bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of Humoral and Cell-Mediated Immune Responses by Hepatitis B Virus Epitope Displayed on the Virus-Like Particles of Prawn Nodavirus
Authors: Yong Chean Yeah , Yeap Swee Keong , Goh Zee Hong , Ho Kok Lian , Omar Abdul Rahman , Tan Wen Siang
Published: November 2014

Hepatitis B virus (HBV) is a deadly pathogen that has killed countless people worldwide.Saccharomyces cerevisiae-derived HBV vaccines based upon hepatitis B surface antigen (HBsAg) is highly effective. However, the emergence of vaccine escape mutants due to mutations on the HBsAg and polymerase genes has produced a continuous need for the development of new HBV vaccines. In this study, the “a” determinant within HBsAg was displayed on the recombinant capsid protein ofMacrobrachium rosenbergiinodavirus (MrNV), which can be purified easily in a single step through immobilized metal affinity chromatography (IMAC). The purified protein self-assembled into virus-like particles (VLPs) when observed under a transmission electron microscope (TEM). Immunization of BALB/c mice with this chimeric protein induced specific antibodies against the “a” determinant. In addition, it induced significantly more natural killer and cytotoxic T cells, as well as an increase in interferon gamma (IFN-γ) secretion, which are vital for virus clearance. Collectively, these findings demonstrated that the MrNV capsid protein is a potential carrier for the HBV “a” determinant, which can be further extended to display other foreign epitopes. This paper is the first to report the application of MrNV VLPs as a novel platform to display foreign epitopes.
Ctk1 Function Is Necessary for Full Translation Initiation Activity in Saccharomyces cerevisiae
Authors: Coordes Britta , Brünger Katharina M. , Burger Kaspar , Soufi Boumediene , Horenk Juliane , Eick Dirk , Olsen Jesper V. , Sträßer Katja
Published: November 2014

Translation is a fundamental and highly regulated cellular process. Previously, we reported that the kinase and transcription elongation factor Ctk1 increases fidelity during translation elongation in
Saccharomyces cerevisiae
. Here, we show that loss of Ctk1 function also affects the initiation step of translation. Translation active extracts from Ctk1-depleted cells show impaired translation activity of capped mRNA, but not mRNA reporters containing the cricket paralysis virus (CrPV) internal ribosome entry site (IRES). Furthermore, the formation of 80S initiation complexes is decreased, which is probably due to reduced subunit joining. In addition, we determined the changes in the phosphorylation pattern of a ribosome enriched fraction after depletion of Ctk1. Thus, we provide a catalogue of phosphoproteomic changes dependent on Ctk1. Taken together, our data suggest a stimulatory function of Ctk1 in 80S formation during translation initiation.
In Vitro
Alterations Do Not Reflect a Requirement for Host Cell Cycle Progression during Plasmodium Liver Stage Infection
Authors: Hanson Kirsten K. , March Sandra , Ng Shengyong , Bhatia Sangeeta N. , Mota Maria M.
Published: November 2014

Prior to invading nonreplicative erythrocytes,
Plasmodium
parasites undergo their first obligate step in the mammalian host inside hepatocytes, where each sporozoite replicates to generate thousands of merozoites. While normally quiescent, hepatocytes retain proliferative capacity and can readily reenter the cell cycle in response to diverse stimuli. Many intracellular pathogens, including protozoan parasites, manipulate the cell cycle progression of their host cells for their own benefit, but it is not known whether the hepatocyte cell cycle plays a role during
Plasmodium
liver stage infection. Here, we show that
Plasmodium
parasites can be observed in mitotic hepatoma cells throughout liver stage development, where they initially reduce the likelihood of mitosis and ultimately lead to significant acquisition of a binucleate phenotype. However, hepatoma cells pharmacologically arrested in S phase still support robust and complete
Plasmodium
liver stage development, which thus does not require cell cycle progression in the infected cell
in vitro
. Furthermore, murine hepatocytes remain quiescent throughout
in vivo
infection with either
Plasmodium berghei
or
Plasmodium yoelii
, as do
Plasmodium falciparum
-infected primary human hepatocytes, demonstrating that the rapid and prodigious growth of liver stage parasites is accomplished independent of host hepatocyte cell cycle progression during natural infection.
The Krebs Cycle Enzyme α-Ketoglutarate Decarboxylase Is an Essential Glycosomal Protein in Bloodstream African Trypanosomes
Authors: Sykes Steven , Szempruch Anthony , Hajduk Stephen
Published: November 2014

α-Ketoglutarate decarboxylase (α-KDE1) is a Krebs cycle enzyme found in the mitochondrion of the procyclic form (PF) of
Trypanosoma brucei
. The bloodstream form (BF) of
T. brucei
lacks a functional Krebs cycle and relies exclusively on glycolysis for ATP production. Despite the lack of a functional Krebs cycle, α-KDE1 was expressed in BF
T. brucei
and RNA interference knockdown of α-KDE1 mRNA resulted in rapid growth arrest and killing. Cell death was preceded by progressive swelling of the flagellar pocket as a consequence of recruitment of both flagellar and plasma membranes into the pocket. BF
T. brucei
expressing an epitope-tagged copy of α-KDE1 showed localization to glycosomes and not the mitochondrion. We used a cell line transfected with a reporter construct containing the N-terminal sequence of α-KDE1 fused to green fluorescent protein to examine the requirements for glycosome targeting. We found that the N-terminal 18 amino acids of α-KDE1 contain overlapping mitochondrion- and peroxisome-targeting sequences and are sufficient to direct localization to the glycosome in BF
T. brucei
. These results suggest that α-KDE1 has a novel moonlighting function outside the mitochondrion in BF
T. brucei
.
Insect Stage-Specific Adenylate Cyclases Regulate Social Motility in African Trypanosomes
Authors: Lopez Miguel A. , Saada Edwin A. , Hill Kent L.
Published: November 2014

