The Painless Stop Smoking Cure

Quit Smoking Magic

Mike Avery is the author of the quit smoking magic program. He is an ex-smoker (20 year habit) and a researcher who has carried out lots of tests on this topic for many years. He used himself as a test subject, after trying everything you can think of to stop smoking. He then tested his quit smoking magic theory on himself and got the results needed. Mike Avery's program of quit smoking magic has successfully helped hundreds of people all over the world quit smoking, including his family members and co- workers. He should be trusted because he has been in the shoes of being a smoker and has cured himself from smoking addiction. So if you are planning on doing the same, you should go to the one person who understands what you are going through. This program will provide you with information about smoking in general and ways on how to stop the smoking addiction from eating you up. Its contents are based on real-life experiences rather than theories that were imagined by someone. It is an e-book program on the subject of quitting smoking and comes with three different bonus e-books on the following topics; how to whiten your teeth, end bad breath and how to clean your lungs. Purchasing this program does not require you to have any technical skill to be able to use it, it only requires you to read and understand. Read more here...

Quit Smoking Magic Summary


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Lung Cancer Screening Future Directions

The current wealth of emerging technologies for the early detection of lung cancer provides hope that we may be able to reduce the burden of this 20th century disease in the early 21st century 21 . To date, LDCT and advanced sputum analysis techniques appear to be the most promising emerging technologies for lung cancer screening, but ongoing advances in other techniques may change this perspective in the near future. Because of their proclivities for different cell types, LDCT and sputum analysis should be considered complementary rather than competitive screening tools. Important questions to answer before proceeding to mass screening include the effect of screening on lung cancer mortality, the cost-effectiveness of widespread screening, the optimal screening tools to use, and the subsets of present and former smokers who are most likely to benefit from screening. National studies are being planned to answer these questions.

Nicotinestimulated Dopamine Release From Nigrostriatal Neurons

The findings that the concentration of DA in the striatum is about ten times higher than any other brain area, and the recognition that this area plays a major role in motor function, suggested that nicotine might act to release DA from striatal tissue. The technique of in vitro perfusion of specific brain areas developed in the late 1960s allowed a determination to be made of the concentration and efficacy of drug-induced effects on neurotransmitter systems in living brain tissue. Besson and coworkers (1969) studied the effect of cholinergic stimulation on DA release in rat striatal tissue and found that the application of acetylcholine produced a marked increase in newly synthesized 3H DA release. The first direct evidence of nicotine-stimulated DA release in striatum was reported by Westfall (1974), and this finding was soon confirmed by a number of other investigators (Goodman, 1974 Giorguieff et al. 1977 Arqueros et al., 1978). These initial studies, which employed relatively...

Nicotinestimulated Dopamine Release From Mesolimbic Neurons

A number of studies beginning in the late 1970s demonstrated that increased levels of DA at the terminal fields of mesolimbic neurons, particularly in the NAc, appeared to be a common feature of many reinforcing drugs (Robertson and Mogenson, 1978 Lyness et al., 1979 Singer et al., 1982 Wise and Bozarth, 1985 Smith et al., 1985 Taylor and Robbins, 1986). These studies suggested that nicotine, like the other psychostimulant drugs, might also elevate synaptic levels of DA in this brain area. The first evidence was demonstrated by Imperato and coworkers (1986) using the technique of in vivo microdialysis. They showed that the systemic injection of 0.6 mg kg nicotine caused a 100 increase in DA release from the NAc, and this activity was blocked by the centrally acting nicotinic antagonist, mecamylamine. It was also shown that the NAc was several times more sensitive to the effects of nicotine than was the striatum. In vitro superfusion studies with isolated nucleus accumbens tissue soon...

Dedrosomatic And Terminal Sites Of Nicotines Action

The experiments considered above provide evidence that nicotine can act directly at the terminals of mesocorticolimbic and nigrostriatal neurons to release nicotine, ostensibly by acting upon nicotinic receptors on the presynaptic nerve terminal. FIGURE 3.1 Concentration-response relationship of nicotine in synaptosomes from striatum, nucleus accumbens, frontal cortex, and amygdala. Tissue, prepared and perfused as described, was challenged with 30 second pulses of L-nicotine at the concentrations indicated. The resulting increase in the baseline release (extrapolated from the period preceding the pulse) is presented as the percent increase over baseline at each concentration. FIGURE 3.1 Concentration-response relationship of nicotine in synaptosomes from striatum, nucleus accumbens, frontal cortex, and amygdala. Tissue, prepared and perfused as described, was challenged with 30 second pulses of L-nicotine at the concentrations indicated. The resulting increase in the baseline release...

Nicotineinduced Desensitization Of Da Release

As discussed above, the most tenable explanation to account for the ability of chronic nicotine treatment to produce an upregulation of nAChRs in the brain is that nicotine acts as a functional antagonist by producing long-term nAChR desensitization (Marks et al., 1983 Schwartz and Kellar, 1985 Wonnacott, 1990 Ochoa and FIGURE 3.2 Nicotine-induced desensitization of 3H DA release from rat striatal synaptosomes. Striatal synaptosomes, prepared as described in Figure 3.1 were exposed to 0, 10 or 100-nM nicotine for 20 min followed by a 2 min challenge with 5 jiM nicotine. Samples of the superfusate were collected every 2 min the resulting profile of 3H DA release during this time is presented. FIGURE 3.2 Nicotine-induced desensitization of 3H DA release from rat striatal synaptosomes. Striatal synaptosomes, prepared as described in Figure 3.1 were exposed to 0, 10 or 100-nM nicotine for 20 min followed by a 2 min challenge with 5 jiM nicotine. Samples of the superfusate were collected...

Patterns of use epidemiology adverse effects and specific issues concerning treatment for nicotine dependence

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Cigarette smoking and nicotine dependence

Drug taking aspects of cigarette smoking were largely ignored until the 1970s, but since then an accumulation of research findings from a variety of disciplines and from both human and animal work has led to a consensus that cigarette smoking is essentially a form of addiction to nicotine. (8) Understanding of nicotine's role is fundamental to an appreciation of smoking uptake, maintenance, and cessation. It does not follow that cigarette smoking is explicable solely in terms of pharmacological factors. Nicotine effects provide a rich substrate for conditioning and social learning mechanisms, and for broad social, economic, and societal influences. In this respect it is no different from other drug dependencies. The evidence relevant to nicotine's properties as an addictive drug comes from a number of areas. (919 Some of the main lines of evidence are briefly summarized here.

Regulation of blood nicotine intake from different tobacco products and from cigarettes with differing deliveries

Peak blood nicotine levels among cigarette smokers and dependent users of either oral (19 or nasal(29 snuff are remarkably similar, averaging in each case about 35 ng ml. Manufactured cigarettes contain 10 to 14 mg of nicotine, an amount that does not vary greatly between brands. But by techniques such as filtration and ventilation, machine-smoked yields of nicotine range from as little as 0.1 mg to over 1 mg, with concomitant tar ranging from 1 to 15 mg or more. The relevance of these machine-smoked yields to human smoking is open to serious question, since smokers extract a similar amount of nicotine (about 1 mg on average) from cigarettes of widely differing yields 2.1) Smokers's characteristic tendency to adjust the way they smoke so as to maintain similar nicotine intakes from cigarettes with widely differing deliveries is termed nicotine compensation or titration.(17) A boundary model of nicotine regulation has been proposed, whereby chronic users seek to avoid the adverse...

Nicotine replacement therapy

The rationale for nicotine replacement therapy is that many of the difficulties of cessation stem from problems posed by nicotine withdrawal. Numerous experimental and clinical studies have shown that nicotine replacement therapy reliably attenuates the severity of withdrawal, thereby making it easier for would-be ex-smokers to cope with abstinence while unlearning the deeply ingrained habit elements of smoking. Nicotine replacement products are available in a number of forms, including gum, transdermal patch, nasal spray, lozenge, and inhaler. The various forms of nicotine replacement therapy differ in terms of route of administration and speed of absorption, as well as in the extent to which they offer a situational response to craving and a behavioural ritual to replace the rituals of cigarette smoking. None give the high concentration arterial bolus of nicotine characteristic of cigarette smoking, and the overall dose of nicotine they provide is typically only one-third to...

Nonnicotine pharmacological treatments

Many other drugs to aid smoking cessation have been tested, but most have so far failed to yield evidence of efficacy (including most anxiolytics and antidepressants that have been tested), while in others such as clonidine signs of promise have been offset by an unacceptable side-effect profile. Recently, the drug bupropion, an atypical antidepressant with some noradrenergic and dopaminergic activity, became the first non-nicotine medicine licensed for smoking cessation in the United States, Canada, and Mexico. The mechanism of action appears not to be related to the drug's antidepressant effect but rather to pathways common to addiction. Clinical trials, among non-depressed smokers, have shown clear advantage over placebo,(60) and there is evidence that bupropion and the nicotine skin patch have additive effects in enhancing outcomes. (61)

ENOS and Oxidative Stress of Smokers

The effects of smoking on white matter lesions, such as lacunar infarction and leukoaraiosis, are still controversial recently the hypothesis that the eNOS T-786C genotype was a modulating factor for the effect of smoking on cerebral circulation was examined. Smokers were showed greater oxidative stress, as estimated by urinary F(2)-isoprostane excretion. In smokers, 786CC homozygotes showed a significant decrease of cerebral blood flow and a significant increase of cerebrovascular resistance, whereas the eNOS genotype did not affect these parameters in nonsmokers (102). Further evidence for a role of smoking in modulating the activity of eNOS was demonstrated in vitro using luciferase reporter vectors with the various haplotype combinations of the 786T C and intron 4 repeat polymorphisms. Transcription efficiency in the T promoter was lower than in the C promoter. Treatment of the constructs with cigarette smoking extract increased the transcription efficiency significantly in the T...

