Результати клініко-економічного аналізу споживання лікарських препаратів хворими на гострий лімфоїдний та мієлоїдний лейкоз в Україні

The article presents an analysis of the consumption of drugs by patients with acute leukemia in specialized health institutions of Ukraine. A patient with acute lymphocytic leukemia by doctors was made almost twice as prescribing drugs than patients with acute myeloid leukemia. It was found that the structure of consumption of drugs dominated those names, which are necessary for pathogenetic treatment of acute leukemia. Thus, anticancer drugs are one of three leaders as the frequency of medical prescriptions and on the amount of consumption of drugs. More than half of the resources were spent on the consumption of drugs, which are essential to meet the requirements of the legal framework, which regulates the organization of medical and pharmaceutical process providing patients with hematological malignancies. Given the fact that the vast majority of patients belonged to socially vulnerable groups of the population, the introduction of effective mechanisms to compensate for the cost of the high-value of anticancer drugs is presented as the main direction of enhancing the efficiency of pharmaceutical provision patients with hematological malignancies.В статье представлены результаты анализа потребления лекарственных препаратов больными острыми лейкозами в специализированных учреждениях здравоохранения Украины. Больным острым лимфоцитарным лейкозом было сделано практически в два раза больше врачебных назначений препаратов, чем больным острым миелоидным лейкозом. Установлено, что в структуре потребления препаратов доминировали те наименования, которые используються в патогенетическом лечении острых лейкозов. Так, противоопухолевые препараты входили в тройку-лидеров как по частоте врачебных назначений, так и по сумме потребления препаратов. Более половины ресурсов было затрачено на потребление препаратов, которые являются жизненно необходимыми в соответствии с требованиями нормативно-правовой базы, которая регулирует вопросы организации лечебного процесса и фармацевтического обеспечения онкогематологических больных. Учитывая тот факт, что подавляющее большинство больных относились к социально незащищенным группам населения, введение действенных механизмов компенсации стоимости высокостоимостных противоопухолевых препаратов представляется как основное направление повышения эффективности фармацевтического обеспечения онкогематологических больных.У статті представлені результати аналізу споживання лікарських препаратів хворими на гострі лейкози у спеціалізованих закладах охорони здоров’я України. Хворим на гострий лімфоїдний лейкоз було здійснено практично у два рази більше лікарських призначень препаратів, ніж  пацієнтами на гострий мієлоїдний лейкоз. Встановлено, що у структурі споживання препаратів домінували ті найменування, які використовуються у патогенетичному лікуванні гострих лейкозів. Так, протипухлинні препарати входили до трійки лідерів як за частотою лікарських призначень, так й за сумою споживання препаратів. Більше половини ресурсів було витрачено на споживання препаратів, що є життєво необхідними за вимогами нормативно-правої бази, яка регулює питання організації лікувального процесу та фармацевтичного забезпечення онкогематологічних хворих. Враховуючи той факт, що переважна кількість хворих належала до соціально вразливих груп населення, впровадження дієвих механізмів компенсації вартості споживання високовартісних препаратів протипухлинної дії виглядає як основний напрямок підвищення ефективності фармацевтичного забезпечення онкогематологічних хворих

Wnt Signaling Is Required for Early Development of Zebrafish Swimbladder

10.1371/journal.pone.0018431PLoS ONE63

Combining Computational Prediction of Cis-Regulatory Elements with a New Enhancer Assay to Efficiently Label Neuronal Structures in the Medaka Fish

The developing vertebrate nervous system contains a remarkable array of neural cells organized into complex, evolutionarily conserved structures. The labeling of living cells in these structures is key for the understanding of brain development and function, yet the generation of stable lines expressing reporter genes in specific spatio-temporal patterns remains a limiting step. In this study we present a fast and reliable pipeline to efficiently generate a set of stable lines expressing a reporter gene in multiple neuronal structures in the developing nervous system in medaka. The pipeline combines both the accurate computational genome-wide prediction of neuronal specific cis-regulatory modules (CRMs) and a newly developed experimental setup to rapidly obtain transgenic lines in a cost-effective and highly reproducible manner. 95% of the CRMs tested in our experimental setup show enhancer activity in various and numerous neuronal structures belonging to all major brain subdivisions. This pipeline represents a significant step towards the dissection of embryonic neuronal development in vertebrates

Alteration of gene expression by alcohol exposure at early neurulation

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated that alcohol exposure at early neurulation induces growth retardation, neural tube abnormalities, and alteration of DNA methylation. To explore the global gene expression changes which may underline these developmental defects, microarray analyses were performed in a whole embryo mouse culture model that allows control over alcohol and embryonic variables.</p> <p>Result</p> <p>Alcohol caused teratogenesis in brain, heart, forelimb, and optic vesicle; a subset of the embryos also showed cranial neural tube defects. In microarray analysis (accession number GSM9545), adopting hypothesis-driven Gene Set Enrichment Analysis (GSEA) informatics and intersection analysis of two independent experiments, we found that there was a collective reduction in expression of neural specification genes (neurogenin, <it>Sox5, Bhlhe22</it>), neural growth factor genes [<it>Igf1, Efemp1</it>, <it>Klf10 </it>(<it>Tieg), and Edil3</it>], and alteration of genes involved in cell growth, apoptosis, histone variants, eye and heart development. There was also a reduction of retinol binding protein 1 (<it>Rbp1</it>), and <it>de novo </it>expression of aldehyde dehydrogenase 1B1 (<it>Aldh1B1</it>). Remarkably, four key hematopoiesis genes (glycophorin A, adducin 2, beta-2 microglobulin, and ceruloplasmin) were absent after alcohol treatment, and histone variant genes were reduced. The down-regulation of the neurospecification and the neurotrophic genes were further confirmed by quantitative RT-PCR. Furthermore, the gene expression profile demonstrated distinct subgroups which corresponded with two distinct alcohol-related neural tube phenotypes: an open (ALC-NTO) and a closed neural tube (ALC-NTC). Further, the epidermal growth factor signaling pathway and histone variants were specifically altered in ALC-NTO, and a greater number of neurotrophic/growth factor genes were down-regulated in the ALC-NTO than in the ALC-NTC embryos.</p> <p>Conclusion</p> <p>This study revealed a set of genes vulnerable to alcohol exposure and genes that were associated with neural tube defects during early neurulation.</p

