bluuebunny/crossref_metadata_2025 huggingface dataset:
Two-Photon Fluorescence Microscopy of Cerebral Hemodynamics
Authors: Lindvere Liis , Dorr Adrienne , Stefanovic Bojana
Published: September 2010

INTRODUCTION

Under physiological conditions, neuronal activity is tightly coupled to hemodynamics of the surrounding microvessels. Conversely, most brain diseases are associated with a disturbance in neurovascular coupling. Measuring the hemodynamic response of the microvascular network to neuronal stimulation in vivo involves two major challenges: maintaining a stable systemic physiological state in the animal and imaging with sufficient temporal and spatial resolution to capture the hemodynamic changes across the three-dimensional cortical microvascular network. Two-photon fluorescence microscopy allows imaging of intact cortex in situ at micrometer spatial and microsecond temporal resolution. However, this modality necessitates focal opening of the skull because of its high scattering of light waves. This protocol describes in detail the requisite surgical preparation and physiological maintenance of an adolescent rat with a closed cranial window. Two-photon fluorescence laser scanning microscopy is then used to image the hemodynamic response of the microvasculature of the primary somatosensory cortex to electrical stimulation of the forepaw, with the end goal of quantitative analysis of brain hemodynamics.
Identification of a Novel Abscisic Acid-Regulated Farnesol Dehydrogenase from Arabidopsis
Authors: Bhandari Jayaram , Fitzpatrick A. Heather , Crowell Dring N.
Published: September 2010

In Arabidopsis (Arabidopsis thaliana), farnesylcysteine is oxidized to farnesal and cysteine by a membrane-associated thioether oxidase called farnesylcysteine lyase. Farnesol and farnesyl phosphate kinases have also been reported in plant membranes. Together, these observations suggest the existence of enzymes that catalyze the interconversion of farnesal and farnesol. In this report, Arabidopsis membranes are shown to possess farnesol dehydrogenase activity. In addition, a gene on chromosome 4 of the Arabidopsis genome (At4g33360), called FLDH, is shown to encode an NAD+-dependent dehydrogenase that oxidizes farnesol more efficiently than other prenyl alcohol substrates. FLDH expression is repressed by abscisic acid (ABA) but is increased in mutants with T-DNA insertions in the FLDH 5′ flanking region. These T-DNA insertion mutants, called fldh-1 and fldh-2, are associated with an ABA-insensitive phenotype, suggesting that FLDH is a negative regulator of ABA signaling.
Y3IP1, a Nucleus-Encoded Thylakoid Protein, Cooperates with the Plastid-Encoded Ycf3 Protein in Photosystem I Assembly of Tobacco and Arabidopsis
Authors: Albus Christin A. , Ruf Stephanie , Schöttler Mark Aurel , Lein Wolfgang , Kehr Julia , Bock Ralph
Published: September 2010

The intricate assembly of photosystem I (PSI), a large multiprotein complex in the thylakoid membrane, depends on auxiliary protein factors. One of the essential assembly factors for PSI is encoded by ycf3 (hypothetical chloroplast reading frame number 3) in the chloroplast genome of algae and higher plants. To identify novel factors involved in PSI assembly, we constructed an epitope-tagged version of ycf3 from tobacco (Nicotiana tabacum) and introduced it into the tobacco chloroplast genome by genetic transformation. Immunoaffinity purification of Ycf3 complexes from the transplastomic plants identified a novel nucleus-encoded thylakoid protein, Y3IP1 (for Ycf3-interacting protein 1), that specifically interacts with the Ycf3 protein. Subsequent reverse genetics analysis of Y3IP1 function in tobacco and Arabidopsis thaliana revealed that knockdown of Y3IP1 leads to a specific deficiency in PSI but does not result in loss of Ycf3. Our data indicate that Y3IP1 represents a novel factor for PSI biogenesis that cooperates with the plastid genome-encoded Ycf3 in the assembly of stable PSI units in the thylakoid membrane.
Down‐regulation of ING4 is associated with initiation and progression of lung cancer
Authors: Wang Qiu‐shi , Li Ming , Zhang Lin‐you , Jin Yan , Tong Dan‐dan , Yu Yang , Bai Jing , Huang Qi , Liu Fang‐Li , Liu An , Lee Ki‐Young , Fu Song‐bin
Published: September 2010

Wang Q‐s, Li M, Zhang L‐y, Jin Y, Tong D‐d, Yu Y, Bai J, Huang Q, Liu F‐L, Liu A, Lee K‐Y & Fu S‐b (2010) Histopathology 57, 271–281 Down‐regulation of ING4 is associated with initiation and progression of lung cancer

Aims:  Tumour suppressor ING4 is one of ING family genes, which are involved in cell cycle arrest, gene transcription regulation, DNA repair and apoptosis. ING4 inhibition has been reported in various tumours, including gliomas, breast tumours, and stomach adenocarcinoma. The aim was to evaluate ING4 expression in lung cancers.

Method and results:  By immunohistochemistry of 246 lung tumour tissues, reduced ING4 nuclear and cytoplasmic expression were both revealed in lung cancer and associated with tumour grade. Interestingly, compared with normal tissues, we found more tumours with ING4 expression in the cytoplasm higher than in the nucleus. Nuclear ING4 inhibition correlated with the tumour stage and lymph node metastasis. Consistent with these findings, semiquantitative reverse transcriptase‐polymerase chain reaction and Western blotting demonstrated decreased ING4 mRNA and expression in 100% (50/50) tumour tissues. Furthermore, ING4 expression was lower in grade III than in grades I–II tumours. Reduced ING4 mRNA correlated with lymph node metastasis.

