Lipid rafts are small, dynamic membrane areas characterized by the clustering of selected membrane lipids as the result of the spontaneous separation of glycolipids, sphingolipids, and cholesterol in ...a liquid-ordered phase. The exact dynamics underlying phase separation of membrane lipids in the complex biological membranes are still not fully understood. Nevertheless, alterations in the membrane lipid composition affect the lateral organization of molecules belonging to lipid rafts. Neural lipid rafts are found in brain cells, including neurons, astrocytes, and microglia, and are characterized by a high enrichment of specific lipids depending on the cell type. These lipid rafts seem to organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating the homeostasis of the brain. The progressive decline of brain performance along with physiological aging is at least in part associated with alterations in the composition and structure of neural lipid rafts. In addition, neurodegenerative conditions, such as lysosomal storage disorders, multiple sclerosis, and Parkinson's, Huntington's, and Alzheimer's diseases, are frequently characterized by dysregulated lipid metabolism, which in turn affects the structure of lipid rafts. Several events underlying the pathogenesis of these diseases appear to depend on the altered composition of lipid rafts. Thus, the structure and function of lipid rafts play a central role in the pathogenesis of many common neurodegenerative diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Many species of ganglioside GM1, differing for the sialic acid and ceramide content, have been characterized and their physico-chemical properties have been studied in detail since 1963. Scientists ...were immediately attracted to the GM1 molecule and have carried on an ever-increasing number of studies to understand its binding properties and its neurotrophic and neuroprotective role. GM1 displays a well balanced amphiphilic behavior that allows to establish strong both hydrophobic and hydrophilic interactions. The peculiar structure of GM1 reduces the fluidity of the plasma membrane which implies a retention and enrichment of the ganglioside in specific membrane domains called lipid rafts. The dynamism of the GM1 oligosaccharide head allows it to assume different conformations and, in this way, to interact through hydrogen or ionic bonds with a wide range of membrane receptors as well as with extracellular ligands. After more than 60 years of studies, it is a milestone that GM1 is one of the main actors in determining the neuronal functions that allows humans to have an intellectual life. The progressive reduction of its biosynthesis along the lifespan is being considered as one of the causes underlying neuronal loss in aged people and severe neuronal decline in neurodegenerative diseases. In this review, we report on the main knowledge on ganglioside GM1, with an emphasis on the recent discoveries about its bioactive component.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objectives This study sought to evaluate 4-year outcomes of percutaneous repair versus surgery for mitral regurgitation. Background Transcatheter therapies are being developed to treat valvular heart ...disease. In the EVEREST (Endovascular Valve Edge-to-Edge Repair Study) II trial, treatment of mitral valve regurgitation (MR) with a novel percutaneous device was compared with surgery and showed superior safety, but less reduction in MR at 1 year overall. We report the 4-year outcomes from the EVEREST II trial. Methods Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the MitraClip (Abbott, Menlo Park, California) device or conventional mitral valve surgery in a 2:1 ratio (184:95). Patients prospectively consented to 5 years of follow-up. Results At 4 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the intention-to-treat population was 39.8% versus 53.4% in the percutaneous repair group and surgical groups, respectively (p = 0.070). Rates of death were 17.4% versus 17.8% (p = 0.914), and 3+ or 4+ MR was present in 21.7% versus 24.7% (p = 0.745) at 4 years of follow-up, respectively. Surgery for mitral valve dysfunction, however, occurred in 20.4% versus 2.2% (p < 0.001) at 1 year and 24.8% versus 5.5% (p < 0.001) at 4 years. Conclusions Patients treated with percutaneous repair of the mitral valve more commonly required surgery to treat residual MR; however, after the first year of follow-up, there were few surgeries required after either percutaneous or surgical treatment and no difference in the prevalence of moderate-severe and severe MR or mortality at 4 years. (Endovascular Valve Edge-to-Edge Repair Study EVEREST II; NCT00209274 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Treatment with aspirin and a P2Y12 inhibitor is