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1.  Immunotherapy using slow-cycling tumor cells prolonged overall survival of tumor-bearing mice 
BMC Medicine  2012;10:172.
Background
Despite considerable progress in the development of anticancer therapies, there is still a high mortality rate caused by cancer relapse and metastasis. Dormant or slow-cycling residual tumor cells are thought to be a source of tumor relapse and metastasis, and are therefore an obstacle to therapy. In this study, we assessed the drug resistance of tumor cells in mice, and investigated whether vaccination could promote survival.
Methods
The mouse colon carcinoma cell line CT-26 was treated with 5-fluorouracil to assess its sensitivity to drug treatment. Mice with colon tumors were immunized with inactivated slow-cycling CT-26 cells to estimate the efficacy of this vaccine.
Results
We identified a small population of slow-cycling tumor cells in the mouse colon carcinoma CT-26 cell line, which was resistant to conventional chemotherapy. To inhibit tumor recurrence and metastasis more effectively, treatments that selectively target the slow-cycling tumor cells should be developed to complement conventional therapies. We found that drug-treated, slow-cycling tumor cells induced a more intense immune response in vitro. Moreover, vaccination with inactivated slow-cycling tumor cells caused a reduction in tumor volume and prolonged the overall survival of tumor-bearing mice.
Conclusions
These findings suggest that targeting of slow-cycling tumor cells application using immunotherapy is a possible treatment to complement traditional antitumor therapy.
doi:10.1186/1741-7015-10-172
PMCID: PMC3568736  PMID: 23270473
cancer relapse; drug resistance; slow-cycling tumor cells; tumor vaccine
2.  Substantial and reversible brain gray matter reduction but no acute brain lesions in ultramarathon runners: experience from the TransEurope-FootRace Project 
BMC Medicine  2012;10:170.
Background
During the extremely challenging 4,487 km ultramarathon TransEurope-FootRace 2009, runners showed considerable reduction of body weight. The effects of this endurance run on brain volume changes but also possible formation of brain edema or new lesions were explored by repeated magnetic resonance imaging (MRI) studies.
Methods
A total of 15 runners signed an informed consent to participate in this study of planned brain scans before, twice during, and about 8 months after the race. Because of dropouts, global gray matter volume analysis could only be performed in ten runners covering three timepoints, and in seven runners who also had a follow-up scan. Scanning was performed on three identical 1.5 T Siemens MAGNETOM Avanto scanners, two of them located at our university. The third MRI scanner with identical sequence parameters was a mobile MRI unit escorting the runners. Volumetric 3D datasets were acquired using a magnetization prepared rapid acquisition gradient echo (MPRAGE) sequence. Additionally, diffusion-weighted (DWI) and fluid attenuated inversion recovery (FLAIR) imaging was performed.
Results
Average global gray matter volume as well as body weight significantly decreased by 6% during the race. After 8 months, gray matter volume returned to baseline as well as body weight. No new brain lesions were detected by DWI or FLAIR imaging.
Conclusions
Physiological brain volume reduction during aging is less than 0.2% per year. Therefore a volume reduction of about 6% during the 2 months of extreme running appears to be substantial. The reconstitution in global volume measures after 8 months shows the process to be reversible. As possible mechanisms we discuss loss of protein, hypercortisolism and hyponatremia to account for both substantiality and reversibility of gray matter volume reductions. Reversible brain volume reduction during an ultramarathon suggests that extreme running might serve as a model to investigate possible mechanisms of transient brain volume changes. However, despite massive metabolic load, we found no new lesions in trained athletes participating in a multistage ultramarathon.
See related commentary http://www.biomedcentral.com/1741-7015/10/171
doi:10.1186/1741-7015-10-170
PMCID: PMC3566943  PMID: 23259507
body weight; brain volume; catabolism; DWI; lesion; MRI; ultramarathon
3.  Evidence from neuroimaging to explore brain plasticity in humans during an ultra-endurance burden 
BMC Medicine  2012;10:171.
Physical activity, likely through induction of neuroplasticity, is a promising intervention to promote brain health. In athletes it is clear that training can and does, by physiological adaptations, extend the frontiers of performance capacity. The limits of our endurance capacity lie deeply in the human brain, determined by various personal factors yet to be explored. The human brain, with its vast neural connections and its potential for seemingly endless behaviors, constitutes one of the final frontiers of medicine. In a recent study published in BMC Medicine, the TransEurope FootRace Project followed 10 ultra-endurance runners over around 4,500 km across Europe and recorded a large data collection of brain imaging scans. This study indicates that the cerebral atrophy amounting to a reduction of approximately 6% throughout the two months of the race is reversed upon follow-up. While this study will contribute to advances in the limits of human performance on the neurophysiological processes in sports scientists, it will also bring important understanding to clinicians about cerebral atrophy in people who are vulnerable to physical and psychological stress long term.
