Hormone replacement therapy - where are we now?

Hormone replacement therapy (HRT) was the standard of care for menopause management until 2002, when perceptions changed following release of the initial results from the Women's Health Initiative (WHI) trial. Fears of breast cancer and heart attacks engendered by that report were not supported by the data, especially for recently menopausal women. Clinically, HRT is usually initiated near menopause. The WHI tested something different - the effects of HRT started a decade or more after menopause. As it turned out, age at starting HRT is critical in determining benefit/risk. HRT use plummeted following the WHI in 2002 and has remained low, prompting strong interest in alternative treatments. None provide the range of benefits across multiple organ systems offered by estrogen. Most have concerning adverse effects in their own right. HRT can provide effective relief for a wide range of health conditions, potentially avoiding the need for multiple treatments for separate problems. Unfortunately, among many women and clinicians, the perception of HRT benefit/risk is distorted, and its use avoided, leading to unnecessary distress. Following the WHI, many clinicians have not received adequate training to feel comfortable prescribing HRT. When initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementias.

Less favorable body composition and adipokines in South Asians compared with other US ethnic groups: results from the MASALA and MESA studies.

BACKGROUND: Small studies have shown that South Asians (SAs) have more total body, subcutaneous, visceral and hepatic fat and abnormal adipokine levels compared with Whites. However, comprehensive studies of body composition and adipokines in SAs compared with other ethnic groups are lacking. METHODS: Using harmonized data, we performed a cross-sectional analysis of two community-based cohorts: Mediators of Atherosclerosis of South Asians Living in America (MASALA, n=906) and Multi-Ethnic Study of Atherosclerosis (MESA which included 2622 Whites, 803 Chinese Americans, 1893 African Americans and 1496 Latinos). General linear models were developed to assess the ethnic differences in ectopic fat (visceral, intermuscular and pericardial fat; and hepatic attenuation), lean muscle mass and adipokines (adiponectin and resistin). Models were adjusted for age, sex, site, alcohol use, smoking, exercise, education, household income and body mass index. Ectopic fat models were additionally adjusted for hypertension, diabetes, high-density lipoprotein and triglycerides. Adipokine models were adjusted for subcutaneous, visceral, intermuscular and pericardial fat; and hepatic attenuation. RESULTS: Compared with all ethnic groups in MESA (Whites, Chinese Americans, African Americans and Latinos), SAs had greater intermuscular fat (pairwise comparisons with each MESA group, P<0.01), lower hepatic attenuation (P<0.001) and less lean mass (P<0.001). SAs had greater visceral fat compared with Chinese Americans, African Americans and Latinos (P<0.05) and greater pericardial fat compared with African Americans (P<0.001). SAs had lower adiponectin levels compared with other ethnic groups (P<0.01; except Chinese Americans) and higher resistin levels than all groups (P<0.001), even after adjusting for differences in body composition. CONCLUSION: There are significant ethnic differences in ectopic fat, lean mass and adipokines. A less favorable body composition and adipokine profile in SAs may partially explain the increased predisposition to cardiometabolic disease. The mechanisms that underlie these differences warrant further investigation.

