Nanоbiocomposite based on dihydroquercetin and arabinogalactan in the form of a gel for external use as a means for the treatment of chronic venous insufficiency in an experiment

Background. Due to the high prevalence of chronic venous insufficiency among the population, with a decrease in the quality of life of patients and their early disability, there is a need to develop modern effective and safe means for the prevention and treatment of this pathology. We have developed the optimal composition and technology of a gel for external use based on a nanobiocomposite of dihydroquercetin and arabinogalactan, which has a venoprotective effect. The article presents data on the results of a preclinical study of the safety and specific activity of the gel.The aim. To study the specific activity (decongestant, antitranssudative action) and safety of a gel for external use based on nanobiocomposite of dihydroquercetin and arabinogalactan used for the treatment of chronic venous insufficiency in the framework of preclinical studies.Materials and methods. The object of the study was a gel for external use based on dihydroquercetin and arabinogalactan nanobiocomposite. The study was conducted on 32 white male rats of the same age, for 15 days. The study of the pharmacological activity of a gel based on a nanobiocomposite of dihydroquercetin and arabinogalactan, was carried out on a model of acute venous stagnation in the tail of a rat (edema of non-inflammatory genesis), the dynamics of tail volume growth in the experimental and control group of animals was evaluated. The irritant effect of the gel on the skin of animals was also determined, the permeability of the capillaries of the skin was determined.Results. When studying the pharmacological activity of the gel on a model of acute venous stagnation in the tail, it was shown that a soft dosage form for external use developed on the basis of nanobiocomposite of dihydroquercetin and arabinogalactan has decongestant and antitranssudative activity. The presence of a locally irritating effect in the gel under study has not been established in the framework of the experiment.Conclusion. In the course of preclinical study of the gel of the nanobiocomposite dihydroquercetin and arabinogalactan on laboratory animals, its antitranssudative activity and safety have been proven

Disturbance of meromixis in saline Lake Shira (Siberia, Russia): possible reasons and ecosystem response

Saline Lake Shira (Southern Siberia, Russia) was meromictic through the observation period 2002-2015. During the under-ice periods of 2015 and 2016, complete mixing of the water column was recorded for the first time, and hydrogen sulphide temporarily disappeared from the water column of the lake; i.e. in those years the lake turned to holomixis. In the summer of 2015, a sharp increase in chlorophyll a, organic carbon, zooplankton, and phytoflagellates was observed in the lake, which was probably due to the release of nutrients from the monimolimnion. Purple sulfur bacteria completely disappeared from the lake after the first mixing in 2015, and did not reappear despite the restoration of meromixis in 2017. Thus, it was demonstrated that purple sulfur bacteria are sensitive to the weakening of the stratification of Lake Shira. Based on the data of the seasonal monitoring of temperature and salinity profiles over the period 2002-2017, it was presumed that the main cause of deep mixing in 2015 was the weakening of the salinity gradient due to strong wind impact and early ice retreat in the spring of 2014. In addition, it was shown that in previous years a significant contribution to the maintenance of meromixis was made by an additional influx of fresh water, which caused a rise in the lake level in the period 2002-2007. Thus, we identified a relationship between the stratification regime of the lake and the change in its level, which provides valuable information both for the forecast of water quality and for reconstruction of the Holocene climate humidity in this region of Southern Siberia from the sediment cores of Lake Shira

Studying of the Polylactide or Polyglycylidactide Surface Layer Biodegradation in Neutral Media for the Subsequent Layered Composite Creation

  The processes of biodegradation in phosphate buffer with pH 7.4 and 0.9 wt.% NaCl of polymer polylactide or polyglycylidactide films for the subsequent creation of a layered composite with a biodegradable layer on the basis of a nickel-free shape memory alloy TiNbTaZr were studied. The structure of the samples was determined by SEM and an optical microscope. For polylactide films the rate of biodegradation did not depend on the mass of the film. A gradual decrease in the rate of biodegradation at any mass with a similar dependence on time is noted. With an increase in the mass of films based on poly(glycolide-lactide) the rate of biodegradation increased. And even at the initial stage the dissolution rate is 2-3 times higher than in pure polylactide. On day 180, complete dissolution of the polyglycolidelactide was observed (even a precipitate was not observed) and completely entire polylactide films, however, lost  their transparency, was noted

