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Nocturia is frequent among older patients and has been linked to cardiovascular diseases. The aim of this study was to assess the time relationship between the onset of nocturia and coronary heart disease (CHD). Specifically, this study investigated whether nocturia can be identified as a red flag de novo symptom in patients with CHD.This cross-sectional study consisted of patients with CHD-related cardiac complaints who were prospectively recruited from November 2019 till March 2020 at the cardiac catheterization laboratory of the Ghent University Hospital. An analysis was performed to determine the time relationship between nocturia and CHD and to describe the nocturia characteristics.Forty-five patients with nocturia and established CHD were included. Of these patients, 74% (31/42) developed nocturia before their cardiac symptoms occurred, with a median time gap of 57 months (IQR 19-101). Furthermore, 64% (29/45) of them had clinically significant nocturia (≥2 nocturnal voids) and there was a significant correlation between age at which nocturia and cardiac symptoms occurred (r=0.89, p0.001).This is the first study that analysed the time relationship between onset of nocturia and onset of cardiac complaints in patients with CHD. In most of the patients, nocturia had started before they were diagnosed with CHD, meaning that nocturia might precede the development of cardiac symptoms, such as angina and shortness of breath. Keeping this in mind, de novo nocturia may or even should be considered as a red flag for CHD.(cross sectional study with prospectively recruitement) Source: https://www.ciap.health.nsw.gov.au/training/ebp-learning-modules/module1/grading-levels-of-evidence.html.

Atrial fibrillation and non-vitamin K antagonist oral anticoagulants: from clinical trials to real-world clinical practice. For decades, vitamin K antagonists (VKAs) were the only oral anticoagulants available for the prevention of thromboembolism in patients with atrial fibrillation (AF). Since 2012, non-vitamin K antagonist oral anticoagulants (NOACs) are available for this indication, which have proven to be at least as effective and safe as VKAs in randomized controlled trials (RCTs). NOACs have additional benefits, such as a fast onset of action, a fixed-dose regimen without requiring regular monitoring, less interactions and less intracranial bleeding. Their emergence has caused a paradigm shift in anticoagulation therapy, with NOACs being the anticoagulant of choice compared to VKAs. Since strict in- and exclusion criteria were used in the pivotal RCTs, concerns have risen regarding the generalizability of these results to real-life clinical practice in patients with multiple comorbidities. In this manuscript, this extrapolation is discussed, focusing on 4 different topics regarding appropriate NOAC use: the management of AF patients with a single stroke risk factor, the importance of an optimal therapy adherence, potential drug-drug interactions with NOACs and addressing a geriatric AF patient after a fall. Hopefully, this manuscript will help guide clinicians in the optimal use of NOACs in their daily clinical practice.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fund for Scientific Research Flanders (FWO) Background Oral anticoagulants are crucial for preventing systemic thromboembolism in atrial fibrillation (AF), with guidelines preferring non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) in the general AF population. However, as NOACs are administered in fixed doses, concerns of unintentional underdosing in morbidly obese patients and unintentional overdosing in underweight patients have emerged. Moreover, VKAs are still recommended in morbidly obese patients (body mass index (BMI) ≥40 kg/m², body weight >120 kg) due to lack of data for NOACs in these patients. Purpose A critical appraisal of the benefit-risk profile of NOACs in AF patients across the body weight spectrum. Methods After searching the Medline database, phase III randomized controlled trials (RCTs) and longitudinal observational cohort studies on the effectiveness and safety of NOACs versus VKAs in obese (BMI ≥30 kg/m²), and class III obese (BMI ≥40 kg/m²) non-valvular AF patients, and in low body weight (≤60 kg) AF patients during a mean/median follow-up of ≥6 months were included. The meta-analyses were performed using a random effects model with the Mantel-Haenszel method. Results A meta-analysis based on 4 phase III RCTS and 3 longitudinal observational cohort studies demonstrated that NOAC use in obese and class III obese AF patients was associated with significantly lower stroke/systemic embolism (stroke/SE) risks (RR 0.82, 95%CI [0.71-0.96]; and RR 0.75, 95%CI [0.64-0.87], respectively), similar to lower major bleeding risks (RR 0.83, 95%CI [0.69-1.00]; and RR 0.74, 95%CI [0.57-0.95], respectively), and similar mortality risks (RR 0.92, 95%CI [0.73-1.15]; and RR 1.17, 95%CI [0.83-1.64], respectively) as compared to VKAs. In AF patients ≤60 kg, significantly lower stroke/SE (RR 0.63, 95%CI [0.56-0.71]) and major bleeding risks (RR 0.71, 95%CI [0.62-0.80]), and similar mortality risks (RR 0.68, 95%CI [0.42-1.10]) were observed for NOAC- versus VKA-treated patients in a meta-analysis based on 4 phase III RCTs and 2 longitudinal observational cohort studies. Conclusions The benefit-risk profile of NOACs seems preserved in (morbidly) obese AF patients and patients with low body weight of ≤60 kg. However, more data are needed in underweight AF patients (BMI

