Publications

Mutations in the gene for steroid sulfatase (SSase), are responsible for recessive x-linked ichthyosis (RXLI). As a consequence of SSase deficiency, its substrate, cholesterol sulfate (CSO4), accumulates in the epidermis. Accumulation of this amphipathic lipid in the outer epidermis provokes both a typical scaling phenotype and permeability barrier dysfunction. Research on RXLI has illuminated several, potentially overlapping pathogenic mechanisms and provided insights about the role of SSase and CSO4 in normal differentiation, barrier maintenance, and desquamation. We now show here that SSase is concentrated in lamellar bodies (LB), and secreted into the SC interstices, along with other LB-derived lipid hydrolases. There, it degrades CSO4, generating some cholesterol for the barrier, while the progressive decline in CSO4 (a serine protease (SP) inhibitor) permits corneodesmosome (CD) degradation leading to normal desquamation. Two molecular pathways contribute to disease pathogenesis in RXLI: 1) excess CSO4 produces nonlamellar phase separation in the stratum corneum (SC) interstices, explaining the barrier abnormality. 2) The increased CSO4 in the SC interstices inhibit activity sufficiently to delay CD degradation, leading to corneocyte retention. We also show here that increased Ca++ in the SC interstices in RXLI could contribute to corneocyte retention, by increasing CD and interlamellar cohesion. RXLI represents one of the best understood diseases in dermatology--from the gene to the SC interstices, its etiology and pathogenesis are becoming clear, and assessment of disease mechanisms in RXLI led to new insights about the role of SSase and CSO4 in epidermis terminal differentiation.

Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPARalpha and PPARdelta, and TRalpha and TRbeta in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPARgamma coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase Ibeta, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXRalpha, -beta, and -gamma, PPARalpha and -delta, and TRalpha and -beta, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.

An increased level of total plasma homocysteine (tHcy) is a risk factor for poor cardiovascular outcome in the general population. However, a decreased, rather than an increased, tHcy concentration may predict poor outcome in maintenance hemodialysis (MHD) patients, a phenomenon referred to as reverse epidemiology. Associations were examined between tHcy level and markers of malnutrition-inflammation complex syndrome and 12-mo prospective hospitalization and mortality in 367 MHD patients, aged 54.5 +/- 14.7 (mean +/- SD) years, who included 199 men and 55% individuals with diabetes. tHcy was 24.4 +/- 11.8 micro mol/L, and 94% of the patients had hyperhomocysteinemia (tHcy >13.5 micro mol/L). tHcy had weak to moderate but statistically significant bivariate and multivariate correlations with some laboratory markers of nutrition (serum albumin, prealbumin, creatinine, and urea nitrogen) but no significant correlation with serum C-reactive protein or two proinflammatory cytokines (IL-6 and TNF-alpha). During 12 mo of follow-up, 191 MHD patients were hospitalized, 37 died, nine underwent renal transplantation, and 38 transferred out. Hospitalization rates were significantly higher in patients with lower tHcy levels. Mortality rate in the lowest tHcy quartile (17.4%) was significantly higher compared with other three quartiles (6.5 to 9.8%; Kaplan-Meier P = 0.04). Relative risk of death for the lowest tHcy quartile, even after adjustment for case-mix and serum albumin, was 2.27 (95% confidence interval, 1.14 to 4.53; P = 0.02). Hence, tHcy may be a more exclusive nutritional marker in MHD patients with no association with inflammatory measures. Despite a very high prevalence of hyperhomocysteinemia in MHD patients, lower values of tHcy are paradoxically associated with increased hospitalization and mortality. The lowest tHcy quartile confers a twofold increase in risk of death independent of hypoalbuminemia. The nutritional feature of tHcy in MHD patients may explain its reverse association with outcome.

