In Vitro Surfactant and Perfluorocarbon Aerosol Deposition in a Neonatal Physical Model of the Upper Conducting Airways

Objective

Aerosol delivery holds potential to release surfactant or perfluorocarbon (PFC) to the lungs of neonates with respiratory distress syndrome with minimal airway manipulation. Nevertheless, lung deposition in neonates tends to be very low due to extremely low lung volumes, narrow airways and high respiratory rates. In the present study, the feasibility of enhancing lung deposition by intracorporeal delivery of aerosols was investigated using a physical model of neonatal conducting airways.

Methods

The main characteristics of the surfactant and PFC aerosols produced by a nebulization system, including the distal air pressure and air flow rate, liquid flow rate and mass median aerodynamic diameter (MMAD), were measured at different driving pressures (4–7 bar). Then, a three-dimensional model of the upper conducting airways of a neonate was manufactured by rapid prototyping and a deposition study was conducted.

Results

The nebulization system produced relatively large amounts of aerosol ranging between 0.3±0.0 ml/min for surfactant at a driving pressure of 4 bar, and 2.0±0.1 ml/min for distilled water (H₂Od) at 6 bar, with MMADs between 2.61±0.1 µm for PFD at 7 bar and 10.18±0.4 µm for FC-75 at 6 bar. The deposition study showed that for surfactant and H₂Od aerosols, the highest percentage of the aerosolized mass (∼65%) was collected beyond the third generation of branching in the airway model. The use of this delivery system in combination with continuous positive airway pressure set at 5 cmH₂O only increased total airway pressure by 1.59 cmH₂O at the highest driving pressure (7 bar).

Conclusion

This aerosol generating system has the potential to deliver relatively large amounts of surfactant and PFC beyond the third generation of branching in a neonatal airway model with minimal alteration of pre-set respiratory support.     

Relation between Airways Obstruction and CO2 Tension in Chronic Obstructive Airways Disease

The relationship between the F.E.V.₁ as an index of airways obstruction and Pco₂ as an index of hypoventilation was investigated in 13 patients with chronic obstructive airways disease. Patients who had a normal Pco₂ despite severe airways obstruction retained relatively normal sensitivity to CO₂ as assessed by their “inspiratory mechanical work rate” response to CO₂. Others showed a raised Pco₂ in the presence of lesser degrees of airways obstruction and had reduced sensitivity to CO₂.     

Assessment of Upper Airways Obstruction

An indication of obstruction to the upper airways (trachea and larynx) may be obtained by calculating the ratio of the forced expired volume in one second to the peak expiratory flow rate (FEV₁/PEFR). This index was found to be usually less than 10 in normal subjects (mean 7·3), and in patients with asthma (mean 6·9), chronic bronchitis (mean 7·7), or interstitial lung disease (mean 6·3). A study of simulated upper airways obstruction showed that this index rises as the obstruction becomes more severe. All of 18 patients with proved upper airways obstruction had FEV₁/PEFR indices greater than 10 (mean 14·0). This test can be carried out with forced expiratory manoeuvres only, and it does not require the use of complicated equipment. An FEV₁/PEFR ratio greater than 10, when upper airways obstruction is suspected, indicates that significant obstruction may be present. High values suggest that the obstruction may be severe, and that further investigations are indicated.     

Cumulative Damage Survival Models for the Randomized Complete Block Design

A continuous time discrete state cumulative damage process {X(t), t ≥ 0} is considered, based on a non‐homogeneous Poisson hit‐count process and discrete distribution of damage per hit, which can be negative binomial, Neyman type A, Polya‐Aeppli or Lagrangian Poisson. Intensity functions considered for the Poisson process comprise a flexible three‐parameter family. The survival function is S(t) = P(X(t) ≤ L) where L is fixed. Individual variation is accounted for within the construction for the initial damage distribution {P(X(0) = x) | x = 0, 1, …,}. This distribution has an essential cut‐off before x = L and the distribution of L – X(0) may be considered a tolerance distribution. A multivariate extension appropriate for the randomized complete block design is developed by constructing dependence in the initial damage distributions. Our multivariate model is applied (via maximum likelihood) to litter‐matched tumorigenesis data for rats. The litter effect accounts for 5.9 percent of the variance of the individual effect. Cumulative damage hazard functions are compared to nonparametric hazard functions and to hazard functions obtained from the PVF‐Weibull frailty model. The cumulative damage model has greater dimensionality for interpretation compared to other models, owing principally to the intensity function part of the model.     

