Publications

OBJECTIVE

We sought to determine whether nitrogen dioxide (NO2) can enhance airway inflammation after allergen challenge in asthmatic subjects.

METHODS

Fifteen house-dust-mite (HDM)-sensitive asthmatic subjects were exposed for 3 hours to filtered air or 0.4 ppm NO2, followed by inhalational challenge with HDM allergen. Markers of inflammation were measured in sputum at 6 hours and 26 hours after allergen challenge.

RESULTS

After exposure to NO2, eosinophil concentration decreased significantly in the 6-hour postallergen sputum. No significant NO2-related difference was observed for other variables.

CONCLUSIONS

Our results suggest that, in most asthmatic individuals, multi-hour exposure to a high ambient concentration of NO2 does not enhance the inflammatory response to subsequent inhaled allergen as assessed by cell distribution in induced sputum. Because the decrease in airway eosinophils has been reported in previous animal studies, future research should be directed toward the mechanism of this effect.

The immunoreceptor tyrosine-based activation motif (ITAM) is a highly conserved region in the cytoplasmic domain of signaling chains and receptors and is a critical mediator of intracellular signals. ITAM-mediated signals depend on the Syk or zeta-associated protein of 70 kDa tyrosine kinases, and ITAM signaling is required for the differentiation and function of B and T cells in adaptive immunity. ITAM-dependent receptors also regulate the function of innate immune cells, including natural killer cells, and myeloid-derived cells such as macrophages, neutrophils, dendritic cells, and mast cells. Myeloid lineage cells also include osteoclasts (OCLs), the cells required for bone resorption, and recent studies show a critical role for the ITAM-containing adapter proteins DAP12 and the FcRgamma chain (Fcepsilon receptor I gamma chain) in OCL differentiation. Mice deficient in both the DAP12 and FcRgamma ITAM-bearing adapters are significantly osteopetrotic with a severe defect in OCL differentiation, demonstrating the requirement for ITAM signals in bone and further implicating this pathway in the development of highly specialized cell functions in hematopoietic cells. Regulation of osteoclastogenesis by ITAM-dependent receptors suggests that OCLs, similar to related myeloid cells, are tightly controlled by arrays of receptors that allow them to sense and respond to their local microenvironment like other innate immune cells.

Cruzain is an essential cysteine protease of Trypanosoma cruzi and a therapeutic target for Chagas' disease. Eight dogs were infected with T. cruzi; three were treated with an inhibitor of cruzain, K777, for 14 days. Treatment with K777 abrogated myocardial damage by T. cruzi, as documented by histopathological lesion scores and serum troponin I levels.

BACKGROUND

Genetic testing for long QT syndrome (LQTS) has been available in a research setting for the past decade, and a commercial test has recently become available. However, the costs and effectiveness of genetic testing have not been estimated.

OBJECTIVES

The purpose of this study was to conduct a cost-effectiveness analysis of genetic testing in the management of patients who have or are suspected to have familial LQTS.

METHODS

We examined the incremental cost-effectiveness of genetic testing compared with no genetic testing for symptomatic index cases and how this varied according to changes in assumptions and data inputs. Data were obtained from the published literature and a clinical cohort.

RESULTS

We found that genetic testing is more cost-effective than not testing for symptomatic index cases at an estimated cost of 2,500 US dollar per year of life saved. These results were generally robust, although they were sensitive to some data inputs such as the cost of testing and the mortality rate among untreated individuals with LQTS.

CONCLUSION

A genetic test for familial LQTS is cost-effective relative to no testing, given our assumptions about the population to be tested and the relevant probabilities and costs. The primary benefit of testing is to more accurately diagnose and treat individuals based on a combination of clinical scores and test results. Future economic analyses of testing for familial LQTS should consider the potential benefits of genetic testing of broader populations, including family members.

