Coronary Thrombolysis with Intravenous Streptokinase in the Anesthetized Dog: A Dose-Response Study

ABSTRAC

Observations of Energetic-particle Population Enhancements along Intermittent Structures near the Sun from the Parker Solar Probe

Observations at 1 au have confirmed that enhancements in measured energetic-particle (EP) fluxes are statistically associated with "rough" magnetic fields, i.e., fields with atypically large spatial derivatives or increments, as measured by the Partial Variance of Increments (PVI) method. One way to interpret this observation is as an association of the EPs with trapping or channeling within magnetic flux tubes, possibly near their boundaries. However, it remains unclear whether this association is a transport or local effect; i.e., the particles might have been energized at a distant location, perhaps by shocks or reconnection, or they might experience local energization or re-acceleration. The Parker Solar Probe (PSP), even in its first two orbits, offers a unique opportunity to study this statistical correlation closer to the corona. As a first step, we analyze the separate correlation properties of the EPs measured by the Integrated Science Investigation of the Sun (IS⊙IS) instruments during the first solar encounter. The distribution of time intervals between a specific type of event, i.e., the waiting time, can indicate the nature of the underlying process. We find that the IS⊙IS observations show a power-law distribution of waiting times, indicating a correlated (non-Poisson) distribution. Analysis of low-energy (~15 – 200 keV/nuc) IS⊙IS data suggests that the results are consistent with the 1 au studies, although we find hints of some unexpected behavior. A more complete understanding of these statistical distributions will provide valuable insights into the origin and propagation of solar EPs, a picture that should become clear with future PSP orbits

In Vitro and In Vivo Characterization of Intrinsic Sympathomimetic Activity in Normal and Heart Failure Rats

ABSTRACT Clinical studies conducted with carvedilol suggest that ␤-adrenoceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many ␤-adrenoceptor antagonists are weak partial agonists and possess significant intrinsic sympathomimetic activity (ISA), which may be problematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes. At equieffective ␤ 1 -adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffective, and dose-related increase in heart rate in both pithed SD rats (ED 50 ϭ 5 and 40 g/kg, respectively) and SHHF rats (ED 50 ϭ 6 and 30 g/kg, respectively). The maximum effect of both compounds in SHHF rats was approximately 50% of that observed in SD rats. In contrast, carvedilol and bisoprolol had no significant effect on resting heart rate in the pithed SD or SHHF rat. The maximum increase in heart rate elicited by xamoterol and bucindolol was inhibited by treatment with propranolol, carvedilol, and betaxolol (␤ 1 -adrenoceptor antagonist) but not by ICI 118551 (␤ 2 -adrenoceptor antagonist) in neonatal rat. When the ␤-adrenoceptor-mediated cAMP response was examined in cardiomyocytes, an identical partial agonist/antagonist response profile was observed for all compounds, demonstrating a strong correlation with the in vivo results. In contrast, GTP-sensitive ligand binding and tissue adenylate cyclase activity were not sensitive methods for detecting ␤-adrenoceptor partial agonist activity in the heart. In summary, xamoterol and bucindolol, but not carvedilol and bisoprolol, exhibited direct ␤ 1 -adrenoceptor-mediated ISA in normal and heart failure rats

Oxidative stress induced by the Fe2+/ascorbic acid system or model ischemia in vitro: effect of carvedilol and pyridoindole antioxidant SMe1EC2 in young and adult rat brain tissue

New effective strategies and new highly effective neuroprotective agents are being searched for the therapy of human stroke and cerebral ischemia. The compound SMe1EC2 is a new derivative of stobadine, with enhanced antioxidant properties compared to the maternal drug. Carvedilol, a non-selective beta-blocker, possesses besides its cardioprotective and vasculoprotective properties also an antioxidant effect. We compared the effect of carvedilol and SMe1EC2, antioxidants with a similar chemical structure, in two experimental models of oxidative stress in young and adult rat brain tissue. SMe1EC2 was found to improve the resistance of hippocampal neurons to ischemia in vitro in young and even in 18-month-old rats and inhibited formation of protein carbonyl groups induced by the Fe2+/ascorbic acid pro-oxidative system in brain cortex homogenates of young rats. Carvedilol exerted a protective effect only in the hippocampus of 2-month-old rats and that at the concentration 10-times higher than did SMe1EC2. The inhibitory effect of carvedilol on protein carbonyl formation induced by the pro-oxidative system was not proved in the cortex of either young or adult rats. An increased baseline level of the content of protein carbonyl groups in the adult versus young rat brain cortex confirmed age-related changes in neuronal tissue and may be due to increased production of reactive oxygen species and low antioxidant defense mechanisms in the adult rat brain. The results revealed the new pyridoindole SMe1EC2 to be more effective than carvedilol in neuroprotection of rat brain tissue in both experimental models involving oxidative stress

