Modulation of human V alpha 24(+)V beta 11(+) NKT cells by age, malignancy and conventional anticancer therapies

Immunotherapy strategies aimed at increasing human Valpha24(+)Vbeta11(+) natural killer T (NKT) cell numbers are currently a major focus. To provide further information towards the goal of NKT cell-based immunotherapy, we assessed the effects of age, cancer status and prior anticancer treatment on NKT cell numbers and their expansion capacity following alpha-galactosylceramide (alpha-GalCer) stimulation. The percentage and absolute number of peripheral blood NKT cells was assessed in 40 healthy donors and 109 solid cancer patients ( colorectal ( n = 33), breast ( n = 10), melanoma ( n = 17), lung ( n = 8), renal cell carcinoma ( n = 10), other cancers ( n = 31)). Responsiveness to alpha-GalCer stimulation was also assessed in 28 of the cancer patients and 37 of the healthy donors. Natural killer T cell numbers were significantly reduced in melanoma and breast cancer patients. While NKT numbers decreased with age in healthy donors, NKT cells were decreased in these cancer subgroups despite age and sex adjustments. Prior radiation treatment was shown to contribute to the observed reduction in melanoma patients. Although cancer patient NKT cells were significantly less responsive to alpha-GalCer stimulation, they remained capable of substantial expansion. Natural killer T cells are therefore modulated by age, malignancy and prior anticancer treatment; however, cancer patient NKT cells remain capable of responding to alpha-GalCer-based immenotherapies.

Evaluating Patient Education Materials about Radiation Therapy

Targeted treatment education for cancer patients has the potential to promote adjustment through assisting patients to participate in treatment decision making, comply with treatment regimens and cope more effectively with treatment side effects. A quasi-experimental longitudinal pre-test post-test and follow-up design was used to assess the effect of a patient education video about radiation therapy on patients' psychological distress, knowledge about radiation therapy, self-efficacy about coping with treatment and physical symptoms. Patients with head and neck (n = 26) and breast cancer (n = 66) were recruited into the study and allocated into control and intervention groups. No significant differences were found between the control and intervention groups on any of the outcome variables. However, patients in the intervention group reported high levels of satisfaction with the video and all reported that they would recommend the video to other patients preparing for radiation therapy. As well, 90% of patients in the intervention group reported that some or all of the information in the video was new to them. Education materials that have excellent face validity and that are well received by patients may fail to produce significant change using standard controlled study designs. Future research in this area may need to consider alternative paradigms for evaluating the helpfulness of such materials. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

Numerical modeling of 11.1 T MRI of a human head using MoM/FDTD methods

In a recent study, severe distortions in the proton images of an excised, fixed, human brain in an 11.1 Tesla/40 cm MR instrument have been observed, and the effect modeled on phantom images using a finite difference time domain (FDTD) model. in the present study, we extend these simulations to that of a complete human head, employing a hybrid FDTD and method of moments (MoM) approach, which provides a validated method for simulating biological samples in coil structures. The effect of fixative on the image distortions is explored. importantly, temperature distributions within the head are also simulated using a bioheat method based on parameters derived from the electromagnetic simulations. The MoM/FDTD simulations confirm that the transverse magnetic field (B,) from a ReCav resonator exhibits good homogeneity in air but strong inhomogeneity when loaded with the head with or without fixative. The fixative serves to increase the distortions, but they are still significant for the in vivo simulations. The simulated signal intensity (SI) distribution within the sample confirm the distortions in the experimental images are caused by the complex interactions of the incident electromagnetic fields with tissue, which is heterogeneous in terms of conductivity and permittivity. The temperature distribution is likewise heterogeneous, raising concerns regarding hot spot generation in the sample that may exceed acceptable levels in future in vivo studies. As human imaging at 11.1 T is some time away, simulations are important in terms of predicting potential safety issues as well as evaluating practical concerns about the quality of images. Simulation on a whole human head at 11.1 T implies the wave behavior presents significant engineering challenges for ultra-high-field (UHF) MRI. Novel strategies will have to be employed in imaging technique and resonator design for UHF MRI to achieve the theoretical signal-to-noise ratio (SNR) improvements it offers over lower field systems. (C) 2005 Wiley Periodicals, Inc.

