bluuebunny/crossref_metadata_2025 huggingface dataset:
Endocannabinoids modulate human blood–brain barrier permeability in vitro
Authors: Hind William H , Tufarelli Cristina , Neophytou Maria , Anderson Susan I , England Timothy J , O'Sullivan Saoirse E
Published: February 2015

Background and Purpose

Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood–brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model.

Experimental Approach

Human brain microvascular endothelial cell and astrocyte co‐cultures modelled the BBB. Ischaemia was modelled by oxygen‐glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Endocannabinoids or endocannabinoid‐like compounds were assessed for their ability to modulate baseline permeability or OGD‐induced hyperpermeability. Target sites of action were investigated using receptor antagonists and subsequently identified with real‐time PCR.

Key Results

Anandamide (10 μM) and oleoylethanolamide (OEA, 10 μM) decreased BBB permeability (i.e. increased resistance). This was mediated by cannabinoid CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) channels, calcitonin gene‐regulated peptide (CGRP) receptor (anandamide only) and PPARα (OEA only). Application of OEA, palmitoylethanolamide (both PPARα mediated) or virodhamine (all 10 μM) decreased the OGD‐induced increase in permeability during reperfusion. 2‐Arachidonoyl glycerol, noladin ether and oleamide did not affect BBB permeability in normal or OGD conditions. N‐arachidonoyl‐dopamine increased permeability through a cytotoxic mechanism. PPARα and γ, CB1 receptors, TRPV1 channels and CGRP receptors were expressed in both cell types, but mRNA for CB2 receptors was only present in astrocytes.

Conclusion and Implication

The endocannabinoids may play an important modulatory role in normal BBB physiology, and also afford protection to the BBB during ischaemic stroke, through a number of target sites.
Lessons learnt from school‐based health promotion projects in low‐ and middle‐income countries
Authors: Skar M. , Kirstein E. , Kapur A.
Published: February 2015

Background

Non‐communicable diseases (NCD) are now the leading cause of death worldwide. As habits and lifestyle are established in childhood and adolescence, targeting school children before they develop unhealthy habits offers a window of opportunity to halt and reverse the emerging NCD epidemic. However, few experiences from school interventions in low‐ and middle‐income countries have been collected. Therefore, the aim of this study was to review experiences of implementing school‐based health promotion interventions to identify barriers and recommendations for future interventions.

Methods

A qualitative investigation of 17 school‐based health promotion interventions in low‐ and middle‐income countries was conducted. Data were collected through questionnaires (15 project leaders) and in‐depth interviews with nine project leaders. The data from the questionnaires and interviews was triangulated and analysed using content analysis, where themes and categories emerging from the material were explored.

Results

Three key themes emerged from the data: 1) policy environment and stakeholder engagement, 2) health education sessions, and 3) practical health promotion activities. The themes explored the experiences and lessons learned from 17 school‐based health promotion projects in low‐ and middle‐income countries. Stakeholders at different administrative levels were important for the projects; however, stakeholders close to implementation were seen to be more engaged. Most projects conducted traditional health education lectures, which formed the basis of their intervention. Promotion of physical activity and healthy eating through participatory approaches were identified; however, barriers such as lack of areas suitable for physical activity and lack of healthy food alternatives in schools can obstruct the successful implementation of interventions.

Conclusions

This study has documented experiences with school‐based health promotion in low‐ and middle‐income countries, and has shown that schools can play an important role in facilitating NCD‐related behavioural change in children. The study recommends increased emphasis on a whole‐school approach where activities focusing on individual behavioural change are supported by interventions improving the structural environment.
Definition of a pool of epitopes that recapitulates the T cell reactivity against major house dust mite allergens
Authors: Hinz D. , Oseroff C. , Pham J. , Sidney J. , Peters B. , Sette A.
Published: February 2015

Background

Allergens from house dust mites (HDM) are a common cause of asthma. Der p and Der f from Dermatophagoides sp. are strong immunogens in humans. Allergen extracts are used to study T helper (Th2) cell responses to HDM, which are implicated in the development and regulation of allergic disease.

Objective

To define an epitope mixture that recapitulates, and might substitute for, HDM extract in terms of detecting and characterizing Th2 cell responses.

Methods

Peripheral blood mononuclear cells (PBMC) from 52 HDM allergic and 10 non‐allergic individuals were stimulated with HDM extracts and assayed with a set of 178 peptides spanning mite allergens group Der p 1, 2, 23 and Der f group 1 and 2 allergens. A pool of the most dominant T cell epitopes identified in the present study and from published literature was assembled and tested for ex vivo T cell responses. Correlation with HDM‐specific IgE titres was examined.

Results

Patterns of T cell reactivity to Der p and Der f – derived peptides revealed a large number of epitopes. Clear patterns of immunodominance were apparent, with HDM allergen group 1 and 2 dominant over group 23. Furthermore, within a given antigen, 6–11 epitopes accounted for the vast majority of responses. Based on these results and published data, a comprehensive dust mite pool (DMP) of epitopes was designed and found to allow detection of ex vivo T cell responses. DMP ex vivo reactivity correlated with HDM‐specific IgE titres and was similar to that detected with commonly used HDM extracts. Ex vivo DMP stimulation was associated with a predominant Th2 response in allergic donors, and minor reactivity of T cells producing IFNÎ³, IL17 and IL10.

