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This study considers the impact of electron precipitation from Earth's radiation belts on atmospheric composition using observations from the NASA Van Allen Probes and NSF Focused Investigations of Relativistic Electron Burst Intensity, Range, and Dynamics (FIREBIRD II) CubeSats. Ratios of electron flux between the Van Allen Probes (in near‐equatorial orbit in the radiation belts) and FIREBIRD II (in polar low Earth orbit) during spacecraft conjunctions (2015–2017) allow an estimate of precipitation into the atmosphere. Total Radiation Belt Electron Content, calculated from Van Allen Probes RBSP‐ECT MagEIS data, identifies a sustained 10‐day electron loss event in March 2013 that serves as an initial case study. Atmospheric ionization profiles, calculated by integrating monoenergetic ionization rates across the precipitating electron flux spectrum, provide input to the NCAR Whole Atmosphere Community Climate Model in order to quantify enhancements of atmospheric HOx and NOx and subsequent destruction of O3 in the middle atmosphere. Results suggest that current APEEP parameterizations of radiation belt electrons used in Coupled Model Intercomparison Project may underestimate the duration of events as well as higher energy electron contributions to atmospheric ionization and modeled NOx concentrations in the mesosphere and upper stratosphere. Plain Language Summary: High‐energy particles precipitating into the atmosphere from space affect the chemistry and composition of Earth's atmosphere. While there is significant understanding about the atmospheric impacts of auroral electrons, solar protons, and galactic cosmic rays, the effects of electrons from the near‐Earth Van Allen radiation belts remain uncertain. This study helps quantify electrons precipitating into the atmosphere by comparing measurements within the radiation belts from the NASA Van Allen Probes spacecraft to observations from the low‐altitude NSF Focused Investigations of Relativistic Electron Burst Intensity, Range, and Dynamics (FIREBIRD II) CubeSats. Global atmospheric model simulations quantify the impact of estimated electron precipitation on the ionization and chemical composition of Earth's atmosphere. Results from an initial case study using this new method suggest that electrons from the radiation belts may produce more atmospheric ionization at lower altitudes and for longer duration than currently recommended estimates, potentially affecting the chemistry of ozone in the middle atmosphere and as a consequence influencing atmospheric heating and dynamics. Key Points: Conjunctions between Van Allen Probes and FIREBIRD II enable novel estimates of atmospheric electron precipitationEstimates of electron precipitation from Van Allen Probes suggest CMIP6 may underestimate atmospheric ionization from 60 to 70 kmDirect production of NOx by precipitating electrons during March 2013 using this new method suggest 40% enhancements from 60 to 70 km [ABSTRACT FROM AUTHOR]

An effective assessment of future climate change, especially future precipitation forecasting, is an important basis for the rational development of adaptive strategies for Northwest China, where the ecological environment is fragile and encompasses arid and semiarid regions. In this work, the performance of a regional climate model is assessed; then, climate changes in the near future (2018–2037), middle future (2050–2069), and distant future (2080–2099) are analyzed under representative concentration pathways (RCPs) RCP2.6, RCP4.5, and RCP8.5. The following conclusions are drawn: (1) Compared to the Met Office Hadley Centre Earth System (HadGEM2‐ES) global climate model, the latest regional climate model, RegCM4.6, with a community land model land surface process scheme and Tiedtke cumulus convective parameterization, can create a good simulation of the present‐day mean climatology over Northwest China, including temperature, precipitation, and climate extremes, and can also provide finer‐scale climate information in complex terrain and better correct the cold bias than HadGEM2‐ES. At the same time, RegCM4 inherited the bias from HadGEM2‐ES, for example, both the RegCM4 and the HadGEM2‐ES overestimated precipitation in DJF in the southeast of the study area. (2) The future near surface air temperature will experience continuous warming over Northwest China under the RCP8.5 scenario, and the warming will become more significant and exceed 6 °C by the end of the 21st century. In RegCM4, future precipitation will continue to increase and will increase by 50 mm by the end of the 21st century relative to historical data. The extreme climate index summer days will continue to increase, indicating that high temperatures will be more frequent in Northwest China. In contrast, the consecutive dry days will decrease, likely because of the increase in precipitation.Key Points: RegCM4.6, with CLM3.5 and Tiedtke parameters, can create a good simulation of the present‐day mean climatology over Northwest ChinaThe air temperature will increase 6 °C by the later 21st century over Northwest China under the RCP8.5 scenarioThe extreme precipitation index CDD will decrease in future under all three scenarios over Northwest China [ABSTRACT FROM AUTHOR]

Whistler mode chorus waves influence the dynamics of the Earth's radiation belts and the inner magnetosphere through gyroresonant wave particle interactions. Chorus waves are generated by anisotropic hot electrons from a few to tens of keV, called source electrons, which have increased access from the nightside plasma sheet to the inner magnetosphere during geomagnetic storms. The primary drivers of geomagnetic storms are coronal mass ejections (CMEs) and corotating interaction regions (CIRs). Through differences in their characteristic physical parameters, they can each impact the nightside plasma sheet differently. Using Van Allen Probes observations, we have conducted a superposed epoch analysis of chorus wave activity and source electron development across all local times between L = 2–6 during 25 CME‐ and 35 CIR‐driven storms. The superposed epoch analysis shows that chorus wave power follows the storm phase‐dependent access of the source electron population. Chorus waves and source electrons are observed on the dawnside during the main phase, when open drift path access via eastward convective drift from the plasma sheet is enhanced. During the recovery phase, chorus waves and source electrons are observed at all magnetic local times with low intensities, exemplifying the formation of a weak symmetric, trapped electron population. A linear theory approximation for wave growth from source electron observations shows that increased wave growth follows the enhanced source electrons during each storm phase. CME and CIR storms display similar behavior and levels of average wave power; however, chorus wave activity reaches lower L‐shells during CME storms on average. Key Points: A Van Allen Probes superposed epoch analysis of source electrons and chorus waves in MLT/L during CME‐ and CIR‐driven stormsThe local time distribution of chorus wave power reflects storm phase‐dependent access and trapping of ones to tens of keV source electronsStrongest wave power and source access is during the main phase near dawn; transitions to weaker waves across all MLT in the recovery phase [ABSTRACT FROM AUTHOR]

