DECO: decompose heterogeneous population cohorts for patient stratification and discovery of sample biomarkers using omic data profiling.

MOTIVATION: Patient and sample diversity is one of the main challenges when dealing with clinical cohorts in biomedical genomics studies. During last decade, several methods have been developed to identify biomarkers assigned to specific individuals or subtypes of samples. However, current methods still fail to discover markers in complex scenarios where heterogeneity or hidden phenotypical factors are present. Here, we propose a method to analyze and understand heterogeneous data avoiding classical normalization approaches of reducing or removing variation. RESULTS: DEcomposing heterogeneous Cohorts using Omic data profiling (DECO) is a method to find significant association among biological features (biomarkers) and samples (individuals) analyzing large-scale omic data. The method identifies and categorizes biomarkers of specific phenotypic conditions based on a recurrent differential analysis integrated with a non-symmetrical correspondence analysis. DECO integrates both omic data dispersion and predictor-response relationship from non-symmetrical correspondence analysis in a unique statistic (called h-statistic), allowing the identification of closely related sample categories within complex cohorts. The performance is demonstrated using simulated data and five experimental transcriptomic datasets, and comparing to seven other methods. We show DECO greatly enhances the discovery and subtle identification of biomarkers, making it especially suited for deep and accurate patient stratification. AVAILABILITY AND IMPLEMENTATION: DECO is freely available as an R package (including a practical vignette) at Bioconductor repository (http://bioconductor.org/packages/deco/). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Symptomatic myocardial ischemia and everyday life: implications for clinical use of interactive monitoring.

In coronary heart disease (CHD), pathological myocardial ischemic changes do not always occur with the symptom of heart pain. Methodological problems make it difficult to examine the factors that influence silent and symptomatic myocardial ischemia in everyday life. This study uses a computer-assisted monitoring system with an interactive Holter ECG, an actometer, and an electronic diary. Self-report measurements indicate that symptomatic patients tend toward increased neuroticism, whereas asymptomatic patients engage in beneficial and active coping skills more frequently. The results of the monitoring study demonstrate the same degree of ischemia in silent and symptomatic episodes. However, these episodes show differences in certain psychological context variables. Symptomatic episodes are linked to high subjective strain and severe tension. Because angina pectoris is not a reliable warning signal of myocardial ischemia, the use of the interactive monitoring system is recommended for educating CHD patients on how to cope with excessive strain in everyday life.

Verbal memory after three months of intranasal vasopressin in healthy old humans.

In animals, evidence has been accumulated that vasopressin (VP) improves learning and memory. In humans, this effect was not consistently demonstrated, and attempts to restore age-related memory deficits by VP also remained inconsistent. Assuming that in old subjects a beneficial effect on memory occurs only after prolonged treatment with VP, we conducted a study in 26 healthy elderly persons receiving 40 IU of VP for three months through the intranasal route. The trial was randomized, placebo-controlled and held double-blind. Memory was assessed by the Auditory Verbal Learning Test (AVLT) requiring the subject to learn repeatedly presented lists of 15 words. Results demonstrated no general effect of long-term treatment with VP on memory in aged humans. However, recall of an interfering word list was improved, indicating a diminished proactive interference by the peptide. Additionally, VP influenced recall depending on the serial position of an item: it improved the primacy effect (i.e. recall of the first words of a list) and impaired the recency effect. This result may indicate an improved semantic encoding (i.e. a primary effect on processes of attention) after long-term administration of VP.

The use of high-throughput synthesis and purification in the preparation of a directed library of adrenergic agents.

A library of potential agonists and antagonists for adrenergic receptors was prepared using high-throughput solution-phase parallel synthesis. Traditional solution-phase reductive amination reactions followed by rapid purification by ion exchange chromatography yielded products with near-analytical purity. An array of ketones and amines, arranged in an 8 x 12 matrix, were combined to form 96 individual compounds.

Comparison of two mechanical carotid baroreceptor stimulation techniques.

