Publications

The Leishmania major LACK antigen contains an immunodominant epitope at amino acids 156 to 173 (LACK(156-173)) that is believed to nucleate the pathological Th2 immune response in susceptible BALB/c mice. To test this hypothesis, we generated L. major parasites that express a mutated LACK that fails to activate Vbeta4/Valpha8 T-cell receptor transgenic T cells specific for this epitope. Although mutant parasites attenuated the expansion of endogenous LACK-specific, interleukin-4 (IL-4)-expressing, CD4 T cells compared to wild-type parasites in vivo, the overall frequency of IL-4 and gamma interferon-secreting lymphocytes was similar to that elicited by wild-type L. major. Mutant parasites demonstrated diminished amastigote viability and delayed lesion development in mice, although parasites could be recovered over 200 days after infection. Complementation with a wild-type lack fusion construct partially rescued these defects, indicating a role for endogenous LACK in parasitism. Mice inoculated with mutant parasites were not protected against subsequent infection with wild-type L. major.

BACKGROUND

The utility of air-contrast barium enema and colonoscopy for evaluation of the colon has been debated. Air-contrast barium enema is less expensive and invasive than colonoscopy, but it also is less sensitive and specific. Further, although air-contrast barium enema may be less painful than colonoscopy, it often is poorly tolerated by patients. Thus, this study compared the sensitivity and the specificity of air-contrast barium enema and colonoscopy for detection of colonic lesions in patients with fecal occult blood.

METHODS

Over a 30-month period, patients with fecal occult blood were recruited. Patients underwent standard air-contrast barium enema, followed by colonoscopy 7 to 14 days later. Colonoscopists were blinded to the results of air-contrast barium enema until the colonoscopy was completed, after which the results were disclosed. If the findings were discrepant, colonoscopy was repeated.

RESULTS

A total of 100 patients were evaluated. Nine air-contrast barium enemas were reported to be inadequate, and the cecum was not intubated at colonoscopy in two patients. In the remaining patients, 5 cancers were identified (1 each cecum, transverse colon, descending colon, sigmoid colon, and rectum) by both studies. Sixty-six polypoid lesions were identified in 30 patients. Diverticula were identified in 42 patients by air-contrast barium enema and in 18 patients by colonoscopy. Air-contrast barium enema detected 3 of 36 polypoid lesions 5 mm or less in diameter, 5 of 15 adenomas 6 to 9 mm in size, and 4 of 15 adenomas 10 mm or greater in diameter (sensitivity 8%, 33%, and 27%, respectively). After excluding patients with diverticula, air-contrast barium enema detected 3 of 7 adenomas 10 mm or greater in size. Overall, 12 polypoid lesions or filling defects were identified by air-contrast barium enema that could not be verified by colonoscopy. The specificity of air-contrast barium enema for lesions 1.0 cm or greater in size was 100%; for those 6 mm or greater, it was 97%.

CONCLUSIONS

Air-contrast barium enema accurately detects colon cancer and diverticula. Its sensitivity for detection of polypoid lesions or adenomas is poor and was confounded by the presence of diverticula.

BACKGROUND

The Framework Convention on Tobacco Control includes tobacco advertising restrictions that are strongly opposed by the tobacco industry. Marketing strategies used by transnational tobacco companies to open the Japanese market in the absence of such restrictions are described.

METHODS

Analysis of internal company documents.

FINDINGS

Between 1982 and 1987 transnational tobacco companies influenced the Japanese government through the US Trade Representative to open distribution networks and eliminate advertising restrictions. US cigarette exports to Japan increased 10-fold between 1985 and 1996. Television advertising was central to opening the market by projecting a popular image (despite a small actual market share) to attract existing smokers, combined with hero-centred advertisements to attract new smokers. Philip Morris's campaigns featured Hollywood movie personalities popular with young men, including James Coburn, Pierce Brosnan, Roger Moore, and Charlie Sheen. Event sponsorships allowed television access despite restrictions. When reinstatement of television restrictions was threatened in the late 1980s, Philip Morris more than doubled its television advertising budget and increased sponsorship of televised events. By adopting voluntary advertising standards, transnational companies delayed a television advertising ban for over a decade.

CONCLUSIONS

Television image advertising was important to establish a market, and it has been enhanced using Hollywood personalities. Television advertising bans are essential measures to prevent industry penetration of new markets, and are less effective without concurrent limits on sponsorship and promotion. Comprehensive advertising restrictions, as included in the Framework Convention for Tobacco Control, are vital for countries where transnational tobacco companies have yet to penetrate the market.

