Contrast agent-enhanced, free-breathing, three-dimensional coronary magnetic resonance angiography.

For free-breathing, high-resolution, three-dimensional coronary magnetic resonance angiography (MRA), the use of intravascular contrast agents may be helpful for contrast enhancement between coronary blood and myocardium. In six patients, 0.1 mmol/kg of the intravascular contrast agent MS-325/AngioMARK was given intravenously followed by double-oblique, free-breathing, three-dimensional inversion-recovery coronary MRA with real-time navigator gating and motion correction. Contrast-enhanced, three-dimensional coronary MRA images were compared with images obtained with a T2 prepulse (T2Prep) without exogenous contrast. The contrast-enhanced images demonstrated a 69% improvement in the contrast-to-noise ratio (6.6 +/- 1.1 vs. 11.1 +/- 2.5; P < 0.01) compared with the T2Prep approach. By using the intravascular agent, extensive portions (> 80 mm) of the native left and right coronary system could be displayed consistently with sub-millimeter in-plane resolution. The intravascular contrast agent, MS-325/AngioMARK, leads to a considerable enhancement of the blood/muscle contrast for coronary MRA compared with T2Prep techniques. The clinical value of the agent remains to be defined in a larger patient series. J. Magn. Reson. Imaging 1999;10:790-799.

Managing hypertension in high-risk patients: lessons and promises from the STRATHE and ADVANCE trials.

Pharmacological treatment of hypertension represents a cost-effective way of preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment, blood pressure should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Such targets cannot usually be reached using monotherapies. This is especially true in patients who present with a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases the blood pressure control rate. Such combinations are not only efficacious, but are also well tolerated, and some fixed low-dose combinations even have a placebo-like tolerability. This is the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has been shown in controlled trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving the stiffness of large arteries. Using this combination to initiate antihypertensive therapy has been shown in a double-blind trial (Strategies of Treatment in Hypertension: Evaluation; STRATHE) to normalize blood pressure (< 140/90 mmHg) in significantly more patients (62%) than a sequential monotherapy approach based on atenolol, losartan and amlodipine (49%) and a stepped-care strategy based on valsartan and hydrochlorothiazide (47%), with no difference between the three arm groups in terms of tolerability. An ongoing randomized trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ADVANCE) is a study with a 2 x 2 factorial design assessing the effects of the fixed-dose perindopril-indapamide combination and of the intensive gliclazide modified release-based glucose control regimen in type 2 diabetic patients, with or without hypertension. A total of 11 140 patients were randomly selected. Within the first 6 weeks of treatment (run-in phase), the perindopril-indapamide combination lowered blood pressure from 145/81 +/- 22/11 mmHg (mean +/- SD) to 137/78 +/- 20/10 mmHg. Fixed-dose combinations are becoming more and more popular for the management of hypertension, and are even proposed by hypertension guidelines as a first-line option to treat hypertensive patients.

Prevalence of measured and reported multimorbidity in a representative sample of the Swiss population.

BACKGROUND: Little is known on the prevalence of multimorbidity (MM) in the general population. We aimed to assess the prevalence of MM using measured or self-reported data in the Swiss population. METHODS: Cross-sectional, population-based study conducted between 2003 and 2006 in the city of Lausanne, Switzerland, and including 3714 participants (1967 women) aged 35 to 75 years. Clinical evaluation was conducted by thoroughly trained nurses or medical assistants and the psychiatric evaluation by psychologists or psychiatrists. For psychiatric conditions, two definitions were used: either based on the participant's statements, or on psychiatric evaluation. MM was defined as presenting 805;2 morbidities out of a list of 27 (self-reported - definition A, or measured - definition B) or as the Functional Comorbidity Index (FCI) using measured data - definition C. RESULTS: The overall prevalence and (95% confidence interval) of MM was 34.8% (33.3%-36.4%), 56.3% (54.6%-57.9%) and 22.7% (21.4%-24.1%) for definitions A, B and C, respectively. Prevalence of MM was higher in women (40.2%, 61.7% and 27.1% for definitions A, B and C, respectively, vs. 28.7%, 50.1% and 17.9% in men, p < 0.001); Swiss nationals (37.1%, 58.8% and 24.8% for definitions A, B and C, respectively, vs. 31.4%, 52.3% and 19.7% in foreigners, all p < 0.001); elderly (>65 years: 67.0%, 70.0% and 36.7% for definitions A, B and C, respectively, vs. 23.6%, 50.2% and 13.8% for participants <45 years, p < 0.001); participants with lower educational level; former smokers and obese participants. Multivariate analysis confirmed most of these associations: odds ratio (95% Confidence interval) 0.55 (0.47-0.64), 0.61 (0.53-0.71) and 0.51 (0.42-0.61) for men relative to women for definitions A, B and C, respectively; 1.27 (1.09-1.49), 1.29 (1.11-1.49) and 1.41 (1.17-1.71) for Swiss nationals relative to foreigners, for definitions A, B and C, respectively. Conversely, no difference was found for educational level for definitions A and B and abdominally obese participants for all definitions. CONCLUSIONS: Prevalence of MM is high in the Lausanne population, and varies according to the definition or the data collection method.

