According to modern phylogenetic theory of general pathology (V.N. Titov, 2003, 2013) inflammation is a nonspecific biological reaction, providing the removal of excessive amount of highmolecular macromolecules and maintenance of metabolic homeostasis (endoecology). The increase of any metabolite concentration above the physiological range is a violation of the «purity» of intercellular medium. This triggers two nonspecific biological reactions, namely the excretion used to remove «biological waste» of a molecular weight less than 70 kD and the inflammation in case the larger molecules and their complexes should be removed via neutrophils, resident macrophages and endothelial cells. Blood concentration of leukocytes has been used for evaluation of inflammation and intoxication activity for many decades. However, at the molecular level there is a requirement in precise differentiation of metabolites, activating leukocytes, and metabolites, excessively forming as a result of activation, because the last disturb molecular homeostasis and may damage cells and tissues. Validity of leucocytal intoxication index (LII) of Ya.Ya. Kalf-Kalif, concentration ratio of low and medium molecular weight substances, average molecular peptides, total and effective albumin as markers of endogenous intoxication (M.Ya. Malakhova, 2005) are considered. It is shown that primary agent, activating neutrophils and some factors of humoral immunity, is a lipopolysaccharide (endotoxin) of gram-negative microflora (M.Yu. Yakovlev, 2003; O.W. McIntyre, 2011). An excess of endotoxin inflow is possible under intestine and liver pathologies, and due to sympathoadrenal system activation, and also with feed and air. The overload of systems and organs of elimination of endotoxin causes secondary immunodeficiency, which becomes the cause of acute and chronic inflammatory processes of various localizations. It is offered to consider lipopolysaccharide of gramnegative microflora as a primary agent of endogenous intoxication and all the metabolites, produces at increased concentrations as a result of polymorphonuclear leukocytes activation such as reactive oxygen species, oxidated proteins, products of lipid peroxidation and proteolysis, as a secondary one. Such an approach allows to single out various points of application for therapy of endogenous intoxication: i) elimination of excessive concentration of lipopolysaccharide in blood by limiting its production and income from internal and external sources, as well as by a variety of methods of active binding and excretion of endotoxin (S.V. Smirnov et al., 2003; K. Battenschoen et al., 2010); ii) reducing the concentration of «secondary» metabolites in blood and tissues.

A b s t r a c tFree radical lipid oxidation is currently considered as one of the dominant metabolic processes of physiological system functional activity. When it goes beyond regulated limits it is considered as an inductor of free radical pathology oxidative stress. In the conditions of a big dairy cattle breeding farm (Voronezh Province), specialized in Red-and-White breed, the functioning peculiarities of the peroxidation system lipid-oxidant defense in cows at the normal course of gestation and at gestosis, at the normal course of postpartum period and at puerperal endometritis, uterus subinvolution and ovarian dysfunction were studied. The state of lipid peroxidation processes and antioxidant system were evaluated by determining total lipid content, cholesterol, triglycerides, malonic dialdehyde (MDA), nitrogen oxides (NO • ), E and C vitamins concentrations, glutathione peroxidase (GPO), glutathione reductase (GR), catalase, superoxide dismustase (SOD) activity in blood. It is demonstrated that the high activity of lipid peroxidation reactions and the system of nitrogen oxide at decrease of antioxidant defense non-enzymic link capacity is the basis of gestosis and acute postnatal complications. Thus, àn increase of MDA concentration by 42.3-43.0 %, NO • by 31.9-38.0 % was observed in cows with gestosis. At mild gestosis the glutathione peroxidase activity, catalase activity and vitamin C concentration increased by 11.0 %, 14.3 %, 38.0 %, and 24.1 %, respectively, while vitamin Å concentration decreased by 11.7 % due to more consumption for neutralization of the toxic peroxidation products. At more sever pathology, the glutathione peroxidase activity and catalase activity in blood increased by 26.0 % and 17.3 %, respectively, when compared to the healthy animals, while vitamins E and C concentrations decreased by 33.3 % (ð < 0,01) and 17.2 %, respectively. As free radical oxidation intensified, an anaerobic degradation of carbohydrates was activated to supply the tissues of developing fetus with energy under oxygen deficit occurred because of violation of the blood circulation. Postpartum inflammation in the genital organs in cows developed against the background of increase of MDA concentration by 76.0 %, GPO and GR activity by 65.8 % and 14.6 %, respectively, SOD by 46.0 %, catalase by 45.7 %, 2.9 times increase of NO • concentration and reduction of vitamin E content by 35.5 %. Infertile animals with ovarian dysfunction were characterized by high activity of lipid peroxidation processes and by low level of nitrogen oxide generation. This is indicated by an increased concentration of MDA by 57.0 %, activity of GPO by 27.6 %, GR by 10.5 %, SOD by 31.9 %, catalase by 24.3 %, with a reduced content of NO • and vitamin E by 56.9 % and 31.6 %, respectively, in comparison with healthy animals. A decrease in NO • concentration in blood could result from a sharp depression of hormone synthesizing function in ovaries, and low NO • production could disturb functions of the gonads. The high level of peroxidation is...

