Tobacco and cannabis use as moderators of the association between physical activity and alcohol use across the adult lifespan in the United States: NHANES, 2005-2016.

Physically-active adults are more likely to consume alcohol, but this association may vary if adults also use other substances (i.e., tobacco and/or cannabis), which could increase substance-use related harms. This study examined whether tobacco and/or cannabis use moderated the associations between physical activity, odds of drinking and alcohol drinks/week. We used cross-sectional 2005-2016 National Health and Nutrition Examination Survey data (United States of America). Physical activity was assessed using device-based and self-reported moderate-to-vigorous physical activity (MVPA) and total physical activity hours/week. Individuals were categorized into one of four (poly)substance use categories, no tobacco/no cannabis, tobacco, cannabis, or tobacco/cannabis use. Regression models examined substance use as a moderator of the association between physical activity and the odds of drinking versus not drinking and alcohol drinks/week among light/moderate/heavy drinkers (≥12 drinks/year). Using cannabis or tobacco weakened the significant positive associations between total physical activity and self-reported recreational MVPA hours/week on odds of drinking (ORs = 0.978 and 0.967, respectively), such that the effect was negative or null when using cannabis or tobacco, respectively. Greater total physical activity and device-based MVPA hours/week was associated with consuming greater drinks/week (IRRs = 1.003 and 1.035, respectively). Using tobacco weakened the association between device-based MVPA and alcohol drinks/week (IRR = 0.934, 95% CI: [0.888, 0.982]). Cannabis and tobacco use weakened the association between physical activity and alcohol use. The positive association between physical activity and alcohol use may be limited to single substance users of alcohol and could reflect shared reasons for engaging in these behaviors, such as stress management or social motives.

The role of circulating 25 hydroxyvitamin D in asthma: a systematic review.

Asthma is a major public health issue. The co-occurrence of the high prevalence of asthma and vitamin D deficiency documented globally in recent decades has prompted several investigations into a possible association between the two conditions. The objective of this paper was to synthesize the evidence from studies that have measured the association between serum vitamin D and asthma incidence, prevalence, severity and exacerbations. A systematic search of the literature was performed in PubMed, and the available evidence was summarized both qualitatively and by meta-analysis. Only English language, observational studies measuring serum levels of 25(OH)D as the exposure were included, as this is the most robust measure of vitamin D levels. The search identified 23 manuscripts: two case-control, 12 cohort and nine cross-sectional studies. Collectively, the evidence suggests that higher serum levels of 25(OH)D are associated with a reduced risk of asthma exacerbations, but there was little evidence to suggest an association with asthma incidence, prevalence or severity. A significant amount of heterogeneity between study methodology and results restricted the scope for meta-analysis. These results suggest that vitamin D supplementation may be effective for the prevention of asthma exacerbations, but the findings need to be confirmed by clinical trials.

Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord blood, placenta and breast milk.

Treatment of maternal chronic myeloid leukemia with imatinib mesylate is avoided because of potential fetal effects. Two women with progression of disease during pregnancy required imatinib therapy. Concentrations of imatinib in maternal blood, placenta, umbilical cord blood and breast milk were 886, 2452, 0 to 157, and 596 ng/ml, respectively. Concentrations of the active metabolite CGP74588 in maternal blood, placenta, umbilical cord blood and breast milk were 338, 1462, 0 and 1513 ng/ml, respectively. As Imatinib and CGP74588 cross the mature placenta poorly, use of the drug after the first trimester may be reasonable under some circumstances. Imatinib and CGP74588 are found in breast milk, and therefore avoidance of breastfeeding is advisable.

Dosage-Dependent Modifiers of Homoeotic Mutations in Drosophila melanogaster.

