Transcriptional Regulation of Effector and Memory Responses during Acute and Chronic Lymphocytic Choriomeningitis Virus (LCMV) Infection

Transcriptional regulation of CD8+ T cell differentiation during acute and chronic viral infections is an intricate web made up of many of transcription factors. While several transcription factors have been elucidated in this process, there are still many more that remain elusive. In this work, we look into the role of two transcription factors, IRF4 and Runx2, and their role in CD8+ T cell terminal effector cells and memory precursor cells during acute LCMV-Armstrong infection. We found that IRF4 expression was regulated by TCR signal strength during infection, and that IRF4 expression levels directly correlated with the magnitude of the effector cell response. IRF4 was also shown to regulate T-bet and Eomes, two transcription factors critical for CD8+ T cell differentiation into effector and memory cells. From these results, we were interested in the potential role of IRF4 during chronic LCMV-clone 13 infection, where ratios of T-bet and Eomes are critical for viral clearance. We found that haplodeficiency of IRF4 in the T cell compartment lead to an increase in the ratio of Eomes to T-bet in T cells, which in turn affected the proportion of Eomeshi versus T-bethi cells and resulted in a loss in ability to clear viral infection. Irf4+/-Eomes+/- compound heterozygous mice were generated to test if decreasing Eomes expression would rescue the Irf4+/- phenotype. Irf4+/-Eomes+/- mice were phenotypically similar to WT mice in terms of Eomes to T-bet ratios, and were able to clear viral infection, demonstrating a critical role of IRF4 in regulating T-bet and Eomes during chronic viral infection. Next we looked into the role of Runx2 during acute LCMV-Armstrong infection and found that Runx2-deficient pathogen-specific CD8+ T cells had a defect in the total number of memory precursor cells compared to WT controls. We further showed that Runx2 was inversely correlated with TCR signal strength, and that Runx2 expression was repressed by IRF4. From these work, we have introduced two more transcription factors that are critical for CD8+ T cells differentiation during acute and chronic viral infection. Given the sheer number of transcription factors known to regulate these processes, having a full understanding of the transcriptional network will allow us to find the best targets for therapeutic intervention for treatments ranging from vaccine development and autoimmunity to cancer immunotherapy and treatment of chronic viral infections

Фармакологическая антиаритмическая терапия и модулированная кинезотерапия как первичная профилактика фибрилляции предсердий у больных метаболическим синдромом с преждевременными предсердными комплексами: проспективное исследование

