Computational methods for prediction of T-cell epitopes - a framework for modelling, testing, and applications

Computational models complement laboratory experimentation for efficient identification of MHC-binding peptides and T-cell epitopes. Methods for prediction of MHC-binding peptides include binding motifs, quantitative matrices, artificial neural networks, hidden Markov models, and molecular modelling. Models derived by these methods have been successfully used for prediction of T-cell epitopes in cancer, autoimmunity, infectious disease, and allergy. For maximum benefit, the use of computer models must be treated as experiments analogous to standard laboratory procedures and performed according to strict standards. This requires careful selection of data for model building, and adequate testing and validation. A range of web-based databases and MHC-binding prediction programs are available. Although some available prediction programs for particular MHC alleles have reasonable accuracy, there is no guarantee that all models produce good quality predictions. In this article, we present and discuss a framework for modelling, testing, and applications of computational methods used in predictions of T-cell epitopes. (C) 2004 Elsevier Inc. All rights reserved.

How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review

Objective To assess how well B-type natriuretic peptide (BNP) predicts prognosis in patients with heart failure. Design Systematic review of studies assessing BNP for prognosis m patients with heart failure or asymptomatic patients. Data sources Electronic searches of Medline and Embase from January 1994 to March 2004 and reference lists of included studies. Study selection and data extraction We included all studies that estimated the relation between BNP measurement and the risk of death, cardiac death, sudden death, or cardiovascular event in patients with heart failure or asymptomatic patients, including initial values and changes in values in response to treatment. Multivariable models that included both BNP and left ventricular ejection fraction as predictors were used to compare the prognostic value of each variable. Two reviewers independently selected studies and extracted data. Data synthesis 19 studies used BNP to estimate the relative risk of death or cardiovascular events in heart failure patients and five studies in asymptomatic patients. In heart failure patients, each 100 pg/ml increase was associated with a 35% increase in the relative risk of death. BNP was used in 35 multivariable models of prognosis. In nine of the models, it was the only variable to reach significance-that is, other variables contained no prognostic information beyond that of BNP. Even allowing for the scale of the variables, it seems to be a strong indicator of risk. Conclusion Although systematic reviews of prognostic studies have inherent difficulties, including die possibility of publication bias, the results of the studies in this review show that BNP is a strong prognostic indicator for both asymptomatic patients mid for patients with heart failure at all stages of disease.

Trigeminal pain and quantitative sensory testing in painful peripheral diabetic neuropathy

Objective: To evaluate patients with Diabetes Mellitus type 2 and painful peripheral neuropathy in order to investigate oral complaints and facial somatosensory findings. Research design and methods: Case-control study; 29 patients (12 women, mean age 57.86 yo) with Diabetes Mellitus type 2 and 31 age-gender-matched controls were evaluated with a standardized protocol for general characteristics, orofacial pain, research diagnostic criteria for temporomandibular disorders, visual analogue scale and McGill Pain questionnaire, and a systematic protocol of quantitative sensory testing for bilateral facial sensitivity at the areas innervated by the trigeminal branches, which included the thermal detection by ThermoSensi 2, tactile evaluation with vonFrey filaments, and superficial pain thresholds with a superficial algometer (Micromar). Statistical analysis was performed with Wilcoxon, chi-square, confidence intervals and Spearman (p < 0.05). Results: Orofacial pain was reported by 55.2% of patients, and the most common descriptor was fatigue (50%); 17.2% had burning mouth. Myofascial temporomandibular disorders were diagnosed in 9(31%) patients. The study group showed higher sensory thresholds of pain at the right maxillary branch (p = 0.017) but sensorial differences were not associated with pain (p = 0.608). Glycemia and HbA(1c) were positively correlated with the quantitative sensory testing results of pain (p < 0.05) and cold (p = 0.044) perceptions. Higher pain thresholds were correlated with higher glycemia and glycated hemoglobin (p = 0.027 and p = 0.026). Conclusions: There was a high prevalence of orofacial pain and burning mouth was the most common complaint. The association of loss of pain sensation and higher glycemia and glycated hemoglobin can be of clinical use for the follow-up of DM complications. (C) 2010 Elsevier Ltd. All rights reserved.

Myocardial scintigraphy and clinical stratification as predictors of events in renal transplant candidates

Background: We tested the hypothesis that the universal application of myocardial scanning with single-photon emission computed tomography (SPECT) would result in better risk stratification in renal transplant candidates (RTC) compared with SPECT being restricted to patients who, in addition to renal disease, had other clinical risk factors. Methods: RTCs (n=363) underwent SPECT and clinical risk stratification according to the American Society of Transplantation (AST) algorithm and were followed up until a major adverse cardiovascular event (MACE) or death. Results: Of the 363 patients, 79 patients (22%) had an abnormal SPECT scan and 270 (74%) were classified as high risk. Both methods correctly identified patients with increased probability of MACE. However, clinical stratification performed better (sensitivity and negative predictive value 99% and 99% vs. 25% and 87%, respectively). High-risk patients with an abnormal SPECT scan had a modest increased risk of events (log-rank = 0.03; hazard ratio [HR] = 1.37; 95% confidence interval [95% CI], 1.02-1.82). Eighty-six patients underwent coronary angiography, and coronary artery disease (CAD) was found in 60%. High-risk patients with CAD had an increased incidence of events (log-rank = 0.008; HR=3.85; 95% CI, 1.46-13.22), but in those with an abnormal SPECT scan, the incidence of events was not influenced by CAD (log-rank = 0.23). Forty-six patients died. Clinical stratification, but not SPECT, correlated with the probability of death (log-rank = 0.02; HR=3.25; 95% CI, 1.31-10.82). Conclusion: SPECT should be restricted to high-risk patients. Moreover, in contrast to SPECT, the AST algorithm was also useful for predicting death by any cause in RTCs and for selecting patients for invasive coronary testing.

