Hyperhomocysteinemia and functional state of endothelium in patients with peripheral artery disease with arterial reconstructions

АРТЕРИОСКЛЕРОЗ ОБЛИТЕРИРУЮЩИЙАОРТОПОДВЗДОШНЫЙ СЕГМЕНТБЕДРЕННО-ПОДКОЛЕННЫЙ СЕГМЕНТХИРУРГИЧЕСКИЕ ОПЕРАЦИИ ВОССТАНОВИТЕЛЬНЫЕ; РЕКОНСТРУКТИВНЫЕ ХИРУРГИЧЕСКИЕ ОПЕРАЦИИРЕНТГЕНОЭНДОВАСКУЛЯРНЫЕ ВМЕШАТЕЛЬСТВАГОМОЦИСТЕИНЭНДОТЕЛИАЛЬНАЯ ДИСФУНКЦИЯЦель. Изучить взаимоотношения гомоцистеина и маркеров функционального состояния эндотелия у пациентов с облитерирующим атеросклерозом при операциях на аорте и артериях нижних конечностей. Материал и методы. В исследование вошли 68 пациентов с облитерирующим атеросклерозом нижних конечностей, средний возраст 57,8±7,3 года, со IIБ-III степенью хронической артериальной недостаточности по R. Fontaine-А. В. Покровскому, распределенные на три группы: в I группе выполнено бедренно-подколенное шунтирование (n=32), во II – аорто-бедренное шунтирование (n=20), в III – рентгенэдоваскулярная ангиопластика и стентирование подвздошных артерий (n=16). Проведен корреляционный анализ между содержанием гомоцистеина и маркерами функционального состояния эндотелия: окисленными липопротеинами низкой плотности (окисленными ЛПНП), молекулой адгезии сосудистого эндотелия 1 типа (sVCAM-1), ингибитором тканевого активатора плазминогена 1 типа (PAI-1), тканевым активатором плазминогена (t-PA), Аннексином V в системном и местном кровотоке до операции и после артериальных реконструкций. Результаты. Установлены корреляционные взаимосвязи между гомоцистеином и окисленными ЛПНП как в системном кровотоке, так и в пораженной конечности, эта ассоциация сохранялась после реконструктивного вмешательства, была наиболее значимой в местном кровотоке после бедренно-подколенного шунтирования. Отмечена дооперационная положительная корреляция системного уровня гомоцистеина и sVCAM-1 в I группе. Показано влияние гомоцистеина на нарушение фибринолитической функции эндотелия, на что указывали прямые корреляционные взаимосвязи между гомоцистеином и PAI-1 в системном кровотоке и в пораженной конечности, сохраняющиеся после открытых реконструкций. Выявлены значимые связи между гомоцистеином и уровнем Аннексина V преимущественно в группе пациентов с поражением бедренно-подколенного артериального сегмента. Заключение. Гипергомоцистеинемия вносит свой значимый вклад в нарушение функционального состояния эндотелия, оказывая влияние на апоптоз, активацию атерогенных ЛПНП, прокоагулянтный потенциал, сохраняющиеся и после артериальных реконструкций как в системном, так и в местном кровотоке.Objective. To study the relationship between homocysteine and markers of the functional state of the endothelium in patients with obliterating atherosclerosis in operations on the aorta and arteries of the lower limbs. Methods. The study included 68 patients with peripheral artery disease, the average age was 57.8±7.3 years, with II B – III degree of chronic arterial insufficiency according to R. Fontaine-A. V. Pokrovsky, who were divided into three groups: I group underwent the femoro-popliteal bypass (n=32), II – the aorto-femoral bypass (n=20), III – x-ray endovascular angioplasty and stenting of the iliac arteries (n=16). A correlation analysis was made between the content of homocysteine and the markers of the endothelium functional state of: the oxidized low-density lipoproteins (oxidized LDL), a molecule of adhesion of the vascular endothelium type 1 (sVCAM-1), the tissue type 1 plasminogen activator inhibitor (PAI-1), the tissue plasminogen activator (t-PA), Annexin V in the systemic and local bloodstream prior to surgery and after the arterial reconstructions. Results. Correlation relationships between homocysteine and oxidized LDL were established both in the systemic blood flow and the affected limb, this association persisted after the reconstructive intervention, the most significant in the local bloodstream after femoro-popliteal bypass surgery. Preoperative positive correlation of the systemic level of homocysteine and sVCAM-1 in group I was marked. The effect of homocysteine on the fibrinolytic function of the endothelium was shown, as indicated by the direct correlation between homocysteine and PAI-1 in the systemic blood flow and in the affected limb, which persist after open reconstructions. Significant links between homocysteine and the level of Annexin V were revealed in the group of patients with the lesion of the femoro-popliteal arterial segment. Conclusions. Hyperhomocysteinemia contributes significantly to the disturbance of the endothelium functional state, affecting apoptosis, the activation of atherogenic LDL, and the procoagulant potential, which persist even after arterial reconstructions both in the systemic and local bloodstream

