De novo nocturia: A red flag for coronary heart disease patients.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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, p<0.001). CONCLUSION: 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. LEVEL OF EVIDENCE: 4: (cross sectional study with prospectively recruitement) Source: https://www.ciap.health.nsw.gov.au/training/ebp-learning-modules/module1/grading-levels-of-evidence.html.

Sex steroids in relation to cardiac structure and function in men.

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.

Impact of lipid disorders on mortality among Saudi patients with heart failure.

BACKGROUND: Dyslipidemia, a known cardiovascular risk factor, is extremely common among Saudis, both adults and children. The impact, however, of dyslipidemia and several other lipid disorders in patients with congestive heart failure in this particular population has not been documented. This study aims to fill the gap. METHODS: This retrospective, single center study was conducted at King Abdulaziz Medical City, Riyadh, Saudi Arabia. Of the 500 cases seen during the period between 2002 and 2008, 392 were included in the study. Charts were reviewed and information on medical history, medications, and lipid status were documented. RESULTS: Low HDL-cholesterol level was the most common lipid disorder with 82.9%, followed by hypertriglyceridemia (35.2%), atherogenic dyslipidemia (27.8%), and hypercholesterolemia (9.2%). Diabetes mellitus was the single most significant predictor of mortality (p = 0.001). Among the lipid disorders, only low levels of HDL-cholesterol contributed to significant mortality risk [OR 1.29 (Confidence Interval 1.04-1.59) (p-value < 0.01)] adjusted for age, gender and statin use. CONCLUSION: The results of this study suggest that emphasis should be on the elevation of HDL-cholesterol levels among subjects with congestive heart failure, without compromising any ongoing management of LDL-lowering drugs. Management should not be limited to conventional statin use and should promote other treatments to elevate HDL-cholesterol levels.

Miconazole buccal gel and risk for systemic bleeding: how certain topical formula can interfere with anticoagulants.

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.

Measurement of the proton-air cross section at √s=57 TeV with the Pierre Auger Observatory.

We report a measurement of the proton-air cross section for particle production at the center-of-mass energy per nucleon of 57 TeV. This is derived from the distribution of the depths of shower maxima observed with the Pierre Auger Observatory: systematic uncertainties are studied in detail. Analyzing the tail of the distribution of the shower maxima, a proton-air cross section of [505±22(stat)(-36)(+28)(syst)] mb is found.

Cardiovascular toxicity of cancer treatment.

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.

Cardiac toxicity of trastuzumab: experience at the Ghent Unversity Hospital, Belgium.

INTRODUCTION: 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). AIM OF THE STUDY: 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. MATERIALS AND METHODS: 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%. RESULTS: 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 LVEF < 55%, 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. CONCLUSION: 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.

Measurement of the depth of maximum of extensive air showers above 10{18} eV.

We describe the measurement of the depth of maximum, X{max}, of the longitudinal development of air showers induced by cosmic rays. Almost 4000 events above 10;{18} eV observed by the fluorescence detector of the Pierre Auger Observatory in coincidence with at least one surface detector station are selected for the analysis. The average shower maximum was found to evolve with energy at a rate of (106{-21}{+35}) g/cm{2}/decade below 10{18.24+/-0.05} eV, and (24+/-3) g/cm{2}/decade above this energy. The measured shower-to-shower fluctuations decrease from about 55 to 26 g/cm{2}. The interpretation of these results in terms of the cosmic ray mass composition is briefly discussed.

Silence of the limbs pharmacological symptomatic treatment of intermittent claudication.

Several oral "vasoactive" drugs claim to increase walking capacity in patients with intermittent claudication (IC). Naftidrofuryl, cilostazol, buflomedil, and pentoxifylline are the most studied molecules. Although spanning several decades, several studies underlying these claims were not properly designed, underpowered or showed clinically doubtful outcomes. The evidence for these "vasoactive" drugs has always been received with scepticism, creating the need for systematic reviews and meta-analyses. This brief review discusses the benefit-risk assessment of vasoactive drugs, by applying a systematic review to evaluate randomized, placebo-controlled trials. Oral naftidrofuryl and cilostazol have an acceptable safety profile as well as sustained evidence (documented by Cochrane analyses) of increased walking capacity. Subsequently, these drugs entered recommendations for peripheral arterial disease (PAD). In contrast, buflomedil and pentoxifylline have limited and/or doubtful evidence to increase walking capacity. Moreover, there were safety concerns about the narrow therapeutic range of buflomedil. Most other "vasoactive" drugs were either inappropriately or insufficiently tested or showed no significant if not negative effects on IC. "Vasoactive" drugs are no substitutes for lifestyle or exercise therapy but are adjuvant treatment to the well-appreciated triad of cardiovascular prevention (antiplatelet agents, statins and ACE-inhibitors), of which statins in their own right have documented claims to significantly increase walking capacity. "Vasoactive" drugs may have a place in the pharmacological management of symptomatic PAD in addition to the basic cardiovascular pharmacotherapy, when revascularization is not indicated, when exercise therapy is not feasible or when there is still insufficient benefit.

Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient data.

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.

