Differences in Treatment and Management of Indigenous and Non-Indigenous Patients Presenting with Chest Pain: Results of the Heart Protection Partnership (HPP) Study

BACKGROUND: Indigenous patients with acute coronary syndromes represent a high-risk group. There are however few contemporary datasets addressing differences in the presentation and management of Indigenous and non-Indigenous patients with chest pain. METHODS: The Heart Protection Project, is a multicentre retrospective audit of consecutive medical records from patients presenting with chest pain. Patients were identified as Indigenous or non-Indigenous, and time to presentation and cardiac investigations as well as rates of cardiac investigations and procedures were compared between the two groups. RESULTS: Of the 2380 patients included, 199 (8.4%) identified as Indigenous, and 2174 (91.6%) as non-Indigenous. Indigenous patients were younger, had higher rates hyperlipidaemia, diabetes, smoking, known coronary artery disease and a lower rate of prior PCI; and were significantly less likely to have private health insurance, be admitted to an interventional facility or to have a cardiologist as primary physician. Following adjustment for difference in baseline characteristics, Indigenous patients had comparable rates of cardiac investigations and delay times to presentation and investigations. CONCLUSIONS: Although the Indigenous population was identified as a high-risk group, in this analysis of selected Australian hospitals there were no significant differences in treatment or management of Indigenous patients in comparison to non-Indigenous.

The effect of red blood cell orientation on the electrical impedance of pulsatile blood with implications for impedance cardiography

