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Objectives Acute otitis media is the single diagnosis responsible for most prescriptions of antibiotics in Sweden and the USA. The treatment of acute otitis media has significant impact on child health, healthcare costs, and the development of anti-microbial resistance. In the Swedish national guidelines from the year 2000, watchful waiting was recommended for most children over 2 years of age. The aims of the present study were to assess the degree of adherence to acute otitis media guidelines at a busy pediatric emergency department of a university hospital and to determine whether an information campaign changed the result. Methods Audit of 91 patient records before and 80 patient records after an information campaign consisting of an oral presentation, posting of flow charts, and sending of educational material to prescribing physicians. Four endpoints were studied: choosing to use antibiotics, choice of antibiotic, dosage of antibiotic, and duration of treatment. Results Before the information campaign, adherence to guidelines was between 70% (dosage) and around 90% (duration). No significant change was seen after the information campaign. The endpoint choosing to use antibiotics showed a large divergence in adherence in children under 2 years (96%) compared to older children (39%). Conclusions Overall adherence to recommendations was 70–90% but adherence to watchful waiting was poor. Information did not improve adherence, suggesting insufficient educational power or the existence of barriers other than lack of knowledge. Specific barriers should be identified, and implementation and follow-up should be part of producing guidelines in order to achieve the desired results.

Numerous interacting abiotic and biotic factors shape an organism's spatial distribution, and these factors vary spatially and temporally, such that habitat used for breeding may differ from habitat used at other times of the life cycle. We address this complex issue in the context of citizen science and opportunistic species occurrence records, a valuable data source for biogeography and conservation. We focus on the insect order Odonata, the dragonflies and damselflies, which as adults are popular in citizen science programs. Our goal was to devise a means to estimate with high confidence whether a site supports a breeding population if only opportunistic data are available. Our approach fitted logistic curves from occupancy models of observations of tenerals (newly emerged adults that cannot yet disperse from a natal site) against counts of all adults, adult females only, and incidence of breeding behaviors (ovipositing, mate guarding, tandem pairs). Models included median body size and abundance class as covariates of detectability. We subjected logistic curves to a Bayesian two-segment piecewise regression to obtain best estimates of the threshold (with associated credible intervals as an estimate of uncertainty) to assess if a given predictor (e.g., adult count) or combination of predictors was associated with breeding occurrence. We found that no single threshold fit all odonates: thresholds of varying precision were identified for the suborders (dragonflies, damselflies) and for families and select genera in each suborder. Counts of females greatly reduced the required threshold, whereas breeding behavior data reduced the threshold in some cases. Our study shows it is possible to identify breeding occurrences in opportunistic adult Odonata records. It also highlights how citizen scientists should record not only a sound species list with rudimentary counts of adults but also note the sex and breeding behavior. The identification of breeding occurrences in extensive opportunistic data is pertinent to understanding species' distributions and habitat requirements along with their ecological sensitivity and value as bioindicators.

Aim To describe presence of risk indicators of recurrence 6months after hospitalisation due to coronary artery disease at a university clinic. Methods The presence of risk indicators, including tobacco use, lipid levels, blood pressure and glucometabolic status, including 24-hour blood pressure monitoring and an oral glucose-tolerance test, was analysed. Results Of 1465 patients who were screened, 402 took part in the survey (50% previous myocardial infarction and 50% angina pectoris). Mean age was 64years (range 40–85years) and 23% were women. Present medications were: lipid lowering drugs (statins; 94%), beta-blockers (85%), aspirin or warfarin (100%) and ACE-inhibitors or angiotensin II blockers (66%). Values above target levels recommended in guidelines were: a) low density lipoprotein (LDL) in 40%; b) mean blood pressure (day or night) in 38% and c) smoking in 13%. Of all patients, 66% had at least one risk factor (LDL or blood pressure above target levels or current smoking). An abnormal glucose-tolerance test was found in 59% of patients without known diabetes. If no history of diabetes, 85% had either LDL or blood pressure above target levels, current smoking or an abnormal glucose-tolerance test. However, with treatment intensification to patients with elevated risk factors 56% reached target levels for blood pressure and 79% reached target levels for LDL. Conclusion Six months after hospitalisation due to coronary artery disease, despite the high use of medication aimed at prophylaxis against recurrence, the majority were either above target levels for LDL or blood pressure or continued to smoke.

This study measured the postures of older people during cooking and laundry. A sample of men and women aged 75+ years (n=27) was recruited and observed in a home-like environment. Postures were recorded with a measurement system in an objective and detailed manner. The participants were videotaped to be able to see where 'critical' postures occurred, as defined by a trunk inclination of ≥60°. Analysis of data was facilitated by specially developed software. Critical postures accounted for 3% of cooking and 10% of laundry, occurring primarily during retrieving from and putting in lower cabinets, the refrigerator, laundry basket or washing machine as well as disposing into the waste bin. These tasks involve a great variation in postural changes and pose a particular risk to older people. The results suggest that the use of stressful postures may decrease efficiency and increase fatigue, eventually leading to difficulties with daily activities. The specific tasks identified during which critical postures occurred should be targeted by designers in order to improve the activities. A few examples are given of how better design can reduce or eliminate some of the postural constraints.