MAIN STAGES OF CONTINENTAL CRUST FORMATION IN THE WESTERN ALDAN SHIELD: CONSTRAINTS FROM SM-ND ISOTOPE SYSTEMATICS OF CENOZOIC SANDS IN THE CHARA AND TOKKA BASINS

Previous geochronological and Sm-Nd isotopegeochemical studies have identified the main stages of the Precambrian continental crust formation in the central and eastern parts of the Aldan Shield [Kotov et al., 2006], while its western part (Chara-Olekma Geoblock) has not been adequately investigated yet in this respect.Previous geochronological and Sm-Nd isotopegeochemical studies have identified the main stages of the Precambrian continental crust formation in the central and eastern parts of the Aldan Shield [Kotov et al., 2006], while its western part (Chara-Olekma Geoblock) has not been adequately investigated yet in this respect

In Vivo Simulation of the Purulent Peritonitis

Currently, purulent-inflammatory diseases of the abdominal organs are the prevalent causes of complications and mortality. Treatment of these diseases complicated by peritonitis is one of the urgent problems in modern clinical medicine. Experiment is important for testing new treatment methods. This article provides a systematic analysis of the current in vivo models of the purulent peritonitis, which are used to test the options for surgical treatment and combinations of antibacterial drugs. We describe the most common models as well as rare simulations of specific peritonitis. It should be noted that despite the wide use of minimally invasive techniques, the literature has few reports on simulation of peritonitis through the laparoscopic approach

Сывороточные биомаркеры сердечной недостаточности и параметры механики левого желудочка в ранней диагностике диастолической дисфункции у пациентов с эпикардиальным ожирением

