Calcium metabolism and blood pressure in children

Raised urinary calcium excretion has been reported in patients with essential hypertension, but it is not known whether this finding is an early expression of altered calcium metabolism or a consequence of longstanding high blood pressure (BP). BP and 24 h urinary excretion of calcium, sodium and creatinine were measured in a representative sample of healthy normotensive sixth grade school boys (n = 146: mean age 11.2 +/- 0.1 yrs, SEM). A significantly higher calcium output was found in children in the upper quarter of the BP distribution, even when differences due to body size, urinary creatinine and sodium excretion were excluded. The same result was obtained when students from the upper BP quartile were compared with age, height and weight-matched students from the rest of the study population (urinary calcium: 2.63 +/- 0.42 vs 1.54 +/- 0.23 mmol/24 h, P less than 0.02). Enhanced urinary calcium excretion is thus found in children in the upper part of the BP distribution for their age and sex and who are therefore at higher risk of hypertension in adulthood. This finding is compatible with the hypothesis of a primary abnormality of calcium metabolism in essential hypertension.     

The relationship of various measures of end-systole to left ventricular maximum time-varying elastance in man

This investigation was designed to calculate left ventricular maximum time-varying elastance (Emax), to define the relationship between Emax and pressure-volume (P-V) relations at other, more easily defined measured of end-systole, and to determine whether these measures of left ventricular contractile function can be normalized in man. Accordingly, we studied 10 subjects with simultaneous high-fidelity micromanometer left ventricular and ascending aortic pressure recordings and biplane contrast cineangiograms at control conditions and during infusion of methoxamine and nitroprusside. Emax was defined as the maximum slope of the linear relation of isochronal, instantaneous P-V data points obtained from each of the three loading conditions. Left ventricular end-systole was also defined for each loading condition as: the time of the maximum P-V ratio (maxPV), minimum ventricular volume (minPV), (-)dP/dtmin [(-)dP/dtPV], and zero systolic flow approximated by the central aortic dicrotic notch (AodiPV). The mean heart rates and LV (+)dP/dtmax were insignificantly altered during the three loading conditions. Isochronal Emax ranged from 3.38 to 6.73 mm Hg/ml (mean 5.48 +/- 1.23 [SD] mm Hg/ml) and the volume-axis intercepts at zero pressure ranged from -2 to 51 ml (mean 18 +/- 16 ml). The isochronal slope calculations were reproducible (r = .97 to .99). The end-systolic P-V slope values for the maxPV, minPV, (-)dP/dtPV, and AodiPV relations correlated with isochronal Emax (r = .90, .88, .69, and .74, respectively). The average slope values for these end-systolic P-V relations, however, underestimated the mean Emax (p less than .01 to p less than .001). The mean extrapolated volume-axis intercepts for these end-systolic P-V relations also underestimated that for Emax. Finally, the isochronal Emax and other end-systolic P-V relation slope values demonstrated inverse linear relationships with left ventricular mass (r = -.68 to -.91, p less than .05 to p less than .001). Only the Emax volume-axis intercepts showed a linear relationship with left ventricular end-diastolic volume (r = .75). Thus we conclude that the time-varying elastic properties of the left ventricle can be calculated in man, that commonly used end-systolic P-V relations significantly underestimate isochronal Emax, and that normalization of isochronal Emax and other end-systolic P-V relation slope values might be performed in man with left ventricular mass; no obvious relationship between volume-axis intercepts and measures of left ventricular or body size was apparent.     