Observation of the suppression of the flux of cosmic rays above 4 x 10 (19) eV.

The energy spectrum of cosmic rays above 2.5 x 10;{18} eV, derived from 20,000 events recorded at the Pierre Auger Observatory, is described. The spectral index gamma of the particle flux, J proportional, variantE;{-gamma}, at energies between 4 x 10;{18} eV and 4 x 10;{19} eV is 2.69+/-0.02(stat)+/-0.06(syst), steepening to 4.2+/-0.4(stat)+/-0.06(syst) at higher energies. The hypothesis of a single power law is rejected with a significance greater than 6 standard deviations. The data are consistent with the prediction by Greisen and by Zatsepin and Kuz'min.

Upper limit on the diffuse flux of ultrahigh energy tau neutrinos from the Pierre Auger Observatory.

The surface detector array of the Pierre Auger Observatory is sensitive to Earth-skimming tau neutrinos that interact in Earth's crust. Tau leptons from nu(tau) charged-current interactions can emerge and decay in the atmosphere to produce a nearly horizontal shower with a significant electromagnetic component. The data collected between 1 January 2004 and 31 August 2007 are used to place an upper limit on the diffuse flux of nu(tau) at EeV energies. Assuming an E(nu)(-2) differential energy spectrum the limit set at 90% C.L. is E(nu)(2)dN(nu)(tau)/dE(nu)<1.3 x 10(-7) GeV cm(-2) s(-1) sr(-1) in the energy range 2 x 10(17) eV< E(nu)< 2 x 10(19) eV.

Naftidrofuryl for intermittent claudication.

BACKGROUND: Lifestyle changes and cardiovascular prevention measures are a primary treatment for intermittent claudication (IC). Symptomatic treatment with vasoactive agents (Anatomic Therapeutic Chemical Classification (ATC) for medicines from the World Health Organisation class CO4A) is controversial. OBJECTIVES: To evaluate evidence on the efficacy and safety of oral naftidrofuryl (ATC CO4 21) versus placebo on the pain-free walking distance (PFWD) of people with IC by using a meta-analysis based on individual patient data (IPD). SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases Group searched their Trials Register (last searched December 2007) and CENTRAL (last searched 2007, Issue 4). We searched MEDLINE, EMBASE, International Pharmaceutical Abstracts, the Science Citation Index and contacted the authors and checked the reference lists of retrieved articles. We asked the manufacturing company for IPD. SELECTION CRITERIA: We included only randomized controlled trials (RCTs) with low or moderate risk of bias for which the IPD were available. DATA COLLECTION AND ANALYSIS: We collected data from the electronic data file or from the case report form and checked the data by a statistical quality control procedure. All randomized patients were analyzed following the intention-to-treat (ITT) principle. The geometric mean of the relative improvement in PFWD was calculated for both treatment groups in all identified studies. The effect of the drug was assessed compared with placebo on final walking distance (WDf) using multilevel and random-effect models and adjusting for baseline walking distance (WD0). For the responder analysis, therapeutic success was defined as an improvement of walking distance of at least 50%. MAIN RESULTS: We included seven studies in the IPD (n = 1266 patients). One of these studies (n = 183) was only used in the sensitivity analysis so that the main analysis included 1083 patients. The ratio of the relative improvement in PFWD (naftidrofuryl compared with placebo) was 1.37 (95% confidence interval (CI) 1.32 to 1.51, P < 0.001). The absolute difference in responder rate, or proportion successfully treated, was 22.3% (95% CI 17.1% to 27.6%). The calculated number needed to treat was 4.5 (95% CI 3.6 to 5.8). AUTHORS' CONCLUSIONS: Naftidrofuryl has a statistically significant and clinically meaningful effect of improving walking distance in the six months after initiation of therapy for people with intermittent claudication. Access by researchers to data from RCTs that is suitable for IPD analysis should be possible through repositories of data from pharmacological trials. Regular formal appraisal of the balance of risk and benefit is needed for older pharmaceutical products.

Buflomedil for intermittent claudication.

BACKGROUND: Intermittent claudication (IC) is pain caused by chronic occlusive arterial disease, that develops in a limb during exercise and is relieved with rest. Buflomedil is a vasoactive agent used to treat peripheral vascular disease. However, its clinical efficacy for IC has not yet been critically examined. OBJECTIVES: To evaluate the available evidence on the efficacy of buflomedil for IC. SEARCH STRATEGY: We searched the specialized trials register of the Cochrane Peripheral Vascular Diseases Review Group (last searched November 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4, 2007), MEDLINE (1966 to November 2007), International Pharmaceutical Abstracts (IPA) (from inception to November 2007), Science Citation Index (from inception to November 2007). We contacted Abbott Laboratories (buflomedil distributor) for controlled clinical trial data and approached authors for additional trial information. SELECTION CRITERIA: Double-blinded, randomized controlled trials (RCTs) in patients with IC (Fontaine stage II) receiving oral buflomedil compared to placebo. Pain-free walking distance (PFWD) and maximum walking distance (MWD) were analysed by standardized exercise test. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We included two RCTS with 127 participants. Both RCTs showed moderate improvements in PFWD for patients on buflomedil. This improvement was statistically significant for both trials (WMD 75.1 m, 95% confidence interval (CI) 20.6 to 129.6; WMD 80.6 m, 95% CI 3.0 to 158.2), the latter being a wholly diabetic population. For both RCTs, MWD gains were statistically significant with wide confidence intervals (WMD 80.7 m, 95% CI 9.4 to 152; WMD 171.4 m, 95% CI 51.3 to 291.5), respectively. AUTHORS' CONCLUSIONS: There is little evidence available to evaluate the efficacy of buflomedil for IC. Most trials were excluded due to poor quality. The two included trials showed moderately positive results; these are undermined by publication bias since we know of at least another four unpublished, irretrievable, and inconclusive studies.Buflomedil's benefit is small in relation to safety issues and its narrow therapeutic range.

