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Objectives: To describe a family with heterozygous P67S and D91A SOD1 mutations. Methods: The ALS profile of the proband was described. SOD1 gene sequencing was performed in the proband and his chi...

Amyotrophic lateral sclerosis (ALS) is the most common and severe adult-onset motoneuron disease and has currently no effective therapy. Approximately 20% of familial ALS cases are caused by dominantly-inherited mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), which represents one of the most frequent genetic cause of ALS. Despite the overwhelming majority of ALS-causing missense mutations in SOD1, a minority of premature termination codons (PTCs) have been identified. mRNA harboring PTCs are known to be rapidly degraded by nonsense-mediated mRNA decay (NMD), which limits the production of truncated proteins. The rules of NMD surveillance varying with PTC location in mRNA, we analyzed the localization of PTCs in SOD1 mRNA to evaluate whether or not those PTCs can be triggered to degradation by the NMD pathway. Our study shows that all pathogenic PTCs described in SOD1 so far can theoretically escape the NMD, resulting in the production of truncated protein. This finding supports the hypothesis that haploinsufficiency is not an underlying mechanism of SOD1 mutant-associated ALS and suggests that PTCs found in the regions that trigger NMD are not pathogenic. Such a consideration is particularly important since the availability of SOD1 antisense strategies, in view of variant treatment assignment.

International audience; Background: In familial amyotrophic lateral sclerosis (ALS) cases, the presence of an abnormal C9ORF72 repeat expansion (C9RE) is the most frequent genetic cause identified. Various clinical phenotypes have been described in relation to the presence of C9RE, including psychiatric disorders or Huntington-like symptoms. In a subset of sporadic ALS, C9RE has also been described. In the present study, all index cases with ALS and C9RE identified in our center and their clinical profile, as well as neurological and psychiatric characteristics of identified family members, were described. Clinical characteristics of ALS patients were compared to 999 patients with sporadic ALS (SALS) from our database.Results: From the 70 index cases with ALS identified, a total of 200 individuals were studied, 118 with ALS, 32 with fronto-temporal lobe degeneration (FTD), 37 with ALS/FTD, and 13 with psychiatric disorders. A familial history was present in 57 of the index cases (81%). In ALS and ALS/FTD cases with C9RE, the age of onset (AoO) was earlier than that in SALS cases, p < 0.0001 and p = 0.008, respectively. Sporadic cases with C9REALS (n = 13) had an earlier AoO compared to familial C9REALS ones, p < 0.0001. Within families, there was an earlier AoO in index cases and their siblings compared to their parental generation (p < 0.01). There was also a significant intrafamilial correlation for bulbar onset of ALS. The parental generation had significant female predominance compared to index cases and their siblings (sex ratio 0.47 vs. 1.4, p = 0.004), and this predominance was also present when considering parent-child pairs. In the group with psychiatric disorders, suicide was prominent (n = 9) and mean age was 54 years.Conclusion: Although our sample size is rather limited, the earlier AoO in index cases and their siblings compared to the parental generation may suggest an anticipation. Reasons for predominance of female transmission are unclear, but the hypothesis that gender influences transmission of the genetic trait or C9RE size variation may be taken into account. Intrafamilial correlation suggests that genetic aspects underlie the occurrence of bulbar onset in ALS patients. Studies on larger samples are warranted to confirm those results.

International audience; Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among their numerous physiological roles, they act as central cholesterol-lowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have additional roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both molecular diagnosis and as promising pharmacological targets in the treatment of ALS, AD, or MS patients.

Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.

International audience; Cholesterol plays a central role in numerous nervous system functions. Cholesterol is the major constituent of myelin sheaths, is essential for synapse and dendrite formation, axon guidance as well as neurotransmission. Among regulators of cholesterol homeostasis, liver X receptors (LXRs), two members of the nuclear receptor superfamily, play a determinant role. LXRs act as cholesterol sensors and respond to high intracellular cholesterol concentration by decreasing plasmatic and intracellular cholesterol content. Beyond their cholesterol-lowering role, LXRs have been proposed as regulators of immunity and anti-inflammatory factors. Dysregulation of cholesterol metabolism combined to neuroinflammatory context have been described in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS is characterized by the progressive loss of motoneurons in the brain and spinal cord, leading to severe paralytic condition and death of patients in a median time of 3 years. Motoneuron degeneration is accompanied by chronic neuroinflammatory response, involving microglial and astrocytic activation, infiltration of blood-derived immune cells and release of pro-inflammatory factors. We propose to discuss here the role of LXRs as a molecular link between the central nervous system cholesterol metabolism, neuroinflammation, motoneuron survival and their potential as promising therapeutic candidates for ALS therapy.

