bluuebunny/crossref_metadata_2025 huggingface dataset:
In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients With Early-Stage Colorectal Cancer
Authors: Pagès Franck , Kirilovsky Amos , Mlecnik Bernhard , Asslaber Martin , Tosolini Marie , Bindea Gabriela , Lagorce Christine , Wind Philippe , Marliot Florence , Bruneval Patrick , Zatloukal Kurt , Trajanoski Zlatko , Berger Anne , Fridman Wolf-Herman , Galon Jérôme
Published: October 2009

Purpose

Many patients who present with early-stage colorectal cancer (International Union Against Cancer TNM stages I and II) are nevertheless at high risk of relapse. We hypothesized that intratumoral immune reaction could influence their prognosis.

Patients and Methods

The intratumoral immune reaction was investigated in 29 tumors by large-scale real-time polymerase chain reaction. Cytotoxic (CD8) and memory (CD45RO) T cells were quantified by immunohistochemical analyses of tissue microarrays from the center (CT) and the invasive margin (IM) of the 602 tumors from two independent cohorts. The results were correlated with tumor recurrence and patient survival.

Results

Patients with a strong infiltration of CD45RO+ cells in the tumor exhibited an increased expression of T-helper 1 and cytotoxicity-related genes. Densities of CD45RO+ and CD8+ cells in tumor regions (CT/IM) classified the patients into four distinct prognostic groups based on the presence of high density of each marker in each tumor region. The four groups were associated with dramatic differences in disease-free, disease-specific, and overall survival (all P < .0001). Five years after diagnosis, only 4.8% (95% CI, 0.6% to 8.8%) of patients with high densities of CD8+ plus CD45RO+ cells had tumor recurrence, and 86.2% (CI, 79.4% to 93.6%) survived. In contrast, the tumor recurred in 75% (95% CI, 17% to 92.5%) of patients with low densities of these cells, and only 27.5% (95% CI, 10.5% to 72%) survived (all P < .0001). Multivariate analyses showed that the immune criteria had independent effects on the rates of complete remission and survival.

Conclusion

The combined analysis of CD8+ plus CD45RO+ cells in specific tumor regions could provide a useful criterion for the prediction of tumor recurrence and survival in patients with early-stage colorectal cancer.
Contralateral Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
Authors: Graeser Monika K. , Engel Christoph , Rhiem Kerstin , Gadzicki Dorothea , Bick Ulrich , Kast Karin , Froster Ursula G. , Schlehe Bettina , Bechtold Astrid , Arnold Norbert , Preisler-Adams Sabine , Nestle-Kraemling Carolin , Zaino Mohammad , Loeffler Markus , Kiechle Marion , Meindl Alfons , Varga Dominic , Schmutzler Rita K.
Published: October 2009

Purpose

To estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families and to determine predictive risk factors.

Patients and Methods

A retrospective, multicenter, cohort study was performed from 1996 until 2008 and comprised 2,020 women with unilateral breast cancer (index patients, n = 978; relatives, n = 1.42) from 978 families who had a BRCA1 or BRCA2 mutation. Cox regression analysis was applied to assess the association of age at first breast cancer with time from first to contralateral breast cancer, stratified by the affected BRCA gene.

Results

The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 47.4% (95% CI, 38.8% to 56.0%) for patients from families with BRCA1 or BRCA2 mutations. Members of families with BRCA1 mutations had a 1.6-fold (95% CI, 1.2-fold to 2.3-fold) higher risk of contralateral breast cancer than members of families with BRCA2 mutations. Younger age at first breast cancer was associated with a significantly higher risk of contralateral breast cancer in patients with BRCA1 mutation, and a trend was observed in patients with BRCA2 mutation. After 25 years, 62.9% (95% CI, 50.4% to 75.4%) of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer developed contralateral breast cancer, compared with only 19.6% (95% CI, 5.3% to 33.9%) of those who were older than 50 years of age at first breast cancer.

Conclusion

Contralateral breast cancer risk depends on age at first breast cancer and on the affected BRCA gene, and this risk should be considered in treatment planning.
Prospective Study of Prostate Tumor Angiogenesis and Cancer-Specific Mortality in the Health Professionals Follow-Up Study
Authors: Mucci Lorelei A. , Powolny Anna , Giovannucci Edward , Liao Zhiming , Kenfield Stacey A. , Shen Rulong , Stampfer Meir J. , Clinton Steven K.
Published: October 2009

Purpose

Tumor growth requires the development of independent vascular networks that are often primitive in morphology and function. We examined whether microvessel morphology contributes to the considerable biologic heterogeneity of prostate cancer.

Methods

We evaluated microvessel morphology as a predictor of prostate cancer mortality among 572 men in the Health Professionals Follow-Up Study diagnosed with cancer during 1986 to 2000. We immunostained prostatectomy tumor block sections for endothelial marker CD34 and assessed microvessel density, vessel size (area and diameter), and irregularity of vessel lumen using image analysis. Proportional hazards models were used to assess microvessel density and morphology in relation to lethal prostate cancer.