BackgroundIn contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity.Methods and resultsCLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest.ConclusionIn patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes.ClinicalTrials identifierISRCTN43070564

Summary Background Increased blood pressure is the biggest contributor to the global burden of disease and mortality. Data suggest that less than half of the population with hypertension is aware of it. May Measurement Month was initiated to raise awareness of the importance of blood pressure and as a pragmatic interim solution to the shortfall in screening programmes. Methods This cross-sectional survey included volunteer adults (≥18 years) who ideally had not had their blood pressures measured in the past year. Each participant had their blood pressure measured three times and received a a questionnaire about demographic, lifestyle, and environmental factors. The primary objective was to raise awareness of blood pressure, measured by number of countries involved, number of people screened, and number of people who have untreated or inadequately treated hypertension (defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, or on the basis of receiving antihypertensive medication). Multiple imputation was used to estimate the mean of the second and third blood pressure readings if these were not recorded. Measures of association were analysed using linear mixed models. Findings Data were collected from 1 201 570 individuals in 80 countries. After imputation, of the 1 128 635 individuals for whom a mean of the second and third readings was available, 393 924 (34·9%) individuals had hypertension. 153 905 (17·3%) of 888 616 individuals who were not receiving antihypertensive treatment were hypertensive, and 105 456 (46·3%) of the 227 721 individuals receiving treatment did not have controlled blood pressure. Significant differences in adjusted blood pressures and hypertension prevalence were apparent between regions. Adjusted blood pressure was higher in association with antihypertensive medication, diabetes, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm than on the left arm, and blood pressure was highest on Saturdays. Interpretation Inexpensive global screening of blood pressure is achievable using volunteers and convenience sampling. Pending the set-up of systematic surveillance systems worldwide, MMM will be repeated annually to raise awareness of blood pressure. Funding International Society of Hypertension, Centers for Disease Control and Prevention, Servier Pharmaceutical Co.

Background Mitral valve prolapse (MVP) is a common cause of chronic mitral regurgitation (MR). Barlow’s disease (BD) and fibro-elastic deficiency (FED) are two major entities of MVP affecting the connective tissue of the mitral valve, but both have a different underlying pathophysiology and phenotype. In some connective tissue diseases (CTD), it has been suggested that ventricular dysfunction occurs despite absence of MR, suggesting that CTD directly involve the myocardium. We therefore investigated whether patients with BD have different cardiac dimensions compared to FED, after correcting for MR severity grade. Methods 134 patients with MVP and chronic MR were prospectively included. MR was graded carefully by echocardiography using a multi-parametric approach. The morphology of the mitral valve prolapse was specified as definite Barlow (n = 45) or non-Barlow (n = 89; FED, flail leaflet or unspecified etiology) by two experienced echocardiographers. Results In our cohort, MR was significantly more severe in the non-Barlow group compared to typical BD group (regurgitant volume (RV) 51 vs 33 ml, p = 0.021; right ventricular systolic pressure, 40 vs 34 mmHg, p= 0.05, left atrial volume index, 51 vs 42 ml/m², p = 0.07, respectively). However, there was a trend towards higher left ventricular end-diastolic diameter index (LVEDDi, 27.7 vs 29 mm, p = 0.07) and a significantly higher end-diastolic volume index (LVEDVi, 62 vs 71 ml/m², p= 0.02) in the Barlow group, despite similar ejection fractions and much less MR in the Barlow group. This resulted in a significantly higher RV/LVEDV ratio in the non-Barlow group compared to the Barlow group (42% vs 23%, p = 0.001). Similarly, the LA volume/LVEDV ratio was significantly lower in the Barlow cohort (63 vs 79%, p= 0.026). There were no significant differences in aortic dimensions between groups. Conclusions We describe for the first time that compared to non-Barlow (mostly FED), patients with MVP due to typical Barlow disease have larger ventricular dimensions and volumes, which are disproportionate to the degree of MR. We therefore hypothesize that the connective tissue alterations in these patients may also involve the myocardium resulting in LV dilation independent of MR. Further investigation and clinical implications of these findings is mandatory.

