Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective

Defining the cellular electrophysiological mechanisms for ventricular tachyarrhythmias is difficult, given the wide array of potential mechanisms, ranging from abnormal automaticity to various types of reentry and kk activity. The degree of difficulty is increased further by the fact that any particular mechanism may be influenced by the evolving ionic and anatomic environments associated with many forms of heart disease. Consequently, static measures of a single electrophysiological characteristic are unlikely to be useful in establishing mechanisms. Rather, the dynamics of the electrophysiological triggers and substrates that predispose to arrhythmia development need to be considered. Moreover, the dynamics need to be considered in the context of a system, one that displays certain predictable behaviors, but also one that may contain seemingly stochastic elements. It also is essential to recognize that even the predictable behaviors of this complex nonlinear system are subject to small changes in the state of the system at any given time. Here we briefly review some of the short-, medium-, and long-term alterations of the electrophysiological substrate that accompany myocardial disease and their potential impact on the initiation and maintenance of ventricular arrhythmias. We also provide examples of cases in which small changes in the electrophysiological substrate can result in rather large differences in arrhythmia outcome. These results suggest that an interrogation of cardiac electrical dynamics is required to provide a meaningful assessment of the immediate risk for arrhythmia development and for evaluating the effects of putative antiarrhythmic interventions.     

Crosstalk between adenosine A1 and β1-adrenergic receptors regulates translocation of PKCε in isolated rat cardiomyocytes

Adenosine A(1) receptor (A(1)R)-induced translocation of PKCε to transverse (t) tubular membranes in isolated rat cardiomyocytes is associated with a reduction in β(1)-adrenergic-stimulated contractile function. The PKCε-mediated activation of protein kinase D (PKD) by endothelin-1 is inhibited by β(1)-adrenergic stimulated protein kinase A (PKA) suggesting a similar mechanism of A(1)R signal transduction modulation by adrenergic agonists may exist in the heart. We have investigated the influence of β(1)-adrenergic stimulation on PKCε translocation elicited by A(1)R. Immunofluorescence imaging and Western blotting with PKCε and β-COP antibodies were used to quantify the co-localization of PKCε and t-tubular structures in isolated rat cardiomyocytes. The A(1)R agonist CCPA increased the co-localization of PKCε and t-tubules as detected by imaging. The β(1)-adrenergic receptor agonist isoproterenol (ISO) inhibited this effect of CCPA. Forskolin, a potent activator of PKA, mimicked, and H89, a pharmacological PKA inhibitor, and PKI, a membrane-permeable PKA peptide PKA inhibitor, attenuated the negative effect of ISO on the A(1)R-mediated PKCε translocation. Western blotting with isolated intact hearts revealed an increase in PKCε/β-COP co-localization induced by A(1)R. This increase was attenuated by the A(1)R antagonist DPCPX and ISO. The ISO-induced attenuation was reversed by H89. It is concluded that adrenergic stimulation inhibits A(1)R-induced PKCε translocation to the PKCε anchor site RACK2 constituent of a coatomer containing β-COP and associated with the t-tubular structures of the heart. In that this translocation has been previously associated with the antiadrenergic property of A(1)R, it is apparent that the interactive effects of adenosine and β(1)-adrenergic agonists on function are complex in the heart.     

Species loss of stoneflies (Plecoptera) in the Czech Republic during the 20th century

1. Rapid expansion and intensification of anthropogenic activities in the 20th century has caused profound changes in freshwater assemblages. Unfortunately, knowledge of the extent and causes of species loss (SL) is limited due to the lack of reliable historical data. An unusual data set allows us to compare changes in the most sensitive of aquatic insect orders, the Plecoptera, at some 170 locations in the Czech Republic between two time periods, 1955–1960 and 2006–2010. Historical data (1890–1911) on assemblages of six lowland rivers allow us to infer even earlier changes. 2. Regional stonefly diversity decreased in the first half of the 20th century. Streams at lower altitudes lost a substantial number of species, which were never recovered. In the second half of the century, large‐scale anthropogenic pressure caused SL in all habitats, leading to a dissimilarity of contemporary and previous assemblages. The greatest changes were found at sites affected by organic pollution and a mixture of organic pollution and channelisation or impoundment. Colonisation of new habitats was observed in only three of the 80 species evaluated. 3. Species of moderate habitat specialisation and tolerance to organic pollution were most likely to be lost. Those with narrow specialisations in protected habitats were present in both historical and contemporary collections. 4. Contemporary assemblages are the consequence of more than a 100 years of anthropogenic impacts. In particular, streams at lower altitude and draining intensively exploited landscapes host a mere fragment of the original species complement. Most stonefly species are less frequently present than before, although their assemblages remain almost intact in near‐natural mountain streams. Our analyses demonstrate dramatic restriction of species ranges and, in some cases, apparent changes in altitudinal preference throughout the area.     

