Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients

Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD

The predictive role of serum and bronchoalveolar lavage cytokines and adhesion molecules for acute respiratory distress syndrome development and outcome

BACKGROUND: The predictive role of many cytokines and adhesion molecules has not been studied systematically in acute respiratory distress syndrome (ARDS). METHODS: We measured prospectively tumour necrosis factor alpha (TNF-α), interleukin (IL)-1, soluble vascular adhesion molecule-1 (VCAM-1) and soluble intercellular adhesion molecule-1 (ICAM-1) in serum and bronchoalveolar lavage fluid (BALF) within 2 hours following admission, in 65 patients. The patients were divided into: those fulfilling the criteria for ARDS (n = 23, group A), those who were pre-ARDS and who developed ARDS within 24 hours (n = 14, group B), and those on pre-ARDS but who never developed ARDS (n = 28, group C). RESULTS: All the measured molecules were only found at higher levels in the serum of patients that died either with or without ARDS (P < 0.05 – P < 0.0001). Patients at risk exhibited a good negative predictive value (NPV) of the measured molecules for ARDS development both in their serum (89 to 95%) and BALF (86 to 92%) levels. In contrast to BALF, serum levels of IL-1 and adhesion molecules exhibited a good NPV (68 to 96%), sensitivity (60 to 88%) and survival specificity (74 to 96%) in all groups. All molecules in serum and BALF IL-1 were correlated with the APACHE II (P < 0.05 – P < 0.0001). Serum and BALF IL-1 as well as BALF TNF-α were negatively correlated to PaO(2)/FiO(2) (all P < 0.05). CONCLUSIONS: The studied molecules have good NPV for ARDS development both in serum and BALF. Serum rather than BALF levels seem to be related to outcome

The clinical significance of serum and bronchoalveolar lavage inflammatory cytokines in patients at risk for Acute Respiratory Distress Syndrome

BACKGROUND: The predictive role of many cytokines has not been well defined in Acute Respiratory Distress Syndrome (ARDS). METHODS: We measured prospectively IL-4, IL-6, IL-6 receptor, IL-8, and IL-10, in the serum and bronchoalveolar lavage fluid (BALF) in 59 patients who were admitted to ICU in order to identify predictive factors for the course and outcome of ARDS. The patients were divided into three groups: those fulfilling the criteria for ARDS (n = 20, group A), those at risk for ARDS and developed ARDS within 48 hours (n = 12, group B), and those at risk for ARDS but never developed ARDS (n = 27, group C). RESULTS: An excellent negative predictive value for ARDS development was found for IL-6 in BALF and serum (100% and 95%, respectively). IL-8 in BALF and IL-8 and IL-10 serum levels were higher in non-survivors in all studied groups, and were associated with a high negative predictive value. A significant correlation was found between IL-8 and APACHE score (r = 0.60, p < 0.0001). Similarly, IL-6 and IL-6r were highly correlated with PaO2/FiO2 (r = -0.27, p < 0.05 and r = -0.55, p < 0.0001, respectively). CONCLUSIONS: BALF and serum levels of the studied cytokines on admission may provide valuable information for ARDS development in patients at risk, and outcome in patients either in ARDS or in at risk for ARDS

Artificial Neural Networks Versus Multiple Logistic Regression to Predict 30-Day Mortality After Operations For Type A Ascending Aortic Dissection§

There are few comparative reports on the overall accuracy of neural networks (NN), assessed only versus multiple logistic regression (LR), to predict events in cardiovascular surgery studies and none has been performed among acute aortic dissection (AAD) Type A patients. OBJECTIVES: We aimed at investigating the predictive potential of 30-day mortality by a large series of risk factors in AAD Type A patients comparing the overall performance of NN versus LR. METHODS: We investigated 121 plus 87 AAD Type A patients consecutively operated during 7 years in two Centres. Forced and stepwise NN and LR solutions were obtained and compared, using receiver operating characteristic area under the curve (AUC) and their 95% confidence intervals (CI) and Gini's coefficients. Both NN and LR models were re-applied to data from the second Centre to adhere to a methodological imperative with NN. RESULTS: Forced LR solutions provided AUC 87.9+/-4.1% (CI: 80.7 to 93.2%) and 85.7+/-5.2% (CI: 78.5 to 91.1%) in the first and second Centre, respectively. Stepwise NN solution of the first Centre had AUC 90.5+/-3.7% (CI: 83.8 to 95.1%). The Gini's coefficients for LR and NN stepwise solutions of the first Centre were 0.712 and 0.816, respectively. When the LR and NN stepwise solutions were re-applied to the second Centre data, Gini's coefficients were, respectively, 0.761 and 0.850. Few predictors were selected in common by LR and NN models: the presence of pre-operative shock, intubation and neurological symptoms, immediate post-operative presence of dialysis in continuous and the quantity of post-operative bleeding in the first 24 h. The length of extracorporeal circulation, post-operative chronic renal failure and the year of surgery were specifically detected by NN. CONCLUSIONS: Different from the International Registry of AAD, operative and immediate post-operative factors were seen as potential predictors of short-term mortality. We report a higher overall predictive accuracy with NN than with LR. However, the list of potential risk factors to predict 30-day mortality after AAD Type A by NN model is not enlarged significantly