Conclusions:  Our results indicate that overall inhibition of ING4 expression and ING4 expression higher in cytoplasm than in nucleus of tumour cells may be involved in the initiation and progression of lung cancers, and thus, analysis for ING4 expression may be useful as a clinical diagnostic and prognostic tool for lung cancer.
Transient hyperphosphatasemia in pediatric renal transplant patients – Is there a need for concern and when?
Authors: Kutílek Štěpán , Skálová Sylva , Vethamuthu Jennifer , Geier Pavel , Feber Janusz
Published: September 2010

Kutílek Š, Skálová S, Vethamuthu J, Geier P, Feber J. Transient hyperphosphatasemia in pediatric renal transplant patients – Is there a need for concern and when?  Pediatr Transplantation 2012: 16: E5–E9. © 2010 John Wiley & Sons A/S.

Abstract:  TH of infancy and early childhood is characterized by transiently increased S‐ALP, predominantly its bone or liver isoforms. There are neither signs of metabolic bone disease or hepatopathy corresponding to the increased S‐ALP, nor a common underlying/triggering disease. TH may also occur in children post‐renal Tx, which may raise significant concerns and anxiety. We describe four patients aged 2.8–7 yr in whom the TH occurred at 11–34 (median = 28) months after Tx and lasted from 40 to 105 (median = 63) days. No obvious cause/trigger of TH could be found; the clinical status and bone turnover were not altered. In cases of TH post‐Tx, we recommend the evaluation of basic biochemical indices and wrist X‐ray. If these results are normal, TH is most likely the diagnosis and the S‐ALP can be monitored over the next three months without further testing. In patients with persisting TH for more than three months and/or in children with pre‐existing or suspected metabolic bone disease, further evaluation may be indicated. In conclusion, TH is a benign disorder in patients post‐Tx. Detailed investigation including bone biopsy is only indicated in patients with persisting TH.
A case of pediatric PTLD following autologous stem cell transplantation and review of the literature
Authors: Eckrich Michael J. , Frangoul Haydar , Knight Jennifer , Mosse Claudio , Domm Jennifer
Published: September 2010

Eckrich MJ, Frangoul H, Knight J, Mosse C, Domm J. A case of pediatric PTLD following autologous stem cell transplantation and review of the literature.  Pediatr Transplantation 2012: 16: E15–E18. © 2010 John Wiley & Sons A/S.

Abstract:  The development of PTLD is a rare severe adverse event following ASCT. We report on a child with DS who developed PTLD following autologous transplant for relapsed Hodgkin’s disease. He was successfully treated with cyclophosphamide, prednisone and rituximab. We also present a comprehensive review of the literature of PTLD in pediatric patients following ASCT.
Technique for a hybrid system of real‐time transrectal ultrasound with preoperative magnetic resonance imaging in the guidance of targeted prostate biopsy
Authors: Ukimura Osamu , Hirahara Naoki , Fujihara Atsuko , Yamada Takeshi , Iwata Tsuyoshi , Kamoi Kazumi , Okihara Koji , Ito Hirotoshi , Nishimura Tsunehiko , Miki Tsuneharu
Published: September 2010

Diagnostic magnetic resonance imaging (MRI) for prostate has achieved increasingly higher levels of accuracy. Because real‐time MR‐guided targeted biopsy is still a complicated and expensive procedure, there is considerable interest in a technique of MR/transrectal ultrasound (TRUS) hybridized image‐guided biopsy. However, because the 3‐D shapes of the prostate at the time of image‐acquisition at preoperative MRI are likely to be different from the intra‐operative TRUS images, the precise registration of each 3‐D volume data is critical. To reduce the potential errors in registration of TRUS with MRI, we introduce new procedural techniques in a rigid image fusion technique. First, preoperative MR images were obtained with a specifically‐made plastic outer‐frame, with exactly the same shape as the real TRUS probe, placed in the rectum, in order to simulate the deformation of the prostate caused by the absence or presence of a TRUS probe during the acquisition of MR or TRUS images. Second, instead of using a single plane of longitudinal image, we applied biplane TRUS images to be shown in parallel on a multiplanar display with corresponding reconstructed MRI, in order to register both horizontal and longitudinal images of the prostate simultaneously, thereby achieving improved 3‐D anatomical matching.
Genes for selenium dependent and independent formate dehydrogenase in the gut microbial communities of three lower, wood‐feeding termites and a wood‐feeding roach
Authors: Zhang Xinning , Matson Eric G. , Leadbetter Jared R.
Published: September 2010

