Vol 89, No 11 (2017)

Editorial
Hepatitis C can be cured: will hepatitis B become next?
Chulanov V.P., Zueva A.P., Kostyushev D.S., Brezgin S.A., Volchkova E.V., Maleyev V.V.
Abstract
Chronic hepatitis B (CHB) and C (CHC) are one of the leading causes of cirrhosis and liver cancer with over a million of people dying annually from their consequences. In Russia CHB and CHC morbidity and related mortality show an upward trend. As a result of recent breakthroughs in antiviral therapeutics CHC became a curable disease. Modern therapeutics effectively suppress viral replication in CHB patients, but withdrawal of antivirals usually results in disease relapse. Loss of HBsAg required for the so called «functional cure» is a very rare event. Moreover, «complete cure» when the virus is entirely eliminated from the body is not possible due to a persistent form of covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) in hepatocytes refractory to modern antivirals. Today, there is a plethora of new promising medications being at different stages of development that target different steps of viral life cycle, including inhibitors of interaction between HBV and its entry receptor NTCP, inhibitors of HBV cccDNA, inhibitors of nucleocapsid assembly, technologies of genome editing (TALENs, CRISPR/Cas etc) and RNA-interference. In addition to direct acting antivirals, there is a number of approaches aimed at enhancement of the innate and adaptive immune responses. In experimental conditions, some of these approaches or their combinations help to achieve functional cure. However, complete elimination of the virus is possible only using technologies of genome editing, capable of specific cccDNA degradation. Nuclease systems are currently at their early stages of development, and there is a long way to prove their efficacy and safety. Nevertheless, highly promising results of the recent years leave no doubt that CRISPR/Cas systems and similar technologies can become the basis of CHB therapy.
Terapevticheskii arkhiv. 2017;89(11):4-13
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Lymphocyte subpopulations, levels of interferon, and expression of their receptors in patients with chronic hepatitis B and C: Correlation with the species of viruses and the degree of liver fibrosis
Kalyuzhin O.V., Ponezheva Z.B., Semenova I.V., Khokhlova O.N., Serebrovskaya L.V., Guseva T.S., Parshina O.V., Maleev V.V.
Abstract
Aim. To determine whether there is a correlation of the composition of circulating lymphocyte subpopulations, the serum concentrations of interferon (IFN)-α, IFN-γ, and IFN-λ3, and the lymphocyte expression of types I and II IFN receptors with the species of a disease pathogen and the degree of liver fibrosis (LF) in patients with chronic hepatitis B (CHB) and in those with chronic hepatitis C (CHC). Subjects and methods. The investigation enrolled 44 patients with CHC, 9 patients with CHB, and 13 clinically healthy donors. The degree of LF in the patients was determined using transient elastography. The composition of peripheral blood lymphocyte subpopulations was examined; the concentrations of IFN-α, IFN-γ, and IL-28B were estimated. Results. Lymphocyte counts were higher in patients with CHC and in those with CHB than those in healthy donors; and the number of neutrophils was lower. There were no differences between the groups in the composition of lymphocyte subpopulations with the exception of the number of CD3CD4cells, which in patients with CHC was larger than in those with CHB. In CHC and CHB patients, the counts of CD118lymphocytes were higher than those in healthy donors. Patients with CHB and those with CHC did not differ between themselves and from healthy donors in the expression of CD119 on the lymphocytes. In CHC patients, the relative CD119cell counts were higher between CD4lymphocytes than those in healthy donors. The serum levels of IFN-α and IFN-γ in CHC and CHB patients were similar, but higher in healthy donors. The concentration of IL-28B genotype in patients with CHC was twice as high as in those with CHB, but the differences were statistically insignificant. The number of lymphocytes increased with the progression of fibrosis; that of neutrophils decreased. There was an inverse relationship between platelet counts and LF severity. Multiple comparisons of the clusters of patients with different degrees of LF revealed no differences in the number of major lymphocyte subpopulations. However, the number of CD3CD16CD56natural killer-like T (NKT) cells correlated with fibrosis severity. Patients with different degrees of LF showed no differences in the proportion of CD118and CD119 cells between lymphocytes and in the serum levels of IFN-α, IFN-γ, and IL-28B levels. Patients with grade IV LF displayed a higher proportion of CD4CD119lymphocytes between CD45cells than did those with grade III LF. Conclusion. Several new clinical and laboratory trends were identified and the nature and extent of previously described hematological and immunological changes were clarified in CHC or CHB patients with various degrees of LF. Some indicators may be used as additional criteria for the prognosis of the above forms of hepatitis, and a number of newly described facts suggest that it is necessary to revise the protective/phlogogenic value of types I, II, and III IFNs in chronic viral hepatitis C and B.
