Butyrylcholinesterase and Acetylcholinesterase polymorphisms in Multiple Sclerosis patients: Implication in peripheral inflammation

Multiple Sclerosis (MS) is an autoimmune disease, having not fully understood aetiology, and both genetic and environmental factors contribute to the pathogenesis of the disease. The cholinergic system has been indicated as a mediator of neuro-immune interactions, as well as an internal regulator of immune responses. The aim of the present research was to assess the associations between BChE and AChE genetic variations and serum cholinergic and inflammatory profiles in 102 Relapsing Remitting-MS patients and 117 healthy controls. An increased frequency of the BChE K-allele in MS patients as compared to controls was found. In addition, data showed that patients had higher BChE enzymatic activity, which is increased by the presence of the polymorphic allele and reduced amounts of circulating ACh. AChE polymorphism was significantly associated to reduced activity in both patients and controls. We propose that serum BChE and AChE activity may be used as a secondary markers to assess the role of non-neuronal cholinergic system in regulating peripheral inflammation via ACh regulation. This pilot study shed light on the role of the non-neuronal cholinergic system in immune cells to better understand MS pathogenesis. The cross-talk between the periphery and the CNS could have a new undescribed crucial role for MS, regarded as a systemic disease

Butyrylcholinesterase Genetic Variants: Association with Cocaine Dependence and Related Phenotypes

Objective: the search for genetic vulnerability factors in cocaine dependence has focused on the role that neuroplasticity plays in addiction. However, like many other drugs, the ability of an individual to metabolize cocaine can also influence susceptibility to dependence. Butyrylcholinesterase (BChE) metabolizes cocaine, and genetic variants of the BChE gene (BCHE) alter its catalytic activity. Therefore, we hypothesize that cocaine users with polymorphisms in BCHE can show diverse addictive behaviors due to differences in effective plasma concentrations of cocaine. Those polymorphisms might also influence users to prefer one of the two main preparations (crack or powder cocaine), despite having equal access to both. the present work investigates polymorphisms in BCHE and if those genetic variants constitute risk factors for cocaine dependence and for crack cocaine use.Methods: A total of 1,436 individuals (698 cocaine-dependent patients and 738 controls) were genotyped for three single nucleotide polymorphisms (SNPs) in BCHE: rs1803274, rs4263329, and rs4680662.Results: for rs4263329, a nominal difference was found between cases and controls. for rs1803274 (the functional SNP), a statistically significant difference was found between patients who used crack cocaine exclusively and those who used only powder cocaine (P = 0.027; OR = 4.36; 95% CI = 1.18-16.04). Allele frequencies and genotypes related to other markers did not differ between cases and controls or between the two cocaine subgroups.Conclusions: Our findings suggest that the AA genotype of rs1803274 is a risk factor for crack cocaine use, which is more addictive than powder cocaine use. Further studies are needed in order to confirm this preliminary result and clarify the role of BCHE and its variants in cocaine dependence.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Sch Med, Dept & Inst Psychiat LIM 23, São Paulo, BrazilUniv São Paulo, Sch Med, Lab Genet & Mol Cardiol LIM 13, Heart Inst InCor, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Clin Neurosci Lab, São Paulo, BrazilUniv São Paulo, Sch Publ Hlth, São Paulo, BrazilUniversidade Federal de São Paulo, Natl Inst Alcohol & Drug Policies, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Clin Neurosci Lab, São Paulo, BrazilUniversidade Federal de São Paulo, Natl Inst Alcohol & Drug Policies, São Paulo, BrazilCNPq: 141762/2008-0Web of Scienc

Context, ethics and pharmacogenetics

Most of the literature on pharmacogenetics assumes that the main problems in implementing the technology will be institutional ones (due to funding or regulation) and that although it involves genetic testing, the ethical issues involved in pharmacogenetics are different from, even less than, 'traditional' genetic testing. Very little attention has been paid to how clinicians will accept this technology, their attitudes towards it and how it will affect clinical practice. This paper presents results from interviews with clinicians who are beginning to use pharmacogenetics and explores how they view the ethics of pharmacogenetic testing, its use to exclude some patients from treatment, and how this kind of testing fits into broader debates around genetics. In particular this paper examines the attitudes of breast cancer and Alzheimer's disease specialists. The results of these interviews will be compared with the picture of pharmacogenetics painted in the published literature, as a way of rooting this somewhat speculative writing in clinical practice

Forensic Pharmacogenetics

Current pharmacogenetics research in the clinical and medico-legal settings provides new options for disease treatment and prevention of ADR avoiding correlated death, and for screening interactions with the polymorphic P450 enzymes early on in drug development

