Maturation of nasal microbiota and antibiotic exposures during early childhood: a population-based cohort study.

OBJECTIVES: Little is known about maturation of the airway microbiota during early childhood and the consequences of early-life antibiotic exposure. METHODS: In a population-based birth cohort of 902 healthy Finnish children, we applied deep neural network models to investigate the relationship between the nasal microbiota (measured by 16S rRNA gene sequencing at up to three time points) and child age during the first 24 months. We also performed stratified analyses according to antibiotic exposure during the age period 0-2 months. RESULTS: The dense deep neural network analysis successfully modelled the relationship between 232 bacterial genera and child age with a mean absolute error of 4.3 (95%CI 4.0-4.7) months. Similarly, the recurrent neural network analysis also successfully modelled the relationship between 215 genera and child age with a mean absolute error of 0.45 (95%CI 0.42-0.47) months. Among the genera, Staphylococcus spp. and members of the Corynebacteriaceae decreased with age, while Dolosigranulum and Moraxella increased with age in the first 2 years of life (all false discovery rate (FDR) = 0.001). In children without early-life antibiotic exposure, Dolosigranulum increased with age (FDR = 0.001). By contrast, in those with early-life antibiotic exposure, Haemophilus increased with age (FDR = 0.002). CONCLUSIONS: In this prospective birth cohort of healthy children, we demonstrated the development of the nasal microbiota, with shifts in specific genera constituting maturation, in the first 2 years of life. Antibiotic exposures during early infancy were related to different age-discriminatory bacteria.

Prospective clinical and serological follow-up in early childhood reveals a high rate of subclinical RSV infection and a relatively high reinfection rate within the first 3 years of life.

Children encounter repeated respiratory tract infections during their early life. We conducted a prospective clinical and serological follow-up study to estimate the respiratory syncytial virus (RSV) primary infection and reinfection rates in early childhood. Sera were collected from 291 healthy children at the ages of 13, 24 and 36 months and antibody levels against RSV antigens were determined by enzyme immunoassay. The RT-PCR method was also used for identifying the possible presence of RSV in symptomatic patients. At ages 1, 2 and 3 years, 37%, 68% and 86%, respectively, of studied children were seropositive for RSV. In children seropositive at age 1 year, RSV reinfection rate was at least 37%. Only one of reinfected children showed evidence for a third reinfection by age 3 years. Of children who turned RSV seropositive between ages 1 and 2 years, the reinfection rate was 32% during the third year of life. The mean antibody levels at primary infection were very similar in all age groups. The average decrease of antibody levels was 25-30% within a year. In 66 cases RSV infection was identified by RT-PCR. RSV infection rate in early childhood is 86% and reinfection rate is around 35%. This prospective serological follow-up study also provided evidence for the presence of RSV infections in children that did not show clinical signs warranting RSV RNA detection.

Interference between respiratory syncytial virus and rhinovirus in respiratory tract infections in children.

An acute viral respiratory tract infection might prevent infections by other viruses because of the antiviral innate immune response. However, with the use of PCR methods, simultaneous detection of two or more respiratory viruses is frequent. We analysed the effect of respiratory syncytial virus (RSV) infection on the occurrence of simultaneous rhinovirus (RV) infection in children within a birth cohort study setting. We used PCR for virus detection in nasal swabs collected from children with an acute respiratory tract infection at the age of 0-24 months and from healthy control children, who were matched for age and date of sample collection. Of 226 children with RSV infections, 18 (8.0%) had co-infections with RV, whereas RV was detected in 31 (14%) of 226 control children (p 0.049 by chi-square test). Adjustment for sex, number of siblings and socio-economic status strengthened the negative association between RSV and RV (OR 0.46, 95% CI 0.24-0.90; p 0.02). The median durations of symptoms (cough, rhinorrhoea, or fever) were 11 days in children with single RSV infections and 14 days in children with RSV-RV co-infections (p 0.02). Our results suggest that the presence of RSV reduces the probability of RV infection, but that, if a co-infection occurs, both viruses cause clinical symptoms.

Minimizing right ventricular pacing in pacemaker patients with intact and compromised atrioventricular conduction : Results from the EVITA Trial.

