Physical activity in adults with and without rheumatoid arthritis: cross-sectional results from the Survey of Health, Ageing and Retirement in Europe (SHARE).

OBJECTIVE: Studies examining habitual physical activity levels and patterns in adults with rheumatoid arthritis (RA) using raw data from modern accelerometers are lacking. We aimed (i) to examine physical activity levels and patterns in adults with RA in their familiar environment, and (ii) to investigate whether physical activity levels differ throughout the day. METHOD: Data were taken from Wave 8 of the Survey of Health, Ageing and Retirement in Europe, including N = 607 men and women who wore a triaxial accelerometer and had adequate information for RA and accelerometry data summarized as Euclidean norm minus one (ENMO, mg). Growth-curve models and simple contrast analysis were used to examine the effect of RA on daily patterns of physical activity levels, including mean total ENMO in mg, mean minutes of light-intensity physical activity (ENMO values ≥ 25 mg and ≤ 75 mg), and moderate-to-vigorous-intensity physical activity (ENMO values > 75 mg). RESULTS: Total physical activity averaged throughout the day was 25.0 and 28.6 mg for respondents with and without RA, respectively. Respondents with RA spent more time in light-intensity physical activity throughout the day (p < 0.001), but less time in moderate-to-vigorous-intensity physical activity between 4 am and 11 pm (p < 0.001) than respondents without RA. CONCLUSION: Adults with RA were less physically active than adults without RA. However, there were no diurnal differences in physical activity.

Validation of inflammatory genetic variants associated with long-term cancer related fatigue in a large breast cancer cohort.

BACKGROUND: Studies to date have reported several associations between single nucleotide polymorphisms (SNPs) and cancer related fatigue (CRF), but have been limited by small sample sizes, missing adjustment for relevant covariates or multiple testing, as well as varying CRF definitions, i.e. time and method of assessment. This study aimed to validate previously reported associations using the largest independent breast cancer sample to date and to evaluate further functional cytokine variants in relation to total CRF and all relevant CRF subdomains (physical, cognitive, and affective CRF). METHOD: 45 candidate SNPs in inflammatory pathway genes were selected based on previous reports (16 SNPs) or regulatory function (29 SNPs). Breast cancer patients recruited between 2002 and 2005 provided information on CRF at first follow-up (FU1) (N = 1389) and second follow-up (FU2) (N = 950), a median of 6.2 years and 11.7 years respectively after diagnosis. SNP associations were assessed using linear regression models on CRF scores separately for FU1 and FU2. Additionally, patients with persistent fatigue (fatigued at both time-points) were compared to those never fatigued using logistic regression models (N = 684). All analyses were adjusted for relevant covariates. Secondary analyses were conducted for CRF subdomains. RESULTS: For total CRF none of the previously reported associations were confirmed after correction for multiple testing. The p-value distribution of all SNPs was not different than the one expected by chance. Analyses of CRF subdomains yielded a significant association between TNF-α rs3093662 and persistent physical CRF (Odds Ratio (OR) = 3.23, 95% Confidence Interval (CI) = 1.71-6.10, p = 0.0003). CONCLUSION: We were unable to confirm previously reported findings, suggesting that individual SNPs are unlikely to be of clinical utility. Further investigations in well powered studies are warranted, which consider genetic heterogeneity according to subdomains of CRF.

[Telescience : Feasibility studies, definition and a fair answer to the scientific brain drain]. / Telewissenschaft ­ Telescience : Machbarkeitsstudie, Definition und eine faire Antwort zum Wissenschafts-Braindrain.

