Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology.

N-methyl-D-aspartate receptors (NMDARs) are a subtype of ionotropic glutamate receptors critical for synaptic transmission and plasticity, and for the development of neural circuits. Rare or de-novo variants in GRIN genes encoding NMDAR subunits have been associated with neurodevelopmental disorders characterized by intellectual disability, developmental delay, autism, schizophrenia, or epilepsy. In recent years, some disease-associated variants in GRIN genes have been characterized using recombinant receptors expressed in non-neuronal cells, and a few variants have also been studied in neuronal preparations or animal models. Here we review the current literature on the functional evaluation of human disease-associated variants in GRIN1, GRIN2A and GRIN2B genes at all levels of analysis. Focusing on the impact of different patient variants at the level of receptor function, we discuss effects on receptor agonist and co-agonist affinity, channel open probability, and receptor cell surface expression. We consider how such receptor-level functional information may be used to classify variants as gain-of-function or loss-of-function, and discuss the limitations of this classification at the synaptic, cellular, or system level. Together this work by many laboratories worldwide yields valuable insights into NMDAR structure and function, and represents significant progress in the effort to understand and treat GRIN disorders. Keywords: NMDA receptor , GRIN genes, Genetic variants, Electrophysiology, Synapse, Animal models.

[Evaluation of the efficacy and safety of application of the drug cortexin in the complex rehabilitation of verticalization in patients with ischemic stroke in the acute period]. / Otsenka éffektivnosti i bezopasnosti primeneniia lekarstvennogo preparata Korteksin v komplekse reabilitatsionnykh meropriiatii po vertikalizatsii u patsientov s ishemicheskim insul'tom v ostrom periode.

AIM: To evaluate the efficacy and safety of cortexin in the complex of rehabilitation measures for verticalization in patients with ischemic stroke in the acute period. MATERIAL AND METHODS: The study included 90 patients with hemispheric ischemic stroke. Patients of the first group (n=30) received cortexin in a dose of 20 mg per day intramuscularly for 10 days, along with basic therapy during early verticalization. Patients of the second group (n=30) received basic therapy during early verticalization and patients of the third group (n=30) received only basic therapy without verticalization. To assess the severity of condition, NIHSS, modified Rankin scale, the Barthel index, the Rivermead mobility index, MMSE, MOCA were used. To study cardiovascular function in patients, the segmental part of the autonomic nervous system was studied: a test with isometric load, a Valsalva test, a test based on the change in heart rate with slow deep breathing. All studies were conducted before and 10-14 days after treatment. RESULTS AND CONCLUSION: The most complete regression of neurological deficits and manifestations of cardiac autonomic neuropathy during the acute period of ischemic stroke was observed in the group of patients treated with cortexin (20 mg per day for 10 days), along with basic therapy and early verticalization, compared to the groups, which received basic therapy with early verticalization or basic therapy without verticalization.

[Efficacy of Korteksin in acute period of hemispheric ischemic stroke]. / Éffektivnost' korteksina v ostrom periode polusharnogo ishemicheskogo insul'ta.

AIM: To study the efficacy and prolonged effect of repeated treatment with low-doses of the neuroprotection drug cortexin (30 mg, (10+10+10, morning, noon, day), daily) in patients in the acute period of hemispheric ischemic stroke. MATERIAL AND METHODS: One hundred and twenty-two patients with hemispheric ischemic stroke were studied. Patients of the first group (n=30) received cortexin in a dose of 20 mg (10+10) intramuscularly along with basic therapy, patients of the second group (n=30) received two courses of cortexin in the same dose for 10 days each with a break of 10 days in-between, patients of the third group (n=30) received only basic therapy, patients of the fourth group (n=32) received cortexin in a dose of 30 mg (10+10+10), two courses for 10 days each with a break of 10 days in-between. NIHSS, modified Rankin scale, Barthel index, Rivermead mobility index, MMSE, MOCA-test were used to evaluate the severity of the condition. RESULTS AND CONCLUSION: The most complete regression of neurological deficit during the acute period of ischemic stroke was observed in the fourth group of patients (30 mg (10+10+10) of cortexin, two courses) compared to the 1-3 groups.