Results

Poorly differentiated tumors exhibited greater microvessel density, greater irregularity of the vessel lumen, and smaller vessels. During 20 years of follow-up, 44 men developed bone metastases or died of cancer. Men with tumors exhibiting the smallest vessel diameter, based on quartiles, were 6.0 times more likely (95% CI, 1.8 to 20.0) to develop lethal prostate cancer. Men with the most irregularly shaped vessels were 17.1 times more likely (95% CI, 2.3 to 128) to develop lethal disease. Adjusting for Gleason grade and prostate-specific antigen levels did not qualitatively change the results. Microvessel density was not linked to cancer-specific mortality after adjusting for clinical factors.

Conclusion

Aggressive tumors form vessels that are primitive in morphology and function, with consequences for metastases. Vascular size and irregularity reflect the angiogenic potential of prostate cancer and may serve as biomarkers to predict prostate cancer mortality several years after diagnosis.
Consensus Report of the National Cancer Institute Clinical Trials Planning Meeting on Pancreas Cancer Treatment
Authors: Philip Philip A. , Mooney Margaret , Jaffe Deborah , Eckhardt Gail , Moore Malcolm , Meropol Neal , Emens Leisha , O'Reilly Eileen , Korc Murray , Ellis Lee , Benedetti Jacqueline , Rothenberg Mace , Willett Christopher , Tempero Margaret , Lowy Andrew , Abbruzzese James , Simeone Diane , Hingorani Sunil , Berlin Jordan , Tepper Joel
Published: October 2009

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.
Evidence-Based Approach to the Introduction of Positron Emission Tomography in Ontario, Canada
Authors: Evans William K. , Laupacis Andreas , Gulenchyn Karen Y. , Levin Les , Levine Mark
Published: October 2009

Purpose

The uptake of new health care technologies is usually driven by industry promotion, physician interest, patient demand, and institutional ability to acquire the technology. The introduction of positron emission tomography (PET) scanning in the province of Ontario, Canada, followed a different path.

Methods

The Ontario provincial government, through its Ministry of Health and Long-Term Care, commissioned a systematic review of the literature. When this found only weak evidence that PET has a positive impact on clinical outcomes, the Ministry introduced a provincial PET evaluation program to close the evidence gap.

Results

This article describes the challenges encountered establishing the PET evaluation program. These included the design and conduct of the initial clinical trials, the establishment of a PET cancer registry, standardizing how PET scans were performed and reported, and gaining acceptance by health professionals for the evaluative program.

Conclusion

The proliferation of health technologies is a key driver of increasing health care costs. The Ontario approach to the introduction of PET is a model worth consideration by health systems seeking to ensure that they receive value for money based on a strong evidentiary base when introducing new health technologies.
VMP (Bortezomib, Melphalan, and Prednisone) Is Active and Well Tolerated in Newly Diagnosed Patients With Multiple Myeloma With Moderately Impaired Renal Function, and Results in Reversal of Renal Impairment: Cohort Analysis of the Phase III VISTA Study
Authors: Dimopoulos Meletios A. , Richardson Paul G. , Schlag Rudolf , Khuageva Nuriet K. , Shpilberg Ofer , Kastritis Efstathios , Kropff Martin , Petrucci Maria T. , Delforge Michel , Alexeeva Julia , Schots Rik , Masszi Tamás , Mateos Maria-Victoria , Deraedt William , Liu Kevin , Cakana Andrew , van de Velde Helgi , San Miguel Jesús F.
Published: October 2009

Purpose

To assess bortezomib plus melphalan and prednisone (VMP) and melphalan and prednisone (MP) in previously untreated patients with multiple myeloma (MM) with renal impairment enrolled on the phase III VISTA study, and to evaluate renal impairment reversibility.

Patients and Methods

Patients received nine 6-week cycles of VMP (bortezomib 1.3 mg/m2, melphalan 9 mg/m2, prednisone 60 mg/m2) or MP. Patients with serum creatinine higher than 2 mg/dL were excluded.

Results

In the VMP/MP arms, 6%/4%, 27%/30%, and 67%/66% of patients had baseline glomerular filtration rate (GFR) of ≤ 30, 31 to 50, and higher than 50 mL/min, respectively. Response rates were higher and time to progression (TTP) and overall survival (OS) longer with VMP versus MP across renal cohorts. Response rates with VMP and TTP in both arms did not appear significantly different between patients with GFR ≤ 50 or higher than 50 mL/min; OS appeared somewhat longer in patients with normal renal function in both arms. Renal impairment reversal (baseline GFR < 50 improving to > 60 mL/min) was seen in 49 (44%) of 111 patients receiving VMP versus 40 (34%) of 116 patients receiving MP. By multivariate analysis, younger age (< 75 years; P = .006) and less severe impairment (GFR ≥ 30 mL/min; P = .027) were associated with higher reversal rates. In addition, treatment with VMP approached significance (P = .07). In both arms, rates of grade 4 and 5 adverse events (AEs) and serious AEs appeared higher in patients with renal impairment; with VMP, rates of discontinuations/bortezomib dose reductions due to AEs did not appear affected.

