Search

ispartof: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE vol:207 issue:8 pages:E71-E72 ispartof: location:United States status: published

It is unclear whether the association between atrial fibrillation (AF) and intra-hospital mortality in patients aged 75 years and older is causal or not. This study aims (1) to describe the prevalence and clinical characteristics of AF in ≥75-year-old inpatients and (2) to study the association between AF and length of stay (LOS) and intra-hospital mortality. This retrospective cohort study includes consecutive patients aged ≥75 years admitted between January 2017 and December 2019 to a Belgian secondary hospital. Survival analysis was conducted on the whole dataset and a propensity score-matched dataset separately. Propensity score matching (PSM) was performed to account for the individual probability of having AF given a set of covariates. In 9,105 patients, 3,137 (34%) had a diagnosis of AF upon hospital admission. AF prevalence increased with age strata (from 29% to 38%), and Charlson Co-morbidity Index (from 28% to 57%). Intra-hospital mortality (20%) was higher in the AF group than in the AF-free group (25% vs 17%, p 10 days (odds ratio 1.08, confidence interval: 0.98 to 1.20, p = 0.13). The risk of intra-hospital death for patients with AF remained higher compared with those without AF (log-rank p = 0.0015 and hazard ratio 1.17; confidence interval: 1.04 to 1.32, p = 0.008). In conclusion, the prevalence of AF was high (34%) in inpatients aged ≥75 years and increased with age and co-morbidity burden. After PSM, patients with AF had a 17% higher risk of intra-hospital mortality than patients without AF.

Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties.

International audience

Acute and chronic physical exercises may enhance the development of statin-related myopathy. In this context, the recent (2019) guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for the management of dyslipidemias recommend that, although individuals with dyslipidemia should be advised to engage in regular moderate physical exercise (for at least 30 min daily), physicians should be alerted with regard to myopathy and creatine kinase (CK) elevation in statin-treated sport athletes. However it is worth emphasizing that abovementioned guidelines, previous and recent ESC/EAS consensus papers on adverse effects of statin therapy as well as other previous attempts on this issue, including the ones from the International Lipid Expert Panel (ILEP), give only general recommendations on how to manage patients requiring statin therapy on regular exercises. Therefore, these guidelines in the form of the Position Paper are the first such an attempt to summary existing, often scarce knowledge, and to present this important issue in the form of step-by-step practical recommendations. It is critically important as we might observe more and more individuals on regular exercises/athletes requiring statin therapy due to their cardiovascular risk.

The difficult road to harmonization of French succession law deals with the noticeable issue of legal pluralism in France before the Civil Code (1804). Moreover, the succession questions concern patrimonial aspects with policy implications. Two systems coexisted: intestate succession and will. The separation in two parts of the territory make the analysis difficult. Practice resulted in new forms and contradict Roman law and Canon law. Hence the King of France wanted the law of succession to be unified or to be standardized. But, unfortunately, this attempt failed. Kings continued to try to solve this problem. Especially, in the 18th century, a political desire tried to solve many problems raised by legal pluralism. As a matter of fact, too many forms of testament led to confusion and undermined justice. But a broad resistance of the main judicial courts scuppered this project. During the French Revolution, different laws triggered a real crisis. In effect, revolutionaries decided to combat against the paternal authority. At least, the removal of the testament standardized the law of succession. The French Civil Code did it with a synthesis of the best of both systems.

