Family case of Potocki-Lupski syndrome.

BACKGROUND: Potocki-Lupski syndrome (PTLS, OMIM # 610883) is a rare genetic developmental disorder resulting from a partial heterozygous microduplication at chromosome 17p11.2. The condition is characterized by a wide variability of clinical expression, which can make its clinical and molecular diagnosis challenging. CASE PRESENTATION: We report here a family (mother and her two children) diagnosed with PTLS. When examining children, neurological and psychological (neuropsychiatric) manifestations (speech delay, mild mental retardation), motor disorders, craniofacial dysmorphism (microcephaly, dolichocephaly, triangular face, wide bulging forehead, long chin, antimongoloid slant, "elfin" ears) were revealed. The suspected clinical diagnosis was confirmed by MLPA and CMA molecular genetic testing which revealed the presence of a segmental aneusomy; microduplication in the 17p11.2 region. CONCLUSIONS: Children with PTLS can have a clinically recognizable and specific phenotype: craniofacial dysmorphism, motor and neurological manifestations, which may implicate a possible genetic disease to the attending physician. Moreover, each child with this syndrome is unique and may have a different clinical picture. The management of such patients requires a multidisciplinary team approach, including medical genetic counseling.

[Correction of serum prooncogenic cytokines and metastases by 5-hydroxypyrimidine derivatives and doxorubicin after removal of a primary tumor node in mice with the Lewis lung epidermoid carcinoma]. / Korrektsiia urovnia syvorotochnykh proonkogennykh tsitokinov i metastazirovaniia proizvodnymi 5-oksipirimidina i doksorubitsinom posle udaleniia pervichnogo opukholevogo uzla u myshei s metastaziruiushchim rakom legkogo LLC.

The effect of a single injection of doxorubicin, 8-day administration of two 5-hydroxypyrimidine derivatives, SNK-411 (2-Isobutyl-4,6-dimethyl-5-hydroxypyrimidine) and SNK-578 (hydrochloride of 2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine), on metastases, lifespan and serum cytokines has been investigated in С57ВL/6 mice after removal of a primary tumor node of Lewis lung carcinoma (LLC). LLC cells (1×106) were injected in the footpad of right hind feet of mice in control and experimental groups; after 14 days of tumor development the hind feet with the tumor were amputated at the ankle level. One hour before the amputation mice received a single injection of doxorubicin (4 mg/kg) and 8-day therapy with the 5-hydroxypyrimidine derivatives started. SNK-578 monotherapy was performed at a dose of 10 mg/kg administered intraperitoneally (i.p.). SNK-411 was administered per os at a dose of 25 mg/kg. In the case of combined therapy mice also received a single injection of doxorubicin (4 mg/kg; i.p.). The metastasis inhibition index in mice-treated with SNK-411 and SNK-578 were 53.3% as compared with control mice (with removed tumor). The mice-treated with SNK-411, doxorubicin, and the combination SNK-578 + doxorubicin had lifespan increased by 60.2%, 53.9%, and 42.9%, respectively. A single injection of doxorubicin, the course administration of the 5-hydroxypyrimidine derivative alone and in combination with single injection of doxorubicin completely decreased serum levels of the prooncogenic Th2-cytokines IL-4, and IL-6 and significantly decreased the level of the Th2-cytokine IL-5. Administration of doxorubicin, SNK-411 and SNK-578 did not influence serum concentration of Th1-cytokine interferon gamma (IFN-γ). These data confirm our previous findings that administration of the compounds studied decreased concentrations of prooncogenic IL-4 and IL-6 in tumor-bearing mice with LLC and had no effect on concentrations of the Th1-cytokine IFN-γ.

[Effect of 5-hydroxypyrimidine derivatives on tumor growth and cytokine concentration in blood serum of female CBA mice with cervical cancer (RSHM-5)]. / Vliianie proizvodnykh 5-oksipirimidina na rost opukholi i soderzhanie interleikinov v syvorotkakh krovi samok myshei linii SVA s rakom sheiki matki (RShM-5).

