Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients

Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and IA115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to this study, the arrhythmia-abolishing effect of neither of the drugs is optimal. iPSC-CMs provide a unique platform for testing drugs for CPVT.Peer reviewe

Use of CFSE staining of borreliae in studies on the interaction between borreliae and human neutrophils

BACKGROUND: Species of the tick-transmitted spirochete group Borrelia burgdorferi sensu lato (B. burgdorferi) cause Lyme borreliosis. Acute borrelial infection of the skin has unusual characteristics with only a mild local inflammatory response suggesting that the interaction between borreliae and the cells of the first-line defence might differ from that of other bacteria. It has been reported that human neutrophils phagocytose motile borreliae through an unconventional mechanism (tube phagocytosis) which is not observed with non-motile borreliae. Therefore, it would be of great interest to visualise the bacteria by a method not affecting motility and viability of borreliae to be able to study their interaction with the cells of the innate immunity. Carboxyfluorescein diacetate, succinimidyl ester (CFSE) labelling has been previously used for studying the adhesion of labelled bacteria to host cells and the uptake of labelled substrates by various cells using flow cytometry. RESULTS: In this study, CFSE was shown to efficiently stain different genospecies of B. burgdorferi without affecting bacterial viability or motility. Use of CFSE staining allowed subsequent quantification of borreliae associated with human neutrophils with flow cytometry and confocal microscopy. As a result, no difference in association between different borrelial genospecies (Borrelia burgdorferi sensu stricto, Borrelia afzelii, Borrelia garinii), or between borreliae and the pyogenic bacterium Streptococcus pyogenes, with neutrophils could be detected. Borrelial virulence, on the other hand, affected association with neutrophils, with significantly higher association of a non-virulent mutant B. burgdorferi sensu stricto strain compared to the parental virulent wild type strain. CONCLUSION: These results suggest that the flow cytometric assay using CFSE labelled borreliae is a valuable tool in the analysis of the interaction between borreliae and human neutrophils. The results also indicate a clear difference in the association with neutrophils between virulent and non-virulent borrelial strains

Effect of maternal weight during pregnancy on offspring muscle strength response to resistance training in late adulthood

Purpose: Maternal obesity can unfavorably influence offspring body composition, muscle strength, and possibly muscle's adaptability to training, but the human studies are scarce. Therefore, we aimed to investigate the effect of maternal obesity on offspring muscle strength responses to resistance training intervention in elderly frail women. Materials/methods: Recruited participants were elderly frail women offspring of lean/normal weight mothers (n = 19, mean body mass index (BMI): 22.8 kg/m2, range: 19.9-24.5) or overweight/obese mothers (n = 16, mean BMI: 29.7 kg/m2, range: 28.2-34.2). Information on maternal BMI immediately prior to delivery was collected from the birth registers. All women participated in a 4-month supervised progressive resistance training intervention three times a week for 60 min. Predicted 1-RM of abdominal crunch, hip abduction, leg curl, leg press, seated row, and total strength were measured at baseline and after each month of training. Results: According to rANOVA, strength increased significantly in both groups (p for time 0.072). On average, muscle strength of the women offspring of overweight/obese mothers tended to be lower than in women offspring of lean/normal weight mothers, but the only significant difference was found in leg curl (p = 0.006). No significant differences between the groups were found in relative strength changes from baseline to 4-months. Conclusions: Muscle strength response to supervised resistance training is not modulated by maternal adiposity in late pregnancy in elderly frail female offspring.Peer reviewe

Seasonality and geographical spread of respiratory syncytial virus epidemics in 15 European countries, 2010 to 2016

