Modern Development Problems of Russian Healthcare: Part 2.

The second part of the article (see the beginning in No. 6-2021) analyzes the negative consequences of the so-called health care optimization. It is shown that as a result of its implementation, the availability of medical care has decreased. A possible way to improve the territorial organization of medical services is considered. The effectiveness of the Russian health care system in the fight against the coronavirus pandemic was assessed.

[Erectile dysfunction: choice of the treatment method].

The 15-year clinical experience with falloendoprosthetic operations (FEPO) in patients with erectile dysfunction is reviewed including algorithm of diagnostic examination, prostheses of different generations, indications and contraindications for falloendoprosthetic surgery. The results of 117 FEPO are outlined with special emphasis on 19 cases of postoperative complications. The conclusion is made that FEPO is most effective in erectile dysfunction by the presented criteria of the erectile dysfunction treatment efficacy.

Modern Development Problems of Russian Healthcare (Part 1).

The paper (part 1) analyzes the dynamics of indicators characterizing the state of health of the Russian population. A comparative analysis of the development of healthcare in Russia and other countries is carried out. The conclusion is confirmed that the main problem in the development of Russian healthcare is the insufficient volume of public funding. The drawbacks and limited potential of the adopted funding model are assessed. A possible way to increase public funding is proposed. It is shown that the availability of medical care is reduced as a result of the so-called optimization of healthcare. A possible way to improve the territorial organization of medical services is considered. The effectiveness of the Russian healthcare system in the fight against the coronavirus pandemic is assessed.

Implications of the VEGA Balloon Results for Venus Atmospheric Dynamics.

Both VEGA balloons encountered vertical winds with typical velocities of 1 to 2 meters per second. These values are consistent with those estimated from mixing length theory of thermal convection. However, small-scale temperature fluctuations for each balloon were sometimes larger than predicted. The approximate 6.5-kelvin difference in temperature consistently seen between VEGA-1 and VEGA-2 is probably due to synoptic or planetary-scale nonaxisymmetric disturbances that propagate westward with respect to the planet. There is also evidence from Doppler data for the existence of solar-fixed nonaxisymmetric motions that may be thermal tides. Surface topography may influence atmospheric motions experienced by the VEGA-2 balloon.

[Penile endoprosthesis in complex rehabilitation of wounded and ill persons with erectile dysfunction].

Morbidity of erectile dysfunction among men of every age is 10%. It's supposed that now-days in the world about 100 mln of men have organic erectile dysfunction. Specialist of the 6th MMCH of Ministry of Defense have elaborated a rehabilitation program for military service men with erectile dysfunction. This program includes a complex clinical-psychological checkup, methods of reconstruction of copulative capacity, evaluation of effectiveness of realized treatment. Evaluation of quality of result of phalloendoprosthesis has shown that 92,3% of patients estimate the result as excellent and good, 5,2%--as satisfactory, 2,5% have not sex life.

[System of rehabilitation in the Armed Forces: history, current situation, and perspectives of development].

There are two main directions of development of medical rehabilitation in the Armed Forces of RF for now-days: medical-psychological rehabilitation of military service men among special contingents, realizing special military duty (air- and NAVY-staff, staff duty shift of Missile Force of Special Purpose) and medical rehabilitation of military service men, participants of battle action in accordance with sub-program "Social support and rehabilitation of invalids in consequence of battle action or battle trauma" of Federal Purpose Program in the sphere of social support of invalids. The authors mark necessity of reorientation of medical strategy from evaluation of determination of symptoms of already existent disease to evaluation of determination of adaptation reserves of organism of military service men, determination of changes in organism on the stage of pre-disease.

Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress.

The p53 tumor suppressor protein plays a key role in the regulation of stress-mediated growth arrest and apoptosis. Stress-induced phosphorylation of p53 tightly regulates its stability and transcriptional activities. Mass spectrometry analysis of p53 phosphorylated in 293T cells by active Jun NH2-terminal kinase (JNK) identified T81 as the JNK phosphorylation site. JNK phosphorylated p53 at T81 in response to DNA damage and stress-inducing agents, as determined by phospho-specific antibodies to T81. Unlike wild-type p53, in response to JNK stimuli p53 mutated on T81 (T81A) did not exhibit increased expression or concomitant activation of transcriptional activity, growth inhibition, and apoptosis. Forced expression of MKP5, a JNK phosphatase, in JNK kinase-expressing cells decreased T81 phosphorylation while reducing p53 transcriptional activity and p53-mediated apoptosis. Similarly transfection of antisense JNK 1 and -2 decreased T81 phosphorylation in response to UV irradiation. More than 180 human tumors have been reported to contain p53 with mutations within the region that encompasses T81 and the JNK binding site (amino acids 81 to 116). Our studies identify an additional mechanism for the regulation of p53 stability and functional activities in response to stress.

Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases.

To elucidate mechanisms underlying glutathione S-transferase p (GSTp)-mediated cellular protection against oxidative stress-induced cell death, the effect of GSTp on stress signaling pathways was investigated before and after H2O2 treatment. Under nonstressed conditions, increased expression of GSTp via a tet-off-inducible GSTp in NIH 3T3 cells increased the phosphorylation of mitogen-activated protein (MAP) kinase kinase 4, p38, extracellular receptor kinase (ERK), and inhibitor of kappa-kinase (IKK), and reduced phosphorylation of MAP kinase kinase 7 and Jun NH2-terminal kinase (JNK). Whereas H2O2 treatment of cells induced JNK, p38, and IKK activities, in the presence of H2O2 and elevated GSTp expression there was an additional increase in ERK, p38, and IKK activities and a decrease in JNK activity. GSTp-mediated protection from H2O2-induced death was attenuated upon inhibition of p38, nuclear factor KB, or MAP kinase by dominant negative or pharmacological inhibitors. Conversely, expression of a dominant negative JNK protected cells from H2O2-mediated death. These data suggest that the coordinated regulation of stress kinases by GSTp, as reflected by increased p38, ERK, and nuclear factor kappaB activities together with suppression of JNK signaling, contributes to protection of cells against reactive oxygen species-mediated death.

[The effect of various iron hydroxide concentrations on the anaerobic fermentation of sulfate-containing model sewage].

The addition of iron hydroxide and iron-reducing bacteria into a fermenter for anaerobic processing of sulfate-containing sewage was shown to decrease sulfate reduction and sulfide concentration, while increasing the total organic carbon (TOC) and methane production. The effect of iron (III) in sulfate-containing sewage depended on its dose, which can be expressed as molar ratio Fe(III)/SO4(2-). Sulfide concentration increased monotonically, reaching 91 mg/l and 45 mg/l after 15 days of processing at Fe(III)/SO4(2-) ratios of 0.06 and 0.5, respectively. However, soluble sulfide production was not observed at ratios equaling 1 and 2. At ratios of 0.06, 0.5, 1, and 2, the maximum rates of TOC removal were 0.75, 1.15, 1.39, and 1.55 g TOC/g of organic matter (OM) per 1 h. Methane production rates were 0.039, 0.047, 0.064, and 0.069 mg/g OM per 1 h, with the mean relative amounts of methane in the biogas being equal to 25, 41, 55, and 62%, respectively. These data can be applied to the development of new methods of anaerobic purification of sulfate-containing sewage.

p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-kappaB activity and Fas expression.

Identifying mechanisms that underlie the resistance of human melanoma to radiation and chemotherapy is expected to assist in developing new strategies for the treatment of this tumor type. We recently demonstrated that through up-regulation of TNFalpha, ATF2 increases the resistance of late stage melanoma cells to apoptosis induced by UV-irradiation. In elucidating the role of ATF2 kinases, we now demonstrate that ASK1/MKK6/p38 elicits suppression of Fas expression. ASK1/p38 downregulates the expression of a Fas via NF-kappaB/SP1 site on the Fas promoter. Deletion or mutation of NF-kappaB/SP1 within the Fas promoter abrogates p38 effect. ASK1/p38 silences the Fas promoter by inhibition of IkappaBalpha phosphorylation - thereby limiting NF-kappaB activity. Forced expression of a dominant negative form of p38 (p38-ASP) or treatment with p38 pharmacological inhibitor, SB203580, increases NF-kappaB activity, Fas expression and the levels of UVC-induced apoptosis in late stage melanoma cells. Inhibition of p38 activity also restored NF-kappaB activity and Fas expression in early-phase melanoma cells, suggesting that p38 elicited suppression of Fas expression is not restricted to late phase melanoma. Identifying p38-mediated down-regulation of Fas expression illustrates a novel regulatory pathway by which ASK1/MKK6/p38 alters the degree and nature of the UV-induced apoptosis of melanoma cells. Oncogene (2000).