Highlights. The results of primary prevention of atrial fibrillation by using antiarrhythmic drug therapy and modulated kinesitherapy in patients with metabolic syndrome with premature atrial complexes are presented.A significant decrease in the development of the disease was revealed in patients with metabolic syndrome and risk of atrial fibrillation within a year after the examination with the help of pharmacological antiarrhythmic therapy of atrial ectopia and modulated kinesotherapy as primary prevention in comparison with therapy aimed at correcting blood pressure, glucose and blood lipids.Aim. To assess the possibility of using antiarrhythmic drug therapy (DT) and modulated kinesitherapy (MK)  in patients with metabolic syndrome (MS) and premature atrial complexes (PAC) as the primary prevention of atrial fibrillation (AF).Methods. 426 MS patients with PAC aged from 58 to 72 years (mean 66.4±0.7 years) were included in the study. All patients had a high probability of developing primary AF within 1 year after the enrollment. Antiarrhythmic DT with class I–III  drugs was used as the primary prophylaxis of AF in 149 (34.97%) patients, MK  – in 121 (28.40%), the correction of blood pressure, glucose and blood lipids – in 156 (36.63%). All patients were followed up for one year and the end point of observation was the maintenance of sinus rhythm or AF registration.Results. Various clinical forms of AF were recorded in 26.45, 31.54% and 95.51% of patients with MS during primary prevention with the help of pharmacological AAT, UA and correction of its potentially modifiable components (arterial pressure, glucose and blood lipids), respectively, during the year after the examination.Conclusion. The use of both antiarrhythmic DT of I–III classes, and MК as a primary prophylaxis of AF in patients with MS with PAC and the risk of AF development within one year after the first examination made it possible to reduce the frequency of the arrhythmia by the correction of blood pressure, glucose and blood lipids.Основные положения. Представлены  результаты   первичной   профилактики   фибрилляции    предсердий  с  помощью медикаментозной  антиаритмической терапии и  модулированной   кинезотерапии у больных  метаболическим синдромом  с преждевременными  предсердными комплексами.У пациентов с  метаболическим синдромом   и  риском фибрилляции    предсердий  в  течение года после  обследования  выявлено   достоверно  значимое  снижение    развития заболевания при  использовании  фармакологической противоаритмической  терапии предсердной эктопии и  модулированной  кинезотерапии как первичной   профилактики   в сравнении  с терапией,  направленной  на коррекцию артериального давления,  содержания   глюкозы и липидов крови.Цель. Оценить   возможность  использования медикаментозной  антиаритмической терапии (ААТ) и модулированной  кинезотерапии (МК) у больных  метаболическим синдромом  (МС) с преждевременными    предсердными  комплексами в качестве первичной  профилактики  фибрилляции   предсердий (ФП).Материалы и методы. Наблюдали  426 пациентов    с  МС и  преждевременными   предсердными комплексами    в  возрасте  от  58 до  72 лет (в   среднем 66,4±0,7). У всех  больных отмечена  высокая  вероятность развития первичной   ФП в течение  года после включения   в исследование.  У 149 (34,97%) больных  для первичной  профилактики ФП использована  медикаментозная   ААТ препаратами  I–III классов, у  121 (28,40%) – МК, у  156 (36,63%) – коррекция   артериального  давления, содержания глюкозы и липидов крови. После включения в исследование всех пациентов наблюдали   в  течение года:  конечной   точкой  явилось  сохранение синусового ритма  или  регистрация ФП.Результаты. У 26,45, 31,54 и 95,51% пациентов   с МС при  первичной   профилактике   с помощью фармакологической ААТ, МК и  коррекции   его потенциально  модифицируемых  компонентов  (артериального давления,  содержания  глюкозы и липидов   крови)    соответственно в  течение  года после  обследования  зарегистрированы  различные  клинические формы ФП.Заключение. Применение   медикаментозной ААТ препаратами  I–III  классов и  МК в качестве первичной   профилактики   у  больных    МС с  преждевременными    предсердными   комплексами и  риском развития  ФП в  течение  года  после   обследования   позволило   в среднем    в три  раза снизить  частоту  возникновения  этой аритмии   в сравнении  с терапией, направленной на коррекцию   артериального давления, содержания глюкозы и липидов крови

A POSSIBILITY TO USE ANTIARRHYTHMIC MEDICATIONS FROM II CLASS AND MODULATED KINESITHERAPY AS PRIMARY PREVENTION OF ATRIAL FIBRILLATION IN METABOLIC SYNDROME PATIENTS

Aim. To evaluate the usage of II class antiarrhythmic drugs and modulated kinesitherapy (MK) as primary prevention of atrial fibrillation (AF) in patients with metabolic syndrome (MS) with revelation of short-term risk for this arrhythmia development.Material and methods. We observed 153 patients with MS at the age 58-75 y. o. without AF in anamnesis, but with short-term risk of its development (2 years after examination), defined via comparative analysis of AF course, induced by transesophageal electrocardiostimulation, in dynamic patients observation. All patients, as primary prevention of AF, used antiarrhythmics of the 2nd class, and in side effects development or in contraindications they underwent MK; polyunsaturated fatty acids also used (PUFA).Results. After inclusion to the study 77 (50,33%) of MS patients used II class drugs additionally to therapy, 42 (27,45%) patients underwent MK, and the rest used PUFA. The best clinical effect was found in II class drugs and MK >63,75% and 74,41%, resp. Efficacy of the therapy in this type of patients highly correlated with the improvement of the left ventricle dysfunction, signal-average electrocardiogram, P-wave dispersion and the decrease of the left atrium volume.Conclusion. If the short-term risk of AF found in MS patients, as primary prevention the method of choice is antiarrhythmic therapy II class drugs and MK

MODULATED KINESIOTHERAPY IN PATIENTS WITH COMPLICATED CORONARY HEART DISEASE

Aim. To study the effects of modulated kinesiotherapy (MK) on the clinical course of atrial fibrillation (AF) and chronic heart failure (CHF) in patients with coronary heart disease (CHD). Material and methods. The study included 175 patients, aged 46-65 years, with CHD and/or essential arterial hypertension, persistent AF, and Functional Class (FC) I-II CHF. All participants underwent general clinical examination, 6-minute walk test, and assessment of quality of life (QoL), hemodynamic parameters, atrial late potentials, and P wave dispersion. After selection of anti-recurrent AF therapy, all patients were followed up for one year. After that, MK was administered to 119 individuals (68,0%), while the rest of the subjects continued anti-recurrent AF treatment. Results. The combination of MK and anti-recurrent AF therapy was associated with improved QoL and left ventricular diastolic function, reduced CHF FC and AF recurrence rates, and decreased left atrium volume and prevalence of atrial late potentials or pathological P wave dispersion values, compared to baseline characteristics. Conclusion. In patients with CHD, CHF, and persistent AF, the combination of MK and anti-recurrent AF therapy was linked to reduced rates of AF recurrence, as well as to improved CHF FC

