EVALUATION OF CYTOKINE-MEDIATED MECHANISMS INVOLVED IN DEVELOPMENT OF RESPIRATORY MUSCLE DYSFUNCTION IN THE PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Respiratory muscle (RM) strength was studied in 85 men with exacerbations of chronic obstructive pulmonary disease (COPD). The strength indicators of expiratory (MEP) and inspiratory pressure (MIP, SNIP) in oral cavity were registered by means of the MicroRPM device (CareFusion, UK), as well as intranasal pressure levels by SNIP test. The measured MEP, MIP и SNIP values were compared to the proper indices. Serum concentrations of cytokines (IL-4, IL-6, IL-10, IL-17A, IL-21, TNFα, IFNγ and TGF-β) were determined. The results of the study were processed by means of canonical analysis and by clustering methods. Expiratory RM dysfunction was recorded in mild COPD, expiratory-inspiratory RM dysfunction was recorded in moderate COPD and the diaphragm dysfunction was recorded in severe COPD. Three groups of patients with different combinations of RM strength indicators and immune parameters were identified by means of cluster analysis. The cytokine profile in the first cluster was characterized by maximal concentrations of IL-17A, IL-21, TNFα and TGF-β, whereas RM strength indexes showed minimal values. In the second cluster, a decrease of RM strength indicators by 25-40% against control was associated with a sharp rise of IL-6, along with moderate increase of IL-21 and TGF-βconcentrations. In the third cluster, maximal levels of IL-6, IL-10 and IFNγwere registered, along with low levels of IL-17A, IL-21 and TGF-β concentrations, whereas MEP, MIP и SNIP values did not sufficiently differ from their levels in second cluster. The results of canonical and correlation analysis indicated to interconnections between either certain cytokines, or their pool with the RM strength indicators, dyspnea severity and functional state of COPD patients, thus suggesting involvement of cytokine-mediated mechanisms in pathogenesis of the respiratory muscle dysfunction

CLINICAL AND IMMUNOLOGICAL COMPARISONS IN Th- DEPENDENT IMMUNE RESPONSE MECHANISMS AMONG PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Chronic obstructive pulmonary disease (COPD) is a global public health problem. Studies in immunological features and their correlations with clinical course of COPD are of importance. The aim of this study was to elucidate clinical and immunological features in COPD of different severity grade, concerning Th1- and Тh17-dependent types of immune response.The study included 132 COPD patients and 32 healthy individuals. According to clinical and functional patterns, the patients with COPD were divided into 3 groups, i.e., 36 cases (28%) of mild severity; 62 individuals (48%), of moderate severity, and 30 patients (23%) of severe clinical grade. We have performed both clinical and immunological evaluation of the patients. The Th1- and Th17-specific lymphocyte subpopulations were assessed according to the serum levels of cytokines, i.e. tumor necrosis factor (TNFα), IL-4, IL-10, IL-17A, IL-21, IFNγ, as well as transforming growth factor β1 (TGF-β1). We have also determined expression of IL-6R receptor (CD126+) on mature T lymphocytes (CD3+) and T helper cells (CD4+) from peripheral blood. We have obtained the following results: the patients with mild-grade COPD exhibited three different T cell phenotypes were determined, with a prevalence of Th1-dependent immune response. The IL-6R were mostly expressed on CD3+CD126+ cells for the Th1/Th17 phenotype, and CD4+CD126+ cells in cases of Th17-dependent type immune response. In patients with COPD of moderate severity, the Th1, Th17, or Th1/Th17 types of immune response was revealed at similar rates. The level of IL-6R expression on mature T lymphocytes and T-helper cells increased to the greatest extent in cases of Th17-dependent immune response. In severe COPD patients, we have found a dominance of Th17 and Th1/Th17 type immune response. The levels of IL-6R expressionwere increased in Th17- and Th1/Th17-dependent types of immune response, the most significant increase was observed for CD4+ cells in Th17 phenotype. Clinical features of COPD proved to be associated with the phenotypes of immune response. These results allow of specifying the inflammatory phenotype, predicting the course of chronic disease, and selecting appropriate therapy