Expression of ring finger-deleted TRAF2 sensitizes metastatic melanoma cells to apoptosis via up-regulation of p38, TNFalpha and suppression of NF-kappaB activities.

Mechanisms underlying radiation and chemotherapy resistance, the hallmark of human melanoma, are not well understood. Here we demonstrate that expression levels of signal adaptor protein TRAF2 coincide with melanoma resistance to UV-irradiation. Altered TRAF2 signaling by a form of TRAF2, which lacks the ring finger domain (TRAF2DeltaN), increases activities of p38 MAPK, ATF2, and the level of TNFalpha expression. Forced expression of TRAF2DeltaN in HHMSX highly metastatic melanoma cells that lack Fas expression and thus utilize the TNFalpha-TNFR1 as the major apoptotic pathway sensitized cells to UV-induced apoptosis. An over twofold increase in degree of apoptosis was observed in TRAF2DeltaN expressing cells that were treated with actinomycin D, anisomycin or with the radiomimetic drug neocarzinostatin. Sensitization by TRAF2DeltaN is selective since it was not observed in response to either Taxol or cis-platinum treatment. TRAF2DeltaN effects are primarily mediated via p38 since inhibition of p38 reduces, whereas activation of p38 promotes the level of UV-induced apoptosis. Conversely, activation of IKK attenuates the sensitization of melanoma by TRAF2DeltaN, indicating that p38-mediated suppression of NF-kappaB activity is among TRAF2DeltaN effects. Our finding identifies p38, TNFalpha and NF-kappaB among key players that efficiently sensitizes melanoma cells to UV-, ribotoxic (anisomycin) and radiomimetic chemicals-induced programmed cell death in response to aberrant TRAF2 signaling.

Role of TRAF2/GCK in melanoma sensitivity to UV-induced apoptosis.

Radiation resistance is a hallmark of human melanoma, and yet mechanisms underlying this resistance are not well understood. We recently established the role of ATF2 in this process, suggesting that stress kinases, which contribute to regulation of ATF2 stability and activity, play an important role in the acquisition of such resistance. Here we demonstrate that changes in the expression and respective activities of TRAF2/GCK occur during melanoma development and regulate its sensitivity to UV-induced apoptosis. Comparing early- and late-stage melanoma cells revealed low expression of TRAF2 and GCK in early-stage melanoma, which coincided with poor resistance to UV-induced, TNF-mediated apoptosis; forced expression of GCK alone or in combination with TRAF2 efficiently increased JNK and NF-kappaB activities, which coincided with increased protection against apoptosis. Conversely, forced expression of the dominant negative form of TRAF2 or GCK in late-stage melanoma cells reduced NF-kappaB activity and decreased Fas expression, resulting in a lower degree of UV-induced, Fas-mediated cell death. Our results illustrate a mechanism in which protection from, or promotion of, UV-induced melanoma cell death depends on the nature of the apoptotic cascade (TNF or Fas) and on the availability of TRAF2/GCK, whose expression increases during melanoma progression. Oncogene (2000) 19, 933 - 942.

Regulation of Fas-dependent activation-induced T cell apoptosis by cAMP signaling: a potential role for transcription factor NF-kappa B.

TCR-mediated activation of T cell hybridomas induces programmed cell death by a Fas-dependent pathway. We now show that costimulation of 2B4 cells, in the absence or presence of transgenic Bcl-2, with anti-CD3 epsilon and forskolin, an activator of cAMP signaling, resulted in antagonism of Fas-dependent activation-induced cell death that was always accompanied by selective downregulation of the nuclear levels of NF-kappa B p65-p50 (RelA-p50) transcription factor. Forskolin not only inhibited activation-induced cell death and NF-kappa B activation, but also suppressed expression of Fas and Fas ligand (Fas-L). Furthermore, NF-kappa B p65 antisense oligonucleotide down-regulated nuclear levels of NF-kappa B, inhibited cell surface expression of Fas-L and apoptosis of 2B4. Collectively, these finding demonstrate a potential role of NF-kappa B in the regulation of activation-induced apoptosis in T lymphocytes.

