[Results of in vitro fertilization in natural cycle or with mild stimulation]. / Résultats de la fécondation in vitro en cycle naturel ou avec une stimulation hormonale minimale.

Natural cycle, modified natural cycle and mild stimulation are different protocols which provide some advantages compared to conventional stimulation: lower medication cost, less injections, less invasive, low risk of ovarian hyperstimulation and multiple pregnancy. There main drawback is high cancellation rate due to premature ovulation and lack of egg recovery at the retrieval. When an embryo transfer can be performed, the cumulative pregnancy rate is similar to the results in con- ventional stimulation. Those protocols don't provide any advantage in term of results for woman with normal ovarian reserve, however it might be considered as a therapeutic alternative in poor responders.

High-sensitivity cardiac troponin T for detection of subtle abnormalities of cardiac phenotype in a general population of elderly individuals.

OBJECTIVE: To investigate the association between circulating cardiac biomarkers and minor abnormalities in cardiac phenotype [left ventricular (LV) mass and midwall fractional shortening (MFS)] in elderly individuals in a general population sample. DESIGN AND SETTING: We examined the relationship between plasma concentrations of high-sensitivity cardiac troponin T (hs-cTnT) or N-terminal probrain natriuretic peptide (NT-proBNP) and elevated LV mass (LV mass/body surface area >95 g m(-2) for women and 115 g m(-2) for men), reduced MFS (<15%) or isolated LV diastolic dysfunction in 1973 elderly subjects (mean age 73 ± 5 years, range 65-84) resident in the Lazio region of Italy and enrolled in the PREDICTOR study. RESULTS: Overall, 24.8% of subjects had elevated LV mass, and 30.4% had reduced MFS. Median [quartile 1-3] plasma concentrations of hs-cTnT and NT-proBNP were higher in individuals with elevated than those with normal LV mass: 6.6 [3.5-11.6] and 147 [64-296] ng L(-1) vs. 4.6 [3.0-8.1] and 79 [41-151] ng L(-1) respectively (P < 0.001). There was a graded increase in median hs-cTnT concentrations across clinical categories of LV hypertrophy: 4.6 [3.0-8.1], 5.8 [3.1-10.2], 7.6 [3.8-13.7] and 8.4 [3.8-17.6] ng L(-1) for subjects with normal LV mass and mild, moderate or severe LV hypertrophy respectively (P < 0.0001); hs-cTnT also increased with increasing quartiles of MFS or grades of isolated LV diastolic dysfunction. CONCLUSIONS: Within an extremely low range of concentrations, increased hs-cTnT amongst community-dwelling elderly subjects is associated with subtle alterations in cardiac phenotype, suggesting that minor injury to cardiac myocytes and subsequent release of troponin reflect subclinical pathophysiological LV deterioration in this population.

Ultrafast and widely tuneable vertical-external-cavity surface-emitting laser, mode-locked by a graphene-integrated distributed Bragg reflector.

We report a versatile way of controlling the unsaturated loss, modulation depth and saturation fluence of graphene-based saturable absorbers (GSAs), by changing the thickness of a spacer between a single layer graphene (SLG) and a high-reflection mirror. This allows us to modulate the electric field intensity enhancement at the GSA from 0 up to 400%, due to the interference of incident and reflected light at the mirror. The unsaturated loss of the SLG-mirror-assembly can be reduced to ∼0. We use this to mode-lock a vertical-external-cavity surface-emitting laser (VECSEL) from 935 to 981 nm. This approach can be applied to integrate SLG into various optical components, such as output coupler mirrors, dispersive mirrors or dielectric coatings on gain materials. Conversely, it can also be used to increase the absorption (up to 10%) in various graphene based photonics and optoelectronics devices, such as photodetectors.

Low repetition rate SESAM modelocked VECSEL using an extendable active multipass-cavity approach.

Ultrafast VECSELs are compact pulsed laser sources with more flexibility in the emission wavelength compared to diode-pumped solid-state lasers. Typically, the reduction of the pulse repetition rate is a straightforward method to increase both pulse energy and peak power. However, the relatively short carrier lifetime of semiconductor gain materials of a few nanoseconds sets a lower limit to the repetition rate of passively modelocked VECSELs. This fast gain recovery combined with low pulse repetition rates leads to the buildup of multiple pulses in the cavity. Therefore, we applied an active multipass approach with which demonstrate fundamental modelocking at a repetition rate of 253 MHz with 400 mW average output power in 11.3 ps pulses.

Gain characterization and passive modelocking of electrically pumped VECSELs.