BACKGROUND: What is telescience? Is it feasible to transfer academic information with the help of telematics to educate and teach young scientists over large distances? The term telescience has so far not been defined but covers a variety of possibilities, which could be successfully implemented worldwide. This article gives examples and highlights the feasibility analysis of telescience. METHODS: We have carried out feasibility analyses for neurological functional diagnostics, an epidemiological cross-sectional study as well as a laboratory study for detection of thrombocyte function during dengue fever with the help of telemedicine. The basis for all these projects was a telemedical transcontinental cooperation over a distance of 12,000 km. RESULTS: All performed studies demonstrated the feasibility. With the help of telematics the laboratory techniques, planning, conduction and interpretation of results as well as publication skills can be transferred. DISCUSSION: Telescience is feasible. Our studies showed that telescience is a very promising option to transfer knowledge, which will help to enable professional expertise to be transferred directly to the region/country without a brain drain. All too often young motivated scientists are enticed to move to well-known institutions, which involves the danger of a brain drain. Brain drain can be avoided in favor of local implementation of scientific projects. Our results illustrate that it is feasible to educate and guide scientists with the help of telematics infrastructures.

Stroke due to atrial fibrillation in a population-based stroke registry (Ludwigshafen Stroke Study) CHADS(2) , CHA(2) DS(2) -VASc score, underuse of oral anticoagulation, and implications for preventive measures.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is amongst the most important etiologies of ischaemic stroke. In a population-based stroke registry, we tested the hypothesis of low adherence to current guidelines as a main cause of high rates of AF-associated stroke. METHODS: Within the Ludwigshafen Stroke Study (LuSSt), a prospective ongoing population-based stroke register, we analyzed all patients with a first-ever ischaemic stroke (FEIS) owing to AF in 2006 and 2007. We determined whether AF was diagnosed before stroke and assessed pre-stroke CHADS(2) and CHA(2) DS(2) -VASc scores. RESULTS: In total, 187 of 626 patients with FEIS suffered from cardioembolic stroke owing to AF, which was newly diagnosed in 57 (31%) patients. Retrospective pre-stroke risk stratification according to CHADS(2) score indicated low/intermediate risk in 34 patients (18%) and high risk (CHADS(2)  ≥ 2) in 153 patients (82%). Application of CHA(2) DS(2) -VASc score reduced number of patients at low/intermediate risk (CHA(2) DS(2) -VASc score 0-1) to five patients (2.7%). In patients with a CHADS(2) score ≥ 2 and known AF (n = 106) before stroke, 38 (36%) were on treatment with vitamin K antagonists on admission whilst only in 16 patients (15%) treatment was in therapeutic range. CONCLUSIONS: Our study strongly supports the hypothesis that underuse of oral anticoagulants in high-risk patients importantly contributes to AF-associated stroke. CHA(2) DS(2) -VASc score appears to be a more valuable risk stratification tool than CHADS(2) score. Preventive measures should focus on optimizing pre-stroke detection of AF and better implementation of present AF-guidelines with respect to anticoagulation therapy.

A feasibility study of perioperative vitamin D supplementation in patients undergoing colorectal cancer resection.

Background: Vitamin D supplementation improves colorectal cancer (CRC) survival outcomes in randomized trials. The aim of this study was to test the feasibility, safety and efficacy of vitamin D supplementation in the pre- and perioperative period in patients undergoing CRC surgery. Methods: Patients were given 3200IU oral cholecalciferol (D3) per day perioperatively. Serial serum 25-hydroxyvitamin (25OHD) was measured by liquid chromatography tandem mass spectrometry and compared to untreated CRC controls. 25OHD and C-reactive protein (CRP) levels were compared using adjusted generalized linear mixed-effects models. Results: A total of 122 patients underwent serial perioperative sampling, including 41 patients given high-dose perioperative supplementation. Supplementation was well-tolerated with no adverse or serious adverse events related to supplementation reported. Pre-operative supplementation increased 25OHD levels on the day of surgery (103.9 vs. 42.5 nmol/l, P = 8.2E-12). Supplementation increased 25OHD levels at all post-operative timepoints (P < 0.001) and attenuated the post-operative drop in 25OHD (46 vs. 24% drop, P = 3.0E-4). Rate of vitamin D peri-operative insufficiency was significantly less in those on supplementation (e.g., day 3-5, 14 vs. 84%, P = 1.41E-08), with multivariate modeling across all timepoints indicating a ∼59 nmol/l higher 25OHD compared to control patients (P = 3.7E-21). Post-operative CRP was lower in patients taking supplementation (e.g., day 3-5 timepoint; 129 vs. 81 mg/l, P = 0.04). Conclusion: High dose pre-operative vitamin D supplementation is associated with higher perioperative 25OHD levels, lower rates of vitamin D insufficiency and reduced early post-operative CRP. Alongside published evidence for a beneficial effect of vitamin D on CRC survival outcomes, these novel findings provide strong rationale for early initiation of vitamin D supplementation after a diagnosis of CRC.

