Publications

OBJECTIVES

This article describes the tobacco industry's use of bars and nightclubs to encourage smoking among young adults.

METHODS

Previously secret tobacco industry marketing documents were analyzed.

RESULTS

Tobacco industry bar and nightclub promotions in the 1980s and 1990s included aggressive advertising, tobacco brand--sponsored activities, and distribution of samples. Financial incentives for club owners and staff were used to encourage smoking through peer influence. Increased use of these strategies occurred concurrently with an increase in smoking among persons aged 18 through 24 years.

CONCLUSIONS

The tobacco industry's bar and nightclub promotions are not yet politically controversial and are not regulated by the 1998 Master Settlement Agreement between the industry and the states. Tobacco control advocates should include young adults in research and advocacy efforts and should design interventions to counter this industry strategy to solidify smoking patterns and recruit young adult smokers.

Expression microarrays are a powerful tool that could provide new information about the molecular pathways regulating common lung diseases. To exemplify how this tool can be useful, selected examples of informative experiments are reviewed. In studies relevant to asthma, the cytokine interleukin-13 has been shown to produce many of the phenotypic features of this disease, but the cellular targets in the airways and the molecular pathways activated are largely unknown. We have used microarrays to begin to dissect the different transcriptional responses of primary lung cells to this cytokine. In experiments designed to identify global transcriptional programs responsible for regulating lung inflammation and pulmonary fibrosis, we performed microarray experiments on lung tissue from wild-type mice and mice lacking a member of the integrin family know to be involved in activation of latent transforming growth factor (TGF)-beta. In addition to identifying distinct cluster of genes involved in each of these processes, these studies led to the identification of novel pathways by which TGF-beta can regulate acute lung injury and emphysema. Together, these examples demonstrate how careful application and thorough analysis of expression microarrays can facilitate the discovery of novel molecular targets for intervening in common lung diseases.

This study was undertaken to estimate the magnitude of medical care expenditures among persons with respiratory conditions in the USA in 1996, and the increment in expenditures attributable to these conditions. The study data were derived from the 1996 Medical Expenditure Panel Survey, a national sample of 21,571 persons. Of the 21,571, 1,027 reported one or more respiratory condition. After weighting, the individuals may represent about 12.1 million persons in the USA. All medical care expenditures of these individuals were tabulated, stratified by comorbidity status, and then compared to those among persons with nonrespiratory conditions or with no conditions. Regression techniques were then used to estimate the increment of healthcare expenditures attributable to the respiratory conditions. From a national total of $45.3 billion, medical care expenditures averaged $3,753 among persons with respiratory conditions. Hospital stays comprised the largest component (45%). The per capita increment in total expenditures attributable to respiratory conditions ranged from $1,003-2,588, from a national total ranging from $12.1-31.3 billion. The total medical care expenditure of persons with respiratory conditions was estimated to be $45.3 billion, of which $12.1-31.3 billion represents an increment in expenditures associated with the conditions themselves.

Abstract Advances in our understanding of the mechanisms involved in immune activation and immune tolerance have laid the foundation for the development of new strategies for treating autoimmune diseases. In particular, the dissection of the two-signal process of T-cell activation has identified distinct targets that may provide a means of blocking pathological autoimmune responses without causing sustained blockade of protective immune responses. These strategies have shown great promise in animal models for autoimmune diseases, and they are currently the focus of clinical investigation in several autoimmune diseases of humans.

We previously demonstrated that noxious peripheral stimulation (e.g. subdermal capsaicin injection in the hind paw) produces antinociception that is mediated by opioid receptors in nucleus accumbens. The current study used the trigeminal jaw-opening nociceptive reflex responses in the rat to assess the role of intra-accumbens mu-, delta- and kappa-opioid receptors in the antinociceptive effect of noxious stimulation and intra-accumbens opioid agonism. Whilst intra-accumbens injection of either the mu-receptor-selective antagonist Cys2,Tyr3,Orn5,Pen7amide (CTOP) or the delta-receptor-selective antagonist naltrindole blocked capsaicin-induced antinociception, neither the selective mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO; 150 or 300 ng) nor the selective delta-agonist D-Pen2,5-enkephalin (DPDPE; 150 or 300 ng) alone induced antinociception. Simultaneous injection of DAMGO and DPDPE (150 ng each), however, produced significant antinociception. Capsaicin-induced antinociception was not blocked by the selective kappa-receptor antagonist nor-binaltorphimine, but was blocked by the kappa-agonist U69,593. U69,593 also antagonized the antinociceptive effect of the DAMGO/DPDPE combination. Thus, in nucleus accumbens, mu- and delta- but not kappa-opioid receptors contributed to capsaicin-induced antinociception; selective activation of individual receptor subtypes was insufficient, but coactivation of mu- and delta-opioid receptors induced antinociception, and kappa-receptors appeared to play an antianalgesic role in nucleus accumbens.