The bacterial Wood–Ljungdahl pathway for CO2‐reductive acetogenesis is important for the nutritional mutualism occurring between wood‐feeding insects and their hindgut microbiota. A key step in this pathway is the reduction of CO2 to formate, catalysed by the enzyme formate dehydrogenase (FDH). Putative selenocysteine‐ (Sec) and cysteine‐ (Cys) containing paralogues of hydrogenase‐linked FDH (FDHH) have been identified in the termite gut acetogenic spirochete, Treponema primitia, but knowledge of their relevance in the termite gut environment remains limited. In this study, we designed degenerate PCR primers for FDHH genes (fdhF) and assessed fdhF diversity in insect gut bacterial isolates and the gut microbial communities of termites and cockroaches. The insects examined herein represent three wood‐feeding termite families, Termopsidae, Kalotermitidae and Rhinotermitidae (phylogenetically ‘lower’ termite taxa); the wood‐feeding roach family Cryptocercidae (the sister taxon to termites); and the omnivorous roach family Blattidae. Sec and Cys FDHH variants were identified in every wood‐feeding insect but not the omnivorous roach. Of 68 novel alleles obtained from inventories, 66 affiliated phylogenetically with enzymes from T. primitia. These formed two subclades (37 and 29 phylotypes) almost completely comprised of Sec‐containing and Cys‐containing enzymes respectively. A gut cDNA inventory showed transcription of both variants in the termite Zootermopsis nevadensis (family Termopsidae). The gene patterns suggest that FDHH enzymes are important for the CO2‐reductive metabolism of uncultured acetogenic treponemes and imply that the availability of selenium, a trace element, shaped microbial gene content in the last common ancestor of dictyopteran, wood‐feeding insects, and continues to shape it to this day.
Dry Sliding Friction Experiments at Elevated Velocities
Authors: Lodygowski A. , Faure L. , Voyiadjis G. Z. , Philippon S.
Published: September 2010

Abstract:  An enhancement of an existing tribometer device developed by Philippon et al. (2004, Wear257, 777–784) is presented in this work. This experimental device is made up of a dynamometer ring and a specific load sensor allowing to apply an apparent normal force on specimens and to measure frictional forces respectively. Problems such as static calibration of both distinct parts supported by conducted numerical simulations is given and described in detail. Further discussion, again supported by numerical analysis, validates the placing of the strain gauges and explains the problems of sensitivity of loading surface and cross‐sensitivity. The entire experimental setup is then discussed explaining the mounting of the strain gauges located on the tribometer device, showing the configuration of the Wheatstone quarter‐bridges, presenting the signal conditioning amplifier system and the digital oscilloscopes which all together create one uniform data acquisition system. The set up is adapted on a gas gun to carry the Steel 1080 on Steel VascoMax 300 experiments. The main set of experiments with sliding velocities varying from 10 to 60 m s−1 are performed in the same tested setup. The recordings of normal and tangential forces leading to the friction coefficient determination are discussed. The values of dry friction coefficient μ according to the experimental parameters are in good agreement with those observed in the literature. Using this new configuration, the effects of the sliding velocity on the surface roughness changes and on the dry fiction coefficient are also investigated. Moreover, very interesting relations between wear and sliding velocity are observed.
The Comprehensive Care Project: Measuring Physician Performance in Ambulatory Practice
Authors: Holmboe Eric S. , Weng Weifeng , Arnold Gerald K. , Kaplan Sherrie H. , Normand Sharon‐Lise , Greenfield Sheldon , Hood Sarah , Lipner Rebecca S.
Published: September 2010

Objective. To investigate the feasibility, reliability, and validity of comprehensively assessing physician‐level performance in ambulatory practice.

Data Sources/Study Setting. Ambulatory‐based general internists in 13 states participated in the assessment.

Study Design. We assessed physician‐level performance, adjusted for patient factors, on 46 individual measures, an overall composite measure, and composite measures for chronic, acute, and preventive care. Between‐ versus within‐physician variation was quantified by intraclass correlation coefficients (ICC). External validity was assessed by correlating performance on a certification exam.

Data Collection/Extraction Methods. Medical records for 236 physicians were audited for seven chronic and four acute care conditions, and six age‐ and gender‐appropriate preventive services.

Principal Findings. Performance on the individual and composite measures varied substantially within (range 5–86 percent compliance on 46 measures) and between physicians (ICC range 0.12–0.88). Reliabilities for the composite measures were robust: 0.88 for chronic care and 0.87 for preventive services. Higher certification exam scores were associated with better performance on the overall (r=0.19; p<.01), chronic care (r=0.14, p=.04), and preventive services composites (r=0.17, p=.01).

Conclusions. Our results suggest that reliable and valid comprehensive assessment of the quality of chronic and preventive care can be achieved by creating composite measures and by sampling feasible numbers of patients for each condition.
Risk‐Adjusted Capitation Rates for Children: How Useful Are the Survey‐Based Measures?
Authors: Yu Hao , Dick Andrew W.
Published: September 2010

Objective. Despite the recognition by some experts that survey measures have the potential to improve capitation rates for those with chronic conditions, few studies have examined risk‐adjustment models for children, and fewer still have focused on survey measures. This study evaluates the performance of risk‐adjustment models for children and examines the potential of survey‐based measures for improving capitation rates for children.

Data Sources. The study sample includes 8,352 Medicaid children who were followed up for 2 years by the Medical Expenditure Panel Survey in 2000–2005.

Study Methods. Children's information in 1 year was used to predict their expenditures in the next year. Five models were estimated, including one each that used demographic characteristics, subjectively rated health status, survey measures about children with special health care needs (CSHCN), prior year expenditures, and Hierarchical Condition Category (HCC), which is a diagnosis‐based model. The models were tested at the individual level using multiple regression methods and at the group level using split‐half validation to evaluate their impact on expenditure predictions for CSHCN.

Principal Findings. The CSHCN information explained higher proportion of the variance in annual expenditures than the subjectively rated health status, but less than HCC measures and prior expenditures. Adding the CSHCN information into demographic factors as adjusters would remarkably increase capitation rates for CSHCN.

