bluuebunny/crossref_metadata_2025 huggingface dataset:
China's island building is destroying reefs
Authors: Larson Christina
Published: September 2015

Land creation and dredging in the South China Sea come at the expense of corals and fisheries.
NEON jobs plentiful but problematic
Authors: Mervis Jeffrey
Published: September 2015

A large organization has trouble retaining talented scientists.
Addressing challenges in data collection: The role of automation in complex translational research
Authors: Quintana Francisco J. , Plätzer Kristjan
Published: September 2015

For a better and deeper understanding of the biological processes involved in diseases, as well as finding relevant therapeutic approaches, more and more complex methods and applications are being developed and used every day. Drug discovery and translational research is not only found in biopharma R&D laboratories, but also becoming an increasingly larger part of the academic environment. The need for automation in such labs is therefore growing dramatically. However, automation has many advantages beyond simply higher throughput. Robots and other automation tools enable the development of robust and reliable workflows that meet the requirements of new and complex translational research methods. Manual approaches often do not deliver the reproducibility and the accuracy needed for acceptable data quality. In such cases, small-scale automation devices—such as state-of-the-art multimode microplate readers and microplate washers, highly sensitive microarray scanners, and high throughput hybridization stations—can play a critical role in providing the necessary reliability and publication quality data. Using examples from neuroscience and cancer research, this webinar will discuss how small-scale automation in typical academic labs can be used to collect data that cannot be produced by standard manual approaches.
Thinking differently
NeuroTribes The Legacy of Autism and the Future of Neurodiversity
Steve Silberman
Avery, 2015. 544 pp.
Authors: Happé Francesca
Published: September 2015

The history of autism and what it means for the future.
GATA get a hold on senescence
Authors: Cassidy Liam D. , Narita Masashi
Published: September 2015

A transcription factor's abundance connects autophagy to cellular senescence and a secretory phenotype

[Also see Research Article by

Kang
et al.

]
Interaction between Reverse Transcriptase and Integrase Is Required for Reverse Transcription during HIV-1 Replication
Authors: Tekeste Shewit S. , Wilkinson Thomas A. , Weiner Ethan M. , Xu Xiaowen , Miller Jennifer T. , Le Grice Stuart F. J. , Clubb Robert T. , Chow Samson A.
Published: September 2015

Human immunodeficiency virus type 1 (HIV-1) replication requires reverse transcription of its RNA genome into a double-stranded cDNA copy, which is then integrated into the host cell chromosome. The essential steps of reverse transcription and integration are catalyzed by the viral enzymes reverse transcriptase (RT) and integrase (IN), respectively.In vitro, HIV-1 RT can bind with IN, and the C-terminal domain (CTD) of IN is necessary and sufficient for this binding. To better define the RT-IN interaction, we performed nuclear magnetic resonance (NMR) spectroscopy experiments to map a binding surface on the IN CTD in the presence of RT prebound to a duplex DNA construct that mimics the primer-binding site in the HIV-1 genome. To determine the biological significance of the RT-IN interaction during viral replication, we used the NMR chemical shift mapping information as a guide to introduce single amino acid substitutions of nine different residues on the putative RT-binding surface in the IN CTD. We found that six viral clones bearing such IN substitutions (R231E, W243E, G247E, A248E, V250E, and I251E) were noninfectious. Further analyses of the replication-defective IN mutants indicated that the block in replication took place specifically during early reverse transcription. The recombinant INs purified from these mutants, though retaining enzymatic activities, had diminished ability to bind RT in a cosedimentation assay. The results indicate that the RT-IN interaction is functionally relevant during the reverse transcription step of the HIV-1 life cycle.

IMPORTANCETo establish a productive infection, human immunodeficiency virus type 1 (HIV-1) needs to reverse transcribe its RNA genome to create a double-stranded DNA copy and then integrate this viral DNA genome into the chromosome of the host cell. These two essential steps are catalyzed by the HIV-1 enzymes reverse transcriptase (RT) and integrase (IN), respectively. We have shown previously that IN physically interacts with RT, but the importance of this interaction during HIV-1 replication has not been fully characterized. In this study, we have established the biological significance of the HIV-1 RT-IN interaction during the viral life cycle by demonstrating that altering the RT-binding surface on IN disrupts both reverse transcription and viral replication. These findings contribute to our understanding of the RT-IN binding mechanism, as well as indicate that the RT-IN interaction can be exploited as a new antiviral drug target.
Human Cytomegalovirus pUL93 Is Required for Viral Genome Cleavage and Packaging
Authors: DeRussy Bernadette M. , Tandon Ritesh
Published: September 2015

Human cytomegalovirus (HCMV) pUL93 is essential for virus growth, but its precise function in the virus life cycle is unknown. Here, we characterize a UL93 stop mutant virus (UL93st-TB40/E-BAC) to demonstrate that the absence of this protein does not restrict viral gene expression; however, cleavage of viral DNA into unit-length genomes as well as genome packaging is abolished. Thus, pUL93 is required for viral genome cleavage and packaging.
Interplay between the Herpes Simplex Virus 1 gB Cytodomain and the gH Cytotail during Cell-Cell Fusion
Authors: Rogalin Henry B. , Heldwein Ekaterina E.
Published: September 2015