BACKGROUND

DNA topoisomerase II inhibitors and poisons are among the most efficacious drugs for the treatment of cancer. Sensitivity of cancer cells to the cytotoxic effects of topoisomerase II targeting agents is thought to depend on the expression of the topoisomerase IIalpha isoform, and drug resistance is often associated with loss or mutation of topoisomerase IIalpha. Histone deacetylase inhibitors (HDACi) are a novel class of compounds that potentiate the antitumor effects of topoisomerase II-targeting agents.

METHODS

The interaction between HDACi and topoisomerase II-targeting agents in cancer cells was evaluated as a function of topoisomerase IIalpha and topoisomerase IIbeta expression. Topoisomerase II isoforms were selectively depleted using small interfering RNA and antisense. Drug-induced formation of cleavable complexes involving topoisomerase IIalpha and topoisomerase IIbeta was evaluated by trapped-in-agarose DNA immunostaining and band depletion assays in the presence and absence of HDACi.

RESULTS

Preexposure to HDACi increased the cytotoxicity of topoisomerase II poisons. This was associated with a down-regulation of topoisomerase IIalpha expression but had no effects on topoisomerase IIbeta. In the setting of HDACi-induced chromatin decondensation and topoisomerase IIalpha depletion, topoisomerase II poison cytotoxicity was mediated through topoisomerase IIbeta cleavable complex formation. The HDACi-induced sensitization was also observed in cells with target-specific resistance to topoisomerase II poisons.

CONCLUSIONS

The recruitment of topoisomerase IIbeta as a target may overcome primary or emergent drug resistance to topoisomerase II-targeting agents and hence may broaden the applicability of this important class of anticancer agents.

Histone deacetylase inhibitors (HDACi) are a promising class of anticancer agents, yet the specific biological effects resulting in cell death are still poorly understood and clinically relevant markers of response are not adequately defined. The anticonvulsant valproic acid has recently emerged as an HDACi, and in vitro studies suggested that valproic acid may potentiate cytotoxic agents. We evaluated the pharmacologic and biological effects of valproic acid on histone acetylation, chromatin structure, and DNA damage induced by topoisomerase II inhibitors in mice bearing breast cancer tumors and developed an ex vivo methodology for response prediction using comet assays. The exposure of mice to valproic acid before exposure to epirubicin led to tumor regression when valproic acid was given for 48 hours at concentrations sufficient for histone hyperacetylation, down-regulation of heterochromatin maintenance proteins, and chromatin decondensation. Tumor response was accurately predicted by ex vivo comet moments. Valproic acid did not exacerbate epirubicin-related toxicity. Antitumor effects were not observed with valproic acid alone despite biologically active valproic acid concentrations. These findings suggest that exposure of tumor-bearing mice to valproic acid potentiated the antitumor effects of topoisomerase II inhibitors without enhancing toxicity. The HDACi-induced histone acetylation and modulation of heterochromatin correlated with potentiation of epirubicin-mediated DNA damage. However, these effects did not result in antitumor activity when using a HDACi alone and hence should not be considered a surrogate marker. Ex vivo comet assays may be useful as a predictive tool when tumor cells are limited and serial biopsies are difficult to obtain.

BACKGROUND

Evidence suggests that women diagnosed with early-stage breast carcinoma may experience cognitive problems as a consequence of adjuvant chemotherapy treatment. The present study was conducted to examine whether there are differences in cognitive performance and cognitive complaints between women treated with and without chemotherapy for TNM Stage 0 to II breast carcinoma.

METHODS

As part of a larger study on quality of life, women were recruited with newly diagnosed Stage 0 to II breast carcinoma scheduled to be treated with chemotherapy plus radiotherapy (n = 60) or radiotherapy only (n = 83). Six months after the completion of treatment, participants were administered a standard neuropsychologic battery to assess cognitive performance and a self-report measure to assess perceived cognitive problems.