Linear and nonlinear gain characterization of electrically pumped vertical external cavity surface emitting lasers (EP-VECSELs) is presented with spectrally resolved measurements of the gain and with gain saturation measurements of two EP-VECSEL samples with different field enhancement in the quantum-well gain layers. The spectral bandwidth, small-signal gain and saturation fluence of the devices are compared. Using the sample with the larger bandwidth, we have demonstrated the shortest pulses generated from a passively modelocked EP-VECSEL to date. With a low-saturation-fluence SESAM for passive modelocking we have achieved 9.5-ps pulses with 7.6 mW average output power at a repetition rate of 1.4 GHz. With a higher output coupler transmission the pulse duration was increased to 31 ps with an average output power of 13.6 mW. The pulses were chirped mainly due to the group delay dispersion (GDD) introduced by the intermediate DBR, which compensates the optical loss in the structure.

Venous reflux and venous distensibility in varicose and healthy veins.

OBJECTIVES: The aim of this study was to analyse venous diameter changes and venous reflux parameters, assessed during a standardised Valsalva manoeuvre in healthy subjects and in patients with varicose veins. METHODS: Measurements were carried out in 444 vein segments, (96 legs of 48 healthy volunteers, 52 legs of 35 patients with varicose veins). The common femoral vein (CVF), the femoral vein (FV) and the great saphenous vein (GSV) were investigated. The parameters of reflux and the relative venous diameter change (VD diff %) were measured simultaneously during a standardised Valsalva manoeuvre. RESULTS: Venous diameter changes during Valsalva manoeuvre (VD diff) were significantly greater in the GSV and in the deep veins of varicose patients compared to healthy subjects. The median (Interquartile range) of VD max in the CFV was: 13.1 (3.5) mm and 11.2 (3.4) mm (p=0.0002, Mann-Whitney - U test), in the FV 7.8 (2.7) mm and 6.9 (2.0) mm (p=0.01, Mann-Whitney), in the GSV: 7.3 (3.7) mm and 4.2 (1.1) mm (p<0.0001, Mann-Whitney) for the varicose and healthy veins respectively. Good correlation was seen for the retrograde peak reflux velocity (PRV) and VD diff % in varicose veins (r=0.71 (0.57 - 0.81) p<0.0001, Mann-Whitney). CONCLUSION: Relative venous diameter--changes during a standardised Valsalva manoeuvre are significantly larger in the deep and superficial veins of varicose vein patients compared with healthy veins, the increased distensibility correlates with venous reflux parameters in varicose vein patients.

[Pharmacological basis of antihypertensive drug therapy]. / Pharmakologische Grundlagen der medikamentösen antihypertensiven Therapie.

In order to lower arterial blood pressure, antihypertensive drugs decrease cardiac output, total peripheral resistance or both. Diuretics, beta-blockers, and central adrenergic inhibitors decrease cardiac output. ACE inhibitors, angiotensin II antagonists, calcium antagonists, alpha-blockers, central adrenergic inhibitors, and after a delay also diuretics and beta-blockers decrease peripheral resistance. Diuretics are first line therapy for treating low renin hypertension. Beta blockers are used for treating high renin hypertension and patients suffering additional coronary artery disease. ACE inihibitors can be given for treating high renin hypertension particularly in conjunction with diabetes, heart failure or left ventricular hypertrophy. Combining ACE inhibitors with diuretics potentiates the antihypertensive effect. Angiotensin II antagonists exert fewer side effects and better renal protection than ACE inhibitors. The main indication for calcium antagonists is low renin hypertension, their advantages being strong blood pressure reduction as well as in preventing stroke. Central alpha2 receptor agonists and other vasodilators are chosen only in selected cases and mostly in combination with other antihypertensive drugs.

Myocardial function and energy metabolism in carnitine-deficient rats.

Carnitine is essential for mitochondrial metabolism of long-chain fatty acids and thus for myocardial energy production. Accordingly, carnitine deficiency can be associated with cardiomyopathy. To better understand this disease, we determined myocardial function and energy metabolism in a rat model of carnitine deficiency. Carnitine deficiency was induced by a 3- or 6-week diet containing N-trimethyl-hydrazine-3-propionate, reducing cardiac and plasma carnitine by 70-85%. Myocardial function was investigated in isolated isovolumic heart preparations. Carnitine-deficient hearts showed left ventricular systolic dysfunction, reduced contractile reserve, and a blunted frequency-force relationship independently of the substrate used (glucose or palmitate). After glycogen depletion, palmitate could not sustain myocardial function. Histology and activities of carnitine palmitoyl transferase, citrate synthase, and cytochrome c oxidase were unaltered. Thus, as little as 3-6 weeks of systemic carnitine deficiency can lead to abnormalities in myocardial function. These abnormalities are masked by endogenous glycogen and are not accompanied by structural alterations of the myocardium or by altered activities of important mitochondrial enzymes.

