Features of Interferon Status and Methods of Its Correction in the Treatment of Patients with Atypical Chronic Active Herpesvirus Infections.

It is known that the imbalance of the IFN system is the cornerstone of the immunopathogenesis of atypical chronic active herpesvirus infections and is often associated not only with congenital, genetically determined defects, but also with acquired system dysregulation at different levels: receptor, molecular, at the level of a nuclear transducer of signal transmission. Based on the studied features of immunopathogenesis and the revealed disturbances in the antiviral immune defense system and the IFN system in patients with atypical chronic herpes viral infections, an integration program for correcting IFN status was developed, its clinical and immunological effectiveness was evaluated. Improved effectiveness of complex rehabilitation of immunocompromised patients with atypical chronic active herpes viral infections was demonstrated.

[The impact of disbalance of regulatory cytokines and osteocalcin on osteogenesis in children with congenital cleft lip and palate in postnatal ontogenesis]. / Vliianie disbalansa reguliatornykh tsitokinov i osteokal'tsina na osteogenez u detei s vrozhdennoi rasshchelinoi guby i neba v postnatal'nom ontogeneze.

The aim of the work was a comprehensive assessment of the system of cytokines and peripheral blood osteocalcin with the establishment of features of their interconnections in children with congenital cleft lip and palate (CCLP) in comparison with the corresponding controls at different age periods. In the peripheral blood of 80 children (0-12 months, 1-3 years, 4-9 years, 10-15 years) with osteocalcin and IL17, IL4, congenital cleft lip and palate and age-appropriate control of healthy individuals (40 people) IL6, IL1ß, IFNγ by enzyme immunoassay. An analysis of the data obtained with CCLP revealed significant differences in the dynamics of the relationship between pro-inflammatory (IL1ß, IL6, IL17), regulatory (IFNγ), anti-inflammatory (IL4) cytokines and osteocalcin compared with controls. The patterns of changes and effects of IL17, IFNγ, IL4 and osteocalcin in healthy children and in children with congenital cleft lip and palate in postnatal ontogenesis were established. Cytokine dysregulation of immunosteogenesis in CCLP, leading to a significant deficit of osteocalcin in the first year of life due to an imbalance of the cytokine profile: discordant IL17, IFNγ and IL4 were detected. Thus, the data obtained are undoubtedly important in the future for developing new strategies for targeted therapy aimed at normalizing osteocalcin levels at different age periods in children with congenital cleft lip and palate.

[Protective Activity of Prion Protein Fragments after Immunization of Annimals with Experimentally Induced Alzheimer's Disease].

The prion protein is considered as one of the membrane targets of neurotoxic beta-amyloid during Alzheimer's disease development. We have chosen and synthesized 17-33, 23-33, 95-110 and 101-115 prion fragments involved in beta-amyloid binding. The effect of immunization with the peptides on the features of Alzheimer's disease was investigated in animals with an experimentally induced form of the disease. It was shown that immunization either with peptide 17-33 or with protein conjugates of peptides 23-33 and 101-115 increases the level of brain beta-amyloid and improves morfofunctional state of the brain.

Immunization with either prion protein fragment 95-123 or the fragment-specific antibodies rescue memory loss and neurodegenerative phenotype of neurons in olfactory bulbectomized mice.

Epidemiological studies demonstrated association between head injury (HI) and the subsequent development of Alzheimer's disease (AD). Certain hallmarks of AD, e.g. amyloid-ß (Aß) containing deposits, may be found in patients following traumatic BI (TBI). Recent studies uncover the cellular prion protein, PrP(C), as a receptor for soluble polymeric forms of Aß (sAß) which are an intermediate of such deposits. We aimed to test the hypothesis that targeting of PrP(C) can prevent Aß related spatial memory deficits in olfactory bulbectomized (OBX) mice utilized here to resemble some clinical features of AD, such as increased level of Aß, memory loss and deficit of the CNS cholin- and serotonin-ergic systems. We demonstrated that immunization with the a.a. 95-123 fragment of cellular prion (PrP-I) recovered cortical and hippocampus neurons from OBX induced degeneration, rescued spatial memory loss in Morris water maze test and significantly decrease the Aß level in brain tissue of these animals. Affinity purified anti-PrP-I antibodies rescued pre-synaptic biomarker synaptophysin eliciting similar effect on memory of OBX mice, and protected hippocampal neurones from Aß25-35-induced toxicity in vitro. Immunization OBX mice with a.a. 200-213 fragment of cellular prion (PrP-II) did not reach a significance in memory protection albeit having similar to PrP-I immunization impact on Aß level in brain tissue. The observed positive effect of targeting the PrP-I by either active or passive immunization on memory of OBX mice revealed the involvement of the PrP(C) in AD-like pathology induced by olfactory bulbectomy. This OBX model may be a useful tool for mechanistic and preclinical therapeutic investigations into the association between PrP(C) and AD.