Etiology, risk factors and sex differences in ischemic stroke in the Ludwigshafen Stroke Study, a population-based stroke registry.

BACKGROUND: Stroke etiology in ischemic stroke guides preventive measures and etiological stroke subgroups may show considerable differences between both sexes. In a population-based stroke registry we analyzed etiological subgroups of ischemic stroke and calculated sex-specific incidence and mortality rates. METHODS: The Ludwigshafen Stroke Study is a prospective ongoing population-based stroke registry. Multiple overlapping methods of case ascertainment were used to identify all patients with incident stroke or transient ischemic attack. Modified TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria were applied for subgroup analysis in ischemic stroke. RESULTS: Out of 626 patients with first-ever ischemic stroke in 2006 and 2007, women (n = 327) were older (73.5 ± 12.6 years) than men (n = 299; 69.7 ± 11.5 years; p < 0.001). The age-adjusted incidence rate of ischemic stroke was significantly higher in men (1.37; 95% CI 1.20-1.56) than in women (1.12; 95% CI 0.97-1.29; p = 0.04). Cardioembolism (n = 219; 35.0%), small-artery occlusion (n = 164; 26.2%), large-artery atherosclerosis (n = 98; 15.7%) and 'probable atherothrombotic stroke' (n = 84; 13.4%) were common subgroups of ischemic stroke. Stroke due to large-artery atherosclerosis (p = 0.025), current smoking (p = 0.008), history of smoking (p < 0.001), coronary artery disease (p = 0.0015) and peripheral artery disease (p = 0.024) was significantly more common in men than in women. Overall, 1-year survival was not different between both sexes; however, a significant age-sex interaction with higher mortality in elderly women (>85 years) was detected. CONCLUSIONS: Cardioembolism is the main source for ischemic stroke in our population. Etiology of ischemic stroke differs between sexes, with large-artery atherosclerotic stroke and associated diseases (coronary artery disease and peripheral artery disease) being more common in men.

[Death due to tuberculosis requiring treatment or an accompanying disease? A contribution to the lethality and mortality of tuberculosis in Germany]. / Tod an behandlungsbedürftiger Tuberkulose oder an Begleitkrankheiten? Ein Beitrag zur Letalität und Mortalität der Tuberkulose in Deutschland.

BACKGROUND: Tuberculosis (TB) is a curable disease. Nevertheless, patients in Germany also die of TB. Although mortality is decreasing, there are indications for an increase in lethality. This observation provided the impetus for a detailed analysis that sought to investigate the validity of the statistics on deaths caused by TB. METHOD: The study population consists of the 926 fatal cases that were classified either as "death from TB" or as "death due to other causes" out of the 6044 TB patients in the DZK study. For the analysis, health authorities were asked to provide additional information and such documents as the death certificate, the autopsy protocol and the final medical report. In 778 cases, there was at least one additional piece of information available. Three teams of two experts each conducted independent evaluations of the documents. RESULTS: Based on the findings of the experts, every second death caused by TB in 1997 and 1998 was not recorded correctly during the post-mortem examination. Every third TB death was not diagnosed during the patient's lifetime. Patients who died due to TB were, on average, older and more likely to be born in Germany. This indicates that age-related comorbidity among the native German population plays a relevant role. Yet, the unicausal death registration did not acknowledge comorbidity as a contributing factor to the fatal outcome. Pulmonary TB with positive microscopy and culture, miliary TB and meningeal TB were more common among the deaths due to TB than among the general study population, and led more often to a fatal outcome than other organ manifestations. However, the two groups did not differ with regard to multi-drug resistant TB. Alcohol abuse was a leading risk factor for death caused by TB in patients under 65 years. Patient's delay ranged from six to 34 days, and doctor's delay from eight to 46 days. For example, alcohol abusers, on average, visited a physician much later, but were diagnosed more rapidly after the first visit than patients who were not alcohol-dependent. A period of 32 - 200 days elapsed between diagnosis and death caused by TB. CONCLUSIONS: The post-mortem examination often missed TB as the cause of death. Many native German TB patients showed age-related comorbidity. Pulmonary TB with positive microscopy, miliary TB and meningeal TB led more often to a fatal outcome than other organ manifestations. Alcohol abuse was a leading risk factor for TB deaths in patients younger the 65 years. The average period between the onset of symptoms and the diagnosis was significantly longer than the one month generally considered acceptable. The experts could not confirm an increase in lethality for the period under investigation.