commonly used in patients with cardiovascular disorders. The overall effect of such treatment on all-cause mortality is unknown. In ...the Dual Antiplatelet Therapy (DAPT) Study, continuation of dual antiplatelet therapy beyond 12 months after coronary stenting was associated with an unexpected increase in non-cardiovascular death. In view of the potential public health importance of these findings, we aimed to assess the effect of extended duration dual antiplatelet therapy on mortality by doing a meta-analysis of all randomised, controlled trials of treatment duration in various cardiovascular disorders. Methods We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomised controlled trials assessing the effect of extended duration versus no or short duration dual antiplatelet therapy, published before Oct 1, 2014. We did a meta-analysis to pool results with a hierarchical Bayesian random-effects model. The primary outcomes were hazard ratios comparing rates of all-cause, cardiovascular, and non-cardiovascular death. Findings Including the DAPT Study, we identified 14 eligible trials that randomly assigned 69 644 participants to different durations of dual antiplatelet therapy. Compared with aspirin alone or short duration dual antiplatelet therapy (≤6 months), continued treatment was not associated with a difference in all-cause mortality (hazard ratio HR 1·04, 95% credible interval CrI 0·96–1·18; p=0·17). Similarly, cardiovascular (1·01, 0·93–1·12; p=0·81) and non-cardiovascular mortality (1·04, 0·90–1·26; p=0·66) were no different with extended duration versus short duration dual antiplatelet therapy or aspirin alone. Interpretation Extended duration dual antiplatelet therapy was not associated with a difference in the risk of all-cause, cardiovascular, or non-cardiovascular death compared with aspirin alone or short duration dual antiplatelet therapy. Funding None.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In this large trial, denervation of the kidneys with use of a radiofrequency ablation catheter in the renal arteries had no significant effect on blood pressure in patients with resistant ...hypertension. This contradicts results of smaller trials that did not include a sham control.
Because of the aging of the population and rising rates of obesity, hypertension is increasing in prevalence worldwide.
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Approximately 10% of patients with diagnosed hypertension have resistant hypertension, defined as a systolic blood pressure of 140 mm Hg or higher despite adherence to at least three maximally tolerated doses of antihypertensive medications from complementary classes, including a diuretic at an appropriate dose.
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Patients with resistant hypertension who are receiving appropriate medical therapy have high rates of cardiovascular complications, with few treatment options.
The sympathetic nervous system — in particular, sympathetic cross-talk between the kidneys and the brain — appears . . .
IMPORTANCE: Dual antiplatelet therapy after percutaneous coronary intervention (PCI) reduces ischemia but increases bleeding. OBJECTIVE: To develop a clinical decision tool to identify patients ...expected to derive benefit vs harm from continuing thienopyridine beyond 1 year after PCI. DESIGN, SETTING, AND PARTICIPANTS: Among 11 648 randomized DAPT Study patients from 11 countries (August 2009-May 2014), a prediction rule was derived stratifying patients into groups to distinguish ischemic and bleeding risk 12 to 30 months after PCI. Validation was internal via bootstrap resampling and external among 8136 patients from 36 countries randomized in the PROTECT trial (June 2007-July 2014). EXPOSURES: Twelve months of open-label thienopyridine plus aspirin, then randomized to 18 months of continued thienopyridine plus aspirin vs placebo plus aspirin. MAIN OUTCOMES AND MEASURES: Ischemia (myocardial infarction or stent thrombosis) and bleeding (moderate or severe) 12 to 30 months after PCI. RESULTS: Among DAPT Study patients (derivation cohort; mean age, 61.3 years; women, 25.1%), ischemia occurred in 348 patients (3.0%) and bleeding in 215 (1.8%). Derivation cohort models predicting ischemia and bleeding had c statistics of 0.70 and 0.68, respectively. The prediction rule assigned 1 point each for myocardial infarction at presentation, prior myocardial infarction or PCI, diabetes, stent diameter less than 3 mm, smoking, and paclitaxel-eluting stent; 2 points each for history of congestive heart failure/low ejection fraction and vein graft intervention; −1 point for age 65 to younger than 75 years; and −2 points for age 75 years or older. Among the high score group (score ≥2, n = 5917), continued thienopyridine vs placebo was associated