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In this study, Monte Carlo codes, Geant4 and MCNP6, were used to characterize the fast neutron therapeutic beam produced at iThemba LABS in South Africa. Experimental and simulation results were compared using the latest generation of Silicon on Insulator (SOI) microdosimeters from the Centre for Medical Radiation Physics (CMRP). Geant4 and MCNP6 were able to successfully model the neutron gantry and simulate the expected neutron energy spectrum produced from the reaction by protons bombarding a 9 Be target. The neutron beam was simulated in a water phantom and its characteristics recorded by the silicon microdosimeters; bare and covered by a 10 B enriched boron carbide converter, at different positions. The microdosimetric quantities calculated using Geant4 and MCNP6 are in agreement with experimental measurements. The thermal neutron sensitivity and production of 10 B capture products in the p+ boron-implanted dopant regions of the Bridge microdosimeter is investigated. The obtained results are useful for the future development of dedicated SOI microdosimeters for Boron Neutron Capture Therapy (BNCT). This paper provides a benchmark comparison of Geant4 and MCNP6 capabilities in the context of further applications of these codes for neutron microdosimetry., (Copyright © 2021 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: Data from real-life populations about vedolizumab as first-line biological therapy for ulcerative colitis (UC) and Crohn's disease (CD) are emerging., Objective: To investigate the efficacy and safety of vedolizumab in bio-naïve patients with UC and CD., Methods: A Danish nationwide cohort study was conducted between November 2014 and November 2019. Primary outcomes were clinical remission, steroid-free clinical remission, and sustained clinical remission from weeks 14 through 52., Results: The study included 56 patients (UC:31, CD:25) who initiated treatment with vedolizumab mainly because of contraindications to anti-TNFs, of whom 54.8 and 24.0%, respectively received systemic steroids at the initiation. Rates of clinical remission at weeks 6, 14, and 52 were 32.0, 48.0, and 40.0%, respectively, in UC, and 36.8, 36.8, and 47.4% in CD. Steroid-free clinical remission at week 52 was achieved among 36.0 and 47.4% of UC and CD patients, while sustained clinical remission was achieved in 32.0 and 36.8%. Lack of remission was associated with being female (68.8 vs. 11.1%, p =  .01) in UC and non-structuring, non-penetrating behavior in CD (90.0 vs. 44.4%, p  = .03); however, this was not confirmed in multivariate analysis. Discontinuation due to primary non-response occurred in 20.0 and 5.3% of UC and CD patients, respectively, while rates of secondary loss of response were 12.0 and 5.3% after 52 weeks of follow-up. Vedolizumab was well-tolerated as only one UC patient experienced a serious adverse event., Conclusion: Vedolizumab is effective in the achievement of short-term, long-term, and steroid-free clinical remission in bio-naïve UC and CD patients.

Introduction: Disturbed sleep in inflammatory disorders such as allergy and rheumatoid arthritis (RA) is common and may be directly or indirectly related to disease processes, but has not been well characterized in these patient groups, especially not with objective methods., Aim: The present study aimed to characterize objective and subjective sleep in patients with allergy or RA using sleep diaries, one-channel EEG and actigraphy. It also aimed to investigate if sleep measures were associated with central immune activation, assessed using translocator protein (TSPO) positron emission tomography, as well as cytokine markers of peripheral inflammation and disease-specific symptoms or general symptoms of sickness., Methods: In total, 18 patients with seasonal pollen allergy, 18 patients with RA and 26 healthy controls were included in the study. Allergy patients and matched controls were assessed twice, in and out of pollen season, and RA patients and controls were assessed once. Sleep was recorded for approximately 1 week at each occasion., Results: Patients with allergy had increased levels of slow-wave sleep during pollen season. In contrast, patients with RA had less SWS compared to healthy controls, while no differences were observed in sleep duration or subjective sleep quality. Across groups, neither proinflammatory cytokines, grey matter TSPO levels nor general sickness symptoms were associated with objective or subjective measures of sleep. Rhinitis, but not conjunctivitis, was correlated to worse subjective sleep and more slow wave sleep in allergy. Functional status, but not disease activity, predicted lower subjective sleep in RA., Conclusion: This study tentatively indicates that both patients with allergy and RA display sleep alterations but does not support inflammation as an independent predictor of the sleep disturbance across these patient groups., Competing Interests: Professor John Axelsson reports Financial disclosures: Funding from Swedish Research Council, Riksbankens Jubileumsfond and AFA Insurance. Served as a paid panel member for The Research Council of Norway. Consulting fees or speaker honorarium from Lifesum, Banqit, Game Intelligence, Norra Stockholm Psychiatry, Svensk Kiropraktik, Swedish Agency for Marine and Water Management, and the Swedish Professional Associations for Physical Activity. Dr Caroline Olgart Höglund reports grants from The Swedish Heart Lung Foundation, grants from Swedish Asthma and Allergy Association, grants from Center for Allergy Research, grants from Karolinska Institutet, grants from Stockholm Stress Center, grants from Osher Center for Integrative Medicine, grants from Hedlund Foundation, grants from Swedish Council for Working Life and Social Research, during the conduct of the study, grants from Swedish Social Insurance Agency, outside the submitted work. Dr Simon Cervenka reports grants from Otsuka, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Tamm et al.)