Gemcitabine (2',2'-difluorodeoxycytidine) is a major antimetabolite cytotoxic drug with a wide spectrum of activity against solid tumors. Hepatic elimination of gemcitabine depends on a catabolic pathway through a deamination step driven by the enzyme cytidine deaminase (CDA). Severe hematologic toxicity to gemcitabine was reported in patients harboring genetic polymorphisms in CDA gene. High-resolution melting (HRM) analysis of polymerase chain reaction amplicon emerges today as a powerful technique for both genotyping and gene scanning strategies. In this study, 46 DNA samples from gemcitabine-treated patients were subjected to HRM analysis on a LightCycler 480 platform. Residual serum CDA activity was assayed as a surrogate marker for the overall functionality of this enzyme. Genotyping of three well-described single nucleotide polymorphisms in coding region (c.79A>C, c.208G>A and c.435C>T) was successfully achieved by HRM analysis of small polymerase chain reaction fragments, whereas unknown single nucleotide polymorphisms were searched by a gene scanning strategy with longer amplicons (up to 622 bp). The gene scanning strategy allowed us to find a new intronic mutation c.246+37G>A in a female patient displaying marked CDA deficiency and who had an extreme toxic reaction with a fatal outcome to gemcitabine treatment. Our work demonstrates that HRM-based methods, owing to their simplicity, reliability, and speed, are useful tools for diagnosis of CDA deficiency and could be of interest for personalized medicine.

Background and objectives As B-type Natriuretic Peptide (BNP) is a marker of ventricular wall stress, the present study was aimed at determining whether plasma BNP concentration could predict fluid responsiveness in critically ill patients with acute circulatory failure. Methods This prospective and non randomized interventional study included 33 sedated, mechanically ventilated patients, with acute circulatory failure requiring cardiac output measurement and fluid challenge. Plasma BNP concentration was measured before and after fluid challenge (250 to 500 ml with infusion rate = 999 ml/h). An increase in stroke index (SI) greater than or equal to 15% allowed separation of responders from nonresponders. Receiver operating characteristic (ROC) curves were generated for BNP and compared to that of central venous pressure (CVP) that is routinely considered as a marker of cardiac preload. Results Among 33 patients, there were 24 responders. At baseline, BNP plasma values were less in responders (328 [35–1190] pg/ml versus 535 [223–5000] pg/ml, p Conclusion In critically ill patients with acute circulatory failure, BNP does not accurately predict fluid responsiveness.

Objectives: The aim of this study was to establish the diagnostic sensitivity of combinations of well-selected monoclonal antibodies (mAbs) against cardiac troponin I (cTnI) to allow an earlier rule-in of acute coronary syndrome (ACS) patients. Design and methods: Using several combinations of mAbs, four new experimental cTnI immunoassays were evaluated to analyze plasma samples from 62 patients suffering from angina (16/62), patients having a chest pain of extracardiovascular origin (19/62) and ACS without ST elevation (NSTE-ACS) (27/62). Results: Assay 2, which relies on a capture mAb directed against the central part of cTnI and two conjugated mAbs directed against the N-ter region, provided the best clinical sensitivity. In 11 out of 27 patients with NSTE-ACS, it detected an early rise of cTnI within 0 and 1 h upon admission, contributing to the detection of 53% of samples found to be negative by the reference AccuTnI Assay upon admission (Beckman Coulter), thereby reducing the delay in diagnosis. Conclusions: Assay 2 can identify early cTnI elevation in NSTE-ACS, possibly facilitating the rule-in procedure for these patients once the assay is automated.