Can Models of Soft-Sediment Community Structure Be Complete Without Parasites?

Most of the organisms that live in marine, soft-sediment environmentsare hosts for parasites. Rates of infection by micro- or macroparasitescan be quite high, but vary in space and time. Despite the prevalenceof parasites, their potential influence on soft-sediment communitiesis poorly understood. None of the conceptual models of soft-sedimentcommunity structure or dynamics published to date considersthe impact of parasitism. A variety of potential direct andindirect effects of parasites on host populations and communitiesare discussed. The greatest challenge for future research inthis area is the development of experimental methods for manipulatingthe abundance of parasites under field conditions.     

裸项栉鰕虎鱼的全人工繁殖及其胚胎发育

目的研究裸项栉鰕虎鱼全人工繁殖及胚胎发育,为该鱼的实验动物化研究奠定基础。方法对胚胎和仔稚幼鱼各个发育期的连续取样,系统地观察了裸项栉鰕虎鱼各发育期的形态变化及生长特征。结果水温25．8℃～26．5℃,裸项栉鰕虎鱼受精后约82h仔鱼开始出膜,初孵仔鱼全长1．42～1．73mm,1d开口摄食,3d卵黄囊消失,23d第一背鳍形成,鳞片出现;33d全身被鳞;初孵仔鱼经97d发育成熟,繁殖周期约为36d;雌鱼性腺成熟系数可达40％,个体相对生殖力达每克8193．5粒。结论裸项栉鰕虎鱼具有个体小、性成熟早、生殖季节长、繁殖周期短、繁殖力强等特点,可进行室内规模化人工繁殖和培育。     

The Effect of Measles on Health-Related Quality of Life: A Patient-Based Survey

Background

Measles is a highly contagious and potentially fatal illness preventable through vaccination. Outbreaks in the UK and many other European countries have been increasing over recent years, with over 3,207 laboratory-confirmed cases reported by Public Health England from January 2012 to the end of June 2013. To aid rational decision making regarding measles control versus other use of healthcare resources, it is important to measure the severity of measles in units that are comparable to other diseases. The standard metric for this in the UK is the quality-adjust life year (QALY). To our knowledge, the impact of measles on health-related quality of life (HRQoL) in terms of QALYs has not been quantified.

Methods and Findings

Individuals with confirmed measles were sent questionnaires requesting information on the short-term impact of the illness on their HRQoL using the EuroQol EQ-5D-3L questionnaire. HRQoL was reported for the day the questionnaire was received, the worst day of infection and at follow-up three weeks later. 507 questionnaires were sent to individuals with confirmed measles with 203 returned (40%). The majority of respondents were not vaccinated. The mean time off work or school was 9.6 days. The mean duration of perceived illness was 13.8 days. The mean number of QALYs lost was 0.019 (equivalent to 6.9 days). The overall burden of disease in terms of QALYs lost in England based on the total number of confirmed cases in the twelve month period from 1^st June 2012 was estimated to be 44.2 QALYs.

Conclusion

The short-term impact of measles infection on HRQoL is substantial, both at the level of the individual patient and in terms of the overall disease burden. This is the first attempt to quantify QALY-loss due to measles at a population level, and provides important parameters to guide future intervention and control measures.     

Development of Mathematical Models for the Analysis of Hepatitis Delta Virus Viral Dynamics

Background

Mathematical models have shown to be extremely helpful in understanding the dynamics of different virus diseases, including hepatitis B. Hepatitis D virus (HDV) is a satellite virus of the hepatitis B virus (HBV). In the liver, production of new HDV virions depends on the presence of HBV. There are two ways in which HDV can occur in an individual: co-infection and super-infection. Co-infection occurs when an individual is simultaneously infected by HBV and HDV, while super-infection occurs in persons with an existing chronic HBV infection.

Methodology/Principal Findings

In this work a mathematical model based on differential equations is proposed for the viral dynamics of the hepatitis D virus (HDV) across different scenarios. This model takes into consideration the knowledge of the biology of the virus and its interaction with the host. In this work we will present the results of a simulation study where two scenarios were considered, co-infection and super-infection, together with different antiviral therapies. Although, in general the predicted course of HDV infection is similar to that observed for HBV, we observe a faster increase in the number of HBV infected cells and viral load. In most tested scenarios, the number of HDV infected cells and viral load values remain below corresponding predicted values for HBV.

