The effects of acute exercise-induced cortisol on CCR2 expression on human monocytes

CC-chemokine receptor 2 (CCR2) and its ligand, monocyte chemotactic protein-1 (MCP-1, also known as CCL2), are crucial for the recruitment of monocytes/macrophages to sites of inflammation. We conducted a series of experiments to investigate the relationship between stress, monocyte CCR2 expression and migration activity. First, we collected peripheral blood mononuclear cells (PBMC) from untrained subjects (n=8) and measured CCR2 expression on CD14(+) monocytes cultured with cortisol, epinephrine and norepinephrine. Second, we collected PBMC from the subjects before and after they cycled for 60 min at 70% peak O(2) uptake (VO2(peak)), and measured alterations in CCR2 expression on monocytes following exercise. Third, we cultured PBMC with serum obtained before and after exercise and the glucocorticoid antagonist RU-486 to determine the effect of cortisol on CCR2 expression in vitro. Last, we measured the ability of PBMC treated with serum or cortisol to migrate through membrane filters in response to CCL2. Cortisol (but not epinephrine or norepinephrine) increased CCR2 expression on monocytes in a dose- and time-dependent manner. Exercise did not influence CCR2 expression on PBMC, whereas incubation of PBMC with post-exercise serum significantly increased CCR2 expression. Both cortisol and post-exercise serum increased the migration of PBMC toward CCL2. The increase in CCR2 expression on PBMC following stimulation with cortisol and serum was blocked by the glucocorticoid receptor antagonist RU-486. In conclusion, cortisol released during exercise increased monocyte CCR2 expression and migration activity in vitro. These alterations may influence inflammation and regeneration of damaged tissue after acute stress.

Consumer product-related injuries in Queensland children : A snapshot of current problem areas for potential action

This report presents a snapshot from work which was funded by the Queensland Injury Prevention Council in 2010-11 titled “Feasibility of Using Health Data Sources to Inform Product Safety Surveillance in Queensland children”. The project provided an evaluation of the current available evidence-base for identification and surveillance of product-related injuries in children in Queensland and Australia. A comprehensive 300 page report was produced (available at: http://eprints.qut.edu.au/46518/) and a series of recommendations were made which proposed: improvements in the product safety data system, increased utilisation of health data for proactive and reactive surveillance, enhanced collaboration between the health sector and the product safety sector, and improved ability of health data to meet the needs of product safety surveillance. At the conclusion of the project, a Consumer Product Injury Research Advisory group (CPIRAG) was established as a working party to the Queensland Injury Prevention Council (QIPC), to prioritise and advance these recommendations and to work collaboratively with key stakeholders to promote the role of injury data to support product safety policy decisions at the Queensland and national level. This group continues to meet monthly and is comprised of the organisations represented on the second page of this report. One of the key priorities of the CPIRAG group for 2012 was to produce a snapshot report to highlight problem areas for potential action arising out of the larger report. Subsequent funding to write this snapshot report was provided by the Institute for Health and Biomedical Innovation, Injury Prevention and Rehabilitation Domain at QUT in 2012. This work was undertaken by Dr Kirsten McKenzie and researchers from QUT's Centre for Accident Research and Road Safety - Queensland. This snapshot report provides an evidence base for potential further action on a range of children’s products that are significantly represented in injury data. Further information regarding injury hazards, safety advice and regulatory responses are available on the Office of Fair Trading (OFT) Queensland website and the Product Safety Australia websites. Links to these resources are provided for each product reviewed.

A hierarchical structural model of assessing innovation and project performance

Research in construction innovation highlights construction industry as having many barriers and resistance to innovations and suggests that it needs champions. A hierarchical structural model is presented, to assess the impact of the role of the project manager (PM) on the levels of innovation and project performance. The model adopts the structural equation modelling technique and uses the survey data collected from PMs and project team members working for general contractors in Singapore. The model fits well to the observed data, accounting for 24%, 37% and 49% of the variance in championing behaviour, the level of innovation and project performance, respectively. The results of this study show the importance of the championing role of PMs in construction innovation. However, in order to increase their effectiveness, such a role should be complemented by their competency and professionalism, tactical use of influence tactics, and decision authority. Moreover, senior management should provide adequate resources and a sustained support to innovation and create a conducive environment or organizational culture that nurtures and facilitates the PM’s role in the construction project as a champion of innovation.