Objectives The purpose of this study was to determine whether coenzyme Q10 is an independent predictor of prognosis in heart failure. Background Blood and tissue concentrations of the essential cofactor coenzyme Q10 are decreased by statins, and this could be harmful in patients with heart failure. Methods We measured serum coenzyme Q10 in 1,191 patients with ischemic systolic heart failure enrolled in CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) and related this to clinical outcomes. Results Patients with lower coenzyme Q10 concentrations were older and had more advanced heart failure. Mortality was significantly higher among patients in the lowest compared to the highest coenzyme Q10 tertile in a univariate analysis (hazard ratio: 1.50, 95% confidence interval: 1.04 to 2.6, p = 0.03) but not in a multivariable analysis. Coenzyme Q10 was not an independent predictor of any other clinical outcome. Rosuvastatin reduced coenzyme Q10 but there was no interaction between coenzyme Q10 and the effect of rosuvastatin. Conclusions Coenzyme Q10 is not an independent prognostic variable in heart failure. Rosuvastatin reduced coenzyme Q10, but even in patients with a low baseline coenzyme Q10, rosuvastatin treatment was not associated with a significantly worse outcome. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310 )

Objectives We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective. Background Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile. Methods In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke. Results Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin. Conclusions Patients with heart failure due to ischemic heart disease who have NT-proBNP values

Background: Limited information is available on the risk and impact of renal dysfunction on the response to beta-blockade and mode of death in systolic heart failure (HF).Methods and Results: Renal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR(MDRD) > 60 (n = 2496), eGFR(MDRD) 45 to 60 (n = 976), and eGFR(MDRD) 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR 60; corresponding data for the combined end point was HR. 0.44 (95% CI, 0.31 to 0.63; P Conclusions: Renal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR 60. (J Cardiac Fail 2009;15:310-318)

Nosocomial lower respiratory tract infections are a common cause of morbidity and mortality in ICU patients receiving mechanical ventilation. Many studies have investigated the management and prevention of ventilator-associated pneumonia (VAP), but few have focused on the role of ventilator-associated tracheobronchitis (VAT). The pathogenesis of lower respiratory tract infections often begins with tracheal colonization that may progress to VAT, and in selected patients to VAP. Since there is no well-established definition of VAT, discrimination between VAT and VAP can be challenging. VAT is a localized disease with clinical signs (fever, leukocytosis, and purulent sputum), microbiologic information (Gram stain with bacteria and leukocytes, with either a positive semiquantitative or a quantitative sputum culture), and the absence of a new infiltrate on chest radiograph. Monitoring endotracheal aspirates has been used to identify and quantify pathogens colonizing the lower airway, to diagnose VAT or VAP, and to initiate early, targeted antibiotic therapy. Recent data suggest that VAT appears to be an important risk factor for VAP and that targeted antibiotic therapy for VAT may be a new paradigm for VAP prevention and better patient outcomes.

Atomistic models of the Si(1 0 0)/SiO2 interface were generated using a classical reactive force field, and subsequently optimized using density functional theory. The interfaces consist of amorphous oxide bound to crystalline silicon substrate. Each system has a sub-oxide layer of partially oxidized silicon atoms at the interface, and a distribution of oxygen-deficient centers in the oxide. Both periodic and slab configurations are considered.

The key effects of combined transient neutron and ionizing radiation on silicon diodes and bipolar junctions transistors are described. The results show that interstitial defect reactions dominate the annealing effects in the first stage of annealing for certain devices. Furthermore, the results show that oxide trapped charge can influence the effects of bulk silicon displacement damage for particular devices.

Glimpses of new results from Odin’s fourth to sixth years of operation are presented: the first detection of interstellar O 2 ; the high water abundance in the M 42/Orion KL interface region; new results from the Orion KL spectral scan, including considerably improved knowledge of source physics and chemistry; the constant H 2 O/HCO + abundance ratio observed in diffuse, spiral arm clouds; mapping of shock-enhanced water emission in some nearby bipolar outflows; meaningful upper limits to the water abundance in nearby starburst galaxies; new mapping of the water emissions and absorptions in the Galactic Centre region – Sgr A; abundant self-absorbing water observed in the circumstellar envelope of R Doradus; very successful observations of many comets – including Tempel 1 (the target of Deep Impact) and recent observations of an outburst in the disintegrating Comet 73P/Schwassmann–Wachmann 3; and finally a note on our Odin searches for primordial molecules – potential structure probes during the dark ages of the evolution of the Universe.

The study examined first-year engineering students’ responses to a statistics task that asked them to generate a procedure for quantifying variability in a data set from an engineering context. Teams used technological tools to perform computations, and their final product was a ranking procedure. The students could use any statistical measures, and they needed to explain their ranking procedure in detail. The responses were first categorized by the statistical measures used. The responses were categorized using a cyclic model development perspective moving from primitive to more sophisticated responses. The modeling cycle framework provided a developmental view of students’ responses and use of statistics. The study raised questions related to the measurement of variability, the application of statistics, and the process teams go through when designing an analysis procedure.

We investigate molecular scale mechanisms for radiation-induced release of hydrogen from precursor sites using density functional theory applied to a fully periodic model of SiO 2 . We focus on proton release from H-decorated oxygen vacancies in the bulk oxide. After hole-capture at the vacancy, a proton can hop to an energetically favorable bound state at a neighboring oxygen atom. In α-quartz, this release mechanism has an activation energy of about 1.2 eV. In amorphous silica, this hop has a range of low barriers, from 0.1 to 0.5 eV. Furthermore, another proton release mechanism involves cracking of H 2 molecules by a reaction with an isolated, positively charged Si-dangling bond.