Background Dynamic changes in functional mitral regurgitation (FMR) during exercise echocardiography were shown to be of prognostic value. However grading of FMR is challenging, especially during exercise echocardiography and therefore questioning its applicability in clinical practice. We recently introduced and validated the Average Pixel Intensity (API) for grading MR based on the pixel intensity of the continuous wave Doppler signal. In the current study we investigate the use of the API method using leg lift and exercise echocardiography in FMR. Methods We prospectively included 50 heart failure patients (mean ejection fraction 36%) in sinus rhythm with different grades of pure, FMR. After assessment of FMR severity at rest, the same acquisitions were repeated during leg lift and exercise echocardiography. FMR was assessed using the API method, color Doppler and quantitative grading methods (proximal isovelocity surface area (PISA) and vena contracta width (VCW)). Results The API method could be performed in all patients (100%) with leg lift (n = 50) and in 94% of the patients undergoing exercise echocardiography (n = 44), which was more than PISA and VCW (p During leg lift, there was a small but significant increase on visual color Doppler grading (grade 1.93 to 2.11 (p = 0.004); increase of FMR in 35% of patients, and no difference in 65%). For API, we found the same significant increase (93 to 101 au), however, API values showed increase of MR in 62% and decrease of FMR in 20%. During exercise echocardiography, we found no differences in color Doppler grade and API in the overall cohort (p 0.252 and p 0.832, respectively), despite 62% of patients showing some degree of increase in API during leg lift. On multivariate analysis, no specific echo parameter could be identified as independent predictor of API increase. Conclusions The novel API method is highly feasible for assessing dynamic FMR and may be of added value for in this setting, allowing the detection of even small increments of FMR severity. In the current study, we found only mild increases of FMR during exercise echocardiography. Leg lift testing however proved to be a simple and quick loading approach that induced a significant rise in FMR compared to exercise echocardiography. The prognostic relevance of the findings during leg lift remains to be determined.

Background Functional mitral regurgitation (FMR) is a frequent finding in patients with systolic heart failure. However, the echocardiographic grading of MR is challenging and different severity cut-offs are recommended by international guidelines. We developed and validated a novel echocardiographic parameter to grade MR, the average pixel intensity (API) method, based on pixel intensity analysis of the continuous wave Doppler signal. Purpose In this study, we assessed the long-term predictive value of the API method on clinical endpoints in FMR. Methods Transthoracic echocardiography was performed in consecutive heart failure patients with reduced EF (HF-REF) (n=221). MR was assessed using the API method, vena contracta width (VCW), effective regurgitant orifice area (PISA-EROA) and regurgitant volume (PISA-RV). The primary clinical events were major adverse cardiac events (MACE: cardiovascular mortality, mitral valve surgery, percutaneous mitral intervention or heart failure hospitalization). Results The API method was feasible in 97% of all FMR patients, which was significantly higher than parameters such as VCW, PISA-EROA and PISA-RV. 84 patients (37%) had one or more clinical events during the follow-up period (cardiovascular mortality (20%), mitral valve surgery (5%), percutaneous mitral intervention (5%), heart failure hospitalization (16%) or heart transplantation (2%)). Based on ROC curves, an API cut-off of 121 au was defined as “severe” MVP-MR with an overall better sensitivity and specificity than current guideline-recommended parameters. On multivariate analysis, MR graded with API was independently predictive for clinical events, whereas PISA-based methods were not independent. In addition, pulmonary pressures and NYHA class were powerful independent predictors of clinical outcome in FMR on multivariate analysis. Conclusions The API method better predicts clinical events and outcome in FMR compared to established grading methods. Therefore, the API method may be considered for grading FMR severity in clinical practice.

Background The emergence of non-vitamin K antagonist oral anticoagulants (NOAC) has caused a paradigm shift in anticoagulation therapy, with NOAC being increasingly used compared to vitamin K antagonists. Despite the numerous RCTs with NOAC, further follow-up on how this high risk new drug class is used in real-world clinical practice is warranted. Purpose This study aimed to describe NOAC use in a primary care sample of long-term NOAC users, and investigated (i) adherence, (ii) patients' perceptions, (iii) drug interactions and (iv) appropriateness of dosing. Methods A cross-sectional observational study was conducted in 158 community pharmacies. Participants were home-dwelling adults treated with a NOAC for at least one year. They completed a questionnaire collecting data on socio-demographics, clinical characteristics, current medication use, self-reported adherence to NOAC (via Medication Adherence Report Scale, MARS), and beliefs and perceptions about NOAC (via Beliefs about Medicines Questionnaire, BMQ). Adherence to NOAC (self-reported (MARS) and calculated using pharmacy dispensing data (Medication Possession Ratio (MPR)); patients' beliefs and perceptions about NOAC (BMQ); and prevalence of drug interactions and inappropriate dosing (using the recommendations in the summary of product characteristics (SmPC) and the 2018 European Heart Rhythm Association (EHRA) Practical Guide) were assessed. Results Participants (n=766) had a mean age of 76.2±8.8 years, several co-morbidities (median of 5 (IQR 4–6)) and high thromboembolic risk (median CHA2DS2-VASc score of 4 (IQR 3–4)). The majority (93.5%) used NOAC for non-valvular atrial fibrillation, while the other 6.5% used it for the prevention of recurrent deep vein thrombosis or pulmonary embolism. Forty point five percent of the study sample used rivaroxaban, 36.2% apixaban, 21.1% dabigatran and 2.2% edoxaban. About 85% was adherent according to MPR (MPR ≥80%) and self-reported adherence was also high (mean MARS score 24.6±1.0). Two-thirds reported at least one adverse event of the NOAC, with easy bruising/bleeding being most prevalent (40.2% of patients). BMQ showed that 91.3% of patients favoured the “necessity” over the “concerns” of NOAC use. Thirty-one percent of patients had ≥1 drug interaction(s) with NOAC; amiodarone (10.4% of patients), antiplatelet agents (9.7%) and NSAIDs (9.0%) were the most common interacting drugs. NOAC dosing was inappropriate in 15.9% of patients according to SmPC and in 23.1% according to EHRA. Intriguingly, underdosing was more common using the SmPC as reference, while overdosing was more common using the EHRA guideline. Conclusions This real-world analysis of NOAC use revealed high adherence and necessity beliefs, drug interactions in 30% of patients, and suboptimal dosing in about one fifth of patients. These findings can inform the design of targeted community pharmacist interventions to improve quality of NOAC use.

