Relationship between cigarette smoking and other coronary risk factors in atherosclerosis: risk of cardiovascular disease and preventive measures

Among the major Coronary Risk Factors (CRF) cigarette smoking has shown undoubtedly harmful effects on the heart and blood vessels either as active smoking (smoking a cigarette) or passive smoking (exposure to environmental tobacco smoke -ETS). The strong relationship between cigarette smoking and cardiovascular disease has been seen independent of the other CRF in a number of well-designated epidemiologic studies. However, a strong increase in the excess of cardiovascular risk has been defined along with the interaction of cigarette smoking and other major CRF. Thousands of pharmacologically active substances are present in tobacco smoke, and a large number of direct and indirect effects have been demonstrated. Different responses are also related to these types of exposure: active exposure or passive exposure. The cardiovascular risk increases with increasing levels of blood pressure and/or serum cholesterol and diabetes mellitus, and at each level of these three risk factors, distributed with different rates according to age and gender in individuals, the risk in active smokers or passive smokers is greater than the risk in nonsmokers. Further analytical and methodological observations are needed for better understanding of the chemical and biological synergism. Nevertheless, evidence is clear that cigarette smoking greatly increases the risk of cardiovascular diseases in individuals already at increased risk because of other CRF. Preventive measures must be absolutely conducted to prevent the CRF interaction. These are the changes in lifestyle (i.e. to give up smoking and make physical activity), drug administration, diet supplementation especially by those substances with antioxidant effects.     

In vitro models for human skin disease

Modern tissue culture technology has made it possible to generate human skin equivalents that represent either epidermis or epidermis plus dermis (full-thickness skin) in vitro. Commercially available skin equivalents and in-house models are used for safety analysis of cosmetics and toxicity screening of various pharmaceutical compounds. Recently, tissue culture technology has also been used to develop in vitro models of skin disease, in particular to promote cutaneous drug research while sparing experimental animals. The spectrum of model diseases available covers a range from inflammatory disease to cancer. It has, thus, been possible to gain more insight into the role of active pharmaceutical ingredients of various dermatologically relevant drug classes as well as conventional and innovative formulations.     

In vitro and in vivo models for assessing the host response to biomaterials

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In vitro and in vivo models for assessing drug efflux transporter activity

Determining the activity of drug efflux transport proteins has important implications in the identification of substrates and/or inhibitors of the various transport systems, as well as mechanistic determination of localization, and functional role of the transporters in absorption, distribution and elimination of compounds in the body. This review examines both in vitro and in vivo approaches used to determine drug efflux transporter activity, their applications, and advantages and potential limitations.     

The potential for CETP inhibition to reduce cardiovascular disease risk

ABSTRACT

Background: Although reductions in cardiovascular risk can be achieved by lowering low-density lipoprotein cholesterol, treated patients remain at substantial risk. Epidemiological studies have established that higher levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with reduced cardiovascular risk, and therefore raising levels of HDL-C may be beneficial. The activity of cholesteryl ester transfer protein (CETP) appears to be inversely correlated with HDL-C levels and thus CETP is an attractive target for intervention to raise levels of HDL-C and potentially reduce residual cardiovascular risk.

Objectives: This paper reviews the evidence for an atheroprotective role of higher levels of HDL‐C, the function of CETP in cholesterol metabolism, and the concept of CETP inhibition as a potential new strategy for decreasing cardiovascular risk. An analysis of clinical studies of CETP inhibition was also performed.

Methods: MEDLINE (1966 to June 2006), EMBASE (1974 to June 2006), and cardiology conference proceedings were searched for clinical trials of CETP inhibition.

Results: Thirteen reports involving vaccine-based and pharmacological inhibition of CETP were found. Modest and inconsistent elevation of HDL‐C was observed with vaccine-based therapy, whereas HDL-C elevation with pharmacological inhibitors was greater and more consistent.

Conclusions: Elevation of HDL‐C via CETP inhibition appears to be a potentially promising approach to reduce cardiovascular disease. Preliminary studies suggest benefits of CETP inhibition on serum lipid levels, and ongoing studies should establish the effects on atherosclerosis and cardiovascular events.     

In vitro models for the evaluation of angiogenic potential in bone engineering

Blood vessels have a fundamental role both in skeletal homeostasis and in bone repair. Angiogenesis is also important for a successful bone engineering. Therefore, scaffolds should be tested for their ability to favour endothelial cell adhesion, proliferation and functions. The type of endothelial cell to use for in vitro assays should be carefully considered, because the properties of these cells may depend on their source. Morphological and functional relationships between endothelial cells and osteoblasts are evaluated with co-cultures, but this model should still be standardized, particularly for distinguishing the two cell types. Platelet-rich plasma and recombinant growth factors may be useful for stimulating angiogenesis.     