Whole Transcriptome Sequencing Reveals Gene Expression and Splicing Differences in Brain Regions Affected by Alzheimer's Disease

Recent studies strongly indicate that aberrations in the control of gene expression might contribute to the initiation and progression of Alzheimer's disease (AD). In particular, alternative splicing has been suggested to play a role in spontaneous cases of AD. Previous transcriptome profiling of AD models and patient samples using microarrays delivered conflicting results. This study provides, for the first time, transcriptomic analysis for distinct regions of the AD brain using RNA-Seq next-generation sequencing technology. Illumina RNA-Seq analysis was used to survey transcriptome profiles from total brain, frontal and temporal lobe of healthy and AD post-mortem tissue. We quantified gene expression levels, splicing isoforms and alternative transcript start sites. Gene Ontology term enrichment analysis revealed an overrepresentation of genes associated with a neuron's cytological structure and synapse function in AD brain samples. Analysis of the temporal lobe with the Cufflinks tool revealed that transcriptional isoforms of the apolipoprotein E gene, APOE-001, -002 and -005, are under the control of different promoters in normal and AD brain tissue. We also observed differing expression levels of APOE-001 and -002 splice variants in the AD temporal lobe. Our results indicate that alternative splicing and promoter usage of the APOE gene in AD brain tissue might reflect the progression of neurodegeneration

Influence of preoperative nucleus pulposus status and radiculopathy on outcomes in mono-segmental lumbar total disc replacement: results from a nationwide registry

Background: Currently, herniated nucleus pulposus (HNP) with radiculopathy and other preconditions are regarded as relative or absolute contraindications for lumbar total disc replacement (TDR). In Switzerland it is left to the surgeon's discretion when to operate. The present study is based on the dataset of SWISSspine, a governmentally mandated health technology assessment registry. We hypothesized that preoperative nucleus pulposus status and presence or absence of radiculopathy has an influence on clinical outcomes in patients treated with mono-segmental lumbar TDR. Methods. Between March 2005 and April 2009, 416 patients underwent mono-segmental lumbar TDR, which was documented in a prospective observational multicenter mode. The data collection consisted of perioperative and follow-up data (physician based) and clinical outcomes (NASS, EQ-5D). Patients were divided into four groups according to their preoperative status: 1) group degenerative disc disease ("DDD"): 160 patients without HNP and no radiculopathy, classic precondition for TDR; 2) group "HNP-No radiculopathy": 68 patients with HNP but without radiculopathy; 3) group "Stenosis": 73 patients without HNP but with radiculopathy, and 4) group "HNP-Radiculopathy": 132 patients with HNP and radiculopathy. The groups were compared regarding preoperative patient characteristics and pre- and postoperative VAS and EQ-5D scores using general linear modeling. Results: Demographics in all four groups were comparable. Regarding the improvement of quality of life (EQ-5D) there were no differences across the four groups. For the two main groups DDD and HNP-Radiculopathy no differences were found in the adjusted postoperative back- and leg pain alleviation levels, in the stenosis group back- and leg pain relief were lower. Conclusions: Despite higher preoperative leg pain levels, outcomes in lumbar TDR patients with HNP and radiculopathy were similar to outcomes in patients with the classic indication; this because patients with higher preoperative leg pain levels benefit from a relatively greater leg pain alleviation. The group with absence of HNP but presence of radiculopathy showed considerably less benefits from the operation, which is probably related to ongoing degenerative processes of the posterior segmental structures. This observational multicenter study suggests that the diagnoses HNP and radiculopathy, combined or alone, may not have to be considered as absolute or relative contraindications for mono-segmental lumbar TDR anymore, whereas patients without HNP but with radiculopathy seem to be suboptimal candidates for the procedure. © 2011 Zweig et al; licensee BioMed Central Ltd