Publications

The ADAM (a disintegrin and metalloprotease) family of proteins possess both proteolytic and adhesive domains. We have established previously that the disintegrin domain of ADAM28, an ADAM expressed by human lymphocytes, is recognized by the integrin alpha4beta1. The present study characterizes the integrin binding properties of the disintegrin-like domains of human ADAM7, ADAM28 and ADAM33 with the integrins alpha4beta1, alpha4beta7 and alpha9beta1. Cell-adhesion assays demonstrated that, similar to ADAM28, the ADAM7 disintegrin domain supported alpha4beta1-dependent Jurkat cell adhesion, whereas the ADAM33 disintegrin domain did not. The lymphocyte integrin alpha4beta7 was also found to recognize both disintegrin domains of ADAM7 and ADAM28, but not of ADAM33. This is the first demonstration that mammalian disintegrins are capable of interacting with alpha4beta7. All three disintegrin domains supported alpha9beta1-dependent cell adhesion. Recognition by both alpha4beta1 and alpha4beta7 of ADAM7 and ADAM28 was activation-dependent, requiring either the presence of Mn2+ or an activating monoclonal antibody for cell attachment. Charge-to-alanine mutagenesis experiments revealed that the same residues within an individual ADAM disintegrin domain function in recognizing multiple integrins. However, the residues within a specific region of each ADAM disintegrin-like domain required for integrin binding were distinct. These results establish that ADAM7 and ADAM28 are recognized by the leucocyte integrins alpha4beta1, alpha4beta7 and alpha9beta1. ADAM33 exclusively supported only alpha9beta1-dependent adhesion.

OBJECTIVE

We sought to better use qualitative approaches in occupational health research and integrate them with quantitative methods.

METHODS

We systematically reviewed, selected, and adapted qualitative research methods as part of a multisite study of the predictors and outcomes of work-related musculoskeletal disorders among hospital workers in two large urban tertiary hospitals.

RESULTS

The methods selected included participant observation; informal, open-ended, and semistructured interviews with individuals or small groups; and archival study. The nature of the work and social life of the hospitals and the foci of the study all favored using more participant observation methods in the case study than initially anticipated.

CONCLUSIONS

Exploiting the full methodological spectrum of qualitative methods in occupational health is increasingly relevant. Although labor-intensive, these approaches may increase the yield of established quantitative approaches otherwise used in isolation.

OBJECTIVE

We sought to study the combined effects of multiple home indoor environmental exposures in adult asthma and rhinitis.

METHODS

We studied 226 adults with asthma and rhinitis by structured interviews and home assessments. Environmental factors included dust allergen, endotoxin and glucan concentrations, and indoor air quality (IAQ) variables. Outcomes included forced expiratory volume in 1 second (FEV1) percent predicted, Severity of Asthma Score (SAS), Short-Form (SF)-12 Physical Component Scale (PCS), and asthma Quality of Life (QOL) score.

RESULTS

House dust-associated exposures together with limited IAQ variables were related to FEV1 % predicted (R = 0.24; P = 0.0001) and SAS (R = 0.18; P = 0.007). IAQ and limited dust variables were associated with SF-12 PCS (R = 0.15; P = 0.02), but not QOL (R = 0.13; P = 0.16).

CONCLUSIONS

The home environment is strongly linked to lung function, health status, and disease severity in adult asthma and rhinitis.

OBJECTIVES

The organic anion transporter, OAT1 (SLC22A6), plays a role in the renal elimination of many drugs and environmental toxins. The goal of this study was to identify and functionally characterize OAT1 variants as a first step towards understanding whether genetic variation in OAT1 may contribute to interindividual differences in renal elimination of xenobiotics.

METHODS

As part of a larger study, 276 DNA samples from an ethnically diverse population were screened and 12 coding region variants of OAT1 were identified. The non-synonymous variants were then constructed and characterized in Xenopus laevis oocytes. A small family-based clinical study was conducted to determine the renal elimination of a model OAT1 substrate, adefovir (an antiviral agent) in human subjects who possessed a non-functional variant, OAT1-R454Q.

RESULTS

Six non-synonymous variants were identified; two (OAT1-R50 H and OAT1-R293W) were present at > or = 1% in at least one ethnic population. These two variants exhibited normal uptake of p-aminohippurate, ochratoxin A and methotrexate assayed in X. laevis oocytes. One variant, OAT1-R454Q, was non-functional with respect to the above substrates. In the clinical study, there was no significant decrease in the renal secretory clearance of adefovir in family members heterozygous for OAT1-454Q in comparison to those with the reference transporter, OAT1-454R.

CONCLUSIONS

These data indicate that the coding region of OAT1 has low genetic and functional diversity and suggest that coding region variants of OAT1 may not contribute substantially to interindividual differences in renal elimination of xenobiotics.

