bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Proinflammatory CD68
+
Mannose Receptor
−
Macrophages in Peroxiredoxin-1 Expression and in Abdominal Aortic Aneurysms in Humans
Authors: Boytard Ludovic , Spear Rafaelle , Chinetti-Gbaguidi Giulia , Acosta-Martin Adelina E. , Vanhoutte Jonathan , Lamblin Nicolas , Staels Bart , Amouyel Philippe , Haulon Stephan , Pinet Florence
Published: December 2012

Objective—

Abdominal aortic aneurysms (AAAs), dilations of the infrarenal aorta, are characterized by inflammation and oxidative stress. We previously showed increased levels of peroxiredoxin-1 (PRDX-1) in macrophages cultured from AAA patients. The purpose of the study was to determine which subpopulation of macrophages is present in AAAs and is involved in upregulation of PRDX-1 in aneurysmal disease.

Methods and Results—

This study used immunohistochemistry with antibodies against CD68 and mannose receptor (MR) to determine the subtype of macrophages in AAA tissue samples (n=33); laser capture microdissection to isolate each subtype; and quantitative–reverse transcriptase-polymerase chain reaction, Western blot, and ELISA to assess
PRDX-1
mRNA and PRDX-1protein levels in both types. Proinflammatory CD68
+
MR
−
macrophages predominated in adventitial tissue, whereas the intraluminal thrombus contained CD68
+
MR
+
macrophages. The presence of lipids and iron-containing deposits confirmed their phagocytic phenotype. Laser capture microdissection-isolated CD68
+
MR
−
and CD68
+
MR
+
macrophages, characterized by quantitative–reverse transcriptase-polymerase chain reaction (
TNF
,
IL1B
,
MRC1
, and
CCL18
) and Western blot (stabilin and hemoglobin), validated the microdissected subtypes. PRDX-1 expression was colocalized with CD68
+
MR
−
macrophages.
PRDX-1
mRNA and PRDX-1 protein were both more abundant in CD68
+
MR
−
than CD68
+
MR
+
macrophages in AAA.

Conclusion—

These findings suggest that the proteins or mRNAs expressed by the proinflammatory CD68
+
MR
−
macrophages may contribute to aneurysmal pathology.
Association of Arginine Vasopressin Levels With Outcomes and the Effect of V2 Blockade in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction
Authors: Lanfear David E. , Sabbah Hani N. , Goldsmith Steven R. , Greene Stephen J. , Ambrosy Andrew P. , Fought Angela J. , Kwasny Mary J. , Swedberg Karl , Yancy Clyde W. , Konstam Marvin A. , Maggioni Aldo P. , Zannad Faiez , Gheorghiade Mihai
Published: December 2012

Background—

Arginine vasopressin (AVP) levels are elevated in proportion to heart failure severity and are associated with higher cardiovascular mortality in ambulatory patients. However, the relationship between baseline and trends in AVP with outcomes in patients hospitalized for worsening heart failure with reduced ejection fraction is unclear.

Methods and Results—

The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial investigated the effects of tolvaptan in patients with worsening heart failure and ejection fraction ≤40%. The present analysis examined baseline and follow-up AVP levels in 3196 EVEREST patients with valid AVP measurements. Coprimary end points included all-cause mortality, and the composite of cardiovascular mortality or heart failure hospitalization. Median follow-up was 9.9 months. Times to events were compared with univariate log-rank tests and multivariable Cox regression models, adjusted for baseline risk factors. After adjusting for baseline covariates, elevated AVP levels were associated with increased all-cause mortality (hazard ratio, 1.33; 95% confidence interval, 1.13–1.55) and cardiovascular mortality or heart failure hospitalization (hazard ratio, 1.23; 95% confidence interval, 1.08–1.39). There was no interaction of baseline AVP with treatment assignment in terms of survival (
P
=0.515). Tolvaptan therapy increased the proportion of patients with elevated AVP (
P
<0.001), but this had no effect on mortality (hazard ratio, 0.95; 95% confidence interval, 0.72–1.24).

Conclusions—

Elevated baseline AVP level was independently predictive of mortality, but did not identify a group of patients who had improved outcomes with tolvaptan treatment. Tolvaptan treatment increased AVP levels during follow-up, but this incremental increase was not associated with worsened outcomes.
Global Increasing Trends in Annual Maximum Daily Precipitation
Authors: Westra Seth , Alexander Lisa V. , Zwiers Francis W.
Published: December 2012

This study investigates the presence of trends in annual maximum daily precipitation time series obtained from a global dataset of 8326 high-quality land-based observing stations with more than 30 years of record over the period from 1900 to 2009. Two complementary statistical techniques were adopted to evaluate the possible nonstationary behavior of these precipitation data. The first was a Mann–Kendall nonparametric trend test, and it was used to evaluate the existence of monotonic trends. The second was a nonstationary generalized extreme value analysis, and it was used to determine the strength of association between the precipitation extremes and globally averaged near-surface temperature. The outcomes are that statistically significant increasing trends can be detected at the global scale, with close to two-thirds of stations showing increases. Furthermore, there is a statistically significant association with globally averaged near-surface temperature, with the median intensity of extreme precipitation changing in proportion with changes in global mean temperature at a rate of between 5.9% and 7.7% K−1, depending on the method of analysis. This ratio was robust irrespective of record length or time period considered and was not strongly biased by the uneven global coverage of precipitation data. Finally, there is a distinct meridional variation, with the greatest sensitivity occurring in the tropics and higher latitudes and the minima around 13°S and 11°N. The greatest uncertainty was near the equator because of the limited number of sufficiently long precipitation records, and there remains an urgent need to improve data collection in this region to better constrain future changes in tropical precipitation.
Readiness and DADT Repeal
Authors: Belkin Aaron , Ender Morten G. , Frank Nathaniel , Furia Stacie R. , Lucas George , Packard Gary , Samuels Steven M. , Schultz Tammy , Segal David R.
Published: December 2012