Dependence of enhanced maximal exercise performance on increased peak skeletal muscle perfusion during long-term captopril therapy in heart failure

Maximal oxygen uptake (VO2), skeletal muscle blood flow by xenon-133 washout technique and femoral vein arteriovenous oxygen difference and lactate were measured at rest and during maximal bicycle exercise in eight patients with severe congestive heart failure before and after 8 weeks of therapy with captopril. During therapy, skeletal muscle blood flow at rest increased significantly from 1.5 +/- 0.6 to 2.6 +/- 1.0 ml/100 g per min (p less than 0.05), with a concomitant decrease in the femoral arteriovenous oxygen difference from 10.0 +/- 1.7 to 8.3 +/- 1.9 ml/100 ml (p less than 0.05). Maximal VO2 increased significantly from 13.4 +/- 3.0 to 15.5 +/- 4.1 ml/kg per min (p less than 0.05). In four patients, the increase in maximal VO2 averaged 3.7 ml/kg per min (range 2.7 to 4.9), whereas in the remaining four patients, it was less than 1 ml/kg per min. Overall, peak skeletal muscle blood flow attained during exercise did not change significantly during long-term therapy with captopril (19.6 +/- 6.2 versus 27.6 +/- 14.3 ml/100 g per min, p = NS). However, the four patients with a significant increase in maximal VO2 experienced substantial increases in peak skeletal muscle blood flow and the latter changes were linearly correlated with changes in maximal VO2 (r = 0.95, p less than 0.001). Femoral arteriovenous oxygen difference at peak exercise was unchanged (12.6 +/- 2.6 versus 12.6 +/- 2.4 ml/100 ml). Thus, improvement in maximal VO2 produced by long-term therapy with captopril is associated with an increased peripheral vasodilatory response to exercise, and this improvement only occurs when the peak blood flow is augmented.(ABSTRACT TRUNCATED AT 250 WORDS)     

DNA-mediated immunization to the hepatitis B surface antigen in mice: aspects of the humoral response mimic hepatitis B viral infection in humans.

Intramuscular injection of plasmid DNA expression vectors encoding the three envelope proteins of the hepatitis B virus (HBV) induced humoral responses in C57BL/6 mice specific to several antigenic determinants of the viral envelope. The first antibodies appeared within 1-2 weeks after injection of DNA and included antibodies of the IgM isotype. Over the next few weeks, an IgM to IgG class switch occurred, indicating helper T-lymphocyte activity. Peak IgG titers were reached by 4-8 weeks after a single DNA injection and were maintained for at least 6 months without further DNA injections. The antibodies to the envelope proteins reacted with group- and subtype-specific antigenic determinants of the HBV surface antigen (HBsAg). Expression vectors encoding the major (S) and middle (preS2 plus S) envelope proteins induced antibodies specific to the S protein and preS2 domain, and preS2 antibodies were prominent at early time points. In general, the expression vectors induced humoral responses in mice that mimic those observed in humans during the course of natural HBV infection.     

Cell surface nucleolin antagonist causes endothelial cell apoptosis and normalization of tumor vasculature

Nucleolin is specifically transported to the surface of proliferating endothelial cells in vitro and in vivo. In contrast to its well defined functions in the nucleus and cytoplasm, the function of cell surface nucleolin is poorly defined. We have previously identified the nucleolin-binding antibody NCL3 that specifically binds to cell surface nucleolin on angiogenic blood vessels in vivo and is internalized into the cell. Here, we show that NCL3 inhibits endothelial tube formation in vitro as well as angiogenesis in the matrigel plaque assay and subcutaneous tumor models in vivo. Intriguingly, the specific targeting of proliferating endothelial cells by NCL3 in subcutaneous tumor models leads to the normalization of the tumor vasculature and as a result to an increase in tumor oxygenation. Treatment of endothelial cells with anti-nucleolin antibody NCL3 leads to a decrease of mRNA levels of the anti-apoptotic molecule Bcl-2 and as a consequence induces endothelial cell apoptosis as evidenced by PARP cleavage. These data reveal a novel mode of action for anti-angiogenic therapy and identify cell surface nucleolin as a novel target for combinatorial chemotherapy.     