Fatty Acid Content and Composition of Fly Larvae Lucilia sericata (Family Calliphoridae) Grown on Diets with Different Content of Polyunsaturated Fatty Acids and the Amino Acid Composition of this Species

Аквакультура – быстроразвивающаяся отрасль сельского хозяйства, однако сейчас она столкнулась с недостатком кормов, основу которых составляют уловы дикой рыбы, и, как следствие, повышением их стоимости. Для дальнейшего устойчивого развития аквакультуры необходимо разработать альтернативные корма, производимые не из дикой рыбы. Насекомые рассматриваются как подходящий источник кормового белка для рыб, однако их жирнокислотный (ЖК) состав часто не соответствует требованиям аквакультуры. В рыбьем жире среди ПНЖК доминируют кислоты семейства омега‑3, а в наземных насекомых – семейства омега‑6. Исследование возможности модификации ЖК состава личинок насекомых для увеличения содержания омега‑3 ПНЖК является актуальной задачей. Целью данной работы было изучить состав и содержание жирных кислот в личинках мухи Lucilia sericata, выращенных на стандартном корме и корме с добавлением рыжикового масла, богатом альфа-линоленовой кислотой (АЛК, 18:3n‑3), и проанализировать аминокислотный состав (АК) личинок данного вида мух. ЖК анализ проводили на газовом хроматографе с масс-спектрометрическим детектором. АК анализ выполняли на жидкостном хроматографе. АК состав исследованных личинок мух, как и других насекомых отряда Diptera, был близок к АК составу рыбной муки. Состав и содержание жирных кислот личинок мухи на стандартном корме характеризовались низким соотношением омега‑3 / омега‑6 ПНЖК и доминированием 18:1n‑9 и 18:2n‑6 – жирных кислот, которые суммарно составляли от 40 % до 60 % от суммы ЖК. Добавление рыжикового масла изменило соотношение омега‑3 / омега‑6 ПНЖК с 0,11 до 0,46, главным образом за счёт увеличения содержания АЛК. Таким образом, ЖК состав личинок L. sericata может быть существенно модифицирован пищейAquaculture is a fast-growing branch of agriculture, but it faces fish feed shortages due to a decrease in wild fish catches. As a result, the price of feed increases. For further development it requires alternative feed sources. Insects are considered a suitable protein source for fish, but their fatty acid (FA) composition often does not meet the requirements of aquaculture. In fish oil, PUFAs are dominated by the omega‑3 family, and in terrestrial insects, by the omega‑6 family. A question arises whether insect larvae lipid composition can be modified to increase the content of omega‑3 PUFAs. For this purpose, Lucilia sericata larvae were grown on standard feed and feed with addition of camelina oil rich in alpha-linolenic acid (ALA, 18:3n‑3), and their FA content and composition were compared. To evaluate the quality of these larvae protein, their amino acid (AA) composition was determined. The FA analysis was performed on a gas chromatograph equipped with a mass-spectrometer detector. The AA analysis was performed on a liquid chromatograph. The AA composition of the examined fly larvae, similarly to other insects (Diptera), was close to the AA composition of fish meal. Fatty acid composition and content of fly larvae grown on standard food was characterized by a low ratio of omega‑3/omega‑6 PUFAs and by the dominance of 18:1n‑9 and 18:2n‑6 fatty acids, which together comprised 40–60 % of the total of FAs. The addition of camelina oil changed the ratio of omega‑3/ omega‑6 PUFAs from 0.11 to 0.46, mainly due to the increase in ALA content. Thus, FA content and composition of L. sericata larvae can be significantly modified by a die