International audience; Low peak plasma concentrations (Cmax) of amikacin and gentamicin are reported in intensive care unit (ICU) patients after administration of the first dose. The present study aimed to describe the proportion of ICU patients in whom an adequate Cmax was achieved throughout the course of therapy. Septic ICU patients with an indication for intravenous amikacin or gentamicin were eligible for inclusion in this single-centre observational study. The first and subsequent doses and the corresponding Cmax values were recorded. The target Cmax was ≥60mg/L for amikacin and ≥30mg/L for gentamicin. Amikacin and gentamicin plasma concentrations were available in 66 and 24 patients, respectively (59±17 years; 79±19kg; height 169±12cm; SAPS II score 46±19). Pulmonary, abdominal and urinary tract infections were diagnosed in 64 patients. Culture-positive infection was confirmed in 65 patients (72%). A target first Cmax was achieved in 17/90 patients (19%). For amikacin, the target Cmax was achieved in 16/66 patients (24%) after the initial dose. In the 50 remaining patients, a change in dosing was performed in 14 patients, leading adequate peak plasma level in 2 patients. For gentamicin, the targeted Cmax was achieved in only 1/24 patient (4%) after the initial dose and was never achieved after the third dose. In conclusion, standard dosing of amikacin or gentamicin led to adequate Cmax in only 19% of patients. Subtherapeutic Cmax were not significantly corrected after subsequent doses.

BackgroundHeart failure (HF) symptoms, related to pulmonary capillary hypertension, are frequent in hypertrophic cardiomyopathy (HCM). Pulmonary hypertension (PH) is the consequence of left ventricular (LV) diastolic pressure elevation and/or functional mitral regurgitation. We aimed to evaluate determinants and prognostic significance of rest and exercise PH in HCM.Methods and ResultsWe included 235 patients referred for clinical work-up of HCM. Rest pulmonary artery systolic pressure (PASP) was measurable in 214 (91%) patients (48±16 years, 161 males). A symptom-limited semi-supine bicycle exercise was carried out in 188 patients. PASP was measurable during exercise in 108 patients (57%). Resting PH (≥36mm Hg) was present in 56 patients (26.2%) and exercise PH (≥60mm Hg) in 38 patients (35.2%). Mutivariate correlates of rest PASP were sinus rhythm (β= –0.15, P=0.021), LV obstruction tract (LVOT) peak gradient (β= 0.22, P=0.001) and left atrial volume (β= 0.39, P

Background The prognostic value of cardiac troponin T (cTn-T) in a mixture of patients with both acute and chronic congestive heart failure (CHF), simultaneously assessed and compared with neurohormonal factors, has not yet been thoroughly evaluated. Thus, we focused on the prognostic value of cTn-T in comparison with atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and plasma norepinephrine (PNE) in this population. Methods Prognostic correlates of elevation of cTn-T, ANP, BNP, PNE were analyzed in 63 acute and chronic CHF patients followed up to record worsening CHF and cardiac death. Results cTn-T (≥0.03 μg/L) was found in 17.4% (11 of 63) of patients. cTn-T correlated with ANP, BNP, PNE. Acute CHF patients were more positive for cTn-T and BNP. In our cohort, neither cTn-T (≥0.03 μg/L) nor PNE were associated with increased mortality and worsening HF in CHF patients. After adjustment, BNP was the only independent predictor of cardiac events (RR, 3.23; p=0.01). Conclusions BNP emerged as the only independent predictor of cardiac events in a mixture of patients with both acute and chronic CHF, suggesting that it is the analyte that best reflects long-term prognosis in a diverse population enrolled to mirror the “real world” situation.

International audience; We report the third case of amyotrophic lateral sclerosis related to p.E121G Superoxide dismutase-1 (SOD1) mutation. Besides a sporadic presentation and a slow progressive course, as described in the 2 previously cases, our patient presented with prominent sensory and cerebellar signs. This case report strengthens that p.E121G should be considered as a causal mutation. Slowly upper and lower motor neuron degeneration, even with non-motor clinical features, should prompt a sequencing of SOD1.

Background: Cardiac troponins I (cTnI) and T (cTnT) have been shown to be highly sensitive and specific markers of myocardial cell injury. We investigated the diagnostic value of cTnI and cTnT for the diagnosis of myocardial damage in a rat model of doxorubicin (DOX)-induced cardiomyopathy, and we examined the relationship between serial cTnI and cTnT with the development of cardiac disorders monitored by echocardiography and histological examinations in this model. Methods: Thirty-five Wistar rats were given 1.5 mg/kg DOX, i.v., weekly for up to 8 weeks for a total cumulative dose of 12 mg/kg BW. Ten rats received saline as a control group. cTnI was measured with Access® (ng/ml) and a research immunoassay (pg/ml), and compared with cTnT, CK-MB mass and CK. By using transthoracic echocardiography, anterior and posterior wall thickness, LV diameters and LV fractional shortening (FS) were measured in all rats before DOX or saline, and at weeks 6 and 9 after treatment in all surviving rats. Histology was performed in DOX-rats at 6 and 9 weeks after the last DOX dose and in all controls. Results: Eighteen of the DOX rats died prematurely of general toxicity during the 9-week period. End-diastolic (ED) and end-systolic (ES) LV diameters/BW significantly increased, whereas LV FS was decreased after 9 weeks in the DOX group (p

