bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell intrinsic and extrinsic factors contribute to enhance neural circuit reconstruction following transplantation in Parkinsonian mice
Authors: Kauhausen Jessica , Thompson Lachlan H. , Parish Clare L. 
Published: October 2012

Key points
Ectopic cell transplantation for Parkinson's disease improves dopamine neurotransmission but fails to restore the neural circuit important for controlled motor function, and may thereby underlie suboptimal and variable outcomes in patients. However, homotopic grafts, into the site of cell loss, survive poorly and show limited integration.
Here we explore intrinsic and extrinsic factors to improve homotopic grafting.
The use of fetal donor tissue, younger than conventionally used, generates significantly larger grafts with increased innervation and circuit reconstruction. These effects can be enhanced by exposure of the graft to glial derived neurotrophic factor.
Furthermore, improved homotypic grafts are capable of enhancing functional recovery in Parkinsonian mice.
These findings have important implications for the development of cell‐ and stem cell‐based therapies to promote neural circuit reconstruction in the treatment of Parkinson's disease.
Abstract  Cell replacement therapy for Parkinson's disease has predominantly focused on ectopic transplantation of fetal dopamine (DA) neurons into the striatum as a means to restore neurotransmission, rather than homotopic grafts into the site of cell loss, which would require extensive axonal growth. However, ectopic grafts fail to restore important aspects of DA circuitry necessary for controlled basal ganglia output, and this may underlie the suboptimal and variable functional outcomes in patients. We recently showed that DA neurons in homotopic allografts of embryonic ventral mesencephalon (VM) can send long axonal projections along the nigrostriatal pathway in order to innervate forebrain targets, although the extent of striatal reinnervation remains substantially less than can be achieved with ectopic placement directly into the striatal target. Here, we examined the possible benefits of using younger VM donor tissue and over‐expression of glial cell‐derived neurotrophic factor (GDNF) in the striatal target to improve the degree of striatal innervation from homotopic grafts. Younger donor tissue, collected on embryonic day (E)10, generated 4‐fold larger grafts with greater striatal targeting, compared to grafts generated from more conventional E12 donor VM. Over‐expression of GDNF in the host brain also significantly increased DA axonal growth and striatal innervation. Furthermore, a notable increase in the number and proportion of A9 DA neurons, essential for functional recovery, was observed in younger donor grafts treated with GDNF. Behavioural testing confirmed functional integration of younger donor tissue and demonstrated that improved motor function could be attributed to both local midbrain and striatal innervation. Together, these findings suggest there is significant scope for further development of intra‐nigral grafting as a restorative approach for Parkinson's disease.
Unfolding linac photon spectra and incident electron energies from experimental transmission data, with direct independent validation
Authors: Ali E. S. M. , McEwen M. R. , Rogers D. W. O. 
Published: October 2012

Purpose:In a recent computational study, an improved physics‐based approach was proposed for unfolding linac photon spectra and incident electron energies from transmission data. In this approach, energy differentiation is improved by simultaneously using transmission data for multiple attenuators and detectors, and the unfolding robustness is improved by using a four‐parameter functional form to describe the photon spectrum. The purpose of the current study is to validate this approach experimentally, and to demonstrate its application on a typical clinical linac.Methods:The validation makes use of the recent transmission measurements performed on the Vickers research linac of National Research Council Canada. For this linac, the photon spectra were previously measured using a NaI detector, and the incident electron parameters are independently known. The transmission data are for eight beams in the range 10–30 MV using thick Be, Al and Pb bremsstrahlung targets. To demonstrate the approach on a typical clinical linac, new measurements are performed on an ElektaPrecise linac for 6, 10 and 25 MV beams. The different experimental setups are modeled using EGSnrc, with the newly added photonuclear attenuation included.Results:For the validation on the research linac, the 95% confidence bounds of the unfolded spectra fall within the noise of the NaI data. The unfolded spectra agree with theEGSnrc spectra (calculated using independently known electron parameters) with RMS energy fluence deviations of 4.5%. The accuracy of unfolding the incident electron energy is shown to be ∼3%. A transmission cutoff of only 10% is suitable for accurate unfolding, provided that the other components of the proposed approach are implemented. For the demonstration on a clinical linac, the unfolded incident electron energies and their 68% confidence bounds for the 6, 10 and 25 MV beams are 6.1 ± 0.1, 9.3 ± 0.1, and 19.3 ± 0.2 MeV, respectively. The unfolded spectra for the clinical linac agree with the EGSnrc spectra (calculated using the unfolded electron energies) with RMS energy fluence deviations of 3.7%. The corresponding measured and EGSnrc‐calculated transmission data agree within 1.5%, where the typical transmission measurement uncertainty on the clinical linac is 0.4% (not including the uncertainties on the incident electron parameters).Conclusions:The approach proposed in an earlier study for unfolding photon spectra and incident electron energies from transmission data is accurate and practical for clinical use.
Technical Note: Precision and accuracy of a commercially available CT optically stimulated luminescent dosimetry system for the measurement of CT dose index
Authors: Vrieze Thomas J. , Sturchio Glenn M. , McCollough Cynthia H. 
Published: October 2012

