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- Ashizawa, T., et al.
(författare)
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Consensus-based care recommendations for adults with myotonic dystrophy type 1
- 2018
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Ingår i: Neurology-Clinical Practice. - : Ovid Technologies (Wolters Kluwer Health). - 2163-0402 .- 2163-0933. ; 8:6, s. 507-520
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Forskningsöversikt (refereegranskat)abstract
- Purpose of review Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.
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| 2. |
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| 3. |
- Kular, L, et al.
(författare)
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DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2397-
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Tidskriftsartikel (refereegranskat)abstract
- The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
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| 4. |
- Contreras, ZA, et al.
(författare)
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Does early onset asthma increase childhood obesity risk? A pooled analysis of 16 European cohorts
- 2018
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 52:3
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Tidskriftsartikel (refereegranskat)abstract
- The parallel epidemics of childhood asthma and obesity over the past few decades have spurred research into obesity as a risk factor for asthma. However, little is known regarding the role of asthma in obesity incidence. We examined whether early-onset asthma and related phenotypes are associated with the risk of developing obesity in childhood.This study includes 21 130 children born from 1990 to 2008 in Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, Sweden and the UK. We followed non-obese children at 3–4 years of age for incident obesity up to 8 years of age. Physician-diagnosed asthma, wheezing and allergic rhinitis were assessed up to 3–4 years of age.Children with physician-diagnosed asthma had a higher risk for incident obesity than those without asthma (adjusted hazard ratio (aHR) 1.66, 95% CI 1.18–2.33). Children with active asthma (wheeze in the last 12 months and physician-diagnosed asthma) exhibited a higher risk for obesity (aHR 1.98, 95% CI 1.31–3.00) than those without wheeze and asthma. Persistent wheezing was associated with increased risk for incident obesity compared to never wheezers (aHR 1.51, 95% CI 1.08–2.09).Early-onset asthma and wheezing may contribute to an increased risk of developing obesity in later childhood.
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| 7. |
- Marabita, F, et al.
(författare)
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Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 14589-
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Tidskriftsartikel (refereegranskat)abstract
- Cigarette smoking is an established environmental risk factor for Multiple Sclerosis (MS), a chronic inflammatory and neurodegenerative disease, although a mechanistic basis remains largely unknown. We aimed at investigating how smoking affects blood DNA methylation in MS patients, by assaying genome-wide DNA methylation and comparing smokers, former smokers and never smokers in two Swedish cohorts, differing for known MS risk factors. Smoking affects DNA methylation genome-wide significantly, an exposure-response relationship exists and the time since smoking cessation affects methylation levels. The results also show that the changes were larger in the cohort bearing the major genetic risk factors for MS (female sex and HLA risk haplotypes). Furthermore, CpG sites mapping to genes with known genetic or functional role in the disease are differentially methylated by smoking. Modeling of the methylation levels for a CpG site in the AHRR gene indicates that MS modifies the effect of smoking on methylation changes, by significantly interacting with the effect of smoking load. Alongside, we report that the gene expression of AHRR increased in MS patients after smoking. Our results suggest that epigenetic modifications may reveal the link between a modifiable risk factor and the pathogenetic mechanisms.
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| 8. |
- Paquet-Durand, F., et al.
