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1.

Background

Catheter ablation of ventricular tachycardia (VT) can reduce the burden of ventricular arrhythmia (VA) but its effect on health care utilization and costs after such therapy is poorly known. We sought to compare the rates of cardiovascular (CV)-related hospitalizations, survival, and health care costs in patients with recurrent VT treated either with VT ablation or with medical therapy.

Methods

One-hundred implantable cardioverter-defibrillator patients with structural heart disease who underwent VT ablation were included. Propensity score-matched patients with recurrent VT treated with medical therapy were identified from a prospective registry of approximately 7000 de novo implantable cardioverter-defibrillator patients. Outcomes and costs were ascertained using health administrative databases.

Results

Among patients who underwent VT ablation, the cumulative rates of VA-related hospitalizations were lower in the 2 years after their ablation procedure compared with the year before (rate ratio, 0.3; 95% confidence interval [CI], 0.22-0.43). Rates of CV-related hospitalization and hospitalization because of VA post index date were similar between the VT ablation and medical therapy groups (hazard ratio [HR], 0.94; 95% CI, 0.57-1.54 and HR, 1.04; 95% CI, 0.57-1.91, respectively). Health care costs in the VT ablation patients were not increased post-ablation compared with the medical management group. The risk of all-cause mortality was lower among patients in the VT ablation group relative to the medical therapy group (HR, 0.64; 95% CI, 0.4-0.99).

Conclusions

Patients who underwent VT ablation experienced a significant reduction in their rate of VA-related hospitalizations. Patients treated with VT ablation had similar rates of CV-related hospitalization compared with those treated with medical therapy without increased health care-related costs.  相似文献   
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3.
BackgroundIn the past two decades, enhanced understanding of the biology of G-protein-coupled receptors (GPRs) has led to the identification of several such receptors as novel targets for free fatty acids (FFAs). Two GPRs, FFAR1 and FFAR4, have received special attention in the context of chronic inflammatory diseases, thanks to their anti-inflammatory activities.MethodsThe present study investigates the influence of prolonged treatment with GW9508 – agonist of FFAR1 and FFAR4 – on the development of atherosclerosis plaque in apoE-knockout mice, using morphometric and molecular methods.ResultsGW9508 administration has led to the reduction of atheroscletoric plaque size in an apoE-knockout mice model. Moreover, a FFAR1/FFAR4 agonist reduced the content of macrophages by almost 20%, attributed by immunohistochemical phenotyping to the pro-inflammatory M1-like activation state macrophages.ConclusionsProlonged administration of GW9508 resulted in significant amelioration of atherogenesis, providing evidence that the strategy based on macrophage phenotype switching toward an M2-like activation state via stimulation of FFAR1/FFAR4 receptors holds promise for a new approach to the prevention or treatment of atherosclerosis.  相似文献   
4.
Acute kidney injury (AKI) to chronic kidney disease (CKD) progression has become a life-threatening disease. However, an effective therapeutic strategy is still needed. The pathophysiology of AKI-to-CKD progression involves chronic inflammation and renal fibrosis driven by macrophage activation, which is physiologically dependent on colony-stimulating factor-1 receptor (CSF-1R) signaling. In this study, we modulated macrophage infiltration through oral administration of the CSF-1R inhibitor GW2580 in an ischemia–reperfusion (I/R)-induced AKI model to evaluate its therapeutic effects on preventing the progression of AKI to CKD. We found that GW2580 induced a significant reduction in the number of macrophages in I/R-injured kidneys and attenuated I/R-induced renal injury and subsequent interstitial fibrosis. By flow cytometry, we observed that the reduced macrophages were primarily Ly6C+ inflammatory macrophages in the GW2580-treated kidneys, while there was no significant difference in the number and percentage of Ly6CCX3CR1+ macrophages. We further found that these reduced macrophages also demonstrated some characteristics of M2-like macrophages, which have been generally regarded as profibrotic subtypes in chronic inflammation. These results indicate the existence of phenotypic and functional crossover between Ly6C+ and M2-like macrophages in I/R kidneys, which induces AKI worsening to CKD. In conclusion, therapeutic GW2580 treatment alleviates acute renal injury and subsequent fibrosis by reducing Ly6C+ M2-like macrophage infiltration in ischemia-induced AKI.  相似文献   
5.
Background: Genetic studies have shown that mutations in several genes may be linked to Parkinson's disease including leucine-rich repeat kinase-2 (LRRK2). The most common of the LRRK2 mutants is the Gly2019Ser mutant.

Objective/methods: A paper suggesting that inhibitors of Gly2019Ser mutant may be useful in the treatment of Parkinson's disease associated with this mutant is evaluated.

Results: Overexpression of the wild-type LRRK2 or the Gly2019Ser LRRK2 mutant type produced cortical neuron injury in cell culture, and the mutant also caused cell death; this was reduced by GW5074. Administered intraperitoneally to mice, GW5074 prevented the loss of neurons induced by the Gly2019Ser LRRK2 mutant.