Impedance cardiography is an application of bioimpedance analysis primarily used in a research setting to determine cardiac output. It is a non invasive technique that measures the change in the impedance of the thorax which is attributed to the ejection of a volume of blood from the heart. The cardiac output is calculated from the measured impedance using the parallel conductor theory and a constant value for the resistivity of blood. However, the resistivity of blood has been shown to be velocity dependent due to changes in the orientation of red blood cells induced by changing shear forces during flow. The overall goal of this thesis was to study the effect that flow deviations have on the electrical impedance of blood, both experimentally and theoretically, and to apply the results to a clinical setting. The resistivity of stationary blood is isotropic as the red blood cells are randomly orientated due to Brownian motion. In the case of blood flowing through rigid tubes, the resistivity is anisotropic due to the biconcave discoidal shape and orientation of the cells. The generation of shear forces across the width of the tube during flow causes the cells to align with the minimal cross sectional area facing the direction of flow. This is in order to minimise the shear stress experienced by the cells. This in turn results in a larger cross sectional area of plasma and a reduction in the resistivity of the blood as the flow increases. Understanding the contribution of this effect on the thoracic impedance change is a vital step in achieving clinical acceptance of impedance cardiography. Published literature investigates the resistivity variations for constant blood flow. In this case, the shear forces are constant and the impedance remains constant during flow at a magnitude which is less than that for stationary blood. The research presented in this thesis, however, investigates the variations in resistivity of blood during pulsataile flow through rigid tubes and the relationship between impedance, velocity and acceleration. Using rigid tubes isolates the impedance change to variations associated with changes in cell orientation only. The implications of red blood cell orientation changes for clinical impedance cardiography were also explored. This was achieved through measurement and analysis of the experimental impedance of pulsatile blood flowing through rigid tubes in a mock circulatory system. A novel theoretical model including cell orientation dynamics was developed for the impedance of pulsatile blood through rigid tubes. The impedance of flowing blood was theoretically calculated using analytical methods for flow through straight tubes and the numerical Lattice Boltzmann method for flow through complex geometries such as aortic valve stenosis. The result of the analytical theoretical model was compared to the experimental impedance measurements through rigid tubes. The impedance calculated for flow through a stenosis using the Lattice Boltzmann method provides results for comparison with impedance cardiography measurements collected as part of a pilot clinical trial to assess the suitability of using bioimpedance techniques to assess the presence of aortic stenosis. The experimental and theoretical impedance of blood was shown to inversely follow the blood velocity during pulsatile flow with a correlation of -0.72 and -0.74 respectively. The results for both the experimental and theoretical investigations demonstrate that the acceleration of the blood is an important factor in determining the impedance, in addition to the velocity. During acceleration, the relationship between impedance and velocity is linear (r2 = 0.98, experimental and r2 = 0.94, theoretical). The relationship between the impedance and velocity during the deceleration phase is characterised by a time decay constant, ô , ranging from 10 to 50 s. The high level of agreement between the experimental and theoretically modelled impedance demonstrates the accuracy of the model developed here. An increase in the haematocrit of the blood resulted in an increase in the magnitude of the impedance change due to changes in the orientation of red blood cells. The time decay constant was shown to decrease linearly with the haematocrit for both experimental and theoretical results, although the slope of this decrease was larger in the experimental case. The radius of the tube influences the experimental and theoretical impedance given the same velocity of flow. However, when the velocity was divided by the radius of the tube (labelled the reduced average velocity) the impedance response was the same for two experimental tubes with equivalent reduced average velocity but with different radii. The temperature of the blood was also shown to affect the impedance with the impedance decreasing as the temperature increased. These results are the first published for the impedance of pulsatile blood. The experimental impedance change measured orthogonal to the direction of flow is in the opposite direction to that measured in the direction of flow. These results indicate that the impedance of blood flowing through rigid cylindrical tubes is axisymmetric along the radius. This has not previously been verified experimentally. Time frequency analysis of the experimental results demonstrated that the measured impedance contains the same frequency components occuring at the same time point in the cycle as the velocity signal contains. This suggests that the impedance contains many of the fluctuations of the velocity signal. Application of a theoretical steady flow model to pulsatile flow presented here has verified that the steady flow model is not adequate in calculating the impedance of pulsatile blood flow. The success of the new theoretical model over the steady flow model demonstrates that the velocity profile is important in determining the impedance of pulsatile blood. The clinical application of the impedance of blood flow through a stenosis was theoretically modelled using the Lattice Boltzman method (LBM) for fluid flow through complex geometeries. The impedance of blood exiting a narrow orifice was calculated for varying degrees of stenosis. Clincial impedance cardiography measurements were also recorded for both aortic valvular stenosis patients (n = 4) and control subjects (n = 4) with structurally normal hearts. This pilot trial was used to corroborate the results of the LBM. Results from both investigations showed that the decay time constant for impedance has potential in the assessment of aortic valve stenosis. In the theoretically modelled case (LBM results), the decay time constant increased with an increase in the degree of stenosis. The clinical results also showed a statistically significant difference in time decay constant between control and test subjects (P = 0.03). The time decay constant calculated for test subjects (ô = 180 - 250 s) is consistently larger than that determined for control subjects (ô = 50 - 130 s). This difference is thought to be due to difference in the orientation response of the cells as blood flows through the stenosis. Such a non-invasive technique using the time decay constant for screening of aortic stenosis provides additional information to that currently given by impedance cardiography techniques and improves the value of the device to practitioners. However, the results still need to be verified in a larger study. While impedance cardiography has not been widely adopted clinically, it is research such as this that will enable future acceptance of the method.