Prior to the repeal of “don't ask, don't tell” (DADT) on September 20, 2011, many observers predicted that allowing lesbian, gay and bisexual troops to serve openly would harm the military, and a group of more than 1,000 retired general and flag officers predicted that repeal could “break the All-Volunteer Force.” This study is the first scholarly effort to assess the accuracy of such predictions about the impact of DADT repeal on military readiness. We conducted our research during the half-year period starting six months after repeal and concluding at the one year mark, and we pursued ten separate research strategies including in-depth interviews, survey analysis, on-site field observations, pretest/posttest quasi experimentation, secondary source analysis, and a comprehensive review of media articles. Our goal was to maximize the likelihood of identifying evidence of damage caused by repeal, and we made vigorous efforts to collect data from repeal opponents including anti-repeal generals and admirals, activists, academic experts, service members and watchdog organizations. Our conclusion, based on all of the evidence available to us, is that DADT repeal has had no overall negative impact on military readiness or its component dimensions, including cohesion, recruitment, retention, assaults, harassment, or morale. If anything, DADT repeal appears to have enhanced the military's ability to pursue its mission.
Data Centre Energy Efficiency Analysis to minimize total cost of ownership
Authors: Flucker Sophia , Tozer Robert
Published: December 2012

The data centre industry grows with our increasing demand for IT services; energy forms a large part of data centre operating costs. Operators face increasing pressure to reduce their environmental impact and deliver competitively priced services to support users. However, many existing data centres were designed without a ‘green’ design brief; priorities were focussed around infrastructure redundancy. There are significant opportunities to implement modifications to design and operation and reduce operating costs, particularly to cooling systems, including managing data hall air, operating at higher temperatures, using free cooling and optimising for part load operation. Energy analysis can identify areas for improvement, often with short payback periods. This enables operators to realise massive reductions in energy (and sometimes capital) costs, whilst still delivering a reliable service.

Practical application: The paper describes the challenges of reducing energy consumption and operating cost faced by those working in the data centre industry, along with tools and solutions. Details on where and how to achieve energy savings are presented, whilst maintaining the required availability for both new build and legacy facilities. Practical examples of how to put theory into practice are explained, including case studies where real clients have implemented improvements.
Prostate Effect in Dogs with the Aldosterone Receptor Blocker Eplerenone
Authors: Levin Stuart , McMahon Ellen , John-Baptiste Annette , Bell Rosonald R.
Published: December 2012

Eplerenone (Inspra®) is an aldosterone receptor antagonist approved for the treatment of hypertension and heart failure after a myocardial infarction. In vitro receptor binding and transactivation studies showed eplerenone had high selectivity for the mineralocorticoid receptor over other steroid receptors (glucocorticoid, androgen, and progesterone). The most sensitive off-target effect of orally administered eplerenone preclinically was prostate atrophy in dogs. Dose-related prostate atrophy was observed at eplerenone dosages ≥15 mg/kg/day for 13 weeks or longer. The no observed adverse effect level (NOAEL) for the prostate effect in dogs was 5 mg/kg/day. The maximal effect was seen by 13 weeks and the atrophy was reversible even after 1 year of daily treatment. An additional study demonstrated dogs with eplerenone-induced prostate atrophy (confirmed by intrarectal ultrasound) had slightly decreased semen volume but no compound-related effects on libido, semen protein content, sperm motility, daily sperm production, or epididymal sperm transit time. Four possible mechanisms for prostate effect were investigated: (1) inhibition of testosterone synthesis and secretion; (2) inhibition of 5α-reductase, the enzyme within the prostate that converts testosterone into the more active growth factor dihydrotestosterone (DHT); (3) competitive antagonism of the androgen receptor; and (4) inhibition of 5α-reductase or competitive antagonism of the androgen receptor by aldosterone, which increased in dogs treated with eplerenone. Data from these studies supported blockade of androgen receptors at suprapharmacological concentrations of eplerenone. Another mineralocorticoid blocker, spironolactone, had greater antiandrogenic activity than eplerenone both in vivo and in vitro, and it has well known clinically significant antiandrogenic effects in humans, whereas eplerenone does not.
Clinical Practice Guideline Development Manual, Third Edition
Authors: Rosenfeld Richard M. , Shiffman Richard N. , Robertson Peter
Published: December 2012

Background

Guidelines translate best evidence into best practice. A well‐crafted guideline promotes quality by reducing health care variations, improving diagnostic accuracy, promoting effective therapy, and discouraging ineffective—or potentially harmful—interventions. Despite a plethora of published guidelines, methodology is often poorly defined and varies greatly within and among organizations.

