Stress-related reduction in personal mastery is associated with reduced immune cell beta2-adrenergic receptor sensitivity

Background: A growing body of literature suggests that caregiving burden is associated with impaired immune system functioning, which may contribute to elevated morbidity and mortality risk among dementia caregivers. However, potential mechanisms linking these relationships are not well understood. The purpose of this study was to investigate whether stress-related experience of depressive symptoms and reductions in personal mastery were related to alterations in ss2-adrenergic receptor sensitivity.Methods: Spousal Alzheimer's caregivers (N = 106) completed measures assessing the extent to which they felt overloaded by their caregiving responsibilities, experienced depressive symptoms, and believed their life circumstances were under their control. We hypothesized that caregivers reporting elevated stress would report increased depressive symptoms and reduced mastery, which in turn would be associated with reduced ss2- adrenergic receptor sensitivity on peripheral blood mononuclear cells (PBMC), as assessed by in vitro isoproterenol stimulation.Results: Regression analyses indicated that overload was negatively associated with mastery (beta = -0.36, p = 0.001) and receptor sensitivity (beta = -0.24, p = 0.030), whereas mastery was positively associated with receptor sensitivity (beta = 0.29, p = 0.005). Finally, the relationship between overload and receptor sensitivity diminshed upon simultaneous entry of mastery. Sobel's test confirmed that mastery significantly mediated some of the relationship between overload and receptor sensitivity (z = -2.02, p = 0.044).Conclusions: These results suggest that a reduced sense of mastery may help explain the association between caregiving burden and reduced immune cell ss2-receptor sensitivity.

On the Accelerated Failure Time Model for Current Status and Interval Censored Data

This paper introduces a novel approach to making inference about the regression parameters in the accelerated failure time (AFT) model for current status and interval censored data. The estimator is constructed by inverting a Wald type test for testing a null proportional hazards model. A numerically efficient Markov chain Monte Carlo (MCMC) based resampling method is proposed to simultaneously obtain the point estimator and a consistent estimator of its variance-covariance matrix. We illustrate our approach with interval censored data sets from two clinical studies. Extensive numerical studies are conducted to evaluate the finite sample performance of the new estimators.

Cost-effectiveness of pharmacogenetic testing to predict treatment response to angiotensin-converting enzyme inhibitor

OBJECTIVE: This study aimed to assess the potential cost-effectiveness of testing patients with nephropathies for the I/D polymorphism before starting angiotensin-converting enzyme (ACE) inhibitor therapy, using a 3-year time horizon and a healthcare perspective. METHODS: We used a combination of a decision analysis and Markov modeling technique to evaluate the potential economic value of this pharmacogenetic test by preventing unfavorable treatment in patients with nephropathies. The estimation of the predictive value of the I/D polymorphism is based on a systematic review showing that DD carriers tend to respond well to ACE inhibitors, while II carriers seem not to benefit adequately from this treatment. Data on the ACE inhibitor effectiveness in nephropathy were derived from the REIN (Ramipril Efficacy in Nephropathy) trial. We calculated the number of patients with end-stage renal disease (ESRD) prevented and the differences in the incremental costs and incremental effect expressed as life-years free of ESRD. A probabilistic sensitivity analysis was conducted to determine the robustness of the results. RESULTS: Compared with unselective treatment, testing patients for their ACE genotype could save 12 patients per 1000 from developing ESRD during the 3 years covered by the model. As the mean net cost savings was euro 356,000 per 1000 patient-years, and 9 life-years free of ESRD were gained, selective treatment seems to be dominant. CONCLUSION: The study suggests that genetic testing of the I/D polymorphism in patients with nephropathy before initiating ACE therapy will most likely be cost-effective, even if the risk for II carriers to develop ESRD when treated with ACE inhibitors is only 1.4% higher than for DD carriers. Further studies, however, are required to corroborate the difference in treatment response between ACE genotypes, before genetic testing can be justified in clinical practice.

