Pathways to cannabis abuse: a multi-stage model from cannabis availability, cannabis initiation and progression to abuse

Aims   Although previous twin studies have modeled the association between drug initiation and abuse, none has included the obvious risk factor of drug availability. Our aim is to determine whether the genetic and environmental risk factors for cannabis availability also generate variation in cannabis initiation and/or progression to DSM-IV symptoms of abuse.
Design   We used multi-stage modeling, also known as causal-common-contingent (CCC) analysis, to partition the genetic and environmental factors into common and stage-specific components.
Participants   This report is based on data collected from 1772 adult males from the Mid Atlantic Twin Registry.
Measurements   The twins participated in two structured interviews which included clinical and non-clinical measures of cannabis abuse as well as retrospective assessments of perceived cannabis availability between ages 8 and 25 years.
Findings   Cannabis availability explained almost all the shared environmental risks in cannabis initiation and abuse. The influence of availability on the symptoms of abuse was indirect and mediated entirely by cannabis initiation.
Conclusion   These findings have begun to elucidate the causal processes underlying the liability to drug use and abuse in terms of putative risk factors. Specifically, our results show that the latent shared environmental factors in cannabis initiation and abuse can be explained by measured aspects of the shared environment—those responsible for variation in cannabis availability.     

Silane plus molecular hydrogen as a possible pathway to metallic hydrogen

The high-pressure behavior of silane, SiH₄, plus molecular hydrogen was investigated using a structural search method and ab initio molecular dynamics to predict the structures and examine the physical origin of the pressure-induced drop in hydrogen intramolecular vibrational (vibron) frequencies. A structural distortion is predicted at 15 GPa from a slightly strained fcc cell to a rhombohedral cell that involves a small volume change. The predicted equation of state and the pressure-induced drop in the hydrogen vibron frequencies reproduces well the experimental data (Strobel TA, Somayazulu M, Hemley RJ (2009) Phys Rev Lett 103:065701). The bond weakening in H₂ is induced by intermolecular interactions between the H₂ and SiH₄ molecules. A significant feature of the high-pressure structures of SiH₄(H₂)₂ is the dynamical behavior of the H₂ molecules. It is found that H₂ molecules are rotating in this pressure range whereas the SiH₄ molecules remain rigid. The detailed nature of the interactions of molecular hydrogen with SiH₄ in SiH₄(H₂)₂ is therefore strongly influenced by the dynamical behavior of the H₂ molecules in the high-pressure structure. The phase with the calculated structure is predicted to become metallic near 120 GPa, which is significantly lower than the currently suggested pressure for metallization of bulk molecular hydrogen.     

Socio-environmental influences on adolescents' alcohol outcome expectancies: a prospective analysis

AIMS: To investigate the prospective influence of social influence and social bonding variables on the development of alcohol outcome expectancies among adolescents with and without drinking experience. DESIGN: Longitudinal data from students in the control schools of a field trial designed to evaluate a school-based drug prevention program. SETTING: A total of 19 middle schools in South Dakota, USA. MEASUREMENTS: An alcohol outcome expectancy scale administered to 1410 students in grades 8 and 9. After using confirmatory factor analysis (CFA) to develop an expectancies measure, multiple-group (grade 8 drinkers versus grade 8 non-drinkers) path analysis was used to model 9th grade alcohol expectancies. Grade 8 social influence and bonding variables were used as predictors, controlling for grade 8 expectancies. FINDINGS: At the bivariate level, peer and adult influences and social bonding variables were related consistently to alcohol outcome expectancies among drinkers and non-drinkers. A bivariate relationship between alcohol advertising and alcohol expectancies was found among drinkers only. In the multivariate model, greater alcohol use by important adults predicted independently increased alcohol positivity among drinkers; greater perceived approval of alcohol use by parents and peers predicted diminished perceived potency of alcohol among non-drinkers. Advertisement exposure and social bonding variables were not independent predictors of alcohol expectancies in the multivariate model. CONCLUSIONS: These findings suggest that attempts to alter adolescents' alcohol expectancies are likely to fail unless they address the influence of immediate social models on these beliefs.     