Features of immune response in different phenotypes of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is considered a heterogeneous disorder exhibiting different phenotypes. Chronic systemic inflammation is an important link in the COPD pathogenesis. The studies of immune response in the context of clinical and functional phenotypes seems relevant. Objective of our work was to study the features of immune response in clinical and functional phenotypes of COPD.Eighty-three COPD patients of different severity grade and 22 apparently healthy volunteers were examined. After determining the COPD phenotype by clinical and functional signs, the patients were divided in two groups, i.e., 38 subjects with bronchitis, and 45 patients with emphysematous phenotype. Clinical, functional and laboratory research was carried out in standard mode. Static lung volumes and respiratory capacities were investigated, i.e., functional residual capacity, residual lung volume, total lung capacity, bronchial resistance on inspiration and expiration to assess phenotype of the disease. Subpopulations of Th1 and Th17 lymphocytes were determined by the level of blood serum cytokines, tumor necrosis factor (TNFá), interleukins (IL) IL-4, IL-10, IL-17A, IFNã).Different features of immune response were revealed in bronchitic and emphysematous phenotypes of the COPD patients. Activation of inflammatory process with differentiation of naive T lymphocytes along the Th1-dependent pathway was found in 68% of cases with bronchitis and 16% of patients with emphysematous phenotypes. As compared with control group, the patients showed a statistically significant increase in the level of TNFá, IFNã, along with decrease in IL-4. Development of immune response by the Th17 type was found in 32% of cases with bronchitis, and 84% of cases with emphysematous phenotypes. Its emergence was associated with increased IL-17A and IL-10 levels, and a decrease in IFNã/IL-17A compared to the control. Differentiation of T helper cells towards Th1 pathway of immune response has been shown to predominate in bronchitic phenotype and at early stages of the disease. The Th17 type of immune response prevailed with increasing severity of the disorder. In emphysematous phenotype of COPD, the Th17-pathway of immune response develops at early stages of the disease. Some relationships are revealed between the systemic inflammation indexes and functional parameters of external respiration. An inverse relationship between TNFá and the OOL/OEL ratio in Th1 type of immune response has been shown. A direct correlation was found between the level of IL-17A and the parameters of external respiration function (FEV1, FEV1/FVC), as well as between IFNã/IL-17A and functional residual capacity in Th17 type of immune response.The type of immune response is associated with severity of the disease, as well with clinical and functional phenotype of COPD. Progression of the disease, broncho-obstructive disorders and hyperinflation are associated with increased levels of cytokines that provide cell polarization along the Th17 pathway. Determination of COPD phenotype and the type of immune response already at an early stage of the disease will enable prediction of its course and justify the choice of phenotype-oriented therapy

