bluuebunny/crossref_metadata_2025 huggingface dataset:
Hijacking of RIG-I Signaling Proteins into Virus-Induced Cytoplasmic Structures Correlates with the Inhibition of Type I Interferon Responses
Authors: Santiago Felix W. , Covaleda Lina M. , Sanchez-Aparicio Maria T. , Silvas Jesus A. , Diaz-Vizarreta Ana C. , Patel Jenish R. , Popov Vsevolod , Yu Xue-jie , García-Sastre Adolfo , Aguilar Patricia V.
Published: January 2014

Recognition of viral pathogens by the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family results in the activation of type I interferon (IFN) responses. To avoid this response, most viruses have evolved strategies that target different essential steps in the activation of host innate immunity. In this study, we report that the nonstructural protein NSs of the newly described severe fever with thrombocytopenia syndrome virus (SFTSV) is a potent inhibitor of IFN responses. The SFTSV NSs protein was found to inhibit the activation of the beta interferon (IFN-β) promoter induced by viral infection and by a RIG-I ligand. Astonishingly, we found that SFTSV NSs interacts with and relocalizes RIG-I, the E3 ubiquitin ligase TRIM25, and TANK-binding kinase 1 (TBK1) into SFTSV NSs-induced cytoplasmic structures. Interestingly, formation of these SFTSV NSs-induced structures occurred in the absence of the Atg7 gene, a gene essential for autophagy. Furthermore, confocal microscopy studies revealed that these SFTSV NSs-induced structures colocalize with Rab5 but not with Golgi apparatus or endoplasmic reticulum markers. Altogether, the data suggest that sequestration of RIG-I signaling molecules into endosome-like structures may be the mechanism used by SFTSV to inhibit IFN responses and point toward a novel mechanism for the suppression of IFN responses.

IMPORTANCE
The mechanism by which the newly described SFTSV inhibits host antiviral responses has not yet been fully characterized. In this study, we describe the redistribution of RIG-I signaling components into virus-induced cytoplasmic structures in cells infected with SFTSV. This redistribution correlates with the inhibition of host antiviral responses. Further characterization of the interplay between the viral protein and components of the IFN responses could potentially provide targets for the rational development of therapeutic interventions.
Functional Implications of the Binding Mode of a Human Conformation-Dependent V2 Monoclonal Antibody against HIV
Authors: Spurrier Brett , Sampson Jared , Gorny Miroslaw K. , Zolla-Pazner Susan , Kong Xiang-Peng
Published: January 2014

Data from the RV144 HIV vaccine trial indicated that gp120 V2 antibodies were associated with a lower risk of infection; thus, the mapping of V2 epitopes can contribute to the design of an effective HIV vaccine. We solved the crystal structure of human monoclonal antibody (MAb) 2158, which targets a conformational V2 epitope overlapping the α4β7 integrin binding site, and constructed a full-length model of V1V2. Comparison of computational energy stability to experimental enzyme-linked immunosorbent assay (ELISA) results identified a hydrophobic core that stabilizes the V2 region for optimal 2158 binding, as well as residues that directly mediate side chain interactions with MAb 2158. These data define the binding surface recognized by MAb 2158 and offer a structural explanation for why a mismatched mutation at position 181 (I181X) in the V2 loop was associated with a higher vaccine efficiency in the RV144 clinical vaccine trial.

IMPORTANCECorrelate analysis of the RV144 HIV-1 vaccine trial suggested that the presence of antibodies to the second variable region (V2) of HIV-1 gp120 was responsible for the modest protection observed in the trial. V2 is a highly variable and immunogenic region, and structural information on its antigenic landscape will be important for rational design of an effective HIV-1 vaccine. Using X-ray crystallography, computational design tools, and mutagenesis assays, we carried out a detailed and systematic investigation of the epitope recognition of human V2 MAb 2158 and demonstrated that its epitope region overlaps the integrin binding site within V2. In addition, we propose a structure-based mechanism for mismatching of the isoleucine at position 181 and the increased vaccine efficacy seen in the RV144 vaccine trial.
Novel Avian-Origin Influenza A (H7N9) Virus Attachment to the Respiratory Tract of Five Animal Models
Authors: Siegers Jurre Y. , Short Kirsty R. , Leijten Lonneke M. E. , de Graaf Miranda , Spronken Monique I. J. , Schrauwen Eefje J. A. , Marshall Nicolle , Lowen Anice C. , Gabriel Gülsah , Osterhaus Albert D. M. E. , Kuiken Thijs , van Riel Debby
Published: January 2014

We determined the pattern of attachment of the avian-origin H7N9 influenza viruses A/Anhui/1/2013 and A/Shanghai/1/2013 to the respiratory tract in ferrets, macaques, mice, pigs, and guinea pigs and compared it to that in humans. The H7N9 attachment pattern in macaques, mice, and to a lesser extent pigs and guinea pigs resembled that in humans more closely than the attachment pattern in ferrets. This information contributes to our knowledge of the different animal models for influenza.
Chimeric Bovine/Human Parainfluenza Virus Type 3 Expressing Respiratory Syncytial Virus (RSV) F Glycoprotein: Effect of Insert Position on Expression, Replication, Immunogenicity, Stability, and Protection against RSV Infection
Authors: Liang Bo , Munir Shirin , Amaro-Carambot Emerito , Surman Sonja , Mackow Natalie , Yang Lijuan , Buchholz Ursula J. , Collins Peter L. , Schaap-Nutt Anne
Published: January 2014