Abdominal fat radiodensity, quantity and cardiometabolic risk: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Fat radiodensity, as measured by fat attenuation on computed tomography (CT), has emerged as a potential biomarker of "fat quality." We sought to characterize the relationship between fat radiodensity and quantity in subcutaneous, visceral, and intermuscular fat depots, and its role in inflammation, insulin resistance, and metabolic syndrome (MetS). METHODS AND RESULTS: We studied 1511 individuals from the Multi-Ethnic Study of Atherosclerosis who underwent CT for measurement of regional fat distribution and radiodensity, along with biomarker assessments and adjudication of incident metabolic syndrome (MetS). Linear, logistic and Cox regression analyses were used to measure association between fat radiodensity and (1) fat quantity, (2) biomarkers of cardiometabolic dysfunction, and (3) both prevalent and incident MetS. In each fat depot, radiodensity was strongly and inversely associated with quantity (e.g., visceral fat radiodensity vs. quantity: ρ = -0.82, P < 0.01). After adjustment for age, sex and race, lower visceral fat radiodensity was associated with greater C-reactive protein, leptin and insulin, but lower adiponectin (P < 0.01 for all). After full adjustment for cardiovascular disease risk factors, visceral (but not subcutaneous or intermuscular) fat radiodensity was associated with prevalent MetS (OR = 0.96, 95% CI = 0.93-0.99, P = 0.01). Moreover, lower visceral fat radiodensity was associated with incident MetS after the same adjustment (HR = 0.95, 95% CI 0.93-0.98, P < 0.01). However, this association became non-significant after further adjustment for visceral fat quantity. CONCLUSION: Fat radiodensity is strongly correlated with fat quantity and relevant inflammatory biomarkers. Fat radiodensity (especially for visceral fat) may be a complementary, easily assessed marker of cardiometabolic risk.

Diet and adipose tissue distributions: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Dietary quality affects cardiometabolic risk, yet its pathways of influence on regional adipose tissue depots involved in metabolic and diabetes risk are not well established. We aimed to investigate the relationship between dietary quality and regional adiposity. METHODS AND RESULTS: We investigated 5079 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) who had food-frequency questionnaires and measurement of pericardial fat and hepatic attenuation at the baseline study visit in MESA, as well as a subgroup with imaging for visceral and subcutaneous fat (N = 1390). A dietary quality score (DietQuality) was constructed to include established food group constituents of a Mediterranean-type diet. Linear models estimated associations of dietary score as well as its constituents with regional adiposity. Baseline mean age was 61 (± 10) years, and approximately half of the participants (47%) were male. Those with a higher DietQuality score were generally older, female, with a lower body mass index, C-reactive protein, and markers of insulin resistance. After adjustment, a higher DietQuality score was associated with lower visceral fat (lowest vs. highest dietary score quartile: 523.6 vs. 460.5 cm(2)/m; P < 0.01 for trend), pericardial fat (47.5 vs. 41.3 cm(3)/m; P < 0.01 for trend), lesser hepatic steatosis (by hepatic attenuation; 58.6 vs. 60.7 Hounsfield units; P < 0.01 for trend), but not subcutaneous fat (P = 0.39). Greater fruits, vegetables, whole grains, seeds/nuts and yogurt intake were associated with decreased adiposity, while red/processed meats were associated with greater regional adiposity. CONCLUSION: A higher quality diet pattern is associated with less regional adiposity, suggesting a potential mechanism of beneficial dietary effects on diabetes, metabolic, and cardiovascular risk.

Adiponectin is independently associated with NT-proBNP: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: To investigate the associations between selected adipokines and the N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). METHODS AND RESULTS: As many as 1489 individuals enrolled in the Multi-Ethnic Study of Atherosclerosis were evaluated at 4 clinic visits about every 2 years. The evaluation included fasting venous blood, which was analyzed for NT-proBNP (at visits 1 and 3) and the adipokines adiponectin and leptin (at visits 2 and 3). The mean age was 64.8 ± 9.6 years and 48% were female. After multivariable adjustment, a 1-SD increment in adiponectin was associated with a 14 pg/ml higher NT-proBNP level (p < 0.01), while, compared to the 1st quartile of adiponectin, the 2nd, 3rd and 4th quartiles had 28, 45 and 67% higher NT-proBNP levels (p < 0.01 for all). For changes in NT-proBNP over the follow-up period, and after multivariable adjustment including baseline NT-proBNP, a 1-SD increment in adiponectin was associated with a 25 pg/ml absolute increase in NT-proBNP (p < 0.01), while those in the 2nd, 3rd and 4th quartiles of adiponectin were associated with increases of 5, 28 and 65 pg/ml (p = 0.74, 0.09 and <0.01, respectively). There was a significant interaction between adiponectin and sex for visit 3 NT-proBNP (p-interaction < 0.01), with significantly stronger associations in men. Leptin was not associated with NT-proBNP. CONCLUSION: Higher adiponectin, but not leptin, is significantly associated with higher levels of NT-proBNP, as well as with greater longitudinal increases in NT-proBNP. The associations were stronger in men.