See related research article http://www.biomedcentral.com/1741-7015/10/170
doi:10.1186/1741-7015-10-171
PMCID: PMC3566949  PMID: 23259535
cerebral atrophy; exercise behavior; fatigue; overload; plasticity; running
4.  Cycling and bone health: a systematic review 
BMC Medicine  2012;10:168.
Background
Cycling is considered to be a highly beneficial sport for significantly enhancing cardiovascular fitness in individuals, yet studies show little or no corresponding improvements in bone mass.
Methods
A scientific literature search on studies discussing bone mass and bone metabolism in cyclists was performed to collect all relevant published material up to April 2012. Descriptive, cross-sectional, longitudinal and interventional studies were all reviewed. Inclusion criteria were met by 31 studies.
Results
Heterogeneous studies in terms of gender, age, data source, group of comparison, cycling level or modality practiced among others factors showed minor but important differences in results. Despite some controversial results, it has been observed that adult road cyclists participating in regular training have low bone mineral density in key regions (for example, lumbar spine). Conversely, other types of cycling (such as mountain biking), or combination with other sports could reduce this unsafe effect. These results cannot yet be explained by differences in dietary patterns or endocrine factors.
Conclusions
From our comprehensive survey of the current available literature it can be concluded that road cycling does not appear to confer any significant osteogenic benefit. The cause of this may be related to spending long hours in a weight-supported position on the bike in combination with the necessary enforced recovery time that involves a large amount of time sitting or lying supine, especially at the competitive level.
doi:10.1186/1741-7015-10-168
PMCID: PMC3554602  PMID: 23256921
cyclists; osteopenia; osteoporosis; sport; training
5.  Bike racing, recreational riding, impact sport and bone health 
BMC Medicine  2012;10:169.
Cycling has been shown to confer considerable benefits in terms of health, leading to reductions in death rates principally due to cardiovascular improvements and adaptation.
Given the disparity between the benefits of cycling on cardiovascular fitness and previous research finding that cycling may not be beneficial for bone health, Hugo Olmedillas and colleagues performed a systematic review of the literature. They concluded that road cycling does not appear to confer any significant osteogenic benefit. They postulate that the cause of this is that, particularly at a competitive level, riders spend long periods of time in a weight-supported position on the bike.
Training programs may be supplemented with impact loading to preserve bone health; however, the small increased risk of soft tissue injury must also be considered.
See related commentary http://www.biomedcentral.com/1741-7015/10/168
doi:10.1186/1741-7015-10-169
PMCID: PMC3568009  PMID: 23256478
cycling; mountain biking; osteoporosis; anterior cruciate ligament
6.  Exercise therapy for bone and muscle health: an overview of systematic reviews 
BMC Medicine  2012;10:167.
Background
Musculoskeletal conditions (MSCs) are widely prevalent in present-day society, with resultant high healthcare costs and substantial negative effects on patient health and quality of life. The main aim of this overview was to synthesize evidence from systematic reviews on the effects of exercise therapy (ET) on pain and physical function for patients with MSCs. In addition, the evidence for the effect of ET on disease pathogenesis, and whether particular components of exercise programs are associated with the size of the treatment effects, was also explored.
Methods
We included four common conditions: fibromyalgia (FM), low back pain (LBP), neck pain (NP), and shoulder pain (SP), and four specific musculoskeletal diseases: osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and osteoporosis (OP). We first included Cochrane reviews with the most recent update being January 2007 or later, and then searched for non-Cochrane reviews published after this date. Pain and physical functioning were selected as primary outcomes.
Results
We identified 9 reviews, comprising a total of 224 trials and 24,059 patients. In addition, one review addressing the effect of exercise on pathogenesis was included. Overall, we found solid evidence supporting ET in the management of MSCs, but there were substantial differences in the level of research evidence between the included diagnostic groups. The standardized mean differences for knee OA, LBP, FM, and SP varied between 0.30 and 0.65 and were significantly in favor of exercise for both pain and function. For NP, hip OA, RA, and AS, the effect estimates were generally smaller and not always significant. There was little or no evidence that ET can influence disease pathogenesis. The only exception was for osteoporosis, where there was evidence that ET increases bone mineral density in postmenopausal women, but no significant effects were found for clinically relevant outcomes (fractures). For LBP and knee OA, there was evidence suggesting that the treatment effect increases with the number of exercise sessions.
Conclusions
There is empirical evidence that ET has beneficial clinical effects for most MSCs. Except for osteoporosis, there seems to be a gap in the understanding of the ways in which ET influences disease mechanisms.
doi:10.1186/1741-7015-10-167
PMCID: PMC3568719  PMID: 23253613
fibromyalgia; low back pain; neck pain; shoulder pain; osteoarthritis; rheumatoid arthritis; ankylosing spondylitis; osteoporosis; pain; physical function
7.  Pre-cooling for endurance exercise performance in the heat: a systematic review 
BMC Medicine  2012;10:166.
Background
Endurance exercise capacity diminishes under hot environmental conditions. Time to exhaustion can be increased by lowering body temperature prior to exercise (pre-cooling). This systematic literature review synthesizes the current findings of the effects of pre-cooling on endurance exercise performance, providing guidance for clinical practice and further research.