The determination of segment identity in Drosophila melanogaster appears to be controlled by a small number of genes. In order to identity new components in the process, we have systematically screened the autosomal complement for loci that show a dosage-dependent interaction with mutations in previously characterized genes thought to be important in the determination of segment identity. The dominant homoeotic phenotype of mutations at four loci involved in thoracic leg determination (Pc, Pcl, Antp and Scr) were quantitated in flies bearing a series of synthetic duplications covering more than 99% of the autosomal complement. Twelve regions were identified that when present in three wild-type copies strongly enhanced or suppressed the phenotype of mutations at one or more of the four homoeotic loci examined. The effects of five of these regions appear to correspond to previously described homoeotic loci; the effects of the remaining seven appear to identify new loci involved in the determination of segment identity.

Homoeosis in Drosophila: a new enhancer of polycomb and related homoeotic mutations.

A new recessive lethal mutation in Drosophila melanogaster , Enhancer of Polycomb [E(Pc)], and chromosomal deficiencies lacking this locus act as dominant enhancers of the Polycomb mutant syndrome in adults. Thus, although E(Pc)/+ flies are phenotypically normal, this locus is haplo-abnormal with respect to its effect on the Polycomb phenotype. Recombinational and deficiency mapping localize the E(Pc) locus on chromosome 2 proximally and very closely linked ( approximately 0.1 map unit) to the engrailed gene. E(Pc) enhances the expression of all Polycomb point mutations examined including that of a deficiency, indicating that this interaction does not depend on the presence of an altered Polycomb gene product. In several respects the mutations extra sex comb, lethal(4)29, and Polycomblike resemble those at the Polycomb locus. In the presence of E(Pc), recessive alleles of extra sex comb and lethal(4)29 are rendered slightly pseudodominant, and the homoeotic effects of Polycomblike heterozygotes are also enhanced. However, E(Pc) does not affect the expression of dominant mutations within the Bithorax gene complex (Cbx) or Antennapedia gene complex (Antp(Ns), Antp(73b), Antp(scx ), Antp(EfW15), Scr(Msc)) which give homoeotic transformations resembling those of the Polycomb syndrome. Available evidence from the study of adult phenotypes suggests that mutations at E(Pc) do not result in homoeotic changes directly but instead modify the expression of a specific set of functionally related homoeotic variants.

Genetic and molecular analysis of vgU and vgW: two dominant vg alleles associated with gene fusions in Drosophila.

In the absence of a vg+ gene, extensive cell death occurs in third instar imaginal discs, which results in a complete loss of adult wing margin structures. Essentially all molecularly characterized vg alleles are associated with deletions or insertions of DNA into the vg locus. These alterations reduce or eliminate a 3.8-kb vg-specific transcript, resulting in recessive loss of function alleles. We report here the analysis of two dominant vg alleles which have been identified (vgU and vgW). The vgU allele is associated with a chromosomal inversion which splits the vg locus, resulting in a gene fusion between vg and the mastermind (mam) neurogenic locus. Reversion analysis of vgU indicates that sequences from the mam locus are required for vgU dominance. The vgW allele is also the result of a chromosomal inversion, in this case resulting in a gene fusion between vg and the homeobox-containing invected (inv) gene. It is also associated with novel dominant homeotic transformations. Revertant analysis indicates that sequences from inv are required for the dominant wing and dominant homeotic effects of vgW. The vg dominance does not appear to be mediated through a reduction of vg expression or a novel fusion transcript in either vgU or vgW. The results are consistent with a model in which inappropriate expression of inv causes the dominant homeotic effects seen in vgW.

Transglutaminase II: a new class of GTP-binding protein with new biological functions.

Tissue type transglutaminase (TGase II) is historically a member of the transglutaminase family, which covalently cross-links cellular proteins and polyamines. A recent new finding in the TGase II field is that the enzyme functions as a signal mediator from receptors to an effector in transmembrane signaling. This review will discuss the recent development of TGase II. This new signal transducer was termed Gh when initially discovered and was recently found to be TGase II. To help the reader understand the role of Gh as a signal mediator, the role of heterotrimeric G-proteins in hormone-mediated transmembrane signaling is briefly discussed. We have highlighted how Gh transmits the alpha 1-adrenoceptor signal to the phospholipase C-delta 1 and how Gh is activated and deactivated compared to the prototype of heterotrimeric G-proteins. Recent developments regarding the structure-function of Gh and other biological functions of Gh are discussed to facilitate understanding the impact of Gh in cells.