A recombinant chimeric bovine/human parainfluenza type 3 virus (rB/HPIV3) vector expressing the respiratory syncytial virus (RSV) fusion F glycoprotein previously exhibited disappointing levels of RSV F immunogenicity and genetic stability in children (D. Bernstein et al., Pediatr. Infect. Dis. J. 31:109–114, 2012; C.-F. Yang et al., Vaccine 31:2822–2827, 2013). To investigate parameters that might affect vaccine performance and stability, we constructed and characterized rB/HPIV3 viruses expressing RSV F from the first (pre-N), second (N-P), third (P-M), and sixth (HN-L) genome positions. There was a 30- to 69-fold gradient in RSV F expression from the first to the sixth position. The inserts moderately attenuated vector replication
in vitro
and in the upper and lower respiratory tracts of hamsters: this was not influenced by the level of RSV F expression and syncytium formation. Surprisingly, inserts in the second, third, and sixth positions conferred increased temperature sensitivity: this was greatest for the third position and was the most attenuating
in vivo
. Each rB/HPIV3 vector induced a high titer of neutralizing antibodies in hamsters against RSV and HPIV3. Protection against RSV challenge was greater for position 2 than for position 6. Evaluation of insert stability suggested that RSV F is under selective pressure to be silenced during vector replication
in vivo
, but this was not exacerbated by a high level of RSV F expression and generally involved a small percentage of recovered vector. Vector passaged
in vitro
accumulated mutations in the HN open reading frame, causing a dramatic increase in plaque size that may have implications for vaccine production and immunogenicity.

IMPORTANCE
The research findings presented here will be instrumental for improving the design of a bivalent pediatric vaccine for respiratory syncytial virus and parainfluenza virus type 3, two major causes of severe respiratory tract infection in infants and young children. Moreover, this knowledge has general application to the development and clinical evaluation of other mononegavirus vectors and vaccines.
Murine Leukemia Virus Uses NXF1 for Nuclear Export of Spliced and Unspliced Viral Transcripts
Authors: Sakuma Toshie , Davila Jaime I. , Malcolm Jessica A. , Kocher Jean-Pierre A. , Tonne Jason M. , Ikeda Yasuhiro
Published: January 2014

Intron-containing mRNAs are subject to restricted nuclear export in higher eukaryotes. Retroviral replication requires the nucleocytoplasmic transport of both spliced and unspliced RNA transcripts, and RNA export mechanisms of gammaretroviruses are poorly characterized. Here, we report the involvement of the nuclear export receptor NXF1/TAP in the nuclear export of gammaretroviral RNA transcripts. We identified a conserved
cis
-acting element in the
pol
gene of gammaretroviruses, including murine leukemia virus (MLV) and xenotropic murine leukemia virus (XMRV), named the CAE (cytoplasmic accumulation element). The CAE enhanced the cytoplasmic accumulation of viral RNA transcripts and the expression of viral proteins without significantly affecting the stability, splicing, or translation efficiency of the transcripts. Insertion of the CAE sequence also facilitated Rev-independent HIV Gag expression. We found that the CAE sequence interacted with NXF1, whereas disruption of NXF1 ablated CAE function. Thus, the CAE sequence mediates the cytoplasmic accumulation of gammaretroviral transcripts in an NXF1-dependent manner. Disruption of NXF1 expression impaired cytoplasmic accumulations of both spliced and unspliced RNA transcripts of XMRV and MLV, resulting in their nuclear retention or degradation. Thus, our results demonstrate that gammaretroviruses use NXF1 for the cytoplasmic accumulation of both spliced and nonspliced viral RNA transcripts.

IMPORTANCE
Murine leukemia virus (MLV) has been studied as one of the classic models of retrovirology. Although unspliced host messenger RNAs are rarely exported from the nucleus, MLV actively exports unspliced viral RNAs to the cytoplasm. Despite extensive studies, how MLV achieves this difficult task has remained a mystery. Here, we have studied the RNA export mechanism of MLV and found that (i) the genome contains a sequence which supports the efficient nuclear export of viral RNAs, (ii) the cellular factor NXF1 is involved in the nuclear export of both spliced and unspliced viral RNAs, and, finally, (iii) depletion of NXF1 results in nuclear retention or degradation of viral RNAs. Our study provides a novel insight into MLV nuclear export.
Kaposi's Sarcoma-Associated Herpesvirus-Encoded LANA Contributes to Viral Latent Replication by Activating Phosphorylation of Survivin
Authors: Lu Jie , Jha Hem C. , Verma Subhash C. , Sun Zhiguo , Banerjee Shuvomoy , Dzeng Richard , Robertson Erle S.
Published: January 2014

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus casually linked to Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). Previously, we showed that LANA encoded by KSHV upregulates expression of survivin, a member of the inhibitor of apoptosis (IAP) family. This leads to an increase in the rate of cell proliferation of KSHV-infected B cells. LANA is required for tethering of the KSHV episome to the host chromosomes and efficiently segregates the viral genomes into dividing tumor cells. Here we show that LANA interacts with Aurora kinase B (AK-B) and induces phosphorylation of survivin at residue T34. Phosphorylation of survivin specifically on residue T34 enhances the activity of p300 and inhibits the activity of histone deacetylase 1 (HDAC-1), which then leads to an increase in acetylation of histone H3 on the viral genome. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases, which then leads to an increase in viral copy number in KSHV-infected B cells. This results in a boost of KSHV replication in latently infected B-lymphoma cells. The studies showed that LANA can also function to regulate viral replication prior to mitosis of the latently infected cells, suggesting that LANA possesses a novel role in regulating KSHV replication in infected B cells.

