Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia.

A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson's disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.

Phosphodiesterase 9 inhibition prolongs the antiparkinsonian action of l-DOPA in parkinsonian non-human primates.

Phosphodiesterase 9 (PDE9) degrades selectively the second messenger cGMP, which is an important molecule of dopamine signaling pathways in striatal projection neurons (SPNs). In this study, we assessed the effects of a selective PDE9 inhibitor (PDE9i) in the primate model of Parkinson's disease (PD). Six macaques with advanced parkinsonism were used in the study. PDE9i was administered as monotherapy and co-administration with l-DOPA at two predetermined doses (suboptimal and threshold s.c. doses of l-Dopa methyl ester plus benserazide) using a controlled blinded protocol to assess motor disability, l-DOPA -induced dyskinesias (LID), and other neurologic drug effects. While PDE9i was ineffective as monotherapy, 2.5 and 5 mg/kg (s.c.) of PDE9i significantly potentiated the antiparkinsonian effects of l-DOPA with a clear prolongation of the "on" state (p < 0.01) induced by either the suboptimal or threshold l-DOPA dose. Co-administration of PDE9i had no interaction with l-DOPA pharmacokinetics. PDE9i did not affect the intensity of LID. These results indicate that cGMP upregulation interacts with dopamine signaling to enhance the l-DOPA reversal of parkinsonian motor disability. Therefore, striatal PDE9 inhibition may be further explored as a strategy to improve motor responses to l-DOPA in PD.

[COVID-19 pandemia: Impact on the cariovascular system. Data of 1st April 2020]. / Pandémie COVID-19 : impact sur le systeme cardiovasculaire. Données disponibles au 1er avril 2020.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells with angiotensin receptors, leading to pneumonia linked to COVID-19. The virus has a double impact on the cardiovascular system, the infection will be more intense if the host has cardiovascular co-morbidities and the virus can cause life-threatening cardiovascular lesions. Therapies associated with COVID-19 may have adverse cardiovascular effects. Therefore, special attention should be given to cardiovascular protection during COVID-19 infection.

Phenotypic and genotypic characterization of meningococcal isolates in Tunis, Tunisia: High diversity and impact on vaccination strategies.

OBJECTIVES: The aim of this study was to characterize Neisseria meningitidis (Men) isolates in Tunisian paediatric patients with invasive meningococcal disease (IMD) in order to target therapeutic and preventive strategies. METHODS: Fifty-nine isolates of Men and four cerebrospinal fluid samples that were culture-negative but Men-positive by PCR (NC-MenPPCR) (2009-2016) were collected from IMD patients. Isolates were analysed for their antimicrobial susceptibility. Whole-genome sequencing (WGS) was used to characterize isolates and multilocus sequence typing for NC-MenPPCR. Coverage of Men serogroup B (MenB) was determined by Genetic Meningococcal Antigen Typing System (gMATS) and fHbp expression by ELISA. RESULTS: MenB was the predominant type (88.9%). The majority of isolates (81%) had reduced susceptibility to penicillin G with altered penA alleles. The clonal complex CC461 (27.1%) was the most frequent. Among the MenB vaccine targets neisserial heparin binding antigen (NHBA) and fHbp, the predominant variants were NHBA118 (30.8%) and fHbp peptide 47 (25%), respectively. The nadA gene was present in 17.3% of isolates. Using gMATS, 36.5% of MenB were predicted to be covered by the 4CMenB vaccine. ELISA showed that 92.4% of the MenB were expected to be killed by anti-fHbp antibodies. CONCLUSIONS: MenB was the leading serogroup in IMD, and more than 90% had a sufficient level of fHbp expression for vaccine coverage. The study results will be useful for the Tunisian vaccination programme.

The Third International Intercomparison on EPR Tooth Dosimetry: part 2, final analysis.