This paper presents observations of electromagnetic ion cyclotron (EMIC) waves from multiple data sources during the four Geospace Environment Modeling challenge events in 2013 selected by the Geospace Environment Modeling Quantitative Assessment of Radiation Belt Modeling focus group: 17 and 18 March (stormtime enhancement), 31 May to 2 June (stormtime dropout), 19 and 20 September (nonstorm enhancement), and 23–25 September (nonstorm dropout). Observations include EMIC wave data from the Van Allen Probes, Geostationary Operational Environmental Satellite, and Time History of Events and Macroscale Interactions during Substorms spacecraft in the near‐equatorial magnetosphere and from several arrays of ground‐based search coil magnetometers worldwide, as well as localized ring current proton precipitation data from low‐altitude Polar Operational Environmental Satellite spacecraft. Each of these data sets provides only limited spatial coverage, but their combination shows consistent occurrence patterns and reveals some events that would not be identified as significant using near‐equatorial spacecraft alone. Relativistic and ultrarelativistic electron flux observations, phase space density data, and pitch angle distributions based on data from the Relativistic Electron‐Proton Telescope and Magnetic Electron Ion Spectrometer instruments on the Van Allen Probes during these events show two cases during which EMIC waves are likely to have played an important role in causing major flux dropouts of ultrarelativistic electrons, particularly near L* ~4.0. In three other cases, identifiable smaller and more short‐lived dropouts appeared, and in five other cases, these waves evidently had little or no effect. Key Points: EMIC waves can rapidly deplete fluxes of ultrarelativistic electrons, but their occurrences are limited in both space and timeEMIC wave observations by magnetospheric spacecraft are supplemented by observations from ground‐based magnetometers and POES satellitesMany but not all EMIC wave events correlated with major or minor depletions of ultrarelativistic electrons observed by the Van Allen Probes [ABSTRACT FROM AUTHOR]

Diuretics are commonly prescribed for treatment in patients with hypertension, edema, or heart failure. Studies on hypertensive and salt-losing disorders and on urea transporters have contributed to better understanding of mechanisms of renal salt and water reabsorption and their regulation. Proteins involved in the regulatory pathways are emerging targets for diuretic and aquaretic therapy. Integrative high-throughput screening, protein structure analysis, and chemical modification have identified promising agents for preclinical testing in animals. These include WNK-SPAK inhibitors, ClC-K channel antagonists, ROMK channel antagonists, and pendrin and urea transporter inhibitors. We discuss the potential advantages and side effects of these potential diuretics. [ABSTRACT FROM AUTHOR]

Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage-gated, sodium (Na+) channel α-subunits (Nav1.5). We summarize experimental studies of physiological and clinical consequences of loss-of-function Na+ channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, ventricular tachycardia (VT) or fibrillation. Mouse Scn5a+/− hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Nav1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Nav1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Nav1.5 haploinsufficient males in producing clinical arrhythmia. [ABSTRACT FROM AUTHOR]

Aims Cardiac ryanodine receptor mutations are associated with catecholaminergic polymorphic ventricular tachycardia ( CPVT), and some, including RyR2-P2328S, also predispose to atrial fibrillation. Recent work associates reduced atrial Nav1.5 currents in homozygous RyR2-P2328S ( RyR2S/S) mice with slowed conduction and increased arrhythmogenicity. Yet clinically, and in murine models, the Nav1.5 blocker flecainide reduces ventricular arrhythmogenicity in CPVT. We aimed to determine whether, and how, flecainide influences atrial arrhythmogenicity in RyR2S/S mice and their wild-type ( WT) littermates. Methods We explored effects of 1 μ m flecainide on WT and RyR2S/S atria. Arrhythmic incidence, action potential ( AP) conduction velocity ( CV), atrial effective refractory period ( AERP) and AP wavelength ( λ = CV × AERP) were measured using multi-electrode array recordings in Langendorff-perfused hearts; Na+ currents ( INa) were recorded using loose patch clamping of superfused atria. Results RyR2 S/S showed more frequent atrial arrhythmias, slower CV, reduced INa and unchanged AERP compared to WT. Flecainide was anti-arrhythmic in RyR2S/S but pro-arrhythmic in WT. It increased INa in RyR2S/S atria, whereas it reduced INa as expected in WT. It increased AERP while sparing CV in RyR2 S/S, but reduced CV while sparing AERP in WT. Thus, RyR2 S/S hearts have low λ relative to WT; flecainide then increases λ in RyR2 S/S but decreases λ in WT. Conclusions Flecainide (1 μ m) rescues the RyR2-P2328S atrial arrhythmogenic phenotype by restoring compromised INa and λ, changes recently attributed to increased sarcoplasmic reticular Ca2+ release. This contrasts with the increased arrhythmic incidence and reduced INa and λ with flecainide in WT. [ABSTRACT FROM AUTHOR]

Aim To test a hypothesis attributing arrhythmia in Brugada Syndrome to right ventricular ( RV) outflow tract ( RVOT) conduction abnormalities arising from Nav1.5 insufficiency and fibrotic change. Methods Arrhythmic properties of Langendorff-perfused Scn5a+/− and wild-type mouse hearts were correlated with ventricular effective refractory periods ( VERPs), multi-electrode array ( MEA) measurements of action potential ( AP) conduction velocities and dispersions in conduction direction (CD), Nav1.5 expression levels, and fibrotic change, as measured at the RVOT and RV. Two-way anova was used to test for both independent and interacting effects of anatomical region and genotype on these parameters. Results Scn5a+/− hearts showed greater arrhythmic frequencies during programmed electrical stimulation at the RVOT but not the RV. The Scn5a+/− genotype caused an independent increase of VERP regardless of whether the recording site was the RVOT or RV. Effective AP conduction velocities ( CV†s), derived from fitting regression planes to arrays of observed local activation times were reduced in Scn5a+/− hearts and at the RVOT independently. AP conduction velocity magnitudes derived by averaging MEA results from local vector analyses, CV*, were reduced by the Scn5a+/− genotype alone. In contrast, dispersions in conduction direction, were greater in the RVOT than the RV, when the atrioventricular node was used as the pacing site. The observed reductions in Nav1.5 expression were attributable to Scn5a+/−, whereas increased levels of fibrosis were associated with the RVOT. Conclusions The Scn5a+/− RVOT recapitulates clinical findings of increased arrhythmogenicity through reduced CV† reflecting reduced CV* attributable to reduced Nav1.5 expression and increased CD attributable to fibrosis. [ABSTRACT FROM AUTHOR]

