Study parameters influencing NOAEL and LOAEL in toxicity feeding studies for pesticides: exposure duration versus dose decrement, dose spacing, group size and chemical class

The effect of exposure duration on no observed adverse effect levels (NOAEL) and lowest observed adverse effect levels (LOAEL) in rodent pesticide feeding studies was evaluated. Ratios of NOAEL (and LOAEL), expressed as pesticide concentrations in feed, were calculated from subacute to subchronic, subchronic to chronic and subacute to chronic studies. There was no statistical significant effect of exposure duration on ratio distributions. Whereas geometric means of ratios were in a narrow range of 1.1–2.5, the geometric standard deviations and 95th percentiles increased with dose spacing of the involved studies. With the exception of carbamates, the chemical class of pesticides had no influence on the ratio distributions. However, the number of animals in the shorter-term study of ratio couples being ?1 was statistically significantly higher than in ratio couples being >1. Ratios ?1 may be partly explained by the dose decrement over time observed in feeding studies applying the test substances in constant concentrations. The dose decrement possibly converts initially toxic doses to less toxic doses beyond the subacute phase. Ratios >1 seem to be caused predominantly by differences in study design parameters. In dietary risk assessment, the acceptable daily intake (ADI) is compared to pesticide intake estimates based on mean food consumption (i.e. the so called theoretical maximum daily intake, TMDI) being orders of magnitude lower than actual food consumption on eating occasions for certain food commodities. As subacute, subchronic and chronic NOAEL (and LOAEL), expressed as pesticide concentration in feed did not differ statistically significantly, the TMDI as benchmark for the ADI may underestimate the significance of the toxicity of subacute exposure.     

Interdependence of measures in pavlovian conditioned freezing

Pavlovian conditioned freezing is an intensively utilized paradigm that has become a standard model of memory and cognition. Despite its widespread use, the interdependence among each measure commonly reported in fear conditioning studies has not been described. Using mice, we examine the relationship of each common freezing measure (Training Baseline, Post-Shock freezing, Contextual Fear, Tone Baseline, and Tone Fear), as well as baseline locomotor activity measures, to better understand the significance of each. Of particular interest, Post-Shock freezing appears to be a good measure of immediate contextual memory. In contrast, Tone Baseline freezing, as typically measured in a novel context, appears to be contaminated with multiple sources of fear. Finally, Contextual and Tone Fear show a weak interdependence.     

Increased short latency afferent inhibition after anodal transcranial direct current stimulation

Transcranial direct current stimulation (tDCS), a technique for central neuromodulation, has been recently proposed as possible treatment in several neurological and psychiatric diseases. Although shifts on focal brain excitability have been proposed to explain the clinical effects of tDCS, how tDCS-induced functional changes influence cortical interneurones is still largely unknown. The assessment of short latency afferent inhibition (SLAI) of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS), provides the opportunity to test non-invasively interneuronal cholinergic circuits in the human motor cortex. The aim of the present study was to assess whether anodal tDCS can modulate interneuronal circuits involved in SLAI. Resting motor threshold (RMT), amplitude of unconditioned MEPs and SLAI were assessed in the dominant hemisphere of 12 healthy subjects (aged 21-37) before and after anodal tDCS (primary motor cortex, 13min, 1mA). SLAI was assessed delivering electrical conditioning stimuli to the median nerve at the wrist prior to test TMS given at the interstimulus interval (ISI) of 2ms. Whereas RMT and the amplitude of unconditioned MEPs did not change after anodal tDCS, SLAI significantly increased. In conclusion, anodal tDCS-induced effects depend also on the modulation of cortical interneuronal circuits. The enhancement of cortical cholinergic activity assessed by SLAI could be an important mechanism explaining anodal tDCS action in several pathological conditions.     