Purpose

The third edition of this manual describes the principles and practices used successfully by the American Academy of Otolaryngology—Head and Neck Surgery Foundation to produce quality‐driven, evidence‐based guidelines using efficient and transparent methodology for actionable recommendations with multidisciplinary applicability. The development process emphasizes a logical sequence of key action statements supported by amplifying text, action statement profiles, and recommendation grades linking action to evidence. New material in this edition includes standards for trustworthy guidelines, updated classification of evidence levels, increased patient and public involvement, assessing confidence in the evidence, documenting differences of opinion, expanded discussion of conflict of interest, and use of computerized decision support for crafting actionable recommendations.

Conclusion

As clinical practice guidelines become more prominent as a key metric of quality health care, organizations must develop efficient production strategies that balance rigor and pragmatism. Equally important, clinicians must become savvy in understanding what guidelines are—and are not—and how they are best used to improve care. The information in this manual should help clinicians and organizations achieve these goals.
Information-seeking by print media journalists in Rajshahi, Bangladesh
Authors: Hossain Md Arman , Islam Md. Shariful
Published: December 2012

This study reports the results of investigating the information behavior of print media journalists in the city of Rashahi, Bangladesh. It attempts to identify how successful the journalists are in finding information and what information sources are preferred. The Internet was the most frequently used information source. The study also tried to explore the information services required by journalists from libraries and information centres. This paper suggests that journalism schools may include courses in their curriculum about information behavior, types of information, various types of information sources, information retrieval, search strategies, etc.
Inflation and Marriage in Israel
Authors: Schellekens Jona , Gliksberg David
Published: December 2012

At the end of the 1970s and the beginning of the 1980s, inflation in Israel exceeded 100 percent. Using the twenty percent samples of the 1972, 1983, 1995, and 2008 Israeli Census, we show that inflation had a substantial negative effect on the decision to marry. More specifically, we show that high inflation influenced marriage by creating economic uncertainty. Without the episode of high inflation, the decline in marriage would have been delayed for several years. We also show that there were educational differences in the effect of inflation on marriage formation.
Improvement of satellite conflict prediction reliability through use of the adaptive splitting technique
Authors: Pastel Rudy , Morio Jérôme , Gland François Le
Published: December 2012

Collision between satellites and debris is a rare event but with high financial consequences. This risk therefore has to be addressed carefully. To support the decision to start a collision avoidance maneuver, a dedicated tool to characterize the risk uncertainty is the probability of collision between the debris and the satellite. 1 Crude Monte Carlo could be a way if it could cope with very small probabilities, say 10−6, within the available simulation budget and time. The methodology nowadays in use is a numerical integration made tractable by physical hypothesis and numerical approximation. 2 We advocate the adaptive splitting technique, presented in Cérou et al., 3 as it avoids all the hypothesis needed for the numerical integration and clearly outperforms Crude Monte Carlo with respect to rare events. A direct comparison between Crude Monte Carlo and adaptive splitting technique approach is also given on real-life examples.
Comparative effectiveness of isolation techniques for contemporary Influenza A virus strains circulating in exhibition swine
Authors: Bowman Andrew S. , Nelson Sarah W. , Edwards Jody L. , Hofer Christian C. , Nolting Jacqueline M. , Davis Ian C. , Slemons Richard D.
Published: December 2012

The current study sought to compare the effectiveness of 2 virus isolation methods for the recovery of contemporary Influenza A virus (FLUAV) strains circulating in swine at agricultural exhibitions. Following the emergence of the influenza A (H1N1)pdm09 virus, increased surveillance of FLUAV strains among swine was recommended for early detection of emerging strains that threaten animal and human health. The increase in genetic drift and genomic reassortment among FLUAV strains infecting swine since 1998 necessitates that detection protocols be periodically validated for contemporary FLUAV strains. During 2009, nasal swabs were collected from 221 clinically healthy pigs at 12 agricultural exhibitions in Ohio. Nasal swabs were tested in parallel for the presence of FLUAV strains using 3 methodologies: 2 passages through Madin–Darby canine kidney (MDCK) cells adapted to serum-free medium (SFM), 2 passages through embryonated chicken eggs (ECEs), and real-time reverse transcription polymerase chain reaction (real-time RT-PCR). Of the 221 samples, 40 (18.1%) were positive for FLUAV recovery in MDCK cell culture and 13 (5.9%) were positive in ECEs ( P = 0.015). All samples positive in ECEs were also positive in MDCK cell culture. MDCK cell culture virus isolation results were in perfect agreement with results of the real-time RT-PCR. Hemagglutinin and neuraminidase combinations of the recovered isolates were H1N2 and H3N2, which were consistent with FLUAV strains circulating in U.S. pigs. Effectiveness and cost savings justify the use of SFM-adapted MDCK cell culture over ECEs for the recovery of contemporary FLUAV strains from exhibition swine.
Associations Between Three School-Based Measures of Health
Authors: Morgan Emily H. , Houser Robert F. , Au Lauren E. , Sacheck Jennifer M.
Published: December 2012

