Pilot Study of Endothelin Receptor Blockade in Heart Failure with Diastolic Dysfunction and Pulmonary Hypertension (BADDHY-Trial).

BACKGROUND: In this multi-centre, randomised, placebo-controlled pilot trial, we investigated the clinical and haemodynamic effects of the endothelin-receptor blocker Bosentan in patients with heart failure, preserved ejection fraction and pulmonary hypertension (PH-HFpEF). MATERIALS AND METHODS: Eligible patients received either 12 weeks of Bosentan therapy, or a placebo drug. Patients were thereafter followed for a further period of 12 weeks without the study medication. At three points during the study (study Commencement, Week 12 and Week 24), a six-minute walk test (6MWT), echocardiographic and laboratory assessments were performed, as well as a quality of life survey. Right heart catheterisation (RHC) was undertaken at commencement only. The study was aborted early, after an interim analysis favoured the placebo. RESULTS: Six-minute walk distance (6MWD) did not change in the Bosentan group (309.7±96.3m (Commencement), 317.0±126.1m (Week 12), 307.0±84.4m (Week 24); p=0.86), but almost reached statistical significance in the placebo group from 328.8±79.6m, to 361.6±98.2m and 384.0±74.9m (Week 24); p=0.075. In the placebo group, estimated systolic pulmonary artery pressure (measured via echocardiography) significantly decreased (from 62.3±16.7mmHg [Commencement], 45.3±13.9mmHg [Week 12], to 44.6±14.5mmHg [Week 24]; p=0.014) as did right atrial pressure (13.1±5.3 [Commencement], 10.0±3.8 [Week 12], to 9.4±3.2 [Week 24]; p=0.046). CONCLUSION: Despite this study's limited sample size and premature cessation, it nevertheless suggests that endothelin receptor blockade in patients with PH-HFpEF may have no beneficial effects and could even be detrimental in comparison to a placebo.

Evaluation of a resectable ultrasound liver phantom for testing of surgical navigation systems.

A formerly developed ultrasound liver phantom for testing of surgical navigation systems and liver resection trainings was evaluated experimentally. The phantom was scanned with CT and the dataset was analyzed with existing segmentation techniques. A virtual 3D model was generated on the basis of the segmentation; it was later used for phantom registration in a surgical assistance navigation system. Within an experiment, ten test persons have tried to touch three tumor models hidden in the phantom with the tip of a resection instrument. In 67% of overall 30 touch trials it was a successful touch at the first go. It means that the developed liver phantom is appropriate for testing of surgical navigation systems, as well as for computer assisted liver resection trainings.

MiMed liver: a planning system for liver surgery.

In clinical routine of liver surgery there are a multitude of risks such as vessel injuries, blood loss, incomplete tumor resection, etc. In order to avoid these risks the surgeons perform a planning of a surgical intervention. A good graphical representation of the liver and its inner structures is of great importance for a good planning. In this work we introduce a new planning system for liver surgery, which is meant for computer tomography (CT) data analysis and graphical representation. The system is based on automatic and semiautomatic segmentation techniques as well as on a simple and intuitive user interface and was developed with the intention to help surgeons by planning an operation and increasing the efficiency in open liver surgery.

Prevalence of primary headaches and cranial neuralgias in men and women aged 55-94 years (Bruneck Study).

The aim of the current study was to estimate the prevalence of all primary headaches and cranial neuralgias in the general community. As part of the population-based Bruneck Study, 574 men and women aged 55-94 years underwent extensive neurological and laboratory examinations involving a standardized headache interview. In the Bruneck Study population the lifetime prevalence of all primary headaches combined and of cranial neuralgias was 51.7 and 1.6%, respectively. Tension-type headache (40.9%) and migraine (19.3%) emerged as the most common types of headache. In men and women aged 55-94 years the 1-year prevalence of primary headaches was high at 40.5%. In this age range headaches caused significant impairment of health-related quality of life. The Bruneck Study has confirmed the high lifetime prevalence of primary headaches and cranial neuralgias in the general population and provided first valid prevalence data for all primary headaches based on International Classification of Headache Disorders, 2nd edition criteria.