RESULTS

There were no statistically significant differences between women who received chemotherapy and those who did not with regard to their average performance on tests of episodic memory, attention, complex cognition, motor performance, or language. Likewise, there were no significant differences between the treatment groups in the prevalence of impairment in each of these cognitive domains. Women who underwent chemotherapy also did not report significantly more problems with cognitive functioning than women treated without chemotherapy.

CONCLUSIONS

The findings failed to confirm previous reports suggesting adjuvant chemotherapy is associated with problems in cognitive functioning among women who receive treatment for Stage 0 to II breast carcinoma. Future research should use prospective longitudinal research designs incorporating appropriate comparison groups to further explore this issue.

Although experiences of racism in day-to-day life may affect minority patients' interaction with the health system and may influence health outcomes, little is known about these experiences in patients with chronic diseases. The goal of this study was to explore the frequency and correlates of perceived societal racism in 42 African Americans aged 50 and older with type 2 diabetes mellitus. Twenty-seven items of the McNeilly Perceived Racism Scale were used to assess exposure to racist incidents in employment and public domains and emotional and coping responses to perceived racism in general. Mean age was 62, 71% were women, and more than half rated their health as fair/poor (55%). Overall, 95.2% of the participants reported at least some exposure to perceived societal racism. Higher mean lifetime exposure to societal racism, based on summary scores on the perceived racism scale, was reported by men (35.0+/-19.1) than women (19.7+/-14.4) (P<.01) and by those with higher household income (30.7+/-17.3) than those with lower household income (18.6+/-15.1) (P<.05). Greater passive coping (e.g., "avoiding it," "ignoring it") was associated with being female and having lower household income and fair/poor self-rated health. The findings that perception of racism and a range of emotional and coping responses were common in older African-American patients attending two diabetes clinics suggest that physicians and other healthcare providers may need to be more aware of patients' day-to-day experiences of societal racism and the influence these experiences may have on patient trust in the medical system and their adherence to medical advice or engagement in self-management of their chronic conditions.

RATIONALE

Several studies suggest that patients with asthma who are homozygous for arginine at the 16th position of the beta2-adrenergic receptor may not benefit from short-acting beta-agonists.

OBJECTIVES

We investigated whether such genotype-specific effects occur when patients are treated with long-acting beta-agonists and whether such effects are modified by concurrent inhaled corticosteroid (ICS) use.

METHODS

We compared salmeterol response in patients with asthma homozygous for arginine at B16 (B16Arg/Arg) with those homozygous for glycine at B16 (B16Gly/Gly) in two separate cohorts. In the first, subjects were randomized to regular therapy with salmeterol while simultaneously discontinuing ICS therapy. In the second, subjects were randomized to regular therapy with salmeterol while continuing concomitant ICS.

RESULTS

In both trials, B16Arg/Arg subjects did not benefit compared with B16Gly/Gly subjects after salmeterol was initiated. In the first cohort, compared with placebo, the addition of salmeterol was associated with a 51.4 L/min lower A.M. peak expiratory flow (PEF; p = 0.005) in B16Arg/Arg subjects(salmeterol, n = 12; placebo, n = 5) as compared with B16Gly/Gly subjects (salmeterol, n = 13; placebo, n = 13). In the second cohort, B16Arg/Arg subjects treated with salmeterol and ICS concurrently (n = 8) had a lower A.M. PEF (36.8 L/min difference, p = 0.048) than B16Gly/Gly subjects (n = 22) treated with the same regimen. In addition, B16 Arg/Arg subjects in the second cohort had lower FEV1 (0.42 L, p = 0.003), increased symptom scores (0.2 units, p = 0.034), and increased albuterol rescue use (0.95 puffs/d, p = 0.004) compared with B16Gly/Gly subjects.

CONCLUSIONS

Relative to B16Gly/Gly patients with asthma, B16Arg/Arg patients with asthma may have an impaired therapeutic response to salmeterol in either the absence or presence of concurrent ICS use. Investigation of alternate treatment strategies may benefit this group.