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Both environmental and genetic factors contribute to individual susceptibility to initiation of substance use and vulnerability to addiction. Determining genetic risk factors can make an important contribution to understanding the processes leading to addiction. In order to identify gene(s) and mechanisms associated with substance addiction, a custom platform array search for a genetic association in a case/control of homogenous Jordanian Arab population was undertaken. Patients meeting the DSM-VI criteria for substance dependence (n = 220) and entering eight week treatment program at two Jordanian Drug Rehabilitation Centres were genotyped. In addition, 240 healthy controls were also genotyped. The sequenom MassARRAY system (iPLEX GOLD) was used to genotype 49 single nucleotide polymorphisms (SNPs) within 8 genes (DRD1, DRD2, DRD3, DRD4, DRD5, BDNF, SLC6A3 and COMT).
This study revealed six new associations involving SNPs within DRD2 gene on chromosome 11. These six SNPs within the DRD2 were found to be most strongly associated with substance addiction in the Jordanian Arabic sample. The strongest statistical evidence for these new association signals were from rs1799732 in the C/−C promoter and rs1125394 in A/G intron 1 regions of DRD2, with the overall estimate of effects returning an odds ratio of 3.37 (χ2 (2, N = 460) = 21, p-value = 0.000026) and 1.78 (χ2 (2, N = 460) = 8, p-value = 0.001), respectively. It has been suggested that DRD2, dopamine receptor D2, plays an important role in dopamine secretion and the signal pathways of dopaminergic reward and drug addiction.
This study is the first to show a genetic link to substance addiction in a Jordanian population of Arab descent. These findings may contribute to our understanding of drug addiction mechanisms in Middle Eastern populations and how to manage or dictate therapy for individuals. Comparative analysis with different ethnic groups could assist further improving our understanding of these mechanisms.
SNP; DRD2; Opiates; Cocaine; Association; Substance addiction; Jordan; ArabBackground
Substance addiction and dependency has been influenced by both genetic and environmental risk factors [1]. It has been estimated that genetic factors contribute to 40%–60% of the vulnerability to drug addiction, and environmental factors provide the remainder [2-6]. However, there is also evidence for shared genetic vulnerability to two or more drugs such as cannabis, sedatives, stimulants and opiates which may explain the finding that addicted patients are often dependent on more than one category of drug [2-9]. The presence of unique and shared genetic factors for substance addiction [5,7] leads to the hypothesis that there is an association between specific genetic polymorphisms and increased risk of substance addiction.
Genetic susceptibility to addiction is the result of the interaction of many genes related to the central nervous system (CNS) [9-12]. In this system, dopamine is thought to be the primary neurotransmitter involved in the mechanisms of reward and reinforcement [13-16]. The function of dopamine is mediated by two classes of dopamine receptors termed D1 like and D2 like families. The D1 like family (D1 and D5 dopamine receptors) mediate a reduction in the drive to seek reinforcement effects, in contrast to the family of D2-like receptors (including D2, D3, and D4 dopamine receptors) mediate both reward and reinforcement effects [6,15-19]. The dopamine receptor gene family, which comprises DRD1 (MIM *126449), DRD2 (MIM *126450), DRD3 (MIM *126451), DRD4 (MIM * 126452) and DRD5 (MIM *126453) is a prime candidate gene family for influencing substance abuse because this gene family is thought to play one of the most important roles in the neurobehavioral signaling pathways implicated in substance addiction [15,18].
Several studies have implicated a role for the products of dopamine receptor gene variants in mediating the behavioral and neurochemical properties of opiates such as heroin [8,16]. It has also been suggested that the endogenous dopamine system may also contribute to the development of dependence on other drugs of abuse such as alcohol, cannabis, cocaine and amphetamines [7,11,12]. Various studies have shown that dopamine receptors are involved in reinforcement of drug use in addicted individuals [15]. Other neurotransmitters are also thought to play a role in reinforcement including the dopamine active transporter (DAT; gene symbol SLC6A3, MIM *126455) [20], neurotrophines such as Brain-derived neurotrophic factor (gene symbol BDNF, MIM *113505) [21-24] and enzymes systems such as catechol-O-methyltransferase (gene symbol COMT, MIM *116790) [25]. All of these genes are expressed within the meso-corticolimibic dopamine system or associated structures such as the nucleus accumbens, ventral tegmental area, amygdala, prefrontal cortex, hippocampus and cerebral cortex [5,11,12,21].
Human molecular genetic studies are also implicating the dopamine receptor gene family in substance use disorders. The rs5326 SNP is located in the 5'-UTR of DRD1 gene and has been linked to heroin dependence in African Americans [26]. While there are no similar confirmed associations between DRD2 gene and substance addiction [15,27], some variants within DRD2 gene such as the rs1799732 SNP (C/-C, 5'-UTR) warrant further investigation as these variants have a functional effect on gene expression [28]. The DRD3 gene has been reported to be associated with substance abuse [29] and cocaine [30] and heroin abuse [31] but others have not reported association with abuse of either drug [32,33]. The rs3758653 SNP located in the 5'-UTR of the DRD4 gene has been reported to be associated with heroin dependence in 53 heroin Hungarian addicts [34]. The DRD5 gene has not been the subject of many genetic studies.
The dopamine active transporter (DATSLC6A3) is widely distributed throughout the brain in areas of dopaminergic activity [20]. The DA transporter DAT1 mediates the active reuptake of DA from the synapse and is a principal regulator of dopaminergic neurotransmission. Its addictive effects are thought to be principally mediated through blockage of DAT, resulting in a substantial increase in the concentration of extracellular DA and stimulation of neurons in brain regions involved in reward and reinforcement behavior [35]. Family and twin studies suggest that DAT1 is a substantial genetic factor in the vulnerability of individuals to cocaine dependence after exposure [36-38]. Therefore, polymorphic functional variants in the DAT gene may act to modify susceptibility to substance abuse and dependence.
Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family. This family is a group of structurally related secretory proteins widely expressed in neurons and their target cells [39]. Induced by cortical neurons, BDNF is required to support existing neurons in the brain and help in the growth and differentiation of new neurons and synapses [40-42]. Studies in animals and humans suggest that BDNF influences the dopaminergic and serotonergic functions that are heavily linked to substance addiction [43-47]. In mice, BDNF administration or BDNF genetic knockouts have shown that this factor can alter drug preference or drug-induced behavior. In humans, Uhl et al. (2001) used 1494 SNPs to scan for vulnerability genes for polysubstance abuse. Using 1004 European American and African American samples; they found that positive association markers flank the BDNF gene and Val66Met at rs6265 position was associated with drug addiction vulnerability [46]. Recently, various studies have shown that the Val66Met substitution in the prodomain may affect intracellular trafficking and activity-dependent secretion of BDNF[47,48]. Overall these animal and human studies indicate that BDNF may be involved in the mechanisms underlying substance addiction [49].