Accomodating Pharmacogenomics: Fulfilling the Promise of Individualized Medicine

Pharmacogenomic technologies promise to usher in an era of individualized medicine, but also pose challenges to a regulatory regime without experience dealing with the sorts of data produced by these techniques. Pharmacogenomics as a field encompasses both pharmacogenetic techniques, which tend to focus on polymorphisms in cytochromes and other proteins involved in drug metabolism, and pharmacogenomic techniques such as microarray technologies, which examine disease and drug interactions on the level of the entire genome. In 2003, the FDA produced a guidance recommending procedures for the submission of pharmacogenomic data at the IND or NDA stage. While pharmacogenomic information used in decision making; during trials is required, most pharmacogenomic data of an exploratory nature may be submitted voluntarily under a separate protocol. Though these procedures seem a reasonable means by which the FDA can open a dialogue with pharmaceutical manufacturers regarding the use of pharmacogenomic data, more action is necessary to develop the infrastructure necessary to develop the technology such that in may be incorporated in regulatory decisions with confidence

An analysis of modifiable risk factors, genetic underpinnings, and current medications for Alzheimer's disease

Alzheimer’s disease (AD) is a widespread neurodegenerative disorder that affects tens of millions of patients worldwide. Throughout the last two decades an incredible amount of time and resources have been funneled into hopefully finding medications that would provide a cure. Unfortunately, no such compound has been identified and instead the only FDA approved medications for AD to date target symptomatic management and may not even be effective for longer than a couple of years. To this end, this paper sets out to identify modifiable risk factors for AD as well as provide recommendations for clinicians on how best to utilize the tools currently available to them to treat AD. Additionally this paper addresses common flaws in AD clinical trial study designs and provides future research directions to expand outside of the popular amyloid hypothesis and instead potentially focus on a multi-pathway mechanism of the disease. The following thesis will outline several potential mechanisms that can lead to the hallmark pathologies seen in AD, primarily amyloid deposition and neurofibrillary tangles as well as neuronal death. The majority of commercial and research interest into AD has been focused on the amyloid hypothesis and the notion that stopping the formation of amyloid plaques would stop the disease course. However, in recent years other mechanisms and neurotoxic pathways such as inhibition of tricarboxylic acid (TCA) cycle enzymes, neuroinflammation, and tauopathy have been shown to contribute both to the formation of amyloid plaques as well as contributing to AD pathology in their own right. The modifiable risk factors explored in this paper include the effects of triglycerides as well as intake of antioxidant vitamins and omega-3-fatty acids, both of which are beneficial for brain health. This paper will also highlight some of the extensive research on the Apolipoprotein E gene and the effects the various alleles have on AD risk. These being the putative protective effect of the APOE2 allele, “neutral” effect of the most commonly found APOE3 allele, and finally the deleterious effects of the APOE4 allele, believed to be the strongest genetic risk factor for late-onset AD

Environmental Exposure and Health Effects Associated with Malathion Toxicity

Malathion (O,O-dimethyl-S-1,2-bis ethoxy carbonyl ethyl phosphorodithionate) is a non-systemic, wide-spectrum pesticide. It is widely used throughout the world for agricultural, residential, and public health purposes, mainly to enhance food production and to provide protection from disease vectors. Malathion preference over other organophosphate pesticides relates to its low persistence in the environment as it is highly susceptible to hydrolysis, photolysis, and biodegradation. However, numerous malathion poisoning incidents including acute and chronic cases have been reported among pesticide workers and small children through accidental exposure. Malathion toxicity is compounded by its reactive metabolites and also depends upon the product purity, route of exposure, nutritional status, and gender of exposed individuals. Its metabolic oxidation in mammals, insects, and plants leads to the formation of malaoxon which appears to be several times more acutely toxic and represents the primary cause of malathion’s toxicity. Depending on the level of exposure, several signs and symptoms of toxicity including numbness, tingling sensation, headache, dizziness, difficulty breathing, weakness, irritation of skin, exacerbation of asthma, abdominal cramps, and death have been reported. Similar to other organophosphate pesticides, malathion exerts it toxic action by binding to acetylcholinesterase enzyme and inhibiting its activity, leading to accumulation of acetylcholine in synaptic junctions, which in turn results in overstimulation of cholinergic, muscarinic, and nicotinic receptors, and subsequent induction of adverse biologic effects. This chapter provides an update and analysis of the production and use, environmental occurrence, molecular mechanisms of toxicity, genotoxicity and carcinogenicity, and adverse human health effects associated with malathion exposure

Personalized pediatric anesthesia and pain management: problem-based review

Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.' Although oncology spearheaded the clinical implementation of personalized medicine, other specialties are rapidly catching up. In anesthesia, classical examples of genetically mediated idiosyncratic reactions have been long known (e.g., malignant hyperthermia and prolonged apnea after succinylcholine). The last two decades have witnessed an expanding body of pharmacogenetic evidence in anesthesia. This review highlights some of the prominent pharmacogenetic associations studied in anesthesia and pain management, with special focus on pediatric anesthesia

Abnormal reactivity of resting-state EEG alpha rhythms during eyes open in patients with Alzheimer's and Lewy body diseases