Methods
The MEDLINE, EMBASE, CINAHL, Web of Science and SPORTDiscus databases were searched in May 2012 for studies evaluating the effectiveness of pre-cooling to enhance endurance exercise performance in hot environmental conditions (≥ 28°C). Studies involving participants with increased susceptibility to heat strain, cooling during or between bouts of exercise, and protocols where aerobic endurance was not the principle performance outcome were excluded. Potential publications were assessed by two independent reviewers for inclusion and quality. Means and standard deviations of exercise performance variables were extracted or sought from original authors to enable effect size calculations.
Results
In all, 13 studies were identified. The majority of studies contained low participant numbers and/or absence of sample size calculations. Six studies used cold water immersion, four crushed ice ingestion and three cooling garments. The remaining study utilized mixed methods. Large heterogeneity in methodological design and exercise protocols was identified. Effect size calculations indicated moderate evidence that cold water immersion effectively improved endurance performance, and limited evidence that ice slurry ingestion improved performance. Cooling garments were ineffective. Most studies failed to document or report adverse events. Low participant numbers in each study limited the statistical power of certain reported trends and lack of blinding could potentially have introduced either participant or researcher bias in some studies.
Conclusions
Current evidence indicates cold water immersion may be the most effective method of pre-cooling to improve endurance performance in hot conditions, although practicality must be considered. Ice slurry ingestion appears to be the most promising practical alternative. Interestingly, cooling garments appear of limited efficacy, despite their frequent use. Mechanisms behind effective pre-cooling remain uncertain, and optimal protocols have yet to be established. Future research should focus on standardizing exercise performance protocols, recruiting larger participant numbers to enable direct comparisons of effectiveness and practicality for each method, and ensuring potential adverse events are evaluated.
doi:10.1186/1741-7015-10-166
PMCID: PMC3568721  PMID: 23249542
Pacing; thermoregulation; internal cooling; cooling garment; cold water immersion; ice slurry ingestion
8.  Real-time numerical forecast of global epidemic spreading: case study of 2009 A/H1N1pdm 
BMC Medicine  2012;10:165.
Background
Mathematical and computational models for infectious diseases are increasingly used to support public-health decisions; however, their reliability is currently under debate. Real-time forecasts of epidemic spread using data-driven models have been hindered by the technical challenges posed by parameter estimation and validation. Data gathered for the 2009 H1N1 influenza crisis represent an unprecedented opportunity to validate real-time model predictions and define the main success criteria for different approaches.
Methods
We used the Global Epidemic and Mobility Model to generate stochastic simulations of epidemic spread worldwide, yielding (among other measures) the incidence and seeding events at a daily resolution for 3,362 subpopulations in 220 countries. Using a Monte Carlo Maximum Likelihood analysis, the model provided an estimate of the seasonal transmission potential during the early phase of the H1N1 pandemic and generated ensemble forecasts for the activity peaks in the northern hemisphere in the fall/winter wave. These results were validated against the real-life surveillance data collected in 48 countries, and their robustness assessed by focusing on 1) the peak timing of the pandemic; 2) the level of spatial resolution allowed by the model; and 3) the clinical attack rate and the effectiveness of the vaccine. In addition, we studied the effect of data incompleteness on the prediction reliability.
Results
Real-time predictions of the peak timing are found to be in good agreement with the empirical data, showing strong robustness to data that may not be accessible in real time (such as pre-exposure immunity and adherence to vaccination campaigns), but that affect the predictions for the attack rates. The timing and spatial unfolding of the pandemic are critically sensitive to the level of mobility data integrated into the model.
Conclusions
Our results show that large-scale models can be used to provide valuable real-time forecasts of influenza spreading, but they require high-performance computing. The quality of the forecast depends on the level of data integration, thus stressing the need for high-quality data in population-based models, and of progressive updates of validated available empirical knowledge to inform these models.
doi:10.1186/1741-7015-10-165
PMCID: PMC3585792  PMID: 23237460
computational epidemiology; H1N1 influenza pandemic; prediction; validation.
9.  The age distribution of mortality due to influenza: pandemic and peri-pandemic 
BMC Medicine  2012;10:162.
Background
Pandemic influenza is said to 'shift mortality' to younger age groups; but also to spare a subpopulation of the elderly population. Does one of these effects dominate? Might this have important ramifications?
Methods
We estimated age-specific excess mortality rates for all-years for which data were available in the 20th century for Australia, Canada, France, Japan, the UK, and the USA for people older than 44 years of age. We modeled variation with age, and standardized estimates to allow direct comparison across age groups and countries. Attack rate data for four pandemics were assembled.
