Gene-environment interactions between adult lead exposure and Apolipoprotein E4 on adult hippocampal neurogenesis and cognitive behavior in mice

Thesis (Ph.D.)--University of Washington, 2016-06

The independent effects of attention and lead stimulus properties on the acoustic blink reflex

The effects of attention to a lead stimulus and of its sensory properties on modulation of the acoustic blink reflex were investigated. Participants performed a reaction time task cued by an acoustic or a visual lead stimulus. In Experiment 1, half the participants were presented with sustained lead stimuli. For the remainder, the lead stimulus was discrete and consisted of two brief presentations that marked the onset and offset of a stimulus-free interval. In Experiment 2, sustained lead stimuli were presented at a low or high intensity. The attentional demands of the task enhanced blink latency and magnitude modulation during acoustic and visual lead stimuli, with blink modulation being largest at a late point during the lead stimulus. Independent of the attentional effects, blink latency and magnitude modulation were larger during sustained than during discrete acoustic lead stimuli, whereas there was no difference for visual lead stimuli. Increases in the intensity of the lead stimulus enhanced blink modulation regardless of lead stimulus modality. Attention to a lead stimulus and the properties of the lead stimulus appear to have independent effects on blink reflex modulation.

Attentional blink modulation during sustained and after discrete lead stimuli presented in three sensory modalities

Previous studies found larger attentional modulation of acoustic blinks during task-relevant than during task-irrelevant acoustic or visual, but not tactile, lead stimuli. Moreover, blink modulation was larger overall during acoustic lead stimuli. The present experiment investigated whether these results reflect modality specificity of attentional blink modulation or effects of continuous stimulation. Participants performed a discrimination and counting task with acoustic, visual, or tactile lead stimuli. Stimuli were presented Sustained or consisted of two short discrete stimuli. The sustained condition replicated previous results. In the discrete condition, blinks were larger during task-relevant than during task-irrelevant stimuli in all groups regardless of lead stimulus modality. Thus, previous results that seemed consistent with modality-specific accounts of attentional blink modulation reflect effects of continuous stimulus input.

Serious lead poisoning in childhood: Still a problem after a century

Objective: To describe a series of patients with clinically significant lead poisoning. Methodology: A case series of nine patients with lead poisoning who required inpatient management, identified through a Clinical Toxicology Service. Results: Nine children presented with clinically significant lead poisoning. The median serum lead was 2.5 mumol/L (range 1.38-4.83). Eight of the children were exposed to lead-based paint, with seven due to dust from sanded lead paint during house renovations. Serial blood determinations suggested re-exposure in four of the patients, and in one of these patients the re-exposure was from a different source of lead. Eight of the patients required chelation therapy. Conclusions: Serious lead poisoning continues to occur and there appears to be complacency regarding the hazard posed by lead paint in old houses.

Psychometric properties of the drinking expectancy questionnaire: A review of the factor structure and a proposed new scoring method

Objective: Expectancies about the outcomes of alcohol consumption are widely accepted as important determinants of drinking. This construct is increasingly recognized as a significant element of psychological interventions for alcohol-related problems. Much effort has been invested in producing reliable and valid instruments to measure this construct for research and clinical purposes, but very few have had their factor structure subjected to adequate validation. Among them, the Drinking Expectancies Questionnaire (DEQ) was developed to address some theoretical and design issues with earlier expectancy scales. Exploratory factor analyses, in addition to validity and reliability analyses, were performed when the original questionnaire was developed. The object of this study was to undertake a confirmatory analysis of the factor structure of the DEQ. Method: Confirmatory factor analysis through LISREL 8 was performed using a randomly split sample of 679 drinkers. Results: Results suggested that a new 5-factor model, which differs slightly from the original 6-factor version, was a more robust measure of expectancies. A new method of scoring the DEQ consistent with this factor structure is presented. Conclusions: The present study shows more robust psychometric properties of the DEQ using the new factor structure.

Capturing expert knowledge for threatened species assessments: a case study using NatureServe conservation status ranks

Assessments for assigning the conservation status of threatened species that are based purely on subjective judgements become problematic because assessments can be influenced by hidden assumptions, personal biases and perceptions of risks, making the assessment process difficult to repeat. This can result in inconsistent assessments and misclassifications, which can lead to a lack of confidence in species assessments. It is almost impossible to Understand an expert's logic or visualise the underlying reasoning behind the many hidden assumptions used throughout the assessment process. In this paper, we formalise the decision making process of experts, by capturing their logical ordering of information, their assumptions and reasoning, and transferring them into a set of decisions rules. We illustrate this through the process used to evaluate the conservation status of species under the NatureServe system (Master, 1991). NatureServe status assessments have been used for over two decades to set conservation priorities for threatened species throughout North America. We develop a conditional point-scoring method, to reflect the current subjective process. In two test comparisons, 77% of species' assessments using the explicit NatureServe method matched the qualitative assessments done subjectively by NatureServe staff. Of those that differed, no rank varied by more than one rank level under the two methods. In general, the explicit NatureServe method tended to be more precautionary than the subjective assessments. The rank differences that emerged from the comparisons may be due, at least in part, to the flexibility of the qualitative system, which allows different factors to be weighted on a species-by-species basis according to expert judgement. The method outlined in this study is the first documented attempt to explicitly define a transparent process for weighting and combining factors under the NatureServe system. The process of eliciting expert knowledge identifies how information is combined and highlights any inconsistent logic that may not be obvious in Subjective decisions. The method provides a repeatable, transparent, and explicit benchmark for feedback, further development, and improvement. (C) 2004 Elsevier SAS. All rights reserved.

