Chronic cerebrospinal venous insufficiency is not associated with multiple sclerosis and its severity: a blind-verified study.

BACKGROUND: Chronic Cerebrospinal Venous Insufficiency (CCSVI) has been associated with multiple sclerosis (MS) with a risk ranging from as high as two-hundred-fold to a protective effect. However, not all studies were blinded, and the efficacy of blinding was never assessed. OBJECTIVE: To evaluate the association of CCSVI with MS in a cross-sectional blinded study and look for any association of CCSVI with the severity of MS. METHODOLOGY/PRINCIPAL FINDINGS: The Echo-color Doppler examination was carried out in accordance with Zamboni's five criteria in 68 consecutive MS patients and 68 healthy controls, matched by gender and age (±5 years). Four experienced neurosonologists, blinded to the status of cases and controls, performed the study and were then asked to guess the status (case or control) of each participant. The number of positive CCSVI criteria was similar in the two groups. CCSVI, defined as the presence of two or more criteria, was detected in 21 cases (30.9%) and 23 controls (33.8%), with an OR of 0.9 (95%CL = 0.4-1.8, p = 0.71). The prevalence of CCSVI was related to age in cases (OR increasing from 0.2 to 1.4), but not in controls. CCSVI positive (N = 21) and negative (N = 47) MS patients were similar in clinical type, age at disease onset, disability, and fatigue. Disease duration was longer (16.5±9.8 years) in CCSVI positive than negative patients (11.5±7.4; p = 0.04). The operators correctly guessed 34/68 cases (50%) and 45/68 controls (66%) (p = 0.06), indicating a different success of blinding. CONCLUSIONS/SIGNIFICANCE: CCSVI was not associated with MS itself, nor its severity. We cannot rule out the possibility that CCSVI is a consequence of MS or of aging. Blinding of sonographers is a key point in studying CCSVI and its verification should be a requisite of future studies

Inhibition of FGF23 is a therapeutic strategy to target hematopoietic stem cell niche defects in β-thalassemia

Clinical evidence highlights a relationship between the blood and the bone, but the underlying mechanism linking these two tissues is not fully elucidated. Here, we used beta-thalassemia as a model of congenital anemia with bone and bone marrow (BM) niche defects. We demonstrate that fibroblast growth factor 23 (FGF23) is increased in patients and mice with beta-thalassemia because erythropoietin induces FGF23 overproduction in bone and BM erythroid cells via ERK1/2 and STAT5 pathways. We show that in vivo inhibition of FGF23 signaling by carboxyl-terminal FGF23 peptide is a safe and efficacious therapeutic strategy to rescue bone mineralization and deposition in mice with beta-thalassemia, normalizing the expression of niche factors and restoring hematopoietic stem cell (HSC) function. FGF23 may thus represent a molecular link connecting anemia, bone, and the HSC niche. This study provides a translational approach to targeting bone defects and rescuing HSC niche interactions, with potential clinical relevance for improving HSC transplantation and gene therapy for hematopoietic disorders

Prevalence of CCSVI criteria in cases and controls (N, %).

<p>Prevalence of CCSVI criteria in cases and controls (N, %).</p

Prevalence of CCSVI criteria by age-groups (N, %).

<p>p = 0.09 for cases and 0.80 for controls (chi-square for trend test).</p

Number of CCSVI criteria in cases and controls.

<p>p = 0.57 (chi-square for trend test).</p

Characteristics of the case-control studies on CCSVI and MS.

<p>NE = not estimable; SD = Standard Deviation; HC = healthy controls; OD = other diseases;</p

Clinical and demographic data of multiple sclerosis (MS) patients and healthy control subjects.

<p>SD = Standard Deviation; IQ = Interquartile Range; EDSS = Expanded Disability Status Scale; MSSS = Multiple Sclerosis Severity Score; FSS = Fatigue Severity Scale; DMD = Disease Modifying Drugs; ISA = immunosuppressive agents.</p

Data from: A reliability study of colour-Doppler sonography for the diagnosis of chronic cerebrospinal venous insufficiency shows low inter-rater agreement

Objective: Chronic cerebrospinal venous insufficiency (CCSVI) has been extremely variable associated with multiple sclerosis in color-Doppler sonographic studies. We aimed to evaluate inter-rater agreement in color doppler sonograpy venous examination. Design: Inter-rater agreement study. Setting: First-referral multiple sclerosis centre. Participants: thirty-eight multiple sclerosis patients, and 55 age-matched (± 5 years) controls. Intervention: sonography was carried out in accordance with Zamboni's five criteria by 8 sonographers with different expertise, blinded to the status of cases and controls. Each subject was evaluated by two operators. Primary and secondary outcome measures: inter-rater agreement was measured through the Kappa statistics and the Intraclass Correlation Coefficient. Results: The agreement was no higher than chance for criterion 2-reflux in the deep cerebral veins (Kappa=-0.02) and 4-flow not Doppler-detectable in one or both the internal jugular (IJVs) or vertebral veins (VVs) (-0.09). It was substantially low for criterion 1-reflux in the IJVs and/or VVs (0.29), criterion 3-IJV stenosis or malformations (0.23), and criterion 5-absence of IJV diameter increase when passing from sitting to supine position (0.22). The Kappa value for CCSVI as a whole was 0.20 (95% confidence limits=-0.01 - 0.42). Intraclass Correlation Coefficients for the measure of cross-sectional area ranged from 0.05 to 0.25. Inter-rater agreement was low for CCSVI experts (kappa= 0.24; -0.11 to 0.59), and non-experts (0.20; -0.33 to 0.73); neurologists (0.21; -0.06 to 0.47) and non neurologists (0.18; -0.20 to 0.56); cases (0.19; -0.14 to 0.52) and controls (0.21; -0.08 to 0.49). Zamboni-trained neurosonographers ascertained CCSVI more frequently than non-trained. Conclusions: Agreement was unsatisfactory for the diagnosis of CCSVI as a whole, for each of its five criteria, and according to different subgroups. Standardization of the method is urgently needed prior to its further application in studies of patients with multiple sclerosis or other neurological diseases