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Biomedical subjects

C Lerman

Publications and source records attributed to C Lerman.

At least 19 recordsLinked to original sources
PubMed2006

Association of OPRM1 A118G variant with the relative reinforcing value of nicotine.

RATIONALE: The endogenous opioid system has been implicated in substance abuse and response to pharmacotherapies for nicotine and alcohol addiction. We examined (1) the association of the functional OPRM1 A118G variant with the relative reinforcing value of nicotine and (2) the main and interacting effects of the mu-opioid receptor antagonist naltrexone on nicotine reinforcement. METHODS: In a within-subject, double-blind human laboratory study, 30 smokers of each OPRM1 genotype (A/A vs. A/G or G/G) participated in two experimental sessions following 4 days of orally administered naltrexone 50 mg or placebo. Participants completed a validated assessment of the relative reinforcing value of nicotine. This cigarette choice paradigm assesses self-administration of 0.6 mg nicotine vs. 0.05 mg (denicotinized) cigarettes after a brief period of nicotine abstinence. RESULTS: The relative reinforcing value of nicotine (number of nicotine cigarette puffs) was predicted by a significant OPRM1 by gender interaction. Among women, the low-activity G allele (A/G and G/G) was associated with a reduced reinforcing value of nicotine; among male smokers, there was no association with genotype. Smokers carrying a G allele were also significantly less likely to differentiate the nicotine vs. denicotinized cigarettes by subjective ratings of satisfaction and strength. No evidence for an effect of naltrexone on nicotine reinforcement was found in the overall sample or in the genotype or gender subgroups. CONCLUSIONS: This study provides initial evidence for an association of the OPRM1 A118G variant with nicotine reinforcement in women.

Adaptation, Psychological↗
PubMed2006

Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy.

We investigated the effect of slow metabolism of nicotine, predicted by CYP2A6 genotypes resulting in less than or equal to 50% activity, on baseline smoking behaviours and treatment variables in an open-label nicotine replacement therapy (NRT) clinical trial. Caucasian smokers with CYP2A6 slow vs normal metabolism had lower metabolic activity, indicated by the 3-hydroxycotinine/cotinine ratio (0.23+/-0.17 vs 0.45+/-0.22, P<0.01, respectively). CYP2A6 slow metabolizers also smoked fewer cigarettes per day compared to normal metabolizers (20+/-7 vs 24+/-10, respectively, P<0.04). With nicotine patch use, slow metabolizers had higher nicotine plasma levels compared to normal metabolizers (22.8+/-4.6 vs 15.8+/-7.6 ng/ml, respectively, P=0.02) while using the same numbers of patches/week. With nicotine spray use, where like in smoking the nicotine intake can be easily adjusted to adapt to rates of metabolism, slow metabolizers achieved similar nicotine levels compared to normal metabolizers (5.8+/-4.1 vs 8.0+/-9.1 ng/ml, P=0.82), by using fewer doses of nicotine spray/day (4.8+/-3.6 vs 10.5+/-8.0, respectively, P<0.02). These findings indicate that CYP2A6 genotype influences smoking behaviour in a Caucasian treatment-seeking population and that CYP2A6 genotype affects plasma levels obtained from, and usage of, NRT.

Administration, Cutaneous↗
PubMed2005

Monoamine reuptake inhibition and nicotine receptor antagonism reduce amplitude and gating of auditory evoked potentials.