IMPORTANCE
This work represents a report of KSHV latent protein LANA and its interactions with AK-B leading to induction of phosphorylation of the oncoprotein survivin at residue T34. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases. This leads to an increase in viral copy number in KSHV-infected B cells. These studies support a role for LANA in regulating KSHV replication through posttranslation modification in KSHV-infected B cells.
Orbital metastasis as the inaugural presentation of occult rectal cancer
Authors: Cherif Eya , Ben Hassine Lamia , Azzabi Samira , Khalfallah Narjess
Published: January 2014

Orbital metastasis is uncommon and occurs in 2–3% of patients with cancer. It is rarely the initial manifestation of a systemic malignancy. It usually indicates extensive haematogenous dissemination of a primary cancer and is associated with poor prognosis. Breast, lungs and prostate cancers are the most common primary cancers leading to orbital metastasis. However, orbital tumour revealing a rectal adenocarcinoma is exceptional. We describe a case of orbital tumour in a 67-year-old man with no history of systemic cancer while presenting with ophthalmic symptoms. Investigations revealed rectal adenocarcinoma as the primary malignant tumour.
Florid cystic endosalpingiosis, masquerading as malignancy in a young patient: a brief review
Authors: Singh Neeta , Murali Subbaiah , Zangmo Rinchen
Published: January 2014

Endosalpingiosis is a rare condition characterised by the presence of tubal epithelium outside the fallopian tube. Most of the previous case reports have described this condition in women in their fifth decade or older. We report a case of a woman presenting at 31 years with a history of heavy bleeding during menses and pain in the lower abdomen for the past 2 years. An ultrasound examination showed a left ovarian cyst of 4.3×3.2 cm with multiple septations. CA 125 was within normal range. Laparoscopy was performed with the plan of ovarian cystectomy, peroperatively; there were papillary projections all over the uterus and the peritoneal surface. The left ovary was enlarged with papillary projections on the surface. Multiple biopsies were taken from the surface of the uterus, ovary and the peritoneum as the picture was quite suspicious of malignancy. Histopathological examination gave the picture of endosalpingiosis. The patient underwent laparoscopic ovariotomy with fulguration of lesions 4 months later, in view of persistent pain and discomfort, and increase in the size of the cyst on ultrasound monitoring. Presently, she is free of symptoms.
Denosumab should be the treatment of choice for bisphosphonate refractory hypercalcaemia of malignancy
Authors: Adhikaree Jason , Newby Yvette , Sundar Santhanam
Published: January 2014

Denosumab, a fully humanised monoclonal antibody, is licensed for treatment of postmenopausal osteoporosis, hormone ablation-induced bone loss and for prevention of skeleton-related events in patients with bone metastases from solid tumours. In pivotal phase 3 randomised trials, denosumab caused profound hypocalcaemia in patients with normocalcaemia despite oral calcium and vitamin D supplementation. This significant hypocalcaemic effect can be exploited to treat hypercalcaemia of malignancy (HCM). Recent reports from the USA suggest that denosumab is an effective treatment of HCM. According to our knowledge, we report the first two cases in UK with bisphosphonate refractory hypercalcaemia who responded to denosumab injections. Our first case gained 7 months of stabilisation of hypercalcaemia following prolonged admissions with life-threatening levels, while our second case achieved rapid normalisation of serum calcium levels for the first time in 14 months. We conclude that denosumab should be the treatment of choice for patients with bisphosphonate refractory hypercalcaemia.
Northern Territory Heart Failure Initiative–Clinical Audit (NTHFI–CA)–a prospective database on the quality of care and outcomes for acute decompensated heart failure admission in the Northern Territory: study design and rationale
Authors: Iyngkaran Pupalan , Tinsley Jeff , Smith David , Haste Mark , Nadarajan Kangaharan , Ilton Marcus , Battersby Malcolm , Stewart Simon , Brown Alex
Published: January 2014

Introduction

Congestive heart failure is a significant cause of morbidity and mortality in Australia. Accurate data for the Northern Territory and Indigenous Australians are not presently available. The economic burden of this chronic cardiovascular disease is felt by all funding bodies and it still remains unclear what impact current measures have on preventing the ongoing disease burden and how much of this filters down to more remote areas. Clear differentials also exist in rural areas including a larger Indigenous community, greater disease burden, differing aetiologies for heart failure as well as service and infrastructure discrepancies. It is becoming increasingly clear that urban solutions will not affect regional outcomes. To understand regional issues relevant to heart failure management, an understanding of the key performance indicators in that setting is critical.