Observations of Energetic-particle Population Enhancements along Intermittent Structures near the Sun from the Parker Solar Probe

Observations at 1 au have confirmed that enhancements in measured energetic-particle (EP) fluxes are statistically associated with "rough" magnetic fields, i.e., fields with atypically large spatial derivatives or increments, as measured by the Partial Variance of Increments (PVI) method. One way to interpret this observation is as an association of the EPs with trapping or channeling within magnetic flux tubes, possibly near their boundaries. However, it remains unclear whether this association is a transport or local effect; i.e., the particles might have been energized at a distant location, perhaps by shocks or reconnection, or they might experience local energization or re-acceleration. The Parker Solar Probe (PSP), even in its first two orbits, offers a unique opportunity to study this statistical correlation closer to the corona. As a first step, we analyze the separate correlation properties of the EPs measured by the Integrated Science Investigation of the Sun (IS⊙IS) instruments during the first solar encounter. The distribution of time intervals between a specific type of event, i.e., the waiting time, can indicate the nature of the underlying process. We find that the IS⊙IS observations show a power-law distribution of waiting times, indicating a correlated (non-Poisson) distribution. Analysis of low-energy (~15 – 200 keV/nuc) IS⊙IS data suggests that the results are consistent with the 1 au studies, although we find hints of some unexpected behavior. A more complete understanding of these statistical distributions will provide valuable insights into the origin and propagation of solar EPs, a picture that should become clear with future PSP orbits

Observations of Energetic-Particle Population Enhancements along Intermittent Structures near the Sun from Parker Solar Probe

Observations at 1 au have confirmed that enhancements in measured energetic particle fluxes are statistically associated with "rough" magnetic fields, i.e., fields having atypically large spatial derivatives or increments, as measured by the Partial Variance of Increments (PVI) method. One way to interpret this observation is as an association of the energetic particles with trapping or channeling within magnetic flux tubes, possibly near their boundaries. However, it remains unclear whether this association is a transport or local effect; i.e., the particles might have been energized at a distant location, perhaps by shocks or reconnection, or they might experience local energization or re-acceleration. The Parker Solar Probe (PSP), even in its first two orbits, offers a unique opportunity to study this statistical correlation closer to the corona. As a first step, we analyze the separate correlation properties of the energetic particles measured by the \isois instruments during the first solar encounter. The distribution of time intervals between a specific type of event, i.e., the waiting time, can indicate the nature of the underlying process. We find that the \isois observations show a power-law distribution of waiting times, indicating a correlated (non-Poisson) distribution. Analysis of low-energy \isois data suggests that the results are consistent with the 1 au studies, although we find hints of some unexpected behavior. A more complete understanding of these statistical distributions will provide valuable insights into the origin and propagation of solar energetic particles, a picture that should become clear with future PSP orbits.Comment: Accepted for publication in The Astrophysical Journal Supplement, PSP special issu

Cooperative Regulation of Non-Small Cell Lung Carcinoma by Nicotinic and Beta-Adrenergic Receptors: A Novel Target for Intervention

Lung cancer is the leading cause of cancer death; 80–85% of lung cancer cases are non-small cell lung cancer (NSCLC). Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299), we identified the cooperation of nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs) as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the α7nAChR and α4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the α7nAChR antagonist α-BTX or the β-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing β-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by β blocker may lower the risk for NSCLC development among smokers and could be used to enhance the clinical outcome of standard cancer therapy

The 20 year evolution of dobutamine stress cardiovascular magnetic resonance

Over the past 20 years, investigators world-wide have developed and utilized dobutamine magnetic resonance stress testing procedures for the purpose of identifying ischemia, viability, and cardiac prognosis. This article traces these developments and reviews the data utilized to substantiate this relatively new noninvasive imaging procedure