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice., Author Summary Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. Mutations altering genes involved in the junction between brain cells have been repeatedly associated in ASD. For example, SHANK1, SHANK2 and SHANK3 emerged as one family of genes that are associated with ASD. However, little was known about the number of patients carrying these mutations and the clinical outcome. Here, we performed a new genetic screen of SHANK mutations and these results were analyzed in combination with those of the literature. In summary, SHANK mutations account for ∼1% of patients with ASD and were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. Given the high frequency and impact of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—this gene should be screened for mutations in clinical practice.

Background The aims of the Langendorff-perfused rabbit heart study were to evaluate the arrhythmogenic consequences of myocardial contusion and to determine the mechanism of arrhythmia. Methods Six hearts were in the control group, and 24 hearts (intact heart protocol) were submitted to one of four different contusion kinetic energies (75, 100, 150, or 200 millijoules [mJ]; n = 6). Occurrence of arrhythmia, of an electrically silent area (i.e., area with no electrical activity), and of line of fixed conduction block were reported before and for 1 h after contusion. In 16 hearts (frozen hearts) submitted to cryoprocedure and contusion impact of 100 or 200 mJ, ventricular conduction velocities, anisotropic ratio, wavelengths, ventricular effective refractory period, and its dispersion were measured before and for 1 h after contusion. Using high-resolution mapping, arrhythmias were recorded and analyzed. Results The intact heart study showed that the number and seriousness of contusion-induced arrhythmias increased with increasing contusion kinetic energy, as did the number of electrically silent areas (five of six ventricular fibrillations and five of six electrically silent areas at 200 mJ). In the frozen heart study, immediately after contusion ventricular effective refractory periods were shortened and dispersed, and wavelengths were also shortened. The arrhythmia analysis showed that all ventricular tachycardias but one were based on reentry developed around an electrically silent area or a line of fixed conduction block. Conclusions Myocardial contusion has direct arrhythmogenic effects, and the seriousness of arrhythmia increases with the level of contusion kinetic energy. The mechanism of arrhythmia was mainly based on reentrant circuit around a fixed obstacle.

The analytical and clinical performances of the new fluorescent immunoassay (CK‐MB mass Vidas‐BioMerieux) were examined and compared to the chemiluminescent test (CK‐MB mass Access‐Sanofi‐Pasteur). Assay precisions of the CK‐MB Vidas test within‐assay or between‐assay were less than 5.4 and 5.3%, respectively. Linearity was tested up to 214 μg/L. The CK‐MB Vidas test was free of interference with CK‐BB, CK‐MM, and macro‐CK. One hundred nineteen blood samples from patients with ischemic myocardial injury (IMI): acute myocardial infarction (AMI), suspected myocardial contusion (SMC), and unstable angina pectoris (UA), were tested using both immunoassays. In AMI, a good correlation was found (Y [CK‐MB Access] = 1.1372 × [CK‐MB Vidas] – 6.3902; r(2) = 0.96). In UA and SMC, low values were observed and both methods were well correlated (Y [CK‐MB Access] = 1.3662 × [CK‐MB Vidas] + 0.0671; r(2) = 0.97). Clinical data were in good agreement with both immunoassays. ROC analysis performed in AMI demonstrated that the clinical performances of the two assays were similar. J. Clin. Lab. Anal. 14:43–47, 2000. © 2000 Wiley‐Liss, Inc.