Conclusions & Clinical Relevance

A detailed map of Der p and Der f antigens defined a pool of epitopes that can be used to detect ex vivo HDM responses.
Evidence that FcRn mediates the transplacental passage of maternal IgE in the form of IgG anti‐IgE/IgE immune complexes
Authors: Bundhoo A. , Paveglio S. , Rafti E. , Dhongade A. , Blumberg R. S. , Matson A. P.
Published: February 2015

Background

The mechanism(s) responsible for acquisition of maternal antibody isotypes other than IgG are not fully understood. This uncertainty is a major reason underlying the continued controversy regarding whether cord blood (CB) IgE originates in the mother or fetus.

Objective

To investigate the capacity of maternal IgE to be transported across the placenta in the form of IgG anti‐IgE/IgE immune complexes (ICs) and to determine the role of the neonatal Fc receptor (FcRn) in mediating this process.

Methods

Maternal and CB serum concentrations of IgE, IgG anti‐IgE, and IgG anti‐IgE/IgE ICs were determined in a cohort of allergic and non‐allergic mother/infant dyads. Madin–Darby canine kidney (MDCK) cells stably transfected with human FcRn were used to study the binding and transcytosis of IgE in the form of IgG anti‐IgE/IgE ICs.

Results

Maternal and CB serum concentrations of IgG anti‐IgE/IgE ICs were highly correlated, regardless of maternal allergic status. IgG anti‐IgE/IgE ICs generated in vitro bound strongly to FcRn‐expressing MDCK cells and were transcytosed in an FcRn‐dependent manner. Conversely, monomeric IgE did not bind to FcRn and was not transcytosed. IgE was detected in solutions of transcytosed IgG anti‐IgE/IgE ICs, even though essentially all the IgE remained in complex form. Similarly, the majority of IgE in CB sera was found to be complexed to IgG.

Conclusions and Clinical Relevance

These data indicate that human FcRn facilitates the transepithelial transport of IgE in the form of IgG anti‐IgE/IgE ICs. They also strongly suggest that the majority of IgE in CB sera is the result of FcRn‐mediated transcytosis of maternal‐derived IgG anti‐IgE/IgE ICs. These findings challenge the widespread perception that maternal IgE does not cross the placenta. Measuring maternal or CB levels of IgG anti‐IgE/IgE ICs may be a more accurate predictor of allergic risk.
Is there a role for an ultrasensitive thyroglobulin assay in patients with serum antithyroglobulin antibodies? A large (Australian) cohort study in differentiated thyroid cancer
Authors: McGrath Rachel T. , Preda Veronica A. , Clifton‐Bligh Philip , Robinson Bruce , Sywak Mark , Delbridge Leigh , Ward Peter , Clifton‐Bligh Roderick J. , Learoyd Diana L.
Published: February 2015

Objective

Serum thyroglobulin (Tg) is a marker of residual differentiated thyroid cancer (DTC) after total thyroidectomy; however, circulating antithyroglobulin antibodies (TgAb) may interfere with the immunoassay for Tg. Ultrasensitive assays may have a more significant role in detecting circulating Tg in the context of samples containing TgAb. The aim of this study was to evaluate the utility of ultrasensitive thyroglobulin (US‐Tg) measurement compared to standard Tg measurement and to assess the influence of serum TgAb positivity on Tg detection in a large tertiary referral centre cohort in Australia.

Design

All patients with DTC who had undergone total thyroidectomy were included in this retrospective, observational cohort study.

Patients

Patients providing samples for the period of June 2006 until January 2014 were analysed. Three thousand two hundred and eight samples were measured at the same points in time, enabling serum Tg assays to be compared for the same TSH status (stimulated or suppressed).

Measurements

The standard assay, the Siemens Immulite 2000 Tg assay, was compared to the serum ultrasensitive ELISA RSR™ Tg. TgAb were simultaneously measured using Abbott Architect or Immulite 2000.

Results

There were 3019 samples included in the final analysis for comparison of the standard and ultrasensitive assays along with TgAb status. The majority of samples were TgAb negative (87%), with 48% of TgAb‐negative samples associated with an undetectable serum Tg, suggestive of disease‐free status at the time of sampling. Of note, 26% (n = 104) of the TgAb‐positive samples were positive for Tg on the ultrasensitive Tg assay, but negative on the immulite Tg assay, and 62·5% (n = 65) of these samples corresponded to DTC recurrence.

Conclusion

The US‐Tg assay has greater clinical utility than the standard immulite Tg assay specifically in the scenario of antibody positivity, with a significant number of samples corresponding to clinically relevant recurrent or metastatic disease.
Improving the uptake of predictive testing and colorectal screening in Lynch syndrome: a regional primary care survey
Authors: Barrow P. , Green K. , Clancy T. , Lalloo F. , Hill J. , Evans D.G.
Published: February 2015

Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome with a 60–80% lifetime risk of colorectal cancer. We assessed the uptake of predictive testing and colorectal screening among first‐degree relatives (FDRs) in LS families and explored novel methods for informing and engaging at‐risk relatives. Uptake of predictive testing was explored using Kaplan–Meier analysis and engagement with colorectal screening was ascertained. A questionnaire was distributed to 216 general practitioners (GPs) of registered LS family members to determine their prior experience and opinion of an enhanced role. Of 591, 329 (55.7%) FDRs had undergone predictive testing. Uptake was significantly lower in males (p = 0.012) and individuals <25 years (p < 0.001). Mutation carriers were more likely to undergo colorectal screening than untested FDRs (97.2% vs 34.9%; P ≤ 0.0001). Of 216, 63 (29.2%) questionnaires were returned. Most GPs (55/63; 87.3%) were not confident to discuss the details of LS with patients and relatives. The main barriers were lack of knowledge and concerns about confidentiality. Compliance with colorectal screening is excellent following a mutation positive predictive test. Uptake of predictive testing could be substantially improved, particularly among males and younger age groups. GPs are unlikely to actively participate in communication with at‐risk relatives without considerable support.
Safety and effectiveness of propofol‐based monitored anesthesia care without intubation during endoscopic submucosal dissection for early gastric and esophageal cancers
Authors: Nonaka Satoru , Kawaguchi Yosuke , Oda Ichiro , Nakamura Jun , Sato Chiko , Kinjo Yuzuru , Abe Seiichiro , Suzuki Haruhisa , Yoshinaga Shigetaka , Sato Tetsufumi , Saito Yutaka
Published: February 2015

