Publications

PURPOSE

Squamous metaplasia occurs in ocular surface diseases like Sjögren's syndrome (SS). It is a phenotypic change whereby epithelial cells initiate synthesis of squamous cell-specific proteins such as small proline-rich protein 1B (SPRR1B) that result in pathologic keratin formation on the ocular surface. The authors hypothesized that inflammation is a key inducer of pathologic keratinization and that SPRR1B represents an analytical biomarker for the study of the molecular mechanisms.

METHODS

Real-time quantitative RT-PCR and immunohistochemistry were used to examine SPRR1B mRNA and protein in two different mouse models of dry eye and patients with SS. Adoptive transfer of mature lymphocytes from mice lacking the autoimmune regulator (aire) gene was performed to examine the role of inflammation as an inducer of squamous metaplasia. SPRR1B expression in response to several cytokines was examined in vitro, whereas the expression of cytokines IL1beta and IFNgamma was quantified in ocular tissues of aire-deficient mice and patients with SS.

RESULTS

SPRR1B was increased across the ocular surface of mice with both desiccating stress and autoimmune-mediated, aqueous-deficient dry eye and in patients with SS. Adoptive transfer of CD4(+) T cells from aire-deficient mice to immunodeficient recipients caused advanced ocular surface keratinization. IL1alpha, IL1beta, IL6, IFNgamma, and TNFalpha induced SPRR1B expression in vitro and the local expression of IL1beta and IFNgamma was elevated in ocular tissues of patients with SS and aire-deficient mice.

CONCLUSIONS

SPRR1B is a valid biomarker for the study of the molecular mechanisms of squamous metaplasia. There is a definitive link between inflammation and squamous metaplasia in autoimmune-mediated dry eye disease, with IL1beta and IFNgamma likely acting as key participants.

BACKGROUND

Inequalities in the use of new medications may contribute to health disparities. We analyzed socioeconomic gradients in the use of tiotropium for chronic obstructive pulmonary disease (COPD).

METHODS

In a cohort of adults with COPD aged > or = 55 years identified through population-based sampling, we elicited questionnaire responses on demographics, socioeconomic status (SES; lower SES defined as high school education or less or annual household income < US $20,000), and medication use and other clinical variables. In a subset we obtained pulmonary function testing. We used multiple logistic regression analysis to estimate the associations between SES and tiotropium use in COPD, adjusting for disease severity measured by a COPD Severity Score.

RESULTS

Of 427 subjects, 44 (10.3%) reported using tiotropium in 2006. Adjusting for COPD severity, lower SES was associated with reduced odds of tiotropium use (OR 0.3; 95% CI 0.1-0.7; p = 0.005). Among the subset with lung function data (n = 95), after including COPD Global Obstructive Lung Disease (GOLD) Stage > or = 2 in the model, lower SES remained associated with reduced odds oftiotropium use (OR 0.03; 95% CI < 0.001-0.7; p = 0.03). Including forced expiratory volume in one second in the model as a continuous variable instead of GOLD Stage > or = 2 yielded similar results for lower SES (OR 0.1; 95% CI < 0.001-0.5; p = 0.02).

CONCLUSION

There was a strong SES gradient in tiotropium use such that there was less use with lower SES. To the extent that this is an efficacious medication for COPD, this gradient represents a potential source of health disparities.

BACKGROUND

Although untreated human immunodeficiency virus (HIV)-infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency.

METHODS

We compared percentages of activated (CD38(+)HLA-DR(+)) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels.

RESULTS

Although the median CD4(+) cell count in controllers was 727 cells/mm(3), 3 (10%) had CD4(+) cell counts <350 cells/mm(3) and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4(+) and CD8(+) cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8(+) cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4(+) and CD8(+) T cell activation was associated with lower CD4(+) cell counts (P = .009 and P = .047). Controllers had higher LPS levels than HIV-negative subjects (P < .001), and in controllers higher LPS level was associated with higher CD8(+) T cell activation (P = .039).

CONCLUSION

HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.