DEAD-Box Protein Ddx46 Is Required for the Development of the Digestive Organs and Brain in Zebrafish

Spatially and temporally controlled gene expression, including transcription, several mRNA processing steps, and the export of mature mRNA to the cytoplasm, is essential for developmental processes. It is well known that RNA helicases of the DExD/H-box protein family are involved in these gene expression processes, including transcription, pre-mRNA splicing, and rRNA biogenesis. Although one DExD/H-box protein, Prp5, a homologue of vertebrate Ddx46, has been shown to play important roles in pre-mRNA splicing in yeast, the in vivo function of Ddx46 remains to be fully elucidated in metazoans. In this study, we isolated zebrafish morendo (mor), a mutant that shows developmental defects in the digestive organs and brain, and found that it encodes Ddx46. The Ddx46 transcript is maternally supplied, and as development proceeds in zebrafish larvae, its ubiquitous expression gradually becomes restricted to those organs. The results of whole-mount in situ hybridization showed that the expression of various molecular markers in these organs is considerably reduced in the Ddx46 mutant. Furthermore, splicing status analysis with RT-PCR revealed unspliced forms of mRNAs in the digestive organ and brain tissues of the Ddx46 mutant, suggesting that Ddx46 may be required for pre-mRNA splicing during zebrafish development. Therefore, our results suggest a model in which zebrafish Ddx46 is required for the development of the digestive organs and brain, possibly through the control of pre-mRNA splicing

Receptor Heteromerization Expands the Repertoire of Cannabinoid Signaling in Rodent Neurons

A fundamental question in G protein coupled receptor biology is how a single ligand acting at a specific receptor is able to induce a range of signaling that results in a variety of physiological responses. We focused on Type 1 cannabinoid receptor (CB1R) as a model GPCR involved in a variety of processes spanning from analgesia and euphoria to neuronal development, survival and differentiation. We examined receptor dimerization as a possible mechanism underlying expanded signaling responses by a single ligand and focused on interactions between CB1R and delta opioid receptor (DOR). Using co-immunoprecipitation assays as well as analysis of changes in receptor subcellular localization upon co-expression, we show that CB1R and DOR form receptor heteromers. We find that heteromerization affects receptor signaling since the potency of the CB1R ligand to stimulate G-protein activity is increased in the absence of DOR, suggesting that the decrease in CB1R activity in the presence of DOR could, at least in part, be due to heteromerization. We also find that the decrease in activity is associated with enhanced PLC-dependent recruitment of arrestin3 to the CB1R-DOR complex, suggesting that interaction with DOR enhances arrestin-mediated CB1R desensitization. Additionally, presence of DOR facilitates signaling via a new CB1R-mediated anti-apoptotic pathway leading to enhanced neuronal survival. Taken together, these results support a role for CB1R-DOR heteromerization in diversification of endocannabinoid signaling and highlight the importance of heteromer-directed signal trafficking in enhancing the repertoire of GPCR signaling

Semi-Classical Theory of Magnetoresistance Anomalies in Ballistic Multi-Probe Conductors

Wetensch. publicatieFaculteit der Wiskunde en Natuurwetenschappe

Global burden of peripheral artery disease and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Peripheral artery disease is a growing public health problem. We aimed to estimate the global disease burden of peripheral artery disease, its risk factors, and temporospatial trends to inform policy and public measures. Methods: Data on peripheral artery disease were modelled using the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 database. Prevalence, disability-adjusted life years (DALYs), and mortality estimates of peripheral artery disease were extracted from GBD 2019. Total DALYs and age-standardised DALY rate of peripheral artery disease attributed to modifiable risk factors were also assessed. Findings: In 2019, the number of people aged 40 years and older with peripheral artery disease was 113 million (95% uncertainty interval [UI] 99·2–128·4), with a global prevalence of 1·52% (95% UI 1·33–1·72), of which 42·6% was in countries with low to middle Socio-demographic Index (SDI). The global prevalence of peripheral artery disease was higher in older people, (14·91% [12·41–17·87] in those aged 80–84 years), and was generally higher in females than in males. Globally, the total number of DALYs attributable to modifiable risk factors in 2019 accounted for 69·4% (64·2–74·3) of total peripheral artery disease DALYs. The prevalence of peripheral artery disease was highest in countries with high SDI and lowest in countries with low SDI, whereas DALY and mortality rates showed U-shaped curves, with the highest burden in the high and low SDI quintiles. Interpretation: The total number of people with peripheral artery disease has increased globally from 1990 to 2019. Despite the lower prevalence of peripheral artery disease in males and low-income countries, these groups showed similar DALY rates to females and higher-income countries, highlighting disproportionate burden in these groups. Modifiable risk factors were responsible for around 70% of the global peripheral artery disease burden. Public measures could mitigate the burden of peripheral artery disease by modifying risk factors. Funding: Bill & Melinda Gates Foundation

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms