bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virus‐mediated swapping of zolpidem‐insensitive with zolpidem‐sensitive GABAA receptors in cortical pyramidal cells
Authors: Sumegi Mate , Fukazawa Yugo , Matsui Ko , Lorincz Andrea , Eyre Mark D. , Nusser Zoltan , Shigemoto Ryuichi 
Published: February 2012

Key points
We generated lenti‐ and adeno‐associated viruses which were used to replace the zolpidem‐insensitive GABAA receptors of a transgenic mouse line with wild‐type, zolpidem‐sensitive ones.
The virally expressed wild‐type, zolpidem‐sensitive GABAA receptor γ2 subunits were tagged with a small immunotag (AU1).
Light microscopic fluorescent and electron microscopic freeze‐fracture immunogold labelling revealed that the virally introduced AU1‐tagged γ2 subunit‐containing receptors had a normal synaptic distribution on cortical pyramidal cells.
In vitro patch‐clamp recordings demonstrated that the insertion of this immunotag did not alter the kinetic and pharmacological properties of the virally inserted γ2 subunits.
Our results demonstrate a novel transgenic–viral pharmacogenetic approach, which allows the selective silencing of well‐defined neuronal populations in the brain.
Closely Related Archaeal Haloarcula hispanica Icosahedral Viruses HHIV-2 and SH1 Have Nonhomologous Genes Encoding Host Recognition Functions
Authors: Jaakkola Salla T. , Penttinen Reetta K. , Vilén Silja T. , Jalasvuori Matti , Rönnholm Gunilla , Bamford Jaana K. H. , Bamford Dennis H. , Oksanen Hanna M. 
Published: February 2012

ABSTRACTStudies on viral capsid architectures and coat protein folds have revealed the evolutionary lineages of viruses branching to all three domains of life. A widespread group of icosahedral tailless viruses, the PRD1-adenovirus lineage, was the first to be established. A double β-barrel fold for a single major capsid protein is characteristic of these viruses. Similar viruses carrying genes coding for two major capsid proteins with a more complex structure, such asThermusphage P23-77 and haloarchaeal virus SH1, have been isolated. Here, we studied the host range, life cycle, biochemical composition, and genomic sequence of a new isolate,Haloarcula hispanicaicosahedral virus 2 (HHIV-2), which resembles SH1 despite being isolated from a different location. Comparative analysis of these viruses revealed that their overall architectures are very similar except that the genes for the receptor recognition vertex complexes are unrelated even though these viruses infect the same hosts.
Genetic Divergence of Rotavirus Nonstructural Protein 4 Results in Distinct Serogroup-Specific Viroporin Activity and Intracellular Punctate Structure Morphologies
Authors: Hyser Joseph M. , Utama Budi , Crawford Sue E. , Estes Mary K. 
Published: February 2012

ABSTRACT

Nonstructural protein 4 (NSP4) viroporin activity is critical for the replication and assembly of serogroup A rotavirus (RVA); however, the dramatic primary sequence divergence of NSP4s across serogroups raises the possibility that viroporin activity is not a common feature among RVs. We tested for NSP4 viroporin activity from divergent strains, including RVA (EC and Ty-1), RVB (IDIR), and RVC (Cowden). Canonical viroporin motifs were identified in RVA, RVB, and RVC NSP4s, but the arrangement of basic residues and the amphipathic α-helices was substantially different between serogroups. Using
Escherichia coli
and mammalian cell expression, we showed that each NSP4 tested had viroporin activity, but serogroup-specific viroporin phenotypes were identified. Only mammalian RVA and RVC NSP4s induced BL21-pLysS
E. coli
cell lysis, a classical viroporin activity assay. In contrast, RVA, RVB, and RVC NSP4 expression was universally cytotoxic to
E. coli
and disrupted reduction-oxidation activities, as measured by a new redox dye assay. In mammalian cells, RVB and RVC NSP4s were initially localized in the endoplasmic reticulum (ER) and trafficked into punctate structures that were mutually exclusive with RVA NSP4. The punctate structures partially localized to the ER-Golgi intermediate compartment (ERGIC) but primarily colocalized with punctate LC3, a marker for autophagosomes. Similar to RVA NSP4, expression of RVB and RVC NSP4s significantly elevated cytosolic calcium levels, demonstrating that despite strong primary sequence divergence, RV NSP4 has maintained viroporin activity across serogroups A to C. These data suggest that elevated cytosolic calcium is a common critical process for all rotavirus strains.
Epstein-Barr Virus-Encoded Latent Membrane Protein 1 (LMP1) and LMP2A Function Cooperatively To Promote Carcinoma Development in a Mouse Carcinogenesis Model
Authors: Shair Kathy H. Y. , Bendt Katharine M. , Edwards Rachel H. , Nielsen Judith N. , Moore Dominic T. , Raab-Traub Nancy 
Published: February 2012