Terapevticheskii arkhiv. 2017;89(11):14-20
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Overexpression of DNA-methyltransferases in persistency of cccDNA pool in chronic hepatitis B
Kostyushev D.S., Zueva A.P., Brezgin S.A., Lipatnikov A.D., Simirskii V.N., Glebe D., Volchkova E.V., Shipulin G.A., Chulanov V.P.
Abstract
Aim. To define the role of DNA-methyltransferases of type 1 and type 3A in hepatitis B viral cycle. Materials and methods. Human hepatoma cells HepG2 with stable expression of 1.1-mer HBV genome were transfected with vectors encoding DNA-methyltransferase 1 (DNMT1), DNA-methyltransferase 3A (DNMT3A) or were co-transfected with these vectors. Total HBV DNA copy number, relative expression of pregenomic RNA (pgRNA), S-protein-encoding RNA (S-RNA) and cccDNA were analyzed by quantitative and semi-quantitative real-time PCR-analysis with TaqMan probes for assessment of DNMTs-mediated effects on HBV. Results. DNMT1 and DNMT3A suppress HBV transcription and replication, though to different magnitude. cccDNA pool is enlarged statistically significantly ≈2-fold (P<0.005) after transfection of DNMT3A, but is unaltered under DNMT1 treatment. Conclusion. DNMT3A regulates the size of cccDNA pool and is important for persistency of HBV infection.
Terapevticheskii arkhiv. 2017;89(11):21-26
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Impact of current approaches to laboratory screening of donated blood and its components on hepatitis B virus infection in patients with blood system diseases
Ignatova E.N., Tupoleva T.A., Ovchinnikova E.N., Romanova T.Y., Yaroslavtseva N.G., Filatov F.P., Troitskaya V.V., Kuzmina L.A., Parovichnikova E.N., Gaponova T.V., Savchenko V.G.
Abstract
Aim. To evaluate the detection rate of markers for hepatitis B virus (HBV) in the blood samples taken from patients with blood system diseases, by applying the current approaches to examining donated blood and its components for markers of viral infections. Materials and methods. The investigation included blood samples from patients with blood system diseases (n=364) and donors (n=5,011). The results of laboratory screening of donated blood samples (n=13,081) were retrospectively analyzed. Commercial kits of reagents were used for immunochemical assay and polymerase chain reaction. Results. Patients with blood system diseases were recorded to have markers of active HBV infection in 12.6% of cases, anti-HBc in 31.3%, and anti-HBs in 37.6%. A retrospective analysis of the results of screening donated blood samples showed the presence of markers for active HBV infection in 0.28% of cases. A prospective examination of blood donors revealed markers of HBV infection in 4.83% of cases, including those of active forms in 0.54% and anti-HBc in 4.79%. The markers of active HBV infection in donors were only anti-HBc IgM in 0.42% of cases. The blood samples from donors with an anti-HBs titer of >200 mIU/ml contained anti-HBc IgM in 10.5%. Conclusion. In the last 5-7 years, the detection rate of markers of HBV infection in the blood samples of patients with blood system diseases have remained at a high level. Screening for decreed markers fails to identify people with inapparent infections among the donors. Even high anti-HBs concentrations in the donated blood may be a risk for HBV transmission by transfusion to a recipient.
Terapevticheskii arkhiv. 2017;89(11):27-34
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Clinical presentation of Ixodes tick-borne borreliosis caused by Borrelia miyamotoi in the context of an immune response to the pathogen
Platonov A.E., Toporkova M.G., Kolyasnikova N.M., Stukolova O.A., Dolgova A.S., Brodovikova A.V., Makhneva N.A., Karan L.S., Koetsveld J., Shipulin G.A., Maleev V.V.