Background Smoking tobacco is a global health problem, and this study highlights adolescent smoking in Taiwan. Smoking was completely banned on campuses under the Tobacco Hazards Prevention Act and School Health Regulations. Few have investigated the association between personnel smoking/school smoking policies and adolescent smoking in Taiwan. The smoking rate has gradually increased for senior high school students in Taiwan from 10.7% in 1994 to 14.7% in 2011. Aim This study examined the influence of family and friends' smoking on the association between the presence of teachers smoking and each stage of adolescents' smoking behaviour. Methods A cross-sectional survey was conducted in nine high schools ( n = 921). Logistic regression analysis was used to examine the association between smoking stage, father smoking, mother smoking, sibling smoking, friends smoking and the presence of smoking teachers. Results After adjusting for gender, school type and grade, fathers', siblings' and friends' smoking were significantly associated with adolescents' ever and current smoking behaviours, but mothers' smoking was only associated with adolescents' current smoking behaviours. Friends' smoking was strongly associated with being a smoker. While there was an interaction between friends' smoking and the presence of smoking teachers on current smoking behaviours indicating the effect of the presence of smoking teachers was increased when friends did not smoke. Discussion The results suggest that teachers smoking on school may increase the likelihood of being a current smoker as their friends do not smoke. Family and friends smoking are associated with adolescent smoking. Conclusion The Taiwanese government has regulated a comprehensive smoking ban in schools to prohibit both student and staff smoking on all school premises. To achieve this, schools should make tobacco control communication efforts. Nurses could address the combined influence of family and friends as well as the effect of school smoking restrictions to help prevent adolescents from smoking. [ABSTRACT FROM AUTHOR]

Aim To investigate factors affecting smoking cessation in male smokers with coronary artery disease. Design A descriptive, correlation, cross-sectional study was conducted. Methods Data were collected using a questionnaire constructed by a literature review of research on smoking cessation in male smokers including demographics and smoking background, as well as psychological, interpersonal and environmental factors. A total of 130 male patients with coronary artery disease were recruited from the cardiac clinic at a regional hospital in Taiwan from August to December 2008. The response rate was 93% ( n = 121). Descriptive statistics, chi-square, t-tests and logistic regression analysis were conducted. Results During the survey, 64.5% of the respondents reported that they had stopped smoking after a coronary event. Five factors were significantly associated with smoking cessation after diagnosis of coronary artery disease: age, the severity of heart diagnoses, antismoking norms (perceived that smoking was against the social norms), nicotine dependence level, and contrary views of smoking (perceived negative expectancy of smoking). Multivariate analysis revealed antismoking norms to be the most important predictor ( AOR = 4.27; P < .05) after adjusting age. Conclusion The study highlights the need to develop smoking cessation interventions that specifically counsel patients with coronary artery disease about these information, such as the disease risk and development, health consequences of smoking, and dependence therapy. Additionally, government support for tobacco control programmes in hospitals and elsewhere is designed to have a beneficial effect on patients' smoking behaviours primarily by increasing antismoking norms. [ABSTRACT FROM AUTHOR]

Aim Ry R2 mutations are associated with catecholaminergic polymorphic tachycardia, a condition characterized by ventricular and atrial arrhythmias. The present experiments investigate the atrial electrophysiology of homozygotic murine Ry R2- P2328 S ( Ry R2S/S) hearts for ectopic triggering events and for conduction abnormalities that might provide a re-entrant substrate. Methods Electrocardiograph recordings were made from regularly stimulated Ry R2S/S and wild type ( WT) hearts, perfused using a novel modified Langendorff preparation. This permitted the simultaneous use of either floating intracellular microelectrodes to measure action potential ( AP) parameters, or a multielectrode array to measure epicardial conduction velocity ( CV). Results Ry R2S/S showed frequent sustained tachyarrhythmias, delayed afterdepolarizations and ectopic APs, increased interatrial conduction delays, reduced epicardial CVs and reduced maximum rates of AP depolarization ((d V/d t)max), despite similar effective refractory periods, AP durations and AP amplitudes. Effective interatrial CVs and (d V/d t)max values of APs following ectopic ( S2) stimulation were lower than those of APs following regular stimulation and decreased with shortening S1 S2 intervals. However, although Ry R2 S/S atria showed arrhythmias over a wider range of S1 S2 intervals, the interatrial CV and (d V/d t)max of S2 APs provoking such arrhythmias were similar in Ry R2 S/S and WT. Conclusions These results suggest that abnormal intracellular Ca2+ homoeostasis produces both arrhythmic triggers and a slow-conducting arrhythmic substrate in Ry R2S/S atria. A similar mechanism might also contribute to arrhythmogenesis in other conditions, associated with diastolic Ca2+release, such as atrial fibrillation. [ABSTRACT FROM AUTHOR]

Background Smoking tobacco is a global health problem, and this study highlights adolescent smoking in Taiwan. Smoking was completely banned on campuses under the Tobacco Hazards Prevention Act and School Health Regulations. Few have investigated the association between personnel smoking/school smoking policies and adolescent smoking in Taiwan. The smoking rate has gradually increased for senior high school students in Taiwan from 10.7% in 1994 to 14.7% in 2011. Aim This study examined the influence of family and friends' smoking on the association between the presence of teachers smoking and each stage of adolescents' smoking behaviour. Methods A cross-sectional survey was conducted in nine high schools ( n = 921). Logistic regression analysis was used to examine the association between smoking stage, father smoking, mother smoking, sibling smoking, friends smoking and the presence of smoking teachers. Results After adjusting for gender, school type and grade, fathers', siblings' and friends' smoking were significantly associated with adolescents' ever and current smoking behaviours, but mothers' smoking was only associated with adolescents' current smoking behaviours. Friends' smoking was strongly associated with being a smoker. While there was an interaction between friends' smoking and the presence of smoking teachers on current smoking behaviours indicating the effect of the presence of smoking teachers was increased when friends did not smoke. Discussion The results suggest that teachers smoking on school may increase the likelihood of being a current smoker as their friends do not smoke. Family and friends smoking are associated with adolescent smoking. Conclusion The Taiwanese government has regulated a comprehensive smoking ban in schools to prohibit both student and staff smoking on all school premises. To achieve this, schools should make tobacco control communication efforts. Nurses could address the combined influence of family and friends as well as the effect of school smoking restrictions to help prevent adolescents from smoking. [ABSTRACT FROM AUTHOR]