Background and Aim

Endoscopic submucosal dissection (ESD) becomes more difficult with an increased risk of complications if patient sedation is insufficient. We assessed the safety and effectiveness of propofol‐based monitored anesthesia care (MAC) without intubation during ESD for early esophageal cancer (EEC) or early gastric cancer (EGC) in the endoscopy room.

Methods

We investigated 1013 consecutive patients with 1126 lesions who underwent ESD for EGC/EEC with either MAC or regular sedation by endoscopists (control group) between July 2010 and March 2013. Patient characteristics, endoscopic findings, technical results, body movement, oxygen saturation (SpO2), and drug dosages were then examined.

Results

MAC was carried out in 137 EGC (16%) and 82 EEC patients (57%), whereas regular sedation was used in 731 EGC (84%) and 63 EEC patients (43%). MAC was conducted in 21% of all ESD procedures. In the MAC and control groups, body movement requiring a third person for control occurred in 30 (22%) and 533 (72%) cases during gastric ESD (P < 0.0001) and in 36 (44%) and 53 (84%) cases during esophageal ESD (P < 0.0001), respectively. The median minimum SpO2 was significantly lower in the MAC group than in the control group during both gastric and esophageal ESD (96% vs 98%, P < 0.0001; 96% vs 98%, P < 0.0004, respectively). MAC did not cause any adverse effects requiring prolongation of hospitalization.

Conclusions

Propofol‐based MAC without intubation provided a safer treatment environment by significantly reduced body movement and was very effective for difficult cases requiring longer procedure times or more powerful sedation.
Structured endoscopic ultrasonography (EUS) training program improved knowledge and skills of trainees: Results from the Asian EUS Group
Authors: Wang Myrna Huixian , Dy Frederick , Vu Van Khien , Lim Lee Guan , Tayyab Ghias Un Nabi , Ratanachu‐ek Thawee , Samarasekera Dharmabandhu N , Dhir Vinay , Jin Zheng‐Dong , Kida Mitsuhiro , Seo Dong Wang , Wang Hsiu‐Po , Teoh Anthony , Hawes Robert , Varadarajulu Shyam , Yasuda Ken , Ho Khek Yu
Published: February 2015

Background and Aim

A major reason impeding the growth of endoscopic ultrasound (EUS) in Asia is the lack of training availability. We aimed to prospectively evaluate the effectiveness of a short‐term structured EUS training program in improving the knowledge and skill of EUS among trainees.

Methods

The study was conducted in six workshops in six countries including Sri Lanka, Pakistan, Thailand, Vietnam, Singapore and Philippines, within a year. Trainees were evaluated using written and skill tests before and after completion of the training.

Results

Pre‐ and post‐workshop written tests from a total of 62 trainees were analyzed. Compared with pre‐training, the trainees improved significantly in the overall mean (± SD) scores after the training (66.0 ± 0.3% to 77.5 ± 0.2%, P < 0.0001). Thirty‐one trainees were randomly selected to undergo a skill test before and after the course. Compared with pre‐training, the proportions of trainees who succeeded in locating each structure post‐training were: celiac axis (36–80.5%), pancreatic body (51.5–80.5%), pancreatic body and tail (42–77.5%), splenic vein and artery (48.5–84%), left kidney (60–83%), and spleen (47–83%). Overall, there was a significant improvement in the proportion of trainees’ successful localization of structures post‐training compared to before training (P < 0.0001).

Conclusion

Following a structured training program, trainees’ knowledge and skills in EUS improved significantly. Structured training courses appear to be an effective way of imparting EUS knowledge and skills to aspiring endosonographers in the Asian region.
Cardiovascular safety of the glucagon‐like peptide‐1 receptor agonist taspoglutide in people with type 2 diabetes: an individual participant data meta‐analysis of randomized controlled trials
Authors: Seshasai S. R. K. , Bennett R. L. , Petrie J. R. , Bengus M. , Ekman S. , Dixon M. , Herz M. , Buse J. B. , Ray K. K.
Published: February 2015

Aims

To study the short‐term cardiovascular effects of the once‐weekly glucagon‐like peptide‐1 receptor agonist taspoglutide.

Methods

We conducted a meta‐analysis of individual‐participant data from nine randomized controlled trials in the T‐Emerge programme, which assessed the efficacy and safety of taspoglutide in type 2 diabetes. Our primary outcome was a composite of death from cardiovascular disease (CVD) and acute myocardial infarction, stroke and hospitalization for unstable angina.

Results

Overall, 7056 individuals were included in the analysis, and there were 67 primary endpoint events during 7478 person‐years of follow‐up (40 vs 27 events in the intervention vs control groups, respectively). The odds ratio for the composite endpoint among people randomized to taspoglutide was 0.94 (95% confidence interval 0.57–1.56), which was robust across multiple subgroups. Longer‐term data were not available as the development of taspoglutide was stopped because of gastrointestinal intolerance and serious hypersensitivity reactions.