Quality of life and genetics in men with prostate cancer

As family history has been established as a risk factor for prostate cancer, attempts have been made to isolate predisposing genetic variants that are related to hereditary prostate cancer. With many genetic variants still to be identified and investigated, it is not yet possible to fully understand the impact of genetic variants on prostate cancer development. The high survival rates among men with prostate cancer have meant that other issues, such as quality of life (QoL), have also become important. Through their effect on a person’s health, a range of inherited genetic variants may potentially influence QoL in men with prostate cancer, even prior to treatment. Until now, limited research has been conducted on the relationship between genetics and QoL. Thus, this study contributes to an emerging field by aiming to identify certain genetic variants related to the QoL found in men with prostate cancer. It is hoped that this study may lead to future research that will identify men who have an increased risk of a poor QoL following prostate cancer treatment, which will aid in developing treatments that are individually tailored to support them. Previous studies have established that genetic variants of Vascular Endothelial Growth Factor (VEGF) and Insulin-like Growth Factor 1 (IGF-1) may play a role in prostate cancer development. VEGF and IGF-1 have also been reported to be associated with QoL in people with ovarian cancer and colorectal cancer, respectively. This study completed a series of secondary analyses using two major data-sets (from 850 men newly diagnosed with prostate cancer, and approximately 550 men from the general Queensland population), in which genetic variants of VEGF and IGF-1 were investigated for associations with prostate cancer susceptibility and QoL. The first aim of this research was to investigate genetic variants in the VEGF and IGF-I gene for an association with the risk of prostate cancer. It was found that one IGF-1 genetic variant (rs35765) had a statistically significant association with prostate cancer (p = 0.04), and one VEGF genetic variant (rs2146323) had a statistically significant association with advanced prostate cancer (p = 0.02). The estimates suggest that carriers of the CA and AA genotype for rs35765 may have a reduced risk of developing prostate cancer (Odds Ratio (OR) = 0.72, 95% Confidence Interval (CI) = 0.55, 0.95, OR = 0.60, 95% CI = 0.26, 1.39, respectively). Meanwhile, carriers of the CA and AA genotype for rs2146323 may be at increased risk of advanced prostate cancer, which was determined by a Gleason score of above 7 (OR = 1.72, 95% CI = 1.12, 2.63, OR = 1.90, 95% CI = 1.08, 3.34, respectively). Utilising the widely used short-form health survey, the SF-36v2, the second aim of this study was to investigate the relationship between prostate cancer and QoL prior to treatment. Assessing QoL at this time-point was important as little research has been conducted to evaluate if prostate cancer affects QoL regardless of treatment. The analyses found that mean SF-36v2 scale scores related to physical health were higher by at least 0.3 Standard Deviations (SD) among men with prostate cancer than the general population comparison group. This difference was considered clinically significant (defined by group differences in mean SF-36v2 scores by at least 0.3 SD). These differences were also statistically significant (p<0.05). Mean QoL scale scores related to mental health were similar between men with prostate cancer and those from the general population comparison group. The third aim of this study was to investigate genetic variants in the VEGF and IGF-1 gene for an association with QoL in prostate cancer patients prior to their treatment. It was essential to evaluate these relationships prior to treatment, before the involvement of these genes was potentially interrupted by treatment. The analyses found that some genetic variants had a small clinically significant association (0.3 SD) to some QoL domains experienced by these men. However, most relationships were not statistically significant (p>0.05). Most of the associations found identified that a small sub-group of men with prostate cancer (approximately 2%) reported, on average, a slightly better QoL than the majority of the prostate cancer patients. The fourth aim of this research was to investigate whether associations between genetic variants in VEGF and IGF-1 and QoL were specific to men with prostate cancer, or were also applicable to the general male population. It was found that twenty out of one-hundred relationships between the genetic variants of VEGF and IGF-1 and QoL health-measures and scales examined differed between these groups. In the majority of the relationships involving VEGF SNPs that differed, a clinically significant difference (0.3 or more SD) between mean scores among the genotype groups in prostate cancer patients was found, while mean scores among men from the general-population comparison group were similar. For example, prostate cancer participants who carried at least one T allele (CT or TT genotype) for rs3024994 had a clinically significant higher (0.3 SD) mean QoL score in terms of the role-physical scale, than participants who carried the CC genotype. This was not seen among men from the general population sample, as the mean score was similar between genotype groups. The opposite was seen in regards to the IGF-1 SNPs examined. Overall, these relationships were not considered to directly impact on the clinical options for men with prostate cancer. As this study utilised secondary data from two separate studies, there are a number of important limitations that should be acknowledged including issues of multiple comparisons, power, and missing or unavailable data. It is recommended that this study be replicated as a better-designed study that takes greater consideration of the many factors involved in prostate cancer and QoL. Investigation into other genetic variants of VEGF or IGF-1 is also warranted, as is consideration of other genes and their relationship with QoL. Through identifying certain genetic variants that have a modest association to prostate cancer, this project adds to the knowledge surrounding VEGF and IGF-1 and their role in prostate cancer susceptibility. Importantly, this project has also introduced the potential role genetics plays in QoL, through investigating the relationships between genetic variants of VEGF and IGF-1 and QoL.