OBJECTIVES

We investigated whether inhibition of endogenous angiotensin II signaling reduces the recurrence rate of atrial fibrillation (AF) in patients enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.

BACKGROUND

Structural and electrical remodeling contribute to AF. Previous experimental studies have implicated the angiotensin II signaling pathway in this process, and recent clinical evidence supports a beneficial effect of inhibiting angiotensin II activity.

METHODS

Using the AFFIRM database, we retrospectively identified a cohort of patients randomized to the rhythm-control arm who were in sinus rhythm. Exposure to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (ANGI) was determined, and the time to first recurrence of AF was compared between ANGI users and nonusers.

RESULTS

The study cohort included 732 patients not taking ANGI through the initial 2-month follow-up and 421 patients taking ANGI during this time. Patients in the ANGI group more likely had hypertension, diabetes, coronary artery disease, and congestive heart failure compared to patients not taking ANGI. Risk of AF recurrence in the ANGI treatment group did not differ from the risk observed in patients not taking the drugs (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.77-1.09). However, in patients with congestive heart failure or impaired left ventricular function, ANGI use was associated with a lower risk of AF recurrence.

CONCLUSIONS

This analysis provides evidence that ANGI use may be beneficial in some patient subgroups with AF and underscores the need for randomized clinical trials defining more fully the role of angiotensin II inhibition in treating AF.

Life on Earth evolved in the presence of gravity, and thus it is of interest from the perspective of space exploration to determine if diminished gravity affects biological processes. Cultivation of Escherichia coli under low-shear simulated microgravity (SMG) conditions resulted in enhanced stress resistance in both exponential- and stationary-phase cells, making the latter superresistant. Given that microgravity of space and SMG also compromise human immune response, this phenomenon constitutes a potential threat to astronauts. As low-shear environments are encountered by pathogens on Earth as well, SMG-conferred resistance is also relevant to controlling infectious disease on this planet. The SMG effect resembles the general stress response on Earth, which makes bacteria resistant to multiple stresses; this response is sigma s dependent, irrespective of the growth phase. However, SMG-induced increased resistance was dependent on sigma s only in stationary phase, being independent of this sigma factor in exponential phase. sigma s concentration was some 30% lower in exponential-phase SMG cells than in normal gravity cells but was twofold higher in stationary-phase SMG cells. While SMG affected sigma s synthesis at all levels of control, the main reasons for the differential effect of this gravity condition on sigma s levels were that it rendered the sigma protein less stable in exponential phase and increased rpoS mRNA translational efficiency. Since sigma s regulatory processes are influenced by mRNA and protein-folding patterns, the data suggest that SMG may affect these configurations.

People with depression and other mental illness comprise a growing proportion of individuals living with HIV in the United States; at the same time, the prevalence of HIV among mentally ill individuals is at least seven times higher than in the general population. Individuals with mental illness are particularly vulnerable to infection with HIV because of several factors, including the higher prevalence of poverty, homelessness, high-risk sexual activities, drug abuse, sexual abuse, and social marginalization found in this population. Nevertheless, mentally ill individuals are often not screened for HIV and may not be appropriately targeted in current HIV prevention efforts. Moreover, despite widespread access to antiretroviral treatment in the United States, HIV outcomes among mentally ill individuals continue to be poor. This disparity can be explained by several interrelated factors, including lower rates of highly active antiretroviral therapy (HAART) utilization, lower rates of adherence to HAART, and immunologic changes associated with mental illness itself. We need to improve our design of prevention, screening, and treatment programs to better reach individuals with comorbid HIV and mental illness.

Antimalarial resistance to sulfadoxine-pyrimethamine (SP) is mediated by mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes. However, the relative importance of different mutations is incompletely understood and has not been studied with combination therapy. Samples from 812 patients treated for uncomplicated malaria in Kampala, Uganda were tested for the presence of mutations commonly found in Africa. The dhps Glu-540 mutation was the strongest independent predictor of treatment failure. The dhfr Arg-59 mutation was only predictive of treatment failure in the presence of the dhps Glu-540 mutation. Comparing combination regimens with SP monotherapy, the addition of chloroquine to SP did not improve efficacy, the addition of artesunate lowered the risk of treatment failure only for infections with both the dhfr Arg-59 and dhps Glu-540 mutations, and the addition of amodiaquine lowered this risk for all dhfr/dhps mutation patterns. The dhps Glu-540 mutation played a principal role and the dhfr Arg-59 mutation a secondary role in mediating resistance to SP alone and in combination.