Application of theory in developing peer-support based intervention to improve self-management for cardiac patients with diabetes

The biosafety of carbon nanomaterial needs to be critically evaluated with both experimental and theoretical validations before extensive biomedical applications. In this letter, we present an analysis of the binding ability of two dimensional monolayer carbon nanomaterial on actin by molecular simulation to understand their adhesive characteristics on F-actin cytoskeleton. The modelling results indicate that the positively charged carbon nanomaterial has higher binding stability on actin. Compared to crystalline graphene, graphene oxide shows higher binding influence on actin when carrying 11 positive surface charge. This theoretical investigation provides insights into the sensitivity of actin-related cellular activities on carbon nanomaterial.

Calculation of dose kernels for radiotherapy applications using the GEANT 4 Monte Carlo toolkit

Dose kernels may be used to calculate dose distributions in radiotherapy (as described by Ahnesjo et al., 1999). Their calculation requires use of Monte Carlo methods, usually by forcing interactions to occur at a point. The Geant4 Monte Carlo toolkit provides a capability to force interactions to occur in a particular volume. We have modified this capability and created a Geant4 application to calculate dose kernels in cartesian, cylindrical, and spherical scoring systems. The simulation considers monoenergetic photons incident at the origin of a 3 m x 3 x 9 3 m water volume. Photons interact via compton, photo-electric, pair production, and rayleigh scattering. By default, Geant4 models photon interactions by sampling a physical interaction length (PIL) for each process. The process returning the smallest PIL is then considered to occur. In order to force the interaction to occur within a given length, L_FIL, we scale each PIL according to the formula: PIL_forced = L_FIL 9 (1 - exp(-PIL/PILo)) where PILo is a constant. This ensures that the process occurs within L_FIL, whilst correctly modelling the relative probability of each process. Dose kernels were produced for an incident photon energy of 0.1, 1.0, and 10.0 MeV. In order to benchmark the code, dose kernels were also calculated using the EGSnrc Edknrc user code. Identical scoring systems were used; namely, the collapsed cone approach of the Edknrc code. Relative dose difference images were then produced. Preliminary results demonstrate the ability of the Geant4 application to reproduce the shape of the dose kernels; median relative dose differences of 12.6, 5.75, and 12.6 % were found for an incident photon energy of 0.1, 1.0, and 10.0 MeV respectively.

Determinants of regional innovation capacity in China

Since the 1980s, when the concept of innovation systems(IS) was first presented(Freeman, 2004), a large body of work has been done on IS. IS is a framework that consists of elements related to innovation activities, such as innovation actors,institutional environments, and the relationship between those elements (Lundvall,1992; Nelson, 1993). Studies on NIS/RIS aim to understand the structures and dynamics of IS (Lundvall, 1992; Nelson, 1993), mainly through case studies and comparative case studies(Archibugi, 1996; MacDowall, 1984; Mowery, 1998;Radosevic, 2000). Research on IS has extended from the national level (NIS) to the regional level (RIS) (Cooke, Uranga, & Etxebarria, 1997; Cooke, Uranga, & Etxebarria, 1998), and from developed economies to developing economies. RIS is vital, especially for a large and diverse countries(Edquist, 2004) like China. More recently, based on the literature of NIS, Furman, Porter and Scott (2002)introduced the framework of national innovation capacity (NIC), which employs a quantitative approach to understanding to what degree elements of NIS impact on innovation capacity. Regional innovation capacity (RIC) is the adaption of NIC at the regional level. Although regional level research is important there is limited work done on RIC and there is even less in transitional economies, which are different to developed countries. To better understand RIC in transitional countries this thesis conducted a study of 30 administrative regions in Mainland China between 1991 and 2005. To establish the key factors driving RIC in China the study explored the impact of three elements in the innovation system;(a) innovation actors, (b) innovation inputs, and (c)international and domestic innovation system interactions.

Business model experimentation : what is the role of deign-led prototyping in developing novel business models?