The key effects of ionizing radiation on silicon dioxide are described and computed. Inclusion of bimolecular electron–hole recombination is shown to produce a saturation of fixed charge at high total dose and to a reduction in interface trap density at high dose-rates. These results can explain the enhanced low dose rate sensitivity (ELDRS) phenomenon. These results also predict a new dose-rate dependence at very high dose rates.

Background The MERIT-HF trial demonstrated improved survival and fewer hospitalizations for worsening heart failure with extended-release (ER) metoprolol succinate in patients with heart failure. This study sought to estimate the economic implications of this trial from a US perspective. Methods and Results A discrete event simulation was developed to examine the course of patients with heart failure. Characteristics of the population modeled, probabilities of hospitalization and death with standard therapy, and risk reductions with ER metoprolol succinate were obtained from Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) and evaluated in weekly cycles. Direct medical costs were estimated from US databases in 2001 US dollars. Uncertainty in inputs was incorporated and analyses were carried out to estimate events prevented total and net costs. The model predicts that ER metoprolol succinate will prevent approximately 7 deaths and 15 hospitalizations from heart failure per 100 patients over 2 years. Compared with standard therapy alone, this translates to a cost reduction between $395 and $1112 per patient, depending on whether the costs of hospitalizations for other causes are included. Savings were maintained in 90% of the simulations. Conclusion This analysis predicts that the positive effect of ER metoprolol succinate on mortality and morbidity demonstrated in MERIT-HF leads to substantial savings.

Background Psychologists can play an important role in helping their clients stop using tobacco. The extent to which they do so, or quit themselves, has not been reported previously. The utility of snus in reducing smoking prevalence is also questioned and merits study. Method A 36-item self-completion questionnaire was mailed to a random sample of 1000 Swedish psychologists. Results The response rate was 85%. Very few psychologists (1%) ‘often’ helped clients to stop using tobacco. While a majority (72%) believed that quitting tobacco use would improve their client's quality of life, most (75%) thought that it was not their responsibility to help clients stop and 74% felt they lacked the necessary skills. About 8% of psychologists smoked cigarettes daily. Use of snus as an aid to cigarette cessation was common in men, but not women, although overall, the percentage of smokers who had quit smoking (72%) did not differ by gender. Conclusions Most Swedish psychologists have stopped smoking, but very few help their clients to quit. Targeted campaigns aimed at encouraging and supporting psychologists to treat nicotine dependence are needed. This could increase cessation rates in the population. Snus helped reduce smoking prevalence among men and is a potentially useful harm reduction tool.

Objectives The goal of this study was to explore the question: what resting heart rate (HR) should one aim for when treating patients with heart failure with a beta-blocker? Background The interaction of pretreatment and achieved resting HR with the risk-reducing effect of beta-blocker treatment needs further evaluation. Methods Cardiovascular risk and risk reduction were analyzed in five subgroups defined by quintiles (Q) of pretreatment resting HR in the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). Results Mean baseline HR in the 5 Qs were 71, 76, 81, 87, and 98 beats/min; achieved HR 63, 66, 68, 72, and 75 beats/min; and net change −8, −10, −11, −13, and −14 beats/min, respectively. Baseline HR was related to a number of baseline characteristics. Cardiovascular risk was no different in Q1 toQ 4 (placebo groups) but increased in Q5 (HR above 90 beats/min). No relationship was observed between the risk-reducing effect of metoprolol controlled release/extended release (CR/XL) and baseline HR in the five Qs of baseline HR, or achieved HR, or change in HR during follow-up, respectively. Conclusions Metoprolol CR/XL significantly reduced mortality and hospitalizations independent of resting baseline HR, achieved HR, and change in HR. Achieved HR and change in HR during follow-up were closely related to baseline HR; therefore, it was not possible to answer the question posed. Instead, one has to apply a very simple rule: aim for the target beta-blocker dose used in clinical trials, and strive for the highest tolerated dose in all patients with heart failure, regardless of baseline and achieved HR.

Objective To test whether infants with bronchopulmonary dysplasia (BPD) express the same functional impairments at term as healthy, preterm infants, and whether clinical severity of BPD is qualitatively or quantitatively related. Study design Prospective measurements on a consecutive sample of 50 infants with BPD and 19 healthy preterm controls in a university hospital. BPD infants were classified as "severe," "moderate," or "mild," according to their need for oxygen. A multiple-breath nitrogen wash-out method was used to assess functional residual capacity (FRC) and gas mixing efficiency. Mechanical variables were estimated by the occlusion test. Results Infants with severe BPD had lower FRC, less efficient gas mixing, and higher specific conductance than those with mild and moderate BPD, and the preterm controls. Mild and moderate BPD did not differ in any property from each other but differed from controls in the same variables. The elastic properties of the respiratory system appeared unaffected by BPD. Conclusions The ventilatory impairments in BPD were of the same nature as in healthy preterm infants when compared with term infants, but their magnitude was related to the clinical severity of the BPD. Gas mixing efficiency together with FRC appears to be useful to assess lung development in BPD.

Marketing researchers have studied consideration sets for a long time and many different operationalizations of this concept have been used. This empirical study, with 670 households, compares two widely used operationalizations, recognition-based and recall-based measures of consideration sets. The results indicate several differences between the measures. The recognition-based measure produces larger sets than the recall-based measure. However, some strong brands are found to be included more often with the recall-based measure. Further, the recognition-based measure generates increased price sensitivity as well as reduced loyalty as compared to a recall-based measure.