Results
For nearly all seasons, an exponential model characterized mortality data extremely well. For seasons of emergence and a variable number of seasons following, however, a subpopulation above a threshold age invariably enjoyed reduced mortality. 'Immune escape', a stepwise increase in mortality among the oldest elderly, was observed a number of seasons after both the A(H2N2) and A(H3N2) pandemics. The number of seasons from emergence to escape varied by country. For the latter pandemic, mortality rates in four countries increased for younger age groups but only in the season following that of emergence. Adaptation to both emergent viruses was apparent as a progressive decrease in mortality rates, which, with two exceptions, was seen only in younger age groups. Pandemic attack rate variation with age was estimated to be similar across four pandemics with very different mortality impact.
Conclusions
In all influenza pandemics of the 20th century, emergent viruses resembled those that had circulated previously within the lifespan of then-living people. Such individuals were relatively immune to the emergent strain, but this immunity waned with mutation of the emergent virus. An immune subpopulation complicates and may invalidate vaccine trials. Pandemic influenza does not 'shift' mortality to younger age groups; rather, the mortality level is reset by the virulence of the emerging virus and is moderated by immunity of past experience. In this study, we found that after immune escape, older age groups showed no further mortality reduction, despite their being the principal target of conventional influenza vaccines. Vaccines incorporating variants of pandemic viruses seem to provide little benefit to those previously immune. If attack rates truly are similar across pandemics, it must be the case that immunity to the pandemic virus does not prevent infection, but only mitigates the consequences.
doi:10.1186/1741-7015-10-162
PMCID: PMC3554498  PMID: 23234604
Pandemic influenza; mortality due to influenza; recycling; pandemic attack rates; vaccination; protective immunity
10.  Breast cancer screening: evidence of benefit depends on the method used 
BMC Medicine  2012;10:163.
In this article, we discuss the most common epidemiological methods used for evaluating the ability of mammography screening to decrease the risk of breast cancer death in general populations (effectiveness). Case-control studies usually find substantial effectiveness. However when breast cancer mortality decreases for reasons unrelated to screening, the case-control design may attribute to screening mortality reductions due to other causes. Studies based on incidence-based mortality have obtained contrasted results compatible with modest to considerable effectiveness, probably because of differences in study design and statistical analysis. In areas where screening has been widespread for a long time, the incidence of advanced breast cancer should be decreasing, which in turn would translate into reduced mortality. However, no or modest declines in the incidence of advanced breast cancer has been observed in these areas. Breast cancer mortality should decrease more rapidly in areas with early introduction of screening than in areas with late introduction of screening. Nonetheless, no difference in breast mortality trends has been observed between areas with early or late screening start. When effectiveness is assessed using incidence-based mortality studies, or the monitoring of advanced cancer incidence, or trends in mortality, the ecological bias is an inherent limitation that is not easy to control. Minimization of this bias requires data over long periods of time, careful selection of populations being compared and availability of data on major confounding factors. If case-control studies seem apparently more adequate for evaluating screening effectiveness, this design has its own limitations and results must be viewed with caution.
See related Opinion article: http://www.biomedcentral.com/1741-7015/10/106 and Commentary http://www.biomedcentral.com/1741-7015/10/164
doi:10.1186/1741-7015-10-163
PMCID: PMC3554519  PMID: 23234249
breast cancer; case-control; effectiveness; epidemiology; incidence; mortality; screening
11.  Mammographic screening debate on study design: a need to move the field forward 
BMC Medicine  2012;10:164.
The mammographic screening debate has been running for decades. The temperature of this debate is unusually high, and all participants, regardless of viewpoint, seem to have a conflict of interest. Another unusual aspect of this debate is the focus on study design, and in particular on designs that some think exceeded their usefulness decades ago. What are the questions that remain to be answered in this debate? Are there methodological issues that have not been adequately addressed? Do we have the right tools to provide up-to-date answers to how women can best protect themselves against dying from breast cancer? This commentary discusses some of the current issues.
See related Opinion articles http://www.biomedcentral.com/1741-7015/10/106 and http://www.biomedcentral.com/1741-7015/10/163
doi:10.1186/1741-7015-10-164
PMCID: PMC3599232  PMID: 23234258
breast cancer; mammographic screening; study design
12.  Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment 
BMC Medicine  2012;10:161.
The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer. In recent years, the results of the first phase I clinical trials with PI3K inhibitors have become available. In comparison to other targeted agents such v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors in melanoma or crizotinib in anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors, the number of objective responses to PI3K inhibitors is less dramatic. In this review we propose possible strategies to optimize the clinical development of PI3K inhibitors: by exploring the potential role of PI3K isoform-specific inhibitors in improving the therapeutic index, molecular characterization as a basis for patient selection, and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug resistance. The main focus of this review will be on PI3K isoform-specific inhibitors by describing the functions of different PI3K isoforms, the preclinical activity of selective PI3K isoform-specific inhibitors and the early clinical data of these compounds.
doi:10.1186/1741-7015-10-161
PMCID: PMC3552942  PMID: 23232172
PI3K; isoform; neoplasm; patient selection; clinical trials; cancer
13.  Passive smoking, invasive meningococcal disease and preventive measures: a commentary 
BMC Medicine  2012;10:160.
