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.

Expression of Adolescent Violence Towards Parents and It Association with Sense of Parents' Competence and Parenting Styles

Bakalaura darba pētījuma mērķis bija noskaidrot, vai pastāv statistiski nozīmīgas sakarības starp vecāku uztvertās pusaudža vardarbības izpausmēm pret vecākiem saistību ar vecāku kompetences izjūtu un vecāku audzināšanas pieejām, kā arī, vai pastāv atšķirības saistībās starp māšu un tēvu vērtējumiem par vecāku uztvertās pusaudžu vardabības izpausmēm pret vecākiem. Pētījumā piedalījās 150 pusaudžu vecāki, 100 mātes un 50 tēvi, kuru bērni ir vecumā no 12 – 15 gadiem. Pētījumā izmantotās metodes: Alabamas audzināšanas aptauja (The Alabama Parenting Questionnaire (APQ), Frick, Shelton, & Wooton, 1996), kuras adaptāciju latviešu valodā 2006. gadā veikusi L. Kalniņa sava maģistra darba ietvaros (Kalniņa, 2006); Vecāku kompetences izjūtas skala (Parenting Sense of Competence Scale, (PSOC), Johnston & Mash, 1989), kuru latviešu valodā adaptējušas Inga Skreitule-Pikše un Sandra Sebre 2008. gadā (Skreitule-Pikše&Sebre, 2008), Aptauja “Bērnu vardarbība pret vecākiem”, versija vecākiem (Child-to-Parent Violence Questionnaire (CPV-Q-P) Parents’ Version, Contreras, León, & Cano-Lozano, 2020), bakalaura darba ietvaros aptaujas tulkojumu latviešu valodā veikusi šī darba autore Iveta Petrova (Petrova, 2022). Pētījumā iegūtie rezultāti uzrādīja, ka pastāv statistiski nozīmīgas negatīvas sakarības starp vecāku kompetences izjūtu un vecāku uztvertās pusaudža vardarbības vairākām izpausmēm uzvedībā gan pret tēviem, gan pret mātēm. Statistiski nozīmīgas sakarības pastāv starp vecāku audzināšanas pieejām pretrunīga disciplinēšana un fiziska sodīšana gan tēviem, gan mātēm ar uztvertās pusaudža vardarbības vairākām izpausmēm uzvedībā. Mātēm pastāv statistiski nozīmīgas negatīvas sakarības starp pozitīvas audzināšanas un iesaistīšanās ar uztverto no pusaudža vērsto instrumentālu agresiju. Tēviem pastāv statistiski nozīmīgas sakarības starp sliktu uzraudzību un uztverto no pusaudža fizisko vardarbību. Mainīgo lielumu saistībās atklājas statistiski nozīmīgas saistību atšķirības starp māšu un tēvu vērtējumiem par vecāku uztvertās pusaudžu vardabības izpausmēm pret vecākiem, mātēm ir ciešāka saistība starp savu vērtējumu par pusaudža vērsto reaktīvo agresiju un izjusto neapmierinātību pildot mātes pienākumus, nekā tēviem.The objective of the study was to find out whether there are statistically significant relationships between the manifestations of adolescent violence perceived by parents, the relationship with the sense of parental competence and parenting approaches, as well as whether there are differences in the relationship between mothers' and fathers' assessments of the manifestations of adolescent violence perceived by parents. The study involved 150 adolescents’ parents, 100 mothers and 50 fathers, of adolescents aged 12 to 15 years old. The methods used in the research: The Alabama Parenting Questionnaire (APQ), (Frick, Shelton, & Wooton, 1996), adapted in Latvian by L. Kalniņa in 2006 as part of her master's thesis (Kalniņa, 2006); Parental competences the Parenting Sense of Competence Scale (PSOC), (Johnston & Mash, 1989), adapted in Latvian by Inga Skreitule-Pikše and Sandra Sebre in 2008 (Skreitule-Pikše & Sebre, 2008), Child-to-Parent Violence Questionnaire (CPV-Q-P) Parents' Version (Contreras, León, & Cano-Lozano, 2020), the translation of the questionnaire into Latvian was made by the author of this work, Iveta Petrova (Petrova, 2022), as part of her bachelor thesis. The results obtained in the study show that there are statistically significant negative relationships between parents' sense of competence and several manifestations of adolescent violence perceived by parents in behavior towards both fathers and mothers. The presence of a statistically significant relationship between the parenting approaches of adversarial disciplining and physical punishment for both fathers and mothers with multiple behavioral manifestations of perceived adolescent violence were observed. The assessment of the mothers shows statistically significant negative associations between positive parenting and involvement with perceived adolescent-directed instrumental aggression. For the fathers, the statistically significant associations between poor supervision and perceived adolescent physical abuse were observed. The statistically significant relationship differences between mothers' and fathers' assessments of the manifestations of adolescent violence towards parents, perceived by parents, are revealed in relation to the variables; mothers have a closer relationship between their assessment of the adolescent's reactive aggression and the felt dissatisfaction in fulfilling their mother's duties than fathers