Respiratory syncytial virus (RSV) is considered the major pathogen causing severe lower respiratory tract infections among infants and young children [1]. RSV is the most common cause of hospitalisation for acute lower respiratory tract infection in children younger than 5 years and is estimated to cause between 66,000 and 199,000 deaths worldwide every year [2]. Its significance in causing substantial morbidity and hospitalisation in the first year of life has been affirmed in a recent study and a meta-analysis [3,4]. In England, average annual hospital admission rates are 35.1 per 1,000 children younger than 1 year and 5.31 per 1,000 children aged 1–4 years [5]. In addition to children, RSV causes a substantial disease burden in elderly people and patients with chronic obstructive pulmonary disease [6,7]. RSV causes seasonal epidemics worldwide [8], with one to two epidemics each year [9] following latitudinal gradients in timing, duration, seasonal amplitude and between-year variability [8,9]. In some studies, the seasonal periodicity has been connected to climatic factors [9-11], but a common factor that explains all observed periodicity has not been established. Meteorological conditions such as temperature and high relative humidity have been reported as important predictors of RSV epidemics [9,12]. In the United States (US) and Japan, annual national and regional variation of RSV season onset and end has been reported [13-15]. In the Nordic countries, a major outbreak often alternates with a minor one, with the minor peak in the spring and a major one the following winter [16-19], a phenomenon reported also in Croatia [20], Denmark [21] and Germany [22]. RSV antigenic groups A and B alternate in two-year cycles in Finland, with dominance of the group A viruses in years 1981–82, 1985–86 and 1989–90 and the group B viruses 1983–84 and 1987–88 [17,19], and different genotypes dominate the circulation in consecutive epidemics in Korea [23]. In Spain, no biennial rhythm has been detected but rather a stable annual epidemic with a peak between week 52 and week 1 and circulation 2–8 weeks earlier than influenza viruses [24]. Similarly, in the United Kingdom (UK), one stable epidemic per year is observed [5]. Immunoprophylaxis to prevent RSV infection with a neutralising monoclonal antibody, palivizumab, has been developed for administration to target groups on a monthly basis during the RSV season [25]. However, this drug is limited to high-risk infants, the cost prohibits its use in low- and middle-income countries and the data on effectiveness of the drug in children at high risk other than infants born at gestational age < 33 weeks and in children with chronic lung and heart diseases are limited [26]. The demonstrated high disease burden of RSV infection has created a longstanding interest in RSV vaccines. Approximately 60 RSV vaccine candidates are in preclinical to phase III clinical trials [27,28], with potential target groups including elderly people, pregnant women and infants. A vaccine is expected to enter the market within 5–10 years, presumably by 2025 [29]. As natural infection provides only limited protective immunity owing to evolution of the surface protein G and alternating dominance of antigenic groups A and B [30], most of the vaccine candidates target the fusion protein F, which is cross-reactive across RSV subtypes [27]. To circumvent issues with alternating strains, it has been also suggested to consider inclusion of both RSV A and B in a future RSV vaccine [30]. To plan optimal future vaccination strategies, it is critically important to understand who is affected by RSV and to identify which groups are at risk of more severe RSV infection requiring hospitalisation or intensive care. RSV infection is not notifiable in the European Union (EU) and European Economic Area (EEA), except in Ireland, but many countries have a long tradition of reporting laboratory-confirmed RSV infections at national and international level. The European Influenza Surveillance Network (EISN) collects RSV data for the purpose of interpreting the reports of influenza-like-illness (ILI); these data can also be used to analyse seasonality of RSV [31]. Inter-country comparative analysis of seasonal circulation of RSV across Europe is lacking as most of the published literature focuses on individual countries. Our study describes the seasonality of RSV in 15 countries in the EU/EEA, specifically the start and peak of the season, length of the season and geographical spread, as a baseline description of RSV circulation in Europe. We further aimed to test if the data reported through influenza surveillance systems in use in EU/EEA countries are appropriate to analyse RSV seasonality, including more countries and a more detailed analysis than previous studies.Peer Reviewe

Intra-Cavity Frequency-Doubled VECSEL System for Narrow Linewidth Rydberg EIT Spectroscopy

Vertical external-cavity surface-emitting lasers (VECSELs) augmented by intra-cavity nonlinear optical frequency conversion have emerged as an attractive light source of ultraviolet to visible light for demanding scientific applications, relative to other laser technologies. They offer high power, low phase noise, wide frequency tunability, and excellent beam quality in a simple and inexpensive system architecture. Here, we characterize the frequency stability of an intra-cavity frequency-doubled VECSEL with 690 mW of output power at 475 nm using the delayed self-heterodyne technique and direct comparison with a commercial external-cavity diode laser (ECDL). We measure the fundamental's Lorentzian linewidth to be $2\pi\times5.3(2)$ kHz, and the total linewidth to be $2\pi\times23(2)$ kHz. In addition, we perform Rydberg-state spectroscopy via electromagnetically induced transparency (EIT), observing narrow 3.5 MHz full-width half-maximum EIT. By doing so, we demonstrate that intra-cavity frequency-doubled VECSELs can perform precision spectroscopy at the MHz level, and are a promising tool for contemporary, and future, quantum technologies.Comment: 13 pages, 5 figure