Tired of feeling tired - The role of circulating inflammatory biomarkers and long-term cancer related fatigue in breast cancer survivors.

BACKGROUND: Low-grade inflammation has been associated with cancer related fatigue (CRF). However, most studies focused on CRF during or shortly after treatment. Longitudinal studies are rare with inconsistent results. We assessed the association of inflammatory biomarkers with total CRF and all subdomains (physical, cognitive, affective) in long-term breast cancer survivors. METHOD: Patients recruited between 2002 and 2005 provided information on CRF at first follow-up (FU1) (N = 1292) and second follow-up (FU2) (N = 1205), after a median of 6.2 years and 11.7 years, respectively. Associations of 11 inflammatory biomarkers with CRF at FU1 and at FU2 were assessed using linear regression models. Logistic regression models were used to compare patients fatigued at both time-points and those never fatigued (N = 932). RESULTS: C-reactive protein (CRP) was significantly associated with total CRF at FU1 (ß = 1.47, 95%CI = 0.62-2.31, p = 0.0007), at FU2 (ß = 1.98, 95 %CI = 0.96-2.99, p = 0.0001) and with persistent CRF (OR = 1.29, 95%CI = 1.13-1.47, p < 0.0001). IL-6 levels were associated with total CRF at FU1 (ß = 1.01, 95%CI = 0.43-1.59, p = 0.0006), but not with CRF at FU2 or persistent CRF. No association remained significant after adjustment for relevant covariates. DISCUSSION: CRP and Il-6 were associated with risk of CRF in long-term breast cancer survivors, but were not independent of other known risk factors, suggesting that currently studied inflammatory markers are not suitable to identify patients at risk of long-term CRF.

Validity and representativeness of the "Disease Analyzer" patient database for use in pharmacoepidemiological and pharmacoeconomic studies.

OBJECTIVES: Patient and health care databases are available in many countries. These are often based on routinely collected diagnosis and prescription data. Various research questions, such as those related to pharmacoepidemiological health services or drug supply, can be evaluated on the basis of these databases. In Germany, the Disease Analyzer patient database is the largest database of its kind. Using various validity criteria, the representativeness of this database is examined with respect to variables relevant to pharmacoepidemiological and pharmacoeconomic studies. METHODS: The Disease Analyzer patient database contains data on diagnoses, prescriptions, risk factors (such as smoking and obesity), and laboratory values for approximately 10 million patients from Germany, the UK, France, and Austria. The database also contains data from various groups of specialist physicians as well as from general practitioners and specialists for internal medicine. Data from physicians' practices in Germany form the basis of this investigation. To check the validity and representativeness of the data, the distributions of several variables are analyzed. These variables refer partly to the physicians' practices participating in the study and partly to the patients in these practices. The factors observed include prescriptions for generic drugs, the distribution of diagnostic groups among participating physicians' practices, the distribution of patients according to health insurance fund, the most frequent products, the distribution of package sizes prescribed, and the age structure of patients with various incident cancer diagnoses. These factors were compared with available reference statistics. RESULTS: The sampling methods for the selection of physicians' practices appear to be appropriate. Prescription statistics for several drugs were very similar to available data from the pharmaceutical prescriptions report (Arzneimittelverordnungsreport). The age structures for given diagnoses in Disease Analyzer also agreed well with those from corresponding disease registries. Additional comparisons were also in good agreement with data from available sources. CONCLUSION: The analyses carried out in comparison with reference statistics find no indication of lack of representativeness or validity of the Disease Analyzer database. In principle, the database appears suitable for pharmacoepidemiological and pharmacoeconomic studies. Development and maintenance of large pharmacoepidemiological databases is needed for modern health services. Such databases allow assessment of health care quality and rare adverse drug effects.