Correlation of the highest-energy cosmic rays with nearby extragalactic objects.

Using data collected at the Pierre Auger Observatory during the past 3.7 years, we demonstrated a correlation between the arrival directions of cosmic rays with energy above 6 x 10(19) electron volts and the positions of active galactic nuclei (AGN) lying within approximately 75 megaparsecs. We rejected the hypothesis of an isotropic distribution of these cosmic rays with at least a 99% confidence level from a prescribed a priori test. The correlation we observed is compatible with the hypothesis that the highest-energy particles originate from nearby extragalactic sources whose flux has not been substantially reduced by interaction with the cosmic background radiation. AGN or objects having a similar spatial distribution are possible sources.

Buflomedil for intermittent claudication.

BACKGROUND: Intermittent claudication (IC) is pain caused by chronic occlusive arterial disease, that develops in a limb during exercise and is relieved with rest. Buflomedil is a vasoactive agent used to treat peripheral vascular disease. However, its clinical efficacy for IC has not yet been critically examined. OBJECTIVES: To evaluate the available evidence on the efficacy of buflomedil for IC. SEARCH STRATEGY: We searched the specialized trials register of the Cochrane Peripheral Vascular Diseases Review Group (last searched August 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 3, 2007), MEDLINE (1966 to August 2007), International Pharmaceutical Abstracts (IPA) (from inception to August 2007), Science Citation Index (from inception to August 2007). We contacted Abbott Laboratories (buflomedil distributor) for controlled clinical trial data and approached authors for additional trial information. SELECTION CRITERIA: Double-blinded, randomized controlled trials (RCTs) in patients with IC (Fontaine stage II) receiving oral buflomedil compared to placebo. Pain-free walking distance (PFWD) and maximum walking distance (MWD) were analysed by standardized exercise test. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We included two RCTS with 127 participants. Both RCTs showed moderate improvements in PFWD for patients on buflomedil. This improvement was statistically significant for both trials (WMD 75.1 m, 95% confidence interval (CI) 20.6 to 129.6; WMD 80.6 m, 95% CI 3.0 to 158.2), the latter being a wholly diabetic population. For both RCTs, MWD gains were statistically significant with wide confidence intervals (WMD 80.7 m, 95% CI 9.4 to 152; WMD 171.4 m, 95% CI 51.3 to 291.5), respectively. AUTHORS' CONCLUSIONS: There is little evidence available to evaluate the efficacy of buflomedil for IC. Most trials were excluded due to poor quality. The two included trials showed moderately positive results; these are undermined by publication bias since we know of at least another four unpublished, irretrievable, and inconclusive studies.Buflomedil's benefit is small in relation to safety issues and its narrow therapeutic range.

Ultrafiltration improves aortic compliance in haemodialysis patients.

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.

On-line electrical impedance measurement for monitoring blood viscosity during on-pump heart surgery.

BACKGROUND: The viscosity of blood (eta) as well as its electrical impedance at 20 kHz at high shear rate depends on hematocrit, temperature, concentration of macromolecules and red cell deformability. The aim of our study was to investigate the relation between viscosity and electrical impedance in a heart-lung machine-like set-up, because during on-pump heart surgery considerable viscosity changes occur. METHODS: Blood of 10 healthy volunteers was examined under temperature variation between 18.5 and 37 degrees C at four different levels of hemodilution. Blood viscosity was examined with a golden-standard technique, i.e. a Contraves LS 30 Couette viscometer, and the results were compared with measurements of the electrical resistivity (R) at 20 kHz by a specially designed device in series with the tubing system of a heart-lung machine. All measurements were performed at a shear rate of 87 s(-1). RESULTS: Using stepwise multiparameter regression analysis (SPSS) a highly significant correlation was found (r(2) = 0.882) between viscosity (eta) and resistivity (R). Adding the variables sodium ([Na(+)]) and fibrinogen ([Fibr]) concentration the coefficient of correlation further improved to r(2) = 0.928 and the relation became: eta = -0.6844 + 0.038 R + 0.038 [Na(+)] + 0.514 [Fibr]. All coefficients showed a statistical significance of p < 0. 001. CONCLUSIONS: Electrical impedance measurement is feasible in a heart-lung machine-like set-up and allows accurate continuous on-line estimation of blood viscosity; it may offer an adequate way to record and control viscosity changes during on-pump heart surgery.