Conclusions. Survey measures, such as the CSHCN information, can improve risk‐adjustment models, and their inclusion into capitation adjustment may help provide appropriate payments to managed‐care plans serving this vulnerable group of children.
High rate of fistula placement in a cohort of dialysis patients in a single payer system
Authors: BLOSSER Christopher D. , AYEHU Gashu , WU Sam , LOMAGRO Ruth M. , MALONE Ellen , BRUNELLI Steven M. , ITKIN Max , GOLDEN Michael , MCCOMBS Peter , LIPSCHUTZ Joshua H.
Published: September 2010

Arteriovenous fistulas (AVFs) are considered superior to arteriovenous grafts and catheters. Nevertheless, AVF prevalence in the United States remains under the established target. The complication rates and financial cost of vascular access continue to rise and disproportionately contribute to the burgeoning health care costs. The relationship between financial incentives for a type of vascular access and rate of access placement is unclear. All chronic hemodialysis patients (n=99) receiving care at Philadelphia Veterans Affairs Medical Center as of August 1, 2008 were participants. Demographic characteristics, vascular access type, and nonrelative value unit compensation were assessed as predictors, and the vascular access prevalence rate, operative times, and frequency of access interventions were analyzed. A 73.7% AVF rate was achieved in this cohort of patients with 51.5% diabetes mellitus. The number of access procedures per patient per year remained constant over time. The Philadelphia Veterans Affairs Medical Center, a single payer system, achieved superior AVF prevalence and exceeded the national AVF target. Financial incentives for arteriovenous graft placement currently exist in the United States, as there is similar Medicare reimbursement for arteriovenous graft and basilic vein transposition, despite longer operative times for basilic vein transpositions. The high AVF prevalence at the Philadelphia Veterans Affairs Medical Center may be due to the VA nonrelative value unit‐driven system that allows for interdisciplinary care, priority of AVFs, and frequent use of basilic vein transposition surgery, when appropriate. We have identified an important, hypothesis‐generating example of a nonrelative value unit‐based approach to vascular access yielding superior results with respect to patient care and cost.
Reflections on the Mutual Impact of Violence and Religious Change in Latin America
Authors: Levine Daniel H.
Published: September 2010

The mutual impact of violence and religious transformation in the recent experience of Latin America has reshaped the public presence of churches (both Catholic and Protestant) and altered their discourse and appeal. Many churches turned to promotion of human rights, protection of victims, and opposition to authoritarian rule. Others allied with repressive regimes in the name of a kind of Christian nationalism. The violence at issue ranges from the massive violence of repression, torture, and revolutionary struggle to the institutionalized violence of poverty, disease, and injustice, which is often accompanied by the violence of daily life and linked with migration, drugs, gangs, and domestic abuse. Religion itself has changed: the Catholic monopoly has been replaced by pluralism, as Protestant and Pentecostal churches reach new populations and offer potential converts a way of opting out of the violence of daily life through rebirth in a new religious community.
Effects of recombinant human erythropoietin in normal humans
Authors: Lundby Carsten , Olsen Niels Vidiendal
Published: September 2010

This review describes some of the physiological effects of recombinant human erythropoietin (EPO) in healthy humans. At the blood level EPO increases the arterial O2 content not only by increasing red blood cell volume, but also by an equally important decrease in plasma volume. Well before that, EPO causes a prompt decrease in plasma levels of renin and aldosterone. Renal clearance studies suggest that EPO decreases renal proximal tubular reabsorption rate leading to activation of the tubuloglomerular feedback mechanism and a fall in glomerular filtration rate. Thus, treatment with EPO may result in suppression of endogenous EPO production through a decrease in intrarenal oxygen consumption. EPO elevates the arterial blood pressure even in healthy subjects. The receptor for EPO is present in many tissues. However, the functional effects of EPO in the skeletal muscle seem limited, and although it has been speculated that non‐erythropoietic effects of EPO (angiogenesis, shift in muscle fibre types, cognitive effects) may be responsible for the increase in exercise performance, this has not been confirmed. EPO‐induced haemodynamic effects call for careful monitoring during the administration period. The metabolic, hormonal and renal effects of EPO do not seem to range beyond physiologically acceptable limits and are reversible. Taken together, EPO seems safe to use for experimental purposes in healthy volunteers.
Computational Fluid Dynamics Application of the Diffusion-Inertia Model to Bubble Flows and Boiling Water Problems
Authors: Filippov Alexander S. , Alipchenkov Vladimir M. , Drobyshevsky Nickolay I. , Mukin Roman V. , Strizhov Valeri F. , Zaichik Leonid I.
Published: September 2010

This paper is aimed at the application of a model for simulating the dispersed turbulent flows. The presented model proceeds from a kinetic equation for the probability density function of the particle velocity distribution in turbulent flow. This approach is called the diffusion-inertia model (DIM). Applications of the model to droplet and bubble flows are presented. In the case of vaporized liquid, the interphase heat and mass transfer is introduced by adding the corresponding governing equations. This extended version of the DIM was applied to simulating the boiling water flow in a heated pipe.
Stiffness Matrix Properties for Reduced Order Models of Linear Structural Systems
Authors: Yu Jun , Imbimbo Maura , Betti Raimondo
Published: September 2010

This paper discusses a theoretical approach to investigate the dependency relationship between the stiffness matrix and the complex eigenvectors in the identification of structural systems for the case of insufficient instrumentation setup. The main result of the study consists of proving, in the case of classical damping, the independency of the stiffness subpartition corresponding to the measured degrees-of-freedom from the unmeasured ones. The same result is shown to be valid in the case of nonclassical damping but only for tridiagonal sparse stiffness matrix systems. A numerical procedure proves the above results and also shows the dependency relationship for the general nonclassical damping cases.
Buckling Analyses of Double-Wall Carbon Nanotubes: A Shell Theory Based on the Interatomic Potential
Authors: Lu W. B. , Wu J. , Feng X. , Hwang K. C. , Huang Y.
Published: September 2010