BACKGROUND: Sensory encoding deficits have been extensively studied as endophenotypic markers of schizophrenia using auditory evoked potentials. In order to increase understanding of the neurochemical basis of such deficits, we utilized an animal model to test whether monoamine reuptake inhibition and nicotine receptor antagonism reduce the amplitude and gating of the P20 and N40 auditory components. METHODS: C57BL/6J mice received 12 days of chronic vehicle, bupropion, haloperidol or bupropion plus haloperidol. Auditory evoked potentials were then recorded in alert mice to measure the amplitude and gating of evoked components during a paired click paradigm similar to tasks used to measure the P50 and N100 auditory potentials in schizophrenia. Evoked potentials were recorded prior to and following acute nicotine. RESULTS: Bupropion reduced the amplitude and gating of the N40 evoked potential in mice, similar to the P50 and N100 endophenotypes associated with sensory encoding deficits in schizophrenia. This deficit was fully reversed only by the combination of haloperidol and nicotine, suggesting that dopamine reuptake inhibition and nicotine antagonism both contribute to the observed phenotype. Furthermore, nicotine increased P20 amplitude across all groups supporting a role for nicotine agonists in pre-attentive sensory encoding deficits. CONCLUSIONS: We propose that the combination of monoamine inhibition and nicotine receptor antagonism may serve as a useful model for preclinical screening of pharmaceutical compounds aimed at treating sensory encoding deficits in schizophrenia.

Animals↗
PubMed2005

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers.

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian smokers. Based on the animal literature, the study's objective was to test the hypothesis that smokers carrying specific variants in dopamine-related genes previously associated with risk for addictive behaviors would exhibit heightened levels of cigarette craving following laboratory exposure to cues. To this end, cigarette craving was induced in healthy African-American smokers (n=88) through laboratory exposure to smoking cues. Smokers carrying either the DRD2 (D2 dopamine receptor gene) TaqI A1 RFLP or the SLC6A3 (dopamine transporter gene) 9-repeat VNTR polymorphisms had stronger cue-induced cravings than noncarriers (Ps <0.05 and 0.01, respectively). Consistent with the separate biological pathways involved (receptor, transporter), carriers of both polymorphisms had markedly higher craving responses compared to those with neither (P<0.0006), reflecting additive effects. Findings provide support for the role of dopamine in cue-induced craving in humans, and suggest a possible genetic risk factor for persistent smoking behavior in African-American smokers.

Adult↗
PubMed2005

Is Swedish snus associated with smoking initiation or smoking cessation?

Nicotine replacement therapies (NRT) are an effective treatment for tobacco dependence, yet most smokers do not quit or remain abstinent. We investigated whether Swedish snus (snuff) use was associated with smoking cessation among males participating in a large population based twin study in Sweden. Snus use was associated with smoking cessation but not initiation. Given that snus delivers comparable nicotine concentrations but carries lesser cancer risk than cigarettes, snus may be a widely used, non-medical form of NRT. Evaluation of the efficacy of snus for smoking cessation should be evaluated in randomised clinical trials.

Adult↗
PubMed2004

Stress-induced cigarette craving: effects of the DRD2 TaqI RFLP and SLC6A3 VNTR polymorphisms.

Animal models have long implicated dopamine in stress-induced craving for a variety of addictive substances. However, translational studies of dopamine, stress and craving in humans are lacking. Based on the animal literature, this study's objective was to test the hypothesis that cigarette smokers carrying specific variants in dopamine-related genes would have heightened levels of cigarette craving following exposure to a laboratory stressor. Cigarette craving induced by controlled exposure to a laboratory stressor was assessed in healthy adult smokers (n=108) recruited by advertisement. Significantly stronger stress-induced cigarette craving was found for individuals carrying either the DRD2 (D2 dopamine receptor gene) A1, or the SLC6A3 (dopamine transporter gene) nine-repeat allelic variants. Stress-induced craving was markedly higher for those carrying both alleles, compared to those with neither, consistent with the separate biological pathways involved (receptor, transporter). Findings provide strong support for the possibility that dopamine involvement in stress-induced craving well established in animal models also applies to humans, and suggest a potential genetic risk factor for persistent smoking behavior.

Adult↗
PubMed2004

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial.

To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n=82) were significantly more likely than those homozygous for the Asn40 variant (n=238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.

