Diabetes mellitus type 2 in adults

Public organization “Russian Association of Endocrinologists”. Clinical guidelines.&nbsp

Aneuploidy and Confined Chromosomal Mosaicism in the Developing Human Brain

BACKGROUND: Understanding the mechanisms underlying generation of neuronal variability and complexity remains the central challenge for neuroscience. Structural variation in the neuronal genome is likely to be one important mechanism for neuronal diversity and brain diseases. Large-scale genomic variations due to loss or gain of whole chromosomes (aneuploidy) have been described in cells of the normal and diseased human brain, which are generated from neural stem cells during intrauterine period of life. However, the incidence of aneuploidy in the developing human brain and its impact on the brain development and function are obscure. METHODOLOGY/PRINCIPAL FINDINGS: To address genomic variation during development we surveyed aneuploidy/polyploidy in the human fetal tissues by advanced molecular-cytogenetic techniques at the single-cell level. Here we show that the human developing brain has mosaic nature, being composed of euploid and aneuploid neural cells. Studying over 600,000 neural cells, we have determined the average aneuploidy frequency as 1.25-1.45% per chromosome, with the overall percentage of aneuploidy tending to approach 30-35%. Furthermore, we found that mosaic aneuploidy can be exclusively confined to the brain. CONCLUSIONS/SIGNIFICANCE: Our data indicates aneuploidization to be an additional pathological mechanism for neuronal genome diversification. These findings highlight the involvement of aneuploidy in the human brain development and suggest an unexpected link between developmental chromosomal instability, intercellural/intertissular genome diversity and human brain diseases

Diabetes mellitus type 1 in adults

Public organization “Russian Association of Endocrinologists”. Clinical guidlines

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Catalytic Hydrogenation of Pentanoic Acid over VIII Group Metals

Изучен процесс жидкофазного гидрирования пентановой кислоты (ПК) в неполярных средах (180 °C, давление водорода 25 атм) на немодифицированном рениевом катализаторе, нанесенном на диоксид титана, а также рениевом катализаторе, модифицированном металлами VIII группы – платиной, палладием, рутением и родием. Показано, что в ходе гидрирования пентановой кислоты образуется пентанол, который взаимодействует с пентановой кислотой с образованием соответствующего пентилового эфира, при этом устанавливается равновесие пентановая кислота – пентанол – пентилпентаноат. Конверсия пентановой кислоты увеличивается в ряду PdReOx/TiO2 < RuReOx/TiO2 < RhReOx/TiO2 < ReOx/TiO2 < PtReOx/TiO2. Селективность образования пентанола возрастает в ряду модифицированных катализаторов RhReOx/TiO2 ~ PtReOx/TiO2 < PdReOx/TiO2 ~ RuReOx/ TiO2 и значительно отличается от селективности катализатора ReOx/TiO2. Наибольшая селективность образования пентанола наблюдается на ReOx, нанесенном на термически модифицированный оксид титана, в то время как Re на немодифицированном оксиде титана не проявляет активности в сопоставимых условияхLiquid phase pentanoic acid hydrogenation in nonpolar hydrocarbon solutions (180 °C, 25 bar) was studied over rhenium on titanium oxide catalysts modified also with group VIII metals – platinum, palladium, ruthenium and rhodium. It was shown that during hydrogenation pentanoic acid was converted into pentanol followed by esterification with unreacted pentanoic acid into its pentyl ester, resulting in an equilibrium mixture of pentanoic acid – pentanol – pentyl pentanoate. Conversion of pentanoic acid increased in the row PdRe/TiO2 <RuRe/TiO2 <RhRe/TiO2 <ReOx/TiO2 < PtRe/TiO2. Selectivity to pentanol was elevated over bimetallic catalysts in the sequence RhRe/TiO2 ~ PtRe/TiO2 <PdRe/TiO2 ~ RuRe/TiO2 and was significantly different from ReOx/TiO2. The highest selectivity to pentanol was observed over ReOx, supported on the thermally modified titanium oxide while Re over unmodified titania was completely inactive under the same reaction condition