Active smoking is a recognized risk factor of various infectious diseases. In a systematic review published in BMC Public Health, Murray et al. demonstrated that exposure to passive smoking significantly increased the risk of meningococcal disease among children. Their review especially highlights that the risk remains high even if the exposure occurs during pregnancy or after birth, although the authors could not disentangle the independent effects of smoking during pregnancy from those in the postnatal period. How passive smoking increases the risk of childhood meningococcal disease is not precisely known. Both exposure to 'smoke', or 'smokers' (who are highly susceptible to pharyngeal carriage of meningococci) are postulated mechanisms, but unfortunately very few studies have examined the risk of exposure by considering these two variables separately, and this therefore remains a research priority. Quitting may well be the mainstay of preventing tobacco-related hazards but the available global data suggest that most smokers are reluctant to quit. Among other interventions, immunizing children with a meningococcal conjugate vaccine could, theoretically, reduce the risk of meningococcal disease among children and their smoker household contacts through herd immunity.
See related article http://www.biomedcentral.com/1471-2458/12/1062
doi:10.1186/1741-7015-10-160
PMCID: PMC3568012  PMID: 23228079
Conjugate meningococcal vaccine; invasive meningococcal disease; meningococcal carriage; passive smoking; quitting ratio
14.  Modeling rapidly disseminating infectious disease during mass gatherings 
BMC Medicine  2012;10:159.
We discuss models for rapidly disseminating infectious diseases during mass gatherings (MGs), using influenza as a case study. Recent innovations in modeling and forecasting influenza transmission dynamics at local, regional, and global scales have made influenza a particularly attractive model scenario for MG. We discuss the behavioral, medical, and population factors for modeling MG disease transmission, review existing model formulations, and highlight key data and modeling gaps related to modeling MG disease transmission. We argue that the proposed improvements will help integrate infectious-disease models in MG health contingency plans in the near future, echoing modeling efforts that have helped shape influenza pandemic preparedness plans in recent years.
doi:10.1186/1741-7015-10-159
PMCID: PMC3532170  PMID: 23217051
Model; mathematical; epidemic; outbreaks; epidemiology; mass gathering; school closure; clustering; reactive vaccination; movement; social networks/
15.  Validation of a model to investigate the effects of modifying cardiovascular disease (CVD) risk factors on the burden of CVD: the rotterdam ischemic heart disease and stroke computer simulation (RISC) model 
BMC Medicine  2012;10:158.
Background
We developed a Monte Carlo Markov model designed to investigate the effects of modifying cardiovascular disease (CVD) risk factors on the burden of CVD. Internal, predictive, and external validity of the model have not yet been established.
Methods
The Rotterdam Ischemic Heart Disease and Stroke Computer Simulation (RISC) model was developed using data covering 5 years of follow-up from the Rotterdam Study. To prove 1) internal and 2) predictive validity, the incidences of coronary heart disease (CHD), stroke, CVD death, and non-CVD death simulated by the model over a 13-year period were compared with those recorded for 3,478 participants in the Rotterdam Study with at least 13 years of follow-up. 3) External validity was verified using 10 years of follow-up data from the European Prospective Investigation of Cancer (EPIC)-Norfolk study of 25,492 participants, for whom CVD and non-CVD mortality was compared.
Results
At year 5, the observed incidences (with simulated incidences in brackets) of CHD, stroke, and CVD and non-CVD mortality for the 3,478 Rotterdam Study participants were 5.30% (4.68%), 3.60% (3.23%), 4.70% (4.80%), and 7.50% (7.96%), respectively. At year 13, these percentages were 10.60% (10.91%), 9.90% (9.13%), 14.20% (15.12%), and 24.30% (23.42%). After recalibrating the model for the EPIC-Norfolk population, the 10-year observed (simulated) incidences of CVD and non-CVD mortality were 3.70% (4.95%) and 6.50% (6.29%). All observed incidences fell well within the 95% credibility intervals of the simulated incidences.
Conclusions
We have confirmed the internal, predictive, and external validity of the RISC model. These findings provide a basis for analyzing the effects of modifying cardiovascular disease risk factors on the burden of CVD with the RISC model.
doi:10.1186/1741-7015-10-158
PMCID: PMC3566939  PMID: 23217019
Cardiovascular disease prevention; Simulation modeling; Model validation
16.  Serum protein profiles predict coronary artery disease in symptomatic patients referred for coronary angiography 
BMC Medicine  2012;10:157.
Background
More than a million diagnostic cardiac catheterizations are performed annually in the US for evaluation of coronary artery anatomy and the presence of atherosclerosis. Nearly half of these patients have no significant coronary lesions or do not require mechanical or surgical revascularization. Consequently, the ability to rule out clinically significant coronary artery disease (CAD) using low cost, low risk tests of serum biomarkers in even a small percentage of patients with normal coronary arteries could be highly beneficial.