Highlights. Patients with epicardial obesity develop myocardial fibrosis (the underlying mechanism of left ventricular diastolic dysfunction) the preclinical diagnosis of which is difficult to perform. In this regard, the search for non-invasive methods for diagnosing diastolic dysfunction at an early stage, including the methods of determining the serum level of biomarkers of heart failure and studying the parameters of left ventricular mechanics using speckle-tracking echocardiography, seems quite relevant.Background. Currently, the search for serum biomarkers and non-invasive methods for diagnosing diastolic dysfunction (DD) of the left ventricle (LV) at the preclinical stage in obese patients is relevant.Aim. To study the levels of heart failure biomarkers and their association with profibrotic factors and LV mechanics in patients depending on the presence of epicardial obesity (EO).Methods. Out of 143 men with general obesity, depending on the severity of EO, determined by the thickness of epicardial adipose tissue (tEАT), 2 groups of patients were identified: the EO (+) group with tEАT 7 mm or more (n = 70), and the EO (–) group with tEАT less than 7 mm (n = 40). The exclusion criteria from the study were: arterial hypertension, type 2 diabetes mellitus, coronary artery disease, and the presence of LVDD detected by echocardiography (echo). Levels of profibrotic factors (type I and type III collagen, procollagen type I C-terminal propeptide (PICP), matrix metalloproteinase-3 (MMP-3), transforming growth factor-β (TGF-β), vascular endothelial growth factor A (VEGF-A), sST2, and NT-proBNP were determined in all patients using enzyme immunoassay. With the help of speckle-tracking echocardiography, the mechanics of LV were analyzed.Results. The EO (+) group presented with increased sST2 level (22.11±7.36 ng/mL) compared to the EO (–) group (sST2 level 9.79±3.14 ng/mL (p<0.0001). In the EO (+) group, a significant influence of tEAT on sST2 level was identified (F = 8.57; p = 0.005). In the EO (+) group, an increase in the level of MMP-3, type I collagen, type III collagen, PICP, transforming growth factor-β, and VEGF-A was revealed. Moreover, in the EO (+) group, a statistically significant relationship between sST2 and type III collagen was revealed (p = 0.01). When comparing the parameters of speckle-tracking echo, the EO group (+) presented with increased LV untwisting rate of –128.31 (–142.0; –118.0) deg/s-1 (p = 0.002), and increased time to LV peak untwisting rate of – 476.44 (510.0; 411.0) msec compared with the EO group (–) (p = 0.03). Moreover, a significant association between LV untwisting rate and sST2 level was revealed in the EO (+) group (r = 0.35; p = 0.02).>˂0.0001). In the EO (+) group, a significant influence of tEAT on sST2 level was identified (F = 8.57; p = 0.005). In the EO (+) group, an increase in the level of MMP-3, type I collagen, type III collagen, PICP, transforming growth factor-β, and VEGF-A was revealed. Moreover, in the EO (+) group, a statistically significant relationship between sST2 and type III collagen was revealed (p = 0.01). When comparing the parameters of speckle-tracking echo, the EO group (+) presented with increased LV untwisting rate of –128.31 (–142.0; –118.0) deg/s-1 (p = 0.002), and increased time to LV peak untwisting rate of – 476.44 (510.0; 411.0) msec compared with the EO group (–) (p = 0.03). Moreover, a significant association between LV untwisting rate and sST2 level was revealed in the EO (+) group (r = 0.35; p = 0.02).Conclusion. The data obtained indicate that patients with EO have LVDD, which could not be detected using echo criteria for LVDD, and the determination of serum levels of the heart failure biomarker - sST2 can be used for the diagnosis of LVDD at the early stage.