Purpose:To determine the precision and accuracy of CTDI100 measurements made using commercially available optically stimulated luminescent (OSL) dosimeters (Landaur, Inc.) as beam width, tube potential, and attenuating material were varied.Methods:One hundred forty OSL dosimeters were individually exposed to a single axial CT scan, either in air, a 16‐cm (head), or 32‐cm (body) CTDI phantom at both center and peripheral positions. Scans were performed using nominal total beam widths of 3.6, 6, 19.2, and 28.8 mm at 120 kV and 28.8 mm at 80 kV. Five measurements were made for each of 28 parameter combinations. Measurements were made under the same conditions using a 100‐mm long CTDI ion chamber. Exposed OSL dosimeters were returned to the manufacturer, who reported dose to air (in mGy) as a function of distance along the probe, integrated dose, and CTDI100.Results:The mean precision averaged over 28 datasets containing five measurements each was 1.4% ± 0.6%, range = 0.6%–2.7% for OSL and 0.08% ± 0.06%, range = 0.02%–0.3% for ion chamber. The root mean square (RMS) percent differences between OSL and ion chamber CTDI100 values were 13.8%, 6.4%, and 8.7% for in‐air, head, and body measurements, respectively, with an overall RMS percent difference of 10.1%. OSL underestimated CTDI100 relative to the ion chamber 21/28 times (75%). After manual correction of the 80 kV measurements, the RMS percent differences between OSL and ion chamber measurements were 9.9% and 10.0% for 80 and 120 kV, respectively.Conclusions:Measurements of CTDI100 with commercially available CT OSL dosimeters had a percent standard deviation of 1.4%. After energy‐dependent correction factors were applied, the RMS percent difference in the measured CTDI100 values was about 10%, with a tendency of OSL to underestimate CTDI relative to the ion chamber. Unlike ion chamber methods, however, OSL dosimeters allow measurement of the radiation dose profile.
Dosing Nomograms for Attaining Optimum Concentrations of Meropenem by Continuous Infusion in Critically Ill Patients with Severe Gram-Negative Infections: a Pharmacokinetics/Pharmacodynamics-Based Approach
Authors: Pea Federico , Viale Pierluigi , Cojutti Piergiorgio , Furlanut Mario 
Published: October 2012

ABSTRACT

The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems and of carbapenemase-producing
Enterobacteriaceae
has significantly undermined their efficacy. Continuous infusion may be the best way to maximize the time-dependent activity of meropenem. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL
Cr
) estimates for use in daily clinical practice to target the steady-state concentrations (
C
ss
s) of meropenem during continuous infusion at 8 to 16 mg/liter (after the administration of an initial loading dose of 1 to 2 g over 30 min). The correlation between meropenem clearance (CL
m
) and CL
Cr
was retrospectively assessed in a cohort of critically ill patients (group 1,
n
= 67) to create a formula for dosage calculation to target
C
ss
. The performance of this formula was validated in a similar cohort (group 2,
n
= 56) by comparison of the observed and the predicted
C
ss
s. A significant relationship between CL
m
and CL
Cr
was observed in group 1 (
r
= 0.72,
P
< 0.001). The application of the formula to meropenem dosing in group 2, infusion rate (g/24 h) = [0.078 × CL
Cr
(ml/min) + 2.85] × target
C
ss
× (24/1,000), led to a significant correlation between the observed and the predicted
C
ss
s (
r
= 0.92,
P
< 0.001). Dosing nomograms based on CL
Cr
were created to target the meropenem
C
ss
at 8, 12, and 16 mg/liter in critically ill patients. These nomograms could be helpful in improving the treatment of severe Gram-negative infections with meropenem, especially in the presence of borderline susceptible pathogens or even of carbapenemase producers and/or of pathophysiological conditions which may enhance meropenem clearance.
Genetic Markers of Widespread Extensively Drug-Resistant Pseudomonas aeruginosa High-Risk Clones
Authors: Cabot Gabriel , Ocampo-Sosa Alain A. , Domínguez M. Angeles , Gago Juan F. , Juan Carlos , Tubau Fe , Rodríguez Cristina , Moyà Bartolomé , Peña Carmen , Martínez-Martínez Luis , Oliver Antonio 
Published: October 2012