Viirelevance Of NfjB To Cigarette Smoking

There are several reasons to believe NF-kB is a good target by which to examine CS-induced lung cancer development and its chemoprevention. First, benzo a pyrene, a component of CS, has recently been shown to activate NF-kB in lung adenocarcinoma cells (37) and in vascular smooth muscle cells (50). Second, CS is also a potent source of ROIs (44-46), which are required for NF-kB activation (47). Our laboratory and others have shown that antioxidants and overexpression of cells with antioxidant enzymes such as Mn superoxide dismutase or with y-glutamylcysteinyl synthase (51-53) block NF-kB activation. Third, NF-kB activation has been implicated in chemical carcinogenesis and tumorigenesis (54,55). Fourth, CS has been shown to induce NF-KB-regulated chemokine genes in bronchial epithelium (Ref. 38 and references therein). Lastly our laboratory and others have shown that most chemopreventive agents suppress NF-kB activation (56-60).

Smallcell lung cancer and oesophageal cancer

Chemo-irradiation of intra-thoracic tumours is hindered by risk of serious morbidity, in particular pneumonitis and oesophagitis. Nonetheless, small cell-lung cancer is an excellent target for this approach although chemosensitive local failure is inevitable with chemotherapy alone, and even with conventional consolidation radiotherapy, 40-50 of these patients have locally recurrent disease. The results of combination etoposide, cisplatin, and thoracic irradiation are promising. Toxicity, especially oesophagitis, is considerable.

Genetic Models For The Analysis Of The Effects Of Nicotine

Various mouse models that have been used, or can be used in the future, to study the genetic influences on nicotine responses will be discussed in the sections that follow. Specific examples of experimental results will be included. The initial screen for genetic effects almost universally involves the measurement of the effects of nicotine in several inbred mouse strains. Inbred mice can be obtained from several suppliers including Jackson Laboratories, which maintains a large number of inbred strains. Inbred mice are a stable breeding population and, barring mutations leading to genetic drift, maintain a constant genotype over time. Consequently, it is not necessary to measure all phenotypes of interest at once. Comparison of results obtained with inbred mice collected at different times and different places is feasible. However, care must be taken to consider that environmental factors such as housing conditions, season, and experimental differences among laboratories can affect...

Project Title Efficacy Of Bupropion For Treating Spit Tobacco Users

Summary Although overall rates of cigarette smoking have declined over the past 40 years, the use of spit tobacco (ST) has tripled. The use of ST can lead to nicotine addiction and physical dependence. ST use is known to increase the risk of periodontal disease and oral cancer. Moreover, ST use increases the risk for cancer of the esophagus, larynx, stomach and pancreas and the risk of cardiovascular disease. Effective interventions are needed to assist ST users to stop. Bupropion, a monocyclic anti-depressant that inhibits the neuronal re-uptake of norepinephrine and dopamine and may also selectively inhibit neuronal nicotinic receptors, has demonstrated efficacy for smoking cessation. In a placebo-controlled pilot study, we have shown possible treatment effects of sustained release bupropion (SR) in ST user. Our aims are 1) To evaluate the efficacy of a 12-week course of bupropion SR rates of abstinence from all tobacco use 2) To evaluate the efficacy of a 12-week course of...

Chronic Nicotine Agonist Effects

From a therapeutic point of view, it is crucial for a drug effective in an acute form to remain efficacious with repeated administration. Interestingly, and in contrast to many of the other effects of nicotine, no tolerance is seen to the memory improving effects of chronic nicotine administration. In fact, the memory improvement caused by nicotine seems to become more robust over time. A series of studies has shown that chronic infusion of either a high dose of 12 mg kg day of nicotine38,40,42 or a Chronic Nicotine Infusions and Radial-Arm Maze Accuracy Control Nicotine Control Nicotine FIGURE 7.1 Chronic nicotine effects on radial-arm maze choice accuracy (entries to repeat mean sem). more moderate dose of 5 mg kg day of nicotine for 3-4 weeks significantly improves memory performance on the radial-arm maze in both male and female rats.3035'37'4449 To wit after a standard 18-session training on the radial-arm maze, rats were implanted subcutaneously with an osmotic minipump...

Effects of Alcohol and Tobacco

While smoking has been implicated in increased upper airway resistance via upper airway inflammation, edema, and mucous secretion (61,62), an association between smoking and OSA has not been conclusively established. Nonetheless, alcohol and tobacco use and dependence, as determined by nationwide survey studies, do not differ significantly between men and women (63), and cannot explain the gender differences observed in the prevalence of OSA. Also, as stated previously, women with OSA are more likely to present with atypical symptoms, such as insomnia. Medications targeted at this primary complaint, such as sedatives, may exacerbate the underlying disease by promoting upper airway relaxation and increasing the threshold for arousal however, there are no data supporting such a hypothesis.

Case Study I Trials of bCarotene Supplementation and Lung Cancer Chemoprevention

Following Peto's paper, four large-scale randomized placebo-controlled clinical trials of b-carotene (summarized in Table 23.1) revealed no protection but rather adverse effects or no difference in rates of lung cancer among participants in the b-carotene arm compared to the placebo arm. Two trials enrolled high-risk individuals while the other two enrolled apparently healthy individuals. The Alpha-Tocopherol b-Carotene Trial (ATBC) in Finland included male smokers at high risk of lung cancer (mean, 36 years of smoking) who were administered b-carotene, a-tocopherol, both, or a placebo for 6 years on average. The b-Carotene Retinol Efficacy Trial (CARET) in the United States enrolled men and women who were either smokers (mean, 49 years) or asbestos-exposed workers, and administered b-carotene, retinyl palmitate, both, or a placebo for 4 years on average. In these two trials, the b-carotene-supplemented group experienced an increased risk of lung cancer (by 18 in ATBC and 36 in CARET)...

Efficacy of Risk Reduction Tobacco

Tobacco use can be reduced by smoking cessation. As compared with smokers, the excess risk of lung cancer decreases sharply in ex-smokers after approximately 5 years since quitting. Although an excess risk from smoking most likely persists through life, the excess risk approaches that of a never smoker after 15 to 20 years since quitting.4 After quitting, the risk of oral, pharyngeal, and laryngeal cancers decreases, approaching that of a never smoker in approximately 15 years.5,6 Also, within 2 years of quitting, the risk of pancreatic cancer decreases by approximately 50 .7-9

Tobacco nicotine dependence

Tobacco dependence is the most common of all substance use disorders in the elderly population in a 1994 American national survey, among people aged 65 and older, 13 per cent of men and 11 per cent of women reported regular daily cigarette smoking. (25) Tobacco use is the leading preventable cause of death in adults. Smoking doubles the risk of death from combined causes in people aged 35 to 70,(6) and longevity is inversely associated with cigarette consumption. Smoking in older people is also associated with loss of mobility and poorer physical function, and may alter the metabolism of many prescribed drugs. Older smokers who quit have a reduced risk of death compared with current smokers that becomes evident within 1 to 2 years after quitting, and their overall risk of death approaches that of never-smokers after 15 to 20 years of abstinence 26' Among smoking cessation methods, some, like rapid smoking aversion therapy or medicinal nicotine substitutes (e.g. polacrilex gum,...

Effectiveness of Physician Counseling Tobacco

Of all the health behaviors, the most agreement exists regarding the efficacy of physician counseling. Several well-designed randomized controlled trials have established that physician counseling helps smokers quit.47 Providing self-help brochures without clinical advice has limited efficacy, but physician advice alone can increase quit rates by as much as 10 .48,49 Cummings and colleagues observed that training internists for 3 hours and providing self-help books to smokers increased smoking cessation rates by approximately 2 .48 The 1996 and 2000 Clinical Practice Guidelines contain a summary of this evidence.47,50 The guidelines emphasized the role of (1) identification of smokers in practice, such as using smoking as a vital sign, 51 (2) physician advice to quit, and (3) the use of medications to assist smokers in their quitting attempts. Several studies have also shown that feedback about smoking-specific risk factors such as pulmonary function and carbon monoxide testing by...

Recommendations of Professional Groups Tobacco

Professional groups are in broad agreement that tobacco use in any form and in any amount is not safe and should be discontinued. No safe level of smoking has ever been identified.10 Groups agree that tobacco use in the form of cigarette smoking, cigar smoking, snuff, and chewing are all carcinogenic and should be discontinued.47,50,92,93 Professional groups agree that physicians should advise their patients to discontinue tobacco use and to use pharmacotherapy as appropriate.47,50,92,93

Nicotineresponsive Elementary Phenotypes In Schizophrenia

Schizophrenia is a complex genetic disorder i.e., the illness does not have a pattern of inheritance resulting from a single genetic abnormality.10 Two nicotine-responsive neurophysiological abnormalities, one in auditory sensory gating and the other in smooth pursuit eye movements, are currently under investigation as potential elementary phenotypes representing gene effects that, in combination with other specific gene effects, may result in the development of schizophrenic illness.1112 These neurophysiological abnormalities appear to be transmitted as autosomal dominant characteristics in some families with high occurrence rates for schizophrenia, and they are both normalized by nicotine administration. The subjective experience of this normalization may contribute to the drive to smoke among patients with schizophrenia. In nearly all neuronal systems, when stimuli are repeated, the electroencephalo-graphic response to the second stimulus is less than that to the first. The first...