Conclusions: Selective Gly2019Ser LRRK2 mutant inhibitors may have potential in the treatment of Parkinsonism associated with mutations of this gene and GW5074 is a lead compound for this.  相似文献   
6.
Ras and c-Raf constitute an important part of mitogen-activated protein (MAP) kinase family as Ras/Raf/MEK/ERK2 signaling cascade and the role of MAP kinases has been well defined in neuropathic pain. The present study investigates the analgesic potential of farnesyl thiosalicylic acid, a novel Ras inhibitor, and GW 5074, a selective c-Raf1 inhibitor, in vincristine-induced neuropathic pain. Peripheral neuropathy was induced in rats by administering vincristine (50 μg/kg i.p.) for 10 consecutive days. Pain development was assessed on 14th day in terms of cold allodynia; mechanical hyperalgesia and mechanical allodynia by performing acetone test, pin-prick and von frey tests, respectively. Farnesyl thiosalicylic acid and GW 5074 were injected intrathecally on 14th day following vincristine administration. Administration of vincristine produced significant neuropathic pain manifestations in terms of cold and mechanical allodynia, and mechanical hyperalgesia. Single intrathecal administration of farnesyl thiosalicylic acid (5 and 10 μg) as well as GW 5074 (2 and 4 μg) significantly attenuated vincristine-induced hyperalgesia and allodynia. The analgesic effects of farnesyl thiosalicylic acid and GW 5074 in vincristine model suggests that pharmacological inhibition of Ras and c-Raf-1 signalling may be potentially useful for managing neuropathic pain.  相似文献   
7.
目的 观察过氧化物酶体增殖物激活受体(peroxisome proliferators-activated receptor β/δ,PPARβ/δ)激动剂GW0742对硝酸甘油诱导偏头痛大鼠的影响.方法 48只(SD大鼠)随机分为模型组、GW0742组和正常对照组.模型组按Tassorelli Cristina法复制大鼠偏头痛模型,GW0742组于造模后30min给药.取三叉神经颈复合体,采用免疫组织化学和Western blot法测定PPARβ/δ及白细胞介素-6(interleukin-6,IL-6)、细胞间粘附分子(intercellular adhesion molecule-1,ICAM-1)、基质金属蛋白酶-9(Matrix metallopeptidase 9,MMP-9)的表达.结果 模型组三叉神经颈复合体中PPARβ/δ的表达明显高于对照组,差异有统计学意义,同时模型组大鼠IL-6、ICAM-1、MMP-9高于对照组,给予GW0742大鼠IL-6、ICAM-1、MMP-9表达明显下降.结论 PPARβ/δ在偏头痛时高度表达,PPARβ/δ激动剂对偏头痛有保护作用.  相似文献   
8.
《COPD》2013,10(5):383-385
  相似文献   
9.
Abstract

An estimated 9% of the American population experiences type II diabetes mellitus (T2DM) due to diet or genetic predisposition. Recent reports indicate that patients with T2DM are at increased risk for cognitive dysfunctions, as observed in conditions like Alzheimer’s disease (AD). In addition, AD is the leading cause of dementia, highlighting the urgency of developing novel therapeutic targets for T2DM-induced cognitive deficits. The peroxisome proliferator activated receptor-δ (PPAR-δ) is highly expressed in the brain and has been shown to play an important role in spatial memory and hippocampal neurogenesis. However, the effect of PPAR-δ agonists on T2DM-induced cognitive impairment has not been explored. In this study, the effects of GW0742 (a selective PPAR-δ agonist) on hippocampal synaptic transmission, plasticity, and spatial memory were investigated in the db/db mouse model of T2DM. Oral administration of GW0742 for 2 weeks significantly improved hippocampal long-term potentiation. In addition, GW0742 effectively prevented deficits in hippocampal dependent spatial memory in db/db mice. PPAR-δ–mediated improvements in synaptic plasticity and behavior were accompanied by a significant recovery in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated synaptic transmission. Our findings suggest that activation of PPAR-δ might ameliorate T2DM-induced impairments in hippocampal synaptic plasticity and memory.  相似文献   
10.

BACKGROUND AND PURPOSE

Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of cannabinoid receptor-mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour.

EXPERIMENTAL APPROACH

Effects of pre-treatment with a single dose, versus 4 day repeated dosing with the selective FAAH inhibitor, URB597 (i.p. 0.3 mg·kg−1), on carrageenan-induced inflammatory pain behaviour and spinal pro-inflammatory gene induction were determined in rats. Effects of pain induction and of the drug treatments on levels of arachidonoyl ethanolamide (AEA), palmitoyl ethanolamide (PEA) and oleolyl ethanolamide (OEA) in the spinal cord were determined.

KEY RESULTS

Single, but not repeated, URB597 treatment significantly attenuated the development of inflammatory hyperalgesia (P < 0.001, vs. vehicle-treated animals). Neither mode of URB597 treatment altered levels of AEA, PEA and OEA in the hind paw, or carrageenan-induced paw oedema. Single URB597 treatment produced larger increases in AEA, PEA and OEA in the spinal cord, compared with those after repeated administration. Single and repeated URB597 treatment decreased levels of immunoreactive N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) in the spinal cord and attenuated carrageenan-induced spinal pro-inflammatory gene induction.

CONCLUSION AND IMPLICATIONS

Changes in the endocannabinoid system may contribute to the loss of analgesic effects following repeated administration of low dose URB597 in this model of inflammatory pain.  相似文献   
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