The key Odin instrumental features are summarised, and the advantages vs Submillimeter Wave Astronomy Satellite (SWAS) are identified. We highlight results from Odin’s first year of sub-millimetre and millimetre wave observations of H2O, H218O, NH3, and O2, focussing on a number of new results where Odin’s high angular resolution, high frequency resolution, large spectrometer band widths, high sensitivity, or/and frequency tuning capability are crucial. We also show, by means of a quantitative comparison of Orion KL H2O results, that the Odin and SWAS observational data sets are very consistently calibrated.

Objectives We performed a post-hoc subgroup analysis in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) with the aim of reporting on the heart rate (HR) response during the titration phase and clinical outcomes from the three-month follow-up visit to end of study in two dosage subgroups: one that had reached more than 100 mg of metoprolol CR/XL once daily (high-dose group; n = 1,202; mean 192 mg) and one that had reached 100 mg or less (low-dose group; n = 412; mean 76 mg). Background Clinicians have questioned whether patients need to reach the target beta-blocker dose to receive benefit. Methods Outcome (Cox-adjusted) was compared with all placebo patients with dose available at the three-month visit (n = 1,845). Results Data indicated somewhat higher risk in the low-dose group compared with the high-dose group. Heart rate was reduced to a similar degree in the two dose groups, indicating higher sensitivity for beta-blockade in the low-dose group. The reduction in total mortality with metoprolol CR/XL compared with placebo was similar: 38% (95% confidence interval [CI], 16 to 55) in high-dose group (p = 0.0022) and also 38% (95% CI, 11 to 57) in the low-dose group (p = 0.010). Conclusions Risk reduction was similar in the high- and low-dose subgroups, which, at least partly, may be the result of similar beta-blockade as judged from the HR response. The results support the idea of an individualized dose-titration regimen, which is guided by patient tolerability and the HR response. Further research is needed to shed light on why some patients respond with a marked HR reduction and reduced mortality risk on a relatively small dose of a beta-blocker.

OBJECTIVES This study analyzed the effect of the beta1-selective beta-blocker metoprolol succinate controlled release/extended release (CR/XL) once daily on mortality, hospitalizations and tolerability in patients with severe heart failure. BACKGROUND There continues to be resistance to the incorporation of beta-blockers into clinical care, largely due to concerns about their benefit in patients with more severe heart failure. METHODS A subgroup of patients from Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF) in New York Heart Association (NYHA) functional class III/IV with left ventricular ejection fraction

Background International placebo-controlled survival trials (Metoprolol Controlled-Release Randomised Intervention Trial in Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS-II], and Carvedilol Prospective Randomized Cumulative Survival trial [COPERNICUS]) evaluating the effects of β-blockade in patients with heart failure have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization. Also, the analysis of the US Carvedilol Program indicated an effect on these end points. Although none of these trials are large enough to provide definitive results in any particular subgroup, it is natural for physicians to examine the consistency of results across various subgroups or risk groups. Our purpose was to examine both predefined and post hoc subgroups in the MERIT-HF trial to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. Methods The study was conducted at 313 clinical sites in 16 randomization regions across 14 countries, with a total of 3991 patients. Total mortality (first primary end point) and total mortality plus all-cause hospitalization (second primary end point) were analyzed on a time to first event. The first secondary end point was total mortality plus hospitalization for heart failure. Results Overall, MERIT-HF demonstrated a hazard ratio of 0.66 for total mortality and 0.81 for mortality plus all-cause hospitalization. The hazard ratio of the first secondary end point of mortality plus hospitalization for heart failure was 0.69. The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as for nearly all post hoc subgroups. The results of the post hoc US subgroup showed a mortality hazard ratio of 1.05. However, the US results regarding both the second primary combined outcome of total mortality plus all-cause hospitalization and of the first secondary combined outcome of total mortality plus heart failure hospitalization were in concordance with the overall results of MERIT-HF. Tests of country by treatment interaction (14 countries) revealed a nonsignificant P value of .22 for total mortality. The mortality hazard ratio for US patients in New York Heart Association (NYHA) class III/IV was 0.80, and it was 2.24 for patients in NYHA class II, which is not consistent with causality by biologic gradient. We have not been able to identify any confounding factor in baseline characteristics, baseline treatment, or treatment during follow-up that could account for any treatment by country interaction. Thus we attribute the US subgroup mortality hazard ratio to be due to chance. Conclusions Just as we must be extremely cautious in overinterpreting positive effects in subgroups, even those that are predefined, we must also be cautious in focusing on subgroups with an apparent neutral or negative trend. We should examine subgroups to obtain a general sense of consistency, which is clearly the case in MERIT-HF. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups because of small sample size in subgroups and chance. Thus the best estimate of the treatment effect on total mortality for any subgroup is the estimate of the hazard ratio for the overall trial. (Am Heart J 2001;142:502-11.)

The aim of this study was to assess to which extent community-run projects including physical activity could be identified, described and analysed in terms of objectives, organisation, evaluation and financing, as a resource in prevention and treatment of common lifestyle-related medical problems. The Swedish database Spriline was used as a main source of information. Identification of ongoing Swedish activities was followed by a mail questionnaire. In total, 151 projects were eventually identified. A semistructured questionnaire containing about 30 questions was mailed to the individual listed as responsible for the project, with a reminder 2 months later. Only 52 projects were viable; a follow-up of nonresponders showed that no relevant activity program had ever existed or that the person responsible had left. Walking, aerobics and water activities were the dominating types of activity. Most projects addressed both sexes, but eight weight reduction programs were designed for women only. Evaluation ranged from ‘measuring attendance’ to ‘scientific evaluation’. Physical activity programs may not be as systematically organised as the Swedish database suggests and cannot generally be relied upon as support in patient care, unless critically evaluated in advance.