Sophisticated systems for cell-cell communication enable unicellular microbes to act as multicellular entities capable of group-level behaviors that are not evident in individuals. These group behaviors influence microbe physiology, and the underlying signaling pathways are considered potential drug targets in microbial pathogens.
Trypanosoma brucei
is a protozoan parasite that causes substantial human suffering and economic hardship in some of the most impoverished regions of the world.
T. brucei
lives on host tissue surfaces during transmission through its tsetse fly vector, and cultivation on surfaces causes the parasites to assemble into multicellular communities in which individual cells coordinate their movements in response to external signals. This behavior is termed “social motility,” based on its similarities with surface-induced social motility in bacteria, and it demonstrates that trypanosomes are capable of group-level behavior. Mechanisms governing
T. brucei
social motility are unknown. Here we report that a subset of receptor-type adenylate cyclases (ACs) in the trypanosome flagellum regulate social motility. RNA interference-mediated knockdown of adenylate cyclase 6 (AC6), or dual knockdown of AC1 and AC2, causes a hypersocial phenotype but has no discernible effect on individual cells in suspension culture. Mutation of the AC6 catalytic domain phenocopies AC6 knockdown, demonstrating that loss of adenylate cyclase activity is responsible for the phenotype. Notably, knockdown of other ACs did not affect social motility, indicating segregation of AC functions. These studies reveal interesting parallels in systems that control social behavior in trypanosomes and bacteria and provide insight into a feature of parasite biology that may be exploited for novel intervention strategies.
Choosing the right dose of tacrolimus
Authors: Lancia Pauline , Jacqz-Aigrain Evelyne , Zhao Wei
Published: November 2014

Choosing the right dose of tacrolimus ‘adapted to each individual patient’ is a central question after transplantation. The pharmacokinetic behaviour of tacrolimus in paediatric patients is significantly influenced by clinical factors growth and maturation, as well as genetic factors. Large interindividual variability and narrow therapeutic index make dosage individualisation mandatory in children. CYP3A5 expressers require a 1.8-fold higher tacrolimus dose than non-expressers. A visual patient-tailored dosing chart, taking into consideration the child's weight, recent haematocrit level and CYP3A5 genotype, was developed based on a population pharmacokinetic–pharmacogenetic model, and can be used routinely to individualise tacrolimus starting dose. Area under the concentration-time curve-based dosage adaptation through limited sampling strategy and Bayesian estimation is more reliable than trough concentration. Therapeutic drug monitoring and dosage adaptation can be included in routine post-transplantation consultation and should be considered in the urgent situations (eg, rejection, adverse event, lack of compliance, change of coadministration drug with potential drug–drug interaction and other situations).
Catamenial psychosis in an adolescent girl
Authors: Fernando Myra Deanne , Grizzaffi Joseph , Crapanzano Kathleen A , Jones Glenn N
Published: November 2014

We report the case of an adolescent girl who was 14 years old at initial presentation. A shy, immature and timid individual, she began to have recurring, progressive episodes characterised by insomnia, paranoia, distorted thinking and mood instability with a mix of depressive and manic-like symptoms. An extensive medical work up was unrevealing. Her family noted a pattern that coincided with her menstrual cycle. An endocrine consult was obtained, and the diagnosis of catamenial psychosis was performed. After treatment with leuprolide, resulting in a shutdown of the hypothalamic-pituitary-ovarian axis, the patient’s symptoms were resolved completely.
Perilunate dislocation in an asymptomatic SNAC wrist: an uncommon presentation requiring a scaphoidectomy and four corner fusion
Authors: Samson Deepak , Power Dominic M
Published: November 2014

This report describes a 53-year-old man who presented, following a motocross injury, with a Mayfield stage 1 perilunate dislocation through a pre-existing asymptomatic scaphoid non-union with a degenerative midcarpal joint. A salvage reconstruction with scaphoid excision and four corner midcarpal arthrodesis resulted in a satisfactory outcome. Follow-up at 6 years demonstrated no instability and no further progression of the osteoarthritis.
Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis
Authors: Laudy Augustinus B M , Bakker Eric W P , Rekers Mark , Moen Maarten H
Published: November 2014

Background

The effectiveness of platelet-rich plasma (PRP) injections for osteoarthritis (OA) is still controversial. We investigated the effect of PRP injections in patients with knee OA based on decreasing pain, improving function, global assessment and changes regarding joint imaging.

Methods

We performed a comprehensive, systematic literature search in computerised databases (MEDLINE, EMBASE, CINAHL, CENTRAL, Web of Science and PEDro) until June 2014 for randomised or non-randomised controlled trials. These were graded for risk of bias and a level of evidence was provided. If possible, meta-analysis was performed.