ABSTRACT

The Epstein-Barr virus (EBV) proteins latent membrane proteins 1 and 2 (LMP1 and LMP2) are frequently expressed in EBV-associated lymphoid and epithelial cancers and have complex effects on cell signaling and growth. The effects of these proteins on epithelial cell growth were assessed
in vivo
using transgenic mice driven by the keratin 14 promoter (K14). The development of papillomas and carcinomas was determined in the tumor initiator and promoter model using dimethyl benzanthracene (DMBA), followed by repeated treatments of 12-
O
-tetradecanoyl phorbol 13-acetate (TPA). In these assays, LMP1 functioned as a weak tumor promoter and increased papilloma formation. In contrast, mice expressing LMP2A did not induce or promote papilloma formation. Transgenic LMP1 mice had slightly increased development of squamous cell carcinoma; however, the development of carcinoma was significantly increased in the doubly transgenic mice expressing both LMP1 and LMP2A. DMBA treatment induces an activating mutation in the
Harvey-ras
(
H-ras

61

) oncogene, and this mutation was identified in most papillomas and carcinomas although several papillomas and carcinomas in K14-LMP1 and K14-LMP1/LMP2A mice lacked the mutation. Analysis of signaling pathways that are known to be activated by LMP1 and/or LMP2 indicated that all genotypes had high levels of activated extracellular signal-regulated kinase (ERK) and Stat3 in carcinomas with significantly higher activation in the doubly transgenic carcinomas. These findings suggest that, in combination, LMP1 and LMP2 contribute to carcinoma progression and that this may reflect the combined effects of the proteins on activation of multiple signaling pathways. This study is the first to characterize the effects of LMP2 on tumor initiation and promotion and to identify an effect of the combined expression of LMP1 and LMP2 on the increase of carcinoma development.
What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients
Authors: Beswick Andrew David , Wylde Vikki , Gooberman-Hill Rachael , Blom Ashley , Dieppe Paul 
Published: February 2012

BackgroundTotal hip or knee replacement is highly successful when judged by prosthesis-related outcomes. However, some people experience long-term pain.ObjectivesTo review published studies in representative populations with total hip or knee replacement for the treatment of osteoarthritis reporting proportions of people by pain intensity.Data sourcesMEDLINE and EMBASE databases searched to January 2011 with no language restrictions. Citations of key articles in ISI Web of Science and reference lists were checked.Study eligibility criteria, participants and interventionsProspective studies of consecutive, unselected osteoarthritis patients representative of the primary total hip or knee replacement population, with intensities of patient-centred pain measured after 3 months to 5-year follow-up.Study appraisal and synthesis methodsTwo authors screened titles and abstracts. Data extracted by one author were checked independently against original articles by a second. For each study, the authors summarised the proportions of people with different severities of pain in the operated joint.ResultsSearches identified 1308 articles of which 115 reported patient-centred pain outcomes. Fourteen articles describing 17 cohorts (6 with hip and 11 with knee replacement) presented appropriate data on pain intensity. The proportion of people with an unfavourable long-term pain outcome in studies ranged from about 7% to 23% after hip and 10% to 34% after knee replacement. In the best quality studies, an unfavourable pain outcome was reported in 9% or more of patients after hip and about 20% of patients after knee replacement.LimitationsOther studies reported mean values of pain outcomes. These and routine clinical studies are potential sources of relevant data.Conclusions and implications of key findingsAfter hip and knee replacement, a significant proportion of people have painful joints. There is an urgent need to improve general awareness of this possibility and to address determinants of good and bad outcomes.
Payer decision-making with limited comparative and cost effectiveness data: the case of new pharmacological treatments for gout
Authors: Meltzer Michele , Pizzi Laura T , Jutkowitz Eric 
Published: February 2012