The human β1-adrenoceptor is an immune target for autoantibodies with functional activity in cardiovascular diseases. Different epitopes on the extracellular domains of the receptor are involved. To study the immunological and pharmacological properties of these epitopes, rabbits were immunized with peptides corresponding to a large domain in the N-terminal part of the receptor and to its first and second extracellular loops. In contrast to the two other peptides, the first extracellular loop did not have immunogenic properties but acted as a hapten. Antibodies affinity-purified with the three synthetic peptides were able to significantly immunoprecipitate the solubilized receptor, confirming that they recognized the target receptor. While antibodies against the N-terminal domain did not inhibit the binding of a radiolabelled antagonist to the receptor, those against the first and second extracellular loop showed non-competitive inhibition. Similarly, only the two latter antibodies exerted a specific agonist-like effect on the receptor, as assessed on neonatal rat cardiomyocytes in culture. Our results are in accordance with those found for human anti-receptor autoantibodies with functional effects. We conclude that not all extracellular epitopes give rise to functional autoantibodies with potential physiopathological relevance in cardiac diseases with an autoimmune component.

BACKGROUND: Metoprolol can improve haemodynamics in chronic heart failure, but survival benefit has not been proven. We investigated whether metoprolol controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure. METHODS: We enrolled 3991 patients with chronic heart failure in New York Heart Association (NYHA) functional class II-IV and with ejection fraction of 0.40 or less, stabilised with optimum standard therapy, in a double-blind randomised controlled study. Randomisation was preceded by a 2-week single-blind placebo run-in period. 1990 patients were randomly assigned metoprolol CR/XL 12.5 mg (NYHA III-IV) or 25.0 mg once daily (NYHA II) and 2001 were assigned placebo. The target dose was 200 mg once daily and doses were up-titrated over 8 weeks. Our primary endpoint was all-cause mortality, analysed by intention to treat. FINDINGS: The study was stopped early on the recommendation of the independent safety committee. Mean follow-up time was 1 year. All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group (145 [7.2%, per patient-year of follow-up]) vs 217 deaths [11.0%], relative risk 0.66 [95% CI 0.53-0.81]; p=0.00009 or adjusted for interim analyses p=0.0062). There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs 132, 0.59 [0.45-0.78]; p=0.0002) and deaths from worsening heart failure (30 vs 58, 0.51 [0.33-0.79]; p=0.0023). INTERPRETATION: Metoprolol CR/XL once daily in addition to optimum standard therapy improved survival. The drug was well tolerated.

β-Blockers reduce mortality in patients with congestive heart failure and a proposed mechanism has been changes of autonomic tone. Heart rate variability is a non-invasive tool to estimate cardiac autonomic tone. The aim was to study changes of heart rate variability in patients with congestive heart failure on placebo, on the β 1 -selective antagonist metoprolol or 24 h after metoprolol withdrawal. Forty-five patients with congestive heart failure were studied with Holter recordings. Heart rate variability measurements were performed before, after 6–12 months of treatment with 150 mg metoprolol/placebo, or 24 h after discontinued metoprolol. After treatment, patients on β-blockade had a significantly longer mean RR interval and changes of heart rate variability, suggesting elevated vagal tone. Patients monitored in the rebound phase of β-blocker withdrawal had a significant vagal reduction to the level of the placebo group. There was also a nonsignificant trend towards increased sympathetic tone (LF/HF over 24 h), compared with the β-blockade group. Heart rate variability indicates an elevated vagal tone during treatment with metoprolol but β-blockade withdrawal shifts the autonomic balance towards lower vagal and higher sympathetic tone within 24 h. These results could imply a potential risk when abruptly discontinuing β-blockade medication in these patients.

Circulating autoantibodies against the human M2 muscarinic receptors have been previously shown in 38% of patients with idiopathic dilated cardiomyopathy. The functional properties of these autoantibodies are reported herein. They were able to decrease the cell beating frequency of myocytes in cultured neonatal rat heart cells in a dose-dependent manner without desensitization over a period of more than 5 hours whereas the non-specific muscarinic receptor agonist carbachol also inhibited the heart cell beating frequency but was desensitized within 1 hour. In the same cell culture, anti-M2 muscarinic receptor autoantibodies were not able to induce internalization of muscarinic receptor whereas carbachol did. These results demonstrate for the first time that anti-M2 muscarinic receptor autoantibodies from patients with idiopathic dilated cardiomyopathy have stimulatory muscarinic activity in vitro, which differ from normal muscarinic agonists by non-desensitization.

The aim of this study is to describe the impact of early treatment with metoprolol on prognosis during 1 year of follow-up in patients with suspected acute myocardial infarction (AMI) and indirect signs of congestive heart failure (CHF). Patients aged 40-74 years who presented within 48 hours of onset of symptoms raising suspicion of AMI were assessed for inclusion. All patients participated in the Goteborg Metoprolol Trial and had indirect indices of CHF according to various clinical criteria. As soon as possible after hospital admission, patients received either placebo or metoprolol (15 mg) divided into 3 intravenous injections, then oral treatment, 200 mg daily for 3 months. Thereafter, most patients in both treatment groups received metoprolol in an open manner. Among the 1,395 randomized patients, 262 (19%) had signs of mild-to-moderate CHF before randomization. Of these, 131 were randomized to metoprolol and 131 to placebo. During the first 3 months, mortality was 10% among patients randomized to metoprolol versus 19% among patients randomized to placebo (p = 0.036). The corresponding figures for the first year were 14% and 27%, respectively (p = 0.0099). Patients randomized to placebo who showed signs of CHF had a 1-year mortality rate of 28% compared with 10% among patients without such signs (p