[Common biostatistical errors in clinical studies]. / Häufige Fehler in der Biostatistik medizinischer Studien.

Roughly half to two third of all published biomedical studies that use statistical methods contain unacceptable errors. The present article points at common errors that may be avoided without requiring profound statistical knowledge. These errors mainly concern the minimal number of patients and sample size (statistical power), agreement between aim and conclusion, distribution of data as well as description of location and variability of data. An analysis of 150 papers in the New England Journal of Medicine and in Circulation demonstrates that these errors can also commonly be found in respected journals after statistical peer review. Editors of biomedical journals could reduce the problem by means of statistical guidelines.

[Circadian rhythm of cardiovascular emergencies]. / Zirkadiane Rhythmen bei kardiovaskulären Notfällen.

Many cardiovascular emergencies occur predominantly in the morning hours. This diurnal distribution is due to synchronized exogenous and endogenous rhythms, the latter being controlled by a biological clock. In the morning, these rhythms raise blood pressure, heart rate, platelet aggregability, coronary vascular tone and thus, increase the risk of cardiovascular events.

When calcium turns arrhythmogenic: intracellular calcium handling during the development of hypertrophy and heart failure.

Alterations of intracellular Ca2+ handling in hypertrophied myocardium have been proposed as a mechanism of ventricular tachyarrhythmias, which are a major cause of sudden death in patients with heart failure. In this review, alterations in intracellular Ca2+ handling and Ca2+ handling proteins in the development of myocardial hypertrophy and the transition to heart failure are discussed. The leading question is at what stage of hypertrophy or heart failure Ca2+ handling can turn arrhythmogenic. During the development of myocardial hypertrophy and the transition to failure, Ca2+ handling is progressively altered. Recordings of free myocyte Ca2+ concentrations during a cardiac cycle (Ca2+ transients) are prolonged early in the development of hypertrophy. However, resting (or diastolic) Ca2+ does not increase before end-stage heart failure has developed. These alterations are due to progressively defective Ca2+ uptake into the sarcoplasmic reticulum that seems to be caused by quantitative changes of gene expression of the Ca2+ ATPase of the sarcoplasmic reticulum. Increased expression and activity of the Na+/Ca2+ exchanger might compensate for this defective Ca2+ uptake, probably at the expense of increased arrhythmogenicity. When the Ca2+ handling proteins no longer efficiently counterbalance increasing intracellular Ca2+ - during stress conditions, resulting Ca2+ overload can lead to spontaneous intracellular Ca2+ oscillations, after depolarizations. Thus, after the transition to heart failure, Ca2+ overloaded sarcoplasmic reticulum, increasing resting intracellular Ca2+, and increased Na+/Ca2+ activity may all provoke afterdepolarizations, triggered activity, and finally, life-threatening ventricular arrhythmias. This increased susceptibility to ventricular arrhythmias in heart failure should not be treated with calcium antagonists.

Combined blockade of endothelin-1 and thromboxane A(2) receptors against postischaemic contractile dysfunction in rat hearts.

1. Endothelin-1 (ET-1) may play a role in myocardial ischaemia/reperfusion injury because both the release and vasoconstrictor effect of ET-1 are increased after ischaemia. Since the increased vasoconstrictor effect of ET-1 can be mediated by ET-1-induced release of thromboxane A(2) (TXA(2)), the aim of this study was to test whether combined blockade of ET and TXA(2) receptors protects the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion. 2. Bosentan (antagonist for ET(A) and ET(B) receptors, 1 microM based on concentration-response curves of ET-1), SQ 30,741 (antagonist of TXA(2) receptors, 0.1 microM), or the combination thereof was administered to isolated perfused rat hearts undergoing 15 min of global ischaemia and 60 min of reperfusion. 3. Neither bosentan or SQ 30,741 alone, nor the combination thereof, improved the incomplete postischaemic recovery of coronary flow, left ventricular developed pressure, phosphocreatine, or ATP. However, they attenuated ischaemia-induced acidosis but this did not translate into a measurable effect on haemodynamic or metabolic variables. 4. Thus, combined blockade of ET and TXA(2) receptors does not protect the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion in isolated perfused rat hearts. This finding suggests that neither ET-1 nor ET-1-induced release of TXA(2) play a major role in the postischaemic recovery of the cardiac contractile function and energy metabolism.

Secreted aspartic proteinase family of Candida tropicalis.