We compared two mechanical carotid baroreceptor stimulation techniques, the phase related external suction (PRES) method and the conventional neck suction techniques concerning their effects on blood pressure and heart rate responses in a group of 10 normotensive men. The cuff pressure using the PRES method was phase-locked in time to the R-wave of the ECG. During the conventional neck suction technique the cuff pressure changes were not related to the cardiac cycle, it was either negative or positive. Blood pressure was measured in four of the patients both invasively and noninvasively to compare the two baroreceptor stimulating methods. The results have indicated that (1) both mechanical carotid baroreceptor stimulation technique showed a significant heart rate deceleration to baroreceptor stimulation. (2) The heart rate changes were more pronounced during the continuous neck cuff technique, and the heart rate recovered sooner to the baseline. The variation of baroreceptor activity as induced by the PRES method seems to prevent habituation much more than the continuous neck suction method. (3) The systolic blood pressure decrease was significant both during PRES and continuous neck suction stimulation. A higher decrease in systolic blood pressure was shown during continuous neck suction stimulation compare to the PRES stimulation. (4) The diastolic blood pressure changes showed the same alteration for baroreceptor stimulation as compared to the control condition but there was no difference between the two stimulation methods. (5) The noninvasive Finapres blood pressure device measures blood pressure reliably.

Central effects of baroreceptor activation in humans: attenuation of skeletal reflexes and pain perception.

Activating the arterial baroreceptors blunts pain sensation and produces other forms of central nervous system inhibition in animals. These effects may be important to blood pressure regulation but have not been rigorously verified in humans. We describe (i) a noninvasive behaviorally unbiased method for baroreceptor stimulation and (ii) the application of this method to measurement of baroreceptor-mediated attenuation of pain perception and of the Achilles tendon reflex. The findings are relevant to basic mechanisms of blood pressure stabilization and cardiovascular reactivity and may also have implications for noncompliance with antihypertensive medications and for the pathophysiology of essential hypertension.

Reduced pain during baroreceptor stimulation in patients with symptomatic and silent myocardial ischaemia.

OBJECTIVE: Baroreceptor activation has been shown to reduce pain, and the accumulation of such pain reduction has been implicated in the operant learning (under certain circumstances) of hypertension. The current study is an examination of differences in the pain dampening effects of baroreceptor activity in patients with symptomatic and asymptomatic myocardial ischaemia. The objective was to determine whether there are differences between patients with symptomatic and silent myocardial ischaemia with respect to their antinociceptive response to baroreceptor stimulation, and, if so, whether these differences could be related to the absence of angina pectoris pain in patients with silent myocardial ischaemia. METHODS: Sensory detection and electrical pain thresholds were compared in nine symptomatic and 10 asymptomatic patients with replicable myocardial ischaemia during PRES (phase related external suction) carotid baroreceptor manipulation in which the pressure inside a neck cuff was phase locked in time to the R wave of the ECG and negative pressure was applied during either systole or diastole. Tourniquet pain thresholds were also determined. RESULTS: It was found that (1) external baroreceptor manipulation had no effect on detection thresholds; (2) painful stimuli were judged by both symptomatic and asymptomatic patients as less intense when delivered during maximum baroreceptor activity; (3) symptomatic and asymptomatic patients did not differ in their sensory detection thresholds; and (4) asymptomatic patients had significantly higher ischaemic (tourniquet) pain thresholds than symptomatic patients. CONCLUSIONS: The results indicate that baroreceptor activity can modify the intensity of painful stimuli. The degree to which baroreceptor manipulation affects pain does not appear to differ between patients with painful and silent myocardial ischaemia. Thus the baroreceptor dependent pain inhibition effects seems not to be responsible for the higher ischaemic pain threshold found in the silent myocardial ischaemia group.

Baroreceptor stimulation: pain perception and sensory thresholds.

Baroreceptor activity has been implicated in the modulation of pain. Sensory detection thresholds and pain ratings were measured in a group of 28 men during carotid baroreceptor manipulation with the PRES (phase-related external suction) neck suction technique. Brief, cardiac phase-related electrical impulses were delivered intracutaneously to the finger. The results indicate that minimum baroreceptor activity was associated with more severe pain, but had no effect on sensory detection threshold. The results are discussed in terms of the learned model of hypertension.

