Manganese-Enhanced T1 Mapping in the Myocardium of Normal and Infarcted Hearts.

Background: Manganese-enhanced MRI (MEMRI) has the potential to identify viable myocardium and quantify calcium influx and handling. Two distinct manganese contrast media have been developed for clinical application, mangafodipir and EVP1001-1, employing different strategies to mitigate against adverse effects resulting from calcium-channel agonism. Mangafodipir delivers manganese ions as a chelate, and EVP1001-1 coadministers calcium gluconate. Using myocardial T1 mapping, we aimed to explore chelated and nonchelated manganese contrast agents, their mechanism of myocardial uptake, and their application to infarcted hearts. Methods: T1 mapping was performed in healthy adult male Sprague-Dawley rats using a 7T MRI scanner before and after nonchelated (EVP1001-1 or MnCl2 (22 µmol/kg)) or chelated (mangafodipir (22-44 µmol/kg)) manganese-based contrast media in the presence of calcium channel blockade (diltiazem (100-200 µmol/kg/min)) or sodium chloride (0.9%). A second cohort of rats underwent surgery to induce anterior myocardial infarction by permanent coronary artery ligation or sham surgery. Infarcted rats were imaged with standard gadolinium delayed enhancement MRI (DEMRI) with inversion recovery techniques (DEMRI inversion recovery) as well as DEMRI T1 mapping. A subsequent MEMRI scan was performed 48 h later using either nonchelated or chelated manganese and T1 mapping. Finally, animals were culled at 12 weeks, and infarct size was quantified histologically with Masson's trichrome (MTC). Results: Both manganese agents induced concentration-dependent shortening of myocardial T1 values. This was greatest with nonchelated manganese, and could be inhibited by 30-43% with calcium-channel blockade. Manganese imaging successfully delineated the area of myocardial infarction. Indeed, irrespective of the manganese agent, there was good agreement between infarct size on MEMRI T1 mapping and histology (bias 1.4%, 95% CI -14.8 to 17.1 P>0.05). In contrast, DEMRI inversion recovery overestimated infarct size (bias 11.4%, 95% CI -9.1 to 31.8 P=0.002), as did DEMRI T1 mapping (bias 8.2%, 95% CI -10.7 to 27.2 P=0.008). Increased manganese uptake was also observed in the remote myocardium, with remote myocardial ∆T1 inversely correlating with left ventricular ejection fraction after myocardial infarction (r=-0.61, P=0.022). Conclusions: MEMRI causes concentration and calcium channel-dependent myocardial T1 shortening. MEMRI with T1 mapping provides an accurate assessment of infarct size and can also identify changes in calcium handling in the remote myocardium. This technique has potential applications for the assessment of myocardial viability, remodelling, and regeneration.

Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests.

BACKGROUND: Systematic screening for liver fibrosis in heavy-drinking patients is a challenge. Aims To assess Fibroscan for non-invasive diagnosis of asymptomatic liver fibrosis in alcohol abuse patients, to determine diagnostic liver stiffness cut-off values and to compare performance of Fibroscan with seven non-invasive laboratory tests. METHODS: One hundred and three alcoholic patients were studied. Liver fibrosis was staged by METAVIR system. Fibroscan, Fibrotest, Fibrometer, Hepascore, APRI, PGA, PGAA and hyaluronic acid tests were performed. Liver stiffness cut-offs were determined using receiver-operating characteristic (ROC) curves. RESULTS: Liver stiffness was correlated with fibrosis (r = 0.72, P < 0.014), with median at 5.7, 6.3, 8.4, 15 and 47.3 kPa for F0 (n = 8), F1 (n = 18), F2 (n = 24), F3 (n = 20) and F4 (n = 33) stage fibrosis respectively. For Fibroscan, areas under ROC curves (AUROCs) were 0.84 (95% CI: 0.73-0.95) (F > or = 1), 0.91 (0.85-0.98) (F > or = 2), 0.90 (0.82-0.97) (F > or = 3) and 0.92 (0.87-0.98) (F = 4), yielding diagnostic stiffness cut-offs of 5.9 (F > or = 1), 7.8 (F > or = 2), 11 (F > or = 3) and 19.5 (F4) kPa. Sensitivity, specificity, PPV and NPV were 80%, 90.5%, 93% and 70% for F > or = 2, and 85.7%, 84.2%, 68.6% and 87.9% for F = 4. Performance of Fibroscan was higher than seven laboratory tests, for which AUROCs ranged from 0.66 to 0.77 (F > or = 1), from 0.54 to 0.82 (F > or = 2), from 0.43 to 0.88 (F > or = 3) and from 0.56 to 0.89 (F = 4), with significant difference only vs. APRI (P < 0.001) and Hepascore (P = 0.04). Combining Fibroscan with each tests did not improve performance. CONCLUSIONS: Fibroscan is effective to assess liver fibrosis in alcoholic patients. Instant screening of liver fibrosis in heavy drinkers is feasible without liver biopsy.