Effects of Cigarette Smoking on Behavior of Leukocytes in the Microcirculation

In assessing the effects of cigarette smoke on leukocyte rheology and passage through the microcirculation, one must consider potential modifications in their mechanical and adhesive properties, and also possible effects on the endothelial cells that can promote adhesion. In general, studies of the effects of cigarette smoke or its constituents on leukocyte behavior fall into one of the following categories (i) studies in which humans or animals are acutely exposed to cigarette smoke and observations are made on changes in circulatory behavior in vivo (ii) studies in which blood is withdrawn from human cigarette smokers or non-smokers (with or without additional acute smoking), and It is possible to extract leukocytes (usually neutrophils) from blood, to radiolabel them, and then to reinject them, in order to examine their fate in the circulation. Such an approach can be used to locate sites of inflammation where cells accumulate, but can also be used to study the kinetics of passage...

Oncogenes in lung cancer

Themselves and may be of use as diagnostic or prognostic tools. Lung cancers can be divided broadly into two groups - the small-cell lung cancers (SCLCs) and the non-small-cell lung cancers (NSCLCs). The latter group can be subdivided into adenocarcinomas, squamous cell carcinomas (SQCs) and large-cell carcinomas with different genes being associated with each group. Over-expression of the growth factor receptor group of oncogenes is a common abnormality in lung cancers. Over-expression of EGFR is consistently seen, primarily in NSCLCs of the SQC type. One study showed that over-expression was not associated with a survival difference (Rusch et al., 1995) but suggested that this growth factor receptor loop was more important for lung tumour formation than for tumour progression. However, others have found an association between over-expression of the receptor and poor prognosis (Brabender et al., 2001 Pastorino et al., 1997). HER2 amplification is seen in approximately a third of...

Nicotine Is the Main Tobacco Constituent with Addictive Properties

Among tobacco's 3500 different constituents, nicotine has been considered the most likely responsible for tobacco's addictive effects (7). When smoked, tobacco releases nicotine, which readily enters the blood circulatory system and rapidly accumulates in the brain, exerting its neuroactive action. To date, the neurobiology of nicotine dependence is only partially understood the knowledge about the underlying molecular mechanisms so far accumulated is based mostly on findings obtained in animal models of nicotine dependence and, to a lesser extent, on observations in humans. According to a well-accepted psychopharmacological model (8), substance use or drug-seeking behavior is controlled by four main processes the positive reinforcing effects, the aversive effects, the discriminative effects, and the stimulus-conditioned effects of the drug. In more explicit terms, an individual consumes nicotine because it

Drug Taking Is the Key Behavioral Trait in Smokers to Be Modeled in Animals for Understanding the Nicotine Reward

This review is focused mainly on in vivo drug-taking paradigms as a way to study the neurobiology of dependence. In naturalistic conditions, smokers titrate their optimal nicotine dose by taking different numbers of puffs per unit of time using inhalation devices (cigarettes, cigars, etc.). They consume several cigarettes per day, often clustering them around specific events, for example, at home after work, or after lunch. Similarly, in an experimental setting, smokers can be trained to self-administer nicotine intravenously and to titrate their optimal dose per session or daily (11). The determinants leading to the way nicotine is abused, that is, smoking, chewing, or intravenous nicotine self-administration are described elsewhere. The most commonly accepted reason for taking an addictive drug is because of its positive reinforcing effects. A drug serves as positive reinforcer when its use increases the probability of eliciting a response on which it is contingent (i.e., smoke...

The Reward System as Neural Substrates of the Reinforcing Properties of Nicotine

Most of our knowledge about the neural mechanism of reinforcement stems from the experiments of Olds and Milner (15) using intracranial self-stimulation (ICSS) procedures. ICSS can be triggered when the electrodes are targeting several discrete brain regions, spanning from the ventral tegmental area (VTA) to the lateral hypothalamus, via the medial forebrain bundle, to the nucleus accumbens and prefrontal cortex. The ensemble of these structures has been loosely defined as reward system (16). At first, nicotine (0.2-0.4 mg kg) was shown to enhance the rate of responding for ICSS in the rat VTA or medial prefrontal cortex without changing the current threshold (17). Years later, Huston-Lyon et al. (18), using an auto-titration procedure, showed that nicotine indeed lowered the current threshold for ICSS in a dose-dependent fashion, demonstrating the reinforcing efficacy of low-dose nicotine. More recently, nicotine was shown to produce a leftward shift of the ICSS curve relating the...

The Role of Nicotine Reward

The authors are aware that if a drug sustains drug-taking behavior, that is, nicotine self-administration or smoking, this does not tell how it does so. Many factors have been proposed to contribute to the overall positive reinforcing efficacy of the drug, that is, nicotine reward, and these have been reviewed extensively (8,10,12,22). Accordingly, a drug may In drug self-administration the subject starts by learning about the response-outcome contingency (incentive, stimulus-reward learning, goal-oriented behavior), and then the action gradually becomes a habit (stimulus-response learning). Certain addictive drugs may influence self-administration behavior by acting on stimulus-reward learning, leading to the acquisition of a drug-reinforced habit over time (23,24). In this case environmental stimuli can become associated with the effects of the drugs, acquiring secondary reinforcing properties (conditioned reinforcer). Interestingly, using so called second-order schedules,...

Smoking cessation pharmacotherapy

The symptoms of withdrawal begin within a few hours and peak at 24-48 hours after quitting. Anxiety, hostility and anger are the most common symptoms, along with a craving for cigarettes, difficulty concentrating, restlessness, and insomnia. Symptoms usually last about 4 weeks. Nicotine gum (Nicorette) Nicotine patch (Habitrol, Nicoderm CQ) Nicotine nasal spray (Nicotrol NS) Rapid nicotine delivery nasal irritation initially Nicotine inhaler Mimics smoking behavior provides low doses of nicotine B. Nicotine polacrilex (Nicorette) is available OTC. The patient should use1-2 pieces per hour. A 2-mg dose is recommended for those who smoke fewer than 25 cigarettes per day, and 4 mg for heavier smokers. It is used for 6 weeks, followed by 6 weeks of tapering. Nicotine gum improves smoking cessation rates by about 40 -60 . Drawbacks include poor compliance and unpleasant taste. The smoker should be instructed to bite down on the gum to release the nicotine and then place it between the...

NAChR as Primary Site of the Reinforcing Effects of Nicotine

The involvement of nAChR in the reinforcing properties of nicotine is also supported by evidence that the nonselective antagonist mecamylamine reduces nicotine self-administration in rats (41 Tessari and Chiamulera, unpublished data). Experiments performed on mutant mice lacking the 2 subunit and previously trained for cocaine self-administration showed a marked attenuation of nicotine self-administration when cocaine was substituted with nicotine (51). The Q2 mutant mice were also able to lever-press for food, and the selective attenuation of lever pressing contingent to nicotine infusions indicates the key role of Q2-contaning nAChR in sustaining nicotine self-administration. Again, this effect was clearly mediated by the mesolimbic DA system (51). In the next section the role of the mesocorticolimbic DA system will be discussed extensively.

Involvement of the Mesocorticolimbic DA System in the Positive Reinforcement Effects of Nicotine

The involvement of mesocorticolimbic DA system in the reinforcing effects of nicotine is supported by several experimental data. 1. Selective 6-hydroxydopamine (OHDA) lesions of the nucleus accumbens reduce nicotine self-administration (95). 2. Low doses of systemic administration of neuroleptics attenuate nicotine self-administration in rats (96). 3. In humans, neuroleptics increase nicotine plasma levels in smokers (97), suggesting that the individuals smoke more to counteract the effects of the drug and experience rewarding effects. 4. Postmortem DA and DA metabolite levels were found to beincreased in the striatum of smokers when compared with nonsmoker controls (61). 5. The indirect DA agonist bupropion has been used successfully to reduce the relapse rate in smokers who have manifested the intention to quit smoking (98). In rats, nicotine self-administration is attenuated by VTA microinfusions of the 4D2-preferential competitive antagonist dihydro-D-erythroidine, but not by the...

Of the Mesocorticolimbic DA System Associated with the DADependent Positive Reinforcing Effects of Nicotine

Chronic exposure to addictive drugs indirectly stimulates transcription of specific genes by increasing intracellular cyclic adenosine monophosphate (cAMP), which in turn results in activation of multifunctional protein kinases and phosphorylation of several cellular proteins, including transcription factors, in target neurons of the mesocorticolimbic DA system (69,100,101). A limited but growing number of scientific reports indicate that nicotine also produces some adaptive changes in the target neurons of DA terminal fields, namely, the nucleus accumbens, striatum, and prefron-tal cortex, most likely via DA release and D1 receptor mediation. One of the most well studied effects of D1 receptor activation in target neurons is the transcriptional regulation of the immediate early gene (IEG) c-fos, and medium-late genes of the Fos-related antigen family (100,102). Expression of c-fos has been used largely to provide tran- scriptional activation brain maps induced by various stimuli,...