Cannabis use and other illicit drug use: testing the cannabis gateway hypothesis

AIM: To examine the associations between the frequency of cannabis use and the use of other illicit drugs. DESIGN: A 25-year longitudinal study of the health, development and adjustment of a birth cohort of 1,265 New Zealand children. MEASUREMENTS: Annual assessments of the frequency of cannabis use were obtained for the period 14-25 years, together with measures of the use of other illicit drugs from the same time period. FINDINGS: The frequency of cannabis use was associated significantly with the use of other illicit drugs, other illicit drug abuse/dependence and the use of a diversity of other drugs. This association was found to be particularly strong during adolescence but declined rapidly as age increased. Statistical control for confounding by both fixed and time dynamic factors using random- and fixed-effects regression models reduced the strength of association between frequency of cannabis use and other illicit drug use, but a strong association between frequency of cannabis use and other illicit drug use remained even after control for non-observed and time-dynamic sources of confounding. CONCLUSIONS: Regular or heavy cannabis use was associated with an increased risk of using other illicit drugs, abusing or becoming dependent upon other illicit drugs, and using a wider variety of other illicit drugs. The risks of use, abuse/dependence, and use of a diversity of other drugs declined with increasing age. The findings may support a general causal model such as the cannabis gateway hypothesis, but the actual causal mechanisms underlying such a gateway, and the extent to which these causal mechanisms are direct or indirect, remain unclear.     

Alcohol use in the year before marriage: alcohol expectancies and peer drinking as proximal influences on husband and wife alcohol involvement

BACKGROUND: Models of adolescent alcohol involvement that include individual difference, family, and peer risk factors indicate a significant association between the drinking of adolescents and that of their peers. Peer drinking influences, however, have not been investigated extensively in integrative models of adult drinking. The purpose of this study was to test a model of adult drinking that incorporated the potentially important risk factor of partner drinking and in which proximal risk factors (peer drinking, alcohol expectancies) were hypothesized to be strongly associated with adult alcohol use and to mediate relationships between more distal risk factors and drinking. METHODS: Couples (n = 389) were assessed at the time of their first marriage. Separate, self-administered questionnaires were completed at home by both husbands and wives. Distal risk factors included family history of alcoholism, antisocial behavior, and depressive symptomatology. Substantive relationships were tested in a model that included spousal associations with respect to distal risk factors, proximal risk factors, and drinking. RESULTS: Findings demonstrate the unique association of alcohol expectancies and peer drinking with adult alcohol use. Of particular relevance is the significance of the social network as a correlate of adult drinking. A peer network characterized by a higher level of alcohol involvement was strongly associated with heavier drinking among both men and women. This relationship was independent of sociodemographic and individual difference factors, alcohol expectancies, and partner's drinking. Results also demonstrate the similarity between husband and wife drinking, an association that cannot be attributed to assorting with respect to the other risk factors. CONCLUSIONS: The social network continues to significantly impact drinking behavior in adulthood. The relevancy of peer and partner drinking influences to adult alcohol involvement suggests that the immediate social environment may have a prominent role in the continuity/discontinuity of heavy or problem drinking during the transition to marriage.     

Validation of multidimensional scaling-based modeling of alcohol expectancies in memory: age and drinking-related differences in expectancies of children assessed as first associates

BACKGROUND: As evidence has accumulated that alcohol expectancies mediate the effects of other drinking antecedents, attempts to understand the mechanism by which expectancies influence behavior have focused on modeling memory processes. Previous expectancy work, however, has used relatively indirect approaches to retrieve and model information stored in memory. By using the method most recommended by memory researchers for directly obtaining uncontaminated memory contents, we assessed children's expectancies and related findings to empirically modeled organization and activation of expectancies in memory based on scaled instruments. METHODS: Individual interviews were conducted with 462 children in 2nd through 5th grades, and surveys were completed by 1,003 children in 3rd, 6th, 9th, and 12th grades. Interviews and surveys consisted of a measure designed to retrieve participants' first expectancy associate to an alcohol prompt and several drinking quantity/frequency questions. RESULTS: Older and higher drinking children were more likely to report positive expectancies as their first associate to an alcohol prompt. Age and drinking-based findings were consistent with organizational structure, dimension emphasis shift, and paths of association identified by prior multidimensional scaling techniques. CONCLUSIONS: Consumption of alcohol among children corresponded to accessibility of positive expectancies in memory. In addition, the use of multidimensional scaling to study the organization and activation of alcohol expectancies in memory was validated.     

The surgeon as endoscopist: A look back with a view to the future

Endoscopy emerged as a field of study as early as the 1800s with surgeons as significant innovators and visionaries from the beginning. Seminal work by surgeons has been instrumental in expanding both understanding and therapy of gastrointestinal diseases enhancing the care of patients. This review will explore the history of endoscopy in surgical practice, discuss the interfusion of endoscopic and intraperitoneal procedures, and advocate for the routine use of endoscopy in modern surgical practice.     

