Clinical manifestations and outcome of anti-PL7 positive patients with antisynthetase syndrome

BackgroundThe aims of the present study were to determine both clinical manifestations and outcome of anti-PL7 patients with antisynthetase syndrome (ASS).MethodsThe medical records of 15 consecutive anti-PL7 patients with biopsy proven ASS were retrospectively analyzed without prior selection.ResultsAnti-PL7 patients exhibited polymyositis (n = 14) and dermatomyositis (n = 1); extra-pulmonary manifestations of ASS included: Raynaud's phenomenon (40%), mechanic's hands (33.3%), joint impairment (26.7%), pericardial effusion (20%) and esophageal/gastrointestinal involvement (20%). The outcome of myositis was as follows: remission/improvement (91.7%) and deterioration (8.3%). Fourteen patients (93.3%) experienced interstitial lung disease (ILD). ILD preceded ASS diagnosis (n = 5), was identified concomitantly with ASS (n = 8) and occurred after ASS diagnosis (n = 1). Patients could be divided into 3 groups according to their presenting lung manifestations: acute onset of lung disease (n = 1), progressive onset of lung signs (n = 11) and asymptomatic patients exhibiting abnormalities consistent with ILD on PFT and HRCT-scan (n = 2). No patient had resolution of ILD, whereas 64.3% and 35.7% experienced improvement and deterioration of ILD, respectively. ILD resulted in respiratory insufficiency requiring O₂ therapy in 14.3% of cases. Two patients died. Predictive parameters of ILD deterioration were: DLCO < 45% at ILD diagnosis and HRCT-scan pattern of usual interstitial pneumonia (UIP).ConclusionOur series mainly underscores that ILD is frequent in anti-PL7 patients, leading to high morbidity. Our study further suggests that patients with predictive factors of ILD deterioration may require more aggressive therapy, especially the group of patients with DLCO < 45% at ILD diagnosis and UIP pattern on HRCT-scan.     

Comparison of long-term outcome between anti-Jo1- and anti-PL7/PL12 positive patients with antisynthetase syndrome

The aims of the present study were to: compare the characteristics between antisynthetase syndrome (ASS) patients with anti-Jo1 antibody and those with anti-PL7/PL12 antibody. The medical records of 95 consecutive patients with ASS were reviewed. Seventy-five of these patients had anti-Jo1 antibody; the other patients had anti-PL7 (n=15) or anti-PL12 (n=5) antibody. At ASS diagnosis, the prevalence of myalgia (p=0.007) and muscle weakness (p=0.02) was significantly lower in the group of anti-PL7/PL12-positive patients than in those with anti-Jo1 antibody; median value of CK (p=0.00003) was also lower in anti-PL7/PL12 patients. Anti-Jo1 positive patients developed more rarely myositis resolution (21.3% vs. 46.2%); in addition, the overall recurrence rate of myositis was higher in anti-Jo1 positive patients than in patients with anti-PL7/PL12 antibody (65.9% vs. 19.4%). Anti-Jo1-positive patients, compared with those with anti-PL7/PL12 antibody, more often experienced: joint involvement (63.3%vs. 40%) and cancer (13.3% vs. 5%). By contrast, anti-PL7/PL12 positive patients, compared with those with anti-Jo1 antibody, more commonly exhibited: ILD (90% vs. 68%); in anti-PL7/PL12 positive patients, ILD was more often symptomatic at diagnosis, and led more rarely to resolution of lung manifestations (5.6% vs. 29.4%). Finally, the group of anti-PL7/PL12 positive patients more commonly experienced gastrointestinal manifestations related to ASS (p=0.02). Taken together, although anti-Jo1 positive patients with ASS share some features with those with anti-PL7/PL12 antibody, they exhibit many differences regarding clinical phenotype and long-term outcome. Our study underscores that the presence of anti-Jo1 antibody results in more severe myositis, joint impairment and increased risk of cancer. On the other hand, the presence of anti-PL7/PL12 antibody is markedly associated with: early and severe ILD, and gastrointestinal complications. Thus, our study interestingly indicates that the finding for anti-Jo1 and anti-PL7/PL12 antibodies impacts both the long-term outcome and prognosis of patients with ASS.     

Identification of early target genes of aflatoxin B1 in human hepatocytes, inter-individual variability and comparison with other genotoxic compounds

Gene expression profiling has recently emerged as a promising approach to identify early target genes and discriminate genotoxic carcinogens from non-genotoxic carcinogens and non-carcinogens. However, early gene changes induced by genotoxic compounds in human liver remain largely unknown. Primary human hepatocytes and differentiated HepaRG cells were exposed to aflatoxin B1 (AFB1) that induces DNA damage following enzyme-mediated bioactivation. Gene expression profile changes induced by a 24 h exposure of these hepatocyte models to 0.05 and 0.25 μM AFB1 were analyzed by using oligonucleotide pangenomic microarrays. The main altered signaling pathway was the p53 pathway and related functions such as cell cycle, apoptosis and DNA repair. Direct involvement of the p53 protein in response to AFB1 was verified by using siRNA directed against p53. Among the 83 well-annotated genes commonly modulated in two pools of three human hepatocyte populations and HepaRG cells, several genes were identified as altered by AFB1 for the first time. In addition, a subset of 10 AFB1-altered genes, selected upon basis of their function or tumor suppressor role, was tested in four human hepatocyte populations and in response to other chemicals. Although they exhibited large variable inter-donor fold-changes, several of these genes, particularly FHIT, BCAS3 and SMYD3, were found to be altered by various direct and other indirect genotoxic compounds and unaffected by non-genotoxic compounds. Overall, this comprehensive analysis of early gene expression changes induced by AFB1 in human hepatocytes identified a gene subset that included several genes representing potential biomarkers of genotoxic compounds.     