This book presents readers with the opportunity to fundamentally re-evaluate the processes of innovation and entrepreneurship, and to rethink how they might best be stimulated and fostered within our organizations and communities. The fundamental thesis of the book is that the entrepreneurial process is not a linear progression from novel idea to successful innovation, but is an iterative series of experiments, where progress depends on the persistence and resilience of the individuals involved, and their ability and to learn from failure as well as success. From this premise, the authors argue that the ideal environment for new venture creation is a form of “experimental laboratory,” a community of innovators where ideas are generated, shared, and refined; experiments are encouraged; and which in itself serves as a test environment for those ideas and experiments. This environment is quite different from the traditional “incubator,” which may impose the disciplines of the established firm too early in the development of the new venture.

Development of an integrated metabolomic profiling approach for infectious diseases research

Metabolomic profiling offers direct insights into the chemical environment and metabolic pathway activities at sites of human disease. During infection, this environment may receive important contributions from both host and pathogen. Here we apply an untargeted metabolomics approach to identify compounds associated with an E. coli urinary tract infection population. Correlative and structural data from minimally processed samples were obtained using an optimized LC-MS platform capable of resolving ~2300 molecular features. Principal component analysis readily distinguished patient groups and multiple supervised chemometric analyses resolved robust metabolomic shifts between groups. These analyses revealed nine compounds whose provisional structures suggest candidate infection-associated endocrine, catabolic, and lipid pathways. Several of these metabolite signatures may derive from microbial processing of host metabolites. Overall, this study highlights the ability of metabolomic approaches to directly identify compounds encountered by, and produced from, bacterial pathogens within human hosts.

Prospective imaging study of asymptomatic patellar tendinopathy in elite junior basketball players

To evaluate the ability of ultrasonography to predict eventual symptoms in an at-risk population, 52 elite junior basketball players' patellar tendons were studied at baseline and again 16 months later. The group consisted of 10 study tendons (ultrasonographically hypoechoic at baseline) and 42 control tendons (ultrasonographically normal at baseline). By design, all tendons were asymptomatic at baseline. No differences were noted between subjects and controls at baseline for age, height, weight, training hours, and vertical jump. Functional (P < 0.01) and symptomatic outcome (P < 0.05) were poorer for subjects' tendons than for controls. Relative risk for developing symptoms of jumper's knee was 4.2 times greater in case tendons than in control tendons. Men were more likely to develop ultrasonographic changes than women (P < 0.025), and they also had significantly increased training hours per week (P < 0.01) in the study period. Half (50%) of abnormal tendons in women became ultrasonographically normal in the study period. Our data suggest that presence of an ultrasonographic hypoechoic area is associated with a greater risk of developing jumper's knee symptoms. Ultrasonographic patellar tendon changes may resolve, but this is not necessary for an athlete to become asymptomatic. Qualitative or quantitative analysis of baseline ultrasonographic images revealed it was not possible to predict which tendons would develop symptoms or resolve ultrasonographically.

Sexual desire, erectile dysfunction and the biomedicalization of sex in older heterosexual men

Aim To examine sexual desire in older age and the use of pharmaceuticals for sexual enhancement in the context of erectile dysfunction. Background The ability of the older person to fulfil sexual desire has not been well supported in Western society. Design The paper draws on themes that emerged during a phenomenological study of sexual desire in older age. Method Narratives were collected between 2008–2010 from in-depth interviews with six men and two women aged 65–84 years who were part of a larger Australian study of sexual desire in older age. Findings Emergent themes reveal that for some older people, the biomedicalization of sex can be a disappointing experience. Conclusion The findings illuminate the need for nurses who are at the front line of health care, health policy makers and educators, to consider sexual desire experienced in older age in the context of sexual health and healthy ageing. This study will contribute to a growing body of knowledge about sexual desire in older age

The role of immunoglobulins and their transporters in urogenital Chlamydial infections