Localization and differentiation pattern of transplanted human multipotent mesenchymal stromal cells in the brain of bulbectomized mice.

Replacement cell therapy with transplantation of stem cells is a promising approach for the therapy of various neurodegenerative diseases, e.g. Alzheimer's disease. However, the behavior of transplanted cells in the damaged tissue should be thoroughly studied before introduction of this method into clinical practice. We studied the pathways of migration of human multipotent mesenchymal stromal cells after their systemic transplantation into the brain of bulbectomized mice characterized by the development of Alzheimer-type neurodegenerative process. Immunohistochemical analysis with antibodies to human nuclear antigen (HNA) and immunofluorescent analysis of the results of transplantation of multipotent mesenchymal stromal cells carrying green fluorescent protein (GFP) gene showed that these cells can cross the blood-brain barrier and penetrate into some structures of recipient brain. Analysis of differentiation of transplanted human cells using antibodies to neurospecific enolase (NSE) or astroglial marker (GFAP) with parallel staining for human nuclear antigen revealed no neural differentiation of transplanted cells in the brains of bulbectomized animals. However, some of these cells differentiated into astrocytes, which brought us to an assumption on important role of astroglial abnormalities in the pathogenesis of Alzheimer's disease.

[Risk stratification in selective surgery of abdominal aortic aneurysm].

A retrospective analysis of data of 188 patients, who underwent a selective surgery for abdominal aortic aneurism showed, that all the patients had a cardiac pathology. Ischemic heart disease and arterial hypertension had 175 (93.0%) and 177 (94.1%) of patients, respectively. Chronic nonspecific lung disease was noted in 65.4% patients and kidney disease--in 48.9%. Different complications developed in early postoperative period in 47 (25%) patients, that resulted in fatal outcome in 20(10,6%). The most frequent complication was an acute renal insufficiency, which led to fatal outcome in 40% patients. Myocardial infarction and pneumonia took the second place in the structure of postoperative complications, one half of the fatal cases was due to these. Retrospective risk stratification assessment of the development of early postoperative complications and lethality was made by Glasgow Aneurysm Score (GAS) and angiosurgical model scale V-POSSUM. It was stated, that score was up to 84 according to GAS scale and up to 28 (V-POSSUM). That fact is the evidence of high risk of the operation. On the basis of ROC curves building, the conclusion was made about greater predictive ability of V-POSSUM scoring system.

[The characteristics of medical activities in families fostering disabled children].

The characteristics of medical activities in families fostering disabled children are given. The assessment is implemented according the system of specific indicators developed by the authors to determine corresponding social hygienic, medical organizational and social psychological factors. The analysis of medical activities indicators is carried out to reveal the groups of higher medical social risk and to establish the requirements in different types of medical care.

[The characteristics of children disability on the Northern Territories].

The materials related to the regional characteristics of health formation in the disabled children are presented. The corresponding evaluation was made using the conventional and new methodological approach based on the so-called "three-dimensional concept". The obtained data is the initial base for developing and implementation of the integrated programs of the medical social, psychological pedagogical and social economical rehabilitation of the disabled children and their families.

Morphofunctional state of neurons in the temporal cortex and hippocampus in relation to the level of spatial memory in rats after ablation of the olfactory bulbs.

Ablation of the olfactory bulbs (bulbectomy) in mice and guinea pigs evokes a neurodegenerative process which, in terms of its morphological, biochemical, and behavioral features, is similar to Alzheimer's disease. We report here studies of the long-term sequelae of bulbectomy in rats. One year after surgery, testing of spatial memory in bulbectomized rats (BER) allowed the animals to be divided into two groups-those with good memory (BER-gm) and those with poor memory (BER-pm). Quantitative analysis of the morphofunctional state of neurons showed that BER-pm, as compared with the BER-gm group, had more marked pathological lesions in neurons of the temporal cortex and hippocampus, with significant increases in the numbers of cells showing pyknosis, karyolysis, cytolysis, and vacuolization. Both groups showed decreases in the distribution density of cells in the cortex. In terms of the level of brain beta-amyloid, the study groups fell in the order: BER-pm>BER-gm>control sham-operated rats. These results provide evidence of the long-term nature of changes in the morphofunctional state of neurons in the brains of BER, correlating with their levels of spatial memory.