Reumatoid Arthritis (RA) is an autoimmune disorder characterized by peripheral joint inflammation. Recently, an engagement of the brain immune system has been proposed. The aim with the current investigation was to study the glial cell activation marker translocator protein (TSPO) in a well characterized cohort of RA patients and to relate it to disease activity, peripheral markers of inflammation and autonomic activity. Fifteen RA patients and fifteen healthy controls matched for age, sex and TSPO genotype (rs6971) were included in the study. TSPO was measured using Positron emission tomography (PET) and the radioligand [ 11 C]PBR28. The outcome measure was total distribution volume (V T ) estimated using Logan graphical analysis, with grey matter (GM) as the primary region of interest. Additional regions of interest analyses as well as voxel-wise analyses were also performed. Clinical evaluation of disease activity, symptom assessments, serum analyses of cytokines and heart rate variability (HRV) analysis of 24 h ambulatory ECG were performed in all subjects. There were no statistically significant group differences in TSPO binding, either when using the primary outcome V T or when normalizing V T to the lateral occipital cortex (p > 0.05). RA patients had numerically lower V T values than healthy controls (Cohen's D for GM = -0.21). In the RA group, there was a strong negative correlation between [ 11 C]PBR28 V T in GM and disease activity (DAS28)(r = -0.745, p = 0.002, corrected for rs6971 genotype). Higher serum levels of IFNγ and TNF-α were found in RA patients compared to controls (p < 0.05) and several measures of autonomic activity showed significant differences between RA and controls (p < 0.05). However, no associations between markers of systemic inflammation or autonomic activity and cerebral TSPO binding were found. In conclusion, no statistically significant group differences in TSPO binding as measured with [ 11 C]PBR28 PET were detected. Within the RA group, lower cerebral TSPO binding was associated with higher disease activity, suggesting that cerebral TSPO expression may be related to disease modifying mechanisms in RA. In light of the earlier confirmed neuro-immune features of RA, these results warrant further investigations regarding neuro-immune joint-to-CNS signalling to open up for potentially new treatment strategies., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status., Methods: Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were compared to placebo in two double-blind randomized experiments. In Experiment 1, 8 individuals (mean 24 years; SD = 3.7) received lipopolysaccharide 0.8 ng/kg once and placebo once in a cross-over design, and in Experiment 2, 52 individuals received either lipopolysaccharide 0.6 ng/kg or placebo once (28.6 years; SD = 7.1). Main outcomes were perceived health (general and current), sickness behaviour (like fatigue, pain and negative affect), and plasma interleukin-6, interleukin-8 and tumour necrosis factor-α, before and after injection., Results: Compared to placebo, lipopolysaccharide lead to a deterioration in both self-rated general (Experiment 1, b = 1.88 for 0.8 ng/kg) and current health (Experiment 1 b = -3.00; and Experiment 2 b = -1.79) 1.5h after injection (p's<0.01), effects that remained after 4.5 to 5 hours (p's<0.05). The effect on current health in Experiment 2 was mediated by increased inflammation and sickness behaviour in response to lipopolysaccharide injection (β = -0.28, p = 0.01)., Conclusion: Health is drastically re-evaluated during inflammatory activation. The findings are consistent with notions that inflammation forms part of health-relevant interoceptive computations of bodily state, and hint at one mechanism as to why subjective health predicts longevity., Competing Interests: The authors have declared that no competing interests exist.

The Multi-Blade is a boron-10-based gaseous detector developed for neutron reflectometry instruments at the European Spallation Source in Sweden. The main challenges for neutron reflectometry detectors are the instantaneous counting rate and spatial resolution. The Multi-Blade has been tested on the CRISP reflectometer at the ISIS Neutron and Muon Source in the UK. A campaign of scientific measurements has been performed to study the Multi-Blade response in real instrumental conditions. The results of these tests are discussed in this paper., Competing Interests: We have no competing interests.

Allergy is associated with non-specific symptoms such as fatigue, sleep problems and impaired cognition. One explanation could be that the allergic inflammatory state includes activation of immune cells in the brain, but this hypothesis has not been tested in humans. The aim of the present study was therefore to investigate seasonal changes in the glial cell marker translocator protein (TSPO), and to relate this to peripheral inflammation, fatigue and sleep, in allergy. We examined 18 patients with severe seasonal allergy, and 13 healthy subjects in and out-of pollen season using positron emission tomography (n = 15/13) and the TSPO radioligand [ 11 C]PBR28. In addition, TNF-α, IL-5, IL-6, IL-8 and IFN-γ were measured in peripheral blood, and subjective ratings of fatigue and sleepiness as well as objective and subjective sleep were investigated. No difference in levels of TSPO was seen between patients and healthy subjects, nor in relation to pollen season. However, allergic subjects displayed both increased fatigue, sleepiness and increased percentage of deep sleep, as well as increased levels of IL-5 and TNF-α during pollen season, compared to healthy subjects. Allergic subjects also had shorter total sleep time, regardless of season. In conclusion, allergic subjects are indicated to respond to allergen exposure during pollen season with a clear pattern of behavioral disruption and peripheral inflammatory activation, but not with changes in brain TSPO levels. This underscores a need for development and use of more specific markers to understand brain consequences of peripheral inflammation that will be applicable in human subjects., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Low-temperature chemical vapor deposition (CVD) of B-C thin films is of importance for neutron voltaics and semiconductor technology. The highly reactive trialkylboranes, with alkyl groups of 1-4 carbon atoms, are a class of precursors that have been less explored for low-temperature CVD of B-C films. Herein, we demonstrate plasma CVD of B-C thin films using triethylboron (TEB) as a single source precursor in an Ar plasma. We show that the film density and B/C ratio increases with increasing plasma power, reaching a density of 2.20 g/cm 3 and B/C = 1.7. This is attributed to a more intense energetic bombardment during deposition and more complete dissociation of the TEB molecule in the plasma at higher plasma power. The hydrogen content in the films ranges between 14 and 20 at. %. Optical emission spectroscopy of the plasma shows that BH, CH, C 2 , and H are the optically active plasma species from TEB. We suggest a plasma chemical model based on β-hydrogen elimination of C 2 H 4 to form BH 3 , in which BH 3 and C 2 H 4 are then dehydrogenated to form BH and C 2 H 2 . Furthermore, C 2 H 2 decomposes in the plasma to produce C 2 and CH, which together with BH and possibly BH 3-x (C 2 H 5 ) x are the film forming species.