Effects of cigarette smoking and exposure to cadmium and lead on phenotypic variability of hepatic CYP2A6 and renal function biomarkers in men

Effects of cigarette smoking and exposure to dietary cadmium (Cd) and lead (Pb) on urinary biomarkers of renal function and phenotypic variability of cytochrome P450 2A6 (CYP2A6) were investigated in a group of 96 healthy Thai men with mean age of 36.7 year (19-57 years). In non-smokers, Cd burden increased with age (r = 0.47, P < 0.001). In current smokers, Cd burden increased with both age (r = 0.45, P = 0.01) and number of cigarettes smoked per day (r = 0.32, P = 0.05). Cd-linked renal tubular dysfunction was seen in both smokers and non-smokers, but Pb-linked glomerular dysfunction was seen in smokers only, possibly due to more recent exposure to high levels of Cd and Pb, as reflected by 30-50% higher serum Cd and Pb levels in smokers than non-smokers (P < 0.05). Exposure to dietary Cd and Pb appeared to be associated with mild tubular dysfunction whereas dietary exposure plus cigarette smoking was associated with tubular plus glomerular dysfunction. Hepatic CYP2A6 activity in non-smokers showed a positive association with Cd burden (adjusted P = 0.38, P = 0.006), but it showed an inverse correlation with Pb (adjusted beta = -0.29, P = 0.003), suggesting opposing effects of Cd and Pb on hepatic CYP2A6 phenotype. In contrast, CYP2A6 activity in current smokers did not correlate with Cd or Pb, but it showed a positive correlation with serum ferritin levels (r = 0.45, P = 0.01). These finding suggest that Pb concentrations in the liver probably were too low to inhibit hepatic synthesis of heme and CYP2A6 and that the concurrent induction of hepatic CYP2A6 and ferritin was probably due to cigarette smoke constituents other than the Cd and Pb. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Evidence for Concurrent Effects of Exposure to Environmental Cadmium and Lead on Hepatic CYP2A6 Phenotype and Renal Function Biomarkers in Non Smokers

We examined the interrelationships between phenotype of hepatic cytochrome P450 2A6 (CYP2A6), nephropathy, and exposure to cadmium and lead in a group of 118 healthy Thai men and women who had never smoked. Their urinary Cd excretion ranged from 0.05 to 2.36 mug/g creatinine, whereas their urinary Pb excretion ranged from 0.1 to 12 mug/g creatinine. Average age and Cd burden of women and men did not differ. Women, however, on average showed a 46% higher urinary Pb excretion (p < 0.001) and lower zinc status, suggested by lower average serum Zn and urinary Zn excretion compared with those in men. Cd-linked nephropathy was detected in both men and women. However, Pb-linked nephropathy was seen only in women, possibly because of higher Pb burden coupled with lower protective factors, notably of Zn (P < 0.001), in women compared with men. In men, Pb burden showed a negative association with CYP2A6 activity (adjusted beta = -0.29, p = 0.003), whereas Cd burden showed a positive association with CYP2A6 activity (adjusted beta = 0.38, p = 0.001), suggesting opposing effects of Cd and Pb on hepatic CYP2A6 phenotype. The weaker correlation between Cd burden CYP2A6 activity in women despite similarity in Cd burden between men and women is consistent with opposing effects of Pb and Cd on hepatic CYP2A6 phenotypic expression. A positive correlation between Cd-linked nephropathy (urinary N-acetyl-beta-D-glucosaminidase excretion) and CYP2A6 activity in men (r = 0.39, p = 0.002) and women (r = 0.37, p = 0.001) suggests that Cd induction of hepatic CYP2A6 expression and Cd-linked nephropathy occurred simultaneously.

Wurst: a protein threading server with a structural scoring function, sequence profiles and optimized substitution matrices

Wurst is a protein threading program with an emphasis on high quality sequence to structure alignments (http://www.zbh.uni-hamburg.de/wurst). Submitted sequences are aligned to each of about 3000 templates with a conventional dynamic programming algorithm, but using a score function with sophisticated structure and sequence terms. The structure terms are a log-odds probability of sequence to structure fragment compatibility, obtained from a Bayesian classification procedure. A simplex optimization was used to optimize the sequence-based terms for the goal of alignment and model quality and to balance the sequence and structural contributions against each other. Both sequence and structural terms operate with sequence profiles.

The effects of lead stimulus and reflex stimulus modality on modulation of the blink reflex at very short, short, and long lead intervals

The blink reflex is modulated if a weak lead stimulus precedes the blink-eliciting stimulus. In two experiments, we examined the effects of the sensory modality of the lead and blink-eliciting stimuli on blink modulation. Acoustic, visual, or tactile lead stimuli were followed by an acoustic (Experiment 1) or an electrotactile (Experiment 2) blink-eliciting stimulus at lead intervals of -30, 0, 30, 60, 120, 240, 360, and 4,500 msec. The inhibition of blink magnitude at the short (60- to 360-msec) lead intervals and the facilitation of blink magnitude at the long (4,500-msec) lead interval observed for each lead stimulus modality was relatively unaffected by the blink-eliciting stimulus modality. The facilitation of blink magnitude at the very short (-30- to 30-msec) lead intervals was dependent on the combination of the lead and the blink-eliciting stimulus modalities. Modality specific and nonspecific processes operate at different levels of perceptual processing.