Ethnic differences in positive alcohol expectancies during childhood: the Pittsburgh Girls Study

Background: Positive expectancies about alcohol’s effects are more likely to be endorsed with increasing age through adolescence, and the strength of positive alcohol expectancies in children appears to differ by ethnicity. Little is known about the extent to which differences in a measure’s psychometric properties as a function of development and ethnicity may account for changes that are observed over time and ethnic differences. This study used measurement invariance methods to examine ethnic differences in the development of alcohol expectancies, and examined risk factors associated with girls’ positive expectancies. Methods: African‐American (56%) and Caucasian (44%) girls (n = 570) in the age 7 cohort of the Pittsburgh Girls Study, and the girl’s primary caretaker, were followed annually for 4 years (ages 7–10). Girls reported on alcohol expectancies at each wave, and physical aggression at Year 1. In Year 1, caretakers reported on neighborhood drug use, their own substance‐related problems, and depression in the girl. Structural equation modeling was used to examine measurement invariance of positive alcohol expectancies, and to test associations of risk factors to initial level and change in expectancies. Results: Five of 8 positive alcohol expectancy items showed measurement equivalence for African‐American and Caucasian girls in cross‐sectional, but not longitudinal, analyses. Measurement equivalence over ages 7–10 was demonstrated for Caucasian girls, and over ages 7–8 and 9–10 (i.e., a two‐part model) for African‐American girls. Risk factor analyses indicated that, for Caucasian girls, greater physical aggression was associated with higher initial positive expectancies. Conclusions: Some developmental change and ethnic differences in the performance of positive expectancy items were identified, highlighting the utility of measurement invariance methods. Risk factor analyses suggest the potential benefit of targeted alcohol prevention interventions for certain girls.     

A simple view on lung cancer biology: the MET pathway

MET is a cell membrane tyrosine kinase receptor for its ligand the hepatocyte growth factor (HGF), also called scatter factor (SF). MET conveys mitogenic, motogenic and proangiogenic signals, important during embryonic development and during the development of cancer. Activation of the HGF-MET pathway seems to be associated with a poor prognosis in lung cancer. Activation in lung cancer may be related to several molecular anomalies: ligand overexpression, receptor overexpression, genomic amplification or MET mutation. In MET amplified or mutated lung cancer, MET may be an important oncogene, as the tumor appears "MET addicted". In other lung cancers, MET may be implicated in tumour progression by tissue invasion and formation of metastases. MET amplification is also a mechanism known to be implicated in 20% of secondary resistance to EGFR inhibitors in patients presenting EGFR mutated lung cancer. Different strategies of MET inhibition in lung cancer are being studied, particularly in EGFR mutated lung cancer. In this review we discuss the structure of the MET receptor, the activated pathways, the main genomic anomalies in lung cancer and the development of MET inhibitors.     

The association between alcohol use trajectories from adolescence to adulthood and cannabis use disorder in adulthood: a 22-year longitudinal study

Background: Due to the increasing prevalence of cannabis use disorder (CUD), the impact of cannabis use on public health may be significant. Objective: The present study seeks the possible precursors (e.g., alcohol use) of CUD in order to minimize the potential negative consequences of CUD such as impaired coordination and performance. Method: The Harlem Longitudinal Development Study included 674 participants (53% African Americans, 47% Puerto Ricans), with 60% females (n=405) from a six wave survey. We used a growth mixture model to obtain the trajectories of alcohol use from the mean ages of 14 to 36. To examine the associations between alcohol use trajectories and CUD, we used logistic regression analyses with the indicator of CUD as the dependent variable and the indicator of membership in each trajectory group as the independent variables. Results: A three alcohol use trajectory group model was selected. Male gender, higher frequency of cannabis use in adolescence, and a lower educational level were associated with an increased likelihood of having CUD. Membership in the increasing alcohol use group (OR=27.44, p < .01; AOR=15.54, p < .01) and the moderate alcohol use group (OR=10.40, p < .05; AOR=8.63, p < .05) were associated with an increased likelihood of having CUD compared with the membership in the no or low alcohol use group. Conclusions: The findings of our study support the hypothesis that addressing alcohol use at an early age could impact later CUD.     