VENTRICULAR EXTRASYSTOLY WITH HIGH RISK OF LIFE-THREATENING ARRHYTHMIAS DEVELOPMENT IN ACUTE CORONARY SYNDROME WITHOUT ST ELEVATION: EVALUATION OF REVASCULARIZATION EFFECTIVENESS

Aim. To study the role of early myocardial revascularization in the clinical course of the acute coronary syndrome (NSTEACS) without ST elevation, complicated with ventricular extrasystoly (VE) and high risk of life-threatening ventricular arrhythmias (LVA) development.Material and methods. Totally 124 patients with NSTEACS with VE II-V Lown and high risk of LVA that was assessed if there are pathologic values of linear shift of preectopic VE interval and LVA index, ≤10 ms and ≤0,5, respectively. To all patients having informed consent during the first 24 h since admittance the evaluation of coronary arteries flow grade was performed and for those having indications — revascularization preformed. In refusion of invasive treatment — in addition to conservative therapy the drugs of III class were used (mostly amiodarone).Results. The best positive effect of revascularization in NSTEACS with VE and LVA risk was if it had been performed during the first 2 h since hospitalization: fatal ventricular arrhythmias during hospitalization and before were not registered.Efficacy of fatal arrhythmias prevention in NSTEACS with VE and high risk of LVA during 2-24 h after hospitalization and with revascularization if indicated, was nearly same with the use of additional III class drugs — i.e. amiodarone, and was about 76,19% and 79,41%, resp.Conclusion. All patients with NSTEACS with VE and high risk of LVA the revascularization is indicated if indicated, in first 2 h after hospitalization

Clinical assessment of transoesophageal electrostimulation in first-diagnosed Type I atrial flutter

In total, 1283 patients with coronary heart disease and fist-diagnosed atrial flutter (AFL) episodes were followed up from 1996 to 2007. In all participants, AF was treated with transoesophageal electrocardiostimulation (TOECS). Sinus rhythm was restored in 83,48 %: in 67,3 % without any antiarrhythmic therapy (AAT), and in others - with AAT before TOECS. The best effect was observed in patients receiving amiodarone or its combination with chinidin durules. Only in 2,88 %, AFL or atrial fibrillation remained after TOECS

Identification of potentially effective antiarrhythmic drugs to individualize premature ventricular contraction therapy in patients without structural cardiac changes

Aim. To individualize premature ventricular contraction (PVC) therapy in patients without structural cardiac changes by identifying potentially effective antiarrhythmic agents.Material and methods. The study included 122 patients aged 20 to 43 years without structural cardiac changes with class IV-V PVC (Rayn B. classification (1984)) and subjective arrhythmia signs. After 24-hour Holter monitoring, the selection of potentially effective antiarrhythmic agents for terminating PVC was carried out on the basis of an increase in premature beat index after the third dose compared with the initial data of >2 relative units. The accuracy of drug choice was evaluated according to 24-hour ECG monitoring after a short course of therapy for each tested antiarrhythmic agent for at least 5 days. The follow-up duration ranged from 1 to 4-5 years. The endpoint was the duration of positive antiarrhythmic effect of the drugs used.Results. In 55,74% of patients, a positive antiarrhythmic effect was detected in two agents, in 34,43% — in three, and in the rest — in four antiarrhythmic drugs. The accuracy of drug choice averaged over 90%. In 18,85% of patients, the antiarrhythmic effect of PVC therapy maintained for less than 1 year (on average 0,8±0,05 years), in other patients, from 1 year to 5 years (on average 3,7±0,09 years) (p<0,05). The duration of maintaining a positive clinical effect for 1 year or more correlated with true positive results (r=0,94), and less than 1 year — with false negative results of testing with antiarrhythmic drugs (r=0,92).Conclusion. In all patients without structural cardiac changes with PVC, a potential positive antiarrhythmic effect was detected for two or more drugs. The accuracy of choosing potentially effective drugs for terminating PVC in these patients averaged over 90%