The KIDSCREEN-27 quality of life measure for children and adolescents: psychometric results from a cross-cultural survey in 13 European countries

OBJECTIVE: To assess the construct and criterion validity of the KIDSCREEN-27 health-related quality of life (HRQoL) questionnaire, a shorter version of the KIDSCREEN-52. METHODS: The five-dimensional KIDSCREEN-27 was tested in a sample of 22,827. For criterion validity the correlation with and the percentage explained variance of the scores of the KIDSCREEN-52 instrument were examined. Construct validity was assessed by testing a priori expected associations with other generic HRQoL measures (YQOL-S, PedsQL, CHIP), indicators of physical and mental health, and socioeconomic status. Age and gender differences were investigated. RESULTS: Correlation with corresponding scales of the KIDSCREEN-52 ranged from r = 0.63 to r = 0.96, and r2 ranged from 0.39 to 0.92. Correlations between other HRQoL questionnaires and KIDSCREEN-27 dimensions were moderate to high for those assessing similar constructs (r = 0.36 to 0.63). Statistically significant and sizeable differences between physically and mentally healthy and ill children were found in all KIDSCREEN-27 dimensions together with strong associations with psychosomatic complaints (r = -0.52). Most of the KIDSCREEN-27 dimensions showed a gradient according to socio-economic status, age and gender. CONCLUSIONS: The KIDSCREEN-27 seems to be a valid measure of HRQoL in children and adolescents. Further research is needed to assess longitudinal validity and sensitivity to change.

Oxidative stress in brain during experimental bacterial meningitis: differential effects of alpha-phenyl-tert-butyl nitrone and N-acetylcysteine treatment

Antioxidant treatment has previously been shown to be neuroprotective in experimental bacterial meningitis. To obtain quantitative evidence for oxidative stress in this disease, we measured the major brain antioxidants ascorbate and reduced glutathione, and the lipid peroxidation endproduct malondialdehyde in the cortex of infant rats infected with Streptococcus pneumoniae. Cortical levels of the two antioxidants were markedly decreased 22 h after infection, when animals were severely ill. Total pyridine nucleotide levels in the cortex were unaltered, suggesting that the loss of the two antioxidants was not due to cell necrosis. Bacterial meningitis was accompanied by a moderate, significant increase in cortical malondialdehyde. While treatment with either of the antioxidants alpha-phenyl-tert-butyl nitrone or N-acetylcysteine significantly inhibited this increase, only the former attenuated the loss of endogenous antioxidants. Cerebrospinal fluid bacterial titer, nitrite and nitrate levels, and myeloperoxidase activity at 18 h after infection were unaffected by antioxidant treatment, suggesting that they acted by mechanisms other than modulation of inflammation. The results demonstrate that bacterial meningitis is accompanied by oxidative stress in the brain parenchyma. Furthermore, increased cortical lipid peroxidation does not appear to be the result of parenchymal oxidative stress, because it was prevented by NAC, which had no effect on the loss of brain antioxidants.

Hardware accelerated ray cast of volume data and volume gradient for an optimized splines-based multi-resolution 2D-3D registration

This paper describes a method for DRR generation as well as for volume gradients projection using hardware accelerated 2D texture mapping and accumulation buffering and demonstrates its application in 2D-3D registration of X-ray fluoroscopy to CT images. The robustness of the present registration scheme are guaranteed by taking advantage of a coarse-to-fine processing of the volume/image pyramids based on cubic B-splines. A human cadaveric spine specimen together with its ground truth was used to compare the present scheme with a purely software-based scheme in three aspects: accuracy, speed, and capture ranges. Our experiments revealed an equivalent accuracy and capture ranges but with much shorter registration time with the present scheme. More specifically, the results showed 0.8 mm average target registration error, 55 second average execution time per registration, and 10 mm and 10° capture ranges for the present scheme when tested on a 3.0 GHz Pentium 4 computer.

Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis

ABSTRACT: INTRODUCTION: In transgenic animal models of sepsis, members of the Bcl-2-family of proteins regulate lymphocyte apoptosis and survival of sepsis. This study investigates the gene regulation of pro- and anti-apoptotic members of the Bcl-2-family of proteins in patients with early stage severe sepsis. METHODS: In this prospective case-control study patients were recruited from three intensive care units in a university hospital. Sixteen patients were enrolled as soon as they fulfilled the criteria of severe sepsis. Ten critically ill but non-septic patients and eleven healthy volunteers served as controls. Blood samples were immediately obtained at inclusion. To confirm the presence of accelerated apoptosis in the patient groups, caspase-3 activation and phosphatidylserine (PS) externalization in CD4+, CD8+ and CD19+ lymphocyte subsets were assessed by flow cytometry. Specific mRNA's of Bcl-2 family members were quantified from whole blood by real-time polymerase chain reaction. To test for statistical significance, Kruskal-Wallis testing with Dunn's multiple comparison test for post hoc testing was performed. RESULTS: In all lymphocyte populations caspase-3 (p<0.05) was activated, which was reflected in an increased PS externalization (p<0.05). Accordingly, lymphocyte counts were decreased in early severe sepsis. In CD4+ T-cells (p<005) and in B-cells (p<0.001) the Bcl-2 protein was decreased in severe sepsis. Gene expression of the BH3-only Bim was massively upregulated as compared to critically ill patients (p<0.001) and 51.6 fold as compared to healthy controls (p<0.05). Bid was increased 12.9 fold compared to critically ill (p<0.001). In the group of the mitochondrial apoptosis-inducers, Bak was upregulated 5.6 fold, while the expression of Bax showed no significant variations. By contrast, the pro-survival members Bcl-2 and Bcl-xl were both downregulated in severe sepsis (p<0.001, p<0.05). CONCLUSIONS: In early severe sepsis a gene expression pattern with induction of the pro-apoptotic Bcl-2 family members Bim, Bid and Bak and a downregulation of the anti-apoptotic Bcl-2 and Bcl-xl was observed in peripheral blood. This constellation may affect cellular susceptibility to apoptosis and complex immune dysfunction in sepsis.

Structured training in intraosseous infusion to improve potentially life saving skills in pediatric emergencies - Results of an open prospective national quality development project over 3 years

BACKGROUND: Children in emergencies need peripheral intravenous (IV) access in order to receive drugs or fluids. The success of IV access is associated with the age of patients and fails in up to 50% of children younger than 6 years. In such situations, it is essential that physicians and paramedics have a tool and easily learnable skills with a high chance of success. According to international guidelines intraosseous (IO) access would be the next step after failed IV access. Our hypothesis was that the success rate in IO puncturing can be improved by standardizing the training; so we developed an IO workshop. METHODS: Twenty-eight hospitals and ambulance services participated in an evaluation process over 3 years. IO workshops and the distribution of standardized IO sets were coordinated by the study group of the University Hospital of Berne. Any attempted or successful IO punctures were evaluated with a standardized interview. RESULTS: We investigated 35 applications in 30 patients (a total of 49 punctures) between November 2001 and December 2004. IO puncture was not successful in 5 patients. The success rate depended neither on the occupation nor the experience of users. Attendance at a standardized IO workshop increased the overall success rate from 77% to 100%, which was statistically not significant (P = 0.074). CONCLUSIONS: Standardized training in IO puncturing seems to improve success more than previous experience and occupation of providers. However, we could not show a significant increase in success rate after this training. Larger supranational studies are needed to show a significant impact of teaching on rarely used emergency skills.