Conclusions

The available data suggest that short‐term, once‐weekly administration of taspoglutide was not associated with an excess risk of CVD, and provide insights relevant to the development of other novel once‐weekly incretin mimetics.
Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly
Authors: Paciorkowski Alex R. , McDaniel Sharon S. , Jansen Laura A. , Tully Hannah , Tuttle Emily , Ghoneim Dalia H. , Tupal Srinivasan , Gunter Sonya A. , Vasta Valeria , Zhang Qing , Tran Thao , Liu Yi B. , Ozelius Laurie J. , Brashear Allison , Sweadner Kathleen J. , Dobyns William B. , Hahn Sihoun
Published: February 2015

Objective

Mutations of ATP1A3 have been associated with rapid onset dystonia‐parkinsonism and more recently with alternating hemiplegia of childhood. Here we report one child with catastrophic early life epilepsy and shortened survival, and another with epilepsy, episodic prolonged apnea, postnatal microcephaly, and severe developmental disability. Novel heterozygous mutations (p.Gly358Val and p.Ile363Asn) were identified in ATP1A3 in these children.

Methods

Subjects underwent next‐generation sequencing under a research protocol. Clinical data were collected retrospectively. The biochemical effects of the mutations on ATP1A3 protein function were investigated. Postmortem neuropathologic specimens from control and affected subjects were studied.

Results

The mutations localized to the P domain of the Na,K‐ATPase α3 protein, and resulted in significant reduction of Na,K‐ATPase activity in vitro. We demonstrate in both control human brain tissue and that from the subject with the p.Gly358Val mutation that ATP1A3 immunofluorescence is prominently associated with interneurons in the cortex, which may provide some insight into the pathogenesis of the disease.

Significance

The findings indicate these mutations cause severe phenotypes of ATP1A3‐related disorder spectrum that include catastrophic early life epilepsy, episodic apnea, and postnatal microcephaly.
Sertraline‐induced potentiation of the CYP3A4‐dependent neurotoxicity of carbamazepine: An in vitro study
Authors: Ghosh Chaitali , Hossain Mohammad , Spriggs Addison , Ghosh Arnab , Grant Gerald A. , Marchi Nicola , Perucca Emilio , Janigro Damir
Published: February 2015

Objective

Drug toxicity is a hurdle to drug development and to clinical translation of basic research. Antiepileptic drugs such as carbamazepine (CBZ) and selective serotonin reuptake inhibitors such as sertraline (SRT) are commonly co‐prescribed to patients with epilepsy and comorbid depression. Because SRT may interfere with cytochrome P450 (CYP) enzyme activity and CYPs have been implicated in the conversion of CBZ to reactive cytotoxic metabolites, we investigated in vitro models to determine whether SRT affects the neurotoxic potential of CBZ and the mechanisms involved.

Methods

Human fetal brain‐derived dopaminergic neurons, human brain microvascular endothelial cells (HBMECs), and embryonic kidney (HEK) cells were used to evaluate cytotoxicity of CBZ and SRT individually and in combination. Nitrite and glutathione (GSH) levels were measured with drug exposure. To validate the role of CYP3A4 in causing neurotoxicity, drug metabolism was compared to cell death in HEK CYP3A4 overexpressed and cells pretreated with the CYP3A4 inhibitor ketoconazole.

Results

In all cellular systems tested, exposure to CBZ (127 μm) or SRT (5 μm) alone caused negligible cytotoxicity. By contrast CBZ, tested at a much lower concentration (17 μm) in combination with SRT (5 μm), produced prominent cytotoxicity within 15 min exposure. In neurons and HBMECs, cytotoxicity was associated with increased nitrite levels, suggesting involvement of free radicals as a pathogenetic mechanism. Pretreatment of HBMECs with reduced GSH or with the GSH precursor N‐acetyl‐l‐cysteine prevented cytotoxic response. In HEK cells, the cytotoxic response to the CBZ + SRT combination correlated with the rate of CBZ biotransformation and production of 2‐hydroxy CBZ, further suggesting a causative role of reactive metabolites. In the same system, cytotoxicity was potentiated by overexpression of CYP3A4, and prevented by CYP3A4 inhibitor.

Significance

These results demonstrate an unexpected neurotoxic interaction between CBZ and SRT, apparently related to increased CYP3A4‐mediated production of reactive CBZ metabolites. The potential clinical implications of these findings are discussed.
The core‐independent promoter‐specific binding of Bacillus subtilis σB
Authors: Kuo Heng‐Hsu , Huang Wei‐Cheng , Lin Tzu‐Feng , Yeh Hsin‐Yi , Liou Kung‐Ming , Chang Ban‐Yang
Published: February 2015

Bacillus subtilis σD is an alternative σ factor that possesses a core‐independent promoter −10 element binding specificity despite the lack of a distinct footprint on its cognate promoter. We wished to determine whether this property is common to alternative σ factors. To this end, we over‐expressed B. subtilis σB in Escherichia coli and analyzed its DNA binding ability by electrophoretic mobility shift assay and DNase I footprinting. The major complex formed by σB and its cognate promoter DNA is heparin‐sensitive. However, in contrast to the −10 element binding specificity observed for B. subtilis σD, the promoter binding of σB is specific for the −35 element. These and other results clearly demonstrate that alternative σ factors possess different promoter‐binding characteristics, and make core‐independent contributions to recognition of their cognate promoters.
Biocatalytic carboxylation of phenol derivatives: kinetics and thermodynamics of the biological Kolbe–Schmitt synthesis
Authors: Pesci Lorenzo , Glueck Silvia M. , Gurikov Pavel , Smirnova Irina , Faber Kurt , Liese Andreas
Published: February 2015

