An Extensive New Literature Concerning Low-Dose Effects of Bisphenol A Shows the Need for a New Risk Assessment

Bisphenol A (BPA) is the monomer used to manufacture polycarbonate plastic, the resin lining of cans, and other products, with global capacity in excess of 6.4 billion lb/year. Because the ester bonds in these BPA-based polymers are subject to hydrolysis, leaching of BPA has led to widespread human exposure. A recent report prepared by the Harvard Center for Risk Analysis and funded by the American Plastics Council concluded that evidence for low-dose effects of BPA is weak on the basis of a review of only 19 studies; the report was issued after a delay of 2.5 years. A current comprehensive review of the literature reveals that the opposite is true. As of December 2004, there were 115 published in vivo studies concerning low-dose effects of BPA, and 94 of these report significant effects. In 31 publications with vertebrate and invertebrate animals, significant effects occurred below the predicted “safe� or reference dose of 50 μg/kg/day BPA. An estrogenic mode of action of BPA is confirmed by in vitro experiments, which describe disruption of cell function at 10– 12 M or 0.23 ppt. Nonetheless, chemical manufacturers continue to discount these published findings because no industry-funded studies have reported significant effects of low doses of BPA, although > 90% of government-funded studies have reported significant effects. Some industry-funded studies have ignored the results of positive controls, and many studies reporting no significant effects used a strain of rat that is inappropriate for the study of estrogenic responses. We propose that a new risk assessment for BPA is needed based on a) the extensive new literature reporting adverse effects in animals at doses below the current reference dose; b) the high rate of leaching of BPA from food and beverage containers, leading to widespread human exposure; c) reports that the median BPA level in human blood and tissues, including in human fetal blood, is higher than the level that causes adverse effects in mice; and d) recent epidemiologic evidence that BPA is related to disease in women. Originally published Environmental Health Perspectives, Vol. 113, No. 8, Aug 200

A Pre-Birth Guide to Personhood: How Genetic, Epigenetic and Developmental Milieu Factors Influence Pre-Fertilization, Embryonic, Fetal and Neonatal Attributes of Future Individual Humans

Discrete events and processes influence development of individual future humans. While we do not wish to redefine personhood, we relate a newly discovered epigenetic event to sources of individuality of future humans. Genetic and epigenetic events and developmental milieu processes diversify developmental trajectories of future individual humans prior to societal entry via parturition. First, fertilization and epigenetic resetting of each individual’s organismic clock to time zero (t=0) at day 15 of embryogenesis, are two discrete discreet biological events that impact a future individual human’s attributes. Second, those two discrete discreet biological events are immersed in the continuous developmental process spanning pre-fertilization and gestation, further driving individualization of diverse attributes of each future human before the discrete blatant biological event of parturition (birth) and societal entry. Exposures of the gravida to multiple diverse exogenous exposures means that morphogenesis and physiogenesis of every embryo/fetus has individualized attributes for its future human lifespan

Translational toxicology: a developmental focus for integrated research strategies

Background Given that toxicology studies the potential adverse effects of environmental exposures on various forms of life and that clinical toxicology typically focuses on human health effects, what can and should the relatively new term of translational toxicology be taken to mean? Discussion Our assertion is that the core concept of translational toxicology must incorporate existing principles of toxicology and epidemiology, but be driven by the aim of developing safe and effective interventions beyond simple reduction or avoidance of exposure to prevent, mitigate or reverse adverse human health effects of exposures. The field of toxicology has now reached a point where advances in multiple areas of biomedical research and information technologies empower us to make fundamental transitions in directly impacting human health. Translational toxicology must encompass four action elements as follows: 1) Assessing human exposures in critical windows across the lifespan 2) Defining modes of action and relevance of data from animal models 3) Use of mathematical models to develop plausible predictions as the basis for 4) Protective and restorative human health interventions. The discussion focuses on the critical window of in-utero development. Summary Exposure assessment, basic toxicology and development of certain categories of mathematical models are not new areas of research; however overtly integrating these in order to conceive, assess and validate effective interventions to mitigate or reverse adverse effects of environmental exposures is our novel opportunity. This is what we should do in translational toxicology so that we have a portfolio of interventional options to improve human health that include both minimizing exposures and specific preventative/restorative/mitigative therapeutics

Pre-birth acquisition of personhood: Incremental accrual of attributes as the framework for individualization by serial and concurrently acting developmental factors