INTRODUCTION: Unnecessary ventricular pacing is associated with increased morbidity and mortality. Over the years different algorithms have been developed to reduce right ventricular pacing. OBJECTIVES: Goal of the present study was to test the efficacy of the ventricular intrinsic preference (VIP) algorithm in patients with atrioventricular intact (AVi) and atrioventricular compromised (AVc) AV-conduction. METHODS: Evaluation of VIP feature in pacemaker patients (EVITA) was a multicenter, prospective, randomized trial (Trials.gov Identifier: NCT00366158). In total, 389 patients were randomized to AVc group: n = 140/132 VIP OFF/VIP On, AVi group: n = 54/63 VIP OFF/VIP ON). One-month post-implantation AV conduction testing (AVc: PR/AR interval > 210 ms) was performed. Follow-up visits occurred 6 and 12 months after DDD-pacemaker implantation. RESULTS: In AVi and AVc-patients initiation of the VIP feature significantly reduced incidence of ventricular pacing (AVi: 53 ± 38 vs. 9 ± 21%, p = 0.0001; AVc: 79 ± 31 vs. 28 ± 35%, p = 0.0001). DDD-pacemaker implantation per se significantly reduced incidence of AF in VIP ON (AVi 27 vs. 0%, p < 0.0001; AVc 29 vs. 3%, p < 0.0001) and VIP OFF patients (AVi 43 vs. 4%, p < 0.0001; AVc 33 vs. 3, p < 0.0001), without significant differences between VIP ON and OFF groups (p > 0.05). In the AVc group activation of VIP significantly reduced incidence of adverse events (AE). All-cause mortality was not significantly different in VIP ON (n = 5) and VIP OFF (n = 4, p > 0.05) patients. CONCLUSION: AV search hysteresis (VIP) markedly reduces ventricular pacing both in patients with normal AV conduction and in patients with prolonged PR interval or intermittent AV block.

Work stress and the long QT syndrome: high job strain and effort-reward imbalance at work associated with arrhythmic risk in the long QT syndrome.

OBJECTIVES: To examine whether work stress is associated with a symptomatic status of the long QT syndrome (LQTS). METHODS: The sample comprised 173 KCNQ1, KCNH2, or SCN5A gene mutation carriers (70 symptomatic) and control groups of 203 relatives without the family mutation, and of 1209 population-based young Finns control subjects. Work stress was assessed using the Job Content Questionnaire and Occupational Stress Questionnaire. RESULTS: We found an association between the occurrence of symptoms in the LQTS and high work stress, higher job demands/effort, lower job control, and lower rewards compared with control subjects. We also found that symptomatic LQTS mutation carriers had higher work stress than asymptomatic LQTS mutation carriers. CONCLUSIONS: Higher work stress is related to arrhythmic risk in the LQTS. It may be useful to incorporate assessment of work conditions and stress interventions into management of high-risk patients.

A history of stressful life events, prolonged mental stress and arrhythmic events in inherited long QT syndrome.

OBJECTIVE: To examine whether a history of stressful life events and prolonged mental stress are associated with arrhythmic events in inherited long QT syndrome (LQTS). METHODS: Participants who had a molecularly established mutation of KCNQ1, KCNH2 or SCN5A channel and were thus diagnosed as patients with LQT1, LQT2 and LQT3 (n=566), accordingly. The control group consisted of their 614 non-affected relatives. A history of stressful life events was indexed by the major stressful life events. Prolonged mental stress was indexed by vital exhaustion (VE), which was measured with the Maastricht Questionnaire. RESULTS: Multinomial logistic regression analysis including patients with LQTS with and without arrhythmic events and the control subjects showed an age- and sex-adjusted association of stressful life events OR=1.15 (95% CI 1.08 to 1.22) and VE (OR=3.33 (95% CI 1.63 to 6.78)) with symptomatic status of LQTS. Symptomatic patients with LQTS had experienced more stressful life events (OR=1.16 (95% CI 1.08 to 1.24)) and the level of VE (OR=3.40 (95% CI 1.44 to 8.03)) was more than three times higher among patients with LQTS with arrhythmic events than in asymptomatic LQTS mutation carriers. The association between stressful life events and arrhythmic events was independent of age, sex, specifically focused medication and LQTS subtype. CONCLUSIONS: A history of stressful life events and prolonged mental stress are associated with arrhythmic events in LQTS in this large sample of molecularly defined patients with LQTS. It is important for future studies to assess how strong these predisposing factors are for arrhythmic events in LQTS.

Common candidate gene variants are associated with QT interval duration in the general population.