Aim QT interval prolongation reflecting delayed action potential ( AP) repolarization is associated with polymorphic ventricular tachycardia and early after depolarizations potentially initiating extrasystolic APs if of sufficient amplitude. The current experiments explored contributions of altered re-excitation thresholds for, and conduction of, such extrasystolic APs to arrhythmogenesis in Langendorff-perfused, normokalaemic, control wild-type hearts and two experimental groups modelling long QT ( LQT). The two LQT groups consisted of genetically modified, Scn5a+/Δ KPQ and hypokalaemic wild-type murine hearts. Methods Hearts were paced from their right ventricles and monophasic AP electrode recordings obtained from their left ventricular epicardia, with recording and pacing electrodes separated by 1 cm. An adaptive programmed electrical stimulation protocol applied pacing ( S1) stimulus trains followed by premature ( S2) extrastimuli whose amplitudes were progressively increased with progressive decrements in S1 S2 interval to maintain stimulus capture. Such protocols culminated in either arrhythmic or refractory endpoints. Results Arrhythmic outcomes were associated with (1) lower conduction velocities in their initiating extrasystolic APs than refractory outcomes and (2) higher conduction velocities in the LQT groups than in controls. Furthermore, (3) the endpoints were reached at longer S1S2 coupling intervals and with smaller stimulus amplitudes in the LQT groups compared with controls. This was despite (4) similar relationships between conduction velocity and S1S2 coupling interval and between re-excitation thresholds and S1S2 coupling interval in all three experimental groups. Conclusions Arrhythmias induced by extrasystolic APs in the LQT groups thus occur under conditions of higher conduction velocity and greater sensitivity to extrastimuli than in controls. [ABSTRACT FROM AUTHOR]

Background and purpose: The association between glucocerebrosidase ( GBA) mutations and Parkinson's disease (PD) is attracting increased attention worldwide. In patients of Chinese ethnicity, other than the common L444P mutation, a few mutations have been reported. However, the contribution of GBA to PD can be answered only by a thorough investigation of its mutations in a unique large population. Methods: We enrolled 1747 participants: 967 PD patients and 780 healthy individuals. We screened entire GBA coding regions and exon-intron boundaries in 30 randomly chosen PD patients, followed by testing five variants (L444P, D409H, R120W, L174P, and Q497R) in all participants. The G2385R and R1628P in LRRK2 had been previously studied in almost all participants. Results: In total, 36 patients (3.72%) carried a heterozygous mutant GBA allele (27 L444P, 7 Rec NciI, and 2 D409H). Only two controls (0.26%) carried heterozygous GBA mutation (1 L444P and 1 Rec NciI). In PD group, the mean age at onset in carriers was younger than in non-carriers. The difference in percentage of mutation frequencies between patients and controls was highly significant for the L444P mutation ( P < 0.0001). One L444P carrier was also associated with LRRK2 G2385R variant, but no atypical Parkinsonism was observed. Conclusions: The present study ascertains that L444P mutation in GBA gene may contribute to an earlier onset of development of PD in Han/Chinese population. Following LRRK2 variants, GBA is the second most frequent mutations indicated for sporadic PD development in the Han/Chinese population. These GBA carriers are associated with an earlier onset of Parkinsonism. [ABSTRACT FROM AUTHOR]

Scrub typhus and tick-borne spotted fever group (SFG) rickettsioses are transmitted by chiggers (larval trombiculid mites) and hard ticks, respectively. We assessed exposure to these disease vectors by extensively sampling both chiggers and ticks and their small mammal hosts in eastern Taiwan during 2007 and 2008. The striped field mouse Apodemus agrarius Pallas (Rodentia: Muridae) was the most common of the small mammals (36.1% of 1393 captures) and presented the highest rate of infestation with both chiggers (47.8% of 110 760) and ticks (78.1% of 1431). Leptotrombidium imphalum Vercammen-Grandjean & Langston (Trombidiformes: Trombiculidae) and immature Rhipicephalus haemaphysaloides Supino (Ixodida: Ixodidae) were the most abundant chiggers (84.5%) and ticks (>99%) identified, respectively. Immunofluorescent antibody assay revealed high seropositive rates of rodents against Orientia tsutsugamushi Hyashi (Rickettsiales: Rickettsiaceae), the aetiological agent of scrub typhus (70.0% of 437 rodents), and tick-borne SFG rickettsiae (91.9% of 418 rodents). The current study represents a first step towards elucidating the potential hosts and vectors in the enzootic transmission of O. tsutsugamushi and tick-borne SFG rickettsiae in Taiwan. Further studies should focus on characterizing pathogens in L. imphalum and R. haemaphysaloides, as well as the proclivity of both vectors to humans. Uncovering the main hosts of adult ticks is also critical for the prevention of SFG rickettsial infections. [ABSTRACT FROM AUTHOR]

Aim: Clinical observations suggest that alternans in action potential (AP) characteristics presages breakdown of normal ordered cardiac electrical activity culminating in ventricular arrhythmogenesis. We compared such temporal nonuniformities in monophasic action potential (MAP) waveforms in left (LV) and right ventricular (RV) epicardia and endocardia of Langendorff-perfused murine wild-type (WT), and Scn5a+/− hearts modelling Brugada syndrome (BrS) for the first time. Methods: A dynamic pacing protocol imposed successively incremented steady pacing rates between 5.5 and 33 Hz. A signal analysis algorithm detected sequences of >10 beats showing alternans. Results were compared before and following the introduction of flecainide (10 μm) and quinidine (5 μm) known to exert pro- and anti-arrhythmic effects in BrS. Results: Sustained and transient amplitude and duration alternans were both frequently followed by ventricular ectopic beats and ventricular tachycardia or fibrillation. Diastolic intervals (DIs) that coincided with onsets of transient (tr) or sustained (ss) alternans in MAP duration (DI*) and amplitude (DI′) were determined. Kruskal–Wallis tests followed by Bonferroni-corrected Mann–Whitney U-tests were applied to these DI results sorted by recording site, pharmacological conditions or experimental populations. WT hearts showed no significant heterogeneities in any DI. Untreated Scn5a+/− hearts showed earlier onsets of transient but not sustained duration alternans in LV endocardium compared with RV endocardium or LV epicardium. Flecainide administration caused earlier onsets of both transient and sustained duration alternans selectively in the RV epicardium in the Scn5a+/− hearts. Conclusion: These findings in a genetic model thus implicate RV epicardial changes in the arrhythmogenicity produced by flecainide challenge in previously asymptomatic clinical BrS. [ABSTRACT FROM AUTHOR]