The search for a substrate that may serve as a probe to quantitatively predict the in vivo kinetics of cytochrome P450 3A (CYP3A) drugs has been of particular interest because more than half of all human drugs appear to be substrates for this enzyme. Even three closely related 1,4-benzodiazepines-alprazolam, midazolam, and triazolam-are inadequate probes to predict the pharmacokinetics of each other in an individual. If these drugs--all metabolized through the same CYP3A pathways in humans, all FDA Biopharmaceutical Classification System Class 1 compounds exhibiting high solubility and high permeability and thus unaffected by transporter differences--cannot quantitatively predict the pharmacokinetics of their closely related congeners, there is little hope that any quantitative CYP3A probe will ever be found.

This study investigated 2 hypotheses about genotype-phenotype relationships for the efflux transporter, P-glycoprotein: (1) the presence of a synonymous C3435T variant in exon 26 of the MDR1 gene correlates to higher plasma concentrations of a P-glycoprotein substrate, dicloxacillin, and (2) the effects of genotypic differences decrease under conditions of P-glycoprotein induction by rifampin. Eighteen healthy volunteers received two 1-g doses of dicloxacillin, one on the 1st study day and the other on the 11th day of rifampin dosing (600 mg daily). Dicloxacillin and its 5-hydroxymethyl metabolite were analyzed using liquid chromatography/tandem mass spectrometry. Mean dicloxacillin C(max) measurements were 30.5 +/- 13.5, 33.3 +/- 4.7, and 31.1 +/- 12.8 mug/mL in individuals with the CC, CT, and TT genotype at position 3435 in exon 26 of the MDR1 gene. Following rifampin dosing, the mean dicloxacillin C(max) across genotypes decreased from 31.4 +/- 10.8 to 22.9 +/- 7.0 microg/mL (P < .05), whereas the mean oral clearance increased from 235 +/- 82 to 297 +/- 71 mL/min (P < .001), and the mean absorption time increased from 0.71 +/- 0.55 to 1.34 +/- 0.77 h (P < .05). Rifampin treatment increased the formation clearance, C(max), and AUC of the 5-hydroxymethyl metabolite by 135%, 119%, and 59%, respectively. The C3435T variant had no effect on dicloxacillin pharmacokinetics. The data suggested that rifampin induced intestinal P-glycoprotein and increased dicloxacillin metabolism.

The objective of this paper was to determine predictors of complementary and alternative medicine (CAM) use among individuals with specific health problems. Data were derived from the 1998 Medical Expenditure Panel Survey (MEPS). After adjustment for potential confounders, individuals with perceived barriers to obtaining care were more likely to use any CAM treatment (OR 2.16), herbal therapy (OR 2.70) and spiritual care (OR 3.99) for a specific health problem. Individuals dissatisfied with their family's access to care were more likely to use acupuncture (OR 3.43). Dissatisfaction with quality of care was associated with increased use of spiritual therapy (OR 4.74). Perceptions of inadequate access to health care may contribute to utilization of CAM therapies; such therapies in this instance appear to be used as an alternative to mainstream medicine.

BACKGROUND

Although inhaled corticosteroids (ICSs) are effective in preventing deterioration in asthma control, at least half of subjects with mild-to-moderate asthma will remain stable when these agents are discontinued.

OBJECTIVE

We sought to determine whether noninvasive markers of inflammation predict which individuals maintain asthma control after discontinuation of ICSs.

METHODS

We analyzed data obtained from 164 subjects with mild-to-moderate asthma who participated in a 16-week trial comparing the effects of continued ICS use with the effects of a switch to salmeterol or placebo.

RESULTS

In comparison with continued ICS use, a switch to salmeterol or placebo was associated with increased rates of asthma deterioration over 16 weeks (9.3% vs 24.1% and 37.5%, respectively; P = .04 and P < .001, respectively). We found that neither exhaled nitric oxide nor methacholine PC 20 , when measured at randomization or 2 weeks after randomization, were significant predictors of subsequent asthma control in subjects who discontinued ICSs. However, both induced sputum eosinophil counts measured 2 weeks after a switch from ICS to placebo and changes in sputum eosinophil counts from before cessation of ICSs to after a switch to placebo predicted subsequent asthma deterioration (area under the receiver-operating characteristic curve, 0.771 [ P < .001] and 0.825 [ P < .001], respectively).

CONCLUSION

On the basis of a model treatment strategy, we estimate that allocating subjects to ICS therapy on the basis of changes in sputum eosinophil counts after a trial discontinuation could allow 48% of subjects with mild-to-moderate asthma to discontinue ICS therapy without an increased risk of asthma deterioration over a period of at least 14 weeks.