Previous studies suggest that resting-state electroencephalographic (rsEEG) rhythms recorded in old patients with dementia due to different neurodegenerative diseases have a significant heuristic and clinical potential in identifying peculiar abnormalities of the ascending activating systems and reciprocal thalamocortical circuits in which oscillatory (de)synchronizing signals dynamically underpin cortical arousal in the regulation of quiet vigilance. In the present PhD program, a new methodological approach based on rsEEG cortical source estimation and individually-based frequency bands was used to test the hypothesis of significant abnormalities in the neurophysiological oscillatory mechanisms underlying the regulation of the quiet vigilance during the transition from an eyes-closed to an eyes-open condition in patients with the most prevalent neurodegenerative dementing disorders such as Alzheimer’s disease and Lewy Body and Parkinson’s diseases and initial abnormalities in the prodromal stage of ADD, characterized by mild cognitive impairment. Three rsEEG studies were performed for that purpose. In the first study, we tested if the reactivity of posterior rsEEG alpha rhythms from the eye- closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer’s disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy) seniors, 42 DLB, and 48 ADD participants. The eLORETA freeware estimated rsEEG cortical sources at individual delta, theta, and alpha frequencies. Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. The reduction in the occipital region was lower in the DLB than in the ADD group. These results suggest that DLB patients may suffer a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients. In the second study, we hypothesized that the vigilance dysregulation seen in PDD patients might be reflected by altered reactivity of posterior rsEEG alpha rhythms during the vigilance transition from an eyes-closed to an eyes-open condition. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy), 73 PDD, and 35 ADD participants. We have applied the same methodology used for the first study. Results showed substantial (> -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the Healthy and the ADD groups. These results suggest that PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in quiet wakefulness in PDD patients. Indeed, such biomarkers may provide endpoints for pharmacological intervention and brain electromagnetic stimulations to improve the PDD patients’ general ability to regulate vigilance and primary visual consciousness in the activities of daily living. In the third study, we tested the exploratory hypothesis that rsEEG alpha rhythms may predict and be sensitive to mild cognitive impairment due to AD (ADMCI) progression at a 6-month follow- up (a relevant feature for intervention clinical trials). Clinical, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy seniors were used. We applied the same methodology used for the first and the second studies. Results showed a substantial (> -10%) reduction in the posterior alpha source activities during the eyes-open condition in about 90% and 70% of the Healthy and ADMCI participants, respectively. In the younger ADMCI patients (mean age of 64.3±1.1) with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes closed condition predicted the global cognitive status at the 6-month follow-up. In all ADMCI participants with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes-closed condition reduced in magnitude at that follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. These results suggest that in ADMCI patients, the true (“reactive”) posterior rsEEG alpha rhythms, when present, predict (in relation to younger age) and are quite sensitive to the effects of the disease progression on neurophysiological mechanisms underpinning vigilance regulation. The results of the three studies unveiled the significant extent to which the well-known impairments in the cholinergic and dopaminergic neuromodulatory ascending systems could affect the brain neurophysiological oscillatory mechanisms underpinning the reactivity of rsEEG alpha rhythms during eyes open and, then, the regulation of quiet vigilance in ADD, PDD, and DLB patients, thus enriching the neurophysiological model underlying their known difficulties to remain awake in quiet environmental conditions during daytime

Predloženi modeli genetskog savetovanja: koji indikatori kvaliteta Donabedijanovog modela su primenljiviji?

Genetic counselling is a complex process that helps people to understand and adopt medical, psychological and genetic aspects of the disease and enable them to make an appropriate decision. In this framework, we revisited all the existing models for decision-making and suggested their use in the process of genetic counselling, which may lead to more equitable and more favourable outcomes. Also, Donabedian's (Structure-Process-Outcome) model for the development of key performance indicators was applied to assess the quality in the process of genetic counselling. Quality indicators at SPO model in the process of genetic counselling were proposed. The social, economic and humanistic outcomes have also been identified. All defined quality indicators together represent a framework for monitoring, evaluation and continuous improvement of the process of genetic counselling. Although the new medical services of genetic counselling tend to be developed as a powerful multidisciplinary field, the implementation of quality management model will certainly help the development of collaborative practice.Genetsko savetovanje je složen proces koji pomaže ljudima da razumeju i prihvate medicinske, psihološke i genetske aspekte bolesti, kao i da donesu odgovarajuću odluku u vezi sa njima. U ovom radu, revidirani su svi postojeći modeli za donošenje odluka i predložena je njihova upotreba u procesu genetskog savetovanja, što može da dovede do pravičnijih i povoljnijih ishoda. Za procenu kvaliteta u procesu genetskog savetovanja primenjen je Donabedijanov model (Struktura–proces–ishod), za razvoj ključnih pokazatelja performansi. Predloženi su pokazatelji kvaliteta na „Struktura–proces–ishod” modelu u procesu genetskog savetovanja. Takođe, utvrđeni su socijalni, ekonomski i humanistički ishodi. Svi definisani indikatori kvaliteta zajedno predstavljaju okvir za praćenje, procenu i kontinuirano unapređenje procesa genetskog savetovanja. Iako se nova medicinska usluga genetskog savetovanja razvija, kao snažno multidisciplinarno polje, primena modela upravljanja kvalitetom sigurno će doprineti razvoju kolaborativne prakse