ABSTRACT
Several teratogenic agents, including ionizing radiation and xenobiotics such as phenytoin, benzo[a]pyrene, thalidomide, and methamphetamine, can initiate the formation of reactive oxygen species (ROS) that oxidatively damage cellular macromolecules including DNA. Oxidative DNA damage, and particularly the most prevalent 8-oxoguanine lesion, may adversely affect development, likely via alterations in gene transcription rather than via a mutational mechanism. Contributions from oxidative DNA damage do not exclude roles for alternative mechanisms of initiation like receptor-mediated processes or the formation of covalent xenobiotic-macromolecular adducts, damage to other macromolecular targets like proteins and lipids, and other effects of ROS like altered signal transduction. Even in the absence of teratogen exposure, endogenous developmental oxidative stress can have embryopathic consequences in the absence of key pathways for detoxifying ROS or repairing DNA damage. Critical proteins in pathways for DNA damage detection/repair signaling, like p53 and ataxia telangiectasia mutated, and DNA repair itself, like oxoguanine glycosylase 1 and Cockayne syndrome B, can often, but not always, protect the embryo from ROS-initiating teratogens. Protection may be variably dependent upon such factors as the nature of the teratogen and its concentration within the embryo, the stage of development, the species, strain, gender, target tissue and cell type, among other factors.
Subject(s)
DNA Damage , Fetal Diseases/chemically induced , Animals , Benzo(a)pyrene/pharmacology , DNA/metabolism , DNA/pharmacology , DNA Repair , Embryo, Mammalian , Female , Fetal Diseases/genetics , Guanine/analogs & derivatives , Inactivation, Metabolic , Male , Mice , Mice, Knockout , Oxidation-Reduction , Oxidative Stress/drug effects , Oxidative Stress/physiology , Phenytoin/pharmacology , Proteins/drug effects , Proteins/metabolism , Proteins/pharmacology , Reactive Oxygen Species/metabolism , Reactive Oxygen Species/pharmacology , Signal Transduction/drug effects , Teratogens/pharmacology , Thalidomide/pharmacology , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/pharmacology , Xenobiotics/pharmacologyABSTRACT
STUDY OBJECTIVE: To assess the efficacy of botulinum toxin type A in lowering the frequency of migraine headaches in patients with episodic migraines. DESIGN: Meta-analysis of eight randomized, double-blind, placebo-controlled trials. PATIENTS: A total of 1601 patients with a history of episodic migraine headaches classified as those experiencing headaches fewer than 15 times/month over a 3-month period. MEASUREMENTS AND MAIN RESULTS: PubMed, Google Scholar, and the Cochrane Library were searched from inception to October 2007 in order to locate randomized, double-blind, placebo-controlled trials that compared the efficacy of pericranial botulinum toxin A injections with placebo in the prevention of migraines in patients with a history of episodic migraine headaches. The primary outcome of interest was change from baseline to end point in migraine frequency (number of migraines/month). A random effects model was used to combine study results, and the standardized mean difference (Cohen's d) in migraine frequency between the placebo and botulinum toxin A groups was reported. Effect sizes (d) less than 0.2 were considered small. Quality assessment was performed by using the Downs and Black scale. Eight randomized, double-blind, placebo-controlled clinical trials (1601 patients) presented a quantitative assessment of the efficacy of botulinum toxin A versus placebo. The overall treatment effect size of botulinum toxin A over placebo for 30, 60, and 90 days after injection was d -0.06 (95% confidence interval [CI] - 0.14-0.03, z=1.33, p=0.18), d -0.05 (95% CI -0.14-0.03, z=1.22, p=0.22), and d -0.05 (95% CI -0.13-0.04, z=1.07, p=0.28), respectively. Even after controlling for a high placebo effect, and after dose stratification, no significant effect of botulinum toxin A in reducing migraine frequency/month was seen over placebo. CONCLUSION: Botulinum toxin A for the prophylactic treatment of episodic migraine headaches was not significantly different from placebo, both from a clinical and statistical perspective.
Subject(s)
Botulinum Toxins, Type A/therapeutic use , Migraine Disorders/prevention & control , Neuromuscular Agents/therapeutic use , Adult , Botulinum Toxins, Type A/administration & dosage , Data Interpretation, Statistical , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Middle Aged , Neuromuscular Agents/administration & dosage , Randomized Controlled Trials as TopicABSTRACT
Dysregulation of iron homeostasis is implicated in Alzheimer's disease (AD). In this pilot study, common variants of the apolipoprotein E (APOE) and HFE genes resulting in the iron overload disorder of hereditary hemochromatosis (C282Y, H63D and S65C) were evaluated as factors in sporadic AD in an Ontario sample in which folic acid fortification has been mandatory since 1998. Laboratory studies also were done to search for genetic effects on blood markers of iron status, red cell folates and serum B12. Participants included 58 healthy volunteers (25 males, 33 females) and 54 patients with probable AD (20 males, 34 females). Statistical analyses were interpreted at the 95% confidence level. Contingency table and odds ratio analyses supported the hypothesis that in females of the given age range, E4 significantly predisposed to AD in the presence but not absence of H63D. In males, E4 significantly predisposed to AD in the absence of H63D, and H63D in the absence of E4 appeared protective against AD. Among E4+ AD patients, H63D was associated with significant lowering of red cell folate concentration, possibly as the result of excessive oxidative stress. However, folate levels in the lowest population quartile did not affect the risk of AD. A model is presented to explain the experimental findings.