ContextThe need for comparative effectiveness (CE) data continues to grow, fuelled by market demand as well as health reform. There may be an assumption that new drugs result in improved efficacy compared with the standard of care, therefore warranting premium prices. Gout treatment has recently become controversial, as expensive new drugs enter the market with limited CE data.MethodsThe authors reviewed published clinical trials and conducted a cost effectiveness analysis on a new drug (febuxostat) versus the standard (allopurinol) to illustrate the limitations in using these data to inform evidence-based decision-making.FindingsAlthough febuxostat trials included allopurinol as a comparator, methodological limitations make comparative effectiveness evaluations difficult. However, when available trial data were input to a decision analytic model, the authors found that a significant reduction in febuxostat cost would be required in order for it to dominate allopurinol in cost effectiveness analysis. This case exemplifies the challenges of using clinical trial data in comparative and cost effectiveness analyses.
How much doctoral research on clinical topics is published?: Table 1
Authors: Caan Woody , Cole Michael 
Published: February 2012

ObjectiveTo determine how often clinical research from doctoral degree programmes is unpublished and to see if one can characterise differences between those researchers who do or do not publish their work or between the institutions where they studied.DesignSecondary research with data in the public domain: combining a national dataset of healthcare doctoral theses with related publications traceable in two widely accessible databases.Data sourcesThe Index to Theses was searched for UK doctoral theses and the databases Web of Knowledge and SCOPUS searched by author name for literature derived from each thesis. Confirmatory details about student names or their doctoral programmes were obtained from university websites, if required.Eligibility criteriaSearch terms were chosen to identify only projects directly related to human health. Thesis records included ‘clinical trials’ or ‘clinical research’. The awards were all doctorate-level degrees between 2000 and 2010. ‘Related’ publication in the Web of Knowledge or SCOPUS was interpreted very broadly to include publications with any research commonality with the degree project as recorded in the Index to Theses.ResultsA sample of 82 theses from 39 universities provided the initial material for a literature search. The Web of Knowledge contained more publications from more students than SCOPUS held. Of the doctoral research samples, 39 out of 82 theses (47.6%) produced no discernable publications. The 43 students whose research was published typically began publishing before completing their degree (mean time 1.3 years preceding their award). Not all types of doctorates were associated equally with publication: all 11 MD theses in our sample had related publications (100%).ConclusionsResearch evidence associated with doctoral degrees is often left unpublished, across many settings. Sharing such evidence is a scientific and ethical duty. Supporting students in publishing preliminary work while they are still in doctoral programmes may be the most productive response. The large number of doctorates awarded in ‘medical’ disciplines every year represents a substantial investment in training and a resource for evidence-based medicine that should not be squandered.
Low-profile visible intraluminal support device: immediate outcome of the first three US cases
Authors: Turner Raymond D , Turk Aquilla , Chaudry Imran 
Published: February 2012

IntroductionDissecting and wide-necked aneurysms that incorporate a large portion of the parent artery can be challenging to treat with currently available devices. This study reports three cases treated with a new hybrid stent design that incorporates a smaller cell size and more pliable design than current generation stents and results in some flow diversion characteristics.MethodsIn all three cases, use of the low-profile visible intraluminal support (LVIS) device in conjunction with coil embolization was determined to provide the best opportunity to achieve aneurysm occlusion while mitigating adverse events. The institutional review board reviewed all cases and approval was obtained. All cases were performed under emergent use exemption from the US Food and Drug Administration.ResultsAll three patients were successfully stent coiled with the LVIS device. One patient was completely occluded initially and remained so at follow-up, one patient progressed to complete occlusion at follow-up, and the last patient had stable incomplete occlusion of their fusiform aneurysm. There were no complications related to the procedures and the patients were maintained on dual-antiplatelet therapy.ConclusionThe LVIS device offers promise as a stent-assisted coil device with certain characteristics that may be advantageous over currently available microstents.
Pre-intervention triage incorporating perfusion imaging improves outcomes in patients undergoing endovascular stroke therapy: a comparison with the device trials
Authors: Rai Ansaar T , Raghuram Karthikram , Domico Jennifer , Hobbs Gerald , Carpenter Jeffrey 
Published: February 2012