FEATURES OF CYTOKINE PROFILE IN PATIENTS WITH BRONCHIAL ASTHMA COMBINED WITH OBESITY

Combination of bronchial asthma (BA) and obesity is a difficult-to-control phenotype. Studies of inflammatory process with respect to severity of the disease are important for understanding the potential influence of obesity on the BA clinical course. The objective of this study was to determine cytokine profile in patients with mild BA combined with obesity. The study involved fifty-three patients with partially controlled mild BA. The patients were recruited as volunteers and signed an informed consent. The first observation group consisted of 27 asthma patients with normal body weight, the second observation group consisted of 26 patients with BA combined with obesity. A control group included 25 healthy volunteers. All the patients underwent clinical and laboratory examination in accordance with clinical standards for BA and obesity. The levels of TNFα, IL-2, IL-4, IL-6, IL-10 were evaluated in blood serum by means of flow cytometry. The ratios of proand anti-inflammatory cytokines (TNFα/IL-4, TNFα/IL-10, IL-6/IL-4, IL-6/IL-10) were calculated. Asthma patients with obesity (the 2nd group) had elevated levels of IL-2 over control group and group 1, by 38% and 44% respectively(p < 0.05). The concentration of proinflammatory cytokines TNFα and IL-6 was significanty increased in the both patient groups. Mean TNFα level was increased 2.5 times (p < 0.05), and IL-6 levels were increased by 30% (p < 0.05) in the 1st group as compared to the controls. TNFα and IL-6 concentrations showed a 3-fold increase over control values (p < 0.05) in the 2nd group. The level of antiinflammatory cytokine IL-4 was increased in patients with BA, independently of body mass. It should be noted that the concentration of this cytokine in obese patients was higher by 29% than in patients with normal body weight. IL-10 levels in patients from the 2nd group were reduced more than 2 times than in the 1st group. The patients of the 1st group showed a decrease in the IL-6/IL-10 index, in comparison with control parameters, thus indicative of an imbalance due to the elevation of the anti-inflammatory IL-10 cytokine. Among BA patients with obesity (group 2) the TNFα/IL-10 and IL-6/IL-10 indexes were higher than those of the control group (2.3- and 5.5-fold, respectively) and the group 1 (2.6- and 2.5-fold, respectively). Dynamics of these indexes confirms the systemic nature of inflammation and a predominance of non-atopic  inflammation in asthma patients with obesity. Thus, features of the cytokine profile in BA with obesity consist of a significant increase in pro-inflammatory IL-2, IL-6, TNFα cytokines, and a relative decrease in anti-inflammatory IL- 10 cytokine. The development of BA with obesity, even in mild-severity BA, is accompanied by development of a cytokine disbalance, which is typical for a mixed-type inflammation, with a prevalence of neutrophil inflammation

Оценка взаимосвязи силы дыхательных мышц и показателей цитокинового статуса у больных внебольничной пневмонией

Aim. Assessment of the role of cytokine-mediated changes in the development of respiratory muscle (RM) dysfunction in patients with community-acquired pneumonia (СAP). Methods. 84 men aged 18 – 26 years with a median of age 19.5 [18.4; 22.8]. Mild to moderate CAP (MCAP) was diagnosed in 62 (73.8%) patients and severe (SCAP) in 22 (26.2%). The expiratory (MEP, MRPDout) and inspiratory (MIP, MRPDin. SNIP) strength indices of RM were recorded on a MicrоRPM apparatus (CareFusion, UK). The severity of endogenous intoxication was verified using the following indices: hematologic (HII), leukocyte (LII), and nuclear. Serum concentrations of interleukins-2, -8, -10, basic fibroblast growth factor, transforming growth factor-beta, tumor necrosis factor-alpha (TNF-α), and a soluble receptor for TNF-α. Data processing was performed by cluster and correlation analysis methods. Results. Three clusters of patients with CAP were identified by the characteristic combinations of indicators of RM strength, endogenous intoxication, and cytokine status. The first cluster had MCAP, the second – both MCAP and SCAP, the third – SCAP. In the first cluster, dysfunction of expiratory RM prevailed, and in the second and third – dysfunction of inspiratory RM. In the midst of CAP, significant negative correlations of RM strength indicators with LII, HII, TNF-α, IL-10, IL-8, and IL-2 levels were recorded. The endogenous intoxication indices reached control values in all patients during recovery. The first cluster showed a decrease in the level of analyzed cytokines against isolated dysfunction of expiratory RM. The second cluster showed a tendency toward restoration of TNF-α and IL-8 levels, and only their SNIP index was normal. The third cluster showed minimal medians of RM strength against the continuing imbalance in the profile of pro- and anti-inflammatory cytokines during recovery. Conclusion. RM dysfunction in CAP is associated with cytokine-mediated dysfunction. The degree of cytokine involvement in this process depends on the severity of endogenous intoxication and the volume of alveolar inflammation.Целью исследования явилась оценка роли цитокин-опосредованных механизмов в развитии дисфункции дыхательных мышц (ДМ) у больных внебольничной пневмонией (ВП). Материалы и методы. Обследованы мужчины (n = 84; возраст – 18–26 лет; медиана – 19,5 (18,4; 22,8) года), госпитализированные в стационар по поводу ВП. Нетяжелая ВП (НВП) диагностирована у 62 (73,8 %) больных, тяжелая (ТВП) – у 22 (26,2 %). При помощи аппарата MicrоRPM (CareFusion, Великобритания) зарегистрированы показатели силы экспираторных (MEP, MRPDвыд.) и инспираторных (MIP, MRPDвд., SNIP) ДМ. Верификация тяжести эндогенной интоксикации проводилась с использованием гематологического (ГИИ), лейкоцитарного (ЛИИ) и ядерного индексов. В сыворотке крови определялась концентрация интерлейкинов (IL)-2, -8, -10, базисного фактора роста фибробластов, трансформирующего фактора роста-β, фактора некроза опухоли-α (TNF-α) и растворимого рецептора к TNF-α. Обработка данных выполнялась методами кластерного и корреляционного анализа. Результаты. Выделены 3 кластера больных ВП с характерными комбинациями индикаторов силы ДМ, эндогенной интоксикации и цитокинового статуса. Первый из них представлен больными НВП, 2-й – НВП и ТВП, 3-й – лицами с ТВП. У лиц 1-го кластера преобладала дисфункция экспираторных, 2-го и 3-го – инспираторных ДМ. В разгар ВП зарегистрированы достоверные отрицательные взаимосвязи показателей силы ДМ с ЛИИ, ГИИ, TNF-α, IL-10, IL-8, IL-2. В период реконвалесценции у всех пациентов индексы эндогенной интоксикации достигали контрольных значений. У лиц 1-го кластера установлено снижение уровня анализируемых цитокинов на фоне изолированной дисфункции экспираторных ДМ. У пациентов 2-го кластера зафиксирована тенденция к восстановлению TNF-α и IL-8, а уровню, наблюдаемому у здоровых, соответствовал только показатель SNIP. У реконвалесцентов 3-го кластера отмечены минимальные средние показатели силы ДМ на фоне сохраняющегося дисбаланса в профиле про- и противовоспалительных цитокинов. Заключение. Дисфункция ДМ при ВП ассоциируется с участием в ее патогенезе цитокин-опосредованных механизмов, интенсивность вовлечения которых в данный процесс зависит от тяжести эндогенной интоксикации и распространенности альвеолярного воспаления