Medically important yeasts of the genus Candida secrete aspartic proteinases (Saps), which are of particular interest as virulence factors. Like Candida albicans, Candida tropicalis secretes in vitro one dominant Sap (Sapt1p) in a medium containing bovine serum albumin (BSA) as the sole source of nitrogen. Using the gene SAPT1 as a probe and under low-stringency hybridization conditions, three new closely related gene sequences, SAPT2 to SAPT4, encoding secreted proteinases were cloned from a C. tropicalis lambdaEMBL3 genomic library. All bands identified by Southern blotting of EcoRI-digested C. tropicalis genomic DNA with SAPT1 could be assigned to a specific SAP gene. Therefore, the SAPT gene family of C. tropicalis is likely to contain only four members. Interestingly, the SAPT2 and SAPT3 gene products, Sapt2p and Sapt3p, which have not yet been detected in C. tropicalis cultures in vitro, were produced as active recombinant enzymes with the methylotrophic yeast Pichia pastoris as an expression system. As expected, reverse transcriptase PCR experiments revealed a strong SAPT1 signal with RNA extracted from cells grown in BSA medium. However, a weak signal was obtained with all other SAPT genes under several conditions tested, showing that these SAPT genes could be expressed at a basic level. Together, these experiments suggest that the gene products Sapt2p, Sapt3p, and Sapt4p could be produced under conditions yet to be described in vitro or during infection.

Accuracy of biplane analysis of left ventricular ejection fraction based on two consecutive single plane studies.

BACKGROUND AND PURPOSE: Mainly due to the high costs of biplane equipment many cardiac laboratories run single plane angiographic equipment only. Consequently, a biplane ventriculogram may only be done with two consecutive single plane studies. The aim of this investigation was to assess the accuracy of a biplane analysis of two consecutive single plane studies. METHODS: A total of 42 patients (62 +/- 10 years, 76% males), able to tolerate two consecutive ventriculograms without arrhythmia during the first study underwent two consecutive biplane studies (LAO 60, RA0 30), using 40 ml of contrast each. After the first injection, the x-ray tube was moved in a neutral position, and then was replaced in the 30 RAO/60 LAO position. Digital data was analyzed by two separate investigators using commercially available software. RESULTS: Intra-observer variability of left ventricular ejection fraction (LVEF) showed a high degree of agreement (single plane 1 vs. 2: r = 0.98; standard error of regression (Sy.x.): 2.8); the variability was slightly higher with two investigators (single plane: r = 0.92, Sy.x: 5.5 ) and with biplane analysis (biplane 1 vs. 2: r = 0.90, Sy. x: 5.7). End-diastolic volume index (EDVI) increased significantly from the first to the second study (84 +/- 28 ml/m2 vs 87 +/- 30 ml/m2; p = 0.017): Still LVEF of the two consecutive biplane studies showed very good agreement (biplane 1 vs. 2: mean difference (MD), -1.0; standard deviation of the difference (SDD), 5.2%). This agreement was almost as good as the one of LVEF values calculated from two consecutive single plane, but biplane analyzed studies compared to simultaneous biplane studies (MD, -0.5; SDD, 4.3%). CONCLUSION: Despite the significant increase in EDVI after contrast injection, LVEF values determined from two consecutive studies remained virtually unchanged. Biplane analysis of LVEF values based on consecutive single plane studies resulted in similar and reliable values as determined by two consecutive biplane studies.

Bradykinin-dependent cardioprotective effects of losartan against ischemia and reperfusion in rat hearts.

It is unclear whether losartan, an angiotensin II type 1 (AT1) receptor antagonist, protects the heart against acute ischemia-reperfusion injury. Therefore we evaluated cardiac protection conferred by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, we sought to determine both the extent of this protection and its dependence on bradykinin in comparison with quinaprilat, a cardioprotective angiotensin-converting enzyme inhibitor. Cardiac protection was assessed as recovery of coronary flow, left ventricular developed pressure, phosphocreatine, and adenosine triphosphate (ATP) in isolated perfused rat hearts after 15 min of global ischemia and 30 min of postischemic reperfusion. We found that, in hearts pre- and postischemically treated with losartan (1 microM) or quinaprilat (0.1 microM), these variables all recovered significantly better than those in untreated control hearts. In hearts that were only postischemically treated with losartan, these variables also recovered significantly better than those in control hearts. In contrast, in hearts treated with the combination of the bradykinin B2 receptor antagonist Hoe 140 with quinaprilat or losartan, the recovery of the variables no longer differed from that in control hearts. In conclusion, losartan protects the heart against acute ischemia-reperfusion injury. This protection can be achieved by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, the extent of this protection is equivalent to that conferred by quinaprilat and, unexpectedly, dependent on bradykinin.