Sensory effects of baroreceptor activation and perceived stress together predict long-term blood pressure elevations.

Activating the arterial baroreceptors in animals has been shown to blunt pain sensation and provide other forms of central nervous system inhibition. This study tested the hypothesis that, among human subjects, a tonic increase in blood pressure (BP) could be a learned response to environmental stressors among subjects in whom the baroreceptor inhibitory mechanism is active. In a sample of 96 healthy, normotensive men and women, amount of pain-reduction produced by baroreceptor stimulation predicted an increase in resting BP 20 months later: the increase was proportional to self-assessed daily life stress. Among the subjects reporting the greatest amount of stress, the pain inhibition effect accounted for more than 80% of the BP variance. These results support the hypothesis that the reduction in perceived stress produced by baroreceptor stimulation may reward learned increases in BP.

Development of angina pectoris pain and cardiac events in asymptomatic patients with myocardial ischemia.

A total of 389 patients with angiographically determined coronary artery disease, who exhibited a complete absence of angina pectoris in the presence of reproducible myocardial ischemia, were studied in a follow-up investigation. After an initial coronary angiogram, anti-ischemic medication was prescribed as treatment. After a mean follow-up time of 4.9 years (maximum 13.4 years) patients were sent a questionnaire that assessed any new development of angina pectoris pain and cardiac events. In 48 of these patients a second angiogram was recorded after a mean period of 4.2 years. Asymptomatic patients had a worse prognosis than an age-adjusted normal population. After 5 and 10 years, 9 and 26% of the patients, respectively, had died, nonfatal cardiac events (myocardial infarction, bypass surgery or percutaneous transluminal coronary angioplasty) occurred after 5 and 10 years in 19 and 46%, respectively. A large number of initially asymptomatic patients developed angina pectoris pain over the follow-up period (34% after 5 years, 58% after 10 years). Novel angina pectoris pain often preceded cardiac events by months to years. Multivariate analysis indicated that vessel disease (p = 0.0001) and degree of ischemia (defined by ST-segment depression free exercise tolerance, p = 0.04) proved to have independent predictive value with respect to mortality rate. Newly developed angina pectoris was associated with an increase in objective signs of myocardial ischemia and a progression in coronary stenosis. The results indicate that patients who originally had myocardial ischemia with a marked absence of pain can develop angina pectoris over the course of years and that newly developed pain often precedes cardiac events.

Blood pressure changes validate phase related external suction, a controlled method for stimulation of human baroreceptors.

Phase related external suction (PRES), a new controlled method for manipulating activity in human baroreceptors, applies precisely timed bursts of suction and pressure within the cardiac cycle through an external neck cuff. Seven healthy adult men participated in 32 pseudo-random trials of baroreceptor stimulation and inhibition. Blood pressure was assessed both intra-arterially and with a noninvasive device. In the present study, PRES baroreceptor stimulation elicited invasively measured blood pressure decreases of about 2.5 mmHg (0.33 kPa) and heart rate decreases of about 5 beats,min-1, while baroreceptor inhibition increased invasively measured blood pressure by about 1.5 mmHg (0.20 kPa) and heart rate about 2.5 beats.min-1. It was concluded that PRES is an effective method for baroreceptor manipulation with weaker size effect but better control of nonspecific factors in human subjects than other baroreceptor manipulation techniques. The noninvasive blood pressure measurement device was less sensitive to experimental variation than was the invasive device.

[Interval resistance exercise in comparison with bicycle ergometry stress. Studies with resistance endurance training in coronary patients]. / Intervall-Kraftbelastung im Vergleich zur Fahrradergometer-Belastung. Untersuchung zum Einsatz von Kraftausdauertraining bei Koronarpatienten.