Coronary artery disease screening in diabetic patients: how good is guideline adherence?

INTRODUCTION: Diabetic patients are at high risk for coronary artery disease (CAD), which is the leading cause of death in this population. The Swiss Society of Endocrinology-Diabetology (SSED) recommends CAD screening for diabetic patients with > or = 2 additional cardiovascular risk factors (CVRF), by stress echocardiography (SE) or myocardial perfusion imaging (MPI). The aim of this study was to assess the application of these guidelines and the treatment of CVRF in the diabetes outpatient clinics of the five Swiss University Hospitals. METHODS: The study was initiated in Lausanne and the study questionnaires were circulated to the endocrinologists of the five Swiss University Hospitals. Practitioners were asked to include consecutive patients attending the diabetes outpatient clinics over one month. Prevalence of CAD, screening methods for CAD, prevalence of CVRF, biological analyses over the last 6 months and medical therapy were recorded. RESULTS: A total of 302 subjects were included. The mean age was 53 +/- 14 years, 68% had type 2 diabetes, 27% type 1 and 5% other types. Among T2DM with > or = 2 CVRF, 45% were screened for CAD according to SSED guidelines. In T2DM 25% had blood pressure < or = 130/80 mm Hg, 15% a lipid profile within target, 23% HbA1c < or = 7.0%. Overall, 2% achieved all 3 targets. CONCLUSIONS: Only 45% of T2DM with > or = 2 CVRF were screened for CAD according to SSED guidelines and 2% of T2DM had proper control over all CVRF. Efforts are still necessary to improve CAD prevention and screening of diabetic patients in Swiss University Hospitals.

Les complications de la cirrhose hépatique: varices oesophagiennes, ascite et carcinome hépato-cellulaire [Complications of liver cirrhosis: oesophageal varices, ascites and hepato-cellular carcinoma]

The principal treatment for bleeding oesophageal varices is endoscopic ligation. Non-cardioselective beta-blockers are the gold-standard of primary prophylaxis. The principal treatment for ascites is a salt-free diet and diuretics, mainly spironolactone, if necessary associated with a loop diuretic. In refractory ascites, paracentesis or installation of a transjugular intrahepatic portosystemic shunt (TIPS) are two possible treatment options. Cirrhosis patients are at higher risk of developing hepato-cellular carcinoma. Surgery is only possible in a small number of cases. Percutaneous destruction techniques have nearly the same survival rate as that obtained by surgery and should be proposed to patients where surgery is not an option.

Comparison between a linear ion trap and a triple quadruple MS in the sensitive detection of large peptides at femtomole amounts on column.

In addition to the importance of sample preparation and extract separation, MS detection is a key factor in the sensitive quantification of large undigested peptides. In this article, a linear ion trap MS (LIT-MS) and a triple quadrupole MS (TQ-MS) have been compared in the detection of large peptides at subnanomolar concentrations. Natural brain natriuretic peptide, C-peptide, substance P and D-Junk-inhibitor peptide, a full D-amino acid therapeutic peptide, were chosen. They were detected by ESI and simultaneous MS(1) and MS(2) acquisitions. With direct peptide infusion, MS(2) spectra revealed that fragmentation was peptide dependent, milder on the LIT-MS and required high collision energies on the TQ-MS to obtain high-intensity product ions. Peptide adsorption on surfaces was overcome and peptide dilutions ranging from 0.1 to 25 nM were injected onto an ultra high-pressure LC system with a 1 mm id analytical column and coupled with the MS instruments. No difference was observed between the two instruments when recording in LC-MS(1) acquisitions. However, in LC-MS(2) acquisitions, a better sensitivity in the detection of large peptides was observed with the LIT-MS. Indeed, with the three longer peptides, the typical fragmentation in the TQ-MS resulted in a dramatic loss of sensitivity (> or = 10x).