Abstract
Ixodes tick-borne borreliosis caused by Borrelia miyamotoi (ITBB-BM) is a previously unknown infectious disease discovered in Russia. Aim. The present study continues the investigation of the clinical features of ITBB-BM in the context of an immune system-pathogen interaction. Subjects and methods. The study enrolled 117 patients with ITBB-BM and a comparison group of 71 patients with Lyme disease (LD) that is ITBB with erythema migrans. All the patients were treated at the New Hospital, Yekateringburg. More than 100 clinical, epidemiological and laboratory parameters were obtained from each patient’s medical history and included in the general database. A subset of patients hospitalized in 2015 and 2016 underwent additional laboratory examinations. Namely, the levels of B. miyamotoi-specific IgM and IgG antibodies were measured by the protein microarray containing GlpQ protein and four variable major proteins (VMPs): Vlp15/16, Vlp18, Vsp1, and Vlp5. The blood concentration of Borrelia was estimated by quantitative real-time PCR. Results. In contrast to LD, first of all (p<0.001) the following clinical features were typical for ITBB-BM: the absence of erythema migrans (in 95% of patients), fever (93%), fatigue (96%), headache (82%), chill (41%), nausea (28%), lymphopenia (56%), thrombocytopenia (46%), the abnormal levels of alanine aminotransferase (54%) and C-reactive protein (98%), proteinuria (61%). Given the set of these indicators, the course of ITBB-BM was more severe in approximately 70% of patients. At admission, only 13% and 38% of patients had antibodies to GlpQ and VMPs, respectively; at discharge, antibodies to GlpQ and VMPs were detected in 88% of patients. There was no statistically significant association of the antibody response with individual clinical manifestations and laboratory parameters of the disease. However, patients with more severe ITBB-BM produced less IgM antibodies to VMPs and GlpQ at the time of discharge. Conclusion. ITBB-BM is a moderate systemic disease accompanied by the production of specific antibodies in virtually all patients.
Terapevticheskii arkhiv. 2017;89(11):35-43
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Molecular epidemiological analysis of HIV-1 variants circulating in Russia in 1987—2015
Lapovok I.A., Lopatukhin A.E., Kireev D.E., Kazennova E.V., Lebedev A.V., Bobkova M.R., Kolomeets A.N., Turbina G.I., Shipulin G.A., Ladnaya N.N., Pokrovsky V.V.
Abstract
Aim. To simultaneously analyze HIV-1 samples from all Russian regions to characterize the epidemiology of HIV infection in the country as a whole. Subjects and methods. The most extensive study was conducted to examine nucleotide sequences of the pol gene of HIV-1 samples isolated from HIV-positive persons in different regions of Russia, with the diagnosis date being fixed during 1987—2015. The nucleotide sequences of the HIV-1 genome were analyzed using computer programs and on-line applications to identify a virus subtype and new recombinant forms. Results. The nucleotide sequences of the pol gene were analyzed in 1697 HIV-1 samples and the findings were that the genetic variant subtype A1 (IDU-A) was dominant throughout the entire territory of Russia (in more than 80% of all infection cases). Other virus variants circulating in Russia were analyzed; the phenomenon of the higher distribution of the recombinant form CRF63/02A in Siberia, which had been previously described in the literature, was also confirmed. Four new recombinant forms generated by the virus subtype A1 (IDU-A) and B and two AG recombinant forms were found. There was a larger genetic distance between the viruses of IDU-A variant circulating among the injecting drug users and those infected through heterosexual contact, as well as a change in the viruses of subtype G that caused the outbreak in the south of the country over time in 1988—1989. Conclusion. The findings demonstrate continuous HIV-1 genetic variability and recombination over time in Russia, as well as increased genetic diversity with higher HIV infection rates in the population.
Terapevticheskii arkhiv. 2017;89(11):44-49
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The spectrum of primary drug resistance of Mycobacterium tuberculosis in patients with tuberculosis in relation to human immunodeficiency virus status
Zimina V.N., Mikova O.E., Varetskaya T.A., Oborin D.A., Degtyareva S.Y., Sergevnin V.I.