PCSK9 inhibitors: an overview on a new promising lipid-lowering therapy

Atherosclerosis is characterized by cholesterol deposition in the arterial intima, with subsequent plaque formation and arterial disease. Low-density lipoprotein cholesterol (LDL-C) plays the most important role in the atherogenesis process, which is the substrate of cardiovascular disease and is the leading cause of death worldwide. Several studies show that a strict control of risk factors, particularly the reduction of LDL-C levels, is a cornerstone in primary and secondary prevention of coronary heart disease. Statins are currently the most effective drugs for lowering LDL-C, but the discovery of proprotein convertase subtilisin kexin 9 (PCSK9) has opened up new therapeutic options in lipid management. PCSK9 reduces LDL-receptors' recycling resulting in a decrease of LDL-C receptors on the surface of hepatocytes and an increase of LDL-C levels in plasma. Obviously, inhibition of PCSK9 has been associated with an increase of LDL-C receptors with subsequent lowering of plasma levels of LDL-C. The clinical development of monoclonal antibodies against PCSK9 has been achieved through phase I and II studies, and nowadays there are many ongoing phase III trials with promising preliminary results. The aim of this review is to update the evidence for PCSK9 monoclonal antibodies, such as evolocumab, alirocumab and bococizumab, in LDL-C management and to discuss their therapeutic perspectives based on the most recent clinical studies, with attention to side-effects

Inhibitors of PCSK9

Observational data show a consistent association between elevated low density lipoproteins (LDL-C) and cardiovascular disease (CVD). Reduction of LDL-C reduces the risk of CVD as has been shown by many trials. Statins are currently the most effective drugs for lowering LDL-C, but can present side effects which might limit the prescribed dosage and prevent patients from reaching the recommended LDL levels. Although treated with statins important residual cardiovascular event risk remains in patients in primary and secondary prevention for CVD. The discovery of protein convertase subtilisin kexin 9 antibodies is a very promising new hypolipidemic treatment and the aim of this review is to explain their mechanism of action and to discuss safety and efficacy results of some phase III studies

Drosophila Ror is a nervous system-specific co-receptor for Wnt ligands

Wnt ligands are secreted glycoproteins that control many developmental processes and are crucial for homeostasis of numerous tissues in the adult organism. Signal transduction of Wnts involves the binding of Wnts to receptor complexes at the surface of target cells. These receptor complexes are commonly formed between a member of the Frizzled family of seven-pass transmembrane proteins and a co-receptor, which is usually a single-pass transmembrane protein. Among these co-receptors are several with structural homology to receptor tyrosine kinases, including Ror, PTK7, Ryk and MUSK. In vertebrates, Ror-2 and PTK7 are important regulators of planar cell polarity (PCP). By contrast, PCP phenotypes were not reported for mutations in off-track (otk) and off-track2 (otk2), encoding the Drosophila orthologs of PTK7. Here we show that Drosophila Ror is expressed in the nervous system and localizes to the plasma membrane of perikarya and neurites. A null allele of Ror is homozygous viable and fertile, does not display PCP phenotypes and interacts genetically with mutations in otk and otk2. We show that Ror binds specifically to Wingless (Wg), Wnt4 and Wnt5 and also to Frizzled2 (Fz2) and Otk. Our findings establish Drosophila Ror as a Wnt co-receptor expressed in the nervous system

Синтез и цитотоксическая активность производных трет-бутилового эфира 7Z-ацетилметилен-3-метил-3-цефем-4-карбоновой кислоты