Herpesvirus entry into cells is mediated by the viral fusogen gB, which is thought to refold from the prefusion to the postfusion form in a series of large conformational changes that energetically couple refolding to membrane fusion. In contrast to most viral fusogens, gB requires a conserved heterodimer, gH/gL, as well as other nonconserved proteins. In a further mechanistic twist, gB-mediated cell-cell fusion appears restricted by its intraviral or cytoplasmic domain (cytodomain) because mutations within it result in a hyperfusogenic phenotype. Here, we characterized a panel of hyperfusogenic HSV-1 gB cytodomain mutants and show that they are fully functional in cell-cell fusion at shorter coincubation times and at lower temperatures than those for wild-type (WT) gB, which suggests that these mutations reduce the kinetic energy barrier to fusion. Despite this, the mutants require both gH/gL and gD. We confirm previous observations that the gH cytotail is an essential component of the cell-cell fusion mechanism and show that the N-terminal portion of the gH cytotail is critical for this process. Moreover, the fusion levels achieved by all gB constructs, WT and mutant, were proportionate to the length of the gH cytotail. Putting these results together, we propose that the gH cytotail, in addition to the gH/gL ectodomain, plays an essential role in gB activation, potentially acting as a “wedge” to release the gB cytodomain “clamp” and enable gB activation.

IMPORTANCE
Herpesviruses infect their hosts for life and cause a substantial disease burden. Herpes simplex viruses cause oral and genital sores as well as rare yet severe encephalitis and a panoply of ocular ailments. Infection initiates when the viral envelope fuses with the host cell membrane in a process orchestrated by the viral fusogen gB, assisted by the viral glycoproteins gH, gL, and gD and a cellular gD receptor. This process is more complicated than that of most other viruses and is subject to multiple regulatory inputs. Antiviral and vaccine development would benefit from a detailed mechanistic knowledge of this process and how it is regulated.
A challenging case due to uncommon aberrancies
Authors: Waleed Mohammad , Raza Ali , Minhaj Tariq , Houghton Timothy
Published: September 2015

A 71-year-old man was referred to a rapid access chest pain clinic by his general practitioner. He presented with a 6-month history of twice weekly central chest pain lasting 2–3 min with walking and exertion, relieved with rest or co-codamol tablets. After initial investigations and a positive myoview scan, he was listed for an elective coronary angiogram. Unfortunately, the procedure was abandoned due to unclear course of the guide wire and a possible aberrant aortic course. Further non-invasive tests were arranged to clarify the anatomy of the vessels. After getting a clear idea of the aberrancies, coronary angiogram was replanned, and the patient underwent successful angiography with angioplasty to one of the coronary arteries, without any complications.
Effects of evidence-based prevention training on neuromuscular and biomechanical risk factors for ACL injury in adolescent female athletes: a randomised controlled trial
Authors: Zebis Mette K , Andersen Lars L , Brandt Mikkel , Myklebust Grethe , Bencke Jesper , Lauridsen Hanne Bloch , Bandholm Thomas , Thorborg Kristian , Hölmich Per , Aagaard Per
Published: September 2015

Background

Adolescent female football and handball players are among the athletes with the highest risk of sustaining anterior cruciate ligament (ACL) injuries.

Aim

This study evaluated the effects of evidence-based lower extremity injury prevention training on neuromuscular and biomechanical risk factors for non-contact ACL injury.

Methods

40 adolescent female football and handball players (15–16 years) were randomly allocated to a control group (CON, n=20) or neuromuscular training group (NMT, n=20). The NMT group performed an injury prevention programme as a warm-up before their usual training 3 times weekly for 12 weeks. The CON group completed their regular warm-up exercise programme before training. Players were tested while performing a side cutting movement at baseline and 12-week follow-up, using surface electromyography (EMG) and three-dimensional movement analysis. We calculated: (1) EMG amplitude from vastus lateralis (VL), semitendinosus (ST) and biceps femoris 10 ms prior to initial contact (IC) normalised to peak EMG amplitude recorded during maximal voluntary isometric contraction and (2) VL-ST EMG preactivity difference during the 10 ms prior to foot contact (primary outcome). We measured maximal knee joint valgus moment and knee valgus angle at IC.

Results

There was a difference between groups at follow-up in VL-ST preactivity (43% between-group difference; 95% CI 32% to 55%). No between-group differences were observed for kinematic and kinetic variables.

Conclusions

A 12-week injury prevention programme in addition to training and match play in adolescent females altered the pattern of agonist-antagonist muscle preactivity during side cutting. This may represent a more ACL-protective motor strategy.
Glomerular filtration rate (GFR) during and after STEMI: a single-centre, methodological study comparing estimated and measured GFR
Authors: Venetsanos Dimitrios , Alfredsson Joakim , Segelmark Mårten , Swahn Eva , Lawesson Sofia Sederholm
Published: September 2015

Objectives

To validate the performance of the most commonly used formulas for estimation of glomerular filtration rate (GFR) against measured GFR during the index hospitalisation for ST-elevation myocardial infarction (STEMI).

Setting

Single centre, methodological study.

Participants

40 patients with percutaneous coronary intervention-treated STEMI were included between November 2011 and February 2013. Patients on dialysis, cardiogenic shock or known allergy to iodine were excluded.

Outcome measures

Creatinine and cystatin C were determined at admission and before discharge in 40 patients with STEMI. Clearance of iohexol was measured (mGFR) before discharge. We evaluated and compared the Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD-IDMS), the Chronic Kidney Disease Epidemiology (CKD-EPI) and the Grubb relative cystatin C (rG-CystC) with GFR regarding correlation, bias, precision and accuracy (P30). Agreement between eGFR and mGFR to discriminate CKD was assessed by Cohen's κ statistics.