The effects of intraperitoneal administration of SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine) in a dose of 25 mg/kg (the total dose of 350 mg/kg) and SNK-578 (hydrochloride of 2-isobutyl-4,6-dimethyl-5- hydroxypyrimidine) in a dose of 10 mg/kg (the total dose of 140 mg/kg) on tumor growth and concentration of cytokines in the blood serum were studied in female CBA mice. Substances were administrated from the 2nd to 15th days of tumor development. Tumor growth inhibition (TGI) and serum cytokine level were studied on the 7th day after the end of compounds administration (21st day of tumor growth). In intact control group (n=10) median tumor mass was 1255 mg. TGI in the group of animals treated with SNK-411 was 47%; in the group of mice treated with SNK-578 TGI was 87%, tumor mass demonstrated 7.4-fold reduction. Serum concentrations of cytokines (IL-6, IL-10, IL-17A and IFN-γ) in tumor-bearing group of mice were higher versus the intact control group by 229%, 40%, 60% and 81%, respectively. Highly active SNK-578 decreased concentrations of prooncogenic IL-10, IL-17A and proinflammatory IL-6, by 61%, 70% and 29% as compared to tumor-bearing control group. SNK-411 decreased concentrations of prooncogenic IL-10 and IL-17A by 48% and 60%, respectively, and did not affect concentration of IL-6. Taking into consideration that IL-6 participates in autoimmune reactions, we can assume that the immune control is one of the crucial mechanisms of antitumor effect of SNK-578. All results are statistically significant.

[The regional experience of implementation of program of prevention of abortions with non-medical indications].

The unfavorable demographic situation in the Russian Federation determines need of developing medical, organizational and social technologies for preventing abortions because of non-medical reasons. The purpose of the study was to analyze consensus opinion of physicians about reasons women refusing to continue pregnancy, to establish directions of preventing abortions and to evaluate efficiency of the Municipal Competition "Life is sacred gift", the initiative of the All-Russian Program "Sanctity of Motherhood". The study applied such sociological technique as questionnaire survey of 20 obstetricians gynecologists about causes of miscarriage and main directions of prevention of abortion. The analysis was implemented of dynamics of rate of abortions during last 5 years before the introduction of innovative program of prevention of abortion with participation of physicians, psychologists, representatives of public and religious organizations in the form of the competition "Life is sacred gift" (2006-2010) and in program implementation (2012 -2016 GG.) Also were applied the concordance technique, the Fisher's angular transform and rank correlation. The consistency of opinions of physicians about place of lacking of knowledge about risks of abortion and reproductive health in woman decision making about abortion (W = 0.32; χ² = 44.8; p<0.001), about motivation of preserving pregnancy as the main focus on non-medical abortion prevention (W = 0.33; χ² = 33.3; p<0.001). The implementation of innovation program permitted to increase percentage of women who refused abortion from 3.3% to 17.5% (p<0.01), to reduce number of non-medical abortions from 37.9 to 16.9 per 100 births, and from 17,5 to 10.5 per 1000 women of fertile age (p<0.01). The implementation of innovative program increases effectiveness of standard interventions to prevent abortions.

Effects of 5-Hydroxypyrimidine Derivatives on Tumor Growth and Lifespan of C57BL/6 Mice with Epidermoid Lung Carcinoma.

The effects of 5-hydroxypyrimidine derivatives SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine) and SNK-578 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine chlorohydrate) on the tumor growth and survival of male C57BL/6 mice with transplanted Lewis lung epidermoid carcinoma (LLC) were studied in animals receiving intraperitoneal treatment on days 2-15 of tumor development. Compound SNK-578 in a dose of 10 mg/kg significantly inhibited tumor growth (by 3.6 times; 72.2%) in 7 days after the treatment was discontinued, while compound SNK-411 in a dose of 25 mg/kg only negligibly reduced tumor volume (by 41.7%). A combination of course of SNK-411 (25 mg/kg) and single intraperitoneal dose of doxorubicin (4 mg/kg) significantly inhibited the tumor growth (by 2.2 times; 55.2%), while the combination of SNK-578 (10 mg/kg) with doxorubicin (4 mg/kg) was in fact ineffective. The median survival of animals with untreated LLC was 28 days. Median survival of mice injected with SNK-578 (10 mg/kg) was 43 days, hence, the lifespan of mice with LLC was by 38.6% longer after the treatment. Two of ten mice in this group developed no tumors.

