Amanda L. C. Chen

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.

LG839: Anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome

IntroductionThis study systematically assessed the weight management effects of a novel experimental DNA-customized nutraceutical, LG839 (LifeGen®, Inc., La Jolla, CA, USA).MethodsA total of 1058 subjects who participated in the overall D.I.E.T. study were genotyped and administered an LG839 variant based on polymorphic outcomes. A subset of 27 self-identified obese subjects of Dutch descent, having the same DNA pattern of four out of the five candidate genes tested (chi-square analysis) as the entire data set, was subsequently evaluated. Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed.ResultsSignificant results were observed for weight loss, sugar craving reduction, appetite suppression, snack reduction, reduction of late night eating (all P<0.01), increased perception of overeating, enhanced quality of sleep, increased happiness (all P<0.05), and increased energy (P<0.001). Polymorphic correlates were obtained for a number of genes (LEP, PPAR-γ2, MTHFR, 5-HT2A, and DRD2 genes) with positive clinical parameters tested in this study. Of all the outcomes and gene polymorphisms, only the DRD2 gene polymorphism (A1 allele) had a significant Pearson correlation with days on treatment (r=0.42, P=0.045).ConclusionIf these results are confirmed in additional rigorous, controlled studies, we carefully suggest that DNA-directed targeting of certain regulator genes, along with customized nutraceutical intervention, provides a unique framework and strategic modality to combat obesity.

Hypothesizing that brain reward circuitry genes are genetic antecedents of pain sensitivity and critical diagnostic and pharmacogenomic treatment targets for chronic pain conditions.

While it is well established that the principal ascending pathways for pain originate in the dorsal horn of the spinal cord and in the medulla, the control and sensitivity to pain may reside in additional neurological loci, especially in the mesolimbic system of the brain (i.e., a reward center), and a number of genes and associated polymorphisms may indeed impact pain tolerance and or sensitivity. It is hypothesized that these polymorphisms associate with a predisposition to intolerance or tolerance to pain. It is further hypothesized that identification of certain gene polymorphisms provides a unique therapeutic target to assist in the treatment of pain. It is hereby proposed that pharmacogenetic testing of certain candidate genes (i.e., mu receptors, PENK etc.) will result in pharmacogenomic solutions personalized to the individual patient, with potential improvement in clinical outcomes.

Nutrigenomic targeting of carbohydrate craving behavior: can we manage obesity and aberrant craving behaviors with neurochemical pathway manipulation by Immunological Compatible Substances (nutrients) using a Genetic Positioning System (GPS) Map?

Genetic mediated physiological processes that rely on both pharmacological and nutritional principles hold great promise for the successful therapeutic targeting of reduced carbohydrate craving, body-friendly fat loss, healthy body recomposition, and overall wellness. By integrating an assembly of scientific knowledge on inheritable characteristics and environmental mediators of gene expression, we review the relationship of genes, hormones, neurotransmitters, and nutrients as they correct unwanted weight gain coupled with unhappiness. In contrast to a simple one-locus, one-mechanism focus on pharmaceuticals alone, we hypothesize that the use of nutrigenomic treatment targeting multi-physiological neurological, immunological, and metabolic pathways will enable clinicians to intercede in the process of lipogenesis by promoting lipolysis while attenuating aberrant glucose cravings. In turn, this approach will enhance wellness in a safe and predictable manner through the use of a Genetic Positioning System (GPS) Map. The GPS Map, while presently incomplete, ultimately will serve not only as a blueprint for personalized medicine in the treatment of obesity, but also for the development of strategies for reducing many harmful addictive behaviors and promoting optimal health by using substances compatible with the bodys immune system.

Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential?

Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence, the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. After three decades of extensive research, the federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with addiction disorders by providing increased access to options for treatment. DATA allows physicians who complete a brief specialty-training course to become certified to prescribe buprenorphine and buprenorphine/naloxone (Subutex, Suboxone) for treatment of patients with opioid dependence. Clinical studies indicate that buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and in reducing illicit opioid use. With that stated, we must consider the long-term benefits or potential toxicity attributed to Subutex or Suboxone. We describe a mechanism whereby chronic blockade of opiate receptors, in spite of only partial opiate agonist action, may ultimately block dopaminergic activity causing anti-reward and relapse potential. While the direct comparison is not as yet available, toxicity to buprenorphine can be found in the scientific literature. In considering our cautionary note in this commentary, we are cognizant that, to date, this is what we have available, and until such a time when the real magic bullet is discovered, we will have to endure. However, more than anything else this commentary should at least encourage the development of thoughtful new strategies to target the specific brain regions responsible for relapse prevention.

Hypothesizing that Marijuana Smokers are at a Significantly Lower Risk of Carcinogenicity Relative to Tobacco-Non-Marijuana Smokers: Evidenced Based on Statistical Reevaluation of Current Literature

Abstract A hypothetical link between marijuana smoking and cancer has been established based on a number of misleading assumptions. However, recent studies tend to suggest, if anything, an inverse association between marijuana use and cancers. To test the hypothesis that marijuana smoking significantly lowers the risk of developing cancer in humans, we analyzed published data from a prospective cohort study on cancer incidence among nonsmokers (NS), marijuana-only smokers (MS), tobacco-only smokers (TS), and marijuana and tobacco smokers (MTS). Using the log linear model to calculate the probability of developing each cancer form as a function of the interaction between marijuana and tobacco smoking, as well as functions of marijuana and tobacco smoking main effects whereby chi square statistics were calculated for the interaction and main effect estimates, we found that in all cases tested there was a significantly lower risk for MS compared to TS. Male and female TS had a greater probability of developing lung cancer than did MS. Males and females TS had a greater probability of developing lung cancer compared with NS. Males and female MTS had a slightly higher probability of developing lung cancer than did MS. This difference was statistically significant: χ2 = 30.5l, p < .00001, with a correlation coefficient of −0.75, Z = −7.84, p < .05. Male and female MTS had a lower probability of developing lung cancer than did TS. This difference was statistically significant: χ2 = 71.61, p = .00003, with a correlation coefficient oro .61, Z = 5.06, p < .05.

The H-Wave® Device Is an Effective and Safe Non-Pharmacological Analgesic for Chronic Pain : a Meta-Analysis

IntroductionThis meta-analysis was conducted to systematically review the efficacy and safety of the H-Wave® (Electronic Waveform Lab, Inc, Huntington Beach, CA, USA) device and programme as a non-pharmacological analgesic treatment in chronic soft tissue inflammation and neuropathic pain.MethodsFive studies related to pain relief, reduction in pain medication and increased functionality obtained with the H-Wave device were included in the analysis. Data were analysed using the random effects model, including adjustment to evaluate variability, size of study and bias in effect size. A total of 6535 participants were included in the meta-analysis; there were 8065 participants′ outcomes measured due to multiple measurements per participant.ResultsThe H-Wave device decreased pain ratings across various chronic soft tissue inflammation and neuropathic pain conditions. The mean weighted effect size was 0.59, and the estimated effect size variance was 0.00003 (95% confidence intervals [CI]: 0.580, 0.600). The H-Wave device also decreased the intake of pain medication in patients with various chronic soft tissue inflammation and neuropathic pain conditions. The mean weighted effect size was 0.56, and the estimated effect size variance was 0.000013 (95% CI: 0.553, 0.567). Patient functionality was also improved with use of the H-Wave device. The mean weighted effect size was 0.70, and the estimated effect size variance was 0.00002 (95% CI: 0.691, 0.709). A chi-square test for homogeneous effect sizes found highly significant (P<0.00001) variability, indicating a robust significant effect size for increased functionality relative to both pain relief and reduction in pain medication. There was little to no evidence of any adverse effects associated with the use of the H-Wave device.ConclusionThe findings indicate a moderate to strong effect of the H-Wave device in providing pain relief, reducing the requirement for pain medication and increasing functionality. The most robust effect was observed for improved functionality, suggesting that the H-Wave device may facilitate a quicker return to work and other related daily activities.