Results

MDRD-IDMS and CKD-EPI demonstrated good performance to estimate GFR (correlation 0.78 vs 0.81%, bias −1.3% vs 1.5%, precision 17.9 vs 17.1 mL/min 1.73 m2and P30 82.5% vs 82.5% for MDRD-IDMS vs CKD-EPI). CKD was best classified by CKD-EPI (κ 0.83). CG showed the worst performance (correlation 0.73%, bias −1% to 3%, precision 22.5 mL/min 1.73 m2and P30 75%). The rG-CystC formula had a marked bias of −17.8% and significantly underestimated mGFR (p=0.03). At arrival, CKD-EPI and rG-CystC had almost perfect agreement in CKD classification (κ=0.87), whereas at discharge agreement was substantially lower (κ=0.59) and showed a significant discrepancy in CKD classification (p=0.02). Median cystatin C concentration increased by 19%.

Conclusions

In acute STEMI, CKD-EPI showed the best CKD-classification ability followed by MDRD-IDMS, whereas CG performed the worst. STEMI altered the performance of the cystatin C equation during the acute phase, suggesting that other factors might be involved in the rise of cystatin C.
Identification of reciprocal causality between non-alcoholic fatty liver disease and metabolic syndrome by a simplified Bayesian network in a Chinese population
Authors: Zhang Yongyuan , Zhang Tao , Zhang Chengqi , Tang Fang , Zhong Nvjuan , Li Hongkai , Song Xinhong , Lin Haiyan , Liu Yanxun , Xue Fuzhong
Published: September 2015

Objectives

It remains unclear whether non-alcoholic fatty liver disease (NAFLD) is a cause or a consequence of metabolic syndrome (MetS). We proposed a simplified Bayesian network (BN) and attempted to confirm their reciprocal causality.

Setting

Bidirectional longitudinal cohorts (subcohorts A and B) were designed and followed up from 2005 to 2011 based on a large-scale health check-up in a Chinese population.

Participants

Subcohort A (from NAFLD to MetS, n=8426) included the participants with or without NAFLD at baseline to follow-up the incidence of MetS, while subcohort B (from MetS to NAFLD, n=16 110) included the participants with or without MetS at baseline to follow-up the incidence of NAFLD.

Results

Incidence densities were 2.47 and 17.39 per 100 person-years in subcohorts A and B, respectively. Generalised estimating equation analyses demonstrated that NAFLD was a potential causal factor for MetS (relative risk, RR, 95% CI 5.23, 3.50 to 7.81), while MetS was also a factor for NAFLD (2.55, 2.23 to 2.92). A BN with 5 simplification strategies was used for the reciprocal causal inference. The BN's causal inference illustrated that the total effect of NAFLD on MetS (attributable risks, AR%) was 2.49%, while it was 19.92% for MetS on NAFLD. The total effect of NAFLD on MetS components was different, with dyslipidemia having the greatest (AR%, 10.15%), followed by obesity (7.63%), diabetes (3.90%) and hypertension (3.51%). Similar patterns were inferred for MetS components on NAFLD, with obesity having the greatest (16.37%) effect, followed by diabetes (10.85%), dyslipidemia (10.74%) and hypertension (7.36%). Furthermore, the most important causal pathway from NAFLD to MetS was that NAFLD led to elevated GGT, then to MetS components, while the dominant causal pathway from MetS to NAFLD began with dyslipidaemia.

Conclusions

The findings suggest a reciprocal causality between NAFLD and MetS, and the effect of MetS on NAFLD is significantly greater than that of NAFLD on MetS.
Tobacco control policies and perinatal and child health: a systematic review and meta-analysis protocol
Authors: Been Jasper V , Mackenbach Johan P , Millett Christopher , Basu Sanjay , Sheikh Aziz
Published: September 2015

Introduction

Children experience considerable morbidity and mortality due to tobacco smoke exposure. Tobacco control policies may benefit child health by reducing this exposure. We aim to comprehensively assess the effects of the range of tobacco control policies advocated by the WHO on perinatal and child health.

Methods and analysis

We will systematically search 19 electronic literature databases (from inception) for published studies, and the WHO International Clinical Trials Registry Platform for unpublished studies. Additional work will be identified via handsearching references and citations, and through consulting an international panel of experts. No language restrictions will apply. Following Cochrane Effective Practice and Organisation of Care (EPOC) guidelines, randomised and clinical controlled trials, controlled before-and-after studies, and interrupted time series designs, are eligible. Studies of interest will assess the impact of any of the WHO-advocated tobacco control policies contained in the MPOWER acronym (except ‘Monitoring tobacco use’) on at least one outcome of interest among children aged 0–12 years. The primary outcomes are: perinatal mortality, preterm birth, asthma exacerbations requiring hospital attendance and respiratory infections requiring hospital attendance. Data will be extracted using customised forms and authors will be contacted to obtain missing information. Risk of bias will be assessed using EPOC criteria. Findings will be reported in narrative and tabular form. Between-study heterogeneity will be assessed clinically and statistically using I2. If appropriate and possible, random-effects meta-analysis will be conducted for each unique combination of intervention and outcome. Subgroup analyses will be performed to assess the influence of the comprehensiveness of each policy, and to explore the impact of each policy according to socioeconomic status.

