Validating, deconstructing and refining Baveno criteria for ruling out high-risk varices in patients with compensated cirrhosis.

BACKGROUND: Guidelines recommend variceal screening in patients with cirrhosis to identify varices at high risk of bleeding requiring primary prophylaxis. Non-invasive criteria to rule out high-risk varices will avoid unnecessary endoscopies. Recent Baveno VI criteria define patients with compensated cirrhosis in whom endoscopy can be avoided as those with a liver stiffness by transient elastography <20 kPa and a platelet count >150 000/mm3. AIMS: To validate Baveno criteria in two cohorts with a different prevalence of high-risk varices and to determine whether alternate parameters not including liver stiffness would be equal/more accurate in ruling out high-risk varices. METHODS: Retrospective study evaluating patients with liver stiffness >10 kPa who had liver stiffness and endoscopy within 1 year of each other. RESULTS: This study included 161 patients from the US cohort (14 [9%] with high-risk varices) and 101 patients from an Italian cohort (17 [17%] with high-risk varices). Of patients meeting Baveno criteria (41 in the US, 16 in Italy), none had high-risk varices and therefore 26% (US) and 16% (Italy) endoscopies could have been avoided. Sensitivity and negative predictive value were 100%. A stepwise strategy using platelet count >150 000 and MELD=6, increased the number of endoscopies avoided to 54% (US) while maintaining a sensitivity and negative predictive value of 100%. Excellent sensitivity and negative predictive value were validated in the Italian cohort and in another cohort of patients with a clinical diagnosis of cirrhosis. CONCLUSIONS: This study validates Baveno VI criteria, particularly in sites with a low prevalence of high-risk varices and describes a new accurate strategy that does not include liver stiffness.

Fingolimod impedes Schwann cell-mediated myelination: implications for the treatment of immune neuropathies?

BACKGROUND: Fingolimod (FTY720), a first-in-class sphingosine-1-phosphate (S1P) receptor agonist, is a recently approved drug for treating relapsing multiple sclerosis. Experimental evidence suggests that FTY720 not only exhibits anti-inflammatory properties but also promotes myelination in the central nervous system by direct interaction with oligodendrocytes. OBJECTIVE: To assess the effects of FTY720 on Schwann cells (SCs) and peripheral nerve myelination. DESIGN: Receptor expression studies and myelination were investigated in primary rat SCs and rat neuronal/SC cocultures. Cells were treated with physiologically relevant concentrations of the active phosphorylated form of FTY720 (FTY720P). In addition, S1P receptor expression was corroborated in human and rat peripheral nerve tissue sections. RESULTS: Schwann cells express all known S1P receptors on the RNA level, not altered by FTY720P. In the myelination model, treatment with FTY720P resulted in a significant reduction of quantitative myelin formation. FTY720P induced reactive oxygen species in SCs associated with apoptosis of these cells, as demonstrated by the detection of cysteine aspartic acid­specific protease 3 and 7, as well as terminal deoxynucleotidyl transferase dUTP nick-end labeling. This effect was dependent of S1P signaling because the blocking of S1P receptors ameliorated reactive oxygen species production, SC apoptosis, and myelin loss. CONCLUSIONS: FTY720P at greater concentrations induces apoptosis in SCs and may interfere with peripheral nerve myelination.

Adrenoleukodystrophy in female heterozygotes: underrecognized and undertreated.

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease resulting from mutations in the gene ABCD1 and alterations in peroxisomal beta-oxidation of long chain fatty acids. As it has been frequently discussed, it manifests a wide range of phenotypes in male, with progressive myelopathy being the most common. Even though the gene is localized to the X-chromosome and a region subject to X-inactivation, female carriers still are affected significantly by this condition. It has been stated that between 20 and 50% of women who are carriers may manifest some symptoms and recent evidence has suggested the differences in disease manifestations and relative rates of progression between men and women. However there have been only limited studies specifically addressing this and to date there has been no comprehensive review discussing the different phenotypes in female carriers, as well as the differences in disease onset, progression, disability, nervous system pathology and neuroimaging patterns compared to affected males. This is of key importance as similarities and differences between genders will assist in determining how best to target therapies in all affected individuals as opportunities for treatment present themselves. As will be further addressed in this review, we need to improve our understanding of the associations of emergent neuroimaging techniques to physical disability in this population. We reviewed the clinical presentations in the carrier population, the distinct disability profile and neuroimaging findings in order to put together pieces of this neglected segment in X-ALD and give direction to further studies.

Autoantibody-mediated dysfunction of sympathetic neurons in guillain-barre syndrome.