Mouse IgG1 heterogeneity: variable binding of monoclonal IgG1 antibodies to protein A-sepharose.

Binding strength to protein A discriminates three definitive types of mouse monoclonal IgG1. Each of these types of IgG1 elutes from protein A-Sepharose as a coherent peak representing the great majority of IgG1 protein. One type of IgG1 is not present to any significant extent in polyclonal mouse IgG preparations, and to our knowledge has not been reported previously. This type of IgG1 does not bind firmly to protein A at pH 8.0, but is retarded sufficiently that it can be purified by protein A-Sepharose chromatography in high yields.

Adjustment of smokers to dilution of tobacco smoke by ventilated cigarette holders.

This study was designed to examine the extent to which smokers would compensate for the dilution of smoke produced by ventilated cigarette holders. Peak plasma nicotine and carboxyhemoglobin levels were measured in 18 smokers when they had been smoking normally and when they had been using holders which dilute the smoke by about 20% (holder 1) and 60% (holder 2) for periods of 2 days and 7 days. Comparison of the observed blood levels with the "expected" levels estimated from the dilution factors of the holders showed that subjects partially compensated on holder 2 but showed little or no compensation on holder 1. There were no changes in the number of cigarettes smoked when using the holders so any compensation achieved must have been due to increasing the intake from each cigarette. There was wide individual variation in the amount of compensation with about 50% of subjects compensating fairly consistently on both holders. Degree of compensation was not significantly associated with usual cigarette consumption, plasma nicotine and carboxyhemoglobin levels when smoking without a holder, the nicotine yields of the subjects' cigarettes, or the experience of withdrawal symptoms and the degree of satisfaction when using the holders. It cannot be determined from this study whether the compensation observed was mediated by a need to regulate the intake of nicotine rather than some other factor.

Is nicotine important to tobacco smoking?

Tobacco smoking is generally regarded as a form of nicotine dependence, but the evidence for this is slender. Two experiments are described here which examine the hypothesis that habitual smokers need nicotine and that they regulate their intakes of this drug. A laboratory test for smoking was devised which permitted the continuous monitoring of puffing as well as of selected physiologic variables; the procedure was also designed to reduce the influence of smoking habits and rituals. In the first experiment, inhaled amounts of tobacco smoke reduced subsequent ad libitum smoking in a dose-related way. In the second experiment comparable doses of nicotine were given intravenously to the same subjects, but they failed to affect ongoing smoking. However, both the inhaled and intravenous doses of the drug produced very similar physiologic effects. These experiments do not, therefore, support the nicotine-dependence hypothesis; thus the ways, if any, in which this drug sustains the tobacco-smoking habit merit further examination.

Smokers' response to shortened cigarettes: dose reduction without dilution of tobacco smoke.

This study was designed to examine the response of smokers to shortening their usual brand of cigarettes. The shortening reduces the dose of smoke available from each cigarette without affecting concentration and therefore differs from dose reduction by dilution, which occurs when smokers switch to cigarettes with lower tar and nicotine deliveries. Measures of smoking behavior (e.g., cigarette consumption, puff rate), mouth-level nicotine intake (calculated from butt content), and intake to the lungs (plasma nicotine and COHb) were made in 10 smokers after 48 hr ad libitum smoking of full, three-quarter, and half-length cigarettes in a Latin square design. Mouth-level smoke intake was maintained on shortened cigarettes due to a combination of 2 types of compensatory maneuver: (1) by increasing the intensity of puffing and thereby extracting proportionately more of the smoke available from each cigarette and (2) by smoking more cigarettes. The amount of smoke inhaled, on the other hand, was only partially maintained (58% compensation). This was achieved by increase in cigarette consumption alone. There was achieved by increase in cigarette consumption alone. There was no evidence of any compensatory increase in the amount of smoke inhaled from each cigarette. Increase in consumption was thus the only maneuver that contributed to maintaining smoke intake at lung level; mouth-level intake was regulated by increasing intake per cigarette as well as consumption.