EXTRAVASCULAR LUNG WATER IS A PREDICTOR OF DEVELOPMENT OF MULTIPLE ORGAN FAILURE IN CHILDREN WITH SEVERE BURN INJURY.

THE AIM: to determine if an increased extravascular lung water level (EVLW) would be a predictor of multiple organ failure in pediatric patients with severe burn injury. MATERIALS AND METHODS: a prospective study included 33 pediatric patients with burn surface from 30 to 90% of the total body surface area, admitted to PICU. All the patients were monitored with PICCO-technology advanced hemodynamic monitoring, that included an analysis ofEVLW level every 6 hours during first 48 hours after PICU admission. RESULTS: the diagnosis of multiple organ failure received according to DENVERII score. Normal values of weight indexed ELWI (extravascular lung water index)were 9-29 ml/kg for children under 1-year-oldage, 7-25 ml/kg for children from 1 to 5 years old and 5-13 ml/kg for children older than 5 years. CONCLUSIONS: a normal value of height indexed ELWI was up to 315 ml/m. The height indexed ELWI level correlated reliably with multiple organ dysfunction syndrome rate in all time measurements. So ELWI can be used as a MOD prognostic factor There was no correlation between surface of burned skin and EVLW level.

[Cognitive impairment in patients poluchennym ischemic stroke in the acute and early recovery periods in the process of neuroprotection low-dose drug cortexin]. / Dinamika kognitivnykh narushenii u bol'nykh s polusharnym ishemicheskim insul'tom v ostrom i rannem vosstanovitel'nom periodakh na fone nizkodoznoi neiroprotektsii preparatom korteksin.

AIM: To study the effect of repeated low-dose course of neuroprotection by drug cortexin on cognitive impairment in the acute and early recovery periods of hemispheric ischemic stroke. MATERIAL AND METHODS: The study involved 90 patients with poluchennym ischemic stroke. Patients of the first group received cortexin 20 mg (10+10) intramuscularly on the background of basic therapy, patients of the second group (n=30) received cortexin 20 mg (10+10) two courses for 10 days each with a break in between of 10 days, the patients of the third group - only basic therapy. For the objectification of cognitive impairment used a scale MMSE, a test of 5 words, the battery of frontal dysfunction, clock drawing test, MOCA test. RESULTS: It was noted more rapid and complete regression of cognitive disorders in patients of the 1st and 2nd groups, in comparison with patients of the 3rd group. However, the best effect of the therapy was observed still in the group of patients treated with the double rate of the drug cortexin.

[Efficacy of cortexin in acute and recovery periodes of hemispheric ischemic stroke]. / Effektivnost' korteksina v ostrom i vosstanovitel'nom periodakh polusharnogo ishemicheskogo insul'ta.

AIM: To study the effectiveness and sustained effects of early appointment of a repeated course of low-dose drug cortexin neuroprotection in patients in acute and recovery period of hemispheric ischemic stroke. MATERIAL AND METHODS: The study included 90 patients with hemispheric ischemic stroke. Patients of the first group received 20 mg cortexin (10+10) intramuscularly on basic therapy, the patients of the second group (n=30) was obtained cortexin 20 mg (10+10) in the two courses each for 10 days with an interval between them in 10 days, patients of the third group - only basic therapy. For objectification severity used NIH stroke scale, modified Rankin scale, the Barthel index, the Rivermead mobility index, MMSE. RESULTS AND CONCLUSION: Appointment in acute hemispheric ischemic stroke drug cortexin repeated course leads to more complete regression of neurological deficit, compared to the comparison group and the group of patients who received one course of medication cortexin, for all acute and early recovery period of ischemic stroke from 11-13 days of illness.

[EFFECT OF CORTEXIN ON THE QUALITY OF LIFE IN THE EARLY REHABILITATIVE PERIOD AFTER HEMISPHERIC ISCHEMIC STROKE].