Pharmacogenetic studies of low-dose metoprolol – a selective, s1-adrenergic receptor antagonist metabolised by the highly-polymorphic CYP2D6 enzyme – have demonstrated diverse pharmacokinetic and pharmacodynamic responses. We explored the impact of CYP2D6 genotype in heart failure patients

We have previously shown the presence of functional autoantibodies against the second extracellular loop of the human M2 acetylcholine receptor as an autoimmune epitope in 39% of patients with idiopathic dilated cardiomyopathy (DCM). To see if this autoimmune DCM can be experimentally reproduced, a synthetic peptide corresponding to the above autoimmune epitope was used as an autoantigen to monthly immunize rabbits for 6 months. Affinity-purified antibodies were able to display the negative chronotropic effects on neonatal rat cardiomyocytes in culture. The density of the M2 acetylcholine receptors was increased in the immunized rabbits compared to controls but the receptors showed only low-affinity binding sites for the agonist carbachol. Ultrastructural changes such as moderate sarcolemma alterations, mitochondrial swelling, disruption of cristae, and formation of myelin-like structures in the myocardial cells of rabbits immunized for 6 months suggest an immune-induced cardiotoxicity. With only a limited infiltration of inflammatory cells, these results point toward a pathophysiological role of anti M2 acetylcholine receptor autoantibodies.

Objectives.This study sought to determine the prevalence of autoantibodies directed against the beta-adrenoceptors in patients with primary electrical cardiac abnormalities, including atrial arrhythmias, ventricular arrhythmias and conduction disturbances, in the absence of any other cardiac abnormality.Background.Using synthetic peptides corresponding to the predicted sequences for the second extracellular loop of the human beta1- and beta2-adrenoceptors as antigenic targets, autoantibodies directed against the beta-adrenoceptors were recently shown to occur in patients with idiopathic dilated cardiomyopathy and Chagas' heart disease.Methods.Eighty-six patients (57 with primary electrical abnormalities, 29 with idiopathic dilated cardiomyopathy) and 101 healthy and cardiopathic control subjects were studied. Antibodies against the beta1- and beta2-peptides were detected with an enzyme immunoassay performed in blinded manner. In nine selected (seropositive) cases, the immunoglobulin G (IgG) fraction was tested for functional effects on the rate of beating of cultured neonatal rat cardiomyocytes.Results.Antibodies recognizing the beta1- and beta2-peptides were found in 11 (52.3%) of 21 patients with ventricular arrhythmias (p < 0.01), 5 (35.7%) of 14 patients with conduction disturbances (p < 0.05), 3 (13.6%) of 22 patients with atrial arrhythmias (p > 0.05) and 11 (37.9%) of 29 patients with dilated cardiomyopathy (p < 0.05) compared with 15 (14.8%) of 101 control subjects. A rapid increase in the rate of beating of the cultured cardiomyocytes was induced by IgG from a selected group of patients, suggesting an agonist-like interaction with a functional epitope. This response was mediated by stimulation of both the beta1- and beta2-adrenoceptors in the patients with primary ventricular arrhythmias but only the beta1-adrenoceptors in the patients with idiopathic dilated cardiomyopathy.Conclusions.Primary ventricular arrhythmias and conduction disturbances, like idiopathic cardiomyopathy, show a high prevalence of antibodies interacting with functional epitopes of the beta-adrenoceptors, suggesting a common or similar abnormal immunoregulatory process.

Immunocytochemistry of muscarinic receptors on human heart biopsies from patients with heart disease was studied using rabbit antibodies against a synthetic peptide corresponding to amino acids 168–192 of the second extracellular loop of the human M2 muscarinic receptor. By using both light and electron microscopic immunocytochemistry techniques, muscarinic receptors were visualized on sarcolemma of human myocytes from patients with different heart diseases such as coronary heart disease and dilated cardiomyopathy in adults and congenital heart disease in children. The patchy distribution of immunoreactivity suggests a muscarinergic activity in vivo . These reactivities were abolished by preincubation of antibodies with antigenic peptide and were not shown in the absence of antibodies. Moreover, these antibodies were able to interfere with muscarinic ligand binding in myocardium from human dilated cardiomyopathy as shown by decreases in binding sites and antagonist affinity. These results demonstrate that the antibodies against the second extracellular loop of the human M2 muscarinic receptor can specifically recognize muscarinic receptors in human tissue and display pharmacological activity in human diseased myocardium, confirming their usefulness for the study of localization and function of muscarinergic activity in the human heart.

Two synthetic peptides corresponding to amino acids 172-181 and 169-193 of the second extracellular loop of the human M2 muscarinic receptor respectively were used to raise antibodies in rabbits. Affinity-purified antibodies were able not only to recognize a major band with a molecular weight of about 80 kDa on the electrotransferred membrane proteins of rat ventricular membranes but also to localize the muscarinic receptors on the sarcolemma and t-tubules of rat cardiomyocytes. Antibodies were also able to mimic muscarinic agonist stimulation as demonstrated by a negative chronotropic effect on cultured neonatal cardiomyocytes. In contrast with the antibodies raised against the peptide 169-193, the antibodies against the peptide 172-181 were unable to inhibit muscarinic ligand binding. These results suggest that the decapeptide 172-181 contains the B-cell epitope responsible for the functional effect of antibodies directed against the second extracellular loop of the receptor. Coupling this peptide by cystein 177 blocks the induction of antibodies with pharmacological effects but induces antibodies which are able to recognize the denatured receptor protein and to exert a negative chronotropic effect.