Visceral adiposity and left ventricular remodeling: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Visceral fat (VF) is a source of pro-inflammatory adipokines implicated in cardiac remodeling. We sought to determine the impact of visceral fat and subcutaneous fat (SQ) depots on left ventricular (LV) structure, function, and geometry in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS AND RESULTS: We performed a post-hoc analysis on 1151 participants from MESA with cardiac magnetic resonance quantification of LV mass and LV mass-to-volume ratio (LVMV, an index of concentricity) and computed tomographic-derived SQ and VF area. Multivariable regression models to estimate association between height-indexed SQ and VF area (per cm(2)/m) with height-indexed LV mass (per height(2.7)) and LVMV were constructed, adjusted for clinical, biochemical, and demographic covariates. We found that both VF and SQ area were associated with height-indexed LV mass (ρ = 0.36 and 0.12, P < 0.0001, respectively), while only VF area was associated with LVMV (ρ = 0.28, P < 0.0001). Individuals with above-median VF had lower LV ejection fraction, greater indexed LV volumes and mass, and higher LVMV (all P < 0.001). In multivariable models adjusted for weight, VF (but not SQ) area was associated with LV concentricity and LV mass index, across both sexes. CONCLUSION: Visceral adiposity is independently associated with LV concentricity, a precursor to heart failure. Further study into the role of VF in LV remodeling as a potential therapeutic target is warranted.

Association of anthropometric measures and hemostatic factors in postmenopausal women: a longitudinal study.

BACKGROUND AND AIMS: Obesity has been associated with increased levels of hemostatic factors. However, few studies have compared change in different anthropometric measures of adiposity in relation to change in levels of hemostatic factors. Our aim was to examine prospectively the association of change in body mass index (BMI), waist-hip ratio (WHR), waist circumference (WC), and waist circumference-height ratio (WHtR) with change in markers of hemostasis in a population of postmenopausal women. METHODS AND RESULTS: A subsample of women in the Women's Health Initiative (WHI) cohort had fasting blood samples and anthropometric measurements obtained at multiple time points over 12.8 years of follow-up. Of these, we studied the 2593 women who were not in the intervention arm of any WHI clinical trial. Their blood samples were used to measure plasma fibrinogen, factor VII antigen activity, and factor VII concentration at baseline, and at years 1, 3, and 6. We conducted mixed-effects linear regression analyses to examine the longitudinal association between change in anthropometric factors and change in hemostatic factors, adjusting for a wide range of potential confounding factors. In longitudinal analyses using repeated measures, change in BMI, WC, and WHtR were all positively associated with change in all 3 hemostatic factors. Change in anthropometric variables was most strongly associated with change in fibrinogen. CONCLUSIONS: Our results suggest that an increase in adiposity over time is robustly associated with increased levels of hemostatic factors. Registration number of clinical trial: NCT00000611.

Have we come full circle - or moved forward? The Women's Health Initiative 10 years on.

