Pathogenesis of the atherosclerotic lesion. Implications for diabetes mellitus.

In this review, we have highlighted pivotal cellular and molecular events in the initiation and progression of atherosclerosis. Key components of lesion initiation are an enhanced focal intimal influx and accumulation of lipoproteins, including LDL in hemodynamically determined lesion-prone areas, focal monocyte-macrophage recruitment, intimal generation of ROS, and oxidative modification of lipoproteins (including LDL [Ox-LDL]). Modified lipoproteins are taken up by the non-downregulating macrophage scavenger receptor, with foam cell formation and the development of the so-called fatty streak. One transitional event in lesion progression is foam cell necrosis, likely attributable to the cytotoxicity of both intimal free radicals and Ox-LDL, with development of an extracellular metabolically inert lipid core. Another is the migration to and proliferation within the intima of medial SMCs, leading to the synthesis of plaque collagens, elastin, and proteoglycans. Mural thrombosis plays a significant role in the late-stage progression of lesions. Regression of lesions is considered a function of the dynamic balance among components of initiation, progression, plaque stabilization, and removal of plaque constituents--the so-called regression quartet. Here, we critically examine how components of diabetes mellitus might impact not only lesion development, but also lesion regression. It is concluded that some components of diabetes mellitus augment key mechanisms in lesion initiation and progression and will likely retard the processes of plaque regression. Specifically, we focus on the various influences of diabetes mellitus on lipoprotein influx and accumulation, free radical generation and Ox-LDL, monocyte-macrophage recruitment, thrombosis and impaired fibrinolysis, and the reverse cholesterol transport system. The importance of nonenzymatic protein glycosylation in modifying a number of these processes is emphasized.     

Identification of a possible role for atrial natriuretic peptide in MDMA-induced hyperthermia

MDMA (3,4-methylenedioxymethamphetamine) induces thermogenesis in a mitochondrial uncoupling protein 3-dependent manner. There is evidence that this hyperthermia is mediated in part by the lipolytic release of free fatty acids, that subsequently activate uncoupling protein 3 in skeletal muscle mitochondria. We hypothesize that atrial natriuretic peptide (ANP), a strong lipolytic mediator, may contribute to the induction and maintenance of MDMA-induced thermogenesis. The specific aims of this study were to (1) determine if ANP is released following MDMA administration, and (2) use the ANP receptor antagonist, Anantin, to ascertain the role of ANP in MDMA-induced hyperthermia. ANP levels were measured in plasma at baseline, 10, 20, 30 and 60 min following MDMA (40 mg/kg, sc) administration in 16 male Sprague-Dawley rats. A robust increase in ANP was seen within 10 min of MDMA administration. ANP levels returned to baseline at 20 min and then gradually rose over the 60 min monitoring period. The administration of Anantin (40 mg, ip), 15 min before and after MDMA, significantly attenuated the MDMA-induced hyperthermia. We conclude that ANP signaling contributes to the hyperthermia induced by MDMA.     

PTSD and postpartum mental health in a sample of Caucasian, Asian, and Pacific Islander women

To better understand the role of posttraumatic stress disorder (PTSD) in postpartum health, this study investigates the relationship of PTSD and associated perinatal behavioral risk factors in a sample of Caucasian, Asian, and Pacific Islander women. As part of a larger longitudinal study, 54 women (18–35 years of age) were interviewed at their postpartum clinic visit for PTSD, anxiety, depression, and alcohol and substance use. PTSD and subclinical PTSD during the postpartum period were associated with behavioral health risks, with PTSD at the onset of pregnancy being a predictor of postpartum PTSD by a factor of three. Women with PTSD and subclinical PTSD were more likely to also experience stress (73%), anxiety (64%), and depression (73%) during the postpartum period compared to those without PTSD. No significant differences were found by ethnicity for postpartum PTSD, depression, or anxiety. Regardless of ethnicity or PTSD status, one in four women in the sample had a probable mental health disorder or risk behavior of some type during the postpartum period. Given the rates of associated mental health risks with PTSD, these findings suggest further research examining the fluctuations of PTSD symptomatology throughout each pregnancy trimester to determine its role as a potential mediator during the perinatal period. Further research is also needed to elucidate the role of ethnic or cultural differences in trauma and PTSD and perinatal health.     

Paramedic transtelephonic communication to cardiologist of clinical and electrocardiographic assessment for rapid reperfusion of ST-elevation myocardial infarction

Background/purpose

We tested the hypothesis that paramedic recognition of ST-elevation myocardial infarction (STEMI) and cardiologist activation of the cardiac catheterization laboratory without transmission of the electrocardiogram reduces door-to-balloon times.

Methods

We studied a consecutive series of patients suspected to have STEMI who were taken to the cardiac catheterization laboratory in the 6-month period before hotline implementation (historical controls) and during the first year of hotline use (intervention group, hotline; emergency medical service patients without hotline, concurrent controls).