[Morpho-functional state of neurons in temporal cortex and hippocampus in bulbectomized rats with different level of spatial memory].

Olfactory bulbs removal (bulbectomy) induced neurodegeneration in the brain of mice and guinea pigs which, according to its morphological, biochemical and behavioral features was simular to manifestations of Alzheimer's disease. In the present work long-term effects of bulbectomy were examined in rats. It was shown that 1 year after the operation bulbectomized animals (BEA) could be divided into two subgroups: animals with good results of testing spatial memory(BEA-GM), and with poor memory (BEA-PM). The quantitative analysis of neurons morpho-functional state has shown more expressed pathological changes (an increase in the number of cells with pyknosis, karyolysis, cytolysis, and vacuolization) in neurons of temporal cortex and hippocampus in BEA-PM as compared to those in BEA-GM. In both animal groups the reduction of cellular density was marked in the cortex. According to the content of brain beta-amyloid the groups of experimental animals were distributed in the following order: BEA-PM>BEA-GM>control group of sham-operated rats. The results indicate the long-term changes of morpho-functional state of neurons in the brain of BEA, which correlated with the level of their spatial memory.

[The medical social risk factors of the disabled children].

The results of medical sociological study of the risk factors in the families bringing up a disabled child is presented. The comparative analysis of the structure of the children's disability considering various methodological approaches and regional characteristics. The description of the social status of the families with disabled children is given. The particular attention is drew to the studying of the medical demographic, social economic and psychological educational risk factors of the studied family contingent.

The Y-Box Binding Protein 1 Suppresses Alzheimer's Disease Progression in Two Animal Models.

The Y-box binding protein 1 (YB-1) is a member of the family of DNA- and RNA binding proteins. It is involved in a wide variety of DNA/RNA-dependent events including cell proliferation and differentiation, stress response, and malignant cell transformation. Previously, YB-1 was detected in neurons of the neocortex and hippocampus, but its precise role in the brain remains undefined. Here we show that subchronic intranasal injections of recombinant YB-1, as well as its fragment YB-11-219, suppress impairment of spatial memory in olfactory bulbectomized (OBX) mice with Alzheimer's type degeneration and improve learning in transgenic 5XFAD mice used as a model of cerebral amyloidosis. YB-1-treated OBX and 5XFAD mice showed a decreased level of brain ß-amyloid. In OBX animals, an improved morphological state of neurons was revealed in the neocortex and hippocampus; in 5XFAD mice, a delay in amyloid plaque progression was observed. Intranasally administered YB-1 penetrated into the brain and could enter neurons. In vitro co-incubation of YB-1 with monomeric ß-amyloid (1-42) inhibited formation of ß-amyloid fibrils, as confirmed by electron microscopy. This suggests that YB-1 interaction with ß-amyloid prevents formation of filaments that are responsible for neurotoxicity and neuronal death. Our data are the first evidence for a potential therapeutic benefit of YB-1 for treatment of Alzheimer's disease.

Behavioural, biochemical and histochemical effects of locus coeruleus transplantation in rats with neurotoxic lesions of the catecholaminergic system.

Exploratory activity in the open field and noradrenaline concentration in the neocortex and brain stem were investigated in intact rats (n = 10) and in the following groups of rats with early postnatal neurotoxic (6-hydroxydopamine) lesion of the catecholaminergic system: (i) rats with embryonal locus coeruleus grafts in the frontal neocortex (n = 5); (ii) rats with the same grafts in lateral ventricles (n = 4); (iii) a control group with intracortical hippocampal tissue grafts (n = 3); (iv) sham-operated rats (n = 3). Experiments were performed by four independent groups of investigators using a double-blind method. In sham-operated rats as well as in rats with hippocampal grafts, and with locus coeruleus grafts in the ventricles, both exploratory activity and noradrenaline content of the forebrain were significantly lowered. In the rats with intracortical locus coeruleus grafts the level of exploratory activity was much higher (almost as in intact controls). This improvement of exploratory behaviour correlated highly with increased noradrenaline concentration in the forebrain. In all animals with locus coeruleus in lateral ventricles a significant increase in noradrenaline level of the brain stem was present, but no change of exploratory behaviour was observed. The grafts with the 3-mm-thick slabs of the adjacent tissue were dissected from the brain and used for histological analysis. The presence of typical locus coeruleus cells was shown in neocortex of all animals which received the grafts of corresponding tissue. The data show the possibility of stable compensation of the forebrain noradrenaline level and exploratory behaviour by embryonic noradrenergic neurons grafted into the neocortex, but not into lateral ventricles.