Widespread brain activity during an abdominal task markedly reduced after pain physiology education: fMRI evaluation of a single patient with chronic low back pain

The way people with chronic low back pain think about pain can affect the way they move. This case report concerns a patient with chronic disabling low back pain who underwent functional magnetic resonance imaging scans during performance of a voluntary trunk muscle task under three conditions: directly after training in the task and, after one week of practice, before and after a 2.5 hour pain physiology education session. Before education there was widespread brain activity during performance of the task, including activity in cortical regions known to be involved in pain, although the task was not painful. After education widespread activity was absent so that there was no brain activation outside of the primary somatosensory cortex. The results suggest that pain physiology education markedly altered brain activity during performance of the task. The data offer a possible mechanism for difficulty in acquisition of trunk muscle training in people with pain and suggest that the change in activity associated with education may reflect reduced threat value of the task.

Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation

Aim To develop an appropriate dosing strategy for continuous intravenous infusions (CII) of enoxaparin by minimizing the percentage of steady-state anti-Xa concentration (C-ss) outside the therapeutic range of 0.5-1.2 IU ml(-1). Methods A nonlinear mixed effects model was developed with NONMEM (R) for 48 adult patients who received CII of enoxaparin with infusion durations that ranged from 8 to 894 h at rates between 100 and 1600 IU h(-1). Three hundred and sixty-three anti-Xa concentration measurements were available from patients who received CII. These were combined with 309 anti-Xa concentrations from 35 patients who received subcutaneous enoxaparin. The effects of age, body size, height, sex, creatinine clearance (CrCL) and patient location [intensive care unit (ICU) or general medical unit] on pharmacokinetic (PK) parameters were evaluated. Monte Carlo simulations were used to (i) evaluate covariate effects on C-ss and (ii) compare the impact of different infusion rates on predicted C-ss. The best dose was selected based on the highest probability that the C-ss achieved would lie within the therapeutic range. Results A two-compartment linear model with additive and proportional residual error for general medical unit patients and only a proportional error for patients in ICU provided the best description of the data. Both CrCL and weight were found to affect significantly clearance and volume of distribution of the central compartment, respectively. Simulations suggested that the best doses for patients in the ICU setting were 50 IU kg(-1) per 12 h (4.2 IU kg(-1) h(-1)) if CrCL < 30 ml min(-1); 60 IU kg(-1) per 12 h (5.0 IU kg(-1) h(-1)) if CrCL was 30-50 ml min(-1); and 70 IU kg(-1) per 12 h (5.8 IU kg(-1) h(-1)) if CrCL > 50 ml min(-1). The best doses for patients in the general medical unit were 60 IU kg(-1) per 12 h (5.0 IU kg(-1) h(-1)) if CrCL < 30 ml min(-1); 70 IU kg(-1) per 12 h (5.8 IU kg(-1) h(-1)) if CrCL was 30-50 ml min(-1); and 100 IU kg(-1) per 12 h (8.3 IU kg(-1) h(-1)) if CrCL > 50 ml min(-1). These best doses were selected based on providing the lowest equal probability of either being above or below the therapeutic range and the highest probability that the C-ss achieved would lie within the therapeutic range. Conclusion The dose of enoxaparin should be individualized to the patients' renal function and weight. There is some evidence to support slightly lower doses of CII enoxaparin in patients in the ICU setting.

Electrodynamic heart model construction and ECG simulation

Objectives: In this paper, we present a unified electrodynamic heart model that permits simulations of the body surface potentials generated by the heart in motion. The inclusion of motion in the heart model significantly improves the accuracy of the simulated body surface potentials and therefore also the 12-lead ECG. Methods: The key step is to construct an electromechanical heart model. The cardiac excitation propagation is simulated by an electrical heart model, and the resulting cardiac active forces are used to calculate the ventricular wall motion based on a mechanical model. The source-field point relative position changes during heart systole and diastole. These can be obtained, and then used to calculate body surface ECG based on the electrical heart-torso model. Results: An electromechanical biventricular heart model is constructed and a standard 12-lead ECG is simulated. Compared with a simulated ECG based on the static electrical heart model, the simulated ECG based on the dynamic heart model is more accordant with a clinically recorded ECG, especially for the ST segment and T wave of a V1-V6 lead ECG. For slight-degree myocardial ischemia ECG simulation, the ST segment and T wave changes can be observed from the simulated ECG based on a dynamic heart model, while the ST segment and T wave of simulated ECG based on a static heart model is almost unchanged when compared with a normal ECG. Conclusions: This study confirms the importance of the mechanical factor in the ECG simulation. The dynamic heart model could provide more accurate ECG simulation, especially for myocardial ischemia or infarction simulation, since the main ECG changes occur at the ST segment and T wave, which correspond with cardiac systole and diastole phases.