1.1. Cardiovascular disease and dyslipidemia: prevalence and global economic impact Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, reaching 31% of deaths in 2012 [1]. In particular, atherosclerosis and ischemic heart disease (IHD) are the main causes of premature death in Europe and are responsible for 42% of deaths in women and 38% in men under 75 years old [2]. The global economic impact of CVD is estimated to have been US $906 billion in 2015 and is expected to rise by 22% by 2030 [3]. Cardiovascular diseases also represent the major cause of disability in developed countries. It has been estimated that their growing burden could lead to a global increase in loss of disability-adjusted life years (DALYs), from a loss of 85 million DALYs in 1990 to a loss of ~150 million DALYs in 2020, becoming a major non-psychological cause of lost productivity [4]. Several risk factors contribute to the etiology and development of CVD; they are divided into those modifiable through lifestyle changes or by taking a pharmacologic treatment (e.g. for hypertension, smoking, diabetes mellitus, hypercholesterolemia) and those that are not modifiable (age, male gender, and family history) [5]. Elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) blood concentrations are the major modifiable risk factors for coronary heart disease (CHD), whereas high concentrations of plasma high-density lipoprotein cholesterol (HDL-C) in certain conditions are considered protective [6]. Moreover, LDL-C remains a fundamental CV risk factor (and a main target of therapy) even when statins are largely used in the general population [7]. An examination of the data of 18 053 participants aged ≥ 20 years who participated in the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2006 showed that the unadjusted prevalence of hypercholesterolemia ranged from 53.2% to 56.1% in United States adults [8]. Differences related to gender and race or ethnicity were observed; in particular, a lower rate of control was found among women than men and lower rates of having a cholesterol check and being told about hypercholesterolemia were reported by African Americans and Mexican Americans than whites [8]. A recent report from the American Heart Association confirmed that in the US only 75.7% of children and 46.6% of adults present targeted TC levels (TC < 170 mg/dl for children and < 200 mg/dl for adults, in untreated individuals) [9]. The pattern is similar in other Western countries [10, 11].

Acute coronary syndrome patients receive DAPT up to one year after their initial event. Exceptions to the guideline-recommended one-year rule, however, are not uncommon. The reasoning behind shorter treatments, such as unacceptable bleeding risk or urgent surgery, should be well documented in the patient's charts and discharge letter. Based on recent evidence, patients at high risk for repetitive events should continue on low-dose ticagrelor without a significant interruption at one year and indefinitely in the absence of excess bleeding risk. As there is currently no reimbursement, policy makers and insurers should be made aware of the continuing risk and unmet clinical need in this patient population. Nevertheless, many unsolved questions need to be answered, both through additional analyses from recent trials such as PEGASUS-TIMI 54 or DAPT, as well as new carefully designed clinical studies.

Alzheimer's disease (AD) is characterized by neuronal and synaptic loss. One process that could contribute to this loss is the intracellular caspase cleavage of the amyloid precursor protein (APP) resulting in release of the toxic C-terminal 31-amino acid peptide APP-C31 along with the production of APPΔC31, full-length APP minus the C-terminal 31 amino acids. We previously found that a mutation in APP that prevents this caspase cleavage ameliorated synaptic loss and cognitive impairment in a murine AD model. Thus, inhibition of this cleavage is a reasonable target for new therapeutic development. In order to identify small molecules that inhibit the generation of APP-C31, we first used an APPΔC31 cleavage site-specific antibody to develop an AlphaLISA to screen several chemical compound libraries for the level of N-terminal fragment production. This antibody was also used to develop an ELISA for validation studies. In both high throughput screening (HTS) and validation testing, the ability of compounds to inhibit simvastatin- (HTS) or cerivastatin- (validation studies) induced caspase cleavage at the APP-D720 cleavage site was determined in Chinese hamster ovary (CHO) cells stably transfected with wildtype (wt) human APP (CHO-7W). Several compounds, as well as control pan-caspase inhibitor Q-VD-OPh, inhibited APPΔC31 production (measured fragment) and rescued cell death in a dose-dependent manner. The effective compounds fell into several classes including SERCA inhibitors, inhibitors of Wnt signaling, and calcium channel antagonists. Further studies are underway to evaluate the efficacy of lead compounds - identified here using cells and tissues expressing wt human APP - in mouse models of AD expressing mutated human APP, as well as to identify additional compounds and determine the mechanisms by which they exert their effects.

In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipid-lowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting.

Familial hypercholesterolemia (FH) is underdiagnosed and undertreated in most countries. We report our first experience from a national pilot project of cascade screening with the help of two field nurses amongst the relatives of FH index patients, recruited in two extended regions of the country by

The canonical pathogenesis of Alzheimer's disease links the expression of apolipoprotein E ε4 allele (ApoE) to amyloid precursor protein (APP) processing and Aβ peptide accumulation by a set of mechanisms that is incompletely defined. The development of a simple system that focuses not on a single variable but on multiple factors and pathways would be valuable both for dissecting the underlying mechanisms and for identifying candidate therapeutics. Here we show that, although both ApoE3 and ApoE4 associate with APP with nanomolar affinities, only ApoE4 significantly (i) reduces the ratio of soluble amyloid precursor protein alpha (sAPPα) to Aβ; (ii) reduces Sirtuin T1 (SirT1) expression, resulting in markedly differing ratios of neuroprotective SirT1 to neurotoxic SirT2; (iii) triggers Tau phosphorylation and APP phosphorylation; and (iv) induces programmed cell death. We describe a subset of drug candidates that interferes with the APP-ApoE interaction and returns the parameters noted above to normal. Our data support the hypothesis that neuronal connectivity, as reflected in the ratios of critical mediators such as sAPPα:Aβ, SirT1:SirT2, APP:phosphorylated (p)-APP, and Tau:p-Tau, is programmatically altered by ApoE4 and offer a simple system for the identification of program mediators and therapeutic candidates.