In vitro models for the study of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease is regarded as the hepatic manifestation of metabolic syndrome and is an important and common cause of chronic liver disease with a potential to develop end-stage liver disease. While important advances in the pathophysiology have been achieved using genetically modified and diet-induced animal models, in-vitro models have been only recently proposed. These models include primary culture and immortalized cell lines. Here we critically review the characteristics of the in vitro models described, the advantages and limitations of the in vitro approach, and the results derived.     

Diacetyl and 2,3-pentanedione exposures associated with cigarette smoking: implications for risk assessment of food and flavoring workers

Diacetyl and 2,3-pentanedione inhalation have been suggested as causes of severe respiratory disease, including bronchiolitis obliterans, in food/flavoring manufacturing workers. Both compounds are present in many food items, tobacco, and other consumer products, but estimates of exposures associated with the use of these goods are scant. A study was conducted to characterize exposures to diacetyl and 2,3-pentanedione associated with cigarette smoking. The yields (μg/cigarette) of diacetyl and 2,3-pentanedione in mainstream (MS) cigarette smoke were evaluated for six tobacco products under three smoking regimens (ISO, Massachusetts Department of Public Health, and Health Canada Intense) using a standard smoking machine. Mean diacetyl concentrations in MS smoke ranged from 250 to 361 ppm for all tobacco products and smoking regimens, and mean cumulative exposures associated with 1 pack-year ranged from 1.1 to 1.9 ppm-years. Mean 2,3-pentanedione concentrations in MS smoke ranged from 32.2 to 50.1 ppm, and mean cumulative exposures associated with 1 pack-year ranged from 0.14 to 0.26 ppm-years. We found that diacetyl and 2,3-pentanedione exposures from cigarette smoking far exceed occupational exposures for most food/flavoring workers who smoke. This suggests that previous claims of a significant exposure–response relationship between diacetyl inhalation and respiratory disease in food/flavoring workers were confounded, because none of the investigations considered or quantified the non-occupational diacetyl exposure from cigarette smoke, yet all of the cohorts evaluated had considerable smoking histories. Further, because smoking has not been shown to be a risk factor for bronchiolitis obliterans, our findings are inconsistent with claims that diacetyl and/or 2,3-pentanedione exposure are risk factors for this disease.     

Cigarette smoking as a risk for cardiovascular disease III: Biochemical effects with higher nicotine yield cigarettes

Subjects who smoked a medium range nicotine yield cigarette were given a higher nicotine yield cigarette (an increase of 0.34 mg nicotine) to smoke ad libitum for two weeks. Plasma nicotine, cotinine, thiocyanate and blood carboxyhemoglobin levels were determined as well as various physiological parameters including heart rate and blood pressure. Increases in plasma nicotine were most directly correlated to heart rate when smokers were first challenged with a higher nicotine yield cigarette (r = 0.85); less directly correlated after a two-week acclimatization period (r = 0.42) and poorly related to their customary product (r = 0.23). Interestingly, it was noted that subjects did not compensate for higher nicotine yield by smoking fewer cigarettes per day when incremental nicotine changes were realistic. They did, however, show higher plasma nicotine, thiocyanate and an upward trend in plasma cotinine with the stronger cigarettes. These increases in cigarette constituents present in plasma, coupled with increasing correlation of heart rate and nicotine uptake, lead us to suggest that uptitration of smokers might cause them to establish new baseline levels. These findings have important health implications in light of recent suggestions to increase the nicotine yet decrease the tar of cigarettes in an attempt to overcome smoker compensation phenomena observed with low yield products.     

Gender differences in risk factors for cigarette smoking initiation in childhood

IntroductionWe investigated whether established risk factors for initiating cigarette smoking during adolescence (parents, siblings, friends smoke; home smoking rules, smokers at home, exposure to smoking in cars, academic performance, susceptibility to smoking, depressive symptoms, self-esteem, school connectedness, use of other tobacco products) are associated with initiation in preadolescents, and whether the effects of these factors differ by gender.MethodsIn spring 2005, baseline data were collected in self-report questionnaires from 1801 5th grade students including 1553 never-smokers (mean age = 10.7 years), in the longitudinal AdoQuest I Study in Montréal, Canada. Follow-up data were collected in the fall and spring of 6th grade (2005–2006). Poisson regression analyses with robust variance estimated the effects of each risk factor on initiation and additive interactions with gender were computed to assess the excess risk of each risk factor in girls compared to boys.Results101 of 1399 participants in the analytic sample (6.7% of boys; 7.7% of girls) initiated smoking during follow-up. After adjustment for age, gender and maternal education, all risk factors except academic performance and school connectedness were statistically significantly associated with initiation. Paternal and sibling smoking were associated with initiation in girls only, and girls with lower self-esteem had a significant excess risk of initiating smoking in 6th grade.ConclusionsRisk factors for smoking initiation in preadolescents mirror those in adolescents; their effects do not differ markedly by gender. Preventive programs targeting children should focus on reducing smoking in the social environment and the dangers of poly-tobacco use.     

In vitro and in vivo models of celiac disease

ABSTRACT

Introduction: Human in vitro blood-brain barrier (BBB) models could be important tools for studying BBB development, maintenance and regulation. However, our capacity to obtain information from these models is still limited in part because only in recent years have (i) these models been derived from non-brain cell sources (e.g. stem cells), (ii) microfluidic systems been developed to recapitulate aspects of BBB physiology and (iii) new insights into the molecular and cellular mechanisms of BBB diseases (e.g. Huntington´s, Allan-Herndon-Dudley Syndrome) been described.

Area covered: This article reviews the technological advances in the derivation of human cells from the neurovascular unit using stem cells and the creation of personalized BBB models generated from patients with neurodegenerative diseases. It also reviews the scientific advances generated from in vitro BBB models.

Expert opinion: The recent technological advances in the derivation of human cells from the neurovascular unit from stem cells as well as in the generation of BBB-on-a-chip that recapitulate in vitro part of the BBB physiology are significant to generate more robust BBB models; however, a considerable effort is still needed to validate the potential of these models to recapitulate the in vivo cellular and molecular mechanisms, in particular regarding BBB function in health and disease.     

Cigarette smoking as a risk for cardiovascular disease V: Biochemical parameters with increased and decreased nicotine content cigarettes

Cigarette smokers were assessed for customary smoking behavior and then were assigned a cigarette which was 0.4 mg higher or lower in nicotine and after 4 weeks, were returned to their customary brand. Biochemical indices of smoking behavior including blood carboxyhemoglobin (COHb), plasma nicotine, cotinine and thiocyanate (-SCN) were measured every 2 weeks. When nicotine availability was increased, smokers received an increased nicotine bolus per puff as determined by plasma nicotine and did not alter smoking topography or cigarettes per day. Over the 4 weeks, plasma cotinine increased without corresponding increases in COHb and -SCN. The return to standard brand resulted in declining cotinine levels but increasing COHb and -SCN, suggesting altered inhalation patterns. In smokers switched to a low yield cigarette, there was a decrease in the nicotine obtained per cigarette followed by a steady rise in plasma cotinine, -SCN and blood COHb over the 4-week period. A positive correlation was observed between cotinine and the gas phase constituents during the change to lower yield and back to standard brand cigarettes. These results indicate that cigarette smokers compensate for decreased nicotine yield with concomitant increases in gas phase components. In addition, increased nicotine availability results in an increased body burden of nicotine and “tar,” but not gas phase constituents. The relative risks of cardiovascular disease under these two situations, which increase exposure to nicotine or gas phase components, deserve careful consideration.     

Environmental and occupational exposure to lead as a potential risk factor for cardiovascular disease

We have evaluated current knowledge on relations between environmental and occupational exposure to lead with a strong emphasis on cardiovascular disease risk factors, such as the influence of lead compounds on lipid disturbances and arterial blood pressure. In addition, "novel" biochemical and vascular risk factors for cardiovascular diseases were discussed, as well as the combination of lead exposure and genetic predisposition to cardiovascular diseases. Occupationally and educationally, awareness of the unfavourable effects of lead on cardiovascular diseases risk factors should be emphasised. Indeed, accurate identification of the various mechanisms that might account for the effects of lead on the cardiovascular system should be of the highest priority in this field of research.     

Development of human cell models for assessing the carcinogenic potential of chemicals

To develop human cell models for assessing the carcinogenic potential of chemicals, we established transgenic human cell lines and tested the sensitivity of known carcinogens using a cell transformation assay. A retroviral vector encoding an oncogenic allele of H-Ras (HBER) or c-Myc (HBEM) was introduced into human bronchial epithelial cells (HBE) immortalized by SV40 large T (LT) antigen, leading to increased cell proliferation but failing to confer a transformed phenotype characterized by anchorage-independent cell growth and tumor formation of immunodeficient mice. When these pre-transformed cells were treated with nickel sulfate (NiSO₄), we found that it shortened the latency of malignant transformation at least by 19 wk in HBER cells or 16 wk in HBEM cells compared to vector control cells. Similarly, the latency of cell transformation was shorter by 15 wk in HBER cells or 9 wk in HBEM cells when cells were treated with benzo(a)pyrenediol epoxide (BPDE). HBER cells appeared to be more sensitive to TPA, NiSO₄ or BPDE-induced cell transformation compared to human embryonic kidney cells expressing H-Ras (HEKR), implying that cell-type specificity is one of important factors determining the effectiveness of the assay. Using AFB₁ and BaP as the representative pro-carcinogens, we also compared the efficiency of three different metabolic conditions in mediating cell transformation. Low dose chemical induction seems to be a prospective system used for metabolic activation of pro-carcinogens. Our findings provided direct evidence that a genetically modified human cell transformation model can be applied to the assessment of potent carcinogens.