The Canadian Neuromuscular Disease Registry 2010-2019: A Decade of Facilitating Clinical Research Througha Nationwide, Pan-NeuromuscularDisease Registry.

We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.

Canadian association of gastroenterology clinical practice guideline for the management of Luminal Crohn's Disease

Crohn's disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.

Relationship between human intestinal dendritic cells, gut microbiota, and disease activity in Crohn's disease.

BACKGROUND: Altered intestinal dendritic cell (DC) function underlies dysregulated T-cell responses to bacteria in Crohn's disease (CD) but it is unclear whether composition of the intestinal microbiota impacts local DC function. We assessed the relationship between DC function with disease activity and intestinal microbiota in patients with CD. METHODS: Surface expression of Toll-like receptor (TLR)-2, TLR-4, and spontaneous intracellular interleukin (IL)-10, IL-12p40, IL-6 production by freshly isolated DC were analyzed by multicolor flow cytometry of cells extracted from rectal tissue of 10 controls and 28 CD patients. Myeloid DC were identified as CD11c(+) HLA-DR(+lin-/dim) cells (lin = anti-CD3, CD14, CD16, CD19, CD34). Intestinal microbiota were analyzed by fluorescent in situ hybridization of fecal samples with oligonucleotide probes targeting 16S rRNA of bifidobacteria, bacteroides-prevotella, C. coccoides-E. rectale, and Faecalibacterium prausnitzii. RESULTS: DC from CD produced higher amounts of IL-12p40 and IL-6 than control DC. IL-6(+) DC were associated with the CD Activity Index (r = 0.425; P = 0.024) and serum C-reactive protein (CRP) (r = 0.643; P = 0.004). DC expression of TLR-4 correlated with disease activity. IL-12p40(+) DC correlated with ratio of bacteroides: bifidobacteria (r = 0.535, P = 0.003). IL-10(+) DC correlated with bifidobacteria, and IL-6(+) DC correlated negatively with F. prausnitzii (r = -0.50; P = 0.008). The amount of TLR-4 on DC correlated negatively with the concentration of F. prausnitzii. CONCLUSIONS: IL-6 production by intestinal DC is increased in CD and correlates with disease activity and CRP. Bacterially driven local IL-6 production by intestinal DC may overcome regulatory activity, resulting in unopposed effector function and tissue damage. Intestinal DC function may be influenced by the composition of the commensal microbiota.

A novel population of human CD56+ human leucocyte antigen D-related (HLA-DR+) colonic lamina propria cells is associated with inflammation in ulcerative colitis.

Ulcerative colitis (UC) involves inappropriate mucosal immune responses to intestinal microbiota. Gut dendritic cells (DC) are central immunoregulators of the response to commensal bacteria, and the subset of CD11c(+) cells within the human leucocyte antigen D-related (HLA-DR(+)) lineage (lin)(-/dim) population are activated in inflammatory bowel disease. We hypothesized that CD11c(-) cells within this population may also be involved in intestinal inflammation. HLA-DR(+) lin(-/dim) cells were identified in freshly isolated lamina propria mononuclear cells by multi-colour flow cytometry in 54 UC patients and 22 controls. Proportion and number of CD11c(+) and CD11c(-) cells, and surface expression of activation markers CD40, CD86, Toll-like receptor (TLR)-2, TLR-4, and CD56(+)[natural killer (NK) marker], were determined. Cytokine production was assessed by intracellular staining. Lamina propria colonic CD11c(-) HLA-DR(+) lin(-/dim) cells were increased significantly in inflamed and 'non-inflamed' UC tissue, compared with control tissue. CD11c(+) HLA-DR(+) lin(-/dim) cells were unchanged. Fewer CD11c(-) cells expressed activation markers and produced intracellular cytokines than their CD11c(+) counterparts, and they were weakly stimulatory in mixed leucocyte reactions. Few CD11c(-) cells expressed blood plasmacytoid DC markers, but a major subset expressed high levels of CD56. CD11c(-) cells decreased after inflammation resolved. Intestinal inflammation in UC is associated with the presence of cells that share phenotypic features of both DC and NK cells. This novel population of human colonic CD56(+) HLA-DR(+) cells may play a role in immune regulation or tissue repair. Their increase in quiescent UC may be a marker of subclinical inflammation.

Prospective assessment of the effect on quality of life of anti-tumour necrosis factor therapy for perineal Crohn's fistulas.