Phase Formation, Crystal Structure and Ion Conductivity of Silver Antimonate-Molybdates.

The features of the formation of compounds based on silver antimonate obtained in the AgNO3-Sb2O3-MoO3 system by the solid-phase reaction were investigated. For a synthesis temperature of 1023 K, a homogeneous concentration region of the Ag2-xSb2-xMoxO6 solid solution with a structure of the defective pyrochlore type in the range of 0.0 ≤ x ≤ 2.0 was detected. The Rietveld method, within the constraints of the Fd-3m space group, was used to refinement of X-ray diffraction data, specify the structural parameters of powders, and the correlation of structural disorder with their electrically conductive properties. Relative density and average particle size for ceramic samples sintered at 1223 K were determined using scanning electron microscopy.

Effects of 5-Pyrimidinol Derivative SNK-41 on Cytokine Profile of Mice with Lewis Lung Carcinoma.

We studied the effects of SNK-411, a new 5-pyrimidinol derivative, on serum cytokine profile of C57Bl/6 mice with Lewis lung carcinoma. The compound was injected intraperitoneally in doses of 25 and 50 mg/kg. A significant (by 3.5 times) increase in serum IL-4 content was detected in mice with tumors on day 9 of tumor development. In mice receiving SNK-411 in doses of 25 and 50 mg/kg, IL-4 content significantly decreased (by 4.0 and 3.6 times) on days 2-8 of carcinoma development; IL-2 content decreased by 1.4 and 1.2 times and IL-6 content decreased by 2.7 and 1.6 times, respectively, in comparison with control mice with tumors. Injections of SNK-411 in the same doses on days 8-15 of carcinoma development led to a significant decrease in IL-4 levels (by 2.2 and 4.5 times, respectively, in comparison with control mice with tumors) and did not affect serum levels of other cytokines.

Correcting effect of ladasten on variations in the subpopulation composition of T lymphocytes in C57BL/6 mice on the experimental model of an anxious-depressive state.

We studied the effect of Ladasten (30 mg/kg intraperitoneally for 5 days) on the subpopulation composition of T cells in immunocompetent organs of male C57Bl/6 mice during modeling of an anxious-depressive state (chronic zoosocial stress). Stress exposure of animals for 30 days was followed by a decrease in the relative weight of the thymus, increase in the weight of the spleen, reduction of the percentage of T cell populations, and shift in the CD4(+)/CD8(+) ratio toward cytotoxic T cells. Administration of Ladasten had a normalizing effect on the relative weights of study organs and subpopulation composition of T cells in immunocompetent organs, which returned to the control level.

[The magnitude of fatigue and its association with depression, pain, and inflammatory activity in rheumatoid arthritis].

AIM: To analyze the rate of clinically significant fatigue and to search for its predictors in patients with rheumatoid arthritis (RA). SUBJECTS AND METHODS: The investigation included 95 patients with a valid RA diagnosis. The majority of the patients were women (87.4%); mean age was 46.7 +/- 1.2 years; mean disease duration was 135.5 +/- 11.6 months. The authors evaluated RA activity by the Disease Activity Score (DAS28), magnitude of fatigue by the Fatigue Severity Scale (FSS), that of pain by the Brief Pain Inventory, and functional status and quality of life by the Health Assessment Questionnaire and EQ-5D. A psychiatrist diagnosed mental disorders in accordance with ICD-10 and using the psychiatric and psychological scales and procedures. RESULTS: 80% of the patients felt clinically significant fatigue (FSS scores of > or = 4). Multivariate analysis yielded a prognostic model that made it possible to state that clinically significant fatigue was primarily associated with the magnitude of depression by the Hospital Anxiety and Depression Scale, the presence of a depressive episode, the duration of anxiety and depressive spectrum, the magnitude of pain (Ritchie index), DAS28, and the presence of osteoporosis. CONCLUSION: The presence and magnitude of depression along with the magnitude of pain are an important factor that influences the formation of fatigue in RA, which gives rise to evident functional failure and a low quality of life. Combination therapy for RA may be effective when mental disorders, mainly the anxiety and depressive spectrum, are timely diagnosed.