Aim: To investigate the interacting effects of age and sex on electrocardiographic (ECG) features of Scn5a +/− mice modelling Brugada syndrome. Methods: Recordings were performed on anaesthetized wild-type (WT) and Scn5a +/− mice and differences attributable to these risk factors statistically stratified. Results: Scn5a +/− exerted sex-dependent effects upon sino-atrial function that only became apparent with age. RR intervals were greater in old male than in old female Scn5a +/−. Atrio-ventricular (AV) conduction was slower in young female mice, whether WT and Scn5a +/−, than the corresponding young male WT and Scn5a +/− . However, PR intervals lengthened with age in male but not in female Scn5a +/− giving the greatest PR intervals in old male Scn5a +/− compared with either old male WT or young male Scn5a +/− mice. In contrast, PR intervals were similar in old female Scn5a +/− and in old female WT. QTc was prolonged in Scn5a+/ − compared with WT, and female Scn5a+/ − compared with female WT. Age-dependent alterations in durations of ventricular repolarization relative to WT affected male but not female Scn5a +/− . Thus, T-wave durations were greater in old male Scn5a +/− compared with old male WT, but indistinguishable between old female Scn5a +/− and old female WT. Finally, analysis for combined interactions of genotype, age and sex demonstrated no effects on P wave and QRS durations and QTc intervals. Conclusion: We demonstrate for the first time that age, sex and genotype exert both independent and interacting ECG effects. The latter suggest alterations in cardiac pacemaker function, atrio-ventricular conduction and ventricular repolarization greatest in ageing male Scn5a +/− . [ABSTRACT FROM AUTHOR]

Aim: To investigate the effect of increases in extracellular Ca2+ entry produced by the L-type Ca2+ channel agonist FPL-64176 (FPL) upon acute atrial arrhythmogenesis in intact Langendorff-perfused mouse hearts and its dependence upon diastolic Ca2+ release from sarcoplasmic reticular Ca2+ stores. Methods: Confocal microscope studies of Fluo-3 fluorescence in isolated atrial myocytes were performed in parallel with electrophysiological examination of Langendorff-perfused mouse hearts. Results: Atrial myocytes stimulated at 1 Hz and exposed to FPL (0.1 μm) initially showed (<10 min) frequent, often multiple, diastolic peaks following the evoked Ca2+ transients whose amplitudes remained close to control values. With continued pacing (>10 min) this reverted to a regular pattern of evoked transients with increased amplitudes but in which diastolic peaks were absent. Higher FPL concentrations (1.0 μm) produced sustained and irregular patterns of cytosolic Ca2+ activity, independent of pacing. Nifedipine (0.5 μm), and caffeine (1.0 mm) and cyclopiazonic acid (CPA) (0.15 μm) pre-treatments respectively produced immediate and gradual reductions in the F/ F0 peaks. Such nifedipine and caffeine, or CPA pre-treatments, abolished, or reduced, the effects of 0.1 and 1.0 μm FPL on cytosolic Ca2+ signals. FPL (1.0 μm) increased the incidence of atrial tachycardia and fibrillation in intact Langendorff-perfused hearts without altering atrial effective refractory periods. These effects were inhibited by nifedipine and caffeine, and reduced by CPA. Conclusion: Enhanced extracellular Ca2+ entry exerts acute atrial arrhythmogenic effects that is nevertheless dependent upon diastolic Ca2+ release. These findings complement reports that associate established, chronic, atrial arrhythmogenesis with decreased overall inward Ca2+ current. [ABSTRACT FROM AUTHOR]

Aim: In contrast to extensive reports on the roles of Nav1.5 α-subunits, there have been few studies associating the β-subunits with cardiac arrhythmogenesis. We investigated the sino-atrial and conduction properties in the hearts of Scn3b−/− mice. Methods: The following properties were compared in the hearts of wild-type (WT) and Scn3b−/− mice: (1) mRNA expression levels of Scn3b, Scn1b and Scn5a in atrial tissue. (2) Expression of the β3 protein in isolated cardiac myocytes. (3) Electrocardiographic recordings in intact anaesthetized preparations. (4) Bipolar electrogram recordings from the atria of spontaneously beating and electrically stimulated Langendorff-perfused hearts. Results: Scn3b mRNA was expressed in the atria of WT but not Scn3b −/− hearts. This was in contrast to similar expression levels of Scn1b and Scn5a mRNA. Immunofluorescence experiments confirmed that the β3 protein was expressed in WT and absent in Scn3b−/− cardiac myocytes. Lead I electrocardiograms from Scn3b −/− mice showed slower heart rates, longer P wave durations and prolonged PR intervals than WT hearts. Spontaneously beating Langendorff-perfused Scn3b −/− hearts demonstrated both abnormal atrial electrophysiological properties and evidence of partial or complete dissociation of atrial and ventricular activity. Atrial burst pacing protocols induced atrial tachycardia and fibrillation in all Scn3b −/− but hardly any WT hearts. Scn3b −/− hearts also demonstrated significantly longer sinus node recovery times than WT hearts. Conclusion: These findings demonstrate, for the first time, that a deficiency in Scn3b results in significant atrial electrophysiological and intracardiac conduction abnormalities, complementing the changes in ventricular electrophysiology reported on an earlier occasion. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Depolarization vs. repolarization: what is the mechanism of ventricular arrhythmogenesis underlying sodium channel haploinsufficiency in mouse hearts?" by K. Jeevaratnam and colleagues that was published in a previous issue is presented.

Aim: The multifunctional signal molecule calmodulin kinase II (CaMKII) has been associated with cardiac arrhythmogenesis under conditions where its activity is chronically elevated. Recent studies report that its activity is also acutely elevated during acidosis. We test a hypothesis implicating CaMKII in the arrhythmogenesis accompanying metabolic acidification. Methods: We obtained monophasic action potential recordings from Langendorff-perfused whole heart preparations and single cell action potentials (AP) using whole-cell patch-clamped ventricular myocytes. Spontaneous sarcoplasmic reticular (SR) Ca2+release events during metabolic acidification were investigated using confocal microscope imaging of Fluo-4-loaded ventricular myocytes. Results: In Langendorff-perfused murine hearts, introduction of lactic acid into the Krebs-Henseleit perfusate resulted in abnormal electrical activity and ventricular tachycardia. The CaMKII inhibitor, KN-93 (2 μm), reversibly suppressed this spontaneous arrhythmogenesis during intrinsic rhythm and regular 8 Hz pacing. However, it failed to suppress arrhythmia evoked by programmed electrical stimulation. These findings paralleled a CaMKII-independent reduction in the transmural repolarization gradients during acidosis, which previously has been associated with the re-entrant substrate under other conditions. Similar acidification produced spontaneous AP firing and membrane potential oscillations in patch-clamped isolated ventricular myocytes when pipette solutions permitted cytosolic Ca2+ to increase following acidification. However, these were abolished by both KN-93 and use of pipette solutions that held cytosolic Ca2+ constant during acidosis. Acidosis also induced spontaneous Ca2+ waves in isolated intact Fluo-4-loaded myocytes studied using confocal microscopy that were abolished by KN-93. Conclusion: These findings together implicate CaMKII-dependent SR Ca2+ waves in spontaneous arrhythmic events during metabolic acidification. [ABSTRACT FROM AUTHOR]