ObjectivesEndovascular therapy of acute ischemic stroke is evolving towards thrombectomy devices for vessel recanalization. High rates of revascularization have been reported in stroke device trials. However, the discrepancy between recanalization and outcomes raises the question whether patients with irreversible ischemic injury are being exposed to these interventions. This study evaluated a triage methodology that incorporates perfusion imaging against previous device trials that treated all patients within a certain time frame.Methods99 consecutive patients were identified with anterior circulation strokes who had undergone endovascular therapy. All patients had a baseline NIHSS score ≥8 and had undergone pre-intervention CT perfusion. Rates of recanalization and functional outcomes were compared with the MERCI, Multi-MERCI and Penumbra trials.ResultsThis study's recanalization rate of 55.6% is not significantly different from the 46% for MERCI (p=0.15) and 68% for Multi-MERCI (p=0.08) but was significantly lower than the 82% for the Penumbra trial (p<0.0001). Successfully recanalized patients had a significantly higher good outcome of 67% in this cohort versus 46% in MERCI, 49% in Multi-MERCI and 29% in Penumbra. The rate of futile recanalization was 33% compared with 54% for MERCI, 51% for Multi-MERCI and 71% for Penumbra. A small cerebral blood volume (CBV) abnormality (p<0.0001) and large mean transit time–CBV mismatch (p<0.0001) were strong predictors of a good outcome.ConclusionDespite similar or lower recanalization rates, there was a significantly higher rate of good outcomes in the recanalized population and thus a significantly lower rate of futile recanalization in this study versus the device trials, suggesting a role for pre-intervention perfusion imaging for patient selection.
A multicenter registry of hydrocephalus following coil embolization of unruptured aneurysms: which patients are at risk and why it occurs
Authors: Turner Raymond D , da Costa LeoDante B , terBrugge Karel G 
Published: February 2012

IntroductionUnexplained post-procedural events such as cerebral edema, inflammation, aseptic meningitis and hydrocephalus have been reported following unruptured cerebral aneurysm coiling. However, understanding of the etiology for these occurrences is limited due to their rare occurrence. A multicenter registry was developed to investigate further the occurrence of these events.MethodThis registry consisted of a retrospective analysis of unruptured aneurysms treated with hydrocoil that evolved to develop focal cerebral edema, inflammation, aseptic meningitis, or ventricular enlargement/hydrocephalus following uncomplicated coil embolization. Data points included pre, intra, and postoperative imaging, patient demographics, aneurysm demographics, procedural details such as coils used, medications administered, and intraprocedural complications, and all post-procedure follow-up including clinical status of the patients and all adverse events.ResultsTwenty-five patients (26 aneurysm coiling procedures) were found at 12 centers over an 8-year period. The mean aneurysm size was 13.7 mm. The average time from treatment to onset of symptoms was 8.5 months (2 weeks to 30 months, median 6 months). Delayed hydrocephalus was the most common clinical presentation. Six of the 25 patients were asymptomatic and did not require treatment.ConclusionPatients undergoing endovascular coiling may be at risk of developing delayed complications, which may or may not be symptomatic. This risk appeared low and was restricted mostly to larger aneurysms. These events can be difficult to detect due to delayed presentation.
Incidence and risk factors associated with chlamydia in men who have sex with men: a cohort analysis of Victorian Primary Care Network for Sentinel Surveillance data
Authors: Wilkinson Anna , El-Hayek Carol , Fairley Christopher K , Leslie David , Roth Norm , Tee B K , Hellard Margaret E , Stoové Mark 
Published: February 2012