Conclusion

VMP is a feasible, active, and well-tolerated treatment option for previously untreated patients with MM with moderate renal impairment, resulting in 44% renal impairment reversal.
Evaluating the Combined Effect of Comorbidity and Prostate-Specific Antigen Kinetics on the Risk of Death in Men After Prostate-Specific Antigen Recurrence
Authors: Wo Jennifer Y. , Chen Ming-Hui , Nguyen Paul L. , Renshaw Andrew A. , Loffredo Marian J. , Kantoff Philip W. , D'Amico Anthony V.
Published: October 2009

Purpose

We examined whether time-dependent continuous prostate-specific antigen (PSA) velocity at recurrence was associated with all cause mortality (ACM) adjusting for comorbidity levels among men treated with definitive radiation therapy (RT) alone with or without androgen suppression therapy (AST) in the setting of a randomized controlled trial.

Patients and Methods

From 1995 to 2001, 206 men with localized, unfavorable prostate cancer were randomly assigned to receive RT alone or RT and AST combined. Cox multivariate regression analysis was performed to evaluate the relationship between PSA velocity at recurrence and ACM, adjusting for known prostate cancer prognostic factors, including Adult Comorbidity Evaluation 27 comorbidity level.

Results

With a median follow-up of 8.4 years, 89 biochemical recurrences and 74 ACM deaths occurred. Among all patients, higher PSA velocity was associated with increased ACM (hazard ratio [HR], 1.47; 95% CI, 1.07 to 1.44; P < .001) after adjusting for age, treatment arm, comorbidity score, and salvage AST. For 89 patients with biochemical recurrence, increasing PSA velocity at recurrence (HR, 1.60; 95% CI, 1.23 to 2.09; P ≤ .001) and moderate to severe comorbidity score (HR, 7.94; 95% CI, 1.55 to 40.52; P = .01) were associated with increased ACM. PSA velocity at recurrence was associated with significantly higher risk of ACM among patients with no or minimal comorbidity (P < .001), but not moderate to severe comorbidity (P = .12).

Conclusion

Rapid PSA velocity at recurrence is significantly associated with an increased risk of ACM among patients with no or minimal comorbidity but not moderate to severe comorbidity. These findings support judicious use of salvage AST, particularly in men with moderate to severe comorbidities, where prospective surveillance protocols are needed.
Quality of Life Supersedes the Classic Prognosticators for Long-Term Survival in Locally Advanced Non–Small-Cell Lung Cancer: An Analysis of RTOG 9801
Authors: Movsas Benjamin , Moughan Jennifer , Sarna Linda , Langer Corey , Werner-Wasik Maria , Nicolaou Nicos , Komaki Ritsuko , Machtay Mitchell , Wasserman Todd , Bruner Deborah Watkins
Published: October 2009

Purpose

To determine the added value of quality of life (QOL) as a prognostic factor for overall survival (OS) in patients with locally advanced non–small-cell lung cancer (NSCLC) treated on Radiation Therapy Oncology Group RTOG-9801.

Patients and Methods

Two hundred forty-three patients with stage II/IIIAB NSCLC received induction paclitaxel and carboplatin (PC) and then concurrent weekly PC and hyperfractionated radiation (to 69.6 Gy). Patients were randomly assigned to amifostine (AM) or no AM during chemoradiotherapy. The following pretreatment factors were analyzed as prognostic factors for OS: Karnofsky performance status, stage, sex, age, race, marital status, histology, tumor location, hemoglobin, tobacco use, treatment arm (AM v no AM) and QOL scores (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [QLQ-C30] and Lung Cancer 13 [LC-13]). A multivariate (MVA) Cox proportional hazards model was performed using a backwards selection process.

Results

Of the 239 analyzable patients, 91% had a baseline global QOL score. Median follow-up time was 59 months for patients still alive and 17 months for all patients. Median baseline QLQ-C30 global QOL score was 66.7 on both treatment arms. Whether the global QOL score was treated as a dichotomized variable (based on the median score) or a continuous variable, all other variables fell out of the MVA for OS. Patients with a global QOL score less than 66.7 had an approximately 70% higher rate of death than patients with scores ≥ 66.7 (P = .004). A 10-point higher baseline global QOL score corresponded to a decrease in the hazard of death by approximately 10% (P = .004). The other independent QOL predictors for OS were the QLQ-C30 physical functioning (P = .011) and LC-13 dyspnea scores (P = .012).

Conclusion

In this analysis, baseline global QOL score replaced known prognostic factors as the sole predictor of long-term OS for patients with locally advanced NSCLC.
American Petroleum Institute welding neck flange design for subsea pipelines
Authors: Lumsden S , Black I
Published: October 2009

Flange design has been a subject of intensive research and discussion over many decades as engineers strive to maximize the capacity of flanges in application while reducing costs and providing effective seals. Calculation frameworks such as those contained within American Society of Mechanical Engineers (ASME) VIII have been used for a considerable number of years to provide reasonably accurate models for analysing the various factors contributing to flange selection. However, they do not cover all situations and this is especially significant within the oil and gas industry where American Petroleum Institute standards can ‘confuse’ the design and selection process for flanges. Therefore, in this article the authors present a revised approach to the design of welding neck flanges used in subsea applications that is based on the existing design approaches contained within ASME VIII, Kellogg, Kuppan and PD8010. This revised approach to welding neck flange design also examines the key influences of gasket geometry and loading, as well as the matching of a particular flange to its pipe capacity. Finally, results of the authors’ calculations are compared against existing finite element-derived data contained within API 6AF.
Robust global stability of discrete-time recurrent neural networks
Authors: Mahmoud M S
Published: October 2009