Liquid Phase Pentanol Guerbet-Markovnikov Condensation Over VIII Group Metals

Изучен процесс жидкофазной конденсации н-пентанола в неполярных средах, а также в отсутствие растворителя на металлах платиновой группы (платина, палладий, иридий, рутений и родий), нанесенных на мезопористый углеродный носитель сибунит, а также оксиды металлов с различными кислотно-основными свойствами – алюминия, циркония, церия. Реакцию проводили в автоклаве (150 мл) при температуре 140-200 °C, давлении азота 1-10 атм в присутствии металлов VIII группы и щелочного агента NaOH. Показано, что в ходе конденсации пентанола образуется 2-пропилгептанол (спирт Гербе), который является целевым продуктом реакции, а также пропаналь, 2-пропил-2-гептеналь, 2-пропил- 1-гептаналь, 2-пропил-1-гептенол. Исследовано влияние природы металла и условий реакции на конверсию пентанола и селективность образования продуктов реакции. Установлено, что увеличение температуры реакции приводит к увеличению скорости реакции и существенному росту селективности по 2-пропилгептанолу. Показано, что конверсия пентанола увеличивается в ряду катализаторов Ir/CeO2 << Rh/Al2O3 < Pd/ZrO2 < Ru/C < Ir/C < Pd/C < Pt/C < Pt/Al2O3. Селективность образования 2-пропилгептанола возрастает в ряду катализаторов Ir/CeO2 << Ir/C < Ru/C < Rh/Al2O3 ~ Pd/C ~ Pt/C ~ Pd/ZrO2 ~ Pt/Al2O3 и значительно увеличивается с ростом температуры. Наибольшую эффективность в синтезе 2-пропилгептанола в сопоставимых условиях демонстрируют катализаторы Pd/C, Pt/C и Pt/Al2O3Liquid phase pentanol condensation in solutions of nonpolar hydrocarbons as well as in solventfree conditions was studied in the presence of platinum group metals (platinum, palladium, iridium, ruthenium, and rhodium) supported on mesoporous carbon support Sibunit as well as on metal oxides – alumina, zirconia and ceria. This reaction was carried out in a batch mode in the temperature range 140-200 °C, under nitrogen pressure 1 – 10 bar in the presence of catalysts and a base – NaOH. It was shown that pentanol condensation mainly resulted in formation of the target product 2-propylheptanol (Guerbet alcohol), whereas pentanal, 2-propyl-2-heptenal, 2-propyl-1-heptanal, 2-propyl-1-heptenol were observed in minor quantities. The effect of metals as catalysts and reaction conditions on pentanol conversion and selectivity to 2-propylheptanol was studied. The reaction temperature increase not only as expected accelerates the reaction rate but in addition improves selectivity to 2-propylheptanol. Conversion of pentanol increased in the row Ir/CeO2 << Rh/Al2O3 < Pd/ZrO2 < Ru/C < Ir/C < Pd/C < Pt/C < Pt/Al2O3. Selectivity to 2-propylheptanol was elevated over metallic catalysts in the sequence Ir/CeO2 << Ir/C < Ru/C < Rh/Al2O3 ~ Pd/C ~ Pt/C ~ Pd/ZrO2 ~ Pt/Al2O3 being substantially influenced by temperature increase. The highest yield of 2-propylheptanol under comparable conditions was demonstrated for Pd/C, Pt/C и Pt/Al2O3 catalyst

Hydrogenation of Pentanoic Acid into Pentanol Over Ir and Ir-Re Catalysts: Effect of Support and Ir Dispersion

