How to calculate left ventricular mass in routine practice? An echocardiographic versus cardiac magnetic resonance study.

BACKGROUND: An accurate assessment of left ventricular (LV) mass is important for the detection of LV hypertrophy. AIMS: To assess the accuracy of four echocardiographic imaging modalities for assessing LV mass compared with cardiac magnetic resonance (CMR). METHODS: We prospectively studied 40 consecutive patients, who underwent an echocardiographic examination using four imaging modalities (M-mode fundamental imaging [FI], M-mode harmonic imaging [HI], two-dimensional [2D] FI and 2D HI) and CMR (our gold standard for LV mass measurement). All echocardiographic measurements were performed by two independent observers. RESULTS: All echocardiographic modes significantly overestimated LV mass compared with CMR (P≤0.04), except 2D FI (P=0.25). This overestimation was significantly higher with HI (up to 15.5%) compared with FI (up to 5.7%; P≤0.04). Significant correlations were observed between the different echocardiographic methods and the two observers. The interobserver agreement over LV mass measurement was lower with FI (intraclass coefficient [ICC] range, 0.66-0.73) than with HI (ICC range, 0.72-0.82), and the best agreement was obtained with 2D HI (ICC, 0.82). Good agreement between CMR and all echocardiographic methods was observed among the smallest LV diameters (ICC range, 0.62-0.85), but not among the largest LV diameters (ICC range, 0-0.22). CONCLUSIONS: HI overestimates LV mass compared with FI and CMR; this leads to overestimation of prevalence of LV hypertrophy in a population of hypertensive patients. HI improves interobserver reproducibility of LV mass measurement compared with FI, leading to a significant decrease in the number of patients required for clinical trials evaluating LV mass regression. Accuracy of LV mass measurement by echocardiography is affected by LV geometry.

Anemia normalization in patients with type 2 diabetes and chronic kidney disease: results of the NEPHRODIAB2 randomized trial.

STATEMENTS OF THE PROBLEM: Correction of anemia in type 2 diabetes (T2DM) patients with chronic kidney disease stages 3-4 may slow the decline of kidney function but may increase cardiovascular risk through higher hematocrit. The NEPHRODIAB2 study was designed to assess efficacy and safety of complete hemoglobin (Hb) normalization in these patients. METHODS: We randomly assigned 89 T2DM patients with an estimated glomerular filtration rate (eGFR; abbreviated 175 Modification of Diet in Renal Disease formula) of 25 to 60 ml/min per 1.73 m(2) and moderate anemia (Hb, 100-129 g/l) to a target Hb value in subnormal range (110-129g/l, group 1, n=43) or normal range (130-149 g/l, group 2, n=46). The primary end point was eGFR decline after 2 years of follow-up. Secondary end points included iron and erythropoietin dosage, quality of life (Medical Outcomes Study 36-item Short-Form Health Survey scores) and adverse events. RESULTS: Six months after randomization, the mean Hb levels were <120 g/l in group 1 and >130 g/l in group 2 (P<.05 at 6, 12, 18 and 24 months). Blood pressure, 24-h proteinuria and HbA1c did not differ during follow-up (P>.05). Two-year declines in eGFR were -8.7±12.2 in group 1 and -5.1±7.8 ml/min per 1.73 m(2) in group 2 (P=.29). Mean weekly use of erythropoietin was 7.8±11.6 µg in group 1 and 30.1±33.6 µg in group 2 (P<.0001). There was no significant difference regarding Medical Outcomes Study 36-item Short-Form Health Survey score change or adverse event occurrence. CONCLUSIONS: In this trial, normalization of Hb level in T2DM patients with chronic kidney disease was safe but did not significantly slow renal function decline and increased treatment cost due to erythropoietin use.

Colectomia eletiva laparoscópica esquerda para a doença diverticular: estudo monocêntrico sobre 205 pacientes consecutivos / Elective laparoscopic left colectomy for diverticular disease: a monocentric study on 205 consecutive patients

RACIONAL: O aumento da prevalência de doença diverticular tornou o seu manuseio mais adequado uma questão de debate constante. Especialmente para os casos de diverticulite, progresso considerável tem sido feito em termos de diagnóstico e tratamento. A ressecção cirúrgica do cólon envolvido é a única maneira de erradicar definitivamente essa condição e, portanto, a colectomia laparoscópica eletiva surgiu como uma opção segura e interessante entre as várias formas de tratamento. OBJETIVO: Analisar os resultados das colectomias laparoscópicas esquerdas para a doença diverticular realizadas durante um período de 17 anos em uma única instituição. MÉTODOS: Entre abril de 1990 e maio de 2007, um total de 205 colectomias consecutivas esquerdas laparoscópicas foram revistas retrospectivamente. Os dados obtidos incluíram o pré-operatório, indicações para a operação, os dados cirúrgicos, complicações e seguimento. Análises estatísticas univariada e multivariada foram realizadas em um esforço para identificar os fatores de risco e efeitos adversos na série. RESULTADOS: As indicações foram diverticulite aguda (80 por cento) não-complicada, diverticulite aguda ou crônica complicada (18,05 por cento) e sangramento na doença diverticular (1,95 por cento). A taxa de conversão foi de 5,85 por cento (12 casos). A mediana do tempo operatório foi de 180 minutos (100-420), com internação hospitalar de 7 (5-44) dias. O comprimento médio do espécime ressecado foi 29,12 centímetros. A maioria dos casos (88,3 por cento) teve curso pós-operatório normal, mas complicações ocorreram em 24 (11,7 por cento) pacientes. Em ordem de frequência foram: íleo paralítico (n = 6), coleções pélvica (n = 4), obstruções intestinais (n = 4) e fístulas (n = 2), entre outros. Re-operação foi necessária em oito casos e houve um óbito (0,48 por cento). O seguimento mediano foi de 26,5 (1-156) meses, com resultado satisfatório em 179 (87,32 por cento) dos pacientes. Em 18 (8,78 por cento) casos...

BACKGROUND: The increased prevalence of diverticular disease has made its most appropriate management a matter of constant debate. Especially for the cases of diverticulitis, considerable progress has been made in terms of diagnosis and management. The surgical resection of the involved colon is the only means of definitely eradicate this condition and so, the elective laparoscopic colectomy has emerged as a safe and interesting choice among the options of treatment. AIM: To analyze the outcomes of the laparoscopic left colectomy for diverticular disease performed over a 17-year period at a single institution. METHODS: Between April 1990 and May 2007, a total of 205 consecutive left laparoscopic colectomies were retrospectively reviewed. Data obtained included the pre-operative work-up, indications for surgery, operative results, complications and follow-up. Univariate and multivariate statistical analyzes were performed in an effort to identity risk factors for adverse outcomes in the series. RESULTS: Indications were for non-complicated acute diverticulitis (80 percent), acute or chronic complicated diverticulitis (18.05 percent) and bleeding diverticular disease (1.95 percent). The conversion rate was 5.85 percent (12 cases). The median operative time was 180 (100-420) min with a hospital stay of 7 (5-44) days. The mean length of the resected specimen was 29.12 (+8.2) cm. Most cases (88.3 percent) had an unremarkable postoperative course but complications occurred in 24 (11.7 percent) patients. In order of frequency, these were: paralytic ileus (n=6), pelvic collections (n=4), bowel obstructions (n=4) and fistulas (n=2), among others. A re-operation was necessary in eight cases and there was one death (0.48 percent). Median follow-up was 26.5 (1-156) months with a satisfying result seen in 179 (87.32 percent) of the patients. In 18 (8.78 percent) cases, persistent symptoms of functional colonic disorders were noted. There were 7 (3.41 percent)...

No effect of a homoeopathic combination of Arnica montana and Bryonia alba on bleeding, inflammation, and ischaemia after aortic valve surgery.

AIMS: " Arnica montana is a popular homoeopathic treatment with potential haemostatic and anti-inflammatory properties. A homoeopathic combination of A. montana and Bryonia alba was used in aortic valve surgery to evaluate its effectiveness in reducing bleeding, inflammation, pain and myocardial ischaemia. METHODS: One day before surgery, 92 adult patients were randomly assigned to a double-blind parallel trial with either homoeopathic granules or a matching placebo until 4 days after surgery. The primary outcome was the volume of blood/liquid in the drains at their removal. The secondary outcomes included postoperative blood/liquid losses at 12 and 24 h as well as C-reactive protein (CRP), pain, temperature and plasma troponin Ic. RESULTS: At 12 h and 24 h after surgery, then at drain removal, blood losses in homoeopathy and placebo groups were not statistically significant (362 +/- 218, 520 +/- 269 and 640 +/- 297 ml vs. 456 +/- 440, 620 +/- 477 and 796 +/- 717 ml; P= 0.19, 0.23 and 0.35, respectively). The statistical modelling did not show significantly different patterns of CRP, troponin and body temperature changes or of pain perception. The number of transfused packed red cells was not significantly different either (P= 0.58). Two patients from each group died during the study period and the number of serious adverse events was not statistically different (six in homoeopathy vs. 10 in placebo groups; Fisher's exact test P= 0.41). CONCLUSIONS: In the study setting, there was no evidence of effects of A. montana and B. alba combination on bleeding, inflammation, pain or myocardial ischaemia.

Self-perception of quality of life by adolescents with neuromuscular diseases.

PURPOSE: Little is known about quality of life of adolescents with neuromuscular diseases or the factors that influence it. We searched whether physical impairment, physical disability, and medical complications were predictors of low quality of life. METHODS: Motor function, health, orthopedic status, and rehabilitation were assessed in 43 adolescents with neuromuscular diseases (mean age, 13.8 years, standard deviation 1.7 year; sex ratio 2.9/1). Quality of life was measured with the VSP-A ("Vécu Santé Perçu par l'Adolescent"; self-perceived health state in adolescents), a validated health-related quality of life self-perception test. A mixed linear regression related quality of life to impairment, disability, and respiratory status. Comparisons were made with results from an age/sex-matched nondisabled group. RESULTS: On the average, the VSP-A scores in physically disabled adolescents were: (1) similar to those of the nondisabled group with regard to vitality, body image, relationships with parents and friends, and physical and psychological well-being; (2) higher with regard to school performance (score 68 vs. 52.8) and relationships with teachers (67.4 vs. 43.2); and (3) lower with regard to leisure activities (43.9 vs. 60.9). Physical disability and physical impairment were not negatively associated with seven of the nine VSP-A dimensions, but physical impairment was negatively associated with leisure activities and vitality (p < .001 and p < .01, respectively). Adolescents with ventilatory support did not express lower scores than adolescents not requiring ventilatory support (67.7+/-11 vs. 62.9+/-15, p=.39). CONCLUSIONS: These surprising results should lead us question our medical, educational, and rehabilitation practices. Already well-managed disabled adolescents should benefit from less compassionate but more daring and dynamic interpersonal contacts.

A beat-by-beat cardiovascular index, CARDEAN: a prospective randomized assessment of its utility for the reduction of movement during colonoscopy.

BACKGROUND: We sought to determine whether online use of a beat-by-beat cardiovascular index, CARDEAN (Alpha-2, Lyon, France), modifies the incidence of patient movement during colonoscopy under anesthesia. METHODS: Monitoring included an electrocardiogram, oscillometric and noninvasive beat-by-beat arterial blood pressure, O2 saturation, bispectral index (BIS), and CARDEAN. CARDEAN consists of beat-by-beat Finapres (Ohmeda, Madison, WI) combined with an algorithm that detects hypertension followed by tachycardia and produces an index scaled 0 to 100. The anesthesiologist was denied access to Finapres and CARDEAN. Propofol was adjusted to keep 4060. The primary outcome was the number of observed movements. RESULTS: Data were analyzed in 146 patients (control: 75; CARDEAN: 71). The doses of propofol and alfentanil were similar in both groups. When BIS was <60, movements were less frequent in the CARDEAN group (3.3 movements/100 min [2.3-4.8]) than in the control group (6.7 [5.3-8.5]) (odds ratio: 0.5 [0.32; 0.76], P = 0.001). During the first 10 minutes of the procedure, the incidence of movements was 38% and 59% in the CARDEAN and control groups, respectively (P = 0.04). CONCLUSION: With BIS <60, CARDEAN-guided opioid administration is associated with a reduction of 51% of clinically unpredictable movements in unparalyzed patients undergoing colonoscopy. More studies are required to refine the role of CARDEAN in surgical settings.

A positioning pillow to improve lumbar puncture success rate in paediatric haematology-oncology patients: a randomized controlled trial.

BACKGROUND: Lumbar punctures (LPs) are common in children with cancer. Although pain management during the lumbar puncture has been well standardized, dealing with stress and anxiety is not well addressed yet. Our objective was to evaluate the potential improvement of the LP success rate using a positioning pillow, to ensure maximum lumbar flexion, and allow paravertebral muscles to relax, in children who are awake, with either conscious sedation or no sedation. METHODS: Children aged 2-18 years undergoing LP were randomly assigned to a positioning pillow or no intervention. The primary outcome was the rate of success, i.e. achieving the LP (sampling or injection) at the first attempt, without bleeding (RBC < 50/mm3). The secondary outcomes included: the child's pain, assessed by a self-administered visual analogical scales (VAS) for children over 6 years of age; the parents' and caregivers' perception of the child's pain; the satisfaction of the children, the parents, the caregivers and the physician. The child's cooperation and the occurrence of post-LP syndrome were also evaluated. RESULTS: 124 children (62 in each group) were included. The LP pillow tended to increase the success rate of LPs (67% vs. 57%, p = 0.23), and decreased the post-LP syndromes (15% vs. 24%, p = 0.17) but the differences were not statistically significant. In children over 6-year of age (n = 72), the rate of success was significantly higher in the pillow group (58.5% vs. 41.5%, p = 0.031), with a tendency to feel less pain (median VAS 25 vs. 15 mm, p = 0.39) and being more satisfied (84.4% vs. 75.0%, p = 0.34). CONCLUSION: Overall results do not demonstrate a benefit in using this pillow for lumbar punctures. This study results also suggest a benefit in the sub group of children over 6-year of age; this result needs confirmation.

Evaluation of T2-weighted and dynamic contrast-enhanced MRI in localizing prostate cancer before repeat biopsy.

We assessed the accuracy of T2-weighted (T2w) and dynamic contrast-enhanced (DCE) 1.5-T magnetic resonance imaging (MRI) in localizing prostate cancer before transrectal ultrasound-guided repeat biopsy. Ninety-three patients with abnormal PSA level and negative prostate biopsy underwent T2w and DCE prostate MRI using pelvic coil before repeat biopsy. T2w and DCE images were interpreted using visual criteria only. MR results were correlated with repeat biopsy findings in ten prostate sectors. Repeat biopsy found prostate cancer in 23 patients (24.7%) and 44 sectors (6.6%). At per patient analysis, the sensitivity, specificity, positive and negative predictive values were 47.8%, 44.3%, 20.4% and 79.5% for T2w imaging and 82.6%, 20%, 24.4% and 93.3% for DCE imaging. When all suspicious areas (on T2w or DCE imaging) were taken into account, a sensitivity of 82.6% and a negative predictive value of 100% could be achieved. At per sector analysis, DCE imaging was significantly less specific (83.5% vs. 89.7%, p < 0.002) than T2w imaging; it was more sensitive (52.4% vs. 32.1%), but the difference was hardly significant (p = 0.09). T2w and DCE MRI using pelvic coil and visual diagnostic criteria can guide prostate repeat biopsy, with a good sensitivity and NPV.

N-terminal pro-brain natriuretic peptide--a promising biomarker for the diagnosis of left ventricular hypertrophy in hypertensive women.

INTRODUCTION: No agreement has been reached regarding the best strategy to detect left ventricular hypertrophy (LVH). This study examined the role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the diagnosis of LVH in hypertensive patients and the potential factors that may influence its diagnostic performance. METHODS: The global accuracy of NT-proBNP in diagnosing LVH was assessed using a receiver-operating characteristic (ROC) curve. The influence of patients' characteristics on test accuracy was studied with a ROC regression based on a probit model. Ninety-three subjects were included. All had NT-proBNP measured and underwent electrocardiography and echocardiography, with calculation of the left ventricular mass index (LVMI). RESULTS: The diagnostic performance of NT-proBNP in LVH varied slightly depending on the indexation mode of LVMI. In cases of body surface area indexation, the area under the ROC curve of 81.6% suggested a good performance. The accuracy of the marker was significantly higher in women than in men (p<0.0001). There were no significant effects of age, treatment, body mass index, left ventricular mass index, 24-h systolic blood pressure, or creatinine clearance on the test performance. Slight differences were observed when an indexation to height(2.7) instead of body surface area was used. CONCLUSIONS: The present results may lead to a new strategy for risk stratification in hypertension: in women, NT-proBNP alone or preferably in combination with electrocardiography seems sufficient to confirm or exclude diagnosis of LVH. In men, echocardiography would only be needed in cases of negative electrocardiography and NT-proBNP test.

Influence of blood sampling procedure on plasma concentrations of matrix metalloproteinases and their tissue inhibitors.

1. Plasma levels of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) are potential markers of many diseases involving extracellular matrix remodelling such as hypertension. Our aim was to determine whether the anticoagulant used to collect plasma and several freeze-thaw cycles may influence the accuracy of plasma MMP and TIMP determinations. 2. Plasma samples of 18 healthy volunteers were collected on three anticoagulants: heparinate, citrate and EDTA. For each anticoagulant, we compared: (i) MMP-2 and MMP-9 levels using gelatin zymography and TIMP-1 and TIMP-2 concentrations using enzyme-linked immunosorbent assay; (ii) intra- and interassay coefficients of variation (CV); and (iii) MMP and TIMP levels after up to five freeze-thaw cycles. 3. The choice of anticoagulant influenced TIMP-2 and TIMP-1 concentrations (TIMP-2, P < 0.0001; paired comparisons, citrate vs EDTA, P < 0.0001; EDTA vs heparin, P < 0.0001; citrate vs heparin, P < 0.0001; TIMP-1, P < 0.001; paired comparisons, citrate vs EDTA, P = 0.10; EDTA vs heparin, P < 0.01; citrate vs heparin, P < 0.0001), but not those of MMP. We observed a bias with heparinate for TIMP-2, TIMP-1 and MMP-9 determinations. The anticoagulant did not influence intra-assay or interassay CV. Performing freeze-thaw cycles led to alterations in the TIMP-1 plasma levels (P < 0.0001), regardless of the anticoagulant used, whereas MMP and TIMP-2 concentrations were not significantly affected. 4. Anticoagulant influences the measured levels of MMP and TIMP in plasma and should be systematically reported. However, it does not influence the reproducibility of the measurements. Repeated freeze-thaw cycles alter the measurement of TIMP-1 levels and should be avoided.

Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals.

BACKGROUND AND OBJECTIVES: An AT1 receptor antagonist induces a counterregulatory renin release whose intensity and duration reflect the magnitude of the renin-angiotensin blockade. We investigated whether a renin inhibitor may neutralize this counterregulation and amplify the effects of AT1 receptor antagonists. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In 12 normotensive male individuals who were on a high-sodium diet, a double-blind, placebo-controlled, randomized, crossover design was used to study the hormonal and BP effects of single oral administrations of 300 mg of the renin inhibitor aliskiren, 320 mg of valsartan, and a combination of these two drugs, each at half dosage (150 mg of aliskiren and 160 mg of valsartan). RESULTS: Valsartan (320 mg) increased plasma renin activity and angiotensin I and angiotensin II levels, but 300 mg of aliskiren decreased them for 48 h. Aliskiren (300 mg) stimulated immunoreactive renin release more strongly than 320 mg of valsartan, decreased urinary aldosterone excretion for longer than 320 mg of valsartan, and had a similar BP-lowering effect as 320 mg of valsartan. In combination, 150 mg of aliskiren neutralized the valsartan (160 mg)-induced increase in plasma angiotensins for 48 h. The renin and aldosterone effects of the combination of 150 mg of aliskiren and 160 mg of valsartan were similar to those of 300 mg of aliskiren and greater than those of 320 mg of valsartan. When plasma drug concentrations were taken into account, the combination of 150 mg of aliskiren and 160 mg of valsartan had a synergistic effect on renin release. The BP-lowering effect of 150 mg of aliskiren and 160 mg of valsartan was similar to that of 300 mg of aliskiren and 320 mg of valsartan at peak but was more prolonged. CONCLUSION: The stronger and longer lasting effects on plasma active renin and urinary aldosterone of aliskiren, alone or in combination, demonstrate a more effective blockade of the renin-angiotensin system than that obtained with 320 mg of valsartan alone.

Prostate dynamic contrast-enhanced MRI with simple visual diagnostic criteria: is it reasonable?

UNLABELLED: The purpose of this study was to evaluate the accuracy of prostate cancer localization with simple visual diagnostic criteria using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). A total of 46 consecutive patients with biopsy-proven prostate cancer underwent prostate 1.5 T MRI with pelvic phased-array coils before prostatectomy. Besides the usual T2-weighted sequences, a 30-s DCE sequence was acquired three times after gadoterate injection. On DCE images, all early enhancing lesions of the peripheral zone were considered malignant. In the central gland, only early enhancing lesions appearing homogeneous or invading the peripheral zone were considered malignant. Three readers specified the presence of cancer in 20 prostate sectors and the location of distinct tumors. Results were compared with histology; p < 0.05 was considered significant. For localization of cancer in the sectors, DCE imaging had a significantly higher sensitivity [logistic regression, odds ratio (OR): 3.9, p < 0.0001] and a slightly but significantly lower specificity (OR: 0.57, p < 0.0001). Of the tumors >0.3 cc, 50-60% and 78-81% were correctly depicted with T2-weighted and DCE imaging, respectively. For both techniques, the depiction rate of tumors >0.3 cc was significantly influenced by the Gleason score (most Gleason

Investigation of aldosterone-synthase inhibition in rats.

BACKGROUND: In-vivo investigation of aldosterone-synthase inhibitors requires experimental models to characterize the biological effects of these compounds. METHODS: Seven successive experiments were performed in groups of 2-month-old male spontaneously hypertensive rats. Urinary free aldosterone was the main end-point measured during two contrasted diets: low sodium-high potassium (LS), inducing high urinary aldosterone (839 pmol/24 h, 95% confidence interval 654-1077), and high sodium-normal potassium (HS), inducing low urinary aldosterone (38.1 pmol/24 h; 95% confidence interval, 32.4-44.9). RESULTS: FAD 286 A (10 and 30 mg/kg) decreased urinary free aldosterone by 53 and 87% on the LS diet, and 50 and 75% on the HS. Plasma renin concentration increased three-fold after a 4-week treatment of 30 mg/kg FAD 286 A on the LS diet and did not change on the HS. The combination of FAD 286 A (30 mg/kg) and spironolactone (30 mg/kg) on the LS diet induced a biological picture of severe hypoaldosteronism and was not tolerated, whereas the HS diet prevented these abnormalities. The combination of FAD 286 A (30 mg/kg) and furosemide (30 mg/kg) on the HS diet corrected the diuretic-induced hypokalemia (4.1 +/- 0.2 versus 3.7 +/- 2.2 mEq/l, P < 0.033). CONCLUSION: This experimental model will be useful to screen future aldosterone-synthase inhibitors and study their biological effects in various experimental conditions.

Alcohol-attributable injuries in admissions to a swiss emergency room--an analysis of the link between volume of drinking, drinking patterns, and preattendance drinking.

BACKGROUND: An association between alcohol consumption and injury is clearly established from volume of drinking, heavy episodic drinking (HED), and consumption before injury. Little is known, however, about how their interaction raises risk of injury and what combination of factors carries the highest risk. This study explores which of 11 specified groups of drinkers (a) are at high risk and (b) contribute most to alcohol-attributable injuries. METHODS: In all, 8,736 patients, of whom 5,077 were injured, admitted to the surgical ward of the emergency department of Lausanne University Hospital between January 1, 2003, and June 30, 2004, were screened for alcohol use. Eleven groups were constructed on the basis of usual patterns of intake and preattendance drinking. Odds ratios (ORs) comparing injured and noninjured were derived, and alcohol-attributable fractions of injuries were calculated from ORs and prevalence of exposure groups. RESULTS: Risk of injury increased with volume of drinking, HED, and preattendance drinking. For both sexes, the highest risk was associated with low intake, HED, and 4 (women), 5 (men), or more drinks before injury. At the same level of preattendance drinking, high-volume drinkers were at lower risk than low-volume drinkers. In women, the group of low-risk non-HED drinkers taking fewer than 4 drinks suffered 47.5% of the alcohol-attributable injuries in contrast to only 20.4% for men. Low-volume male drinkers with HED had more alcohol-attributable injuries than that of low-volume female drinkers with HED (46.9% vs 23.2%). CONCLUSIONS: Although all groups of drinkers are at increased risk of alcohol-related injury, those who usually drink little but on occasion heavily are at particular risk. The lower risk of chronic heavy drinkers may be due to higher tolerance of alcohol. Prevention should thus target heavy-drinking occasions. Low-volume drinking women without HED and with only little preattendance drinking experienced a high proportion of injuries; such women would be well advised to drink very little or to take other special precautions in risky circumstances.

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans.

OBJECTIVE: Our objective was to define the pharmacodynamic profile of the new dual neutral endopeptidase (NEP)/angiotensin-converting enzyme (ACE) inhibitor AVE7688. METHODS: We compared the effects of single oral doses of AVE7688 (5 and 25 mg) with those of 10 mg ramipril (R10), a selective ACE inhibitor, in a placebo-controlled crossover study in sodium-depleted normotensive subjects. We also compared the effects of 25 mg AVE7688 with those of a renin-angiotensin system (RAS) blockade induced by a high dose of an angiotensin II receptor antagonist (300 mg irbesartan) and a dual blockade of the RAS (150 mg irbesartan plus 10 mg ramipril) in sodium-replete normotensive subjects by use of the same study design. The in vivo inhibition of ACE and NEP was monitored by measuring the urinary excretion of N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) and atrial natriuretic peptide (ANP), respectively. The intensity of RAS blockade was assessed by the increase in plasma active renin concentration. RESULTS: The 24-hour urine AcSDKP cumulative excretion increased significantly more after 25 mg AVE7688 (919 nmol [95% confidence interval (CI), 803-1052 nmol], P < .05) than after 5 mg AVE7688 (706 nmol [95% CI, 612-813 nmol]) or 10 mg ramipril (511 nmol [95% CI, 440-593 nmol]). The 25-mg dose of AVE7866 significantly and transiently (4 to 8 hours after drug intake) increased urinary ANP (2.02 +/- 1.05 ng/h, P < .05), whereas 5 mg AVE7688 (1.14 +/- 0.77 ng/h) and 10 mg ramipril (0.93 +/- 0.65 ng/h) had no effect compared with placebo (0.80 +/- 0.37 ng/h). In the low-salt panel the rise in plasma active renin concentration achieved 24 hours after dosing by 25 mg AVE7688 (247 pg/mL [95% CI, 157-389 pg/mL], P < .05) was significantly higher than that achieved by 5 mg AVE7688 (129 pg/mL [95% CI, 75-221 pg/mL]) or 10 mg ramipril (113 pg/mL [95% CI, 67-193 pg/mL]), which did not differ. In the high-salt panel group the effects of 25 mg AVE7688 on renin release did not significantly differ from those after administration of the combination of 150 mg irbesartan plus 10 mg ramipril or 300 mg irbesartan alone. All of these active drugs similarly decreased blood pressure compared with placebo. CONCLUSION: AVE7688 at a dose of 25 mg has a favorable pharmacodynamic profile compared with other RAS blockers. These results support further clinical studies of its long-term effects in essential or resistant hypertension, chronic proteinuric nephropathy, and chronic heart failure.

Elevated growth-arrest-specific protein 6 plasma levels in patients with severe sepsis.

OBJECTIVE: Growth-arrest-specific protein 6 (Gas6), an intracellular protein released by apoptotic cells, has been detected in normal plasma. As the Gas6 system has been implicated in mouse susceptibility to sepsis, and as leukocyte apoptosis is thought to play a major role in the physiopathology of human severe sepsis, we studied Gas6 plasma levels and possibly related variables in patients with severe sepsis. DESIGN: Matched case-control study. SETTING: Adult intensive care unit in a university hospital. PATIENTS: Thirty patients with severe sepsis, 30 patients with organ failure not related to infection, and 30 healthy subjects matched for age and gender. INTERVENTIONS: Blood draw. MEASUREMENTS AND MAIN RESULTS: Gas6 plasma levels were quantified using enzyme-linked immunosorbent assay. Whole-blood gas6 messenger RNA levels were measured by quantitative real-time polymerase chain reaction. Gas6 plasma levels were elevated (110 ng/mL [75, 139]; median values [interquartile range]) in severe sepsis patients compared with organ failure patients (85 ng/mL [56, 101]) and healthy subjects (54 ng/mL [49, 68]). In patients with severe sepsis, this increase correlated with the Acute Physiology and Chronic Health Evaluation II severity score, the organ failure Organ Dysfunction and Infection (ODIN) score, and the existence of a septic shock. Gas6 messenger RNA levels were increased in patients with severe sepsis and correlated specifically with the monocyte count. CONCLUSIONS: In severe sepsis, the recently described anti-apoptotic protein Gas6 was found at high levels in plasma and correlated well with the degree of organ dysfunction.

Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study.

BACKGROUND: Heart failure develops after myocardial infarction and is a major cause of morbidity and mortality. The ability to direct differentiation of embryonic stem cells (ESC) towards a cardiomyogenic phenotype makes them an attractive therapeutic option for cardiac repair, but species-specific and individual-specific immunological imprinting remains a hurdle. Our aim was to ascertain whether the purported immune privilege of ESC allows for their cross-species engraftment in a clinically relevant large-animal model. METHODS: We studied engraftment and differentiation of cardiac-committed mouse ESC in 18 sheep in which a myocardial infarction had been induced; nine controls received medium and nine sheep (five of which were immunosuppressed) received ESC. The gain in myocardial function was measured by echocardiography 1 month after cell transplantation. FINDINGS: Cardiac-committed murine ESC engrafted in infarcted myocardium of immunosuppressed and immunocompetent sheep, and differentiated into mature cardiomyocytes that expressed connexins. Colonisation of the scar area by ESC was accompanied by a functional benefit of the damaged myocardium. Left-ventricular ejection fraction deteriorated in the control group by a median of 9.9% (range -20 to 0.3) relative to baseline (p=0.011) whereas in the treated group it improved by 6.6% (-5.7 to 50.8; comparison between groups p=0.002). INTERPRETATION: These findings obtained in a clinically relevant large-animal model of heart failure strengthen the potential therapeutic use of ESC to regenerate the severely dysfunctional myocardium and bring additional evidence for an immune privilege of these cells.

Can cold or heat shock improve skeletal myoblast engraftment in infarcted myocardium?

OBJECTIVE: Cell death remains a major limitation of skeletal myoblast (SM) transplantation but the patterns of cell survival and proliferation in heart and their potential modulation by thermic stresses like heat shock (HS) and cryopreservation (Cryo) are still incompletely characterized. METHODS: To track SMs in situ, we developed a dual-marker system based on the semiconservative expression of the foreign soluble protein, beta-Galactosidase (beta-Gal) and the constitutive expression of the Y chromosome in a myocardial infarction model. Control medium or Lewis male rat SMs (fresh or subjected to Cryo or HS) were injected in Lewis female rats. RESULTS: There was a massive cell loss early after transplantation in the fresh group, which was only partially compensated for by a subsequent proliferation. Conversely, both Cryo and HS significantly improved early cell survival but blunted subsequent proliferation so that, at 15 days posttransplantation, the total number of engrafted donor-derived Y-positive cells did not differ significantly between the three groups. Most of them expressed a skeletal muscle phenotype. CONCLUSIONS: These data confirm the high death rate of in-scar transplanted myoblasts, demonstrate the ability of those that survive to proliferate and differentiate along the myogenic pathway but do not support the efficacy of either Cryo or HS for increasing the ultimate magnitude of myoblast engraftment.

Compliance of abdominal aortic aneurysms evaluated by tissue Doppler imaging: correlation with aneurysm size.

OBJECTIVES: Several studies have shown that an increase in abdominal aortic aneurysm (AAA) growth rate occurs when the diameter reaches 40 to 50 mm. AAA expansion is related to remodeling of the parietal extracellular matrix. The parietal mechanisms involved in this critical phase of sudden increase remain unexplained. Analysis of AAA wall movements and determination of AAA compliance may provide information about the constitution of the arterial wall. If a change in parietal wall motion somewhere between 40 and 50 mm could be shown, this would contribute to the understanding of the growth of AAA. Furthermore, it would provide a valuable additional parameter for AAA monitoring. This study had two aims: first, to evaluate the relationship between AAA compliance and maximum diameter using the tissue Doppler imaging system; and second, to test the hypothesis of a change in AAA behavior at around 45 mm in diameter. METHODS: Fifty-six patients with AAA (mean diameter, 39 mm) were prospectively investigated using the tissue Doppler imaging system, which provides information concerning arterial wall motion. Maximum mean segmental dilation (MMSD), segmental compliance, pressure strain elastic modulus (Ep), and stiffness were determined and related to the maximum diameter of AAA. Results After natural log transformation of all variables, there was a significant positive linear relationship between maximum diameter and both MMSD (P < .001) and segmental compliance (P < .001) but not with Ep or stiffness (P = .37 and .22, respectively). MMSD and segmental compliance were significantly higher in AAA > or = 45 mm than in AAA < 45 mm (P < .0002 and <. 004, respectively). Ep and stiffness tended to decrease in larger AAAs, but this was not statistically significant (P < .43 and .24, respectively). Dispersion of Ep and stiffness values seemed to be wider among AAA < 45 mm compared with those > or = 45 mm. CONCLUSION: Compliance parameters can easily be measured during routine AAA ultrasound monitoring using the tissue Doppler imaging system. The study showed an increase in MMSD and segmental compliance as well as a nonsignificant trend toward increased distensibility (decreased Ep and stiffness) with increased AAA diameter. A change in dispersion of AAA distensibility may appear around 45 mm in diameter, but a larger study will be needed to clarify this.

Enhancement of the functional benefits of skeletal myoblast transplantation by means of coadministration of hypoxia-inducible factor 1alpha.

OBJECTIVE: Early cell death remains a major limitation of skeletal myoblast transplantation. Because the poor vascularization of the target scars contributes to cell loss, we assessed the effects of combining skeletal myoblast transplantation with administration of hypoxia-inducible factor 1alpha, a master gene that controls the expression of a wide array of angiogenic factors. METHODS: A myocardial infarction was created in 56 rats by means of coronary artery ligation. Eight days later, rats were randomly allocated to receive in-scar injections of culture medium (control animals, n = 11), skeletal myoblasts (5 x 10(6) , n = 13), adenovirus-encoded hypoxia-inducible factor 1alpha (1.0 x 10(10) pfu/mL, n = 7), or skeletal myoblasts (5 x 10(6)) in combination with an empty vector (n = 3) or active hypoxia-inducible factor 1alpha (1.0 x 10(10) pfu/mL, n = 13). A fifth group (n = 9) underwent a staged approach in which hypoxia-inducible factor 1alpha (1.0 x 10(10) pfu/mL) was injected at the time of infarction, followed 8 days later by skeletal myoblasts (5 x 10(6)). Left ventricular function was assessed echocardiographically before transplantation and 1 month thereafter. Explanted hearts were then processed for the immunohistochemical detection of myotubes, quantification of angiogenesis, myoblast engraftment, and cell survival. RESULTS: Baseline ejection fractions were not significantly different among groups (35%-40%). One month later, ejection fraction had decreased from baseline in control hearts and in those injected with hypoxia-inducible factor 1alpha. In contrast, it did not deteriorate after injections of skeletal myoblasts alone or combined with either the empty vector or active hypoxia-inducible factor 1alpha administered sequentially. The most striking change occurred in the skeletal myoblast plus hypoxia-inducible factor 1alpha combined group in which ejection fraction increased dramatically (by 27%) above baseline levels and was thus markedly higher than in all other groups ( P = .0001 and P = .001 vs control animals and animals receiving hypoxia-inducible factor 1alpha, respectively). Compared with skeletal myoblasts alone, the coadministration of hypoxia-inducible factor 1alpha resulted in a significantly greater degree of angiogenesis, cell engraftment, and cell survival. CONCLUSION: Induction of angiogenesis is an effective means of potentiating the functional benefits of myoblast transplantation, and hypoxia-inducible factor 1alpha can successfully achieve this goal.