To date, most studies have focused on the characterization of HIV-1-specific cellular immune responses in the peripheral blood (PB) of infected individuals. Much less is known about the comparative magnitude and breadth of responses in the lymphoid tissue. This study analyzed HIV-1-specific CD8+ T cell responses simultaneously in PB and lymph nodes (LNs) of persons with chronic HIV-1 infection and assessed the dynamics of these responses during antiretroviral treatment and supervised treatment interruption (STI). In untreated chronic infection, the magnitude of epitope-specific CD8+ T cell activity was significantly higher in LNs than in PB. Responses decreased in both compartments during highly active antiretroviral therapy, but this decline was more pronounced in PB. During STI, HIV-1-specific CD8+ T cell responses in PB increased significantly. Enhancement in breadth and magnitude was largely due to the expansion of pre-existing responses in the LNs, with new epitopes infrequently targeted. Taken together, these data demonstrate that HIV-1-specific CD8+ T cells are preferentially located in the LNs, with a subset of responses exclusively detectable in this compartment. Furthermore, the enhanced CD8+ T cell responses observed during STI in chronically infected individuals is largely due to expansion of pre-existing virus-specific CD8+ T cells, rather than the induction of novel responses.

Drug efflux by intestinal P-glycoprotein (P-gp) is known to decrease the oral bioavailability of many CYP3A4 substrates. We hypothesized that the interplay occurring between P-gp and CYP3A4 at the apical membrane would increase the opportunity for drug metabolism. To define the roles of P-glycoprotein (P-gp) and CYP3A4 in controlling the extent of intestinal absorption and metabolism, two substrates were tested. The transport, metabolism, and intracellular levels of N-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K77, a cysteine protease inhibitor; P-gp and CYP3A4 substrate) and felodipine (CYP3A4 substrate only) were measured across CYP3A4-transfected Caco-2 cells in the presence of an inhibitor of CYP3A4 and P-gp, cyclosporine (CsA), or an inhibitor of P-gp and not CYP3A4, GG918 (N-[4-[2-(1,2,3,4-tetrahydro-6,7- dimethoxy-2-isoquinolinyl)-ethyl]-phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine). The extent of metabolism was measured by calculating the extraction ratio (ER) across the cells, while accounting for intracellular changes occurring with P-gp inhibition. The (A)pical to (B)asolateral and B-->A ERs for K77 were 0.33 and 0.06, respectively. These changed with GG918 to 0.14 and 0.12 and with CsA to 0.06 and 0.04. Felodipine ERs were similar in both directions, 0.26 and 0.24 (A-->B and B-->A), and were unchanged in the presence of GG918 but decreased with CsA (0.14 and 0.11). The K77 absorption rate was increased 5 and 4.2-fold in the presence of CsA and GG918, respectively, whereas no change was observed for felodipine absorption. The decreased A-->B ER and increased absorption of K77 with GG918 suggest that P-gp influences the extent of drug metabolism in the intestine via prolonging the access of drugs to CYP3A4 near the apical membrane and decreasing transport across the cells.

Cyclosporine and tacrolimus are substrates and potent inhibitors of the multidrug transporter, P-glycoprotein, in vitro. The authors have investigated the effect of chronic therapy with these and other immunosuppressive drugs on the expression and function of P-glycoprotein in T lymphocytes. Using a P-gp antibody, the authors studied the level of expression of P-gp in CD4 and CD8 T cells over a period of time in renal transplant patients. For comparison, a group of healthy volunteers and patients who did not receive any calcineurin inhibitors but were maintained on mycophenolate mofetil was included. The P-gp expression on lymphocytes from these two groups remained constant (over several months' time). However, patients who were started on tacrolimus or cyclosporine had an initial decline in expression of P-gp on CD4 T cells. Patients who were initiated on calcineurin therapy on day 1 posttransplant also had a decrease in expression of P-gp on CD4 T lymphocytes. This preliminary analysis suggests that the calcineurin inhibitors might be modulating the expression and function of transporters in lymphocytes, thus changing not only the drug concentration but also the apparent efficacy of these drugs. Further understanding and elucidation of such effects would be important in understanding the relationship between pharmacokinetics and pharmacodynamics of these and other drugs, especially for immunosuppressive and anti-AIDS therapy.