OBJECTIVES: QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30-40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample. METHODS: We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. RESULTS: The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT(Nc) interval (P=3.6 x 10(-11)) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QT(Nc) interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P=4.7 x 10(-5)], KCNH2 K897T [-2.6 ms (SE 0.5) or -0.14 SD, P=2.1 x 10(-7)] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P=3.2 x 10(-24)] under additive models. CONCLUSIONS: We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.

Comparison of current density viability imaging at rest with FDG-PET in patients after myocardial infarction.

The assessment of myocardial viability is a major diagnostic challenge in patients with coronary artery disease (CAD) after myocardial infarction. Novel threedimensional current density (CD) imaging algorithms use high-resolution magnetic field mapping to determine the electrical activity of myocardial segments at rest. We, for the first time, compared CD activity obtained with several algorithms to 18-F-fluoro-deoxyglucose positron emission tomography (FDG-PET) in evaluation of myocardial viability. Magnetic field maps were obtained in nine adult patients (pt) with CAD and a history of infarction. The criterion for non-viable myocardium was an FDG-PET uptake with less than 45% of the maximum in the respective segments. CD imaging was applied to the left ventricle by using six different methods to solve the inverse problem. Mean CD activity was calculated for a close meshed grid of 90 locations of the left ventricle. A cardiologist compared bull's eye plots of CD and FDG-PET activity by eye. Spearman's correlation coefficients and specificity at a given level of sensitivity (70%) were calculated. Bull's eye plots revealed a significant correlation of CD/PET in 5 pt and no correlation in 3 pt. One pt had a negative correlation. The six different CD reconstruction methods performed similar. While CD reconstruction has the principal potential to image viable myocardium, we found that the reconstructed CD magnitude was low in scar segments but also reduced in some segments with preserved metabolic activity under resting conditions. New vector measurement techniques, the use of additional stress testing and advances in mathematical methodology are expected to improve CD imaging in future.

The hemodynamic and pharmacokinetic interactions between chronic use of oral levosimendan and digoxin in patients with NYHA Classes II-III heart failure.

OBJECTIVE: Levosimendan is a calcium-sensitizing drug for the treatment of heart failure. The aim of this exploratory study was to assess the hemodynamic and pharmacokinetic interactions between digoxin and oral levosimendan as well as the proarrhythmic potential of this combination in patients with chronic heart failure. MATERIALS: Male or female patients (n = 24) with chronic heart failure of NYHA Classes II-III. METHODS: A randomized, placebo-controlled, double-blind, parallel-group trial. After a 1-week digoxin-free washout period, the patients were randomized to receive either digoxin and levosimendan (digoxin + levosimendan), or digoxin and placebo (digoxin) orally for 14 +/- 2 days. The levosimendan dose was 1 mg 3 times daily, and the digoxin dose was 0.125-0.25 mg once daily. Systolic time intervals, electrocardiography (ECG), magneto-cardiography (MCG) and 24-h ambulatory ECG were performed at baseline and at the end of each treatment period. Pharmacokinetic variables of levosimendan and digoxin were calculated in both treatment periods. Steady-state concentrations of the active metabolites OR-1855 and OR-1896 were determined at baseline at Visit 2. RESULTS: There tended to be a greater shortening of QS2i (suggesting trend to positive inotropy) in the digoxin + levosimendan group (-14ms) compared with the digoxin group (-5ms), although the difference was not statistically significant (p=0.359). However, the change from baseline in QS2i after digoxin + levosimendan was of statistically borderline significance (p=0.05). The change from baseline in the digoxin group was not statistically significant. ECG and MCG repolarization measures and occurrence of nonsustained ventricular tachycardia showed no substantial differences. After 2 weeks of digoxin + levosimendan treatment, mean area under the curve (AUC) of levosimendan increased approximately by 49% (p<0.01). The maximum plasma concentration (Cmax) of levosimendan increased from 17 to 23 ng/ml. The mean concentrations of the metabolites OR-1855 and OR-1896 in plasma were 4.3 and 8.3 ng/ml, respectively. CONCLUSIONS: The addition of oral levosimendan to digoxin therapy produced only a modest statistically nonsignificant additive inotropic effect. In contrast to the earlier data with intravenous levosimendan, the results indicate a pharmacokinetic interaction between levosimendan and digoxin. Data obtained from repolarization analyses and ambulatory ECG did not indicate any possible proarrhythmic effects of the combination.

