Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants

Individual differences in detoxication capacities for specific organophosphorous (OP) compounds are due largely to differences in catalytic efficiency or abundance of the HDL-associated enzyme, paraoxonase (PON1). First, we provide evidence that children less than 2 years of age represent a particularly susceptible population for OP exposure due to low abundance of PON1 and variable onset of plasma PON1 activity. Second, we describe studies examining the neurotoxic effects of chronic, low-level OP pesticide exposure in mice. PON1 knockout (PON1(-/-)) and wild-type mice were exposed chronically (PN4 to PN21) to low levels of chlorpyrifos oxon (CPO). Endpoints included cholinesterase activity, histopathology, gene expression, and behavior. Even at PN4, when PON1 levels were low in wild-type mice, PON1(-/-) mice were more sensitive to inhibition of brain cholinesterase by CPO. At PN22, and persisting as long as 4 months, chronic developmental exposure to 0.18 mg/kg/d or 0.25 mg/kg/d CPO resulted in perinuclear vacuolization of cells in a discrete area of the neocortex and irregular distribution of neurons in the cortical plate, with an increase in the number of affected cells at 0.25mg/kg/d. Third, we describe a transgenic mouse model in which human transgenes encoding either hPON1Q192 or hPON1R192 were expressed at equal levels in place of mouse PON1. The developmental onset of expression followed the mouse time course and was identical for the two transgenes, allowing these mice to be used to assess the importance of the Q192R polymorphism during development. Adult mice expressing hPON1R192 were significantly more resistant than hPON1Q192 mice to CPO toxicity. Our studies indicate that children less than 2 years old, especially those homozygous for PON1Q192, would be predicted to be particularly susceptible to CPO toxicity.     

Verbal fluency in institutionalized patients with schizophrenia: age-related performance decline

Several studies have reported a relatively stable level of cognitive deficits among patients with schizophrenia regardless of age, while others have suggested continued deterioration with age. We compared the performance of 42 institutionalized patients with schizophrenia and 42 age- and education-matched healthy controls on a semantic and phonemic verbal fluency test. Each group was divided into young participants (<65 years old) and elderly participants (> or =65 years old). We found a fluency condition x diagnostic group x age group interaction on total words produced, a fluency condition x diagnostic group interaction on the number of cluster-related words, and a fluency condition x age group interaction on the number of switches. Patients with schizophrenia generally used similar strategies (i.e., semantic or phonemic cluster-related words and switches) as healthy individuals when generating words, but to a lesser degree. We found a disproportionate decline in the elderly schizophrenic patients relative to that of healthy controls only on the phonemic, relative to the semantic test. This decline in performance appears related to the effects of aging rather than severity or chronicity of illness, duration of institutionalization, or a progressive degenerative process associated with the disorder.     

Fast whole-body assessment of metastatic disease using a novel magnetic resonance imaging system: initial experiences

OBJECTIVE: The objective of this study was to investigate the clinical use of a novel whole-body magnetic resonance imaging (MRI) system for comprehensive assessment of tumor spread in clinical routine. MATERIAL AND METHODS: Sixty-five patients with different tumors with known metastatic disease and 6 healthy volunteers were included. High-resolution MRI from head to toe was performed using multiple phased-array surface coil elements, 24 independent receiver channels, and an integrated parallel acquisition technique (iPAT). A total room time of less than 60 minutes was required. Whole-body MRI and conventional spiral computed tomography (CT) were independently evaluated and compared in terms of feasibility, location/number of detected metastases, and therapeutic relevance. RESULTS: Whole-body MRI was successfully performed in 68 of 71 subjects. Compared with CT, more metastases were detected by MRI in 11 of 63 patients (17%), particularly in brain, liver, spleen, lymph nodes, bone marrow, muscle, and subcutaneous fat tissue. According to these findings, therapy had to be modified in 6 of 63 patients (10%). CONCLUSIONS: High-resolution whole-body MRI is feasible in clinical routine within 1 single examination and offers great potential for fast assessment of individual tumor spread and total tumor burden.     