This paper establishes new delay-range-dependent, robust global stability for a class of discrete-time recurrent neural networks with interval time-varying delays and norm-bounded time-varying parameter uncertainties. A new Lyapunov-Krasovskii functional is constructed to exhibit the delay-dependent dynamics and compensate for the enlarged time-span. The developed stability method eliminates the need for over bounding and utilizes a smaller number of linear matrix inequality (LMI) decision variables. New and less conservative solutions to the global stability problem are provided in terms of feasibility testing of new parametrized LMIs. Numerical examples are presented to illustrate the effectiveness of the developed technique.
Asymmetric motion profile planning for nanopositioning and nanomeasuring machines
Authors: Amthor A , Werner J , Lorenz A , Zschaeck S , Ament C
Published: October 2009

This work presents an analytic fourth-order trajectory planning algorithm, which is able to plan asymmetric motions with arbitrary initial and final velocities. Furthermore, the proposed algorithm is based on a set of quadratic derivates of jerk (djerk) functions and generates continuously differentiable trajectories in jerk, acceleration, velocity, and position under consideration of kinematic constraints in all these kinematical values. The trajectories planned by the algorithm also have time-optimal characteristics, and a synchronization between the three motion axes of the Cartesian coordinate system is ensured by the proposed method. These characteristics make it ideally suited for use as a trajectory planning algorithm in high-precision applications such as nanopositioning and nanomeasuring machines.
Luminescence Properties of Yttrium Borate Samples with the Morphologies Controlled by Solvothermal Method
Authors: Hosokawa Saburo , Inoue Masashi
Published: October 2009

Solvothermal reaction of yttrium chloride hydrate and trimethoxyborane in 1,4-butanediol in the presence of amines at 315 °C directly yielded YBO3 crystals having flower-like morphology (particle size; 3–8 μm). The crystal growth toward the c axis was inhibited by adsorption of amines on the ab plane, and plate-like crystals were formed. The luminescence chromaticity of Y0.9Eu0.1BO3 samples synthesized by solvothermal reaction was different from that prepared by solid-state reaction; samples synthesized by the solvothermal reaction exhibited larger relative intensity ratio of the emission at 580 nm to that at 610 nm than samples prepared by the solid-state reaction.
A preliminary investigation into the practicality of use and duration of action of slow-release preparations of morphine and hydromorphone in laboratory rats
Authors: Leach M C , Bailey H E , Dickinson A L , Roughan J V , Flecknell P A
Published: October 2009

Significant advances have been made in our ability to assess pain and administer appropriate pain relief in laboratory animals. However, providing long-lasting analgesia using a route that does not involve animal restraint remains difficult. The objective of this study was to investigate whether oral administration of slow-release morphine or hydromorphone results in increased thermal nociception in laboratory rats. The results showed that 64 mg/kg morphine and 16 mg/kg hydromorphone induced comparable increases in foot withdrawal latencies for up to three hours postadministration; however, slow-release morphine increased response latencies for up to 11 hours. Whether these dose rates provide clinically effective pain relief has yet to be determined; however, these data suggest that using slow-release preparations could be an effective and highly practical method of elevating pain thresholds for a relatively prolonged period.
Permanent catheterization of the carotid artery induces kidney infection and inflammation in the rat
Authors: Fonseca Uno N K , Nielsen Sanne Gram , Hau Jann , Hansen Axel Kornerup
Published: October 2009

Catheterization of the carotid artery and the jugular vein is one of the most commonly applied techniques used to gain intravascular access in pharmacology studies on rodents. We catheterized 10 rats by conventional clean techniques, 10 rats by aseptic techniques and 10 rats by conventional clean techniques using a heparin-coated catheter rather than an ordinary non-coated polyvinyl chloride catheter. In all groups, approximately 80% of the rats developed kidney infection and 10-30% of the rats were septicaemic. Clinical chemistry did not indicate severe kidney damage, but serum haptoglobin and body temperature rises indicated an inflammatory response in rats independent of the surgical method. Heparin coating did not seem to improve the usability of the catheter. It is concluded that this commonly used method for catheterization has an impact on animals that may very well render them unsuitable for the purpose, e.g. pharmacological research, and therefore an alternative method would be preferable.
Influence of preferred foodstuffs on the antinociceptive effects of orally administered buprenorphine in laboratory rats
Authors: Leach Matthew C , Forrester Alison R , Flecknell Paul A
Published: October 2009

