Autocrine regulation of endothelial exocytosis: von Willebrand factor release is induced by prostacyclin in cultured endothelial cells

Vascular endothelial cells respond to external stimuli by altering the secretion of several bioactive molecules, including von Willebrand factor (vWf), prostacyclin (PGI2) and nitric oxide (NO). The release of all three molecules is regulated by a rise in cytosolic calcium ([Ca2+]i). In the present study we investigated whether cAMP-dependent signaling provides differential regulation of these effector systems by modulating the effect of [Ca2+]i in cultured human endothelial cells. The stable PGI2 analog iloprost, like other cAMP-raising agents (forskolin and adenosine), caused an acute dose-dependent increase in vWf release and potentiated the secretory response to thrombin. In contrast, iloprost, forskolin and adenosine failed to induce PGI2 release and inhibit thrombin-induced release. Our findings indicate cAMP-raising agents have opposite effects on [Ca2+]i-mediated vWf secretion and PGI2 release. PGI2 may potentiate vWf release and inhibit its own release in an autocrine manner

The Association Between the Body Mass Index and 4-Year All-Cause Mortality in Older Hospitalized Patients

BACKGROUND: Association between body mass index (BMI) and long-term mortality is poorly studied in older hospitalized populations. METHODS: The researchers prospectively studied the impact of the BMI, comorbidities, and malnutrition on long-term mortality in 444 patients (mean age 85.3+/-6.7 years; 74.0% women) receiving geriatric inpatient care. All-cause mortality was determined using simple and multiple Cox proportional hazard models. RESULTS: Higher BMI was associated with a higher prevalence of diabetes, hypertension, and heart failure, but with a lower prevalence of malignancies. Four-year all-cause mortality was inversely associated with a BMI greater than or equal to 30kg/m(2) (hazard ratio = 0.59, p = .037) and positively associated with age, male gender, several individual comorbidities, and the global disease load determined by the Cumulative Illness Rating scale. The inverse association between a BMI greater than or equal to 30 and mortality remained significant after adjustment for age, gender, smoking, individual comorbidities (including heart failure and malignancies), Cumulative Illness Rating scale scores, and malnutrition parameters (hazard ratio = 0.52, p = .015). One-year mortality was associated with the Cumulative Illness Rating scale score but not with BMI categories. There were no survival differences between patients in low (<20.0) and intermediate (20.0-24.9 and 25.0-29.9) BMI categories. CONCLUSIONS: A BMI greater than or equal to 30 is associated with better long-term survival in hospitalized older patients, even after extensive adjustment for comorbidities, malnutrition, and smoking. Conversely, a low BMI (<20-25) is not associated with excess mortality, likely due to the overriding impact of multiple comorbidities. The researchers' observations have important implications for the mortality risk stratification in older high-risk patients

L'anémie du sujet âgé: une pathologie fréquente à ne pas banaliser

Anemia is a frequent disease in elderly persons, but is often undertreated and misunderstood as a physiologic consequence of aging. Nevertheless, its association with some negative clinical impacts is well known and widely documented in the literature

Protein kinase C-delta mediates von Willebrand factor secretion from endothelial cells in response to vascular endothelial growth factor (VEGF) but not histamine

BACKGROUND: Vascular endothelial growth factor (VEGF) and histamine induce von Willebrand factor (VWF) release from vascular endothelial cells. Protein kinase C (PKC) is involved in the control of exocytosis in many secretory cell types. OBJECTIVES: We investigated the role of PKC and the interactions between PKC and Ca2+ signaling in both VEGF-induced and histamine-induced VWF secretion from human umbilical vein endothelial cells (HUVECs). RESULTS: Several PKC inhibitors (staurosporine, Ro31-8220, myristoylated PKC peptide inhibitor and Go6983) block VEGF-induced but not histamine-induced VWF secretion. PKC-alpha and novel PKCs (PKC-delta, PKC-epsilon, and PKC-eta), but not PKC-beta, are expressed in HUVECs. Both VEGF and histamine activate PKC-delta. However, gene inactivation experiments using small interfering RNA indicate that PKC-delta (but not PKC-alpha) is involved in the regulation of VEGF-induced but not histamine-induced secretion. Both VEGF and histamine induce a rise in cytosolic free Ca2+ ([Ca2+]c), but the response to VEGF is weaker and even absent in a significant subset of cells. Furthermore, VEGF-induced secretion is largely preserved when the rise in [Ca2+]c is prevented by BAPTA-AM. CONCLUSIONS: Our study identifies striking agonist specificities in signal-secretion coupling. Histamine-induced secretion is dependent on [Ca2+]c but not PKC, whereas VEGF-induced secretion is largely dependent on PKC-delta and significantly less on [Ca2+]c. Our data firmly establish the key role of PKC-delta in VEGF-induced VWF release, but suggest that a third, VEGF-specific, signaling intermediate is required as a PKC-delta coactivator

Attitudes and approaches to decision making about antihypertensive treatment in elderly patients

Optimal antihypertensive therapy in very old subjects requires their understanding and acceptance. We investigated elderly patients' willingness to accept antihypertensive therapy and their desire for information and for participation in medical decisions

The prevalence, characteristics and metabolic consequences of renal insufficiency in very old hospitalized diabetic patients

AIMS: We aimed to characterize the determinants and characteristics of renal disease in very old diabetic patients in geriatric care. METHODS: Consecutive diabetic patients (96 women, 38 men) admitted to a geriatric service were studied. Glomerular filtration rate (GFR), albuminuria, vascular and general comorbidities, glycaemic control, malnutrition (using the Mini-Nutritional Assessment [MNA], serum albumin and cholesterol levels), haemoglobin and inflammation (CRP levels) were assessed. RESULTS: (a) 51.2 and 12.4% patients had moderate or severe renal insufficiency. The prevalence of normo-, micro- and macroalbuminuria was 45.0, 38.9 and 16.0% in the whole population, and was similar in patients with or without moderate renal insufficiency. Renal insufficiency was associated with previous stroke (P=0.024), heart failure (P=0.024), and atrial fibrillation (P=0.008), and possibly myocardial infarction (P=0.059, Mann-Whitney test). (b) Albuminaemia was associated with albuminuria, MNA scores, haemoglobin, total and HDL-cholesterol and CRP. However, in multiple linear regression analysis CRP was the only robust determinant of albuminaemia (P<0.0001). (c) Renal insufficiency was not associated with the MNA, serum albumin, haemoglobin and cholesterol levels. CONCLUSION: Renal insufficiency often occurs without albuminuria, suggesting aetiologies distinct from classical diabetic nephropathy, and is strongly associated with vascular comorbidities. Hypoalbuminaemia is more strongly associated with inflammation than with albuminuria and malnutrition. Malnutrition, hypoalbuminaemia, low cholesterol levels and anaemia are not associated with renal insufficiency, likely due to the very high prevalence of these abnormalities in the whole population. These features must be taken into account when organizing the global care of elderly diabetic patients