Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent

B-type natriuretic peptide (BNP) is a member of the natriuretic peptide family, a group of widely distributed, but evolutionarily conserved, polypeptide mediators that exert myriad cardiovascular effects. BNP is a potent vasodilator with mitogenic, hypertrophic and pro-inflammatory properties that is upregulated in pulmonary hypertensive diseases. Circulating levels of BNP correlate with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH). Elevated plasma BNP levels are associated with increased mortality in patients with PAH and a fall in BNP levels after therapy is associated with improved survival. These findings have important clinical implications in that a noninvasive blood test may be used to identify PAH patients at high-risk of decompensation and to guide pulmonary vasodilator therapy. BNP also has several biologic effects that could be beneficial to patients with PAH. However, lack of a convenient method for achieving sustained increases in circulating BNP levels has impeded the development of BNP as a therapy for treating pulmonary hypertension. New technologies that allow transdermal or oral administration of the natriuretic peptides have the potential to greatly accelerate research into therapeutic use of BNP for cor pulmonale and pulmonary vascular diseases. This review will examine the basic science and clinical research that has led to our understanding of the role of BNP in cardiovascular physiology, its use as a biomarker of right ventricular function and its therapeutic potential for managing patients with pulmonary vascular disease

Ambrisentan for the treatment of pulmonary arterial hypertension

Ambrisentan is an endothelin receptor antagonist (ERA) that was recently approved for treatment of pulmonary arterial hypertension (PAH). Endothelin (ET) is a potent vasoconstrictor with mitogenic, hypertrophic and pro-inflammatory properties that is upregulated in pulmonary hypertensive diseases. The biologic effects of ET are mediated by 2 cell surface receptors termed ETA and ETB. ETA mediates the vasoconstrictor effect of ET on vascular smooth muscle, whereas ETB is expressed primarily on vascular endothelial cells where it induces nitric oxide synthesis and acts to clear ET from the circulation. Ambrisentan is the first ETA selective ERA approved for use in the US. Recently published clinical trials in patients with PAH demonstrate improvement in functional capacity and pulmonary hemodynamics similar to other ETA selective and non-selective ERAs. Its once daily dosing and lower incidence of serum aminotransferase elevation offer potential advantages over other ERAs, but further experience with this agent is needed to fully understand its long-term efficacy and safety. This review discusses the endothelin family of proteins and receptors and their role in the pathophysiology of pulmonary hypertensive diseases. It also examines the development process, safety profile and clinical trials that have resulted in ambrisentan being approved for treatment of PAH

Diagnosis and Management of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a rare disease, which requires a high index of suspicion to diagnose when patients initially present. Initial symptoms can be nonspecific and include complaints such as fatigue and mild dyspnea. Once the disease is suspected, echocardiography is used to estimate the pulmonary arterial (PA) pressure and to exclude secondary causes of elevated PA pressures such as left heart disease. Right heart catheterization with vasodilator challenge is critical to the proper assessment of pulmonary hemodynamics and to determine whether patients are likely to benefit from vasodilator therapy. Pathologically, the disease is characterized by deleterious remodeling of the distal pulmonary arterial and arteriolar circulation, which results in increased pulmonary vascular resistance. In the last fifteen years, medications from three different classes have been approved for the treatment of pulmonary arterial hypertension. These include the prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors

Off-fault Damage Patterns Due to Supershear Ruptures with Application to the 2001 Mw 8.1 Kokoxili (Kunlun) Tibet Earthquake

We extend a model of a two-dimensional self-healing slip pulse, propagating dynamically in steady state with slip-weakening failure criterion, to the supershear regime in order to study the off-fault stressing induced by such a slip pulse and investigate features unique to the supershear range. Specifically, we show that there exists a nonattenuating stress field behind the Mach front that radiates high stresses arbitrarily far from the fault (practically this would be limited to distances comparable to the depth of the seismogenic zone), thus being capable of creating fresh damage or inducing Coulomb failure in known structures at large distances away from the main fault. We allow for both strike-slip and dip-slip failure induced by such a slip pulse. We show that off-fault damage is controlled by the speed of the slip-pulse, scaled stress drop, and principal stress orientation of the prestress field. We apply this model to study damage features induced during the 2001 Kokoxili (Kunlun) event in Tibet, for which it has been suggested that much of the rupture was supershear. We argue that an interval of simultaneous induced normal faulting is more likely due to a slip partitioning mechanism suggested previously than to the special features of supershear rupture. However, those features do provide an explanation for otherwise anomalous ground cracking at several kilometers from the main fault. We also make some estimates of fracture energy which, for a given net slip and dynamic stress drop, is lower than for a sub-Rayleigh slip pulse because part of the energy fed by the far-field stress is radiated back along the Mach fronts.Earth and Planetary SciencesEngineering and Applied Science

Riociguat: Clinical research and evolving role in therapy

Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud\u27s phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension

An introduction to neonatal EEG

Electroencephalography (EEG) is used in neonatal care to assess encephalopathy, seizure recognition and classification, to make epilepsy syndrome diagnoses and to assess the maturity of neonatal brain activity. A basic understanding of the EEG is very helpful in ensuring that clinicians gain as much information as possible from this helpful, non-invasive investigation. The neonatal EEG is complex and accurate reporting requires detailed clinical information to be provided on request forms. Even when this is provided EEG reports are frequently returned to the neonatal unit loaded with technical details, making it difficult for neonatal staff to fully understand them. This article reviews the basics of EEG, the changes seen with increasing gestational age, and changes seen in common pathologies. We also provide a structured approach to the interpretation of the neonatal EEG report, and discuss its role in prognostication. Amplitude integrated EEG is reviewed in our companion paper

The mechanics of blue growth: Management of oceanic natural resource use with multiple, interacting sectors

Publisher's version (útgefin grein)Integrated management of multiple economic sectors is a central tenet of blue growth and socially optimal use of ocean-based natural resources, but the mechanisms of implementation remain poorly understood. In this review, we explore the challenges and opportunities of multi-sector management. We describe the roles of key existing sectors (fisheries, transportation, and offshore hydrocarbon) and emerging sectors (aquaculture, tourism, and seabed mining) and the likely synergistic and antagonistic inter-sector interactions. We then review methods to help characterize and quantify interactions and decision-support tools to help managers balance and optimize around interactions.This work is a deliverable of the project Green Growth Based on Marine Resources: Ecological and Socio-Economic Constraints (GreenMAR), which is funded by Nordforsk. We would also like to acknowledge the National Science Foundation grant GEO-1211972.Peer Reviewe

Contribution of fibrinolysis to the physical component summary of the SF-36 after acute submassive pulmonary embolism

Acute pulmonary embolism (PE) can diminish patient quality of life (QoL). The objective was to test whether treatment with tenecteplase has an independent effect on a measurement that reflects QoL in patients with submassive PE. This was a secondary analysis of an 8-center, prospective randomized controlled trial, utilizing multivariate regression to control for predefined predictors of worsened QoL including: age, active malignancy, history of PE or deep venous thrombosis (DVT), recurrent PE or DVT, chronic obstructive pulmonary disease and heart failure. QoL was measured with the physical component summary (PCS) of the SF-36. Analysis included 76 patients (37 randomized to tenecteplase, 39 to placebo). Multivariate regression yielded an equation f(8, 67), P<0.001, with R2 = 0.303. Obesity had the largest effect on PCS (β = −8.6, P<0.001), with tenecteplase second (β = 4.73, P = 0.056). After controlling for all interactions, tenecteplase increased the PCS by +5.37 points (P = 0.027). In patients without any of the defined comorbidities, the coefficient on the tenecteplase variable was not significant (−0.835, P = 0.777). In patients with submassive PE, obesity had the greatest influence on QoL, followed by use of fibrinolysis. Fibrinolysis had a marginal independent effect on patient QoL after controlling for comorbidities, but was not significant in patients without comorbid conditions

Cosmogenic ^(10)Be and ^(36)Cl geochronology of offset alluvial fans along the northern Death Valley fault zone: Implications for transient strain in the eastern California shear zone

The northern Death Valley fault zone (NDVFZ) has long been recognized as a major right-lateral strike-slip fault in the eastern California shear zone (ECSZ). However, its geologic slip rate has been difficult to determine. Using high-resolution digital topographic imagery and terrestrial cosmogenic nuclide dating, we present the first geochronologically determined slip rate for the NDVFZ. Our study focuses on the Red Wall Canyon alluvial fan, which exposes clean dextral offsets of seven channels. Analysis of airborne laser swath mapping data indicates ∼297 ± 9 m of right-lateral displacement on the fault system since the late Pleistocene. In situ terrestrial cosmogenic ^(10)Be and ^(36)Cl geochronology was used to date the Red Wall Canyon fan and a second, correlative fan also cut by the fault. Beryllium 10 dates from large cobbles and boulders provide a maximum age of 70 +22/−20 ka for the offset landforms. The minimum age of the alluvial fan deposits based on ^(36)Cl depth profiles is 63 ± 8 ka. Combining the offset measurement with the cosmogenic ^(10)Be date yields a geologic fault slip rate of 4.2 +1.9/−1.1 mm yr^(−1), whereas the ^(36)Cl data indicate 4.7 +0.9/−0.6 mm yr^(−1) of slip. Summing these slip rates with known rates on the Owens Valley, Hunter Mountain, and Stateline faults at similar latitudes suggests a total geologic slip rate across the northern ECSZ of ∼8.5 to 10 mm yr^(−1). This rate is commensurate with the overall geodetic rate and implies that the apparent discrepancy between geologic and geodetic data observed in the Mojave section of the ECSZ does not extend north of the Garlock fault. Although the overall geodetic rates are similar, the best estimates based on geology predict higher strain rates in the eastern part of the ECSZ than to the west, whereas the observed geodetic strain is relatively constant

Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat

Dual combination therapy with a phosphodiesterase‐5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate‐risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open‐ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from −5 (strongly disagree) to +5 (strongly agree) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus‐based recommendations may be helpful to clinicians and beneficial for patients when evidence‐based guidance is unavailable