Microbial decarboxylases, which catalyse the reversible regioselective ortho‐carboxylation of phenolic derivatives in anaerobic detoxification pathways, have been studied for their reverse carboxylation activities on electron‐rich aromatic substrates. Ortho‐hydroxybenzoic acids are important building blocks in the chemical and pharmaceutical industries and are currently produced via the Kolbe–Schmitt process, which requires elevated pressures and temperatures (≥ 5 bar, ≥ 100 °C) and often shows incomplete regioselectivities. In order to resolve bottlenecks in view of preparative‐scale applications, we studied the kinetic parameters for 2,6‐dihydroxybenzoic acid decarboxylase from Rhizobium sp. in the carboxylation‐ and decarboxylation‐direction using 1,2‐dihydroxybenzene (catechol) as starting material. The catalytic properties (Km, Vmax) are correlated with the overall thermodynamic equilibrium via the Haldane equation, according to a reversible random bi–uni mechanism. The model was subsequently verified by comparing experimental results with simulations. This study provides insights into the catalytic behaviour of a nonoxidative aromatic decarboxylase and reveals key limitations (e.g. substrate oxidation, CO2 pressure, enzyme deactivation, low turnover frequency) in view of the employment of this system as a ‘green’ alternative to the Kolbe–Schmitt processes.
Hypoalbuminemia, influenza vaccination and other factors related to the development of pneumonia acquired outside hospitals in southern Japan: A case–control study
Authors: Washio Masakazu , Kondo Kyoko , Fujisawa Nobumitsu , Harada Eiji , Tashiro Hideki , Mizokami Tetsuya , Nogami Hiroko , Iwanaga Tomoaki , Nakanishi Yoichi , Suzuki Kanzo , Ohfuji Satoko , Fukushima Wakaba , Hirota Yoshio ,   the Kyushu Task Force for CAP Risk in the Elderly
Published: February 2015

Aim

Pneumonia is the third largest cause of death in Japan. Pneumonia continues to be one of the most common causes of morbidity, hospitalization and mortality, especially in the elderly. The aim of the present study was to evaluate the factors related to the development of pneumonia acquired outside hospitals among the Japanese elderly.

Methods

We carried out a hospital‐based, case–control study. Cases were patients who had been newly diagnosed with pneumonia acquired outside hospitals. For each case, one to three controls were defined as outpatients with other diseases (not pneumonia) at the same hospitals. All participants (i.e. 50 cases and 110 controls) were aged 65 years and older.

Results

Compared with control participants, hypoalbuminemia (<3.5 g/dL) and low body mass index (<18.0) were more common in pneumonia patients, whereas the proportion of those who could go out by themselves (i.e. self‐support in activities of daily living) and the vaccination rate of seasonal influenza were lower in patients with pneumonia than control participants. Even after controlling for age, sex, hospital and aforementioned four factors, hypoalbuminemia (OR 9.19, 95% CI 3.70–22.81) increased the risk of pneumonia, whereas seasonal influenza vaccination (OR 0.37, 95% CI 0.16–0.85) reduced the risk. Even after excluding those who lived in a nursing home, hypoalbuminemina (OR 12.19, 95% CI 4.29–34.63) increased the risk of pneumonia.

Conclusions

Hypoalbuminemia might be a risk factor for pneumonia among the elderly living in the community. Geriatr Gerontol Int 2016; 16: 223–229.
Exportin‐5 mediates nuclear export of SRP RNA in vertebrates
Authors: Takeiwa Toshihiko , Taniguchi Ichiro , Ohno Mutsuhito
Published: February 2015

The signal recognition particle is a ribonucleoprotein complex that is essential for the translocation of nascent proteins into the endoplasmic reticulum. It has been shown that the RNA component (SRP RNA) is exported from the nucleus by CRM1 in the budding yeast. However, how SRP RNA is exported in higher species has been elusive. Here, we show that SRP RNA does not use the CRM1 pathway in Xenopus oocytes. Instead, SRP RNA uses the same export pathway as pre‐miRNA and tRNA as showed by cross‐competition experiments. Consistently, the recombinant Exportin‐5 protein specifically stimulated export of SRP RNA as well as of pre‐miRNA and tRNA, whereas an antibody raised against Exportin‐5 specifically inhibited export of the same RNA species. Moreover, biotinylated SRP RNA can pull down Exportin‐5 but not CRM1 from HeLa cell nuclear extracts in a RanGTP‐dependent manner. These results, taken together, strongly suggest that the principal export receptor for SRP RNA in vertebrates is Exportin‐5 unlike in the budding yeast.
Geranylgeranyltransferase Cwg2‐Rho4/Rho5 module is implicated in the Pmk1 MAP kinase‐mediated cell wall integrity pathway in fission yeast
Authors: Doi Akira , Kita Ayako , Kanda Yuki , Uno Takaya , Asami Keita , Satoh Ryosuke , Nakano Kentaro , Sugiura Reiko
Published: February 2015

