[Pharmacotherapy of heart failure with reduced ejection fraction: heart failure basic therapy and an episode of decompensation].

A qualitative change in the risk profile after an episode of decompensated heart failure (HF) calls for an as immediate as possible therapeutic response. In the absence of uniform guidelines for the sequence and timing of administering the background therapy during the hospitalization period and the subsequent "vulnerable" period, clinicians have to rely on available expert opinions and results of conducted studies. The article focuses on an evidence base for the use of background therapy for HF during the above-mentioned periods. Special attention is paid to the conditions and principles of initiating this therapy.

[Chest pain and chronic heart failure as a manifestation of tertiary syphilis: clinical case].

In cardiological practice, there may be patients with chest pain and heart failure of a specific etiology, including an association with cardiovascular syphilis. This article describes a 49-year patient with chest pain, heart failure, and neurological symptoms associated with ongoing tertiary syphilis. The history included an antisyphilitic treatment 30 years before the current hospitalization. Further evaluation confirmed neuro- and cardiovascular syphilis with severe aortic regurgitation and syphilitic myocarditis. Tertiary syphilis is a rare but relevant challenge for various medical specialists, including cardiologists. This pathology requires increased medical alertness and interdisciplinary interaction for early diagnosis, effective and safe treatment, and improved prognosis.

Short-term outcomes of a multicentre randomized clinical trial comparing D2 versus D3 lymph node dissection for colonic cancer (COLD trial).

BACKGROUND: It remains unclear whether extended lymphadenectomy provides oncological advantages in colorectal cancer. This multicentre RCT aimed to address this issue. METHODS: Patients with resectable primary colonic cancer were enrolled in four hospitals registered in the COLD trial, and randomized to D2 or D3 dissection in a 1 : 1 ratio. Data were analysed to assess the safety of D3 dissection. RESULTS: The study included the first 100 patients randomized in this ongoing trial. Ninety-nine patients were included in the intention-to-treat (ITT) analysis (43 D2, 56 D3). Ninety-two patients received the allocated treatment and were included in the per-protocol (PP) analysis: 39 of 43 in the D2 group and 53 of 56 in the D3 group. There were no deaths. The 30-day postoperative morbidity rate was 47 per cent in the D2 group and 48 per cent in the D3 group, with a risk ratio of 1·04 (95 per cent c.i. 0·68 to 1·58) (P = 0·867). There were two anastomotic leaks (5 per cent) in the D2 group and none in the D3 group. Postoperative recovery, complication and readmission rates did not differ between the groups in ITT and PP analyses. Mean lymph node yield was 26·6 and 27·8 in D2 and D3 procedures respectively. Good quality of complete mesocolic excision was more frequently noted in the D3 group (P = 0·048). Three patients in the D3 group (5 per cent) had metastases in D3 lymph nodes. D3 was never the only affected level of lymph nodes. N-positive status was more common in the D3 group (46 per cent versus 26 per cent in D2), with a risk ratio of 1·81 (95 per cent c.i. 1·01 to 3·24) (P = 0·044). CONCLUSION: D3 lymph node dissection is feasible and may be associated with better N staging. Registration number: NCT03009227 ( http://www.clinicaltrials.gov).