Catechol-O-methyltransferase (COMT) is one of several enzymes that metabolises catecholamine such as dopamine, epinephrine and norepinephrine and play a role in the reinforcement mechanism [5,7]. Nikoshkov et al. (2008) suggests that heroin addicts with homozygous genotype at position rs4680 Met158/Met158 have a significant up-regulation of COMT gene expression [50]. In contrast, heroin addicts with the heterozygous genotype (Vall158/Met158) or homozygous genotype of Vall158 at this position show a down-regulation of COMT gene expression. Goldman (2005) reported that the Val158 variant catabolizes dopamine up to four times the rate of its methionine counterpart, resulting in significant lower synaptic dopamine levels following neurotransmitter release. This ultimately reduces dopaminergic stimulation of the post-synaptic neuron [5]. Therefore, due to the role of COMT in prefrontal dopamine degradation, the Val158Met polymorphism is thought to be associated with increased risk of substance addiction by modulating dopamine signaling in the frontal lobes.
In the present study, we examined 49 SNPs within eight candidate genes, the dopamine receptors DRD1, DRD2, DRD3, DRD4 and DRD5, the dopamine transporter (SLC6A3) brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) for genetic association analysis with substance addiction in Arab individuals. To the best of our knowledge, this report is the first genetic association study for substance addiction in a Middle Eastern population of Arab descent. These findings may prove crucial to our understanding of substance addiction mechanisms in Arab populations. At the individual level, this knowledge may improve patient management and treatment.
All substance addiction subjects were recruited from the National Centre for Rehabilitation of Addicts (NCRA) at Jordanian Ministry of Health and the Drug Rehabilitation Centre at the Jordanian Public Security Directorate (DRC-PSD). They were diagnosed as having substance addiction using DSM-IV criteria (American Psychiatric Association, 1994) [51]. A semi-structured interview based on the Addiction Severity Index (ASI) criteria [52] was used to collect clinical and demographic data for each subject. The clinical and demographic data were collected by an administering officer from each of the addiction treatment Centres. The clinical data included current drug of abuse, age at first use of drug, onset and years of drug use, substance and psychiatric treatment, drug overdose and history of substance abuse. Demographic data collected included date of birth, gender, nationality was also provided. All data was coded and no specific individual was identified. The mean age (±SD) of these subjects was 32.7 (±8.4) years with an age range of 18 to 58 years.
In addition, 240 healthy males from an ethnically homogenous Jordanian Arab population with no lifetime history of psychosis or mood disorders, or alcohol or heroin dependence according to the DSM-IV, were used as controls. These controls were recruited from the Blood Bank of the King Abdullah Hospital University, Jordan University of Science and Technology. These controls were frequency matched by age, sex and ethnicity to the case subjects. The mean age (±SD) of the controls was 31.5 (± 5.6) years with an age range of 18 years to 54 years.
This study was conducted according to the provisions of the Australian Medical Association Code of Ethics (2006) and the World Medical Association Declaration of Helsinki (World Medical Association, 2008). The study was also subject to, and in compliance with, the National Statement on Ethical Conduct in Human Research, Australia (2007). Ethical approval to conduct this research was granted by the Human Research Ethics Committee of The University of Western Australia (Ref No. RA/4/1/4344). This study was also approved by the Human Ethics Committee of the Jordanian Ministry of Health (Ref No. Development/Trainees/535) and by the Institutional Review Board of the Jordan University of Science and Technology (Ref No. RA/16/1/2010). Written informed consent was obtained from all subjects and controls before participation in the study.
DNA extraction
After blood was drawn into EDTA tubes, genomic DNA ® Blood Kit (Qiagen, Valencia, CA, USA) according to the recommendations of the manufacturer. Briefly, 300 μl of whole blood from each sample was mixed with 200 μl of lysis buffer (50 mM Tris pH 8.0, 100 mM EDTA, 100 mM NaCl, 1% SDS) and 40 μl of Proteinase K. 100 μl of isopropanol and 500 μl of Inhibitor Removal Buffer (5 M guanidine-HCl, 20 mM Tris–HCl pH 6.6) was then added. The DNA was washed with a buffer (20 mM NaCl; 2 mM Tris- HCl; pH 7.5) and centrifuged twice at 2,000 rpm. The DNA was washed using cold 70% ethanol, centrifuged at 3,000 rpm and the supernatant was discarded, leaving a pellet that contained purified genomic DNA. The DNA pellet was diluted in TE buffer (1 mM EDTA; 10 mM Tris–HCl, pH 7.5) to a concentration of approximately 50 ng.μl-1. DNA concentration (ng/μl) and purity (A260/280) were also verified using the Nano-Drop ND-1000 UV–vis Spectrophotometer (NanoDrop Technology, Wilmington, DE) and subsequently adjusted to approximately 100 ng/μL. Purified DNA was stored at −80°C before use.
In this study, 49 single nucleotide polymorphisms (SNPs) within eight genes (DRD1, DRD2, DRD3, DRD4, DRD5, BDNF, SLC6A3 and COMT) were selected from public databases including the SNP database of the National Centre for Biotechnology Information (NCBI; http://www.ncbi.nlm.nih.gov/SNP/ webcite), the Applied Biosystems SNP database (http://www.appliedbiosystems.com webcite) and the International HapMap Project (http://www.hapmap.org/ webcite). The positions of the SNPs in these selected genes and the relative distance to the translation initiation site are given in Table 1.
Table 1. List of Genes, their SNPs and positions, and genotyping data based on the whole cohort (460 subjects)
SNP genotyping using the sequenom MassARRAY® system (iPLEX GOLD) (Sequenom, San Diego, CA, USA) was performed according to the manufacturer's recommendations (Sequenom, San Diego, CA, USA). Briefly, PCR and single base extension primers (SBE) were designed using MassARRAY assay design 3.1 software (Sequenom MassARRAY system) that allows iPLEX reactions for SBE designs with the modified masses associated with the termination mix. Manufacturer's instructions for the multiplex reaction were followed in the whole process, including the PCR amplification (Sequenom, San Diego, CA, USA), the shrimp alkaline phosphatase (SAP) enzyme (Sequenom, San Diego, CA, USA) treatment to dephosphorylate dNTPs unincorporated in the PCR, the SBE reactions using an iPLEX GOLD assay (Sequenom, San Diego, CA, USA), and the clean-up with a resin kit (Sequenom, San Diego, CA, USA) to desalt the iPLEX reaction products. PCR and SBE primers sequences and all protocol conditions are available upon request. Reaction products were dispensed onto a 384-element SpectroCHIP bioarray (Sequenom) using a MassARRAY nanodispenser and assayed on the MassARRAY platform. Mass differences were detected with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). MassARRAY Workstation v.3.3 software was used to process and analyse the iPLEX SpectroCHIP bioarray. Typer Analyzer v.4.0.2 software was used to analyse all genotypes obtained from the assays. Scatter plots of rs1125394 and rs1799732 SNPs within DRD2 gene were colored according to genotype calls: AA (green), GA (yellow) GG (blue) and no call (red) (Figure 1).