Results

Ten trials were included. In these, intra-articular PRP injections were more effective for pain reduction (mean difference (MD) −2.45; 95% CI −2.92 to −1.98; p value <0.00001 and MD −2.07; 95% CI −2.59 to −1.55; p value <0.00001, single and double PRP injections, respectively) compared with placebo at 6 months postinjection. Intra-articular PRP injections were compared with hyaluronic acid and showed a statistically significant difference in favour of PRP on pain reduction based on the visual analogue scale and numeric rating scale (standardised mean difference −0.92; 95% CI −1.20 to −0.63; p value <0.00001) at 6 months postinjection. Almost all trials revealed a high risk of bias.

Conclusions

On the basis of the current evidence, PRP injections reduced pain more effectively than did placebo injections in OA of the knee (level of evidence: limited due to a high risk of bias). This significant effect on pain was also seen when PRP injections were compared with hyaluronic acid injections (level of evidence: moderate due to a generally high risk of bias). Additionally, function improved significantly more when PRP injections were compared with controls (limited to moderate evidence). More large randomised studies of good quality and low risk of bias are needed to test whether PRP injections should be a routine part of management of patients with OA of the knee.
Increased bronchial parasympathetic tone in elite cross-country and biathlon skiers: a randomised crossover study
Authors: Stang J , Couto M , Carlsen K-H , Stensrud T
Published: November 2014

This article has been retracted.
Early socioeconomic position and self-rated health among civil servants in Brazil: a cross-sectional analysis from the Pró-Saúde cohort study
Authors: Guimarães Joanna Miguez Nery , Werneck Guilherme Loureiro , Faerstein Eduardo , Lopes Claudia S , Chor Dora
Published: November 2014

Objectives

Although there is evidence that socioeconomic conditions in adulthood are associated with worse self-rated health, the putative effect of early adverse life circumstances on adult self-rated health is not consistent. Besides, little is known on this subject in the context of middle-income countries. We aimed to investigate the association between indicators of socioeconomic position in early life and self-rated health in adulthood, taking into account the influence of current socioeconomic position.

Design

Cross-sectional.

Participants

3339 civil servants (44.5% male) working at a public university in Rio de Janeiro, Brazil, participants of the Pró-Saúde cohort study.

Measurements

Through a lifecourse approach, we evaluated if seven indicators of participants’ socioeconomic position earlier in life were associated with worse self-rated health in adulthood. Ordinal logistic regression analysis with a proportional odds model was used.

Results

After adjusting for socioeconomic position in adulthood (education and income), the indicators of early socioeconomic position associated with poor self-rated health were as follows: not eating at home due to lack of money at the age of 12 (OR=1.29 95% CI 1.06 to 1.57) and having lived in a small city or rural area at the age of 12 (OR=1.51 95% CI 1.21 to 1.89).

Conclusions

Self-rated health was associated with two indicators of remarkable experiences of poverty in early life, even when socioeconomic conditions improved throughout life. Our findings have shown a long-term impact of extreme socioeconomic hardship during childhood and/or adolescence on the development of social inequalities in health. In terms of implications for public health, our work emphasises that health policies, usually focused on adult lifestyle interventions, should be complemented by initiatives aimed at reducing socioeconomic inequalities during the earliest stages of development, such as childhood and adolescence.
Mental health problems of undocumented migrants (UMs) in the Netherlands: a qualitative exploration of help-seeking behaviour and experiences with primary care
Authors: Teunissen Erik , Sherally Jamilah , van den Muijsenbergh Maria , Dowrick Chris , van Weel-Baumgarten Evelyn , van Weel Chris
Published: November 2014

Objective

To explore health-seeking behaviour and experiences of undocumented migrants (UMs) in general practice in relation to mental health problems.

Design

Qualitative study using semistructured interviews and thematic analysis.

Participants

15 UMs in the Netherlands, varying in age, gender, country of origin and education; inclusion until theoretical saturation was reached.

Setting

4 cities in the Netherlands.

Results

UMs consider mental health problems to be directly related to their precarious living conditions. For support, they refer to friends and religion first, the general practitioner (GP) is their last resort. Barriers for seeking help include taboo on mental health problems, lack of knowledge of and trust in GPs competencies regarding mental health and general barriers in accessing healthcare as an UM (lack of knowledge of the right to access healthcare, fear of prosecution, financial constraints and practical difficulties). Once access has been gained, satisfaction with care is high. This is primarily due to the attitude of the GPs and the effectiveness of the treatment. Reasons for dissatisfaction with GP care are an experienced lack of time, lack of personal attention and absence of physical examination. Expectations of the GP vary, medication for mental health problems is not necessarily seen as a good practice.

Conclusions

UMs often see their precarious living conditions as an important determinant of their mental health; they do not easily seek help for mental health problems and various barriers hamper access to healthcare for them. Rather than for medication, UMs are looking for encouragement and support from their GP. We recommend that barriers experienced in seeking professional care are tackled at an institutional level as well as at the level of GP.
Adverse outcomes of (post-)term births and differences in professional organisational contexts: an integral descriptive system approach
Authors: Harmsen Loes , Schaaf Hans
Published: November 2014

Objective

The development and application of an integral descriptive model for monitoring and evaluation of patient flows and adverse outcomes of childbirth related to distinct categories of professional organisational contexts.

