Clinical follow-up of 411 patients with relapsing and progressive multiple sclerosis 10 years after discontinuing mitoxantrone treatment: a real-life cohort study.

BACKGROUND AND PURPOSE: Mitoxantrone (MITOX) has been used to treat patients with aggressive multiple sclerosis (MS) for decades. We aimed to describe the effectiveness and adverse events over 10 years post-MITOX in patients with relapsing and progressive MS from an exhaustive real-life database. METHODS: Data from patients who received MITOX before 1 January 2006 were collected from the MS Lorraine registry. Expanded Disability Status Scale (EDSS) scores and annual relapse rates (ARRs) year by year during follow-up and the year prior to MITOX were compared. Time to the first relapse and a 1-point increase in EDSS score were used in Cox multivariate models to find associations with potential predictive factors. RESULTS: A total of 411 patients were included. The ARR for the 155 relapsing patients had decreased from 2.0 (SD 1.20) the year before treatment to 0.3 (SD 0.31) by year 10 (P < 0.0001). The EDSS score increased from 2.8 (SD 1.44) to 4.8 (SD 1.90) by year 10 (P < 0.0001). A high ARR at MITOX initiation was associated with a longer time to a 1-point increase in EDSS score (hazard ratio, 0.81; 95% confidence interval, 0.67-0.99; P = 0.04). The EDSS score in 256 progressive patients increased from 5.0 (SD 1.33) to 6.5 (SD 1.26) by year 10 (P < 0.0001). We identified four cases of acute myeloid leukemias. CONCLUSIONS: Patients with the most active forms of MS are the most likely to benefit from MITOX in the long term.

A crosstalk between muscarinic and CRF2 receptors regulates cellular adhesion properties of human colon cancer cells.

Patients with inflammatory bowel disease often suffer from chronic and relapsing intestinal inflammation that favor the development of colitis associated cancer. An alteration of the epithelial intestinal barrier function observed in IBD is supposed to be a consequence of stress. It has been proposed that corticotrophin-releasing factor receptor (CRF2), one of the two receptors of CRF, the principal neuromediator of stress, acts on cholinergic nerves to induce stress-mediated epithelial barrier dysfunction. Non-neuronal acetylcholine (Ach) and muscarinic receptors (mAchR) also contribute to alterations of epithelial cell functions. In this study, we investigated the mechanisms through which stress and Ach modulate epithelial cell adhesive properties. We show that Ach-induced activation of mAchR in HT-29 cells results in cell dissociation together with changes in cell-matrix contacts, which correlates with the acquisition of invasive potential consistent with a matrix metalloproteinase (MMP) mode of invasion. These processes result from mAchR subsequent stimulation of the cascade of src/Erk and FAK activation. Ach-induced secretion of laminin 332 leads to α3ß1 integrin activation and RhoA-dependent reorganization of the actin cytoskeleton. We show that Ach-mediated effects on cell adhesion are blocked by astressin 2b, a CRF2 antagonist, suggesting that Ach action depends partly on CRF2 signaling. This is reinforced by the fact that Ach-mediated activation of mAchR stimulates both the synthesis and the release of CRF2 ligands in HT-29 cells (effects blocked by atropine). In summary, our data provides evidence for a novel intracellular circuit involving mAchR acting on CRF2-signaling that could mediate colonic mucosal barrier dysfunction and exacerbate mucosal inflammation.

Intratester and intertester reliability and criterion validity of the parallelogram and universal goniometers for active knee flexion in healthy subjects.

BACKGROUND AND PURPOSE: A new parallelogram goniometer was designed by the Rehabilitation Centre of the Royal Ottawa Health Care Group in 1983. The advantage of using such a goniometer is that the clinician is not required to estimate the joint axis of rotation when taking a measurement. The parallelogram goniometer has obtained a good intratester and intertester reliability when measuring active range of motion of hip abduction on eight individuals with hip pathologies. However, the validity of the parallelogram goniometer has not been examined. The purposes of this study were to examine the intratester and intertester reliability and the criterion validity of the parallelogram and universal goniometers for active knee flexion on healthy individuals. SUBJECTS: Sixty healthy university students (44 females and 16 males; mean age of 20.6 yrs.) participated to this study. METHODS: Measurements with the universal and parallelogram goniometers were taken in two different positions, the smaller and larger angles of active knee flexion. All measurements were taken by two trained testers. A radiograph was taken in both positions to serve as the 'gold standard'. The sequence of the measurements and radiographs were randomly selected. The intra and intertester reliability of both goniometers were established by calculating the intraclass correlation coefficients (ICCs) using the repeated-measures ANOVA. The criterion validity was examined by calculating Pearson product-moment correlation coefficients (tau) between each goniometric and radiologic measurements. A 0.05 level of significance was chosen for each statistical test. RESULTS: Intratester reliability ranged from good to excellent for the small angles (ICC = 0.85 and 0.87) and the large angles (ICC = 0.91 and 0.96) when using the parallelogram goniometer. Intertester reliability was fair for the small angles of flexion (ICC = 0.43 to 0.52) and good to excellent for the large angles of flexion (ICC = 0.82 to 0.88). The parallelogram goniometer was found to have greater validity when measuring the large angles of knee flexion (r = 0.73 and 0.77) compared to the small angles of knee flexion (r = 0.33 and 0.41). Similar results of reliability and validity were obtained with the universal goniometer. CONCLUSION: The results of this study have clinical importance. The use of the parallelogram goniometer was found to be as reliable and valid as the universal goniometer when measuring active knee flexion. However, the parallelogram goniometer offered clinicians the advantages of obtaining precise angular measurements with fewer adjustments, and a faster application technique. Further studies on the parallelogram goniometer are necessary among individuals presenting with altered range of motion at different joints.