Transcranial Doppler ultrasound is a diagnostic and predicting tool for movement disorders in children after hypoxic ischemic encephalopathy

K.A. Pugolovkin, E.A. Efimova, E.A. Dombrovskaya, I.Yu. Platonova, A.A. Solov’ev Research Practical Center for Children’s Psychoneurology, Moscow, Russia Aim: to assess brain circulation in the regions supplied by the basilar artery (BA) in children with movement disorders and motor skill delay in the late rehabilitative period after hypoxic ischemic encephalopathy and its importance for the objectivity of clinical data and evaluation of rehabilitative effect. Patients and Methods: 28 children (mean age one year seven months) with movement disorders and motor skill delay (after hypoxic ischemic CNS lesion in the perinatal period) without lower extremity paraparesis or Willis circle abnormalities (by Doppler ultrasound) were examined. Doppler ultrasound was performed using the suboccipital approach at 3–8 months with 3–4-month intervals. The parameters of blood flow in BA, i.e., resistivity index (RI) and mean blood flow velocity (Vm), were measured. Retrospectively, children were divided into three groups based on motor skill delay severity (mild, moderate, or severe) and time for standing unaided to walking. Mean values in the groups and relative deviations (increase/decrease) from reference values in a given age group were compared. Results: motor skill delay severity and predicting time for standing unaided to walking correlated with RI and Vm. RI was a diagnostically valuable parameter whose reference values differed from motor skill delay severity. Isolated increase in Vm and normal RI were reported in children with motor skill dela y 1–3 months before standing unaided to walking. This type of blood circulation is a transitional one during clinical improvement in some children. Conclusions: a set of instrumental data allow for describing motor skill delay severity depending on RI deviations from normal values in the regions supplied by BA. The sequence of brain circulation parameter changes is in line with the clinical course, e.g., RI normalization and further gradual recovery of blood flow velocity. Keywords: movement disorders, motor skill delay, Transcranial Doppler ultrasound, basilar artery, resistivity index RI, mean blood flow velocity Vm. For citation: Pugolovkin K.A., Efimova E.A., Dombrovskaya E.A. et al. Transcranial Doppler ultrasound is a diagnostic and predicting tool for movement disorders in children after hypoxic ischemic encephalopathy. Russian Journal of Woman and Child Health. 2021;4(3):254–259 (in Russ.). DOI: 10.32364/2618-8430-2021-4-3-254-259. </p

Additive effect of brimonidine in maximum tolerated medical therapy for primary open-angle glaucoma

D.A. Dorofeev1, V.P. Balukhtina2, M.V.&nbsp;Es’kova1, K.A. Efimova1, E.V. Kirilik1, K.O.&nbsp;Luk’yanova1 1City Clinical Hospital No. 2, Polyclinic № 1, Chelyabinsk, Russian Federation 2South Ural State Medical University, Chelyabinsk, Russian Federation Aim: to evaluate additive IOP-lowering effect of brimonidine 0.2% to achieve target IOP via enhancing maximum tolerated medical therapy for primary open-angle glaucoma (POAG). Patients and Methods: 63 patients (63 eyes) with advanced POAG and poorly controlled IOP who received prostaglandin analogs and a fixed-dose carbonic anhydrase inhibitor/beta-blocker combination were enrolled. All patients were additionally prescribed with brimonidine 0.2%. After a month, patients were divided into two groups based on achieved IOP level. In group 1, target IOP was achieved, and these patients were followed up. In group 2, target IOP was not achieved, and these patients underwent trabeculectomy. IOP was measured by elastotonometry and using the iCare tonometer. Results: a month after prescribing α2 agonist, true IOP level reduced to 14.0 (9.5; 17.0) mm Hg in group 1 and to 17.0 (13.0; 20.0) mm Hg in group 2. At the final visit, IOP levels were within target ranges in both groups, i.e., 13.0 (11.0; 18.5) mm Hg and 13.5 (9.7; 17.2) mm Hg, respectively. Meanwhile, changes in IOP measured by various methods were significantly different. IOP reduced by 5.4% (-7.1%; 17.6%) in group 1 and by 20.7% (4.4%; 30.7%) in group 2 (p&lt;0.05) as measured by elastotonometry and by 8.3% (-11.8%; 28.6%) in group 1 and by 33.3% (13.9%; 50.7%) in group 2 as measured by iCare tonometer. Conclusions: brimonidine 0.2% provides additional IOP reduction to enhance maximum tolerated medical therapy for advanced POAG. An estimated effect of brimonidine is a 8% reduction of IOP from the baseline. If target IOP is not achieved, a patient should be scheduled for surgery. IOP should be measured using the iCare tonometer since this device is more sensitive to minor IOP fluctuations. Keywords: brimonidine 0.2%, maximum tolerated medical therapy for glaucoma, tonometry, elastotonometry, glaucoma, trabeculectomy, additive effect, target IOP. For citation: Dorofeev D.A., Balukhtina V.P., Es’kova M.V. et al. Additive effect of brimonidine in maximum tolerated medical therapy for primary open-angle glaucoma. Russian Journal of Clinical Ophthalmology. 2021;21(3):129–134 (in Russ.). DOI: 10.32364/2311-7729-2021-21-3-129-134. </p