Circulating p53 antibodies (ELISA method), p53genetic alterations (SSCP), and protein overexpression(immunohistochemistry) were studied in 41 patients withcolorectal adenocarcinomas and 10 control patients. Carcinoembryonic antigen (CEA) and carbohydrateantigen 19.9 (CA 19-9) were evaluated in parallel. Tenpatients with p53 antibodies and p53 overexpression wereselected. Tumor DNA extracts from these 10 patients were analyzed by SSCP. Of all 41patients, 10 (24%) showed significant levels of p53antibodies, and p53 accumulation was detected in 20(48%) patients. In six patients, p53 antibodieconcentrations decreased rapidly after surgery; in twopatients, these levels returned to normal values. Of the10 selected tumors, eight revealed TP53 gene mutations.Only two patients with high values of both CEA and CA 19-9 developed p53 antibodies. Inconclusion, beside classical tumor markers, circulatingp53 antibodies may be considered as additional markersfor the management of patients with colorectaladenocarcinomas.

Objective: to compare amino acid concentrations in healthy and malnourished elderly patients Method: plasma amino acid concentrations were examined in 24 men and women (80-100 years of age) with protein energy malnutrition (PEM) and compared with those of 44 healthy, similarly-aged controls. Plasma samples were determined by using cation exchange columns with ninhydrin detection in an high performance liquid chromatography system. Results: essential amino acid and non-essential amino acid plasma concentrations were significantly decreased in PEM (0.01 < P < 0.0001). Branched-chain amino acids and urea cycle amino acid plasma concentrations fell significantly (P < 0.0001). Plasma concentrations of alanine and glutamic acid + glutamine were also significantly reduced (P < 0.0001). Conclusions: in underweight elderly patients, the plasma amino acid pattern reflects the severity of the metabolic disturbance.

BackgroundHeart failure (HF) symptoms, related to pulmonary capillary hypertension, are frequent in hypertrophic cardiomyopathy (HCM). Pulmonary hypertension (PH) is the consequence of left ventricular (LV) diastolic pressure elevation and/or functional mitral regurgitation. We aimed to evaluate determinants and prognostic significance of rest and exercise in HCM.Methods and resultsWe included 235 patients referred for clinical work-up of HCM. Rest pulmonary artery systolic pressure (PASP) was measurable in 214 (91%) patients (48±16 years, 161 males). A symptom-limited semi-supine bicycle exercise was carried out in 188 patients. PASP was measurable during exercise in 108 patients (57%). Resting PH (≥36mmHg) was present in 56 patients (26.2%) and exercise PH (≥60mmHg) in 38 patients (35.2%). Mutivariate correlates of rest PASP were sinus rhythm (β=–0.15, P=0.021), LV obstruction tract (LVOT) peak gradient (β=0.22, P=0.001) and left atrial volume (β=0.39, P

Background Preeclampsia is a frequent complication of pregnancy and a leading cause of perinatal mortality. Both genetic and environmental risk factors have been identified. Lipid metabolism, particularly cholesterol metabolism, is associated with this disease. Liver X receptors alpha (NR1H3, also known as LXRalpha) and beta (NR1H2, also known as LXRbeta) play a key role in lipid metabolism. They belong to the nuclear receptor superfamily and are activated by cholesterol derivatives. They have been implicated in preeclampsia because they modulate trophoblast invasion and regulate the expression of the endoglin (CD105) gene, a marker of preeclampsia. The aim of this study was to investigate associations between the NR1H3 and NR1H2 genes and preeclampsia. Methods We assessed associations between single nucleotide polymorphisms of NR1H3 (rs2279238 and rs7120118) and NR1H2 (rs35463555 and rs2695121) and the disease in 155 individuals with preeclampsia and 305 controls. Genotypes were determined by high-resolution melting analysis. We then used a logistic regression model to analyze the different alleles and genotypes for those polymorphisms as a function of case/control status. Results We found no association between NR1H3 SNPs and the disease, but the NR1H2 polymorphism rs2695121 was found to be strongly associated with preeclampsia (genotype C/C: adjusted odds ratio, 2.05; 95% CI, 1.04-4.05; p = 0.039 and genotype T/C: adjusted odds ratio, 1.85; 95% CI, 1.01-3.42; p = 0.049). Conclusions This study provides the first evidence of an association between the NR1H2 gene and preeclampsia, adding to our understanding of the links between cholesterol metabolism and this disease.