The H-Wave® Device Induces NO-dependent Augmented Microcirculation and Angiogenesis, Providing Both Analgesia and Tissue Healing in Sports Injuries

Abstract The hypothesis that the H-Wave® device (Electronic Waveform Lab, Inc., Huntington Beach, CA), a small-diameter fiber stimulator, is a paradigm shift of electrotherapeutic treatment of pain associated with human neuropathies and sports injuries is based on a number of its properties. The primary effect of H-Wave® device stimulation (H-WDS) is the stimulation of “red-slow-twitch” skeletal muscle fibers. The authors propose, based on the unique waveform, that the H-Wave® device specifically and directly stimulates the small smooth muscle fibers within the lymphatic vessels ultimately leading to fluid shifts and reduced edema. In unpublished rat studies, it has been observed that HWDS induces protein clearance. The H-Wave® device was designed to stimulate an ultra low frequency (1–2 Hz), low tension, nontetanizing, and nonfatiguing contraction, which closely mimics voluntary or natural muscle contractions. The H-Wave® device can stimulate small fibers due in part to its exponentially decaying waveform and constant current generator activity. The main advantage of these technologies over currently applied electrical stimulators (eg, transcutaneous electrical nerve stimulator [TENS], interferential [IF], neuromuscular electrical stimulation [NMES], high-volt galvanic, etc.) is that H-Waves® small fiber contraction does not trigger an activation of the motor nerves of the large white muscle fibers or the sensory delta and C pain nerve fibers, thus eliminating the negative and painful effects of tetanizing fatigue, which reduces transcapillary fluid shifts. Another function of the H-Wave® device is an anesthetic effect on pain conditions, unlike a TENS unit which in the short term activates a hypersensory overload effect (gate theory) to stop pain signals from reaching the thalamic region of the brain. When the H-Wave® device is used at high frequency (60 Hz), it acts intrinsically on the nerve to deactivate the sodium pump within the nerve fiber, leading to a long-lasting anesthetic/analgesic effect due to an accumulative postsynaptic depression. Moreover, HWDS produces a nitric oxide (NO)-dependent enhancement of microcirculation and angiogenesis in rats. Thus, the authors hypothesize that because of these innate properties of the H-Wave® device, it may provide a paradigm shift for the treatment of both short- and long-term inflammatory conditions associated with pain due to sports injuries. A recent meta-analysis found a moderate-to-strong effect of the H-Wave® device in providing pain relief, reducing the requirement for pain medication, and increasing functionality. The most robust effect was observed for improved functionality, suggesting that the H-Wave® device may facilitate a quicker return to the field.

Trends in Major Incidents of Semiconductor-Related Industry in Taiwan

Reactive chemicals and combustible materials have led to numerous losses in semiconductor industry in Taiwan. Fifty nine incidents were collected and analyzed on related information to provide the integrated overviews of such events in the past thirteen years. Various types of factories either in the upstream or downstream of semiconductor industry were reviewed to deduce which kind of plant is feasible to possesses the higher risk of occurrence. Different kinds of chemicals or processes were compared with each other to verify the causes which led to the higher or largest loss already happened. Accidental fires caused by silane or flammable vapors are the dominant types of incidents in the semiconductor plant in comparison to any other types of materials. Besides, explosions, release of hazardous chemicals, and injuries by hazardous or corrosive chemicals are the three kinds of most common incidents encountered. Fire spread from the common exhaust duct or relief header always resulted in the largest loss among the reported events. The most serious lesson learnt from these losses was about three hundred million US dollars.