BackgroundChlamydia is the most commonly notified sexually transmitted infection (STI) in Australia. Incidence studies of chlamydia in men who have sex with men (MSM) are rare and offer important public health information.ObjectiveTo determine chlamydia incidence in MSM presenting at high caseload clinics and describe predictors of infection.MethodsThe Victorian Primary Care Network for Sentinel Surveillance of bloodborne viruses and STIs (VPCNSS) links testing, demographic and behavioural data from individual testers at participating clinics. Data from MSM with more than one chlamydia test at the VPCNSS site between April 2006 and June 2010 were included. Chlamydia incidence per 100 person-years (PY) was calculated and Cox regression used to examine predictors of incidence.Results1206 positive tests for chlamydia were detected among 6333 MSM across 11 409 PY of follow-up. Overall chlamydia incidence was 10.6/100 PY (95% CI 10.0 to 11.2) and was highest among MSM aged 16–29 years (12.9/100 PY, 95% CI 11.7 to 14.1), presenting with STI symptoms (16.0/100 PY, 95% CI 14.2 to 18.0), HIV positive (18.5/100 PY, 95% CI 16.6 to 20.6) and self-identified sex workers (14.3/100 PY, 95% CI 10.0 to 20.6). Significant predictors of chlamydia infection among MSM were younger age (adjusted hazard ratio (aHR)=1.9, 95% CI 1.5 to 2.3), self-identifying as a sex worker (aHR=1.6, 95% CI 1.0 to 2.6), being HIV positive (aHR=2.6, 95% CI 1.8 to 3.8), presenting with STI symptoms (aHR=1.7, 95% CI 1.4 to 2.1) and reporting >10 sex partners in the past 6 months (aHR=2.5 95% CI 1.4 to 4.6).ConclusionThese results show that MSM represent a key risk population for chlamydia in Australia and identify a number of high-risk MSM subpopulations for whom clinical and public health interventions are warranted.
RORα Suppresses Breast Tumor Invasion by Inducing SEMA3F Expression
Authors: Xiong Gaofeng , Wang Chi , Evers B. Mark , Zhou Binhua P. , Xu Ren 
Published: February 2012

Abstract
Inactivation of tumor suppressors and inhibitory microenvironmental factors is necessary for breast cancer invasion; therefore, identifying those suppressors and factors is crucial not only to advancing our knowledge of breast cancer, but also to discovering potential therapeutic targets. By analyzing gene expression profiles of polarized and disorganized human mammary epithelial cells in a physiologically relevant three-dimensional (3D) culture system, we identified retinoid orphan nuclear receptor alpha (RORα) as a transcription regulator of semaphorin 3F (SEMA3F), a suppressive microenvironmental factor. We showed that expression of RORα was downregulated in human breast cancer tissue and cell lines, and that reduced mRNA levels of RORα and SEMA3F correlated with poor prognosis. Restoring RORα expression reprogrammed breast cancer cells to form noninvasiveness structures in 3D culture and inhibited tumor growth in nude mice, accompanied by enhanced SEMA3F expression. Inactivation of RORα in nonmalignant human mammary epithelial cells inhibited SEMA3F transcription and impaired polarized acinar morphogenesis. Using chromatin immunoprecipitation and luciferase reporter assays, we showed that transcription of SEMA3F is directly regulated by RORα. Knockdown of SEMA3F in RORα-expressing cancer cells rescued the aggressive 3D phenotypes and tumor invasion. These findings indicate that RORα is a potential tumor suppressor and inhibits tumor invasion by inducing suppressive cell microenvironment. Cancer Res; 72(7); 1728–39. ©2012 AACR.
miRNA-130a Targets ATG2B and DICER1 to Inhibit Autophagy and Trigger Killing of Chronic Lymphocytic Leukemia Cells
Authors: Kovaleva Valentina , Mora Rodrigo , Park Yoon Jung , Plass Christoph , Chiramel Abhilash I. , Bartenschlager Ralf , Döhner Hartmut , Stilgenbauer Stephan , Pscherer Armin , Lichter Peter , Seiffert Martina 
Published: February 2012

Abstract
Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference–mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival. Cancer Res; 72(7); 1763–72. ©2012 AACR.