Pharmacokinetics of nicotine carbomer enemas: a new treatment modality for ulcerative colitis.

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers, and transdermal nicotine is of therapeutic value in the active disease. Because side effects are common, we developed a topical enema formulation of nicotine. OBJECTIVE: To study the pharmacokinetics of nicotine complexed with a polyacrylic carbomer and administered by enema to eight healthy volunteers and to eight patients with active ulcerative colitis, verified sigmoidoscopically. PATIENTS AND METHODS: All 16 subjects were nonsmokers. The mean age for normal subjects was 33 years; the mean for patients with ulcerative colitis was 60 years. Median stool frequency for patients with ulcerative colitis was four daily. Patients were taking 5-amino salicylic acid compounds and five were taking oral prednisolone (median dose, 12 mg daily). Nicotine, 6 mg, complexed with carbomer 974P, 400 mg, was administered in a 100 ml enema after an overnight fast, with serial blood measurements taken over 8 hours. Serum nicotine and cotinine were measured by gas liquid chromatography. Area under the concentration-time curves were calculated by the trapezoidal method, and the terminal elimination half-life was derived by extrapolation of the log-linear terminal phase. RESULTS: With the exception of nicotine time to reach peak concentration, which was longer in patients (median of 60 minutes compared with 45 minutes; p < 0.005), other comparisons between normal subjects and patients showed no statistically significant difference, although there was considerable inter-subject variation. Maximum concentration of nicotine, 8.1 +/- 3.5 ng/ml, in the 16 subjects occurred after a median of 60 minutes (range, 30 to 180 minutes); maximum cotinine concentrations of 60.4 +/- 11.5 ng/ml occurred after 4 hours. Side effects in five subjects were mild (four subjects) or moderate (one subject) and included lightheadedness, nausea, and headache; these five subjects were female lifelong nonsmokers of low body weight. CONCLUSION: Because most of the active ingredient of nicotine is converted to continine on the first pass through the liver, substantial concentrations can be achieved at the site of disease with only modest rises in serum nicotine, which are responsible for side effects; cotinine has low pharmacologic activity. Topical administration of nicotine may be useful treatment for distal ulcerative colitis.

Molecular genetic analysis of type-4 pilus biogenesis and twitching motility using Pseudomonas aeruginosa as a model system--a review.

Genetic analysis of Pseudomonas aeruginosa pilus biogenesis and twitching motility has revealed the requirement for several pil loci which have been localized to different regions of the chromosome. One pil locus, designated pilE, resides at approx. 71 min on the PAO genetic map, a region of the chromosome previously shown to harbor a number of genes required for pilus assembly (i.e., pilA, -B, -C, -D, -R and -S). The PilE protein shows significant sequence identity to the N-terminal domain of PilA as well as to the pilin precursors from a variety of type-4 pilus producers. Included within this homologous region is a short, positively charged leader sequence followed by a prepilin peptidase cleavage site and a largely hydrophobic region. Additionally, an unlinked set of pil genes, designated pilG, -H, -I, -J and -K, has been localized to the SpeI fragment H which corresponds to approx. 20 min on the PAO genetic map. This gene cluster encodes proteins that demonstrate remarkable similarity to the chemotaxis proteins of enterics and the gliding bacterium Myxococcus xanthus and are thought to be part of a signal transduction system that controls P. aeruginosa pilus biosynthesis and twitching motility.

Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase.

Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.

Allosteric regulation of [3H]vinblastine binding to P-glycoprotein of MCF-7 ADR cells by dexniguldipine.

Plasma membranes were prepared from the P-glycoprotein expressing human breast cancer cell line MCF-7 ADR. [3H]Vinblastine bound to these membranes saturably with a Bmax of 24 pmol/mg of protein and KD of 23 nM. In contrast, membranes from the parent cells MCF-7 WT, which do not express P-glycoprotein, did not bind [3H]vinblastine with high affinity. Cytotoxics known to be transported by P-glycoprotein inhibited the binding of [3H]vinblastine, as did multidrug reversing agents including the 1,4-dihydropyridine, dexniguldipine-HCl (Ki, 15 nM). In dissociation kinetic experiments, dexniguldipine-HCl accelerated the dissociation of [3H]vinblastine from P-glycoprotein, indicating a negative heterotropic allosteric mechanism of action through a drug binding site distinct from that of vinblastine. Other 1,4-dihydropyridines tested also accelerated [3H]vinblastine dissociation from P-glycoprotein, however, multidrug reversing drugs of different chemical classes, including quinidine, verapamil and cyclosporin A did not. These results suggest that P-glycoprotein of MCF-7 ADR cell membranes possesses at least two drug acceptor sites which are allosterically coupled: receptor site-1 which binds vinca alkaloids, and receptor site-2 which binds 1,4-dihydropyridines such as dexniguldipine-HCl, which had the highest affinity of the tested derivatives.

Nicotine enemas for active ulcerative colitis--a pilot study.

BACKGROUND: Since transdermal nicotine is of value in the treatment of active ulcerative colitis but is often associated with side-effects, an alternative in the form of topical therapy with nicotine enemas has been developed. METHODS: In an open study, 22 patients with active colitis, all non-smokers, were asked to take a 100 mL enema containing 6 mg of nicotine every night for 4 weeks. Pre-trial treatment using mesalazine (n = 16), oral prednisolone (8), cyclosporin (1) and azathioprine (1) was kept constant for the month prior to assessment and during the study period. Symptoms, with stool frequency, were recorded on a diary card and an endoscopy was performed with rectal biopsy at the beginning of the study and after 4 weeks. RESULTS: Seventeen of the 22 patients completed 1 month of treatment. Mean duration of relapse was 29 weeks, range 3-94. Sixteen of 17 improved their St Mark's score. Urgency and stool frequency improved in 12 patients, sigmoidoscopic and histological scores in 10. Three patients had a full remission of symptoms with normal sigmoidoscopy. Six of 10 with a partial response continued with the enemas for a second month and five showed further improvement with full remission in two. The enema appeared effective when added to conventional treatment and produced few side-effects. CONCLUSION: Topical nicotine therapy for ulcerative colitis may have a place in future management, but controlled studies are needed.

Subjective and behavioural effects of nicotine in humans: some sources of individual variation.