Chlamydia trachomatis infections of the male and female reproductive tracts are the world's leading sexually transmitted bacterial disease, and can lead to damaging pathology, scarring and infertility. The resolution of chlamydial infection requires the development of adaptive immune responses to infection, and includes cell-mediated and humoral immunity. Whilst cluster of differentiation (CD)4+ T cells are known to be essential in clearance of infection [1], they are also associated with immune cell infiltration, autoimmunity and infertility in the testes [2-3]. Conversely, antibodies are less associated with inflammation, are readily transported into the reproductive tracts, and can offer lumenal neutralization of chlamydiae prior to infection. Antibodies, or immunoglobulins (Ig), play a supportive role in the resolution of chlamydial infections, and this thesis sought to define the function of IgA and IgG, against a variety of chlamydial antigens expressed during the intracellular and extracellular stages of the chlamydial developmental cycle. Transport of IgA and IgG into the mucosal lumen is facilitated by receptor-mediated transcytosis yet the expression profile (under normal conditions and during urogenital chlamydial infection) of the polymeric immunoglobulin receptor (pIgR) and the neonatal Fc receptor (FcRn) remains unknown. The expression profile of pIgR and FcRn in the murine male reproductive tract was found to be polarized to the lower and upper reproductive tract tissues respectively. This demonstrates that the two receptors have a tissue tropism, which must be considered when targeting pathogens that colonize different sites. In contrast, the expression of pIgR and FcRn in the female mouse was found to be distributed in both the upper and lower reproductive tracts. When urogenitally infected with Chlamydia muridarum, both male and female reproductive tracts up-regulated expression of pIgR and down-regulated expression of FcRn. Unsurprisingly, the up-regulation of pIgR increased the concentration of IgA in the lumen. However, down-regulation of FcRn, prevented IgG uptake and led to an increase or pooling of IgG in lumenal secretions. As previous studies have identified the importance of pIgR-mediated delivery of IgA, as well as the potential of IgA to bind and neutralize intracellular pathogens, IgA against a variety of chlamydial antigens was investigated. The protection afforded by IgA against the extracellular antigen major outer membrane protein (MOMP), was found to be dependent on pIgR expression in vitro and in vivo. It was also found that in the absence of pIgR, no protection was afforded to mice previously immunized with MOMP. The protection afforded from polyclonal IgA against the intracellular chlamydial antigens; inclusion membrane protein A (IncA), inclusion membrane proteins (IncMem) and secreted chlamydial protease-like activity factor (CPAF) were produced and investigated in vitro. Antigen-specific intracellular IgA was found to bind to the respective antigen within the infected cell, but did not significantly reduce inclusion formation (p > 0.05). This suggests that whilst IgA specific for the selected antigens was transported by pIgR to the chlamydial inclusion, it was unable to prevent growth. Similarly, immunization of male mice with intracellular chlamydial antigens (IncA or IncMem), followed by depletion CD4+ T cells, and subsequent urogenital C. muridarum challenge, provided minimal pIgR-mediated protection. Wild type male mice immunized with IncA showed a 57 % reduction (p < 0.05), and mice deficient in pIgR showed a 35 % reduction (p < 0.05) in reproductive tract chlamydial burden compared to control antigen, and in the absence of CD4+ T cells. This suggests that pIgR and secretory IgA (SIgA) were playing a protective role (21 % pIgR-mediated) in unison with another antigen-specific immune mechanism (36 %). Interestingly, IgA generated during a primary respiratory C. muridarum infection did not provide a significant amount of protection to secondary urogenital C. muridarum challenge. Together, these data suggest that IgA specific for an extracellular antigen (MOMP) can play a strong protective role in chlamydial infections, and that IgA targeting intracellular antigens is also effective but dependent on pIgR expression in tissues. However, whilst not investigated here, IgA targeting and blocking other intracellular chlamydial antigens, that are more essential for replication or type III secretion, may be more efficacious in subunit vaccines. Recently, studies have demonstrated that IgG can neutralize influenza virus by trafficking IgG-bound virus to lysosomes [4]. We sought to determine if this process could also traffic chlamydial antigens for degradation by lysosomes, despite Chlamydia spp. actively inhibiting fusion with the host endocytic pathway. As observed in pIgR-mediated delivery of anti-IncA IgA, FcRn similarly transported IgG specific for IncA which bound the inclusion membrane. Interestingly, FcRn-mediated delivery of anti-IncA IgG significantly decreased inclusion formation by 36 % (p < 0.01), and induced aberrant inclusion morphology. This suggests that unlike IgA, IgG can facilitate additional host cellular responses which affect the intracellular niche of chlamydial growth. Fluorescence microscopy revealed that IgG also bound the inclusion, but unlike influenza studies, did not induce the recruitment of lysosomes. Notably, anti-IncA IgG recruited sequestosomes to the inclusion membrane, markers of the ubiquitin/proteasome pathway and major histocompatibility complex (MHC) class I loading. To determine if the protection against C. muridarum infection afforded by IncA IgG in vitro translated in vivo, wild type mice and mice deficient in functional FcRn and MHC-I, were immunized, depleted of CD4+, and urogenitally infected with C. muridarum. Unlike in pIgR-deficient mice, the protection afforded from IncA immunization was completely abrogated in mice lacking functional FcRn and MHC-I/CD8+. Thus, both anti-IncA IgA and IgG can bind the inclusion in a pIgR and FcRn-mediated manner, respectively. However, only IgG mediates a higher reduction in chlamydial infection in vitro and in vivo suggesting more than steric blocking of IncA had occurred. Unlike anti-MOMP IgA, which reduced chlamydial infection of epithelial cells and male mouse tissues, IgG was found to enhance infectivity in vitro, and in vivo. Opsonization of EBs with MOMP-IgG enhanced inclusion formation of epithelial cells in a MOMP-IgG dose-dependent and FcRn-dependent manner. When MOMP-IgG opsonized EBs were inoculated into the vagina of female mice, a small but non-significant (p > 0.05) enhancement of cervicovaginal C. muridarum shedding was observed three days post infection in mice with functional FcRn. Interestingly, infection with opsonized EBs reduced the intensity of the peak of infection (day six) but protracted the duration of infection by 60 % in wild type mice only. Infection with EBs opsonized in IgG also significantly increased (p < 0.05) hydrosalpinx formation in the oviducts and induced lymphocyte infiltration uterine horns. As MOMP is an immunodominant antigen, and is widely used in vaccines, the ability of IgG specific to extracellular chlamydial antigens to enhance infection and induce pathology needs to be considered. Together, these data suggest that immunoglobulins play a dichotomous role in chlamydial infections, and are dependent on antigen specificity, FcRn and pIgR expression. FcRn was found to be highly expressed in upper male reproductive tract, whilst pIgR was dominantly expressed in the lower reproductive tract. Conversely, female mice expressed FcRn and pIgR in both the lower and upper reproductive tracts. In response to a normal chlamydial infection, pIgR is up-regulated increasing secretory IgA release, but FcRn is down-regulated preventing IgG uptake. Similarly to other studies [5-6], we demonstrate that IgA and IgG generated during primary chlamydial infections plays a minor role in recall immunity, and that antigen-specific subunit vaccines can offer more protection. We also show that both IgA and IgG can be used to target intracellular chlamydial antigens, but that IgG is more effective. Finally, IgA against the extracellular antigen MOMP can afford protection, whist IgG plays a deleterious role by increasing infectivity and inducing damaging immunopathology. Further investigations with additional antigens or combination subunit vaccines will enhance our understanding the protection afforded by antibodies against intracellular and extracellular pathogenic antigens, and help improve the development of an efficacious chlamydial vaccine.

