Publications

OBJECTIVE

Development of arthritis in the K/BxN mouse model depends on the induction of high titers of antibodies against the enzyme glucose-6-phosphate isomerase (GPI), promoted by CD4(+) T cells expressing a GPI-specific transgenic T cell receptor (TCR). This study was undertaken to determine whether this strong autoantibody response depends on T cell differentiation to the Th1 or Th2 phenotype.

METHODS

The roles of Th cell-biasing cytokines were investigated by introducing the interleukin-4 (IL-4) and IL-12-specific subunit p35 (IL-12p35)-knockout mutations into the K/BxN model and evaluating the impact of these deficiencies on disease. The IL-4-expressing cell types in K/BxN mice were revealed by crossing in a knockin alteration, which resulted in green fluorescent protein expression controlled by endogenous IL-4 gene-regulatory elements. Transfer experiments permitted the identification of the IL-4-producing cell type required for arthritis, and quantitative reverse transcriptase-polymerase chain reaction allowed for determination of the cytokine profile of K/BxN T cells.

RESULTS

While IL-12p35 appeared dispensable for the development of arthritis, IL-4 was crucial for full development of disease. The GPI-reactive TCR of standard K/BxN mice induced the transcriptional activation of the IL-4 locus in CD4(+) T cells and eosinophils, and CD4(+) T cells were the obligatory source of IL-4 for disease. However, the cytokine profile of K/BxN T cells revealed that K/BxN arthritis is not a "pure" Th2 disease.

CONCLUSION

The K/BxN model, although not a classic Th2 disease, depends critically on IL-4. The potential of IL-4 to promote inflammatory arthritis should be considered when proposing therapies for rheumatoid arthritis aimed at biasing T cells toward IL-4 production.

BACKGROUND & AIMS

Proton pump inhibitors (PPIs) are often taken for short-term treatment of heartburn. We performed a systematic review of the efficacy of PPIs for heartburn relief within the first 1-2 days of therapy.

METHODS

Bibliographic databases were searched for clinical trials of PPIs in patients with heartburn that provided information about the proportion with heartburn relief at day 1-2. The sample size-weighted pooled proportions of patients with complete or sustained (7 consecutive days) relief were calculated. Meta-analyses of randomized comparisons of PPIs were also performed.

RESULTS

Eighteen trials met inclusion criteria. At day 1 of PPI therapy, complete 24-hour, daytime, nighttime, and sustained heartburn relief occurred in 0.31 (95% confidence interval [CI], 0.30-0.32), 0.49 (95% CI, 0.48-0.50), 0.55 (95% CI, 0.53-0.56), and 0.21 (95% CI, 0.20-0.22) of patients. Up to 37% of the heartburn relief achievable with 28 days of PPIs occurred on day 1. Placebo was significantly less effective than PPIs for 24-hour relief on day 1 (relative risk [RR], 0.41; 95% CI, 0.29-0.58), and single-dose PPI therapy was less effective than double-dose therapy (RR, 0.82; 95% CI, 0.74-0.92).

CONCLUSIONS

Complete heartburn relief for the entire day occurs in approximately 30% of patients after their first PPI dose and 9% of patients after their first placebo (RR for relief on day 1 for placebo versus PPI was 0.41 [95% CI, 0.28-0.58]). Although PPIs might provide benefit from the first day of therapy, most patients will not have symptom relief with 1 or 2 days of PPI therapy.