Micromechanical Properties of Injection-Molded Starch–Wood Particle Composites

The micromechanical properties of injection molded starch–wood particle composites were investigated as a function of particle content and humidity conditions. The composite materials were characterized by scanning electron microscopy and X-ray diffraction methods. The microhardness of the composites was shown to increase notably with the concentration of the wood particles. In addition,creep behavior under the indenter and temperature dependence were evaluated in terms of the independent contribution of the starch matrix and the wood microparticles to the hardness value. The influence of drying time on the density and weight uptake of the injection-molded composites was highlighted. The results revealed the role of the mechanism of water evaporation, showing that the dependence of water uptake and temperature was greater for the starch–wood composites than for the pure starch sample. Experiments performed during the drying process at 70°C indicated that the wood in the starch composites did not prevent water loss from the samples.Peer reviewe

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

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Новая мутация в гене TYMP: клинико-морфологическая характеристика пациента с синдромом MNGIE

Mitochondrial neurogastrointestinal encephalomyopathy is an extremely rare (1–9:1 000 000, Orphanet, 2021) multisystem genetic disease caused by mutations in the TYMP gene encoding the enzyme thymidine phosphorylase.The article presents the data of a thirteen‑year survey on 40‑year‑old patient D. with clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy syndrome associated with the previously undescribed missense mutation c.1301G&gt;T (p.Gly434Val) of the TYMP gene. Detailed clinical picture (gastrointestinal dysfunction, cachexia, blepharoptosis, ophthalmoparesis, peripheral polyneuropathy and leukoaraiosis), electroneuromyography data (demyelination with secondary axonopathy), high blood serum level of dihydrothymine together with normal levels of thymidine and deoxyuridine made it possible to verify the diagnosis. Histopathological examination revealed atrophy of the longitudinal (outer) muscle layer of the small and large intestines and a significant decrease in the number of CD117+ cells (telocytes), signs of damage to the striated skeletal muscles of a mixed nature with a predominance of the myogenic pattern, as well the destruction of the myelin sheaths of peripheral nerves. Histochemical examination did not reveal “ragged red fibers” characteristic of mitochondrial pathology. Transmission electron microscopy demonstrated the presence of megalomitochondria in the myocardium.Синдром митохондриальной нейрогастроинтестинальной энцефаломиопатии – редкое (1–9:1000000, Orphanet, 2021) генетическое мультисистемное заболевание, обусловленное мутациями в ядерном гене TYMP, кодирующем фермент тимидинфосфорилазу.Представлены данные 13‑летнего наблюдения пациентки Д., 40 лет, с синдромом митохондриальной нейрогастроинтестинальной энцефаломиопатии, связанным с ранее не описанной миссенс‑заменой c.1301G&gt;T (p.Gly434Val) в гене TYMP. Диагноз синдрома митохондриальной нейрогастроинтестинальной энцефаломиопатии был поставлен на основании клинических проявлений (дисфункция желудочно‑кишечного тракта, кахексия, блефароптоз, офтальмопарез, периферическая полинейропатия и лейкоэнцефалопатия), результатов электронейромиографии (демиелинизация с вторичной аксонопатией), а также повышения уровня дигидротимина в сыворотке крови при нормальных уровнях тимидина и дезоксиуридина. Патогистологическое исследование выявило атрофию продольного (наружного) мышечного слоя тонкой и толстой кишок и значимое уменьшение количества CD117+‑клеток (телоцитов), поражение скелетных мышц смешанного характера с преобладанием миогенного паттерна, а также деструкцию миелиновых оболочек периферических нервов. Исследование S100‑положительных вегетативных образований кишечной стенки не выявило патологических изменений. При гистохимическом исследовании не были обнаружены «рваные красные волокна», характерные для митохондриопатий. Трансмиссионная электронная микроскопия продемонстрировала наличие полиморфизма митохондрий кардиомиоцитов и мегаломитохондрий лейомиоцитов кишечника

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years