Основные положения. У пациентов с эпикардиальным ожирением развивается фиброз миокарда, лежащий в основе нарушения диастолической функции левого желудочка, доклиническая диагностика которого затруднительна. В связи с этим крайне актуален поиск неинвазивных методов диагностики диастолической дисфункции на ранней стадии, в том числе с помощью определения сывороточного уровня биомаркеров сердечной недостаточности и изучения параметров механики левого желудочка с применением speckle-tracking эхокардиографии.Актуальность. В настоящее время актуален поиск неинвазивных методов диагностики диастолической дисфункции (ДД) левого желудочка (ЛЖ) на доклиническом этапе, в том числе у пациентов с ожирением.Цель. Изучить уровни биомаркеров сердечной недостаточности и их ассоциацию с профибротическими факторами и параметрами механики ЛЖ у пациентов в зависимости от наличия эпикардиального ожирения (ЭО).Материалы и методы. Из 143 мужчин с общим ожирением в зависимости от степени выраженности ЭО, определенного по толщине эпикардиальной жировой ткани (тЭЖТ), выделены две группы: ЭО(+) – тЭЖТ 7 и более мм (n = 70), ЭО(–) – тЭЖТ менее 7 мм (n = 40). Критерии исключения из исследования: артериальная гипертензия, сахарный диабет 2-го типа, ишемическая болезнь сердца, а также наличие ДД ЛЖ, выявленной по данным эхокардиографии (ЭхоКГ). Всем пациентам определяли уровень профибротических факторов (коллаген I и III типов, проколлаген I C-концевого пропептида (PICP), матриксная металлопротеиназа-3 (MMП-3), трансформирующий фактор роста-β (TGF-β), сосудистый эндотелиальный фактор рост (VEGFA)), sST2 и NT-proBNP исследовали с использованием иммуноферментного анализа. С помощью speckle-tracking ЭхоКГ изучена механика ЛЖ.Результаты. В группе ЭО(+) выявлено повышение уровня sST2 до 22,11±7,36 нг/мл в сравнении с группой ЭО(–), где уровень sST2 составил 9,79±3,14 нг/мл (р<0,0001). В группе ЭО(+) определено значимое влияние тЭЖТ на уровень sST2 (F = 8,57; p = 0,005). Также в группе ЭО(+) зарегистрировано увеличение уровня ММП-3, коллагена I и III типов, PICP, TGF-β, VEGFA; определена статистически значимая взаимосвязь sST2 и коллагена III типа (p = 0,01). При сравнении показателей speckle-tracking ЭхоКГ в группе ЭО(+) в сравнении с группой ЭО(–) отмечено повышение скорости раскручивания ЛЖ до –128,31 (–142,0; –118,0) градуса/с–1 (p = 0,002) и времени до пика раскручивания ЛЖ до 476,44 (510,0; 411,0) мсек (p = 0,03). В данной группе выявлена взаимосвязь скорости раскручивания ЛЖ и уровня sST2 (r = 0,35; p = 0,02). >˂0,0001). В группе ЭО(+) определено значимое влияние тЭЖТ на уровень sST2 (F = 8,57; p = 0,005). Также в группе ЭО(+) зарегистрировано увеличение уровня ММП-3, коллагена I и III типов, PICP, TGF-β, VEGFA; определена статистически значимая взаимосвязь sST2 и коллагена III типа (p = 0,01). При сравнении показателей speckle-tracking ЭхоКГ в группе ЭО(+) в сравнении с группой ЭО(–) отмечено повышение скорости раскручивания ЛЖ до –128,31 (–142,0; –118,0) градуса/с–1 (p = 0,002) и времени до пика раскручивания ЛЖ до 476,44 (510,0; 411,0) мсек (p = 0,03). В данной группе выявлена взаимосвязь скорости раскручивания ЛЖ и уровня sST2 (r = 0,35; p = 0,02).Заключение. Полученные данные позволяют предположить, что у пациентов с ЭО может быть ДД ЛЖ, не выявленная с помощью ЭхоКГ-критериев нарушения диастолической функции ЛЖ, а определение уровня сывороточного биомаркера сердечной недостаточности sST2 возможно для диагностики ДД на ранней стадии