School-based body mass index (BMI) notification programs are often used to raise parental awareness of childhood overweight and obesity, but how BMI results are associated with physical fitness and diet is less clear. This study examined the relationship between BMI, fitness, and diet quality in a diverse sample of urban schoolchildren ( n = 122) utilizing a school-based cardiorespiratory fitness test and a food frequency questionnaire. Fifty-two percent of children were overweight/obese. Fit children were more likely to be normal weight than unfit children ( p < .001). Weight status was not associated with adherence to any specific dietary guidelines; however, greater overall adherence to the recommendations was associated with normal weight ( p < .05). These findings suggest a potential benefit may be gained by combining BMI reports with results of in-school fitness testing and basic information on how children’s diets compare to recommendations.
Quality characteristics and acceptability of ‘amala’ (yam-based thick paste) as influenced by particle size categorization of yam (Dioscorea rotundata) flour
Authors: Ayodele BC , Bolade MK , Usman MA
Published: December 2012

The study was essentially an investigation on the influence of size-categorized yam ( Dioscorea rotundata) flour on the quality characteristics and acceptability of amala (yam-based thick paste). Yam flour was separated into three major particle size categories (i.e. 75–150 µm, 150–300 µm and whole meal [<300 µm]), while the physicochemical properties of each category were evaluated and flour samples finally used to prepare amala. Both the protein and ash contents of the yam flours were found to decrease with the decrease in the particle size giving 2.87% and 2.27% in 75–150 µm flour category, respectively. The loose bulk density and packed bulk density of the whole meal (<300 µm) were higher than that of others giving 0.50 g/cm3 and 0.78 g/cm3, respectively, while 150–300 µm flour category gave the highest value (2.88 g/g) in water absorption capacity. The colour characteristics of the flour samples showed that the whole meal (<300 µm) had the highest lightness index, L*-value (76.4). The 75–150 µm flour category had the highest chroma, C-value (19.2), while that of 150–300 µm had the lowest value (18.7) with no significant difference at p < 0.05. The pasting characteristics of the flour samples showed that 75–150 µm flour category exhibited highest peak viscosity (257.1 RVU), while the whole meal (<300 µm) exhibited highest breakdown viscosity (40.9 RVU), final viscosity (364.0 RVU) and setback viscosity (99.7 RVU). The amala prepared from 150–300 µm flour category gave the highest softness index (19.6 mm) while that obtained from 75–150 µm flour category gave the lowest value (16.6 mm). The sensory quality rating of amala prepared from the flour samples showed that amala from 150–300 µm flour category was rated the highest in terms of colour, texture (ease of mouldability), aroma and overall acceptability. Both positive and negative correlations were found between some properties of size-categorized yam flours and sensory quality characteristics of amala.
Simulation analysis of UAV and ground teams for surveillance and interdiction
Authors: Muratore Mark , Silvestrini Rachel T. , Chung Timothy H.
Published: December 2012

As unmanned aerial vehicles (UAVs) become more prevalent on the battlefield, ground forces will increasingly have to rely on them for intelligence, surveillance and reconnaissance, as well as target marking and overwatch operations. This paper presents the use of the Situational Awareness for Surveillance and Interdiction Operations simulation analysis tool in conjunction with the design and analysis of experiments to study aspects of UAVs’ surveillance characteristics in conjunction with ground-based interdiction teams to aid in increasing the number of targets cleared from the area of interest. Different teaming strategies and coordination measures between searching and interdicting assets are studied in order to understand the effectiveness of the interdictor possessing an organic tracker UAV. The objective of this research is to quantify the benefit or penalty of an additional UAV asset that is organic to a quick reaction force in the context of the overall surveillance and interdiction operation.
Risk-analytic approaches to the allocation of defence operating funds
Authors: Hurley WJ , Brimberg Jack , Fisher Brent
Published: December 2012

We develop two risk-analytic approaches for allocating operating funding among defence organization activities. In one, termed the priority method, activities are put in rank order and as many high-priority activities as possible are undertaken while ensuring that the budget holder’s probability of overspending his budget is acceptably small. In the second, termed the knapsack method, there are two kinds of activities: must-do activities and optional activities. Optional activities are selected using a nonlinear integer program that maximizes the value of the optional activities while keeping the probability of overspending sufficiently low. Both approaches are applied in the context of the Department of National Defence in Canada.
Updates in the Management of Acute Lung Injury
Authors: Dharia Ajay , Calfee Carolyn S.
Published: December 2012

Acute lung injury (ALI) is commonly encountered in the ICU and is associated with significant mortality. The mainstay of therapy continues to be aggressive supportive care, including low tidal volume ventilation and fluid conservative strategies. Recent developments in the field of ALI include a proposal to modify the diagnostic criteria for ALI in the Berlin Definition and recent randomized controlled trials of the use of neuromuscular blockade, beta-agonists, and feeding strategies. The goal of this article is to review, summarize, and comment on these emerging data and offer practical recommendations for the evidence-based management of ALI.
Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection
Authors: Leeansyah Edwin , Ganesh Anupama , Quigley Máire F. , Sönnerborg Anders , Andersson Jan , Hunt Peter W. , Somsouk Ma , Deeks Steven G. , Martin Jeffrey N. , Moll Markus , Shacklett Barbara L. , Sandberg Johan K.
Published: December 2012