Methods and analysis

TheNorthernTerritoryHeartFailureInitiative—ClinicalAudit (NTHFI-CA) is a prospective registry of acute heart failure admissions over a 12-month period across the two main Northern Territory tertiary hospitals. The study collects information across six domains and five dimensions of healthcare. The study aims to set in place an evidenced and reproducible audit system for heart failure and inform the developing heart failure disease management programme. The findings, is believed, will assist the development of solutions to narrow the outcomes divide between remote and urban Australia and between Indigenous and Non-Indigenous Australians, in case they exist. A combination of descriptive statistics and mixed effects modelling will be used to analyse the data.

Ethics and dissemination

This study has been approved by respective ethics committees of both the admitting institutions. All participants will be provided a written informed consent which will be completed prior to enrolment in the study. The study results will be disseminated through local and international health conferences and peer reviewed manuscripts.
Association among work exposure, alcohol intake, smoking and Dupuytren's disease in a large cohort study (GAZEL)
Authors: Descatha Alexis , Carton Matthieu , Mediouni Zakia , Dumontier Christian , Roquelaure Yves , Goldberg Marcel , Zins Marie , Leclerc Annette
Published: January 2014

Objectives

In view of the debate of factors in Dupuytren’s disease, we aimed to describe its relationship with certain occupational factors, alcohol intake and smoking.

Setting

The French GAZEL cohort (employees of Electricité de France and Gaz de France).

Participants

Participants of the cohort who answered a questionnaire in 2012, that is, 13 587 participants (73.7% of the questionnaire sent). In 2007, self-assessed lifetime occupational biomechanical exposure was recorded (carrying loads, manipulating a vibrating tool and climbing stairs), as well as alcohol intake, smoking and diabetes mellitus. Analyses were performed on high alcohol intake, smoking and duration of relevant work exposure, stratified by gender.

Primary and secondary outcome measures

From a specific question on Dupuytren’s disease assessed in 2012, the outcome measures were self-reported Dupuytren’s disease (yes/no) and disabling Dupuytren’s disease (including surgery).

Results

A total of 10 017 men and 3570 women, aged 64–73 years, were included; the mean age for men was 68 years and for women was 65 years. Among men, the following were significantly associated with Dupuytren’s disease: age (OR 1.03 (1.00; 1.06)), diabetes (OR 1.31 (1.07; 1.60)), heavy drinking (OR 1.36 (1.10; 1.69)) and over 15 years of manipulating a vibrating tool at work (OR 1.52 (1.15; 2.02)); except for diabetes, the association with these factors was stronger for disabling Dupuytren’s disease (or surgery), with OR 1.07 (1.03; 1.11), 1.71 (1.25; 2.33) and 1.98(1.34; 2.91), respectively, for age, heavy drinking and over 15 years of manipulating a vibrating tool at work. Among the 3570 women included, 160 reported Dupuytren’s disease (4.5%). The number of cases in the group of women was too low to reach conclusions, although the findings seemed similar for age, diabetes and vibration exposure.

Conclusions

In this large French cohort study, Dupuytren’s disease in men was associated with high levels of alcohol consumption and exposure to hand-transmitted vibration. It is likely that the same applied to women.
A cohort study on mental disorders, stage of cancer at diagnosis and subsequent survival
Authors: Chang Chin-Kuo , Hayes Richard D , Broadbent Matthew T M , Hotopf Matthew , Davies Elizabeth , Møller Henrik , Stewart Robert
Published: January 2014

Objectives

To assess the stage at cancer diagnosis and survival after cancer diagnosis among people served by secondary mental health services, compared with other local people.

Setting

Using the anonymised linkage between a regional monopoly secondary mental health service provider in southeast London of four London boroughs, Croydon, Lambeth, Lewisham and Southwark, and a population-based cancer register, a historical cohort study was constructed.

Participants

A total of 28 477 cancer cases aged 15+ years with stage of cancer recorded at diagnosis were identified. Among these, 2206 participants had been previously assessed or treated in secondary mental healthcare before their cancer diagnosis and 125 for severe mental illness (schizophrenia, schizoaffective or bipolar disorders).

Primary and secondary outcome measures

Stage when cancer was diagnosed and all-cause mortality after cancer diagnosis among cancer cases registered in the geographical area of southeast London.

Results

Comparisons between people with and without specific psychiatric diagnosis in the same residence area for risks of advanced stage of cancer at diagnosis and general survival after cancer diagnosed were analysed using logistic and Cox models. No associations were found between specific mental disorder diagnoses and beyond local spread of cancer at presentation. However, people with severe mental disorders, depression, dementia and substance use disorders had significantly worse survival after cancer diagnosis, independent of cancer stage at diagnosis and other potential confounders.

Conclusions

Previous findings of associations between mental disorders and cancer mortality are more likely to be accounted for by differences in survival after cancer diagnosis rather than by delayed diagnosis.
The accuracy of caries risk assessment in children attending South Australian School Dental Service: a longitudinal study
Authors: Ha Diep H , Spencer A John , Slade Gary D , Chartier Andrew D
Published: January 2014

Objectives

To determine the accuracy of the caries risk assessment system and performance of clinicians in their attempts to predict caries for children during routine practice.

Design

Longitudinal study.

Setting and participants

Data on caries risk assessment conducted by clinicians during routine practice while providing care for children in the South Australian School Dental Service (SA SDS) were collected from electronic patient records. Baseline data on caries experience, clinicians’ ratings of caries risk status and child demographics were obtained for all SA SDS patients aged 5–15 years examined during 2002–2005.

