Please die during office hours : periodicity of cardiovascular events in switzerland between 1969 and 2007

Purpose: to evaluate and compare the periodical patterns of death from cardiovascular disease (CVD), including acute myocardial infarction (AMI) and stroke in the Swiss population between the years 1969 and 2007.¦Methods: Swiss mortality database for the period of 1969- 2007 (2'362'430 deaths overall). The number of deaths due to CVD, AMI and stroke according to the time of day, day of the week and month were assessed, overall and after dividing the events according to gender and age (< 65 or ≥65 years old).¦Results: In general and for all four subgroups according to age and sex, there is a daily variation in the number of deaths with a first peak in the morning (8h00 -12h00) and a smaller second peak in the late afternoon (14h - 18h). Both males and females have similar hourly patterns, although the magnitude of the difference diminishes in older patients particularly for people who die from stroke. For the weekly variation, there seems to be a significant trend only in the younger population with the lowest mortality rates on Sunday and the highest on Mondays for all diseases. When it comes to seasonal variation according to month, the trend is more significant in the elder patients with the highest death rates during the winter months (+31%) and the lowest in the summer (July/August).¦Conclusion: There is a timely pattern for CVD, AMI and stroke deaths in Switzerland. This pattern changes according to the age and sex of the patients. Knowing this trend, its triggering factors and consequences, perhaps there could be measures put in place to prevent, diagnose and treat the population which is the most vulnerable at certain times.

Risc cardiovascular dels fitoesterols

Els fitoesterols són components importants de la dieta Mediterrània. La seva ingesta augmenta les concentracions en sang i les concentracions elevades s’han relacionat amb un augment de risc cardiovascular. Però el síndrome metabòlic (SMet) s’associa a concentracions baixes de fitoesterols. S’ha investigat la relació entre fitoesterols del plasma i la dieta amb la presència de factors de risc cardiovascular, incloent el SMet, i malaltia cardiovascular. També s’han avaluat factors socioeconòmics que influencien els hàbits dietètics. Per dur-ho a terme s’ha realitzat un anàlisi retrospectiu en l’estudi Prevención con Dieta Mediterránea (PREDIMED) amb dades basals i a l’any d’una intervenció dietètica per avaluar la influència dels fitosterols de la dieta en el perfil lipídic dels participants. En l’estudi European Prospective Investigation into Cancer and Nutrition (EPIC) d’Espanya s’ha realitzat una anàlisi transversal per analitzar factors socials i dieta, i un estudi cas-control per avaluar el risc de desenvolupar malaltia cardiovascular segons les concentracions plasmàtiques de fitoesterols. Resultats: el consum de fitoesterols amb la dieta habitual s’ha relacionat amb la ingesta d’aliments saludables, amb una millora del perfil lipídic en els participants del PREDIMED i amb un increment dels fitoesterols plasmàtics. Aquest increment es va associar en l’estudi EPIC amb una millora dels factors de risc cardiovascular, una disminució del risc de patir malaltia cardiovascular o qualsevol component del SMet o el propi síndrome. Fa 10 anys la població espanyola seguia un patró de dieta mediterrània i era accessible a tothom independentment de la posició socioeconòmica. Conclusions. Les concentracions de fitoesterols plasmàtics semblen ser marcadors fiables d’un risc cardiometabòlic menor i un menor risc de patir malaltia cardiovascular. Ja que aquests elements són abundants en els aliments que característicament es consumeixen a Espanya, és necessari evitar que siguin difícils d’aconseguir per un encariment en el mercat i es generin desigualtats en salut a causa de l’alimentació.

Evidence for a role of sphingosine-1 phosphate in cardiovascular remodelling in Fabry disease.

AIMS: A hallmark of Fabry disease is the concomitant development of left-ventricular hypertrophy and arterial intima-media thickening, the pathogenesis of which is thought to be related to the presence of a plasmatic circulating growth-promoting factor. We therefore characterized the plasma of patients with Fabry disease in order to identify this factor. METHODS AND RESULTS: Using a classical biochemical strategy, we isolated and identified sphingosine-1 phosphate (S1P) as a proliferative factor present in the plasma of patients with Fabry disease. Plasma S1P levels were significantly higher in 17 patients with Fabry disease compared with 17 healthy controls (225 +/- 40 vs. 164 +/- 17 ng/mL; P = 0.005). There was a positive correlation between plasma S1P levels and both common carotid artery intima-media thickness and left-ventricular mass index (r(2) = 0.47; P = 0.006 and r(2) = 0.53; P = 0.0007, respectively). In an experimental model, mice treated with S1P developed cardiovascular remodelling similar to that observed in patients with Fabry disease. CONCLUSION: Sphingosine-1 phosphate participates in cardiovascular remodelling in Fabry disease. Our findings have implications for the treatment of cardiovascular involvement in Fabry disease.