Re: One year perspective on COURAGE

Objectives: This study aimed to analyze the impact of replacing heparin with bivalirudin in octogenarians undergoing percutaneous coronary intervention (PCI) on postprocedure hemorrhage and 6‐month mortality. Background: Randomized trials comparing the antithrombin agent bivalirudin with heparin as the intraprocedural anticoagulant identify a reduction in periprocedural bleeding after PCI. Further, the occurrence of such bleeding seems to predict an increased risk of death or myocardial infarction both in‐hospital and at long‐term follow‐up. Importantly, elderly people who are at the greatest risk of post‐PCI bleeding complications are underrepresented in these randomized trials. Methods: From 2000 to 2007, 2,766 consecutive patients from our center who were ≥80 years of age underwent PCI with stent implantation and were included in this analysis. Bivalirudin was used in 1,207 (43.6%) patients and heparin in 1,559 (56.4%). We compared the rates of post‐PCI bleeding complications and 6‐month mortality. Results: The overall in‐hospital bleeding and 6‐month mortality rates were 4.6% and 11.8%, respectively. By multivariate logistic regression and after adjustment by propensity score analysis, bivalirudin was associated with a significant decrease in in‐hospital bleedings (HR = 0.41, 95% CI = 0.23–0.73, P = 0.003). By multivariate Cox analysis, bivalirudin was also associated with a significant decrease (HR = 0.6, 95% CI = 0.4–0.9, P = 0.01) and in‐hospital bleedings with a significant increase in the 6‐month mortality (HR = 2.5, 95% CI = 1.6–3.9, P < 0.001). Conclusion: This study suggests an important subset for use of bivalirudin in lieu of heparin that will benefit the very elderly. © 2009 Wiley‐Liss, Inc.     

Respiratory Muscle Overloading and Dyspnoea During Bronchoconstriction in Asthma: Protective Effects of Fenoterol

Whether, and to what extent, β₂-agonists protect against respiratory muscle overloading and breathlessness during bronchoconstriction remains to be defined in patients with asthma. In a double blind placebo-controlled study, 100 μg of fenoterol were administered to six stable asthmatics before a bronchial provocation test, performed by inhaling doubling concentrations of histamine from a Devilbiss 646 nebulizer. We recorded breathing pattern (tidal volume V_T, inspiratory time T_I, total time of the respiratory cycle T_TOT), inspiratory capacity (IC), dynamic pleural pressure swing (P_plsw), total lung resistance (R_L) and FEV₁. V_Twas expressed both in actual values and as % of IC. Changes in V_T(%IC) during histamine inhalation reflected changes in dynamic end-inspiratory lung volume (EILV). P_plswwas expressed as % of maximal (the most negative in sign) pleural pressure, obtained under control conditions during a sniff manoeuvre (P_plsn). P_plsw(%P_plsn) is an index of inspiratory muscle effort. The test ended when the concentration of histamine which caused a decrease in FEV₁of ≥40% post-saline was reached. Dyspnoea rating was scored by a modified Borg scale. At the ultimate degree of bronchoconstriction (UDB) with histamine: (i) decrease in FEV₁was similar after placebo and fenoterol, while increase in R_Lwas lower after fenoterol (P<0.005); (ii) V_T(%IC) increased less after fenoterol (P<0.027); (iii) increases in P_plsw(%P_plsn) was lower after fenoterol (P<0.001); (iv) ΔBorg (from saline) was lower (P<0.01) after fenoterol; (v) differences in ΔBorg, from placebo to fenoterol, related to concurrent changes in V_T(%IC) (r²=0.67). In conclusion, at UDB 100 μg of fenoterol produced a beneficial effect on the degree of inspiratory muscle loading and breathlessness, an effect greater than it would be expected from measuring FEV₁alone.     

Specific vaccine therapy in chronic hepatitis B: induction of T cell proliferative responses specific for envelope antigens.