Setting

After categorisation of the individual professional contexts in which deliveries take place, the resulting framework has been superimposed on the 2002–2010 database of the Netherlands Perinatal Registry.

Participants

All Dutch hospitals and almost all first-line midwife practices recorded 1 469 955 (post-)term births from which only the patients with a spontaneous onset of labour (n=1 120 508) were included in a study on the quality of obstetric care outside office hours.

Main outcome measures

For the performance of professional organisational contexts the difference in relative incidence of perinatal death or Apgar score <7 between the related patient groups and the reference patient groups has been used. These differences have been expressed as risk ratio (RR) with a 95% CI.

Results

Only the group of patients who started labour spontaneously under the supervision of the first-line midwife shows a proportional distribution over the parts of the day. In all other groups the distribution of patients is disproportional. The perinatal mortality rate declines by about 30% in the successive periods. This decline concerns mainly those patients who gave birth outside office hours.

Conclusions

The complexity and the dynamics of the obstetric care system make it virtually impossible to demonstrate fixed patterns in the relationships between the separate contextual factors and the (adverse) outcomes of births. To generate useful knowledge, it is necessary to evaluate changes in the obstetric care system periodically and systematically. Thus, the longitudinal application of the model demonstrated that the differences in perinatal mortality rate between the parts of the day have disappeared in recent years.
Effects of female genital cutting on physical health outcomes: a systematic review and meta-analysis
Authors: Berg Rigmor C , Underland Vigdis , Odgaard-Jensen Jan , Fretheim Atle , Vist Gunn E
Published: November 2014

Objective

Worldwide, an estimated 125 million girls and women live with female genital mutilation/cutting (FGM/C). We aimed to systematically review the evidence for physical health risks associated with FGM/C.

Design

We searched 15 databases to identify studies (up to January 2012). Selection criteria were empirical studies reporting physical health outcomes from FGM/C, affecting females with any type of FGM/C, irrespective of ethnicity, nationality and age. Two review authors independently screened titles and abstracts, applied eligibility criteria, assessed methodological study quality and extracted full-text data. To derive overall risk estimates, we combined data from included studies using the Mantel-Haenszel method for unadjusted dichotomous data and the generic inverse-variance method for adjusted data. Outcomes that were sufficiently similar across studies and reasonably resistant to biases were aggregated in meta-analyses. We applied the instrument Grading of Recommendations Assessment, Development and Evaluation to assess the extent to which we have confidence in the effect estimates.

Results

Our search returned 5109 results, of which 185 studies (3.17 million women) satisfied the inclusion criteria. The risks of systematic and random errors were variable and we focused on key outcomes from the 57 studies with the best available evidence. The most common immediate complications were excessive bleeding, urine retention and genital tissue swelling. The most valid and statistically significant associations for the physical health sequelae of FGM/C were seen on urinary tract infections (unadjusted RR=3.01), bacterial vaginosis (adjusted OR (AOR)=1.68), dyspareunia (RR=1.53), prolonged labour (AOR=1.49), caesarean section (AOR=1.60), and difficult delivery (AOR=1.88).

Conclusions

While the precise estimation of the frequency and risk of immediate, gynaecological, sexual and obstetric complications is not possible, the results weigh against the continuation of FGM/C and support the diagnosis and management of girls and women suffering the physical risks of FGM/C.

Trial registration number

This study is registered with PROSPERO, number CRD42012003321.
TheBokSmartintervention programme is associated with improvements in injury prevention behaviours of rugby union players: an ecological cross-sectional study
Authors: Brown James C , Gardner-Lubbe Sugnet , Lambert Michael Ian , Van Mechelen Willem , Verhagen Evert
Published: November 2014

Background/aim

Participants of rugby union (‘rugby’) have an above-average risk of injury compared with other popular sports. Thus,BokSmart, a nationwide injury prevention programme for rugby, was introduced in South Africa in 2009. Improvements in injury-preventing behaviour of players are critical to the success of an intervention. The aim of this study was to assess whetherBokSmarthas been associated with improvements in rugby player behaviour.

Methods

An anonymous knowledge, attitude and self-reported behaviour questionnaire was completed by junior (under-18) and senior (adult) tournament players who attended merit-based tournaments (2008–2012). The questionnaire was completed by 2279 junior players (99% of total estimated population) from 111 teams and 1642 senior players (96% of population) from 81 teams. A generalised linear model assessed behavioural changes over this time period.

Results

Nine (50%) of the behaviours improved significantly (p<0.005) between 2008 and 2012 and the remaining behaviours remained unchanged. Improved behaviours included the targeted, catastrophic injury-preventing behaviours of the intervention: practising of tackling (adjusted overall improvement in odds: 56%) and scrummaging, in forwards only (58%), techniques. Other behaviours that improved significantly were postinjury compression and elevation as well as alcohol avoidance, mouthguard use (training and matches) and cooling down (training and matches). Practising of safe rucking techniques; warming up before training/matches; ice use; heat, massage and alcohol avoidance postinjury; and preseason and off-season conditioning remained unchanged.