Initial multi-target approach shows importance of improved caprine arthritis-encephalitis virus control program in Russia for hobbyist goat farms

Background and Aim: Several reports described the detection of specific caprine arthritis-encephalitis virus (CAEV) antibodies in Russian goat populations, which indicates the circulation of CAEV in Russian goat farms. The aim of this study was to use a multi-target approach to testing with both serological tests and an in-house real-time (RT) molecular test to investigate the prevalence of CAEV in goats from three hobbyist farms in the Republic of Tatarstan, Russia. Materials and Methods: We applied a multi-target approach to testing with both enzyme-linked immunosorbent assay (ELISA) and an in-house RT polymerase chain reaction test to investigate the prevalence of CAEV in goats. Animals from the three hobbyist farms were used in this study. The animals from two farms (n=13 for F1 and n=8 for F2) had clinical signs of arthritis and mastitis. In the third farm (n=15 for F3), all goats were home-bred and had no contact with imported animals. Results: CAEV antibodies (ELISA targets TM env and gag genes) were detected in serum samples from two farms (F1 and F2), indicating seroprevalence of 87.50-92.31%. Specific CAEV antibodies were also detected in milk samples. CAEV proviral DNA was detected in 53.85-62.50%. The results from all tests performed in the third farm (F3) were negative, indicating that all tests were 100% specific. Conclusion: The results showed that CAEV is circulating and present in small hobbyist goat farms in Russia. Serological and molecular tests could be important for programs to control and eradicate CAEV in Russia for hobbyist goat farms

Influence of plasma concentration of hsa-mir-370-3p and cyp2d6*4 on equilibrium concentration of phenazepam in patients with recurrent depressive disorder t

Introduction: Phenazepam is commonly administered to patients diagnosed with major depressive disorder. Some proportion of such patients do not show adequate response to treatment regimen containing phenazepam, whereas many of them experience type A adverse drug reactions. Previous studies showed that CYP2D6 RE IS involved in the biotransformation of phenazepam, the activity of which is highly dependent on the polymorphism of the gene encoding it. Objective. The objective of the study was to evaluate the impact of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of phenazepam, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma concentration levels in patients suffering from major depressive disorder. Material and methods: The study enrolled 191 patients with recurrent depressive disorder (age −40.0 ± 16.3 years). Treatment regimen included phenazepam in an average daily dose of 6.0 ± 2.3 mg per day. Treatment efficacy was assessed using the validated psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels we performed the real-time polymerase chain reaction (PCR Real-time). The activity of CYP2D6 was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/ pinoline). Therapeutic drug monitoring has been performed using HPLC-MS/MS. Results: Our findings didn’t reveal the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 6.0 [4.0; 8.0] and (GA) 6.0 [5.0; 7.8], p > 0.999; the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 3.0 [3.0; 3.0], p > 0.999. We didn’t reveal a statistical significance for concentration/dose indicator of phenazepam in patients with different genotypes: (GG) 0.812 [0.558; 1.348] and (GA) 0.931 [0.630; 1.271], p = 0.645). Analysis of the results of the pharmacotranscriptomic part of the study didn’t show the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 22.5 [16.9; 29.8], (GA) 22.7 [15.7; 31.5], p = 0.695. At the same time, correlation analysis didn’t reveal a statistically significant relationship between the phenazepam efficacy profile evaluated by changes in HAMA scale scores and the hsa-miR-370-3p plasma concentration: rs = −0.01, p = 0.866. Also, we didn’t reveal the correlation between the miRNA concentration and safety profile: rs = 0.07, p = 0.348. Also we did not reveal the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR370-3p plasma concentration: rs = −0.14, p = 0.056. At the same time, correlation analysis did not reveal a statistically significant relationship between the phenazepam concentration and the hsa-miR-370-3p plasma concentration: rs = −0.05, p = 0.468. Conclusion: The effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of phenazepam was not demonstrated in a group of 191 patients with recurrent depressive disorder. At the same time, hsa-miR-370-3p does not remain a promising biomarker for assessing the level of CYP2D6 expression, because it does not correlate with encoded isoenzyme activity. Psychopharmacology Bulletin. 2021;51(4):87–104. OT FOR REPRIN. © 2021, MedWorks Media LLC. All rights reserved