Larynx Cancer Relative Risk Cigarettes

Global Cancer Incidence

Effect follows a multiplicative rather than additive model 285,772,1607,1608, 1800,1943,2647,2885 . The increased relative risk (RR) for alcohol consumption differs by site, and is higher for the supraglottis and hypopharynx and lower for the glottis and subglottis 2647 . The impact of increased RR (10x) for smoking is stronger for glottic than supraglot-tic SCC 2647 . Studies in several populations have shown a direct dose-related response between smoking and SCC and the benefits of cessation. Smoking black tobacco cigarettes entails a stronger risk than smoking blond tobacco 2235 . Other smoking habits that increase the RR of laryngeal SCC include smoking at a young age, long duration, high number of cigarettes per day, and deep smoke inhalation 195,1035 . The influence of tobacco on RR of laryngeal SCC is confirmed even for non-drinkers 308,2833 . Case controlled studies from Italy and Switzerland show an increased RR of 2.46 for heavy drinkers and laryngeal SCC. The RR for current...

Small cell lung cancerradiotherapy

Patients with small cell lung cancer (SCLC) are usually treated by primary chemotherapy because of its chemo-responsiveness and frequent dissemination at time of diagnosis. SCLC is, however, also the most radio-responsive variety of bronchial carcinoma and radiotherapy has an important role in its management. In patients with a localized tumour, thoracic irradiation (TI) and prophylactic cranial irradiation (PCI) improve disease control at these sites and lead to prolongation of survival when compared to chemotherapy alone. In addition, radiotherapy is a useful palliative treatment for patients relapsing after, resistant to, or refusing chemotherapy.

Notes on Neuroadaptation to Nicotine Exposure of Neurotransmitter Systems Other Than DA

Are all the positive reinforcing effects of nicotine mediated only by meso-corticolimbic DA Some discrepancies in the experiments cited above, and evidence of neuroadaptation in other neurotransmitter systems, may open some alternatives. Two examples follow. 2. In rats, cocaine self-administration completely downregulates c-fos expression in the nucleus accumbens, whereas nicotine does not, suggesting a D1 receptor-independent mechanism for activating transcription of c-fos (108,110). In fact, here, as in the anterior cingulate cortex, nicotine may act directly either on postsynaptic nAChR located in cortical or accumbens interneurons, or in pre-synaptic nAChR located on nordadrenaline, glutamate, or GABAergic terminals, exerting important modulatory roles. Below we list some other examples of possible involvement as substrate for the addictive properties of nicotine, organized along the major neurotransmitter systems (see also ref. 33). Nicotine stimulates the in vitro release of NE...

Methodological Aspects of Intravenous Nicotine Self Administration in Experimental Animals

Initially, nicotine self-administration was successfully developed in subhuman primates (34,35). Some early works also described different protocols in rats (36-40). It was only during late 1980s that Corrigalll and Coen (1989) developed reliable schedules of iv nicotine self-administration in rats (41), which were replicated and used by other groups (42-44). Under these specific methodological conditions, rats acquire stable self-administration. Critical schedule parameters are 2. The limitation of aversive effects due to nicotine overdosing overload (e.g., limited daily access to self-administration session, a timeout period after each infusion, checking nicotine solutions pH) 3. The fixed-ratio schedule between responding and nicotine infusion delivery Overdosing, high intake levels, and any other exposure to potential aversive effects of nicotine need to be controlled into the schedule of reinforcement and in the protocol (43-45). Most of the published studies described schedule...

Chronic Nicotine Administration Produces AchR Upregulation

Recent reports consistently indicate that 3H-nicotine binding, but not 125I-D-bungarotoxin binding, is upregulated in human postmortem prefrontal cortex, hippocampus, entorhinal cortex, and, to a lesser extent, striatum of smokers when compared with age-matched controls (60-62). Interestingly, nicotine binding is normalized in ex-smokers, confirming the reversibility of the upregulation of 3H-nicotine-binding sites observed in rodent brain following chronic passive nicotine administration (63,64). These results indicate that smoking and nicotine exposure produces upregulation of nAChR, most likely D4H2, but does not directly support receptor hypersensitivity, that is, increased effects of nicotine on postsynaptic target cells. Recent unpublished results obtained in rats self-administering nicotine (0.03 mg kg injection) for at least 3 wk (Tessari and Mugnaini, personal communication) indicate that 3H-nicotine-binding sites are upregulated in the parieto-frontal cortex, but not the...

Analgesic Effects Of Nicotine And nAChRs Agonists In Different Pain Models

Abbreviations CFA, complete Freund's adjuvant CYT, cytisine DMPP, dimethylphenylpiperazin-ium EPI, epibatidine EPX, epiboxidine M, mechanical (Randall-Selitto) M-vF, mehcanical (von Frey) META, metanicotine (RJR-2403) NIC, nicotine NMCC, N-methylcarbamylcholine T, thermal (Hargreaves). Another promising avenue of research involves the evaluation of combinatorial antinociceptive effects produced by the coadministration of nicotine and opioids. For example, intrathecal or intracerebroventricular nicotine, at doses which had little effect by themselves, potentiated the antinociception produced by morphine.1920 Similarly, Zarrindast et al.,21 found that doses of nicotine as low as 0.0001 mg kg, which had no antinociceptive effects alone, potentiated morphine-induced antinoci-ception in the tail-flick assay. It is interesting that whereas naloxone predictably reduced the response to morphine in the presence or absence of nicotine, atropine but not mecamylamine blocked the potentiating...

The Other Side of the Coin Relevance of Nicotine Withdrawal and the Negative Reinforcing Effects of Nicotine in Self

Difficulties in giving up the habit of smoking are often reported to be also related to the nicotine withdrawal syndrome, that is, increase nervousness, frustration, anger, and desire to smoke (7,28). Nicotine withdrawal syndrome can also be seen in rats passively infused with high doses of nicotine and then acutely treated with mecamylamine (29,30). Stress, depression, and other negative affective states, and peripheral signs induced by nicotine withdrawal, have been suggested to be the basis of nicotine craving, and may constitute an important component of the maintenance of drug-taking behavior (21,31). In smokers, the time to the first cigarette in the morning after awakening is considered a main feature in the Fargenstrom Questionaire for Smoking Dependence (32). The value of such an indicator is based on the overnight abstinence from smoking due to sleep, which should induce a state of physiological unbalance (i.e., withdrawal) that will drive a motivation for drug-seeking...

The Mesocorticolimbic DA System Pharmacological Neuroadaptation to Nicotine Exposure

Midbrain DA neurons contain mRNA for all the principal nAChR subunits (70). However, it is not clear if all of them form functional receptors. High-affinity binding for 125I-D-bungarotoxin and 3H-nicotine suggests that D7 and Q2-containing nAChR proteins, respectively, are actually expressed. Antibodies against D4 have been recently used to confirm the presence of this subunit as translated protein, strongly supporting the presence of a functioning D4D2 nAChR (71). Pharmacological doses of nicotine are known to stimulate DA neurons of the VTA preferentially (72,73) vs those of the substantia nigra (74), and most likely by a direct action. Pioneering studies by Fuxe and collaborators using the Falk-Hillarp and related techniques showed that exposure to nicotine or smoked tobacco increases the rate of disappearance of fluorescent DA from mesolimbic DA terminals in rats (75,76). These data suggest that nicotine enhances the impulse flow and release of DA in nucleus accumbens....

Sexually Dimorphic Mnemonic Responses To Nicotine In Aged Monkeys

Nicotinic receptor agonists have been shown to exert sexually dimorphic actions in laboratory animals. These nicotinic effects are as broadly physiological as sensory gating phenomenon,63 tuberoinfundibular dopaminergic neuron activity,64 active avoidance learning,65 and analgesia.66 The same may be said for nicotine's action in Nicotine Optimal Doses Young Monkeys

Lung Cancer Screening A Historical Perspective

Screening studies for lung cancer date to the 1950s and 1960s when several studies were undertaken using a variety of screening protocols that combined chest radiography and sputum analysis. The protocols employed different screening time intervals and the study design was either uncontrolled or controlled but nonrandomized. The most widely publicized study was the Philadelphia Pulmonary Neoplasm Research Project, in which only 6 of 94 patients with lung cancer detected at screening survived more than 5 years 4 . No study showed an advantage for lung cancer screening. The subsequent development of more sophisticated techniques of chest radiography and sputum analysis in the 1960s and the methodologic limitations of the early studies led to the concept that lung cancer screening might prove efficacious if a more rigorous study design was used. In that context, three large randomized controlled studies (National Cancer Institute Cooperative Early Lung Cancer Group) were initiated among...

Absorption Distribution and Excretion of Nicotine

Nicotine is well absorbed from the mucous membranes in the oral cavity, gastrointestinal tract, and respiratory system. If tobacco smoke is held in the mouth for 2 seconds, 66 to 77 of the nicotine in the smoke will be absorbed across the oral mucosa. If tobacco smoke is inhaled, approximately 90 to 98 of the nicotine will be absorbed. Nicotine is distributed throughout the body, readily crossing the blood-brain and placental barriers. The liver, kidney, and lung metabolize approximately 80 to 90 of the alkaloid. The kidney rapidly eliminates nicotine and its metabolites.

The Protracted Mnemonic Response To Nicotine

As more experience working with nicotine in primates developed, it was noted that, when animals were tested on the day following nicotine pretreatment (in the absence of further drug or vehicle treatment), significant enhancement of performance efficiency continued to be maintained.23 Performance levels returned to prenicotine levels on the following day (i.e., within 36 hours after injection). This protracted feature of nicotine's beneficial mnemonic actions was unexpected, particularly in view of the short plasma half-life of the drug in rhesus monkeys.24 Levin and colleagues10 reported similar findings in rats. In fact, they demonstrated that this protracted effect of nicotine was not dependent upon the presence of the drug at the time of behavioral training. The improvement in task efficiency measured on the day after nicotine administration generally occurred for trials associated with long delay intervals, as they had for the previous day's session. This pattern (of retention...