Objective:Despite effective treatments, blood pressure (BP) control remains low. This study identifies key drivers of therapeutic inertia in Belgium and Luxembourg, and evaluates how uncontrolled treated hypertension is managed in primary care.Design and method:In a 2017 cross-sectional survey,245 g

An elevated pulse pressure leads to an increased pulsatile cardiac load, and results from arterial stiffening. The aim of our study was to test whether a reduction in volume overload by ultrafiltration (UF) during haemodialysis (HD) leads to an improvement of aortic compliance. In 18 patients, aortic compliance was estimated noninvasively before and after HD with UF using a pulse pressure method based on the Windkessel model. This technique has not been applied before in a dialysis population, and combines carotid pulse contour analysis by applanation tonometry with aortic outflow measurements by Doppler echocardiography. The median UF volume was 2450 ml (range 1000-4000 ml). The aortic outflow volume after HD (39 ml; 32-53 ml) was lower (P=0.01) than before (46 ml; 29-60 ml). Carotid pulse pressure after HD (42 mmHg; 25-85 mmHg) was lower (P=0.01) than before (46 mmHg; 35-93 mmHg). Carotid augmentation index after HD (22%; 3-30%) was lower (P=0.001) than before (31%; 7-53%). Carotid-femoral pulse wave velocity was not different after HD (8.7 m/s; 5.6-28.9 m/s vs 7.7 m/s; 4.7-36.8 m/s). Aortic compliance after HD (1.10 ml/mmHg; 0.60-2.43 ml/mmHg) was higher (P=0.02) than before (1.05 ml/mmHg; 0.45-1.69 ml/mmHg). The increase in aortic stiffness in HD patients is partly caused by a reversible reduction of aortic compliance due to volume expansion. Volume withdrawal by HD moves the arterial wall characteristics back to a more favourable position on the nonlinear pressure-volume curve, reflected in a concomitant decrease in arterial pressure and improved aortic compliance.

The association of miconazole and oral anticoagulants should be carried out with great caution because of potentially serious side effects. This phenomenon is well known in the case of systemic administration of miconazole, but there is limited awareness that also topical oral administration of miconazole can provoke these effects. In this paper we describe four patients followed at the Cardiology Department of the Ghent University Hospital, who used an oral mucosal miconazole preparation, and who developed an increased international normalized ratio.

Abstract —The augmentation index (AIx) and “oscillatory” compliance (C 2 ) are wave contour analysis parameters for the central aorta (P ao ) and radial artery pressure wave (P rad ), respectively. Both are sensitive to cardiovascular risk factors such as aging, hypertension, and diabetes and have been proposed as prognostic markers for cardiovascular disease. In this work, we studied the relation between both. We first calculated P rad corresponding to a typical aortic A-type (AIx >0.15) and C-type wave (AIx rad corresponding to C-type waves yielded the highest C 2 value. We further used simultaneously measured aortic and radial artery pressure in 45 human subjects age 34 to 84 years (63±12 [SD]) at baseline and after administration of nitroglycerin to calculate AIx meas and C 2 , respectively. Transfer function was used to calculate reconstructed aortic pressure and AIx rec . AIx rec underestimates AIx meas by 0.03±0.16, but both values correlate well ( r =0.64; P 2 and AIx were inversely correlated ( r =−0.36; P meas ; r =−0.30; P rec ). Both AIx meas (0.06±0.17 versus 0.20±0.21; P rec (0.04±0.12 versus 0.16±0.16; P 2 increased only nonsignificantly (0.080±0.036 versus 0.071±0.042). C 2 is related to AIx and reflects, at least in part, hemodynamic changes affecting central aortic pressure. Nevertheless, given the model assumptions and computational steps associated with calculating C 2 , AIx could be a more appropriate parameter to use in the clinical setting because it is determined directly from the pressure wave contour.