Key Points

Antimicrobial CD8+ MAIT cells are activated, exhausted, and progressively and persistently depleted during chronic HIV-1 infection. This decline in MAIT cell level and function may seriously impair the ability to mount immune responses to bacterial and fungal pathogens.
Protocol for ADDITION-PRO: a longitudinal cohort study of the cardiovascular experience of individuals at high risk for diabetes recruited from Danish primary care
Authors: Johansen Nanna B , Hansen Anne-Louise S , Jensen Troels M , Philipsen Annelotte , Rasmussen Signe S , Jørgensen Marit E , Simmons Rebecca K , Lauritzen Torsten , Sandbæk Annelli , Witte Daniel R
Published: December 2012

Background

Screening programmes for type 2 diabetes inevitably find more individuals at high risk for diabetes than people with undiagnosed prevalent disease. While well established guidelines for the treatment of diabetes exist, less is known about treatment or prevention strategies for individuals found at high risk following screening. In order to make better use of the opportunities for primary prevention of diabetes and its complications among this high risk group, it is important to quantify diabetes progression rates and to examine the development of early markers of cardiovascular disease and microvascular diabetic complications. We also require a better understanding of the mechanisms that underlie and drive early changes in cardiometabolic physiology. The ADDITION-PRO study was designed to address these issues among individuals at different levels of diabetes risk recruited from Danish primary care.

Methods/Design

ADDITION-PRO is a population-based, longitudinal cohort study of individuals at high risk for diabetes. 16,136 eligible individuals were identified at high risk following participation in a stepwise screening programme in Danish general practice between 2001 and 2006. All individuals with impaired glucose regulation at screening, those who developed diabetes following screening, and a random sub-sample of those at lower levels of diabetes risk were invited to attend a follow-up health assessment in 2009–2011 (n = 4,188), of whom 2,082 (50%) attended. The health assessment included detailed measurement of anthropometry, body composition, biochemistry, physical activity and cardiovascular risk factors including aortic stiffness and central blood pressure. All ADDITION-PRO participants are being followed for incident cardiovascular disease and death.

Discussion

The ADDITION-PRO study is designed to increase understanding of cardiovascular risk and its underlying mechanisms among individuals at high risk of diabetes. Key features of this study include (i) a carefully characterised cohort at different levels of diabetes risk; (ii) detailed measurement of cardiovascular and metabolic risk factors; (iii) objective measurement of physical activity behaviour; and (iv) long-term follow-up of hard clinical outcomes including mortality and cardiovascular disease. Results will inform policy recommendations concerning cardiovascular risk reduction and treatment among individuals at high risk for diabetes. The detailed phenotyping of this cohort will also allow a number of research questions concerning early changes in cardiometabolic physiology to be addressed.
Participant experiences from chronic administration of a multivitamin versus placebo on subjective health and wellbeing: a double-blind qualitative analysis of a randomised controlled trial
Authors: Sarris Jerome , Cox Katherine H M , Camfield David A , Scholey Andrew , Stough Con , Fogg Erin , Kras Marni , White David J , Sali Avni , Pipingas Andrew
Published: December 2012

Background

While many randomised controlled trials have been conducted on multivitamins, to our knowledge no qualitative research exploring the subjective experience of taking a multivitamin during a clinical trial has been reported.

Methods

Semi-structured and open-ended written questions were incorporated into a 16-week double-blind, randomised, placebo-controlled, parallel groups trial of once-daily multivitamin administration. At the final study visit (week 16), three open-ended questions were posed to elucidate any positive, negative or unusual experiences from taking either the multivitamin or matched placebo. Qualitative thematic analysis was undertaken by researchers who were blind as to treatment condition of participants, and triangulation (independent analysis from three researchers) was employed to ensure methodological rigour. Participant’s experiences were categorised as “positive” or “negative” and a Chi Square analysis was then applied to each of the experiential themes, to compare experiences between the multivitamin and placebo groups, (subdividing the groups by gender). Usual experiences were categorised and discussed separately.

Results

Of the 182 participants enrolled, 116 completed the study and qualitative data were available from 114 participants. Thematic analysis revealed significant effects in favour of the multivitamin over placebo for participants experiencing increased energy levels (p=.022) and enhanced mood (p=.027). The beneficial effect on energy levels was particularly evident among female participants. A trend was found for participants reporting better sleep in the multivitamin over placebo. The multivitamin and placebo groups did not significantly differ in perceived positive or negative effects in areas relating to other aspects of mental function or physical health. No significant negative effects were revealed, although there was a non-significant trend for more people in the multivitamin group having minor digestive complaints.

Conclusion

This represents the first documented qualitative investigation of participants’ experience of chronic administration of a multivitamin. Results uncovered a range of subjective beneficial effects that are consistent with quantitative data from previously published randomised controlled trials examining the effects of multivitamins and B vitamin complexes on mood and well-being.