ANTECEDENTES: El beneficio oncológico de la linfadenectomía extendida en el cáncer colorrectal es controvertido. Este ensayo clínico aleatorizado multicéntrico tuvo como objetivo abordar esta discrepancia. MÉTODOS: Se analizaron los datos de los primeros 100 pacientes aleatorizados en un ensayo en curso para evaluar la seguridad de la disección D3. Los pacientes con cáncer de colon primario resecable incluidos en 4 hospitales participantes en el ensayo COLD, se aleatorizaron para la disección D2 y D3 en una proporción 1: 1. RESULTADOS: Se incluyeron 99 pacientes en el análisis por intención de tratamiento (intention-to-treat, ITT) (43 en D2, 56 en D3). Un total de 92 pacientes recibieron el tratamiento asignado y se incluyeron en el análisis por protocolo (per-protocol, PP): 90,7% (39 de 43) en D2, 94,6% (53 de 56) en D3. No hubo mortalidad. La morbilidad postoperatoria a los 30 días fue del 46,5% en el grupo D2 y del 48,2% en el grupo D3 con un riesgo relativo (RR) de 1,04 (i.c. del 95%: 0,68 a 1,58), P = 0,86. Hubo dos casos de fuga anastomótica (4,7%) en el grupo D2 y ninguna en D3. La recuperación postoperatoria, las complicaciones y las tasas de reingreso no difirieron entre los análisis ITT y PP. El recuento medio de ganglios linfáticos fue 26,6 y 27,8 en D2 y D3, respectivamente. Se observó una resección completa del mesorrecto de buena calidad con mayor frecuencia en el grupo D3 (P = 0,048). En el grupo D3, 3 pacientes (5,4%) tenían metástasis en los ganglios linfáticos D3. D3 nunca fue el único nivel afectado de ganglios linfáticos. El estadio pN positivo fue más frecuente en el grupo D3: 46,4% versus 25,6% en D2, con un RR para revelar enfermedad N positiva de 1,81 (i.c. del 95% 1,01 a 3,2), P = 0,04. CONCLUSIÓN: La disección de ganglios linfáticos D3 es factible y puede estar asociada con una mejor estadificación N.

KH-Domain Poly(C)-Binding Proteins as Versatile Regulators of Multiple Biological Processes.

Five known members of the family of KH-domain poly(C)-binding proteins (Pcbp1-4, hnRNP-K) have an unusually broad spectrum of cellular functions that include regulation of gene transcription, regulation of pre-mRNA processing, splicing, mRNA stability, translational silencing and enhancement, the control of iron turnover, and many others. Mechanistically, these proteins act via nucleic acid binding and protein-protein interactions. Through performing these multiple tasks, the KH-domain poly(C)-binding family members are involved in a wide variety of biological processes such as embryonic development, cell differentiation, and cancer. Deregulation of KH-domain protein expression is frequently associated with severe developmental defects and neoplasia. This review summarizes progress in studies of the KH-domain proteins made over past two decades. The review also reports our recent finding implying an involvement of the KH-factor Pcbp1 into control of transition from naïve to primed pluripotency cell state.

[Local recurrences of colon cancer (in Russian only)]. / Mestnyi retsidiv raka obodochnoi kishki: rezul'taty lecheniia.

AIM: To evaluate the outcomes in patients with local recurrences (LR) of colon cancer. MATERIAL AND METHODS: Prospective study included 52 patients with local recurrences of colon cancer MR and no distant metastases or disseminated carcinomatosis. Patients have been treated at Ryzhikh State Research Center for Coloproctology for the period 2009-2017. Median of local recurrence was 17.6 months. By the moment of diagnosis, CEA was increased in 24 (46.2%), CA 19-9 - in 4 (7.7%) patients. Forty-eight (92%) patients underwent surgery for local recurrences of colon cancer. In 26 (54%) cases, low ligation of supplying vessel was made during primary tumor excision that was confirmed by significant fragment of intact mesentery of the colon. RESULTS: Radical surgery for LR was possible in 34 (70.8%) patients, resection of more than one organ was required in 60% of cases. R1-resection was obtained in 12 (25.0%) cases, palliative resections - in 2 (4.2%) patients. Various complications occurred in 34 (70.8%) patients. Additional intraperitoneal chemotherapy was need in 12 (23.1%) cases. Lethal outcomes were absent. Forty-six out of 48 (95.8%) patients were followed-up. Mean follow-up was 19.5 (8.6-34.7) months. Twelve (26.1%) patients were free from recurrent cancer. Only distant metastases developed in 16 (34.8%) patients. Redo LR occurred in 18 (39.1%) patients including 12 of them with distant metastases. Overall 5-year survival was 38%, disease-free survival - 17.5%, median overall survival - 42.8 months, median disease-free survival - 15.2 months. Intraperitoneal chemotherapy did not significantly affect overall survival. Multivariate analysis confirmed high level of CEA and CA 19-9, positive resection margin as negative predictors. Moreover, impaired survival (p=0.03) was noted in case of LR after non-radical surgery for primary tumor with high ligation of the vessel. CONCLUSION: R0-resection is essential to improve survival and reduce incidence of recurrences. Intraoperative intra-abdominal chemotherapy does not affect the outcomes in patients with LR of colon cancer. Adherence to surgical principles for cancer can reduce the incidence of LR.

