Management of Dyslipidaemia in Real-world Clinical Practice: Rationale and Design of the VIPFARMA ISCP Project.

Dyslipidaemia plays a major role in the pathogenesis of atherosclerosis. Every year, scientific institutions publish cardiovascular prevention guidelines with updated goals and recommendations based on new evidence. However, medical barriers exist that make achieving these goals difficult and gaps between guidelines and best daily clinical practice still persist. The International Society of Cardiovascular Pharmacotherapy designed the Surveillance of Prescription Drugs in the Real World Project (VIPFARMA ISCP), a survey for physicians who manage lipid disorders in high-risk patients. Seven clusters of questions will be analysed comprising demographics, institution profile, access to continuing medical education, clinical practice profile, attitude regarding use of statins, knowledge regarding proprotein convertase subtilisin/kexin type 9 inhibitors and attitudes regarding medical decisions about triglycerides. The present study will be the first part of a larger programme and aims to shed light on barriers between lipid-lowering drug therapy recommendations in the 2019 European Society of Cardiology guidelines and clinical practice in different countries

Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein

Background: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.Methods: We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.Results: the trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. the rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. the rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.Conclusions: in this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.).AstraZenecaNovartisMerckAbbottRocheSanofi-AventisMerck-Schering-PloughIsisDade BehringVascular BiogenicsPfizerMerck FrosstResverlogixDupontAegerionArisaphKowaGenentechMartekReliantGenzymeGlaxoSmithKlineBoehringer IngelheimDiaDexusMedlogixAntheraBristol-Myers SquibbVIA PharmaceuticalsInterleukin GeneticsKowa Research InstituteTakedaBG MedicineOxford BiosciencesHarvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Boston, MA 02215 USAHarvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02215 USAUniversidade Federal de São Paulo, São Paulo, BrazilMcGill Univ, Ctr Hlth, Montreal, PQ, CanadaCornell Univ, Weill Cornell Med Coll, New York, NY 10021 USAUniv Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, NetherlandsUniv Ulm, Med Ctr, Ulm, GermanyHosp Cordoba, Cordoba, ArgentinaCopenhagen Univ Hosp, Herlev Hosp, Herlev, DenmarkUniv Glasgow, Glasgow, Lanark, ScotlandSt Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX 77030 USAUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Analysis and implementation of fractional-order chaotic system with standard components

This paper is devoted to the problem of uncertainty in fractional-order Chaotic systems implemented by means of standard electronic components. The fractional order element (FOE) is typically substituted by one complex impedance network containing a huge number of discrete resistors and capacitors. In order to balance the complexity and accuracy of the circuit, a sparse optimization based parameter selection method is proposed. The random error and the uncertainty of system implementation are analyzed through numerical simulations. The effectiveness of the method is verified by numerical and circuit simulations, tested experimentally with electronic circuit implementations. The simulations and experiments show that the proposed method reduces the order of circuit systems and finds a minimum number for the combination of commercially available standard components.This work was supported in part by the National Natural Science Foundation of China under Grant 61501385, in part by the National Nuclear Energy Development Project of State Administration for Science, Technology and Industry for National Defense, PRC under Grant 18zg6103, and in part by Sichuan Science and Technology Program under Grant 2018JY0522. We would like to thank Xinghua Feng for meaningful discussion.info:eu-repo/semantics/publishedVersio