Sepsis is a common, life-threatening disease for which there is little treatment. The cysteine protease dipeptidyl peptidase I (DPPI) activates granule-associated serine proteases, several of which play important roles in host responses to bacterial infection. To examine DPPI's role in sepsis, we compared DPPI(-/-) and DPPI(+/+) mice using the cecal ligation and puncture (CLP) model of septic peritonitis, finding that DPPI(-/-) mice are far more likely to survive sepsis. Outcomes of CLP in mice lacking mast cell DPPI reveal that the absence of DPPI in mast cells, rather than in other cell types, is responsible for the survival advantage. Among several cytokines surveyed in peritoneal fluid and serum, IL-6 is highly and differentially expressed in DPPI(-/-) mice compared with DPPI(+/+) mice. Remarkably, deleting IL-6 expression in DPPI(-/-) mice eliminates the survival advantage. The increase in IL-6 in septic DPPI(-/-) mice, which appears to protect these mice from death, may be related to reduced DPPI-mediated activation of mast cell tryptase and other peptidases, which we show cleave IL-6 in vitro. These results indicate that mast cell DPPI harms the septic host and that DPPI is a novel potential therapeutic target for treatment of sepsis.

Many painful conditions are associated with alterations in the extracellular matrix (ECM) of affected tissues. While several integrins, the receptors for ECM proteins, are present on sensory neurons that mediate pain, the possible role of these cell adhesion molecules in inflammatory or neuropathic pain has not been explored. We found that the intradermal injection of peptide fragments of domains of laminin and fibronectin important for adhesive signaling selectively inhibited the hyperalgesia caused by prostaglandin E2 (PGE2) and epinephrine (EPI), respectively. The block of EPI hyperalgesia was mimicked by other peptides containing the RGD integrin-binding sequence. Monoclonal antibodies (mAbs) against the alpha1 or alpha3 integrin subunits, which participate in laminin binding, selectively blocked PGE2 hyperalgesia, while a mAb against the alpha5 subunit, which participates in fibronectin binding, blocked only EPI-induced hyperalgesia. A mAb against the beta1 integrin subunit, common to receptors for both laminin and fibronectin, inhibited hyperalgesia caused by both agents, as did the knockdown of beta1 integrin expression by intrathecal injection of antisense oligodeoxynucleotides. The laminin peptide, but not the fibronectin peptides, also reversibly abolished the longer lasting inflammatory hyperalgesia induced by carrageenan. Finally, the neuropathic hyperalgesia caused by systemic administration of the cancer chemotherapy agent taxol was reversibly inhibited by antisense knockdown of beta1 integrin. These results strongly implicate specific integrins in the maintenance of inflammatory and neuropathic hyperalgesia.

OBJECTIVES

To develop a framework of factors to characterize health plans, to identify how plan characteristics were measured in a national survey, and to apply our findings to an analysis of the predictors of screening mammography.

DATA SOURCE

The primary data were from the 1996 Medical Expenditure Panel Survey.

STUDY DESIGN

Women ages 40+, with private insurance, and no history of breast cancer were included in the study (N = 2,909). We used multivariate logistic regression to estimate mammography utilization in the past two years relative to health plan and demographic factors. Health plan measures included whether there is a defined provider network, whether coverage is restricted to a network, use of gatekeepers, level of cost containment, copayment and deductible amounts, coinsurance rate, and breadth of benefit coverage.

PRINCIPAL FINDINGS

We found no significant difference in reported mammography utilization using a dichotomous comparison of individuals enrolled in managed care versus indemnity plans. However, women in health plans with a defined provider network were more likely to report having received a mammogram in the past two years than those without networks (adjusted OR= 1.21, 95 percent CI = 1.07-1.36), and women in gatekeeper plans were more likely to report receiving mammography than those without gatekeepers (adjusted OR = 1.18, 95 percent CI = 1.03-1.36). Restricted out-of-network coverage, use of cost containment, enrollee cost sharing, and breadth of benefit coverage did not appear to affect mammography use.

CONCLUSIONS

It is important to examine the effect of individual health plan components on the utilization of health care, rather than use the traditional broader categorizations of managed versus nonmanaged care or simple health plan typologies.