DETECTION OF AUTOANTIBODIES RECOGNIZING CANCERRETINA ANTIGEN RECOVERIN IN BLOOD OF PATIENTS WITH NON-INVASIVE FOLLICULAR THYROID NEOPLASMS WITH PAPILLARY-LIKE NUCLEAR FEATURES (NIFTP)

Autoantibodies recognizing the cancer-retina autoantigen called recoverin (RCVRN-AutoAb) may serve as a highly specific biomarker of cancer-associated retinopathy. However, they may also be found in some cancer patients without clinical evidence of retinopathy. In the present study, dot-ELISA and Western blot assays were used to demonstrate the presence of circulating RCVRN-AutoAb in 4/7 (57%) of patients with recently recognized pathological entity, non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP); other thyroid tumors represented by follicular adenomas, and classical and follicular variants of papillary thyroid carcinomas, demonstrated low frequencies of RCVRN-AutoAb (0/15, 1/20 (5%) and 1/15 (7%), respectively), with no significant differences from healthy individuals (0/15). Our data implicate the circulating RCVRN-AutoAb as a potential biomarker of NIFTP capable of discrimination of this novel pathological entity from other thyroid tumors

PKA regulatory subunits mediate synergy among conserved G-protein-coupled receptor cascades

G-protein-coupled receptors sense extracellular chemical or physical stimuli and transmit these signals to distinct trimeric G-proteins. Activated Gα-proteins route signals to interconnected effector cascades, thus regulating thresholds, amplitudes and durations of signalling. Gαs- or Gαi-coupled receptor cascades are mechanistically conserved and mediate many sensory processes, including synaptic transmission, cell proliferation and chemotaxis. Here we show that a central, conserved component of Gαs-coupled receptor cascades, the regulatory subunit type-II (RII) of protein kinase A undergoes adenosine 3′-5′-cyclic monophosphate (cAMP)-dependent binding to Gαi. Stimulation of a mammalian Gαi-coupled receptor and concomitant cAMP-RII binding to Gαi, augments the sensitivity, amplitude and duration of Gαi:βγ activity and downstream mitogen-activated protein kinase signalling, independent of protein kinase A kinase activity. The mechanism is conserved in budding yeast, causing nutrient-dependent modulation of a pheromone response. These findings suggest a direct mechanism by which coincident activation of Gαs-coupled receptors controls the precision of adaptive responses of activated Gαi-coupled receptor cascades

Dichotomy of Tyrosine Hydroxylase and Dopamine Regulation between Somatodendritic and Terminal Field Areas of Nigrostriatal and Mesoaccumbens Pathways

Measures of dopamine-regulating proteins in somatodendritic regions are often used only as static indicators of neuron viability, overlooking the possible impact of somatodendritic dopamine (DA) signaling on behavior and the potential autonomy of DA regulation between somatodendritic and terminal field compartments. DA reuptake capacity is less in somatodendritic regions, possibly placing a greater burden on de novo DA biosynthesis within this compartment to maintain DA signaling. Therefore, regulation of tyrosine hydroxylase (TH) activity may be particularly critical for somatodendritic DA signaling. Phosphorylation of TH at ser31 or ser40 can increase activity, but their impact on L-DOPA biosynthesis in vivo is unknown. Thus, determining their relationship with L-DOPA tissue content could reveal a mechanism by which DA signaling is normally maintained. In Brown-Norway Fischer 344 F1 hybrid rats, we quantified TH phosphorylation versus L-DOPA accumulation. After inhibition of aromatic acid decarboxylase, L-DOPA tissue content per recovered TH protein was greatest in NAc, matched by differences in ser31, but not ser40, phosphorylation. The L-DOPA per catecholamine and DA turnover ratios were significantly greater in SN and VTA, suggesting greater reliance on de novo DA biosynthesis therein. These compartmental differences reflected an overall autonomy of DA regulation, as seen by decreased DA content in SN and VTA, but not in striatum or NAc, following short-term DA biosynthesis inhibition from local infusion of the TH inhibitor α-methyl-p-tyrosine, as well as in the long-term process of aging. Such data suggest ser31 phosphorylation plays a significant role in regulating TH activity in vivo, particularly in somatodendritic regions, which may have a greater reliance on de novo DA biosynthesis. Thus, to the extent that somatodendritic DA release affects behavior, TH regulation in the midbrain may be critical for DA bioavailability to influence behavior

LIPID PROFILE AND HEMORHEOLOGY DYNAMICS IN PATIENTS WITH LOWER EXTREMITY PERIPHERAL ARTERY DISEASE IN THE PREOPERATIVE AND POSTOPERATIVE PERIOD

