Functional phenotypes of macrophages and the M1-M2 polarization concept. Part I. Proinflammatory phenotype.

Current concepts concerning the main functional phenotypes of mononuclear phagocytes are systematized, molecular mechanisms of their formation are considered, and the functional polarization concept of macrophages is critically analyzed. Mechanisms of macrophage priming activation mediated by pattern recognition receptors TLR, NLR, RLR, and CLR are described, and the features of each phenotype acquired via various pattern recognition receptors are emphasized. It is concluded that there is a huge variety of proinflammatory phenotypes from highly to poorly polarized ones. Thus the widespread notion of "classical activation" of macrophage concerns just a particular case of proinflammatory phenotype formation.

Highest prevalence of the Mycobacterium tuberculosis Beijing genotype isolates in patients newly diagnosed with tuberculosis in the Novosibirsk oblast, Russian Federation.

In order to assess the genetic diversity of Mycobacterium tuberculosis in the Novosibirsk Region and determine profiles of resistance, 106 M. tuberculosis isolates were analysed. Fifty (47 %) isolates were identified using variable number tandem repeat typing as being in the Beijing family, of which eight (16 %) were type M2 isolates with the genetic profile 233325153533424 and eight (16 %) were type M11 isolates with the genetic profile 233325173533424, both of which are widespread in Russia. Mutations associated with resistance to isoniazid and rifampicin were identified. Of 48 isolates with resistance to isoniazid, 42 (87.5 %) contained a Ser(315)→Thr substitution in the katG gene and one contained a T→A substitution at position -34 of the promoter region of the ahpC gene. Of 31 isolates with resistance to rifampicin, 19 (61 %) each contained a mutation (TCG→TTG) at codon 531 of the rpoB gene. Two isolates each contained a mutation (GAC→GTC) at codon 516 of the rpoB gene and two others each contained a substitution at codon 526 of the rpoB gene, leading to a His→Asn substitution in one case and a His→Asp substitution in another case. One isolate contained a mutation (CTG→CCG) at codon 533 of the rpoB gene. An association between the Beijing genotype and multidrug resistance was demonstrated (R = 0.2, P = 0.032). However, it was interesting to note that a significant proportion (46 %) of isolates were sensitive to all drugs tested.

Tuberculosis in North Siberian and Far East inhabitants.

Novosibirsk TB Research Institute is a center of the pursuance and coordination of scientific investigations and the providing of an antituberculosis cure in Siberian and Far East federal regions. Northern territories are included in the zone of Institute supervision. We have chosen two territories (Taimyr and Koryakia) to study peculiarities of the TB problem on the North. We have estimated social, demography, ethnic, ecological, political, economical, epidemic, technology factors, and quality of TB control work in considering the situation on TB. We have marked out problem areas in the sphere of TB control in Northern territories. Novosibirsk TB Research Institute, in cooperation with other Scientific Centers, provides actions on improving the system of support to TB control facilities of the Northern territories, taking into account peculiarities in the situation with TB in the following directions: organizational activities on interaction with authorities and general health care; prediction of clinical course and treatment outcome based on study of the clinical, immunogenetic, and morphological peculiarities of TB; study of bacteriological and immunogenetic peculiarities of Mycobacterium tuberculosis to improve TB diagnostics, to use TB drugs in accordance to the data on drug-resistance and to provide timely correction of treatment course.

Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis.

Mycobacterium tuberculosis is an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 microg/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.

[Effectiveness of liposomal antibacterial drugs in the inhalation therapy of experimental tuberculosis]. / Effectivnost liposomalnoi lekarstvennoi formy antibakterialnykh preparatov v ingaliatsionnoi terapii éksperimentalnogo tuberkulëza.

The model of generalized tuberculosis in BALB/c mice was used to compare efficacy of daily and intermittent (2 times a week) regimens of ultrasound inhalation therapy. This employed water-soluble and liposomal dosages of antituberculous drugs. The highest effect was achieved in daily inhalations of liposomal drugs. In spite of the fact that intermittent regime of the liposomal drugs required a 2-fold lowered dosage, its efficacy was not inferior to daily water-soluble drug therapy and was only by 22% less than maximum. High response to liposomal form stems from prolonged persistence of high rifampicin concentrations in pulmonary tissue.