The objective of the Third International Intercomparison on EPR Tooth Dosimetry was to evaluate laboratories performing tooth enamel dosimetry <300 mGy. Final analysis of results included a correlation analysis between features of laboratory dose reconstruction protocols and dosimetry performance. Applicability of electron paramagnetic resonance (EPR) tooth dosimetry at low dose was shown at two applied dose levels of 79 and 176 mGy. Most (9 of 12) laboratories reported the dose to be within 50 mGy of the delivered dose of 79 mGy, and 10 of 12 laboratories reported the dose to be within 100 mGy of the delivered dose of 176 mGy. At the high-dose tested (704 mGy) agreement within 25% of the delivered dose was found in 10 laboratories. Features of EPR dose reconstruction protocols that affect dosimetry performance were found to be magnetic field modulation amplitude in EPR spectrum recording, EPR signal model in spectrum deconvolution and duration of latency period for tooth enamel samples after preparation.

[IRAP-and REMAP-analyses of barley varieties of Odessa breeding].

Application of polylocus biallelic systems of PCR along with monolocus SSR-analysis is very promising approach for detailed characterization, differentiation and identification of crop varieties. Microsatellite sequences and LTR retratransposon fragments are known to be the most variable in plant genome. They can be used in PCR analysis as IRAP and REMAP. Conditions of IRAP and REMAP analyses of intra- and intervariety polymorphism of the barley varieties of Odessa breeding have been elaborated. The detailed genotype formulas are represented which reflect the intravariety polimorphism and make it possible to detect the changes in variety structure in the course of seed production process.

Kinetics of chemotaxis, cytokine, and chemokine release of NR8383 macrophages after exposure to inflammatory and inert granular insoluble particles.

Accumulation of macrophages and neutrophil granulocytes in the lung are key events in the inflammatory response to inhaled particles. The present study aims at the time course of chemotaxis in vitro in response to the challenge of various biopersistent particles and its functional relation to the transcription of inflammatory mediators. NR8383 rat alveolar macrophages were challenged with particles of coarse quartz, barium sulfate, and nanosized silica for one, four, and 16h and with coarse and nanosized titanium dioxide particles (rutile and anatase) for 16h only. The cell supernatants were used to investigate the chemotaxis of unexposed NR8383 macrophages. The transcription of inflammatory mediators in cells exposed to quartz, silica, and barium sulfate was analyzed by quantitative real-time PCR. Challenge with quartz, silica, and rutile particles induced significant chemotaxis of unexposed NR8383 macrophages. Chemotaxis caused by quartz and silica was accompanied by an elevated transcription of CCL3, CCL4, CXCL1, CXCL3, and TNFα. Quartz exposure showed an earlier onset of both effects compared to the nanosized silica. The strength of this response roughly paralleled the cytotoxic effects. Barium sulfate and anatase did not induce chemotaxis and barium sulfate as well caused no elevated transcription. In conclusion, NR8383 macrophages respond to the challenge with inflammatory particles with the release of chemotactic compounds that act on unexposed macrophages. The kinetics of the response differs between the various particles.

Variation of long-lived free radicals responsible for the EPR native signal in bone of aged or diseased human females and ovariectomized adult rats.

The purpose of this study was to gain insights into the variations seen in the electron paramagnetic resonance (EPR) spectroscopy of the native signals of teeth and bones used for retrospective dosimetry measurements. We determined that changes occur in the long-lived free radicals responsible for the native signal of cortical bone in aging or diseased human females and aged ovariectomized rats. This was done by measuring the magnitude of the broad (BC) and narrow (NC) components of the native EPR signal of bone following chemical extraction, aging, crushing and thermal annealing. Bone from the upper midshaft of femora of young (17-34 years old, n=5) and elderly (70-92 years old, n=18) females was examined. The results showed that the elderly women had significantly higher BC than the younger women (P<0.01). A similar interpretation was made of the data from an aging female rat osteoporosis model. The results for the NC signals were similar. Finally, dramatic decreases in both NC and BC signals were seen in HIV positive and uncontrolled diabetic (one each) patients indicating the need for studying this signal for a broad spectrum of metabolic disorders. Experiments were performed which strongly indicate that iron liganded with organic molecules is the source of the BC signal. Finally, the accuracy achieved in this study indicates that resolving the dosimetric signal (g=2.0018) should be improved by subtraction of the deconvoluted NC and BC signals from the original spectrum.