[Perception of pain in rheumatoid arthritis: relation to inflammation, psychic disorders, functional status, and quality of life].

Pain perception was analyzed depending on the inflammatory activity of rheumatoid arthritis (RA), variants and manifestations of psychic disorders (including depressive, anxious and moderate cognitive ones), chronic fatigue, changes in the functional status and quality of life. The study included 125 patients (mean age 47.4 +/- 1.01 yr) with definitive diagnosis of RA 138.4 +/- 10.1 months in duration. RA activity was estimated from the DAS28 index, pain intensity and degree of fatigue by BPI and FSS scales respectively, the functional status and life quality by HAQ and EQ-5D. Psychic disorders were diagnosed by a psychiatrist in accordance with ICD-10 with the use of relevant psychiatric and psychological scales and methods. Pain perception was unrelated to the patients' age and RA duration. The multifactor analysis provided a basis for the prognostic model suggesting that the most severe pain in RA is related to the functional status and quality of life (VAS of general health status), hsCRP level, inflammatory activity index RA DAS28, peripheral platelet count, degree of fatigue (FSS) and depression (YADS), female sex. Depression and its severity is one more factor influencing pain perception in RA and accounting for functional insufficiency and low quality of life. Early diagnostics of psychic disorders (in the first place anxious and depressive ones) is mandatory to ensure effective combined therapy of pain in RA patients.

[An experimental study of the anti-inflammatory action of noopept and its effect on the level of cytokines].

The anti-inflammatory effects of noopept (dipeptide analog of piracetam) upon a single intraperitoneal (i.p.) administration at doses of 1, 5, and 10 mg/kg in comparison to the reference drug diclofenac (10 mg/kg, i.p.) have been studied on a model of acute exudative inflammation induced by carrageenan in outbred rats and concanavalin A (Con A) in CBA mice. The level of cytokines was studied on the lipopolysaccharide (LPS) model (single administration, 100 mg/kg, i.p.) with 5-day administration of noopept at a dose of 5 mg/kg (i.p., before endotoxin injection) in C57BL/6 mice. The administration of noopept led to a significant suppression of the inflammatory response to both carrageenan and Con A. The administration of Con A caused a 16-fold increase in the level of IL-6 interleukin in the blood serum of mice as compared to control. Noopept (5 mg/kg) reduced the level of IL-6 by a factor of 1.8 in the inflammatory response to Con A. The administration of LPS led to pronounced increase in the levels ofpro-inflammatory IL-6 and TNF-alpha in the blood serum of test mice as compared to intact animals. The course administration of noopept (5 mg/kg) significantly decreased the level of IL-6 and reduced by half the level of TNF-alpha.

Study of anti-inflammatory effects of GB-115, a glycine-containing retropeptide cholecystokinin analog.

Anti-inflammatory effects of GB-115 compound (N-phenylhexanoyl-glycyl-L-tryptophan amide) injected intraperitoneally in doses of 0.1, 1, and 10 mg/kg were demonstrated on the model of ConA- and carrageenan-induced inflammation. Intraperitoneal injection of GB-115 in a dose of 1 mg/kg to C57Bl/6 female mice with experimental autoimmune encephalomyelitis significantly alleviated the pathological symptoms, improved spontaneous locomotor activity, promoted recovery of thymus weight, and reduced edema and neutrophil infiltration of the perivascular space of the brain tissue. Intraperitoneal injection of GB-115 in a dose of 1 mg/kg suppressed generation of active oxygen forms by neutrophils in the chemiluminescence test.