Gastrin can induce mitotic stimulation in the oxyntic mucosa of the stomach, sometimes leading to abnormal growth. We examined whether gastrin was able to influence cell proliferation in the oesophageal epithelium. Rats were treated with gastrin, omeprazole or saline for 3 days, or were subjected to fundectomy or sham operation. Bromodeoxyuridine labelling (LI) and mitotic (MI) indices were counted in the proliferative zone of the squamous epithelium. Infusion of exogenous gastrin, treatment with omeprazole or fundectomy raised the LI and the MI values in the oesophageal epithelium, indicating that gastrin stimulates cell proliferation in the oesophageal mucosa in the rat.

The prevalence of testosterone substitution as well as of androgen deprivation therapy in men is increasing. This review aims to summarise available knowledge of the effects of sex steroids on cardiac structure and function in men. MEDLINE was searched through PubMed. Original studies, systematic reviews and meta-analyses, and relevant citations were screened. A short-term hormonal intervention study in healthy young men with respect to echocardiographic parameters of structure and function was performed. Preclinical research provides sufficient evidence for the heart as a substrate for sex hormones. In animals, administration of oestradiol appears to have beneficial effects on cardiac structure and function, whereas administration of testosterone to noncastrated animals adversely affects cardiac function. However, the effects of sex steroids on cardiac function and structure appear more heterogeneous in human observational studies while comparative, prospective studies in humans are lacking. It is concluded that although effects of testosterone substitution as well as of androgen deprivation on cardiac structure and function can be expected based on pre-clinical research, there exists an important knowledge gap of the effects of hormonal intervention in men. As such, there is a need to address this question in future prospective intervention trials.

Drugs with potential cardiac toxicity are prominent in cancer treatment, not only the old chemotherapeutic agents, but also the newer targeted drugs and biologic agents. As the long-term survival of patients with malignancies has improved and cancer turned into a chronic disease, physicians must take into account the short-term as well as long-term consequences of cancer treatment, such as chemotherapy-induced cardiotoxicity. We summarize some general characteristics and subsequently review specific antineoplastic agents that are associated with cardiac toxicity.

Trastuzumab (TRAS) is a humanised monoclonal antibody that is targeted against the HER2 growth factor receptor. Over-expression of the receptor occurs in around 15-25% of women with early breast cancer (CA). Four major adjuvant trials compared trastuzumab treatment with observation after neoadjuvant or adjuvant chemotherapy in women with high risk HER2-positive breast cancer. Results of these trials showed that trastuzumab treatment given every 3 weeks for 1 year achieved a significant improvement of disease free survival and overall survival. However, cardiac toxicity occurred more in the trastuzumab arm than in the observation arm resulting in symptomatic congestive heart failure and a significant drop in left ventricular ejection function (LVEF).The purpose of this analysis is to evaluate cardiac toxicity of adjuvant trastuzumab treatment in 30 breast cancer patients. Study parameters were cardiac toxicity assessed by LV function, disease free survival and overall survival.Based on the adjuvant trials and in expectation of the reimbursement of trastuzumab in the adjuvant setting, a convention was set up between the Belgian National Institute for Health and Disability Insurance and hospital centres specialized in the treatment of breast cancer. In this convention, trastuzumab was offered to patients diagnosed with invasive, non-metastatic breast cancer with an over-expression of HER2 proven by a positive FISH test. Metastatic lymph nodes or a tumour measuring more than 10 mm had to be present. At least 4 cycles of adjuvant or neoadjuvant chemotherapy had to be given to the patient. Radiotherapy could be administered. The time interval between chemotherapy or radiotherapy and treatment with trastuzumab could not be more than 6 months. LVEF determined by MUGA scan or by ultrasonography at the start of trastuzumab treatment had to be more than 55%.30 breast cancer patients were treated with adjuvant trastuzumab in our hospital between June 2006 and July 2007. All patients met the inclusion criteria. Six patients stopped trastuzumab treatment because of cardiac toxicity. All these patients had received prior anthracycline neoadjuvant or adjuvant chemotherapy. Five of these patients were found to have a LVEF55%, one showing symptoms of congestive cardiomyopathy.The sixth patient was diagnosed with a newly developed tricuspid valve insufficiency grade 3. Follow-up data of 20 months since the start of trastuzumab treatment showed that 27 patients were disease-free. Two patients died because of progressive breast cancer disease. One patient was lost of follow-up.In this small group of breast cancer patients, treated with adjuvant trastuzumab, cardiac toxicity expressed as a decreased left ventricular function seems to have a higher incidence compared to the other adjuvant trials. Therefore, a close cardiac monitoring for several years should be recommended in patients treated with trastuzumab.

