Thyroid homeostasis in B6C3F1 mice upon sub-chronic exposure to trifluoroiodomethane (CFI).

Trifluoroiodomethane (CFI) is a fire suppressant gas with potential for use in low global-warming refrigerant blends. Data from studies in rats suggest that the most sensitive health effect of CFI is thyroid hormone perturbation, but the rat is a particularly sensitive species for disruption of thyroid homeostasis. Mice appear to be less sensitive than rats but still a conservative model with respect to humans.

Pulmonary hypertension in patients with interstitial pneumonia with autoimmune features.

Pulmonary hypertension in interstitial lung diseases is associated with increased mortality and hospitalizations and reduced exercise capacity. Interstitial pneumonia with autoimmune features (IPAF) is a recently described interstitial lung disease. The characteristics of pulmonary hypertension in IPAF patients are unknown.

Valve-in-valve transcatheter aortic valve replacement to treat multijet paravalvular regurgitation: A case series and review.

Treatment advances for severe symptomatic aortic stenosis including transcatheter and open surgical valve replacement have improved patient survival, length of stay, and speed to recovery. However, paravalvular regurgitation (PVR) is occasionally seen and when moderate or greater in severity is associated with an at least 2-fold increase in 1 year mortality. While several treatment approaches focused on single-jet PVR have been described in the literature, few reports describe multijet PVR.

Evaluating the Application of Decision Analysis Methods in Simulated Alternatives Assessment Case Studies: Potential Benefits and Challenges of Using MCDA.

We compare how several forms of multicriteria decision analysis (MCDA) can enhance the practice of alternatives assessment (AA). We report on a workshop in which 12 practitioners from US corporations, government agencies, NGOs, and consulting organizations applied different MCDA techniques to 3 AA case studies to understand how they improved the decision process. Participants were asked to select a preferred alternative in each case using a different decision analysis approach: their unaided decision-making method, individual or lightly facilitated group multiattribute value theory (MAVT), and more extensively facilitated group structured decision making (SDM).

Discovery of piperazic acid peptide deformylase inhibitors with in vivo activity for respiratory tract and skin infections.

The discovery of a novel series of peptide deformylase inhibitors incorporating a piperazic acid amino acid found in nature is described. These compounds demonstrated potent in vitro enzymatic potency and antimicrobial activity. Crystal structure analysis revealed the piperazic acid optimized a key contact with the PDF protein that accounted for the increased enzymatic potency of these compounds.

A Robust Pneumonia Model in Immunocompetent Rodents to Evaluate Antibacterial Efficacy against S. pneumoniae, H. influenzae, K. pneumoniae, P. aeruginosa or A. baumannii.

Efficacy of candidate antibacterial treatments must be demonstrated in animal models of infection as part of the discovery and development process, preferably in models which mimic the intended clinical indication. A method for inducing robust lung infections in immunocompetent rats and mice is described which allows for the assessment of treatments in a model of serious pneumonia caused by S. pneumoniae, H.

Derivation of the critical effect size/benchmark response for the dose-response analysis of the uptake of radioactive iodine in the human thyroid.

Potential adverse effects of chemical substances on thyroid function are usually examined by measuring serum levels of thyroid-related hormones. Instead, recent risk assessments for thyroid-active chemicals have focussed on iodine uptake inhibition, an upstream event that by itself is not necessarily adverse. Establishing the extent of uptake inhibition that can be considered de minimis, the chosen benchmark response (BMR), is therefore critical.

Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection.

GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitro activity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivo pharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniae and Haemophilus influenzae (mouse lung model) and with Staphylococcus aureus (rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses.

Iodine supplementation and drinking-water perchlorate mitigation.

Ensuring adequate iodine intake is important, particularly among women of reproductive age, because iodine is necessary for early life development. Biologically based dose-response modeling of the relationships among iodide status, perchlorate dose, and thyroid hormone production in pregnant women has indicated that iodide intake has a profound effect on the likelihood that exposure to goitrogens will produce hypothyroxinemia. We evaluated the possibility of increasing iodine intake to offset potential risks from perchlorate exposure.