Conclusions

BokSmartis associated with improvements in targeted injury-preventing behaviours in players. Future research should ascertain whether self-reported behaviours reflect actual behaviour and whether the observed improvements translate into changes in injury rates.
Lesion stability characteristics outperform degree of stenosis in predicting outcomes following stenting for symptomatic intracranial atherosclerosis
Authors: Alexander M D , Cooke D L , Meyers P M , Amans M R , Dowd C F , Halbach V V , Higashida R T , Hetts S W
Published: November 2014

Background

Intracranial atherosclerotic disease (ICAD) causes substantial morbidity and mortality. Treatment decisions have most commonly been driven by the degree of luminal stenosis. This study compares ICAD lesion stability features with percentage stenosis for associations with adverse outcomes following treatment with stents.

Materials and methods

Retrospective analysis was performed of prospectively maintained procedure logs. Lesions were classified by symptom type as hypoperfusion, non-hypoperfusion, or indeterminate, and pretreatment asymptomatic intervals were noted. Hypoperfusion lesions and indeterminate or non-hypoperfusion lesions with ≥14 days of asymptomatic interval were classified as stable. Percentage stenosis was calculated and compared against these other symptom features for value in predicting technical complication, ischemic stroke, disability, or death at 90 days and 2 years using univariate and multivariate analysis.

Results

130 lesions were treated in 124 patients. The only statistically significant percent stenosis finding was lesions with 60–99% stenosis were less likely to have technical complications. In univariate analysis, stroke at 2 years was less common with hypoperfusion and stable lesions. In multivariate analysis, only hypoperfusion status was associated with lower stroke rates at 2 years.

Conclusions

Lesion stability features, particularly non-hypoperfusion symptomatology, outperform percentage stenosis in predicting outcomes following treatment of ICAD with stents. Further examination is needed to better classify the natural history of ICAD and more precisely classify lesion stability.
Application of integrated production and economic models to estimate the impact of Schmallenberg virus for various sheep production types in the UK and France
Authors: Alarcon Pablo , Häsler Barbara , Raboisson Didier , Waret‐Szkuta Agnes , Corbière Fabien , Rushton Jonathan
Published: November 2014

Objective

The present study aimed to estimate and compare the economic impact of Schmallenberg virus (SBV) in different sheep production holdings using partial budget and gross margin analyses in combination with production models.

Participants

The sheep production types considered were lowland spring lambing, upland spring lambing and early lambing flocks in the UK, and grass lamb flocks of the Centre and West of France, extensive lambing flocks and dairy sheep flocks in France.

Methodology

Two disease scenarios with distinct input parameters associated with reproductive problems were considered: low and high impact. Sensitivity analyses were performed for the most uncertain input parameters, and the models were run with all of the lowest and highest values to estimate the range of disease impact.

Results

The estimated net SBV disease cost per year and ewe for the UK was £19.65–£20.85 for the high impact scenario and £6.40–£6.58 for the low impact scenario. No major differences were observed between the different production types. For France, the net SBV disease cost per year and ewe for the meat sheep holdings was £15.59–£17.20 for the high impact scenario and £4.75–£5.26 for the low impact scenario. For the dairy sheep, the costs per year and ewe were £29.81 for the high impact scenario and £10.34 for the low impact scenario.

Conclusions

The models represent a useful decision support tool for farmers and veterinarians who are facing decisions regarding disease control measures. They allow estimating disease impact on a farm accounting for differing production practices, which creates the necessary basis for cost effectiveness analysis of intervention strategies, such as vaccination.
One Dimensional Finite Element Method Approach to Study Effect of Ryanodine Receptor and Serca Pump on Calcium Distribution in Oocytes
Authors: Naik Parvaiz Ahmad , Pardasani Kamal Raj
Published: November 2014

Oocyte is a female gametocyte or germ cell involved in reproduction. Calcium ions ( Ca2+) impact nearly all aspects of cellular life as they play an important role in a variety of cellular functions. Calcium ions contributes to egg activation upon fertilization. Since it is the internal stores which provide most of the calcium signal, much attention has been focused on the intracellular channels. There are mainly two types of calcium channels which release calcium from the internal stores to the cytoplasm in many cell types. These channels are IP3-Receptor and Ryanodine Receptor (RyR). Further it is essential to maintain low cytosolic calcium concentration, the cell engages the Serco/Endoplasmic reticulum Ca2+ATPases (SERCA) present on the ER or SR membrane for the re-uptake of cytosolic calcium at the expense of ATP hydrolysis. In view of above an attempt has been made to study the effect of the Ryanodine receptor (RyR) and the SERCA pump on the calcium distribution in oocytes. The main aim of this paper is to study the calcium concentration in absence and presence of these parameters. The FEM is used to solve the proposed Mathematical model under appreciate initial and boundary conditions. The program has been developed in MATLAB 7.10 for the entire problem to get numerical results.
The astronomical calibration of the Givetian (Middle Devonian) timescale (Dinant Synclinorium, Belgium)
Authors: De Vleeschouwer David , Boulvain Frédéric , Da Silva Anne-Christine , Pas Damien , Labaye Corentin , Claeys Philippe
Published: November 2014