The objective of the study was to evaluate the lipid and hemostatic profile in patients with peripheral artery disease of lower extremities at different levels of lesion and methods of surgery.Materials and methods. 330 male patients with peripheral artery disease of lower extremities arteries of II b — III degree were examined: group I consisted of 140 patients with lesions of the femoral-popliteal arterial segment, who underwent femoralpopliteal bypass surgery (58.64±7.73 years), group II — 97 patients with occlusive-stenotic lesions of the aorto-iliac segment, who underwent aortofemoral bypass surgery (56.82±6.69 years), group III — 93 patients with occlusive stenotic changes of the iliac arteries, who underwent transluminal balloon angioplasty and stenting of the iliac arteries. The examination of patients included general clinical, instrumental and laboratory methods with the assessment of lipid profile fractions and plasma-coagulation level of hemostasis.Results. The provided examination showed that patients with peripheral artery disease have disorders of the blood lipid profile, which have significant differences depending on the severity and localization of occlusive-stenotic lesions of the aorta and main arteries. Lipid imbalance persists after correction of arterial blood flow. Significant changes in the hemostatic profile in all groups in the postoperative period were revealed, which were characterized by hypercoagulation in the form of a significant increase in the concentration of fibrinogen, reducing the activity of antithrombin III, shortening of thrombin time in groups I and II and reducing spontaneous fibrinolysis in groups I and II. Thrombin time and spontaneous fibrinolysis in group III increased relative to preoperative values. Open interventions in the volume of femoral-popliteal bypass surgery were accompanied by a more pronounced inhibition of fibrinolysis in comparison with minimally invasive interventions, and in endovascular procedure the anticoagulant potential was more depressed. Open reconstruction of the iliac segment was associated with a large reduction in thrombin time, but less inhibition of anticoagulant potential, compared with endovascular technique, due to large damage to the endothelium.Conclusion. It is necessary to monitor the lipid and hemostatic profile both before and after surgery in patients, admitted to the hospital for reconstructive surgery on the aorta and main arteries of the lower extremities, in order to develop an effective personalized drug prevention of lower extremity peripheral artery disease progression and to prevent the development of thrombotic and stenotic complications of the arterial reconstruction zone

Neonatal immune challenge alters reproductive development in the female rat

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease.". Neonatal lipopolysaccharide (LPS) exposure alters neuroendocrine, immune and behavioural responses in adult rats. Recent findings indicate that neonatal LPS treatment may have a more pronounced effect on the mating behaviours of females compared to males. The current study further explored the impact of neonatal inflammation on reproductive development in the female rat. Wistar rats were administered LPS (0.05. mg/kg, i.p.) or saline (equivolume) on postnatal days (PNDs) 3 and 5. The immediate effect of treatment was assessed on plasma corticosterone and tyrosine hydroxylase (TH) phosphorylation in the adrenal medulla. Weight gain and vaginal opening were recorded, and oestrous cyclicity was monitored post-puberty and in late adulthood. Blood and ovaries were collected throughout development to assess HPA and HPG hormones and to examine ovarian morphology. Reproductive success in the first (F1) generation and reproductive development in the second (F2) generation were also assessed. Neonatal LPS exposure resulted in increased TH phosphorylation in the neonatal adrenals. LPS treatment increased the corticosterone concentrations of females as juveniles, adolescents and adults, and reduced FSH in adolescence. Increased catch-up growth was evident in LPS-treated females, prompting earlier onset of puberty. Diminished follicular reserve was observed in neonatally LPS-treated females along with the advanced reproductive senescence. While fertility rates were not compromised, higher mortality and morbidity were observed in litters born to LPS-treated mothers. Female offspring of LPS-treated mothers displayed increased corticosterone on PND 14, increased catch-up growth and delayed emergence of the first oestrous cycle. No differences in any of the parameters assessed were observed in F2 males. These data suggest that neonatal immunological challenge has a profound impact on the female reproductive development, via the alteration of metabolic and neuroendocrine factors which regulate sexual maturation. Evidence of altered development in the female, but not male offspring of LPS-treated dams suggests increased susceptibility of females to the deleterious effects of neonatal immunological stress and its possible transferability to a subsequent generation. © 2012 Elsevier Inc

MAIN STAGES OF CONTINENTAL CRUST FORMATION IN THE WESTERN ALDAN SHIELD: CONSTRAINTS FROM SM-ND ISOTOPE SYSTEMATICS OF CENOZOIC SANDS IN THE CHARA AND TOKKA BASINS

Previous geochronological and Sm-Nd isotopegeochemical studies have identified the main stages of the Precambrian continental crust formation in the central and eastern parts of the Aldan Shield [Kotov et al., 2006], while its western part (Chara-Olekma Geoblock) has not been adequately investigated yet in this respect