An innovative approach to the assessment of nutrient intake in adults with type 2 diabetes : the development, trial and evaluation of a mobile phone photo/voice dietary record

Nutrition interventions in the form of both self-management education and individualised diet therapy are considered essential for the long-term management of type 2 diabetes mellitus (T2DM). The measurement of diet is essential to inform, support and evaluate nutrition interventions in the management of T2DM. Barriers inherent within health care settings and systems limit ongoing access to personnel and resources, while traditional prospective methods of assessing diet are burdensome for the individual and often result in changes in typical intake to facilitate recording. This thesis investigated the inclusion of information and communication technologies (ICT) to overcome limitations to current approaches in the nutritional management of T2DM, in particular the development, trial and evaluation of the Nutricam dietary assessment method (NuDAM) consisting of a mobile phone photo/voice application to assess nutrient intake in a free-living environment with older adults with T2DM. Study 1: Effectiveness of an automated telephone system in promoting change in dietary intake among adults with T2DM The effectiveness of an automated telephone system, Telephone-Linked Care (TLC) Diabetes, designed to deliver self-management education was evaluated in terms of promoting dietary change in adults with T2DM and sub-optimal glycaemic control. In this secondary data analysis independent of the larger randomised controlled trial, complete data was available for 95 adults (59 male; mean age(±SD)=56.8±8.1 years; mean(±SD)BMI=34.2±7.0kg/m2). The treatment effect showed a reduction in total fat of 1.4% and saturated fat of 0.9% energy intake, body weight of 0.7 kg and waist circumference of 2.0 cm. In addition, a significant increase in the nutrition self-efficacy score of 1.3 (p<0.05) was observed in the TLC group compared to the control group. The modest trends observed in this study indicate that the TLC Diabetes system does support the adoption of positive nutrition behaviours as a result of diabetes self-management education, however caution must be applied in the interpretation of results due to the inherent limitations of the dietary assessment method used. The decision to use a close-list FFQ with known bias may have influenced the accuracy of reporting dietary intake in this instance. This study provided an example of the methodological challenges experienced with measuring changes in absolute diet using a FFQ, and reaffirmed the need for novel prospective assessment methods capable of capturing natural variance in usual intakes. Study 2: The development and trial of NuDAM recording protocol The feasibility of the Nutricam mobile phone photo/voice dietary record was evaluated in 10 adults with T2DM (6 Male; age=64.7±3.8 years; BMI=33.9±7.0 kg/m2). Intake was recorded over a 3-day period using both Nutricam and a written estimated food record (EFR). Compared to the EFR, the Nutricam device was found to be acceptable among subjects, however, energy intake was under-recorded using Nutricam (-0.6±0.8 MJ/day; p<0.05). Beverages and snacks were the items most frequently not recorded using Nutricam; however forgotten meals contributed to the greatest difference in energy intake between records. In addition, the quality of dietary data recorded using Nutricam was unacceptable for just under one-third of entries. It was concluded that an additional mechanism was necessary to complement dietary information collected via Nutricam. Modifications to the method were made to allow for clarification of Nutricam entries and probing forgotten foods during a brief phone call to the subject the following morning. The revised recording protocol was evaluated in Study 4. Study 3: The development and trial of the NuDAM analysis protocol Part A explored the effect of the type of portion size estimation aid (PSEA) on