[Investigation of transcriptional regulation of Oct4 (POU5F1) gene with distal enhancer].

Investigations of transcriptional regulation of Oct4 gene in mouse embryonic stem cells have revealed an important cis-element--the distal enhancer (DE). DE consists of two functionally significant elements--DEa and DEb. Both elements are necessary to complete the DE-mediated expression of Oct4 gene in pluripotent cells. The most likely candidates for the binding site DEb are Oct4 itself in complex with Sox2 protein. It remains unclear which transcriptional proteins bind to the DEa site and what is the mechanism of the co-operation between the DEa and the DEb. Through the use of using the EMSA and chromatographic fractionation of proteins from extracts of mouse embryonic stem cells and mouse tissues, were isolated proteins specifically interacting with the sequence DEa Oct4 gene.

[Lymphocyte metabolism in children with extensive burns].

The results of the study lead to the conclusion that the development of burn disease in children is accompanied by significant lymphocytic structural metabolic changes that determine the functional capabilities of cells and the immune system as a whole. There is an evident activation of the glutathione antioxidant system, a drastic activation of enzymes that ensure Krebs cycle reactions, as well as activation of anaerobic processes. The above changes are mainly caused by the activated sympathoadrenal system that is characteristic of stresses. The knowledge about the metabolic mechanisms responsible for the development of cellular reactions to burn shock and burn disease permits specification of the elements of the pathogenesis of these severe conditions and substantiation of the possibility of using metabolic correction in the complex treatment of children with the above pathology.

[Endocrine homeostasis and its correction with stress protectors in children with severe burn injury].

The use of stress protection with dalargin, clofelin, and pentamine in the treatment of children with severe burn injury was ascertained to result in a reduction in the magnitude of abnormal changes in the endocrine system and in the prevention of depletion of its compensatory capacities. This treatment will assist in reducing the severity of endotoxicosis, as well as the frequency and severity of toxic and pyoseptic complications.

[Peripheral nerve block as a component of anesthesia during operations on lower extremity vessels].

Lumbar plexus block via inguinal paravascular access that was included as part of an anesthetic support at venectomy in the great saphenous vein, was studied for its impact on the development of postoperative pain syndrome and stress responses. The authors revealed a significant postoperative pain relief at rest and in motion, and reductions in the need for analgesics and in the magnitude of a stress response to a surgical injury.

[Continuous epidural anesthesia in patients after surgical treatment for scoliosis].

Analgesia after major spinal orthopedic surgery is a problem to be solved. The authors' original procedure for using continuous epidural anesthesia following scoliosis surgery is an effective mode of upgrading the quality of analgesia within the first 24 hours and diminishing postoperative stress. A visual analogue scale was used to evaluate the efficiency of the procedure. The levels of stress hormones (cortisol, T3, and T4) were measured.

[Correction of temperature homeostasis and microcirculation under the stress-protection anesthesia in hip replacement]. / Korrektsiia temperaturnogo gomeostaza i mikrotsirkuliatsii v usloviiakh stress-protektornoi anestezii pri éndoprotezirovanii tazobedrennogo sustava.

Prolonged epidural anesthesia belongs to the most effective anesthetic management schemes in total hip replacement. However, its use is related with compensatory stress-induced vasoconstriction resulting in an impaired vasoconstriction registered above the block level. It entails, in its turn, an impaired thermoregulation (hypothermia, postoperative muscle trembling), a reduced renal blood flow with diminished diuresis and metabolic lactate-acidosis. The preoperative preparation with daralgin (15 microg/kg, 3 intramuscular injections per day for 2-3 days) with its subsequent intraoperative infusion (30 microg/h) made concurrently with premedication by clofelin (1.5 microg/kg) arrest the above hemostasis impairments. Finally, the ability of stress-protection drugs to diminish the rate of postoperative fever and muscle trembling was registered.