OBJECTIVES

To examine whether there are differential impacts of patient cost sharing and health plan organizational characteristics on the use of a recommended cancer screening service (mammography) versus a controversial cancer screening service (prostate cancer screening [PCS]).

STUDY DESIGN

Observational cohort using the 1996 Medical Expenditure Panel Survey.

PATIENTS AND METHODS

A nationally representative sample of privately insured individuals was examined. Outcome measures were the receipt of mammography and PCS. Logistic regression was used to assess the impact of patient cost sharing and health plan organizational characteristics on the receipt of mammography and PCS, controlling for other covariates.

RESULTS

Patient cost sharing and gatekeeper requirements were strong predictors of PCS but were statistically insignificant predictors of mammography. Men in health plans with a copayment over dollar 10 (odds ratio [OR] = 0.38, 95% confidence interval [CI] = 0.19-0.78) or with deductibles over dollar 250 (OR = 0.38, 95% CI = 0.23-0.62) were significantly less likely to receive PCS than men in plans with no or lower copayments and deductibles. Men in gatekeeper plans were less likely to receive PCS than those without gatekeepers (OR = 0.48, 95% CI = 0.29-0.81).

CONCLUSIONS

We found the impact of cost sharing on utilization is different between mammography and PCS. Prostate cancer screening utilization appears to respond to financial incentives while mammography utilization does not. The use of copayments, deductibles, and gatekeepers may discourage controversial services but may not have an adverse effect on more recommended services. These findings have implications for the design of insurance benefits and plan organizational structure.

OBJECTIVE

There is widespread debate over whether health plans should require enrollees to use "gatekeepers," which are primary care providers that coordinate care and control access to specialists. However, little is known about whether health plan gatekeeper requirements improve or reduce quality-of-care. Our objective was to examine whether gatekeeper requirements are associated with the utilization of cancer screening for breast, cervical, and prostate cancer.

DATA SOURCES

Three linked sources (N = 13,534): (1) 1996 Medical Expenditure Panel Survey (MEPS) Household Survey, a nationally representative, ongoing survey sponsored by the Agency for Healthcare Research and Quality; (2) 1996 MEPS Health Insurance Plan Abstraction, which codes data from health plan booklets obtained from privately insured respondents, and (3) 1995 National Health Interview Survey.

STUDY DESIGN/DATA COLLECTION

Cross-sectional, multivariate logistic regression analysis using secondary data.

PRINCIPAL FINDINGS

We found in multivariate analyses that women in gatekeeper plans were significantly more likely to obtain mammography screening (Odds Ratio [OR] = 1.22, 95 percent Confidence Interval [CI] 1.07-1.40), clinical breast examinations (OR = 1.39, 95 percent CI 1.23-1.57), and Pap smears (OR = 1.33, 95 percent CI 1.16-1.52) than women not in gatekeeper plans. In contrast, gatekeeper requirements were not associated with prostate cancer screening (OR = 1.11, 95 percent CI 0.93-1.33). We found no association between screening utilization and aggregate plan types (HMO, POS, PPO, FFS).

CONCLUSIONS

Gatekeeper requirements are associated with higher utilization of widely recommended cancer screening procedures, but not with utilization of a less uniformly recommended cancer screening procedure. Researchers should consider the analysis of specific plan characteristics rather than aggregate plan types in conducting future research, and insurers and policymakers should consider the potential benefits of gatekeepers with respect to preventive care when designing health plans and legislation.

Last Acts released the first nationwide evaluation of palliative care services in November 2002. Each state was evaluated or "graded" on the following eight measures: advance care planning policies, location of death, hospice use, hospital end-of-life care services, care in ICUs at the end of life, pain among nursing home residents, state pain policies, and palliative care certified physicians and nurses. Kentucky scored well on state pain policies and number of nurses certified in palliative care but received low grades for hospital services and the number of patient deaths occurring in the home. This manuscript explores Kentucky's deficiencies and accomplishments related to the Last Acts evaluation and addresses opportunities for improving end-of-life care across the Commonwealth.