Analysis of Electrophysiological Mechanisms of N-Deacetyllapaconitine Monochlorhydrate, the Main Metabolite of Lappaconitine Hydrobromide.

In in vitro experiments on isolated rat hippocampal neurons, we studied the electrophysiological mechanisms of the antiarrhythmic effects of N-deacetyllappaconitine monochlorhydrate (DALCh), active metabolite of lappaconitine hydrobromide (allapinin). Electrical activity of neurons was recorded by the patch-clamp method in the whole cell configuration. It was shown that DALCh increased the duration of both slow and fast depolarization phases and decreased the amplitude of the action potential. DALCh effectively inhibited transmembrane currents of Na+ ions and partially K+ ions through the corresponding transmembrane voltage-gated ion channels. Thus, DALCh, in contrast to lappaconitine hydrobromide, belongs not to 1C, but to the 1A class of antiarrhythmics according to the Vaughan-Williams classification.

[Search of (-)-Cytisine Derivatives as Potential Inhibitors of NF-κB and STAT1].

Design and synthesis ofnew derivatives of (-)-cytisine with a wide spectrum of pharmacological activity, represents the potential therapeutic interest for development of drug candidates for neurodegenerative disorders, inflammatory diseases, and treatment of nicotine addiction. We used HEK293 cell line transiently transfected with N F-κB and STATI luciferase reporter constructs to screen the (-)-cytisine derivatives for their potency to modulate basal and induced NF-κB and STAT1 activity. Currently, NF-κB, STAT1 and components of their signaling pathways are considered as attractive targets for pharmacological intervention, primarily in chronic inflammation, cancer, autoimmune, neurodegenerative and infectious diseases. The library of compounds included the derivatives of (-)-cytisine with amino-, amide-, thio- and carboxamide groups at 3, 5 and 12 position of the starting molecule, as well as some bimolecular derivatives. Our experimental data revealed compounds with moderate activating as well as inhibitory effects for basal NF-κB and STATI activity (IC50 or EC50 values are mainly in the micromolar range). The structure-activity relationship analysis demonstrated that the character of activity (activation or inhibition of NFκ-B and STAT1) is determined by the topology of the substituents at the (-)-cytisine molecule, whereas the nature of the substituents mainly contributes to severity of the effect (introduction of aromatic and adamantyl substituents, as well as thionyl or keto groups are of the principal importance). When evaluating the effect of (-)-cytisine derivatives on activity of NF-κB and STATI, induced by specific agents (TNFα and IFNγ, respectively) we observed that some compounds inhibited basal and stimulated activity of NF-κB and STAT1, another compounds showed the dual effect (an increase of basal- and a decrease of stimulated NF-κB activity) and several compounds increase both basal and induced activity of NF-κB and STAT1. Thus, obtained results suggest that one of the possible mechanisms of biological action of (-)-cytisine derivatives is their ability to influence the components of NF-κB and STAT1-dependent signaling pathways.

Assessment of the radiological impact of gamma and radon dose rates at former U mining sites in Tajikistan.

An assessment of the radiological situation due to exposure to gamma radiation, radon ((222)Rn) and thoron ((220)Rn) was carried out at former uranium (U) mining and processing sites in Taboshar and at Digmai in Tajikistan. Gamma dose rate measurements were made using various field instruments. (222)Rn/(220)Rn measurements were carried out with field instruments for instantaneous measurements and then discriminative (222)Rn/(220)Rn solid state nuclear track detectors (SSNTD) were used for longer representative measurements. The detectors were exposed for an extended period of time in different outdoor and indoor public and residential environments at the selected U legacy sites. The results showed that gamma, (222)Rn and (220)Rn doses were in general low, which consequently implies a low to relatively low radiological risk. The radiation doses deriving from external radiation (gamma dose rate), indoor (222)Rn and (220)Rn with their short-lived progenies did not exceed national or international standards. At none of the sites investigated did the average individual annual effective doses exceed 10 mSv, the recommended threshold value for the general public. A radiation hazard could be associated with exceptional situations, such as elevated exposures to ionizing radiation at the Digmai tailings site and/or in industrial facilities, where gamma and (222)Rn/(220)Rn dose rates could reach values of several 10 mSv/a. Current doses of ionizing radiation do not represent a hazard to the health of the resident public, with the exception of some specific situations. These issues should be adequately addressed to further reduce needless exposure of the resident public to ionizing radiation.