Modulation of the risk of coronary sclerosis/myocardial infarction by the interaction between factor XIII subunit A Val34Leu polymorphism and fibrinogen concentration in the high risk Hungarian population

INTRODUCTION: The results on the association of factor XIII (FXIII) A subunit (FXIII-A) Val34Leu polymorphism with the risk of myocardial infarction (MI) are rather inconclusive. The original paper and confirmatory reports demonstrated a protective effect of the mutation, but results demonstrating the lack of protection have also been published. Gene-gene and gene-environmental interactions have been proposed to be responsible for the opposing results. As the rate of change in fibrin clot permeability with increasing fibrinogen concentrations decreased stepwise with increasing number of Leu34 alleles it was proposed that the protection by Val34Leu polymorphism become effective only at higher fibrinogen concentrations. However, this hypothesis has not been tested on patients with coronary artery disease. PATIENTS AND METHODS: 955 consecutive patients admitted for coronary angiography were categorized according to the presence or absence of significant coronary sclerosis (CS) and according to positive or negative history of MI. The frequency of FXIII-A Val34Leu polymorphism, and a number of risk factors, including fibrinogen were determined in the patients. FXIII-A Val34Leu polymorphism was also investigated in a population control group of 1146 subjects. RESULTS: The presence of FXIII-A Leu34 allele or homozygous Leu34 genotype did not change the risk of CS or MI in the general Hungarian population. However, when patients with fibrinogen level in the upper quartile were separately investigated, the Leu34 allele provided a statistically significant protection against MI. CONCLUSIONS: Fibrinogen concentration modulates the effect of Leu34 allele on the risk of MI; its protective effect emerges at increasing fibrinogen concentration.     

Aging defined by a chronologic-replicative protein network in Saccharomyces cerevisiae: An interactome analysis

Aging is a multifactorial condition that results in the loss of an organism's fitness over time. Different theories have been formulated to explain the mechanisms of aging, but a synthesis of these theories has not been possible until now. In addition, the increase in molecular data gathered by proteomics projects utilizing different organisms has permitted a better picture of proteins that function in aging. In this sense, the yeast Saccharomyces cerevisiae is a biological model for aging, and it shows two distinct aging states: a replicative state termed the replicative lifespan (RLS) and a quiescent state known as the chronological lifespan (CLS). Interestingly, both RLS and CLS appear to share common groups of proteins, but a combined model of both aging mechanisms has not been defined. Thus, by applying systems biology tools that allow mining of the yeast proteins associated with aging, it was possible to obtain an interactome network in which both RLS and CLS are represented. In addition, four subgraphs comprising ubiquitin-dependent proteasome/regulation of cell growth, nucleic acid metabolism, carbohydrate metabolism/RNA metabolism, and carbohydrate-organic acid-amino acid/DNA metabolism were found within the interactome, defining a new model of aging for yeast termed the chronologic-replicative protein network (CRPN).     

Oversulfated chondroitin sulfate interaction with heparin-binding proteins: New insights into adverse reactions from contaminated heparins

An oversulfated chondroitin sulfate (OSCS) was identified as a contaminant to pharmaceutical heparin and severe anaphylactoid reactions were ascribed to this contaminant. An examination of the biochemistry underlying both the anticoagulant activity and the toxic effects of oversulfated chondroitin sulfate was undertaken. This study demonstrates that the anticoagulant activity of this oversulfated chondroitin sulfate is primarily dependent on heparin cofactor II mediated inhibition of thrombin. Heparin and oversulfated chondroitin sulfate binding to coagulation, kinin-kallikrein and complement proteins were studied by surface plasmon resonance. While oversulfated chondroitin sulfate binds tightly to antithrombin III, unlike heparin, OSCS does not induce antithrombin III to undergo the conformational change required for its inactivation of thrombin and factor Xa. In contrast to heparin, oversulfated chondroitin sulfate tightly binds factor XIIa suggesting a biochemical mechanism for the factor XIIa-based enhancement of vasoactive bradykinin production.