Figure 1. Representative Scatter plot from sequenom data. The left panel (a) and right panel (b) illustrate the scatter plot of rs1799732and rs1125394 SNPs within DRD2 gene, respectively. These two SNPs showed the strongest statistical evidence for association with substance addiction in Arab population. The X and Y axes on both plots denote the mass height measurement for the two alleles (C, C.DEL, low mass allele versus high mass allele) at the rs1799732 SNP (panel a) and for the two alleles (G, A, low mass allele versus high mass allele) at the rs1125394 SNP (panel b). Each point represents the measurements for a single individual. The points in the both panels are colored according to the genotype calls. For example in the left panel (a), green color denotes –C genotype; yellow color denotes C/-C genotype and blue color denotes CC genotype and red color denotes no call. Genotypes determined by sequenom MassARRAY® system (iPLEX GOLD) for all 49 SNPs were highly accurate with average success rate 100%. Genotype discrepancy average (±SD) rate across the 49 loci were only 0.02% (±0.06%) in the whole cohort (460 subjects)
Quality control (QC)
Data cleaning was performed using the PLINK software developed by Purcell et al. (2007) [49]. Using this software, the genotype results of each marker are accepted only if the success rate is at least 90%. SNPs were excluded from the analysis based on the following criteria: (1) minor allele frequency (MAF) < 0.05, or (2) missingness per SNP > 5%, or (3) significant deviation (p-value < 1.0 E-06) from the Hardy-Weinberg equilibrium (HWE).
Statistical methods
Hardy-Weinberg equilibrium
The HWE provides a measure of wether an evolutionary event has influenced an allele frequency. Theoretically calculated, expected and seen genotype frequencies are compared to each other and a Pearson χ2 test is used to test whether they significantly differ from each other. In this study, the estimated genotype frequencies were calculated as follows: p2 + 2pq + q2 = 1, in which p represents the frequency of one allele, and q represents the frequency of the other allele [53]. Significant deviations from HWE may indicate genotyping errors.
Genetic association analysis
The software package PLINK [54] was used to test for association between genetic variants and substance addiction.
Correction for multiple testing
In order to correct for the effect of multiple testing for a given phenotype, the effective number of SNPs using the method of Li and Ji (2005) was estimated [55], which employs a modification of an earlier approach by Nyholt (2004) [56]. After obtaining the effective number of SNPs (Nem), a modified Bonferroni procedure was applied to identify a target alpha level (0.05/ Nem) that would maintain an overall significance level of 0.05 or less.
The study sample
Altogether 460 individuals were analysed in this study to identify potential candidate genes related to substance addiction. The study sample consisted of 220 Jordanian Arab individuals with substance addiction and 240 matched controls. The average age (±SD) was 32.70 (± 8.4) and 31.5 (± 5.6) years, respectively. No drug dependent individual or control had any psychiatric diseases according to the DSM-IV criteria assessment. There were no significant differences found between individuals with drug dependence and controls with regard to age and sex. Clinical and demographic data including gender, age, current drug abuse, dependence variables, drug overdose or toxicity, history of drug use and substance and psychiatric treatment is given in Table 2.
Table 2. Characteristics of 220 substance abuse patients of Arab origin in this study
HWE test
HWE tests were performed in case and control groups for the studied polymorphisms respectively. All polymorphism were in HWE in both case and control groups except for the three SNPs within DRD2 gene (rs1801028, rs2734838, and rs1110976) and two SNPs within SLC6A3 gene (rs27048, rs6347). Two SNPs for COMT gene (rs1544325, rs2239393) had p-values < 1.0 E-06 and were excluded from the study.
Quality control (QC)
All the genotyped SNPs were checked for HWE and Mendelian errors. All duplicates were identical, water controls were clean, markers were in HWE and no Mendelian errors were observed. Genotypes determined by sequenom MassARRAY® system (iPLEX GOLD) for all 49 SNPs were highly accurate with an average success rate of 100%. The genotype discrepancy average (±SD) rate across the 49 loci was only 0.02% (±0.06%) in the whole cohort (460 subjects).
The candidate genes and the SNPs
The NCBI, dbSNP and HapMap databases were used for the SNP selection. The goal was to select SNPs that had significant functional relevance, covered the genes of interest as widely as possible, and had been previously genotyped. Using these criteria, a total of 49 SNPs were selected (Table 2). Of these, 41 (82%) passed quality control and were used in the association analysis.
Association of SNPs candidate genes with substance addiction
Association analysis of eight genes (DRD1 ,DRD2 ,DRD3 ,DRD4 ,DRD5 ,SLC6A3 ,BDNF and COMT) with substance addiction was performed using PLINK Software [54]. The association p- values from the PLINK genetic association analysis are shown in Table 3.
Table 3. Association of genes SNPs with opiate drug dependence
Dopamine receptor genes
The top scoring SNPs for association with substance addiction were from the DRD2 gene (Figure 1). The significant p-values for genotypic frequency ranged from 0.03 to 0.000026 for six SNPs within DRD2 gene on chromosome 6 (Table 3). The strongest statistical evidence for these new association signals were from rs1799732 in the C/−C promoter and rs1125394 in A/G intron 1 regions of DRD2, with the overall estimate of effects returning an odds ratio of 3.37 (χ2 (2, N = 460) = 21, p-value = 0.000026) and 1.78 (χ2 (2, N = 460) = 8, p-value = 0.001), respectively. The p-values for allelic frequency ranged from 0.01 to 0.0001 for five SNPs (rs2283265 (G/T, intron 4), rs1125394 (A/G, rs2075654, intron 1), rs2734836 (G/A, intron 2), and rs1799732 (C/-C, 5'-UTR) (data not shown) within DRD2 gene. The strongest statistical evidence of allelic frequency for these new association signals were from rs1799732 (χ2 (1, N = 460) = 15, p-value = 0.0001) and rs2283265 (χ2 (1, N = 460) = 8, p-value = 0.005).
Solute carrier family 6, member 3(SLC6A3), brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes
There were no significant difference of genotype (Table 3) or allele frequencies (data not shown) of the studied SNPs in the SLC6A3, BDNF and COMT genes between subjects with substance addiction and normal controls.