Administration, Cutaneous↗
PubMed2001

Impact of educational print materials on knowledge, attitudes, and interest in BRCA1/BRCA2: testing among Ashkenazi Jewish women.

BACKGROUND: The recent identification of several BRCA1/BRCA2 founder mutations among Ashkenazi Jewish individuals has led to increased salience of BRCA1/BRCA2 testing for Jewish individuals. Little is known about interest in BRCA1/BRCA2 testing among Ashkenazi Jews from the general population. Furthermore, previous research has not generally evaluated the impact of education on interest in testing among individuals from the general population. The goal of the current study was to examine whether a brief educational booklet regarding BRCA1/BRCA2 testing would influence knowledge, attitudes, and interest in testing among Ashkenazi Jewish women from the general population. METHODS: After a baseline telephone interview, participants were randomized to receive either genetic testing educational print materials (n = 195 women) or general breast cancer education control materials (n = 196 women). One month after receiving these materials, the authors reassessed knowledge, attitudes, and interest in BRCA1/BRCA2 gene testing. RESULTS: Relative to the breast cancer education control materials, the genetic testing education materials led to increased knowledge, increased perception of the risks and limitations of testing, and decreased interest in obtaining a BRCA1/BRCA2 mutation test. CONCLUSIONS: These data indicate that preliminary print education can be used to educate low-risk individuals about BRCA1/BRCA2 genetic testing. This approach may be used to educate low-risk individuals about the benefits and risks/limitations of BRCA1/BRCA2 testing, so that they can make informed decisions about whether to pursue genetic counseling.

BRCA2 Protein↗
PubMed2001

Tryptophan hydroxylase gene variant and smoking behavior.

Approximately 50% of the variance in smoking behavior is attributable to genetic factors. Genes in the serotonin system are plausible candidates because of serotonin's role in mood regulation. The present study examined the association of smoking behavior with a polymorphism in the TPH gene, which codes for a rate limiting enzyme in the biosynthesis of serotonin. A polymorphism in intron 7 has been linked with a variety of traits involving poor impulse control. Participants in this study were 249 Caucasian smokers and 202 nonsmokers recruited through newspaper advertisements. Smokers completed smoking history and nicotine dependence assessments. The overall frequencies of the A- and C-allele were 42% and 58%, respectively. There was no association of TPH alleles with smoking status. However, case series analysis indicated that individuals with the A/A genotype started smoking at age 15.6 years, compared with 17.3 years among smokers with other genotypes. This association was significant in a multivariate regression model controlling for age, education, body mass index (BMI), alcohol use, and medication use. This finding is consistent with previous studies relating the A-allele to impulsive behavior and suggests that it may predispose to early smoking initiation. Future family-based studies are needed to confirm this finding. Published 2001 Wiley-Liss, Inc.

Adult↗
PubMed2001

BRCA1/2 testing: complex themes in result interpretation.

Since the cloning of BRCA1 and BRCA2, genetic testing for breast and ovarian cancer susceptibility has become more widespread. However, interpretation of test results is not always straightforward. To illustrate this point, five vignettes adapted from actual cases are presented. As these cases demonstrate, in many high-risk families, a deleterious mutation in BRCA1 or BRCA2 is not identified in an affected proband. There are several potential explanations for such a finding, namely that an undetected mutation in BRCA1 or BRCA2 may exist, or there could be a mutation in a rare or undiscovered gene. In addition, the possibility that women with breast cancer represent sporadic cases within hereditary cancer families must also be considered. Finally, the occurrence of BRCA1/2 variants of uncertain significance, often missense mutations, further complicates the risk assessment. In some of these instances, extending testing to relatives can be helpful to clarify results. When hereditary breast cancer cannot be ruled out, individuals may still be at increased risk for cancer and therefore need to obtain appropriate surveillance. The process of genetic counseling is critical both before and after testing to ensure that patients understand the potential medical and psychosocial implications of testing and are aware of available options and resources. A multidisciplinary approach to service delivery, which includes clinicians in genetics and oncology, can facilitate patients' decision making and provide continued access to information and support.