Prediction of Recanalization Trumps Prediction of Tissue Fate: The Penumbra: A Dual-edged Sword.

BACKGROUND AND PURPOSE: To determine whether infarct core or penumbra is the more significant predictor of outcome in acute ischemic stroke, and whether the results are affected by the statistical method used. METHODS: Clinical and imaging data were collected in 165 patients with acute ischemic stroke. We reviewed the noncontrast head computed tomography (CT) to determine the Alberta Score Program Early CT score and assess for hyperdense middle cerebral artery. We reviewed CT-angiogram for site of occlusion and collateral flow score. From perfusion-CT, we calculated the volumes of infarct core and ischemic penumbra. Recanalization status was assessed on early follow-up imaging. Clinical data included age, several time points, National Institutes of Health Stroke Scale at admission, treatment type, and modified Rankin score at 90 days. Two multivariate regression analyses were conducted to determine which variables predicted outcome best. In the first analysis, we did not include recanalization status among the potential predicting variables. In the second, we included recanalization status and its interaction between perfusion-CT variables. RESULTS: Among the 165 study patients, 76 had a good outcome (modified Rankin score 804;2) and 89 had a poor outcome (modified Rankin score >2). In our first analysis, the most important predictors were age (P<0.001) and National Institutes of Health Stroke Scale at admission (P=0.001). The imaging variables were not important predictors of outcome (P>0.05). In the second analysis, when the recanalization status and its interaction with perfusion-CT variables were included, recanalization status and perfusion-CT penumbra volume became the significant predictors (P<0.001). CONCLUSIONS: Imaging prediction of tissue fate, more specifically imaging of the ischemic penumbra, matters only if recanalization can also be predicted.

The activity of the anti-apoptotic fragment generated by the caspase-3/p120 RasGAP stress-sensing module displays strict Akt isoform specificity.

The caspase-3/p120 RasGAP module acts as a stress sensor that promotes pro-survival or pro-death signaling depending on the intensity and the duration of the stressful stimuli. Partial cleavage of p120 RasGAP generates a fragment, called fragment N, which protects stressed cells by activating Akt signaling. Akt family members regulate many cellular processes including proliferation, inhibition of apoptosis and metabolism. These cellular processes are regulated by three distinct Akt isoforms: Akt1, Akt2 and Akt3. However, which of these isoforms are required for fragment N mediated protection have not been defined. In this study, we investigated the individual contribution of each isoform in fragment N-mediated cell protection against Fas ligand induced cell death. To this end, DLD1 and HCT116 isogenic cell lines lacking specific Akt isoforms were used. It was found that fragment N could activate Akt1 and Akt2 but that only the former could mediate the protective activity of the RasGAP-derived fragment. Even overexpression of Akt2 or Akt3 could not rescue the inability of fragment N to protect cells lacking Akt1. These results demonstrate a strict Akt isoform requirement for the anti-apoptotic activity of fragment N.

Medical treatment of hypertension in Switzerland. The 2009 Swiss Hypertension Survey (SWISSHYPE).

OBJECTIVES: Despite a broad and efficient pharmacological antihypertensive armamentarium, blood pressure (BP) control is suboptimal and heterogeneous throughout Europe. Recent representative data from Switzerland are limited. The goal of the present survey was therefore to assess the actual control rate of high BP in Switzerland in accordance with current guidelines. The influence of risk factors, target organ damage and medication on BP levels and control was also evaluated.METHODS : A cross-sectional visit-based survey of ambulatory hypertensive patients was performed in 2009 in Switzerland. 281 randomly selected physicians provided data on 5 consecutive hypertensive patients attending their practices for BP follow-up. Data were anonymously collected on demographics, comorbidities and current medication, and BP was recorded. Subsequent modification of pharmacological antihypertensive therapy was assessed.RESULTS : Data from 1376 patients were available. Mean age was 65 +/- 12 years, 53.9% were male subjects. 26.4% had complicated hypertension. Overall, BP control (<140/90 mm Hg for uncomplicated and <130/80 mm Hg for complicated hypertension) was achieved in 48.9%. Compared to patients with complicated hypertension, BP control was better in patients with uncomplicated hypertension (59.4% vs. 19.2%, p < 0.001). As a monotherapy the most prescribed drug class were angiotensin receptor blockers (ARB, 41%), followed by angiotensin converting enzyme (ACE) inhibitors (21.5%), betablockers (20.8%) and calcium channel blockers (CCB, 10.8%). The most prescribed drug combinations were ARB + diuretic (30.1%) and ACE inhibitors + diuretic (15.3%). 46% were receiving a fixed drug combination. In only 32.7% of patients with uncontrolled hypertension was a change in drug therapy made.CONCLUSION : This representative survey on treated adult hypertensive patients shows that, compared to earlier reports, the control rate of hypertension has improved in Switzerland for uncomplicated but not for complicated, particularly diabetes-associated hypertension. ARBs and ACE inhibitors are the most prescribed antihypertensive drugs for monotherapy, whereas diuretics and ARBs were the most used for combination therapy.