Burden of atherosclerosis and risk of venous thromboembolism in patients with migraine.

BACKGROUND: Previous studies have yielded evidence of an enhanced risk of cardiovascular disease, especially stroke, among patients with migraine. Our understanding of the underlying mechanisms is far from complete. The aims of the present study were to investigate the potential association between migraine and atherosclerosis and to assess the risk of venous thromboembolism as a clinical surrogate for a procoagulant state in patients with migraine. METHODS: The examination was part of the population-based Bruneck Study. During the 2005 evaluation, 574 participants aged 55-94 years underwent neurologic and laboratory examinations involving a standardized headache interview and scanning of the carotid and femoral arteries to evaluate presence, severity, and progression (2000-2005) of atherosclerosis. RESULTS: A large number of well-founded and putative cardiovascular risk factors have emerged as being unrelated to migraine status. Prevalence, severity, and 5-year progression of carotid and femoral atherosclerosis did not differ significantly between migraineurs with and without aura and nonmigraineurs. In fact, there was even a tendency for atherosclerosis to be less pronounced among patients with migraine, and for the intima-media thickness to be lower (p = 0.029). As a novel finding migraineurs faced a significantly enhanced risk of venous thromboembolism (18.9% vs 7.6% in nonmigraineurs, age/sex-adjusted p = 0.031). CONCLUSION: This study is the first to compare the burden of atherosclerosis as quantified by high-resolution duplex ultrasound between migraineurs and nonmigraineurs in the general community, and provides solid evidence against the view that migraine predisposes to atherosclerosis. The higher risk for venous thromboembolism among migraineurs (prothrombotic state) awaits confirmation and elaboration in future research.

Ultrastructural effects of pharmaceuticals (carbamazepine, clofibric acid, metoprolol, diclofenac) in rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio).

In order to assess potential effects of human pharmaceuticals in aquatic wildlife, laboratory experiments were conducted with carbamazepine, clofibric acid, metoprolol, and diclofenac using fish as test organisms. For each substance, at least one environmentally relevant concentration was tested. In liver, kidney, and gills of trout and carp exposed to carbamazepine, clofibric acid, and metoprolol, ultrastructural effects were qualitatively described and semi-quantitatively assessed. The obtained assessment values were compared with previously published data for diclofenac-induced effects in rainbow trout tissues. Quantitative analyses of protein accumulated in kidneys of diclofenac-exposed trout corroborated previously published data which indicated that diclofenac induced a severe glomerulonephritis resulting in a hyaline droplet degeneration of proximal kidney tubules. The investigations provided information on the general health status of the pharmaceutical-exposed fish, and allowed a differential diagnosis of harmful effects caused by these human pharmaceuticals in non-target species. For the different cytological effects observed, lowest observed effect concentration (LOECs) for at least three of the test substances (diclofenac, carbamazepine, metoprolol) were in the range of environmentally relevant concentrations (1 microg/L).

A simple score predicts future cardiovascular events in an inception cohort of dialysis patients.

Vascular calcifications are very common in dialysis patients and have been shown to be associated independently with outcome. However, all of these studies used prevalent patients on dialysis since many years. We investigated vascular calcifications in an inception cohort of dialysis patients and followed them for cardiovascular disease outcomes during an average observation period of 66 months. One hundred and fifty-four Caucasian dialysis patients were enrolled in one Austrian dialysis center. Standardized plain radiographs from the pelvis and calves were carried out in all patients at the start of dialysis therapy. Vascular calcifications were assessed by a single radiologist. At the start of renal replacement therapy, 67.5% of the patients showed vascular calcifications. During follow-up, 29.9% of patients suffered a cardiovascular event. An additive 'vascular risk score', constructed from the presence of vascular calcifications and/or previous cardiovascular events before the start of dialysis treatment, showed the strongest independent association with cardiovascular events in the Cox regression model adjusted for various risk factors. The presence of each of these two conditions was associated with a hazard ratio of 2.03 (95% confidence interval 1.19-3.46) and a hazard ratio twice as high if both conditions were present. In summary, vascular calcifications on plain X-rays of pelvis and calves are largely present in incident dialysis patients. A history of a cardiovascular event in the predialysis period together with vascular calcifications at the beginning of dialysis therapy is a more powerful predictor of a cardiovascular event than age, smoking, diabetes, or other traditional risk factors.

