Novel approaches to the treatment of cervical dystonia. The concept of dual navigation control

Сervical dystonia (CD) is the most common type of focal dystonia (up to 50% of all dystonia cases). Botulinum neurotoxin (BoNT) injections is the treatment choice for CD. However, the effectiveness and tolerability of botulinum therapy in CD depends on the correct choice of target muscles and the accuracy of the BoNT injection. The publication presents literature data and our own clinical experience regarding the use of navigation in BoNT injections in CD.According to the majority of authors, the use of navigation equipment, such as ultrasound (US) and electromyography (EMG), definitely increases the effectiveness of CD treatment and reduces the likelihood of adverse events. For the first time, an algorithm for the diagnosis and treatment of CD is proposed, based on the use of the method of «double- (EMG and US) guided navigation», a variant for determining the comparative activity of muscles by the intensity of the EMG signal and the design of an individual «passport» of the CD. The possibilities of analyzing the US of muscles, drawing up an accurate treatment regimen, targeted administration of BoNT, and using a non-injectable EMG electrode are shown. We present 4 clinical cases demonstrating the advantages of the double- (EMG+US) guided navigation method over the EMG-guided navigation for injection. The proposed algorithm for the diagnosis and treatment of CD makes it possible to increase the effectiveness of treatment, optimize the costs of BoNT and diagnostic equipment (injection EMG needle).

Comparative activity of newer β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa from patients hospitalized with pneumonia in European medical centers in 2020

Pseudomonas aeruginosa isolates were consecutively collected from patients with pneumonia in 29 medical centers in 2020 and susceptibility tested by broth microdilution method. Ceftazidime-avibactam (95.5% susceptible), imipenem-relebactam (94.3% susceptible), and ceftolozane-tazobactam (93.3% susceptible) were the most active compounds after colistin (99.5% susceptible). Susceptibility rates for the β-lactam/β-lactamase inhibitor combinations (BL/BLIs) varied against isolates resistant to piperacillin-tazobactam, meropenem, imipenem, and/or ceftazidime. Ceftazidime-avibactam was the most active BL/BLI against resistant subsets from Western Europe, whereas imipenem-relebactam was slightly more active than other BL/BLIs against resistant subsets from Eastern Europe. Susceptibility rates were markedly lower in Eastern Europe than Western Europe.

MO968ROUTINE BIOMARKERS FOR THE SEVERITY OF COVID-19 PNEUMONIA MAY PRESENT DIFFERENTLY IN KIDNEY TRANSPLANT RECIPIENTS

Background and Aims The treatment of coronavirus disease (COVID-19) is based on the patient’s clinical status and levels of inflammatory biomarkers. The comparative activity of these biomarkers in KT patients with COVID-19 pneumonia from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and non-SARS-CoV-2 aetiologies is unknown. The aim of this study was to compare the clinical presentation and inflammatory parameters at admission of KT patients with COVID-19 pneumonia and those with non-COVID-19 pneumonia over the same period. Method Biomarkers were measured and compared between KT patients with COVID-19 pneumonia (n=42) and non-COVID-19 pneumonia (n=18) from March to November 2020. Results Both groups showed comparable demographics. The COVID-19 KT patients had fewer neutrophils (4,650 [2,925-9,498] vs. 9,100 [7,170-11,150],p=0.01) than the non-COVID group, although there was no significant difference in the lymphocyte count. Non-COVID-19 pneumonia was associated with a higher d-dimer (962 [427-1,448] vs. 1,704 [868-2,481],p=0.09) and IL-6 (37 [23-10] vs 254 [53-602],p=0.006) levels. The ferritin level was higher in the COVID-19 group (908 [496-1,377] vs. 340 [264-785],p=0.008). Conclusion COVID-19 pneumonia in KT recipients shows a different presentation of inflammatory biomarkers than other non-COVID pneumonias. It could be usefully to identify KT patients with COVID-19.More detailed studies are necessary to understand the presentation of biomarkers in KT with COVID-19.

Activation of a Cryptic Manumycin-Type Biosynthetic Gene Cluster of Saccharothrix espanaensis DSM44229 by Series of Genetic Manipulations

(1) Background: Manumycins are small actinomycete polyketides with prominent cancerostatic and immunosuppressive activities via inhibition of various eukaryotic enzymes. Their overall activity towards human cells depends on the structural variability of both their polyketide chains, mainly the upper one. In our genetic screening project to find novel producers of anti-inflammatory manumycins, the strain Saccharothrix espanaensis DSM44229 was identified as containing a novel manumycin-type biosynthetic gene cluster (BGC). (2) Methods: The biosynthetic genes appeared to be silent under all assayed laboratory conditions. Several techniques were used to activate the BGC, including: (i) heterologous expression in various hosts, (ii) overexpression of putative pathway-specific regulatory genes, and (iii) overexpression of a bottleneck cyclizing aminolevulinate synthase gene in both natural and heterologous producers. (3) Results: Multiple novel manumycin-type compounds were produced at various levels by genetically-modified strains, sharing a tetraene lower chain structure with a colabomycin subgroup of manumycins, but possessing much shorter and saturated upper chains. (4) Conclusions: A cryptic manumycin-type BGC was successfully activated by genetic means to gain production of novel manumycin-type compounds for future comparative activity assays. Heterologously produced compounds were identical to those found after final activation of the BGC in the original strain, proving the intactness of the cloned BGC.

Phloroglucinol Derivatives from Dryopteris crassirhizoma as Potent Xanthine Oxidase Inhibitors

Dryopteris crassirhizoma rhizomes are used as a traditional medicine in Asia. The EtOAc extract of these roots has shown potent xanthine oxidase (XO) inhibitory activity. However, the main phloroglucinols in D. crassirhizoma rhizomes have not been analyzed. Thus, we investigated the major constituents responsible for this effect. Bioassay-guided purification isolated four compounds: flavaspidic acid AP (1), flavaspidic acid AB (2), flavaspidic acid PB (3), and flavaspidic acid BB (4). Among these, 1 showed the most potent inhibitory activity with a half-maximal inhibitory concentration (IC50) value of 6.3 µM, similar to that of allopurinol (IC50 = 5.7 µM) and better than that of oxypurinol (IC50 = 43.1 µM), which are XO inhibitors. A comparative activity screen indicated that the acetyl group at C3 and C3′ is crucial for XO inhibition. For example, 1 showed nearly 4-fold higher efficacy than 4 (IC50 = 20.9 µM). Representative inhibitors (1–4) in the rhizomes of D. crassirhizoma showed reversible and noncompetitive inhibition toward XO. Furthermore, the potent inhibitors were shown to be present in high quantities in the rhizomes by a UPLC-QTOF-MS analysis. Therefore, the rhizomes of D. crassirhizoma could be used to develop nutraceuticals and medicines for the treatment of gout.