Assessment of the radiological impact of gamma and radon dose rates at former U mining sites in Central Asia.

An assessment of the radiological situation due to exposure to gamma radiation, radon and thoron was carried out at selected former uranium mining and processing sites in the Central Asian countries of Kazakhstan, Kyrgyzstan, Uzbekistan and Tajikistan. Gamma dose rate measurements were made using various field instruments and radon/thoron measurements were carried out using discriminative radon ((222)Rn)/thoron ((220)Rn) solid state nuclear track detectors (SSNTD). The detectors were exposed for an extended period of time, including at least three seasonal periods in a year, in different outdoor and indoor public and residential environments at the selected uranium legacy sites. The results showed that gamma, Rn and Tn doses were in general low, which consequently implies a low/relatively low radiological risk. The major radiation hazard is represented by abandoned radioactive filtration material that was being used as insulation by some Minkush residents (Kyrgyzstan) for a longer period of time. Annual radiation doses of several hundred mSv could be received as a consequence of using this material domestically. In addition, the gamma and Rn/Tn dose rates at Digmai, Tajikistan, could reach values of several 10 mSv/a. The doses of ionizing radiation deriving from external radiation (gamma dose rate), indoor radon and thoron with their short-lived progenies in several cases exceeded the recommended annual effective dose threshold level of 10 mSv. At none of the sites investigated did the individual annual effective doses exceed 30 mSv, the internationally recommended value for considering intervention. Current doses of ionizing radiation do not represent a serious hazard to the health of the resident public, but this issue should be adequately addressed to further reduce needless exposure of the resident public to ionizing radiation.

Environmental impact assessment of radionuclide and metal contamination at the former U sites Taboshar and Digmai, Tajikistan.

Uranium (U) ore mining and processing were initiated in the former Soviet Republics of Tajikistan after the Second World War as part of the USSR nuclear weapon programme. The U mine in Taboshar was opened in 1936, and mining took place from 1945 to 1965, while the Digmai tailings dump was exploited during 1963-1993. The mining, milling and extraction activities have resulted in large amounts of waste rock deposits and U tailing materials placed in the vicinity of inhabited areas. To assess the environmental impact of radionuclides and trace metals in the Taboshar and Digmai mining and tailing sites in Tajikistan, field expeditions were performed in 2006 and 2008. In addition to in situ gamma and radon dose rate measurements, sampling of water, fish, sediments, soils and vegetation including in situ fractionation of water were performed. The U concentrations in water from Taboshar Pit Lake (2.0 mg U/L) were higher than in waters collected in the Digmai area. The Pit Lake and the stream water from the tailing mountain were also characterised by elevated concentrations of As, Mo, Mn and Fe, exceeding the WHO recommended values for drinking water. Uranium, As, Mo and Ni were present as low molecular mass species in the waters, and are therefore considered mobile and potentially bioavailable. The (238)U concentrations in sediments and soils varied between the sites; with peak concentrations (6 kBq/kg dw) in sediments from the Pit Lake, while the soil concentrations were significantly lower (296-590 Bq/kg dw). In contrast, high levels of the radium isotopes ((226)Ra and (228)Ra) were found in the Digmai soil (17-32 kBq/kg dw). Based on sequential extraction results, both U and Pb were found to be quite mobile at the Pit Lake site, showing that these elements were associated with the pH sensitive and redox sensitive amorphous fractions. In tailings, U was found to be quite mobile, but here Pb was rather inert. The transfer of radionuclides and metals from sediments to waters was in general low. In the Pit Lake, U was quite mobile (Kd = 90 L/kg), followed by Ni (1.5 × 10(3) L/kg) and As (6 × 10(3) L/kg), Cu and Cd (1.5 × 10(4) L/kg), while Pb (3 × 10(5) L/kg) was rather inert. The transfer from soil to plant, TFs (kg/kg dw), was in general low, while the bioconcentration factor for water living Poaceae and for fish from water was relatively high (Pb 1.8 × 10(5) and Cd 1 × 10(4)). These legacy sites, containing enhanced levels of natural radioactive material (TENORM) as well as heavy metals, may represent a hazard having a potential radiological and chemical impact on man and the environment, and measures should be taken to reduce the environmental risk to man and biota.