A b s t r a c tInflammatory diseases of the respiratory and gastrointestinal tracts are the actual problem of veterinary medicine. Innate or natural immunity plays the leading role in the initial reactions to microbial agents contaminating sterile mucous membranes of newborn animals. It is implemented through the activation of cellular and humoral factors of nonspecific resistance. Leukocyte concentration, leukogram, content of cationic proteins in neutrophils, blood serum lysozyme activity (BSLA) were studied in 20 red-motley calves in 1 hour after their birth on the days 2, 5-7 and 14-15 of life, together with an impact of these indices on the terms of appearance and clinical course of inflammatory diseases of the respiratory and gastrointestinal tracts, under conditions of a large dairy complex environment (Voronezhpishcheprodukt Co Ltd, Novousmansky district, Voronezh region) in 2014. Blood sampling was implemented in the morning before feeding from the jugular vein. Body temperature, pulse and respiratory rate, state of the visible mucous membranes, time of appearance and intensity of sucking reflex, the presence and nature of cough, dyspnea, nasal expiration, reaction to palpation of the larynx, trachea, intercostal spaces, the abdominal wall, percussion and auscultation of the chest were determined in calves. The markers of intestinal inflammation are soluble protein, erythrocytes (hemoglobin), leukocytes (leukocyte elastase), pH. They were identified in feces by dry-chemistry method during the same period and also selectively at the age of 1-1.5 months. According to clinical and hematological indices the animals were retrospectively divided into 2 groups: group A with leukocyte concentration of (11.0-18.3)½10 9 /l and segmentonuclear neutrophils (SN) more than 4½10 9 /L at birth; group B with leukocyte concentration of 6.5-11.3½10 9 /l and SN lesser than 3.9½10 9 /l at birth. Granulocyte blood concentration dynamics in calves of these groups significantly differed both among themselves and from physiological dynamics (adaptive norm) during the first 15 days of their life. This was determined by various phases of adaptation syndrome (mobilization, resistance, exhaustion) and various possibilities of calves' granulocytic system reaction to irritants impact according to J. Wilder's law of initial values (1957). The increased blood level of SN and rod neutrophils (RN) in animals of group A at birth indicates existing activation of bone marrow and may not significantly increase in response to a rather intensive stimulus. Initial level of SN and RN in calves of group B was close to the physiological one, it significantly increased on the day 2 and decreased by the days 5-7 of life. Cationic protein concentration and BSLA in all the calves during the research period were lower than the indices typical of the animals of this age. Diarrhea developed in all the calves on the day 2 of life. Its duration in animals of groups A and B was 8.6±1.1 and 4.2±0.6 days, respectively. When diarrhea symptoms disappeared, inte...

No abstract

No abstract

No abstract

A bimodal pattern of hazard of relapse among early stage breast cancer patients has been identified in multiple databases from US, Europe and Asia. We have been studying these data to determine if this can lead to new ideas on how to prevent relapse in breast cancer. Using computer simulation and access to a very high quality database from Milan for patients treated with mastectomy only, we proposed that relapses within 3 years of surgery are stimulated somehow by the surgical procedure. During the week post surgery, metastatic development is enhanced 100 fold according to the simulation. Most relapses in breast cancer are in this early category. Retrospective data from a Brussels anesthesiology group suggested a plausible mechanism. Use of ketorolac, a common NSAID analgesic used in surgery was associated with far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. Transient systemic inflammation accompanying surgery (identified by IL-6 in serum) could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Similar bimodal patterns have been identified in other cancers suggesting a general effect. Based on the writings of Galen and Celsus, metastatic development after breast tumors were removed was known to them 2000 years ago. This effect has been demonstrated recently in a mouse model by Krall et al Science Translational Medicine and reviewed in NEJM by Komaroff. In a series of experiments in 273 mice, aggressive mouse breast cancer cells were implanted in various locations. Initially, the tumor cells grew but then became dormant. This dormancy occurred only in mice with intact immunity, which suggests that the immune system can contain certain dormant metastases. Surgery of any type (including resection of a primary tumor) led to aggressive growth of metastases in 60% of animals, compared with 10% of control animals that did not undergo surgery. Surgical procedures caused systemic inflammatory responses. Activated monocytes from the marrow traveled to the sites of the dormant metastases and became tumor associated macrophages. These macrophages suppressed the immune system near the tumor, awakening the metastases from their dormancy. Treating the animals with NSAIDs before and immediately following surgery greatly attenuated growth of these metastases. Since this effect has by now been shown in two Belgian retrospective studies as well as a mouse model we suggest this be tested in one or more clinical trials. We also note that the bleeding potential from using NSAIDs before surgery can apparently be reduced with the use of Tranexamic Acid – currently being tested in a clinical trial for mastectomy. Citation Format: Retsky MW, Baum M, Vaidya JS, Rogers RA, Hrushesky WJ, Demicheli R, Forget P. Early relapses in breast cancer can be prevented by a perioperative NSAID, which would be a solution to a 2000 year old problem [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-01.