Methods
Serum from 359 symptomatic subjects referred for catheterization was interrogated for proteins involved in atherogenesis, atherosclerosis, and plaque vulnerability. Coronary angiography classified 150 patients without flow-limiting CAD who did not require percutaneous intervention (PCI) while 209 required coronary revascularization (stents, angioplasty, or coronary artery bypass graft surgery). Continuous variables were compared across the two patient groups for each analyte including calculation of false discovery rate (FDR ≤ 1%) and Q value (P value for statistical significance adjusted to ≤ 0.01).
Results
Significant differences were detected in circulating proteins from patients requiring revascularization including increased apolipoprotein B100 (APO-B100), C-reactive protein (CRP), fibrinogen, vascular cell adhesion molecule 1 (VCAM-1), myeloperoxidase (MPO), resistin, osteopontin, interleukin (IL)-1β, IL-6, IL-10 and N-terminal fragment protein precursor brain natriuretic peptide (NT-pBNP) and decreased apolipoprotein A1 (APO-A1). Biomarker classification signatures comprising up to 5 analytes were identified using a tunable scoring function trained against 239 samples and validated with 120 additional samples. A total of 14 overlapping signatures classified patients without significant coronary disease (38% to 59% specificity) while maintaining 95% sensitivity for patients requiring revascularization. Osteopontin (14 times) and resistin (10 times) were most frequently represented among these diagnostic signatures. The most efficacious protein signature in validation studies comprised osteopontin (OPN), resistin, matrix metalloproteinase 7 (MMP7) and interferon γ (IFNγ) as a four-marker panel while the addition of either CRP or adiponectin (ACRP-30) yielded comparable results in five protein signatures.
Conclusions
Proteins in the serum of CAD patients predominantly reflected (1) a positive acute phase, inflammatory response and (2) alterations in lipid metabolism, transport, peroxidation and accumulation. There were surprisingly few indicators of growth factor activation or extracellular matrix remodeling in the serum of CAD patients except for elevated OPN. These data suggest that many symptomatic patients without significant CAD could be identified by a targeted multiplex serum protein test without cardiac catheterization thereby eliminating exposure to ionizing radiation and decreasing the economic burden of angiographic testing for these patients.
doi:10.1186/1741-7015-10-157
PMCID: PMC3566965  PMID: 23216991
atherosclerosis; biomarkers; cardiac catheterization; coronary angiography; coronary stenosis; multiplex proteomics
17.  Data-driven subtypes of major depressive disorder: a systematic review 
BMC Medicine  2012;10:156.
Background
According to current classification systems, patients with major depressive disorder (MDD) may have very different combinations of symptoms. This symptomatic diversity hinders the progress of research into the causal mechanisms and treatment allocation. Theoretically founded subtypes of depression such as atypical, psychotic, and melancholic depression have limited clinical applicability. Data-driven analyses of symptom dimensions or subtypes of depression are scarce. In this systematic review, we examine the evidence for the existence of data-driven symptomatic subtypes of depression.
Methods
We undertook a systematic literature search of MEDLINE, PsycINFO and Embase in May 2012. We included studies analyzing the depression criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) of adults with MDD in latent variable analyses.
Results
In total, 1176 articles were retrieved, of which 20 satisfied the inclusion criteria. These reports described a total of 34 latent variable analyses: 6 confirmatory factor analyses, 6 exploratory factor analyses, 12 principal component analyses, and 10 latent class analyses. The latent class techniques distinguished 2 to 5 classes, which mainly reflected subgroups with different overall severity: 62 of 71 significant differences on symptom level were congruent with a latent class solution reflecting severity. The latent class techniques did not consistently identify specific symptom clusters. Latent factor techniques mostly found a factor explaining the variance in the symptoms depressed mood and interest loss (11 of 13 analyses), often complemented by psychomotor retardation or fatigue (8 of 11 analyses). However, differences in found factors and classes were substantial.
Conclusions
The studies performed to date do not provide conclusive evidence for the existence of depressive symptom dimensions or symptomatic subtypes. The wide diversity of identified factors and classes might result either from the absence of patterns to be found, or from the theoretical and modeling choices preceding analysis.
doi:10.1186/1741-7015-10-156
PMCID: PMC3566979  PMID: 23210727
Major depressive disorder; subtypes; depressive symptoms; latent factor analyses; latent class analyses
18.  Personalized medicine and atrial fibrillation: will it ever happen? 
BMC Medicine  2012;10:155.
Atrial fibrillation (AF) is a common arrhythmia of substantial public health importance. Recent evidence demonstrates a heritable component underlying AF, and genetic discoveries have identified common variants associated with the arrhythmia. Ultimately one hopes that the consideration of genetic variation in clinical practice may enhance care and improve health outcomes. In this review we explore areas of potential clinical utility in AF management including those relating to pharmacogenetics and risk prediction.
doi:10.1186/1741-7015-10-155
PMCID: PMC3568716  PMID: 23210687
Atrial fibrillation; genetics; personalized medicine; risk prediction; pharmacogenetics
19.  The impact of statins on psychological wellbeing: a systematic review and meta-analysis 
BMC Medicine  2012;10:154.