Optogenetic tools allow regulation of cellular processes with light, which can be delivered with spatiotemporal resolution. In previous work, we used cryptochrome 2 (CRY2) and CIB1, Arabidopsis proteins that interact upon light illumination, to regulate transcription with light in yeast. While adopting this approach to regulate transcription in mammalian cells, we observed light-dependent redistribution and clearing of CRY2-tethered proteins within the nucleus. The nuclear clearing phenotype was dependent on the presence of a dimerization domain contained within the CRY2-fused transcriptional activators. We used this knowledge to develop two different approaches to regulate cellular protein levels with light: a system using CRY2 and CIB1 to induce protein expression with light through stimulation of transcription, and a system using CRY2 and a LOV-fused degron to simultaneously block transcription and deplete protein levels with light. These tools will allow precise, bi-directional control of gene expression in a variety of cells and model systems., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that women's pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [(11)C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [(11)C]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend-level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Neutron reflectometry is a powerful tool used for studies of surfaces and interfaces. The absorption in the typical studied materials is neglected and this technique is limited only to the reflectivity measurement. For strongly absorbing nuclei, the absorption can be directly measured by using the neutron-induced fluorescence technique which exploits the prompt particle emission of absorbing isotopes. This technique is emerging from soft matter and biology where highly absorbing nuclei, in very small quantities, are used as a label for buried layers. Nowadays, the importance of absorbing layers is rapidly increasing, partially because of their application in neutron detection; a field that has become more active also due to the 3 He -shortage. We extend the neutron-induced fluorescence technique to the study of layers of highly absorbing materials, in particular 10 C. The theory of neutron reflectometry is a commonly studied topic; however, when a strong absorption is present the subtle relationship between the reflection and the absorption of neutrons is not widely known. The theory for a general stack of absorbing layers has been developed and compared to measurements. We also report on the requirements that a 4 C. The theory of neutron reflectometry is a commonly studied topic; however, when a strong absorption is present the subtle relationship between the reflection and the absorption of neutrons is not widely known. The theory for a general stack of absorbing layers has been developed and compared to measurements. We also report on the requirements that a 10 C layer must fulfil in order to be employed as a converter in neutron detection.4 C layer must fulfil in order to be employed as a converter in neutron detection.

An ability to detect subtle signs of sickness in others would be highly beneficial, as it would allow for behaviors that help us avoid contagious pathogens. Recent findings suggest that both animals and humans are able to detect distinctive odor signals of individuals with activated innate immune responses. This study tested whether an innate immune response affects a person's walking speed and whether other people perceive that person as less healthy. 43 subjects watched films of persons who were experiencing experimental immune activation, and rated the walking individuals in the films with respect to health, tiredness, and sadness. Furthermore, the walking speed in the films was analyzed. After LPS injections, participants walked more slowly and were perceived as less healthy and more tired as compared to when injected with placebo. There was also a trend for the subjects to look sadder after LPS injection than after placebo. Furthermore, there were strong associations between walking speed and the appearance of health, tiredness, and sadness. These findings support the notion that walking speed is affected by an activated immune response, and that humans may be able to detect very early signs of sickness in others by merely observing their gait. This ability is likely to aid both a "behavioral immune system", by providing more opportunities for adaptive behaviors such as avoidance, and the anticipatory priming of biochemical immune responses., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P's>.70). Suprathreshold noxious pain was not affected by LPS in men (P's⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women's pain perception and modulation is more sensitive to immune activation than men's., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Observational studies have suggested that with time, some diseases result in a characteristic odor emanating from different sources on the body of a sick individual. Evolutionarily, however, it would be more advantageous if the innate immune response were detectable by healthy individuals as a first line of defense against infection by various pathogens, to optimize avoidance of contagion. We activated the innate immune system in healthy individuals by injecting them with endotoxin (lipopolysaccharide). Within just a few hours, endotoxin-exposed individuals had a more aversive body odor relative to when they were exposed to a placebo. Moreover, this effect was statistically mediated by the individuals' level of immune activation. This chemosensory detection of the early innate immune response in humans represents the first experimental evidence that disease smells and supports the notion of a "behavioral immune response" that protects healthy individuals from sick ones by altering patterns of interpersonal contact.

Disclosure of potential conflicts of interest is used by biomedical journals to guarantee credibility and transparency of the scientific process. Conflict of interest disclosure, however, is not systematically nor consistently dealt with by journals. Recent joint editorial efforts paved the way towards the implementation of uniform vehicles for conflicts of interest disclosure. This paper provides a comprehensive editorial perspective on classical conflict of interest-related issues. New insights into current conflicts of interest policies and practices among European Society of Cardiology national cardiovascular journals, as derived from a cross-sectional survey using a standardized questionnaire, are discussed.

Background: Serotonin (5-HT) is highly involved in pain regulation and serotonin-1A (5-HT1A) receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A) may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP) rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities., Methods: Fourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C-49°C). Nociceptive-flexion reflex (NFR) thresholds were also assessed., Results: Volunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged., Conclusion/significance: To the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a 'hypo- to hyperalgesic' response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain pathologies. Further investigations are therefore warranted.

Little is currently known about the substrate binding site of the human UDP-glucuronosyltransferases (UGTs) and the structural elements that affect their complex substrate selectivity. In order to further understand and extend our earlier findings with phenylalanines 90 and 93 of UGT1A10, we have replaced each of them with Gly, Ala, Val, Leu, Ile or Tyr, and tested the activity of the resulting 12 mutants toward eight different substrates. Apart from scopoletin glucuronidation, the F90 mutants other than F90L were nearly inactive, while the F93 mutants' activity was strongly substrate dependent. Hence, F93L displayed high entacapone and 1-naphthol glucuronidation rates, whereas F93G, which was nearly inactive in entacapone glucuronidation, was highly active toward estradiol, estriol and even ethinylestradiol, a synthetic estrogen that is a poor substrate for the wild-type UGT1A10. Kinetic analyses of 4-nitrophenol, estradiol and ethinylestradiol glucuronidation by the mutants that catalyzed the respective reactions at considerable rates, revealed increased K(m) values for 4-nitrophenol and estradiol in all the mutants, whilst the K(m) values of F93G and F93A for ethinylestradiol were lower than in control UGT1A10. Based on the activity results and a new molecular model of UGT1A10, it is suggested that both F90 and F93 are located in a surface helix at the far end of the substrate binding site. Nevertheless, only F93 directly affects the selectivity of UGT1A10 toward large and rigid estrogens, particularly those with substitutions at the D ring. The effects of F93 mutations on the glucuronidation of smaller or less rigid substrates are indirect, however., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: We evaluated a generic quality of life (QoL) Functional Status Questionnaire (FSQ), in patients with chronic heart failure (CHF). The FSQ assesses the 3 main dimensions of QoL: physical functioning, mental health and social role. It also includes 6 single item questions about: work status, frequency of social interactions, satisfaction with sexual relationships, days in bed, days with restricted activity and overall satisfaction with health status. The FSQ was compared to the Minnesota Living with Heart Failure questionnaire (MLwHF)., Methods and Results: The FSQ was evaluated in a substudy (n = 340) of the second Cardiac Insufficiency Bisoprolol Survival study (CIBIS-II), a placebo-controlled mortality trial. 265 patients (75%) patients completed both questionnaires at 6 months of follow-up. Both questionnaires indicated substantially impaired QoL. The FSQ demonstrated high internal consistency (Cronbach's α > 0.7 for all items except "social activity" = 0.66) and construct and concurrent validity. After 6 months, the only item on either questionnaire to show a difference between the placebo- and bisoprolol-treatment groups was the single item FSQ question about "days in bed" (p = 0.018 in favour of bisoprolol)., Conclusions: The FSQ performed well in this study, provided additional information to the MLwHF questionnaire and allowed interesting comparisons with other chronic medical conditions. The FSQ may be a useful general QoL instrument for studies in CHF.