On the Change of Substances of Strawberry Fruit

1. 水田裏作として栽培されたオランダイチゴ, ダナー種の完熟果実を室温中に貯蔵し, その含有成分の変化の過程を調査した。収穫当日に含まれていた80%エタノール可溶性N化合物, 糖類の含有量は次第に減少したが, 有機酸の量は殆んど変化がなかった。しかし, 収穫後の水分含有率の低下は収穫後の日数と共に著しく。従って各成分の濃度(含有率)は相対的に高くなり, その結果N化合物の含有率の低下は比較的緩慢となり, 糖類の含有率は殆んど変化なく, 有機酸は上昇した。糖の種類は, グルコース, フラクトース, キシロース及び蔗糖であるが, 収穫後次第にグルコース及び蔗糖が減少し, キシロースがやゝ増加した。有機酸は大部分がクエン酸で, リンゴ酸, コハク酸及び痕跡の酒石酸が認められたが, 減少したのはリンゴ酸のみであった。2. 排水良き砂壌土の圃場に於て, 栽培された4品種のオランダイチゴ(紅露・幸玉, アメリカ・ダナー)の果実について収穫後に於ける諸成分の含有率の変化を比較した。N化合物・糖類・有機酸についてみると, その含有率自体は品種の特性を示し, 夫々非常に異なっているが, 含有率の貯蔵中の変化は互に平行的に推移し同様の傾向を示した。この実験の果実成分のペーパークロマトグラフィーの結果は, 水田裏作のダナー種に比べて, 糖類の内, フラクトースが特に多く, 蔗糖が少かった。品種間差異は特にグルコースに認められた。有機酸では, 酒石酸がかなり多く, 紅露及び幸玉ではα-ケトグルタル酸を認めた。品種間の差異は, 大部分をクエン酸に, 次いで酒石酸によって影響された。 / 1. The studies were conducted to obtain the fundamental information on the change of the substances in the postharvest strawberry fruit, which was cultivated for the second crop on the rice field (heavy clay soil). The amounts of soluble total-N (in 80% ethanol), amino-N, total sugar and reducing sugar were decreased in the postharvest period. But the organic acid was constant. In the postharvest period, the water content of the strawberry fruit was decreased extremely. Therefore the percentage of the N-compounds and the sugars were not so low, and the organic acid became high percentage after the harvested. On the paperchromatography in the extracts of the strawberry fruit, glucose, fractose, xylose and sucrose were found. And the xylose was increased and the glucose and sucrose were decreased after the harvested. The most of organic acid was citric acid and there were also found succinic acid, malic acid and trace of tartaric acid. The malic acid was decreased after the harvested. 2. The differences of the contents in the fruit were studied among four varieties of the strawberry (Koro, Kogyoku, America and Danner) cultivated on the field of sandy loam soil. Each % of the substances in the fruit was very different among the four varieties, but the processes of the changing had parallel tendency during the postharvest period. The results of paperchromatographic study were compared with them of strawberry fruit cultivated on the rice field. Consequently, more fractose was recognized and the sucrose was slightly. There were much tartaric acid and the trace of α-keto gulutaric acid

Interleukin 13 (IL-13)-regulated expression of the chondroprotective metalloproteinase ADAM15 is reduced in aging cartilage

Objective: The adamalysin metalloproteinase 15 (ADAM15) has been shown to protect against development of osteoarthritis in mice. Here, we have investigated factors that control ADAM15 levels in cartilage. Design: Secretomes from wild-type and Adam15-/- chondrocytes were compared by label-free quantitative mass spectrometry. mRNA was isolated from murine knee joints, either with or without surgical induction of osteoarthritis on male C57BL/6 mice, and the expression of Adam15 and other related genes quantified by RT-qPCR. ADAM15 in human normal and osteoarthritic cartilage was investigated similarly and by fluorescent immunohistochemistry. Cultured HTB94 chondrosarcoma cells were treated with various anabolic and catabolic stimuli, and ADAM15 mRNA and protein levels evaluated. Results: There were no significant differences in the secretomes of chondrocytes from WT and Adam15-/- cartilage. Expression of ADAM15 was not altered in either human or murine osteoarthritic cartilage relative to disease-free controls. However, expression of ADAM15 was markedly reduced upon aging in both species, to the extent that expression in joints of 18-month-old mice was 45-fold lower than in that 4.5-month-old animals. IL-13 increased expression of ADAM15 in HTB94 cells by 2.5-fold, while modulators of senescence and autophagy pathways had no effect. Expression of Il13 in the joint was reduced with aging, suggesting this cytokine may control ADAM15 levels in the joint. Conclusion: Expression of the chondroprotective metalloproteinase ADAM15 is reduced in aging human and murine joints, possibly due to a concomitant reduction in IL-13 expression. We thus propose IL-13 as a novel factor contributing to increased osteoarthritis risk upon aging

Antiinflammatory therapy with canakinumab for atherosclerotic disease

BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering

New alternative splicing BCR/ABL-OOF shows an oncogenic role by lack of inhibition of BCR GTPase activity and an increased of persistence of Rac activation in chronic myeloid leukemia

In Chronic Myeloid Leukemia 80% of patients present alternative splice variants involving BCR exons 1, 13 or 14 and ABL exon 4, with a consequent impairment in the reading frame of the ABL gene. Therefore BCR/ABL fusion proteins (BCR/ABL-OOF) are characterized by an in-frame BCR portion followed by an amino acids sequence arising from the out of frame (OOF) reading of the ABL gene. The product of this new transcript contains the characteristic BCR domains while lacking the COOH-terminal Rho GTPase GAP domain. The present work aims to characterize the protein functionality in terms of cytoskeleton (re-)modelling, adhesion and activation of canonical oncogenic signalling pathways. Here, we show that BCR/ABL-OOF has a peculiar endosomal localization which affects EGF receptor activation and turnover. Moreover, we demonstrate that BCR/ABL-OOF expression leads to aberrant cellular adhesion due to the activation of Rac GTPase, increase in cellular proliferation, migration and survival. When overexpressed in a BCR/ABL positive cell line, BCR/ABL-OOF induces hyperactivation of Rac signaling axis offering a therapeutic window for Rac-targeted therapy. Our data support a critical role of BCR/ABL-OOF in leukemogenesis and identify a subset of patients that may benefit from Rac-targeted therapies

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .)

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.