Although epidemiologic studies have shown that substance addiction is strongly influenced by genetic factors, the number and identity of vulnerability genes remain unknown [1,3-8]. This is the first study to examine eight candidate genes for association with substance addiction in individuals of Arab descent. These eight genes were the Dopamine receptors (DRD1 ,DRD2 ,DRD2 ,DRD3 and DRD5), Solute Carrier Family 6, Member 3 (SLC6A3), Brain-Derived Neurotrophic Factor (BDNF) and Catechol-O-Methyltransferase (COMT). Altogether 460 individuals were genotyped using 49 SNPs from these eight genes. Of the samples tested, 220 were from substance addicted male subjects of Arab descent. The control group were an ethnically homogenous Jordanian Arab population with no lifetime history of psychosis, mood disorders or substance dependence.
Both dopamine and non-dopamine neurochemical pathways through neurotransmitters (SLC6A3), neurotrophic factors (BDNF) and enzymes (COMT) are influenced by drugs and their psychoactive and addictive effects [8,10,12]. Dopamine is one of the main neurotransmitters involved in the stimulation of reward pathways, which is the important feature of substance addiction [13,15,57]. It has been suggested that dopamine receptor genes play a role in the genetics of substance addiction [58-60]. Previous studies have emphasized the importance of dopamine gene family specifically DRD2 gene as a general risk factor for substance dependence rather than a marker of risk for a particular drug [13,15,18]. However, various genetic association studies reported that there are inconsistencies in the frequency of alleles within DRD2 gene in different populations. For example, Barr and Kidd reported that the A1 allele frequency differs dramatically among the population studied from as low as 0.09 to as high as 0.075 [61].
As many studies indicated that multiple substances influence dopaminergic system activity, the investigation of substance addiction may result in a complete examination of gene risk [7,11,12]. In this study, none of the polymorphisms within the eight genes differed significantly for allele or genotype frequencies, with exception of six polymorphisms (rs2283265, rs10765560, rs2075654, rs1125394, rs2734836 and rs1799732) within the DRD2 gene. The strongest statistical evidence for these association signals was found within the DRD2 gene at two sites: rs1799732 (C/-C, 5'-UTR) and rs1125394 (A/G, intron 1). The strongest evidence of allelic frequency for these association signals were from rs1799732.
The rs1799732 (C/-C, 5'-UTR) is of particular interest because there is evidence that this allele has a functional effect on DRD2 gene expression [27]. The dopaminergic system is involved in reward and reinforcing mechanisms in the brain [13,57] specifically the positive reinforcing effects of substance addiction [59]. Animal and human studies of addiction indicate that DRD2 plays a critical role in the mechanism of reward and reinforcement behavior [60-63]. Various animal studies reported that opiate rewarding effects were absent in mice lacking D2 receptors, while DRD2 overexpression in transgenic mice led to reduced self-administration of alcohol [60,62]. A positron emission tomography study of human brain showed that D2 receptor density in the brain decreased significantly in alcoholic compared with control subjects [63,64]. These findings suggest that genetically determined variation in DRD2 expression and function can alter reward responses to a variety of substances and may contribute to vulnerability to heroin dependence in humans. For example, DRD2 gene was previously studied by Xu et al. (2004) to examine the susceptibility of this gene with heroin dependence in Chinese and German population [65]. This study found that genetic polymorphisms, specifically rs1799732 (C/-C), within DRD2 gene play a role as a susceptibility gene with heroin dependence in Chinese but not in German population [65].
Association with substance addiction was not seen in the studied SNPs within SLC6A3BDNF and COMT genes. Conflicting results have been published in various studies on the influence of these genes on the increased risk of substance addiction [35-37,42-46]. Candidate gene analysis is problematic because the prior probability of seeing true association is exceptionally low [66], unless a very strong case of specific phenotype for involvement of a particular gene can be made. This is not applied to substance addiction because compelling biological evidence implicating particular neurotransmitter receptors in addiction is absent, with the possible exception of the opioid receptor gene family, and prior probability is impossible to determine [58]. Thus p-values of 0.05 are more likely to be chance occurrences, especially when using cases and controls where hidden population stratification as confounding factor is an inherent danger. However, a risk of population stratification as a confounding factor was not found in this study because the Jordanian Arab population are considered to be genetically homogenous population. This offers an advantage for genetic studies. For example, the numbers of different variations in the genes behind phenotypes are expected to be smaller than in more heterogeneous populations. This increases the probability to find genetic associations [67]. Therefore, even a small study sample from a genetically homogenous population, like the sample of subjects used in this study, can give accurate results.
In this study, genotyping was carried out by sequenom MassARRAY® system for 49 SNPs. The NCBI, dbSNP, HapMap databases and previous published data were used to select the studied SNPs, yielding reliable candidate SNPs database for genetic association analysis. In this array we focused on genes of particular interest for drug, alcohol and neuropsychiatric researchers because they were reported to be involved in drug dependence and other neurological and psychiatric disorders [4-12]. The chosen SNPs were also selected because they showed the greatest potential to distinguish between substance addicts' individuals and control subjects in previous studies [4-12]. Therefore, the distribution of SNPs through the selected genes was optimal.
Various studies showed a risk of false positive results due to population stratification. However, a risk of false positive results was not found in this study because genotypic frequencies of chosen SNPs in the patients and controls met HWE expectations. In addition, it is likely that there were genotyping errors. However, genotyping errors were minimized by genotyped each patient twice in order to avoid technical errors as evidenced by the low average rate of genotype discrepancy. Genotyping was conducted for patients under the same conditions and during the same period. Genotypes were also evaluated by investigators who were blind to the status of the subject and any discrepancies were resolved by test replication.
A confounding factor which could have contributed to the observed variations in the between this study and previous studies is the heterogeneity of population based on gender [66,67]. However in our study, only male individuals with substance addiction were genotyped. Therefore, the generalisation of the results to all substance addicts' individuals is limited. Another confounding factor is differences in phenotype in addiction such as polysubstance use, severity of addiction and the use of unstructured clinical interviews to obtain phenotypic data could affect the genetic association analysis. However, these confounding factors are not found in our study as a specific clinical structural interview was designed based on the DSM-IV criteria and the Addiction Severity Index (ASI) for collecting clinical and phenotypic data [52]. The careful and extensive interview based phenotypic data collection has been performed by highly trained psychiatrist consultants, yielding exceptionally reliable phenotype data. In addition, the study sample is strongly enriched with regular substance addicts' individuals giving more statistical power.