OBJECTIVE: To investigate a pathologic immune response to autonomic nerve fibers in Guillain-Barré syndrome (GBS). DESIGN: We compared the effects of purified IgG from patients with GBS, multiple sclerosis, and chronic inflammatory demyelinating polyneuropathy on transmitter synthesis and synaptic transmission in an in vitro model of sympathetic neurons and cardiomyocytes. SUBJECTS: Three patients with GBS, 2 with chronic inflammatory demyelinating polyradiculoneuropathy, and 2 with relapsing-remitting multiple sclerosis. RESULTS: Incubation of sympathetic neurons with GBS-IgG resulted in an upregulation of tyrosine hydroxylase and caused a relative increase of noradrenaline levels. In cocultures of sympathetic neurons and cardiomyocytes, GBS-IgG altered the synaptic transmission, as assessed by changes in the average cardiomyocyte beat rate. These effects could be neutralized by preincubation of sympathetic neurons with intravenous immunoglobulins. CONCLUSION: Our findings indicate that in GBS, circulating antibodies directed against sympathetic neurons may contribute to autonomic dysfunction via functionally relevant changes in the noradrenaline synthesis.

Involvement of ADAM10 in axonal outgrowth and myelination of the peripheral nerve.

The disintegrin and metalloproteinase 10 (ADAM10) is a membrane-anchored metalloproteinase with both proteolytic and disintegrin characteristics. Here, we investigate the expression, regulation, and functional role of ADAM10 in axonal outgrowth and myelination of the peripheral nerve. Expression pattern analysis of 11 ADAM family members in co-cultures of rat dorsal root ganglia (DRG) neurons and Schwann cells (SCs) demonstrated the most pronounced mRNA expression for ADAM10. In further studies, ADAM10 was found to be consistently upregulated in DRG-SC co-cultures before the induction of myelination. Neurons as well as SCs widely expressed ADAM10 at the protein level. In neurons, the expression of ADAM10 was exclusively limited to the axons before the induction of myelination. Inhibition of ADAM10 activity by the hydroxamate-based inhibitors GI254023X and GW280264X resulted in a significant decrease in the mean axonal length. These data suggest that ADAM10 represents a prerequisite for myelination, although its activity is not required during the process of myelination itself as demonstrated by expression analysis of myelin protein zero (P0) and Sudan black staining. Hence, during the process of myelin formation, ADAM10 is highly upregulated and appears to be critically involved in axonal outgrowth that is a requirement for myelination in the peripheral nerve.

Neural precursor cells as a novel target for interferon-beta.

The immunomodulating agent interferon-beta (IFNbeta) is administered therapeutically in several autoimmune diseases and endogenously released by immune cells during diverse infections. As in recent years a variety of pro- and anti-inflammatory substances were shown to influence significantly neural precursor cells that are implicated in a variety of regenerative mechanisms but also in tumor growth, we studied a possible effect of IFNbeta on neural precursor cells derived from murine embryonic day 14 neurospheres. First, we demonstrated that interferon type-I receptors are expressed on neural precursor cells and that these cells respond to IFNbeta treatment by up-regulating IFNbeta inducible genes including Myxovirus 1 and viperin. Furthermore, we could show for the first time that IFNbeta treatment significantly inhibited the proliferation of neural precursor cells possibly through induction of p21, a cyclin-dependent kinase inhibitor. IFNbeta did not exert cytotoxic or neuroprotective effects and we could not see effects on the differentiation of neural precursor cells into total amounts of neurons, astrocytes or oligodendrocytes. However, we found that IFNbeta markedly diminished neurite outgrowth and neuronal maturation of neural precursor-derived neurons.

Matrix metalloproteinase-2 is involved in myelination of dorsal root ganglia neurons.

Matrix metalloproteinases (MMPs) comprise a large family of endopeptidases that are capable of degrading all extracellular matrix components. There is increasing evidence that MMPs are not only involved in tissue destruction but may also exert beneficial effects during axonal regeneration and nerve remyelination. Here, we provide evidence that MMP-2 (gelatinase A) is associated with the physiological process of myelination in the peripheral nervous system (PNS). In a myelinating co-culture model of Schwann cells and dorsal root ganglia neurons, MMP-2 expression correlated with the degree of myelination as determined by immunocytochemistry, zymography, and immunosorbent assay. Modulation of MMP-2 activity by chemical inhibitors led to incomplete and aberrant myelin formation. In vivo MMP-2 expression was detected in the cerebrospinal fluid (CSF) of patients with Guillain-Barré syndrome as well as in CSF and sural nerve biopsies of patients with chronic inflammatory demyelinating polyneuropathy. Our findings suggest an important, previously unrecognized role for MMP-2 during myelination in the PNS. Endogenous or exogenous modulation of MMP-2 activity may be a relevant target to enhance regeneration in demyelinating diseases of the PNS.