Abstract
Aim. To estimate the detection rate and spectrum of primary drug resistance of Mycobacterium tuberculosis (MBT) in patients with tuberculosis (TB) in relation to their human immunodeficiency virus (HIV) status in a region with high HIV infection rates (the Perm Territory) and to compare of drug-resistant MBT (DR-MBT) in patients with HIV/TB co-infection, by using phenotypic and molecular genetic testing (MGT) methods. Subjects and methods. The results of sputum bacteriological examination were analyzed in 178 HIV-infected patients and 354 non-HIV-infected individuals with a TB diagnosis made in the period July 1, 2014 to August 1, 2015. The diagnostic algorithm for all patients involved a duplicate sputum test for MBT by two techniques: fluorescence microscopy (FM) and inoculation into the Levenstein-Jensen dense culture medium. In patients with HIV/TB, the bacteriological examination was complemented with two more methods: detection of MBT DNA by a real-time polymerase chain reaction assay using the AmpliTube-RV system (Synthol, Russia); and inoculation into the Middlebrook liquid nutrient medium, by applying the automated BACTEC MGIT 960 system. Results. In patients with HIV/TB, the sensitivity of FM proved to be lower than in those with TB (24.2 and 32.8%, respectively; p<0.05) and that of inoculations into the dense culture medium was comparable regardless of HIV status (60.7 and 57.1%, respectively; p>0.05). The primary drug resistance of MBT in patients with HIV-TB was higher than that in HIV-negative individuals (60.2 and 41.6%, respectively; p<0.05). The phenotypic method (inoculation into the Levenstein-Jensen culture medium) and MGT revealed their agreement for the resistance of MBT to rifampicin (the most clinically significant drug in the choice of treatment policy) in 88.5% of the patients with HIV/TB. Conclusion. In patients with HIV/TB, the sensitivity of FM for detecting acid-resistant mycobacteria was lower than in those with TB and that of inoculations into the dense medium was comparable regardless of HIV status.
Terapevticheskii arkhiv. 2017;89(11):50-54
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Identification of Shiga toxin in patients with acute intestinal infections in the presence of mono- and mixed-O-antigens of pathogens
Belaia O.F., Yudina Y.V., Volchkova E.V., Payevskaya O.A., Belaya Y.A., Gyulazyan N.M., Zuyevskaya S.N.
Abstract
Aim. To investigate the time course of changes in the detection rates and levels of Shiga toxin antigen (STA) in their stool and middle-molecule circulating immune complexes (CICs) containing IgG (IgG CIC) in patients with acute intestinal infections (AIIs) in the presence of the body’s circulation of mono- and mixed-LPS/O-antigens of intestinal pathogens. Subjects and methods. A total of 147 patients aged 15 to 55 years who had been hospitalized with AIIs were examined. The diagnosis was bacteriologically verified in 19% of the patients; in the others, it was confirmed by the detection of LPS/O-antigens of Shigella, Salmonella, Yersinia, and Campylobacter in their stool by means of the reaction of coagglutination (RCA) on glass slides. Plates for RCA displayed STA in the fecal and IgG CIC samples. Results. Mono- and mixed infections were detected in 32 and 68%, respectively. The RCA plates exhibited STA in 25.2% of the fecal samples and in 90.5% of the IgG CIC ones from patients with AIIs and did not in those from donors. In monoinfection, the detection rates and levels of STA in the feces became lower in the course of the disease and remained unchanged in IgG CIC and the levels of STA also decreased in the feces, but increased in IgG CIC in mixed infection. Conclusion. In 25.2% of the patients with early AIIs, their stools show free STA; its detection rate and levels are significantly higher in mixed infections than those in monoinfection. The level of STA in serum IgG CIC was significantly higher in mixed infection, suggesting an active immune response to the pathogen. Given that the Shiga toxin-producing strains are present in patients with AIIs, caution should be exercised in the choice of an antibacterial drug to prevent horizontal gene transfer and to enhance toxin production and the body’s intoxication. One of the advantages of RCA is the possibility of rapidly changing the spectrum of test systems, depending on the region of their application and the epidemiological situation.
Terapevticheskii arkhiv. 2017;89(11):55-59
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Necrotizing sarcoid granulomatosis with clinical presentations of recurrent acute abdomen. Case report and literature review
Vasilyev V.I., Palshina S.G., Chaltsev B.D., Radenska-Lopovok S.G., Safonova T.N.