Mass spectrometry for the evaluation of cardiovascular diseases based on proteomics and lipidomics.

The identification and quantification of proteins and lipids is of major importance for the diagnosis, prognosis and understanding of the molecular mechanisms involved in disease development. Owing to its selectivity and sensitivity, mass spectrometry has become a key technique in analytical platforms for proteomic and lipidomic investigations. Using this technique, many strategies have been developed based on unbiased or targeted approaches to highlight or monitor molecules of interest from biomatrices. Although these approaches have largely been employed in cancer research, this type of investigation has been met by a growing interest in the field of cardiovascular disorders, potentially leading to the discovery of novel biomarkers and the development of new therapies. In this paper, we will review the different mass spectrometry-based proteomic and lipidomic strategies applied in cardiovascular diseases, especially atherosclerosis. Particular attention will be given to recent developments and the role of bioinformatics in data treatment. This review will be of broad interest to the medical community by providing a tutorial of how mass spectrometric strategies can support clinical trials.

The SPONASTRIME dysplasia: familial short-limb dwarfism with saddle nose, spinal alterations and metaphyseal striation. Report of 4 siblings.

We report clinical, anthropometric and radiological findings in 4 siblings with a new type of skeletal dysplasia. 4 normally intelligent girls exhibit dwarfism between -3.4 and -4.6 standard deviations with accentuated shortening of the lower limbs, moderate deformity of the vertebral bodies, mildly striated metaphyses, saddle nose, frontal bossing, and relatively large head. The family pedigree suggests autosomal recessive inheritance. We propose the designation of SPONASTRIME dysplasia, derived from spondylar and nasal alterations with striation of the metaphyses.

Comparative cost-effectiveness analyses of cardiovascular magnetic resonance and coronary angiography combined with fractional flow reserve for the diagnosis of coronary artery disease.

BACKGROUND: According to recent guidelines, patients with coronary artery disease (CAD) should undergo revascularization if significant myocardial ischemia is present. Both, cardiovascular magnetic resonance (CMR) and fractional flow reserve (FFR) allow for a reliable ischemia assessment and in combination with anatomical information provided by invasive coronary angiography (CXA), such a work-up sets the basis for a decision to revascularize or not. The cost-effectiveness ratio of these two strategies is compared. METHODS: Strategy 1) CMR to assess ischemia followed by CXA in ischemia-positive patients (CMR + CXA), Strategy 2) CXA followed by FFR in angiographically positive stenoses (CXA + FFR). The costs, evaluated from the third party payer perspective in Switzerland, Germany, the United Kingdom (UK), and the United States (US), included public prices of the different outpatient procedures and costs induced by procedural complications and by diagnostic errors. The effectiveness criterion was the correct identification of hemodynamically significant coronary lesion(s) (= significant CAD) complemented by full anatomical information. Test performances were derived from the published literature. Cost-effectiveness ratios for both strategies were compared for hypothetical cohorts with different pretest likelihood of significant CAD. RESULTS: CMR + CXA and CXA + FFR were equally cost-effective at a pretest likelihood of CAD of 62% in Switzerland, 65% in Germany, 83% in the UK, and 82% in the US with costs of CHF 5'794, euro 1'517, £ 2'680, and $ 2'179 per patient correctly diagnosed. Below these thresholds, CMR + CXA showed lower costs per patient correctly diagnosed than CXA + FFR. CONCLUSIONS: The CMR + CXA strategy is more cost-effective than CXA + FFR below a CAD prevalence of 62%, 65%, 83%, and 82% for the Swiss, the German, the UK, and the US health care systems, respectively. These findings may help to optimize resource utilization in the diagnosis of CAD.