[Haematopoietic stem cell transplantation in the treatment of autoimmune diseases]. / Intensification thérapeutique dans les maladies auto-immunes.

PURPOSE: During the past ten years, more than 1000 patients suffering from severe autoimmune disease have received an autologous haematopoietic stem cell transplant. These new therapeutic have been used in systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus. CURRENT KNOWLEDGE AND KEY POINTS: Autologous haematopoietic stem cell transplantation has become a curative option for condition with very poor prognosis as severe systemic sclerosis, lupus erythematosus or other systemic diseases. This review summarizes the current experience in the phase I and II clinical trials in Europe and North America. We describe the main results and the limits of stem cell transplantation in systemic diseases. FUTURE PROSPECTS AND PROJECTS: Autologous haematopoietic stem cell transplant in the treatment of autoimmune disease has evolved from a experimental concept to a clinically feasible and powerful therapy for selected patients with severe disease.

[Grand types of studies 2: analytical studies]. / Les grands types d'étude 2: les études analytiques.

PURPOSE: This paper describes the hierarchy of analytical studies, from the observational studies to the experimental ones. STATE OF THE ART AND MAIN POINTS: Case-control studies, the most frequently performed among analytical studies, may generate or confirm hypotheses. They are of particular use for rare diseases. Cohort studies aim mainly at confirming hypotheses already tested, and at precisely quantifying the magnitude of effect. Randomisation aims at the elimination of confounding factors, and meta-analysis, at decreasing potential selection biases and increasing power. Those goals may not always be achieved. PERSPECTIVES AND PROJETS: The study power, or the beta error, are major factors to be determined when designing a study, before any attempt of realization.

[Grand types of clinical studies]. / Les grands types d'études cliniques 1: de la description à l'analyse.

PURPOSE: This paper provides an overview of the hierarchy between the main descriptives clinical studies, with their respective weaknesses and strength. STATE OF THE ART AND MAIN POINTS: Case-reports and case-series are first described, which do not provide control groups but have been very useful in disease recognition and nosology building. Ecological studies, which are hypothesis generating at the group or population level, but which do not study individuals, and prevalence studies with one simple or a double question, which study individuals within groups but may lead to erroneous conclusions so far are risk factors are involved, are then reviewed. PERSPECTIVES AND PROJECTS: The overview of the descriptive studies leads to the notion of confounding factor, which may be better addressed by analytical studies.

[Incidence of cardiovascular events in giant cell arteritis: preliminary results of a prospective double cohort study (GRACG)]. / Incidence des accidents cardiovasculaires au cours de la maladie de Horton: résultats préliminaires de l'étude prospective en double cohorte GRACG.

UNLABELLED: Giant cell arteritis is the most frequent vasculitis. Cardiovascular events such as cerebrovascular accident or ischemic heart disease may occur in patients with giant cell arteritis. However, their real incidence, as well as their relative risk compared to the general population, remains unknown. PURPOSE: To assess in a prospective, double cohort study, the incidence of cardiovascular events in giant cell arteritis patients compared to controls, after controlling for cardiovascular risk factors. PATIENTS AND METHODS: We included on predefined criteria 432 newly diagnosed patients with giant cell arteritis, each assigned to sex- and age-matched controls randomly selected from the general population. Cardiovascular risk factors (high-blood pressure, diabetes, smoking, hypercholesterolemia and preexisting peripheral vascular disease) were collected at inclusion. During the 24-month follow-up, all cardiovascular events were collected. After stratification for cardiovascular risk factors, a log-rank test was performed to compare cases and controls. A parametric survival model was used for multivariate analysis. RESULTS: Cardiovascular events all combined were significantly increased in patients with giant cell arteritis (RR = 2.15 [1.21-3.81], P = 0.009), and were mainly associated with age (P = 0.0001), past history of cardiovascular disease (P = 0.023) but also with giant cell arteritis (P = 0.009). However, each subset of cerebrovascular accident (RR = 2.42 [0.84-7]) or ischemic heart disease (RR = 1.67 [0.72-3.89]) increased but did not significantly. CONCLUSION: Cardiovascular events incidence is increased in patients with giant cell arteritis, and prescription of preventive antiagregant treatment may be discussed.

[Aetiological spectrum of hyperferritinemia]. / Spectre étiologique des hyperferritinémies.

UNLABELLED: Serum ferritin levels may be increased in many conditions: renal diseases, liver diseases, human immunodeficiency virus infection. The purpose of this study was to assess the aetiological spectrum of high serum ferritin levels in a 1200-bed university hospital, to compare our results with the data already published and to assess a potential association between aetiology and ferritin levels. PATIENTS AND METHODS: Patients with a serum ferritin level higher than 600 microg/l were retrospectively included between 15 November 2003 and 15 January 2004, and their medical records were reviewed. RESULTS: Ninety-eight patients (38 women and 60 men; median age: 59,5 years [19-92]) were recruited in departments of hepatology and gastroenterology (22%), haematology (14%) and internal medicine (18%). Diagnosis performed were: non-HIV systemic infections (23,8%), haematological diseases (16,1%), alcoholism (11,2%) and malignancies (9,8%). Dialysed chronic renal failure, liver diseases, haemochromatosis and systemic inflammatory diseases counted for 4.2 to 5.2% of cases. Serum ferritin level lied between 600 and 1000 microg/l for 50 patients, between 1000 and 1500 microg/l for 24, and over 1500 microg/l for 24. There was no significant difference between the three groups as regards the etiological distribution. DISCUSSION: In our study, chronic renal failure was not a major cause of high ferritin level: this is probably due to the current use of erythropoietin, which has decreased the use of blood transfusions. The two major aetiology of hyperferritinemia were non-HIV infections and malignancies.

[Giant cell arteritis and polymyalgia rheumatica: influence of past pregnancies? The GRACG multicenter case control study]. / Maladie de Horton et pseudopolyarthrite rhizomélique: influence des antécédents de grossesse? Etude cas-témoins prospective GRACG.

BACKGROUND: The overprevalence of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) in women remains unexplained. Microchimerism pathogenicity has been discussed in some systemic diseases. We tested history of pregnancy as a risk factor for GCA. METHODS: Prospective, multicenter case-control study with multiple, age-matched, control groups. Patients have been included in 40 different centers. The first control group has been randomly selected in the general population, consecutive hospitalized patients in two geographically distant departments of internal medicine made up the second and third ones. RESULTS: Three hundred and fifteen patients (249 GCA and 66 PMR), 242 general population controls, 333 in the first hospitalized control group, and 355 in the second, have been included in the 1991-1998 period. Pregnancy has been constantly protective against GCA/PMR (Wilcoxon rank sum test: P = 0.0001, 0.0005, and 0.054, respectively, for the three control groups), more particularly for parity equal or greater than 4 (OR = 0.32, 95% CI: 0.18-0.57, P = 0.00003; OR = 0.44, 95% CI: 0.26-0.74; P = 0.0009, and OR = 0.42; 95% CI: 0.25-0.71, P = 0.0006, respectively). In multivariate analysis, risk for GCA on pre-existing degenerative, vascular disease is decreased by half for each pregnancy (OR = 0.49, 95% CI = 0.27-0.90, P = 0.022). CONCLUSION: Contrary to the initial hypothesis, multiparity is a protective factor against GCA. Mechanism is unknown.