Outcome measure

Children’s caries incidence rate, calculated using examination data after a follow-up period of 6–48 months from baseline, was used as the gold standard to compute the sensitivity (Se) and specificity (Sp) of clinicians’ baseline ratings of caries risk. Multivariate binomial regression models were used to evaluate effects of children's baseline characteristics on Se and Sp.

Results

A total of 133 clinicians rated caries risk status of 71 430 children during 2002–2005. The observed Se and Sp were 0.48 and 0.86, respectively (Se+Sp=1.34). Caries experience at baseline was the strongest factor influencing accuracy in multivariable regression model. Among children with no caries experience at baseline, overall accuracy (Se+Sp) was only 1.05, whereas it was 1.28 among children with at least one tooth surfaces with caries experience at baseline.

Conclusions

Clinicians’ accuracy in predicting caries risk during routine practice was similar to levels reported in research settings that simulated patient care. Accuracy was acceptable in children who had prior caries experience at the baseline examination, while it was poor among children with no caries experience.
The administration of intermittent parathyroid hormone affects functional recovery from pertrochanteric fractured neck of femur: a protocol for a prospective mixed method pilot study with randomisation of treatment allocation and blinded assessment (FRACTT)
Authors: Chesser Tim , Fox Rebecca , Harding Karen , Greenwood Rosemary , Javaid Kassim , Barnfield Steven , Halliday Ruth , Willett Keith , Lamb Sallie
Published: January 2014

Introduction

Pertrochanteric hip fractures occur in an elderly population and cause considerable morbidity and loss of functional ability as the fracture heals. Recently, parathyroid hormone (PTH), which is licensed for the treatment of osteoporosis, has been shown to potentially accelerate bone healing in animal and human studies. If its administration could allow a faster functional recovery after pertrochanteric hip fracture, then a patient's hospital stay may be reduced and rehabilitation could be potentially accelerated. PTH can currently only be administered by subcutaneous injection. The acceptability of this intervention is unknown in this elderly population. The aim of this pilot study is to inform the design of a future powered study comparing the functional recovery after pertrochanteric hip fracture in patients undergoing standard care versus those who undergo administration of subcutaneous injection of PTH.

Methods and analysis

The study is an open label, prospective, randomised, comparative pilot study with blinded outcomes assessment to establish feasibility of the trial design. Patients will be randomised to receive a 6-week course of PTH or usual treatment. Functional outcomes will be assessed at 6 weeks and 12 weeks. Blinded assessment will be used to minimise the effect of bias of an open label study design. A nested qualitative study will investigate the patient experience of, and expectations following, hip fracture and the patient important aspects of recovery compared with the outcome measures proposed.

Results

Results will be analysed to establish the potential recruitment, compliance and retention rates using 95% CIs, and trial outcomes quoted with SDs and 95% CIs for the effect size.

Ethics and dissemination

The study has been approved by the South West 2 Research Ethics committee (reference 10/H0206/34). The findings of this study will be disseminated to the medical community via presentations to orthopaedic, orthogeriatric and osteoporosis societies, and their relevant specialist journals.

Trial Registration

ISRCTN Register reference number:ISRCTN03362357.

Eudract Number: 2010-020081-22
Work-related road traffic injury: a multilevel systems protocol
Authors: Newnam Sharon , Sheppard Dianne M , Griffin Mark A , McClure Roderick J , Heller Gillian , Sim Malcolm R , Stevenson Mark R
Published: January 2014

Background

Although road traffic injury is reported as the leading cause of work-related death in Australia, it is not clear, due to limitations in previous methods used, just how large a burden it is. Many organisations are unaware of the extent of work-related road traffic injury and, importantly, what can be done to reduce the burden. The proposed research will (i) estimate the prevalence of work-related road traffic injury and (ii) identify the organisational determinants associated with work-related road traffic injury.

Methods and design

The current study is designed to enumerate the problem and identify the individual driver-level, the supervisor-level and organisational-level factors associated with work-related road traffic injury. The multilevel systems protocol will involve a series of cross-sectional surveys administered to drivers of fleet vehicles (n=1200), supervisors of the drivers (n=1200) and senior managers (n=300) within the same organisation.

Discussion

The novel use of the multilevel systems protocol is critical to be able to accurately assess the specific determinants of driving safety within each context of an organisation.

Results

The results are expected to highlight that reducing injury in the workplace requires more than just individual compliance with safety procedures. It will also establish, for the first time, an occupational translation taskforce to ensure that the research findings are adopted into work-place practice and thereby directly contribute to reductions in work-related road traffic injury.
Hospital-based financial analysis of endovascular therapy and intravenous thrombolysis for large vessel acute ischemic strokes: the ‘bottom line’
Authors: Rai Ansaar T , Evans Kim
Published: January 2014

Background

Economic viability is important to any hospital striving to be a comprehensive stroke center. An inability to recover cost can strain sustained delivery of advanced stroke care.

Objective

To carry out a comparative financial analysis of intravenous (IV) recombinant tissue plasminogen activator and endovascular (EV) therapy in treating large vessel strokes from a hospital's perspective.