Equity and child-survival strategies.

Recent advances in child survival have often been at the expense of increasing inequity. Successive interventions are applied to the same population sectors, while the same children in other sectors consistently miss out, leading to a trend towards increasing inequity in child survival. This is particularly important in the case of pneumonia, the leading cause of child death, which is closely linked to poverty and malnutrition, and for which effective community-based case management is more difficult to achieve than for other causes of child death. The key strategies for the prevention of childhood pneumonia are case management, mainly through Integrated Management of Childhood Illness (IMCI), and immunization, particularly the newer vaccines against Haemophilus influenzae type b (Hib) and pneumococcus. There is a tendency to introduce both interventions into communities that already have access to basic health care and preventive services, thereby increasing the relative disadvantage experienced by those children without such access. Both strategies can be implemented in such a way as to decrease rather than increase inequity. It is important to monitor equity when introducing child-survival interventions. Economic poverty, as measured by analyses based on wealth quintiles, is an important determinant of inequity in health outcomes but in some settings other factors may be of greater importance. Geography and ethnicity can both lead to failed access to health care, and therefore inequity in child survival. Poorly functioning health facilities are also of major importance. Countries need to be aware of the main determinants of inequity in their communities so that measures can be taken to ensure that IMCI, new vaccine implementation and other child-survival strategies are introduced in an equitable manner.

Late emergence of platypnea orthodeoxia: Chiari network and atrial septal hypertrophy demonstrated with transoesophageal echocardiography.

Platypnea orthodeoxia is a rare syndrome that describes breathlessness on standing that resolves on lying flat. We present a previously healthy patient who developed platypnea orthodeoxia in her eighth decade of life. Cardiovascular imaging demonstrated an atrial septal defect, extensive Chiari network and atrial septal hypertrophy. We propose the development of lipomatous atrial septal hypertrophy led to altered atrial compliance and a baffle to direct flow preferentially to the left heart on standing.

Isopropanolic black cohosh extract and recurrence-free survival after breast cancer.

OBJECTIVE: To investigate the influence of an isopropanolic Cimicifuga racemosa extract (iCR) on recurrence-free survival after breast cancer, including estrogen-dependent tumors. METHODS: This pharmacoepidemiologic observational retrospective cohort study examined breast cancer patients treated at general, gynecological and internal facilities linked to a medical database in Germany. The main endpoint was disease-free survival following a diagnosis of breast cancer. The impact of treatment with iCR following diagnosis was analyzed by Cox-proportional hazards models, controlling for age and other confounders. RESULTS: Of 18,861 patients, a total of 1,102 had received an iCR therapy. The mean overall observation time was 3.6 years. Results showed that iCR was not associated with an increase in the risk of recurrence but associated with prolonged disease-free survival. After 2 years following initial diagnosis, 14% of the control group had developed a recurrence, while the iCR group reached this proportion after 6.5 years. The primary Cox regression model controlling for age, tamoxifen use and other confounders demonstrated a protractive effect of iCR on the rate of recurrence (hazard ratio 0.83, 95% confidence interval 0.69 0.99). This effect remained consistent throughout all variations of the statistical model, including subgroup analyses. TNM status was unknown but did not bias the iCR treatment decision as investigated separately. Hence, it was assumed to be equally distributed between treatment groups. Correlation analyses showed good internal and external validity of the database. CONCLUSION: An increase in the risk of breast cancer recurrence for women having had iCR treatment, compared to women not treated with iCR is unlikely.

Non-specific effects of childhood vaccinations - A case control study nested into a Health and Demographic Surveillance System in rural Burkina Faso.