Oral administration of buprenorphine is becoming a popular method of providing analgesia for laboratory rodents. The mixing of buprenorphine with flavoured jello, which rodents find palatable, is becoming a commonly used method as it is thought to improve the efficacy of oral buprenorphine by increasing the time available for it to be absorbed via the oral mucosa. The aim of this study was to assess the effect of various methods of buprenorphine administration (subcutaneous saline, subcutaneous buprenorphine [0.05 mg/kg], buprenorphine gavage [0.5 mg/kg], buprenorphine in jello [0.5 mg/kg] and buprenorphine in golden syrup [0.5 mg/kg]) on thermal antinociceptive thresholds in laboratory rats. Buprenorphine administered subcutaneously, by gavage, in jello and in syrup induced significant increases in thermal antinociceptive thresholds compared with saline. This effect was observed up to 5 h postadministration for buprenorphine administered subcutaneously and by gavage, but only for one hour postadministration for buprenorphine administered in jello and in syrup.
Kinetics ofα2-macroglobulin andα1-acid glycoprotein in rats subjected to repeated acute inflammatory stimulation
Authors: Honjo Toshio , Kuribayashi Takashi , Matsumoto Mariko , Yamazaki Shunsuke , Yamamoto Shizuo
Published: October 2009

The kinetics of α2-macroglobulin ( α2M) and α1-acid glycoprotein (AAG) in rats repeatedly stimulated with intramuscular injections of turpentine oil at doses 0.05 and 0.4 mL/rat were investigated. Mean serum levels of α2M peaked at 48 h after the first turpentine oil injection, reaching 1.74 and 2.36 mg/mL at 0.05 and 0.4 mL/rat, respectively. AAG peaks were also observed at 48 h after injection, and the mean values were 2.02 and 2.53 mg/mL, respectively. These peak values of α2M and AAG differed significantly between the 0.05 and 0.4 mL/rat injection groups. Mean serum levels of interleukin-6 (IL-6) at 0.05 mL/rat were 52.61 pg/mL at 12 h, 48.86 pg/mL at 36 h and 81.93 pg/mL at 84 h after the first injection. Mean IL-6 serum levels at 0.4 mL/rat were 215.24 pg/mL at 12 h, 56.33 pg/mL at 36 h and 39.25 pg/mL at 84 h after the first injection. Mean serum levels of cytokine-induced chemoattractant-1 (CINC-1) at a dose of 0.05 mL/rat were 5.70 ng/mL at 12 h, 5.58 ng/mL at 36 h and 4.58 ng/mL at 84 h after the first injection. Mean serum levels of CINC-1 after injection at 0.4 mL/rat were 11.57 ng/mL at 12 h, 4.68 ng/mL at 36 h and 4.42 ng/mL at 84 h. Serum levels of IL-6 differed significantly at 12, 24, 72 and 84 h, while those of CINC-1 differed significantly at 12, 24, 48 and 96 h between the 0.05 and 0.4 mL/rat injection groups. Differences in peak serum levels in the 0.05 and 0.4 mL/rat groups were attributed to differences in the production of IL-6 and CINC-1, which are thought to contribute to α2M and AAG production.
Comparison of different aminoglycoside antibiotic treatments to refine ototoxicity studies in adult mice
Authors: Murillo-Cuesta S , Contreras J , Cediel R , Varela-Nieto I
Published: October 2009

Hearing and balance receptors in the inner ear are highly susceptible to damage caused by a wide variety of toxic substances, including aminoglycosides. This class of antibiotics is commonly used in medicine, even though they may produce irreversible bilateral neurosensorial deafness. To identify potential ototoxic agents and novel therapeutic targets, it is necessary to generate standardized animal models of aminoglycoside ototoxicity, which will also serve to explore otic cell repair and regeneration. Although the mouse is the species most often used in biomedical research, due to the genetic information and genetically-modified strains available, there are few standard models of aminoglycoside ototoxicity in adult mice. Most protocols to produce ototoxicity in adult mice employ high doses of aminoglycosides for long periods of time, which causes systemic toxicity, side-effects and high mortality rates. Here, we compare the effects of systemic treatment with four different, yet common, aminoglycoside antibiotics in two mouse strains, evaluating their effects on mortality, cochlear morphology and auditory brainstem responses. Our data indicate that gentamicin and neomycin caused high mortality in the adult mouse without significantly changing the auditory threshold. Amikacin produced a tolerable rate of mortality but at doses that did not exhibit ototoxicity. Finally, intramuscular injection of kanamycin in C57BL/6JOlaHsd mice induced significant dose-dependent bilateral hearing loss with a moderate rate of mortality and less discomfort than following subcutaneous administration.
A novel water delivery system for administering volatile chemicals while minimizing chemical waste in rodent toxicity studies
Authors: Mcdonald A , Killough P , Puckett E , Best D S , Simmons J E , Pressman J G , Narotsky M G
Published: October 2009

Rodent toxicity studies typically use water bottles to administer test chemicals via drinking water. However, water bottles provide inconsistent exposure of volatile chemicals due to varying headspace, and lead to excessive waste of test material. To refine drinking water toxicity studies in rodents by enhancing sample quality and consistency, and minimizing waste, we designed and implemented a novel water delivery system that keeps the water chilled, headspace free and protected from light. Materials used were resistant to chemical interaction. In this gravity-fed system, a 6-L Teflon® water bag, stored in a polystyrene cooler on the cage rack, was connected to a stainless steel manifold delivering water to five cages via specialized drinking valves. Due to the absence of headspace in the water bag, this system allows consistent exposure of volatile chemicals. In addition, small diameter tubing throughout the system reduces the amount of test material residing in the system and minimizes chemical waste.
Flipping DNA to Generate and Regulate Microbial Consortia
Authors: Ramadas Rohini , Thattai Mukund
Published: October 2009

