Short-term endothelin receptor blockade with tezosentan has both immediate and long-term beneficial effects in rats with myocardial infarction

AbstractObjectivesWe investigated the effects of short-term tezosentan treatment on cardiac function, pulmonary edema and long-term evolution of heart failure (HF) in a rat model of myocardial infarction (MI).BackgroundEndothelin (ET) may play a major role in the progression from MI to HF. Tezosentan is a new dual ETA/ETBreceptor antagonist.MethodsRats were subjected to coronary artery ligation and were treated with either vehicle or tezosentan (10 mg/kg IV bolus) at 1 h and 24 h after MI. Cardiac hemodynamics and lung weight were measured at 48 h after MI. Survival was assessed over a five-month period.ResultsAt 48 h after ligation, vehicle-treated rats developed HF, as evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP), reduction in dP/dtmaxand mean arterial pressure (MAP), and development of pulmonary edema. Tezosentan treatment attenuated the increase in LVEDP and in lung weight and slightly reduced MAP without affecting dP/dtmax. Infarct size was not modified by tezosentan. Despite the fact that treatment with tezosentan was stopped after 24 h, the initial tezosentan administration significantly reduced cardiac hypertrophy (22%) and decreased mortality by 51% at five months (50% survival vs. 19% survival in vehicle-treated rats, p < 0.001).ConclusionsTezosentan administered during the first day after MI in rats, in addition to improving acutely hemodynamic conditions, markedly increases long-term survival. This increase is associated with a decrease of pulmonary edema and prevention of cardiac hypertrophy. Tezosentan could be a safe and useful therapeutic agent in the prevention and treatment of ischemic HF

Distributed Robust Multi-Cell Coordinated Beamforming with Imperfect CSI: An ADMM Approach

Multi-cell coordinated beamforming (MCBF), where multiple base stations (BSs) collaborate with each other in the beamforming design for mitigating the inter-cell interference, has been a subject drawing great attention recently. Most MCBF designs assume perfect channel state information (CSI) of mobile stations (MSs); however CSI errors are inevitable at the BSs in practice. Assuming elliptically bounded CSI errors, this paper studies the robust MCBF design problem that minimizes the weighted sum power of BSs subject to worst-case signal-to-interference-plus-noise ratio (SINR) constraints on the MSs. Our goal is to devise a distributed optimization method that can obtain the worst-case robust beamforming solutions in a decentralized fashion, with only local CSI used at each BS and little backhaul signaling for message exchange between BSs. However, the considered problem is difficult to handle even in the centralized form. We first propose an efficient approximation method in the centralized form, based on the semidefinite relaxation (SDR) technique. To obtain the robust beamforming solution in a decentralized fashion, we further propose a distributed robust MCBF algorithm, using a distributed convex optimization technique known as alternating direction method of multipliers (ADMM). We analytically show the convergence of the proposed distributed robust MCBF algorithm to the optimal centralized solution and its better bandwidth efficiency in backhaul signaling over the existing dual decomposition based algorithms. Simulation results are presented to examine the effectiveness of the proposed SDR method and the distributed robust MCBF algorithm

Pavlovian fear memory induced by activation in the anterior cingulate cortex

Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is the focus of many recent studies. Here we show that direct stimulation of the anterior cingulate cortex (ACC) in mice produced fear-like freezing responses and induced long-term fear memory, including contextual and auditory fear memory. Auditory fear memory required the activation of N-methyl-D-aspartate (NMDA) receptors in the amygdala. To test the hypothesis that neuronal activity in the ACC contributes to unpleasantness, we injected a GABA(A )receptor agonist, muscimol bilaterally into the ACC. Both contextual and auditory memories induced by foot shock were blocked. Furthermore, activation of metabotropic glutamate receptors in the ACC enhanced behavioral escape responses in a noxious hot-plate as well as spinal nociceptive tail-flick reflex. Our results provide strong evidence that the excitatory activity in the ACC contribute to pain-related fear memory as well as descending facilitatory modulation of spinal nociception

Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review

Rapamycin, an established mTOR inhibitor in clinical practice, is widely recognized for its therapeutic efficacy. Ridaforolimus, a non-prodrug rapalog, offers improved aqueous solubility, stability, and affinity compared to rapamycin. In recent years, there has been a surge in clinical trials involving ridaforolimus. We searched PubMed for ridaforolimus over the past decade and selected clinical trials of ridaforolimus to make a summary of the research progress of ridaforolimus in clinical trials. The majority of these trials explored the application of ridaforolimus in treating various tumors, including endometrial cancer, ovarian cancer, prostate cancer, breast cancer, renal cell carcinoma, and other solid tumors. These trials employed diverse drug combinations, incorporating agents such as ponatinib, bicalutamide, dalotuzumab, MK-2206, MK-0752, and taxanes. The outcomes of these trials unveiled the diverse potential applications of ridaforolimus in disease treatment. Our review encompassed analyses of signaling pathways, ridaforolimus as a single therapeutic agent, its compatibility in combination with other drugs, and an assessment of adverse events (AEs). We conclude by recommending further research to advance our understanding of ridaforolimus’s clinical applications