Repeated trans-watershed hybridization among haplochromine cichlids (Cichlidae) was triggered by Neogene landscape evolution

The megadiverse haplochromine cichlid radiations of the East African lakes, famous examples of explosive speciation and adaptive radiation, are according to recent studies, introgressed by different riverine lineages. This study is based on the first comprehensive mitochondrial and nuclear DNA dataset from extensive sampling of riverine haplochromine cichlids. It includes species from the lower River Congo and Angolan (River Kwanza) drainages. Reconstruction of phylogenetic hypotheses revealed the paradox of clearly discordant phylogenetic signals. Closely related mtDNA haplotypes are distributed thousands of kilometres apart and across major African watersheds, whereas some neighbouring species carry drastically divergent mtDNA haplotypes. At shallow and deep phylogenetic layers, strong signals of hybridization are attributed to the complex Late Miocene/Early Pliocene palaeohistory of African rivers. Hybridization of multiple lineages across changing watersheds shaped each of the major haplochromine radiations in lakes Tanganyika, Victoria, Malawi and the Kalahari Palaeolakes, as well as a miniature species flock in the Congo basin (River Fwa). On the basis of our results, introgression occurred not only on a spatially restricted scale, but massively over almost the whole range of the haplochromine distribution. This provides an alternative view on the origin and exceptional high diversity of this enigmatic vertebrate group.     

铼-188标记生物分子在肿瘤治疗中的应用

目的：研究铼．188标记生物分子在肿瘤治疗中的应用。方法：选取小白鼠作为实验的研究对象,将荷瘤鼠的肉瘤切成小块接种到小白鼠身上,达到试验条件时使用,即将没有明显差异的小白鼠16只随机分为4组,每组4只,注射含有铼一188的药物后分别在不同的时间将其处死,之后取出重要器官进行测量分析,进而得出铼一188的应用效果。结果：瘤内注射的要去在不同时间放射性在瘤内的保持率分别为（90．5±7．7）D％（1h）,（92．2±8．6）D％（24h）,（88．3±10．9）D％（48h）和（91．5±7．6）D％（72h）,在荷瘤鼠内注入生理盐水、非放硫化铼和188Re．硫化铼混悬液,肿瘤质量分别为2885．3±1241.3、2839．9±1965．2和98．4±45．5mg。188Re-硫化铼混悬液在生理盐水、磷酸盐缓冲液和小牛血清中均可稳定72h,而且188W-188Re发生器的应用还可以降低188Re-硫化铼混悬液的价格。随着处死时间的延迟,小鼠肿瘤质量和体积逐渐减小,相临两组比较,后组测定值均明显小于前组,数据经统计学比较具有显著差异（P〈0．05）。结论：188Re-硫化铼混悬液是一种适宜的肿瘤治疗剂。     

Minimal model for human ventricular action potentials in tissue

Modeling the dynamics of wave propagation in human ventricular tissue and studying wave stability require models that reproduce realistic characteristics in tissue. We present a minimal ventricular (MV) human model that is designed to reproduce important tissue-level characteristics of epicardial, endocardial and midmyocardial cells, including action potential (AP) amplitudes and morphologies, upstroke velocities, steady-state action potential duration (APD) and conduction velocity (CV) restitution curves, minimum APD, and minimum diastolic interval. The model is then compared with three previously published human ventricular cell models, the Priebe and Beuckelmann (PB), the Ten Tusscher–Noble–Noble–Panfilov (TNNP), and the Iyer–Mazhari–Winslow (IMW). For the first time, the stability of reentrant waves for all four models is analyzed, and quantitative comparisons are made among the models in single cells and in tissue. The PB, TNNP, and IMW models exhibit quantitative differences in APD and CV rate adaptation, as well as completely different reentrant wave dynamics of quasi-breakup, stability, and breakup, respectively. All the models have dominant frequencies comparable to clinical values except for the IMW model, which has a large range of frequencies extending beyond the clinical range for both ventricular tachycardia (VT) and ventricular fibrillation (VF). The TNNP and IMW models possess a large degree of short-term memory and we show for the first time the existence of memory in CV restitution. The MV model also can be fitted to reproduce the dynamics of other models and is computationally more efficient: the times required to simulate the MV, TNNP, PB and IMW models follow the ratio 1:31:50:8084.     