To meet federal recommendations to collect case reports of HIV infection, California has adopted a non-name code system to conduct HIV surveillance. The objective of this study was to evaluate among HIV test takers the acceptability and preferences for the 3 major types of HIV infection reporting-name, name-to-code, and non-name code. Interviewer-administered exit surveys with spoken scripts and matching printed materials clearly outlining the 3 HIV reporting options were conducted among HIV test takers immediately following appointments for pretest HIV counseling and blood collection. The study enrolled 208 HIV test takers at 14 publicly funded HIV testing sites in 4 California counties (Los Angeles, Riverside, Fresno, and Santa Clara). Overall with respect to which would be the most acceptable system, 67% reported non-name code, 19% reported name-to-code, and 12% reported name-based HIV reporting (P < 0.0001). A second sample of 226 exit surveys taken 1 year following implementation of California's non-name code HIV infection reporting system continued to show a significant preference for non-name code HIV infection reporting. Significant independent predictors of a preference for coded HIV reporting in both the pre- and postimplementation period were men who have sex with men (odds ratio [OR] = 5.7, 95% CI: 1.2-26 in the preperiod) and having just taken an anonymous HIV test (OR = 3.6, 95% CI: 1.4-9.3, P = 0.009 preperiod). Were the state to adopt name-based HIV reporting, significantly fewer individuals report being likely in the next 12 months to have a confidential HIV test than report being likely to have an anonymous HIV test (51% likely confidential vs. 76% likely anonymous, P < 0.0001). This analysis documents strong support, among HIV test takers in California, for a non-name coded HIV reporting system and indicates a high probability of a shift away from confidential testing toward anonymous testing under a scenario of name-based reporting. This shift is of concern as confidential HIV testing is the basis of US HIV surveillance systems.

OBJECTIVES

Because no prior studies have comprehensively analysed previously secret tobacco industry documents describing marketing female brands, the Virginia Slims brand was studied to explore how Philip Morris and competitors develop and adapt promotional campaigns targeting women.

METHODS

Analysis of previously secret tobacco industry documents. The majority of the documents used were from Philip Morris.

RESULTS

The key to Virginia Slims advertising was creating an aspirational image which women associated with the brand. Virginia Slims co-opted women's liberation slogans to build a modern female image from 1968 through to the 1980s, and its market share grew from 0.24% to 3.16% during that time period. Ironically, the feminist image that worked very well for the brand was also the reason for its subsequent problems. Philip Morris experienced unprecedented losses in market share in the early 1990s, with a decline in market share for four consecutive years from 3.16% to 2.26%; they attributed this decline to both the fact that the brand's feminist image no longer appealed to young women aged 18-24 years, and increased competition from more contemporary and lower priced competitors. Throughout the 1990s, attempts to reacquire young women while retaining Virginia Slims loyal (now older) smokers were made using a "King Size" line extension, new slogans, and loyalty building promotions.

CONCLUSIONS

Tobacco advertisers initially created distinct female brands with aspirational images; continued appeal to young women was critical for long term growth. The need for established brands to evolve to maintain relevance to young women creates an opportunity for tobacco counter-marketing, which should undermine tobacco brand imagery and promote aspirational smoke-free lifestyle images. Young women age 18-24 are extremely valuable to the tobacco industry and should be a focus for tobacco control programmes.

BACKGROUND

Despite a recent surge in tobacco advertising and the recent advertising ban (pending enforcement at the time of this study), there are few studies describing current cigarette marketing in India. This study sought to assess cigarette companies' marketing strategies in Mumbai, India.

METHODS

A two week field study was conducted in Mumbai in September 2003, observing, documenting, and collecting cigarette advertising on billboards, storefronts and at point of sale along two major thoroughfares, and performing a content analysis of news, film industry, and women's magazines and three newspapers.

RESULTS

Cigarette advertising was ubiquitous in the environment, present in news and in film magazines, but not in women's magazines or the newspapers. The four major advertising campaigns all associated smoking with aspiration; the premium brands targeting the higher socioeconomic status market utilised tangible images of westernization and affluence whereas the "bingo" (low priced) segment advertisements invited smokers to belong to a league of their own and "rise to the taste" using intangible images. Women were not depicted smoking, but were present in cigarette advertisements--for example, a woman almost always accompanied a man in "the man with the smooth edge" Four Square campaign. Advertisements and product placements at low heights and next to candies at point of sale were easily accessible by children. In view of the imminent enforcement of the ban on tobacco advertisements, cigarette companies are increasing advertising for the existing brand images, launching brand extensions, and brand stretching.

CONCLUSION

Cigarette companies have developed sophisticated campaigns targeting men, women, and children in different socioeconomic groups. Many of these strategies circumvent the Indian tobacco advertising ban. Understanding these marketing strategies is critical to minimise the exploitation of loopholes in tobacco control legislation.