ABSTRACT

Recent reports have revealed the existence of widespread extensively drug-resistant (XDR)
P. aeruginosa
high-risk clones in health care settings, but there is still scarce information on their specific chromosomal (mutational) and acquired resistance mechanisms. Up to 20 (10.5%) of 190 bloodstream isolates collected from 10 Spanish hospitals met the XDR criteria. A representative number (15 per group) of isolates classified as multidrug-resistant (MDR) (22.6%), resistant to 1 to 2 classes (moderately resistant [modR]) (23.7%), or susceptible to all antibiotics (multiS) (43.2%) were investigated in parallel. Multilocus sequence typing (MLST) analysis revealed that all XDR isolates belonged to sequence type 175 (ST175) (
n
= 19) or ST111 (
n
= 1), both recognized as international high-risk clones. Clonal diversity was higher among the 15 MDR isolates (4 ST175, 2 ST111, and 8 additional STs) and especially high among the 15 modR (13 different STs) and multiS (14 STs) isolates. The XDR/MDR pattern in ST111 isolates correlated with the production of VIM-2, but none of the ST175 isolates produced acquired β-lactamases. In contrast, the analysis of resistance markers in 12 representative isolates (from 7 hospitals) of ST175 revealed that the XDR pattern was driven by the combination of AmpC hyperproduction, OprD inactivation (Q142X), 3 mutations conferring high-level fluoroquinolone resistance (GyrA T83I and D87N and ParC S87W), a G195E mutation in MexZ (involved in MexXY-OprM overexpression), and the production of a class 1 integron harboring the
aadB
gene (gentamicin and tobramycin resistance). Of particular interest, in nearly all the ST175 isolates, AmpC hyperproduction was driven by a novel AmpR-activating mutation (G154R), as demonstrated by complementation studies using an
ampR
mutant of PAO1. This work is the first to describe the specific resistance markers of widespread
P. aeruginosa
XDR high-risk clones producing invasive infections.
Feed-Forward Regulation of Phagocytosis by Entamoeba histolytica
Authors: Sateriale Adam , Vaithilingam Archana , Donnelly Liam , Miller Peter , Huston Christopher D. 
Published: October 2012

ABSTRACTThe parasitic protozoanEntamoeba histolyticais aptly named for its capacity to destroy host tissue. WhenE. histolyticatrophozoites invade the lamina propria of a host colon, extracellular matrices are degraded while host cells are killed and phagocytosed. The ability ofE. histolyticato phagocytose host cells correlates with virulencein vivo. In order to better understand the mechanism of phagocytosis, we used anE. histolyticaAffymetrix microarray chip to measure the total gene expression of phagocytic and nonphagocytic subpopulations. Using paramagnetic beads coated with a known host ligand that stimulates phagocytosis, phagocytic and nonphagocytic amoebae from a single culture were purified. Microarray analysis of the subpopulations identified 121 genes with >2-fold higher expression in phagocytic than in nonphagocytic amoebae. Functional annotation identified genes encoding proteins involved in actin binding and cytoskeletal organization as highly enriched gene clusters.Post hocanalyses of selected genes showed that the gene expression profile identified in the microarray experiment did not exist prior to cell sorting but rather was stimulated through phagocytosis. Further, these expression profiles correlated with an increase in phagocytic ability, asE. histolyticacultures exposed to an initial stimulus of phagocytosis showed increased phagocytic ability upon a second stimulus. To our knowledge, this is the first description of such feed-forward regulation of gene expression and phagocytic ability in a phagocyte.
Antivirulence Genes: Insights into Pathogen Evolution through Gene Loss
Authors: Bliven Kimberly A. , Maurelli Anthony T. 
Published: October 2012