the error associated with quantifying four portions of 15 single foods items contained in photographs. Seventeen dietetic students (1 male; age=24.7±9.1 years; BMI=21.1±1.9 kg/m2) estimated all food portions on two occasions: without aids and with aids (food models or reference food photographs). Overall, the use of a PSEA significantly reduced mean (±SD) group error between estimates compared to no aid (-2.5±11.5% vs. 19.0±28.8%; p<0.05). The type of PSEA (i.e. food models vs. reference food photograph) did not have a notable effect on the group estimation error (-6.7±14.9% vs. 1.4±5.9%, respectively; p=0.321). This exploratory study provided evidence that the use of aids in general, rather than the type, was more effective in reducing estimation error. Findings guided the development of the Dietary Estimation and Assessment Tool (DEAT) for use in the analysis of the Nutricam dietary record. Part B evaluated the effect of the DEAT on the error associated with the quantification of two 3-day Nutricam dietary records in a sample of 29 dietetic students (2 males; age=23.3±5.1 years; BMI=20.6±1.9 kg/m2). Subjects were randomised into two groups: Group A and Group B. For Record 1, the use of the DEAT (Group A) resulted in a smaller error compared to estimations made without the tool (Group B) (17.7±15.8%/day vs. 34.0±22.6%/day, p=0.331; respectively). In comparison, all subjects used the DEAT to estimate Record 2, with resultant error similar between Group A and B (21.2±19.2%/day vs. 25.8±13.6%/day; p=0.377 respectively). In general, the moderate estimation error associated with quantifying food items did not translate into clinically significant differences in the nutrient profile of the Nutricam dietary records, only amorphous foods were notably over-estimated in energy content without the use of the DEAT (57kJ/day vs. 274kJ/day; p<0.001). A large proportion (89.6%) of the group found the DEAT helpful when quantifying food items contained in the Nutricam dietary records. The use of the DEAT reduced quantification error, minimising any potential effect on the estimation of energy and macronutrient intake. Study 4: Evaluation of the NuDAM The accuracy and inter-rater reliability of the NuDAM to assess energy and macronutrient intake was evaluated in a sample of 10 adults (6 males; age=61.2±6.9 years; BMI=31.0±4.5 kg/m2). Intake recorded using both the NuDAM and a weighed food record (WFR) was coded by three dietitians and compared with an objective measure of total energy expenditure (TEE) obtained using the doubly labelled water technique. At the group level, energy intake (EI) was under-reported to a similar extent using both methods, with the ratio of EI:TEE was 0.76±0.20 for the NuDAM and 0.76±0.17 for the WFR. At the individual level, four subjects reported implausible levels of energy intake using the WFR method, compared to three using the NuDAM. Overall, moderate to high correlation coefficients (r=0.57-0.85) were found across energy and macronutrients except fat (r=0.24) between the two dietary measures. High agreement was observed between dietitians for estimates of energy and macronutrient derived for both the NuDAM (ICC=0.77-0.99; p<0.001) and WFR (ICC=0.82-0.99; p<0.001). All subjects preferred using the NuDAM over the WFR to record intake and were willing to use the novel method again over longer recording periods. This research program explored two novel approaches which utilised distinct technologies to aid in the nutritional management of adults with T2DM. In particular, this thesis makes a significant contribution to the evidence base surrounding the use of PhRs through the development, trial and evaluation of a novel mobile phone photo/voice dietary record. The NuDAM is an extremely promising advancement in the nutritional management of individuals with diabetes and other chronic conditions. Future applications lie in integrating the NuDAM with other technologies to facilitate practice across the remaining stages of the nutrition care process.