The aim of this study is to report complications of transcatheter ASD closure using the Amplatzer Septal Occluder (ASO) (St Jude Medical).From December 1999 to October 2013 (April 2014), 760 patients underwent ASD closure with the ASO. Closure was mostly performed under general anaesthesia and transoesophageal echocardiography control. Choice of the device diameter was established after balloon sizing and measurement of the stretched diameter.Mean age of the patients was 31.9±22 years (0.5 month - 84 years). The stretched diameter was 22.5±6.6 mm (5-40mm) and device dimension 22±6.7mm (4-40mm). Duration of the procedure was 41±15 minutes (10-120 minutes) and fluoroscopic time 7.63±6.65 minutes (1-92 minutes). Dose of radiation was 18.7±22 Gy.cm2 (median 12 Gy.cm2).Implantation succeeded in 96.3% of pts and failure was mainly related to deficient rim. No device related death was noticed. Embolization occurred in 4 pts (0.5%): 1 in the aorta, 1 in the left ventricle, and 2 in the pulmonary artery. All but one underwent surgical extraction and ASD closure. The patient with aortic embolization had percutaneous device extraction and underwent subsequently successful implantation with a larger device. No patient required blood transfusion for any groin hematoma. One patient without aortic rim had hemopericardium one month after implantation; this was corrected by drainage with no recurrence and ASD full occlusion was noticed on colour Doppler control. No late complication was observed. The rate of full occlusion on Doppler control is more than 90%, and the remainings have trivial shunt.Transcatheter ASD occlusion with the Amplatzer Septal Occluder is a safe and effective procedure. The rate of immediate complication is very low and need for immediate surgery following the implantation is rare (

Cardiac troponins I (cTnI) and T (cTnT) have been shown to be highly sensitive and specific markers of myocardial cell injury. The purpose of this study was to investigate the diagnostic value of cTnI and cTnT with regard to creatine kinase (CK) and lactate dehydrogenase (LD) and to determine whether they can be used for early diagnosis of myocardial damage in rats, and to examine the relationship between cTnl and cTnT release with histological examinations, using isoprenaline-induced cardiac muscle damage as an experimental model in the rat. Eighteen Wistar rats per group were treated with a single dose of either isoprenaline (iso) or with normal saline as a control group. The anti-cTnI and cTnT monoclonal antibodies (mAbs) employed in the cTnI (Access) and cTnT (Elecsys) assays cross-react with cTnI and cTnT of the rat. A highly significant rise of cTnl or cTnT was found already 2 h after iso. The time-courses of cTnI and cTnT were monophasic in form. The highest cTnI (mean+/-S.D., 1.1+/-2.3 ng/ml) and cTnT (mean+/-S.D. 3.6+/-30 ng/ml) were found 4 h after iso. cTnI and cTnT significantly increased in iso-treated rats in comparison with controls whether the differences between 2-, 4- and 6-h levels and basal levels were considered or not. The areas under cTnl and cTnT curves (AUC) (0-6 h) and the maximal cTnI and cTnT (0-6 h) after iso were significantly different from the controls. For CK and LD, no elevation in comparison with controls could be detected (except a trend for LD whether or not the difference between 6-h levels and basal levels were considered (P=0.08) and for LD AUC (0-6 h) (P=0. 059)). Correlations between maximal cTnI and cTnT and AUC were 0.69 (P=0.0001) and 0.60 (P=0.0066), respectively. Histological examinations of iso-treated rats revealed acute focal or multifocal myofibrillar degeneration of the myocardial tissue in ten out of 14 rats and showed the earliest alterations 4 h after iso in one treated rat. Only four of the controls exhibited evidence of mild changes and slight mononuclear cell infiltration. cTnl and cTnT peak values to at least 0.35 and 1.3 ng/ml, respectively, were necessary to detect histological myocardial cell injury after iso. cTnI and cTnT were found to be early markers for diagnosing iso-induced myocardial damage in comparison with CK and LD. Elevations of cTnI and cTnT appeared to relate to the severity of histologic changes after myocardial injury. Although there was a difference in the absolute concentration of results between cTnI and cTnT assays, due to a lack of standardization and heterogeneity in the cross-reactivities of mAbs to various troponin I and T forms, cTnI and cTnT can be used as easily measurable target parameters for detection of cardiotoxic and/or cardiodegenerative effects in rats.