Aims: We previously reported that the blood-brain barrier (BBB) function was impaired in vessels in the hippocampus in 3-month-old stroke-prone spontaneously hypertensive rats (SHRSP). In this study, we examined gene and protein expressions of P-glycoprotein, a representative efflux transporter of cerebral vessels, in the BBB-damaged hippocampal vessels of SHRSP and in the vessels of Wistar Kyoto (WKY) rats as controls, to clarify roles of the efflux transporter in the BBB-damaged vessels. Methods: The expression of P-glycoprotein in hippocampal and cortical samples was examined by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunoelectron microscopic techniques. Results: Real-time RT-PCR and Western blotting analyses revealed that the gene and protein expressions of P-glycoprotein were increased in the hippocampal samples of 3-month-old SHRSP compared with hippocampal samples of 3-month-old WKY rats or with cortical samples of SHRSP. The gene expression of P-glycoprotein was also increased in the hippocampal samples of 4-week-old SHRSP. Immunoelectron microscopic examination revealed that immunosignals of P-glycoprotein were seen in the luminal and ab-luminal cytoplasmic membranes of endothelial cells and the basal lamina, that the labelling density of P-glycoprotein in the vessel wall was higher in the hippocampus of 3-month-old SHRSP than in other groups and that the immunosignals of P-glycoprotein were occasionally co-located with those of albumin. Conclusions: These findings indicate that the expression of P-glycoprotein is increased in BBB-damaged hippocampal vessels in hypertensive SHRSP compared with those in WKY rats. [ABSTRACT FROM AUTHOR]

Aim: We compared the clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in domain II (S5-S6) of human, hNav1.5, cardiac Na+ channels. Methods: Full clinical evaluation of pedigree members through three generations of a Chinese family combined with SCN5A sequencing from genomic DNA was compared with patch and voltage-clamp results from two independent expression systems. Results: The four mutation carriers showed bradycardia, and slowed sino-atrial, atrioventricular and intraventricular conduction. Two also showed sick sinus syndrome; two had ST elevation in leads V1 and V2. Unlike WT-hNav1.5, whole-cell patch-clamped HEK293 cells expressing R878C-hNav1.5 showed no detectable Na+ currents ( iNa), even with substitution of a similarly charged lysine residue. Voltage-clamped Xenopus oocytes injected with either 0.04 or 1.5 μg μL−1 R878C-hNav1.5 cRNA similarly showed no iNa, yet WT-hNav1.5 cRNA diluted to 0.0004–0.0008 ng μL−1resulted in expression of detectable iNa. iNa was simply determined by the amount of injected WT-hNav1.5: doubling the dose of WT-hNav1.5 cRNA doubled iNa. iNa amplitudes and activation and inactivation characteristics were similar irrespective of whether WT-hNav1.5 cRNA was given alone or combined with equal doses of R878C-hNav1.5 cRNA therefore excluding dominant negative phenotypic effects. Na+ channel function in HEK293 cells transfected with R878C-hNav1.5 was not restored by exposure to mexiletine (200 μm) and lidocaine (100 μm). Fluorescence confocal microscopy using E3-Nav1.5 antibody demonstrated persistent membrane expression of both WT and R878C-hNav1.5. Modelling studies confirmed that such iNa reductions reproduced the SSS phenotype. Conclusion: Clinical consequences of the novel R878C mutation correlate with results of physiological studies. [ABSTRACT FROM AUTHOR]

Aim: To explore the physiological consequences of the ryanodine receptor (RyR2)- P2328S mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). Methods: We generated heterozygotic ( RyR2 p/s) and homozygotic ( RyR2 s/s) transgenic mice and studied Ca2+ signals from regularly stimulated, Fluo-3-loaded, cardiac myocytes. Results were compared with monophasic action potentials (MAPs) in Langendorff-perfused hearts under both regular and programmed electrical stimulation (PES). Results: Evoked Ca2+ transients from wild-type ( WT), heterozygote ( RyR2 p/s) and homozygote ( RyR2 s/s) myocytes had indistinguishable peak amplitudes with RyR2 s/s showing subsidiary events. Adding 100 nm isoproterenol produced both ectopic peaks and subsidiary events in WT but not RyR2 p/s and ectopic peaks and reduced amplitudes of evoked peaks in RyR2 s/s. Regularly stimulated WT, RyR2 p/s and RyR2 s/s hearts showed indistinguishable MAP durations and refractory periods. RyR2 p/s hearts showed non-sustained ventricular tachycardias (nsVTs) only with PES. Both nsVTs and sustained VTs (sVTs) occurred with regular stimuli and PES with isoproterenol treatment. RyR2 s/s hearts showed higher incidences of nsVTs before but mainly sVTs after introduction of isoproterenol with both regular stimuli and PES, particularly at higher pacing frequencies. Additionally, intrinsically beating RyR2 s/s showed extrasystolic events often followed by spontaneous sVT. Conclusion: The RyR2-P2328S mutation results in marked alterations in cellular Ca2+ homeostasis and arrhythmogenic properties resembling CPVT with greater effects in the homozygote than the heterozygote demonstrating an important gene dosage effect. [ABSTRACT FROM AUTHOR]

Aim: We explored the anti-arrhythmic efficacy of K+ channel activation in the hypokalaemic murine heart using NS1643 and nicorandil, compounds which augment IKr and IKATP respectively. Methods: Left ventricular epicardial and endocardial monophasic action potentials were compared in normokalaemic and hypokalaemic preparations in the absence and presence of NS1643 (30 μm) and nicorandil (20 μm). Results: Spontaneously beating hypokalaemic hearts (3 mm K+) all elicited early afterdepolarizations (EADs) and episodes of ventricular tachycardia (VT). Perfusion with NS1643 and nicorandil suppressed EADs and VT in 7 of 13 and five of six hypokalaemic hearts. Provoked arrhythmia studies using programmed electrical stimulation induced VT in all hypokalaemic hearts, but failed to do so in 7 of 13 and five of six hearts perfused with NS1643 and nicorandil respectively. These anti-arrhythmic effects were accompanied by reductions in action potential duration at 90% repolarization (APD90) and changes in the transmural gradient of repolarization, reflected in ΔAPD90. NS1643 and nicorandil reduced epicardial APD90 from 68.3 ± 1.1 to 56.5 ± 4.1 and 51.5 ± 1.5 ms, respectively, but preserved endocardial APD90 in hypokalaemic hearts. NS1643 and nicorandil thus restored ΔAPD90 from −9.6 ± 4.3 ms under baseline hypokalaemic conditions to 3.9 ± 4.1 and 9.9 ± 2.1 ms, respectively, close to normokalaemic values. Conclusion: These findings demonstrate, for the first time, the anti-arrhythmic efficacy of K+ channel activation in the setting of hypokalaemia. NS1643 and nicorandil are anti-arrhythmic through the suppression of EADs, reductions in APD90 and restorations of ΔAPD90. [ABSTRACT FROM AUTHOR]