Background
Cholesterol-lowering medications such as statins have anti-inflammatory and antioxidant properties, which may be beneficial for treating depression and improving mood. However, evidence regarding their effects remains inconsistent, with some studies reporting links to mood disturbances. We aimed to conduct a meta-analysis to determine the impact of statins on psychological wellbeing of individuals with or without hypercholesterolemia.
Methods
Articles were identified using medical, health, psychiatric and social science databases, evaluated for quality, and data were synthesized and analyzed in RevMan-5 software using a random effects model.
Results
The 7 randomized controlled trials included in the analysis represented 2,105 participants. A test for overall effect demonstrated no statistically significant differences in psychological wellbeing between participants receiving statins or a placebo (standardized mean difference (SMD) = -0.08, 95% CI -0.29 to 0.12; P = 0.42). Sensitivity analyses were conducted to separately analyze depression (n = 5) and mood (n = 2) outcomes; statins were associated with statistically significant improvements in mood scores (SMD = -0.43, 95% CI -0.61 to -0.24).
Conclusions
Our findings refute evidence of negative effects of statins on psychological outcomes, providing some support for mood-related benefits. Future studies could examine the effects of statins in depressed populations.
doi:10.1186/1741-7015-10-154
PMCID: PMC3568015  PMID: 23206308
anti-inflammatory; cytokines; depression; hypercholesterolemia; mood; oxidative; statins
20.  Comparison of efficacy between incretin-based therapies for type 2 diabetes mellitus 
BMC Medicine  2012;10:152.
Type 2 diabetes mellitus is widely prevalent and is often coexistent with obesity. Many of the available treatment options have side effects such as weight gain which often affect patient's willingness to continue the treatment. Effective weight loss, lack of significant hypoglycaemia, and favourable cardiometabolic profile make Incretin based therapies an attractive treatment option for type 2 diabetes. Incretin based therapies are available as either incretin mimetics (also called GLP-1 agonists) or incretin enhancers (DPP-4 inhibitors). Although agents in both these classes of incretin based therapy are effective through a common GLP-1 pathway, there are many differences amongst them including the route of administration, frequency of administration, effects on body weight, extent of glycaemic improvement. There are several trials evaluating these individual incretin based agents either as monotherapy or in combination with other anti-diabetic agents, however very few have looked into direct comparison amongst the agents in these two classes. This review is aimed to look at important mechanistic differences between incretin mimetics and enhancers through direct comparison trials and impact of these differences on biochemical, metabolic and patient satisfaction parameters.
doi:10.1186/1741-7015-10-152
PMCID: PMC3599222  PMID: 23198896
GLP-1 analogues; GLP-1 agonists; DPP-4 inhibitors; incretins; head to head comparison; patient satisfaction
21.  Metabolic profiles characterizing different phenotypes of polycystic ovary syndrome: plasma metabolomics analysis 
BMC Medicine  2012;10:153.
Background
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied with an increased risk of developing type 2 diabetes mellitus and cardiovascular disease; despite being a common condition, the pathogenesis of PCOS remains unclear. Our aim was to investigate the potential metabolic profiles for different phenotypes of PCOS, as well as for the early prognosis of complications.
Methods
A total of 217 women with PCOS and 48 healthy women as normal controls were studied. Plasma samples of subjects were tested using two different analytical platforms of metabolomics: 1H nuclear magnetic resonance (NMR) and gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS).
Results
Our results showed that carbohydrate, lipid and amino acid metabolisms were influenced in PCOS. The levels of lactate, long-chain fatty acids, triglyceride and very low-density lipoprotein were elevated, while glucose, phosphatidylcholine and high-density lipoprotein (HDL) concentrations were reduced in PCOS patients as compared with controls. Additionally, the levels of alanine, valine, serine, threonine, ornithine, phenylalanine, tyrosine and tryptophan were generally increased, whereas the levels of glycine and proline were significantly reduced in PCOS samples compared to controls. Furthermore, the ratio of branched-chain amino acid to aromatic amino acid concentrations (BCAA/AAA) in PCOS plasma was significantly reduced in PCOS patients and was insusceptible to obesity and insulin sensitivity.
Conclusions
Our results suggested that the enhanced glycolysis and inhibited tricarboxylic acid cycle (TAC) in women with PCOS. Decrease of BCAA/AAA ratio was directly correlated with the development of PCOS. Ovulatory dysfunction of PCOS patients was associated with raised production of serine, threonine, phenylalanine, tyrosine and ornithine. Elevated levels of valine and leucine, and decreased concentrations of glycine in PCOS plasma could contribute to insulin sensitivity and could be considered as the potential biomarkers for long-term risk assessment of diabetes mellitus.
doi:10.1186/1741-7015-10-153
PMCID: PMC3599233  PMID: 23198915
polycystic ovary syndrome; amino acid metabolism; carbohydrate and lipid metabolism; insulin resistance; inflammation
22.  Increased risk of affective disorders in type 2 diabetes is minimized by sulfonylurea and metformin combination: a population-based cohort study 
BMC Medicine  2012;10:150.