Posttraumatic stress disorder after implantation of a mechanical assist device followed by heart transplantation: evaluation of patients and partners

AIM: We sought to investigate the prevalence of posttraumatic stress disorder, anxiety, and depression in patients and their partners after implantation of a mechanical assist device as a bridge to heart transplantation. METHODS: This was a retrospective assessment of 41 patients (age 46.3 +/- 12.0 years; male-female ratio, 38:3; time since transplantation, 55.3 +/- 34.2 months [range, 7-122 months) and 27 partners (male-female ratio 2:25) by standardized instruments (Impact of Event Scale, Hospital Anxiety and Depression Scale), in 2 University Heart Transplant Centers (Vienna, Austria, Munster, Germany). The duration of the support systems (MicroMed DeBakey-VAD in 17 patients, Novacor in 10, Thoratec in 8, TCI HeartMate in 5, and Berlin Heart Incor in 1 patient) ranged from 28 to 711 (176 +/- 146) days. RESULTS: None of the patients, but 23% of the partners (n = 6), met the criteria for posttraumatic stress disorder (Maercker cutoff >0). The Impact of Event Scale (IES) sum scales differed significantly between the 2 groups (21.2 +/- 15.1, mean +/- SD) for the patients versus 38.1 +/- 27.8 for the partners, respectively; P = .001). Two percent of the patients, but 19% of the partners, showed mild to moderate depression; 4% of patients, but 23% of their partners, reported mild to moderate anxiety. None of the results were significantly influenced by the time since transplantation, patient age, diagnoses, type of assist device, or indication for heart transplantation. CONCLUSIONS: Despite patients being much closer to a life threat, their partners experience significantly more psychologic distress even in the long run. Our findings highlight the need for attention to the supporting persons.

Patients with erythrophobia (fear of blushing) show abnormal autonomic regulation in mental stress conditions

OBJECTIVE: The objective of this study was to analyze the autonomic functions of patients with erythrophobia. METHODS: Forty patients with a diagnosis of erythrophobia (female/male ratio 18/22) without any other organic lesions and 20 healthy volunteers (female/male ratio 10/10) were assessed. Clinical evaluation was performed using a modified version of semistructured interviews. Autonomic testing was performed by means of spectral analysis of heart rate and continuous blood pressure by sparse discrete Fourier transformation at rest and under mental stress. RESULTS: There were no significant difference between the two samples in age, sex distribution, BMI, resting systolic, or diastolic blood pressure, nor was there a difference in autonomic baseline functioning between the 40 patients with erythrophobia and the control subjects. On the other hand, patients with erythrophobia consistently showed higher pulse rates (88 +/- 20 vs. 78 +/- 9 bpm, p <.05), higher total heart rate power values (8.40 +/- 0.63 vs. 8.07 +/- 1.02 p <.05), higher midfrequency spectral values (7.38 +/- 0.66 vs. 7.02 +/- 1.18, p <.01), higher high-frequency spectral values (6.89 +/- 0.86 vs. 6.48 +/- 1.44, p <.05), and lower baroreceptor sensitivity (8.62 +/- 8.16 vs. 11.65 +/- 4.42, p <.005) than the healthy subjects. ANOVA showed a significant group interaction (p <.0001) between the samples. CONCLUSIONS: This study provides evidence for abnormal autonomic functioning in patients with erythrophobia when under mental stress.

Prognostic value of early exercise testing after coronary stent implantation

The clinical value of early exercise stress testing (EST) after coronary stenting to predict long-term clinical outcomes is unknown. Of 1,000 unselected patients who underwent coronary stenting, 446 random patients underwent early EST the day after intervention. Clinical long-term outcomes (41 +/- 20 months) were correlated with normal (n = 314 [70%]) or positive (n = 102 [23%]) EST results. Patients with inconclusive test results (n = 30 [7%]) were excluded from the analysis. Overall mortality was significantly higher in patients with positive EST results (9.3% vs 3.9%, p = 0.04). Major adverse cardiac events and cardiac mortality also tended to be higher in patients with positive stress test results (45.4% vs 35.4%, p = 0.08, and 4.1% vs 1.1%, p = 0.05, respectively). Patients with the combination of positive stress test results and incomplete revascularization appeared to be the group at highest risk for major adverse cardiac events (47.1% vs 33.3% for patients with normal stress test results and complete revascularization, p = NS). Negative stress test results reduced (odds ratio 0.329, 95% confidence interval 0.120 to 0.905, p = 0.031) and a lower ejection fraction increased (odds ratio 0.942, 95% confidence interval 0.897 to 0.989, p = 0.017) the risk for death. In conclusion, an early stress test after coronary stenting provides important prognostic information. Positive stress test results, especially in combination with incomplete revascularization, are associated with higher mortality, a trend toward more repeat revascularization procedures, and higher risk for major adverse cardiac events.