ABSTRACT

The emergence of new pathogens and the exploitation of novel pathogenic niches by bacteria typically require the horizontal transfer of virulence factors and subsequent adaptation—a “fine-tuning” process—for the successful incorporation of these factors into the microbe's genome. The function of newly acquired virulence factors may be hindered by the expression of genes already present in the bacterium. Occasionally, certain genes must be inactivated or deleted for full expression of the pathogen phenotype to occur. These genes are known as antivirulence genes (AVGs). Originally identified in
Shigella
, AVGs have improved our understanding of pathogen evolution and provided a novel approach to drug and vaccine development. In this review, we revisit the AVG definition and update the list of known AVGs, which now includes genes from pathogens such as
Salmonella
,
Yersinia pestis
, and the virulent
Francisella tularensis
subspecies. AVGs encompass a wide variety of different roles within the microbe, including genes involved in metabolism, biofilm synthesis, lipopolysaccharide modification, and host vasoconstriction. More recently, the use of one of these AVGs (
lpxL
) as a potential vaccine candidate highlights the practical application of studying AVG inactivation in microbial pathogens.
The importance of blood-borne viruses in elevated cancer risk among opioid-dependent people: a population-based cohort study
Authors: Swart Alexander , Burns Lucinda , Mao Limin , Grulich Andrew E , Amin Janaki , O'Connell Dianne L , Meagher Nicola S , Randall Deborah A , Degenhardt Louisa , Vajdic Claire M 
Published: October 2012

ObjectiveTo quantify cancer risk in opioid dependence and the association with infection by the oncogenic blood-borne viruses (BBVs) hepatitis C (HCV), hepatitis B (HBV) and HIV.DesignCohort study.SettingNew South Wales, Australia.ParticipantsAll 45 412 adults aged 16 years or over registered for opioid substitution therapy (OST) between 1985 and 2007. Notifications of cancer, death and infection with HCV, HBV and HIV were ascertained by record linkage with registries.Main outcome measuresThe ratios of observed to expected number of cancers, standardised incidence ratios (SIRs), and the average annual per cent change (AAPC) in overall age and sex-standardised cancer incidence.ResultsOverall cancer risk was modestly increased compared to the general population (SIR 1.15, 95% CI 1.07 to 1.23). Excess risk was observed for 11 cancers, particularly lung (4.02, 95% CI 3.32 to 4.82), non-Hodgkin's lymphoma (1.51, 95% CI 1.20 to 1.88) and liver (8.04, 95% CI 6.18 to 10.3). Reduced risk was observed for six cancers, including prostate (0.16, 95% CI 0.06 to 0.32) and breast (0.48, 95% CI 0.35 to 0.62). Individuals notified with HCV or HBV had a markedly increased risk of liver cancer; lung cancer risk was also increased in those with HCV. HIV was associated with an elevated risk of liver, anus and kidney cancer, non-Hodgkin lymphoma and Kaposi sarcoma. Cancer risk was not increased in individuals without a BBV notification, apart from pancreatic cancer (3.92, 95% CI 1.07 to 10.0). Cancer incidence increased significantly over time (AAPC 9.4%, 4.2% to 15%, p=0.001).ConclusionsBBVs play a major role in the cancer risk profile of opioid-dependent individuals registered for OST. To address the dramatic increasing trend in cancer incidence, the OST setting could be utilised for cancer prevention strategies.
Modelling national HIV/AIDS epidemics: revised approach in the UNAIDS Estimation and Projection Package 2011
Authors: Bao Le , Salomon Joshua A , Brown Tim , Raftery Adrian E , Hogan Daniel R 
Published: October 2012

ObjectiveUnited Nations Programme on HIV/AIDS reports regularly on estimated levels and trends in HIV/AIDS epidemics, which are evaluated using an epidemiological model within the Estimation and Projection Package (EPP). The relatively simple four-parameter model of HIV incidence used in EPP through the previous round of estimates has encountered challenges when attempting to fit certain data series on prevalence over time, particularly in settings with long running epidemics where prevalence has increased recently. To address this, the most recent version of the modelling package (EPP 2011) includes a more flexible epidemiological model that allows HIV infection risk to vary over time. This paper describes the technical details of this flexible approach to modelling HIV transmission dynamics within EPP 2011.MethodologyFor the flexible modelling approach, the force of infection parameter, r, is allowed to vary over time through a random walk formulation, and an informative prior distribution is used to improve short-term projections beyond the last year of data. Model parameters are estimated using a Bayesian estimation approach in which models are fit to HIV seroprevalence data from surveillance sites.ResultsThis flexible model can yield better estimates of HIV prevalence over time in situations where the classic EPP model has difficulties, such as in Uganda, where prevalence is no longer falling. Based on formal out-of-sample projection tests, the flexible modelling approach also improves predictions and CIs for extrapolations beyond the last observed data point.ConclusionsWe recommend use of a flexible modelling approach where data are sufficient (eg, where at least 5 years of observations are available), and particularly where an epidemic is beyond its peak.
Geochemistry and tectonic significance of ophiolites along the İzmir–Ankara–Erzincan Suture Zone in northeastern Anatolia
Authors: Parlak Osman , Çolakoğlu Aydin , Dönmez Cahit , Sayak Hüseyin , Yildirim Nail , Türkel Aytekin , Odabaşi İlhan 
Published: October 2012