Aim: To perform an empirical, pharmacological, separation of early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in a genetically modified mouse heart modelling human long QT syndrome (LQT) 3. Methods: Left ventricular endocardial and epicardial monophasic action potentials and arrhythmogenic tendency were compared in isolated wild type (WT) and Scn5a+/Δ hearts perfused with 0.1 and 1 μm propranolol and paced from the right ventricular epicardium. Results: All spontaneously beating bradycardic Scn5a+/Δ hearts displayed EADs, triggered beats and ventricular tachycardia (VT; n = 7), events never seen in WT hearts ( n = 5). Perfusion with 0.1 and 1 μm propranolol suppressed all EADs, triggered beats and episodes of VT. In contrast, triggering of VT persisted following programmed electrical stimulation in 6 of 12 (50%), one of eight (12.5%), but six of eight (75%) Scn5a+/Δ hearts perfused with 0, 0.1 and 1 μm propranolol respectively in parallel with corresponding alterations in repolarization gradients, reflected in action potential duration (ΔAPD90) values. Thus 0.1 μm propranolol reduced epicardial but not endocardial APD90 from 54.7 ± 1.6 to 44.0 ± 2.0 ms, restoring ΔAPD90 from −3.8 ± 1.6 to 3.5 ± 2.5 ms (all n = 5), close to WT values. However, 1 μm propranolol increased epicardial APD90 to 72.5 ± 1.2 ms and decreased endocardial APD90 from 50.9 ± 1.0 to 24.5 ± 0.3 ms, increasing ΔAPD90 to −48.0 ± 1.2 ms. Conclusion: These findings empirically implicate EADs in potentially initiating spontaneous arrhythmogenic phenomena and transmural repolarization gradients in the re-entrant substrate that would sustain such activity when provoked by extrasystolic activity in murine hearts modelling human LQT3 syndrome. [ABSTRACT FROM AUTHOR]

Sudden cardiac death stemming from ventricular arrhythmogenesis is one of the major causes of mortality in the developed world. Congenital and acquired forms of long QT syndrome (LQTS) are in turn associated with life threatening arrhythmias. Over the past decade our understanding of arrhythmogenic mechanisms in the setting of these diseases has increased greatly due to the creation of a number of animal models. Of these, the genetically amenable mouse has proved to be a particularly powerful tool. This review summarizes the congenital and acquired LQTS and describes the various mouse models that have been created to further probe arrhythmogenic mechanisms. [ABSTRACT FROM AUTHOR]

Aims: We previously reported that the blood–brain barrier (BBB) function was deteriorated in vessels located along hippocampal fissures in stroke-prone spontaneously hypertensive rats (SHRSP). In this study, we examined changes of gene expression in the BBB-damaged vessels of SHRSP. Methods: Vascular samples were microdissected from the hippocampi of SHRSP and Wistar-Kyoto (WKY) as a control and the difference in gene expression between the BBB-damaged vessels in SHRSP and vessels without BBB damage in WKY was examined by a microarray. The differences in gene and protein expression between brain tissues in the two strains of rats were examined using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. Results: The microarray assay revealed that the ratio of osteopontin gene expression in the vascular tissue of the hippocampi of SHRSP to that of WKY was the highest among 8435 genes. Real-time RT-PCR analysis revealed that the gene expression of osteopontin was significantly increased in the hippocampal samples of SHRSP compared with that in the hippocampal samples of WKY rats or with that in the cortical samples of SHRSP. Immunohistochemical and Western blot analyses showed that the osteopontin protein expression was seen in perivascular ED1-positive macrophages/microglial cells located around hippocampal fissures and significantly increased in the hippocampi of SHRSP compared with that of WKY. Conclusions: These findings indicate that the expression of osteopontin is increased in BBB-damaged vessels in hypertensive SHRSP compared with that in vessels without BBB impairment in WKY rats, suggesting a role for osteopontin in BBB function. [ABSTRACT FROM AUTHOR]

Aims: We resolved roles for early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in Langendorff-perfused hypokalaemic murine hearts paced from the right ventricular epicardium. Methods: Left ventricular epicardial and endocardial monophasic action potentials (MAPs) and arrhythmogenic tendency were compared in the presence and absence of the L-type Ca2+ channel blocker nifedipine (10 nm–1 μm) and the calmodulin kinase type II inhibitor KN-93 (2 μm). Results: All the hypokalaemic hearts studied showed prolonged epicardial and endocardial MAPs, decreased epicardial-endocardial APD90 difference, EADs, triggered beats and ventricular tachycardia (VT) ( n = 6). In all spontaneously beating hearts, 100 (but not 10) nm nifedipine reduced both the incidence of EADs and triggered beats from 66.9 ± 15.7% to 28.3 ± 8.7% and episodes of VT from 10.8 ± 6.3% to 1.2 ± 0.7% of MAPs ( n = 6 hearts, P < 0.05); 1 μm nifedipine abolished all these phenomena ( n = 6). In contrast programmed electrical stimulation (PES) still triggered VT in six of six hearts with 0, 10 and 100 nm but not 1 μm nifedipine. 1 μm nifedipine selectively reduced epicardial (from 66.1 ± 3.4 to 46.2 ± 2.5 ms) but not endocardial APD90, thereby restoring ΔAPD90 from −5.9 ± 2.5 to 15.5 ± 3.2 ms, close to normokalaemic values. KN-93 similarly reduced EADs, triggered beats and VT in spontaneously beating hearts to 29.6 ± 8.9% and 1.7 ± 1.1% respectively ( n = 6) yet permitted PES-induced VT ( n = 6), in the presence of a persistently negative ΔAPD90. Conclusions: These findings empirically implicate both EADs and triggered beats alongside arrhythmogenic substrate of ΔAPD90 in VT pathogenesis at the whole heart level. [ABSTRACT FROM AUTHOR]