A systematic approach was used to identify AβPP-selective BACE inhibitors (ASBI) and to evaluate their in vivo ability to modulate AβPP processing selectively. We identified a bioflavonoid nutritional supplement as a molecular lead that acts as an ASBI in cell models, and show that increasing brain levels of this bioflavonoid through a pro-drug approach leads to reduction of Aβ42 in an Alzheimer's disease mouse model. ASBIs represent a novel class of candidate therapeutic agents for Alzheimer's disease.

Resumen Introduccion El estudio RECIPE se diseno para evaluar el impacto de la suplementacion de la dieta con leche fermentada enriquecida con esteroles vegetales (LFEV) sobre la conducta nutricional, el estilo de vida y la corresponsabilizacion terapeutica de los pacientes hipercolesterolemicos. Metodos Estudio observacional prospectivo, multicentrico, internacional, en el que se evaluan los habitos dieteticos y otros componentes del estilo de vida en pacientes hipercolesterolemicos en los que el medico de familia indica suplementacion con LFEV. Se recogieron datos nutricionales, estilo de vida y clinicos en la visita inicial y en una segunda visita realizada a los 4 meses. Los datos analiticos y antropometricos se recogieron de la historia clinica obtenidos al inicio y a los 4 meses. Resultados Se comunican los resultados de Espana. Participaron 201 medicos que aportaron datos validos de 1.044 pacientes. La adicion de LFEV se asocio con una mejora del indice nutricional global, siendo adecuada al principio en el 28,2%, y al final en el 75,2% de los pacientes (p Conclusiones La adicion de LFEV a una dieta destinada a reducir las cifras de LDL potencia la actitud del paciente en cuanto a los cambios en el estilo de vida, lo que conduce a un mejor control global de la dislipidemia y a la mejoria antropometrica.

There is currently of a great interest investigating the role of nutrition in the prevention of age-associated disorders. The present study aimed to evaluate, on a particular strain of mice, the efficacy of alternate-day fasting on the mitochondrial production of free radical species and on the incidence of a specific cancer (lymphoma) in aged mice. Alternate fasting, that was initiated in middle age mice through a 4 month period, reduced significantly the incidence of lymphoma (0% versus 33% for controls). No remarkable difference was observed in the overall food consumption between alternate-fed (AF) and ad libitum (AL) mice, suggesting that the efficacy of alternate fasting did not really depend on calorie restriction. A significant decrease in the mitochondrial generation of reactive oxygen species (ROS) that was associated with a significant increase in spleen mitochondria SOD activity was observed when mice were maintained on intermittent fasting. Our results suggest that alternate fasting could exert a beneficial antioxidant effect and a modulation of the oxidative stress associated with aging.

An unbiased screen for compounds that block amyloid-β protein precursor (AβPP) caspase cleavage identified ADDN-1351, which reduced AβPP-C31 by 90%. Target identification studies showed that ADDN-1351 is a TrkA inhibitor, and, in complementary studies, TrkA overexpression increased AβPP-C31 and cell death. TrkA was shown to interact with AβPP and suppress AβPP-mediated transcriptional activation. Moreover, treatment of PDAPP transgenic mice with the known TrkA inhibitor GW441756 increased sAβPPα and the sAβPPα to Aβ ratio. These results suggest TrkA inhibition-rather than NGF activation-as a novel therapeutic approach, and raise the possibility that such an approach may counteract the hyperactive signaling resulting from the accumulation of active NGF-TrkA complexes due to reduced retrograde transport. The results also suggest that one component of an optimal therapy for Alzheimer's disease may be a TrkA inhibitor.

