Assessment of potential cardiotoxic side effects of mitoxantrone in patients with multiple sclerosis

Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m(2) body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 +/- 12 years, range 20-75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 +/- 33.8 mg. The mean follow-up time was 23.4 months (range 10-57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses. Copyright (C) 2005 S. Karger AG, Basel

Several years of experience with automatic DI-flux systems: theory, validation and results

Abstract. The previous release of our automatic DI-flux instrument, called AutoDIF mk2.2, has now been running continuously since June 2012 in the absolute house of Dourbes magnetic observatory performing measurement every 30 min. A second one has been working in the tunnel of Conrad observatory (Austria) since December 2013. After this proof of concept, we improved the AutoDIF to version mk2.3, which was presented at the 16th IAGA workshop in Hyderabad. As of publication, we have successfully deployed six AutoDIFs in various environments: two in Dourbes (DOU), one in Manhay (MAB), one in Conrad (CON), one in Daejeon (South Korea) and one is used for tests. The latter was installed for 10 months in Chambon-la-Forêt (CLF) and, since 2016, has been in Kakioka (KAK). In this paper, we will compare the automatic to the human-made measurements and discuss the advantages and disadvantages of automatic measurements. </jats:p

In situ vector calibration of magnetic observatories

Abstract. The goal of magnetic observatories is to measure and provide a vector magnetic field in a geodetic coordinate system. For that purpose, instrument set-up and calibration are crucial. In particular, the scale factor and orientation of a vector magnetometer may affect the magnetic field measurement. Here, we highlight the baseline concept and demonstrate that it is essential for data quality control. We show how the baselines can highlight a possible calibration error. We also provide a calibration method based on high-frequency absolute measurements. This method determines a transformation matrix for correcting variometer data suffering from scale factor and orientation errors. We finally present a practical case where recovered data have been successfully compared to those coming from a reference magnetometer. </jats:p

Suppression of mitoxantrone cardiotoxicity in multiple sclerosis patients by dexrazoxane

Objective To explore the potential of dexrazoxane to suppress subclinical cardiotoxicity in MS patients receiving mitoxantrone. Methods An open-label study was performed to evaluate possible subclinical cardiotoxicity in multiple sclerosis patients treated quarterly with mitoxantrone (48mg/m 2 cumulative), with and without concomitant dexrazoxane, using blinded serial radionucleide ventriculography. Results No patient experienced symptoms of heart failure. Patients receiving dexrazoxane, which is cardioprotective for anthracyclines, exhibited a significantly lesser decline in left ventricular ejection fraction (mean change, −3.80% vs −8.55%, p < 0.001). Interpretation These results support a cardioprotective effect of dexrazoxane in mitoxantrone treated multiple sclerosis patients. Ann Neurol 2006;59:206–209Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49281/1/20747_ftp.pd

The Level of Isoprostanes as a Non-invasive Marker for in vivo Lipid Peroxidation in Secondary Progressive Multiple Sclerosis

Oxidative stress leads to lipid peroxidation and may contribute to the pathogenesis of lesions in multiple sclerosis (MS), an autoimmune disease characterized by inflammatory as well as degenerative phenomena. Isoprostanes are prostaglandin-like compounds which are formed by free radical catalysed peroxidation of arachidonic acid esterified in membrane phospholipids. They are a new class of sensitive specific markers for in vivo lipid peroxidation. In this study 26 patients (15 females and 11 males; mean age 48.2 ± 15.2 year; mean disease duration 10.0 ± 6.5 year) with secondary progressive MS (SPMS) and 12 healthy controls were enrolled. In patients with multiple sclerosis the lipid peroxidation as the level of urine isoprostanes and the level of thiobarbituric acid reactive species (TBARS) in plasma were estimated. Moreover, we estimated the total antioxidative status (TAS) in plasma. It was found that the urine isoprostanes level was over 6-fold elevated in patients with SPMS than in control (P < 0.001). In SPMS patients TBARS level was also statistically higher than in controls (P < 0.01). However, we did not observed any difference of TAS level in serum between SPMS patients and controls (P > 0.05). In patients with SPMS the lipid peroxidation and oxidative stress measured as the increased level of isoprostanes was observed. Thus, we suggest that the level of isoprostanes may be used as non-invasive marker for a determination of oxidative stress what in turn, together with clinical symptoms, may determine an specific antioxidative therapy in SPMS patients

Bmi-1 Absence Causes Premature Brain Degeneration

Bmi-1, a polycomb transcriptional repressor, is implicated in cell cycle regulation and cell senescence. Its absence results in generalized astrogliosis and epilepsy during the postnatal development, but the underlying mechanisms are poorly understood. Here, we demonstrate the occurrence of oxidative stress in the brain of four-week-old Bmi-1 null mice. The mice showed various hallmarks of neurodegeneration including synaptic loss, axonal demyelination, reactive gliosis and brain mitochondrial damage. Moreover, astroglial glutamate transporters and glutamine synthetase decreased in the Bmi-1 null hippocampus, which might contribute to the sporadic epileptic-like seizures in these mice. These results indicate that Bmi-1 is required for maintaining endogenous antioxidant defenses in the brain, and its absence subsequently causes premature brain degeneration

Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis

Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of pro-inflammatory transcripts with concomitant induction of anti-inflammatory genes including Ptgds and Hsd11b1. Finally, triterpenoids induced oligodendrocyte maturation in vitro and enhanced myelin repair in an LPC-induced non-inflammatory model of demyelination in vivo. These results demonstrate the unique potential of triterpenoid derivatives for the treatment of neuroinflammatory disorders such as MS