The influence of smoking status on malnutrition risk and 1-year mortality in outpatients with chronic obstructive pulmonary disease.

Introduction:  Smoking status in outpatients with chronic obstructive pulmonary disease (COPD) has been associated with a low body mass index (BMI) and reduced mid-arm muscle circumference (Cochrane & Afolabi, 2004). Individuals with COPD identified as malnourished have also been found to be twice as likely to die within 1 year compared to non-malnourished patients (Collins et al., 2010). Although malnutrition is both preventable and treatable, it is not clear what influence current smoking status, another modifiable risk factor, has on malnutrition risk. The current study aimed to establish the influence of smoking status on malnutrition risk and 1-year mortality in outpatients with COPD. Methods:  A prospective nutritional screening survey was carried out between July 2008 and May 2009 at a large teaching hospital (Southampton General Hospital) and a smaller community hospital within Hampshire (Lymington New Forest Hospital). In total, 424 outpatients with a diagnosis of COPD were routinely screened using the ‘Malnutrition Universal Screening Tool’, ‘MUST’ (Elia, 2003); 222 males, 202 females; mean (SD) age 73 (9.9) years; mean (SD) BMI 25.9 (6.4) kg m−2. Smoking status on the date of screening was obtained for 401 of the outpatients. Severity of COPD was assessed using the GOLD criteria, and social deprivation determined using the Index of Multiple Deprivation (Nobel et al., 2008). Results:  The overall prevalence of malnutrition (medium + high risk) was 22%, with 32% of current smokers at risk (who accounted for 19% of the total COPD population). In comparison, 19% of nonsmokers and ex-smokers were likely to be malnourished [odds ratio, 1.965; 95% confidence interval (CI), 1.133–3.394; P = 0.015]. Smoking status remained an independent risk factor for malnutrition even after adjustment for age, social deprivation and disease-severity (odds ratio, 2.048; 95% CI, 1.085–3.866; P = 0.027) using binary logistic regression. After adjusting for age, disease severity, social deprivation, smoking status, malnutrition remained a significant predictor of 1-year mortality [odds ratio (medium + high risk versus low risk), 2.161; 95% CI, 1.021–4.573; P = 0.044], whereas smoking status did not (odds ratio for smokers versus ex-smokers + nonsmokers was 1.968; 95% CI, 0.788–4.913; P = 0.147). Discussion:  This study highlights the potential importance of combined nutritional support and smoking cessation in order to treat malnutrition. The close association between smoking status and malnutrition risk in COPD suggests that smoking is an important consideration in the nutritional management of malnourished COPD outpatients. Conclusions:  Smoking status in COPD outpatients is a significant independent risk factor for malnutrition and a weaker (nonsignificant) predictor of 1-year mortality. Malnutrition significantly predicted 1 year mortality. References:  Cochrane, W.J. & Afolabi, O.A. (2004) Investigation into the nutritional status, dietary intake and smoking habits of patients with chronic obstructive pulmonary disease. J. Hum. Nutr. Diet.17, 3–11. Collins, P.F., Stratton, R.J., Kurukulaaratchym R., Warwick, H. Cawood, A.L. & Elia, M. (2010) ‘MUST’ predicts 1-year survival in outpatients with chronic obstructive pulmonary disease. Clin. Nutr.5, 17. Elia, M. (Ed) (2003) The ‘MUST’ Report. BAPEN. http://www.bapen.org.uk (accessed on March 30 2011). Nobel, M., McLennan, D., Wilkinson, K., Whitworth, A. & Barnes, H. (2008) The English Indices of Deprivation 2007. http://www.communities.gov.uk (accessed on March 30 2011).

Child characteristics associated with delay of gratification in children with Down syndrome

Aim: Children with Down syndrome have been identified as having difficulty delaying gratification when compared to mental age matched children who are developing typically. This study investigated the association between individual characteristics hypopthesized to be associated with ability to delay as well as the strategies children used in a waiting task. Method: Thirty-two children with Down syndrome and 50 typically developing children matched for mental age completed the tasks. Observations of their behaviour while waiting were video-recorded for later analysis. In addition, parents completed questionnaires with respect to their child’s personality and behaviour. Results: Children with Down syndrome were significantly less able to delay gratification than the comparison group. Different patterns of association were found for the two groups between the observational and questionnaire measures and delay time. Conclusions: Children with Down syndrome have greater difficulty delaying gratification than would be predicted on the basis of their mental age. The contributions to delay appear to differ from those for typically developing children and these differences need to be considered when planning interventions for developing this skill