Conclusions/Significance

The simulation study shows that, under the most commonly used and generally accepted therapy approaches for HDV infection, such as lamivudine (LMV) or ribavirine, peggylated alpha-interferon (IFN) or a combination of both, LMV monotherapy and combination therapy of LMV and IFN were predicted to more effectively reduce the HBV and HDV viral loads in the case of super-infection scenarios when compared with the co-infection. In contrast, IFN monotherapy was found to reduce the HDV viral load more efficiently in the case of super-infection while the effect on the HBV viral load was more pronounced during co-infection. The results suggest that there is a need for development of high efficacy therapeutic approaches towards the specific inhibition of HDV replication. These approaches may additionally be directed to the reduction of the half-life of infected cells and life-span of newly produced circulating virions.     

De Novo Inference of Systems-Level Mechanistic Models of Development from Live-Imaging-Based Phenotype Analysis

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Global Flows of Development Models1

In spite of the fact that development is one of the most powerful and malleable contemporary discourses, its dissemination on a global level still needs a framework of analysis. Development entails a vast array of modelling devices of the natural and social worlds. Its dissemination is subject to the logics of dissemination of discourses and models and of their transformation into hegemonic visions of the world. The analysis of global flows of development models supposes the analysis of the dissemination of a discursive matrix, of its different components (of diverse levels of abstraction) and the different modes through which such dissemination occurs. I will explore the existence of the diffuse and concentrated modes of dissemination of development models, their characteristics and dynamics in order to provide a framework to think the different ways development is disseminated and naturalised in today’s globalised world.     

鲤和鲫线粒体(mtDNA)全基因组分析

为研究鲤(Cyprinus carpio)和鲫(Carassius auratus) mtDNA上的基因分布特征,丰富鱼类mtDNA数据库。本研究通过PCR扩增和测序,获得了鲤和鲫mtDNA基因组序列,经比对分析表明,鲤和鲫的mtDNA序列全长均为16 596 bp,共有13个蛋白质编码基因、22个tRNA基因、2个rRNA基因和1个D-Loop区。鲤和鲫的mtDNA序列中(A+T)百分含量分别为57.2%和57.1%,其碱基组成均具有一定的A/T碱基偏向性。N-J系统发育树分析表明,鲤和鲫与琵琶湖鮈亲缘关系最近,与达氏深水尾魟亲缘关系最远。本研究揭示了鲤和鲫mtDNA遗传变异特征及基因分布规律,为鱼类遗传资源保护及开发利用提供了参考依据。     

茜草叶绿体全基因组序列及其系统发育分析

以茜草科(Rubiaceae)植物茜草(Rubia cordifolia L.)为研究对象,采用Illumination高通量测序技术对其叶绿体全基因组进行测序,并运用MAGA11等生信学工具进行全基因组解析及系统发育分析。结果表明,(1)茜草叶绿体基因组呈典型的四分环状结构,总GC含量37.2%,长153 959 bp,其中包含大单拷贝(LSC)区83 844 bp、小单拷贝(SSC)区17 083 bp和2个反向重复(IR)区26 516 bp;共注释得到124个基因,包括79个蛋白质编码基因、37个tRNA和8个rRNA。(2)序列共鉴定到169个SSR位点,以A、T组成为主,包括129个单核苷酸、18个双核苷酸、11个三核苷酸、9个四核苷酸和2个五核苷酸,六核苷酸SSR未检测到;边界分析显示,茜草叶绿体基因组LSC区差异性最大,变异程度最高,而IRa区则差异性最小,最为保守。(3)最大似然法(ML)构建系统发育树显示,样品茜草与同属植物Rubia horrida以100%支持率聚为一类,茜草亚科、仙丹花亚科与金鸡纳亚科聚为姐妹类群,证明茜草科植物在进化过程中保守发育。     

Effects of Salbutamol and Isoprenaline Phenylephrine in Reversible Airways Obstruction

Ventolin (salbutamol) and Medihaler-Duo (isoprenaline/phenylephrine combination) standard pressurized inhalers were used to administer doses of two or six “puffs” to 16 patients with known reversible airways obstruction. The doses were administered in random order over two days. Both the Ventolin and Medihaler-Duo inhalers substantially increased FEV₁, but in the doses used salbutamol was more effective than isoprenaline/phenylephrine (P < 0·01). There was no significant difference between two and six puffs of salbutamol, though there seemed to be an advantage of six puffs of isoprenaline/phenylephrine over two puffs (P < 0·05). Adrenaline (1/1,000) 0·5 ml and atropine 0·6 mg produced similar increases in FEV₁ to those produced by salbutamol.The Pao₂ fell more than 5 mm Hg in three patients after salbutamol and in three after isoprenaline/phenylephrine. There was no significant fall in mean Pao₂ in any of the treatment groups. It is concluded that the Ventolin inhalant, administered in the conventional dose of two puffs, is as effective a bronchodilator as subcutaneous adrenaline and atropine, is more effective than the Medihaler-Duo, and is without detectable side effects.     