BRCA2 Protein↗
PubMed2001

Consent to the use of stored DNA for genetics research: a survey of attitudes in the Jewish population.

The use of anonymized stored tissue is a routine practice in genetic research. Investigators who utilize stored samples are neither required nor able to obtain informed consent before each use. Many genetic studies, however, are conducted on specific ethnic populations (e.g., Ashkenazi Jews). The results in these cases, although individually anonymous, are not anonymous with respect to the ethnicity of the participants. This lack of group anonymity has led to concern about the possibility of stigmatization and discrimination based on the results of the genetic research. In the present study we surveyed Jewish individuals about their attitudes regarding the practice of using stored DNA samples for genetic research. Specifically, we were interested in whether attitudes about informed consent and willingness to participate in genetics research using stored DNA would depend on the circumstances in which the material was collected (i.e., clinical setting vs. research setting) and the characteristics of the disease or trait under investigation. Overall, most respondents reported that written informed consent should be required and that they would be willing to provide such consent. Participants were most willing to provide consent, however, when the sample had been collected in a research rather than clinical setting. Further, participants were more likely to endorse the need for obtaining consent when the sample was collected in a clinical setting. Finally, participants were significantly less willing to participate in research that examined stereotypical or potentially stigmatizing traits as opposed to research that examined medical or mental illnesses.

Adolescent↗
PubMed2001

Parental communication of BRCA1/2 genetic test results to children.

The aim of this study was to evaluate the likelihood, correlates, and psychological impact of parental communication to children of parents' BRCA1/2 genetic test results for breast cancer risk. Subjects were 133 adult members of high risk families. Sociodemographic, clinical, and psychological distress variables were assessed during a baseline telephone interview conducted prior to patient education and test result notification. Parental communication of test results to children and parental psychological distress and coping efforts were assessed 1 month post-genetic counseling and receipt of test results. Mothers (versus fathers), and persons with higher levels of baseline general distress, were significantly more likely to communicate their test results to children. Post-counseling coping efforts, both active and avoidant, were positively associated with post-counseling distress levels. However, communication of test results to children did not relate to changes in distress. In conclusion, parents with higher levels of pre-counseling general psychological distress may be more likely to communicate their genetic test results to children; however, this act does not minimize their distress and could possibly generate distress in their youngsters. Research is needed to evaluate the process and content of post-test disclosure episodes and the impact on participant, child, and family functioning.

Adaptation, Psychological↗
PubMed2001

Attention-Deficit Hyperactivity Disorder (ADHD) symptoms and smoking patterns among participants in a smoking-cessation program.

Previous research has suggested an increased liability to smoking among individuals with Attention-Deficit Hyperactivity Disorder (ADHD). This link is thought to be attributable, in part, to nicotine's beneficial effects on attention and performance. In the present study, we examined the association of ADHD symptoms of inattention and hyperactivity with smoking behavior in a sample of 226 male and female smokers ages 18 and older who were enrolled in a smoking-cessation program. Prior to treatment, they completed measures of ADHD symptoms and standardized measures of smoking patterns. Hierarchical linear regression models were used to characterize the smoking patterns associated with ADHD inattention and hyperactivity symptoms, controlling for potential confounder variables. Smoking for stimulation purposes and the urge to smoke to minimize withdrawal symptoms were the primary patterns associated with ADHD inattention symptoms, while hyperactivity symptoms were not associated with smoking patterns. Consistent with a self-medication hypothesis, these results suggest that smokers with frequent symptoms of inattention may use nicotine as a stimulant drug to help manage these symptoms. Future studies of the role of inattention symptoms in response to smoking treatment are warranted.

Adolescent↗
PubMed2001

Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives.

Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth.

Adult↗
PubMed2001

Nicotine metabolism and CYP2D6 phenotype in smokers.