A Unified Multi-Functional Dynamic Spectrum Access Framework: Tutorial, Theory and Multi-GHz Wideband Testbed

Dynamic spectrum access is a must-have ingredient for future sensors that are ideally cognitive. The goal of this paper is a tutorial treatment of wideband cognitive radio and radar—a convergence of (1) algorithms survey, (2) hardware platforms survey, (3) challenges for multi-function (radar/communications) multi-GHz front end, (4) compressed sensing for multi-GHz waveforms—revolutionary A/D, (5) machine learning for cognitive radio/radar, (6) quickest detection, and (7) overlay/underlay cognitive radio waveforms. One focus of this paper is to address the multi-GHz front end, which is the challenge for the next-generation cognitive sensors. The unifying theme of this paper is to spell out the convergence for cognitive radio, radar, and anti-jamming. Moore’s law drives the system functions into digital parts. From a system viewpoint, this paper gives the first comprehensive treatment for the functions and the challenges of this multi-function (wideband) system. This paper brings together the inter-disciplinary knowledge

Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception

<p>Abstract</p> <p>Background</p> <p>Interstitial cystitis/painful bladder syndrome (IC/PBS), is a severely debilitating chronic condition that is frequently unresponsive to conventional pain medications. The etiology is unknown, however evidence suggests that nervous system sensitization contributes to enhanced pain in IC/PBS. In particular, central nervous system plasticity of glutamatergic signaling involving NMDA and metabotropic glutamate receptors (mGluRs) has been implicated in a variety of chronic pain conditions. Here, we test the hypothesis that mGluR5 mediates both non-inflammatory and inflammatory bladder pain or nociception in a mouse model by monitoring the visceromotor response (VMR) during graded bladder distention.</p> <p>Results</p> <p>Using a combination of genetic and pharmacologic approaches, we provide evidence indicating that mGluR5 is necessary for the full expression of VMR in response to bladder distention in the absence of inflammation. Furthermore, we observed that mice infected with a uropathogenic strain of <it>Escherichia coli </it>(UPEC) develop inflammatory hyperalgesia to bladder distention, and that the selective mGluR5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl) urea], reduces the VMR to bladder distention in UPEC-infected mice.</p> <p>Conclusions</p> <p>Taken together, these data suggest that mGluR5 modulates both inflammatory and non-inflammatory bladder nociception, and highlight the therapeutic potential for mGluR5 antagonists in the alleviation of bladder pain.</p

Hippocampal Synaptic and Neural Network Deficits in Young Mice Carrying the Human APOE4 Gene

Introduction: Apolipoprotein E4 (APOE4) is a major genetic risk factor for late-onset sporadic Alzheimer disease. Emerging evidence demonstrates a hippocampus-associated learning and memory deficit in aged APOE4 human carriers and also in aged mice carrying human APOE4 gene. This suggests that either exogenous APOE4 or endogenous APOE4 alters the cognitive profile and hippocampal structure and function. However, little is known regarding how Apoe4 modulates hippocampal dendritic morphology, synaptic function, and neural network activity in young mice. Aim: In this study, we compared hippocampal dendritic and spine morphology and synaptic function of young (4 months) mice with transgenic expression of the human APOE4 and APOE3 genes. Methods: Hippocampal dendritic and spine morphology and synaptic function were assessed by neuronal imaging and electrophysiological approaches. Results: Morphology results showed that shortened dendritic length and reduced spine density occurred at hippocampal CA1 neurons in Apoe4 mice compared to Apoe3 mice. Electrophysiological results demonstrated that in the hippocampal CA3-CA1 synapses of young Apoe4 mice, basic synaptic transmission, and paired-pulse facilitation were enhanced but long-term potentiation and carbachol-induced hippocampal theta oscillations were impaired compared to young Apoe3 mice. However, both Apoe genotypes responded similarly to persistent stimulations (4, 10, and 40 Hz for 4 seconds). Conclusion: Our results suggest significant alterations in hippocampal dendritic structure and synaptic function in Apoe4 mice, even at an early age