BACKGROUND: Anti-tumour necrosis factor (TNF) therapy effectively treats Crohn's perineal fistulas (CPF); the effect on health-related quality of life (HRQoL) remains unknown. AIMS: To evaluate the effect of anti-TNF therapy on the HRQoL of patients with CPF in daily clinical practice. METHODS: Prospective evaluation of clinical and magnetic resonance imaging (MRI) responses, disease activity (Perianal Disease Activity Index - PDAI), and HRQoL assessment [Inflammatory Bowel Disease Questionnaire (IBDQ)] in patients receiving anti-TNF therapy for CPF treated up to 12 months. RESULTS: In all, 26 patients with CPF were treated (mean age 39 years; 19 infliximab, 7 adalimumab). At baseline, 85% patients had impaired IBDQ scores (mean 137; 'normal' >170). At 12 months, mean increases in IBDQ score for infliximab and adalimumab treated patients were 40 and 41 points respectively (P < 0.05). There were significant improvements in all IBDQ subscores (bowel, emotional, systemic, social) at 12 months (all P < or = 0.003). Fourteen patients (74%) on infliximab and six on adalimumab (86%) achieved IBDQ score > or =170. Mean increase in IBDQ score was 50, 34 and 16 points in patients with clinical fistula closure (P < 0.001), clinical response (P = 0.002) and no response (n = 1) respectively. IBDQ score increased for patients with MRI healing (P < 0.001) and MRI improvement (P = 0.016), but not for those with no MRI change (n = 2). IBDQ correlated significantly with PDAI at baseline and at 12 months. CONCLUSION: Anti-TNF therapy improves HRQoL in patients with CPF at 12 months and this improvement is most pronounced in patients with clinical and MRI healing.

Thalidomide in luminal and fistulizing Crohn's disease resistant to standard therapies.

BACKGROUND: Thalidomide has been shown to be an effective treatment in Crohn's disease. AIM: To assess the efficacy and tolerability of thalidomide in refractory Crohn's disease patients. METHODS: Twenty-five patients were treated. Retrospective 'estimated' Crohn's Disease Activity Indices were assessed at baseline and at the end of follow-up. Clinical response was defined as symptomatic improvement and a reduction in the 'estimated' Crohn's Disease Activity Index of >100 points, > or =50% reduction in draining fistulas or clinical improvement in perianal ulcers. Clinical remission was defined as symptom resolution and an 'estimated' Crohn's Disease Activity Index <150, complete fistula closure or complete ulcer healing. RESULTS: Six of eight patients treated for luminal disease responded to thalidomide at a median follow-up of 12 months (three clinical responses, three clinical remissions). The median reduction in 'estimated' Crohn's Disease Activity Index was 212 points (P = 0.005). Nine of 11 patients with active fistulizing disease responded to thalidomide (six responses; three remissions). The four patients treated for both luminal and fistulizing disease had fistula response. Three of them had a response in luminal disease activity. One of two patients with ulcerating perianal disease responded. Twelve patients discontinued treatment because of adverse effects (three sedation; two abdominal pain; one leucopoenia; six neuropathy). CONCLUSION: Thalidomide is an effective short- to medium-term treatment in selected patients with refractory luminal and fistulizing Crohn's disease. Its long-term use is limited by toxicity.

Novel mimics of sialyl Lewis X: design, synthesis and biological activity of a series of 2- and 3-malonate substituted galactoconjugates.

A series of potent inhibitors of P-selectin as potential anti-inflammatory agents is reported. These compounds are derivatives of galactocerebrosides bearing a malonate side chain in positions 2 and 3 of the galactose moiety. Based on the binding mode of sialyl Lewis X, the two acidic groups of the malonate are designed to form ionic interactions with two important lysines in the active site of P-selectin, Lys113 and Lys111. On the other hand, the 4- and 6-hydroxy groups on the galactose ring are arranged to chelate the calcium ion in the P-selectin active site. The synthesis and the biological activity of this series of compounds are described. Lead compounds having a greater potency than sialyl Lewis X are identified.

Juvenile amyopathic dermatomyositis: results of a case finding descriptive survey.

OBJECTIVE: To review the clinical features of juvenile amyopathic dermatomyositis (ADM) to define an appropriate approach to its diagnosis and management. METHODS: Based on a review of published adult and pediatric cases, a prevalidated, peer reviewed, 3 page questionnaire was sent to all members of the Pediatric Section of the American College of Rheumatology and American Society for Pediatric Dermatology. RESULTS: Thirty-nine questionnaires were submitted for analysis. Twelve cases were excluded due to abnormal test results. Only one case met all criteria. Although 26 cases were incompletely investigated or had inadequate followup, they were not excluded, as all completed tests were normal. Two patients with incomplete data developed calcinosis. Of 27 patients not positively excluded, 10 were treated systemically, with 5 achieving remission, while 11/17 untreated recovered spontaneously. At a mean followup of 32.8 months from disease onset none of the 27 patients has developed clinical myopathy. CONCLUSION: The classic skin changes of juvenile DM can occur in the absence of clinical muscle involvement. Physicians are not routinely performing electromyography, muscle biopsy, or magnetic resonance imaging in the assessment of these patients. A significant proportion of patients with ADM will remit without systemic therapy. Optimum treatment needs to be determined through controlled trials.

Familial dermatomyositis.

Susceptibility, response to therapy, prognosis, and natural history of connective tissue diseases are variably linked to histocompatibility antigens (HLA), although the precise role that such genes play is still not clear. In juvenile dermatomyositis (JDMS) there are few reports of both concordance and discordance in identical twins and occurrence in more than one family member. To further document the familial occurrence of JDMS, we describe 2 sisters, one with classical JDMS and the other with amyopathic dermatomyositis. The 2 patients were shown to share the HLA-DQA1*0501 allele, known to be associated with susceptibility to JDMS.

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.