INTRODUCTION: Previous studies in African countries have been suggestive of non-specific effects (NSE) of vaccination on child survival. Live vaccines (e.g. measles, MV) have been found to reduce child mortality while inactivated vaccines (e.g. diphtheria-tetanus-pertussis, DTP) have been associated with increased mortality; NSE were often found to be sex-specific. METHODS: A case-control study nested into the Health and Demographic Surveillance System (HDSS) cohort of the Centre de Recherche en Santé de Nouna (CRSN) was conducted in northwestern Burkina Faso. A total of 3,010 children born in 2009-11, were included in the study, 375 cases and 2635 age and village matched controls. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. RESULTS: Most deaths occurred in late infancy, and there were significantly more deaths in males as compared to females (OR 1.29, CI 1.04-1.60). Overall, there was no statistically significant association between vaccine status and mortality. However, among children in the age group 2-8 months, there was a consistent sex-differential pattern for all doses of oral polio vaccine combined with pentavalent vaccine (OPV + Penta), with the vaccines being associated with lower mortality in boys, but not in girls. Routine MV + yellow fever vaccine was associated with reduced mortality, but only before mass vaccination campaigns with meningitis and measles vaccines took place. CONCLUSIONS: The findings of this study provide further support on the existence of NSE of childhood vaccinations in a large population of rural Burkina Faso. More randomized controlled trials are needed to confirm these observations.

Prenatal stress perception and coping strategies: Insights from a longitudinal prospective pregnancy cohort.

OBJECTIVE: Prenatal distress has been linked to pregnancy complications and poor offspring's health, despite the fact that longitudinal assessments of various stress dimensions are still lacking. Hence, we aimed to assess perceived stress over the course of pregnancy. Moreover, we examined whether social support and coping styles are linked to prenatal stress trajectories. METHODS: Data from 543 women participating in the PRINCE (Prenatal Identification of Children Health) study, a prospective population-based cohort study, was used for the present analyses. Once per trimester the women completed questionnaires regarding different psychometric measures, including the Perceived Stress Scale (PSS). Linear mixed regression models were used to examine perceived stress development longitudinally and to relate social support and coping styles to stress trajectories during pregnancy. RESULTS: A significant decrease of perceived stress was observed over the course of pregnancy. Stratifying the study sample according to parity, women delivering their first child had continuously lower perceived stress scores compared to women having already one or more children, and a significant decrease during pregnancy was exclusively observed in primiparous women. Both, positive coping strategies and higher perceived and received social support were independently associated with lower perceived stress, while evasive coping strategies were associated with higher levels of perceived stress. CONCLUSION: Our study reveals stress perception trajectories during pregnancies in primi- and multiparous women. Our findings underscore the need for intervention strategies aiming to improve social support and positive coping strategies especially in multiparous women in order to reduce the risks for adverse pregnancy outcomes.

A simple method to estimate tobacco-related lung cancer deaths based on smoking prevalence data.

OBJECTIVE: Tobacco is the major cause of cancer and a relevant risk factor for several other chronic diseases. Due to the epidemiological transition in developing countries with overall increasing life expectancy there is an increasing relevance of chronic diseases to the total burden of diseases. Furthermore, there are indications for a rise in the consumption of tobacco products in developing countries. Since in Africa data on smoking prevalence are scarce and cancer diagnosis is often imprecise or missing, it is difficult to estimate the current and future number of cancer cases attributable to tobacco smoking. In this paper, we present an approach to estimate the effects of smoking on lung cancer in selected developing countries in Africa. METHODS: We combined data on smoking prevalence from different African countries with estimates on age-specific lung cancer rates in smokers and non-smokers from industrialized countries and data on age and sex distribution in African countries. We perform a sensitivity analysis to evaluate the effect of the assumptions necessary for the procedure. RESULTS: If the smoking prevalence in African countries will remain on the current level, we estimate age-specific lung cancer rates lower than those in Germany. Despite the relatively small proportion of adults aged 50 and more which is the age when most cancer cases occur, there is an appreciable number of deaths from lung cancer that could be prevented when smoking prevalence could be reduced. Depending on assumptions we estimate up about 50,000 lung cancer deaths per year in Africa, most of which could be prevented. CONCLUSIONS: Efforts for smoking prevalence reduction are much more needed in the developing world. Better and more comprehensive data on smoking are needed for more precise estimates.