Background: Pulmonary sarcoidosis is an inflammatory disease, characterized by an accumulation of CD4+ lymphocytes and the formation of non-caseating epithelioid cell granulomas in the lungs. The disease either resolves spontaneously or develops into a chronic disease with fibrosis. The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) have been suggested to be important mediators of inflammation and mediate tissue remodelling. In support of this, we have recently reported enhanced NGF levels in the airways of patients with pulmonary sarcoidosis. However, less is known about levels of BDNF and NT-3, and moreover, knowledge in the cellular sources of neurotrophins and the distribution of the corresponding neurotrophin receptors in airway tissue in sarcoidosis is lacking., Methods: The concentrations of NGF, BDNF and NT-3 in bronchoalveolar lavage fluid (BALF) of 41 patients with newly diagnosed pulmonary sarcoidosis and 27 healthy controls were determined with ELISA. The localization of neurotrophins and neurotrophin receptors were examined by immunohistochemistry on transbronchial lung biopsies from sarcoidosis patients., Results: The sarcoidosis patients showed significantly enhanced NT-3 and NGF levels in BALF, whereas BDNF was undetectable in both patients and controls. NT-3 levels in BALF were found higher in patients with non-Löfgren sarcoidosis as compared to patients with Löfgren's syndrome, and in more advanced disease stage. Epithelioid cells and multinucleated giant cells within the sarcoid granulomas showed marked immunoreactivity for NGF, BDNF and NT-3. Also, immunoreactivity for the neurotrophin receptor TrkA, TrkB and TrkC, was found within the granulomas. In addition, alveolar macrophages showed positive immunoreactivity for NGF, BDNF and NT-3 as well as for TrkA, TrkB and TrkC., Conclusions: This study provides evidence of enhanced neurotrophin levels locally within the airways of patients with sarcoidosis. Findings suggest that sarcoid granuloma cells and alveolar macrophages are possible cellular sources of, as well as targets for, neurotrophins in the airways of these patients.

Aims: Information on the effectiveness of beta-blockade in patients with heart failure (HF) and concomitant renal impairment is scarce and beta-blockers are underutilized in these patients., Methods and Results: The Cockcroft-Gault formula normalized for body surface-area was used to estimate renal function (eGFR(BSA)) in 2622 patients with HF, left ventricular ejection fraction < or =35%, New York Heart Association class III/IV and serum creatinine <300 micromol/L (3.4 mg/dL) in the second Cardiac Insufficiency Bisoprolol Study II. Patients were divided into four sub-groups according to baseline eGFR(BSA) (<45, 45-60, 60-75 and > or =75 mL/min per 1.73 m(2)). Cox proportional-hazards models adjusted for pre-specified confounders were used to assess the effect of bisoprolol and potential heterogeneity of effect across the eGFR(BSA) sub-groups. Older age, female-sex, diabetes and ischaemic-aetiology were more common in those with reduced eGFR(BSA). The hazard associated with bisoprolol use for all-cause mortality, the composite of all-cause mortality or HF-hospitalization and HF-hospitalization alone was consistently <1.0 across eGFR(BSA) categories with no treatment by renal-function interaction (P = 0.81, P = 0.66, P = 0.71, respectively). The rate of bisoprolol discontinuation was higher in patients with eGFR(BSA) < 45 mL/min per 1.73 m(2). Nevertheless the absolute benefit of bisoprolol was greater for patients with chronic kidney disease compared with those without., Conclusion: The beneficial effects of bisoprolol on mortality and hospitalization for worsening heart-failure were not modified by baseline eGFR(BSA). Renal impairment should not prevent the use of bisoprolol in patients with HF.

The origin of the anomalous, 400% increase of the piezoelectric coefficient in Sc(x)Al(1-x)N alloys is revealed. Quantum mechanical calculations show that the effect is intrinsic. It comes from a strong change in the response of the internal atomic coordinates to strain and pronounced softening of C33 elastic constant. The underlying mechanism is the flattening of the energy landscape due to a competition between the parent wurtzite and the so far experimentally unknown hexagonal phases of the alloy. Our observation provides a route for the design of materials with high piezoelectric response.

We have examined the glucuronidation of psilocin, a hallucinogenic indole alkaloid, by the 19 recombinant human UDP-glucuronosyltransferases (UGTs) of subfamilies 1A, 2A, and 2B. The glucuronidation of 4-hydroxyindole, a related indole that lacks the N,N-dimethylaminoethyl side chain, was studied as well. UGT1A10 exhibited the highest psilocin glucuronidation activity, whereas the activities of UGTs 1A9, 1A8, 1A7, and 1A6 were significantly lower. On the other hand, UGT1A6 was by far the most active enzyme mediating 4-hydroxyindole glucuronidation, whereas the activities of UGTs 1A7-1A10 toward 4-hydroxyindole resembled their respective psilocin glucuronidation rates. Psilocin glucuronidation by UGT1A10 followed Michaelis-Menten kinetics in which psilocin is a low-affinity high-turnover substrate (K(m) = 3.8 mM; V(max) = 2.5 nmol/min/mg). The kinetics of psilocin glucuronidation by UGT1A9 was more complex and may be best described by biphasic kinetics with both intermediate (K(m1) = 1.0 mM) and very low affinity components. The glucuronidation of 4-hydroxyindole by UGT1A6 exhibited higher affinity (K(m) = 178 microM) and strong substrate inhibition. Experiments with human liver and intestinal microsomes (HLM and HIM, respectively) revealed similar psilocin glucuronidation activity in both samples, but a much higher 4-hydroxyindole glucuronidation rate was found in HLM versus HIM. The expression levels of UGTs 1A6-1A10 in different tissues were studied by quantitative real-time-PCR, and the results, together with the activity assays findings, suggest that whereas psilocin may be subjected to extensive glucuronidation by UGT1A10 in the small intestine, UGT1A9 is likely the main contributor to its glucuronidation once it has been absorbed into the circulation.