Background Few experimental studies report effects of direct contusion on cardiac enzyme release. Cardiac troponins I (cTnI) and T (cTnT) have been shown to be highly sensitive and specific markers of myocardial cell injury. This investigation was designed to determine and compare the acute effects of quantified magnitudes of blunt cardiac trauma upon release of cTnI and cTnT in comparison with creatine kinase (CK) and lactate dehydrogenase (LD). Methods In 24 rabbit hearts prepared on a standard Langendorff apparatus, myocardial contusion (MC) was produced by a single blow with a ball falling from a predefined height, delivered directly to the surface of the heart. Hearts were divided into control (n = 6) and various quantified impacts: 75 mJoules (mJ) (n = 6), 100 mJ (n = 6), 200 mJ (n = 6). Coronary effluent samples for cTnI, cTnT, CK, and LD were collected at baseline, immediately after MC and 5, 15, 30, 45, and 60 minutes after MC. At the end of experiment, histologic condition was evaluated. Results The anti-cTnI and cTnT MAbs used in the cTnI (Access) and cTnT (Elecsys) assays cross-react with cTnI and cTnT of the rabbit. The time-courses of cTnI, cTnT, CK, and LD were monophasic in form. After MC, all parameters rose significantly compared with baseline and with control group. The maximal release occurred immediately after MC. The area under the cTnI curve and the maximal cTnI concentration were linked to the contusion energy when increased at 200 mJ. Maximal concentrations and areas under cTnT, CK, LD time activity curve were not linked to the contusion energy level and showed no between-energy group differences. The correlation found between maximal cTnI and maximal cTnT concentrations was 0.70 (p = 0.0001). Histologic examination showed cellular disruption and after the more severe impact, the extent of pathologic changes was more extensive. Conclusion After graded experimental MC, maximal cTnI concentration and area under cTnI curve increase with the power of impact kinetic energy. Levels of cTnI allow a much higher accuracy in detecting the extent of myocardial injury postMC in comparison with cTnT, CK, and LD in this experimental study. These results should be consistent with the more extensive cTnI release with more severe impact in patients with blunt chest trauma. Furthermore, because specificity and time-course of release, both cTnI and cTnT should have a role in the diagnosis and evaluation of such patients.

There is little information about the relation between mild cardiac troponin I (cTn-I) increase after coronary interventions and late outcome. We therefore focused on the long-term outcome and the clinical, morphologic, and procedural correlates of elevation of cTn-I compared with cardiac troponin T, creatine kinase (CK), CK-MB activity and mass, and myoglobin in 105 patients with successful elective percutaneous transluminal coronary angioplasty (PTCA) for stable or unstable angina. Patients with myocardial infarction and those with unstable angina who had a detectable increase in serum markers before PTCA were excluded. Markers were measured before and after the procedure and for 2 days. Patients were followed up to record recurrent angina, myocardial infarction, cardiac death, repeat PTCA, or elective coronary artery bypass graft surgery. Procedure success was achieved in all cases. Elevation in cTn-I (or =0.1 microg/L) was observed in 23 of 105 patients (22%) (median peak: 0.25 microg/L); 18% had cardiac troponin T (cTn-T) release (or = 0.1 microg/L, median peak 0.21); 11.4% CK-MB mass (or =5 microg/L), and 7.6% myoglobin (or =90 microg/L) release. Five and 2 patients had elevated CK and CK-MB activity, respectively. Fourteen of 18 patients with cTn-T elevation had a corresponding elevation in cTn-I (kappa 0.68; p = 0.001). Patients positive for cTn-I had more unstable angina (p = 0.042) and heparin before PTCA (p = 0.046), and had longest total time (p = 0.004) and single inflation (p = 0.01). By multivariate logistic regression, predictors of postprocedure cTnI elevation were maximum time of each inflation (odds ratio 9.2; p = 0.0012), type B lesions (odds ratio 6.6; p = 0.013), unstable angina (p = 0.041), and ageor =60 years (p = 0.032). Clinical follow-up was available in 103 patients (98%) (mean 19+/-10 months). Kaplan-Meier survival analysis showed that cTn-I elevation was not an important correlate of cardiac events (p = 0.34, by log-rank analysis). The incidence of recurrent angina, myocardial infarction, cardiac death, and repeat revascularization after 12 months was not different in patients positive or negative for cTn-I. We conclude that cTn-I elevation after successful PTCA is not associated with significantly worse late clinical outcome. Levels of cTn-I allow a much higher diagnostic accuracy in detecting minor myocardial injury after PTCA compared with other markers, but there is no association with periprocedural myocardial cell injury and late outcome when cTn-I and other markers are considered.