In mid-summer 2002, the announcement that the Women's Health Initiative (WHI) trial of combination hormone therapy (HRT) had stopped jolted the field of women's health. It set off a cascade that first stunned, then meaningfully changed the future for millions of women, their partners, and tens of thousands of clinicians and scientists. With 10 years' hindsight, we can begin to put the lessons learned from the WHI HRT trials into perspective. These trials were primarily designed to test whether women considerably past menopause, and mostly asymptomatic, experienced treatment benefits from HRT expected from studies of generally symptomatic women who started near menopause. The definitive answer was 'no'. Unfortunately, the findings were generalized to all postmenopausal women regardless of age. Data accumulated from the WHI and other studies over the past decade have shown that, in women with symptoms or other indications, initiating HRT near menopause - the classic pattern of use - will probably provide a favorable benefit : risk ratio. Spurred by the WHI, many hypotheses and some insights about potential mechanisms for HRT effects on diverse organ systems have emerged, along with new perspectives on regimens, compounds, and routes of administration. This overview provides an historical perspective on the WHI design and the evolution of its message; summarizes current perspectives and insights contributed by eminent colleagues; reviews the state of the art; and looks to the future. We have come full circle in some ways, with mounting evidence supporting benefit for HRT started near menopause and with hard lessons learned about pathophysiology, publicity and interpreting data. Now we move on.

Abdominal aortic diameter and vascular atherosclerosis: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVES: To gain insight into early mechanisms of aortic widening, we examined associations between the diameter of the abdominal aorta (AD) and cardiovascular disease (CVD) risk factors and biomarkers, as well as measures of subclinical atherosclerosis, in a multi-ethnic population. DESIGN: Cross-sectional cohort. METHODS: A total of 1926 participants (mean age 62, 50% women) underwent chest and abdomen scanning by computed tomography, ultrasound of the carotid arteries, and CVD risk factor assessment. AD was measured 5 cm above and at the bifurcation. RESULTS: In a model containing traditional CVD risk factors, biomarkers and ethnicity, only age (standardized ß = 0.97), male sex (ß = 1.88), body surface area (standardized ß = 0.92), current smoking (ß = 0.42), D-dimer levels (ß = 0.19) and hypertension (ß = 0.53) were independently and significantly associated with increasing AD (in mm) at the bifurcation; use of cholesterol-lowering medications predicted smaller AD (ß = -0.70) (P < 0.01 for all). These findings were similar for AD 5 cm above the bifurcation with one exception: compared to Caucasian-Americans, Americans of Chinese, African and Hispanic descent had significantly smaller AD 5 cm above the bifurcation (ß's = -0.59, -0.49, and -0.52, respectively, all P < 0.01), whereas AD at the bifurcation did not differ by ethnicity. Physical activity, alcohol consumption, diabetes and levels of IL-6, CRP and homocysteine were not independently associated with AD. Higher aortic and coronary artery calcium burden, but not common carotid artery intima-media thickness, were independently, but modestly (ß = 0.11 to 0.19), associated with larger AD. CONCLUSIONS: Incremental widening of the aortic diameter shared some, but not all, risk factors for occlusive vascular disease.

The associations between anthropometric measurements and left ventricular structure and function: the Echo-SOL Study.

OBJECTIVE: The objective of this study is to determine associations between anthropometry and echocardiographic measures of cardiac structure and function in Hispanic/Latinos. METHODS: A total of 1,824 participants from ECHO-SOL were included. We evaluated associations between echocardiographic measures of left ventricular structure and function and anthropometric measures using multivariable-adjusted linear and logistic regression models adjusting for traditional cardiovascular risk factors. RESULTS: The mean age was 56 ± 0.17 years, 57% were women. The mean body mass index (BMI) was 30 ± 9.4 kg m-2, waist circumference (WC) was 100 ± 18 cm, and waist-to-hip ratio (WHR) was 0.93 ± 0.15. Adjusted analysis showed that 5-unit increment in BMI and 5-cm increase in WC was associated with 3.4 ± 0.6 and 1.05 ± 0.05 g m-2.7 (p < 0.05 for both) higher left ventricular (LV) mass index, respectively. Similarly, 0.1-unit increment in WHR was associated with 2.0 ± 0.16 g m-2.7 higher LV mass index (p < 0.01). WHR was associated with 0.22 ± 0.08% decrease in ejection fraction (p < 0.05). Concomitantly, 5-unit increment in BMI and WC was associated with increased odds of abnormal LV geometry (odds ratio 1.40 and 1.16, p = 0.03 and <0.01, respectively); 0.1-unit increment in WHR was associated with increased odds of abnormal LV geometry (odds ratio 1.51, p < 0.01). CONCLUSIONS: Among Hispanic/Latinos, higher anthropometric measures were associated with adverse cardiac structure and function.

