Differential diagnostic utilities of combined testing for islet cell antibody, glutamic acid decarboxylase antibody, and tyrosine phosphatase antibody

Background. Beta-cell antibody tests are used for the differential diagnosis of diabetes mellitus. They permit to discriminate between the type 1 diabetes (T1D) and non-autoimmune diabetes types. To choose an appropriate test for ruling in or ruling out the T1D a physician needs to know how conclusive test results are. The most powerful estimate of test conclusiveness is its likelihood ratio (LHR). The higher LHR of a positive result (LHR+), the more posttest probability of T1D; the lower LHR of a negative result (LHR), the less posttest probability of T1D. Aims. To compare conclusiveness of single and combined tests for antibodies to islet cells (ICA), glutamate decarboxylase (GADA), and tyrosine phosphatase IA-2 (IA-2A), and to evaluate posttest probabilities of T1D at various pretest probabilities. Methods. All antibodies were tested in parallel in 169 children and adolescents with a new-onset T1D, and in 169 persons without this disease. ICA, GADA, and IA-2A were determined by indirect immunofluorescence, radioimmune assay, and ELISA, respectively. LHR+ and LHR were calculated with the MedCalc Statistical Software. Posttest T1D probabilities were calculated from Bayes theorem-based equation. Results. Among single tests, an ICA test had the greatest LHR+ and the smallest LHR, and consequently was the most reliable either for ruling in or ruling out the T1D. Among test combinations, an ICAGADA combination had the greatest LHR+ and was the most suitable for T1D confirmation. The triple combination ICAGADAIA-2A had the smallest LHR and was the most suitable for T1D exclusion. Conclusions. In the differential diagnosis of diabetes, the most appropriate test for ruling in the T1D is the double combination ICAGADA. With both antibodies positive, this combination provides the highest posttest T1D probabilities at any pretest probability. The most appropriate test for ruling out the T1D is the triple combination ICAGADAIA-2A. With all three antibodies negative, this combination provides the lowest posttest T1D probabilities

sIgG4 и другие предикторы формирования толерантности при пищевой аллергии у детей раннего возраста

Despite modern achievements in child allergology, the question of evaluating tolerance formation and defining the safest time for expanding the child’s ration after an eliminatory diet remains open. This article contains the results of the authors’ own investigation concerning the practical meaning of specific immunoglobulins (sIg) class G4 as tolerance formation markers at food allergies in children. Thus, it has been found that high levels of sIgG4 are not only a favourable prognostic factor for light manifestations of food allergy, but also an index of a tolerance formation. The prevalence of high food allergy sIgG4 was statistically significantly higher in early age children from the comparison group than in patients with food allergy. Thus the authors suggest that the production of sIgG4 is a normal physiological process which hinders the development of hypersensitivity, while high levels of sIgG4 are evidence for the child’s immune system “contacting” this or that product. Clinical tolerance formation predictors define lighter clinical manifestations of food allergies, a non IgE-mediated form of food allergy and the retention of breastfeeding.Несмотря на современные достижения в детской аллергологии, вопрос об оценке формирования толерантности и определении времени наиболее безопасного расширения рациона ребенка после элиминационной диеты до сих пор остается открытым. В настоящей статье приведены результаты собственного исследования по изучению практического значения специфических иммуноглобулинов (sIg) класса G4 в качестве маркеров формирования толерантности при пищевой аллергии у детей раннего возраста. Так, выявлено, что высокие уровни sIgG4 являются благоприятным прогностическим признаком не только легких клинических проявлений пищевой аллергии, но также и показателем формирования толерантности. У детей раннего возраста из группы сравнения частота встречаемости высоких sIgG4 к пищевым аллергенам был статистически значимо выше, чем у пациентов с пищевой аллергией. В связи с этим высказывается предположение, что выработка sIgG4 является физиологическим, нормальным процессом, препятствующим развитию гиперчувствительности, а высокие уровни sIgG4 свидетельствуют о «контакте» иммунной системы ребенка с тем или иным продуктом. Клиническими предикторами формирования толерантности определены более легкие клинические проявления пищевой аллергии, ее не-IgE-опосредованные формы, а также сохранение грудного вскармливания

Clinical, hormonal and molecular-genetic characteristics of monogenic diabetes mellitus associated with the mutations in the <i>INS</i> gene