Ethics and dissemination

No ethical assessment is necessary as we will summarise existing studies. We will publish our findings in a peer-reviewed scientific journal.

Trial registration number

PROSPERO; CRD42015023448.
Risky driving among UK regular armed forces personnel: changes over time
Authors: Sheriff Rebecca J Syed , Forbes Harriet J , Wessely Simon C , Greenberg Neil , Jones Norman , Fertout Mohammed , Harrison Kate , Fear Nicola T
Published: September 2015

Objectives

To compare the prevalence of self-reported risky driving in a sample of UK military personnel at 2 different time points (2004 and 2009), and to identify the incidence of new onset risky driving and possible determinants of becoming a new risky driver.

Methods

Data were used from 2 phases of a military cohort study investigating the health and well-being of UK military personnel between 2004 and 2009. Participants were included if they were undertaking regular (rather than reserve) engagements, had completed both surveys and reported being a driver at both surveys. Univariable and multivariable logistic regression analyses were performed to examine the relationship between risky driving status and sociodemographic and military characteristics. Data analysis was conducted in 2011.

Results

The prevalence of risky driving reduced from 18% to 14%, over an average of 3.3 years. The incidence of new onset risky driving was 7%. Predictors for becoming a new risky driver were: younger age, not being in a relationship at phase 2 and harmful alcohol use. Those deployed after 2007 were less likely to become risky drivers following deployment, compared with those deployed before 2007 (adjusted OR 0.62 (95% CI 0.40 to 0.95)).

Conclusions

The prevalence of becoming a risky driver appears to have reduced over time. This paper suggests a number of explanations for this reduction, including changes in the way that the UK military have dealt with road safety with the introduction of the road safety campaign (in 2007).
Palliative care referral and associated outcomes among patients with cancer in the last 2 weeks of life
Authors: Ledoux Mathilde , Rhondali Wadih , Lafumas Véronique , Berthiller Julien , Teissere Marion , Piegay Céline , Couray-Targe Sandrine , Schott Anne-Marie , Bruera Eduardo , Filbet Marilène
Published: September 2015

Background

Palliative care (PC) improves the quality of life of patients with advanced cancer. Our aim was to describe PC referral among patients with advanced cancer, and associated outcomes in an academic medical centre.

Methods

We reviewed the medical records of 536 inpatients with cancer who had died in 2010. Our retrospective study compared patients who accessed PC services with those who did not. Statistical analysis was conducted using non-parametric tests due to non-normal distribution. We also conducted a multivariate analysis using a logistic regression model including age, gender, type of cancer and metastatic status.

Results

Out of 536 patients, 239 (45%) had PC referral. The most common cancer types were respiratory (22%) and gastrointestinal (19%). Patients with breast cancer (OR 23.76; CI 6.12 to 92.18) and gynaecological cancer (OR 7.64; CI 2.61 to 22.35) had greater PC access than patients with respiratory or haematological cancer. Patients referred to PC had significantly less chemotherapy in the last 2 weeks of life than non-referred patients, with 22 patients (9%) vs 59 (19%; p<0.001). PC-referred patients had significantly fewer admissions to intensive care units in the last month of life than non-referred patients, with 14 (6%) vs 58 (20%; p<0.001).

Conclusions

There was a large variation in access to PC according to the type of cancer. There is a need to improve collaboration between the PC service and the respiratory, cancer and haematology specialists. Further research will be required to determine the modality and the impact of this collaboration.
Suture needle handling in the operating theatre; what is the safest method? A survey of surgical nursing opinion
Authors: Williams Georgina J , Nicolaou Marios , Athanasiou Thanos , Coleman David
Published: September 2015

Introduction

Suture needle handling methods vary extensively between units. Securing the needle tip by locking it against the shaft of the needle holder prior to transfer (protected method) has been suggested to improve safety, although this is not evidence based. Some teams prefer to transfer the needle mounted perpendicularly to the needle holders with the tip exposed (unprotected method). We investigated scrub nurses’ preferred method of needle transfer, and noted the safety of each by investigating their experience of needlestick injuries (NSIs).

Method

Scrub nurses from Oxford University Hospitals Trust, Chelsea and Westminster and Wexham Park Hospitals were surveyed anonymously between November 2013 and August 2014. Nurses selected their preferred method (protected, unprotected or either), and indicated previous NSIs with either technique. Multinomial regression analysis and χ2with Yates correction were used to assess associations.

Results

One hundred and seven scrub nurses from 12 specialities were interviewed. 80/107 (75%) preferred protected transfer, 20/107 (19%) preferred unprotected transfer and 7/107 (6%) expressed no preference. There was no significant association between needle-mounting preference and years of scrub experience or speciality. Significant differences between preferences and four of the six hospitals were observed. Nine (9/107, 8%) scrub nurses reported NSIs with the protected method compared with 40 (40/107, 37%) in the unprotected group, this difference being statistically significant (p<0.001, χ2=25.17). Five (5/107, 5%) reported NSIs with both methods.

Conclusions

Protected needle transfer seems safer than the unprotected method. Needle-handling guidelines and appropriate training are required to help prevent the occurrence of NSIs in the operating theatre.
Systemic lupus erythematosus complicated by diffuse alveolar haemorrhage: risk factors, therapy and survival
Authors: Kazzaz Nayef M , Coit Patrick , Lewis Emily E , McCune W Joseph , Sawalha Amr H , Knight Jason S
Published: September 2015

Objectives

While diffuse alveolar haemorrhage (DAH) is recognised as a life-threatening complication of systemic lupus erythematosus (SLE), little is known about its risk factors and response to treatment. We describe 22 cases of DAH in a US lupus cohort of approximately 1000 patients, and compare them to 66 controls from the same outpatient cohort.

