Pulse pressure responses in patients treated with Valsartan and hydrochlorothiazide combination therapy.

In a randomized, double-blind, parallel-group study of middle-aged and elderly patients, we examined the effects of treatment with the angiotensin receptor blocker valsartan (Val) in combination with hydrochlorothiazide (HCTZ) on pulse pressure (PP). After a 2-week washout period, patients entered a 4-week single-blind Val 160 mg once daily run-in period before randomization to one of three treatment groups: Val 160 mg (n = 666), Val 160 mg/HCTZ 12.5 mg (n = 670) or Val 160 mg/HCTZ 25 mg (n = 666), once daily for eight weeks. Sitting PP at baseline was similar in all groups. From baseline to randomization, Val monotherapy reduced PP by 4.7 +/- 10.2 mmHg (mean +/- SD). At the end of the study, overall reductions in PP were 6.7 mmHg for Val 160/HCTZ 12.5 and 7.5 mmHg for Val 160/HCTZ 25. Val monotherapy reduced PP in mild-to-moderate hypertensive patients. Val combined with HCTZ provides an additional dose-related reduction in PP.

Cardiovascular safety of sublingual apomorphine in patients on stable doses of oral antihypertensive agents and nitrates.

Sublingual (SL) apomorphine (2 to 6 mg) has been shown to be effective for treatment of male erectile dysfunction. Many patients with erectile dysfunction are also being treated for systemic hypertension and/or cardiovascular disease. In a double-blind, randomized, placebo-controlled, crossover trial, SL apomorphine 5 mg and placebo were administered on alternate days to 162 men who were on long-term therapy (> or =4 weeks) with angiotensin-converting enzyme inhibitors, beta blockers, diuretics, calcium channel blockers, alpha(1) blockers, or short- or long-acting nitrates. Blood pressure and heart rate were measured before and after dosing; cardiac rhythm was recorded by 4-hour Holter monitoring. The only potentially clinically significant interactions between SL apomorphine and the antihypertensive agents or short-acting nitrates were greater orthostatic decreases in systolic blood pressure in the alpha-blocker and calcium channel blocker groups (-10 and -6 mm Hg vs placebo, respectively). Administration of SL apomorphine after dosing with long-acting nitrates resulted in significant decreases in blood pressure when patients were standing (mean systolic change, -5 to -9 mm Hg 30 to 60 minutes postdose, p <0.05; mean diastolic change, -3 to -4 mm Hg 50 to 60 minutes postdose, p <0.05). The most common adverse events with SL apomorphine were dizziness, nausea, and headache. Syncope occurred in 1 patient in the beta-blocker group; symptomatic hypotension occurred in 2 patients each in the short- and long-acting nitrate groups. Thus, in patients receiving common antihypertensive agents and short-acting nitrates, as well as in most patients receiving long-acting nitrates, SL apomorphine at higher than recommended doses produced no clinically significant changes in heart rate or blood pressure greater than changes seen with SL apomorphine alone.

alpha(1)-Adrenoceptor-induced Mg2+ extrusion from rat hepatocytes occurs via Na(+)-dependent transport mechanism.

The stimulation of the alpha(1)-adrenergic receptor by phenylephrine results in a sizable extrusion of Mg2+ from liver cells. Phenylephrine-induced Mg2+ extrusion is almost completely abolished by the removal of extracellular Ca2+ or in the presence of SKF-96365, an inhibitor of capacitative Ca2+ entry. In contrast, Mg2+ extrusion is only partially inhibited by the Ca2+-channel blockers verapamil, nifedipine, or (+)BAY-K8644. Furthermore, Mg2+ extrusion is almost completely prevented by TMB-8 (a cell-permeant inhibitor of the inositol trisphosphate receptor), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (an intracellular Ca2+-chelating agent), or W-7 (a calmodulin inhibitor) Thapsigargin can mimic the effect of phenylephrine, and the coaddition of thapsigargin and phenylephrine does not result in an enlarged extrusion of Mg2+ from the hepatocytes. Regardless of the agonist used, Mg2+ extrusion is inhibited by >90% when hepatocytes are incubated in the presence of physiological Ca(2+) but in the absence of extracellular Na(+). Together, these data suggest that the stimulation of the hepatic alpha(1)-adrenergic receptor by phenylephrine results in an extrusion of Mg2+ through a Na(+)-dependent pathway and a Na(+)-independent pathway, both activated by changes in cellular Ca2+.

Different regulatory mechanisms modulate the expression of a dinoflagellate iron-superoxide dismutase.