Objectives: Nerve growth factor (NGF) is a potent neuronal growth factor with inflammatory properties that recently has been proposed to be of importance in airway pathology. A role for NGF in the inflammatory granulomatous lung disease sarcoidosis is not well elucidated. The aims of this study were to investigate the secreted levels of NGF in bronchoalveolar lavage fluid (BALF) from sarcoidosis patients compared with patients with resolved disease, patients with another granulomatous disease--chronic beryllium disease (CBD)--and healthy subjects and also to investigate the relationship between NGF levels and markers of inflammation., Methods and Results: NGF levels in BALF from 56 patients with active sarcoidosis (22 with Löfgren's syndrome), nine subjects with resolved sarcoidosis, six patients with CBD, and 31 healthy subjects were compared. A 10-fold elevation of NGF levels was found in patients with active sarcoidosis compared with subjects with clinically resolved sarcoidosis, patients with CBD and healthy subjects. In sarcoidosis patients, positive correlations between concentrations of NGF and lymphocytes, eosinophils and interferon-gamma, interleukin (IL)-4, IL-10, IL-12 were found., Conclusions: We demonstrate that secreted levels of NGF are markedly enhanced in the airways in active pulmonary sarcoidosis. Furthermore, a relationship between NGF and pulmonary inflammation in sarcoidosis is supported.

The neurotrophin brain-derived neurotrophic factor (BDNF) occurs in elevated levels during airway inflammation, including asthma and hypoxic lung injury, and has been suggested to be associated with airway hyperresponsiveness in these conditions. The aim of the present study was to examine whether airway responses to histamine challenge and levels of exhaled nitric oxide (NO) in vivo might be altered upon BDNF treatment. Pulmonary resistance, lung compliance, insufflation pressure, and levels of exhaled NO were measured in anaesthetized guinea pigs exposed to BDNF prior to challenge with histamine and with intact or inhibited endogenous NO production. BDNF pretreatment significantly enhanced histamine-evoked increase in pulmonary resistance and insufflation pressure, as well as the decrease in lung compliance. BDNF markedly accentuated the reduction in exhaled NO following histamine challenge. In animals with inhibited endogenous NO production BDNF induced a significantly earlier histamine-evoked increase in airway responses. The present data show that BDNF can induce an augmentation of histamine-evoked airway responses and reduce levels of NO in exhaled air in vivo. Endogenous NO seems to exert a braking action on BDNF-induced enhancement of airway responses and a reduced ability to release NO may be one mechanism for increased airway response during elevated BDNF levels. Taken together this indicates that BDNF may be of importance for airway hyperresponsiveness in vivo. The interaction between BDNF and airway NO formation, and its relation to airway responses, merit further investigation.

The neurotrophin nerve growth factor (NGF) is elevated in serum and locally in the lung in asthmatics and has been suggested to evoke airway hyperresponsiveness. The aim of this study was to explore mechanisms behind NGF-evoked changes in airway responsiveness. We studied if NGF could evoke increased airway responsiveness to tachykinins, such as neurokinin A (NKA), in a similar way as for histamine and, if so, whether an NGF-evoked increase in NKA airway responsiveness could involve a histamine receptor-dependent mechanism. Contractile responses to cumulative doses of histamine or NKA were studied in guinea-pig tracheal rings in vitro in organ baths. Furthermore, insufflation pressure (IP), pulmonary resistance, lung compliance and exhaled NO (FeNO) were measured in vivo in anaesthetised guinea-pigs challenged with histamine or NKA. NGF pre-treatment in vitro increased the contractile response evoked by histamine, but not by NKA, in tracheal rings. NGF pre-treatment in vivo increased IP, pulmonary resistance and levels of FeNO, and further decreased lung compliance, upon histamine and NKA challenge. The NGF-evoked enhancement of IP, pulmonary resistance, lung compliance as well as FeNO in response to NKA was reversed by the histamine receptor antagonist mepyramine. We suggest that NGF can induce an increase in tachykinin-evoked airway responses and NO formation via a histamine receptor-dependent pathway. This points to an important role for the mast cell in neurotrophin-evoked airway hyperresponsiveness and changes in exhaled NO.

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) have been found to be upregulated in inflammatory pulmonary diseases, including asthma. The functional role for the neurotrophins in the airways is still not known, but it has been proposed that neurotrophins induce airway hyperreactivity and tissue remodeling. Bronchial smooth muscle cells have been suggested to be involved in the remodeling process through their capacity to proliferate, migrate, and secrete inflammatory mediators and matrix metalloproteinases (MMPs). Therefore, we studied the effect of NGF, BDNF, and NT-3 on human bronchial smooth muscle cell (HBSMC) migration and MMP-2 and MMP-9 secretion. Immunocytochemistry studies showed that HBSMCs expressed the neurotrophin receptors TrkA, TrkB, and TrkC. BDNF, NT-3, and NGF increased MMP-9, but not MMP-2, secretion as shown by zymography. BDNF and NT-3, but not NGF, stimulated HBSMC migration as evaluated by Boyden chamber. Taken together, our data indicate that the neurotrophins may stimulate events important for airway remodeling.

The increased number of lymphocytes in airways during an asthmatic response is believed to be the result of increased recruitment of these cells. However, it is possible that a decreased apoptotic rate could also contribute to the increased number. The aim of the present study was to investigate whether allergen airway provocation influences the apoptotic phenotype of lung and peripheral blood lymphocytes (PBL) in subjects with atopic asthma. Bronchoalveolar lavage (BAL) lymphocytes and PBL from 12 asthmatic subjects previously challenged with allergen (n = 7) or saline (n = 5) were exposed to the apoptotic stimulus tributyltin (TBT) in vitro and assayed for apoptosis. Airway allergen provocation resulted in decreased sensitivity of BAL lymphocytes to TBT-induced apoptosis, with 42.2% (range 33.9-62.5%) apoptotic cells before challenge versus 23.5% (range 15.3-42.4%) after challenge, while PBL were unaffected. The increased apoptosis resistance correlated with higher numbers of Bcl-2-expressing lymphocytes. Interestingly, baseline caspase-3-like activity was significantly elevated in viable BAL lymphocytes compared with viable PBL, and was unaltered by allergen exposure. In conclusion, allergen inhalation renders bronchoalveolar lavage lymphocytes more resistant to apoptosis while peripheral blood lymphocytes were not influenced at all, indicating that the apoptotic phenotype of airway lymphocytes may play a role in asthmatic inflammation.