Bulbectomy-induced loss of raphe neurons is counteracted by antidepressant treatment.

1. Bilateral olfactory bulb ablation was performed in C57B1/6j mice (C57). Separate groups of bulbectomized mice were treated with either antidepressants (trazodone, 20 mg/kg i.p., or amitriptyline, 20 mg/kg i.p.) or saline daily for 14 consecutive days starting 14 days after surgery. 2. Celloidine-imbedded 10 microns-thick brain sections containing the nucleus raphe dorsalis (NRD) or locus coeruleus (LC) were stained for Nissl, and the number of functional and pyknotic cells was counted out of 500 total cell count for each animal in every experimental group: sham-operated, bulbectomized treated with saline or one of the two antidepressants. 3. Bulbectomy produced a significant 4 times increase in the proportion of pyknotic cells in NRD as compared to sham-operated control. Both antidepressants reversed the effect bringing the number of pyknotic cells to control level. The proportion of pyknotic cells in LC was also slightly increased (61%) in the bulbectomized mice, but only amitriptyline was able to reverse the effect. 4. Widespread degeneration of the neurons in NRD caused by bulbectomy may be involved in the serotonergic component of the bulbectomy syndrome. The ability of antidepressants to diminish bulbectomy-induced loss of NRD neurons may underlie their restorative effect on the behavior and neurochemical characteristics of bulbectomized animals.

Antidepressants suppress bulbectomy-induced augmentation of voluntary alcohol consumption in C57B1/6j but not in DBA/2j mice.

Bulbectomy has been previously shown to produce the specific antidepressant-sensitive syndrome in C57Bl/6j, but not DBA/2j mice. The present study examined the effect of the depression on voluntary alcohol consumption. Alcohol consumption and alcohol preference (% of alcohol solution in total liquid) in a free-choice, two-bottle situation was measured in C57BL/6j and DBA/2j mice after sham-operation, anosmia with 10% ZnSO4, or bulbectomy. Both anosmic and bulbectomized mice of both strains consumed more alcohol and showed stronger preference for alcohol than sham-operated mice. In DBA/2j mice both operations altered alcohol consumption of the whole population, and the effect of bulbectomy was stronger. In C57Bl/6j mice bulbectomy and, to a less degree, anosmia seemed to affect predominantly the low-drinking animals. Chronic treatment with antidepressants amitriptyline (20 mg/kg), trazodone (20 mg/kg), and imipramine (10 mg/kg), did not change alcohol consumption in sham-operated C57Bl/6j mice. In anosmic mice antidepressants decreased alcohol preference, but only amitryptyline also decreased alcohol consumption. All antidepressants decreased both alcohol consumption and preference in bulbectomized C57Bl/6j mice. In DBA/2j mice antidepressant treatment either increased, or did not alter alcohol consumption and preference in all groups, though the effects varied among individual antidepressants. The possible connection between the bulbectomy-induced behavioral syndrome and elevated ethanol consumption in C57Bl/6j mice is discussed.

Dissociation of multiple behavioral effects between olfactory bulbectomized C57Bl/6J and DBA/2J mice.

The behavioral effects of bulbectomy and subsequent antidepressant treatment in two mice strains were compared on measures of open field behavior and passive and active avoidance 2 and 4 weeks after surgery. After bulbectomy, both strains displayed elevated locomotion in open field, corrected by antidepressants. Enhanced rearing was decreased by antidepressants in C57Bl/6J, but not in DBA/2J mice. Passive avoidance, being intact 2 weeks after surgery in both strains, was strongly impaired 4 weeks after bulbectomy in C57Bl/6J mice, with antidepressants restoring the performance. Active avoidance acquisition and retention were also dramatically disturbed in C57Bl/6J mice 2 and 4 weeks after surgery, and antidepressants had recuperative effect. In contrast, bulbectomized DBA/2J mice didn't show any significant passive or active avoidance deficits, and antidepressant treatment seemed to have no effect on their learning ability. The observed strain differences suggest that bulbectomy may produce quite diverse neurophysiological and neurochemical alterations in two strains.