Toxic effects of the non-steroidal anti-inflammatory drug diclofenac. Part I: histopathological alterations and bioaccumulation in rainbow trout.

Human and veterinary pharmaceuticals have been shown to occur in considerably high amounts in sewage treatment plant (STP) effluents and surface waters. The non-steroidal inflammatory drug diclofenac represents one of the most commonly detected compounds. Information concerning possible ecotoxicological risks of the substance are rather scarce. So far there are no data available on its possible effects in fish after prolonged exposure. In order to evaluate sublethal toxic effects of diclofenac in fish, rainbow trout (Oncorhynchus mykiss) exposed to diclofenac concentrations ranging from 1 microg/L to 500 microg/L over a 28 day period were investigated by histopathological methods. In addition, diclofenac residues in various organs were analyzed by means of gas chromatography/mass spectrometry (GC/MS). The histopathological examinations of diclofenac-exposed fish revealed alterations of the kidney such as an hyaline droplet degeneration of the tubular epithelial cells and the occurrence of an interstitial nephritis. In the gills, the predominant finding consisted in a necrosis of pillar cells leading to damage of the capillary wall within the secondary lamellae. The lowest observed effect concentration (LOEC) at which both renal lesions and alterations of the gills occurred was 5 microg/L. In contrast, the light microscopical examination of the liver, the gastro-intestinal tract, and the spleen did not reveal any histopathological alterations neither in diclofenac-exposed fish nor in solvent controls or control individuals. Chemical analysis showed a concentration-related accumulation of diclofenac in all organs examined. The highest amounts could be detected in the liver, followed by the kidney, the gills and the muscle tissue. Dependent on the diclofenac concentration used, the bioconcentration factors (BCF) were 12-2732 in the liver, 5-971 in the kidney, 3-763 in the gills, and 0.3-69 in the muscle respectively. From the present findings it can be assumed, that prolonged exposure in environmentally relevant concentrations of diclofenac leads to an impairment of the general health condition of fish.

Toxic effects of the non-steroidal anti-inflammatory drug diclofenac. Part II: cytological effects in liver, kidney, gills and intestine of rainbow trout (Oncorhynchus mykiss).

In the present study, cytopathology was investigated in the liver, kidney, gills and gut of rainbow trout (Oncorhynchus mykiss) exposed to five different concentrations (1, 5, 20, 100 and 500 microg/L) of the anti-inflammatory drug diclofenac under laboratory conditions. The lowest observed effect concentration (LOEC) for cytological alterations in liver, kidney and gills was 1 microg/L. In the gut, however, no diclofenac-induced cytopathology occurred. As the most prominent reactions induced by diclofenac (1) in the kidney, a severe accumulation of protein in the tubular cells (so called hyaline droplet degeneration), macrophage infiltration and structural alterations (dilation, vesiculation) of the endoplasmic reticulum (ER) in the proximal and distal renal tubules were observed. Furthermore, shortening of podocytes and their retraction from the basal lamina, a thickening of the basal lamina, the formation of desmosomes, and necrosis of endothelial cells in the renal corpuscles occurred; (2) in the liver, the most striking reactions were the collapse of the cellular compartmentation as well as the glycogen depletion of hepatocytes; (3) in the gills, pillar cell necrosis, hypertrophy of chloride cells, and epithelium lifting became evident in the secondary lamellae.