Overall our results indicate that the DRD1 ,DRD3 ,DRD4 ,DRD5 ,SLC6A3 ,BDNF and COMT genes are not likely to be a major genetic risk factor for substance addiction in the Arab population, with the exception of strong association between substance addiction and DRD2 gene. However, it has been proposed that defects in various combinations of these genes for these neurotransmitters results in the Reward Deficiency Syndrome (RSD) and that indivuals at risk for abuse of the unnatural rewards [68]. Because of its importance, DRD2 gene was a major candidate gene [68-70]. Several studies in the past decade have shown that in various subject groups the DRD2 gene is associated with alcoholism, drug abuse, smoking, obesity, compulsive gambling, and several personality traits [69,70]. A range of other dopamine, opioid, cannabinoid, norepinephrine, and related genes have since been considered to be candidate genes. Like other behavioral disorders, these genes are polygenically inherited and each gene accounts for only a small per cent of the variance [68,69]. Techniques such as the Multivariate Analysis of Associations, which simultaneously examine the contribution of multiple genes is required for understanding the genetic makeup of polygenic disorders. In the future research could be also directed towards using a genome-wide association analysis and including more specific case–control study with a wider set of phenotypes.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
This manuscript was prepared by AL-EITAN with support from the co-author listed. DNA extraction, SNPs selection; experimental design and statistical analysis were conducted by AL-EITAN with assistance from the co-author listed. Patient samples selection and DNA extraction were done through a collaboration link with JARADAT at Princess Haya Biotechnology Centre (PHBC). JARADAT, HULSE and TAY were assisted in designing the study to proof reading the manuscripts. All authors read and approved the final manuscript.
Publication number LA011-006 of the Centre for Forensic Science at the University of Western Australia. We gratefully acknowledge the contribution of participating patients whose cooperation made this study possible. We also would like to thank the Genomics Research Group at Princess Haya Biotechnology Center (PHBC) for their technical support. We gratefully thank and appreciate all the technical help and support from the AGRF, in particular, Shane Herbert and David Hawkes, along with their staff from the Perth and Melbourne Nodes, respectively. Funding for this project was provided in part by Centre for Forensic Science and Unit for Research and Education in Alcohol and Drugs of the School of Psychiatry and Clinical Neurosciences, The University of Western Australia.
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Higuchi S, Muramatsu T, Muramatsu S, Murayama M: No evidence of association between structural polymorphism at the dopamine D3 receptor locus and alcoholism in the Japanese.
Kotler M, Cohen H, Kremer I, Mel H, Horowitz R, Ohel N, Gristsenko I, Nemanov L: No association between the serotonin transporter promoter region (5-HTTLPR) and the dopamine D3 receptor (BalI D3DR) polymorphisms and heroin addiction.
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Kendler KS, Prescott CA: Cannabis use, abuse, and dependence in a population-based sample of female twins.
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Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS: Variant brain-derived neurotrophic factor (BDNF) (Met66) altersthe intracellular trafficking and activity-dependent secretion of wildtype BDNF in neurosecretory cells and cortical neurons.
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Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR: Effect of COMT Val108/158 Metgenotype on frontal lobe function and risk for schizophrenia.
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Cheng CY, Hong CJ, Yu YW, Chen TJ, Wu HC, Tsai SJ: Brain derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males.
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Nikoshkov A, Drakenberg K, Wang X, Horvath MC, Keller E, Hurd Y: Opioid neuropeptide genotypes in relation to heroin abuse: Dopamine tone contributes to reversed mesolimbic proenkephalin expression.
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Li J, Ji L: Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix.
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Comings DE, Blum K: Reward deficiency syndrome: genetic aspects of behavioral disorders.
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JAMA 1990, 263(15):2055-2060. PubMed Abstract | Publisher Full Text


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Benjamin Stockham HeadshotBenjamin Stockham News Feeds
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THE GRAND BUDAPEST HOTEL, TRUE DETECTIVE, and More Lead 2015 Writers Guild Awards- ALL the Winners (Feb 15, 2015)
Scoop: ABOUT A BOY on NBC - Tuesday, February 17, 2015 (Feb 2, 2015)
Scoop: ABOUT A BOY on NBC - Tuesday, February 10, 2015 (Feb 2, 2015)
BWW TV: One Cast More! LES MISERABLES Welcomes New Broadway Cast Members!BWW TV Exclusive: Renée Fleming & More Get into Character for LIVING ON LOVE; Go Inside the Cast Photo Shoot!BWW TV Exclusive: Spotlight on the Cast of AN AMERICAN IN PARIS- Meet Taeler CyrusVIDEO: Watch Two New Clips from Next Episode of HBO's LOOKINGSTAGE TUBE: Aaron Lazar Performs Cut Song from Sting's THE LAST SHIP at 54 BelowBWW TV: Watch Highlights from Signature Theatre's THE LIQUID PLAIN!BWW TV Exclusive: Spotlight on the Cast of AN AMERICAN IN PARIS- Meet Allison Walsh & Will BurtonSTAGE TUBE: Find Time for Broadway Green Alliance's College Green Captain Prize!VIDEO: Watch CHAPPIE's Hugh Jackman Attend the First Ever Holographic Press ConferenceVIDEO: Judi Dench Teaches Jimmy a Bollywood Dance Move on TONIGHTExtensive New Song-Focused FINDING NEVERLAND Video FeaturetteBWW TV Exclusive: Broadway Legend Barbara Cook Sings the Classics for the AMERICAN SONGBOOK Series!BWW TV Exclusive: Spotlight on the Cast of AN AMERICAN IN PARIS- Meet Victor J. WisehartBWW TV: Watch Highlights of Larry David & More in FISH IN THE DARK on Broadway!