Pmk1, a fission yeast homologue of mammalian ERK MAPK, regulates cell wall integrity, cytokinesis, RNA granule formation and ion homeostasis. Our screen for vic (viable in the presence of immunosuppressant and chloride ion) mutants identified regulators of the Pmk1 MAPK signaling, including Cpp1 and Rho2, based on the genetic interaction between calcineurin and Pmk1 MAPK. Here, we identified the vic2‐1 mutants carrying a mis‐sense mutation in the cwg2+ gene encoding a beta subunit of geranylgeranyltransferase I (GGTase I), which participates in the post‐translational C‐terminal modification of several small GTPases, allowing their targeting to the membrane. Analysis of the vic2‐1/cwg2‐v2 mutant strain showed that the localization of Rho1, Rho4, Rho5 and Cdc42, both at the plasma and vacuolar membranes, was impaired in the vic2‐1/cwg2‐v2 mutant cells. In addition, Rho4 and Rho5 deletion cells exhibited the vic phenotype and cell wall integrity defects, shared phenotypes among the components of the Pmk1 MAPK pathway. Consistently, the phosphorylation of Pmk1 MAPK on heat shock was decreased in the cwg2‐v2 mutants, and rho4‐ and rho5‐null cells. Moreover, Rho4 and Rho5 associate with Pck1/Pck2. Possible roles of Cwg2, Rho4 and Rho5 in the Pmk1 signaling will be discussed.
cnrip1 is a regulator of eye and neural development in Xenopus laevis
Authors: Zheng Xiaona , Suzuki Toshiyasu , Takahashi Chika , Nishida Eisuke , Kusakabe Morioh
Published: February 2015

Cannabinoid receptor interacting protein 1 (CNRIP1), which has been originally identified as the binding partner of cannabinoid receptor 1 (CNR1), is evolutionarily conserved throughout vertebrates, but its physiological function has been unknown. Here, we identify a developmental role of CNRIP1 using Xenopus laevis embryos. During early embryogenesis, expression of Xenopus laevis cnrip1 is highly restricted to the animal region of gastrulae where neural and eye induction occur, and afterward it is seen in neural and other tissues with a temporally and spatially regulated pattern. Morpholino‐mediated knockdown experiments indicate that cnrip1 has an essential role in early eye and neural development by regulating the onset of expression of key transcription factor genes, sox2, otx2, pax6 and rax. Also, over‐expression experiments suggest that cnrip1 has a potential to expand sox2, otx2, pax6 and rax expression. These results suggest an instructive role of Xenopus laevis cnrip1 in early eye and neural development. Furthermore, Xenopus laevis cnr1 knockdown leads to eye defects, which are partly similar to, but milder than, those caused by cnrip1 knockdown, suggesting a possible functional similarity between CNRIP1 and CNR1. This study is the first characterization of an in vivo role of CNRIP1 in the context of whole organisms.
Electronically Conductive Vanadate Glasses for Resistive Plate Chamber Particle Detectors
Authors: Johnson Nicole , Wehr Gene , Hoar Eric , Xian Siyu , Akgun Ugur , Feller Steve , Affatigato Mario , Repond Jose , Xia Lei , Bilki Burak , Onel Yasar
Published: February 2015

Particle detectors are constantly being built and refitted with new technology to improve the spatial resolution, radiation hardness, and speed at which the detector can capture particle events. One of the most crucial components of a modern collider experiment is the hadron calorimeter. One of the proposed improvements on future hadron calorimeters is to utilize resistive plate chambers (RPCs). They provide the spatial and energy resolution as well as could provide speed and radiation hardness. RPCs depend on manufacturing electrically conductive glasses that are mechanically strong, durable, radiation resistant, and not ionically conductive. To achieve such requirements, vanadate glasses were developed as alternatives to current prototypes which use soda lime silicate glasses. The conductivity, oxidation states of vanadium, radiation hardness, as well as the prototype performance, were tested on vanadate glasses. The prototype tests show that using 0.40ZnO−0.40TeO2−0.20V2O5 can improve the RPC detector rate up to 100 times.
Linguistics research articles written in English: comparing native English speakers and Polish writers
Authors: Hryniuk Katarzyna
Published: February 2015

This paper addresses the issue of writing for publication in English to elucidate, on the one hand, how writing styles of scholars from two cultural regions – Polish and Anglo‐American – differ at the level of article structure. On the other, it explores the extent to which internationalizing forces inside one discourse community (specialists in linguistics) can override differences. For this purpose, a qualitative, cross‐linguistic and cross‐cultural study was conducted to compare texts written in English by native speakers with such articles by Polish authors. The issue is increasingly significant because current scientific progress and globalization has stimulated the need to share research findings in all fields of science using English as the main language of international publication.
Impact of phosphomimetic and non‐phosphorylatable mutations of phospholemman on L‐type calcium channels gating in HEK 293T cells
Authors: Guo Kai , Wang Yue‐Peng , Zhou Zhi‐Wen , Jiang Yi‐Bo , Li Wei , Chen Xiao‐Meng , Li Yi‐Gang
Published: February 2015

Background: Phospholemman (PLM) is an important phosphorylation substrate for protein kinases A and C in the heart. Until now, the association between PLM phosphorylation status and L‐type calcium channels (LTCCs) gating has not been fully understood. We investigated the kinetics of LTCCs in HEK 293T cells expressing phosphomimetic or nonphosphorylatable PLM mutants. Methods: The LTCCs gating was measured in HEK 293T cells transfected with LTCC and wild‐type (WT) PLM, phosphomimetic or nonphosphorylatable PLM mutants: 6263AA, 6869AA, AAAA, 6263DD, 6869DD or DDDD. Results: WT PLM significantly slowed LTCCs activation and deactivation while enhanced voltage‐dependent inactivation (VDI). PLM mutants 6869DD and DDDD significantly increased the peak of the currents. 6263DD accelerated channel activation, while 6263AA slowed it more than WT PLM. 6869DD significantly enhanced PLM‐induced increase of VDI. AAAA slowed the channel activation more than 6263AA, and DDDD accelerated the channel VDI more than 6869DD. Conclusions: Our results demonstrate that phosphomimetic PLM could stimulate LTCCs and alter their dynamics, while PLM nonphosphorylatable mutant produced the opposite effects.
Sex‐linked inheritance, genetic correlations and sexual dimorphism in three melanin‐based colour traits in the barn owl
Authors: Roulin A. , Jensen H.
Published: February 2015