Methods

We captured variables pertaining to diagnoses of SLE and secondary antiphospholipid syndrome (APS), and analysed them by univariate testing. Those variables with p values <0.05 were then further considered in a multivariate model. Kaplan-Meier curves were constructed for each group, and survival was analysed by Log-rank test.

Results

Of the 22 patients with DAH, 59% were diagnosed with DAH within 5 years of lupus diagnosis. By univariate testing, several manifestations of SLE and APS were more common in patients with DAH, including history of thrombocytopenia, cardiac valve disease, low C3, leucopenia, neuropsychiatric features, haemolysis, arterial thrombosis, lupus anticoagulant, secondary APS and low C4. On multivariate analysis, history of thrombocytopenia and low C3 were maintained as independent risk factors. Importantly, only two patients had platelet counts <50 000/µL at the time of the DAH episode, arguing that DAH was not simply a haemorrhagic complication of thrombocytopenia. All patients were treated with increased immunosuppression, including various combinations of corticosteroids, plasmapheresis, cyclophosphamide, rituximab and mycophenolate mofetil. Notably, all patients in the cohort survived their initial episode of DAH. While the patients with DAH did well in the short-term, their long-term survival was significantly worse than controls. Several of the deaths were attributable to thrombotic complications after recovering from DAH.

Conclusions

To the best of our knowledge, this is the largest case–control study of lupus DAH to date. History of thrombocytopenia was strongly predictive of DAH (OR ∼40). A number of APS manifestations correlated with DAH by univariate analysis, and deserve further consideration in larger studies.
Non-convulsive status epilepticus: a practical approach to diagnosis in confused older people
Authors: Woodford Henry John , George James , Jackson Margaret
Published: September 2015

Non-convulsive status epilepticus (NCSE) presents with minimal seizure activity clinically, but with evidence on EEG. It is a recognised cause of delirium in older people, but prevalence estimates vary widely. As delirium is a common presentation in older people and because NCSE is potentially reversible, an improved diagnostic ability in this group could be highly beneficial. EEG testing is required to make a definitive diagnosis, but this may be difficult due to access to testing, patient adherence and result interpretation. NCSE has two commonly recognised forms: complex partial status epilepticus (CPSE) and absence status epilepticus (ASE). Clinical features associated with NCSE in older people presenting with confusion include a reduction in level of arousal; aphasia or interrupted speech; myoclonus or subtle jerking; staring; automatisms; perseveration or echolalia; increased tone; nystagmus or eye deviation; emotional lability; disinhibition and anosagnosia. Risk factors include female sex, a history of epilepsy or a tonic–clonic seizure around the time of onset, and recent discontinuation of benzodiazepines. A practical approach to the diagnosis of NCSE in older people is suggested based upon the presence of clinical features suggestive of NCSE and local access to EEG testing.
Epilepsy beyond seizures: a review of the impact of epilepsy and its comorbidities on health‐related quality of life in dogs
Authors: Packer Rowena M. A. , Volk Holger A.
Published: September 2015

Epilepsy is one of the most common chronic neurological conditions in the dog, estimated to affect 0.6 to 0.75 per cent of dogs. Owners of dogs with epilepsy have previously indicated that their dog's quality of life (QoL) is of greatest importance to them above seizure frequency; however, much of the research into canine epilepsy to date has focussed on seizure frequency, and how to reduce it via antiepileptic drug treatment. In people, the impact of epilepsy upon QoL has been widely studied, exploring not only its impact on physical health, but also the psychological health and cognitive capabilities of affected individuals. This paper reviews the existing literature on canine epilepsy, identifies potential threats to QoL, and draws parallels from human epilepsy research. We suggest that canine epilepsy poses threats to both quality and quantity of life, with treatment interventions posing a fine balance of potential benefits and harms to the patient. At present, little is known about the neurobehavioural, emotional and cognitive effects of epilepsy upon affected dogs. Further studies are needed to establish the extent to which unknown QoL‐inhibiting comorbidities exist in the dog, in order to avoid their undertreatment, and to objectively quantify the effects of epilepsy on canine QoL.
Efficient method for rapid multiplication of clean and healthy willow clones via in vitro propagation with broad genotype applicability
Authors: Palomo-Ríos Elena , Macalpine William , Shield Ian , Amey Joanna , Karaoğlu Cuma , West Jevon , Hanley Steven , Krygier Richard , Karp Angela , Jones Huw D.
Published: September 2015

Willow is a versatile crop with considerable potential as a source of renewable biomass for bioenergy. Although breeding new varieties takes less time compared with some other tree species, producing new willow varieties is still a slow, labour-intensive process, partly because clonally propagating the results of each cross is a bottleneck early in the breeding scheme. In this paper, we describe a facile, rapid method for the in vitro culture of a wide range of willow genotypes. We have developed a combination of media and methods for efficient tissue-culture propagation to rapidly multiply individual plants and simultaneously produce clean, stock germplasm applicable to a wide range of willow genotypes that can be phytosanitary tested to demonstrate their disease-free status. The micropropagation method described could generate in the order of 5000 viable, transplantable clones from a single plant in just 24 weeks and was used to produce phytosanitary tested breeding material for export to overcome restriction on the international transport of woody cuttings. This method could represent a valuable biotechnology adjunct to willow breeding programmes and could accommodate early selection via molecular or biochemical markers.
Differences in histone modifications between slow- and fast-twitch muscle of adult rats and following overload, denervation, or valproic acid administration
Authors: Kawano Fuminori , Nimura Keisuke , Ishino Saki , Nakai Naoya , Nakata Ken , Ohira Yoshinobu
Published: September 2015