Recent advances in radiometric dating result in significant improvements in the geological timescale and provide better insight into the timing of various processes and evolutions within the Earth's system. However, no radiometric ages are contained within the Givetian. Consequently, the absolute ages of the Givetian Stage boundaries, as well as the stage's duration, remain poorly constrained. As an alternative, the analysis of sedimentary cycles allows for the estimation of the duration of this stage. We examined the high-resolution magnetic susceptibility signals of four Givetian outcrops in the Givet area for a possible astronomical imprint, to fully understand the rates of evolutionary and environmental change. All four sections are firmly correlated and wavelet analyses of the magnetic susceptibility signals reveal the imprint of astronomical eccentricity forcing. The highly stable 405 kyr cycles constrain the duration of the Givetian Stage at 4.35±0.45 Myr, which is in good agreement with the International Chronostratigraphic Chart (5.0 Myr). The studied sections also exhibit an imprint of obliquity, suggesting a climatic teleconnection between low and high latitudes. The corresponding microfacies curves demonstrate similar astronomical imprint, and thereby indicate that the observed 10
5
year-scale cyclicity is the result of climatic and environmental change.
A climate-driven model using time-series analysis of magnetic susceptibility (χ) datasets to represent a floating-point high-resolution geological timescale for the Middle Devonian Eifelian stage
Authors: Ellwood Brooks B. , El Hassani Ahmed , Tomkin Jonathan H. , Bultynck Pierre
Published: November 2014

Presented here are cyclostratigraphic time-series data, using magnetic susceptibility (χ) results from Devonian Moroccan rocks to establish a floating-point age chronology, and a method that can be applied to any geological stage using geochemical or geophysical datasets as a climate proxy. The χ data are fit to an independent uniform climate model for the entire Eifelian Stage. The procedure used comprised: (a) definition of a uniform
c.
405 kyr eccentricity climate model for the Eifelian, with a published duration for the Eifelian; and (b) graphical testing of the model using χ data derived from outcrop samples, here including data from the Global Boundary Stratotype Section and Point for the Emsian–Eifelian and Eifelian–Givetian stage boundaries, and an overlapping succession from Bou Tchrafine, Morocco. The time-series methods used here identify χ cycles that conform to the
c.
405 kyr by graphically comparing the χ zonation with the climate model. Well-established conodont zonations developed using graphic correlation are then compared with this model, allowing time estimates for Eifelian conodont zone ranges. The time-series data indicate that the Eifelian Stage in the Middle Devonian lasted for
c.
6.28 myr, the Lower Eifelian Choteč bio-event lasted for
c.
600 kyr, and the Kačák bio-event in the Upper Eifelian lasted for
c.
370 kyr.
Imaging cardiac activation sequence during ventricular tachycardia in a canine model of nonischemic heart failure
Authors: Han Chengzong , Pogwizd Steven M. , Yu Long , Zhou Zhaoye , Killingsworth Cheryl R. , He Bin
Published: November 2014

Noninvasive cardiac activation imaging of ventricular tachycardia (VT) is important in the clinical diagnosis and treatment of arrhythmias in heart failure (HF) patients. This study investigated the ability of the three-dimensional cardiac electrical imaging (3DCEI) technique for characterizing the activation patterns of spontaneously occurring and norepinephrine (NE)-induced VTs in a newly developed arrhythmogenic canine model of nonischemic HF. HF was induced by aortic insufficiency followed by aortic constriction in three canines. Up to 128 body-surface ECGs were measured simultaneously with bipolar recordings from up to 232 intramural sites in a closed-chest condition. Data analysis was performed on the spontaneously occurring VTs ( n = 4) and the NE-induced nonsustained VTs ( n = 8) in HF canines. Both spontaneously occurring and NE-induced nonsustained VTs initiated by a focal mechanism primarily from the subendocardium, but occasionally from the subepicardium of left ventricle. Most focal initiation sites were located at apex, right ventricular outflow tract, and left lateral wall. The NE-induced VTs were longer, more rapid, and had more focal sites than the spontaneously occurring VTs. Good correlation was obtained between imaged activation sequence and direct measurements (averaged correlation coefficient of ∼0.70 over 135 VT beats). The reconstructed initiation sites were ∼10 mm from measured initiation sites, suggesting good localization in such a large animal model with cardiac size similar to a human. Both spontaneously occurring and NE-induced nonsustained VTs had focal initiation in this canine model of nonischemic HF. 3DCEI is feasible to image the activation sequence and help define arrhythmia mechanism of nonischemic HF-associated VTs.
Dysautonomias in Parkinson's disease: cardiovascular changes and autonomic modulation in conscious rats after infusion of bilateral 6-OHDA in substantia nigra
Authors: Ariza D. , Sisdeli L. , Crestani C. C. , Fazan R. , Martins-Pinge M. C.
Published: November 2014