Executive "brake failure" following deactivation of human frontal lobe

In the course of daily living, humans frequently encounter situations in which a motor activity, once initiated, becomes unnecessary or inappropriate. Under such circumstances, the ability to inhibit motor responses can be of vital importance. Although the nature of response inhibition has been studied in psychology for several decades, its neural basis remains unclear. Using transcranial magnetic stimulation, we found that temporary deactivation of the pars opercularis in the right inferior frontal gyrus selectively impairs the ability to stop an initiated action. Critically, deactivation of the same region did not affect the ability to execute responses, nor did it influence physiological arousal. These findings confirm and extend recent reports that the inferior frontal gyrus is vital for mediating response inhibition.

INTRACRANIAL PRESSURE MONITORING IN CHILDREN WITH FULMINANT HEPATIC FAILURE

Introduction. We describe a series of 10 children with intracranial hypertension complicating fulminant hepatic failure submitted to intracranial pressure (ICP) monitoring for intensive care an transplantation management. Patients and methods. Information from pediatrics patients acute liver failure admitted to our hospital was collected in a standard protocol form. We analyzed data from 10 patients, medium age 5.2 years old. In this period we studied aspects as ICP transducer used, number of days with ICP monitoring and complications of ICP monitoring. Results. Hepatitis A was diagnosed in five patients and hepatitis B in two cases. The initial ICP were 2 to 24 mmHg in transducer Seven patients died, four due to intracranial hypertension, included the patient operated for subdural hematoma, and three with transplantation failure. Only, a case of hematoma was verified. Conclusions. The application of ICP monitoring allows intensive care for aggressive ICP management. It can be used in children without adaptations. [REV NEUROL 2009: 48: 134-6]

The prevalence and significance of periodic leg movements during sleep in patients with congestive heart failure

The aim of this study was to evaluate (1) the prevalence of periodic leg movements during sleep (PLMs) in a consecutive sample of congestive heart failure (CHF) outpatients; (2) the presence of correlation between PLMs, subjective daytime sleepiness, and sleep architecture; and (3) the heart rate response to PLMs in CHF. Seventy-nine [50 men, age 59 +/- 11 years, body mass index (BMI) 26 +/- 5 kg/m(2)] consecutive adult stable outpatients with CHF [left ventricular ejection fraction (LVEF) 36 +/- 6%] were prospectively evaluated. The patients underwent assessment of echocardiography, sleepiness (Epworth Scale), and overnight in-lab polysomnography. Fifteen patients (19%) had PLM index > 5. These subjects were similar in sex distribution, BMI, subjective somnolence, LVEF, and apnea-hypopnea index (AHI), but were significantly older than subjects without PLMs. Sleep architecture was similar in subjects with and without PLMs. There was a small but significant elevation of heart rate after PLMs (80.1 +/- 9.4 vs. 81.5 +/- 9.2; p < 0.001). The cardiac acceleration was also present in absence of electroencephalogram activation. The prevalence of PLMs in consecutive sample of adult CHF outpatients was 19%. There were no differences in subjective daytime sleepiness, sleep architecture, AHI, and severity of CHF in subjects with and without PLMs. PLMs caused a small but statistically significant cardiac acceleration.

Long-Term Prospective, Randomized, Controlled Study Using Repetitive Education at Six-Month Intervals and Monitoring for Adherence in Heart Failure Outpatients The REMADHE Trial

Background-The effectiveness of heart failure disease management proarams in patients under cardiologists` care over long-term follow-up is not established. Methods and Results-We investigated the effects of a disease management program with repetitive education and telephone monitoring on primary (combined death or unplanned first hospitalization and quality-of-life changes) and secondary end points (hospitalization, death, and adherence). The REMADHE [Repetitive Education and Monitoring for ADherence for Heart Failure] trial is a long-term randomized, prospective, parallel trial designed to compare intervention with control. One hundred seventeen patients were randomized to usual care, and 233 to additional intervention. The mean follow-up was 2.47 +/- 1.75 years, with 54% adherence to the program. In the intervention group, the primary end point composite of death or unplanned hospitalization was reduced (hazard ratio, 0.64; confidence interval, 0.43 to 0.88; P=0.008), driven by reduction in hospitalization. The quality-of-life questionnaire score improved only in the intervention group (P<0.003). Mortality was similar in both groups. Number of hospitalizations (1.3 +/- 1.7 versus 0.8 +/- 1.3, P<0.0001), total hospital days during the follow-up (19.9 +/- 51 versus 11.1 +/- 24 days, P<0.0001), and the need for emergency visits (4.5 +/- 10.6 versus 1.6 +/- 2.4, P<0.0001) were lower in the intervention group. Beneficial effects were homogeneous for sex, race, diabetes and no diabetes, age, functional class, and etiology. Conclusions-For a longer follow-up period than in previous studies, this heart failure disease management program model of patients under the supervision of a cardiologist is associated with a reduction in unplanned hospitalization, a reduction of total hospital days, and a reduced need for emergency care, as well as improved quality of life, despite modest program adherence over time. (Circ Heart Fail. 2008;1:115-124.)

A framework for specification-based testing

Test templates and a test template framework are introduced as useful concepts in specification-based testing. The framework can be defined using any model-based specification notation and used to derive tests from model-based specifications-in this paper, it is demonstrated using the Z notation. The framework formally defines test data sets and their relation to the operations in a specification and to other test data sets, providing structure to the testing process. Flexibility is preserved, so that many testing strategies can be used. Important application areas of the framework are discussed, including refinement of test data, regression testing, and test oracles.