Endocrine effects of environmental pollution on Xenopus laevis and Rana temporaria.

To determine the capacity of sewage treatment work effluents to disrupt the endocrine system under semifield conditions, two amphibian species, Xenopus laevis and Rana temporaria, were exposed to the effluent of a regional sewage treatment plant in South Bavaria during larval development until completion of metamorphosis. Exposure was carried out in river water (Würm) as a reference, and a 1:12-mixture sewage effluent representing the real situation on the spot, and in a higher concentration of sewage using a 1:2 mixture. An accidental impact of industrial wastewater into the reference and dilution medium, Würm, which was caused by a spate in the respective area during the sensitive period of sex differentiation of amphibian larvae, is assumed to be responsible for the relatively high percentage of females observed by histological analysis in all treatment groups. All of these values were higher than those determined in controls exposed to artificial tap water in laboratory experiments conducted in a comparable study design. Sex ratios between species, revealed by the semifield study with decreasing portions of females from control to 1:12 to 1:2, were strongly correlated. Determination of biomarker-mRNA-levels in Xenopus liver using semiquantitative RT-PCR at the end of the experimental phase, when exposure regime has turned into the initially expected situation with the highest load of potential estrogens in the effluent, followed by 1:2 and 1:12 mixture, resulted in a significant increase of Vitellogenin-mRNA in female juveniles exposed to the highest portion of sewage, whereas expression of both androgen and estrogen receptor-mRNA showed no clear differences. The results concerning the induction of estrogenic biomarkers are in accordance with our findings for estrogen receptor binding of sample extracts from the Würm and sewage taken in parallel at the end of the experiment, when sewage extracts possessed a much higher ability to displace [3H]estradiol from the estrogen receptor than the ones extracted from the mixtures.

How estrogenic is nonylphenol? A transgenerational study using rainbow trout (Oncorhynchus mykiss) as a test organism.

The aim of the present study was to evaluate both estrogenic effects in directly NP-exposed sexually mature rainbow trout and possible transgenerational effects in the offspring of exposed fish. Four months prior to spawning, adult rainbow trout of both sexes were exposed intermittently to NP concentrations of 1 and 10 microg/l. At the end of the exposure period, which coincided with the beginning of spawning time, vitellogenin levels in the plasma of adult male rainbow showed a significant increase compared to the control group. After exposure to 10 microg NP/l reproduction was impaired as indicated by significantly reduced hatching rates. Histological examination of the testicular tissue of NP-exposed individuals revealed no morphological differences from the controls. In the offspring, vitellogenin levels of male individuals were not affected, whereas in females they were significantly higher than in the control progeny. The histological examination revealed no alteration in sex ratios. In single cases, intersex occurred in both male and female offspring of exposed fish. The analysis of sex steroid levels revealed a two-fold increase of estradiol in the plasma of male offspring and a 13-fold elevation of testosterone in the plasma of female progeny. The present findings indicate that NP, in an environmentally relevant concentration range, acts as a weak estrogen in directly exposed adult male rainbow trout as indicated by elevated plasma vitellogenin levels. Reproduction success was reduced as indicated by decreased hatching rates. Hormonal imbalances detected in the offspring of exposed fish indicate a transgenerational effect mediated by the endocrine system.

Theta band power changes in normal and dyslexic children.

OBJECTIVE: Tonic and phasic (event-related) theta band power changes were analyzed in a sample of 8 dyslexic and 8 control children. Previous research with healthy subjects suggests that electroencephalograph (EEG) theta activity reflects the encoding of new information into working memory. The aim of the present study was to investigate whether the processing deficits of dyslexics are related to a reduced phasic theta response during reading. METHOD: The EEG was recorded while subjects were reading numbers, words and pseudowords and analyzed in a lower and upper theta band (4--8 Hz). A phasic response is measured in terms of an increase in event related band power during reading with respect to a reference interval. Tonic power is measured in terms of (log) band power during a reference interval. RESULTS: Large group differences in tonic and phasic lower theta were found for occipital sites where dyslexics show a complete lack of pseudoword processing. For words, only controls show a highly selective left hemispheric processing advantage. CONCLUSIONS: Dyslexics have a lack to encode pseudowords in visual working memory with a concomitant lack of frontal processing selectivity. The upper theta band shows a different pattern of results which can be best interpreted to reflect the effort during the encoding process.