Abstract
The authors have described the world’s first case of necrotizing sarcoid granulomatosis (NSG) in a 22-year-old woman with the clinical presentations of acute abdomen, which are associated with abdominal lymph nodal infiltration and necrosis, obvious constitutional disturbances (fever, nocturnal sweats, and significant weight loss), high inflammatory activity (anemia, leukocytosis, high erythrocyte sedimentation rates and C-reactive protein levels), the gradual appearance of splenic and hepatic necrotic foci, and infiltration into the lung and lacrimal glands with the development of unilateral uveitis. The patient underwent five surgical interventions, several needle biopsies for recurrent abdominal syndrome, and long-term antibiotic treatment for presumed sepsis, which had caused drug-induced hepatitis. Bacteriological examination of blood, puncture samples, and removed abdominal cavity tissues, serological tests, and immunomorphogical study of biopsy samples and removed tissues yielded negative results for the presence of bacterial, fungal, and tuberculosis infections. NSG was diagnosed on the basis of the systemic nature of the lesion, the presence of granulomas with severe abdominal lymph nodal necrosis and necrotizing granulomatous/lymphocytic vasculitis in the mesentery and removed spleen, as well as the absence of granulomas in the spleen, appendix, and biopsy materials of the liver, colonic mucosa, and parotid gland. Fludarabine therapy was first used in world practice due to the inefficient treatment with high-dose glucocorticoids and cyclophosphamide and to a disease relapse when reducing their doses. The paper gives a detailed review of the literature on the clinical, laboratory, radiological, and morphological manifestations of the disease, which allow the differential diagnosis of NSG with different variants of granulomatous lesions. Based on the 5-year follow-up of the patient and on the analysis of clinical, laboratory, radiological, and morphological changes, the authors uphold the concept that the disease is an independent nosological entity: necrotizing angiitis with sarcoid reactions, rather than the entity of nodular or classic sarcoidosis.
Terapevticheskii arkhiv. 2017;89(11):60-68
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Difficulties in the diagnosis of diarrhea-associated hemolytic uremic syndrome in adults
Malov V.A., Maleev V.V., Kozlovskaya N.L., Tsvetkova N.A., Smetanina S.V., Gorobchenko A.N., Serova V.V., Chentsov V.B., Volkov A.G., Faller A.P.
Abstract
Hemolytic uremic syndrome (HUS) is a rare, but menacing condition registered mainly in children. The paper gives a detailed description and analysis of a clinical case of HUS with a favorable outcome in an adult woman who developed the syndrome in the presence of bloody diarrhea. It considers an update on the etiology, pathogenesis, and clinical features of HUS associated with diarrheal syndrome and discusses differential diagnostic features, diagnostic problems, and characteristics of management tactics for patients.
Terapevticheskii arkhiv. 2017;89(11):69-78
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The virus-immune hypothesis for cardiac dilatation
Kozhevnikov M.L., Shipulin V.M., Sukhodolo I.V.
Abstract
The paper gives an update on the pathogenetic role of viral infection and immune mechanisms in the development of cardiac dilatation at the cellular, ultrastructural, and molecular levels. Particular attention is given to the discussion of the possible role of herpesvirus infection in the mechanisms of cardiomyocyte damage with the direct or indirect impact of viral infection through immunoinflammatory responses. Data on the protective and damaging action of a number of cytokines in the immunopathogenesis of viral myocarditis are considered.
Terapevticheskii arkhiv. 2017;89(11):79-83
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Clinical efficacy of the immunomodulatory agent cycloferon (tablets) in viral respiratory infections: Results of a systematic review and meta-analysis
Mazina N.K., Sheshunov I.V., Mazin P.V., Mazin V.P., Kovalenko A.L., Zaplutanov V.A.