Communities of interdependent microbes, found in diverse natural contexts, have recently attracted the attention of bioengineers. Such consortia have potential applications in biosynthesis, with metabolic tasks distributed over several phenotypes, and in live-cell microbicide therapies where phenotypic diversity might aid in immune evasion. Here we investigate one route to generate synthetic microbial consortia and to regulate their phenotypic diversity, through programmed genetic interconversions. In our theoretical model, genotypes involve ordered combinations of DNA elements representing promoters, protein-coding genes, and transcription terminators; genotypic interconversions are driven by a recombinase enzyme that inverts DNA segments; and selectable phenotypes correspond to distinct patterns of gene expression. We analyze the microbial population as it evolves along a graph whose nodes are distinct genotypes and whose edges are interconversions. We show that the steady-state proportion of each genotype depends on its own growth advantage, as well as on its connectivity to other genotypes. Multiple phenotypes with identical or distinct growth rates can be indefinitely maintained in the population, while their proportion can be regulated by varying the rate of DNA flipping. Recombinase-based synthetic constructs have already been implemented; the graph-theoretic framework developed here will be useful in adapting them to generate microbial consortia.
Evolution at a High Imposed Mutation Rate: Adaptation Obscures the Load in Phage T7
Authors: Springman R , Keller T , Molineux I J , Bull J J
Published: October 2009

Evolution at high mutation rates is expected to reduce population fitness deterministically by the accumulation of deleterious mutations. A high enough rate should even cause extinction (lethal mutagenesis), a principle motivating the clinical use of mutagenic drugs to treat viral infections. The impact of a high mutation rate on long-term viral fitness was tested here. A large population of the DNA bacteriophage T7 was grown with a mutagen, producing a genomic rate of 4 nonlethal mutations per generation, two to three orders of magnitude above the baseline rate. Fitness—viral growth rate in the mutagenic environment—was predicted to decline substantially; after 200 generations, fitness had increased, rejecting the model. A high mutation load was nonetheless evident from (i) many low- to moderate-frequency mutations in the population (averaging 245 per genome) and (ii) an 80% drop in average burst size. Twenty-eight mutations reached high frequency and were thus presumably adaptive, clustered mostly in DNA metabolism genes, chiefly DNA polymerase. Yet blocking DNA polymerase evolution failed to yield a fitness decrease after 100 generations. Although mutagenic drugs have caused viral extinction in vitro under some conditions, this study is the first to match theory and fitness evolution at a high mutation rate. Failure of the theory challenges the quantitative basis of lethal mutagenesis and highlights the potential for adaptive evolution at high mutation rates.
Health Care Quality-Improvement Approaches to Reducing Child Health Disparities
Authors: Chin Marshall H. , Alexander-Young Morgen , Burnet Deborah L.
Published: October 2009

Relatively few quality-improvement efforts have been aimed at reducing differences in children's care and outcomes across race and ethnicity, socioeconomic status, and insurance status. To inform quality-improvement efforts to reduce child health disparities, we summarize lessons learned from the adult disparities-intervention literature, identify interventions that have reduced disparities in pediatric asthma outcomes and immunization rates, and outline special considerations for child disparity interventions. Key recommendations for providers, health care organizations, and researchers include: (1) examine your performance data stratified according to insurance status, race/ethnicity, language, and socioeconomic status; (2) measure and improve childhood health-related quality of life, development, and condition-specific targets (such as asthma and immunizations); (3) measure and improve anticipatory guidance for early prevention of conditions (such as injuries, violence, substance abuse, and sexually transmitted diseases) and efforts to promote positive growth (such as readership programs to improve low literacy); (4) measure and improve structural aspects of care that affect child health outcomes and can reduce disparities, such as patient-centered medical-home elements; (5) incorporate families into interventions; (6) use multidisciplinary teams with close tracking and follow-up of patients; (7) integrate non–health care partners into quality-improvement interventions; and (8) culturally tailor quality improvement. A key recommendation for payers is to align financial incentives to reduce disparities. The National Institutes of Health and other funders should support (1) disparity-intervention studies on these recommendations that analyze clinical outcomes, intervention-implementation processes, and costs, and (2) creation of new child health services researchers who can find effective quality-improvement approaches for reducing disparities.
Health Literacy and Child Health Outcomes: A Systematic Review of the Literature
Authors: DeWalt Darren A. , Hink Ashley
Published: October 2009

OBJECTIVES: To review the relationship between parent and child literacy and child health outcomes and interventions designed to improve child health outcomes for children or parents with low literacy skills.

METHODS: We searched Medline and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for articles published from 1980 through 2008 and included studies that reported original data, measured literacy and ≥1 health outcome, and assessed the relationship between literacy and health outcomes. Health outcomes included health knowledge, health behaviors, use of health care resources, intermediate markers of disease status, and measures of morbidity. Two abstractors reviewed each study for inclusion. Included studies were abstracted into evidence tables and were assessed by using an 11-item quality scale.