We tested the hypothesis that the polymorphic enzyme CYP2D6 is related to nicotine metabolism in 261 healthy subjects enrolling in a smoking cessation clinic. Subjects completed a questionnaire, were given dextromethorphan, and contributed a urine and blood sample. The CYP2D6 phenotype (based on a determination of dextromethorphan and metabolites in an aliquot of overnight urine) and genotype (based on characterization of CYP2D6 variant alleles by a PCR-based method on a subset) were determined. Seventeen poor metabolizers (6.5%) were observed among 261 phenotyped smokers. Nicotine and it chief metabolites, cotinine and trans-3'-hydroxycotinine were measured in the urine and adjusted for pH. All of the nicotine metabolite levels were significantly related to usual and recent smoking. Neither levels of smoking nor nicotine metabolites overall exhibited a relationship to the CYP2D6-deficient metabolizer phenotype. The ratio of nicotine:cotinine + trans-3'-hydroxycotinine, stratified by time since the last cigarette, was unrelated to gender, age, education, race (white/African American), recent alcohol or caffeine consumption, or smoking practices. Subjects in either the lowest quintile or decile metabolic ratio (ultrametabolizers) exhibited a significantly lower nicotine:cotinine + trans-3'-hydroxycotinine ratio after adjustment for recent smoking, pH, and other factors. These data suggest that the polymorphic CYP2D6 gene is not a major contributor to nicotine metabolism in tobacco smokers but may influence the disposition of nicotine in the small subset of the population who are CYP2D6 ultrametabolizers.

Adult↗
PubMed2001

Cost of genetic counseling and testing for BRCA1 and BRCA2 breast cancer susceptibility mutations.

Counseling and predictive testing are now available for the recently isolated BRCA1 and BRCA2 breast cancer susceptibility genes. We examined the societal costs of providing this counseling and testing to women at risk of having a breast cancer susceptibility mutation. Genetic counselors in a research program prospectively monitored the time necessary to provide counseling and results disclosure. A time-motion study was used to determine time spent on phone calls, preparation, and documentation for counseling. Study participants were surveyed to determine travel time and need for dependent care during counseling. The test cost was calculated using the charge for full BRCA1/2 gene sequencing (Myriad Genetics, Inc.) multiplied by a Medicare-based cost-to-charge ratio. Counselors spent an average of 4.2 h providing genetic counseling for women at risk of having a susceptibility mutation. Genetic counseling without testing cost on average $213, whereas counseling, testing, and disclosure of results totaled $2057. A brief physician-based counseling instead of genetic counselor-based counseling would produce only small reductions in total costs. Providing counseling and testing to the study population averaged $8034 per mutation found. The cost of testing and counseling exceeded $2000. The counseling portion of the cost comprised only 16% of the total cost, with the remainder representing costs associated with testing; thus, alternatives to full genetic counseling that shorten counseling time are unlikely to have a large impact on the overall cost of counseling and testing. The cost of detecting a mutation within a population of women is highly dependent on the prevalence of the mutation in the population.

Adult↗
PubMed2001

Effects of coping style and BRCA1 and BRCA2 test results on anxiety among women participating in genetic counseling and testing for breast and ovarian cancer risk.

Using the monitoring process model (MPM), the authors examined the immediate effects of coping style and test results on the psychological distress of women at increased risk for breast and/or ovarian cancers. Cases selected for analysis were 107 probands and relatives of positive probands participating in genetic counseling and testing for heritable cancer risk. Specifically, the authors explored the relationships among coping style (high and low monitoring), test results (BRCA1 and BRCA2 mutation carrier and noncarrier status), and psychological distress (state anxiety). Consistent with the MPM, higher monitoring was associated with greater psychological distress while anticipating genetic test results. After test results were disclosed, greater distress was associated with testing positive for a mutation. The implications of the findings for breast and ovarian cancer patients are discussed.

Adaptation, Psychological↗