Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with Amyotrophic Lateral Sclerosis.

AIMS: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron degeneration disease with a diagnostic delay of about 1 year after symptoms onset. In ALS, blood neurofilament light chain (NfL) levels are elevated, but it is not entirely clear what drives this increase and what the diagnostic performance of serum NfL is in terms of predictive values and likelihood ratios. The aims of this study were to further explore the prognostic and diagnostic performances of serum NfL to discriminate between patients with ALS and ALS mimics, and to investigate the relationship between serum NfL with motor neuron degeneration. METHODS: The diagnostic performances of serum NfL were based on a cohort of 149 serum samples of patients with ALS, 19 serum samples of patients with a disease mimicking ALS and 82 serum samples of disease control patients. The serum NfL levels were correlated with the number of regions (thoracic, bulbar, upper limb and lower limb) displaying upper and/or lower motor neuron degeneration. The prognostic performances of serum NfL were investigated based on a Cox regression analysis. RESULTS: The associated predictive values and likelihood ratio to discriminate patients with ALS and ALS mimics were established. Serum NfL was associated with motor neuron degeneration driven by upper motor neuron (UMN) degeneration and was independently associated with survival in patients with ALS. CONCLUSIONS: Altogether, these findings suggest that elevated serum NfL levels in ALS are driven by UMN degeneration and the disease progression rate and are independently associated with survival at time of diagnosis.

Xenon anaesthesia for patients undergoing off-pump coronary artery bypass graft surgery: a prospective randomized controlled pilot trial.

BACKGROUND: Off-pump coronary artery bypass (OPCAB) surgery carries a high risk for haemodynamic instability and perioperative organ injury. Favourable haemodynamic effects and organ-protective properties could render xenon an attractive anaesthetic for OPCAB surgery. The primary aim of this study was to assess whether xenon anaesthesia for OPCAB surgery is non-inferior to sevoflurane anaesthesia with regard to intraoperative vasopressor requirements. METHODS: Forty-two patients undergoing elective OPCAB surgery were enrolled in this prospective, single-blind, randomized controlled pilot trial. Patients were randomized to either xenon (50-60 vol%) or sevoflurane (1.1-1.4 vol%) anaesthesia. Primary outcome was intraoperative noradrenaline requirements necessary to achieve predefined haemodynamic goals. Secondary outcomes included safety variables such as the occurrence of adverse events (intraoperatively and during a 6-month follow-up after surgery) and the perioperative cardiorespiratory and inflammatory profile. RESULTS: Baseline and intraoperative data did not differ between groups. Xenon was non-inferior to sevoflurane, as xenon patients required significantly less noradrenaline intraoperatively to achieve the predefined haemodynamic goals {geometric mean 428 [95% confidence interval (CI) 312, 588] vs 1702 [1267, 2285] µg, P<0.0001}. No differences were found for safety. Significantly more sevoflurane patients developed postoperative delirium (POD) (hazard ratio 4.2, P=0.044). The average arterial pressure was lower in the sevoflurane group {median75 [interquartile range (IQR) 6] vs 72 [4] mmHg, P=0.002}. No differences were found for other haemodynamic parameters, the respiratory profile and the perioperative release of inflammatory cytokines, troponin T, serum protein S-100ß and erythropoietin. CONCLUSIONS: Compared with sevoflurane, xenon anaesthesia allows a significant reduction in vasopressor administration in OPCAB surgery. Moreover, xenon anaesthesia was associated with a lower risk for POD, a finding that has to be confirmed in larger studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01757106) and EudraCT (2012-002316-12).

Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype.

BACKGROUND: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. METHODS AND FINDINGS: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (-2578C/A, -1154G/A and -634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. CONCLUSIONS: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.

Diagnostic thresholds for free light chains in multiple myeloma depend on the assay used.

Leukemia accepted article preview online, 20 November 2017. doi:10.1038/leu.2017.335.

Epidemiology of infective endocarditis in a large Belgian non-referral hospital.

OBJECTIVES: Guidelines for diagnosis of infective endocarditis are largely based upon epidemiological studies in referral hospitals. Referral bias, however, might impair the validity of guidelines in non-referral hospitals. Recent studies in non-referral care centres on infective endocarditis are sparse. We conducted a retrospective epidemiological study on infective endocarditis in a large non-referral hospital in a Belgian city (Kortrijk). METHODS: The medical record system was searched for all cases tagged with a putative diagnosis of infective endocarditis in the period 2003-2010. The cases that fulfilled the modified Duke criteria for probable or definite infective endocarditis were included. RESULTS: Compared to referral centres, an older population with infective endocarditis, and fewer predisposing cardiac factors and catheter-related infective endocarditis is seen in our population. Our patients have fewer prosthetic valve endocarditis as well as fewer staphylococcal endocarditis. Our patients undergo less surgery, although mortality rate seems to be highly comparable with referral centres, with nosocomial infective endocarditis as an independent predictor of mortality. CONCLUSION: The present study suggests that characteristics of infective endocarditis as well as associative factors might differ among non-referral hospitals and referral hospitals.

Therapeutic potential of VEGF and VEGF-derived peptide in peripheral neuropathies.

Besides its prominent role in angiogenesis, the vascular endothelial growth factor (VEGF) also exerts important protective effects on neurons. In particular, mice expressing reduced levels of VEGF suffer from late-onset motor neuron degeneration, whereas VEGF delivery significantly delays motor neuron death in ALS mouse models, at least partly through neuroprotective effects. Additionally, VEGF protects dorsal root ganglion (DRG) neurons against paclitaxel-induced neurotoxicity. Here, we demonstrate that VEGF also protects DRG neurons against hyperglycemia-induced neuronal stress as a model of diabetes-induced peripheral neuropathy. Specifically, VEGF decreased expression of the stress-related gene activating transcription factor 3 (ATF3) in DRG neurons isolated from streptozotocin-induced diabetic mice (ex vivo) and in isolated DRG neurons exposed to high glucose concentrations (in vitro). In vivo, local VEGF application also protected against paclitaxel- and diabetes-induced neuropathies without causing side effects. A small synthetic VEGF mimicking pentadecapeptide (QK) exerted similar effects on DRG cultures: the peptide reduced ATF3 expression in vitro and ex vivo in paclitaxel- and hyperglycemia-induced models of neuropathy to a similar extent as the full-length recombinant VEGF protein. By using transgenic mice selectively overexpressing the VEGF receptor 2 in postnatal neurons, these neuroprotective effects were shown to be mediated through VEGF receptor 2. Overall, these results underscore the potential of VEGF and VEGF-derived peptides for the treatment of peripheral neuropathies.