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text: Hamilton: Button success not impacting my formBy Updated 5:47 PM ET, Thu November 10, 2011Lewis Hamilton won the 2008 Formula One drivers' championship but is fifth this season.Story highlightsLewis Hamilton rejects idea Jenson Button's success is putting him under pressureHamilton is fifth in drivers' championship while McLaren teammate Button is secondBritish 2008 world champion says personal problems have affected his seasonHamilton confident that he can improve his fortunes in 2012 seasonMcLaren driver Lewis Hamilton has scotched claims by his own team principal that teammate Jenson Button's success this Formula One season has impacted on his own performances.The British driver, world champion in 2008, is languishing fifth in the drivers' championship -- 172 points behind leader Sebastian Vettel, who has already secured the title, and 38 behind Button, who is second.Hamilton has two victories to Button's three this season and has been involved in a string of collisions, mostly with Ferrari's Brazilian driver Felipe Massa.But he rejected claims by McLaren team boss Martin Whitmarsh that Button's form in 2011 has been a factor in his disappointing campaign."I would not say so," he told Formula One's official web site. "Jenson is good at the moment and that is only good for the team. I always said that if Jenson proves to be better than me I would need to do a better job and improve. "He has put himself in a better position than me this year and on top of that he has managed to stay out of trouble. He has got a good group of people around him and they are there all the time. He has done a great job but this doesn't affect me at all. "Hamilton recently split with his girlfriend, singer Nicole Scherzinger, and is no longer managed by his father Anthony. The 26-year-old says that the settled team Button has assembled around him has helped his teammate's performances, while his own lack of a positive "bubble" has affected his form."Jenson's got his Dad, who's there at every single race, he's got his manager, he's got his friends and his girlfriend there all the time," he said."He's got a great bubble around him and with that he's able to go out there and perform without any worries on his mind. I lost that bubble. It is a priority for me to create that atmosphere around myself because it's a happy bubble."Hamilton admits he already has one eye on next year and is determined to get back into contention for the drivers' championship in 2012."Of course I am thinking about how to change things for the better next year. And I do feel confident about that. I know the right direction to take for next year and I know how to make things better."More from motorsportMercedes and Lewis Hamilton fastest at Circuit de Catalunya testingNico Rosberg leaves rivals trailing as Mercedes shows its hand MotoGP: Marquez fastest in Sepang testing Powered by Livefyre


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6 Rules for Becoming a Prosecutor By Bruce Reilly Bruce Reilly: Hardly any new prosecutor will get a made-for-TV movie case, write a book, and get on the speaking circuit. The real job is very repetetive, threatening to jade and bleed your soul.
Would King Have Spoken Out on LGBTQ Justice? By Rev. Irene Monroe Rev. Irene Monroe: Sadly, Bayard Rustin, the gay man who was chief organizer and strategist for the 1963 March on Washington that further catapulted Martin Luther King onto the world stage, was not the beneficiary of King's dream.


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By Kat Giantis
Rihanna's big night out in London ended with a bloody knee that may or may not have been indirectly caused by Chris Brown.
On Saturday night, the minidress-clad chanteuse was reportedly partying at hot spot The Box with model Cara Delevingne when someone hurled a bottle of energy drink Lucozade in her direction, along with a few choice words about her sometime squeeze, Chris Brown.
While the bottle didn't connect, the resulting tumult apparently caused RiRi to fall against the grate of a shop window and scrape her knee (see photo below). No word on whether the alleged Brown-related insults hit the mark.
The injury, such as it was, seemed to need only a bit of disinfectant and perhaps a SpongeBob-themed Band-Aid.
RiRi is in London for Fashion Week and had just presented her debut collection for British retailer River Island before the club kerfuffle.
Rihanna gives Chris Brown the cold shoulder, gets hot for Mary Jane
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Thursday, August 07, 2014
Post-Storm Rainbow
A rainbow was visible at Westport's Compo Beach Wednesday night following a brief but violent thunderstorm that downed trees and power lines. (CLICK TO ENLARGE) Alexandria Donovan for WestportNow.com
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Follow Wilfred
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In the face of some difficult challenges Ryan begins to lose hope on Wilfred.
After Wilfred suggests it, Ryan decides to hold back information from Jenna on this episode of Wilfred.
Wilfred must face down a new enemy while Ryan helps his mother adjust on Wilfred.
"Patterns" is the sixth episode of Wilfred's fourth season.
Ryan and Wilfred share very different memories of the same disturbing incident on Wilfred.
Ryan perforrms a scientific experiment using Wilfred as his subject on the latest episode.
Ryan and Wilfred end up taking sides in Kristen's custody battle.
While on a camping trip, Wilfred and Ryan are confronted by an unwelcomed guest.
On the season 4 premiere of Wilfred, Ryan gets a second chance.
On the Wilfred season 3 finale, Jenna tells Ryan he can no longer see Wilfred at a time when he needs him the most.
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Ryan: I thought it would make me sound Effete.
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Movie SummaryChop Shop
Web Site: http://noruzfilms.com/ Description: Alejandro, a tough street orphan, lives and works in an auto-body repair shop on the outskirts of Queens, New York. In the confusing and complex world of adults, young Alejandro struggles to make a better life for himself and his sister, Isamar. Movie summaries and listings powered by Cinema-Source
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About Hit-Boy
Born in Fontana, California, Hit-Boy started promoting his music in the early 2000s on Myspace. Polow Da Don got in touch with the young producer with a message that said no more than "Let's Get This Paper". Since, he has produced for major artists such as Kid Cudi, Kanye West, Jay-Z, Eminem, Lil Wayne, Mary J Blige, 50 cent, Chris Brown, Snoop Dogg, Big Sean & Justin Bieber. Hit-Boy is also one of the founders of Surf Club, a collective of beat makers including Chase N Cashe, Bcarr and Chili Chill. They got their first break in 2007 after linking up with Polow Da Don. Hit-Boy's work in 2011 really put him on the map when he signed to GOOD Music and produced smash singles like Kanye West & Jay Z's "N*ggas In Paris" and A$AP Rocky's "Goldie". In 2012 he proved he was more than just a producer with a single of his own, "Jay-Z Interview". In June of 2013, the producer left GOOD Music on what was reported as GOOD terms. Now with Hits Since '87 as an imprint of Interscope records, we are excited to see what 2014 has coming for one of the most talented producers of this generation.
Facts Only
- Hit-Boy's uncle is Rodney Benford from the R&B group TROOP.