Quantitative stress echocardiography in coronary artery disease using contrast-based myocardial blood flow measurements: prospective comparison with coronary angiography

AIM: To test whether quantitative stress echocardiography using contrast-based myocardial blood flow (MBF, ml x min(-1) x g(-1)) measurements can detect coronary artery disease in humans. METHODS: 48 patients eligible for pharmacological stress testing by myocardial contrast echocardiography (MCE) and willing to undergo subsequent coronary angiography were prospectively enrolled in the study. Baseline and adenosine-induced (140 microg x kg(-1) x min(-1)) hyperaemic MBF was analysed according to a three-coronary-artery-territory model. Vascular territories were categorised into three groups with increasing stenosis severity defined as percentage diameter reduction by quantitative coronary angiography. RESULTS: Myocardial blood flow reserve (MBFR)-that is, the ratio of hyperaemic to baseline MBF, was obtained in 128 (89%) territories. Mean (SD) baseline MBF was 1.073 (0.395) ml x min(-1) x g(-1) and did not differ between territories supplied by coronary arteries with mild (<50% stenosis), moderate (50%-74% stenosis) or severe (>or=75% stenosis) disease. Mean (SD) hyperaemic MBF and MBFR were 2.509 (1.078) ml x min(-1) x g(-1) and 2.54 (1.03), respectively, and decreased linearly (r2 = 0.21 and r2 = 0.39) with stenosis severity. ROC analysis revealed that a territorial MBFR <1.94 detected >or=50% stenosis with 89% sensitivity and 92% specificity. CONCLUSION: Quantitative stress testing based on MBF measurements derived from contrast echocardiography is a new method for the non-invasive and reliable assessment of coronary artery disease in humans.

ATP modeling of internal transformer faults for relay performance testing

Transformers are very important elements of any power system. Unfortunately, they are subjected to through-faults and abnormal operating conditions which can affect not only the transformer itself but also other equipment connected to the transformer. Thus, it is essential to provide sufficient protection for transformers as well as the best possible selectivity and sensitivity of the protection. Nowadays microprocessor-based relays are widely used to protect power equipment. Current differential and voltage protection strategies are used in transformer protection applications and provide fast and sensitive multi-level protection and monitoring. The elements responsible for detecting turn-to-turn and turn-to-ground faults are the negative-sequence percentage differential element and restricted earth-fault (REF) element, respectively. During severe internal faults current transformers can saturate and slow down the speed of relay operation which affects the degree of equipment damage. The scope of this work is to develop a modeling methodology to perform simulations and laboratory tests for internal faults such as turn-to-turn and turn-to-ground for two step-down power transformers with capacity ratings of 11.2 MVA and 290 MVA. The simulated current waveforms are injected to a microprocessor relay to check its sensitivity for these internal faults. Saturation of current transformers is also studied in this work. All simulations are performed with the Alternative Transients Program (ATP) utilizing the internal fault model for three-phase two-winding transformers. The tested microprocessor relay is the SEL-487E current differential and voltage protection relay. The results showed that the ATP internal fault model can be used for testing microprocessor relays for any percentage of turns involved in an internal fault. An interesting observation from the experiments was that the SEL-487E relay is more sensitive to turn-to-turn faults than advertized for the transformers studied. The sensitivity of the restricted earth-fault element was confirmed. CT saturation cases showed that low accuracy CTs can be saturated with a high percentage of turn-to-turn faults, where the CT burden will affect the extent of saturation. Recommendations for future work include more accurate simulation of internal faults, transformer energization inrush, and other scenarios involving core saturation, using the newest version of the internal fault model. The SEL-487E relay or other microprocessor relays should again be tested for performance. Also, application of a grounding bank to the delta-connected side of a transformer will increase the zone of protection and relay performance can be tested for internal ground faults on both sides of a transformer.