The wrong tool for the job? The predictive powers of the DBQ in a sample of Queensland motorists

Introduction This study reports on the application of the Manchester Driver Behaviour Questionnaire (DBQ) to examine the self-reported driving behaviours (e.g., speeding, errors & aggressive manoeuvres) and predict crash involvement among a sample of general Queensland motorists. Material and Methods Surveys were completed by 249 general motorists on-line or via a pen-and-paper format. Results A factor analysis revealed a three factor solution for the DBQ which was consistent with previous Australian-based research. It accounted for 40.5% of the total variance, although some cross-loadings were observed on nine of the twenty items. The internal reliability of the DBQ was satisfactory. However, multivariate analysis using the DBQ revealed little predictive ability of the tool to predict crash involvement or demerit point loss e.g. violation notices. Rather, exposure to the road was found to be predictive of crashes, although speeding did make a small contribution to those who recently received a violation notice. Conclusions Taken together, the findings contribute to a growing body of research that raises questions about the predictive ability of the most widely used driving assessment tool globally. Ongoing research (which also includes official crash and offence outcomes) is required to better understand the actual contribution that the DBQ can make to understanding and improving road safety. Future research should also aim to confirm whether this lack of predictive efficacy originates from broader issues inherent within self-report data (e.g., memory recall problems) or issues underpinning the conceptualisation of the scale.