Methodology

Actual hospital's charges, costs, and payments were analyzed for 265 patients who received treatment for large vessel strokes. The patients were divided into an EV (n=141) and an IV group (n=124). The net gain/loss was calculated as the difference between payments received and the total cost.

Results

The charges, costs, and payments were significantly higher for the EV than the IV group (p<0.0001 for all). Medicare A was the main payer. Length of stay was inversely related to net gain/loss (p<0.0001). Favorable outcome was associated with a net gain of $3853 (±$21 155) and poor outcome with a net deficit of $2906 (±$15 088) (p=0.003). The hospital showed a net gain for the EV group versus a net deficit for the IV group in patients who survived the admission (p=0.04), had a favorable outcome (p=0.1), or were discharged to home (p=0.03). There was no difference in the time in hospital based on in-hospital mortality for the EV group but patients who died in the IV group had a significantly shorter length of stay than those who survived (p=0.04). The favorable outcome of 42.3% in the EV group was significantly higher than the 29.4% in the IV group (p=0.03).

Conclusions

Endovascular therapy was associated with better outcomes and higher cost–recovery than IV thrombolysis in patients with large vessel strokes.
Epidemiological study (2006–2012) on the poisoning of small animals by human and veterinary drugs
Authors: Caloni F. , Cortinovis C. , Pizzo F. , Rivolta M. , Davanzo F.
Published: January 2014

A retrospective study was conducted on the exposure of dogs and cats to drugs, reported to the Poison Control Centre of Milan (Centro Antiveleni di Milano (CAV)) between January 2006 and December 2012. Calls related to drugs for human use and veterinary drugs accounted for 23.7 per cent of total inquiries (1415) received by CAV and mostly involved dogs (70 per cent of enquiries). Exposure to drugs for human use accounted for 79 per cent of cases involving dogs, whereas veterinary drugs were the main culprit (77 per cent) in the case of cats. The most common class of drugs for human use proved to be CNS drugs (26.8 per cent), followed by NSAIDs (19.6 per cent) and cardiovascular and endocrine drugs (12.9 per cent each). The majority of calls (95.2 per cent) related to veterinary drugs involved dogs and cats exposed to parasiticides. The outcome was reported in only 58.2 per cent of cases, and fatal poisoning accounted for 8.7 per cent of these cases. Epidemiological data from this Italian survey provide useful information on animal exposure to drugs. The knowledge of agents involved in poisoning episodes can help veterinarians make the correct diagnosis and institute preventive measures to possibly reduce animal exposure to drugs.
Freeze–thaw cycling concurrent with cation exchange and the hydraulic conductivity of geosynthetic clay liners
Authors: Makusa Gregory P. , Bradshaw Sabrina L. , Berns Erin , Benson Craig H. , Knutsson Sven
Published: January 2014

A study was conducted to assess the effect of cation exchange concurrent with freeze–thaw cycling on the hydraulic conductivity of a geosynthetic clay liner (GCL). GCLs were prehydrated by contact with silica flour moistened with synthetic subgrade pore water and subsequently permeated with a solution representing the pore water in the cover soil over a tailings facility. Control tests were conducted using the same procedure, except deionized (DI) water was used as the permeant liquid to preclude cation exchange from the permeant liquid. The GCLs were subjected to 1, 3, 5, 15, and 20 freeze–thaw cycles, and the hydraulic conductivity and exchange complex were determined before and after freeze–thaw cycling to assess chemical changes that occurred during freezing, thawing, and permeation. GCLs undergoing freeze–thaw cycling experienced little to no cation exchange through 5 freeze–thaw cycles. After 20 freeze–thaw cycles, 50% of the sodium (Na+) initially in the exchange complex was replaced by calcium (Ca2+). Dissolution of calcite within the bentonite is a likely source of the Ca2+. Hydraulic conductivity of the GCLs exposed to freeze–thaw cycling was lower than the hydraulic conductivity of a new GCL permeated with DI water (<2.2 × 10−11 m/s). A small increase in hydraulic conductivity (∼2.3 times), which may have been caused by cation exchange, occurred between 15 and 20 freeze–thaw cycles, but the hydraulic conductivity remained below the hydraulic conductivity of a new GCL unexposed to freeze–thaw cycling and permeated with DI water.
Rigorous studies on magnetic susceptibilities of a defective finite Ising chain
Authors: Qi Yan , Du An
Published: January 2014

Exact solution of the magnetic susceptibility for an S = 1/2 defective finite Ising chain is obtained by employing the transfer matrix method. The thermal dependence of susceptibility multiplied by temperature for the chain coupled to different magnetic impurities is investigated at all T ≥ 0. The results show that in the zero temperature limit the product of these two quantities equals the square of the net spin, demonstrating that Curie’s constants are truly invariant at low temperatures. The intrinsic properties of net spin are also reflected through their different responses to the parity of chain length at low temperature. In addition, the impacts of various host–impurity couplings as well as single-ion anisotropies on the susceptibility are discussed as well.
New highly polymorphic microsatellite markers for the aquatic angiosperm Ruppia cirrhosa reveal population diversity and differentiation
Authors: Martínez-Garrido J. , González-Wangüemert M. , Serrão E.A.
Published: January 2014