A new cytokine： the possible effect pathway of methionine enkephalin

AIM: To investigate experimentally the effects of methionine enkephalin on signal transduction of mouse myeloma NS-1 cells. METHODS: The antigen determinate of delta opioid receptor was designed in this lab and the polypeptide fragment of antigen determinate with 12 amino acids residues was synthesized. Monoclonal antibody against this peptide fragment was prepared. Proliferation of Mouse NS-1 cells treated with methionine enkephalin of 1 x 10(-6) mol x L(-1) was observed. The activities of protein kinase A (PKA) and protein kinase C (PKC) were measured and thereby the mechanism of effect of methionine enkephalin was postulated. RESULTS: The results demonstrated that methionine enkephalin could enhance the proliferation of NS-1 cells and the effect of methionine enkephalin could be particularly blocked by monoclonal antibody. The activity of PKA was increased in both cytosol and cell membrane. With reference to PKC, the intracellular activity of PKC in NS-1 cells was elevated at 1 x 10(-7) mol x L(-1) and then declined gradually as the concentration of methionine enkephalin was raised. The effects of methionine enkephalin might be reversed by both naloxone and monoclonal antibody. CONCLUSION: Coupled with the findings, it indicates that the signal transduction systems via PKA and PKC are involved in the effects of methionine enkephalin by binding with the traditional opioid receptors,and therefore resulting in different biological effects.     

Hepatitis B: the pathway to recovery through treatment

Hepatitis B is a major public health problem in the world today. Since 1985, the number of reported cases has declined as a direct result of universal immunization of neonates, vaccination of at-risk populations, lifestyle or behavioral changes in high-risk groups, refinements in the screening of blood donors, and the use of virally inactivated or genetically engineered products in patients with bleeding disorders. New and potent antiviral agents being developed and evaluated provide hope and optimism for those who are chronically infected with hepatitis B virus. Prevention remains the most effective strategy in the global management of hepatitis B virus. Universal immunization programs prevent hepatitis B virus transmission and circumvent acute and chronic infection.     

From the eyes of the beholder: alcohol expectancies and valuations as predictors of hazardous drinking behaviors among female college students

Research has shown that drinking expectancies are associated with alcohol use among college students; however, the bulk of these studies have focused exclusively on researcher-labeled "positive" or "negative" expectancies rather than on the student's valuation (i.e., rating of desirability) of these expectancies. The present study examined the utility of expectancies and valuations in predicting hazardous alcohol use in a sample of 330 female college students (mean age = 20.0; 18-25). Hierarchical regression analyses revealed that negative expectancies and favorable valuations of negative and positive expectancies were predictive of elevated hazardous use (controlling for age, athletic membership, and peer use). Expectancy valuations accounted for additional variance in the model beyond that of expectancies. The present findings shed light on the utility of expectancies and valuations of expectancies in predicting hazardous alcohol use among female college students. Future research directions and potential implications for prevention efforts are discussed.     

Genetics of severe congenital neutropenia as a gateway to personalized therapy

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Metabolic denitrosation of diphenylnitrosamine: a possible bioactivation pathway

Summary Nitrosodiphenylamine was tested for induction of DNA single strand breaks in rat hepatocytes and Chinese hamster V 79 cells with the alkaline filter elution assay. While in rat hepatocytes DNA damage was observed, negative results were obtained in V 79 cells. In view of the metabolic capacity of hepatocytes and the chemical structure of nitrosodiphenylamine it seems likely that cytochrome P-450-dependent, reductive denitrosation might be necessary for exerting this effect. Therefore the metabolism of nitrosodiphenylamine was investigated in phenobarbital-induced mouse liver microsomes and some of the metabolites were also tested. One metabolite was identified as diphenylamine whereas the others were identified as a ring-hydroxylated derivative of diphenylamine and its corresponding quinoneimine. Diphenylhydroxylamine which was not detected in the microsomes as a metabolite produced a significant amount of DNA single strand breaks in V 79 cells. When diphenylhydroxylamine was incubated with microsomes electron spin resonance spectrum was observed which indicated the formation of the diphenylnitroxide radical. This radical seems to be mediated by auto-oxidation rather than by enzymatic catalysis. Whether diphenylhydroxylamine might be responsible for the observed genetoxic effects of nitrosodiphenylamine assumed to be produced via active oxygen species is discussed.Abbreviations NDphA nitrosodiphenylamine - DphA diphenylamine - DphAOH diphenylhydroxylamine - Pb phenobarbital - Cyt. cytochrome - DMSO dimethylsulphoxide - MNNG N-methyl-N-nitro-nitrosoguanidine - NDBA N-nitroso-di-n-butylamine - ESR electron spin resonance - NO nitric oxide Dedicated to Professor Erich Hecker on the occasion of his 60th birthdayThis work is part of the theses of S. Görsdorf and T. Scheper