Особенности регуляции иммунного ответа у пациентов с коморбидным течением хронической обструктивной болезни легких и бронхиальной астмы

The aim of this study was investigation of cellular and humoral immunity and of systemic inflammation in patients with COPD + asthma phenotype. Methods. The study involved 115 patients (60 males) including 44 patients with stable COPD stage I–II, 39 patients with mild controlled or partially controlled asthma and 12 patients with COPD + asthma phenotype. Twenty healthy nonsmokers were included as controls. Results. Immune disorders in patients with COPD + asthma phenotype included increased numbers of T-helpers, cytotoxic T-lymphocytes and B-lymphocytes and increased IgE level. Increased serum concentrations of TNF-α and IL-4 and decreased IFN-γ concentration were also found in these patients. Conclusion. Th2-type of the immune response was observed in patients with COPD + asthma phenotype; these findings could underlie persistent inflammation. Изучено состояние клеточного гуморального иммунитета, уровень эйкозаноидов (ТХВ2 ЛТВ4), про- и противовоспалительных цитокинов (интерферон (IFN)-γ, фактор некроза опухоли (TNF)-α, интерлейкин (IL)-4) у больных с коморбидным течением хронической обструктивной болезни легких и бронхиальной астмы. Выявлены высокий уровень эйкозаноидов, увеличение секреции провоспалительных (TNF-α и IL-4) и снижение продукции противовоспалительного (IFN-γ) цитокинов на фоне дисбаланса клеточного иммунитета с преобладанием В-клеточного звена. Увеличение секреции эйкозаноидов, синтеза оппозиционного IL-4 и снижение продукции цитокинов Th1-типа, сопряженные с увеличением иммуноглобулина Е, указывают на механизмы переключения на Th2-тип иммунного ответа. Выявленные особенности способствуют хронизации воспалительного процесса и развитию бронхиальной обструкции по 1-му и 2-му типам иммунного ответа с привлечением реагинов, цитокинов, эйкозаноидов