Ruppia cirrhosa is a clonal monoecious plant phylogenetically associated to seagrass families such as Posidoniaceae and Cymodoceaceae. It inhabits shallow waters that are important for productivity and as a biodiversity reservoir. In this study, we developed 10 polymorphic microsatellite loci for R. cirrhosa. Additionally, we obtained cross-amplification for two microsatellites previously described for Ruppia maritima. These 12 markers were tested in four R. cirrhosa populations from the southwest of Europe. The number of alleles per locus was high for most of the markers, ranging from 4 to 13. Two populations (Sicily and Cádiz) showed heterozygote deficit (p < 0.001). The four populations (Sicily, Murcia, Cádiz, and Tavira) were significantly differentiated (FST ≠ 0; p < 0.001), corroborating the usefulness of these microsatellites on R. cirrhosa population genetics.
Radiolarian researchers based in Italy during the late nineteenth and early twentieth centuries
Authors: Cortese Giuseppe
Published: January 2014

Abstract. In the second half of the nineteenth century a few Italian radiolarists, including Dante Pantanelli and Senofonte Squinabol, made substantial contributions to the taxonomic study of radiolarians and their utilization in dating Mesozoic rocks. This time interval was very important in the history of science in general, and biology in particular, with numerous scientific expeditions collecting a wealth of biological and sedimentary material from the oceans that took decades to be described and analysed. One of the most famous examples is the Report of the Challenger Expedition, which included a thorough study of radiolarians by Ernst Haeckel which became the basis of radiolarian classification. Haeckel was one of the foremost promoters of the largest cultural revolution of his epoch: Darwinism. He, together with a long list of eminent scientists, used comparative anatomy and embryology to provide evidence of the theory of evolution through natural selection. One of his students, Anton Dohrn, also a fervent Darwinist, founded one of the oldest independent marine biology stations in the world: the Statione Zoologica in Naples. It was here that at the beginning of the twentieth century another eminent Italian radiolarist, Paolo Enriques, worked for many years to revise and improve Haeckel’s classification scheme of radiolarians, although he died before it was completed or published.
Jørgensen’s polycystine radiolarian slide collection and new species
Authors: Dolven Jane K. , Bjørklund Kjell R. , Itaki Takuya
Published: January 2014

Abstract. E. H. Jørgensen’s radiolarian collection is stored at the Natural History Museum in Oslo and holds 93 slides, of these 76 are with plankton from the western and northern coast off Norway. Jørgensen described 43 new polycystine radiolarian species from this material, but did not assign any types. In this present study we have re-examined the collection, registered and photographed all slides and radiolarian specimens, and designated lectotypes and paralectotypes for many of Jørgensen’s species.
Glucose stimulates calcium-activated chloride secretion in small intestinal cells
Authors: Yin Liangjie , Vijaygopal Pooja , MacGregor Gordon G. , Menon Rejeesh , Ranganathan Perungavur , Prabhakaran Sreekala , Zhang Lurong , Zhang Mei , Binder Henry J. , Okunieff Paul , Vidyasagar Sadasivan
Published: January 2014

The sodium-coupled glucose transporter-1 (SGLT1)-based oral rehydration solution (ORS) used in the management of acute diarrhea does not substantially reduce stool output, despite the fact that glucose stimulates the absorption of sodium and water. To explain this phenomenon, we investigated the possibility that glucose might also stimulate anion secretion. Transepithelial electrical measurements and isotope flux measurements in Ussing chambers were used to study the effect of glucose on active chloride and fluid secretion in mouse small intestinal cells and human Caco-2 cells. Confocal fluorescence laser microscopy and immunohistochemistry measured intracellular changes in calcium, sodium-glucose linked transporter, and calcium-activated chloride channel (anoctamin 1) expression. In addition to enhancing active sodium absorption, glucose increased intracellular calcium and stimulated electrogenic chloride secretion. Calcium imaging studies showed increased intracellular calcium when intestinal cells were exposed to glucose. Niflumic acid, but not glibenclamide, inhibited glucose-stimulated chloride secretion in mouse small intestines and in Caco-2 cells. Glucose-stimulated chloride secretion was not seen in ileal tissues incubated with the intracellular calcium chelater BAPTA-AM and the sodium-potassium-2 chloride cotransporter 1 (NKCC1) blocker bumetanide. These observations establish that glucose not only stimulates active Na absorption, a well-established phenomenon, but also induces a Ca-activated chloride secretion. This may explain the failure of glucose-based ORS to markedly reduce stool output in acute diarrhea. These results have immediate potential to improve the treatment outcomes for acute and/or chronic diarrheal diseases by replacing glucose with compounds that do not stimulate chloride secretion.
Role of c-Abl tyrosine kinase in smooth muscle cell migration
Authors: Cleary Rachel A. , Wang Ruping , Waqar Omar , Singer Harold A. , Tang Dale D.
Published: January 2014