Axial length changes with shifts of gaze direction in myopes and emmetropes

Purpose. The purpose of the study was to investigate the changes in axial length occurring with shifts in gaze direction. Methods. Axial length measurements were obtained from the left eye of 30 young adults (10 emmetropes, 10 low myopes, and 10 moderate myopes) through a rotating prism with 15° deviation, along the foveal axis, using a noncontact optical biometer in each of the nine different cardinal directions of gaze over 5 minutes. The subject's fellow eye fixated on an external distance (6 m) target to control accommodation, also with 15° deviation. Axial length measurements were also performed in 15° and 25° downward gaze with the biometer inclined on a tilting table, allowing gaze shifts to be achieved with either full head turn but no eye turn, or full eye turn with no head turn. Results. There was a significant influence of gaze angle and time on axial length (both P < 0.001), with the greatest axial elongation (+18 ± 8 μm) occurring with inferonasal gaze (P < 0.001) and a slight decrease in axial length in superior gaze (−12 ± 17 μm) compared with primary gaze (P < 0.001). In downward gaze, a significant axial elongation occurred when eye turn was used (P < 0.001), but not when head turn was used to shift gaze (P > 0.05). Conclusions. The angle of gaze has a small but significant short-term effect on axial length, with greatest elongation occurring in inferonasal gaze. The elongation of the eye appears to be due to the influence of the extraocular muscles, in particular the oblique muscles.

Relative abundance of full-length and truncated FOXP1 isoforms is associated with differential NFκB activity in Follicular Lymphoma

FOXP1 is a transcriptional repressor that has been proposed to repress the expression of some NFκB-responsive genes. Furthermore, truncated forms of FOXP1 have been associated with a subtype of Diffuse Large B-cell Lymphoma characterised by constitutive NFκB activity, indicating that they may inhibit this repression. We have shown that FL tumors have increased relative abundance of truncated FOXP1 isoforms and this is associated with increased expression of NFκB-associated genes. Our results provide strong evidence that relative FOXP1 isoform abundance is associated with NFκB activity in FL, and could potentially be used as a marker for this gene signature.

An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers

Background: To directly assess tumor oxygenation in resectable non - small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes. Methods: Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes. Results: The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO 2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001). Conclusions: Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors. © 2006 American Association for Cancer Research.

Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2 : prognostic factors and treatment selection based on two large randomized clinical trials

Purpose: Data from two randomized phase III trials were analyzed to evaluate prognostic factors and treatment selection in the first-line management of advanced non-small cell lung cancer patients with performance status (PS) 2. Patients and Methods: Patients randomized to combination chemotherapy (carboplatin and paclitaxel) in one trial and single-agent therapy (gemcitabine or vinorelbine) in the second were included in these analyses. Both studies had identical eligibility criteria and were conducted simultaneously. Comparison of efficacy and safety was performed between the two cohorts. A regression analysis identified prognostic factors and subgroups of patients that may benefit from combination or single-agent therapy. Results: Two hundred one patients were treated with combination and 190 with single-agent therapy. Objective responses were 37 and 15%, respectively. Median time to progression was 4.6 months in the combination arm and 3.5 months in the single-agent arm (p < 0.001). Median survival imes were 8.0 and 6.6 months, and 1-year survival rates were 31 and 26%, respectively. Albumin <3.5 g, extrathoracic metastases, lactate dehydrogenase ≥200 IU, and 2 comorbid conditions predicted outcome. Patients with 0-2 risk factors had similar outcomes independent of treatment, whereas patients with 3-4 factors had a nonsignificant improvement in median survival with combination chemotherapy. Conclusion: Our results show that PS2 non-small cell lung cancer patients are a heterogeneous group who have significantly different outcomes. Patients treated with first-line combination chemotherapy had a higher response and longer time to progression, whereas overall survival did not appear significantly different. A prognostic model may be helpful in selecting PS 2 patients for either treatment strategy. © 2009 by the International Association for the Study of Lung Cancer.

Quantitative analysis of survivin in colorectal adenocarcinoma : increased expression and correlation with telomerase activity

The aims of the present study are to quantitatively analyze survivin expression, its clinicopathologic roles, and correlation with telomerase activity in a large cohort of patients with colorectal adenocarcinoma. Real-time polymerase chain reaction was used to quantitate expression level of survivin messenger RNA and human telomerase reverse transcriptase messenger RNA (telomerase activity) in 51 patients with colorectal adenocarcinomas. The findings were correlated with the clinicopathologic features of patients, which were prospectively collected into a computerized database. Survivin messenger RNA was expressed in all tumor samples. The level of expression in tumor tissues was increased in comparison with matched nontumor mucosa in the same patient (P = .01). The level of expression of survivin was significantly correlated with the level of human telomerase reverse transcriptase expression (P = .008) and size of the colorectal adenocarcinomas (P = .004). Survival of the patients with colorectal adenocarcinoma was associated with the TNM stages (P = .001) and not with the level of expression of survivin. Thus, survivin activity was altered in colorectal adenocarcinoma. The high prevalence of survivin expression and correlation with telomerase activity are important factors for consideration in gene targeting therapy for colorectal adenocarcinoma.