Vasomotor symptoms and the risk of incident venous thrombosis in postmenopausal women.

Essentials Vasomotor symptoms have been proposed as markers of changing cardiovascular risk. In this cohort study, we evaluated these symptoms as markers of venous thrombosis (VT) risk. We found no evidence that vasomotor symptom presence or severity were associated with VT risk. Among these postmenopausal women, vasomotor symptoms are not a useful marker of VT risk. SUMMARY: Background Vasomotor symptoms may be markers of changes in cardiovascular risk, but it is unknown whether these symptoms are associated with the risk of venous thrombosis (VT). Objective To evaluate the association of vasomotor symptom presence and severity with incident VT risk among postmenopausal women, independent of potential explanatory variables. Methods This cohort study included participants of the Women's Health Initiative (WHI) Hormone Therapy Trials (n = 24 508) and Observational Study (n = 87 783), analyzed separately. At baseline, women reported whether hot flashes or night sweats were present and, if so, their severity. Using Cox proportional hazards models, we estimated the VT risk associated with vasomotor symptom presence and severity, adjusted for potential explanatory variables: age, body mass index, smoking status, race/ethnicity, and time-varying current hormone therapy use. Results At baseline, WHI Hormone Therapy Trial participants were aged 64 years and WHI Observational Study participants were aged 63 years, on average. In the WHI Hormone Therapy Trials over a median of 8.2 years of follow-up, 522 women experienced a VT event. In the WHI Observational Study, over 7.9 years of follow-up, 1103 women experienced a VT event. In adjusted analyses, we found no evidence of an association between vasomotor symptom presence (hazard ratio [HR]adj  0.91, 95% confidence interval [CI] 0.75-1.1 in the WHI Hormone Therapy Trials; HRadj  1.1, 95% CI 0.99-1.3 in the WHI Observational Study) or severity (HRadj for severe versus mild 0.99, 95% CI 0.53-1.9 in the WHI Hormone Therapy Trials; HRadj  1.3, 95% CI 0.89-2.0) in the WHI Observational Study) and the risk of incident VT. Conclusions Although vasomotor symptoms have been associated with the risk of other cardiovascular events in published studies, our findings do not suggest that vasomotor symptoms constitute a marker of VT risk.

Lipids, lipoprotein distribution and depressive symptoms: the Multi-Ethnic Study of Atherosclerosis.

Previous studies suggest lower concentrations of total and high-density lipoprotein (HDL) cholesterol to be predictive of depression. We therefore investigated the relationship of lipids and lipoprotein distribution with elevated depressive symptoms (EDS) in healthy men and women from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were followed up over a 9.5-year period. EDS were defined as a Center for Epidemiological Studies Depression (CES-D) score ⩾16 and/or use of antidepressant drugs. Lipoprotein distribution was determined from plasma using nuclear magnetic resonance spectroscopy. Among 4938 MESA participants (mean age=62 years) without EDS at baseline, 1178 (23.9%) developed EDS during follow-up. In multivariable Cox regression analyses, lower total, low-density lipoprotein (LDL) and non-HDL cholesterol concentrations at baseline were associated with incident EDS over 9.5 years (hazards ratio (HR)=1.11-1.12 per s.d. decrease, all P<0.01), after adjusting for demographic factors, traditional risk factors including LDL cholesterol, HDL cholesterol and triglycerides. Lipoprotein particle subclasses and sizes were not associated with incident EDS. Among participants without EDS at both baseline and visit 3, a smaller increase in total or non-HDL cholesterol between these visits was associated with lower risk of incident EDS after visit 3 (HR=0.88-0.90 per s.d. decrease, P<0.05). Lower baseline concentrations of total, LDL and non-HDL cholesterol were significantly associated with a higher risk of incident EDS. However, a short-term increase in cholesterol concentrations did not help to reduce the risk of EDS. Further studies are needed to replicate our findings in cohorts with younger participants.