Tropisetron was identified in a screen for candidates that increase the ratio of the trophic, neurite-extending peptide sAPPα to the anti-trophic, neurite-retractive peptide Aβ, thus reversing this imbalance in Alzheimer's disease (AD). We describe here a hierarchical screening approach to identify such drug candidates, moving from cell lines to primary mouse hippocampal neuronal cultures to in vivo studies. By screening a clinical compound library in the primary assay using CHO-7W cells stably transfected with human APPwt, we identified tropisetron as a candidate that consistently increased sAPPα. Secondary assay testing in neuronal cultures from J20 (PDAPP, huAPP(Swe/Ind)) mice showed that tropisetron consistently increased the sAPPα/Aβ 1-42 ratio. In in vivo studies in J20 mice, tropisetron improved the sAPPα/Aβ ratio along with spatial and working memory in mice, and was effective both during the symptomatic, pre-plaque phase (5-6 months) and in the late plaque phase (14 months). This ameliorative effect occurred at a dose of 0.5mg/kg/d (mkd), translating to a human-equivalent dose of 5mg/day, the current dose for treatment of postoperative nausea and vomiting (PONV). Although tropisetron is a 5-HT3 receptor antagonist and an α7nAChR partial agonist, we found that it also binds to the ectodomain of APP. Direct comparison of tropisetron to the current AD therapeutics memantine (Namenda) and donepezil (Aricept), using similar doses for each, revealed that tropisetron induced greater improvements in memory and the sAPPα/Aβ1-42 ratio. The improvements observed with tropisetron in the J20 AD mouse model, and its known safety profile, suggest that it may be suitable for transition to human trials as a candidate therapeutic for mild cognitive impairment (MCI) and AD, and therefore it has been approved for testing in clinical trials beginning in 2014.

Statins are drugs commonly used to inhibit cholesterol synthesis, with the goal of reducing vascular diseases such as myocardial infarction and stroke. Statins have also been suggested as a therapeutic option for Alzheimer's disease (AD), although their benefit in AD remains controversial. We have previously shown that the intracellular C-terminal cleavage of the amyloid-β protein precursor (AβPP) is a major contributor to the neuronal toxicity seen in AD, and that this cleavage can be induced by amyloid-β. We now report that certain brain permeable statins are also able to induce the C-terminal cleavage of AβPP and associated cell death, whereas other statins do not. This statin effect on AβPP exceeded the effects of all other FDA-approved drugs in a library composed of these compounds, suggesting that this effect on AβPP cleavage is unique to a subset of the statins. Furthermore, the greatest effect occurred with cerivastatin, which has previously been shown to be the statin associated with the greatest risk of rhabdomyolysis. These results may have implications for the choice of which statins to evaluate in AD therapeutic trials; furthermore, the results may inform statin choice in individuals who are at high risk for the development of AD, such as those with an apolipoprotein E e4 allele.

Turkey ham-like products were manufactured with turkey thigh meat and 60% (wt/wt) added brine containing cure ingredients and various combinations of carrageenan, locust bean gum, starch, nonfat dry milk (NFDM), and KCl. The brine was incorporated into the meat by vacuum tumbling (30 min on and 60 min off) for 18 h. After stuffing, cooking to 72 C, and cooling to 10 C, the brine-added products were evaluated for cooked yield, visual appearance, sliceability, bind, freeze and thaw purge, sensory properties, and composition. Incorporation of .5% κ-carrageenan (total weight basis) into the cured turkey thigh meat products significantly (P

Oven-roasted turkey breasts were manufactured with 70% added brine to increase yield. The brine contained salt, phosphate, and various combinations of κ-carrageenan, starch, and nonfat dry milk and was incorporated into the breasts by injecting and vacuum tumbling. After stuffing into casings, the breasts were cooked at 72°C, and then cooled to 4°C. Incorporation of 0.5%κ-carrageenan increased yield, improved visual appearance, sliceability, and rigidity and decreased expressible juice compared with the control product. Addition of 1% starch increased yield, but did not increase rigidity. The brine-added products were rated acceptable by a sensory panel.

The gelling mechanism in oven-roasted turkey breast juice and the effects of k-carrageenan and certain salts were evaluated. In the presence of 2.2% salt and 0.5% phosphate, the soluble protein started to gel at 52°C, and k-carrageenan started to swell at 46°C during heating and gel at 44°C during cooling. When sodium chloride content was changed to 0% or 4.4% and phosphate content to 0% or 1.2%, k-carrageenan started to swell at 28°C and gel at 36°C, or swell at 67°C and gel at 55°C, respectively. The protein and k-carrageenan combination showed a significant (P