[Effect of aluminum and iron on lipid metabolism in aquatic invertebrates].

Methods of thin-layer, gas-liquid, and liquid chromatography were applied to the study of the effect of various concentrations of aluminum and iron salts on the contents of phospholipids, cholesterol, and fatty acids in the aquatic invertebrate Hydropsyche contubernalis L. (Trichoptera). It was found that the effect of the metals under study on lipid contents in living organisms depended on the composition of the aqueous medium and concentrations of the metals. Aluminum and iron altered the value of the cholesterol-to-phospholipid molar ratio. In the absence of lethal effects, this was indicative of attempts to switch adaptational biochemical mechanisms to stabilize cellular structures.

[Age-related features of cataractogenesis in salmon fry. 3. Age-related dynamics of liver lipid composition during cataractogenesis]. / Vozrastnye osobennosti kararaktogeneza v mal'kovom periode razvitiia semgi.III. Vozrastnaia dinamika lipidnogo sostava pecheni pri kataraktogeneze.

When studying the cataract pathogenesis in salmon fry, we found changes in the content of individual; phospholipid fractions and fatty acid composition in the liver of diseased and healthy fish. The age-related changes correlated with the increased antioxidant activity and decreased liver content of malondialdehyde.

[Age-related characteristics of cataractogenesis in salmon fry. II. Biochemical characteristics of eye lens during cataractogenesis]. / Vosrastnye osobennosti kataraktogeneza v mal'kovom periode razvitiia semgi. II. Biokhimicheskie osobennosti khrustalika pri kataraktogeneze.

We studied biochemical features of the lipid and phospholipid composition and patter of fatty acid spectra in lenses of one and two year old salmons bearing cataracts. The lipid complex of lenses of diseased fish underwent significant changes. Cataractogenesis was accompanied by enhanced free radical oxidation and accumulation of malone dialdehyde in lenses of salmons of various age. The intensification of oxidative processes was synchronized with the decreased level of antioxidant protection (reduced glutathione, vitamins A and E). The activity of Ca(2+)-dependent proteolytic enzymes in lenses was determined and its decrease in the case of cataract was shown.

Electrocardiographic assessment of left ventricular hypertrophy with time-voltage QRS and QRST-wave areas.

The sum of time-voltage QRS areas in the 12-lead electrocardiogram (ECG) has outperformed other 12-lead ECG indices for detection of left ventricular hypertrophy (LVH). We assessed indices of time-voltage QRS and T-wave (QRST) areas from body surface potential mapping (BSPM) for detection of and quantitation of the degree of LVH. We studied 42 patients with echocardiographic LVH (LVH group) and 11 healthy controls (controls). QRST area sums were calculated from 123-lead BSPM and from the 12-lead ECG for comparison. Leadwise discriminant indices and correlation coefficients were used to identify optimal recording locations for QRST area-based LVH assessment. BSPM QRS area sum was greater in the LVH group than in controls (3752 +/- 1259 vs 2278 +/- 627 microV s, respectively; P<0.001) and at 91% specificity showed 74% sensitivity for LVH detection. The 12-lead QRS area sum performed similarly. Taking T-wave areas into account did not improve the results. QRS area sum from two most informative leads (located in the upper and lower right precordium) also separated the LVH group from controls (61.1 +/- 23.5 vs 27.8 +/- 6.5 microV s, respectively; P<0.00001). This 2-lead QRS area sum showed 90% sensitivity with 100% specificity for LVH detection and maintained high correlation to indexed left ventricular mass (r=0.732; P<0.001). In conclusion, the BSPM QRS area sum compared to 12-lead QRS area sum does not substantially improve LVH assessment. The 2-lead QRS area sum may improve ECG QRS area-based LVH assessment.

[Age-related features of cataractogenesis in salmon fry. I. Lipid composition of the lens in normal development]. / Vozrastnye osobennosti kataraktogeneza v mal'kovom periode razvitiia semgi. I. Lipidnyi sostav khrustalikov v normal'nom razvitii.

This papers opens a series of publications on the mechanisms of cataractogenesis in the salmon fry. Biochemical features of normal lens development and cataractogenesis in fry of different age and age-related dynamics of the liver lipid composition during upon cataractogenesis will be dealt with, since lipids are most intensely synthesized in the liver, from where they are transported in the lens. Here, we describe the dynamics of lens lipid composition in the salmon fry, including the total lipid content and dynamics of individual classes. The data are analyzed on the fatty acid spectrum of the salmon fry lens, as compared to the human lens.