The 3rd international intercomparison on EPR tooth dosimetry: Part 1, general analysis.

The objective of the 3rd International Intercomparison on Electron Paramagnetic Resonance (EPR) Tooth Dosimetry was the evaluation of laboratories performing tooth enamel dosimetry below 300 mGy. Participants had to reconstruct the absorbed dose in tooth enamel from 11 molars, which were cut into two halves. One half of each tooth was irradiated in a 60Co beam to doses in the ranges of 30-100 mGy (5 samples), 100-300 mGy (5 samples), and 300-900 mGy (1 sample). Fourteen international laboratories participated in this intercomparison programme. A first analysis of the results and an overview of the essential features of methods applied in different laboratories are presented. The relative standard deviation of results of all methods was better than 27% for applied doses in the range of 79-704 mGy. In the analysis of the unirradiated tooth halves 8% of the samples were identified as outliers with additional absorbed dose above background dose.

Pericardial rub in pericardial effusion: lack of correlation with amount of fluid.

The relation between the amount of pericardial fluid and the presence of a pericardial rub was examined in 76 patients with echocardiographic evidence of pericardial effusion. A pericardial rub was noted in 4 of 13 patients with small pericardial effusion (less than 100 ml), in 23 of 40 patients with moderate effusion (100 to 500 ml), and in ten of 23 patients with a large effusion. No difference in the amount of fluid was demonstrated in the group of patients with a rub when compared to the group without one. There was a statistically significant relation between the presence of a rub and the cause of the effusion. No inference as to the amount of pericardial fluid should be drawn from the presence or absence of a pericardial rub.

Temperature stability of carbonate groups in tooth enamel.

The tooth enamel EPR signal at g = 1.9973 consists of several components, which correspond to different functions of the spatial orientation of the CO2- radicals, have different temperature stability and different saturation curves. Using a new technique described in this paper, we have detected and investigated two groups of CO2- radicals with different thermal stability and saturation characteristics.

Metamorphic modifications and EPR dosimetry in tooth enamel.

It is shown that metamorphic modifications in tooth enamel have an essential influence on the results of EPR dosimetry. The metamorphic modifications in minerals of biological origin proceed more quickly than in usual natural minerals. The approaches which at present are applied for reconstruction of doses connected with Chernobyl accident need additional investigation.

Anisotropy effects of EPR signals and mechanisms of mass transfer in tooth enamel and bones.

Peculiarities of the internal construction of tooth enamel and bones that cause anisotropy effects and mass transfer in these objects are described. It is shown that the composition of the mineral component of teeth and bones depends on a mechanical-electrical mechanism, which pumps ions into nanocrystals. Decrease in the efficiency of the mechanical-electrical mechanism results in demineralization of enamel and bones, which progresses most rapidly at a disease of the biomineral or under special conditions, such as in space flights. Effects of signal anisotropy in the practice of retrospective EPR dosimetry are discussed.

Metabolism in tooth enamel and reliability of retrospective dosimetry.

Most of the radiation centers in tooth enamel and bones are formed by the reactions COOH + gamma-->CO2- + H+, and CO2 + e- -->CO2-. These centers can be easily changed by metabolism and have a low stability in living organisms. The efficiency of CO2- radical production by irradiation is substantially different for teeth and bones in living rat, dead rat, and teeth and bone removed from rat. It is shown that the suitability of tooth enamel for retrospective dosimetry can be evaluated from the anisotropy of its EPR signals.

[Molecular-genetic identification and certification of soybean (Glycine max L.) cultivars]. / Molekuliarno-geneticheskaia identifikatsiia i paspoprtizatsiia sortov soi (Glycine max L.).

An approach to certification of soybean genotypes has been developed. The procedure employs three methods of DNA analysis based on polymerase chain reaction (PCR): PCR with arbitrary primers (AP PCR), simple sequence repeat polymorphism (SSRP) analysis, and inter-simple sequence repeat (ISSR) analysis. The approach to certification proposed may be used in both genetic and breeding research and seed production. A "certificate" form that reflects the unique characteristics of each cultivar studied is proposed. The results of molecular genetic analysis of allele distribution in genotypes of soybean from different ecological geographic zones permit estimation of the adaptive significance of individual alleles.