Trial registration

Prior to commencement this trial was registered with the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au) ACTRN12611000092998
Enhanced CD8 T-cell anti-viral function and clinical disease in B7-H1-deficient mice requires CD4 T cells during encephalomyelitis
Authors: Phares Timothy W , Stohlman Stephen A , Hinton David R , Bergmann Cornelia C
Published: December 2012

Background

Anti-viral CD8 T-cell activity is enhanced and prolonged by CD4 T-cell-mediated help, but negatively regulated by inhibitory B7-H1 interactions. During viral encephalomyelitis, the absence of CD4 T cells decreases CD8 T cell activity and impedes viral control in the central nervous system (CNS). By contrast, the absence of B7-H1 enhances CD8 T-cell function and accelerates viral control, but increases morbidity. However, the relative contribution of CD4 T cells to CD8 function in the CNS, in the absence of B7-H1, remains unclear.

Methods

Wild-type (WT) and B7-H1−/−mice were infected with a gliatropic coronavirus and CD4 T cells depleted to specifically block T helper function in the CNS. Flow cytometry and gene expression analysis of purified T-cell populations from lymph nodes and the CNS was used to directly monitorex vivoT-cell effector function. The biological affects of altered T-cell responses were evaluated by analysis of viral control and spinal-cord pathology.

Results

Increased anti-viral activity by CD8 T cells in the CNS of B7-H1−/−mice was lost upon depletion of CD4 T cells; however, despite concomitant loss of viral control, the clinical disease was less severe. CD4 depletion in B7-H1−/−mice also decreased inducible nitric oxide synthase expression by microglia and macrophages, consistent with decreased microglia/macrophage activation and reduced interferon (IFN)-γ. Enhanced production of IFN-γ, interleukin (IL)-10 and IL-21 mRNA was seen in CD4 T cells from infected B7-H1−/−compared with WT mice, suggesting that over-activated CD4 T cells primarily contribute to the increased pathology.

Conclusions

The local requirement of CD4 T-cell help for CD8 T-cell function is not overcome if B7-H1 inhibitory signals are lost. Moreover, the increased effector activity by CD8 T cells in the CNS of B7-H1−/−mice is attributable not only to the absence of B7-H1 upregulation on major histocompatibility complex class I-presenting resident target cells, but also to enhanced local CD4 T-cell function. B7-H1-mediated restraint of CD4 T-cell activity is thus crucial to dampen both CD8 T-cell function and microglia/macrophage activation, thereby providing protection from T-cell-mediated bystander damage.
Does TomoDirect 3DCRT represent a suitable option for post-operative whole breast irradiation? A hypothesis-generating pilot study
Authors: Borca Valeria Casanova , Franco Pierfrancesco , Catuzzo Paola , Migliaccio Fernanda , Zenone Flora , Aimonetto Stefania , Peruzzo Andrea , Pasquino Massimo , Russo Giuliana , La Porta Maria Rosa , Cante Domenico , Sciacero Piera , Girelli Giuseppe , Ricardi Umberto , Tofani Santi
Published: December 2012

Background

This study investigates the use of TomoDirectTM 3DCRT for whole breast adjuvant radiotherapy (AWBRT) that represents a very attractive treatment opportunity, mainly for radiotherapy departments without conventional Linacs and only equipped with helical tomotherapy units.

Methods

Plans were created for 17 breast cancer patients using TomoDirect in 3DCRT and IMRT modality and field-in-field 3DCRT planning (FIF) and compared in terms of PTV coverage, overdosage, homogeneity, conformality and dose to OARs. The possibility to define patient-class solutions for TD-3DCRT employment was investigated, correlating OARs dose constraints to patient specific anatomic parameters.

Results

TD-3DCRT showed PTV coverage and homogeneity significantly higher than TD-IMRT and FIF. PTV conformality was significantly better for FIF, while no differences were found between TD-3DCRT and TD-IMRT. TD-3DCRT showed mean values of the OARs dosimetric endpoints significantly higher than TD-IMRT; with respect to FIF, TD-3DCRT showed values significantly higher for lung V20Gy, mean heart dose and V25Gy, while contralateral lung maximum dose and contralateral breast mean dose resulted significantly lower. The Central Lung Distance (CLD) and the maximal Heart Distance (HD) resulted as useful clinical tools to predict the opportunity to employ TD-3DCRT: positive correlations were found between CLD and both V20Gy and mean lung dose and between HD and both V25Gy and the mean heart dose. TD-3DCRT showed a significantly shorter mean beam-on time than TD-IMRT.

Conclusions

The present study showed that TD-3DCRT and TD-IMRT are two feasible and dosimetrically acceptable treatment approach for AWBRT, with an optimal PTV coverage and adequate OARs sparing. Some concerns might be raised in terms of dose to organs at risks if TD-3DCRT is applied to a general population. A correct patients clusterization according to simple quantitative anatomic measures, would help to correctly allocate patients to the appropriate treatment planning strategy in terms of target coverage, but also of normal tissue sparing.
Clinical and multiple gene expression variables in survival analysis of breast cancer: Analysis with the hypertabastic survival model
Authors: Tabatabai Mohammad A , Eby Wayne M , Nimeh Nadim , Li Hong , Singh Karan P
Published: December 2012

Background

We explore the benefits of applying a new proportional hazard model to analyze survival of breast cancer patients. As a parametric model, the hypertabastic survival model offers a closer fit to experimental data than Cox regression, and furthermore provides explicit survival and hazard functions which can be used as additional tools in the survival analysis. In addition, one of our main concerns is utilization of multiple gene expression variables. Our analysis treats the important issue of interaction of different gene signatures in the survival analysis.