Theory states that genes on the sex chromosomes have stronger effects on sexual dimorphism than genes on the autosomes. Although empirical data are not necessarily consistent with this theory, this situation may prevail because the relative role of sex‐linked and autosomally inherited genes on sexual dimorphism has rarely been evaluated. We estimated the quantitative genetics of three sexually dimorphic melanin‐based traits in the barn owl (Tyto alba), in which females are on average darker reddish pheomelanic and display more and larger black eumelanic feather spots than males. The plumage traits with higher sex‐linked inheritance showed lower heritability and genetic correlations, but contrary to prediction, these traits showed less pronounced sexual dimorphism. Strong offspring sexual dimorphism primarily resulted from daughters not expressing malelike melanin‐based traits and from sons expressing femalelike traits to similar degrees as their sisters. We conclude that in the barn owl, polymorphism at autosomal genes rather than at sex‐linked genes generate variation in sexual dimorphism in melanin‐based traits.
Referral of tuberculosis symptomatic clients from private pharmacies to public sector clinics for diagnosis and treatment in Cambodia
Authors: Bell Carolyn A. , Ilomäki Jenni , Pichenda Koeut , Duncan Gregory J. , Saini Bandana
Published: February 2015

Rationale, aims and objectives

Cambodia is one of the 22 countries with a high burden of tuberculosis (TB). People often first seek treatment for cough and other TB symptoms through private pharmacies. The National Tuberculosis Programme trained willing private sector pharmacies to refer TB symptomatic clients to their closest public sector clinic for diagnosis and treatment. The study objective was to investigate factors associated with referral of TB symptomatic clients from pharmacies to public sector clinics in Phnom Penh, Cambodia.

Method

Face‐to‐face structured interviews were conducted with staff from a stratified random sample of 180 private pharmacies in Phnom Penh in 2012. Trained interviewers were Khmer speakers. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with self‐reported referral during the previous 3 months.

Results

Fifty (29.6%) pharmacies reported that they had referred 125 clients (range 1–10) to public sector clinics during the previous 3 months. In total, 164 (96.5%) pharmacies reported that they always referred all TB symptomatic clients to DOTS (directly observed treatment, short course) clinics. More than 6‐year participation in the programme (OR 5.23, 95% CI 1.93–14.18) and willingness to always continue referring (OR 12.24, 95% CI 11.61–93.10) were associated with referral of one or more clients in the previous 3 months. Referral to the client's closest clinic was negatively associated with referral (OR 0.45, 95% CI 0.23–0.99).

Conclusion

Pharmacies' ongoing commitment to the Referral Programme was strongly associated with referral. Increased advocacy among the high number of non‐referring pharmacies may improve programme performance. Factors negatively associated with referral may need investigation.
AThurstonian Model and Statistical Inference for the 2‐Alternative Choice Test with Both Test Pairs and Placebo Pairs
Authors: Bi Jian , Lee Hye‐Seong , O'Mahony Michael
Published: February 2015

For the paired difference or preference test applied to consumer research, the 2‐Alternative Choice (2‐AC) method that allows a “no difference” or “no preference” option is more suitable. For this method, using both test and placebo pairs is useful for estimating the degree of response bias among the consumers using the test and accurately estimating the degree of difference or preference between the test pairs. This paper proposes aThurstonian model for the 2‐ACfor both test pairs and placebo pairs in a test method. Maximum likelihood estimations are used for the parameters:d′, a perceived distance of difference or preference, and τ, a criterion and a decision parameter. Three methods are used for estimations of the covariance matrix for the parameter estimators: (1) using the built‐in functions in theS‐Plus andRpackages, which are based on maximum likelihood and observedFisher information; (2) the delta method, which is based on theTaylor series approximation; and (3) the bootstrap method, which is computer‐intensive with resampling. Statistical tests are discussed ford′and vectors of responses for test pairs and placebo pairs in both a monadic design and a paired design.R/S‐Plus codes are developed and provided for the calculations.

Practical Applications

This paper proposes aThurstonian model for the 2‐Alternative Choice (2‐AC) difference test or preference test method with both test pairs and placebo pairs. This test method provides more information than the 2‐ACmethod without an embedded placebo pair control. Applying this model, especially for the paired preference test method with a “no‐preference” option can be accurately and readily used for consumer research to achieve various business objectives such as reformulation and claim substantiation. UsingR/S‐Plus and built‐in functions and codes developed and provided in the paper, maximum likelihood estimation of parameters in the model, covariance matrix of the parameter estimators and statistical tests can be obtained and conducted easily and quickly.
Group B streptococcal disease and genotypes in Australian infants
Authors: Ko Danny WH , Zurynski Yvonne , Gilbert Gwendolyn L ,   GBS Study Group
Published: February 2015

Aims

Estimate the incidence, risk factors and clinical features of group B streptococcal (GBS) disease in Australian infants and compare bacterial genotypes between infant disease and maternal carriage.

Methods

The Australian Paediatric Surveillance Unit conducted a study of invasive GBS disease in infants aged 0–90 days between July 2005 and June 2008. Clinical data were obtained by questionnaire. GBS isolates from affected infants and antenatal carriers were referred for genotyping.