[Effect of antiasthenic drug ladasten on the level of cytokines and behavior in experimental model of anxious depression in C57BL/6 male mice].

Effects of the antiasthenic drug ladasten [N-(2-adamantyl)-N-(para-bromophenyl)amine] on the profile of cytokines, behavior, and indexes of immunity organs was studied on zoosocial stress model in depressed C57BL/6 male mice. The anxious depression state in male mice was formed by repeated agonistic interactions according to the sensory contact model. Ladasten (30 mg/kg, i.p.) and reference drug imipramine (10 mg/kg, i.p.) were administered either once after 3-day stressor interaction or for 5 days after 10-day interaction. The concentration of cytokines in blood serum was determined by flow cytometry method. The behavioral changes were studied using an actometer and the elevated plus-maze test. The parameters were studied 24 h after last drug injection. Different stages of depression were manifested by behavioral impairments, increased concentration of pro-inflammatory cytokines IL-6, IL-17, and IL-4, and decreased indexes of immunity organs. Ladasten induced (more significantly than imipramine) a decrease in the level of pro-inflammatory cytokines IL-6, IL-17 and IL-4, removed behavioral changes, and restored indexes of immunity organs. Thus, the antiasthenic drug ladasten limits development of the anxious depressive state and suppresses the level ofproinflammatory cytokines IL-6, IL-17 and IL-4. These findings suggest that ladasten is a possible candidate drug for adjuvant therapy of depressive disorders.

Effect of ladasten on the content of cytokine markers of inflammation and behavior of mice with experimental depression-like syndrome.

The effects of ladasten and reference product imipramine (10 mg/kg) on the content of cytokines TNF-α, IL-6, IL-10, IL-1α, IL-2, IL-4, IL-5, IL-17, IFN-γ, and GM-CSF and behavior of male C57Bl/6 mice were studied on the model of a depression-like state induced by a single intraperitoneal injection of bacterial LPS in a dose of 100 µg/kg. Ladasten was injected 5 times in doses of 30 and 50 mg/kg. LPS was administered 1 h after the last injection of the test agents. Behavioral disturbances and significant increase in the concentration of TNF-α and IL-6 in blood plasma were observed 2 h after LPS treatment. Ladasten was more potent than imipramine in decreasing the content of proinflammatory cytokines TNF-α and IL-6 and preventing the development of behavioral disturbances in mice. Antiasthenic drug ladasten was shown to decrease the elevated level of proinflammatory cytokines TNF-α and IL-6 after LPS treatment. Further studies should be performed to develop new indications for the use of ladasten in adjuvant therapy of depression.

[Preclinical safety investigation of GB-115 dipeptide].

Preclinical safety investigations of newly synthesized dipeptide compound GB-115 (amide N-phenylhexanoyl-glycyl-L-tryptophan), an antagonist of cholecystokinin receptors, were performed. No animals were lost after GB-115 acute oral administration at a maximum dose of 6000 mg/kg in mice and at 3500 mg/kg in rats. GB-115 administered per os during 6 months in rabbits and rats (both males and females) at the doses of 0.1 and 10 mg/kg induced no irreversible pathological changes in organs and systems studied. The tested dipeptide exhibited no allergenic, immunotoxic and mutagenic activity, and did not affect generative function and the antenatal and postnatal development of progeny. GB-115 at a dose of 10 mg/kg produced suppression of the inflammatory reaction to concanavalin A.

Immunocorrecting properties of GB-115 dipeptide.

We studied the effects of a new dipeptide with anxiolytic activity (GB-115, N-phenylhexanoyl-glycyl-L-tryptophan amide) on parameters of the immune in intact mice and in animals with secondary immunodeficiency caused by cyclophosphamide. GB-115 in doses of 0.1-10 mg/kg stimulated phagocytic activity of peritoneal macrophages and humoral immune response in intact mice. GB-115 exhibited immunocorrecting activity in animals with secondary immunodeficiency.