Изучен процесс жидкофазного гидрирования пентановой кислоты (ПК) в декане (180 ºC, давление водорода 25 атм) на монометаллических Ir и биметаллических катализаторах IrRe, нанесенных на оксид алюминия, оксид церия, оксид циркония, а также на углеродный носитель сибунит. Показано, что введение Re приводит к значительному увеличению активности в реакции гидрирования ПК, повышению селективности образования пентанола при практически полном отсутствии побочной реакции декарбоксилирования ПК. Катализаторы предварительно активировали в H2 при 415 ºC в течение 5 ч. Методом РФЭС установлено, что после активации наноразмерные частицы Ir находятся преимущественно в восстановленном состоянии, в то время как Re – в частично окисленном состоянии. Конверсия пентановой кислоты увеличивается в ряду Re/Al2O3 < Ir/CeO2 < Ir/ZrO2 < Ir/Al2O3 < IrRe/ZrO2 < IrRe/Al2O3 ~ IrRe/C. Селективность образования пентанола увеличивается в ряду Ir/Al2O3 < Ir/CeO2 ~ Ir/ZrO2 < IrRe/ZrO2 < Re/Al2O3 ~ IrRe/Al2O3 ~ IrRe/C. Синтезирована серия IrRe/Al2O3 катализаторов, средний размер кластеров Ir которых, согласно данным ПЭМ, варьируется от 0,8 до 1,7 нм. Показан рост конверсии и селективности образования пентанола с увеличением размера частиц Ir до 1,7 нмLiquid phase pentanoic acid hydrogenation in decane as a solvent (180 ºC, hydrogen pressure 25 bar) was studied over monometallic Ir and bimetallic Ir-Re catalysts supported on alumina, ceria and zirconia, as well as carbon support Sibunit. Before catalytic test all catalysts were preliminary treated in Н2 at 415 ºC during 5 h. An XPS study revealed predominant metallic state for Ir in studied catalysts while Re was partially oxidized. Conversion of pentanoic acid changed in the row Ir/CeO2 < Ir/ZrO2 < IrRe/ZrO2 < IrRe/Al2O3 ~ IrRe/C. Selectivity to pentanol was elevated over bimetallic catalysts in the sequence Ir/Al2O3 < Ir/CeO2 ~ Ir/ZrO2 < IrRe/ZrO2 < IrRe/Al2O3 ~ IrRe/C. It was shown that doping of Ir with Re gives a rise of pentanoic acid conversion and selectivity to pentanol in the absence of byside decarboxylation reaction. A series of the most active catalyst IrRe/Al2O3 was prepared varying Ir particle size from 0.8 to 1.7 nm as verified by TEM. Both pentanoic acid conversion and selectivity to pentanol over IrRe/Al2O3 catalyst increased with an increase of mean Ir particle siz

Multiplex Droplet Digital PCR Assay for Detection of MET and HER2 Genes Amplification in Non-Small Cell Lung Cancer

Non-small-cell lung cancer (NSCLC), a subtype of lung cancer, remains one of the most common tumors with a high mortality and morbidity rate. Numerous targeted drugs were implemented or are now developed for the treatment of NSCLC. Two genes, HER2 and MET, are among targets for these specific therapeutic agents. Alterations in HER2 and MET could lead to primary or acquired resistance to commonly used anti-EGFR drugs. Using current methods for detecting HER2 and MET amplifications is time and labor-consuming; alternative methods are required for HER2 and MET testing. We developed the first multiplex droplet digital PCR assay for the simultaneous detection of MET and HER2 amplification in NSCLC samples. The suitability of qPCR was assessed for the optimization of multiplex ddPCR. The optimal elongation temperature, reference genes for DNA quantification, and amplicon length were selected. The developed ddPCR was validated on control samples with various DNA concentrations and ratios of MET and HER2 genes. Using ddPCR, 436 EGFR-negative NSCLC samples were analyzed. Among the tested samples, five specimens (1.15%) showed a higher ratio of MET, and six samples (1.38%) showed a higher ratio of HER2. The reported multiplex ddPCR assay could be used for the routine screening of MET and HER2 amplification in NSCLC samples

A Complex Approach to Control Black Dot Disease in Potato

In recent years, skin blemish diseases of potato (including black dot (BD) caused by Colletotricum coccodes) have begun to be important for global potato marketing, since consumers often reject tubers with an imperfect appearance, which results in financial losses caused by the disposal of unwanted potatoes. Like for many non-fatal plant diseases, BD severity may depend on the immune status of plants influenced by other infectious agents. Using a set of 98 potato cultivars differing in their late blight (LB) resistance, we examined the correlation between the intensity of their infection with LB determined by their LB resistance and the occurrence of the BD disease under field conditions with a high background level of both diseases. Using LB-susceptible (Arizona) and moderately susceptible (Sante) cultivars, we also evaluated the effect of a crop protection against LB on BD development under the same field conditions. A strong negative correlation (r = −0.81, p < 0.05) between the LB resistance and the BD occurrence has been revealed. An experiment using the two cultivars, chemically protected against LB, showed a significant reduction in BD occurrence of 30% (cv. Arizona) and 20% (cv. Sante) compared to the untreated controls; the total yield and marketability of potatoes increased by 103.6 and 62.5% for cv. Arizona and by 65.9 and 43.8% for cv. Sante. The reduction in the LB affection of potato is one of the key factors improving the immune status of potato cultivars in relation to BD infection, so methods of LB protection should be included in a complex approach to BD control