c-Abl is a nonreceptor protein tyrosine kinase that has a role in regulating smooth muscle cell proliferation and contraction. The role of c-Abl in smooth muscle cell migration has not been investigated. In the present study, c-Abl was found in the leading edge of smooth muscle cells. Knockdown of c-Abl by RNA interference attenuated smooth muscle cell motility as evidenced by time-lapse microscopy. Furthermore, the actin-associated proteins cortactin and profilin-1 (Pfn-1) have been implicated in cell migration. In this study, cell adhesion induced cortactin phosphorylation at Tyr-421, an indication of cortactin activation. Phospho-cortactin and Pfn-1 were also found in the cell edge. Pfn-1 directly interacted with cortactin in vitro. Silencing of c-Abl attenuated adhesion-induced cortactin phosphorylation and Pfn-1 localization in the cell edge. To assess the role of cortactin/Pfn-1 coupling, we developed a cell-permeable peptide. Treatment with the peptide inhibited the interaction of cortactin with Pfn-1 without affecting cortactin phosphorylation. Moreover, treatment with the peptide impaired the recruitment of Pfn-1 to the leading edge and cell migration. Finally, β1-integrin was required for the recruitment of c-Abl to the cell edge. Inhibition of actin dynamics impaired the spatial distribution of c-Abl. These results suggest that β1-integrin may recruit c-Abl to the leading cell edge, which may regulate cortactin phosphorylation in response to cell adhesion. Phosphorylated cortactin may facilitate the recruitment of Pfn-1 to the cell edge, which promotes localized actin polymerization, leading edge formation, and cell movement. Conversely, actin dynamics may strengthen the recruitment of c-Abl to the leading edge.
Exposure to rosiglitazone, a PPAR-γ agonist, in late gestation reduces the abundance of factors regulating cardiac metabolism and cardiomyocyte size in the sheep fetus
Authors: Lie Shervi , Hui Melisa , McMillen I. Caroline , Muhlhausler Beverly S. , Posterino Giuseppe S. , Dunn Stacey L. , Wang Kimberley C. , Botting Kimberley J. , Morrison Janna L.
Published: January 2014

It is unknown whether cardiomyocyte hypertrophy and the transition to fatty acid oxidation as the main source of energy after birth is dependent on the maturation of the cardiomyocytes' metabolic system, or on the limitation of substrate availability before birth. This study aimed to investigate whether intrafetal administration of a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, during late gestation can stimulate the expression of factors regulating cardiac growth and metabolism in preparation for birth, and the consequences of cardiac contractility in the fetal sheep at ∼140 days gestation. The mRNA expression and protein abundance of key factors regulating growth and metabolism were quantified using quantitative RT-PCR and Western blot analysis, respectively. Cardiac contractility was determined by measuring the Ca2+ sensitivity and maximum Ca2+-activated force of skinned cardiomyocyte bundles. Rosiglitazone-treated fetuses had a lower cardiac abundance of insulin-signaling molecules, including insulin receptor-β, insulin receptor substrate-1 (IRS-1), phospho-IRS-1 (Tyr-895), phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, PI3K catalytic subunit p110α, phospho-3-phosphoinositide-dependent protein kinase 1 (Ser-241), protein kinase B (Akt-1), phospho-Akt (Ser-273), PKCζ, phospho-PKCζ(Thr-410), Akt substrate 160 kDa (AS160), phospho-AS160 (Thr-642), and glucose transporter type-4. Additionally, cardiac abundance of regulators of fatty acid β-oxidation, including adiponectin receptor 1, AMPKα, phospho-AMPKα (Thr-172), phospho-acetyl CoA carboxylase (Ser-79), carnitine palmitoyltransferase-1, and PGC-1α was lower in the rosiglitazone-treated group. Rosiglitazone administration also resulted in a decrease in cardiomyocyte size. Rosiglitazone administration in the late-gestation sheep fetus resulted in a decreased abundance of factors regulating cardiac glucose uptake, fatty acid β-oxidation, and cardiomyocyte size. These findings suggest that activation of PPAR-γ using rosiglitazone does not promote the maturation of cardiomyocytes; rather, it may decrease cardiac metabolism and compromise cardiac health later in life.
Maternal food restriction modulates cerebrovascular structure and contractility in adult rat offspring: effects of metyrapone
Authors: Durrant Lara M. , Khorram Omid , Buchholz John N. , Pearce William J.
Published: January 2014

Although the effects of prenatal undernutrition on adult cardiovascular health have been well studied, its effects on the cerebrovascular structure and function remain unknown. We used a pair-fed rat model of 50% caloric restriction from day 11 of gestation to term, with ad libitum feeding after birth. We validated that maternal food restriction (MFR) stress is mediated by glucocorticoids by administering metyrapone, a corticosterone synthesis inhibitor, to MFR mothers at day 11 of gestation. At age 8 mo, offspring from Control, MFR, and MFR + Metyrapone groups were killed, and middle cerebral artery (MCA) segments were studied using vessel-bath myography and confocal microscopy. Colocalization of smooth muscle α-actin (SMαA) with nonmuscle (NM), SM1 and SM2 myosin heavy-chain (MHC) isoforms was used to assess smooth muscle phenotype. Our results indicate that artery stiffness and wall thickness were increased, pressure-evoked myogenic reactivity was depressed, and myofilament Ca2+sensitivity was decreased in offspring of MFR compared with Control rats. MCA from MFR offspring exhibited a significantly greater SMαA/NM colocalization, suggesting that the smooth muscle cells had been altered toward a noncontractile phenotype. MET significantly reversed the effects of MFR on stiffness but not myogenic reactivity, lowered SMαA/NM colocalization, and increased SMαA/SM2 colocalization. Together, our data suggest that MFR alters cerebrovascular contractility via both glucocorticoid-dependent and glucocorticoid-independent mechanisms.