Princess Alexandra Hospital model of comprehensive geriatric assessment of cancer patients : methodological and logistical aspects

There is increasing momentum in cancer care to implement a two stage assessment process that accurately determines the ability of older patients to cope with, and benefit from, chemotherapy. The two-step approach aims to ensure that patients clearly fit for chemotherapy can be accurately identified and referred for treatment without undergoing a time- and resource-intensive comprehensive geriatric assessment (CGA). Ideally, this process removes the uncertainty of how to classify and then appropriately treat the older cancer patient. After trialling a two-stage screen and CGA process in the Division of Cancer Services at Princess Alexandra Hospital (PAH) in 2011-2012, we implemented a model of oncogeriatric care based on our findings. In this paper, we explore the methodological and practical aspects of implementing the PAH model and outline further work needed to refine the process in our treatment context.

Analysis of acute-phase proteins, AHSG, C3, CLI, HP and SAA, reveals distinctive expression patterns associated with breast, colorectal and lung cancer

Early detection, clinical management and disease recurrence monitoring are critical areas in cancer treatment in which specific biomarker panels are likely to be very important in each of these key areas. We have previously demonstrated that levels of alpha-2-heremans-schmid-glycoprotein (AHSG), complement component C3 (C3), clusterin (CLI), haptoglobin (HP) and serum amyloid A (SAA) are significantly altered in serum from patients with squamous cell carcinoma of the lung. Here, we report the abundance levels for these proteins in serum samples from patients with advanced breast cancer, colorectal cancer (CRC) and lung cancer compared to healthy controls (age and gender matched) using commercially available enzyme-linked immunosorbent assay kits. Logistic regression (LR) models were fitted to the resulting data, and the classification ability of the proteins was evaluated using receiver-operating characteristic curve and leave-one-out cross-validation (LOOCV). The most accurate individual candidate biomarkers were C3 for breast cancer [area under the curve (AUC) = 0.89, LOOCV = 73%], CLI for CRC (AUC = 0.98, LOOCV = 90%), HP for small cell lung carcinoma (AUC = 0.97, LOOCV = 88%), C3 for lung adenocarcinoma (AUC = 0.94, LOOCV = 89%) and HP for squamous cell carcinoma of the lung (AUC = 0.94, LOOCV = 87%). The best dual combination of biomarkers using LR analysis were found to be AHSG + C3 (AUC = 0.91, LOOCV = 83%) for breast cancer, CLI + HP (AUC = 0.98, LOOCV = 92%) for CRC, C3 + SAA (AUC = 0.97, LOOCV = 91%) for small cell lung carcinoma and HP + SAA for both adenocarcinoma (AUC = 0.98, LOOCV = 96%) and squamous cell carcinoma of the lung (AUC = 0.98, LOOCV = 84%). The high AUC values reported here indicated that these candidate biomarkers have the potential to discriminate accurately between control and cancer groups both individually and in combination with other proteins. Copyright © 2011 UICC.

Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer

OBJECTIVE: This study explored gene expression differences in predicting response to chemoradiotherapy in esophageal cancer. PURPOSE:: A major pathological response to neoadjuvant chemoradiation is observed in about 40% of esophageal cancer patients and is associated with favorable outcomes. However, patients with tumors of similar histology, differentiation, and stage can have vastly different responses to the same neoadjuvant therapy. This dichotomy may be due to differences in the molecular genetic environment of the tumor cells. BACKGROUND DATA: Diagnostic biopsies were obtained from a training cohort of esophageal cancer patients (13), and extracted RNA was hybridized to genome expression microarrays. The resulting gene expression data was verified by qRT-PCR. In a larger, independent validation cohort (27), we examined differential gene expression by qRT-PCR. The ability of differentially-regulated genes to predict response to therapy was assessed in a multivariate leave-one-out cross-validation model. RESULTS: Although 411 genes were differentially expressed between normal and tumor tissue, only 103 genes were altered between responder and non-responder tumor; and 67 genes differentially expressed >2-fold. These included genes previously reported in esophageal cancer and a number of novel genes. In the validation cohort, 8 of 12 selected genes were significantly different between the response groups. In the predictive model, 5 of 8 genes could predict response to therapy with 95% accuracy in a subset (74%) of patients. CONCLUSIONS: This study has identified a gene microarray pattern and a set of genes associated with response to neoadjuvant chemoradiation in esophageal cancer. The potential of these genes as biomarkers of response to treatment warrants further investigation. Copyright © 2009 by Lippincott Williams & Wilkins.