Phase II trial of outpatient interleukin-2 in malignant lymphoma, chronic lymphocytic leukemia, and selected solid tumors.

High-dose interleukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells has been reported to have activity in certain solid tumors, but toxicity has usually required hospitalization for administration. The purpose of this trial was to determine the antineoplastic effect and toxicity of IL-2 administered at a lower dose in an outpatient setting. Eligibility criteria included measurable disease, Karnofsky performance greater than or equal to 70%, age greater than 18 years, and adequate bone marrow, renal, and hepatic function. The median age of 35 patients was 56 years (range, 20 to 75). Diagnoses included malignant lymphoma (ML), (nine patients), chronic lymphocytic leukemia (CLL) (eight), melanoma (eight), colorectal cancer (six), renal cancer (two), and breast cancer (two). The initial 18 patients were treated with 1 mg/m2 (3 x 10(6) U/m2 intravenous [IV] bolus) for five days every other week for a total of 4 treatment weeks (8 weeks total). The subsequent 17 patients were treated with 0.5 mg/m2 (1.5 x 10(6) U/m2). All patients were evaluable for toxicity, and 26 for tumor response. Toxicities included fatigue (71%), nausea (69%), hypotension (54%), fever (51%), chills (40%), weight gain (37%), pruritus or rash (31%), dyspnea (14%), azotemia (6%), confusion (6%), thrombocytopenia (6%), and myocardial infarction (3%). Four patients died from apparently unrelated causes within the first 2 weeks of treatment. Treatment was discontinued before the completion of 8 weeks of treatment because of progressive disease (12 patients), severe hypotension (three), azotemia (one), myocardial infarction (one), early death (four), and miscellaneous causes (two). IL-2 at 1 mg/m2 IV for five days is associated with moderate toxicity, but a dose of 0.5 mg/m2 is tolerable for outpatient administration. Three partial responses (PR) and one minor response (MR) lasting 1 to 17+ months have been observed in 12 patients with ML and CLL evaluable for response. One additional MR was observed in a patient with melanoma. IL-2 deserves further study in patients with ML and CLL.

Phase II study of mitoxantrone, leucovorin, and infusional fluorouracil for treatment of metastatic breast cancer.

A new combination of mitoxantrone, folinic acid (leucovorin), and infusional fluorouracil (5-FU) was administered to 57 previously treated patients with metastatic breast cancer to evaluate the response rate, response duration, and toxicity of this regimen. Fifty-three patients who received 313 courses of therapy were assessable for response and toxicity. Median age was 48 years (range, 33 to 80 years), and the patients had received an average of 1.5 chemotherapy regimens before this study. Of 53 assessable patients, 24 (45%, or 42% of all entered patients) experienced partial responses (PRs) with a median duration of 6 months (range, 2 to 13 months). Nine (69%) of 13 assessable patients without prior doxorubicin treatment responded, compared with 15 (38%) of 40 with prior doxorubicin (P less than .05). Toxicity was generally mild with dose reductions necessitated more often by mucositis and/or diarrhea than by myelosuppression. One patient with prior high-dose doxorubicin treatment developed congestive heart failure. The combination of mitoxantrone, leucovorin, and infusional 5-FU is an active and well-tolerated regimen for metastatic breast cancer and deserves further evaluation in patients without prior doxorubicin therapy.

The associations of adipokines with selected markers of the renin-angiotensinogen-aldosterone system: the multi-ethnic study of atherosclerosis.