STRA13 interacts with STAT3 and modulates transcription of STAT3-dependent targets.

STRA13 is a pVHL-dependent bHLH transcription factor up-regulated on the mRNA level in multiple cancer cell lines and implicated recently in the regulation of immune cell homeostasis and autoimmunity. In searching for STRA13-interacting proteins with oncogenic potential by the yeast two-hybrid screening, we identified STAT3 beta as a STRA13-binding partner. We showed that STRA13 binds predominantly to phosphorylated (active) STAT3 alpha and beta isoforms via its HLH and C-terminal regions. We also found that STRA13 was able to activate transcription from STAT-dependent cis-elements. Expression of endogenous STRA13 was shown to be cytokine-inducible, consistent with STRA13 involvement in STAT-dependent transcription regulation. We demonstrated that the STAT3-regulated promoter of the pro-apoptotic Fas gene was activated upon STRA13 over-expression and that co-expression of STRA13 with STAT3 beta or STAT3 alpha modulated the transcriptional outcome. Forced expression of STRA13 induced apoptosis, in agreement with the STRA13 activation effect on the Fas promoter. Simultaneous expression of STRA13 and STAT3 beta resulted in alleviation of the STRA13 pro-apoptotic effect. Thus, for the first time, we identify STRA13 as a STAT3 partner and provide a consistent line of evidence for STRA13 involvement into regulation of apoptosis via the STAT pathways.

Molecular cloning of a bovine immunoglobulin lambda chain cDNA.

A cDNA library of the bovine mammary gland constructed in pBR322 was screened by mRNA hybrid-selected translation and by differential hybridization. Several immunoglobulin (Ig) lambda light-chain clones were identified and sequenced. Nucleotide sequence comparison of bovine and human Ig lambda chains showed a high degree of homology for constant regions and for J regions. The amino acid (aa) sequence encoded by the constant region of the bovine Ig lambda chain cDNA contains 107 aa with differences at 24 aa positions from the human Ig lambda chain. Three complementarity-determining regions (CDR1,2,3) characteristic of the variable region of bovine Ig lambda chain cDNA can be distinguished. The bovine and human sequences display good homology in the framework region 3 (FR3) but only patches of homology throughout the FR2 region. The 5' end of the bovine Ig lambda chain cDNA fragment of clone 1-14E contains five stop codons: two in CDR1, one in FR1 and two in the hydrophobic prepeptide region. These data suggest that the Ig lambda mRNA of clone 1-14E is transcribed from the V lambda pseudogene.

Identification of bacterial clones encoding bovine caseins by direct immunological screening of the cDNA library.

A sensitive immunoassay was used to identify recombinant plasmids carrying cDNA fragments of bovine caseins in the cDNA library from bovine mammary gland mRNA. Colonies grown on nitrocellulose filters were lysed in situ and proteins from the lysates were blotted onto CNBr-activated cellulose filter paper. Antigens covalently bound to CNBr-activated paper or bound to nitrocellulose filters were detected by reaction with antiserum to caseins, followed by 125I-labelled Staphylococcus aureus protein A and autoradiography. Six clones were found positive among 5400 of the cDNA library: 3-A1, 3-B2, 3-B5, 3-H7, 2-A5 and 2-C9. The molecular weights of chimeric pre-beta-lactamase: casein proteins synthesized in Escherichia coli were estimated by immunoblotting. Colony hybridization and nucleotide sequence analysis showed that clone 3-B5 contained a cDNA fragment of bovine chi-casein, clone 3-H7 contained a cDNA fragment of beta-casein, while clones 2-A5 and 2-C9 carried cDNA fragments of alpha s1-casein.

Quantitative SEM analysis of injury to the endothelium of rabbit aorta and carotid artery during experimental atherosclerosis.