Based on the finite-deformation shell theory for carbon nanotubes established from the interatomic potential and the continuum model for van der Waals (vdW) interactions, we have studied the buckling of double-walled carbon nanotubes subjected to compression or torsion. Prior to buckling, the vdW interactions have essentially no effect on the deformation of the double-walled carbon nanotube. The critical buckling strain of the double-wall carbon nanotubes is always between those for the inner wall and for the outer wall, which means that the vdW interaction decelerates buckling of one wall at the expenses of accelerating the buckle of the other wall.
Mechanistic study of ultralow k-compatible carbon dioxide in situ photoresist ashing processes. I. Process performance and influence on ULK material modification
Authors: Kuo Ming-Shu , Pal A. R. , Oehrlein G. S. , Lazzeri P. , Anderle M.
Published: September 2010

In situ photoresist (PR) ashing processes are attractive because of the ease of process integration with plasma etching processes. The authors have examined the performance of carbon dioxide (CO2) as a source gas for in situ PR ashing processes compatible with ultralow k (ULK) materials and compared it with the results obtained using O2. They performed measurements of 193 nm PR ashing rates in a dual frequency capacitively coupled plasma reactor. The damage to porous ULK feature sidewalls was simulated by exposing blanket ULK films in a non-line-of-sight fashion in a small gap structure to the plasma-generated reactants. The pressure for the in situ ashing processes was varied from 10 to 100 mTorr, and the self-bias voltages ranged from floating potential to ∼−400 V. To increase line-of-sight etching of PR by inert ion bombardment, Ar/CO2 mixtures with up to 75% Ar were investigated. The ULK material modifications were analyzed by x-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectroscopy (ToF-SIMS). Plasma-damage of the ULK material primarily is detected as the removal of carbon from the SiCOH ULK films. To compare the performance of different ashing processes for PR stripping from ULK material, the authors introduced an ashing efficiency (AE) parameter which is defined as the thickness of PR removed over the thickness of ULK simultaneously damaged, and can be considered a process figure of merit. AE with CO2 was about three times greater than AE with O2 for the same process conditions. When a 75% Ar/CO2 gas mixture was used and a −100 V substrate bias was applied during PR ashing, a PR ashing rate of 200 nm/min could be achieved for a 10 mTorr Ar/CO2 plasma. For this process, the measured AE was 230, more than 10× greater than AE achieved with O2 discharges using the same conditions. The authors found that ULK damage showed a direct dependence on the atomic oxygen densities of both CO2 and O2 discharges which was characterized by optical emission of discharges. The question whether in-diffusion of carbon species from CO2 discharges into ULK material was significant was also examined. For this the authors substituted C13O2 for C12O2 and performed ToF-SIMS analysis of the exposed ULK films. No significant amount of C13 from C13O2 plasmas was detected either on the surface or in the bulk of the C13O2 plasma-exposed ULK.
Translational Medicine and the Value of Biomarker Qualification
Authors: Goodsaid Federico M. , Mendrick Donna L.
Published: September 2010

The U.S. Food and Drug Administration's new process for biomarker qualification developed from a need for better biomarkers of renal injury.
M Protein and Hyaluronic Acid Capsule Are Essential for
In Vivo
Selection of
covRS
Mutations Characteristic of Invasive Serotype M1T1 Group A
Streptococcus
Authors: Cole Jason N. , Pence Morgan A. , von Köckritz-Blickwede Maren , Hollands Andrew , Gallo Richard L. , Walker Mark J. , Nizet Victor
Published: September 2010

The initiation of hyperinvasive disease in group A
Streptococcus
(GAS) serotype M1T1 occurs by mutation within the
covRS
two-component regulon (named
covRS
for
c
ontrol
o
f
v
irulence
r
egulatory
s
ensor kinase), which promotes resistance to neutrophil-mediated killing through the upregulation of bacteriophage-encoded Sda1 DNase. To determine whether other virulence factors contribute to this phase-switching phenomenon, we studied a panel of 10 isogenic GAS serotype M1T1 virulence gene knockout mutants. While loss of several individual virulence factors did not prevent GAS
covRS
switching
in vivo
, we found that M1 protein and hyaluronic acid capsule are indispensable for the switching phenotype, a phenomenon previously attributed uniquely to the Sda1 DNase. We demonstrate that like M1 protein and Sda1, capsule expression enhances survival of GAS serotype M1T1 within neutrophil extracellular traps. Furthermore, capsule shares with M1 protein a role in GAS resistance to human cathelicidin antimicrobial peptide LL-37. We conclude that a quorum of GAS serotype M1T1 virulence genes with cooperative roles in resistance to neutrophil extracellular killing is essential for the switch to a hyperinvasive phenotype
in vivo
.