Among obese individuals, increased sympathetic nervous system (SNS) activity results in increased renin and aldosterone production, as well as renal tubular sodium reabsorption. This study determined the associations between adipokines and selected measures of the renin-angiotensinogen-aldosterone system (RAAS). The sample consisted of 1970 men and women from the Multi-Ethnic Study of Atherosclerosis who were free of clinical cardiovascular disease at baseline and had blood assayed for adiponectin, leptin, plasma renin activity (PRA) and aldosterone. The mean age was 64.7 years and 50% were female. The mean (s.d.) PRA and aldosterone were 1.45 (0.56) ng ml(-1) and 150.1 (130.5) pg ml(-1), respectively. After multivariable adjustment, a 1-s.d. increment of leptin was associated with a 0.55 ng ml(-1) higher PRA and 8.4 pg ml(-1) higher aldosterone (P<0.01 for both). Although adiponectin was not significantly associated with PRA levels, the same increment in this adipokine was associated with lower aldosterone levels (-5.5 pg ml(-1), P=0.01). Notably, the associations between aldosterone and both leptin and adiponectin were not materially changed with additional adjustment for PRA. Exclusion of those taking antihypertensive medications modestly attenuated the associations. The associations between leptin and both PRA and aldosterone were not different by gender but were significantly stronger among non-Hispanic Whites and Chinese Americans than African and Hispanic Americans (P<0.01). The findings suggest that both adiponectin and leptin may be relevant to blood pressure regulation via the RAAS, in that the associations appear to be robust to antihypertension medication use and that the associations are likely different by ethnicity.

Reactivated urticaria pigmentosa.

Urticaria pigmentosa is a rare dermatologic disorder characterized by cutaneous mastocytosis either in isolated or diffuse forms. The disease usually occurs before age 4, but does occur in adulthood. When it occurs in adults, it is associated with a higher incidence of systemic involvement and malignancy. We describe a case of reactivated urticaria pigmentosa temporally associated with acute contact dermatitis in an adult. We describe a practical screening method for systemic involvement and an approach to treatment.

Inflammation and peripheral venous disease. The San Diego Population Study.

The inflammatory response to healing in venous thrombosis might cause vein damage and post-thrombotic syndrome. Inflammation may also be involved in venous insufficiency apart from deep-vein thrombosis. We studied the association of inflammation markers with venous insufficiency in a general population sample. We characterised 2,404 men and women in a general population cohort for peripheral venous disease and its severity using physical exam, symptom assessment, and venous ultrasound. Inflammation markers, C-reactive protein (CRP), fibrinogen, interleukin 1-beta (IL-1-beta), IL-8, IL-10, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant-1 (MCP-1) and vascular endothelial cell growth factor (VEGF) were compared in 352 case participants with peripheral venous disease and 352 controls with no venous abnormalities frequency matched to cases by age, sex and race. Associations were also evaluated including a subset of 108 cases of severe venous disease, as previously defined. Odds ratios (95% CI), for peripheral venous disease for biomarkers in the top quartile (adjusting for age, race, sex, body mass index and history of venous thrombosis) were 1.8 (1.1-3.0), 1.6 (1.0-2.5) and 1.5 (0.9-2.3) for CRP, fibrinogen and IL-10, respectively. Associations were larger considering cases of severe venous disease, with odds ratios for these three analytes of 2.6 (1.2-5.9), 3.1 (1.3-7.3) and 2.2 (1.1-4.4), and for IL-8: 2.4 (1.1-5.2). There was no association of IL-1-beta, ICAM-1, VCAM-1, E-selectin, MCP-1 or VEGF with overall cases or severe venous disease. In conclusion, a subset of inflammation markers were associated with increased risk of peripheral venous disease, suggesting potential therapeutic targets for treatment.

Higher leptin is associated with hypertension: the Multi-Ethnic Study of Atherosclerosis.