Regulation of antioxidant enzymes is critical to control the levels of reactive oxygen species in cell compartments highly susceptible to oxidative stress. In this work, we studied the regulation of a chloroplastic iron superoxide dismutase (Fe-SOD) from Lingulodinium polyedrum (formerly Gonyaulax polyedra) under different physiological conditions. A cDNA-encoding Fe-SOD was isolated from this dinoflagellate, showing high sequence similarity to cyanobacterial, algal, and plant Fe-SODs. Under standard growth conditions, on a 12:12-h light-dark cycle, Lingulodinium polyedrum Fe-SOD exhibited a daily rhythm of activity and cellular abundance with the maximum occurring during the middle of the light phase. Northern analyses showed that this rhythmicity is not related to changes in Fe-SOD mRNA levels, indicative of translational regulation. By contrast, conditions of metal-induced oxidative stress resulted in higher levels of Fe-SOD transcripts, suggesting that transcriptional control is responsible for increased protein and activity levels. Daily (circadian) and metal-induced up-regulation of Fe-SOD expression in L. polyedrum are thus mediated by different regulatory pathways, allowing biochemically distinct changes appropriate to oxidative challenges.

Reconstruction of stenotic or occluded iliofemoral veins and inferior vena cava using intravascular stents: re-establishing access for future cardiac catheterization and cardiac surgery.

OBJECTIVES: The study evaluated the safety and efficacy of stent reconstruction of stenotic/occluded iliofemoral veins (IFV) and inferior vena cava (IVC). BACKGROUND: Patients with congenital heart defects and stenotic or occluded IFV/IVC may encounter femoral venous access problems during future cardiac surgeries or catheterizations. METHODS: Twenty-four patients (median age 4.9 years) underwent implantation of 85 stents in 22 IFV and 6 IVC. Fifteen vessels were severely stenotic and 13 were completely occluded. Although guide wires were easily passed across the stenotic vessels, occluded vessels required puncture through the thrombosed sites using a stiff wire or transseptal needle. Once traversed, the occluded site was dilated serially prior to stent implantation. RESULTS: Following stent placement, the mean vessel diameter increased from 0.9 +/- 1.6 to 7.4 +/- 2.6 mm (p < 0.05). Twenty-one of 28 vessels had long segment stenosis/occlusion requiring two to seven overlapping stents. Repeat catheterizations were performed in seven patients (9 stented vessels) at mean follow-up of 1.6 years. Seven vessels remained patent with mean diameter of 6.4 +/- 2.0 mm. Two vessels were occluded, but they were easily recanalized and redilated. Echocardiographic follow-up in two patients with IVC stents demonstrated wide patency. In four additional patients, a stented vessel was utilized for vascular access during subsequent cardiac surgery (n = 3) and endomyocardial biopsy (n = 1). Therefore, 13 of 15 stented vessels (87%) remained patent at follow-up thus far. CONCLUSIONS: Stenotic/obstructed IFV and IVC may be reconstructed using stents to re-establish venous access to the heart for future cardiac catheterization and/or surgeries.

Activation of Na(+)- and Ca(2+)-dependent Mg(2+) extrusion by alpha(1)- and beta-adrenergic agonists in rat liver cells.

The administration of selective alpha(1) (phenylephrine)-, beta (isoproterenol)-, or mixed (epinephrine) adrenergic agonists induces a marked Mg(2+) extrusion from perfused rat livers. In the absence of extracellular Ca(2+), phenylephrine does not induce a detectable Mg(2+) extrusion, isoproterenol-induced Mg(2+) mobilization is unaffected, and epinephrine induces a net Mg(2+) extrusion that is lower than in the presence of extracellular Ca(2+) and quantitatively similar to that elicited by isoproterenol. In the absence of extracellular Na(+), no Mg(2+) is extruded from the liver irrespective of the agonist used. Similar results are observed in perfused livers stimulated by glucagon or 8-chloroadenosine 3', 5'-cyclic monophosphate. In the absence of extracellular Na(+) or Ca(2+), adrenergic-induced glucose extrusion from the liver is also markedly decreased. Together, these results indicate that liver cells extrude Mg(2+) primarily via a Na(+)-dependent mechanism. This extrusion pathway can be activated by the increase in cellular cAMP that follows the stimulation by glucagon or a specific beta-adrenergic receptor agonist or, alternatively, by the changes in cellular Ca(2+) induced by the stimulation of the alpha(1)-adrenoceptor. In addition, the stimulation of the alpha(1)-adrenoceptor appears to activate an auxiliary Ca(2+)-dependent Mg(2+) extrusion pathway. Finally, our data suggest that experimental conditions that affect Mg(2+) mobilization also interfere with glucose extrusion from liver cells.

Practicing school psychology. A turn-of-the-century perspective.

Contemporary school psychology is more than an extrapolation of its early circumstances. However, several aspects remain intact despite changes in child classification, technology and instrumentation, regulation, and professionalization of the field. A snapshot is presented of school psychology practice during its origin period at the turn of the 20th century.

Balloon aortic valvuloplasty in a 1,600-gram infant.