It is important to elucidate the mechanism of dysautonomias in patients with Parkinson's disease; therefore, this study aimed to investigate the cardiovascular and autonomic changes that occur in an animal model of Parkinsonism. Adult male Wistar rats were anesthetized before bilateral microinfusions of 6-hydroxydopamine (6-OHDA) into the substantia nigra. The sham group underwent the same surgical procedure but received vehicle. After 7 days, the mean arterial pressure (MAP) and heart rate (HR) were measured, and various drugs were injected into conscious rats through cannulas previously implanted in the femoral artery and vein. Spectral analyses of systolic arterial pressure (SAP) and pulse interval (PI) were conducted with the CardioSeries software as the spontaneous baroreflex gain and effectivity. The animals were subjected to α-, β-adrenergic, or muscarinic receptor antagonism. For confirmation of the lesion, the levels of dopamine in the striatum were quantified by high-performance liquid chromatography. Animals that underwent 6-OHDA microinfusion had lower MAP and HR compared with those in the sham group. Spectral analysis of SAP showed that 6-OHDA animals exhibited a decrease in the sympathetic component. The PI values did not differ between groups. After the administration of muscarinic and β-adrenergic antagonists, the cardiovascular measures did not differ between the groups. However, upon administration of the α-adrenergic antagonist, the 6-OHDA animals exhibited a lower decrease in the MAP. We report cardiovascular impairments in 6-OHDA animals, possibly due to decreased sympathetic activity. Determination of the origin of these changes (central or peripheral) requires further investigation.
Role of TRP channels in the cardiovascular system
Authors: Yue Zhichao , Xie Jia , Yu Albert S. , Stock Jonathan , Du Jianyang , Yue Lixia
Published: November 2014

The transient receptor potential (TRP) superfamily consists of a large number of nonselective cation channels with variable degree of Ca2+-permeability. The 28 mammalian TRP channel proteins can be grouped into six subfamilies: canonical, vanilloid, melastatin, ankyrin, polycystic, and mucolipin TRPs. The majority of these TRP channels are expressed in different cell types including both excitable and nonexcitable cells of the cardiovascular system. Unlike voltage-gated ion channels, TRP channels do not have a typical voltage sensor, but instead can sense a variety of other stimuli including pressure, shear stress, mechanical stretch, oxidative stress, lipid environment alterations, hypertrophic signals, and inflammation products. By integrating multiple stimuli and transducing their activity to downstream cellular signal pathways via Ca2+entry and/or membrane depolarization, TRP channels play an essential role in regulating fundamental cell functions such as contraction, relaxation, proliferation, differentiation, and cell death. With the use of targeted deletion and transgenic mouse models, recent studies have revealed that TRP channels are involved in numerous cellular functions and play an important role in the pathophysiology of many diseases in the cardiovascular system. Moreover, several TRP channels are involved in inherited diseases of the cardiovascular system. This review presents an overview of current knowledge concerning the physiological functions of TRP channels in the cardiovascular system and their contributions to cardiovascular diseases. Ultimately, TRP channels may become potential therapeutic targets for cardiovascular diseases.
Cholinergic stimulation with pyridostigmine protects myocardial infarcted rats against ischemic-induced arrhythmias and preserves connexin43 protein
Authors: Santos-Almeida Fernanda Machado , Girão Henrique , da Silva Carlos Alberto Aguiar , Salgado Helio Cesar , Fazan Rubens
Published: November 2014

We investigated the effects of acute pyridostigmine (PYR) treatment, an acetylcholinesterase inhibitor, on arterial pressure (AP), heart rate (HR), cardiac sympathovagal balance, and the incidence of arrhythmias during the first 4 h after myocardial infarction (MI) in anesthetized rats. Male Wistar rats were implanted with catheters into the femoral artery and vein for AP recordings and drug administration. Rats received the autonomic receptor blockers methyl-atropine (1 mg/kg iv) and propranolol (2 mg/kg iv) at intervals of 15 min, 1 h after saline ( n = 16) or PYR (0.25 mg/kg iv, n = 18), to indirectly assess sympathovagal balance. Acute treatment with PYR increased cardiac vagal (86 ± 7 vs. 44 ± 5 beats/min) and decreased sympathetic tone (−31 ± 8 vs. −69 ± 7 beats/min). Different animals were implanted with ECG electrodes and catheters. A large MI was induced via left coronary artery ligation after basal recordings. Rats received PYR ( n = 14) or saline ( n = 14) 10–15 min after MI, and the recordings lasted up to 4 h. In part of the animals, hearts were removed for connexin43 quantification after all procedures. MI elicited a fall in AP (−45 ± 5 mmHg), a progressive rise in HR (26 ± 14 beats/min), and an increase in corrected QT interval (33 ± 13 ms). PYR elicited a prompt bradycardia (−50 ± 14 beats/min) that returned to basal levels over time, and it prevented the lengthening of the corrected QT interval. Treatment with PYR increased by ∼20% the occurrence of rats free of arrhythmias after MI. MI markedly decreased connexin43 in left ventricles, and PYR treatment partially prevented this decrease.
Metabolic disturbances of the vitamin A pathway in human diaphragmatic hernia
Authors: Coste Karen , J. E. Beurskens Leonardus W. , Blanc Pierre , Gallot Denis , Delabaere Amélie , Blanchon Loïc , Tibboel Dick , Labbé André , Rottier Robbert J. , Sapin Vincent
Published: November 2014

Congenital diaphragmatic hernia (CDH) is a common life-threatening congenital anomaly resulting in high rates of perinatal death and neonatal respiratory distress. Some of the nonisolated forms are related to single-gene mutations or genomic rearrangements, but the genetics of the isolated forms (60% of cases) still remains a challenging issue. Retinoid signaling (RA) is critical for both diaphragm and lung development, and it has been hypothesized that subtle disruptions of this pathway could contribute to isolated CDH etiology. Here we used time series of normal and CDH lungs in humans, in nitrofen-exposed rats, and in surgically induced hernia in rabbits to perform a systematic transcriptional analysis of the RA pathway key components. The results point to CRPBP2, CY26B1, and ALDH1A2 as deregulated RA signaling genes in human CDH. Furthermore, the expression profile comparisons suggest that ALDH1A2 overexpression is not a primary event, but rather a consequence of the CDH-induced lung injury. Taken together, these data show that RA signaling disruption is part of CDH pathogenesis, and also that dysregulation of this pathway should be considered organ specifically.
Efficient intratracheal delivery of airway epithelial cells in mice and pigs
Authors: Gui Liqiong , Qian Hong , Rocco Kevin A. , Grecu Loreta , Niklason Laura E.
Published: November 2014