Secretory IgA: an actor of the interplay between the commensal flora and the intestinal immune system?

In the gastro-intestinal tract,Peyers patches have been describedas a major inductive site for mucosalsecretory IgA (SIgA) responses directedagainst pathogens. The classicalview is that SIgAserves as the firstline of defense against microorganismsby agglutining potential invadersand faciliting their clearance byperistaltic and mucociliary movements,a mechanism called immuneexclusion. Our laboratory has shownthat SIgA is not only able to be"retrotransported" into Peyers patchesvia the associated M cells, but also todeliver sizeable cargos in the form ofSIgA-based immune complexes, resultingin the onset of non-inflammatorytype of responses. Such a novelfunction raises the question of thepossible role of mucosal SIgA in theinterplay with commensal bacteriaand the contribution of the antibody inbacterial homeostasis. To address thisquestion, Lactobacillus rhamnosus(LPR) was administered into a mouseligated loop comprising a Peyerspatch, in association or not with SIgA.The fate of fluorescently labelled bacteriawas followed by laser scanningconfocal microscopy at different incubationtimes. After 2 hours of incubationin the loop, LPR bacteria arefound more abundantly in thesubepithelial dome (SED) regionwhen they are coated with SIgA thanLPR administered alone despite theyare absent from neighboring villi.Herein, it is shown that this mechanismof entry involves M cells inPeyers pathes. After their sampling byM cells, bacteria are engulfed by thedendritic cells of the subjacent SEDregion. Interestingly, LPR bacteriaare found coated by the endogenousnatural SIgA present in mice intestinalsecretions, confirming the requirementof SIgA for this type of entry.The subsequent effect on the maturationof dendritic cells after interactionwith LPR was investigated in vitroin presence or not of SIgA by measuringthe expression of CD40, CD80and CD86 surface markers with flowcytometry analyses. Results show thatDCs respond in the same way in presenceof SIgA than with LPR bacteriaalone, indicating that SIgA does notmodulate the interaction betweenDCs and bacteria in this context. Thiswork gives new evidences about theinvolvement of SIgA in the mechanismby which the intestinal immunesystem permanently checks the contentof the intestine.

The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials?

Pharmacological treatment of hypertension represents a cost-effective way for preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment blood pressure (BP) should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (&lt; 130/80 mmHg) if diabetes or renal disease co-exists. Most of the time such targets cannot be reached using monotherapies. This is especially true in patients who exhibit a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases BP control. Such preparations are not only efficacious, but also well tolerated, and some fixed low-dose combinations have a tolerability profile similar to placebo. This is for instance the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has recently been shown in controlled interventional trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving macrovascular stiffness. Fixed-dose combinations are becoming more and more popular and are even proposed by current hypertension guidelines as a first-line option to treat hypertensive patients.

The activity of the anti-apoptotic fragment generated by the caspase-3/p120 RasGAP stress-sensing module displays strict Akt isoform specificity.

The caspase-3/p120 RasGAP module acts as a stress sensor that promotes pro-survival or pro-death signaling depending on the intensity and the duration of the stressful stimuli. Partial cleavage of p120 RasGAP generates a fragment, called fragment N, which protects stressed cells by activating Akt signaling. Akt family members regulate many cellular processes including proliferation, inhibition of apoptosis and metabolism. These cellular processes are regulated by three distinct Akt isoforms: Akt1, Akt2 and Akt3. However, which of these isoforms are required for fragment N mediated protection have not been defined. In this study, we investigated the individual contribution of each isoform in fragment N-mediated cell protection against Fas ligand induced cell death. To this end, DLD1 and HCT116 isogenic cell lines lacking specific Akt isoforms were used. It was found that fragment N could activate Akt1 and Akt2 but that only the former could mediate the protective activity of the RasGAP-derived fragment. Even overexpression of Akt2 or Akt3 could not rescue the inability of fragment N to protect cells lacking Akt1. These results demonstrate a strict Akt isoform requirement for the anti-apoptotic activity of fragment N.