RESULTS: We reviewed 4182 new titles and abstracts published since 2003. Fifty-eight articles were retained for full review, and 13 met the inclusion criteria. Eleven articles from the systematic review from 1980 to 2003 met the inclusion criteria, giving us a total of 24 articles. Children with low literacy generally had worse health behaviors. Parents with low literacy had less health knowledge and had behaviors that were less advantageous for their children's health compared with parents with higher literacy. Children whose parents had low literacy often had worse health outcomes, but we found mixed results for the relationship of literacy to the use of health care services. Interventions found that improving written materials can increase health knowledge, and combining good written materials with brief counseling can improve behaviors including adherence. The average quality of the studies was fair to good.

CONCLUSIONS: Child and parent literacy seems associated with important health outcomes. Future research can help us understand under what circumstances this relationship is causal, how literacy and health outcomes are related in noncausal pathways, the relative importance of parent and child literacy, and what interventions effectively reduce health literacy–related disparities.
The Health Literacy of Parents in the United States: A Nationally Representative Study
Authors: Yin H. Shonna , Johnson Matthew , Mendelsohn Alan L. , Abrams Mary Ann , Sanders Lee M. , Dreyer Benard P.
Published: October 2009

OBJECTIVE: To assess the health literacy of US parents and explore the role of health literacy in mediating child health disparities.

METHODS: A cross-sectional study was performed for a nationally representative sample of US parents from the 2003 National Assessment of Adult Literacy. Parent performance on 13 child health-related tasks was assessed by simple weighted analyses. Logistic regression analyses were performed to describe factors associated with low parent health literacy and to explore the relationship between health literacy and self-reported child health insurance status, difficulty understanding over-the-counter medication labeling, and use of food labels.

RESULTS: More than 6100 parents made up the sample (representing 72600098 US parents); 28.7% of the parents had below-basic/basic health literacy, 68.4% were unable to enter names and birth dates correctly on a health insurance form, 65.9% were unable to calculate the annual cost of a health insurance policy on the basis of family size, and 46.4% were unable to perform at least 1 of 2 medication-related tasks. Parents with below-basic health literacy were more likely to have a child without health insurance in their household (adjusted odds ratio: 2.4 [95% confidence interval: 1.1–4.9]) compared with parents with proficient health literacy. Parents with below-basic health literacy had 3.4 times the odds (95% confidence interval: 1.6–7.4) of reporting difficulty understanding over-the-counter medication labels. Parent health literacy was associated with nutrition label use in unadjusted analyses but did not retain significance in multivariate analyses. Health literacy accounted for some of the effect of education, racial/ethnic, immigrant-status, linguistic, and income-related disparities.

CONCLUSIONS: A large proportion of US parents have limited health-literacy skills. Decreasing literacy demands on parents, including simplification of health insurance and other medical forms, as well as medication and food labels, is needed to decrease health care access barriers for children and allow for informed parent decision-making. Addressing low parent health literacy may ameliorate existing child health disparities.
Health Literacy and Child Health Promotion: Implications for Research, Clinical Care, and Public Policy
Authors: Sanders Lee M. , Shaw Judith S. , Guez Ghislaine , Baur Cynthia , Rudd Rima
Published: October 2009

The nation's leading sources of morbidity and health disparities (eg, preterm birth, obesity, chronic lung disease, cardiovascular disease, type 2 diabetes, mental health disorders, and cancer) require an evidence-based approach to the delivery of effective preventive care across the life course (eg, prenatal care, primary preventive care, immunizations, physical activity, nutrition, smoking cessation, and early diagnostic screening). Health literacy may be a critical and modifiable factor for improving preventive care and reducing health disparities. Recent studies among adults have established an independent association between lower health literacy and poorer understanding of preventive care information and poor access to preventive care services. Children of parents with higher literacy skills are more likely to have better outcomes in child health promotion and disease prevention. Adult studies in disease prevention have suggested that addressing health literacy would be an efficacious strategy for reducing health disparities. Future initiatives to reduce child health inequities should include health-promotion strategies that meet the health literacy needs of children, adolescents, and their caregivers.
Health Literacy and Quality: Focus on Chronic Illness Care and Patient Safety
Authors: Rothman Russell L. , Yin H. Shonna , Mulvaney Shelagh , Co John Patrick T. , Homer Charles , Lannon Carole
Published: October 2009

Despite a heightened focus on improving quality, recent studies have suggested that children only receive half of the indicated preventive, acute, or chronic care. Two major areas in need of improvement are chronic illness care and prevention of medical errors. Recently, health literacy has been identified as an important and potentially ameliorable factor for improving quality of care. Studies of adults have documented that lower health literacy is independently associated with poorer understanding of prescriptions and other medical information and worse chronic disease knowledge, self-management behaviors, and clinical outcomes. There is also growing evidence to suggest that health literacy is important in pediatric safety and chronic illness care. Adult studies have suggested that addressing literacy can lead to improved patient knowledge, behaviors, and outcomes. Early studies in the field of pediatrics have shown similar promise. There are significant opportunities to evaluate and demonstrate the importance of health literacy in improving pediatric quality of care. Efforts to address health literacy should be made to apply the 6 Institute of Medicine aims for quality-care that is safe, effective, patient centered, timely, efficient, and equitable. Efforts should also be made to consider the distinct nature of pediatric care and address the “4 D's” unique to child health: the developmental change of children over time; dependency on parents or adults; differential epidemiology of child health; and the different demographic patterns of children and their families.
Novel gene rearrangements in transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations
Authors: Unger Kristian , Wienberg Johannes , Riches Andrew , Hieber Ludwig , Walch Axel , Brown Andreas , O'Brien Patricia C M , Briscoe Cäcilia , Gray Lindsey , Rodriguez Elke , Jackl Gerhard , Knijnenburg Jeroen , Tallini Giovanni , Ferguson-Smith Malcolm , Zitzelsberger Horst
Published: October 2009

