomedical research.

Concerns of newborn blood screening advisory committee members regarding storage and use of residual newborn screening blood spots.

Objectives: We assessed attitudes and opinions of members of newborn blood screening (NBS) advisory committees regarding the storage and secondary research use of residual specimens from NBS.

Methods: We conducted focus groups in 2008 and 2009 with NBS advisory committees (4 focus groups; n = 39 participants) in the Mountain States region (i.e.

Autosomal dominant erythromelalgia.

We present a kindred of 29 persons affected with erythromelalgia (erythermalgia) in 5 generations. This paper updates the family reported by Burbank et al. [1966].

Biomagnetometers for unshielded and well shielded environments.

The paper describes magnetometers for operation in well shielded and unshielded environments. For unshielded environments, the noise cancellation is accomplished by spatial filtering using higher-order gradiometers which are formed in software. The theory of the software formation of high-order gradiometers has been successfully tested experimentally to the second-order gradient level, using a seven-channel prototype system.

The use of a squid third order spatial gradiometer to measure magnetic fields of the brain.

It appears to be clear from the results that the third order gradiometer is able to detect small biomagnetic signals from the brain which are related to evoked potentials and spontaneous electrical activity. The instrument operates reasonably well within a noisy environment, however further development is necessary to balance the first gradient. We intend to pursue this direction with software systems.

Internal mammary artery-to-pulmonary artery fistulas. Case report and review of the literature.

A case of internal mammary artery-to-pulmonary artery fistula is presented, and all previously reported cases are reviewed. This represents a rare cause of a continuous precordial murmur that may be confused clinically with a patent ductus arteriosus. Patients are usually asymptomatic, and routine diagnostic tests may be of little help in establishing a diagnosis.