Results

One hundred fifty confirmed cases were reported: 88 early‐onset (EOD; 0–6 days) and 62 late‐onset disease (LOD). Based on review of selected laboratory records, they represented ∼1/3 of all cases. Estimated national EOD and LOD rates were 0.38 and 0.19/1000 live births, respectively. Admission to intensive care was common (44%), and 7% of infants died. One or more obstetric indications for intrapartum antibiotic prophylaxis (IAP) were identified in 51% of mothers; 53% of mothers were screened for GBS carriage, and screening was positive in 45%; only 25% of women with clinical or microbiological risk factors were given IAP (no significant differences between EOD and LOD groups). Distribution of GBS genotypes differed significantly between invasive and vaginal isolates: virulent serosubtype III‐2/sequence type 17 was strongly associated with LOD but uncommon among EOD and vaginal isolates.

Conclusions

Estimated GBS disease rates remain relatively low despite poor predictive values of clinical and microbiological criteria for, and compliance with, IAP. Clinical and microbiological epidemiology of LOD differs significantly from that of EOD. Further reduction in infant morbidity and mortality from GBS disease will require new strategies.
Recombination Among Begomoviruses on Malvaceous Plants Leads to the Evolution of Okra Enation Leaf Curl Virus in Pakistan
Authors: Serfraz Saad , Amin Imran , Akhtar Khalid P. , Mansoor Shahid
Published: February 2015

Whitefly transmitted begomoviruses (family Geminiviridae) are the major reason for significant yield losses of dicotyledonous crops in tropics and subtropics. Okra (Abelmoschus esculentus) is one of the important vegetable crops, and leaf curl disease caused by geminiviruses is the most important limiting factor for its production in Pakistan. Here, we report a new species of okra‐infecting begomovirus in south‐eastern region of Pakistan and the name Okra enation leaf curl virus (OELCuV) complex is proposed. This okra enation leaf curl disease complex (OELCuD) in Pakistan is found to be associated with Ageratum conyzoides symptomless alphasatellite (AConSLA). All efforts to clone the betasatellite were unsuccessful. Comprehensive sequence analyses suggest that intermalvaceous recombination between okra and cotton‐infecting begomoviruses resulted in the evolution of the new species. Surprisingly, Bhendi yellow vein mosaic virus (BYVMV) which has not been reported previously from Pakistan is the major parent while Cotton leaf curl Multan virus (CLCuMV) acts as a distant parent of the virus. Comparative recombination analysis also reveals that okra‐infecting begomoviruses from south and north‐western India is causing OELCuD in the Pakistan by recombining with CLCuMV at the Rep (1964–1513 nts). Recombination is common among geminiviruses and recombining of BYVMV and CLCuMV resulted in a new species: OELCuV. To the best of our knowledge, this evolution of a new species of okra‐infecting begomovirus is the first report of intermalvaceous recombination where Rep acts as the target region.
First Report of Cucumber mosaic virus Infecting Chinese Mallow in China
Authors: Peng Haoran , Zhao Chenggang , Zhao Xuejun , Chen Dexin , Sun Xianchao
Published: February 2015

The virus in naturally infected, stunted Chinese mallow plants and mosaic leaves was identified as Cucumber mosaic virus (CMV). Six symptomatic plants and one symptomless plant were collected in Chongqing, China. DAS‐ELISA suggested CMV was likely associated with the diseased Chinese mallow. Double‐stranded RNA was extracted from the samples, analysed by RT‐PCR, and the coding sequences of their coat proteins (CPs) were sequenced. The results further confirmed CMV was the pathogen causing Chinese mallow stunted, mosaic disease. The isolate was named CMV‐DXC. The full sequence of CMV‐DXC CP was determined, and it had the highest nucleotide identity (99.4%) of those of CMV‐lily, CMV‐WSJ and CMV‐Hnt, respectively. Phylogenetic analysis shows that CMV‐DXC belongs to CMV subgroup II. To our knowledge, this is the first report of CMV infecting Chinese mallow in China.
A Gentle Introduction to Machine Learning for Natural Language Processing: How to Start in 16 Practical Steps
Authors: Hladka Barbora , Holub Martin
Published: February 2015

We present a gentle introduction to machine learning in natural language processing. Our goal is to navigate readers through basic machine learning concepts and experimental techniques. As an illustrative example we practically address the task of word sense disambiguation using the R software system. We focus especially on students and junior researchers who are not trained in experimenting with machine learning yet and who want to start. To some extent, machine learning process is independent on both addressed task and software system used. Therefore readers who deal with tasks from different research areas or who prefer different software systems will gain useful knowledge as well.
Character, Impropriety, and Success: A Unified Account of Indexicals
Authors: Mount Allyson
Published: February 2015

Core indexicals like ‘I’, ‘here’, and ‘now’ sometimes appear to refer to an object, place, or time other than the speaker, location, or time of utterance. This presents well‐known problems for Kaplan's view, which treats reference shifting as a violation of the character rules that give the meaning of indexicals. I propose a view according to which indexical reference is essentially a matter of the mutually‐accepted perspective of interlocutors. It follows that contexts need not be ‘proper’ in Kaplan's sense, and a successful convergence of perspectives is needed for indexical reference to succeed. I provide reasons for embracing these conclusions.
Neoclassical Concepts
Authors: Leben Derek
Published: February 2015

Linguistic theories of lexical semantics support a Neoclassical Theory of concepts, where entities likeCAUSE,STATE, andMANNERserve as necessary conditions for the possession of individual event concepts. Not all concepts have a neoclassical structure, and whether or not words participate in regular linguistic patterns such as verbal alternations will be proposed as a probe for identifying whether their corresponding concepts do indeed have such structure. I show how the Neoclassical Theory supplements existing theories of concepts and supports a version of analyticity and conceptual analysis.