Discrete events and processes influence development of individual humans. Attribution of personhood to any individual human being cannot be disconnected from the underlying biological events and processes of early human development. Nonetheless, the philosophical, sociological and legal components that are integral to the meaning of the term as commonly used cannot be deduced from biology alone. The challenge for biomedical scientists to inform discussion in this arena then rests on profiling the key biological events and processes that must be assessed when considering how one might objectively reason about the task of superimposing the concept of personhood onto the developing biological entity of a potential human being. Endogenous genetic and epigenetic events and exogenous developmental milieu processes diversify developmental trajectories of potential individual humans prior to livebirth. First, fertilization and epigenetic resetting of each individual's organismic clock to time zero (t = 0) at the gastrulation/primitive streak stage (day 15 of embryogenesis), are two discrete unseen biological events that impact a potential individual human's attributes. Second, those two discrete unseen biological events are immersed in the continuous developmental process spanning pre-fertilization and gestation, further driving individualization of diverse attributes of each future human before the third discrete and blatant biological event of parturition and livebirth. Exposures of the gravida to multiple diverse exogenous exposures means that morphogenesis and physiogenesis of every embryo/fetus has individualized attributes for its future human lifespan. Our proposed framework based on the biological discrete events and processes spanning pre-fertilization and prenatal development, implies that personhood should be incrementally attributed, and societal protections should be graduated and applied progressively across the pre-birth timespan

A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease.

BackgroundLate-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA.ResultsReveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (-0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks.ConclusionsAdditional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease.Trial registrationISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011

Bacterial Contamination of Unused, Disposable Non-sterile Gloves on a Hospital Orthopaedic Ward

BackgroundNon-sterile disposable gloves are used on large hospital wards, however their potential role as a vehicle for pathogen transmission has not been explored in this setting. AimsThis study investigates glove use on a hospital orthopaedic ward to examine whether pathogen contamination occurs prior to contact with patients.Method  Glove samples were aseptically removed from boxes on a hospital orthopaedic ward on opening and days 3, 6 and 9 thereafter. Following elution of bacteria and viable counts, glove isolates were identified by standard techniques and 16s rDNA sequencing. Methicillin resistance of staphylococci was determined by disc diffusion,Epsilon tests and PCR. Gloves were inoculated to determine two isolate survival rates.ResultsTotal bacterial counts ranged from 0 to 9.6 x 103 cfu/glove. Environmental bacteria, particularly Bacillus species, were present on 31/38 (81.6%) of samples. Half (19/38) the samples were contaminated with skin commensals; coagulase negative staphylococci were predominant. Enterococcus faecalis, Klebsiella pneumoniae, Pseudomonas sp. or methicillin susceptible Staphylococcus aureus were recovered from 5/38 (13.2%) of samples. Significantly more skin commensals and pathogens were recovered from samples from days 3, 6, 9 than box-opening samples. Staphylococcus epidermidis and Klebsiella pneumoniae inoculated onto gloves remained viable for several days but counts decreased. ConclusionHealth-care workers introduced skin commensals and pathogenic bacteria into glove boxes indicating that unused, non-sterile gloves are potential pathogen transmission vehicles in hospitals. Findings highlight adherence to hand-washing guidelines, common glove retrieval practice, and glove-box design as targets for decreasing bacteria transmission via gloves on hospital wards

Comparative secretome analyses of two Trichoderma reesei RUT-C30 and CL847 hypersecretory strains

ABSTRACT: BACKGROUND: Due to its capacity to produce large amounts of cellulases, Trichoderma reesei is increasingly been researched in various fields of white biotechnology, especially in biofuel production from lignocellulosic biomass. The commercial enzyme mixtures produced at industrial scales are not well characterized, and their proteinaceous components are poorly identified and quantified. The development of proteomic methods has made it possible to comprehensively overview the enzymes involved in lignocellulosic biomass degradation which are secreted under various environmental conditions. RESULTS: The protein composition of the secretome produced by industrial T. reesei (strain CL847) grown on a medium promoting the production of both cellulases and hemicellulases was explored using two-dimensional electrophoresis and MALDI-TOF or LC-MS/MS protein identification. A total of 22 protein species were identified. As expected, most of them are potentially involved in biomass degradation. The 2D map obtained was then used to compare the secretomes produced by CL847 and another efficient cellulolytic T. reesei strain, Rut-C30, the reference cellulase-overproducing strain using lactose as carbon source and inducer of cellulases. CONCLUSION: This study provides the most complete mapping of the proteins secreted by T. reesei to date. We report on the first use of proteomics to compare secretome composition between two cellulase-overproducing strains Rut-C30 and CL847 grown under similar conditions. Comparison of protein patterns in both strains highlighted many unexpected differences between cellulase cocktails. The results demonstrate that 2D electrophoresis is a promising tool for studying cellulase production profiles, whether for industrial characterization of an entire secretome or for a more fundamental study on cellulase expression at genome-wide scale