Objective To assess the efficacy of naftidrofuryl compared with placebo in treating the symptoms of intermittent claudication. Design Meta-analysis based on individual patient data. Data sources Medline, International Pharmaceutical Abstracts, Embase, Science Citation Index, and the Cochrane trial registers. Reference lists of retrieved articles were checked. Authors and companies were approached for additional information and individual patient data. Inclusion criteria Double blind, randomised controlled trials in patients with intermittent claudication receiving oral naftidrofuryl or placebo and with pain-free walking distance as primary outcome. Data collection Individual patient data were collected from electronic data or from case report forms and checked for integrity. Analysis All randomised patients were analysed following the intention to treat principle. Efficacy was assessed by the ratio of geometric mean of the relative improvement in pain-free walking distance after use of naftidrofuryl compared with placebo. In the analysis of responders, therapeutic success was defined as an improvement of walking distance at baseline by at least 50%. Results In total, 1266 patients were randomised (1083 in the main analysis). The ratio of relative improvement in pain-free walking distance after use of naftidrofuryl compared with placebo was 1.37 (95% confidence interval 1.27 to 1.49). The difference in response rate was 22.3% (95% confidence interval 17.1% to 27.6%) and the number needed to treat for relief of symptoms during six months of treatment was 4.48 (95% confidence interval 3.62 to 5.85). Conclusion This meta-analysis of individual patient data provides evidence that naftidrofuryl has a clinically meaningful effect compared with placebo in improving walking distance in patients with intermittent claudication.

This study is aimed at examining the role of non-hemodynamic factors on the impaired microcirculation in patients with moderate essential hypertension. In a series of 31 patients (mean age, 47.8 +/- 1.1 years) with newly diagnosed untreated moderate essential hypertension (mean systolic blood pressure 161.7 +/- 2.0 mm Hg, mean diastolic blood pressure 102.4 +/- 1.5 mm Hg), parameters of the capillaroscopic examination of the finger microcirculation (mean number of capillaries, NRCAP), length of the capillaries (LECAP, microns), diameter micron) of the efferent (EFDI) and afferent (AFDI) apillaries, and mean red blood cell velocity (RBCV, microns/sec), which was measured by the flying spot technique, were correlated with a number of hormones (sampled after an overnight fast) including: plasma renin activity, aldosterone, and parathyroid hormone (PTH). A significant correlation (P less than .05) could be obtained between several parameters of the microcirculation and PTH:PTH (23.8 +/- 1.4 pg/mL)-NRCAP (14.9 +/- 0.5): r = -0.440, P = .013; PTH-AFDI (4.0 +/- 0.5 microns): r = 0.442, P = .012; PTH-EFDI (2.8 +/- 0.5 microns): r = 0.416, P = .019; PTH-RBCV (711 +/- 69 microns/sec): r = -0.351, P = .05. Furthermore, 24-h urinary norepinephrine (U-NOR) and afferent and efferent diameter of the capillaries intercorrelated significantly: U-NOR (46.0 +/- 6.2 micrograms/24 h)-AFDI: r = 0.439, P = .034; U-NOR-EFDI; r = 0.462, P = .025. This study shows that in patients with moderate essential arterial hypertension nonhemodynamic factors have an influence at the level of the microcirculation.

Nebivolol (R67555), a drug with beta 1 receptor antagonizing properties, was administered once daily (5 mg) for 7 days in 10 healthy volunteers. The hemodynamic parameters were measured noninvasively during postural changes (supine, sitting, standing) and during isometric handgrip at 50% maximal voluntary contraction, before and 3, 8, and 23 hours after the first nebivolol intake of 5 mg; the same measurements were done 23 hours after the last intake. Nebivolol lowered arterial blood pressure acutely and chronically due to a decrease in heart rate and cardiac output. The stroke volume seemed to be preserved, while the total peripheral vascular resistance did not change. Nebivolol did not change the orthostatic responses, except that the absolute value was lowered. Nebivolol was unable to prevent the blood pressure increase during isometric handgrip. However, this blood pressure increase was obtained by an increase in the total peripheral vascular resistance and not by an increase in the cardiac output, as observed during control measurements before nebivolol intake.

In microbroth cultures with RPMI 1640 medium, the growth yield of seven Cryptococcus neoformans isolates was unaffected by augmentation of the normal (0.2%) glucose concentration in the medium to 2%, and the addition of other potential carbon, nitrogen, and vitamin sources to the medium also failed to produce large changes in growth yield. However, macrobroth cultures of C. neoformans in RPMI 1640 that were agitated by rotation in air gave turbidities 6 to 37 times greater than those in identical cultures incubated statically, and similar levels of increase were seen whether the medium contained 0.2 or 2% glucose. Incubation of microplates under an oxygen atmosphere or with agitation by rotation led to an increase of up to twofold in growth turbidity of the yeast. The maximum increase was achieved by incubation with rotation and was dependent on the brand of microplate used. The findings implicate oxygen as a growth-limiting nutrient for C. neoformans. Incubation of microbroth cultures under conditions that enhance oxygen availability for antifungal susceptibility testing purposes may increase the speed of such tests and enhance the determination of MIC endpoints.