Methods

The hypertabastic proportional hazards model was applied in survival analysis of breast cancer patients. This model was compared, using statistical measures of goodness of fit, with models based on the semi-parametric Cox proportional hazards model and the parametric log-logistic and Weibull models. The explicit functions for hazard and survival were then used to analyze the dynamic behavior of hazard and survival functions.

Results

The hypertabastic model provided the best fit among all the models considered. Use of multiple gene expression variables also provided a considerable improvement in the goodness of fit of the model, as compared to use of only one. By utilizing the explicit survival and hazard functions provided by the model, we were able to determine the magnitude of the maximum rate of increase in hazard, and the maximum rate of decrease in survival, as well as the times when these occurred. We explore the influence of each gene expression variable on these extrema. Furthermore, in the cases of continuous gene expression variables, represented by a measure of correlation, we were able to investigate the dynamics with respect to changes in gene expression.

Conclusions

We observed that use of three different gene signatures in the model provided a greater combined effect and allowed us to assess the relative importance of each in determination of outcome in this data set. These results point to the potential to combine gene signatures to a greater effect in cases where each gene signature represents some distinct aspect of the cancer biology. Furthermore we conclude that the hypertabastic survival models can be an effective survival analysis tool for breast cancer patients.
Investigation of motility and biofilm formation by intestinal Campylobacter concisus strains
Authors: Lavrencic Peter , Kaakoush Nadeem O , Huinao Karina D , Kain Nupur , Mitchell Hazel M
Published: December 2012

Motility helps many pathogens swim through the highly viscous intestinal mucus. Given the differing outcomes of Campylobacter concisus infection, the motility of eight C. concisus strains isolated from patients with Crohn’s disease (n=3), acute (n=3) and chronic (n=1) gastroenteritis and a healthy control (n=1) were compared. Following growth on solid or liquid media the eight strains formed two groups; however, the type of growth medium did not affect motility. In contrast, following growth in viscous liquid medium seven of the eight strains demonstrated significantly decreased motility. In media of increasing viscosities the motility of C. concisus UNSWCD had two marked increases at viscosities of 20.0 and 74.7 centipoises. Determination of the ability of UNSWCD to swim through a viscous medium, adhere to and invade intestinal epithelial cells showed that while adherence levels significantly decreased with increasing viscosity, invasion levels did not significantly change. In contrast, adherence to and invasion of UNSWCD to mucus-producing intestinal cells increased upon accumulation of mucus, as did bacterial aggregation. Given this aggregation, we determined the ability of the eight C. concisus strains to form biofilms, and showed that all strains formed biofilms. In conclusion, the finding that C. concisus strains could be differentiated into two groups based on their motility may suggest that strains with high motility have an increased ability to swim through the intestinal mucus and reach the epithelial layer.
Sex difference in race performance and age of peak performance in the Ironman Triathlon World Championship from 1983 to 2012
Authors: Rüst Christoph A , Knechtle Beat , Rosemann Thomas , Lepers Romuald
Published: December 2012

Background

The fastest Ironman race times in ‘Ironman Hawaii’ were achieved in very recent years. This study investigated the change in sex difference in both race performance and the age of peak performance across years in the top ten athletes for split disciplines and overall race time in the ‘Ironman Hawaii’ between 1983 and 2012.

Methods

Changes in split times, overall race times, and age of athletes across years for the top ten overall and the fastest swimmers, cyclists, and runners were investigated using regression analyses and analyses of variance.

Results

Between 1983 and 2012, the overall top ten men and women finishers improved their swimming (only men), cycling, running, and overall race times. The sex difference in overall race time decreased significantly (p = 0.01) from 15.2% to 11.3% across time. For the split disciplines, the sex difference remained unchanged (p > 0.05) for swimming (12.5 ± 3.7%) and cycling (12.5 ± 2.7%) but decreased for running from 13.5 ± 8.1% to 7.3 ± 2.9% (p = 0.03). The time performance of the top ten swimmers remained stable (p > 0.05), while those of the top ten cyclists and top ten runners improved (p < 0.01). The sex difference in performance remained unchanged (p > 0.05) in swimming (8.0 ± 2.4%), cycling (12.7 ± 1.8%), and running (15.2 ± 3.0%). Between 1983 and 2012, the age of the overall top ten finishers and the fastest swimmers, cyclists, and runners increased across years for both women and men (p < 0.01).