Old School Caddy Hit-Boy Feat. KiD CuDi116.8K Views143 Comments
Alert [Tags] Hit-Boy Feat. Nipsey Hussle77.5K Views114 Comments
T.U. Hit-Boy Feat. Audio Push, Problem & Juicy J70.1K Views78 Comments
Grindin' My Whole Life Hit-Boy Feat. Audio Push, Kent M$NEY, B Mac The Queen, N.No, B.Carr & Big Hit63.5K Views72 Comments
Fan (Remix) (Tags) Hit-Boy Feat. 2 Chainz56.2K Views53 Comments
Alert [CDQ] Hit-Boy Feat. Nipsey Hussle49K Views50 Comments
In The Studio With Hit-Boy: Making Of Nicki Minaj & Beyonce's "Feeling Myself"
6.4K Views4 Comments
Hit-Boy On Snoop Dogg's GGN
2.3K Views0 Comments
Hit-Boy "Where I'm From" Short Documentary
2K Views1 Comments
Hit-Boy & HS87 Crew Freestyle On Sway In The Morning
2.2K Views2 Comments
Hit-Boy Feat. Audio Push, Kent M$NEY, B Mac The Queen, N.No, B.Carr & Big Hit "Grindin My Whole Life" Video
4.3K Views6 Comments
All I've Ever Dreamed Of 2013
HITstory 2012
Love Notes 2011
A Hit-Boy Christmas 2010
- Hit-Boy Says SZA Wrote A Part For Nicki Minaj & Beyoncé's "Feeling Myself" 11.7K Views
- Joey Bada$$ Reveals That He Worked With Hit-Boy, DJ Premier And Statik Selektah On "B4.DA.$$" 6.2K Views
- Stream Kent Money's New "Crowned" EP 2.2K Views
- Stream HS87's New Album "We The Plug" 17.4K Views
- Hit-Boy Offers Preview Of New HS87 Album "We The Plug" 8K Views
- Hit-Boy Announces New HS87 Album, "We The Plug" [Update: Release Date Revealed] 14.6K Views
- Hit-Boy Discusses Frustrations With "Trophies" Roll Out & "Alert" 13.2K Views


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WebSphere/DB2/Spring/Hibernate developer Hourly – 3 to 6 months – 30+ hrs/week – Posted 14 hours, 45 minutes ago This is Phase 1 of a longer project and may lead to a lasting relationship and lots of ongoing work. The task is to develop a WebSphere Web Application - based on screen mockups and database schema. Use Spring Framework in your code and Hibernate to access DB2 * Every model and view class will need a JUnit Test Case * UI will use lots of JavaScript * IDE is WebSphere Application Developer To apply, please send me a good sample of your java ... core-java hibernate ibm-db2 ibm-websphere javascript junit spring-framework
Ibm connection mail plugin setup Hourly – Less than 1 week – Less than 10 hrs/week – Posted Feb. 28 2015 need expert for already installed ibm connection do do configuration mail plugin for Exchange (Kerberos, Spenego) ibm-websphere
GroovyOnGrails Java/JEE developers required. INDIVIDUALS ONLY -no companies Hourly – 3 to 6 months – 30+ hrs/week – Posted Feb. 24 2015 Only reply if you fit in Location and are an Individual. Also previously applied candidates, do not reapply. We have a requirement for a JEE developer with atleast 6 years experience with enterprise applications, workflows and complex business logic. The high level tech stack is JEE, Websphere and Tomcat, Eclipse, DB2. Groovy on Grails, Bootstrap UI. Highy Desirable: Graphic design skills, HTML5, CSS 3.0, Responsive. Websphere admin experience. You should be able to work full time (40hrs). Have good ... grails groovy html5 ibm-websphere j2ee
IBM BPM/Lombardi Engineer Hourly – More than 6 months – 30+ hrs/week – Posted Feb. 17 2015 We are looking for an experienced developer with Java skills and hands-on experience with IBM's Business Process Manager product. MUST HAVE: • 8+ years of Distributed Application Development and Engineering experience (both multi-tier and large scale application experience desired) • In depth knowledge of and extensive hands-on experience with the IBM WebSphere (Lombardi) Business Process Manager solution • Experience with application development languages including Java, C++, C (Java preferred including servlet, JSP, EJB, MDB) NICE TO HAVE: • Experience with various scripting languages ... ibm-db2 ibm-websphere java jsp
Looking for Online " Datastage" (part time) Trainer Fixed-Price – Est. Budget: $250.00 Posted Feb. 5 2015 Greetings from BISP SOLUTIONS INC. Currently we are Looking for Online "IBM Websphare" (part time) Trainer, who like to work with us for online training assignments. Our students are located across the globe, we facilitate individuals and corporate to meet their training needs. Position : Part Time Trainer Course Duration: around 30 Hours We would provide below services -Student Registration -Training Fees Management -Feedback and quality guidelines -Scheduling of demo class & regular classes. -Technical Support Activities. -Software licenses to connect to ... datastage data-warehousing etl ibm-websphere


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New Products
LDRA and IAR Systems target safety certification of small-footprint architectures
The interface between the LDRA tool suite and the IAR Embedded Workbench IDE offers users a rich array of tools rarely available in small-footprint environments. With out-of-the-box support for IAR C-SPY Simulator, the LDRA tool suite can be configured to automatically import and perform static analysis on the generated code. LDRA's dynamic analysis and unit testing run on the simulator and the target using IAR C/C++ Compiler and IAR C-SPY Debugger to download and execute the code on the target.
For certifying systems to the most stringent levels, the LDRA tool suite can perform complete code coverage, ensuring that all parts of an application have been fully tested. The LDRA tool suite also provides test harness creation, results capture, and report generation. Artifacts created during analysis can be imported into LDRA's TBreq and TBmanager requirements traceability tools, showing progress of system requirements across the software-development lifecycle. The LDRA tool suite fully documents all aspects of analysis, test and requirements traceability, automatically generating the documentation needed for standards compliance.
Because of the limited resources of some of these platforms, LDRA offers developers alternative methods for creating efficient testing solutions. With evaluation boards such as AVR STK600 and STM34F103ZE where targets have limited memory, the LDRA tool suite streams the data back to the host via the serial port. Further, static analysis and unit testing on both simulator and target can be completely automated and run from a script. Developers can test identical instrumented executables and test harnesses on a target and simulator environment, greatly speeding time to market.
IAR Embedded Workbench reaches beyond the capabilities of native tool chains, providing full ANSI C compliance, support for embedded C++ as well as host-controlled I/O facilities not typically available for these microcontrollers. The LDRA tool suite leverages these capabilities, reading IAR project files and using these files to speed static analysis efforts via included paths, macros and other settings. In addition, the project files are used to compile, control IAR's simulation and device-programming environments, execute on target, and extract the results. With this integration, developers gain a head start on performing system and unit tests using the capabilities already available in the IAR infrastructure. Working together, the LDRA tool suite and IAR Embedded Workbench provide seamless solutions to customer test automation needs.
- TIs SafeTI software development certified to ISO 26262/IEC 61508
- ARM strengthens position in safety-critical applications
- Tool kit is pre-certified for ISO 26262
- Microchip, LDRA collaborate on functional safety
- QNX launches safety-optimised auto operating system
- Static code analysis tools gain ISO26262, IEC61508, EN50128 certification
- Better performance with new compiler
- Green Hills tool certified for functional safety
- Safety-compliant development tools for Renesas' RX series MCUs
- Interface integrates e-vehicles into smart grid
- Requirements lifecycle management tool targets safety-critical FPGA and ASIC design
- Motor control chipset supports functional safety requirements
- Wind River rolls safe and secure partitioning for industrial and automotive applications
- Sensorless sinusoidal motor control IC receives IMQ certification
- PRQA QAC certified for ISO 26262 and IEC 61508 compliance
- Is this the Tesla killer?