Specific Mathematics Assessments that Reveal Thinking: An Online Tool to Build Teachers’ Diagnostic Competence and Support Teaching

In this chapter, we describe the design of an online system for the formative assessment of students’ understanding of mathematics and discuss how it develops diagnostic competence and influences teaching. The smart-test system covers many mathematics topics studied by students between about 10 and 16 years of age. It is programmed to provide teachers with an automated diagnosis of their own students’ stages of development in specific topics and to report on an individual’s errors and misconceptions, in order to inform teaching. Our claim is that teachers’ diagnostic competence increases when they have easy access to information about their own students’ thinking. In turn, this can further improve teaching, and hence learning. By drawing together evaluative data from four sources, we highlight aspects of teachers’ initial responses to formative assessment and the effect of using this system on their knowledge for teaching and the subsequent changes to teaching practice. Overall, teachers report that using the smart-tests has improved their knowledge of the thinking of individual students as well as of students in general (i.e., their pedagogical content knowledge), and that they can use this information in several ways to adjust their teaching. Paradoxically, using smart-tests reduces the demand for teachers to have specific knowledge for diagnosis and at the same time increases this knowledge and so improves their diagnostic competence

Getting SMART about assessment for learning

“Specific Mathematics Assessments that Reveal Thinking”—or smart tests—provide teachers with a quick and easy way to conduct assessment for learning. Using the internet, students in years 7, 8, and 9 undertake a short test that is focussed strongly on a topic selected by their teacher. Students’ stages of development are diagnosed, and sent to the teacher within minutes. Many tests have been produced and are now being trialled in 7 Victorian schools. Where available, on-line teaching resources are linked to each diagnosis, to guide teachers in moving students to the next stage. This project is sponsored by the Australian Research Council and Victoria’s Department of Education and Early Childhood Development

SMART Assessment for Learning

“Specific Mathematics Assessments that Reveal Thinking,” which we abbreviate to “smart tests,” provide teachers with a quick and easy way to conduct assessment for learning. Using the internet, students in Years 7, 8, and 9 undertake a short test that is focused strongly on a topic selected by their teacher. Students’ stages of development are diagnosed, and sent to the teacher immediately. Where available, on-line teaching resources are linked to each diagnosis, to guide teachers in moving students to the next stage. Many smart tests are now being trialled in schools and their impact on students’ and teachers’ learning is being evaluated. Design issues are discussed

Barriers and enablers for older adults participating in a home-based pragmatic exercise program delivered and monitored by Amazon Alexa: a qualitative study

Abstract Background The remote delivery and monitoring of individually-tailored exercise programs using voice-controlled intelligent personal assistants (VIPAs) that support conversation-based interactions may be an acceptable alternative model of digital health delivery for older adults. The aim of this study was to evaluate the enablers and barriers for older adults participating in a home-based exercise program delivered and monitored by VIPAs. Method This qualitative study used videoconferencing to conduct semi-structured interviews following a 12-week, prospective single-arm pilot study in 15 adults aged 60 to 89&nbsp;years living alone in the community. All participants were prescribed an individualized, brief (10&nbsp;min, 2&ndash;4 times per day), home-based muscle strengthening and balance exercise program delivered and monitored using an Amazon Echo Show 5 device (Alexa). Qualitative interview data were analysed using inductive thematic analysis. Results All 15 participants (aged 70.3&thinsp;&plusmn;&thinsp;4.3&nbsp;years, mean&thinsp;&plusmn;&thinsp;SD) attended the semi-structured interview. Themes including enjoyability and ease of use, social engagement and motivation were enablers for participation in the exercise program. Errors in voice recognition, lack of feedback, and preference for other existing digital health modes of exercise delivery were barriers associated with the Alexa technology. Conclusions This qualitative study identified enablers and barriers associated with using an Alexa device to deliver and monitor an individualized, home-based exercise program in older adults living alone. Future interventions using VIPAs should focus on reducing technical errors, providing regular exercise feedback, and comparing participants&rsquo; experiences of exercise programs delivered by VIPAs to programs delivered via other digital health tools. </jats:sec