IMPORTANCE
The pathogen group A
Streptococcus
(GAS) causes a wide range of human infections ranging from the superficial “strep throat” to potentially life-threatening conditions, such as necrotizing fasciitis, also known as “flesh-eating disease.” A marked increase in the number of cases of severe invasive GAS infection during the last 30 years has been traced to the emergence and spread of a single clone of the M1T1 serotype. Recent studies have shown that GAS serotype M1T1 bacteria undergo a genetic “switch”
in vivo
to a hypervirulent state that allows dissemination into the bloodstream. The present study was undertaken to identify specific GAS serotype M1T1 virulence factors required for this switch to hypervirulence. The surface-anchored GAS M1 protein and hyaluronic acid capsule are found to be essential for the switching phenotype, and a novel role for capsule in GAS resistance to host defense peptides and neutrophil extracellular killing is revealed.
Topological Vector Space-Valued Cone Metric Spaces and Fixed Point Theorems
Authors: Kadelburg Zoran , Radenović Stojan , Rakočević Vladimir
Published: September 2010

We develop the theory of topological vector space valued cone metric spaces with nonnormal cones. We prove three general fixed point results in these spaces and deduce as corollaries several extensions of theorems about fixed points and common fixed points, known from the theory of (normed-valued) cone metric spaces. Examples are given to distinguish our results from the known ones.
Some Krasnonsel'skiĭ-Mann Algorithms and the Multiple-Set Split Feasibility Problem
Authors: He Huimin , Liu Sanyang , Noor MuhammadAslam
Published: September 2010

Some variable Krasnonsel'skiĭ-Mann iteration algorithms generate some sequences "Equation missing", "Equation missing", and"Equation missing", respectively, via the formula "Equation missing", "Equation missing", "Equation missing", where "Equation missing" and the mod function takes values in "Equation missing", "Equation missing", "Equation missing", and"Equation missing" are sequences in "Equation missing" and "Equation missing" are sequences of nonexpansive mappings. We will show, in a fairly general Banach space, that the sequence "Equation missing", "Equation missing", "Equation missing" generated by the above formulas converge weakly to the common fixed point of "Equation missing", respectively. These results are used to solve the multiple-set split feasibility problem recently introduced by Censor et al. (2005). The purpose of this paper is to introduce convergence theorems of some variable Krasnonsel'skiĭ-Mann iteration algorithms in Banach space and their applications which solve the multiple-set split feasibility problem.
Metronidazole-Induced Pancreatitis
Authors: O'Halloran E. , Hogan A. , Mealy K.
Published: September 2010

Case Summary. A 25-year-old caucasian lady presented to the Accident & Emergency department complaining of acute onset severe epigastric pain radiating through to the back with associated nausea and vomiting. A diagnosis of acute pancreatitis was made. Symptoms commenced after the third dose of Metronidazole therapy prescribed for a recurrent periodontal abscess. The patient described a similar episode 10 months previously. On neither occasion were any other medications being taken, there was no history of alcohol abuse and no other gastro-intestinal aetiology could be identified on imaging. Symptoms resolved quickly upon discontinuation of the antibiotic agent. We conclude therefore that Metronidazole can reasonably be identified as the only potential causative agent.
Discussion. The proportion of cases of pancreatitis caused by drugs is estimated to be around 2% in the general population. The exact mechanism of action of Metronidazole induced pancreatitis is unclear but a trigger role for the drug seems likely.
Conclusion. This case provides the eighth report of Metronidazole induced pancreatitis. All of the cases were reported in females and ran a benign course.Early diagnosis, discontinuation of the drug and supportive care will lead to a successful recovery in the majority of cases.
Mesotherapy versus Systemic Therapy in the Treatment of Acute Low Back Pain: A Randomized Trial
Authors: Costantino Cosimo , Marangio Emilio , Coruzzi Gabriella
Published: September 2010

Pharmacological therapy of back pain with analgesics and anti‐inflammatory drugs is frequently associated with adverse effects, particularly in the elderly. Aim of this study was to compare mesotherapic versus conventional systemic administration of nonsteroidal anti‐inflammatory drugs (NSAIDs) and corticosteroids in patients with acute low back pain. Eighty‐four patients were randomized to receive anti‐inflammatory therapy according to the following protocols: (a) mesotherapy group received the 1st and 4th day 2% lidocaine (1 mL) + ketoprofen 160 mg (1 mL) + methylprednisolone 40 mg (1 mL), then on 7th, 10th, and 13th day, 2% lidocaine (1 mL) + ketoprofen 160 mg (1 mL) + methylprednisolone 20 mg (1 mL) (b) conventional therapy group received ketoprofen 80 mg × 2/die and esomeprazole 20 mg/die orally for 12 days, methylprednisolone 40 mg/die intramuscularly for 4 days, followed by methylprednisolone 20 mg/die for 3 days, and thereafter, methylprednisolone 20 mg/die at alternate days. Pain intensity and functional disability were assessed at baseline (T0), at the end of treatment (T1), and 6 months thereafter (T2) by using visual analogic scale (VAS) and Roland‐Morris disability questionnaire (RMDQ). In both groups, VAS and RMDQ values were significantly reduced at the end of drug treatment and after 6 months, in comparison with baseline. No significant differences were found between the two groups. This suggests that mesotherapy may be a valid alternative to conventional therapy in the treatment of acute low back pain with corticosteroids and NSAIDs.
Survivin Enhances Motility of Melanoma Cells by Supporting Akt Activation and α5 Integrin Upregulation
Authors: McKenzie Jodi A. , Liu Tong , Goodson Agnessa G. , Grossman Douglas
Published: September 2010