First case of highly pathogenic H5N1 avian influenza virus in Spain

Background  

In August 2006 a major epidemic of bluetongue virus serotype 8 (BTV8) started off in North-West Europe. In the course of 2007 it became evident that BTV8 had survived the winter in North-West Europe, re-emerged and spread exponentially. Recently, the European Union decided to start vaccination against BTV8. In order to improve the understanding of the epidemiological situation, it was necessary to execute a cross-sectional serological study at the end of the BT vector season. Cattle were the target species for cross-sectional serological studies in Europe at the end of 2006 and 2007. However, there was no information on the BTV8-seroprevalence in sheep and goats.     

Predicting the impact of long-term temperature changes on the epidemiology and control of schistosomiasis: a mechanistic model

Background

Many parasites of medical and veterinary importance are transmitted by cold-blooded intermediate hosts or vectors, the abundance of which will vary with ambient temperatures, potentially altering disease prevalence. In particular, if global climate change will increase mean ambient temperature in a region endemic with a human pathogen then it is possible that the incidence of disease will similarly increase. Here we examine this possibility by using a mathematical model to explore the effects of increasing long-term mean ambient temperature on the prevalence and abundance of the parasite Schistosoma mansoni, the causative agent of schistosomiasis in humans.

Principal Findings

The model showed that the impact of temperature on disease prevalence and abundance is not straightforward; the mean infection burden in humans increases up to 30°C, but then crashes at 35°C, primarily due to increased mortalities of the snail intermediate host. In addition, increased temperatures changed the dynamics of disease from stable, endemic infection to unstable, epidemic cycles at 35°C. However, the prevalence of infection was largely unchanged by increasing temperatures. Temperature increases also affected the response of the model to changes in each parameter, indicating certain control strategies may become less effective with local temperature changes. At lower temperatures, the most effective single control strategy is to target the adult parasites through chemotherapy. However, as temperatures increase, targeting the snail intermediate hosts, for example through molluscicide use, becomes more effective.

Conclusions

These results show that S. mansoni will not respond to increased temperatures in a linear fashion, and the optimal control strategy is likely to change as temperatures change. It is only through a mechanistic approach, incorporating the combined effects of temperature on all stages of the life-cycle, that we can begin to predict the consequences of climate change on the incidence and severity of such diseases.     

Analysis of Spix's disc-winged bat association patterns and roosting home ranges reveal a novel social structure among bats

Spix's disc-winged bats, Thyroptera tricolor, roost in young, rolled leaves of Heliconia or Calathea plants. In this paper, we examined how the combination of high habitat availability, low occupancy rate and short longevity of those roosts may affect the pattern of interactions among individuals in the population. We regularly censused a 5.69-ha study area in northeastern Costa Rica and examined patterns of association using mark-recapture data. Thyroptera tricolor formed behaviourally cohesive social groups of mixed sex, ranging in size from four to 14 individuals. Approximately 85% of dyads maintained associations over time periods of up to 100 days, and 40% of dyads maintained longer-term associations of at least 420 days across sex classes. Individuals within social groups did not always roost together, but they shared a small common roosting home range, which averaged just 0.19 ha. Members of different social groups rarely associated, although limited associations between members of select social groups in one subunit were observed. However, roosting home ranges of adjacent social groups often overlapped (up to 39% of home ranges, and up to 92% of the area of the smaller home range), and home range centres were situated less than 100 m apart. Thus, social groups rarely interacted but overlapped in space. The features of this social system are unique among bats and mammals in general, and point to groupings based on kinship or cooperation.