(författare)
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Systemic and intraocular administration of the liposomal formulation of the cyclic GMP analogue CN03 : An exploratory safety and tolerability study in non-human primates
- 2019
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Ingår i: Investigative Ophthalmology and Visual Science. - : ASSOC RESEARCH VISION OPHTHALMOLOGY INC. - 0146-0404 .- 1552-5783. ; 60:9
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Tidskriftsartikel (refereegranskat)abstract
- Purpose : The cGMP analogue CN03 targets cGMP signalling, a disease driver common to different types of retinal degeneration. For efficient targeting to the neuroretina CN03 was combined with a liposomal (LP) drug delivery system. In rodents, LP-CN03 has shown significant photoreceptor protection and preservation of in vivo retinal function, without major adverse events. The objective of the study was to determine the toxicity of CN03 and LP-CN03, following intravitreal (IVT) or intravenous (IV) administration. IVT administration is the intended human therapeutic route, IV injection was tested to investigate systemic toxicity.Methods : Cynomolgus monkeys were assigned to five different groups, consisting of one male and one female (n=2). Group 1 served as saline control for IVT and IV dosing, group 2 served as liposome (LP) control. Groups 3 and 4 received IVT injections of either 1X or 10X of the intended therapeutic dose, of either LP-CN03 (left eye) or CN03 (right). Group 5 received 100X IV bolus injections of LP-CN03 (Day 1) and CN03 (Day 25). Toxicity was assessed based on clinical observations, body weights, ophthalmology, intraocular pressure (IOP), electroretinography (ERG), and clinical and anatomic pathology.Results : IVT administration of LP caused transient white opacity in the vitreous body of all treated eyes, related to the milky consistency of LP. IVT injection of 1X and 10X CN03 was well-tolerated and only showed temporary pupil dilation in one male. IVT injection of 1X and 10X LP-CN03 was additionally associated with particles in the anterior chamber and vitreous body. At 10X, pigmented dots were also noted in the anterior lens capsule. IV injection of 100X LP-CN03 and CN03 was well tolerated and did not cause systemic toxicity. Comparison of pre- and post-dosing ERG did not reveal significant differences (p>0.05) in any of the groups, nor were there any indications of pathological changes in retinal morphology.Conclusions : IVT injection of CN03 and LP-CN03 at the intended therapeutic dose was not associated with any changes in ophthalmoscopy, electroretinography or histopathology, and only revealed slight pupil dilation in one animal. IV slow bolus injection at 100X the intended therapeutic dose was well tolerated.
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| 10. |
- Askenberger, M, et al.
(författare)
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Medial Patellofemoral Ligament Injuries in Children With First-Time Lateral Patellar Dislocations: A Magnetic Resonance Imaging and Arthroscopic Study
- 2016
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Ingår i: The American journal of sports medicine. - : SAGE Publications. - 1552-3365 .- 0363-5465. ; 44:1, s. 152-158
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Tidskriftsartikel (refereegranskat)abstract
- A lateral patellar dislocation (LPD) is the most common knee injury in children with traumatic knee hemarthrosis. The medial patellofemoral ligament (MPFL), the important passive stabilizer against LPDs, is injured in more than 90% of cases. The MPFL injury pattern is most often defined in adults or in mixed-age populations. The injury pattern in the skeletally immature patient may be different. Purpose: To describe MPFL injuries in the skeletally immature patient by magnetic resonance imaging (MRI), and to compare the results with the injury pattern found at arthroscopic surgery. Study Design: Case series; Level of evidence, 4. Methods: This was a prospective series of patients aged 9 to 14 years with acute, first-time traumatic LPDs in whom clinical examinations, radiographs, MRI, and arthroscopic surgery were performed within 2 weeks from the index injury. The MPFL injury was divided into 3 different groups according to the location: patellar site, femoral site, or multifocal. The MPFL injury site was confirmed on MRI by soft tissue edema. The length of the MPFL injury at the patellar site was measured at arthroscopic surgery, and those ≥2 cm were defined as total ruptures. Results: A total of 74 patients (40 girls and 34 boys; mean age, 13.1 years) were included; 73 patients (99%) had an MPFL injury according to MRI and arthroscopic surgery. The MRI scans showed an isolated MPFL injury at the patellar attachment site in 44 of 74 patients (60%), a multifocal injury in 26 patients (35%), an injury at the femoral site in 3 patients (4%), and no injury in 1 patient (1%). Arthroscopic surgery disclosed an isolated MPFL injury at the patellar site in 60 of 74 patients (81%) and a multifocal injury in 13 patients (18%); the MPFL injury at the patellar site was a total rupture in 49 patients (66%). Edema at the patellar attachment site on MRI was proven to be an MPFL rupture at the same site at arthroscopic surgery in 99% of the patients. A patellar-based injury, isolated or as part of a multifocal injury, was present on MRI in 95% (n = 70) of the patients, with a false-negative rate of 5% (n = 4) of patients compared with arthroscopic surgery. Conclusion: Skeletally immature children are more prone to sustaining an MPFL injury at the patellar attachment site. Arthroscopic surgery and MRI complement each other in the investigation of MPFL injuries.
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