Several large-scale epidemiological and intervention studies strongly indicate that postchallenge hyperglycaemia is the main factor associated with increasing the risk of morbidity and mortality in type 2 diabetes. However, the mechanisms that increase the risk of cardiovascular disease remain unclear. We aimed to study the relationship between postchallenge hyperglycaemia and arterial stiffness. We recruited 40 healthy subjects from a physical examination in 2005. Cardio-ankle vascular index (CAVI) was automatically calculated by VaSera VS-1000. For the reliability study, we performed the baseline study in the first 20 subjects who were returned to receive repeated measurements of CAVI 2 weeks later. The determinants of mean CAVI at different timings of oral glucose tolerance test (OGTT) study were analysed by constructing multivariate linear regression models. In reliability test, the inter-observer correlation coefficient was 0.82 for right CAVI, 0.87 for left CAVI and 0.85 for mean CAVI. Age, systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose levels at 60 min (Glu60) and glucose area under the curve of OGTT (GluAUC) are found to be significantly and positively correlated to right CAVI, left CAVI and mean CAVI (p < 0.05). After adjustment for age, gender and SBP, Glu60 and GluAUC are still independent determinants of CAVI. In subjects without clinical diagnosis of type 2 diabetes, postchallenge hyperglycaemic spike is highly associated with CAVI, a good parameter of aortic stiffness, independent of age, gender and blood pressure. [ABSTRACT FROM AUTHOR]

Aim: Hypokalaemia is associated with a lethal form of ventricular tachycardia (VT), torsade de pointes, through pathophysiological mechanisms requiring clarification. Methods: Left ventricular endocardial and epicardial monophasic action potentials were compared in isolated mouse hearts paced from the right ventricular epicardium perfused with hypokalaemic (3 and 4 mm [K+]o) solutions. Corresponding K+ currents were compared in whole-cell patch-clamped epicardial and endocardial myocytes. Results: Hypokalaemia prolonged epicardial action potential durations (APD) from mean APD90s of 37.2 ± 1.7 ms ( n = 7) to 58.4 ± 4.1 ms ( n =7) and 66.7 ± 2.1 ms ( n = 11) at 5.2, 4 and 3 mm [K+]o respectively. Endocardial APD90s correspondingly increased from 51.6 ± 1.9 ms ( n = 7) to 62.8 ± 2.8 ms ( n = 7) and 62.9 ± 5.9 ms ( n = 11) giving reductions in endocardial–epicardial differences, ΔAPD90, from 14.4 ± 2.6 to 4.4 ± 5.0 and −3.4 ± 6.0 ms respectively. Early afterdepolarizations (EADs) occurred in epicardia in three of seven spontaneously beating hearts at 4 mm [K+]o with triggered beats followed by episodes of non-sustained VT in nine of 11 preparations at 3 mm. Programmed electrical stimulation never induced arrhythmic events in preparations perfused with normokalemic solutions yet induced VT in two of seven and nine of 11 preparations at 4 and 3 mm [K+]o respectively. Early outward K+ current correspondingly fell from 73.46 ± 8.45 to 61.16±6.14 pA/pF in isolated epicardial but not endocardial myocytes ( n = 9) (3 mm [K+]o). Conclusions: Hypokalaemic mouse hearts recapitulate the clinical arrhythmogenic phenotype, demonstrating EADs and triggered beats that might initiate VT on the one hand and reduced transmural dispersion of repolarization reflected in ΔAPD90 suggesting arrhythmogenic substrate on the other. [ABSTRACT FROM AUTHOR]

Background: Platonin, a cyanine photosensitizing dye, is a potent immunomodulator that suppresses acute inflammation. Platonin not only inhibits interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α production but also improves circulatory failure in septic rats. In addition, platonin reduces plasma nitric oxide (NO) formation during sepsis. However, the effects of platonin on inducible NO synthase (iNOS) and cationic amino-acid transporter (including CAT-2, CAT-2 A, and CAT-2B) expressions during sepsis remain uninvestigated. Methods: Five groups of confluent murine macrophages (RAW264.7 cells) were randomly allocated to receive a 1-h pretreatment of one of five doses of platonin (0.1 µM, 1 µM, 10 µM, 100 µM, or 1000 µM) followed by lipopolysaccharide (LPS; 100 ng ml−1). For negative, positive, and platonin control, three other groups of cell cultures were randomly allocated to receive phosphate-buffered saline, LPS, or platonin (1000 µM). The cultures were harvested after exposing them to LPS for 18 h or a comparable duration in those groups without LPS. NO production, L-arginine transport, and expression of the relevant enzymes were then evaluated. Results: Platonin significantly attenuated LPS-induced up-regulation of iNOS expression and NO production in stimulated murine macrophages in a dose-dependent manner. Platonin also significantly inhibited up-regulation of CAT-2 and CAT-2B expression as well as L-arginine transport in LPS-stimulated murine macrophages in a dose-dependent manner. In contrast, CAT-2 A expression in murine macrophages was not affected by LPS and/or platonin. Conclusions: Platonin attenuates NO production and L-arginine transport in LPS-stimulated murine macrophages possibly through inhibiting iNOS, CAT-2, and CAT-2B expression. [ABSTRACT FROM AUTHOR]

Background: Hyperbaric oxygen (HBO) attenuates lipopolysaccharide (LPS)-induced acute lung injury. This beneficial effect of HBO involves inhibition of inducible nitric oxide synthase (iNOS) expression and subsequent nitric oxide (NO) biosynthesis. We sought to investigate the role of heme oxygenase-1 (HO-1) on this HBO inhibition of iNOS induction and acute lung injury in septic rat lungs.Methods: Before the experiment, 72 rats were randomly allocated to receive HBO or air treatment. With or without HBO pre-treatment, the rats were further divided into the following subgroups (n = 6): (i) LPS injection, (ii) normal saline (N/S) injection, (iii) hemin (a HO-1 inducer) plus LPS, (iv) hemin alone, (v) tin protoporphyrin (SnPP; a HO-1 inhibitor) plus LPS, and (vi) SnPP alone. All rats were maintained for 6 h and then sacrificed with a high-dose pentobarbital injection. Lung injuries and relevant enzymes expression were thus assayed.Results: Histological analysis, PMNs/alveoli ratio, and wet/dry weight ratio measurements demonstrated that LPS caused significant lung injury and HBO and/or hemin significantly attenuated this LPS-induced lung injury. Increased pulmonary iNOS expression and NO production were associated with lung injury. Induction of HO-1, by HBO and/or hemin, significantly attenuated this LPS-induced iNOS expression and acute lung injury. SnPP, on the contrary, offset the effects of HBO and worsened the LPS-induced lung injury.Conclusions: HBO may act through inhibiting pulmonary iNOS expression to attenuate LPS-induced acute lung injury in septic rats. Furthermore, this HBO attenuation of iNOS expression involves HO-1 induction. [ABSTRACT FROM AUTHOR]