Fracture load and marginal fit of shrinkage-free ZrSiO4 all-ceramic crowns after chewing simulation

The aim of this in vitro study was to evaluate the fracture load and marginal accuracy of crowns made from a shrinkage-free ZrSiO4 ceramic cemented with glass-ionomer or composite cement after chewing simulation. Thirty-two human mandibular molars were randomly divided into two groups. All teeth were prepared for and restored with shrinkage-free ZrSiO4 ceramic crowns (Everest HPC (R), KaVo). The crowns of group A (N = 16) were luted to the teeth using KetacCem (R) and group B (N = 16) were adhesively cemented using Panavia (R) 21EX. Measurements of the marginal accuracy before and after cementation were made using replicas and an image analysis system. All specimens were exposed to 1.2 million cycles of thermo-mechanical fatigue in a chewing simulator. Surviving specimens were subsequently loaded until fracture in a static testing device. Fracture loads (N) were recorded. All specimens survived chewing simulation. The mean fracture loads (+/- s.d.) were Group A, 1622 N (+/- 433); group B, 1957 N (+/- 806). There was no significant difference between the two groups (P > 0.05). The marginal gap values before cementation were (mean +/- s.d.): Group A, 32.7 mu m (+/- 6.8); group B, 33.0 mu m (+/- 6.7).The mean marginal gap values after cementation were (+/- s.d.): Group A, 44.6 mu m (+/- 6.7); group B, 46.6 mu m (+/- 7.7). The marginal openings were significantly higher after cementation for both groups (P < 0.05). All test groups demonstrated fracture load and marginal accuracy values within the range of clinical acceptability.

Simulation of Brugada syndrome using cellular and three-dimensional whole-heart modeling approaches

Brugada syndrome (BS) is a genetic disease identified by an abnormal electrocardiogram ( ECG) ( mainly abnormal ECGs associated with right bundle branch block and ST-elevation in right precordial leads). BS can lead to increased risk of sudden cardiac death. Experimental studies on human ventricular myocardium with BS have been limited due to difficulties in obtaining data. Thus, the use of computer simulation is an important alternative. Most previous BS simulations were based on animal heart cell models. However, due to species differences, the use of human heart cell models, especially a model with three-dimensional whole-heart anatomical structure, is needed. In this study, we developed a model of the human ventricular action potential (AP) based on refining the ten Tusscher et al (2004 Am. J. Physiol. Heart Circ. Physiol. 286 H1573 - 89) model to incorporate newly available experimental data of some major ionic currents of human ventricular myocytes. These modified channels include the L-type calcium current (ICaL), fast sodium current (I-Na), transient outward potassium current (I-to), rapidly and slowly delayed rectifier potassium currents (I-Kr and I-Ks) and inward rectifier potassium current (I-Ki). Transmural heterogeneity of APs for epicardial, endocardial and mid-myocardial (M) cells was simulated by varying the maximum conductance of IKs and Ito. The modified AP models were then used to simulate the effects of BS on cellular AP and body surface potentials using a three-dimensional dynamic heart - torso model. Our main findings are as follows. (1) BS has little effect on the AP of endocardial or mid-myocardial cells, but has a large impact on the AP of epicardial cells. (2) A likely region of BS with abnormal cell AP is near the right ventricular outflow track, and the resulting ST-segment elevation is located in the median precordium area. These simulation results are consistent with experimental findings reported in the literature. The model can reproduce a variety of electrophysiological behaviors and provides a good basis for understanding the genesis of abnormal ECG under the condition of BS disease.

Serologic response to human papillomavirus 16 among Australian women with high-grade cervical intraepithelial neoplasia

This study evaluated the detection of human papillomavirus (HPV) 16 antibody in HPV 16-associated cervical intraepithelial neoplasia (CIN) in Australian women. Seroreactivity to HPV 16 L1 virus-like particles was assessed in patients with CIN 2 (n = 169) and CIN 3 (n = 229) lesions previously tested for the presence of HPV DNA. Seropositivity was significantly commoner in women with HPV 16 DNA-positive lesions (98/184) than in women with no HPV DNA in the lesion (15/47) or with HPV of types other than 16 in the lesion (43/167) (P = 0.0004). In addition, seropositivity was observed in 33% (55/169) of women with CIN 2 and 46% (106/229) of women with CIN 3, in keeping with the lower fraction of CIN 2 (57/169) than CIN 3 (127/229) biopsies positive for HPV 16 DNA. HPV 16 seropositivity is most common in women with HPV 16-associated CIN, but many patients with HPV-associated CIN 3 are seronegative, and HPV 16 seropositivity is common in women with CIN associated with other HPV types. Overall, HPV 16 serology is a poor predictor of presence of HPV 16-associated CIN 3 in patient population studied.