短尾蝮蛇线粒体基因组全序列分析

参照近缘物种的线粒体基因序列设计并筛选得到8对引物,结合TA克隆和步移测序获得了全长17227bp的短尾蝮蛇线粒体基因组全序列.与多数蛇类线粒体基因组类似,其共编码包括13个蛋白、2个rRNA和22个tRNA在内的37个基因,另外还包含2个非编码的富含AT的控制区.基因间排列紧凑,多数基因间间隔极短甚至发生重叠.除nad1、cox1和nad3外,多数蛋白编码基因均以ATG作为起始密码子,终止密码子的使用则存在TAA、AGA、AGG和不完全的T4种情况.基于合并的19个tRNA基因序列组合数据采用NJ、MP和ME3种算法对21种蛇进行了初步的系统发育分析,结果表明,各主要分类单元之间的亲缘关系与前人基于形态学、线粒体12SrRNA和cytb基因序列研究的结论完全一致,这证实了基于合并的线粒体tRNA基因序列进行蛇类物种DNA分子系统学研究的可行性.     

慢性支气管炎动物模型研究进展

慢性支气管炎是呼吸系统发病率和死亡率高的一种重要原因,临床和基础研究进展缓慢。吸入烟雾、空气污染物与职业接触慢性刺激传导气道是慢性支气管炎发病的关键因素。近年来虽提出各种各样动物模型,但具实用价值者仍极有限。复制慢性支气管炎动物模型有周期长、个体差异大、检测困难及可靠性差等问题。本文简要介绍烟熏、吸入SO2与气管内滴注脂多糖等最常用的慢性支气管炎动物模型的研究进展。将有益于抗慢性支气管炎药物研究时的更多选择应用。     

三斑海马线粒体基因组核苷酸全序列结构与分析

通过PCR扩增并测序获得了三斑海马(Hippocampus trimaculatus)线粒体DNA(mt DNA)全序列。三斑海马线粒体基因组全序列长度为16 534 bp(Gen Bank登录号为KJ956892),编码37个基因,包括13个蛋白编码基因、22个t RNA基因和2个r RNA基因。非编码区域包括1个控制区(D-loop)及一个轻链复制起始区域。大部分基因由H-链编码,包括14个t RNA基因、2个r RNA基因、12个蛋白编码基因;只有ND6和8个t RNA基因是在L-链编码。预测的22个t RNA基因的二级结构均为典型的三叶草状。基因间隔一般1~14 bp不等。此外,还存在7处碱基重叠,其中,4处是鱼类和脊椎动物典型的基因重叠位点。总的碱基含量分别为,A 32.7%,C 23.4%,G 14.6%,T 29.3%,A+T含量为62.0%。其线粒体基因组序列的结构与脊椎动物的典型结构近似。邻接法和贝叶斯法构建的三斑海马系统进化树的拓扑结构相似,这与现有的三斑海马的系统演化地位一致。本研究为海马的进化研究以及保护工作提供了基础数据。     

北京鸭线粒体基因组全序列测定和分析

线粒体DNA作为遗传标记,已在家鸡(Gallus gallus)和家鹅(Anser anser)的研究中取得了重大进展,而对家鸭(Anas platyrhychos domesticus)的研究却很少.本研究参照近源物种线粒体基因组序列设计15对引物,通过PCR扩增、测序、拼接,获得北京鸭(A.platyrhychos)线粒体基因组全序列,初步分析其特点和各基因的定位.结果显示,北京鸭线粒体基因组全长16 604 bp,碱基组成为29.19%A、22.20%T、15.80%G、32.81%C,包含13个蛋白质编码基因、2个rRNA基因、22个tRNA基因和1个非编码控制区(D-loop),基因组成及排列顺序与其他鸟类相似.基于线粒体D-loop区全序列,用N-J法构建了7种雁形目鸟类系统进化树,结果表明,北京鸭与绿头鸭(A.platyrhychos)系统进化关系较近.