The Role on Neuronal Nicotinic Acetylcholine Receptors nAChR in Nicotine Self Administration

When nicotine enters the brain, it binds to neuronal nicotinic acetylcholine receptors (nAChR), heterogenously expressed in central nervous system neurons (53). Much like their cousins in the neuromuscular junction, brain nAChR are probably pentameric complexes arranged around a central pore that is permeable to K+, Na+, and Ca2+ (54). In the mammalian brain, eight subunits (D2-D7 and 9-D10) and three subunits ( 2-D4) are differently combined to define two principal subfamilies of receptors the -bungarotoxin-sensitive subfamily, consisting of homopentametic D7 nAChR sub-units, and the hetero-oligomeric subfamily, made of different combinations of the other subunits and the (2-4) subunits (53,55). Experiments performed in mutant mice lacking the D7-subunit nAChR receptors indicate that practically all the high-affinity -bungarotoxin binding found in the mouse brain is due to D7-subunit-containing nAChR (56). Similar experiments performed in mutant mice lacking the H2 (51,57) and D4...

Nicotine As A Cognitive Enhancing Agent In Monkeys

The earliest studies that sought to examine the ability of nicotine to enhance cognitive performance were performed in rodents, and many of these experiments were predicated on the known alerting or nootropic effect of certain CNS stimulant drugs. We entered this area in 19881 and chose to study the potential cognitive-enhancing actions of nicotine in nonhuman primates with the premise that nicotine's actions involved more complex mechanisms than a nonspecific sharpening of attention or arousal. Interest was based largely on two findings. In studying the effects of nicotine in humans 2 years earlier, Wesnes and Warburton2 concluded that nicotine facilitates state-dependent learning and does not affect associative processes. Secondly, the strong relationship between the ability of the centrally acting nicotinic receptor antagonist mecamylamine to impair performance of the retention trial of an inhibitory avoidance task in rats, and its ability to inhibit the biosynthesis of...

Lung cancer

Lung cancer is now the most frequent cause of cancer mortality in both men and women in the UK and US.Its incidence is continuing to rise worldwide, in particular in developing countries, where smoking is increasing. It is estimated that 80 of cancer deaths are due to smoking. The risk of lung cancer relates to the number of cigarettes smoked, the number of years of smoking, early age of starting to smoke, and the type of cigarette (greater risk with unfiltered and high-nicotine). While health education has had some success in reducing tobacco consumption in men, smoking in women and adolescents is increasing. Much less frequent causes of lung cancer are exposure to There is evidence that lung cancers may arise in pluripotent stem cells in the bronchial epithelium, and this would certainly offer an explanation for the mixed histology that is fairly commonly seen. The WHO pathological classification is A Squamous cell carcinoma (30 ) B Small cell carcinoma (20 ) C Adenocarcinoma (40 )...

Smokers Melanosis

Heavy smokers can sometimes develop areas of oral hyperpigmentation. It is more common in women than men. Although any part of the mouth can be affected the anterior gingivae are involved most frequently. The lesions vary in colour from light brown to bluish-black and the lesions may be focal or diffuse. Sometimes the overlying mucosa has a somewhat milky-white appearance, particularly in the buccal mucosa. The condition can slowly resolve if smoking is stopped or reduced 72 . Pigmentation of the soft palate has been reported in a significant number of patients with suppurative lung disease and malignancy 117 . Nearly a quarter of patients with confirmed bronchogenic carcinoma show this feature. Most patients have a long history of cigarette smoking and it is possible that in many cases these lesions were merely smoker's melanosis rather than being related directly to the pulmonary lesions.

Epidemiological aspects

Sudden unexpected cardiac arrest in adults has an incidence of 0.1 to 0.2 per cent in the general population, with 80 per cent of cases due to coronary heart disease. The incidence of cardiac arrest increases exponentially with age, reflecting the escalating frequency of coronary heart disease, but at all ages men are at greater risk than women. For coronary heart disease populations, hereditary factors producing hypertension, diabetes, lipid abnormalities, and male-pattern baldness predispose to cardiac arrest. Racial characteristics are important, with increased risks in colored populations, although the reasons for this are unclear. Cigarette smoking is the major acquired (and preventable) risk factor, although sedentary occupation and diet also play significant roles.

Oral Cavity and Oropharynx

Squamous intraepithelial lesions in the oral cavity and oropharynx are associated with tobacco, whether smoked, chewed or used as snuff, which seems to be the major carcinogen in this region 165, 171, 247, 298, 316, 389 . Smoking 20 or more cigarettes per day, particularly non-filtered, as well as drinking alcohol, particularly fortified wines and spirits, is an important risk for the development of oral dysplasia in the European population. Tobacco is a stronger independent risk factor for oral SILs than alcohol 165 . The use of smokeless tobacco in the western world has a rather lower correlation with oral precancerous and cancerous lesions than south-east Asia, where chewing habits, including betel quid, strongly correlate with oral precancer and cancer development 298 . Alcohol has been considered the second most important risk factor for oral and pharyn-geal cancer development 247 , and its synergistic effect with tobacco is particularly evident 170, 171 . The risk of the...

Brigitte L Kieffer and Frdric Simonin 1 Introduction

Opioids have been classified as narcotic drugs (from the Greek word for stupor), due to their pharmacological profile very distinct from that of other drugs of abuse, such as pyschostimulants (cocaine, amphetamine), cannabinoids, nicotine, or alcohol (3). As for other substances of abuse, though, opioid addiction typically develops in four stages (4) (a) the initiation phase, in which drug exposure produces positive subjective effects (euphoria) (b) the maintenance phase, in which drug-taking becomes compulsive, indicating that dependence has developed (c) withdrawal, which develops when drug levels decrease in the body and is recurrently experienced by drug abusers and (d) craving or the intense desire to use the drug and relapse, which are most critical from a therapeutic standpoint. Not every individual exposed to opioids will develop addiction, depending on social, contextual, or perhaps genetic factors (5). However, opioids are considered strongly addictive, and it has been...

And Oropharyngeal Leukoplakia Proliferative Verrucous Leukoplakia and Erythroplakia

Oral leukoplakia is a clinical diagnosis of exclusion. If any oral white patch can be diagnosed as some other condition, such as candidiasis, leukoedema, white sponge naevus, lichen planus, frictional keratosis, nicotine stomatitis, etc. then the lesion should not be considered a case of OL 263 . The white appearance of OL is most often related to an increase in the surface keratin layer. OL affects approximately 3 of white adults 46 . It is most frequently seen in middle-aged and older men with an increasing prevalence with age, reaching 8 in men over 70 years 48, 49 . However, recent studies reported a tendency towards a lower prevalence of OL, compared with the past, which might be the result of the massive public health education campaign against tobacco 314 .

Who Should Give Dietary Advice

A trial by Henkin et al12 randomised 70 hypercholesterolemic patients to dietary counseling by a physician only and 66 to counseling by a physician and a dietitian. The physician sessions were 30 minutes long and included reevaluation of cardiovascular risk factors, a brief physical examination, and counseling on smoking cessation, physical activity, weight control, and the Step I diet. Those receiving the additional time to discuss dietetic issues were offered 2 to 4 individual counseling sessions within 3 months (as needed), the use of food diaries, and Step II advice where appropriate. After 3 months, some participants in the physician-only group were given dietetic

The Obesity Epedemic in America

Finally, obesity steals years of life. Compared to a non-obese, non-smoker, the Framingham Heart Study has shown that an obese, non-smoking male will die 5.8 years earlier and an obese, non-smoking female 7.1 years earlier. At age 40, a male, obese smoker will die 13.7 years prematurely and an obese, female smoker 13.1 years prematurely 22 . Obesity affects the majority of young and old Americans it may well become the number one actual cause of death in the 21st century.

Analytic Epidemiology

The first study of HCL suggested (with very few cases) a link with solvent exposure.78 Subsequent studies found no such links.77,79 A related study found risks associated with chemical exposure.80 No association has been found with cigarette smokers.77,80 A new occupational risk noted by a French study was an association with farming,81 which was not clearly seen in other studies.

Low Dose Spiral Computed Tomography

Computed tomography plays an established role in the assessment of patients with clinically suspected and proven bronchogenic carcinoma. Recently, LDCT has been explored as a tool for detecting early lung cancer in asymptomatic individuals at risk for this disease, with encouraging preliminary results 18-20 . ence with LDCT screening at two large teaching hospitals in New York. The promising results of these preliminary studies have led many researchers, clinicians, health care policy officials and lung cancer patient advocates to revisit the topic of lung cancer screening 21 . In 1996, Kaneko et al. reported the use of biannual chest radiographs and spiral CT scans in screening 1369 Japanese adults at high risk for developing lung cancer 18 . Peripheral lung cancer was detected in 15 (1 ) subjects by CT but in only 4 (0.3 ) by chest radiography. A vast majority (93 ) of detected cancers was classified as Stage I. In 1998, Sone et al. published their experience in screening 5483...

Conclusion and Perspectives

Finally, a number of knockout models have been tested for cocaine or nicotine (for example D1, D3, D4, nAChR-D2 knockout mice, reviewed in ref. 110), but not morphine. It is likely that the genes inactivated in those mice are also implicated in responses to chronic opioid exposure, and this should be tested in future studies. More generally, a systematic screen of mice genetically modified in the central nervous system could be considered, because many genes involved in opioid addiction remain to be discovered.