Alpha and beta band power changes in normal and dyslexic children.

OBJECTIVE: Previous research with healthy subjects suggests that the lower alpha band reflects attentional whereas the upper alpha band semantic processes. The aim of the present study was to investigate whether dyslexics show deficits in attentional control and/or semantic encoding. METHOD: The EEG was recorded while subjects were reading numbers, words and pseudowords and analyzed in a lower and upper alpha and two beta bands (spanning a range of about 8--16 Hz). A phasic response is measured in terms of a decrease in event related band power during reading with respect to a reference interval. Tonic power is measured in terms of (log) band power during a reference interval. RESULTS: In the lower alpha band dyslexics show an increased phasic response to words and pseudowords at right hemispheric sites but a lack to respond to words at O1. The upper alpha band exhibits a highly selective phasic response to words at left frontal sites but for controls only, whereas dyslexics show a general increase in tonic upper alpha power. Whereas the low frequency beta band (beta-1a) exhibits a rather diffuse pattern, a highly selective finding was obtained for the beta-1b band. CONCLUSIONS: Dyslexics have a lack of attentional control during the encoding of words at left occipital sites and a lack of a selective topographic activation pattern during the semantic encoding of words. Because only in controls reading of words is associated with a strong beta-1b desynchronization at those recording sites which correspond to Broca's area (FC5) and the angular gyrus (CP5, P3), we may conclude that this frequency band reflects the graphemicphonetic encoding of words.

Chronic toxicity of nonylphenol and ethinylestradiol: haematological and histopathological effects in juvenile Common carp (Cyprinus carpio).

In recent ecotoxicological research, there is an increasing concern about alkylphenolic industrial chemicals, such as nonylphenol (NP), because of their estrogenic properties. Data on the general fish toxicity of these wide spread aquatic pollutants are scarce. In order to evaluate sublethal toxic effects of environmentally relevant concentrations of NP, juvenile Common carp (Cyprinus carpio) were exposed to NP concentrations ranging from 1 to 15 microg NP/l over a 70-day period. Classical toxicological endpoints, such as various haematological parameters and histopathological alterations were investigated. In a comprehensive protocol, besides NP-induced effects also alterations due to a treatment with the synthetic estrogen ethinylestradiol (EE2) were evaluated. After both the NP-exposure as well as the EE2-treatment, the predominant haematological finding was a severe anaemia. Histopathological alterations in the kidney, the liver and the spleen occurred exclusively after treatment with EE2, whereas NP-exposed fish did not show any tissue lesions. Depending on the haematological parameter examined, a NOEC between 1 and 5 microg NP/l could be established. From the present findings, it is assumed, that under field conditions, the NP-induced, general toxic effects, might outbalance the relatively weak estrogenic effects of this compound and possibly might disturb ecologically relevant processes such as fish reproduction.

Theta oscillations and the ERP old/new effect: independent phenomena?

OBJECTIVES: The hypothesis is examined whether a memory-related change in induced band power (oscillatory old/new effect) is functionally related to a memory-related increase in ERP positivity (ERP old/new effect). METHODS: In order to avoid a confounding on the measurement level, induced band power (IBP) was used as a measure that is devoid of the influence of evoked components. The EEG was recorded during a recognition memory task. RESULTS: The results show that compared to correctly rejected words, targets (remembered words) elicit a significantly larger P300. An oscillatory old/new effect was found for the delta and theta but not for the alpha band. It is manifested by an increase in delta and theta IBP which is significantly larger for targets than for correctly rejected words. It can be observed during the same time interval and shows the same topographic distribution as the ERP old/new effect. Most importantly, however, the ERP old/new effect (as well as the P300 itself) is generated by very slow frequencies which lie below the delta band. CONCLUSIONS: These findings demonstrate that the two types of old/new effects are functionally related. Possible physiological mechanisms underlying this relationship are discussed in terms of a threshold change in the cortex (generating the P300) that occurs during an increase in hippocampal theta activity (generating an increase in induced theta power).