Synthesis of triterpenoid acylates: Effective reproduction inhibitors of influenza A (H1N1) and papilloma viruses.

The synthesis of a new group of triterpenoid acylates has been conducted on the basis of oleanolic, glycyrrhetic, and ursolic acids and betulin. 28-ortho-Methoxycynnamoylbetulin has been demonstrated to possess high activity against the influenza type A (H1N1) virus with the selectivity index SI > 100 while studying the activity of the synthesized compounds in relation to the reproduction of viral pathogens of respiratory infections. The high activity of 3,28-dinicotinoylbetulin against the papilloma virus (strain HPV-11) was detected with the selectivity index SI 35.

Optimizing a canine survival model of orthotopic lung transplantation.

INTRODUCTION: While acute models of orthotopic lung transplantation have been described in dogs, the technical considerations of developing a survival model in this species have not been elaborated. Herein, we describe optimization of a canine survival model of orthotopic lung transplantation. METHODS: Protocols of orthotopic left lung transplantation and single lung ventilation were established in acute experiments (n=9). Four dogs, serving as controls, received autologous, orthotopic lung transplants. Allogeneic transplants were performed in 16 DLA-identical and 16 DLA-mismatched unrelated recipient dogs. Selective right lung ventilation was utilized in all animals. A Malecot tube was left in the pleural space connected to a Heimlich valve for up to 24 hours. To date, animals have been followed up to 24 months by chest radiography, pulmonary function tests, bronchoscopy with lavage, and open biopsies. RESULTS: Long-term survival was achieved in 34/36 animals. Two recipients died intraoperatively secondary to cardiac arrest. All animals were extubated on the operating table, and in all cases the chest tube was removed within 24 hours. Major complications included thrombosis of the pulmonary artery and subcritical stenosis of bronchial anastamosis. One recipient underwent successful treatment of a small bowel intussusception. CONCLUSIONS: We report our experience in developing a survival canine model of orthotopic single lung transplantation. While short-term survival following canine lung transplantation is achievable, we report particular considerations that facilitate animal comfort, early extubation, and lung reexpansion in the immediate postoperative period, further optimizing use of this species for experimental modeling of long-term complications after lung transplantation.

Cones of skin occur where hypertrophic scar occurs.

Hypertrophic scarring is devastating for the patient, however the pathophysiology and treatment remain unknown after decades of research. The process follows deep dermal injury, occurs only on certain body parts, does not occur in the early fetus or in animals, and is a localized event. This suggests that an anatomic structure in human, deep dermis may be involved. The dermis is a matrix perforated by cones containing many structures including skin appendages and fat domes. We hypothesized that studying the cones might reveal a structure related to scarring. We examined tangential wounds from various body parts on human cadavers along with skin histology from various human body parts, the early fetus, partial thickness burns, hypertrophic scars, and two other species-rats and rabbits. We found that the cones may in fact be the structure. They exist where hypertrophic scar occurs-cheek, neck, chest, abdomen, back, buttock, arm, forearm, dorsal hand, thigh, leg, dorsal foot, helix and ear lobe. They do not exist where hypertrophic scar does not occur-scalp, forehead, concha, eyelid, palm, early fetus, and in rat, or rabbit. It also became apparent that the cones have been omitted from most considerations of skin histology. We suggest that the cones need to be studied in relation to hypertrophic scarring and restored to skin diagrams.