Cancer Risk Near a Polluted River in Finland

The River Kymijoki in southern Finland is heavily polluted with polychlorinated dibenzo-p-dioxins and dibenzofurans and may pose a health threat to local residents, especially farmers. In this study we investigated cancer risk in people living near the river (< 20.0 km) in 1980. We used a geographic information system, which stores registry data, in 500 m × 500 m grid squares, from the Population Register Centre, Statistics Finland, and Finnish Cancer Registry. From 1981 to 2000, cancer incidence in all people (N = 188,884) and in farmers (n = 11,132) residing in the study area was at the level expected based on national rates. Relative risks for total cancer and 27 cancer subtypes were calculated by distance of individuals to the river in 1980 (reference: 5.0–19.9 km, 1.0–4.9 km, < 1.0 km), adjusting for sex, age, time period, socioeconomic status, and distance of individuals to the sea. The respective relative risks for total cancer were 1.00, 1.09 [95% confidence interval (CI), 1.04–1.13], and 1.04 (95% CI, 0.99–1.09) among all residents, and 1.00, 0.99 (95% CI, 0.85–1.15), and 1.13 (95% CI, 0.97–1.32) among farmers. A statistically significant increase was observed for basal cell carcinoma of the skin (not included in total cancers) in all residents < 5.0 km. Several other common cancers, including cancers of the breast, uterine cervix, gallbladder, and nervous system, showed slightly elevated risk estimates at < 5.0 km from the river. Despite the limitations of exposure assessment, we cannot exclude the possibility that residence near the river may have contributed to a small increase in cancer risk, especially among farmers

Seasonality and geographical spread of respiratory syncytial virus epidemics in 15 European countries, 2010 to 2016

Respiratory syncytial virus (RSV) is considered the most common pathogen causing severe lower respiratory tract infections among infants and young children. We describe the seasonality and geographical spread of RSV infection in 15 countries of the European Union and European Economic Area. We performed a retrospective descriptive study of weekly laboratory-confirmed RSV detections between weeks 40/2010 and 20/2016, in patients investigated for influenzalike illness, acute respiratory infection or following the clinician's judgment. Six countries reported 4,230 sentinel RSV laboratory diagnoses from primary care and 14 countries reported 156,188 non-sentinel laboratory diagnoses from primary care or hospitals. The median length of the RSV season based on sentinel and non-sentinel surveillance was 16 (range: 9-24) and 18 (range: 8-24) weeks, respectively. The median peak weeks for sentinel and non-sentinel detections were week 4 (range: 48 to 11) and week 4.5 (range: 49 to 17), respectively. RSV detections peaked later (r = 0.56; p = 0.0360) and seasons lasted longer with increasing latitude (r = 0.57; p = 0.0329). Our data demonstrated regular seasonality with moderate correlation between timing of the epidemic and increasing latitude of the country. This study supports the use of RSV diagnostics within influenza or other surveillance systems to monitor RSV seasonality and geographical spread

Early-stage breast cancer is not associated with the risk of marital dissolution in a large prospective study of women

Background: As breast cancer and its treatment are likely to interfere with traditional expectations of womanhood, it may affect marital stability. Methods: The risk of marital dissolution was analysed with respect to diagnosis of early-stage (T1-4N0-3M0) breast cancer in a cohort of 134 435 married Finnish women followed for a median of 17.0 married years. Age, socioeconomic status, education, number of children, duration of marriage and earlier marriages were taken into account and the effects of surgery, chemotherapy, radiotherapy and endocrine therapy were analysed separately. Results: Women with a diagnosis of early-stage breast cancer did not show increase in marital dissolution (hazard ratio -0.96, 95% confidence interval = 0.79-1.17). Neither the type of surgical procedure nor any of the oncologic treatments was associated with an increase in the risk of divorce. Conclusions: Any evidence of excess risk of marital breakdown after the diagnosis of early-stage breast cancer and its treatment was not demonstrated.Peer reviewe