Total arterial compliance (TAC), defined as dV/dP, is a major component of the arterial system. A decreased TAC increases left ventricular load and has a detrimental effect on coronary perfusion. We sought to assess the influence of TAC on the functional reserve (VO/sub 2/max). 14 patients (mean age 64/spl plusmn/14y) with known or suspected coronary artery disease and 11 controls (34/spl plusmn/5y) underwent supine bicycle exercise echocardiography. The audio Doppler signal output of the echocardiographic machine was digitized with a customized hardware and software interface simultaneously with carotid tonometry and ECG. TAC at rest was calculated by the pulse-pressure method (PPM). By step-wise forward multivariate analysis, independent predictors of VO/sub 2/max were: patient vs. control status, peak exercise cardiac output and TAC. The described PC-based acquisition system for tonometry and Doppler signals permits the assessment of ventricular function and arterial biomechanics.

We report a case of a young lady with an extensive deep vein thrombosis (DVT) diagnosed by CT scan and duplex ultrasound examination. Contributory factors were relative immobilisation, oral contraception and hyperhomocysteinemia after methionine loading. No other thrombophilic factors could be found. The three main causes of hyperhomocysteinemia are genetic defects, nutritional deficiencies and insufficient elimination. In our case a genetic defect for one of the key enzymes of homocysteine metabolism, may be the underlying cause. Besides stopping oral contraceptive drugs, anticoagulation and supplementation with pyridoxine and folate was started. Family screening was carried out and revealed other members with hyperhomocysteinemia. Whether therapy with pyridoxine and folate can substantially reduce the recurrence of venous thromboembolic disease remains to be established.

Objective: To evaluate the role of orally administered vasoactive medication in the management of intermittent claudication. Setting: We limited our study to the products on the market in Belgium: cinnarizine, cyclandelate, isoxsuprine, naftidrofuryl, pentoxifylline, xanthinol nicotinate and buflomedil. Data sources: We conducted a systematic literature search involving Medline, International Pharmaceutical Abstracts, the Cochrane Library, direct contact with marketing companies and key authors, snowballing and Science Citation Index search. We looked for randomised placebo-controlled trials (RCTs) in patients with Fontaine stage II, in which pain-free and/or maximal walking distance were measured using a standardised exercise test. For isoxsuprine and xanthinol nicotinate, no trials conforming to these criteria were found. Thirty-six trials on cinnarizine, cyclandelate, buflomedil, naftidrofuryl and pentoxifylline met our inclusion criteria. Study selection: After quality assessment, 26 trials were excluded, mainly because of short trial duration (less than 12 weeks), small sample size (less than 30 patients) and/or failure to report details on variability (standard deviation or confidence limits). For cinnarizine and cyclandelate, none of the three selected RCTs was included. Data extraction: For buflomedil, of six published RCTs, two were included after quality assessment, each showing a marginally positive effect of buflomedil versus placebo. For naftidrofuryl, nine RCTs were selected; six were included of which five showed a significant positive result. The likelihood of publication bias and the heterogeneity of the results within and between trials precluded a meta-analysis. For pentoxifylline, of the 18 selected RCTs, only two could be included, both with inconclusive results. Conclusion: A national consensus conference, based on this review, concluded that health resources should be allocated to prevention and rehabilitation of intermittent claudication rather than to reimbursement of these products with doubtful efficacy.

We report the details of a 40-year-old farmer, a cigarette smoker, who was admitted with general malaise, nausea, vomiting, upper abdominal pain, with ST-elevation on ECG suggestive of an acute anterolateral myocardial infarction. He was treated with nitrates, heparin, beta-blockade and angiotensin-converting enzyme (ACE) inhibitors. Because of the presence of some blood while vomiting no thrombolysis was given and abdominal echography was performed. This revealed a nodular mass at the right adrenal gland. Urinary catecholamines and abdominal magnetic resonance imaging confirmed the suspected diagnosis of pheochromocytoma. Before adrenectomy, a coronary angiography under alpha blocker therapy was performed, which demonstrated no significant coronary artery disease, although the patient showed ST-elevations on ECG. Pathological examination of the adrenal tumor was compatible with a diagnosis of pheochromocytoma. Postoperatively urinary catecholamines dropped dramatically, and the ECG normalised slowly over time. After 8 months the patient is still well. Blood pressure is well controlled with no antihypertensive drugs and exercise testing shows no evidence of myocardial ischaemia.

