Amanda S. Persad

Vascular Factors and Risk of Dementia: Design of the Three-City Study and Baseline Characteristics of the Study Population

Objective: To describe the baseline characteristics of the participants in the Three-City (3C) Study, a study aiming to evaluate the risk of dementia and cognitive impairment attributable to vascular factors. Methods: Between 1999 and 2001, 9,693 persons aged 65 years and over, noninstitutionalized, were recruited from the electoral rolls of three French cities, i.e. Bordeaux, Dijon and Montpellier. Health-related data were collected during face-to-face interviews using standardized questionnaires. The baseline examination included cognitive testing and diagnosis of dementia, and assessment of vascular risk factors, including blood pressure measurements, ultrasound examination of the carotid arteries, and measurement of biological parameters (glycemia, total, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, creatinemia); 3,442 magnetic resonance imaging (MRI) examinations were performed in subjects aged 65–79. Measurements of ultrasound, blood, and MRI parameters were centralized. Two follow-up examinations (at 2 and 4 years) were planned. Results: After exclusion of the participants who had subsequently refused the medical interview, the 3C Study sample consisted of 3,649 men (39.3%) and 5,645 women, mean age 74.4 years, with a relatively high level of education and income. Forty-two percent of the participants reported to be followed up for hypertension, about one third for hypercholesterolemia, and 8% for diabetes; 65% had elevated blood pressure measures (systolic blood pressure ≧140 or diastolic blood pressure ≧90). The proportion of Mini-Mental State Examination scores below 24 was 7% and dementia was diagnosed in 2.2% of the participants. Conclusion: Distribution of baseline characteristics of the 3C Study participants suggests that this study will provide a unique opportunity to estimate the risk of dementia attributable to vascular factors.

Susceptibility Loci to Coronary Arteritis in Animal Model of Kawasaki Disease Induced with Candida albicans-Derived Substances

We have established an animal model of coronary arteritis which is histopathologically similar to that observed in cases of Kawasaki disease (KD), is a well‐known childhood vasculitis syndrome. Coronary arteritis in this mouse model has been induced by intraperitoneal injection of Candida albicans‐derived substances (CADS). Arteritis varied by mouse strain with the highest incidence by 71.1% (27/38) found in C3H/HeN mice, but absent in CBA/JN mice (0%, 0/27), suggesting association of genomic background to develop the disease. The present study aims to elucidate the susceptibility loci associated with coronary arteritis by using this animal model. The association of the onset of arteritis with polymorphic microsatellite markers between the two strains was examined using one hundred and fifteen of N1 backcross progeny [(CBA×C3H)F1×C3H]. Based on our analysis, arteritis‐susceptibility loci with suggestive linkage were mapped on D1Mit171 and D1Mit245 (map position 20.2 cM) on chromosome 1 (P=0.0019). These loci include several kinds of inflammatory cytokine receptors, such as interleukin 1 receptor and tumor necrosis factor receptor. We also found the cytokine response against CADS, levels of inflammatory cytokines interleukin‐1β, tumor necrosis factor‐α, and interleukin‐6 in sera increased within 24 hr after CADS injection. Our results may indicate based on genomics that ligand‐receptor interaction between these inflammatory cytokines and the receptors of these cytokines may affect the onset of arteritis.

Septin 3 gene polymorphism in Alzheimer's disease.

Septin 3 is a novel member of the septin subfamily of GTPase domain proteins that was recently identified in human neuronal cells. These proteins are involved in vesicle trafficking, neurite outgrowth, and neurofibrillary tangle formation; however, the expression and functional role of septin 3 in normal neuronal tissues and as an etiological agent in neurological disorders is currently unclear. To further characterize these parameters, the present study analyzed the expression of three isoforms of septin 3 (A, B, and C) in fetal and adult human brains and polymorphism of the septin 3 exon 11 microsatellite in control, pure Alzheimers disease (AD), Lewy body variant (LBV) of AD, and Parkinsons disease. Septin 3 mRNAs for isoforms A and B, but not C, were detected in the frontal cortex of fetus and adult human samples, as measured by reverse transcription-coupled polymerase chain reaction. Genotype analyses indicated that polymorphic septin 3 alleles were distributed in two peaks of frequency in both control and disease groups. Categorization of the alleles into short (S) and long (L) types revealed a significant difference between AD patients and controls (p = 0.034 by chi-square test). Furthermore, the S-allele homozygosity was significantly underrepresented in AD compared with control (p = 0.015 by chi-square test). These results suggest that polymorphism in exon 11 of septin 3 may have a determinative role in the pathogenesis of AD.