Adipokines are secreted from adipose tissue, influence energy homeostasis and may contribute to the association between obesity and hypertension. Among 1897 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, we examined associations between blood pressure and leptin, tumor necrosis factor-α (TNFα), resistin and total adiponectin. The mean age and body mass index (BMI) was 64.7 years and 28.1, respectively, and 50% were female. After adjustment for risk factors, a 1-s.d.-increment higher leptin level was significantly associated with higher systolic (5.0 mm Hg), diastolic (1.9), mean arterial (2.8) and pulse pressures (3.6), as well as a 34% higher odds for being hypertensive (P<0.01 for all). These associations were not materially different when the other adipokines, as well as BMI, waist circumference or waist-to-hip ratio, were additionally added to the model. Notably, the associations between leptin and hypertension were stronger in men, but were not different by race/ethnic group, BMI or smoking status. Adiponectin, resistin and TNFα were not independently associated with blood pressure or hypertension. Higher serum leptin, but not adiponectin, resistin or TNFα, is associated with higher levels of all measures of blood pressure, as well as a higher odds of hypertension, independent of risk factors, anthropometric measures and other selected adipokines.

Adipokines are associated with lower extremity venous disease: the San Diego population study.

BACKGROUND: Obesity is a risk factor for venous disease. We tested the associations between adipokines and the presence and severity of venous disease. METHODS: Participants for this analysis were drawn from a cohort of 2408 employees and retirees of a university in San Diego who were examined for venous disease using duplex ultrasonography. From this cohort, a case-control study sample of all 352 subjects with venous disease and 352 age-, sex- and race-matched subjects without venous disease were included in this analysis. All subjects completed health history questionnaires, had a physical examination with anthropometric measurements and had venous blood analyzed for adipokines. RESULTS: After adjustment for age, sex and race, those with venous disease had significantly higher levels of body mass index (BMI), leptin and interleukin-6. Levels of resistin and tumor necrosis factor-alpha were also higher but of borderline significance (0.05 < P < 0.10). Compared with the lowest tertile and with adjustment for age, sex, race and BMI, the 2nd and 3rd tertiles of resistin (odds ratios, 1.9 and 1.7, respectively), leptin (1.7 and 1.7) and tumor necrosis factor-alpha (1.4 and 1.7) were associated with increasing severity of venous disease. Conversely, a 5 kg m⁻² increment in BMI was associated with a higher odds ratio (1.5) for venous disease, which was independent of the adipokines included in this study. CONCLUSIONS: Both obesity and adipokines are significantly associated with venous disease. These associations appear to be independent of each other, suggesting potentially different pathways to venous disease.

The science of hypoxia in the Northern Gulf of Mexico: a review.

The Mississippi River is one of the world's 10 largest rivers, with average freshwater discharge into the northern Gulf of Mexico (GOM) of 380km(3) year(-1). In the northern GOM, anthropogenic nitrogen is primarily derived from agricultural fertilizer and delivered via the Mississippi River. The general consensus is that hypoxia in the northern Gulf of Mexico is caused primarily by algal production stimulated by excess nitrogen delivered from the Mississippi-Atchafalaya River Basin and seasonal vertical stratification of incoming stream flow and Gulf waters, which restricts replenishment of oxygen from the atmosphere. In this paper, we review the controversial aspects of the largely nutrient-centric view of the hypoxic region, and introduce the role of non-riverine organic matter inputs as other oxygen-consuming mechanisms. Similarly, we discuss non-nutrient physically-controlled impacts of freshwater stratification as an alternative mechanism for controlling in part, the seasonality of hypoxia. We then explore why hypoxia in this dynamic river-dominated margin (RiOMar) is not comparable to many of the other traditional estuarine systems (e.g., Chesapeake Bay, Baltic Sea, and Long Island Sound). The presence of mobile muds and the proximity of the Mississippi Canyon are discussed as possible reasons for the amelioration of hypoxia (e.g., healthy fisheries) in this region. The most recent prediction of hypoxia area for 2009, using the current nutrient-centric models, failed due to the limited scope of these simple models and the complexity of this system. Predictive models should not be the main driver for management decisions. We postulate that a better management plan for this region can only be reached through a more comprehensive understanding of this RiOMar system-not just more information on river fluxes (e.g., nutrients) and coastal hypoxia monitoring programs.