Histopathological alterations induced by non-viable cells and biochemical fractions from Paracoccidioides brasiliensis in mice

Non-viable cells and biochemical fractions from Paracoccidioides brasiliens were obtained for experimental inoculation in mice and posterior histopatological analysis. Dead total fungus, total fungus disrupted by sonorous waves, lipids of the fungus, supernatant of the lipid purification, integral and disrupted fungus free of lipids were obtained. The six preparations arised from masses of lyophilized yeasts of a recent isolate of P. brasiliensis (strain JT-1) and from a "Pool" equitably constituted by four strains maintained in laboratory for a long time (SN, 2, 18 and 192). Different doses of the 12 preparations were intraperitonially inoculated and histopathological analysis were done 30 days later. This analysis showed that all the inoculated preparations gave origin to inflamatory foci, except the one designated "supernatant of lipid purification". The alterations were detected exclusively in the liver of the animals and occurred from the smallest dose tested (1 mg), with exception of the lipids of the fungus, where the foci appeared only from a 3 mg dose onwards. No difference in the capacity of inducing histopathological alterations was found between the preparations obtained from the recent isolate (JT-1) and from the older ones ("Pool"). On the other hand, an increase of the number of inflammatory foci in function of the inoculated dose was observed.

Differences in self-reported prevalence and management of cardiovascular risk factors in Switzerland, 2007

Purpose: To assess the prevalence of four self-reported cardiovascular risk factors (CV RFs: smoking, hypertension, dyslipidaemia and diabetes) and their reported management in seven Swiss regions (Léman, MiUelland, Zurich, North-West Switzerland, Oriental Switzerland, Central Switzerland and Tessin). Methods: National health interview survey conducted in 2007 in a representative sample of the Swiss population (17,879 subjects). Age-adjusted data on prevalence of self-reported CV RFs, treatment among participants reporting a RF, control of RFs among treated participants and CV RF screening in the last 12 months levels were computed after weighting. Results: The prevalence of hypertension was highest in North-West Switzerland (27.3%) and lowest in Central Switzerland (21.0%, p<0.001). Antihypertensive treatment was highest in Léman region (62.7%) and lowest in Oriental Switzerland (55.2%, p<0.001). Screening was higher in Tessin (89.3%) and lowest in Léman region (81.8%, p<0.001). Prevalence of dyslipidaemia was highest in Tessin and Léman region (20.7% and 20.1 %, respectively) and lowest in Oriental Switzerland (14.5%, p<0.001). Lipid-Iowering treatment was highest in Tessin and Léman region (44.3% each) and lowest in Central Switzerland (30.7%, p<0.001). Dyslipidaemia screening was highest in Tessin (76.6%) and lowest in Central Switzerland (58.6%, p<0.001). Prevalence of diabetes was highest in North-West Switzerland (5.4%) and lowest in Central Switzerland (3.3%, p<0.05). Diabetes screening was highest in Tessin (78.1%) and lowest in Oriental Switzerland (64.0%, p<0.001). Conversely, no between-region differences were found for hypertension or dyslipidaemia control (see table). Conclusion: there are significant differences between the Swiss regions in self-reported prevalence and management of CV RFs. Screening is beUer in Tessin than in the other regions.

Cost evaluation of cardiovascular magnetic resonance versus coronary angiography for the diagnostic work-up of coronary artery disease: Application of the European Cardiovascular Magnetic Resonance registry data to the German, United Kingdom, Swiss, and United States health care systems.

ABSTRACT: BACKGROUND: Cardiovascular magnetic resonance (CMR) has favorable characteristics for diagnostic evaluation and risk stratification of patients with known or suspected CAD. CMR utilization in CAD detection is growing fast. However, data on its cost-effectiveness are scarce. The goal of this study is to compare the costs of two strategies for detection of significant coronary artery stenoses in patients with suspected coronary artery disease (CAD): 1) Performing CMR first to assess myocardial ischemia and/or infarct scar before referring positive patients (defined as presence of ischemia and/or infarct scar to coronary angiography (CXA) versus 2) a hypothetical CXA performed in all patients as a single test to detect CAD. METHODS: A subgroup of the European CMR pilot registry was used including 2,717 consecutive patients who underwent stress-CMR. From these patients, 21% were positive for CAD (ischemia and/or infarct scar), 73% negative, and 6% uncertain and underwent additional testing. The diagnostic costs were evaluated using invoicing costs of each test performed. Costs analysis was performed from a health care payer perspective in German, United Kingdom, Swiss, and United States health care settings. RESULTS: In the public sectors of the German, United Kingdom, and Swiss health care systems, cost savings from the CMR-driven strategy were 50%, 25% and 23%, respectively, versus outpatient CXA. If CXA was carried out as an inpatient procedure, cost savings were 46%, 50% and 48%, respectively. In the United States context, cost savings were 51% when compared with inpatient CXA, but higher for CMR by 8% versus outpatient CXA. CONCLUSION: This analysis suggests that from an economic perspective, the use of CMR should be encouraged as a management option for patients with suspected CAD.