We present a 1,600 g infant who underwent successful balloon aortic valvuloplasty from the right carotid artery approach. A simple technique to facilitate access to the left ventricle and expedite the procedure is described. Issues unique to performing balloon aortic valvuloplasty on such a small child are discussed.

Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: a parasite adhesion trait implicated in cerebral malaria.

Binding of infected erythrocytes to brain venules is a central pathogenic event in the lethal malaria disease complication, cerebral malaria. The only parasite adhesion trait linked to cerebral sequestration is binding to intercellular adhesion molecule-1 (ICAM-1). In this report, we show that Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) binds ICAM-1. We have cloned and expressed PfEMP1 recombinant proteins from the A4tres parasite. Using heterologous expression in mammalian cells, the minimal ICAM-1 binding domain was a complex domain consisting of the second Duffy binding-like (DBL) domain and the C2 domain. Constructs that contained either domain alone did not bind ICAM-1. Based on phylogenetic criteria, there are five distinct PfEMP1 DBL types designated alpha, beta, gamma, delta, and epsilon. The DBL domain from the A4tres that binds ICAM-1 is DBLbeta type. A PfEMP1 cloned from a distinct ICAM-1 binding variant, the A4 parasite, contains a DBLbeta domain and a C2 domain in tandem arrangement similar to the A4tres PfEMP1. Anti-PfEMP1 antisera implicate the DBLbeta domain from A4var PfEMP1 in ICAM-1 adhesion. The identification of a P. falciparum ICAM-1 binding domain may clarify mechanisms responsible for the pathogenesis of cerebral malaria and lead to interventions or vaccines that reduce malarial disease.

Stenting of stenosed aortopulmonary collaterals and shunts for palliation of pulmonary atresia/ventricular septal defect.

Patients with unrepaired pulmonary artery atresia and ventricular septal defect (PA/VSD) depend on aortoplumonary collaterals and surgically created shunts for pulmonary blood flow. These vessels frequently develop stenoses with time, leading to hypoperfusion of lung segments and systemic hypoxemia. The purpose of this article is to describe catheter palliation of hypoxemic patients with PA/VSD who were not candidates for surgical repair. We present our experience with stent implantation for stenosis of aortopulmonary collaterals and shunts in these patients. Three patients with hypoplastic pulmonary arteries underwent stent placement in aortopulmonary collateral arteries (APCAs) or their shunts. Technical aspects of the interventional catheterization procedure are discussed in detail. Case 1 underwent placement of five stents in collateral vessels and one stent in the Blalock-Taussig shunt (BT) with dramatic increase in vessel size and improvement in saturations from 70% to 89%. Case 2 underwent placement of two overlapping stents in a collateral vessel with an increase in diameter of the collateral vessel from 2.3 to 6 mm and an improvement in saturation from 68% to 88%. Case 3 underwent placement of three overlapping stents in a BT shunt with an increase in diameter of the shunt from 2.2 to 6.6 mm and an improvement in saturation from 71% to 89%. All three patients had excellent clinical improvement and stable saturation at follow-up. Stent placement for maintaining patency of APCAs and aortopulmonary shunts is feasible and safe.

Cytoadherence, pathogenesis and the infected red cell surface in Plasmodium falciparum.

The particular virulence of Plasmodium falciparum compared with the other malaria species which naturally infect humans is thought to be due to the way in which the parasite modifies the surface of the infected red cell. Approximately 16 hours into the asexual cycle, parasite encoded proteins appear on the red cell surface which mediate adherence to a variety of host tissues. Binding of infected red cells to vascular endothelium, a process which occurs in all infections, is thought to be an important factor in the pathogenesis of severe disease where concentration of organisms in particular organs such as the brain occurs. Binding to uninfected red cells to form erythrocyte rosettes, a property of some isolates, is linked to disease severity. Here we summarise the data on the molecular basis of these interactions on both the host and parasite surfaces and review the evidence for the involvement of particular receptors in specific disease syndromes. Finally we discuss the relevance of these data to the development of new treatments for malaria.

Circadian synthesis of a nuclear-encoded chloroplast glyceraldehyde-3-phosphate dehydrogenase in the dinoflagellate Gonyaulax polyedra is translationally controlled.

The circadian clock has previously been shown to restrict synthesis of several proteins in the dinoflagellate Gonyaulax polyedra to only a few hours each day. We have identified one of these proteins as glyceraldehyde-3-phosphate dehydrogenase. Two nuclear genes encoding the enzyme have been cloned, one corresponding to a cytoplasmic isoform and the other to a plastid targeted protein. On the basis of protein microsequence data, we conclude that the synthesis of the plastid isoform is clock-regulated. This regulation is not related to mRNA levels, which remain constant throughout the cycle, suggesting a translational control mechanism, in contrast to the transcriptional regulation of GAPDH that has been demonstrated in Neurospora. Although the rhythm of synthesis has a high amplitude, the abundance and activity rhythms are greatly attenuated, which is attributed to the long half-life of the protein.