VENTRICULAR EXTRASYSTOLIA IN PATIENTS WITH NON-ST ELEVATION ACUTE CORONARY SYNDROME: ASSESSING THE RISK OF LIFE-THREATENING VENTRICULAR ARRHYTHMIAS (CLINICO-EXPERIMENTAL STUDY)

The study aimed to assess the risk of life-threatening ventricular arrhythmias (LTVA) in patients with non-ST elevation acute coronary syndrome (ACS) and ventricular extrasystolia (VE) developing in the first 24 hours of ACS. In 46 dogs, VE with early, postponed post-depolarisation, re-entry and ischemic mechanisms was modelled. In total, 168 patients with non-ST elevation ACS and Class II-V Lawn VE were examined. All patients underwent general clinical examination as well as the assessment of late ventricular potentials (LVP), QT interval dispersion (QTd), and heart rate turbulence (HRT). In the experimental study, persistent ventricular tachycardia and/or ventricular fibrillation developed in 100%, 75%, and 85,71% of the animals with early post-depolarisation, re-entry and ischemic VE mechanisms, respectively. In the clinical study, LTVA was observed in 13,76 % of ACS patients, including 69,32 % with arrhythmia development in the first 3 days. Positive predictive value for LVP, QTd>80 ms and pathologic HRT was no more than 42%. LTVA risk could be assessed by the formula: LTVAR = А ÷ В, where LTVAR is LTVA risk in units, A – linear deviation of corrected pre-ectopic interval (ms) for at least 20 ventricular extrasystoles, calculated separately for left and right VE, and B – analysed ventricular extrasystole number (per hour). LTVAR<0,5 could be a marker of high LTVA risk, with positive predictive value of 96,34%, in non-ST elevation ACS patients with VE

ATRIAL FIBRILLATION ONSET RISK IN PATIENTS WITH METABOLIC SYNDROME: PROSPECTIVE STUDY

Aim. To evaluate the usefulness of atrial fibrillation (AF) risk predictors for assessment for long-term and short-term risk of its development in patients with metabolic syndrome (MS) during prospective study.Material and methods. During 1998-2008 y. we studied 1968 patients with MS at the age of 45-75 y. o. All patients underwent common clinical investigation, hemodynamics assessment, late atrial potentials (LAP), P-wave dispersions (Pd), transesophageal electrocardiostimulation with AF risk index (AFRI). After inclusion into the study the patients were followed-up during 1-5 years. The endpoint was absence or presence of AF.Results. In 176 (8,94%) of the patients studied during 4-4,5 year prospective study we marked the onset of paroxysmal and persistent types of AF. If during single assessment of the patients with MS older than 55 y. o. and BMI ≥30 kg/sq.m there is atrial dilatation and/or LAP, pathological values of Pd, and induction of AF with electrocardiostimulation which presuppose long-term risk of AF. Short-term risk (during 1-2 years after the first year postobservational) of AF development in MS can be evaluated only in dynamics: while lowering of AFRI by 20% and more every 3-4 months of observation leads to development of AF during 1-2 years in MS, and in AFRI less than 3 Units with further decline of this parameter by 90% and more during 1-3 months — during 6 months after investigation.Conclusion. Complex investigation of MS patients, that includes assesssment of LAP, Pd, AFRI, improves the evaluation of longand short-term risks of AF development

Environmental DNA Reveals Seasonal Shifts and Potential Interactions in a Marine Community

Environmental DNA (eDNA) analysis allows the simultaneous examination of organisms across multiple trophic levels and domains of life, providing critical information about the complex biotic interactions related to ecosystem change. Here we used multilocus amplicon sequencing of eDNA to survey biodiversity from an eighteen-month (2015–2016) time-series of seawater samples from Monterey Bay, California. The resulting dataset encompasses 663 taxonomic groups (at Family or higher taxonomic rank) ranging from microorganisms to mammals. We inferred changes in the composition of communities, revealing putative interactions among taxa and identifying correlations between these communities and environmental properties over time. Community network analysis provided evidence of expected predator-prey relationships, trophic linkages, and seasonal shifts across all domains of life. We conclude that eDNA-based analyses can provide detailed information about marine ecosystem dynamics and identify sensitive biological indicators that can suggest ecosystem changes and inform conservation strategies