Sputum Cytology and Advanced Sputum Analysis Techniques

In screening studies, the sensitivity of sputum cytology for detecting lung cancer is approximately 20 to 30 and the specificity is approximately 98 6,47,53 . Improvement in sensitivity can be achieved by adherence to proper techniques for collection, processing, and interpretation of samples 48 . Sputum cytology demonstrates the highest sensitivity for squamous cell carcinoma and the lowest yield for adenocarcinoma 21 . In recent years, there have been several exciting advances in sputum analysis techniques, most notably the development of automated analysis of sputum specimens for biomarkers 49,50-56 . This technology capitalizes on advances in our understanding of the molecular events that lead to lung cancer. In the future, it is likely that a panel of biomarkers (Table 4) will be used to identify the early clonal phase of lung cancer, thus allowing detection of lung cancers at a very early stage 52 . Importantly, biomarker characterization may also allow for targeted treatment of...

Second Primary Tumours

The risk of developing an SPT closely correlates with the use of tobacco and alcohol abuse, and is more than doubled in patients who smoke and drink compared with those who do not smoke and drink 207 . Moreover, there is a direct dose-dependent relationship between tobacco and alcohol exposure and the risk of SPT.

Genetic Variation and Pharmacology

Consequence of the genetic variation. For individuals with reduced enzyme activity, the toxicity is reduced to normal levels, but the efficacy of the drug is nearly normal when the dosage is reduced (Weinshilboum, 2001). The existence of individuals with disease but with neither obvious genetic risks nor exposure to compounds illustrates the difficulty of identifying both the exposure and genetic factors. Nonsmokers have lung cancer, just at a much lower rate than smokers, and some heavy, long-term smokers are disease free.

Spontaneous pneumothorax

Secondary spontaneous pneumothorax is a complication of many lung diseases, mainly chronic obstructive pulmonary disease, cystic fibrosis and, more recently, AIDS. In chronic obstructive pulmonary disease, airway inflammation increases airway resistance which results in hyperinflation with intrinsic positive end-expiratory pressure (PEEP). Subsequently, pulmonary emphysema and thinning of the lung parenchyma occur. If the transpleural pressure gradient exceeds a certain level because of a high intrinsic PEEP, the overdistended emphysematous bulla and visceral pleura rupture, causing pneumothorax. As severity of chronic obstructive pulmonary disease and level of intrinsic PEEP are closely related, the risk of secondary spontaneous pneumothorax is higher in patients with chronic obstructive pulmonary disease who are more critically ill. Pneumocystis carinii pneumonia, treatment with inhaled pentamidine, and cigarette smoking are risk factors for spontaneous pneumothorax in AIDS...

Cultural Aspects of Substance Abuse

The views of drug use differ among cultures around the world. Some drugs considered illegal in one culture are accepted in another culture. Alcohol, caffeine, and nicotine are addictive drugs that are widely accepted in the United States and elsewhere throughout the world.

Aortobronchial fistulas

Aortobronchial fistulas are a rare and life-threatening complication seen in pulmonary tuberculosis, staphylococcal pneumonia, bronchogenic lung cancer, aortic dissection without aneurysm, thoracic aortic aneurysm, and mycotic aneurysms, and after aortic valve replacement, repair of aortic coarctation, and unilateral lung transplantation.

Aortoesophageal fistulas

Asamura, H., Naruke, T., Tsuchiya, R., Goya, T., Kondo, H., and Suemasu, K. (1992). Bronchopleural fistulas associated with lung cancer operations. Journal of Thoracic and Cardiovascular Surgery, 104, 1456. Asamura, H., Naruke, T., Tsuchiya, R., Goya, T., Kondo, H., and Suemasu, K. (1992). Bronchopleural fistulas associated with lung cancer operations. Journal of Thoracic and Cardiovascular Surgery, 104, 1456.

Growth Factor Receptor Targeting for Radiosensitization

The epidermal growth factor receptor family has four transmembrane receptor tyrosine kinases, including HER2, HER3, HER4, and epidermal growth factor receptor (EGFR), which are involved in cell proliferation and survival responses, mediated through ligand binding. EGRF is known to be overexpressed in a majority of several tumors including non-small cell lung cancer, head and neck cancers, and glioblastoma multiforme. Clinical studies confirm that EGRF overexpression is associated with clinical radioresistance in these tumors. HER2 overexpression in breast cancer is also associated with clinical radioresistance. Thus, targeting the EGFR family clearly has the potential for radiosensitization. The preliminary results of a Phase III clinical trial comparing radiation therapy + the chimeric monoclonal antibody against EGRF (Cetuximab, Erbitux ImClone Systems, New York, NY, and Bristol-Myers Squibb Company, Princeton, NJ, USA) were recently reported showing improved local control and...

Ivpredictive Models And Decision Analysis

Many nodules remain indeterminate in etiology after comprehensive noninvasive radiological assessment. At this point, a decision to observe, biopsy, or resect the nodule is made. This decision is usually made based on the subjective perception of probability of malignacy using clinical parameters such as patient age and cigarette-smoking history as well as the radiologic features of the nodule 57 . Unfortunately, clinical judgment incorrectly classifies a high proportion of malignant nodules as benign 57,58 . Accordingly, there have been ongoing attempts to develop more accurate, objective methods to optimize decision making in this regard.

C T De Rosa PhD H Hansen S Wilbur H R Pohl H A ElMasri M M Mumtaz

Thus it is important that exposure to environmental chemicals be viewed in the context of overall chemical exposures. Concurrent exposures to chemicals such as welding fumes, indoor air pollutants, tobacco smoke, alcohol, and prescription and nonprescription drugs complicate the health risk assessment of low-level, involuntary, environmental exposure such as may occur at hazardous waste sites. Voluntary exposures to some chemicals frequently entail exposures to relatively high chemical concentrations and are usually well defined and quantifiable, whereas involuntary exposures from waste sites may be at low concentrations and difficult to characterize and quantify. Individual control over exposure varies across personal, occupational, and environmental chemical exposure pathways (Fig. 6.2). Personal exposures such as firsthand tobacco smoke or alcohol are voluntary. Occupational exposure is voluntary, but the individual generally has less control over these exposures. On the other...

Cardiovascular System

The effects of nicotine on the cardiovascular system mimic those seen after activation of the sympathoad-renal system, and they are principally the result of a release of epinephrine and norepinephrine from the adrenal medulla and adrenergic nerve terminals. These effects include a positive inotropic and chronotropic effect on the myocardium as well as an increase in cardiac output. In addition, both systolic and diastolic blood pressures are increased secondary to stimulation of the sympathoadrenal system. These effects are the end result of a summation of adrenergic and cholinergic stimulation.

Central Nervous System

The actions of nicotine on the central nervous system are the result of a composite of stimulatory and depressant effects. These can include tremors, convulsions, respiratory stimulation or depression, and release of antid-iuretic hormone from the pituitary. Nausea and emesis are frequently observed after the initial use of nicotine in the form of tobacco smoke. However, tolerance to these effects rapidly develops. This is in contrast to the effects of nicotine on the cardiovascular system, where tolerance develops much more slowly.

Mechanism of Action

Ganglionic nicotinic blockers can be divided into two groups. The first group, characterized by nicotine and related drugs (e.g., lobeline, tetraethylammonium), initially stimulates the ganglia and then blocks them (discussed earlier). These agents are not therapeutically useful. The second group of drugs, which have some therapeutic usefulness but are rarely used, inhibit the postsynaptic action of ACh and do not themselves produce depolarization, thereby blocking transmission without causing initial stimulation.

Supplemental Reading

Nicotine Safety and Toxicity. New York Oxford University Press, 1998. Fant RV, Owen CC, and Henningfield JE. Nicotine replacement therapy. Prim. Care 1999 26 633-652. Lee EW and D'Alonzo GE. Cigarette smoking, nicotine addiction and its pharmacological treatment. Arch Intern Med 1993 153 34-48. Sargent PB. The diversity of neuronal nicotine acetyl-choline receptors. Annu Rev Neurosci 1993 16 403-443. Case Study Smoking Cessation A patient who has been a heavy smoker (2 packs of cigarettes per day for 30 years) comes to you for advice to quit smoking. You inform your patient that sudden cessation of smoking will result in withdrawal symptoms that may include restlessness, irritability, anxiety, tension, stress, intolerance, drowsiness, frequent awakenings from sleep, fatigue, depression, impotence, confusion, impaired concentration, gastrointestinal disturbances, decreased heart rate, and impaired reaction times. You advise your patient that successful cessation of...

Dynamics Of Da Release

Although the studies cited above suggest that the nicotine-evoked release of DA from terminals of mesocorticolimbic and nigrostriatal neurons is primarily a direct result of the stimulation of postsynaptic receptors in the VTA and NA, respectively, the evidence indicates that nicotine's effect at the nerve terminals is modulated by the firing pattern of dopaminergic neurons which, in turn, is affected by amino acid neurotransmitter actions. In the early 1980s, electrophysiological measurements of the activity of dopaminergic neurons in the SN found that, in addition to spontaneous single depolarizations, characteristic bursting patterns of multiple spikes were also observed (Grace and Bunney, 1983, 1984). It was soon discovered that neurons in the VTA had higher burst firing activity than those in the SN (Grenhoff et al., 1986, 1988 Clark and Chiodo, 1988) and the administration of nicotine to animals More direct measurements of glutamatergic modulation of nigrostriatal and mesolimbic...