Estimation of scots pine defoliation by the common pine sawfly (Diprion pini L.) using multi-temporal radar data

In 1998-2001 Finland suffered the most severe insect outbreak ever recorded, over 500,000 hectares. The outbreak was caused by the common pine sawfly (Diprion pini L.). The outbreak has continued in the study area, Palokangas, ever since. To find a good method to monitor this type of outbreaks, the purpose of this study was to examine the efficacy of multi-temporal ERS-2 and ENVISAT SAR imagery for estimating Scots pine (Pinus sylvestris L.) defoliation. Three methods were tested: unsupervised k-means clustering, supervised linear discriminant analysis (LDA) and logistic regression. In addition, I assessed if harvested areas could be differentiated from the defoliated forest using the same methods. Two different speckle filters were used to determine the effect of filtering on the SAR imagery and subsequent results. The logistic regression performed best, producing a classification accuracy of 81.6% (kappa 0.62) with two classes (no defoliation, >20% defoliation). LDA accuracy was with two classes at best 77.7% (kappa 0.54) and k-means 72.8 (0.46). In general, the largest speckle filter, 5 x 5 image window, performed best. When additional classes were added the accuracy was usually degraded on a step-by-step basis. The results were good, but because of the restrictions in the study they should be confirmed with independent data, before full conclusions can be made that results are reliable. The restrictions include the small size field data and, thus, the problems with accuracy assessment (no separate testing data) as well as the lack of meteorological data from the imaging dates.

Omega-3 fatty acids and the neurovascular responses to mental stress in humans

Hypertension is the most prevalent form of cardiovascular disease (CVD) in the world, and is known to increase the risk for developing other diseases. Recently, the American Heart Association introduced a new classification of blood pressure, prehypertension (PHT). The criteria for PHT include a systolic of 120-139 mmHg and/or a diastolic blood pressure of 80-89 mmHg. It has been observed that individuals with PHT have a higher risk of developing hypertension later in life. Therefore, it is important to understand the mechanisms contributing to PHT in order to possibly prevent hypertension. Omega-3 fatty acids found in fish oils have been suggested as a means of lowering blood pressure. However, little is known on the effects of fish oil in PHT humans. Therefore we conducted two studies. In Study 1 we investigated PHT and normotensive (NT) individuals during a mental stress task. Mental stress is known to contribute to the development of hypertension. In Study 2 PHT and NT subjects were placed in an eight week double-blind placebo controlled study in which subjects consumed 9g/day of either fish oil or placebo (olive oil) in addition to their regular diets. Subjects were tested during a resting baseline (seated and supine), 5 minutes of a mental stress task, and 5 minutes of recovery both pre and post supplementation. We measured arterial pressure (AP), heart rate (HR), muscle sympathetic nerve activity (MSNA), and forearm and calf vascular responses. In Study 1 PHT demonstrated augmented AP and blunted vasodilation during mental stress, but MSNA did not change. In Study 2, fish oil did not directly influence blood pressure, MSNA or vascular responses to mental stress. However, it became clear that fish oil had an effect on some but not all subjects (both PHT and NT). Specifically, subjects who experienced a reduced blood pressure response to fish oil also demonstrated a decrease in MSNA and HR during mental stress. Collectively, the investigations in this dissertation had several novel findings. First, PHT individuals demonstrate an augmented pressor and blunted vascular response to mental stress, a response that may be contributing to the development of hypertension. Second, fish oil does not consistently lower resting blood pressure, but the interindividual responses may be related to MSNA. Third, fish oil attenuated the heart rate and MSNA responses and to mental stress in both PHT and NT. In conclusion, we found that there are both similarities and differences in the way PHT and NT individuals respond to mental stress and fish oil.