Numerous studies have reported alterations in skeletal muscle properties and phenotypes in response to various stimuli such as exercise, unloading, and gene mutation. However, a shift in muscle fiber phenotype from fast twitch to slow twitch is not completely induced by stimuli. This limitation is hypothesized to result from the epigenetic differences between muscle types. The main purpose of the present study was to identify the differences in histone modification for the plantaris (fast) and soleus (slow) muscles of adult rats. Genome-wide analysis by chromatin immunoprecipitation followed by DNA sequencing revealed that trimethylation at lysine 4 and acetylation of histone 3, which occurs at transcriptionally active gene loci, was less prevalent in the genes specific to the slow-twitch soleus muscle. Conversely, gene loci specific to the fast-twitch plantaris muscle were associated with the aforementioned histone modifications. We also found that upregulation of slow genes in the plantaris muscle, which are related to enhanced muscular activity, is not associated with activating histone modifications. Furthermore, silencing of muscle activity by denervation caused the displacement of acetylated histone and RNA polymerase II (Pol II) in 5′ ends of genes in plantaris, but minor effects were observed in soleus. Increased recruitment of Pol II induced by forced acetylation of histone was also suppressed in valproic acid-treated soleus. Our present data indicate that the slow-twitch soleus muscle has a unique set of histone modifications, which may relate to the preservation of the genetic backbone against physiological stimuli.
Reduced voluntary drive during sustained but not during brief maximal voluntary contractions in the first dorsal interosseous weakened by spinal cord injury
Authors: Prak Roeland F. , Doestzada Marwah , Thomas Christine K. , Tepper Marga , Zijdewind Inge
Published: September 2015

In able-bodied (AB) individuals, voluntary muscle activation progressively declines during sustained contractions. However, few data are available on voluntary muscle activation during sustained contractions in muscles weakened by spinal cord injury (SCI), where greater force declines may limit task performance. SCI-related impairment of muscle activation complicates interpretation of the interpolated twitch technique commonly used to assess muscle activation. We attempted to estimate and correct for the SCI-related-superimposed twitch. Seventeen participants, both AB and with SCI (American Spinal Injury Association Impairment Scale C/D) produced brief and sustained (2-min) maximal voluntary contractions (MVCs) with the first dorsal interosseous. Force and electromyography were recorded together with superimposed (doublet) twitches. MVCs of participants with SCI were weaker than those of AB participants (20.3 N, SD 7.1 vs. 37.9 N, SD 9.5; P < 0.001); MVC-superimposed twitches were larger in participants with SCI (SCI median 10.1%, range 2.0-63.2%; AB median 4.7%, range 0.0–18.4% rest twitch; P = 0.007). No difference was found after correction for the SCI-related-superimposed twitch (median 6.7%, 0.0–17.5% rest twitch, P = 0.402). Thus during brief contractions, the maximal corticofugal output that participants with SCI could exert was similar to that of AB participants. During the sustained contraction, force decline (SCI, 58.0%, SD 15.1; AB, 57.2% SD 13.3) was similar ( P = 0.887) because participants with SCI developed less peripheral ( P = 0.048) but more central fatigue than AB participants. The largest change occurred at the start of the sustained contraction when the (corrected) superimposed twitches increased more in participants with SCI (SCI, 16.3% rest twitch, SD 20.8; AB, 2.7%, SD 4.7; P = 0.01). The greater reduction in muscle activation after SCI may relate to a reduced capacity to overcome fast fatigue-related excitability changes at the spinal level.
Characterizing and modeling the intrinsic light response of rat ganglion-cell photoreceptors
Authors: Walch Olivia J. , Zhang L. Samantha , Reifler Aaron N. , Dolikian Michael E. , Forger Daniel B. , Wong Kwoon Y.
Published: September 2015

Intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate both image-forming vision and non-image-forming visual responses such as pupillary constriction and circadian photoentrainment. Five types of ipRGCs, named M1–M5, have been discovered in rodents. To further investigate their photoresponse properties, we made multielectrode array spike recordings from rat ipRGCs, classified them into M1, M2/M4, and M3/M5 clusters, and measured their intrinsic, melanopsin-based responses to single and flickering light pulses. Results showed that ipRGC spiking can track flickers up to ∼0.2 Hz in frequency and that flicker intervals between 5 and 14 s evoke the most spikes. We also learned that melanopsin’s integration time is intensity and cluster dependent. Using these data, we constructed a mathematical model for each cluster’s intrinsic photoresponse. We found that the data for the M1 cluster are best fit by a model that assumes a large photoresponse, causing the cell to enter depolarization block. Our models also led us to hypothesize that the M2/M4 and M3/M5 clusters experience comparable photoexcitation but that the M3/M5 cascade decays significantly faster than the M2/M4 cascade, resulting in different response waveforms between these clusters. These mathematical models will help predict how each ipRGC cluster might respond to stimuli of any waveform and could inform the invention of lighting technologies that promote health through melanopsin stimulation.
Store-Operated Calcium Channels
Authors: Prakriya Murali , Lewis Richard S.
Published: September 2015