Parkinson’s Disease and CYP2D6 Polymorphism in Asian Populations: A Meta-Analysis

Polymorphism of CYP2D6 and its relationship with the development of Parkinson’s disease (PD) has been controversial. The distribution of the B-mutation of CYP2D6, a mutation that results in the absence of a functional protein, differs by ethnicity and accounts for less than 1% of the ‘poor metabolizer’ phenotype in Asians. Thus, a meta-analysis was conducted to determine if polymorphism, other than the B-mutation, within the CYP2D6 gene confers a greater susceptibility to PD outcome among Asian populations. Eleven studies were identified, two of which were excluded due to unavailability in the English language or availability of the same original data in more detail in another publication. None of the studies showed a statistically significant association between CYP2D6 polymorphism and PD (p < 0.05). The overall odds ratio was 0.84 (95% confidence interval 0.66–1.08). We conclude that among Asian populations, there is no convincing evidence of an association between CYP2D6 polymorphism and the risk of developing PD.

Selective inhibition of acetylcholinesterase in the cerebellum and hippocampus of mice following an acute treatment with malathion.

Adult male ICR mice were treated by intraperitoneal injection with 250 mg/kg of bodyweight of commercial malathion (a dose corresponding to 1/12 the LD50). After 6 h, acetylcholinesterase (AChE) activity in blood, liver, and six brain regions was determined. A statistically significant inhibition was observed in whole blood (23%), liver (21%), and, in particular, the central nervous system; the greatest degree of AChE inhibition was observed in the cerebellum (45%), followed by the hippocampus (29%). There was no significant change in AChE activity in the caudate putamen, frontal cortex, midbrain, or pons medulla. These results demonstrate that the magnitude of AChE inhibition in peripheral tissues does not accurately reflect the central-inhibitory effects of malathion on AChE activity in specific brain regions.

Arginine to cysteine mutation (R499C) found in a Japanese patient with complete myeloperoxidase deficiency.

Animal models suggest that a deficiency in myeloperoxidase (MPO; EC 1.11.1.7), a lysosomal hemoprotein involved in host defense, may be associated with a decreased level of immunity. A nonsynonymous mutation, resulting in an arginine to cysteine substitution (Arg499Cys or R499C), has been identified in the exon 9 genetic coding region of a Japanese patient with complete MPO deficiency. Genetic analysis revealed that the mRNA of the patient could be correctly transcribed then further translated into a peptide sequence. However, the Western blot analysis confirmed the absence of MPO peptides. An initial screening assay of the patients blood exhibited an abnormal hematograph, and no MPO activity was detected. To determine if this mutation might be associated with MPO deficiency, DNA samples for 387 controls were examined. Genetic analysis was performed using standard PCR techniques for amplification and sequencing. None of the control samples possessed the R499C substitution. This mutation is in close proximity to a different mutation (G501S) previously found in another Japanese MPO-deficient patient, and the amino acid, H502, which is strongly involved in heme binding, leading to the speculation that heme binding may play a role in complete MPO deficiency.

Chapter 46 – Risk Assessment

Publisher Summary Within the scope of toxicology, human health risk assessment is defined as the “systematic scientific characterization of potential adverse health effects resulting from human exposures to hazardous agents or situations.” It is a process by which toxicology, epidemiology, and environmental research are meshed to provide an overall understanding of risk. Hazard identification, the first in the four-step risk assessment paradigm, is the process used to determine whether exposure to a chemical or other agent may result in an adverse human health effect. Today, risk assessment research has widespread applications and influences fields that may seem far removed from its regulatory toxicology roots. This chapter provides resources for both human health and ecological risk assessment. The information resources provided are presented in the following order: “Books,” “Journals,” “Journal articles,” “Organi- zations,” “Databases,” and “Other resources.”