Nerve growth factor (NGF) is a neurotrophic factor essential for the development and survival of neurons, and is also an important mediator of inflammation. It is released by airway cells stimulated by interleukin (IL)-1beta. As IL-1beta induces airway hyperresponsiveness (AHR) to the tachykinin NK-1 receptor agonist [Sar9,Met(O2)11]-substance P in human isolated bronchi, the aim of this study was to determine whether IL-1beta was able to induce NGF release from isolated bronchi, and whether NGF might participate into IL-1beta-induced AHR. IL-1beta (10 ng x mL(-1); 21 degrees C; 15 h) increased the release of NGF from human isolated bronchi in vitro, and, in organ bath studies, the response of human bronchi to [Sar9,Met(O2)11]-substance P (0.1 microm). A significant correlation was found between these responses. AHR induced by IL-1beta was abolished by a blocking anti-human NGF antibody. Finally, NGF (1 ng x mL(-1); 37 degrees C; 0.5 h) by itself induced a significant increase in [Sar9,Met(O2)11]-substance P responsiveness. By contrast, it did not change the maximal contraction to acetylcholine. In conclusion, the present study clearly demonstrated that nerve growth factor may participate in the airway hyperresponsiveness induced by interleukin-1beta, which supports the neuro-immune cross-talk that may be active in the development of hyperresponsiveness in the human airways, and suggests nerve growth factor is active in the airways in asthma.

Nerve growth factor (NGF) has recently been suggested to be an important mediator of inflammation. In support of this, serum levels of NGF have been shown to be enhanced in asthmatics. However, it has not yet been shown whether the levels of NGF are also altered locally in asthmatic airways, when compared with healthy subjects, and the localisation of potential sources of NGF in the human bronchus have not yet been described. The aim of the present study was to assess NGF levels in bronchoalveolar lavage fluid (BALF) from asthmatics and to compare them to those of control subjects. Furthermore, the authors wanted to localise potential sources of NGF in bronchial tissue, and to number NGF-immunopositive infiltrating cells in the bronchial submucosa. BALF and bronchial biopsies were obtained from seven control subjects and seven asthmatic patients by fibreoptic bronchoscopy. NGF protein levels were quantified by enzyme-linked immunosorbent assay in BALF. NGF localisation was examined by immunohistochemistry on bronchial biopsy sections. The asthmatics exhibited significantly enhanced NGF levels in BALF. Intense NGF-immunoreactivity was observed in bronchial epithelium, smooth muscle cells and infiltrating inflammatory cells in the submucosa, and to a lesser extent in the connective tissue. The asthmatics exhibited a higher number of NGF-immunoreactive infiltrating cells in the bronchial submucosa than control subjects. This study provides evidence that nerve growth factor is locally produced in the airways, and shows that this production is enhanced in asthmatics. These findings suggest that nerve growth factor is produced by both structural cells and infiltrating inflammatory cells in human bronchus in vivo, and the authors suggest that the increase in nerve growth factor protein in bronchoalveolar lavage fluid observed in asthmatic patients may originate both from structural cells, producing increased nerve growth factor levels in inflammatory conditons, and from the increase in nerve growth factor-immunopositive cells determined in the bronchial submucosa.

The acute effects of smoking on left ventricular (LV) function were studied in 36 healthy participants (mean age 38 +/- 10 years). The studies were made before and immediately and 30 minutes after smoking a cigarette. From apical 4- and 2-chamber views, the mitral annular velocities, determined by pulsed wave Doppler tissue imaging, were measured at 4 LV sites corresponding to the septum and the anterior, lateral, and inferior walls. A mean value from the 4 sites was used to assess LV function. The peak systolic, early diastolic, late diastolic, and the ratio of early to late diastolic velocities were recorded. In addition, other conventional Doppler echocardiographic diastolic parameters were also determined. Heart rate was increased immediately after smoking (from 67 +/- 8 to 74 +/- 10 bpm, P <.001). There was no change in systolic mitral annular velocity. Diastolic LV function was changed significantly immediately after smoking. The transmitral A wave increased (0.55 +/- 0.1 vs 0.7 +/- 0.1 m/s, P <.001), the transmitral E/A ratio decreased (1.5 +/- 0.6 vs 1.1 +/- 0.3, P <.001), and the transmitral E-wave deceleration time increased (186 +/- 42 vs 211 +/- 44 ms, P <.05). The diastolic myocardial velocity at the mitral annulus also changed significantly: the early diastolic velocity decreased (16 +/- 3 vs 15 +/- 3 cm/s, P <.001), the late diastolic velocity increased (10.9 +/- 2.2 vs 12 +/- 2.4 cm/s, P <.001), and the ratio of early to late diastolic annular velocities decreased (1.5 +/- 0.5 vs 1.2 +/- 0.4, P <.001). The changes in the transmitral flow velocities remained unaltered even 30 minutes afterward, although the heart rate returned to normal. The results were similar in both smokers and nonsmokers. Acute smoking of a cigarette influences LV diastolic function in healthy participants. The mechanism behind this effect cannot be explained only by changes in the heart rate or loading conditions. The mechanism is probably more complex.

A screening-level quantitative microbial risk assessment (QMRA) was undertaken for a urine separating sewerage system. Exposures evaluated included the handling of stored and unstored urine as well as consumption of crops fertilised with urine. Faecal cross-contamination was the source of risk and Campylobacter jejuni, Cryptosporidium parvum and rotavirus were the organisms chosen to represent different groups of enteric pathogens. Accidental ingestion of unstored urine implied a high risk (Pinf = 0.56) for infection from rotavirus whereas the risks for infection from bacteria and protozoa were approximately 1:10 000. After six months storage at 20 degrees C the risk for viral infections by accidental ingestion of 1 ml of urine was < 10(-3), the suggested acceptable risk benchmark. Ingestion of crops contaminated with urine resulted in risks of < 10(-5) after a 3-week (<10(-7) after 4 weeks) withholding period between fertilising and harvesting.