Survivin expression in melanoma is inversely correlated with patient survival. Transgenic mice harboring melanocyte-specific overexpression of survivin exhibit increased susceptibility to UV-induced melanoma and metastatic progression. To understand the mechanistic basis for metastatic progression, we investigated the effects of survivin on the motility of human melanocytes and melanoma cells. We found that survivin overexpression enhanced migration on fibronectin and invasion through Matrigel, whereas survivin knockdown under subapoptotic conditions blocked migration and invasion. In melanocytes, survivin overexpression activated the Akt and mitogen-activated protein kinase pathways. Akt phosphorylation was required for survivin-enhanced migration and invasion, whereas Erk phosphorylation was required only for enhanced invasion. In both melanocytes and melanoma cells, survivin overexpression was associated with upregulation of α5 integrin (fibronectin receptor component), the antibody-mediated blockade or RNA interference-mediated knockdown of which blocked survivin-enhanced migration. Knockdown of α5 integrin did not affect Akt activation, but inhibition of Akt phosphorylation prevented α5 integrin upregulation elicited by survivin overexpression. Together, our results showed that survivin enhanced the migration and invasion of melanocytic cells and suggested that survivin may promote melanoma metastasis by supporting Akt-dependent upregulation of α5 integrin. Cancer Res; 70(20); 7927–37. ©2010 AACR.
Amplifying TLR-MyD88 Signals within Tumor-Specific T Cells Enhances Antitumor Activity to Suboptimal Levels of Weakly Immunogenic Tumor Antigens
Authors: Geng Degui , Zheng Liqin , Srivastava Ratika , Velasco-Gonzalez Cruz , Riker Adam , Markovic Svetomir N. , Davila Eduardo
Published: September 2010

The efficacy of T cell–based immunotherapy to treat cancer patients remains a challenge partly because of the weak activity toward subdominant tumor antigens (TAg) and to tumors expressing suboptimal TAg levels. Recent reports indicate that Toll-like receptor (TLR) stimulation on T cells can lower the activation threshold. In this study, we examined the antitumor activity and survival of TLR2-MyD88–stimulated CD8 T cells derived from melanoma patients and T-cell receptor transgenic pmel mice. TLR2-stimulated pmel CD8 T cells, but not TLR2−/−pmel or MyD88−/−pmel T cells, responded to significantly lower TAg levels and resulted in increased production of effector molecules and cytotoxicity. Wild-type or MyD88−/− mice treated with TLR2 ligand and pmel T cells, but not TLR2−/−pmel or MyD88−/−pmel T cells, showed tumor regression of an established melanoma tumor. Overexpressing TLR2 in TAg-specific T cells eradicated tumors; four times fewer cells were needed to generate antitumor responses. The enhanced antitumor activity of TLR2-MyD88–stimulated T cells was associated with increased effector function but perhaps more importantly with improved survival of T cells. Activating TLR-MyD88 signals in patient-derived T cells also reduced the activation threshold to several weakly immunogenic TAgs, resulting in increased cytokine production, expansion, and cytotoxicity. These data highlight a previously unappreciated role for activating TLR-MyD88 signals in tumor-reactive T lymphocytes. Cancer Res; 70(19); 7442–54. ©2010 AACR.
Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk
Authors: Zhang Hong , Löwenberg Ester C. , Crosby Jeffrey R. , MacLeod A. Robert , Zhao Chenguang , Gao Dacao , Black Chris , Revenko Alexey S. , Meijers Joost C. M. , Stroes Erik S. , Levi Marcel , Monia Brett P.
Published: September 2010

Existing anticoagulants effectively inhibit the activity of coagulation factors of the extrinsic and common pathway but have substantial limitations and can cause severe bleeding complications. Here we describe a novel therapeutic approach to thrombosis treatment. We have developed and characterized the efficacy and safety of selective second-generation antisense oligonucleotides (ASOs) targeting coagulation factor XI (FXI), a member of the intrinsic coagulation pathway. Systemic treatment of mice with FXI ASO led to a potent, specific, and dose-dependent reduction of FXI mRNA levels in the liver with corresponding reductions in plasma levels of FXI protein and activity. FXIASO treatment produced potent, dose-dependent antithrombotic activity in various venous and arterial thrombosis models, comparable with warfarin or enoxaparin. However, unlike warfarin or enoxaparin, FXI inhibition did not cause bleeding. Coadministration of FXI ASO with enoxaparin or the antiplatelet drug clopidogrel produced improved antithrombotic activity without increased bleeding. Finally, plasma-derived FXI concentrate was shown to effectively and rapidly reverse the anticoagulant effect of FXI antisense therapy. These results support the concept that inhibition of FXI through antisense therapy might serve as a new and effective strategy for the treatment and prevention of venous thromboembolism with improved specificity and safety.
The arterial load in pulmonary hypertension
Authors: Saouti N. , Westerhof N. , Postmus P.E. , Vonk-Noordegraaf A.
Published: September 2010

The anatomical differences between the pulmonary and systemic arterial system are the main cause of the difference in distribution of compliance. In the pulmonary arterial system compliance is distributed over the entire arterial system, and stands at the basis of the constancy of the RC-time. This distribution depends on the number of peripheral vessels, which is ∼8–10 times more in the pulmonary system than the systemic tree. In the systemic arterial tree the compliance is mainly located in the aorta (80% of total compliance in thoracic-abdominal aorta).