AIM: To study the neuroprotective effect of a repeated course of low dose cortexin therapy on the quality of life in the early rehabilitative period after hemispheric ischemic stroke (IS). MATERIALS AND METHODS: 90 patients were divided into group 1 treated with cortexin (10 mg i/m twice daily (morning and afternoon) in addition to basal treatment, group 2 given the repeated course of the same treatment, and control group (basal therapy alone). The standard SF-36 questionnaire was used to assess the quality of life. RESULTS: Treatment of patients following acute hemispheric ischemic stroke with cortexin (10 mg i/m twice daily) and the repeated course of the same treatment after 10 days resulted in the accelerated and more complete normalization of the quality of life in the early rehabilitation petriod (starting from days 21-27 days after the onset of disease) than in the patients given a single course of cortexin therapy or basal treatment alone.

[Efficacy of cytoflavin in patients with hypertonic encephalopathy and constitutional venous insufficiency].

We examined 60 patients with constitutional venous insufficiency, suffering from hypertensive encephalopathy of I and II stages, mean age 43,4± 6,3 years. Patients of the main group (n=30) received Cytoflavin (2 tablets twice a day) and standard therapy (acetylsalicylic acid and antihypertensive drugs). Thirty patients of the parallel group received only standard therapy. At the 25th day of the study, there were the decrease in the number of complaints, including specific "venous complaints", the reduction of cephalalgia syndrome, asthenic and autonomic disorders; the improvement of quality of life and better cerebral hemodynamics on all structural and functional levels.

[Hypernatremia as a predictor of poor outcomes in children with severe brain injury].

The aim of the study was to elucidate a relationship between the development of hypernatremia and the frequency of poor outcomes in children with severe brain injury (SBI). The retrospective study enrolled 77 children (54 boys and 23 girls) aged 1 month to 18 years, who had SBI in the period of January 2008 to September 2009, and were divided into 3 groups after treatment termination. The admission injury severity criterion was Glasgow coma scale (8 scores or less) rating. Group A comprised 51 children with SBI without hypernatremia; Group B included 14 children with SBI and hypernatremia. Group C consisted of 12 children with SBI, hypernatremia, and polyuremia. The latter group was appraised as a group with evolving central diabetes insipidus. A total of 26 (33.8%) patients had hypernatremia. Poor outcomes (Glasgow outcome scores of 1-3) at 30 days were noted in only Groups B and C: comparison of outcomes in Groups B and C showed the higher incidence of poor outcomes in 10 (84%) Group C patients (with hypernatremia and polyuria) and 4 (28%) children in Group B. Comparison of Groups B and C children indicated that the hazard ratio was 0.3. Therefore, the risk of poor outcomes is much higher in the development of central diabetes insipidous in the presence of hypernatremia.

[Prolonged venovenous hemofiltration in the complex therapy of children with severe thermal injury complicated by multiple organ failure].

The paper describes the authors' experience in using prolonged venovenous hemofiltration in the complex treatment of children with severe thermal injury complicated with multiple organ dysfunction, showing the higher efficiency of treatment in patients with the above condition and the reduction in the number of complications and mortality. This technique is not limited by renal function replacement.

[Prolonged venovenous hemofiltration in intensive care of children with severe thermal injury].

The efficiency of using prolonged venovenous hemofiltration (PVVH) was studied in 12 children with severe thermal injury in the presence of multiple organ dysfunctions. All the children were critically ill (having artificial ventilation, inotropic support, states of coma, renal dysfunction) and received the whole package of intensive care measures. Five of the 12 children were diagnosed as having sepsis, as verified by the procalcitonin ( >10 ng/ml) test. All the patients received 2 to 10 sessions PVVH on a PRIZMA apparatus ("Gambra", Sweden). Five of the 12 children died; the remaining children were observed to feel better; they were all transferred to somatic units. Thus, PWVVH is the method of choice in complex therapy for severe thermal injury followed by the development of multiple organ dysfunctions.