Dephosphorylation of histone gamma-H2AX during repair of DNA double-strand breaks in mammalian cells and its inhibition by calyculin A.

The induction of DNA double-strand breaks (DSBs) by ionizing radiation in mammalian chromosomes leads to the phosphorylation of Ser-139 in the replacement histone H2AX, but the molecular mechanism(s) of the elimination of phosphorylated H2AX (called gamma-H2AX) from chromatin in the course of DSB repair remains unknown. We showed earlier that gamma-H2AX cannot be replaced by exchange with free H2AX, suggesting the direct dephosphorylation of H2AX in chromatin by a protein phosphatase. Here we studied the dynamics of dephosphorylation of gamma-H2AX in vivo and found that more than 50% was dephosphorylated in 3 h, but a significant amount of gamma-H2AX could be detected even 6 h after the induction of DSBs. At this time, a significant fraction of the gamma-H2AX nuclear foci co-localized with the foci of RAD50 protein that did not co-localize with replication sites. However, gamma-H2AX could be detected in some cells treated with methyl methanesulfonate which accumulated RAD18 protein at stalled replication sites. We also found that calyculin A inhibited early elimination of gamma-H2AX and DSB rejoining in vivo and that protein phosphatase 1 was able to remove phosphate groups from gamma-H2AX-containing chromatin in vitro. Our results confirm the tight association between DSBs and gamma-H2AX and the coupling of its in situ dephosphorylation to DSB repair.

The angiotensin converting enzyme I/D polymorphism in Russian athletes.

The deletion (D) allele of the human ACE gene is associated with higher ACE activity than the insertion (I) allele. There is controversy as to whether the ACE genotype may be associated with elite athletic status; recent studies have identified no significant associations amongst those drawn from mixed sporting disciplines. However, such lack of association may reflect the mixed nature of such cohorts, given that an excess frequency of the I allele has been reported amongst elite endurance athletes, and an excess of the D allele amongst those engaged in more power-orientated sports. We examined this hypothesis by determining ACE I/D allele frequency amongst 217 Russian athletes (swimmers, skiers, triathletes and track-and-field participants) prospectively stratified by performance ('outstanding' or 'average'), and the duration of their event (SDA (<1 min), MDA (1 to 20 min), and LDA (>20 min): short, middle and long distance athletes respectively). ACE genotype and allele frequencies were compared to 449 controls. ACE genotype frequency amongst the whole cohort, or the outstanding athletes alone, was no different to that amongst sedentary controls. However, there was an excess of the D allele (frequency 0.72, P=0.001) amongst the outstanding SDA group, and an excess of the I allele (frequency 0.63, P=0.032) amongst the outstanding MDA group. These findings were replicated in the outstanding swimmers, with track and field SDA similarly demonstrating an excess of the D allele (P=0.01). There was no association found between the outstanding LDA and ACE genotype (P=0.27). These data not only confirm an excess of the D allele in elite SDA, and I allele in elite MDA, but also offer an explanation as to why any such association may be hard to detect amongst a heterogeneous cohort of mixed athletic ability and discipline.

The dynamics of nitrous oxide emission from the use of mineral fertilizers in Russia.

The intensity of nitrous oxide (N2O) emission was considered based on literature data on the single input of mineral N (nitrogen) fertilizers into different agricultural soil types in Russia. Ambient environmental factors exert a combined effect on the process of gaseous nitrogen formation from fertilizers applied. To reduce the uncertainty of estimates as much as possible, only experimental results obtained under conditions similar to natural were selected for the assessments. Mineral nitric fertilizers were applied to soil at a rate of 40 to 75 kg/ha and the N2O emissions were measured for approximately 140 days. Daily average emission values varied from 0.08 to 0.45% of fertilizer nitrogen. Correspondingly, 1.26 and 2.38% of fertilizer nitrogen were emitted as N2O from chernozems and soddy podzols. In 1990, the use of fertilizers in Russian agricultural practices for 53 Gg N2O-N, which equates to approximately 6.1% of global nitrous oxide emissions from nitric fertilizers. Later, the emission dropped because of a decrease in the input of nitric fertilizers to agricultural crops, and in 1998, it constituted just 20.5% of the 1990 level. In the period from 2008 to 2012, the nitrous oxide emission is expected to vary from 0.5 to 65.0 Gg N2O-N due to possible changes in national agricultural development. In the most likely scenario, the use of mineral fertilizers in Russia will account for approximately 34 to 40 Gg N2O-N emissions annually from 2008-2012.