Effects of bulbectomy and subsequent antidepressant treatment on brain 5-HT2 and 5-HT1A receptors in mice.

The effects of bilateral olfactory bulbectomy on serotonergic 5-HT2 and 5-HT1A receptor binding were studied in the frontal cortex (FC), limbic structures (LS), including the hippocampus, amygdala, olfactory tubercule, and piriform cortex, and hypothalamus (HTH) in mice. Bulbectomy resulted in the increase of Bmax for [3H]spiperone binding with 5-HT2 receptors in FC in C57Bl/6j. The receptors in LS and HTH remained unchanged. Subchronic treatment of the bulbectomized mice with antidepressant trazodone (20 mg/kg/day, IP, 14 days) induced downregulation of 5-HT2 receptors in FC and LS. The other two antidepressants used, amitriptyline (20 mg/kg/day, IP, 14 days) and imipramine (10 mg/kg/day, IP, 14 days), did not alter these receptors. [3H]8-OH-DPAT binding with 5-HT1A receptors was not altered by bulbectomy in any brain area in C57Bl/6j mice. Amitriptyline and trazodone decreased Bmax for these receptors in FC in the bulbectomized mice while imipramine was ineffective. Amitriptyline and imipramine significantly increased Bmax and decreased Kd in HTH, and trazodone displayed the same tendency. Bulbectomy did not alter 5-HT2 receptors in DBA/2j mice. Amitriptyline increased Kd in the all brain areas without changing Bmax in the bulbectomized DBA/2j mice. Trazodone significantly decreased Bmax in FC and increased Kd in FC and LS. Imipramine decreased Bmax while increasing Kd in LS. The possible involvement of the serotonin receptor subtypes in the bulbectomy-induced behavioral deficits and in the restorative action of the antidepressants is discussed.

Lesioning of spatial memory in mice treated with agroclavin.

This report presents results obtained from studies of the mnemotropic activity of the ergot alkaloid agroclavin. The effects of this substance were studied at concentrations of 1, 10, 25, 50, and 200 microg/kg on the learning and retention of a spatial habit in a Morris water maze. These doses of agroclavin had no effect on the process of formation of the spatial habit, but sharply disturbed retention of the habit. A long-lasting effect of memory trace disturbance was seen over a period of 48 h after dosage. On retraining, animals showed no delayed effects with agroclavin on learning a new spatial habit. The possible mechanisms for the effect of agroclavin on memory are discussed.

Influence of local injection of 5,7-DHT and 6-OH-DA into the neocortex on learning and exploratory behavior of rats in the open field.

The features of the exploratory behavior in the open field, of the learning of a conditioned-reflex food-procuring reaction, and of the shift in the level of biogenic amines of the brain was studied in Wistar rats with local injections of the specific neurotoxins 6-hydroxydopamine (6-OH-DA) and 5,7-dihydroxytryptamine (5,7-DHT). It was shown that damage to the structure of the serotoninergic or catecholaminergic systems of the frontal cortex and hippocampus caused by local injection of 6-OH-DA and 5,7-DHT into the neocortex is accompanied by multidirectional changes in the exploratory behavior and learning of the animals.

[Morpho-functional changes of neurons in temporal cortex in comparison with spatial memory in bulbectomized mice after treatment with minerals and ascorbates]. / Morfofunktsional'nye izmeneniia neironov visochnoi kory mozga v sopostavlenii s prostranstvennoi pamiat'iu u bul'béktomirovannykh myshei posle primeneniia mineralaskorbatov.

The effect of antioxidant mixture of mineralascorbates (MA) on the status of neurons of brain temporal cortex and behavior of mice after olfactory bulbectomy (BE) was studied, as it was previously shown by us that these animals were characterized by a deficit of spatial memory and development of neurodegenerative process in brain structures, which are affected by Alzheimer disease. Disorganization of cytoarchitectonics of temporal cortex with the deletion of its layers as a result of dystrophy of pyramidal neurons and foci of their complete disappearance were shown 1 month after BE. The increased number of neurons with the phenomena of karyopyknosis, karyolysis and vacuolysis was observed with a concomitant reduction in neuronal density. Addition of MA to the diet for three weeks prevented the development of deterioration of spatial memory in mice after BE and protected the neurons of brain temporal cortex from the degenerative changes. The results obtained suggest the possibility of realization of prophylaxis aimed at the prevention of the development of Alzheimer-type neurodestructive processes.