Store-operated calcium channels (SOCs) are a major pathway for calcium signaling in virtually all metozoan cells and serve a wide variety of functions ranging from gene expression, motility, and secretion to tissue and organ development and the immune response. SOCs are activated by the depletion of Ca2+from the endoplasmic reticulum (ER), triggered physiologically through stimulation of a diverse set of surface receptors. Over 15 years after the first characterization of SOCs through electrophysiology, the identification of the STIM proteins as ER Ca2+sensors and the Orai proteins as store-operated channels has enabled rapid progress in understanding the unique mechanism of store-operate calcium entry (SOCE). Depletion of Ca2+from the ER causes STIM to accumulate at ER-plasma membrane (PM) junctions where it traps and activates Orai channels diffusing in the closely apposed PM. Mutagenesis studies combined with recent structural insights about STIM and Orai proteins are now beginning to reveal the molecular underpinnings of these choreographic events. This review describes the major experimental advances underlying our current understanding of how ER Ca2+depletion is coupled to the activation of SOCs. Particular emphasis is placed on the molecular mechanisms of STIM and Orai activation, Orai channel properties, modulation of STIM and Orai function, pharmacological inhibitors of SOCE, and the functions of STIM and Orai in physiology and disease.
Nutritional Aspects of Depression
Authors: Lang Undine E. , Beglinger Christoph , Schweinfurth Nina , Walter Marc , Borgwardt Stefan
Published: September 2015

Several nutrition, food and dietary compounds have been suggested to be involved in the onset and maintenance of depressive disorders and in the severity of depressive symptoms. Nutritional compounds might modulate depression associated biomarkers and parallel the development of depression, obesity and diabetes. In this context, recent studies revealed new mediators of both energy homeostasis and mood changes (i.e. IGF-1, NPY, BDNF, ghrelin, leptin, CCK, GLP-1, AGE, glucose metabolism and microbiota) acting in gut brain circuits. In this context several healthy foods such as olive oil, fish, fruits, vegetables, nuts, legumes, poultry, dairy and unprocessed meat have been inversely associated with depression risk and even have been postulated to improve depressive symptoms. In contrast, unhealthy western dietary patterns including the consumption of sweetened beverage, refined food, fried food, processed meat, refined grain, and high fat diary, biscuits, snacking and pastries have been shown to be associated with an increased risk of depression in longitudinal studies. However, it is always difficult to conclude a real prospective causal relationship from these mostly retrospective studies as depressed individuals might also change their eating habits secondarily to their depression. Additionally specific selected nutritional compounds, e.g. calcium, chromium, folate, PUFAs, vitamin D, B12, zinc, magnesium and D-serine have been postulated to be used as ad-on strategies in antidepressant treatment. In this context, dietary and lifestyle interventions may be a desirable, effective, pragmatical and non-stigmatizing prevention and treatment strategy for depression. At last, several medications (pioglitazone, metformin, exenatide, atorvastatin, gram-negative antibiotics), which have traditionally been used to treat metabolic disorders showed a certain potential to treat depression in first randomized controlled clinical trials.
Exome Sequencing Identifies a c.148-1G>C Mutation of TBX5 in a Holt-Oram Family with Unusual Genotype-Phenotype Correlations
Authors: Guo Qianqian , Shen Jia , Liu Yang , Pu Tian , Sun Kun , Chen Sun
Published: September 2015

Background/Aims: Congenital heart defects (CHD) can occur with upper limbs deformities. Holt-Oram syndrome is the main type of heart-hand syndromes, characterized by upper limb radial ray malformations, CHD and/or conduction abnormalities. Mutations of the TBX5 gene, most of which are found within the T-box domain, are one cause of the disease. We aimed to find the cause of the disease in a family with two children exhibiting symptoms of Holt-Oram syndrome while the parents tend to be normal. Methods: Chromosomal microarray analysis and exome sequencing were applied in the proband segments bearing the specific mutation and single nucleotide variants (SNVs) suspected of being involved in the disease were analyzed by polymerase chain reaction and direct sequencing. Results: A splice acceptor site mutation c.148-1G>C of TBX5 was detected in both the father and the proband. The mutation may result in an aberrant transcript which will most probably undergo nonsense-mediated decay (NMD) system resulting in haploinsufficiency of TBX5 protein. In the meantime, 3 candidated SNVs were detected. Conclusions: c.148-1G>C of TBX5 should be the pathogenic cause of the disease in this family. Works have been done to find a possible explanation of the unusual genotype-phenotype correlations in this family and further studies are still needed.
Sox9 Activation is Essential for the Recovery of Lung Function after Acute Lung Injury
Authors: Li Lei , Zhang Hong , Min Dong , Zhang Ruyuan , Wu Jun , Qu Hongping , Tang Yaoqing
Published: September 2015

Background/Aims: Acute lung injury (ALI) often predisposes acute respiratory distress syndrome (ARDS) in humans, and is featured with neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Although the pathogenesis of ALI is relatively well studied, the knowledge on the molecular regulation of the post-ALI lung recovery are poorly understood. Methods: Here, we used a widely applied bleomycin-induced ALI model to study the molecular mechanisms that underlie the post-ALI lung recovery in mice. We analyzed Sox9 expression in mouse lung by RT-qPCR, Western blot and immunohistochemistry. We analyzed miR-101 levels in mouse lung by RT-qPCR. We inhibited Sox9 in mouse lung by expressing either shRNA for Sox9 or miR-101, and analyzed the effects of Sox9 suppression on lung recovery. Results: We detected a significant increase in Sox9 protein but not mRNA, and a signifcant decrease in miR-101 levels in the mouse lung after ALI. MiR-101 was found to target 3'-UTR of Sox9 mRNA to inhibit its expression. Sox9 inhibition by either shRNA for Sox9 or by miR-101 further impaired the functional recovery of the lung after ALI. Conclusion: Our data suggest that Sox9 activation is essential for the recovery of lung function after ALI, which highlights a previously unappreciated mechanism that controls the post-ALI lung recovery.
Prior Asymptomatic Parenchymal Hemorrhage Does Not Increase the Risk for Intracranial Hemorrhage after Intravenous Thrombolysis
Authors: AbdelRazek Mahmoud AbdelMageed , Mowla Ashkan , Hojnacki David , Zimmer Wendy , Elsadek Rabab , Abdelhamid Nour , Elsadek Lobna , Farooq Salman , Kamal Haris , Crumlish Annemarie , Shirani Peyman , Ching Marilou , Sawyer Robert
Published: September 2015

Background: The NINDS trial demonstrated the efficacy of intravenous (IV) recombinant tissue plasminogen activator (rtPA) in improving the neurologic outcome in patients presenting with acute ischemic strokes. Patients who had a prior history of intracranial hemorrhage (ICH) were excluded from this trial, possibly due to a hypothetical increase in the subsequent bleeding risk. Thus, there is little data available, whether against or in favor of, the use of IV rtPA in patients with prior ICH. We aim to aid in determining the safety of IV rtPA in such patients through a retrospective hospital-based single center study. Methods: We reviewed the brain imaging of all patients who received IV rtPA at our comprehensive stroke center from January 2006 to April 2014 for evidence of prior ICH at the time of IV rtPA administration. Their outcomes were determined in terms of subsequent development of symptomatic ICH as defined by the NINDS trial. Results: Brain imaging for 640 patients was reviewed. A total of 27 patients showed evidence of prior ICH at the time of IV thrombolysis, all intra-parenchymal. Only 1 patient (3.7%) developed subsequent symptomatic ICH after the administration of IV rtPA. Of the remaining 613 patients who received IV rtPA, 25 patients (4.1%) developed symptomatic ICH. Conclusion: This retrospective study provides Level C evidence that patients with imaging evidence of prior asymptomatic intra-parenchymal hemorrhage presenting with an acute ischemic stroke do not show an increased risk of developing symptomatic ICH after IV thrombolysis.
Clinical Significance of Preoperative CD8+ Central Memory T Cells for Operable Pancreatic Adenocarcinoma
Authors: Liu Hai-Liang , Guan Cheng-Jian , Wu Yong-Jie , Hu Ming-Gen , Zhao Zhi-Ming , Liu Rong
Published: September 2015

Background: CD8+ central memory T cells (CD8+ Tcm) have superior roles in antitumor immunity. The purpose of this study was to detect CD8+ Tcm in the peripheral blood of patients with pancreatic adenocarcinoma and to analyze its clinic significance. Methods: Seventy two patients with primary pancreatic adenocarcinoma who underwent curative operation were enrolled. The percentage and absolute count of CD8+ Tcm in the peripheral blood of patients were analyzed through flow cytometry and the multiplatform predicate method, respectively, and these values were compared to those of the healthy control. The correlation between CD8+ Tcm and survival was analyzed by the Kaplan-Meier with log-rank test and Cox's regression methods, respectively. Results: The percentage of CD8+ Tcm from pancreatic adenocarcinoma was higher than the healthy control (16.79 ± 9.43% vs. 11.41 ± 4.67%, p = 0.028), which also had a relationship with the lymph node status. Patients with high-level CD8+ Tcm had a significantly higher median survival than those with low CD8+ Tcm (18 vs. 12 months, p = 0.004); a similar result was obtained in absolute CD8+ Tcm count. It was revealed in multivariate analysis that both percentage and absolute count of CD8+ Tcm was an independent prognostic factor for overall survival. Conclusions: CD8+ Tcm can be considered an independent prognostic factor for operable pancreatic adenocarcinoma, which was also associated with the lymph nodes metastasis.
Холангіт як хірургічна проблема, оновлений погляд згідно з Токійськими клінічними рекомендаціями 2013 р. (TG 13)
Authors: НИЧИТАЙЛО М. Ю. , ГУЦУЛЯК А. І. , БУЛИК І. І. , ЗАГРІЙЧУК М. С. , ГОМАН А. В.
Published: September 2015

У статті висвітлено проблему гострої біліарної інфекції, її актуальність у хірургічній практиці на сьогодні, здійснено аналіз причин виникнення гострого холангіту та спектра інфекційних збудників, які призводять до його розвитку. Розглянуто сучасні класифікації та підходи до діагностики згідно з Токійськими клінічними рекомендаціями 2013 р. (TG13). Представлено комплексний підхід та алгоритм лікування гострого холангіту з врахуванням ступеня тяжкості захворювання, з відповідним моніторингом та корекцією терапії при зміні клінічної картини.