In a pilot study, it was established that specific therapy by standard anti-hepatitis B virus (HBV) vaccination may be effective in reducing HBV replication and canceling the immune tolerance to hepatitis B surface antigen (HBsAg) particles in about 50% of persons with chronic active HBV replication. In the present study, the vaccine-induced immune responses were analyzed during an ongoing controlled multicenter vaccine trial. Vaccination elicited peripheral blood mononuclear cell proliferative responses specific for envelope antigen in 7 of 27 subjects given HBsAg. The responses induced by the vaccines were mediated by CD4+ T lymphocytes, and at least three different epitopes were recognized. HBV-specific CD4+ T lymphocytes produced high levels of interferon-gamma [corrected] and belonged to a T helper 1 subset. Reduction of serum HBV DNA in some of these persons suggests that induction of CD4+ T cell responses could be important in controlling viremia during vaccine therapy of chronic HBV carriers.     

Retrieval and analysis of particulate debris after saphenous vein graft intervention.

OBJECTIVES: This study was designed to evaluate the composition and quantity of particulate debris resulting from vein graft intervention. BACKGROUND: Distal embolization and "no reflow" are frequent and important complications resulting from angioplasty of diseased saphenous vein grafts. Little is known about the composition and quantity of embolic particulate debris associated with vein graft intervention, and no intervention has been shown to protect against its clinical consequences. METHODS: A catheter system, designed to contain, retrieve and protect against distal embolization of this material, was evaluated during 27 percutaneous interventional saphenous vein graft procedures. Clinical, angiographic and pathologic analyses were performed. RESULTS: The duration of distal graft occlusion required to allow intervention and subsequent debris removal was 150 +/- 54 s, decreasing as experience was gained. Thrombolysis in Myocardial Infarction trial (TIMI) flow grade increased from 2.6 +/- 0.8 to 3.0 +/- 0.0. Creatine kinase (CK) rose above normal in three patients (11.1%) exceeding 3x normal in one (3.7%) resulting in the diagnosis of non-Q-myocardial infarction. Particulate material was identified following 21 of 23 procedures suitable for analysis. Particle size was 204 +/- 57 microm in the major axis and 83 +/- 22 microm in the minor axis. Particles consisted predominantly of soft acellular atheromatous material, such as that typically found under a fibrous cap. Semiquantitative analysis suggested that the quantity of particulate material was less following stenting than following balloon dilation. CONCLUSIONS: Particulate matter is commonly present following routine angioplasty and stenting of saphenous vein grafts. Containment, retrieval and analysis of this particulate debris are all feasible. Comparison to prior clinical experience is limited by small sample size. However, to the extent that these particles may contribute to distal embolization, no-reflow and infarction, such a system may contribute to the reduction of complications following vein graft intervention.     

Left ventricular mass and blood pressure during ergometric exercise in primary hypertension

The pathophysiology of left ventricular hypertrophy (LVH) in hypertensive patients is still an intriguing point. The lack of a close relationship between LVH and systolic or diastolic blood pressure at rest, previously observed by other investigators, was confirmed in our group of 45 patients with uncomplicated primary hypertension. The strength of correlation between echocardiographic left ventricular mass (LVMe) and blood pressure, expressed as incremental area (IA = total area under the curve--basal area), however, increased during bicycle exercise testing (r = 0.33, p less than 0.05 for diastolic blood pressure; r = 0.39, p less than 0.01 for systolic blood pressure; r = 0.41, p less than 0.01 for mean arterial pressure). Other echocardiographic parameters of myocardial mass such as LVM index (LVMI) and septal thickness (ST) were also significantly correlated with blood pressure during exercise. These results suggest either that blood pressure during exercise is a better index of the cardiac workload than resting blood pressure or that the pathogenesis of cardiac hypertrophy involves an enhanced reactivity to adrenergic drive, particularly stimulated during ergometric exercise. Increased blood pressure alone, however, only partly accounts (about 20%) for the increase in myocardial mass in hypertensive patients; other factors, therefore, need to be further investigated for a better understanding of the pathophysiology of left ventricular hypertrophy.