Abstract
The Ankara–Erzincan suture zone includes large bodies of ophiolite and ophiolitic melange in northeastern Anatolia. The ophiolitic bodies are (1) Refahiye (Erzincan), (2) Şahvelet (Erzurum), (3) Karadağ (Erzurum) and (4) Kırdağ (Erzurum). The ophiolite-related units include well-preserved sections of oceanic lithospheric and accretionary melanges with local blueschist assemblages. The ophiolite-related units in NE Anatolia are unconformably overlain by Campanian–Maastrichtian-aged sediments that were later imbricated with the ophiolitic rocks. Geochemical data for the individual ophiolite sections indicate a tholeiitic composition, depletion in Nb, enrichment in large ion lithophile elements, parallel to slightly depleted high field strength element patterns (compared with normal-mid ocean ridge basalt), and slightly light rare earth element-depleted to parallel rare earth element trends. These features suggest progressive source depletion towards island arc tholeiites and finally boninites. A fore-arc setting is proposed for the generation of the ophiolites. In contrast, the volcanic rocks from the mélange units exhibit tholeiitic to alkaline compositions and either depletion or enrichment of rare earth element and high field strength elements. Seamount-type alkaline and subduction-related tholeiitic basaltic rocks were apparently juxtaposed during subduction/accretion. Models involving either a single north-dipping subduction zone or two north-dipping subduction zones may be applicable. Both models involve the generation of supra-subduction zone-type ophiolites in a forearc setting, an accretionary prism (with blueschists) and a volcanic arc during the Late Cretaceous. The ophiolites, ophiolitic melange and related blueschists were emplaced either northwards onto the Pontide margin or southwards over the passive margin of the Tauride platform.
Prospero Homeobox 1 Promotes Epithelial–Mesenchymal Transition in Colon Cancer Cells by Inhibiting E-cadherin via miR-9
Authors: Lu Mei-Hsuan , Huang Chao-Cheng , Pan Mei-Ren , Chen Hong-Hwa , Hung Wen-Chun 
Published: October 2012

AbstractPurpose: Prospero homeobox 1 (PROX1) has been shown to function as a tumor suppressor in various types of cancer. However, it promotes colon cancer progression. The aim of this study is to clarify the underlying mechanism by which PROX1 regulates tumorigenicity of colon cancer.Experimental Design: Association of PROX1 and clinicopathological features was studied by immunohistochemical staining. Pri-miR-9-2 and miR-9 were detected by quantitative real-time PCR. Assays of cell invasion, adhesion, and matrix metalloproteinase activity were used to study PROX1-mediated epithelial–mesenchymal transition (EMT).Results: PROX1 was overexpressed in 43% (59/136) of colon cancer tissues and its expression was correlated with E-cadherin downregulation (P = 0.00005), advanced tumor staging (P = 0.005), and lymph node metastasis (P = 0.000009). Enforced expression of PROX1 in DLD-1 cells caused downregulation of E-cadherin and integrins and attenuated cell adhesion. These cells showed increase of matrix metalloproteinase activity and invasive ability. Conversely, knockdown of PROX1 in SW620 cells restored E-cadherin protein expression and reduced invasiveness. Unexpectedly, repression of E-cadherin by PROX1 was not mediated by transcriptional inhibition. We found that PROX1 bound to miR-9-2 promoter and triggered its expression to suppress E-cadherin 3′UTR reporter activity and protein expression. Anti–miR-9 restored E-cadherin in SW620 cells, whereas precursor miR-9 inhibited E-cadherin in PROX1-knockdown cells. The miR-9 level was higher in tumor tissues with high PROX1/low E-cadherin than that of tumor tissues with low PROX1/high E-cadherin.Conclusions: Our results provide mechanistic insights by which PROX1 promotes EMT and colon cancer progression. Targeting of PROX1-mediated oncogenic activity may be helpful for the treatment of colon cancer. Clin Cancer Res; 18(23); 6416–25. ©2012 AACR.