Cardiac arrhythmias continue to pose a major medical challenge and significant public health burden. Atrial fibrillation, the most prevalent arrhythmia, affects more than two million Americans annually and is associated with a twofold increase in mortality. In addition, more than 250,000 Americans each year suffer ventricular arrhythmias, often resulting in sudden cardiac death. Despite the high incidence and societal impact of cardiac arrhythmias, presently there are insufficient insights into the molecular mechanisms involved in arrhythmia generation, propagation, and/or maintenance or into the molecular determinants of disease risk, prognosis, and progression. In addition, present therapeutic strategies for arrhythmia abatement often are ineffective or require palliative device therapy after persistent changes in the electrical and conduction characteristics of the heart have occurred, changes that appear to increase the risk for arrhythmia progression. This article reviews our present understanding of the complexity of mechanisms that regulate cardiac membrane excitability and cardiac function and explores the role of derangements in these mechanisms that interact to induce arrhythmogenic substrates. Approaches are recommended for future investigations focused on providing new mechanistic insights and therapeutic interventions.

The gspB-secY2A2 locus of Streptococcus gordonii strain M99 encodes the platelet-binding glycoprotein GspB, along with proteins that mediate its glycosylation and export. We have identified two additional components of the accessory Sec system (Asp4 and Asp5) encoded just downstream of gtfB in the gspB-secY2A2 locus. These proteins are required for GspB export and for normal levels of platelet binding by M99. Asp4 and Asp5 may be functional homologues of SecE and SecG, respectively.

OBJECTIVE

To develop a comprehensive disease-specific COPD severity instrument for survey-based epidemiologic research.

STUDY DESIGN AND SETTING

Using a population-based sample of 383 US adults with self-reported physician-diagnosed COPD, we developed a disease-specific COPD severity instrument. The severity score was based on structured telephone interview responses and included five overall aspects of COPD severity: respiratory symptoms, systemic corticosteroid use, other COPD medication use, previous hospitalization or intubation, and home oxygen use. We evaluated concurrent validity by examining the association between the COPD severity score and three health status domains: pulmonary function, physical health-related quality of life (HRQL), and physical disability. Pulmonary function was available for a subgroup of the sample (FEV1, n = 49; peak expiratory flow rate [PEFR], n = 93).

RESULTS

The COPD severity score had high internal consistency reliability (Cronbach alpha = 0.80). Among the 49 subjects with FEV1 data, higher COPD severity scores were associated with poorer percentage of predicted FEV1 (r = - 0.40, p = 0.005). In the 93 subjects with available PEFR measurements, greater COPD severity was also related to worse percentage of predicted PEFR (r = - 0.35, p < 0.001). Higher COPD severity scores were strongly associated with poorer physical HRQL (r = - 0.58, p < 0.0001) and greater restricted activity attributed to a respiratory condition (r = 0.59, p < 0.0001). Higher COPD severity scores were also associated with a greater risk of difficulty with activities of daily living (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.8 to 3.0) and inability to work (OR, 4.2; 95% CI, 3.0 to 5.8).

CONCLUSION

The COPD severity score is a reliable and valid measure of disease severity, making it a useful research tool. The severity score, which does not require pulmonary function measurement, can be used as a study outcome or to adjust for disease severity.

The underlying mechanism for nerve growth factor (NGF) evoked pain and long-lasting mechanical hyperalgesia remains poorly understood. Using intrathecal antisense against the NGF receptor, receptor tyrosine kinase (TrkA), we found NGF to act at the primary afferent nociceptor directly in the Sprague-Dawley rat. Inhibitors of the three major pathways for TrkA receptor signalling, extracellular signal-related kinase (ERK)/mitogen-activated protein kinase kinase (MEK) (ERK/MEK), phosphatidylinositol 3-kinase (PI3K), and phospholipase Cgamma (PLCgamma) all attenuate NGF-induced hyperalgesia. Although inhibitors of kinases downstream of PI3K and PLCgamma[glycogen synthetase kinase 3 (GSK3), calmodulin-dependent protein kinase II (CAMII-K) or protein kinase C (PKC)] do not reduce mechanical hyperalgesia, hyperalgesia induced by activation of PI3K was blocked by ERK/MEK inhibitors, suggesting cross-talk from the PI3K to the ERK/MEK signalling pathway. As integrins have been shown to modulate epinephrine and prostaglandin E(2)-induced hyperalgesia, we also evaluated a role for integrins in NGF-induced mechanical hyperalgesia using beta(1)-integrin-specific antisense or antibodies.