It was previously shown that the second extracellular loop of cardiovascular G-protein-coupled receptors is an antigenic target for pharmacologically active autoantibodies in patients with idiopathic dilated cardiomyopathy. To extend these observations to cover patients with the same disease from different geographical origins or to patients with other cardiac diseases, peptides corresponding to the sequences of the second extracellular loops of the human M2 muscarinic receptors and beta adrenoceptors were used as antigens in an enzyme immunoassay. Sera from patients from Sweden and Japan with idiopathic dilated cardiomyopathy (DCM, n = 32), hypertrophic cardiomyopathy (HCM, n = 23), malignant essential hypertension (MEH, n = 11), malignant secondary hypertension (MSH, n = 10), and sera from healthy blood donors (HBD, n = 49) were tested. Sera from patients with DCM recognized the muscarinic receptor peptide in 38% of cases and the beta 1 adrenoceptor peptide in 31% of cases. In 50% of the positive patients, autoantibodies against both peptides coexisted as shown by competition experiments using both peptides as inhibitors. In HCM patients, there was a lower frequency of autoantibodies but with a higher but not significant predominance against the M2 peptide. No autoantibodies were detected in sera from patients with MEH or MSH. Autoantibodies against the M2 muscarinic receptors, affinity-purified from positive patients, displayed pharmacological activity as demonstrated by changes in the affinity and number of radioligand binding sites. In contrast, antibodies purified from positive HBD had no effect. These results confirm that autoantibodies displaying pharmacological activity against G-protein-coupled cardiovascular receptors are mainly restricted to patients with idiopathic dilated cardiomyopathy and that different autoantibody populations are responsible for the recognition of the different receptors.

The least-squares identification of FIR systems is analyzed assuming that the noise is a bounded signal and the input signal is a pseudo random binary sequence. A lower bound on the worst-case transfer function error shows that the least-square estimate of the transfer function diverges as the order of the FIR system is increased. This implies that, in the presence of the worst-case noise, the trade-off between the estimation error due to the disturbance and the bias error (due to unmodeled dynamics) is significantly different from the corresponding trade-off in the random error case: with a worst-case formulation, the model complexity should not increase indefinitely as the size of the data set increases.

In this contribution we discuss the concept of disturbances in system identification We propose that the terms disturbance and noise should be reserved for physical entities, i.e. effects of external, input independent, signals that actually are present in the data. For terms that are needed in addition to the model and the disturbances to account for the data we suggest the term unmodeled effects In an identification procedure these perturbations should be treated separately The reason is that, as we demonstrate, if the input signal can be choosen freely, the influence of physical disturbances can be averaged out regardless of their nature while unmodeled effects typically give biased estimates From this follows that describing physical disturbances as unknown-but-bounded (UBB) gives overly conservative results. We also point out that describing the unmodeled effects as UBB lead to results that could be quite misleading. For example, the recent results on the divergence of linear algorithms, such as the least-squares, when the model order is increased, cannot occur for a quite general family of non-linear time-varying unmodeled effects.

Objectives. This study was performed to investigate exercise hemodynamic status in a double-blind, placebo-controlled trial and was a substudy in the Metoprolol in Dilated Cardiomyopathy Trial.Background. Previous open studies have shown beneficial effects on exercise hemodynamic status after beta-adrenergic blocking agent therapy in patients with congestive heart failure.Methods. The study included 41 patients with idiopathic dilated cardiomyopathy with ejection fraction

We have measured photoluminescence decay kinetics versus temperature for high-quality MOCVD GaAs/Al 0.3 GaAs 0.7 double heterostructures which have been thoroughly characterized at room temperature. The measured lifetime is in good agreement with the lifetime obtained from a kinetic model of interacting free carriers and excitons. This theory explains the evolution from exponential decay at very low temperatures to more nonexponential bimolecular decay at higher temperature in terms of thermal ionization of the excitons. The theory shows that the temperature dependence of the decay kinetics can be nearly entirely in terms of a temperature-independent radiative lifetime.

Properties of the receptor--G protein--adenylyl cyclase system were studied in spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) treated with adriamycin (ADR, 1 mg/kg per week) for 12 weeks. An identical dosing schedule caused a significantly greater decline in body weight gain and a marked elevation of plasma norepinephrine level in SHR than in WKY. A significant increase in the messenger RNA encoding Gi-alpha 2 was found in SHR+ADR group. The activity of the adenylyl cyclase stimulated by guanyliminodiphosphate [Gpp(NH)p] was decreased by 49% in SHR and 73% in SHR+ADR. However, stimulated activities of adenylyl cyclase by both sodium fluoride and forskolin remained unchanged. Functional level of stimulatory G-protein (Gs) as measured by reconstitution assay in sarcolemmal membrane was unaltered among different groups. Furthermore, the density of beta-adrenoceptor was significantly decreased without change of its affinity. Muscarinic receptors exhibited a three-site affinity distribution in SHR+ADR whereas other groups displayed only two-site affinity distribution. These results suggest that SHR exhibited a depressed myocardial adenylyl cyclase signaling system which may not be due to the functional uncoupling of beta-adrenoceptors from Gs but to the increased inhibitory G-protein (Gi) activity as demonstrated by the increased mRNA of Gi-alpha 2, increased inhibition of Gpp(NH)p-mediated adenylyl cyclase and the super high affinity for carbachol of the muscarinic receptors. Decreased beta-adrenoceptor density and functional alteration of Gi might be regarded as the predisposing factors for the increased susceptibility of myocardium of SHR to ADR.

Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy. Our large multicentre study aimed to find out whether metoprolol improves overall survival and morbidity in this disorder. 383 subjects with heart failure from idiopathic dilated cardiomyopathy (ejection fraction < 0.40) were randomly assigned placebo or metoprolol. 94% were in New York Heart Association functional classes II and III, and 80% were receiving background treatment. A test dose of metoprolol (5 mg twice daily) was given for 2-7 days; those tolerating this dose (96%) entered randomisation. Study medication was increased slowly from 10 mg to 100-150 mg daily. There were 34% (95% CI -6 to 62%, p = 0.058) fewer primary endpoints in the metoprolol than the placebo group; 2 and 19 patients, respectively, deteriorated to the point of needing transplantation and 23 and 19 died. The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo (0.13 vs 0.06, p < 0.0001). Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo (5 vs 2 mm Hg, p = 0.06). Exercise time at 12 months was significantly greater (p = 0.046) in metoprolol-treated than in placebo-treated patients. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol prevented clinical deterioration, improved symptoms and cardiac function, and was well tolerated.

Liver transplantation is the only effective treatment for hereditary tyrosinaemia type I (McKusick 276700). We have treated one acute and four subacute-chronic cases with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27), to prevent the formation of maleylacetoacetate and fumarylacetoacetate and their saturated derivatives. The oral daily dose was 0.1-0.6 mg/kg. The excretion of succinylacetoacetate and succinylacetone decreased from 15-103 mmol/mol creatinine to the detection limit or slightly above (ie, to 20-150 mumol/mol creatinine). The concentration of succinylacetone in plasma decreased from 5.8-43 mumol/l to the detection limit (0.1 mumol/l) over 2-5 months of treatment. The almost complete inhibition of porphobilinogen synthase in erythrocytes was abolished and the excretion of 5-aminolevulinate decreased to within or slightly above the reference range. The concentration of alpha-fetoprotein decreased in four patients to 1.3-7.5% of initially high values over 6-8 months. Improved liver function was reflected by normal concentrations of prothrombin complex and in decreased activities of alkaline phosphatase and gamma-glutamyltransferase in serum. Computed tomography revealed regression of hepatic abnormalities in three patients. One patient developed rickets 6 months before treatment and had excreted high concentrations of markers of tubular dysfunction--after 3 weeks of treatment, this excretion had disappeared. No side-effects were encountered. Inhibition of 4-hydroxyphenylpyruvate dioxygenase may prevent the development of liver cirrhosis and abolish or diminish the risk of liver cancer. Normalisation of porphyrin synthesis will eliminate the risk of porphyric crises. This type of treatment may thus offer an alternative to liver transplantation in hereditary tyrosinaemia.

A synthetic peptide corresponding to the second extracellular loop of the beta 1-adrenergic receptor was used as an antigen for antibody production in three rabbits. Antibodies of high titers were obtained in all rabbits. Only one rabbit yielded antibodies which decreased radioligand binding on the receptor in a similar way to that described for autoantibodies in patients with dilated cardiomyopathy. These antibodies recognized the receptor protein in immunoblots. Epitope mapping indicated that the N-terminal sequence of the loop used as antigen was the target of the major antigen fraction. Incubation of antibodies with C6 glioma cell membranes or inner membranes of E. coli, which express the human beta 1-adrenergic receptor, resulted in a decrease in number of radioligand binding sites. This decrease was dependent on the concentration of antibody and of Mg++ ions. It was not affected by the GTP analog GppNHp or the beta 1 subtype-specific antagonist metoprolol. The agonist, isoproterenol, also induced a decrease but the effects of antibody and agonist were not additive. These results suggest that the antibodies induce a Mg(++)-dependent, 'active', labile conformation of the receptor, independent from coupling to the GTP regulatory protein, but similar to that induced by the agonist isoproterenol. This interpretation was corroborated by the beta 1-adrenergic receptor agonist-like effect of the antibodies on cardiomyocytes in culture.

Consecutive patients admitted to our hospital with suspected acute myocardial infarction during 21 months were prospectively evaluated. One-year mortality after discharge from hospital was related to whether or not an infarction developed (infarct versus non-infarct patients). Of patients discharged alive after developing an infarct, there was a mortality of 17% (n = 777) versus 12% (n = 1830) (P less than 0.001) for all patients not developing infarction. In a high risk group (any of the following: age greater than or equal to 75 years, previous history of myocardial infarction, diabetes mellitus or congestive heart failure) patients developing infarction had a mortality of 24% (n = 457) versus 17% (n = 1221) for those who did not (P less than 0.001). In a low risk group (none of the high risk criteria), the corresponding mortality was 8% (n = 316) for patients suffering infarction and 3% (n = 603) for those not having infarction (P less than 0.001). The difference in mortality between patients with and without infarction was most marked in women (21% vs 11%; P less than 0.01) and in hypertensives (25% vs 12%; P less than 0.001), but less marked in men (16% vs 13%; NS) and in patients without hypertension (13% vs 12%; NS). Among patients not suffering infarction, mortality was particularly high in those with previous congestive heart failure (23%) and diabetes mellitus (21%).