Eye rubbing-induced changes in intraocular pressure and corneal thickness measured at five locations, in subjects with ocular allergy

AIM To assess the effects of eye rubbing on corneal thickness (CT) and intraocular pressure (IOP) measurements obtained 0-30min after habitual eye rubbing in symptomatic patients. METHODS Measurements of IOP and CT were obtained at five locations (central, temporal, superior, nasal and inferior) before, and every 5min for 30min interval after 30s of eye rubbing, for 25 randomly selected eyes of 14 subjects with ocular allergy and 11 age-matched normals. Differences in measurements were calculated in each group [Baseline measurements minus measurements recorded at each time interval after eye rubbing (for IOP), and for each corneal location (for CT)] and comparison were then made between groups (allergic versus control) for differences in any observed effects. RESULTS Within groups, baseline mean IOPs in the allergic patient-group (14.2±3.0 mm Hg) and in the control group (13.1±1.9 mm Hg) were similar at all times, after eye rubbing (P >0.05, for all). The maximum reduction in IOP was 0.8 mm Hg in the control subjects and the maximum increase was also 0.8 mm Hg in the allergic subjects. Between groups (allergic versus control), the changes in IOP remained under 1 mm Hg at all times (P=0.2) after 30min of eye rubbing. Between 0 and 30min of CT measurements after eye rubbing, the mean central CT (CCT), inferior CT (ICT), superior CT (SCT), temporal CT (TCT) and nasal CT (NCT) did not vary significantly from baseline values in the control and allergic-subject groups (P>0.05, for both). Between both groups, changes in CT were similar at all locations (P>0.05) except for the TC which was minimally thinner by about 4.4 µm (P=0.001) in the allergic subjects than in the control subjects, 30min following 30s of eye rubbing. CONCLUSION IOP measured in allergic subjects after 30s of habitual eye rubbing was comparable with that obtained in normal subjects at all times between 0 and 30min. Although, CT in the allergic subjects were similar to those of the control subjects at all times, it varied between +10 and -7.5 µm following eye rubbing, with the temporal cornea showing consistent reductions in thickness in the subjects with allergy. However, this reduction was minimal and was considered to not be clinically relevant.

Evaluation of a mobile phone image-based dietary assessment method in adults with type 2 diabetes

Photographic and image-based dietary records have limited evidence evaluating their performance and use among adults with a chronic disease. This study evaluated the performance of a mobile phone image-based dietary record, the Nutricam Dietary Assessment Method (NuDAM), in adults with type 2 diabetes mellitus (T2DM). Criterion validity was determined by comparing energy intake (EI) with total energy expenditure (TEE) measured by the doubly-labelled water technique. Relative validity was established by comparison to a weighed food record (WFR). Inter-rater reliability was assessed by comparing estimates of intake from three dietitians. Ten adults (6 males, age=61.2±6.9 years, BMI=31.0±4.5 kg/m2) participated. Compared to TEE, mean EI was under-reported using both methods, with a mean ratio of EI:TEE 0.76±0.20 for the NuDAM and 0.76±0.17 for the WFR. There was moderate to high correlations between the NuDAM and WFR for energy (r=0.57), carbohydrate (r=0.63, p<0.05), protein (r=0.78, p<0.01) and alcohol (rs=0.85, p<0.01), with a weaker relationship for fat (r=0.24). Agreement between dietitians for nutrient intake for the 3-day NuDAM (ICC = 0.77-0.99) was marginally lower when compared with the 3-day WFR (ICC=0.82-0.99). All subjects preferred using the NuDAM and were willing to use it again for longer recording periods.