Objective: To qualify 302 multinational echocardiography sites to record and read serial studies and to monitor quality in 5010 patients randomized into Valsartan in Heart Failure Trial (Val-HeFT)., Background: Decentralized echocardiography reading is unprecedented in large clinical trials., Methods: Single and duplicate recordings, and triplicate readings of echocardiographic variables were submitted to 3 core laboratories. Quality of recording was defined with a 16-point scoring system; accuracy of reading by agreement with core readings; reproducibility by agreement between the duplicate studies., Results: Seventy-five percent of initial submissions were approved for recording, and 50% for reading. Resubmissions were evaluated until approval. Initial scores of sites approved with 1 versus 2 submissions differed, 13.8 +/- 1.4 versus 10.6 +/- 2.0, P <.001; final score was similar, 13.4 +/- 1.6, P = ns. Initial score of sites approved after 3 or more submissions differed, 9.5 +/- 1.9, P <.001; final score improved to 12.7 +/- 1.9, but remained lower, P <.001. Expressed as 95% limits of agreement (mean difference +/- 1.96 x SD), accuracy = -0.04 +/- 0.74 cm for left ventricular internal end-diastolic diameter (LVIDd); -0.29 +/- 14.3% for ejection fraction (EF); reproducibility = 0.00 +/- 0.53 cm for LVIDd; -0.25 +/- 8.3% for EF. Quality of random sampling at baseline, 4, 12, and 18 months showed recording scores of 11.7 +/- 2.7, 12.3 +/- 2.4, 12.1 +/- 2.2, and 11.4 +/- 2.0, P =.24. Power analysis revealed differences of 0.09 cm for LVIDd, and 0.86% for EF detectable with a power of 90% and alpha of 5%., Conclusion: The qualifying process improved echocardiography recording and reading to bring 95% of the sites to an equivalent level of quality. Monitoring quality found that recording quality and reading accuracy were maintained 18 months into the trial. Reproducibility, given the large sample size, will be able to detect small changes in LVIDd and EF.

The cost-effectiveness of adding the beta blocker bisoprolol to standard treatment in patients with congestive heart failure was investigated, based on data from the Cardiac Insufficiency Bisoprolol Study II (CIBIS II). The medical resource consumption from CIBIS II was combined with Swedish cost data for medication and hospitalisations. Costs of added years of life, i.e. consumption net of production, were also included in the analysis. The health effects were measured in terms of gained years of life. The results of the analysis show that the cost-effectiveness of bisoprolol compares favourably with that of other cardiovascular treatments. Without the inclusion of costs of added years of life, the cost-effectiveness was in the range of SEK 3,351-13,096 per gained year of life, and with the costs of added years of life included, the cost-effectiveness was in the range of SEK 137,533-147,278 per gained year of life.

There is a growing body of evidence supporting the idea that nerve growth factor (NGF) may be involved in the development of asthma-associated symptoms, such as airway hyper-responsiveness. Increased levels of NGF have recently been described in serum and in the airways of asthmatics. We have examined whether exhaled nitric oxide (NO) levels might be altered during the increased airway responses upon NGF treatment in guinea-pigs in vivo. Intravenous (i.v.) administration of histamine normally elicits a rapid peak in insufflation pressure (IP) and in exhaled NO, followed by a period of decreased concentrations of exhaled NO. Anaesthetized guinea-pigs were pre-treated intravenously with either saline, 4 or 80 ng x kg(-1) NGF 30 min before i.v. challenge with 16 microg x kg(-1) histamine. At 80 ng x kg(-1) NGF significantly enhanced the airway obstruction caused by histamine, whereas the peak acute increase in exhaled NO was not enhanced. Following the increase, came a rapid drop, an effect enforced in the NGF treated animals. Subsequently, the time to return to 90% of resting exhaled NO was increased, from 12 min in saline-treated animals to 48 min in NGF-treated animals. Our data confirm that NGF can enhance airway responses to histamine. Moreover, our study shows a decrease in exhaled NO following a histamine challenge, an effect enhanced by NGF. A reduced ability to release exhaled NO may be a mechanism for increased airway responses during elevated NGF levels. The interaction between NGF and airway NO formation, and its relation to airway responses, merit further investigation.

The survival of Cryptosporidium parvum in source separated urine was investigated as part of a broader study on microbial risks associated with the reuse of human urine for sustainable agriculture. A dye permeability assay and in vitro excystation were the primary methods used to assess viability. In the collected urine most of the nitrogen is present as ammonia and the pH is generally around 9. Parallel investigations were made in buffers to compare possible toxic effects of urine to actual pH effects. Oocysts in the untreated urine were inactivated below the detection limit (1/300) within 63 days. This inactivation rate was significantly higher (p < 0.01) than in urine adjusted to pH 5 or 7 according to the dye permeability assay. The corresponding difference between different pH values was not seen in buffers, suggesting that the antiprotozoan effect of urine was mediated by other factors besides pH. The Swedish practice of storing urine for six months before its use thus appears satisfactory for the inactivation of Cryptosporidium oocysts.

Objective: This study was designed to compare the effect of mibefradil, a selective T-type calcium channel antagonist, with the beta-blocker atenolol on regression of left ventricular (LV) hypertrophy in hypertensive patients., Methods: In this multicenter, double-blind, active-controlled, randomized, parallel-group comparison, 66 patients with mild-to-moderate hypertension (sitting diastolic blood pressure, SDBP, 95-114 mm Hg) and LV mass index > 102 g/m2 for males and > 88 g/m2 for females were randomized to an initial treatment with 50 mg of either mibefradil or atenolol for 4 weeks. Doses were increased to 100 mg/day if blood pressure was not normalized to < or = 90 mm Hg, and, if needed, 25 mg of hydrochlorothiazide was added. Treatment continued for a total of 24 weeks. LV hypertrophy was assessed by echocardiography, and trough SDBP and adverse events were recorded., Results: Treatment with mibefradil or atenolol resulted in decreases from baseline in LV mass index of 11.1% (p < 0.001) and 9.1% (p < 0.001), respectively. The treatment difference (mibefradil vs. atenolol) was not statistically significant. Reductions in SDBP with mibefradil and atenolol were 14.3 and 10.7 mm Hg, respectively, again not statistically significant. Both drugs were well tolerated; however, overall there were more potentially drug-related adverse events reported with atenolol (48.5%) than with mibefradil (24.2%)., Conclusions: The reductions in LV hypertrophy and blood pressure achieved with mibefradil were larger but statistically equivalent to those with atenolol, but a lower overall incidence of treatment-related adverse events was seen in the mibefradil-treated patients.