Potent sub-MIC effect of GSK1322322 and other peptide deformylase inhibitors on in vitro growth of Staphylococcus aureus.

Peptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). GSK1322322 is a novel PDF inhibitor that is in phase II clinical development for the treatment of lower respiratory tract and skin infections.

Emissions and risks associated with oxyfuel combustion: state of the science and critical data gaps.

Unlabelled: Oxyfuel combustion is a promising technology that may greatly facilitate carbon capture and sequestration by increasing the relative CO2 content of the combustion emission stream. However, the potential effect of enhanced oxygen combustion conditions on emissions of criteria and hazardous air pollutants (e.g.

Staphylococcus aureus formyl-methionyl transferase mutants demonstrate reduced virulence factor production and pathogenicity.

Inhibitors of peptide deformylase (PDF) represent a new class of antibacterial agents with a novel mechanism of action. Mutations that inactivate formyl methionyl transferase (FMT), the enzyme that formylates initiator methionyl-tRNA, lead to an alternative initiation of protein synthesis that does not require deformylation and are the predominant cause of resistance to PDF inhibitors in Staphylococcus aureus. Here, we report that loss-of-function mutations in FMT impart pleiotropic effects that include a reduced growth rate, a nonhemolytic phenotype, and a drastic reduction in production of multiple extracellular proteins, including key virulence factors, such as α-hemolysin and Panton-Valentine leukocidin (PVL), that have been associated with S.

Acylprolinamides: a new class of peptide deformylase inhibitors with in vivo antibacterial activity.

A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.

Administrative censoring in ecological analyses of autism and a Bayesian solution.

Widely cited ecological analyses of autism have reported associations with mercury emissions, with precipitation, and race at the level of counties or school districts. However, state educational agencies often suppress any low numerical autism counts before releasing data--a phenomenon known as "administrative censoring." Previous analyses did not describe appropriate methods for censored data analysis; common substitution or exclusion methods are known to introduce bias and produce artificially narrow confidence intervals.

Questions regarding environmental mercury release, special education rates, and autism disorder: an ecological study of Texas by Palmer et al.

Palmer et al. present an analysis in which they look for an association between Toxic Release Inventory (TRI) reporting data for mercury and rates of autism and special education enrollment in Texas. In their analysis, the link between TRI release data and actual mercury exposure is not clear at all, and thus the conclusions drawn from the analysis are questionable.

Modeling developmental processes in animals: applications in neurodevelopmental toxicology.

Biologically based dose-response models can provide a framework for incorporating mechanistic information into our assessments of neurotoxicity considering both kinetic and dynamic processes. We have constructed models for normal midbrain and neocortex development and we have extended these models to evaluate the neurodevelopmental toxicity of ethanol and methyl mercury. Using such modeling approaches, we have been able to test hypothesized modes of action for these neurodevelopmental toxicants.

Changes in cell cycle parameters and cell number in the rat midbrain during organogenesis.

We employed 5-bromo-2'-deoxyuridine (BrdU) labeling to identify in vivo changes in the cell cycle patterns of the rat midbrain during the major period of midbrain organogenesis, gestational days (gd) 11 to 16. We also used quantitative stereology to determine changes in absolute cell numbers during these gestational time points. Between gd 12 and 16, the length of S-phase did not change significantly while the fraction of cycling cells decreased from 73 to 11%.

Investigations of methylmercury-induced alterations in neurogenesis.

Methylmercury (MeHg) has been an environmental concern to public health and regulatory agencies for over 50 years because of its toxicity to the human nervous system. Its association with nervous system toxicity in adults and infants near Minamata Bay, Japan, in the 1950s initiated environmental health research inquiries that continue to this day. Observations of greater neurotoxicity with gestational compared with adult exposure suggest a unique susceptibility of the developing nervous system to MeHg.