Comparison of MRI and conventional radiography for assessment of acromial shape

OBJECTIVE: Our aim was to determine the value of different MRI planes independently and in combination for assessment of acromial shape. MATERIALS AND METHODS: Sixty-one patients with subacromial impingement syndrome who had undergone acromioplasty after failure to respond to conservative treatment were included in the study. Parasagittal T2-weighted MR images and outlet view radiographs of the affected shoulders were acquired preoperatively. Three-dimensional models of all acromions were constructed from the MR images, and the Bigliani type of acromion depicted by these models was determined. Results were compared with the acromial type assessed during acromioplasty. To provide a reliable reference for further processing and correlation, we used only those 56 acromions with agreement on acromial shape between intraoperative findings and 3D models. Then, acromial shape was determined for three MRI slice positions (S-1, lateral acromial edge; S-2, just lateral of acromioclavicular joint; and S-3, lateral portion of acromioclavicular joint), for a combination of S-1 and S-2, and for the radiographs. RESULTS: Kappa coefficients were 0.36 (36%) for S-1, 0.41 (41%) for S-2, and -0.10 (-10%) for S-3. For the outlet view radiographs, the kappa coefficient was 0.55 (55%), showing better correlation than any single slice position. Best results, however, were achieved with a combination of S-1 and S-2, with a kappa coefficient of 0.66 (66%). CONCLUSION: For determination of acromial shape, outlet view radiographs are superior to any single MRI slice position, but inferior to a combination of two MRI slices (S-1 and S-2). If a single MRI slice is being used, the slice position just lateral to the acromioclavicular joint is recommended.     

Prevalence, course, and predictors of emotional distress in pregnant and parenting adolescents

This study examines trajectories and correlates of emotional distress symptoms in pregnant adolescents (n = 203) and nulliparous adolescents (n = 188) from economically disadvantaged communities over an 18-month period. For both groups, the prevalence of significant emotional distress exceeded expectation based on adolescent norms; however, the severity of symptoms did not differ between the 2 groups. Results from growth curve modeling revealed a significant decline in symptoms during the study period for both groups, but pregnant adolescents experienced a different pattern of decline. Also, certain interpersonal factors (e.g., history of physical maltreatment, partner support) appeared to play a more important role in the emotional well-being of pregnant and parenting adolescents relative to nulliparous adolescents. Implications for early identification and intervention are discussed.     

Racial discrepancies in the association between paternal vs. maternal educational level and risk of low birthweight in Washington State

Background  

The role of paternal factors in determining the risk of adverse pregnancy outcomes has received less attention than maternal factors. Similarly, the interaction between the effects of race and socioeconomic status (SES) on pregnancy outcomes is not well known. Our objective was to assess the relative importance of paternal vs. maternal education in relation to risk of low birth weight (LBW) across different racial groups.     

Variations in adrenal androgen production among (nonhuman) primates

The synthesis and secretion of the adrenal androgens dehydroepiandrosterone (DHEA) and its sulfate (DS) is a phenomenon apparently unique to humans and nonhuman primates. It occurs at three life stages: in utero from the fetal zone (FZ) cells of the developing adrenal cortex, during adolescence with the onset of adrenarche and the development of the zona reticularis (ZR), and in ever decreasing amounts from the ZR with aging (adrenal senescence). Insufficient data exist to know if any single nonhuman primate exactly mirrors human adrenal androgen secretion through all three life stages, and detailed morphological, biochemical, and endocrinologic studies are required to do so. Androgen synthesis requires that cells express three key enzymes, 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17), nicotinamide-adenine dinucleotide phosphate (NADPH)-cytochrome P450 oxidoreductase (CPR), and cytochrome b5, and that they do not express 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Cytochrome b5 has emerged as a particularly useful marker of androgen synthetic potential. Although a reliable index of the rate of adrenal androgen secretion, DS concentrations may not accurately reflect total adrenal androgen output because rates and routes of androgen metabolism may vary greatly among species. Based on the very limited available data, the most promising nonhuman primate models are marmosets for the human FZ, chimpanzees for human adrenarche, and macaques and baboons for mature ZR function that declines with senescence.