[Lipid metabolism of caddisfly larvae at low pH]. / Lipidnyi metabolizm lichinok rucheinikov pri nizkikh znacheniiakh pH sredy.

The influence of low pH (5.0 and 4.0) on lipid metabolism of caddisworms Hydropsyche contubernalis L. (Trichoptera) was studied in 48 h toxicity experiments. The results were correlated with lipid composition of caddisworms directly isolated from natural water. Phospholipids, cholesterol, mono-, di-, triacylglycerols, and fatty acids were detected by thin-layer and liquid chromatography. Minimal environmental changes were shown to initiate the biochemical adaptation mechanisms strengthening the cellular membranes through their condensation due to additional phospholipid and cholesterol synthesis. In the natural medium the adaptation processes are more active than in the artificial medium. More serious changes, such as pH decrease to 4.0, suppress the adaptation processes in the first medium and terminated them in the second one.

Pre-implant determinants of adequate long-term function of single lead VDD pacemakers.

AIMS: An inherent limitation of single lead VDD pacing is the inability to stimulate the atria. Reprogramming and upgrading the pacemaker system may be required when sinus node dysfunction, atrial undersensing, or atrial fibrillation develop. We evaluated whether routine clinical information is sufficient to select patients to benefit in long-term from VDD pacing. METHODS AND RESULTS: We collected data on 12-lead and monitored electrocardiograms and routine clinical information at implantation of a VDD pacing system in 350 consecutive patients with grade II or III atrioventricular conduction block. The age at implantation was 74.5 +/- 8.0 years, and the follow-up lasted 1.5 +/- 1.5 years. The cumulative maintenance of VDD pacing mode was 91.%. Loss of VDD mode was due to permanent atrial fibrillation in 16 (4.6%), sinus node dysfunction in six (1.7%). atrial undersensing in 11 (3.1%). Chronic atrial fibrillation developed in 23% of patients who had heart enlargement in chest x-ray and a history of paroxysmal atrial fibrillation or flutter. A criterion of normal sinus rate at implantation sufficiently predicted adequate sinus node function. Poor atrial sensing was not predicted by pre-implant characteristics. CONCLUSIONS: According to our data, adequate sinus-driven atrial rate and no history of paroxysmal atrial fibrillation and cardiac enlargement predict maintenance of the VDD pacing mode in elderly patients treated for heart block. Routine information available at implantation is sufficient to guide acceptance of single lead VDD pacing therapy.

Heart rate adjustment of magnetic field map rotation in detection of myocardial ischemia in exercise magnetocardiography.

AIMS: We studied the capability of heart rate (HR) adjusted change in multichannel magnetocardiogram (MCG) to detect exercise-induced ischemia. METHODS AND RESULTS: The MCG and 12-lead ECG were recorded simultaneously during supine exercise testing in 17 healthy controls and 24 patients with single vessel coronary artery disease (CAD). In the MCG analysis, we plotted the orientation of the magnetic field map (MFM) against the HR in each cardiac cycle during recovery. A regression line was fitted to the data and the line slope (degrees/bpm) was determined. In the ECG, the ST-segment depression vs HR (ST/HR) slope was evaluated. The HR adjusted MFM rotation was more extensive in the pooled CAD group, and in all subgroups with different stenosed vessel, than in the control group at the ST-segment (1.5 +/- 2.1 degrees/bpm vs 0.29 +/- 0.25 degrees/bpm, p < 0.0005) and at the T-wave apex (0.95 +/- 0.81 degrees/bpm vs 0.24 +/- 0.25 degrees/bpm, p < 0.0005). Areas under the receiver operating characteristic curves of the HR adjusted MFM rotation at the ST-segment (88.5%) and the T-wave (86.0%) were higher than the ones without HR adjustment (75.5% and 68.1%, respectively), and higher than the area of ST/HR slope in the ECG (80.2%). CONCLUSION: HR adjusted MFM rotation detects transient ischemia independent of the stenosed vessel. HR adjustment improves the performance of the MCG in ischemia detection by the analysis of the ST-segment and the T-wave. The MCG was superior to the 12-lead ECG.