Chromosomal copy number alterations and chromosomal rearrangements are frequent mutations in human cancer. Unlike copy number alterations, little is known about the role and occurrence of chromosomal rearrangements in breast cancer. This may be due to the fact that chromosome-based breakpoint analysis is widely restricted to cultured cells. In order to identify gene rearrangements in breast cancer, we studied the chromosomal breakpoints in radiation-transformed epithelial breast cell lines using a high-resolution array-based approach using 1 Mb bacterial artificial chromosome (BAC) arrays. The breakpoints were further narrowed down by fluorescence in situ hybridisation (FISH) with clones from the 32 k BAC library. The analysis of the cell lines B42-11 and B42-16 revealed rearrangements of chromosomes 7, 8, 10 and 12. We identified the genes Has2, Grid1, Ret, Cpm, Tbx3, Tbx5, Tuba1a, Wnt1 and Arf3 within the breakpoint regions. Quantitative RT-PCR showed a deregulated expression of all of these candidate genes except for Tbx5 and Tbx3. This is the first study demonstrating gene rearrangements and their deregulated mRNA expression in radiation-transformed breast cells. Since the gene rearrangements occurred in the transformed and tumourigenic cell lines only, it is likely that these were generated in conjunction with malignant transformation of the epithelial breast cells and therefore might reflect early molecular events in breast carcinogenesis. Initial studies indicate that these gene alterations are also found in sporadic breast cancers.
Self-compensating autogenous shrinkage in Portland cement—metakaolin—fly ash pastes
Authors: Kinuthia J. M. , Wild S. , Sabir B. B. , Bai J.
Published: October 2009

For concrete containing high amounts of cement, particularly for (but not restricted to) hot climatic conditions, the rate of hydration may be high enough to cause shrinkage problems. Use of some admixtures such as silica fume and pulverized fuel ash (PFA) may further increase shrinkage. Blending Portland cement (PC) with metakaolin (MK) has shown expansive tendencies which may be applicable in suppressing early shrinkage. By blending MK with PFA partially to replace PC, shrinkage may be regulated. The current work is particularly directed towards regulation of autogenous shrinkage. Paste bars in which PC was replaced by up to 20% MK, 30% PFA and 30% MK plus PFA blends were monitored for autogenous shrinkage for up to 200 days during sealed moist curing at room temperature and 100% relative humidity. The results reported show reduced autogenous shrinkage, although cement type was also found to be an important factor in influencing shrinkage. The use of PC-MK-PFA blends should provide technological, economic and environmental advantages by reducing PC production and its associated greenhouse gas emissions, and improving concrete durability
Activated blended cement containing high volume coal fly ash
Authors: Shi Caijun , Qian Jushi
Published: October 2009

This study has investigated the strength and equilibrium water extraction of blended cement containing high volume coal fly ash and activator CaCl2. The addition of CaCl2 increased the strength of cement very significantly. Equilibrium water extraction indicated that the addition of CaCl2 decreased the pH of the pore solution, but accelerated the pozzolanic reactions between coal fly ash and lime, which became more obvious when the volume of fly ash in the cement was increased from 50–70%. Results from both strength and water extraction testing could conclude that CaCl2 is a good activator for the activation of pozzolanic reactivity of fly ash and for the improvement of early properties of fly ash cement and concrete.
Mineralogical and microstructural changes accompanying the interaction of Boom Clay with ordinary Portland cement
Authors: Read D. , Glasser F. P. , Ayora C. , Guardiola M. T. , Sneyers A.
Published: October 2009

The results of in situ tests conducted at the HADES underground laboratory, Mol, Belgium, indicate significant reaction between Boom Clay and ordinary Portland cement over a period of 18 months. Mass transfer of calcium, magnesium, aluminium, iron, silicon and sulphur leads to the development of a distinct zonal structure extending 100–250 μm into both the cement and the clay. The associated mineralogical changes have modified the microstructure of the altered region and there is clear evidence of increased porosity in the zone of portlandite dissolution. Additionally, experiments conducted at 85°C show the presence of a narrow Mg-Al-Si rich band in the clay close to the contact. Analyses indicate the formation of a di-phasic (Mg-aluminate hydroxide and Mgsilicate hydroxide) gel with low crystallinity and compositions close to hydrotalcite and sepiolite, respectively. Reactive transport modelling has been used to simulate phase transformations within the active region and relate these to porosity changes based on simple molar volume considerations. Given the close coupling of mineral chemistry and microstructure in cement±clay systems, such an approach is regarded as essential if reliable estimates are to be made of long-term reactivity.