The constant RC-time in the pulmonary bed results in proportionality of systolic and diastolic pressure with mean pressure and, in turn, in the constant ratio of oscillatory and mean power.
The in vivo efficacy of two administration routes of a phage cocktail to reduce numbers of Campylobacter coli and Campylobacter jejuni in chickens
Authors: Carvalho Carla M , Gannon Ben W , Halfhide Deborah E , Santos Silvio B , Hayes Christine M , Roe John M , Azeredo Joana
Published: September 2010

Background

Poultry meat is one of the most important sources of human campylobacteriosis, an acute bacterial enteritis which is a major problem worldwide. Campylobacter
coli and Campylobacter
jejuni are the most common Campylobacter species associated with this disease. These pathogens live in the intestinal tract of most avian species and under commercial conditions they spread rapidly to infect a high proportion of the flock, which makes their treatment and prevention very difficult. Bacteriophages (phages) are naturally occurring predators of bacteria with high specificity and also the capacity to evolve to overcome bacterial resistance. Therefore phage therapy is a promising alternative to antibiotics in animal production. This study tested the efficacy of a phage cocktail composed of three phages for the control of poultry infected with C. coli and C. jejuni. Moreover, it evaluated the effectiveness of two routes of phage administration (by oral gavage and in feed) in order to provide additional information regarding their future use in a poultry unit.

Results

The results indicate that experimental colonisation of chicks was successful and that the birds showed no signs of disease even at the highest dose of Campylobacter administered. The phage cocktail was able to reduce the titre of both C. coli and C. jejuni in faeces by approximately 2 log10 cfu/g when administered by oral gavage and in feed. This reduction persisted throughout the experimental period and neither pathogen regained their former numbers. The reduction in Campylobacter titre was achieved earlier (2 days post-phage administration) when the phage cocktail was incorporated in the birds' feed. Campylobacter strains resistant to phage infection were recovered from phage-treated chickens at a frequency of 13%. These resistant phenotypes did not exhibit a reduced ability to colonize the chicken guts and did not revert to sensitive types.

Conclusions

Our findings provide further evidence of the efficacy of phage therapy for the control of Campylobacter in poultry. The broad host range of the novel phage cocktail enabled it to target both C. jejuni and C. coli strains. Moreover the reduction of Campylobacter by approximately 2 log10cfu/g, as occurred in our study, could lead to a 30-fold reduction in the incidence of campylobacteriosis associated with consumption of chicken meals (according to mathematical models). To our knowledge this is the first report of phage being administered in feed to Campylobacter- infected chicks and our results show that it lead to an earlier and more sustainable reduction of Campylobacter than administration by oral gavage. Therefore the present study is of extreme importance as it has shown that administering phages to poultry via the food could be successful on a commercial scale.
Benefits of biomarker selection and clinico-pathological covariate inclusion in breast cancer prognostic models
Authors: Parisi Fabio , González Ana M , Nadler Yasmine , Camp Robert L , Rimm David L , Kluger Harriet M , Kluger Yuval
Published: September 2010

Introduction

Multi-marker molecular assays have impacted management of early stage breast cancer, facilitating adjuvant chemotherapy decisions. We generated prognostic models that incorporate protein-based molecular markers and clinico-pathological variables to improve survival prediction.

Methods

We used a quantitative immunofluorescence method to study protein expression of 14 markers included in the Oncotype DX™ assay on a 638 breast cancer patient cohort with 15-year follow-up. We performed cross-validation analyses to assess performance of multivariate Cox models consisting of these markers and standard clinico-pathological covariates, using an average time-dependent Area Under the Receiver Operating Characteristic curves and compared it to nested Cox models obtained by robust backward selection procedures.

Results

A prognostic index derived from of a multivariate Cox regression model incorporating molecular and clinico-pathological covariates (nodal status, tumor size, nuclear grade, and age) is superior to models based on molecular studies alone or clinico-pathological covariates alone. Performance of this composite model can be further improved using feature selection techniques to prune variables. When stratifying patients by Nottingham Prognostic Index (NPI), the most prognostic markers in high and low NPI groups differed. Similarly, for the node-negative, hormone receptor-positive sub-population, we derived a compact model with three clinico-pathological variables and two protein markers that was superior to the full model.

Conclusions

Prognostic models that include both molecular and clinico-pathological covariates can be more accurate than models based on either set of features alone. Furthermore, feature selection can decrease the number of molecular variables needed to predict outcome, potentially resulting in less expensive assays.
Impact of Interdisciplinary Undergraduate Research in Mathematics and Biology on the Development of a New Course Integrating Five STEM Disciplines
Authors: Caudill Lester , Hill April , Hoke Kathy , Lipan Ovidiu
Published: September 2010

Funded by innovative programs at the National Science Foundation and the Howard Hughes Medical Institute, University of Richmond faculty in biology, chemistry, mathematics, physics, and computer science teamed up to offer first- and second-year students the opportunity to contribute to vibrant, interdisciplinary research projects. The result was not only good science but also good science that motivated and informed course development. Here, we describe four recent undergraduate research projects involving students and faculty in biology, physics, mathematics, and computer science and how each contributed in significant ways to the conception and implementation of our new Integrated Quantitative Science course, a course for first-year students that integrates the material in the first course of the major in each of biology, chemistry, mathematics, computer science, and physics.
BioMaPS: A Roadmap for Success
Authors: McCarthy Maeve L. , Fister K. Renee
Published: September 2010

The manuscript outlines the impact that our National Science Foundation Interdisciplinary Training for Undergraduates in Biological and Mathematical Sciences program, BioMaPS, has had on the students and faculty at Murray State University. This interdisciplinary program teams mathematics and biology undergraduate students with mathematics and biology faculty and has produced research insights and curriculum developments at the intersection of these two disciplines. The goals, structure, achievements, and curriculum initiatives are described in relation to the effects they have had to enhance the study of biomathematics.