- Self-driving cars in real-world traffic with real customers
- Flow cell powertrain stuns with extreme data
- Audi launches lighting lab
- Supercapbatteries, thermoelectrics to power future cars
- Porsche rainmaker advocates platooning
- Rear axle becomes steerable by wire
- Xilinx flexes its muscles in the ADAS arena
- Volvo cars share road-condition info in the cloud
- Infineon, Hella make radar sensor more affordable
- Ballard IP to boost Audis fuel cell developments
- Infineon: CAN FD success goes at the expense of FlexRay
- NXP, Freescale plan mega merger
- Four-channel video encoder addresses parking assist systems
- Scalable electric powertrain targets utility vehicles
- Making cars safer through technology innovation
- Supplying DC input power for HEV testing
- NSR Noise Suppressors: Wirewound Resistors
- Virtual Hardware In-the-Loop: Earlier Testing for Automotive Applications
- Open Standards and Product Differentiation
- Camera Solutions with Micrel Power Management and Networking


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Most people that follow me know by now I've been building and finally moved into a new house in Greeneville, TN. Something I researched and decided on early on in the process was installing a whole home audio setup throughout many of the rooms. I looked at two options with NuVo and Sonos, and ultimately decided on the NuVo P-Series ... Read More »
No VCDX Design Is Perfect
I wanted to quickly talk about something from my own personal VCDX experience that may help people a little bit that was in my head today. There are very few IT Professionals that are NOT perfectionists. It's true, admit it, we are all very Type-A and with that comes a need to do everything as perfect as we possibly can. ... Read More »
Thoughts On The New Community VCDX Mentoring
Yesterday I posted on VMTN about the new VCDX Mentoring Process. I wanted to post a quick not about this change and see what people are thinking. Honestly I have not gotten any feedback, good, bad, or indifferent, so I guess no news is good news? Here is some of my personal feelings on the change and why I truly ... Read More »
VCDX is About Validating Architects, Not Teaching Architecture
I am going to be a little controversial here in this post so I warn you. I was actually reading This Post by new VCDX Rob Nolen and we also had a phone conversation that got me thinking a little bit. There has been some conversations lately about obtaining "VCDX Enablement" and other VCDX "training" and there is something I ... Read More »
A Note About 2015 VCDX Defense Dates
People continue to ask about the 2015 VCDX Defense Dates. Instead of answering each tweet, and VMTN Community post every couple of days I just want to let everyone know, it's being worked on. The new Program Manager Karl Childs is working on securing locations for the defenses, and you can make an educated guess about the time we are ... Read More »
My Opinion Of The VCDX Pass Rate
Let me strongly preface this with the fact it's 100% my opinion only, but I wanted to just write quickly about my opinion on the "VCDX Pass Rate" or passing percentage, or whatever you want to call it. Over the last few years there has been some discussion on this as more people are passing. The "pass rate" may seem ... Read More »
VCDX Fear Of Failure – Fuggedaboutit
I'm a student of personal growth, and specifically of John C Maxwell. If you've not read any of his stuff….well frankly, you should. I have so many of his quotes in my head, on my laptop, and all around me. One of the books I enjoyed by him very much was called Failing Forward: Turning Mistakes into Stepping Stones for Success. ... Read More »
Presenting The VCDX Value To Your Boss
I love spending time at events with folks in the community. Mostly because I am able to get some perspective from everyone as they see it from the outside looking in. This week at VeeamON was no exception. Although I was there to do my last presentation on vCloud Air, I was also able to have at least a dozen ... Read More »
VCDX Program Terminology
As with any new role you always get into the weeds on a lot of things. In this case it's the various names floating around and rumblings of what's out there for programs related to VCDX. I wanted to take a quite second to put just put some clarity around a few names and terms tossed out and where I ... Read More »
Conquering Your Fear Of The VCDX Panelists
I wanted to say I had such a great time at the Atlanta VMUG, and most of all the conversations with all the people about this new role. I cannot believe the support for the program, the renewed excitement about it, and I am humbled by the personal support from all the people who I've talked to in the last ... Read More »
How To Give A vCloud Air Virtual Machine Internet Access
The most common initial task that I get asked for help on is connecting a newly deployed virtual machine in vCloud Air from the catalog to the internet so you can install other packages or update the operating system. This post is probably long overdue considering the number of times I have explained the fairly simple process to people so ... Read More »
Time To Take On A New Challenge – VCDX Evangelist
Over the last nearly 7 years I've worked at VMware I have held positions in PSO, the original "Cloud Practice", which then became the COE. I've done a short time with the Nicira folks after the acquisition, and before the Networking BU was formed. Then I went back to Global technology solutions, and finally to the vCloud Air Business Unit ... Read More »


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What about Guinan?
View Single Post
September 24 2008, 02:54 PM
Location: Ayrshire, Scotland
Re: What about Guinan?
RaymondJames wrote:
exodus wrote:
Who would really leave the luxury of the Enterprise to work on a tug boat like Voyager? Wasn't it bad enough they kept bringing back a nobody character like Boothby in uncreative ways?
Q, Riker, Boothby, Barclay, LaForge & Troi, wasn't there enough TNG cast on Voy. without adding Guinan?
Purhaps a personal quest to find more of her people?
Granted not exspecting to be sucked into the Delta quadrant.
Although you say that she wouldn't expect the Voyager to get pulled into the DQ, Voyagers initial mission was simply to head out to the Badlands and locate the Maquis under Commander Chakotay and bring them, and Tuvok, back to Starfleet. Beyond that would assumedly have been general Starship exploration.
Guinan wouldn't also be needed as initially Voyager didn't have a Bar, only a wall with Replicator units on it.
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Reviews for Tear Drops |
PanonLove chapter 1 . 5/26/2012 Though I ship Scorpius and Rose, I have to say that I loved this soooo much! Haha. James was really sweet :) |
lowi chapter 1 . 12/28/2011 Oh my gosh, mew. This was so wonderful, I really really REALLY loved it! 1. The ScorDom. Ofc. &hearts 2. The RoseJames - it was so yummy and James was so funny and protective and bad boy. ;) 3. TROY AND CURTIS. HEY LOVELIES. :3 4. the ending. Aksjdndbdjjsjsdjjd. To sum up: I LOVED THIS. &hearts |
autumn midnights chapter 1 . 12/21/2011 Mmmkay so I just love this couple, and the way you portrayed them. Poor Rose, to find out Scor was cheating on her with her own cousin. That's gotta suck. |


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no longer than 70mm for 25.4mm bars. Preferably with a 4 bolt bar fitting. looking to spend £15 or less
Classifieds - Wanted
WTD: XC style stem...
Posted 2 years ago #
Have a 50mm DDG stem in red, 4 bolt faceplate, 25.4mm bars, some light surface rust on the bolts as my daughter went to Uni by the sea, so £8 delivered, photo on request, email addy in profile.
Posted 2 years ago #
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