with reduced ischemic events (2.7% vs 5.7%; risk difference RD, −3.0% 95% CI, −4.1% to −2.0%, P < .001) compared with the low score group (score <2, n = 5731; 1.7% vs 2.3%; RD, −0.7% 95% CI, −1.4% to 0.09%, P = .07; interaction P < .001). Conversely, continued thienopyridine was associated with smaller increases in bleeding among the high score group (1.8% vs 1.4%; RD, 0.4% 95% CI, −0.3% to 1.0%, P = .26) compared with the low score group (3.0% vs 1.4%; RD, 1.5% 95% CI, 0.8% to 2.3%, P < .001; interaction P = .02). Among PROTECT patients (validation cohort; mean age, 62 years; women, 23.7%), ischemia occurred in 79 patients (1.0%) and bleeding in 37 (0.5%), with a c statistic of 0.64 for ischemia and 0.64 for bleeding. In this cohort, the high-score patients (n = 2848) had increased ischemic events compared with the low-score patients and no significant difference in bleeding. CONCLUSION AND RELEVANCE: Among patients not sustaining major bleeding or ischemic events 1 year after PCI, a prediction rule assessing late ischemic and bleeding risks to inform dual antiplatelet therapy duration showed modest accuracy in derivation and validation cohorts. This rule requires further prospective evaluation to assess potential effects on patient care, as well as validation in other cohorts. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00977938.
The central nervous system is characterized by a high content of sphingolipids and by a high diversity in terms of different structures. Stage- and cell-specific sphingolipid metabolism and ...expression are crucial for brain development and maintenance toward adult age. On the other hand, deep dysregulation of sphingolipid metabolism, leading to altered sphingolipid pattern, is associated with the majority of neurological and neurodegenerative diseases, even those totally lacking a common etiological background. Thus, sphingolipid metabolism has always been regarded as a promising pharmacological target for the treatment of brain disorders. However, any therapeutic hypothesis applied to complex amphipathic sphingolipids, components of cellular membranes, has so far failed probably because of the high regional complexity and specificity of the different biological roles of these structures. Simpler sphingosine-based lipids, including ceramide and sphingosine 1-phosphate, are important regulators of brain homeostasis, and, thanks to the relative simplicity of their metabolic network, they seem a feasible druggable target for the treatment of brain diseases. The enzymes involved in the control of the levels of bioactive sphingoids, as well as the receptors engaged by these molecules, have increasingly allured pharmacologists and clinicians, and eventually fingolimod, a functional antagonist of sphingosine 1-phosphate receptors with immunomodulatory properties, was approved for the therapy of relapsing-remitting multiple sclerosis. Considering the importance of neuroinflammation in many other brain diseases, we would expect an extension of the use of such analogs for the treatment of other ailments in the future. Nevertheless, many aspects other than neuroinflammation are regulated by bioactive sphingoids in healthy brain and dysregulated in brain disease. In this review, we are addressing the multifaceted possibility to address the metabolism and biology of bioactive sphingosine 1-phosphate as novel targets for the development of therapeutic paradigms and the discovery of new drugs.
Patients who had received a drug-eluting stent and then dual antiplatelet therapy for 12 months were randomly assigned to 18 more months of therapy or aspirin alone. Continued therapy resulted in ...lower rates of stent thrombosis and major adverse cardiovascular events but more bleeding.
Millions of patients worldwide undergo coronary stenting each year for the treatment of ischemic heart disease.
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Although drug-eluting stents reduce the rate of restenosis as compared with bare-metal stents, there is concern that drug-eluting stents may be associated with a risk of stent thrombosis beyond 1 year after treatment.
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Stent thrombosis is rare, yet it is frequently associated with myocardial infarction and may be fatal.
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Furthermore, ischemic events, such as myocardial infarction, stroke, or death from cardiovascular causes, that are unrelated to the treated coronary lesion may also occur beyond 1 year.
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The use of dual antiplatelet therapy . . .
This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug ...Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.
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