An association study can be used to investigate how individuals with unique genetic variants respond to a drug treatment. In an association study, individuals may come from different ethnic groups or an admixed population. The heterogeneity of genetic backgrounds among individuals in association studies may lead to false-positive or false-negative results. Confounding caused by population structure and recent admixture may be one major factor that contributes to the lack of replication of association study results. Confounding can be detected and adjusted. Major methods that adjust for population stratification are described and explained in this chapter. Their advantages and disadvantages are discussed.

White blood cell count (WBC) is an important clinical marker that varies among different ethnic groups. African Americans are known to have a lower WBC than European Americans. We surveyed the entire genome for loci underlying this difference in WBC by using admixture mapping. We analyzed data from African American participants in the Health, Aging, and Body Composition Study and the Jackson Heart Study. Participants of both studies were genotyped across >or= 1322 single nucleotide polymorphisms that were pre-selected to be informative for African versus European ancestry and span the entire genome. We used these markers to estimate genetic ancestry in each chromosomal region and then tested the association between WBC and genetic ancestry at each locus. We found a locus on chromosome 1q strongly associated with WBC (p < 10(-12)). The strongest association was with a marker known to affect the expression of the Duffy blood group antigen. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (SD 1.3); participants who had both common European alleles had a mean WBC of 7.1 (SD 1.3). This variant explained approximately 20% of population variation in WBC. We used admixture mapping, a novel method for conducting genetic-association studies, to find a region that was significantly associated with WBC on chromosome 1q. Additional studies are needed to determine the biological mechanism for this effect and its clinical implications.

BACKGROUND

The relationship between body mass index (BMI), weight loss, and changes in activities of daily living (ADL) function and mobility in older adults is not clear. We sought to study the relationship between BMI and weight loss on the rate of decline in ADL function and life-space mobility over a 4-year period among older African Americans and whites.

METHODS

The participants were 983 enrollees in the University of Alabama at Birmingham (UAB) Study of Aging, a longitudinal study of mobility among community-dwelling older adults stratified to achieve a balanced sample in terms of sex, race, and residence. Primary outcome measures were changes in ADL function and mobility assessed by the UAB Study of Aging Life-Space Assessment (LSA) which were measured every 6 months.

RESULTS

Relative to normal weight participants, those with BMI levels in the obese range did not show more rapid ADL functional decline, but a history of unintentional weight loss predicted more rapid decline. Relative to normal-weight participants, other BMI categories were not associated with more rapid decline in LSA scores. However, unintentional weight loss predicted more rapid declines in LSA. Intentional weight loss had no relation to ADL function or LSA decline.

CONCLUSIONS

In this population of community-dwelling older African Americans and whites, neither BMI nor intentional weight loss had an association with rate of functional decline. Unintentional weight loss had a negative relation with rate of functional decline, regardless of baseline BMI. Whether this is causal remains to be determined.

OBJECTIVES

To evaluate the FATE (Family Assessment of Treatment at End of Life) Survey for use as a nationwide quality measure in the VA health care system.

DESIGN

Nationwide telephone survey.

SETTING

Five VA medical centers.

PARTICIPANTS

Eligible patients received inpatient or outpatient care from a participating VA facility in the last month of life. One respondent/patient was selected using predefined eligibility criteria and invited to participate.

MEASUREMENTS

The FATE survey consists of 32 items in 9 domains: Well-being and dignity (4 items), Information and communication (5 items), Respect for treatment preferences (2 items), Emotional and spiritual support (3 items), Management of symptoms (4 items), Choice of inpatient facility (1 item), Care around the time of death (6 items), Access to VA services (4 items), and Access to VA benefits after the patient's death (3 items).

RESULTS

Interviews were completed with 309 respondents. The FATE showed excellent psychometric characteristics, with good homogeneity (e.g., Cronbach (alpha = 0.91) and no evidence of significant ceiling effects. The FATE also demonstrated good discriminant validity. For instance, FATE scores varied across facilities (range 44-72; Kruskal Wallis test p < 0.001). Patients who were seen by a palliative care service had better scores (mean 66 versus 52; rank sum test p < 0.001), as did patients who were referred to hospice (67 versus 49; rank sum test p < 0.001).

CONCLUSIONS

The FATE survey offers an important source of quality data that can be used to improve the end-of-life care of all veterans, regardless of the type of care they receive or their site of death.