Progesterone receptor gene polymorphism is associated with decreased risk for breast cancer by age 50.

In a population-based case-control study for breast cancer before the age of 51 years, 554 cases and 559 age-matched controls were genotyped for the polymorphic progesterone receptor allele PROGINS. Breast cancer risk was decreased in women carrying the PROGINS allele. The odds ratio adjusted for age and study region was 0.76 [95% confidence interval (CI), 0.58-1.00]. Compared with wild-type A1/A1 homozygotes, the odds ratio for A1/A2 heterozygotes and A2/A2 homozygotes was 0.82 (95% CI, 0.62-1.08) and 0.27 (95% CI, 0.10-0.74), respectively, suggesting a gene dosage effect of the A2 allele. There was suggestive evidence for a differential effect by menopausal status (P = 0.07) and by family history of breast cancer (P = 0.15).

Dose and frequency effect in mouse skin tumor promotion.

In order to study the influence of both dose and application frequency of tumor-promoting agents on tumor development, we conducted a large-scale mouse skin two-stage carcinogenesis experiment. The back skins of 1110 CD-1 mice were painted once with 50 micrograms benzo(a)pyrene. These mice were divided into 24 groups according to subsequent schedules of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. Mice were treated with TPA at five different frequencies, i.e., daily, or every second, 4th, 8th, or 16th day, and six different TPA doses per application were used (0.1, 0.2, 0.4, 0.8, 1.6, or 3.2 micrograms), which allowed groups to be established with the same total dose of TPA applied per time unit. Six of the 30 frequency/dose combinations at extreme low or high frequency and dose were excluded. At each fixed frequency of TPA application, there was a good dose-response of TPA in mouse skin papilloma incidence. There was also a good application frequency-response relationship at fixed doses of TPA application. Within the set of groups in which animals received the same total dose of TPA per time unit, some variation was observed with respect to frequency of application. In general, TPA applications every 4th and 8th day tended to yield a small number of tumors.

Clinical evaluation of left heart Doppler contrast enhancement by a saccharide-based transpulmonary contrast agent. The Levovist Cardiac Working Group.

OBJECTIVES: A multicenter study was carried out to evaluate the efficacy with which SHU 508A enhances left heart Doppler signals and improves the clinical quantification of valve disease. BACKGROUND: Poor signal-to-noise ratio often limits the Doppler interrogation of left heart flows. This problem may be resolved by the enhancement of Doppler signals by an ultrasound contrast agent capable of pulmonary transmission, such as the recently developed SHU 508A. METHODS: Left heart contrast enhancement was tested for 1) continuous wave Doppler evaluation in 51 patients with aortic stenosis, 2) pulsed Doppler transthoracic evaluation of pulmonary venous flow in 85 patients, and 3) color Doppler evaluation of mitral regurgitation in 60 patients. Studies were performed immediately before and during the intravenous administration of SHU 508A (16 ml of 200 mg/ml) and compared with unenhanced transesophageal data in representative subsets of patients. RESULTS: SHU 508A had no serious adverse effects. A significant increase in left heart Doppler signal intensity lasted for 30 to 300 s. The continuous wave Doppler velocity envelope was enhanced for all jets, but Doppler peak velocity was not altered in high quality baseline studies. However, Doppler contrast enhancement resulted in higher measured peak gradients (p < 0.001) in 29 patients with aortic stenosis who had poor quality baseline studies. This improved the overall correlation with invasive pressure measurements (r = 0.73 vs. r = 0.89, p < 0.01). The enhanced pulsed Doppler traces of transthoracic pulmonary venous flow allowed quantitative analysis in 92% patients (vs. 27% at baseline) and correlated well with peak velocities and velocity profiles obtained by transesophageal echocardiography (r = 0.91, p < 0.001). The enhanced color Doppler display of regurgitant jets increased jet area with a high interindividual variability (mean 276%), resulting in almost identical jet areas as unenhanced transesophageal values (r = 0.97, p < 0.001). CONCLUSIONS: SHU 508A is a safe transpulmonary contrast agent that significantly enhances both spectral and color Doppler signals in the left heart. In specific patient subsets, the increase in signal-to-noise ratio improved the quantitative assessment of aortic stenosis, pulmonary venous flow and mitral regurgitation.