Abstract
The authors carried out a systematic review and subsequent meta-analysis of randomized clinical trials evaluating the efficacy of the immunomodulator agent cycloferon as tablets in adults and children with viral respiratory diseases. A total estimate of its clinical efficacy was obtained in terms of compared heterogeneous groups and response variables. The data published in 16 articles were used to calculate the formal parameters of the clinical efficacy of cycloferon (increased absolute and relative benefits, odds ratio (OR); the number of patients needed to be additionally treated with cycloferon to achieve a favorable outcome or to prevent a poor outcome in one patient, etc.). High heterogeneity hampered the unequivocal interpretation of results; however, combining the compared homogeneous groups in the meta-analysis (with adjustments for fixed and random effects) increased the statistical power of the investigation. In children aged 6 to 18 years, the OR for the positive effect of the drug (no new cases after its preventive administration) was 5.3 (95% confidence interval (CI), 4.8—5.9), heterogeneity test, χ= 249.5; p=0.000...; I= 94.8% (95% CI, 92.7—96.3%). This suggested the heterogeneity of clinical trial data and extrapolated this estimate to medical practice. The use of cycloferon in adults to treat acute respiratory viral infection enhanced their chances of enduring the disease in a mild form and avoiding serious complications: the OR for positive outcomes was 9.7 (95% CI, 7.0—13.0), while the effect was more homogeneous than in children (heterogeneity test, χ= 7.4; p=0.061...; I= 59.4% (95% CI, 0—86.5). Thus, the use of cycloferon to treat and prevent acute viral respiratory infections showed a more than 5-fold increase in the probability of avoiding the disease or enduring the latter in a mild form.
Terapevticheskii arkhiv. 2017;89(11):84-92
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Safety of the Russian antiviral drug Kagocel
Borovskaya T.G.
Abstract
The review gives summarized information on the preclinical data and clinical trials evaluating the safety of the antiviral drug Kagocel. It notes that the manufacturer of the drug pay special attention to the control of its impurity content. There is information on the development and validation of highly sensitive and specific high-performance liquid chromatography procedures, the application of which can guarantee that free gossypol impurities are absent in the drug. The results of preclinical toxicity study of Kagocel in experiments on laboratory animals are briefly reviewed; particular attention is paid to the investigation of the drug’s safety for the reproductive system of immature animals. It is noted that evaluation of the total toxic properties of Kagocel has revealed no signs of intoxication. Investigations of the reproductive toxicity of Kagocel have showed no effect on spermatogenesis. A set of experimental studies of the long-term effects of the use of Kagocel in different regimens has confirmed that the drug has no negative effect on the reproductive organs in the offspring of experimental rats and on its development. Many clinical trials, including those with participation of children aged 2 years or older, have provided important data on drug safety. The results given in the review lead to the conclusion that the use of the antiviral drug Kagocel in both general and pediatric practice is proven safe.
Terapevticheskii arkhiv. 2017;89(11):93-99
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Clinical and epidemiological features of visceral leishmaniasis in the Republic of Crimea
Baranets M.S., Ermak T.N., Ponirovsky E.N.
Abstract
The paper analyzes official statistical data, as well as visceral leishmaniasis (VL) cases who have visited the Clinical Center, I.M. Sechenov First Moscow State Medical University, and the results of parasitological studies of the materials submitted to the Reference Center for Monitoring of Leishmaniasis, E.I. Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases. Account is taken of the observations made by the Central Research Institute of Epidemiology, Russian Federal Service for Supervision of Consumer Rights Protection and Human Welfare, and of the literature data available in Russian and foreign (Ukraine) scientific journals and monographs. During the period of 1932 to 2015, a total of 14 VL cases acquired in the Crimea were notified, of which there were 4 cases of VL concurrent with HIV infection. The majority of infections occurred in the eastern part of the peninsula. Given that many areas of Crimea have the status of recreation and annually receive millions of vacationists, it is necessary to conduct a more in-depth study of all aspects of this infection.
Terapevticheskii arkhiv. 2017;89(11):100-104
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Evolution of laboratory markers for systemic bacterial infections
Ryabkova N.L., Vezikova N.N.
Abstract
The paper reviews the data available in the literature on existing laboratory markers for systemic bacterial infection, among which C-reactive protein, proinflammatory cytokines, procalcitonin test, and presepsin receive primary emphasis.
Terapevticheskii arkhiv. 2017;89(11):105-110
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Schnitzler syndrome: A review of literature, the authors’ observation, and experience with the interleukin-1 inhibitor canakinumab
Salugina S.O., Gorodetsky V.R., Fedorov E.S., Lopatina N.E., Evsikova M.D.
Abstract
The paper reviews the publications dealing with Schnitzler syndrome, a rare autoinflammatory disease, and describes the authors’ own clinical observation. It describes the first Russian experience in successfully using the interleukin-1 inhibitor canakinumab to treat this disease.
Terapevticheskii arkhiv. 2017;89(11):111-115
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