UNLABELLED: In the rehabilitation of coronary patients there is an increased interest in using complementary resistance exercise training. Therefore, we studied nine patients (males; age: 51 +/- 7 years) with chronic stable coronary heart disease during extensive resistance exercise (ex RE) (legpress, abduction, adduction) (60-s work: 60-s rest; contraction intensity: 65% of 1 RM) and during intensive resistance exercise (int. RE) (legpress) (30-s work: 45-s rest) with 85% of 1 RM. Non-invasive continuously measured blood pressure, heart rate, norepinephrine, epinephrine, lactic acid, and glucose were compared with values from maximal bicycle ergometry (3-min steps, each 25 w; max. performance: mean 156 w; range 125-200 w). RESULTS: 1) Comparing ex RE and int RE with bicycle ergometry there were no differences in blood pressure (systolic: 206 and 204 vs. 210 mm Hg; ns; diastolic: 98 and 104 vs. 92 mm Hg; ns). Heart rates (104 and 103 vs. 125/min; p < .01), norepinephrine (3.8 and 3.3 vs. 8.8 nmol/l; p < .01) and epinephrine (0.7 and 0.6 vs. 1.4 nmol/l; p < .01) were considerably lower. 2) The most significant increase and decrease of blood pressure and heart rate occurred within 15-30 s after the beginning and end, respectively, of isometric exercise. CONCLUSIONS: 1) ex RE is suitable for patients with stable CHD and cardiac exercise tolerances of 1.5-2 W/kg = 125-150 watts. 2) Blood pressure monitoring by the cuff method (RR) immediately after RE did not reflect blood pressure during RE. 3) Controlling RE by the training heart rate prescribed for endurance exercise is not possible.

Ambulatory electrocardiography evaluation of the post-coronary artery bypass graft and post-percutaneous transluminal coronary angioplasty patient. Diagnostic and prognostic value.

Investigations carried out in recent years have shown that patients with coronary heart disease display partial to considerable extent transient ST-segment changes that can be determined with ambulatory ECG. An interesting question is how often transient ST-segment changes are present in patients in whom the indication for an aortocoronary bypass operation or percutaneous transluminal coronary angioplasty (PTCA) has already been determined. In the patients who are waiting for a bypass operation or PTCA, the proof of myocardial ischemia has been determined, and which subgroups of patients display ST changes in the ambulatory ECG must be tested. It is interesting to ask what happens to such transient ischemic episodes as a result of surgical or catheter intervention, how often such episodes are present even after these interventions, and whether the latter has a clinical significance in view of the success of the intervention (graft patency in coronary artery bypass graft patients or reocclusion in PTCA patients). Furthermore, it is to be tested whether transient ST-segment changes take on a prognostic significance in the long-term follow-up after bypass operation or PTCA.

Transient hypoalgesia under physical exercise--relation to silent ischaemia and implications for cardiac rehabilitation.

A series of studies with humans as well as experiments carried out on animals could show that physical exercise leads to temporary hypoalgesia. Reduced sensitivity to pain is not only demonstrable after long-distance exercise (such as marathon run) but also after intensive physical exercise on a laboratory ergometer. Pain threshold elevation is most pronounced during maximal exertion, but hypoalgesia remains present also after exercise is stopped demonstrating that a systemic analgetic effect is induced by the exercise process. Pre-exercise pain threshold level is returned to approximately 60 minutes after the exercise. The cause of the exercise-induced hypoalgesia is probably an activation of central pain inhibitory mechanisms by the "stimulus" of physical exercise (stimulation- or stress-induced analgesia). Central pain inhibitory systems are thereby triggered by the stimulation of afferent nerve endings (group III and IV) in the skeletal muscle. The same trigger mechanism also plays a role as a release stimulus for hormones such for beta-endorphin which is increased under physical exercise. Plasma-beta-endorphin is probably not directly involved in the exercise-induced hypoalgesia but is rather a "marker" for the activating of central analgesia mechanisms. Stress-induced hypoalgesia plays also a role in the coronary heart disease. The activation of endogenous analgetic mechanisms leads to a part of the myocardial ischaemia provoked by exercise being silent under exercise. Completely asymptomatic myocardial ischaemia patients display a generalized hypoalgesia which is demonstrable independent of an exertion stimulus and which indicates a central set-point change in the antinociceptive system.

[Physical exercise, endogenous opiates and pain regulation.]. / Körperliche Belastung, endogene Opiate und Schmerz.