[Continuous-discrete models of the dynamics of an isolated population and of 2 competing species]. / Nepreryvno-diskretnye modeli dinamiki izolirovannoi populiatsii i dvukh konkuriruiushchikh vidov.

The paper presents the analysis of various mathematical models for dynamics of isolated population and for competition between two species. It is assumed that mortality is continuous and birth of individuals of new generations takes place in certain fixed moments. Influence of winter upon the population dynamics and conditions of classic discrete model "deduction" of population dynamics (in particular, Moran-Ricker and Hassel's models) are investigated. Dynamic regimes of models under various assumptions about the birth and death rates upon the population states are also examined. Analysis of models of isolated population dynamics with nonoverlapping generations showed the density changes regularly if the birth rate is constant. Moreover, there exists a unique global stable level and population size stabilizes asymptotically at this equilibrium, i.e. cycle and chaotic regimes in various discrete models depend on correlation between individual productivity and population state in previous time. When the correlation is exponential upon mean population size the discrete Hassel model is realized. Modification of basis model, based on the assumption that during winter survival/death changes are constant, showed that population size at global level is stable. Generally, the dependence of population rate upon "winter parameters" has nonlinear character. Nonparametric models of competition between two species does not vary if the individual productivity is constant. In a phase space there are several stable stationary states and population stabilizes at one or other level asymptotically. So, in discrete models of competition between two species oscillation can be explained by dependence of population growth rate on the population size at previous times.

[State of neuroendocrine systems and immunity in patients with burns]. / Sostoianie neiroéndokrinnykh sistem i immuniteta u bol'nykh s ozhogami.

The study of hormonal shifts and immunity in 95 patients with burns has revealed hyperergic reaction of the neuroendocrine system in the early period after trauma, accompanied by a marked and prolonged inhibition of cellular and humoral immunity. The use of antistress agents (clofelin, pentamine) and intravenous laser blood irradiation leads to a more prompt arrest of hyperergic reaction of the neuroendocrine system and to the reduction of immunosuppressing effect of burn trauma, which decreases the number of pyoseptic complications from 26.4 to 16% and total lethality from 16 to 3.8%.

[The prevention of undesirable changes in the endocrine system in patients in the intraoperative period using stress-preventive preparations]. / Preduprezhdenie neblagopriiatnykh sdvigov éndokrinnoi sistemy u bol'nykh v operatsionnom periode v usloviiakh ispol'zovaniia stress-protektornykh preparatov.

The functions of the adrenal cortex, thyroid gland and carbohydrate metabolism have been analysed in 20 patients to whom current schemes of premedication and anesthesia have been applied, 20 patients who in the nearest preoperative period and intraoperatively have been administered ganglioblockers and adrenolytics, and 20 patients in whom clophelin has been used during premedication and anesthesia. It has been established that the use of stress-protecting agents for premedication and anesthesia almost prevents hyperergic reaction of the adrenal cortex, thyroid gland and carbohydrate metabolism.

[The use of adreno- and gangliolytics for preventing hemodynamic disorders in patients in the immediate preoperative period]. / Ispol'zovanie adreno- i gangliolitikov dlia preduprezhdeniia narushenii gemodinamiki u bol'nykh v neposredstvennom predoperatsionnom periode.

The indices of central and peripheral hemodynamics in 40 patients with the generally accepted scheme of premedication and in 40 patients who were given adrenogangliolytics for medicamentous preparing before narcosis have been analyzed. The inclusion of these drugs in the premedication preparing was established to ensure a sufficiently complete prevention of an excessive preoperative stress reaction.