Publications

During the past several years much new evidence has accumulated regarding the molecular and biochemical mechanisms underlying cardiac responses to hypoxia and to ischemia/reperfusion injury. Studies have involved cell culture, and ex vivo and in vivo preparations. This review focuses on regulation of two transcription factors that are thought to be important in these processes, hypoxia-inducible factor1alpha (HIF-1alpha) and heat shock factor (HSF). Both of these molecules are expressed acutely and chronically in response to hypoxia and ischemia/reperfusion, and both have numerous targets that comprise part of integrated response to ischemic injury aimed at promoting cell survival. Emphasis is placed on new mechanisms of action that regulate HIF-1alpha, HSF, and heat shock proteins as key responses to hypoxia and ischemia, and possible approaches to therapy based on these data are discussed.

BACKGROUND

The recent publication of clinical trial results has led to a dramatic shift in the evidence about postmenopausal hormone therapy.

OBJECTIVE

To examine whether the publication of clinical trial results, specifically the Heart and Estrogen/progestin Replacement Study (HERS) in 1998 and the Women's Health Initiative (WHI) in 2002, has influenced the use of hormone therapy among postmenopausal women.

DESIGN

Observational cohort (1997 to 2003).

SETTING

San Francisco Mammography Registry, San Francisco, California.

PARTICIPANTS

Postmenopausal women between the ages of 50 and 74 years without a personal history of breast cancer who underwent mammography (151862 mammograms).

MEASUREMENTS

Self-reported current use of hormone therapy.

RESULTS

Among menopausal women who had mammography, it was estimated that 41% were currently using hormone therapy in 1997. Before the publication of HERS, the use of hormone therapy was increasing at a rate of 1% (95% CI, 0% to 2%) per quarter. After the publication of HERS, use decreased by 1% (CI, -3% to 0%) per quarter. In contrast, the publication of the WHI in 2002 was associated with a more substantial decline in the use of hormone therapy of 18% (CI, -21% to -16%) per quarter. Similar associations were observed for most subgroups of women, including women older than 65 years of age; women with a previous hysterectomy; and women who described their race or ethnicity as white, African American, Latina, Chinese, or Filipina.

CONCLUSIONS

The release of the HERS data was temporally associated with a modest decline in the use of hormone therapy. In contrast, the release of the principal findings from the WHI was associated with a more substantial decline in use by postmenopausal women. The reason for the differences in decline may relate to the fact that the WHI results were widely publicized or were more applicable to most postmenopausal women because the WHI study was performed in healthy women.

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.

Nitric oxide generation from porcine kidney slices is assessed using a new planar NO-selective amperometric sensor. The planar shape of the sensor allows for direct NO measurements near the surface (10 microm) of renal tissue slices in real time. Renal NO production may be modulated by the addition of L-arginine, arginine homopolymers (R2, R6, R10), and protamine, all of which can potentially transport across cellular membranes and provide a substrate for nitric oxide synthase within kidney parenchyma. Real-time amperometric measurements demonstrate that most L-arginine species can translocate across the cell membrane and rapidly increase NO production. However, no increase in NO generation is observed when the dimer of L-arginine (R2) is added to the solution bathing the tissue, suggesting that this species cannot permeate cell membranes. The degree of enhancement in NO generation observed for L-arginine and the larger peptides depends on the structure and follows the following sequence: R10 (decamer) > protamine > R6 (hexamer) > L-arginine. Protamine and the R10 decamer, especially, induce the largest increases in NO generation owing to their apparent rapid translocation into cells and subsequent cleavage by proteases to create high intracellular levels of L-arginine. The effect of sensor size (for sensor dimensions of 0.15- and 1-mm outer diameters) on the measured surface NO levels is also examined. The larger sensor traps more NO but hinders access of the L-arginine species to the tissue area between the flat distal plane of the sensor and the surface of the kidney slice. The use of such NO-generating peptides may be important in numerous biological systems that depend on NO production, such as ischemia-reperfusion injury and thrombogenesis.