Results

Emergency medical services activated the hotline 47 times, and 25 patients were subsequently taken to the catheterization laboratory. Patients who received PCI involving hotline use (n = 20) had significantly shorter door-to-balloon times (58 minutes; 25th-75th percentile, 52-73 minutes) than historical controls (n = 15) (112 minutes; 25th-75th percentile, 81-137; P < .0001) and concurrent controls (n = 15) (92 minutes; 25th-75th percentile, 76-112; P = .019).

Conclusions

Paramedic transtelephonic communication to cardiologist of clinical and electrocardiogram assessment resulted in a 54-minute reduction in door-to-balloon time for patients with STEMI.     

The contribution of postmenopausal hormone use cessation to the declining incidence of breast cancer

The striking decline in United States breast cancer incidence since 2002 has been widely attributed to a reduction in postmenopausal hormone use, yet very little analysis has been conducted to quantify the contribution of changes in hormone use to the declining trend. We used literature-based estimates of the relative risk and the changing prevalence of hormone use to estimate the impact of hormone use on the decline in breast cancer incidence between 2002 and 2003 among women aged 40–79. For the base case of a 44% decline in hormone use and a relative risk for current use of 1.5, we estimated that 43% of the decline in incidence was attributable to hormone use. By exploring a range of parameter values, we found that high, unlikely values of the relative risk (i.e., ≥ 2.25) and/or the percent decline in hormone use (i.e., ≥ 75%) would be required to account for 100% of the observed decline in breast cancer incidence. We conclude that hormone use is unlikely to account for more than half of the observed decline in breast cancer incidence between 2002 and 2003. Further efforts are needed to quantify the potential contributions of other factors, such as the plateau in screening mammography utilization.     

Circulating Sex Hormones and Mammographic Breast Density among Postmenopausal Women

The use of breast density as an intermediate or predictive marker of breast cancer risk is limited by an incomplete understanding of the etiology of breast density. High blood levels of endogenous estrogens and androgens are associated with increased risk of breast cancer among postmenopausal women. We sought to examine whether these hormones are also associated with breast density. The Wisconsin Breast Density Study enrolled 257 postmenopausal women, ages 55-70 years, with no history of postmenopausal hormone use, from mammography clinics in Madison, Wisconsin. Subjects provided a blood sample for sex hormone analysis, and breast density was measured from subjects' screening mammograms using a computer-assisted thresholding method. Numerous sex hormones were associated with breast density in age-adjusted analyses. However, further adjustment for body mass index and other potentially confounding factors substantially attenuated or eliminated these associations. In the fully adjusted model, there remained a positive association between percent breast density and serum progesterone (P=0.03), with percent density rising from 11.9% (95% CI: 9.8, 14.1%) among women in the lowest quartile of serum progesterone to 15.4% (12.9, 18.2%) among women in the highest quartile. There was also a positive association between sex hormone binding globulin and percent breast density (P=0.06). In contrast, there were no independent associations between percent breast density and estradiol (total, free, or bioavailable), estrone, estrone sulfate, or testosterone (total, free, or bioavailable). These results suggest that breast density has a hormonal etiology; however, it may differ in important ways from that of breast cancer risk.     

l-Carnitine l-tartrate supplementation favorably affects biochemical markers of recovery from physical exertion in middle-aged men and women

The purpose of this study was to examine the effects of Carnipure tartrate (Lonza, Allendale, NJ) supplementation (total dose of 2 g/d of l-carnitine) on markers of performance and recovery from physical exertion in middle-aged men and women. Normally active and healthy men (n = 9, 45.4 ± 5.3 years old) and women (n = 9, 51.9 ± 5.0 years old) volunteered to participate in the investigation. Double-blind, placebo, balanced treatment presentation and crossover design were used with 3 weeks and 3 days of supplementation followed by a 1-week washout period before the other counterbalanced treatment was initiated. After 3 weeks of each supplementation protocol, each participant then performed an acute resistance exercise challenge of 4 sets of 15 repetitions of squat/leg press at 50% 1-repetition maximum and continued supplementation over the recovery period that was evaluated. Blood samples were obtained at preexercise and at 0, 15, 30, and 120 minutes postexercise during the acute resistance exercise challenge and during 4 recovery days as well. Two grams of l-carnitine supplementation had positive effects and significantly (P ≤ .05) attenuated biochemical markers of purine metabolism (ie, hypoxanthine, xanthine oxidase), free radical formation (malondialdehyde), muscle tissue disruption (myoglobin, creatine kinase), and muscle soreness after physical exertion. However, markers of physical performance (ie, strength, power, get up and go) were not affected by supplementation. These findings support our previous findings of l-carnitine in younger people that such supplementation can reduce chemical damage to tissues after exercise and optimize the processes of muscle tissue repair and remodeling.