[The comparative radioresistance of chronically irradiated populations of Arabidopsis]. / Sravnitel'naia radioustoichivost' khronicheski obluchaemykh populiatsii arabidopsisa.

The radioresistance of seeds of populations of Arabidopsis thaliana (L.) Heynh. growing for 5 years in the regions with different levels of radioactive contamination within 30 km zone of Chernobyl NPP was studied. The analysis of comparative radiosensitivity by root test was performed. It has been shown that plants from Arabidopsis population growing under chronic irradiation did not gain an increased radioresistance. The data obtained show that they are more radiosensitive.

[Secretory activity of lactotrophs and its regulation by hypothalamic hormones in primary cultures of pituitary cells of rats of different ages]. / Sekretornaia aktivnost' laktotrofov i ee reguliatsiia gipotalamicheskimi gormonami v pervichnykh kul'turakh gipofizarnykh kletok krys raznogo vozrasta.

Basal prolactin (PRL) secretion and the responses of lactotrophs to thyroliberin, dopamine and somatostatin were studied in the experiments employing primary monolayer cultures of pituitary cells obtained from developing rats of different ages. High responsiveness of PRL-secreting cells to the action of hypothalamic hormones was observed in the group of neonatal rats, although basal PRL release was about two orders lower in pituitary cultures of neonatal rats as compared to the cultures of immature, pubertal and adult animals. The investigation performed could reveal quantitative, but not qualitative differences in the reactions of lactotrophs of various age groups. It is concluded that postnatal development in the rat is coupled with significant changes of basal PRL release and to a lesser extent, with changes of lactotroph responsiveness to hypothalamic hormones.

[Regulation of hormonal secretion and DNA synthesis in the lactotrophs of the rat adenohypophysis in vitro in primary cell cultures]. / Reguliatsiia gormonal'noi sekretsii i sinteza DNK v laktotrofakh adenogipofiza krysy in vitro v pervichnykh kletochnykh kul'turakh.

Changes in DNA synthesis in lactotrophs of primary monolayer cultures of the rat pituitary cells were studied, using immunoperoxidase staining in combination with autoradiography. Pituitary cell cultures were treated for 3 days with thyroliberin (TRH), bromocriptine (CB154) or somatostatin (SRIF). The proportion of lactotrophs labelled with 3H-thymidine in the total pool of labelled cells served as a criterion for the estimation of DNA synthesis in prolactin-secreting cells. Prolactin secretion by the same cultures was measured by homologous radioimmunoassay. TRH (10 ng/ml) stimulated DNA synthesis in the total population of pituitary cells, but not in lactotrophs. SRIF decreased selectively the proliferation of lactotrophs, but failed to depress or even stimulated DNA synthesis in some cell types of the rat pituitary gland in the cultures. The quantitative method of studying DNA synthesis in anterior pituitary may be used to evaluate the effects of a number of biologically active compounds on various cell systems.

[Radioimmunological method of determining the growth hormone of rats]. / Radioimmunologicheskii metod opredeleniia gormona rosta krysy.

The paper is concerned with working out a system of a homologous radioimmunoassay for determination of the growth hormone of rats. The obtaining of all components of the system was described including a specimen of homogeneous highly purified rat STH and a guinea-pig antiserum to it. Conditions for running the RIA which provided for getting a calibrated curve within the range of effective STH doses of 5-1000 ng/ml were described. A study of the specificity of the STH determination method demonstrated that under such conditions LH (rLH-RP-1, NIADDK) and TTH (rTSH-RP-2, NIADDK) did not show activity and rat prolactin revealed insignificant activity equal to 1.3% of STH activity. Using the above method STH levels were determined in the blood plasma of Wistar rats under the following experimental conditions: in intact animals after L-arginine load and 2 weeks after hypophysectomy. STH levels under these conditions were 42 +/- 2.6, 102 +/- 3.8 and 8.6 +/- +/- 1.2 ng/ml, respectively. The authors presented the results of comparative immunological activity of the obtained STH specimen and the STH specimens of rats, NIADDK.