The zebrafish tail immobilization (ZTI) test as a new tool to assess stress-related behavior and a potential screen for drugs affecting despair-like states

Background: Affective disorders, especially depression and anxiety, are highly prevalent, debilitating mental illnesses. Animal experimental models are a valuable tool in translational affective neuroscience research. A hallmark phenotype of clinical and experimental depression, the learned helplessness, has become a key target for 'behavioral despair'-based animal models of depression. The zebrafish (Danio rerio) has recently emerged as a promising novel organism for affective disease modeling and CNS drug screening. Despite being widely used to assess stress and anxiety-like behaviors, there are presently no clear-cut despair-like models in zebrafish.New Method: Here, we introduce a novel behavioral paradigm, the zebrafish tail immobilization (ZTI) test, as a potential tool to assess zebrafish despair-like behavior. Conceptually similar to rodent 'despair' models, the ZTI protocol involves immobilizing the caudal half of the fish body for 5 min, leaving the cranial part to move freely, suspended vertically in a small beaker with water.Results: To validate this model, we used exposure to low-voltage electric shock, alarm pheromone, selected antidepressants (sertraline and amitriptyline) and an anxiolytic drug benzodiazepine (phenazepam), assessing the number of mobility episodes, time spent 'moving', total distance moved and other activity measures of the cranial part of the body, using video-tracking. Both electric shock and alarm pheromone decreased zebrafish activity in this test, antidepressants increased it, and phenazepam was inactive. Furthermore, a 5-min ZTI exposure increased serotonin turnover, elevating the 5-hydroxyindoleacetic acid/serotonin ratio in zebrafish brain, while electric shock prior to ZTI elevated both this and the 3,4-dihydroxyphenylacetic acid/dopamine ratios. In contrast, preexposure to antidepressants sertraline and amitriptyline lowered both ratios, compared to the ZTI test-exposed fish.Comparison with ExistingMethod(s): The ZTI test is the first despair-like experimental model in zebrafish.Conclusions: Collectively, this study suggests the ZTI test as a potentially useful protocol to assess stress-/despairrelated behaviors, potentially relevant to CNS drug screening and behavioral phenotyping of zebrafish

Effects of acute and chronic arecoline in adult zebrafish: Anxiolytic-like activity, elevated brain monoamines and the potential role of microglia

Arecoline is a naturally occurring psychoactive alkaloid with partial agonism at nicotinic and muscarinic acetylcholine receptors. Arecoline consumption is widespread, making it the fourth (after alcohol, nicotine and caffeine) most used substance by humans. However, the mechanisms of acute and chronic action of arecoline in-vivo remain poorly understood. Animal models are a valuable tool for CNS disease modeling and drug screening. Complementing rodent studies, the zebrafish (Danio rerio) emerges as a promising novel model organism for neuroscience research. Here, we assessed the effects of acute and chronic arecoline on adult zebrafish behavior and physiology. Overall, acute and chronic arecoline treatments produced overt anxiolytic-like behavior (without affecting general locomotor activity and whole-body cortisol levels), with similar effects also caused by areca nut water extracts. Acute arecoline at 10 mg/L disrupted shoaling, increased social preference, elevated brain norepinephrine and serotonin levels and reduced serotonin turnover. Acute arecoline also upregulated early protooncogenes c-fos and c-jun in the brain, whereas chronic treatment with 1 mg/L elevated brain expression of microglia-specific biomarker genes egr2 and ym1 (thus, implicating microglial mechanisms in potential effects of long-term arecoline use). Finally, acute 2-h discontinuation of chronic arecoline treatment evoked withdrawal-like anxiogenic behavior in zebrafish. In general, these findings support high sensitivity of zebrafish screens to arecoline and related compounds, and reinforce the growing utility of zebrafish for probing molecular mechanisms of CNS drugs. Our study also suggests that novel anxiolytic drugs can eventually be developed based on arecoline-like molecules, whose integrative mechanisms of CNS action may involve monoaminergic and neuro-immune modulation