Enhancement of mitral regurgitation and normal left atrial color Doppler flow signals with peripheral venous injection of a saccharide-based contrast agent.

OBJECTIVES: The saccharide ultrasound contrast agent SHU 508 A was used to test the hypothesis that an intravenous, transpulmonary contrast method can enhance color Doppler flow signals in the left atrium in a clinically useful manner. BACKGROUND: Color Doppler display of mitral regurgitation may be unreliable because of variable signal to noise ratios that are at times poor. Traditional contrast agents enhance color Doppler flow signals in the right heart chambers. This study describes our observation of a recently developed contrast agent, SHU 508 A, capable of pulmonary transit after peripheral venous injection. METHODS: Control subjects (n = 10) and patients with suspected mitral regurgitation (n = 23) were studied by color Doppler flow imaging before and after 3-g intravenous doses of SHU 508 A. Reference grading of mitral regurgitation (0 to 3) was formulated from left ventricular angiography. In the four-chamber view of the left atrium, we selected for analysis the systolic frame with the maximal retrograde jet of mitral regurgitation (aliased/blue) and the diastolic frame with the maximal color coding from anterograde pulmonary venous flow (red) for planimetry and for grading the intensity of the color Doppler signal (0 to 5). RESULTS: The score of the color Doppler signal intensity increased by > or = 2.5 after 3 g of SHU 508 A (p < 0.001). Flow detection improved, as shown by the increased jet area of mitral regurgitation (> or = 170%), after 3 g of SHU 508 A (3 +/- 3 vs. 12 +/- 8 cm2, p < 0.001) and by a > or = 200% increase in normal anterograde flow area (p < 0.001) in both the mitral regurgitation group and the control group. After contrast enhancement, the correlation between angiographic grading and the relation of jet area to the left atrial area increased from r = 0.79 to r = 0.91. CONCLUSIONS: Contrast-mediated increased echogenicity of the left atrial blood pool improves the signal to noise ratio of Doppler images of mitral regurgitation and anterograde atrial flow. The technique is safe and simple and seems to minimize variability due to instrument design and anatomic signal attenuation.

Prevalence of left atrial chamber and appendage thrombi in patients with atrial flutter and its clinical significance.

OBJECTIVES: The study was done to assess the prevalence of left atrial (LA) chamber and appendage thrombi in patients with atrial flutter (AFl) scheduled for electrophysiologic study (EPS), to evaluate the prevalence of thromboembolic complications after transesophageal echocardiographic (TEE)-guided restoration of sinus rhythm and to evaluate clinical risk factors for a thrombogenic milieu. BACKGROUND: Recent studies showed controversial results on the prevalence of atrial thrombi and the risk of thromboembolism after restoring sinus rhythm in patients with AFl. METHODS: Between 1995 and 1999, patients with AFl who were scheduled for EPS were included in the study. After transesophageal assessment of the left atrial appendage and exclusion of thrombi, an effective anticoagulation was initiated and patients underwent EPS within 24 h. RESULTS: We performed 202 EPSs (radiofrequency catheter ablation, n = 122; overdrive stimulation, n = 64; electrical cardioversion, n = 16) in 139 consecutive patients with AFl. Fifteen patients with a thrombogenic milieu were identified. All of them had paroxysmal atrial fibrillation (AF). Transesophageal echocardiography revealed LA thrombi in two cases (1%). After EPS no thromboembolic complications were observed. Diabetes mellitus, arterial hypertension and a decreased left ventricular ejection fraction were found to be independent risk factors associated with a thrombogenic milieu. CONCLUSIONS: The findings of a low prevalence of LA appendage thrombi (1%) in patients with AFl and a close correlation between a history of previous embolism and paroxysmal AF support the current guidelines that patients with pure AFl do not require anticoagulation therapy, whereas patients with AFl and paroxysmal AF should receive anticoagulation therapy. In addition, the presence of clinical risk factors should alert the physician to an increased likelihood for a thrombogenic milieu.