A series of studies with humans as well as experiments carried out on animals have shown that physical exercise leads to temporary hypoalgesia. Reduced sensitivity to pain is not only demonstrable after long-distance exercise (such as a marathon run) but also during and after intensive physical exercise on a laboratory ergometer. In a double blind study (20 mg naloxone versus placebo) experimental pain thresholds (electrical intracutaneous finger and dental pulp stimulation) and plasma hormone levels (beta-endorphin, cortisol, and catecholamines) were measured in ten healthy athletic men before, during, and after physical exercise on a cycle ergometer. A significant pain threshold elevation during exercise was found for finger (Anova,p<0.004) and dental pulp stimulation (p<0.01). Hypoalgesia remained present after exercise was stopped and the initial pain threshold level was returned to approximately 60 minutes after the exercise. The subjective magnitude estimation of suprathreshold stimuli was significantly reduced (p<0.001) after exercise. Naloxone failed to affect pain thresholds and plasma beta-endorphin did not correlate significantly with pain thresholds. The cause of the exercise-induced hypoalgesia is probably an activation of central pain inhibitory mechanisms by the "stimulus" of physical exercise (stimulation-induced analgesia). Central pain inhibitory systems are probably thereby activated by the stimulation of afferent nerves endings (group III and IV) in the skeletal muscle. The same trigger mechanism also plays a role as a release stimulus for hormones which are secreted in increased measure during physical exercise (catecholamines, pituitary hormones). Plasma beta-endorphin is probably not directly involved in the exercise-induced hypoalgesia but is rather a "marker" for the activating of central analgesia mechanisms.

A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity.

Epidemiological as well as biochemical evidence of recent years has established that a low plasma level of high density lipoprotein-cholesterol is a predictor for the risk of coronary artery disease. However, there is a heterogeneous group of rare familial disorders, characterized by severe high density lipoprotein deficiency, in which the predicted increased risk is not clearly apparent. One such disorder has been called fish eye disease to reflect the massive corneal opacification seen in these patients. In this report, we describe the biochemical and genetic presentation of two German fish eye disease homozygotes and their family members. Vertical transmission of a decrease in the specific activity of lecithin-cholesterol acyltransferase (EC 2.3.1.43) indicated that this enzyme was a candidate gene for harboring the defect responsible for this disorder. Direct sequencing of DNA segments amplified by the polymerase chain reaction (PCR) that encode the exons of the lecithin-cholesterol acyltransferase gene led to the identification of a homozygous mutation resulting in the substitution of threonine at codon 123 for an isoleucine residue in both individuals. Family analysis in an extended pedigree was used to establish a causal relationship between this mutation and the biochemical phenotype for fish eye disease. The homozygous presence of this mutation in two phenotypically homozygous members of an unrelated Dutch family with fish eye disease further supports this finding.

Experimental pain thresholds and plasma beta-endorphin levels during exercise.

Experimental pain thresholds (electrical intracutaneous finger and dental pulp stimulation) and plasma hormone levels (beta-endorphin, cortisol, and catecholamines) were measured in ten healthy sportive men before, during, and after progressively more strenuous physical exercise. In a double-blind study conducted on two different days, 20 mg of the opioid-antagonist naloxone or placebo was administered prior to exercise. A significant pain threshold elevation was found during exercise for finger (ANOVA, P less than 0.004) and dental pulp stimulation (P less than 0.01). Pain threshold elevation was most pronounced during maximal exertion, at which time the subjects reported the greatest subjective fatigue. Thresholds remained elevated 10-15 min after the end of exercise, and, 60 min after exercise, thresholds returned to baseline values. The subjective magnitude estimation of suprathreshold stimuli was significantly reduced (P less than 0.0001) 5-10 min after exercise. Plasma beta-endorphin, cortisol, and catecholamines increased significantly (P less than 0.0005, all values) during exercise. Plasma beta-endorphin levels did not correlate significantly with pain thresholds (r = -0.37, NS). Naloxone failed to affect pain thresholds, although beta-endorphin and cortisol increased significantly more (P less than 0.02) during exercise after naloxone. It is concluded that short-term, exhaustive physical exercise can evoke a transient elevation in pain thresholds. This exercise-induced elevation in pain threshold does not, however, appear to be directly related to plasma endorphin levels.