The luminal surface of the aorta and the carotid artery in normal and cholesterol-fed rabbits (3 weeks, 6 weeks, and 8 months of alimentary hypercholesterolemia) was studied by scanning electron microscopy (SEM). To study endothelial injury the vessels were perfused and stained under physiological pressure. The frequency of large and small endothelial defects was determined per surface unit of endothelium in the normal and experimental groups of rabbits. Loss of endothelial cells was regarded as a large defect, argyrophilic cells, craters, and stomata were regarded as small ones. It was found that the percentage of regions without endothelial cells was similar in both control rabbits and in rabbits with experimental atherosclerosis (0.005--0.04% of the total surface examined). The frequency of small endothelial defects increased in rabbits after 3 weeks of hypercholesterolemia but decreased to the control level after 6 weeks of hypercholesterolemia. In rabbits with 8 months of hypercholesterolemia the frequency and area of defects outside plaques did not differ from the control group. In the group with hypercholesterolemia for 8 months 39.2% of the plaque surface contained endothelial cells in which there were no distinct silver-stained cell borders. Kevex X-ray spectrometric data of silver topography indicated that the plaque surface without distinct cell borders was not an area devoid of cells. The data obtained do not support the assumption that morphological endothelial injury is the structural precursor of plaque formation.

Perioperative neutron brachytherapy with californium-252.

Between 1973 and 1988, 495 patients were treated with Cf-252 neutron brachytherapy. Cf-252 neutron therapy sources developed in the USSR has been used in the trial. A numerical reconstruction method for localization of Cf-252 cell coordinates by projections on orthogonal radiographs has been designed and used for treatment planning. Eight (1.6%) patients with recurrent and persistent head and neck tumors and ages from 32 to 48 years (mean age 43 years) were treated with Cf-252 perioperative neutron brachytherapy. There were three patients with oral cavity, one with oropharynx, three with parotid gland cancers, and one with a skin tumor. The dose rate ranged fro 3.2 cGy/h to 11.1 cG/h, the minimal peripheral dose ranged from 3 Gy to 8 Gy. Initial local control was achieved in all patients. Local recurrence developed in two cases. Three patients died in first year after therapy. Three patients died during the second year. Two patients are long term cures, one patient more than nine years and one eight years, that is 25% of the treated patients.

Neutron brachytherapy in the treatment of melanoma.

PURPOSE: The use of Cf-252 for treatment of cutaneous malignant melanoma is presented. METHODS AND MATERIALS: From 1975 to 1992, plaque Cf-252 applicator neutron brachytherapy was performed in nine patients with skin malignant melanoma of head and neck or chest wall. Neutron brachytherapy alone was applied in six patients; two patients received neutron brachytherapy before and one after photon teletherapy. Tumor neutron brachytherapy doses ranged from 3.9-11.5 Gy. Four patients underwent surgical resection of the primary tumor and in six cases, regional lymph node dissection was done. RESULTS: The patients survival times ranged from 3 months to 12 years; 2-year survival was 50% and 30% of the patients lived 3 years. The mean survival time was 39 months. All but 1 patients died because of distant metastases. Local tumor control was achieved in all cases. CONCLUSION: The clinical study shows the relative sensitivity of melanoma to the neutron irradiation and offer new possibilities in Cf-252 brachytherapy.

Californium-252 interstitial implants in carcinoma of the tongue.

A clinical study using 252Cf sources in brachytherapy of tumors began in the Research Institute of Medical Radiology of the Academy of Medical Sciences of the USSR in 1973. 252Cf afterloading cells were utilized by the method of simple afterloading. Dosimetry and radiation protection of medical personnel were developed. To substantiate optimal therapeutic doses of 252Cf neutrons, a correlation of dose, time, and treatment volume factors with clinical results of 252Cf interstitial implants in carcinoma of the tongue for 47 patients with a minimum follow-up period of 1 year was studied. Forty-nine interstitial implants have been performed. Seventeen patients received 252Cf implants alone (Group I), 17 other patients received 252Cf implants in combination with external radiation (Group II), and 15 patients were treated with interstitial implants for recurrent or residual tumors (Group III). Complete regression of carcinoma of the tongue was obtained in 48 patients (98%). Recurrences occurred in 1 patient (6%) in Group I, 6 patients (35%) in Group II, and 5 patients (33%) in Group III. Thirteen patients (27%) developed radiation necrosis. The therapeutic dose of neutron radiation from 252Cf sources in interstitial radiotherapy of primary tongue carcinomas (Group I) was found to be 7 to 9 Gy. Optimal therapeutic neutron dose in combined interstitial and external radiotherapy of primary tumors (Group II) was 5 to 6 Gy with an external radiation dose of 40 Gy. For recurrent and residual tumors (Group III), favorable results were obtained with tumor doses of 6.5 to 7 Gy.