Regional and hemispheric determinants of language laterality: Implications for preoperative fMRI

Language is typically a function of the left hemisphere but the right hemisphere is also essential in some healthy individuals and patients. This inter‐subject variability necessitates the localization of language function, at the individual level, prior to neurosurgical intervention. Such assessments are typically made by comparing left and right hemisphere language function to determine “language lateralization” using clinical tests or fMRI. Here, we show that language function needs to be assessed at the region and hemisphere specific level, because laterality measures can be misleading. Using fMRI data from 82 healthy participants, we investigated the degree to which activation for a semantic word matching task was lateralized in 50 different brain regions and across the entire cortex. This revealed two novel findings. First, the degree to which language is lateralized across brain regions and between subjects was primarily driven by differences in right hemisphere activation rather than differences in left hemisphere activation. Second, we found that healthy subjects who have relatively high left lateralization in the angular gyrus also have relatively low left lateralization in the ventral precentral gyrus. These findings illustrate spatial heterogeneity in language lateralization that is lost when global laterality measures are considered. It is likely that the complex spatial variability we observed in healthy controls is more exaggerated in patients with brain damage. We therefore highlight the importance of investigating within hemisphere regional variations in fMRI activation, prior to neuro‐surgical intervention, to determine how each hemisphere and each region contributes to language processing. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Normative Bone Mineral Density Z-Scores for Canadians Aged 16 to 24 Years: The Canadian Multicenter Osteoporosis Study

The objectives of the study were to develop bone mineral density (BMD) reference norms and BMD Z-scores at various skeletal sites, to determine whether prior fracture and/or asthma were related to BMD, and to assess possible geographic variation of BMD among Canadian youth aged 16–24 yr. Z-Scores were defined as the number of standard deviations from the mean BMD of a healthy population of the same age, race, and sex. Z-Scores were calculated using the reference sample defined as Canadian Caucasian participants without asthma or prior fracture. Reference standards were created for lumbar spine (L1–L4), femoral neck, total hip, and greater trochanter, by each year of age (16–24 yr), and by sex. The Z-score norms were developed for groups noted earlier. Mean Z-scores between the asthma or fracture subgroups compared with the mean Z-scores in the reference sample were not different. There were minor differences in mean BMD across different Canadian geographic regions. This study provides age, sex, and skeletal site-specific Caucasian reference norms and formulae for the calculation of BMD Z-scores for Canadian youth aged 16–24 yr. This information will be valuable to help to identify individuals with clinically meaningful low BMD.     

High spatial resolution quantitative MR images: an experimental study of dedicated surface coils

Measuring spin-spin relaxation times (T2) by quantitative MR imaging represents a potentially efficient tool to evaluate the physicochemical properties of various media. However, noise in MR images is responsible for uncertainties in the determination of T2 relaxation times, which limits the accuracy of parametric tissue analysis. The required signal-to-noise ratio (SNR) depends on the T2 relaxation behaviour specific to each tissue. Thus, we have previously shown that keeping the uncertainty in T2 measurements within a limit of 10% implies that SNR values be greater than 100 and 300 for mono- and biexponential T2 relaxation behaviours, respectively. Noise reduction can be obtained either by increasing the voxel size (i.e., at the expense of spatial resolution) or by using high sensitivity dedicated surface coils (which allows us to increase SNR without deteriorating spatial resolution in an excessive manner). However, surface coil sensitivity is heterogeneous, i.e., it--and hence SNR--decreases with increasing depth, and the more so as the coil radius is smaller. The use of surface coils is therefore limited to the analysis of superficial structure such as the hypodermic tissue analysed here. The aim of this work was to determine the maximum limits of spatial resolution and depth compatible with reliable in vivo T2 quantitative MR images using dedicated surface coils available on various clinical MR scanners. The average thickness of adipose tissue is around 15 mm, and the results obtained have shown that obtaining reliable biexponential relaxation analysis requires a minimum achievable voxel size of 13 mm3 for a conventional volume birdcage coil and only of 1.7 mm3 for the smallest available surface coil (23 mm in diameter). Further improvement in spatial resolution allowing us to detect low details in MR images without deteriorating parametric T2 images can be obtained by image filtering. By using the non-linear selective blurring filter described in a previous work, the voxel size was reduced to 0.8 mm3, allowing us to detect microstructures such as fibrous septae while preserving precision in T2 measurements. This paper provides practical information allowing us to perform reliable T2 quantitative MR micro images. High resolution imaging with dedicated surface coils, which is only well-suited to near surface organs, might lead to highly valuable results in this context, especially to analyse the hypodermis involved in the lipodystrophy seen in patients with human immuno-deficiency virus (HIV).