The mechanism of gentisic acid-induced relaxation of the guinea pig isolated trachea: the role of potassium channels and vasoactive intestinal peptide receptors

We examined some of the mechanisms by which the aspirin metabolite and the naturally occurring metabolite gentisic acid induced relaxation of the guinea pig trachea in vitro. In preparations with or without epithelium and contracted by histamine, gentisic acid caused concentration-dependent and reproducible relaxation, with mean EC50 values of 18 µM and Emax of 100% (N = 10) or 20 µM and Emax of 92% (N = 10), respectively. The relaxation caused by gentisic acid was of slow onset in comparison to that caused by norepinephrine, theophylline or vasoactive intestinal peptide (VIP). The relative rank order of potency was: salbutamol 7.9 > VIP 7.0 > gentisic acid 4.7 > theophylline 3.7. Gentisic acid-induced relaxation was markedly reduced (24 ± 7.0, 43 ± 3.9 and 78 ± 5.6%) in preparations with elevated potassium concentration in the medium (20, 40 or 80 mM, respectively). Tetraethylammonium (100 µM), a nonselective blocker of the potassium channels, partially inhibited the relaxation response to gentisic acid, while 4-AP (10 µM), a blocker of the voltage potassium channel, inhibited gentisic acid-induced relaxation by 41 ± 12%. Glibenclamide (1 or 3 µM), at a concentration which markedly inhibited the relaxation induced by the opener of ATP-sensitive K+ channels, levcromakalim, had no effect on the relaxation induced by gentisic acid. Charybdotoxin (0.1 or 0.3 µM), a selective blocker of the large-conductance Ca2+-activated K+ channels, caused rightward shifts (6- and 7-fold) of the gentisic acid concentration-relaxation curve. L-N G-nitroarginine (100 µM), a NO synthase inhibitor, had no effect on the relaxant effect of gentisic acid, and caused a slight displacement to the right in the relaxant effect of the gentisic acid curve at 300 µM, while methylene blue (10 or 30 µM) or ODQ (1 µM), the inhibitors of soluble guanylate cyclase, all failed to affect gentisic acid-induced relaxation. D-P-Cl-Phe6,Leu17[VIP] (0.1 µM), a VIP receptor antagonist, significantly inhibited (37 ± 7%) relaxation induced by gentisic acid, whereas CGRP (8-37) (0.1 µM), a CGRP antagonist, only slightly enhanced the action of gentisic acid. Taken together, these results provide functional evidence for the direct activation of voltage and large-conductance Ca+2-activated K+ channels, or indirect modulation of potassium channels induced by VIP receptors and accounts for the predominant relaxation response caused by gentisic acid in the guinea pig trachea.

Attraction to amino acids by Lymnaea acuminata, the snail host of Fasciola species

Adult Lymnaea acuminata (average length 20-22 mm) were collected locally from lakes and low-lying submerged fields from Gorakhpur. The chemoattraction studies were made in round glass aquaria measuring 30 cm in diameter and filled to a depth of 10 mm with 500 ml dechlorinated tap water. Each aquarium was divided into four concentric zones. At the starting time of the assay 10 snails were placed on the circumference of outermost zone 0. Snail attractant pellets (SAP) were added simultaneously in the center of central zone 3. SAP of different amino acids were prepared at concentrations of 10, 20, 50, 80 and 100 mM/2% agar solution and, subsequently, spread to a uniform thickness of 5 mm. After cooling, SAP were cut in small pieces of 5 mm in diameter. Lymnaea acuminata's attraction to amino acids was studied using different amino acid concentrations in SAP. Pellets containing amino acids with non-polar R groups (proline and tryptophan), a charged polar group (arginine) and uncharged polar R groups (serine, citrulline and asparagine) were tested. The snails were more attracted to the uncharged polar R group amino acid serine than to other groups of amino acids. The preferred amino acid concentration was 80 mM. The attraction of snails to different amino acids was concentration dependent. Snails could discriminate amongst the different amino acids at > or = 50 mM.

Modulatory effects of taurine on jejunal contractility

Taurine (2-aminoethanesulfonic acid) is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM) can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca2+dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic β receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic β receptors, and a nitric oxide associated relaxing mechanism.