[Molecular and genetic polymorphism of cultivated soybean detected by AP-PCR, SSRP and SSR]. / Molekuliarno-geneticheskii polimorfizm soi, detektirovannyi PP-PTsR, SSRP i ISSR.

Molecular-genetic polymorphism of cultivated soybean from different geographic regions was analysed using three PCR methods (AP-PCR, SSRP and ISSR). The dendrogram of phenogenetic relationship was constructed on the base of obtained data. The allocation of varieties are in a good agreement with pedigree information. Main parameters such as polymorphism level, expected heterozygosity, and marker index were calculated. It was shown that ISSR is the method of choice for the differentiation of soybean varieties.

[Minerals of biological origin: their structural formation and properties]. / Mineraly biologicheskogo proiskkhozhdeniia: formirovanie struktury i svoistv.

A study is presented of human tooth enamel and its changes during heating. The measurements were done by methods of electron paramagnetic resonance, roentgen structural analysis and gaseous chromatography. A new effect has been found related to changes of enamel structure during heating. It was established that at T 170 degrees C there occurs reorientation of the crystallites of hydrohylapatite that form the structure of tooth enamel as well as changes of the properties of organic layers between these crystallites. Discussed are the general principles determining the structure and properties of minerals of biological origin. It is shown that the organic structure of the biomineral effects the properties of inorganic crystallites by means of the spatial geometric factor. This factor is finally related to the fact, that superficial energy of the crystallite contributes essentially in its general energy. The authors discuss the obtained results from the viewpoint of diagnosis and new treatment methods of diseases related to the biomineral of the human body.

Effects of inhaled thiazinamium chloride on histamine-induced and exercise-induced bronchoconstriction.

The protective efficacy of aerosolized thiazinamium chloride (TC) against histamine-induced and exercise-induced bronchoconstriction was evaluated in 15 subjects with stable, mild asthma. Following reproducible bronchoprovocation with these stimuli, each subject underwent randomized, double-blind, crossover pretreatment with single doses of nebulized TC (300, 600, and 900 micrograms), placebo, and an active control drug (metaproterenol or cromolyn), followed by histamine or exercise challenge (two separate protocols). The results indicated that all doses of TC significantly blocked histamine-induced bronchoconstriction as compared with placebo. Overall, aerosolized TC was ineffective in blocking exercise-induced bronchoconstriction, although 900 micrograms TC tended to be more effective than placebo. Thiazinamium (900 micrograms) produced a modest bronchodilator effect. No clinically significant adverse effects related to TC occurred. We conclude that aerosolized TC is effective in attenuating histamine-induced but not exercise-induced bronchoconstriction in the doses studied. Further studies are warranted to evaluate the role of TC in asthma therapy.

Cetirizine inhibition of histamine-induced bronchospasm.

Cetirizine is a potent, selective H1 antagonist recently made available for investigation. To evaluate this oral drug's efficacy in treating asthma, we examined the bronchodilator effects of 5-, 10-, and 20-mg doses as well as the protective effects of these doses against histamine-provoked bronchospasm. Cetirizine's efficacy was compared with that of a placebo and oral hydroxyzine (25 mg) in 10 patients with mild asthma. The new compound provided significant protection in a dose-dependent manner against histamine-induced bronchospasm. A 25-mg oral dose of hydroxyzine, which is partially metabolized to cetirizine, yielded blood levels of cetirizine comparable to those attained with 5 mg of oral cetirizine. Hydroxyzine 25 mg conferred greater protection against histamine bronchoprovocation than placebo, but it gave less protection than 10- and 20-mg doses of cetirizine. Cetirizine in all doses, as well as hydroxyzine at 25 mg, produced significant bronchodilation. However, the bronchodilator effect of the 25-mg hydroxyzine dose was less than that of cetirizine at 20 mg. In this short-term study, no significant side effects of cetirizine were noted.