We fitted a three-segment transmission line model for the radial-carotid/aorta pressure transfer function (TFF) in 31 controls and 30 patients with coronary artery disease using noninvasively measured (tonometry) radial and carotid artery pressures (Pcar). Except for the distal reflection coefficient (0.85 ± 0.21 in patients vs. 0.71 ± 0.25 in controls; P < 0.05), model parameters were not different between patients or controls. Parameters were not related to blood pressure, age, or heart rate. We further assessed a point-to-point averaged TFF (TFFavg) as well as upper (TFFmax) and lower (TFFmin) enveloping TFF. Pulse pressure (PP) and augmentation index (AIx) were derived on original and reconstructed Pcar (Pcar,r). TFFavg yielded closest morphological agreement between Pcar and Pcar,r (root mean square = 4.3 ± 2.3 mmHg), and TTFavg best predicted PP (41.5 ± 11.8 vs. 41.1 ± 10.0 mmHg measured) and AIx (−0.02 ± 0.19 vs. 0.01 ± 0.19). PP and AIx, calculated from Pcar or Pcar,r, were higher in patients than in controls, irrespectively of the TFF used. We conclude that 1) averaged TFF yield significant discrepancies between reconstructed and measured pressure waveforms and subsequent derived AIx; and 2) different TFFs seem to preserve the information in the pressure wave that discriminates between controls and patients.

Objective - Our aim is to quantify steady and pulsatile components of arterial load in a concise and sensitive way by means of a new non-invasive cardiovascular index (NICI). Methods and results - NICI is based on non-invasively measured pressure (sphygmomanometer), stroke volume index and cardiac index (Doppler echocardiography and ECG) and yields a numerical value (in mm Hg). It expresses the difference between the actual arterial load and reference loading conditions as determined in a control group (29 M/35 F, age 34 ± 13 yr.) of healthy subjects, with blood pressure 116/61 mm Hg (systolic/diastolic), stroke volume index (SVI) 34 ± 18 ml.m -2 and cardiac index (Cl) 2.1 ± 0.5 l.min -1 .m -2 . NICI was calculated in the control group and in 23 borderline hypertensive subjects (10 M/13 F, age 65 ± 12 yr.) with blood pressure 156/79 mm Hg, SVI 36 ± 10 ml.m -2 and Cl 2.4 ± 0.6 l.min -1 .m -2 . NICI was higher in borderline hypertensives (33 ± 51 vs. 0 ± 34 mm Hg; P < 0.001) and was strongly correlated with total peripheral resistance index (r = 0.89; P < 0.001) and with the ratio of SVI and pulse pressure (r = -0.89; P < 0.001), expressing the combined effect of both known determinants of cardiac load. NICI was also correlated with effective arterial elastance index (r = 0.89; P < 0.001). Conclusions - NICI quantifies, within a logical biomechanical framework, the arterial load as seen by the ejecting ventricle. It combines steady and pulsatile components of arterial load and has a single control value of zero mm Hg.

In a randomized double-blind, placebo-controlled, crossover study of isradipine (5 mg twice daily), effects on peripheral hemodynamic reflex responses were studied in nine patients (mean age 48 years) at baseline and after six weeks of active treatment. Assessments included vital signs, resting blood flow in the calf and finger (using an electrocardiograph-triggered venous occlusion plethysmograph), reflex responses during isometric exercise and cold pressor resistance, and venous capacitance in the forearm and calf. Isradipine lowered systolic and diastolic blood pressure as well as mean arterial pressure in patients with mild-to-moderate essential hypertension without reflex tachycardia or venoconstriction. All of the reflex responses studied were attenuated. It is concluded that vasodilatation of the peripheral circulation induced by isradipine contributes partially to the blood pressure-lowering effect.

Summary Necrotizing fasciitis is a soft tissue infection, usually polymicrobial, characterized by necrosis of fascia and subcutaneous tissue. Although it more commonly involves the groin, abdomen and extremities, it may also occur in the head and neck. We report a case of cervical necrotizing fasciitis arising from a dental infection and review the cause, pathophsiology, diagnosis and treatment of this potentially lethal entity. Early detection and accurate intervention are emphasized. Extensive surgical debridement completed with hyperbaric oxygen therapy and antibiotics are the mainstay of treatment.

A case of non-union of a preprosthetic Le Fort I osteotomy using freeze-dried bone as an interpositional graft in a 38 year old woman is presented. The principles of natural bone repair and the different causes of non-union of bone fragments are discussed. How long does nature need for successful ingrowth of connective and vascular tissue and for the resorption-replacement mechanism using freeze-dried bone to bridge an osteotomy gap? Successful treatment of the non-union consisted of curettage of the granulation tissue followed by autogenous cortico-cancellous bone grafting.

A 1-year-old boy with high jejunal membranous stenosis was successfully treated "a minima" by antimesenteric longitudinal enterotomy over the diaphragm, excision of the latter, and transverse closure of the bowel. This was made possible by use of simultaneous peroperative endoscopy, which allowed exact localization of the diaphragm. Peroperative endoscopy is a useful and accurate method for this purpose and should be considered in similar cases.

Reversed day–night ambulatory blood pressure profile and blunted heart rate variability of unknown cause in a hypertensive patient