Detection of protein truncating mutations in exons 1-14 of the APC gene using an in vivo fusion protein assay. Mutations in brief no. 214. Online.

About 80% of the mutations identified to date in the Adenomatous Polyposis Coli (APC) gene have been found in the 5' half of the coding sequence, the vast majority of which (>95%) are nonsense or frameshift mutations that result in the loss of the carboxyl terminus of APC protein. Using a stop codon assay in yeast recently developed by others (Ishioka et al., 1997), we have screened the 5' half of the APC gene for mutations in 7 unrelated families affected with Familial Adenomatous Polyposis. The assay relies on the expression of a yeast reporter gene fused in frame to one of 3 contiguous segments of the APC open reading frame. Here we report on the detection by this assay of 5 germline mutations, 4 of which lie upstream of exon 15, where lesions appear to be sometimes difficult to detect by standard methods.

Ventricular fibrillation-induced intracellular Ca2+ overload causes failed electrical defibrillation and post-shock reinitiation of fibrillation.

Despite high efficacy, electrical defibrillation shocks can fail or ventricular fibrillation (VF) is reinitiated after the application of the initial shock. The goal of this study was to determine whether [Ca2+]i overload, induced by VF itself, can cause failed electrical defibrillation and post-shock reinitiation of VF. For this purpose, we simultaneously measured [Ca2+]i transients (assessed by indo-1 fluorescence) and defibrillation energies (assessed by a modified implantable cardioverter defibrillator) in intact perfused rat hearts during pacing-induced sustained VF (10 min) in the absence of ischemia. We found that increasing [Ca2+]i during VF (by increasing [Ca2+]o from 3 to 6 mM) increased the defibrillation threshold (DFT) from 1.9 +/- 0.6 to 3.5 +/- 0.5 J/g (P<0.05) and also increased the total defibrillation energy (TDE) required for stabilization of sinus rhythm from 15.6 +/- 7.7 to 48.6 +/- 7.42 J/g (P<0.05). In addition, both DFT and TDE correlated linearly with [Ca2+]i (r=0.69 and 0.83, P<0.05). Furthermore, shortening the duration of VF from 10 to 1.5 min tended to limit [Ca2+]i overload and decreased TDE. Finally, all successful defibrillation shocks led to a sudden reduction of VF-induced [Ca2+]i overload (-115 +/- 3%). In contrast, failed shocks did not alter [Ca2+]i. Incomplete reduction of [Ca2+]i overload after initially successful shocks were often followed by synchronized spontaneous [Ca2+]i oscillations and subsequent reinitiation of VF. In conclusion, the present study showed for the first time that VF-induced [Ca2+]i overload can cause failed electrical defibrillation and post-shock reinitiation of VF. Because VF inevitably causes [Ca2+]i overload, this finding might be a crucial mechanism of failed defibrillation and spontaneous reinitiation of VF.

Intracellular Ca2+ handling and vulnerability to ventricular fibrillation in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) with ventricular hypertrophy show an increased vulnerability for the development of potentially lethal ventricular arrhythmias such as ventricular fibrillation (VF). The mechanisms of this increased vulnerability are not fully understood but may be related to abnormal intracellular Ca2+ ([Ca2+]i) handling under stress conditions. We therefore investigated whether [Ca2+]i handling is abnormal in hypertrophied hearts of SHR without heart failure during stimulation stress, and if so whether abnormal [Ca2+]i handling is a determinant of the increased vulnerability to VF in SHR. [Ca2+]i was measured by indo-1 surface fluorescence in perfused hearts of 8- to 10-month-old control Wistar-Kyoto rats (WKY) and age-matched SHR. The state of [Ca2+]i handling was analyzed during three different forms of stimulation stress: rapid pacing, the long rest period after cessation of rapid pacing, and preprogrammed ventricular stimulation that was simultaneously used for the determination of VF threshold. The pulse number VF threshold was used as an index to determine vulnerability to VF and to analyze the relationship of [Ca2+]i handling to vulnerability. Although VF thresholds were lower in SHR than in WKY, we found that both demonstrated similar [Ca2+]i handling during stimulation stress. The extent and rate of [Ca2+]i accumulation during rapid pacing and those of the [Ca2+]i decline after cessation of pacing were similar in SHR and WKY. In addition, the relationship between [Ca2+]i and VF threshold was unaltered in SHR. Thus, we conclude that [Ca2+]i handling is normal in hypertrophied hearts of SHR without heart failure during stimulation stress and that it is not a determinant of the increased vulnerability to VF in SHR.