A review of plasma endothelin-1 levels in CABG patient group

Introduction: Endothelin-1 is a potent vasoconstricting growth peptide. In physiologic conditions basal levels maintain vascular homeostasis, conversely in pathological situations it may be expressed in response to chronic and acute vascular injury. Elevated levels of plasma ET-1 have been identified in sub-populations at risk of ischaemic heart disease (IHD) including smokers, diabetics and hyerlipidaemic subjects and in patients with atherosclerotic disease. This peptide may be chronically expressed, such as in congestive heart failure where it has been used as a prognostic marker of disease severity and also acutely, after cardiac revascularisation surgery, possibly as a result of endothelial injury and ischaemia. Aims: The objectives of this study were to (1) identify basal endothelin-1 concentrations in a young healthy control group with no risk factors for IHD (control group 1); (2) to compare; (1) venous plasma ET-1 levels preoperatively and post-operatively in patients undergoing CABG surgery, (3) to compare pre-operative plasma ET-1 levels from the CABG group with an age and gender matched control group (control group 2) and (4) combine all three groups to assess correlations between plasma ET-1 and the various risk factors for IHD, including smoking, hypertension, hyperlipidemia, diabetes and family history. Methods: Venous specimens were collected in chilled EDTA tubes and samples measured using an ELISA assay (Biomedica), following the standard protocol for human EDTA plasma. Results: Forty CABG patients (5F, 35M, mean age 66 yrs), 15 control group 1 subjects (8F, 7M, mean age 29 yrs) and 30 control group 2 subjects (5F, 25M, mean age 61 yrs) participated in the study. No significant difference was detected in plasma ET-1 levels between the controls (1) and (2), and the CABG group, where plasma ET-1 levels were 3.37+/ 5.19 pmol/L, 1.99+/3.74 pmol/L and 1.28+/1.27 pmol/L, respectively. There was a non-significant elevation in post-op ET-1 plasma in comparison with the pre-op levels (2.50+/0.51 Vs 1.45+/6.44). There were also no statistical correlation between risk factors for IHD including smoking, hypertension, NIDDM, hyperlipidemia or family history when data from both patient and controls groups was merged. Conclusion: Contrary to other findings, plasma ET-1 does not appear to a valid marker for IHD or factors which are strongly associated with the pathogenesis of this disease.

Simulation of air traffic controllers' behaviour using the operator choice model

The Operator Choice Model (OCM) was developed to model the behaviour of operators attending to complex tasks involving interdependent concurrent activities, such as in Air Traffic Control (ATC). The purpose of the OCM is to provide a flexible framework for modelling and simulation that can be used for quantitative analyses in human reliability assessment, comparison between human computer interaction (HCI) designs, and analysis of operator workload. The OCM virtual operator is essentially a cycle of four processes: Scan Classify Decide Action Perform Action. Once a cycle is complete, the operator will return to the Scan process. It is also possible to truncate a cycle and return to Scan after each of the processes. These processes are described using Continuous Time Probabilistic Automata (CTPA). The details of the probability and timing models are specific to the domain of application, and need to be specified using domain experts. We are building an application of the OCM for use in ATC. In order to develop a realistic model we are calibrating the probability and timing models that comprise each process using experimental data from a series of experiments conducted with student subjects. These experiments have identified the factors that influence perception and decision making in simplified conflict detection and resolution tasks. This paper presents an application of the OCM approach to a simple ATC conflict detection experiment. The aim is to calibrate the OCM so that its behaviour resembles that of the experimental subjects when it is challenged with the same task. Its behaviour should also interpolate when challenged with scenarios similar to those used to calibrate it. The approach illustrated here uses logistic regression to model the classifications made by the subjects. This model is fitted to the calibration data, and provides an extrapolation to classifications in scenarios outside of the calibration data. A simple strategy is used to calibrate the timing component of the model, and the results for reaction times are compared between the OCM and the student subjects. While this approach to timing does not capture the full complexity of the reaction time distribution seen in the data from the student subjects, the mean and the tail of the distributions are similar.