Background: Currently more than 50 mutations of the INS gene are known to affect the various stages of insulin biosynthesis in the beta cells of the pancreas. However only individual cases of diabetes mellitus (DM) associated with heterozygous mutations in the coding region of the INS gene were reported in Russian Federation. We report a group of patients with a clinical manifestation of DM caused by mutations in both coding and non-coding regions of the INS gene. The patients with a mutation in the intron of the INS gene are reported for the first time in Russian FederationMaterials and methods: 60 patients with an isolated course of neonatal DM (NDM), 52 patients with a manifestation of DM at the age of 7–12 months and the absence of the main autoimmune markers of type 1 DM, 650 patients with the MODY phenotype were included in the study. NGS technology was used for molecular genetic research. Author’s panel of primers (Custom DNA Panel) was used for multiplex PCR and sequencing using Ion Ampliseq™ technology. The author’s panel “­Diabetes Mellitus” included 28 genes (13 candidate genes of MODY and other genes associated with DM).Results: 13 heterozygous mutations were identified in 16 probands and 9 relatives. The majority of mutations were detected in patients with PNDM (18.75%) and in patients with an onset of DM at the age of 7–12 months (9.6%). Mutations in the INS gene were detected in 2 patients (0.3%) in the group with the MODY phenotype. Mutations in the INS gene were not detected in patients with transient NDM (TNDM). Analysis of clinical data in patients with PND and onset of diabetes at the age of 7–12 months did not show significant differences in the course of the disease. The clinical characteristics of the cases of MODY10 and diabetes caused by a mutation in the intron of the INS gene are reported in details.Conclusion: The role of INS gene mutations in NDM, MODY, and DM with an onset at the age of 7–12 months was analyzed in a large group of patients. The clinical characteristics of DM due to a mutation in the intron of the INS gene are reported for the first time in the Russian Federation

Spermatozoal sensitive biomarkers to defective protaminosis and fragmented DNA

Human sperm DNA damage may have adverse effects on reproductive outcome. Infertile men possess substantially more spermatozoa with damaged DNA compared to fertile donors. Although the extent of this abnormality is closely related to sperm function, the underlying etiology of ensuing male infertility is still largely controversial. Both intra-testicular and post-testicular events have been postulated and different mechanisms have been proposed to explain the presence of damaged DNA in human spermatozoa. Three among them, i.e. abnormal chromatin packaging, oxidative stress and apoptosis, are the most studied and discussed in the present review. Furthermore, results from numerous investigations are presented, including our own findings on these pathological conditions, as well as the techniques applied for their evaluation. The crucial points of each methodology on the successful detection of DNA damage and their validity on the appraisal of infertile patients are also discussed. Along with the conventional parameters examined in the standard semen analysis, evaluation of damaged sperm DNA seems to complement the investigation of factors affecting male fertility and may prove an efficient diagnostic tool in the prediction of pregnancy outcome

Опыт вакцинации 13-валентной конъюгированной пневмококковой вакциной пациентки с ювенильным идиопатическим артритом с частыми респираторными инфекциями на фоне терапии метотрексатом

The article presents the experience of vaccination with a pneumococcal 13-valent conjugate vaccine (PCV13) of a patient aged 5 years with oligoarticular juvenile idiopathic arthritis (JIA) receiving methotrexate at a dose of 15 mg/m2 per week subcutaneously. Treatment with methotrexate provided a remission of JIA, but was accompanied by frequent respiratory infections — up to 8 times a year. During infection progression, methotrexate injections were omitted. Gaps in the treatment with methotrexate were accompanied by an exacerbation of the underlying condition. Vaccination of the patient with PCV13 reduced the frequency of respiratory infections to 2 times a year, which was accompanied by the development of persistent remission of the disease. Adverse events and exacerbation of JIA in a child after vaccination with PCV13 were not registered.Представлен опыт вакцинации 13-валентной конъюгированной пневмококковой вакциной (13ПКВ) пациентки в возрасте 5 лет с олигоартикулярным ювенильным идиопатическим артритом (ЮИА), получавшей метотрексат в дозе 15 мг/м2 в неделю подкожно. Лечение метотрексатом обеспечило ремиссию ЮИА, но сопровождалось частыми респираторными инфекциями — до 8 раз в год. При развитии инфекций инъекции метотрексата пропускались. Перерывы в лечении метотрексатом сопровождались обострением основного заболевания. Вакцинация пациентки 13ПКВ обеспечила снижение частоты респираторных инфекций до 2 раз в год, что сопровождалось развитием стойкой ремиссии заболевания. Нежелательных явлений и обострения ЮИА у ребенка на фоне вакцинации 13ПКВ не зарегистрировано

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The main mission of geochemistry research - definition migration's channel of hydrocarbons to traps

Geochemical surveys are aimed at defining of hydrocarbons trap filling, that is possible only after defining the ways of migration from the center of generation to a trap and from a trap to surface. With wrong interpretation of the geochemical data, without taking in consideration of existing channels of hydrocarbon migration, efficiency of the surveys would be low