Конденсацией ацетилметиленовой группы в трет-бутиловом эфире 7Z-аце- тилметилен-3-метил-3-цефем-4-карбоновой и 7Z-ацетилметилен-3-метил-1,1-ди- оксо-3-цефем-4-карбоновой кислот и в 7Z-ацетилметилен-3-метил-1,1-диоксо- 3-цефеме с арилметоксиаминами и О-алкилированием трет-бутилового эфира 7Z-(2-гидроксимино)пропилиден-3-метил-1,1-диоксо-3-цефем-4-карбоновой киc- лоты замещенными бензилбромидами, а также пиридилметилхлоридами синте- зированы арилметоксимино- и пиридилметоксиминопроизводные этих соединений в син- и анти-изомерной форме. С помощью реагента Вильсмайера введена N,N-диметиламинометиленовая группа в положение 2 цефемового ядра трет-бутиловых эфиров 7Z-[2-(арил- метоксимино)пропилиден]-3-метил-1,1-диоксо-3-цефем-4-карбоновой кислоты. После- дующая трансформация N,N-диметиламинометилензамещенных цефемов гид- роксиламином привела к получению 3Z-[2-(анти-арилметоксимино)пропилиден]-трет-бутоксикарбонилметил-4-(5-метил-4-изоксазолилсульфонил)азетидин-2-онов. Конденсацией ацетильной группы в трет-бутиловом эфире 7Z-ацетил- метилен-3-метил-1,1-диоксо-3-цефем-4-карбоновой кислоты с 4-бромфенил- гидразином синтезирован цефем с 2-(4-бромфенилгидразоно)пропилиденовой группой в положении 7. Ацилированием трет-бутилового эфира 7Z-(2-гидрокс- имино)пропилиден-3-метил-1,1-диоксо-3-цефем-4-карбоновой киcлоты хлорангид- ридом 2-бромбензойной кислоты синтезирован цефем с 2-(2-бромбензоилокс- имино)пропилиденовой группой в положении 7. Биологический скрининг синтезированных соединений в отношении раковых и нормальных клеток in vitro показал, что их противораковая активность и цито- токсическая селективность в отношении раковых и нормальных клеток зависят от строения и конфигурации арилметоксимино- и пиридилметоксиминогруппы в составе 7-алкилиденового заместителя, а также от наличия или отсутствия N,N-диметиламинометиленовой и карбоксильной групп, соответственно, в положениях 2 и 4 цефемового ядра

3D TEE during catheter-based interventions

Guidance of catheter-based procedures is performed using fluoroscopy and 2-dimensional transesophageal echocardiography (TEE). Both of these imaging modalities have significant limitations. Because of its 3-dimensional (3D) nature, 3D TEE allows visualizing the entire scenario in which catheter-based procedures take place (including long segments of catheters, tips, and the devices) in a single 3D view. Despite these undeniable advantages, 3D TEE has not yet gained wide acceptance among most interventional cardiologists and echocardiographists. One reason for this reluctance is probably the absence of standardized approaches for obtaining 3D perspectives that provide the most comprehensive information for any single step of any specific procedure. Therefore, the purpose of this review is to describe what we believe to be the most useful 3D perspectives in the following catheter-based percutaneous interventions: transseptal puncture; patent foramen ovale/atrial septal defect closure; left atrial appendage occlusion; mitral valve repair; and closure of paravalvular leaks

Синтез и противораковые свойства сложных эфиров 3-метил-1,1-диоксо-7α-хлорцеф-3-ем-4-карбоновой кислоты

Синтезированы трет-бутиловые эфиры 3-азидометил-, 3-изотиоцианатометил-, 3-хлор- метил- и 3-пара-нитрофенилвинил-1,1-диоксо-7α-хлорцеф-3-ем-4-карбоновой кислоты, а также сложные эфиры 3-метил-1,1-диоксо-7α-хлорцеф-3-ем-4-карбоновой кислоты и 2-ди-метиламинометилен-3-метил-1,1-диоксо-7α-хлорцеф-3-ем-4-карбоновой кислоты. Обобщены и проанализированы результаты цитотоксического скрининга этих соединений в отно- шении раковых и нормальных клеток in vitro

The amyloid precursor protein is a conserved Wnt receptor

International audienceThe Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full-length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine-Rich Domain (CRD) in the extracellular portion of APP is required for Wnt binding, and deletion of the CRD abrogates the effects of Wnts on flAPP levels and trafficking. Finally, loss of APP results in increased axonal and reduced dendritic growth of mouse embryonic primary cortical neurons. This phenotype can be cell-autonomously rescued by full length, but not CRD-deleted, APP and regulated by Wnt ligands in a CRD-dependent manner