Functional Activity Of Upregulated nAChRs On Dopaminergic Neurons

As indicated above, by the late 1970s it was clear that nicotine could stimulate the release of DA by acting on nAChRs in the brain. At this time, the ligand most often used to characterize nAChR binding sites was 125I alpha-bungarotoxin (aBTX), and it had been demonstrated in dozens of studies that aBTX binding sites were present in a number of brain areas (see reviews by Morley et al., 1979 Oswald and Freeman, 1981). Although the chronic treatment of nicotine had been shown to result in tolerance to a number of the behavioral and neurochemical effects of nicotine, no studies at that time indicated that chronic nicotine treatment produced changes in 125I aBTX binding sites in the brain. In 1983, Schwartz and Kellar (using 3H acetylcholine) and Marks and coworkers (using 3H nicotine) independently discovered that the chronic treatment of animals with nicotine produced an increase in binding sites in the rat cortex (Schwartz and Kellar, 1983) and several mouse brain areas (Marks et...

Keratinising Squamous Cell Carcinoma

The occupational epidemiology of sinonasal squamous cell carcinoma has been strongly related to exposure to nickel 141, 243, 252, 253 and to a lesser extent to chromium, isopropyl alcohol and radium 218 . As in other territories of the respiratory tract, a definite association between sinonasal squamous cell carcinoma and cigarette smoking has been documented 26, 146 . Chronic sinonasal inflammation is considered a predisposing factor. A case of carcinoma of the maxillary antrum after thorotrast exposure has been reported 97 . Nitrosamines and to a lesser extent formaldehyde are strong nasal carcinogens in laboratory rodents 44, 155 .

Overall time and accelerated radiotherapy

In a randomized controlled trial, the CHARTS regime, in which treatment is given 3 times on each of 12 consecutive days, proved superior to conventional radiotherapy in non-small cell lung cancer (NSCLC). A split course regime of accelerated radiotherapy was shown to be superior to conventional radiotherapy in head and neck cancer but there was some increase in normal tissue morbidity.

Degenerative Disc Disease

Mechanical factors such as repetitive trauma due to sports or occupation may also adversely affect the discs. Smoking has a negative impact on the metabolic processes within the discs, as nicotine-mediated vasoconstriction interferes with the discs' oxygen supply and nutrition.

Physiologic Correlates Of Malignancy

They include the glycoprotein Carcinoembryonic Antigen (CEA), which may be elevated in gastrointestinal tumors, breast cancer, lung cancer, pancreas cancer, and ovarian cancer, and in cases of bronchogenic carcinoma and mammary carcinoma. Furthermore, CEA is excreted into the urine in papillary carcinoma of the bladder. There are six forms of CEAs. They are related glycoproteins in fetal intestinal epithelium that are expressed only in trace amounts in healthy adults. Another such tumor marker is the glycoprotein a-1-Fetoprotein (AFP), which is elevated in the blood in 60-90 of patients with hepatocellular carcinoma, 60 of patients with teratoid gonadal tumors, and 13 of patients with metastatic liver tumors. It is also expressed by some pancreas carci-nomata and gastrointestinal tumors. Physiologically, a-1-Fetoprotein is synthesized at high levels in fetal hepatocytes and plasma, but in barely detectable amounts in the adult liver. An isoenzyme of...

Sinonasal Undifferentiated Carcinoma

Sinonasal undifferentiated carcinoma (SNUC) is defined as a high-grade malignant epithelial neoplasm of the nasal cavity and paranasal sinuses, composed of small to medium-sized cells, lacking evidence of squamous or glandular differentiation and of rosette formation 48, 86, 114 . Cigarette smoking 86 and nickel exposure 252 have been associated with SNUC. Epstein-Barr virus (EBV) and the deletion of the retinoblastoma gene have been ruled out as factors involved in the development of this tumour 127 . Ionising radiation is another aetiologic factor, as radiotherapy either for retinoblas-toma or for nasopharyngeal carcinoma has been associated with SNUC 127 .

Conclusion Challenges for the Future

Designing clinical trials to investigate the activity of these novel agents and optimize their use in a defined patient population are critical challenges to the success of targeted therapy. There remains much cause for optimism and enthusiasm, particularly following the notable successes in the past few years that have made it to the clinic, such as trastuzumab for breast cancer, bevacizumab for colorectal cancer, imatinib mesylate for CML and GIST, and gefitinib for lung cancer.

Nervous System Innervation of the Lower Urinary Tract

Acetylcholine is the primary neurotransmitter at the ganglia and the effector sites. The receptors of this system are muscarinic and nicotinic. There are five subtypes of known muscarinic receptors (M1-M5) and they are located on all autonomic effector cells. In the human bladder there is a predominance of M2 receptors. The M3 receptors are primarily responsible for bladder contractions. There are no known muscarinic receptors specific for the bladder. The muscarinic receptors are the targets of anticholiner-gics for the treatment of the overactive detrusor. The nico-tinic receptors are located on autonomic ganglia and the motor end plates of skeletal muscle. Atropine competitively inhibits these muscarinic sites. High doses of nicotine inhibit nicotinic sites.

Radioligand Binding Assays

Pharmacological characterization of nAChR can be assessed based on specific binding of radiolabeled nicotinic ligands and on competition by unlabeled compounds for specific radioligand binding. Central to this approach is identification of a suitable radioligand acting with reasonable selectivity (binding with much lower affinity to other nAChR subtypes) or specificity (showing no binding to other nAChR subtypes) at a given nAChR subtype(s). Most radioligands for nAChR are agonists (e.g., 3H-labeled epibatidine, nicotine, acetylcholine, or cytisine) or competitive antagonists (e.g., 125I-labeled a-bungarotoxin or a-cobratoxin 3H-labeled methyllycaconitine) interacting at overlapping sites on the extracellular face of nAChR. However, high For 125I-labeled a-bungarotoxin binding assays conducted in the laboratory, radiolabeled toxin stocks are supplemented with 1 mg ml of bovine serum albumin, and reaction mixtures contain at least 0.1 mg ml of bovine serum albumin. This precaution...

Methylation detection

To experimentally verify the concept, base-specific cleavage and MALDI-TOF MS have been used to successfully reconstruct the methylation pattern of IGF2 H19, a well-described genomic region commonly hemi-methylated (Ehrich et al., 2005b). It has then been used successfully for large-scale quantitative profiling of methylation patterns in lung cancer. In this study, the me-thylation status of 47 promoter regions (1426 CpG sites in total) was assessed quantitatively in 48 lung cancer tissue samples and compared to their normal adjacent lung tissue to identify differentially methylated CpGs that allow accurate classification of samples (Ehrich et al, 2005b). Using the technology described here, this study was completed within a single day (measurement and analysis time).

Summary And Perspectives

Women in the USA and most of the Western world have a 12 lifetime risk of developing breast cancer, which rivals lung cancer in being the most common cause of cancer-related deaths. Approximately 25 of women diagnosed with breast cancer die of the disease. There is a need for better prognostic markers for accurately predicting clinical outcome. As summarized above, adhesion molecules regulate several mechanisms that control tumor cell survival, proliferation, migration, invasion, and the ability to survive in various microenvironments. Therapeutics targeting various cellular invasive and migratory activities might be useful in treating pathologies that are associated with these cell phenotypes, such as metastasis and angiogenesis. Over the past several years, research has led to the development of integrin and protease inhibitors that are now being tested in clinical trials. As the underlying mechanisms and relevant key molecules become progressively identified, there are...

Overview Of Peripheral Neuronal nAChRS

Nicotinic acetylcholine receptors (nAChRs) belong to the ligand-gated ion channel receptor superfamily nAChRs are composed of 5 subunits arranged to form an integral ion channel that can open upon binding the neurotransmitter, ACh, or exogenous ligands, such as nicotine. Muscle type nAChRs are found at the neuromuscular junction and in the electric organs of fish. The muscle nAChRs are very well-characterized and will be noted but not discussed in this chapter. More recently, neuronal type nAChRs were identified in neurons in the central and peripheral nervous systems and also in epithelia. The nAChR family is found throughout the central nervous system (CNS), in the peripheral autonomic nervous system, in adrenal chromaffin cells, and also in skin, the cornea, cochlear, and bronchial epithelial cells (Nguyen et al., 2000b). Their functions, which are just beginning to be elucidated, are a subject of intense investigation (Cordero-Erausquin et al., 2000 Wessler et al., 1999).

Number and Duration of Conditioning Trials

Drugs with powerful reinforcing properties (amphetamine, cocaine, and morphine) require fewer and shorter conditioning trials then a weaker reinforcing drug (nicotine). Drugs with a very short half-life may allow a researcher to run a drug session in the morning and a vehicle session in the afternoon.

Who uses drugs and why

Recreational drug use is a worldwide phenomenon with considerable national and regional variations. In 1995, 28 per cent of British men and 26 per cent of women admitted to being regular cigarette smokers. The decline in smoking by adults in the developed world has not been mirrored in children, and in particular the rate of initiation among girls under 16 has doubled over the last two decades in the United Kingdom. By the age of 16 years, 94 per cent of young people have tried alcohol, and 78 per cent will have been drunk on at least one occasion. Sixteen-year-olds from the United States and the United Kingdom topped the league in lifetime experience of any illicit drug in a comparison of 23 countries. (5) Forty-one per cent of British school students admitted using cannabis in comparison with 34 per cent of North American, 19 per cent of Italian, 15 per cent of Spanish, 12 per cent of French, and 2 per cent of Greek students. Overall, around one in four of the British population...