The time locked theta response reflects interindividual differences in human memory performance.

Recent research indicates that an increase in theta band power is related to episodic memory performance. In this study with human subjects, the evoked (time locked) and induced (not time locked) theta response is analyzed in a recognition task. The results show a strong evoked theta response during an early retrieval period of up to 400 ms. Only for good memory performers theta is strictly time locked, indicating that theta peaks appear in preferred time windows after a target is presented. This effect--which coincides with a large P3--suggests that good performance requires a strict timing of different processing stages that correspond to cycles of theta activity.

'Paradoxical' alpha synchronization in a memory task.

The results of a specially designed memory search paradigm which maximizes episodic short-term memory (STM) and minimizes semantic long-term memory (LTM) demands show that the upper alpha band synchronizes selectively in those conditions and time intervals where episodic STM demands are maximal. This finding of a selective alpha synchronization occurring only in the upper alpha band and during highest task demands is surprising because it is well known that usually alpha desynchronizes during mental activity. Because experiments from our laboratory indicate that desynchronization in the upper alpha band is related to semantic LTM processes, the present finding suggests that a selective synchronization in this frequency band reflects inhibition of semantic LTM. It is assumed that once the capacity limits of STM are reached or exceeded, processing resources are no longer distributed and that potentially interfering, task irrelevant, brain areas or processing systems are inhibited.

Theta synchronization in the human EEG and episodic retrieval.

Event-related desynchronization (ERD) and synchronization (ERS) was measured during episodic retrieval in a specially designed recognition task which forces subjects to avoid semantic search strategies. ERD represents the percentage of a decrease, ERS an increase in band power. The results show that only the theta band differentiates between good and bad episodic memory performers and that good performance is related to a large degree of theta synchronization. The delta and alpha bands did not yield significant effects. Topographical differences in theta ERS reveal that good performers use primarily their right hemisphere to retrieve episodic information. This finding agrees with respective results from PET studies.

Induced alpha band power changes in the human EEG and attention.

Induced alpha power (in a lower, intermediate and upper band) which is deprived from evoked electroencephalograph (EEG) activity was analyzed in an oddball task in which a warning signal (WS) preceded a target or non-target. The lower band, reflecting phasic alertness, desynchronizes only in response to the WS and target. The intermediate band, reflecting expectancy, desynchronizes about 1 s before a target or non-target appears. Upper alpha desynchronizes only after a target is presented and, thus, reflects the performance of the task which was to count the targets. Thus, only slower alpha frequencies reflect attentional demands such as alertness and expectancy.

Event-related desynchronization (ERD) and the Dm effect: does alpha desynchronization during encoding predict later recall performance?

Based on previous research which has shown that event-related desynchronization (ERD) in the lower and upper alpha band reflects attentional and semantic processing respectively, the present study examines the hypothesis whether event-related shifts in the two alpha bands are capable of predicting later recall performance. In an incidental memory paradigm, subjects first had to judge the category membership for a set of 96 words. Later, without prior warning, subjects were asked to recall the words. The results show that for good performers, the extent of ERD in the lower alpha band during the semantic encoding for words is significantly larger for remembered as compared to not remembered words, whereas for bad performers the ERD in the upper alpha band is significantly more pronounced. This type of Dm effect is particularly strong over parietal recording sites in both hemispheres. In referring to the proposed interpretation of the lower and upper alpha band, the present findings seem to indicate that in contrast to good performers, bad performers are less attentive or alert during encoding. Event-related potentials (ERPs) also yielded significant Dm effects at parietal recording sites.