Cellular therapy via direct intratracheal delivery has gained interest as a novel therapeutic strategy for treating various pulmonary diseases including cystic fibrosis lung disease. However, concerns such as insufficient cell engraftment in lungs and lack of large animal model data remain to be resolved. This study aimed to establish a simple method for evaluating cell retention in lungs and to develop reproducible approaches for efficient cell delivery into mouse and pig lungs. Human lung epithelial cells including normal human bronchial/tracheal epithelial (NHBE) cells and human lung epithelial cell line A549 were infected with pSicoR-green fluorescent protein (GFP) lentivirus. GFP-labeled NHBE cells were delivered via a modified intratracheal cell instillation method into the lungs of C57BL/6J mice. Two days following cell delivery, GFP ELISA-based assay revealed a substantial cell-retention efficiency (10.48 ± 2.86%, n = 7) in mouse lungs preinjured with 2% polidocanol. When GFP-labeled A549 cells were transplanted into Yorkshire pig lungs with a tracheal intubation fiberscope, a robust initial cell attachment (22.32% efficiency) was observed at 24 h. In addition, a lentiviral vector was developed to induce the overexpression and apical localization of cystic fibrosis transmembrane conductance regulator (CFTR)-GFP fusion proteins in NHBE cells as a means of ex vivo CFTR gene transfer in nonprogenitor (relatively differentiated) lung epithelial cells. These results have demonstrated the convenience and efficiency of direct delivery of exogenous epithelial cells to lungs in mouse and pig models and provided important background for future preclinical evaluation of intratracheal cell transplantation to treat lung diseases.
α-1-Antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease
Authors: Sinden Nicola J. , Baker Michael J. , Smith David J. , Kreft Jan-Ulrich , Dafforn Timothy R. , Stockley Robert A.
Published: November 2014

The excessive activities of the serine proteinases neutrophil elastase and proteinase 3 are associated with tissue damage in chronic obstructive pulmonary disease. Reduced concentrations and/or inhibitory efficiency of the main circulating serine proteinase inhibitor α-1-antitrypsin result from point mutations in its gene. In addition, α-2-macroglobulin competes with α-1-antitrypsin for proteinases, and the α-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of α-1-antitrypsin mutations on this partitioning. Subsequently, we have developed a three-dimensional reaction-diffusion model to describe events occurring in the lung interstitium when serine proteinases diffuse from the neutrophil azurophil granule following degranulation and subsequently bind to either α-1-antitrypsin or α-2-macroglobulin. We found that the proteinases remained uninhibited on the order of 0.1 s after release and diffused on the order of 10 μm into the tissue before becoming sequestered. We have shown that proteinases sequestered to α-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with α-2-macroglobulin are able to degrade elastin. Although neutrophil elastase is implicated in the pathophysiology of emphysema, our results highlight a potentially important role for proteinase 3 because of its greater concentration in azurophil granules, its reduced association rate constant with all α-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to α-2-macroglobulin where it retains proteolytic activity.
The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes
Authors: Pugliese Steven C. , Poth Jens M. , Fini Mehdi A. , Olschewski Andrea , El Kasmi Karim C. , Stenmark Kurt R.
Published: November 2014

Hypoxic pulmonary hypertension (PH) comprises a heterogeneous group of diseases sharing the common feature of chronic hypoxia-induced pulmonary vascular remodeling. The disease is usually characterized by mild to moderate pulmonary vascular remodeling that is largely thought to be reversible compared with the progressive irreversible disease seen in World Health Organization (WHO) group I disease. However, in these patients, the presence of PH significantly worsens morbidity and mortality. In addition, a small subset of patients with hypoxic PH develop “out-of-proportion” severe pulmonary hypertension characterized by pulmonary vascular remodeling that is irreversible and similar to that in WHO group I disease. In all cases of hypoxia-related vascular remodeling and PH, inflammation, particularly persistent inflammation, is thought to play a role. This review focuses on the effects of hypoxia on pulmonary vascular cells and the signaling pathways involved in the initiation and perpetuation of vascular inflammation, especially as they relate to vascular remodeling and transition to chronic irreversible PH. We hypothesize that the combination of hypoxia and local tissue factors/cytokines (“second hit”) antagonizes tissue homeostatic cellular interactions between mesenchymal cells (fibroblasts and/or smooth muscle cells) and macrophages and arrests these cells in an epigenetically locked and permanently activated proremodeling and proinflammatory phenotype. This aberrant cellular cross-talk between mesenchymal cells and macrophages promotes transition to chronic nonresolving inflammation and vascular remodeling, perpetuating PH. A better understanding of these signaling pathways may lead to the development of specific therapeutic targets, as none are currently available for WHO group III disease.