Bilateral uveal pigmented alterations with remarkable evolution: long term follow-up in a case of possible bilateral diffuse uveal melanocytic proliferation

Purpose: to describe a case of probable bilateral diffuse uveal melanocytic proliferation (BDUMP) with scleral involvement, free from systemic malignancies and cataract. Methods: fifty months of follow up with recurrent complete ophthalmological examinations, including fundus photography, fluorescein/indocyanine green angiography (FA) and optical coherence tomography (OCT). Investigations also included an electroretinography (ERG) and histological examination of scleral biopsy. Extraocular malignancies were repeatedly searched. Results: the patient was a 61 year-old Italian man with chronic hepatitis type C. At first visit his best corrected visual acuity (BCVA) was 20/32 in OS and 20/25 in OD. Funduscopy showed multiple patch-shaped pigmented alterations involving macular region and mid retinal periphery. FA showed corresponding areas of late-phase hyperfluorescent pinpoints (figure 1a, OS) and intemediate-phase hypocyanescence (figure 1b, OS), with subtle serous neurosensory retinal detachment confirmed by OCT. Photopic and scotopic ERG tested normal. Systemic prednisone was administered for one month without any improvement. After ten months round pigmentary lesions appeared also in superior scleral surface of both eyes. Biopsy allowed to disclose slightly pigmented spindle cells. BCVA worsened for further 10 months, with enlargement of FA alteration areas but lenses still clear. After 30 months spontaneous coalescence and atrophy of retinal lesions started, paralleled by progressive visual recovery. At the end of our follow up BCVA was 20/25 in OU while scleral pigmentary lesions remained unchanged. Conclusions: we report the case of a patient with main features of BDUMP and some unusual findings. Although not all classical diagnostic criteria were fulfilled, the presence of scleral pigmented lesions and spontaneous visual recovery may enlarge clinical spectrum of the disease.

Potassium channel alterations mediate peripheral nerve hyperexcitability in a mouse model of type 2 diabetes mellitus

Diabetes mellitus (DM) is a major cause of peripheral neuropathy. More than 220 million people worldwide suffer from type 2 DM, which will, in approximately half of them, lead to the development of diabetic peripheral neuropathy. While of significant medical importance, the pathophysiological changes present in DPN are still poorly understood. To get more insight into DPN associated with type 2 DM, we decided to use the rodent model of this form of diabetes, the db/db mice. During the in-vivo conduction velocity studies on these animals, we observed the presence of multiple spiking followed by a single stimulation. This prompted us to evaluate the excitability properties of db/db peripheral nerves. Ex-vivo electrophysiological evaluation revealed a significant increase in the excitability of db/db sciatic nerves. While the shape and kinetics of the compound action potential of db/db nerves were the same as for control nerves, we observed an increase in the after-hyperpolarization phase (AHP) under diabetic conditions. Using pharmacological inhibitors we demonstrated that both the peripheral nerve hyperexcitability (PNH) and the increased AHP were mostly mediated by the decreased activity of Kv1-channels. Importantly, we corroborated these data at the molecular level. We observed a strong reduction of Kv1.2 channel presence in the juxtaparanodal regions of teased fibers in db/db mice as compared to control mice. Quantification of the amount of both Kv1.2 isoforms in DRG neurons and in the endoneurial compartment of peripheral nerve by Western blotting revealed that less mature Kv1.2 was integrated into the axonal membranes at the juxtaparanodes. Our observation that peripheral nerve hyperexcitability present in db/db mice is at least in part a consequence of changes in potassium channel distribution suggests that the same mechanism also mediates PNH in diabetic patients. ∗Current address: Department of Physiology, UCSF, San Francisco, CA, USA.

Médicaments et grossesse : modifications pharmacocinétiques et place du suivi thérapeutique pharmacologique [Pharmacokinetic Alterations in Pregnancy and Use of Therapeutic Drug Monitoring].

Following the thalidomide tragedy, pharmacological research in pregnant women focused primarily on drug safety for the unborn child and remains only limited regarding the efficacy and safety of treatment for the mother. Significant physiological changes during pregnancy may yet affect the pharmacokinetics of drugs and thus compromise its efficacy and/or safety. Therapeutic drug monitoring (TDM) would maximize the potential effectiveness of treatments, while minimizing the potential risk of toxicity for the mother and the fetus. At present, because of the lack of concentration-response relationship studies in pregnant women, TDM can rely only on individual assessment (based on an effective concentration before pregnancy) and remains reserved only to unexpected situations such as signs of toxicity or unexplained inefficiency.

Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array.

Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P=1.2×10(-8)). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4×10(-6)). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: <0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.