Exact 95% confidence intervals for differences in binomial proportions.

A method is described that allows exact 95% confidence intervals to be computed for differences in binomial proportions. The method itself is not iterative, but it uses the iteratively computed 95% confidence intervals for the individual binomial proportions. The method converges with the usual normal approximation method, as denominators become large. It correlates very closely with the Yates-corrected chi-square test. The method works regardless of the definition of success or failure in the proportions and regardless of the order of the proportions.

The phylogeny of glyceraldehyde-3-phosphate dehydrogenase indicates lateral gene transfer from cryptomonads to dinoflagellates.

Sequence analysis of two nuclear-encoded glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes isolated from the dinoflagellate Gonyaulax polyedra distinguishes them as cytosolic and chloroplastic forms of the enzyme. Distance analysis of the cytosolic sequence shows the Gonyaulax gene branching early within the cytosolic clade, consistent with other analyses. However, the plastid sequence forms a monophyletic group with the plastid isoforms of cryptomonads, within an otherwise cytosolic clade, distinct from all other plastid GAPDHs. This is attributed to lateral gene transfer from an ancestral cryptomonad to a dinoflagellate, providing the first example of genetic exchange accompanying symbiotic associations between the two, which are common in present day cells.

Effects of candesartan cilexetil in patients with systemic hypertension. Candesartan Cilexetil Study Investigators.

The objectives of this double-blind, multicenter, randomized, parallel-arm, placebo-controlled study were to evaluate the dose-related efficacy, tolerability, and safety of candesartan cilexetil, a potent, AT1 selective, long-acting angiotensin II receptor blocker, in 365 adult patients with systemic hypertension and mean sitting diastolic blood pressure (BP) of 95 to 114 mm Hg. Patients received either placebo or candesartan cilexetil 2, 4, 8, 16, or 32 mg once daily for 8 weeks. All doses of candesartan cilexetil reduced trough (24 hours after treatment) sitting diastolic and systolic BP significantly compared with placebo (p < 0.005). A significant (p < or = 0.0001) dose response was evident, with greater decreases in BP at higher doses. Mean changes in BP were -10.7/-7.8 mm Hg and -12.6/-10.2 mm Hg in the 16- and 32-mg groups, respectively, versus -0.3/-2.6 mm Hg in the placebo group. The 16- and 32-mg doses were consistently significantly superior to placebo in antihypertensive effect with regard to all BP measurements, including peak (6 hours after treatment), trough, sitting, and standing measurements of diastolic and systolic BP. Responder rates (trough sitting diastolic BP < 90 or > or = 10 mm Hg BP decrease) were 54% and 64% for the 16- and 32-mg groups, respectively. Tolerability and safety profiles were similar to placebo at all doses. In conclusion, candesartan cilexetil administered once daily effectively reduces BP in a dose-related manner while maintaining safety and tolerability; doses of 16 and 32 mg are most effective for treatment of hypertension.

Analysis of adhesive domains from the A4VAR Plasmodium falciparum erythrocyte membrane protein-1 identifies a CD36 binding domain.

The A4VAR is a variant antigen expressed by a clonal line that binds CD36 and intercellular adhesion molecule-1, ICAM-1. We have cloned and sequenced the extracellular domain coded by the A4var gene. To probe the relationship between A4var expression and parasite adhesion to ICAM-1, var mRNA and protein expression were analyzed in an enriched population of A4 parasites that displayed higher ICAM-1 binding. By Northern analyses, A4var was the predominant var message and antisera raised against a recombinant A4VAR protein reacted with the majority of infected erythrocytes, reinforcing previous conclusions that A4VAR binds ICAM-1. A4VAR contains five Duffy-binding like (DBL) domains, and two cysteine-rich interdomain regions (CIDR) domains. DBL and CIDR domains from A4VAR were expressed in mammalian cells to determine which regions mediate binding to CD36 and ICAM-1. Using several different binding assays, the A4VAR CIDR1 was the only domain found to bind CD36. In contrast, the same assays were unable to identify the ICAM-1 binding domain in A4VAR. This is the first time that each of the DBL and CIDR domains from a Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) have been systematically expressed and tested for binding. These results confirm that CIDR1 is sufficient to bind CD36 without any apparent contribution from other domains.

Novel approach to transvenous pacemaker implantation in a post-fontan adolescent.

Postoperative bradycardia is not uncommon following the Fontan procedure in patients with a functional single ventricle. The surgical connections created with various Fontan modifications may complicate access to the atria for transvenous implantation of a permanent pacemaker. We describe approaches to overcoming problems with atrial access in an adolescent with complex congenital heart disease who required permanent transvenous atrial pacing for tachycardia-bradycardia after Fontan surgery.