Do school prevention programmes work

Outcome research of prevention programmes in the United States has been the subject of a comprehensive review.(21) Programmes should be guided by awareness that the average age of trying alcohol, cigarettes, solvents, or cannabis for the first time is between 11 and 13 years, and that exposure to drugs is now the norm for older teenagers.(22) The two distinct aims are to delay experimentation in younger children and to minimize harm in those over 13, many of whom can be assumed to be dabbling already or to have friends who are doing so. Only those programmes that actively involve students in discussion and debate, and provide relevant skills training such as assertiveness, ways of resisting social pressure, problem solving, stress management, and confidence boosting, have any measurable benefit. Improvement in knowledge without this practical dimension has no effect on behaviour, and scaremongering or moralizing can be actively counterproductive.

Acetylcholine ReceptorMediated Ca2Influx into Presynaptic Nerve Terminals

Nicotine is an addictive drug that activates a diverse subset of ionotropic acetyl-choline receptors. Most cholinergic actions in brain, both by ionotropic and metabotropic receptors, are modulatory, and very few fast synapses exist that utilize acetylcholine as a transmitter. Interestingly, although some ionotropic acetylcholine receptors are postsynaptic, a relatively large proportion, much larger than observed for other neurotransmitters, appears to be presynaptic. A possible pathway accounting for the addictive actions of nicotine was discovered in the observation that presynaptic nicotinic acetylcholine receptors, when activated, mediate the influx of Ca2+ into presynaptic terminals, and thereby stimulate the release of neurotransmitters (Wannacott, 1997). Interestingly, this effect appears to operate via a class of nico-tinic acetylcholine receptors containing a6 subunits that are relatively enriched in the nigrostriatal pathway, suggesting that nicotine may be addictive by...

General Comments

Due to its relatively high vapor pressure and ease of thermal volatilization, especially significant in metal smelting and refining processes, and the release of highly water-soluble cadmium salts into industrial wastewater, environmental levels of the metal are continually rising and present a considerable public health concern. The metal is seen to concentrate in certain plants, e.g., in tobacco leaves, and to accumulate in animal soft tissue, reaching potentially toxic levels (9). Dietary intake and smoking of tobacco thus are the principal sources of human exposure to cadmium. That among the general population smokers are particularly at risk was demonstrated by significantly elevated cadmium levels measured in their blood and seminal fluid, as compared with the corresponding values seen in nonsmokers (10).

ENOS Glu298Asp G T and Cardiovascular Disease

Leeson et al. (98) studying vascular function by endothelium-dependent, flow-mediated brachial artery dilatation (FMD) and endothelium-independent dilatation response to glyceryl trinitrate observed that vascular function was lower in Asp298 carriers, particularly in smokers and that n-3 fatty acids had a positive effect in this group, but not in Glu298 homozygotes.

Sexual Arousal Disorder

Sexual arousal disorder is the persistent or recurrent inability to attain or maintain sexual excitement, which causes personal distress. This disorder includes poor vaginal lubrication, decreased genital sensation, and poor vaginal smooth muscle relaxation. Arousal disorders are primarily physiologic in nature and can often result from pelvic and colorectal surgery and other pelvic disorders, various medications, atherosclerosis, cigarette smoking, and vascular disease. This disorder most closely parallels ED in the male. In fact, a condition of hyperactive sexual arousal disorder, analogous to the priapism state in the male, has also been described.

Acute psychological effects of cannabis use

The lifetime prevalence of cannabis abuse and dependence (as defined in DSM-IIIR) in the United States has been estimated at 4.4 per cent of adults. (9) Similar estimates have been obtained in New Zealand and Australia.(2) The risk of becoming dependent on cannabis seems to have more similarities with that for alcohol than with that for nicotine or the opioids, with around 10 per cent of those who ever use cannabis meeting criteria for dependence at some point in their lives. (29)

Diseases caused by smoking

Based on the 20-year follow-up of the British doctors's cohort, it was concluded that a young man who persists in smoking will run a 1 in 4 chance of being killed prematurely by tobacco. More recent studies, including the 40-year follow-up of the British doctors (5) and the second large study of the American Cancer Society(6) have forced a re-evaluation of the extent of the risk. It is now apparent that persistent smokers run a 1 in 2 risk of being killed by cigarettes, losing on average 8 years of life. Smoking causes some 30 per cent of deaths from cancer, the great bulk of deaths from chronic respiratory disease, and is a major contributor to circulatory diseases. I ble ,1 summarizes data from the American Cancer Society study of over 1 million men and women aged 35 years and over, giving mortality in cigarette smokers and lifelong non-smokers for the main fatal smoking-related diseases.(6) moking is recognized to cause 80 per cent or more of all lung cancers. In addition it is...

Adult smoking disadvantage and dependence

The most striking feature of the evolution of smoking in developed Western countries over the past 20 years has been the increasing association of cigarettes with markers of disadvantage, whether it be socioeconomic position, or a range of factors indicating stressful living circumstances. (47) High rates of smoking are seen in the unemployed, lone parents, people who are divorced or separated, the homeless (United Kingdom Office of Population Censuses and Surveys), heavy drinkers, (47) drug users (United Kingdom Office of Population Censuses and Surveys), and prisoners. (48) Cigarette smoking is strongly associated with psychiatric illness, whether it be schizophrenia 49,50 depressive illness 51 or a variety of other neurotic disorders. ty The association of cigarettes with lowered levels of psychological well being is not confined to those with a formal psychiatric diagnosis, but extends also into the general population of smokers. (5 53) Between 1973 and 1994 rates of smoking among...

Treatments to promote cessation

The proportion of ever-smokers who have given up varies greatly by factors such as age, socioeconomic status, and dependence, (54) as well as by country. Only about 1 per cent of Chinese smokers have quit, (55 against nearly 50 per cent of American and United Kingdom ever-smokers. In most instances, smokers who quit do so without any formal help, other than the support of family and friends. But the success rate from a single unaided quit attempt is low, with about 1 per cent remaining abstinent 1 year later.(54) Research into treatment methods to enhance rates of cessation has been very actively pursued over the past two decades and is now bearing fruit in the form of well-validated protocols for both intensive clinic-based approaches and interventions in primary care. Evidence-based clinical practice guidelines have been issued in the United States(56) and the United Kingdom 57 emphasizing both the availability of efficacious and cost-effective treatments, and the need for health...

Brief advice from health professionals

Randomized trials have clearly established the value of brief advice from general practitioners, dentists, and others to their smoking patients. (58) Such advice does not require specialist training, can be given in the doctor's own words, and need take no more than a few minutes of face-to-face contact. Its effect is to motivate more cessation attempts rather than to give any specific help in overcoming withdrawal. The Cochrane Collaboration estimates the increment in successful cessation from such interventions to be 2 per cent. While this may seem low, its value from a public health perspective is that it offers the possibility to reach the 70 per cent or more of smokers who consult a health professional each year.

Chapter References

Thun, M.J., Day-Lally, C.A., Calle, E.E., Flanders, W.D., and Heath, C.W. (1995). Excess mortality among cigarette smokers changes in a 20-year interval. American Journal of Public Health, 85,1223-30. 7. Wald, N.J. and Hacksaw, A.K. (1996). Cigarette smoking an epidemiological overview. British Medical Bulletin, 52, 3-11. 8. US Department of Health and Human Services (1988). The health consequences of smoking nicotine addiction. A report of the Surgeon General. DHSS Publication No. (CDC) 88-8406. US Government Printing Office, Washington, DC. 9. Stolerman, I.P. and Jarvis, M.J. (1995). The scientific case that nicotine is addictive. Psychopharmacology, 117, 2-10. 10. Henningfield, J.E. and Keenan, R.M. (1993). The anatomy of nicotine addiction. Health Values, 17, 12-19. 11. Benwell, M.E.M., Balfour, D.J.K., and Anderson, J.M. (1988). Evidence that tobacco smoking increases the density of (-)- (3H)nicotine binding sites in human brain. Journal of Neurochemistry, 50, 1243-7. 12....

Nitrogenprocessing bacteria

A second group of sulphur-processing bacteria can convert this sulphur and sulphide back into sulphate, using oxygen as the electron acceptor. These sulphide-and sulphur-oxidizing bacteria may occur as biofilms above the sulphate-reducing zone. They also bloom copiously around hot, sulphide-rich submarine vents known as 'black smokers', where they play an important role in the food chain of the vent community. Their metabolism results in further 34S depletion of the sulphur isotopes (to - 60 ), which can be measured in the fossil record.

Conclusions and Outlook

The loss of cholinergic activity is a major hallmark of AD, and inhibiting AChE activity continues to be a basis of current AD-based treatments. However, AChE-Is produce some short-term benefits to patients, and, eventually, these agents lose their efficacy over time. Furthermore, AChE-I may lack a detectable effect in preventing disease progression based on pre-clinical findings, inter alia, regarding nicotinic effects that may in fact increase tau phosphorylation and M2 muscarinic effects that may prevent a-APPs release. This may be attributed to elevated synaptic ACh levels following AChE inhibition that activates all muscarinic and nicotinic receptors subtype in a promiscuous way, whether in need or not. The use of nAChR and mAChR agonists may represent another means for activating cholinergic receptors in the AD brain. In this regard, activation of nAChRs by chronic nicotine exposure exacerbates tau pathology in the 3xTg-AD mice by activating p38-MAP kinases (Oddo et al., 2005)....

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