Conclusions

To summarize, for the overall top ten finishers, the sex difference decreased across years for overall race time and running, but not for swimming and cycling. For the top ten per discipline, the sex difference in performance remained unchanged. The athletes improved their performances across years although the age of peak performance increased.
Novel variations in the adiponectin gene (ADIPOQ) may affect distribution of oligomeric complexes
Authors: Kottyan Leah C , Woo Jessica G , Keddache Mehdi , Banach Walter , Crimmins Nancy A , Dolan Lawrence M , Martin Lisa J
Published: December 2012

Adiponectin is an obesity related protein that mediates the risk of type 2 diabetes in obese individuals with its anti-inflammatory and insulin-sensitizing properties. To date, five functional variations have been identified in the adiponectin gene. However, these variations are rare, and fail to fully explain adiponectin variability, suggesting unidentified causal variations exist. Thus, our objective was to identify novel, potentially functional amino acid-changing variations in ADIPOQ exonic regions and relate them to oligomeric forms of adiponectin in serum. We sequenced ADIPOQ exons in 30 adolescents chosen from a school-based cohort based on serum adiponectin and insulin levels. Four coding region changes were identified: a methionine initiation skip (MIS), P32L, R55C, and Y111H, of which R55C and Y111H have been previously identified. Individuals with the novel variations and R55C had low levels of adiponectin and decreased adiponectin oligomerization compared to adolescents with similar body mass index and insulin levels. Further, bioinformatic analysis predicted putative functionality of these variations. In our study, Y111H was unrelated to total circulating adiponectin or adiponectin oligomerization. Given the disruption of adiponectin oligomerization in the individuals with MIS, P32L, and R55C coding changes, these variations may lead to increased metabolic disease risk and warrant further examination in larger cohorts.
2-Arachidonoyl-glycerol- and arachidonic acid-stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV-1, and RSV
Authors: Chouinard François , Turcotte Caroline , Guan Xiaochun , Larose Marie-Chantal , Poirier Samuel , Bouchard Line , Provost Véronique , Flamand Louis , Grandvaux Nathalie , Flamand Nicolas
Published: December 2012

Neutrophils activated with nanomolar concentrations of 2-arachidonoyl-glycerol or arachidonic acid, release antimicrobial effectors, unraveling these lipids as possible regulators of host defense in vivo.

The endocannabinoid 2-AG is highly susceptible to its hydrolysis into AA, which activates neutrophils through de novo LTB4 biosynthesis, independently of CB activation. In this study, we show that 2-AG and AA stimulate neutrophils to release antimicrobial effectors. Supernatants of neutrophils activated with nanomolar concentrations of 2-AG and AA indeed inhibited the infectivity of HSV-1 and RSV. Additionally, the supernatants of 2-AG- and AA-stimulated neutrophils strongly impaired the growth of Escherichia coli and Staphylococcus aureus. This correlated with the release of a large amount (micrograms) of α-defensins, as well as a limited amount (nanograms) of LL-37. All the effects of AA and 2-AG mentioned above were prevented by inhibiting LTB4 biosynthesis or by blocking BLT1. Importantly, neither CB2 receptor agonists nor antagonists could mimic nor prevent the effects of 2-AG, respectively. In fact, qPCR data show that contaminating eosinophils express ∼100-fold more CB2 receptor mRNA than purified neutrophils, suggesting that CB2 receptor expression by human neutrophils is limited and that contaminating eosinophils are likely responsible for the previously documented CB2 expression by freshly isolated human neutrophils. The rapid conversion of 2-AG to AA and their subsequent metabolism into LTB4 promote 2-AG and AA as multifunctional activators of neutrophils, mainly exerting their effects by activating the BLT1. Considering that nanomolar concentrations of AA or 2-AG were sufficient to impair viral infectivity, this suggests potential physiological roles for 2-AG and AA as regulators of host defense in vivo.
Insulin Has Multiple Antiamyloidogenic Effects on Human Neuronal Cells
Authors: Pandini Giuseppe , Pace Vincenza , Copani Agata , Squatrito Sebastiano , Milardi Danilo , Vigneri Riccardo
Published: December 2012

Alzheimer’s disease is increased in diabetic patients. A defective insulin activity on the brain has been hypothesized to contribute to the neuronal cell dysregulation leading to AD, but the mechanism is not clear. We analyzed the effect of insulin on several molecular steps of amyloid precursor protein (APP) processing and β-amyloid (Aβ) intracellular accumulation in a panel of human neuronal cells and in human embryonic kidney 293 cells overexpressing APP-695. The data indicate that insulin, via its own receptor and the phosphatidylinositol-3-kinase/AKT pathway, influences APP phosphorylation at different sites. This rapid-onset, dose-dependent effect lasts many hours and mainly concerns dephosphorylation at the APP-T668 site. This effect of insulin was confirmed also in a human cortical neuronal cell line and in rat primary neurons. Cell fractionation and immunofluorescence studies indicated that insulin-induced APP-T668 dephosphorylation prevents the translocation of the APP intracellular domain fragment into the nucleus. As a consequence, insulin increases the transcription of antiamyloidogenic proteins such as the insulin-degrading enzyme, involved in Aβ degradation, and α-secretase. In contrast, the transcripts of pro-amyloidogenic proteins such as APP, β-secretase, and glycogen synthase kinase (Gsk)-3β are decreased. Moreover, cell exposure to insulin favors the nonamyloidogenic, α-secretase-dependent APP-processing pathway and reduces Aβ40 and Aβ42 intracellular accumulation, promoting their release in the extracellular compartment. The latter effects of insulin are independent of both Gsk-3β phosphorylation and APP-T668 dephosphorylation, as indicated by experiments with Gsk-3β inhibitors and with cells transfected with the nonphosphorylatable mutated APP-T668A analog. In human neuronal cells, therefore, insulin may prevent Aβ formation and accumulation by multiple mechanisms, both Gsk-3β dependent and independent.