Despite its addictiveness, the subjective effects of nicotine in "smoking doses" are of low intensity compared with those of other addictive drugs. Although mildly pleasurable to many regular users, it causes no striking euphoriant effects and its effects on mood, performance and the level of arousal are relatively small. This chapter does not attempt to list or review the numerous effects of nicotine, but focuses instead on some of the multiple sources of individual variation. The subjective and behavioral effects of nicotine in humans differ markedly, not only between individuals but also within individuals, according to the stage of their smoking career, their level of dependence and the time since their last few doses. Some of the influences and mechanisms discussed include innate and acquired factors, pharmacokinetic factors, acute and chronic tolerance, learning and conditioning. It is not clear to what extent the effects of nicotine are primary, or how much they reflect reversal or relief of acquired withdrawal effects. Only one study has found a "rebound" element in the effects of withdrawal and although chronic exposure to nicotine induces an increase in the number of nicotinic receptors, chronic tolerance to nicotine has not been demonstrated in humans. Acute tolerance (tachyphylaxis) develops rapidly to many of the effects of nicotine and is completely reversible after nicotine depletion. Other effects of nicotine are less sensitive to acute tolerance. It is suggested that it is the effects of nicotine at postsynaptic receptors that are most susceptible to acute tolerance and that those mediated by its action at presynaptic receptors are less sensitive to it. Due to accumulation of nicotine and other pharmacokinetic factors, for most of the day and much of the night, regular smokers have high levels of acute tolerance to nicotine. In other words, there is a chronic partial blockade of its agonist effects at postsynaptic receptors. This explains why nicotinic receptors are upregulated rather than downregulated and why heavy smokers experience no subjective effects from a cigarette smoked during the course of a normal smoking day. When the effects of acute tolerance are unmasked after abstinence for 24 h, it is the more addicted heavy smokers who experienced more severe withdrawal effects who also have stronger subjective and heart rate effects following the first post-abstinence cigarette. Their greater sensitivity to nicotine after abstinence may reflect their higher density of unoccupied nicotinic receptors. On the other hand, those who have higher innate sensitivity may be more likely to take up smoking and to become more dependent if they

Factors determining exposure to passive smoking in young adults living at home: quantitative analysis using saliva cotinine concentrations.

Saliva cotinine concentrations were used to examine determinants of exposure to environmental tobacco smoke in 393 non-smoking students (age range 16-19 years) attending a sixth form college and living at home. Average concentrations were low (median 0.60 ng/ml), reflecting partly the warm weather at the time of the survey and partly the predominantly middle class sample. Despite this, cotinine levels were strongly related to the extent of self-reported passive smoking in the past three days (medians 0.30, 0.60, 0.90 and 1.35 ng/ml in those reporting 'None at all', 'A little', 'Some' and 'A lot' respectively, p less than 0.0001). Individual sources of environmental tobacco smoke identified were smoking by mothers (p less than 0.0001), by fathers (p less than 0.01), and exposure at college (p less than 0.001) and when out in the evenings (p less than 0.001). The results indicate that exposure outside the home may become of equal or greater importance than family smoking in determining the overall passive smoking dose received by this age group.

Smoking, alcohol consumption, and leukocyte counts.

Blood was collected from 684 healthy volunteers and examined for total and differential white blood cell (WBC) counts. A subgroup also was tested for numbers of T cells, B cells, and CD4 and CD8 subsets. Smoking status and alcohol consumption were determined by means of questionnaire, and smoking status was verified with serum cotinine concentration. High smoking rate was associated with increases in all counts. Former smokers abstinent less than 5 years still demonstrated elevated counts, whereas those abstinent more than 5 years had WBC counts comparable to those in persons who were never smokers. Compared with levels in those who had never smoked, total WBC counts were 27% higher in current smokers and 14% higher in former smokers who were abstinent for less than 5 years. Lymphocyte counts were 9% higher in those consuming more than one alcoholic drink per day than in those consuming less alcohol, but drinking was not associated with other cell populations.

Cardiovascular and subjective effects of smoking before and after 24 h of abstinence from cigarettes.

Cigarette-induced changes in heart rate, skin temperature and subjective state were measured during the course of a normal smoking day and on smoking after 24 h abstinence in 21 smokers. Heart rate was not affected by smoking a test cigarette during the normal day's smoking, but after 24 h abstinence smoking a cigarette caused an average increase of 14 beats per min. Skin temperature, on the other hand, was reduced by smoking a cigarette under both conditions. Subjective effects of smoking were experienced only after the period of abstinence. The most common was dizziness, but nausea and other effects were also reported. Cigarette-induced changes in heart rate and skin temperature were positively correlated with each other, and the rise in heart rate after abstinence correlated positively with the strength of the subjective response. The results are discussed in terms of similarities and differences between different physiological systems in tolerance to the effects of nicotine.