Background
To confirm whether type 2 diabetes (T2DM) is an affective disorder (AD) precursor, and to establish possible effects of oral anti-hyperglycemic agents (OAAs).
Methods
A representative cohort of 800,000 subjects was obtained from the Taiwanese National Health Insurance database on 1 January 2000. Those with consistent data (n = 762,753) were followed up between 1 January 1996 and 31 December 2007. Over this period, we assessed the presence (n = 62,988) or absence (n = 699,795) of T2DM, and whether any OAA was used (n = 40,232) or not (n = 22,756). To compare the risk of AD by diabetic status, those with T2DM were matched for birth date and gender with those without T2DM. To assess the effect of OAAs, we considered those 50 years and over. Matched AD-free patients with T2DM on OAAs were compared with those without OAAs, for age, gender, locality, health service, Charlson Comorbidity Index. and diabetes diagnosis date to avoid immortal time bias. AD incidence densities, hazard ratios (HR) and 95% confidence intervals (CIs) were calculated.
Results
Compared with diabetes-free subjects, the HR (95% CI) for AD was 2.62 (2.31 to 2.98) for patients with T2DM who were not on OAAs, and 1.08 (0.99 to 1.18) for those who were on OAAs. The AD incidence density decreased from 91.1 to 39.4 per 10,000 person-years for patients on the combination of metformin and sulfonylurea. The HR (95% CI) for AD was 0.92 (0.59 to 1.45) for those on metformin alone, 1.08 (0.84 to 1.38) for those on sulfonylurea alone, and 0.40 (0.32 to 0.50) for the combined treatment, and the decrease was not related to sequence or insulin usage. Similar patterns were seen for incident AD exclusion for up to 3 years, although more so for bipolar than unipolar.
Conclusions
The incident AD risk is increased by 2.6-fold in T2DM, and the combination of sulfonylurea and metformin minimizes this risk.
doi:10.1186/1741-7015-10-150
PMCID: PMC3529194  PMID: 23194378
Neurodegenerative disease; Taiwan; Mood; Depression; Metformin
23.  Pathways to new drug discovery in neuropsychiatry 
BMC Medicine  2012;10:151.
There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success.
See related article http://www.biomedcentral.com/1741-7015/10/150
doi:10.1186/1741-7015-10-151
PMCID: PMC3566919  PMID: 23194414
depression; bipolar disorder; diabetes; treatment; drug discovery; pathophysiology
24.  Moving towards a population health approach to the primary prevention of common mental disorders 
BMC Medicine  2012;10:149.
There is a need for the development of effective universal preventive approaches to the common mental disorders, depression and anxiety, at a population level. Poor diet, physical inactivity and smoking have long been recognized as key contributors to the high prevalence noncommunicable diseases. However, there are now an increasing number of studies suggesting that the same modifiable lifestyle behaviors are also risk factors for common mental disorders. In this paper we point to the emerging data regarding lifestyle risk factors for common mental disorders, with a particular focus on and critique of the newest evidence regarding diet quality. On the basis of this most recent evidence, we consequently argue for the inclusion of depression and anxiety in the ranks of the high prevalence noncommunicable diseases influenced by habitual lifestyle practices. We believe that it is both feasible and timely to begin to develop effective, sustainable, population-level prevention initiatives for the common mental illnesses that build on the established and developing approaches to the noncommunicable somatic diseases.
doi:10.1186/1741-7015-10-149
PMCID: PMC3534562  PMID: 23186355
Anxiety; etiology; common mental disorders; diet; depression; lifestyle; physical activity; prevention; risk; smoking
25.  Co-prescription of medication for bipolar disorder and diabetes mellitus: a nationwide population-based study with focus on gender differences 
BMC Medicine  2012;10:148.
Background
Studies have shown a correlation between bipolar disorder and diabetes mellitus. It is unclear if this correlation is a part of common pathophysiological pathways, or if medication for bipolar disorder has negative effects on blood sugar regulation.
Methods
The Norwegian prescription database was analyzed. Prescriptions for lithium, lamotrigine, carbamazepine and valproate were used as proxies for bipolar disorder. Prescriptions for insulin and oral anti-diabetic agents were used as proxies for diabetes mellitus. We explored the association between medication for bipolar disorder and diabetes medication by logistic regression
Results
We found a strong association between concomitant use of medication to treat diabetes mellitus and mood stabilizers for the treatment of bipolar disorder. Females had a 30% higher risk compared to men of being treated for both disorders. Persons using oral anti-diabetic agents had higher odds of receiving valproate than either lithium or lamotrigine. Use of insulin as monotherapy seemed to have lower odds than oral anti-diabetic agents of co-prescription of mood stabilizers, compared to the general population.
Conclusions
This study showed a strong association between the use of mood stabilizers and anti-diabetic agents. The association was stronger among women than men.
doi:10.1186/1741-7015-10-148
PMCID: PMC3534576  PMID: 23186328

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