The aim of the present study was primarily to evaluate the haemodynamic effects of the ACE-inhibitor ramipril which is active via its metabolite ramiprilat. Ramipril 1.25, 2.5 and 5 mg and placebo was administered orally to 4 groups of 12 patients with heart failure (NYHA III) in a double-blind randomised, parallel study. Haemodynamics were monitored for 24 h and blood was sampled and urine collected for up to 96 h. In the placebo-treated group the cardiac index (CI) was significantly increased (15.8%) and right atrial pressure decreased (26.6%). Ramipril 1.25 mg had insignificant haemodynamic effects compared to placebo and the 2.5 mg dose had significant effects on some haemodynamic variables. Ramipril 5 mg had pronounced and sustained effects on pulmonary artery pressure, which fell by 43.7%, and pulmonary capillary wedge pressure (PCWP; -59.1%); systemic vascular resistance was also decreased 21%. A significant effect on CI was only seen after 2.5 mg ramipril (+7.4%). The mean maximal degree of ACE inhibition was 73.2, 90.4 and 98.5%, respectively, after the three doses of ramipril. Complete inhibition of ACE-activity was seen at a mean plasma concentration of ramiprilat of 4.7 ng.ml-1. The degree of inhibition declined with a half life of about 75 h. There was a significant relation between the degree of ACE-inhibition and change in PCWP but not with the change in SVR. Ramipril was mainly eliminated in the form of ramiprilat and inactive metabolites.

Fired porcelain inlays were cemented in class II cavities with either a dual cured composite or a glass ionomer luting cement. Clinically evaluation according to modified USPHS criteria was done at baseline and after 6, 12 and 24 months. Inlays bonded with the composite resin showed a 2% failure rate, while 15% of the inlays cemented with the glass ionomer were lost or fractured during the evaluation period. The failures were in most cases due to an adhesive bond failure at the cement-porcelain interface.

Echocardiographic recording of the atrioventricular (AV) valve plane displacement was used for serial studies of left ventricular (LV) function in 27 patients with first-time acute myocardial infarction (MI) treated with a thrombolytic agent within 4 h of the onset of symptoms and showing noninvasive signs of early reperfusion. The recordings were made immediately before or during thrombolytic therapy and 24 h, 1 week, 1 month, and 2 months after attempted reperfusion. Regional LV function was assessed by recording the amplitude of systolic descent of the AV plane toward the apex at 4 different sites on left ventricle corresponding to the septal, anterior, lateral, and posterior walls from apical 4- and 2-chamber views. Global LV function was assessed using the mean value of the AV plane displacement from the above 4 sites (AV mean). In 15 patients with anterior MI, the displacement at the septum and anterior wall was significantly decreased compared with the posterior and lateral walls at baseline. The displacement had increased significantly after 1 week, 1 month, and 2 months (p less than 0.01, p less than 0.01, and p less than 0.001). The AV mean also increased significantly (p less than 0.01) during the study period. A corresponding regional increase was observed in inferior MI. The AV mean remained unchanged, however, during the follow-up period. It is concluded that the easy visualization and the simplicity of recording the AV plane displacement makes the method a valuable non-invasive tool for serial echocardiographic studies following acute MI treated with a thrombolytic agent.

Patients with stable, effort-induced angina pectoris and a typical combination of anginal pain and ischemic ST depression in exercise tolerance tests were randomized to treatment for 8 weeks with nicorandil (a newly developed antianginal and anti-ischemic drug) or nifedipine. After 4 weeks, the dosage of nicorandil was increased from 10 mg b.i.d. to 20 mg b.i.d., but the recommended dosage of nifedipine, 20 mg b.i.d., was kept constant during the study period. Double-blind treatment was preceded by a 2-week prephase during which patients were treated with isosorbide dinitrate. During the study period, patients were asked to report the rate of anginal attacks and consumption of sublingual nitroglycerin. Measurements of blood pressure and heart rate at rest and during exercise always were performed 2 h after drug intake. Fifty-eight patients were randomized--29 to nicorandil and 29 to nifedipine. There were large individual variations in anginal attack rates, which makes group comparisons difficult, but in the nicorandil group, the anginal attack rate decreased significantly compared with baseline frequency. Systolic blood pressure at rest was reduced significantly only with the highest dose of nicorandil, but nifedipine had a significant effect on both systolic and diastolic blood pressures as well as on the heart rate. Both treatments significantly increased exercise duration, time to onset of angina pectoris, and time to 1-mm ST depression. In the nicorandil group, an improvement was noted with the 20-mg dose compared with the 10-mg dose, but no significant differences were noted between the nicorandil and nifedipine groups after either 4 or 8 weeks of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of exercise on the displacement of the atrioventricular (AV) plane was studied by echocardiography (echo) in 48 patients with stable angina pectoris without prior myocardial infarction and 20 age-matched healthy subjects. Echo was performed at rest, immediately after and 10 and 30 min after the test. The patients also underwent thallium stress scintigraphy and coronary angiography. From the apical four- and two-chamber views, the atrioventricular plane displacement (AVPD) during the cardiac cycle was recorded at four sites corresponding to the septal, anterior, lateral and posterior walls of the left ventricle and a mean value was calculated (AV-mean). The healthy subjects and patients had almost the same AVPD at all the sites at rest (AV-mean of 14.5 and 14.2 mm respectively). Immediately post-exercise the healthy subjects showed a significant (P less than 0.001) and equally distributed increase in the AVPD at all the sites with an AV-mean value of 19.2 mm. In most of the patients with angiographically confirmed coronary artery disease (CAD), there was a reversible decrease of AVPD (greater than or equal to 3 mm) at one or more of the AV plane sites. The overall sensitivity and specificity were 80% and 100% respectively in identifying CAD patients. The changes correlated well with the reversible ischaemic changes on the thallium scan (sensitivity, 88%, and specificity, 83%). A generalized exercise-induced decrease in AVPD at all the recorded sites had a high specificity (91%) in detecting patients with three-vessel disease.(ABSTRACT TRUNCATED AT 250 WORDS)