Publications

Conducting research in the home setting with homebound older adults presents distinct ethical and practical challenges that require special consideration. This article describes the methodological issues that make studying homebound older adults especially vulnerable to therapeutic misconception and researcher role conflict and offers practical strategies for researchers to deal with these problems when studying this population. In writing this article, we draw on more than a decade of descriptive and intervention research focusing exclusively on the homebound older population in which the authors have collaborated. Therapeutic misconception and researcher role conflict may occur because of methodological issues related to the recruitment of participants, the "homebound" status of participants, and the home setting as the interview site. Particular care is required on the part of the researcher to address these ethical issues. This may be accomplished especially through clear communication during the informed consent process with participants and in scientific communication with colleagues.

Quinacrine (QA), an antimalarial drug used for over seven decades, has been found to have potent antiprion activity in vitro. To determine whether QA can be used to treat prion diseases, we investigated its metabolism and ability to traverse the blood-brain barrier in mice. In vitro and in vivo, we identified by liquid chromatography-tandem mass spectrometry the major metabolic pathway of QA as N-desethylation and compared our results with an authentic reference compound. The major human cytochrome (P450) isoforms involved in QA mono-desethylation were identified as CYP3A4/5 by using specific chemical and antibody inhibition as well as cDNA-expressed P450 studies. QA transport from the basolateral to apical side in multidrug resistance protein 1 gene (MDR1)-transfected Madin-Darby canine kidney (MDCK) cells was markedly greater than in control MDCK cells and was inhibited by the potent P-glycoprotein (P-gp) inhibitor GG918 (N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-iso-1-quinolynyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine). In MDR1-knockout (KO) mice, QA brain levels were 6 to 9 times higher after a single i.v. dose of 2 mg/kg QA and 49 times higher after multiple oral doses of 10 mg/kg/day QA for 7 days, compared with those in wild-type (WT) FVB mice. In contrast, the QA levels in plasma, liver, spleen, and kidney were similar after a single 2 mg/kg i.v. dose and <2 times greater after 10 mg/kg oral doses in MDR1-KO mice compared with WT mice. These results indicate that P-gp plays a critical role in transporting QA from the brain.

Poly(ADP-ribose) polymerase-1 (PARP-1), the most abundant member of the PARP family, is a nuclear enzyme that catalyzes ADP-ribose transfer from NAD+ to specific acceptor proteins in response to DNA damage. Excessive PARP-1 activation is an important cause of infarction and contractile dysfunction in heart tissue during interruptions of blood flow. The mechanisms by which PARP-1 inhibition and disruption dramatically improve metabolic recovery and reduce oxidative stress during cardiac reperfusion have not been fully explored. We developed a mouse heart experimental protocol to test the hypothesis that mitochondrial respiratory complex I is a downstream mediator of beneficial effects of PARP-1 inhibition or disruption. Pharmacological inhibition of PARP-1 activity produced no deterioration of hemodynamic function in C57BL/6 mouse hearts. Hearts from PARP-1 knockout mice also exhibited normal baseline contractility. Prolonged ischemia-reperfusion produced a selective defect in complex I function distal to the NADH dehydrogenase component. PARP-1 inhibition and PARP-1 gene disruption conferred equivalent protection against mitochondrial complex I injury and were strongly associated with improvement in myocardial energetics, contractility, and tissue viability. Interestingly, ischemic preconditioning abolished cardioprotection stimulated by PARP-1 gene disruption. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine or xanthine oxidase inhibitor allopurinol restored the function of preconditioned PARP-1 knockout hearts. This investigation establishes a strong association between PARP-1 hyperactivity and mitochondrial complex I dysfunction in cardiac myocytes. Our findings advance understanding of metabolic regulation in myocardium and identify potential therapeutic targets for prevention and treatment of ischemic heart disease.

Transforming growth factor (TGF)-beta family members regulate multiple aspects of wound repair through effects on cell proliferation, matrix production, and tissue inflammation, but the effects of TGF-beta on wound closure itself have been controversial. We found that blocking antibodies to TGF-beta enhanced the degree of closure of scratch wounds in primary airway epithelial monolayers, while addition of exogenous TGF-beta1 inhibited the degree of closure, suggesting that endogenous activation of TGF-beta normally serves as a brake on the degree of wound closure. Although these cells secreted large amounts of TGF-beta2 and small amounts of TGF-beta1, blockade of TGF-beta1 enhanced the degree of wound closure, whereas blockade of TGF-beta2 had no effect. TGF-beta1 (but not TGF-beta2) can be activated by two members of the integrin family, alphavbeta6 and alphavbeta8, which are both expressed on airway epithelial cells. Wounding induced activation of TGF-beta through effects of both integrins, but antibodies against alphavbeta8 enhanced the degree of wound closure, whereas antibodies against alphavbeta6 did not.

OBJECTIVES

We investigated associations between perceived neighborhood problems and quality of life (QOL), physical functioning, and depressive symptoms among adults with asthma.

METHODS

Using cross-sectional data from adults with asthma in northern California (n=435), we examined associations between 5 types of perceived neighborhood problems (traffic, noise, trash, smells, and fires) and asthma-specific QOL (Marks instrument), physical functioning (Short Form-12 physical component summary), and depressive symptoms (Center for Epidemiological Studies-Depression). We used multivariate regression analysis.

RESULTS

When asthma severity and sociodemographics were taken into account, people reporting a score of 8 or higher on a scale of 0 to 25 for serious problems (the top quartile of seriousness) in their neighborhoods had significantly poorer QOL scores (mean difference=5.91; standard error [SE]=1.63), poorer physical functioning (mean difference=-3.04; SE=1.27), and almost a fivefold increase in depressive symptoms (odds ratio=4.79; 95% confidence interval=2.41, 9.52).

CONCLUSIONS

A high level of perceived neighborhood problems was associated with poorer QOL, poorer physical functioning, and increased depressive symptoms among people with asthma when disease severity and sociodemographic factors were taken into account.