Abstract Objective The aim of this study was to evaluate a series of primary melanomas of the female urogenital tract for oncogenic mutations in KIT , NRAS and BRAF in order to identify patients who ...may be amenable to targeted therapy. Methods We reviewed twenty-four cases of female urogenital tract melanomas and used Sanger sequencing analysis for the detection of oncogenic mutations in exons 9, 11, 13, and 17 of KIT ; exons 2 and 3 of NRAS ; and exon 15 of BRAF. Results Twenty-four patients were included: fourteen vaginal melanomas, four cervical melanomas, five urethral melanomas and one vulvar melanoma. NRAS mutations (4/24, 21%) were more prevalent than KIT mutations (1/24, 4%), while BRAF mutations were absent. Three of four NRAS mutations were present in vaginal melanomas (21%), mainly affecting codon 61 (3/4). They were mutually exclusive with the KIT mutation. The KIT mutation was present in a vaginal melanoma and affected exon 17. Conclusions Melanomas of the female urogenital tract relatively commonly harbor mutations in NRAS ; this makes NRAS an interesting therapeutic target for these patients in the advanced setting. KIT mutations were rare in our study in contrast to some previous reports. We cannot exclude that anatomical site-related differences and/or population related differences in KIT mutation frequency exist within urogenital tract melanomas.
Background
Specific force, that is the amount of force generated per unit of muscle tissue, is reduced in patients with facioscapulohumeral muscular dystrophy (FSHD). The causes of reduced specific ...force and its relation with FSHD disease severity are unknown.
Methods
Quantitative muscle magnetic resonance imaging (MRI), measurement of voluntary maximum force generation and quadriceps force‐frequency relationship, and vastus lateralis muscle biopsies were performed in 12 genetically confirmed patients with FSHD and 12 controls.
Results
Specific force was reduced by ~33% in all FSHD patients independent of disease severity. Quadriceps force‐frequency relationship shifted to the right in severe FSHD compared to controls. Fiber type distribution in vastus lateralis muscle biopsies did not differ between groups.
Conclusions
Reduced quadriceps specific force is present in all FSHD patients regardless of disease severity or fatty infiltration. Early myopathic changes, including fibrosis, and non‐muscle factors, such as physical fatigue and musculoskeletal pain, may contribute to reduced specific force.
InP/InGaAs is a powerful material system for a variety of devices including HFETs. The quality of the heterointerface is very sensitive to growth parameters, especially to the switching sequence of ...the reactive gases. Improvement of the interface with respect to electron transport was achieved by growth interruptions without group-V stabilization of the surface before growth of the subsequent layer is started.< >
We propose a method to evaluate the stress generated at the local scale by the spatial variations of the gravitational potential energy (GPE), which is related to inhomogeneous topography and mass ...distribution in the lithosphere. We show that it is possible to infer these local stress sources from the second spatial derivatives of a geoid height grid, used as a proxy of the GPE. The coherence of the method is validated on a passive margin, the Bay of Biscay. The result is that expected in such a geological configuration, with extensional local stress sources with the maximum horizontal principal stress parallel to the margin and compressive sources with the maximum horizontal principal stress perpendicular to the margin in the continental and oceanic lithosphere, respectively.We apply the method to Western Europe in order to provide a better understanding of the complex spatial variation of the present-day tectonic activity. Our results indicate a stress pattern from the local sources dominated by short-space-wavelength (of the order of a few tens of kilometers) variations in the tectonic style and in the direction of the maximal horizontal principal stress σH. A comparison of the σH orientations and tectonic style from the local sources with the ones of the World Stress Map (WSM) data set indicates that the local stress sources can be representative of the deviatoric stress state in some regions. Our results explain 71% of the faulting styles for the earthquake fault-plane solutions in the WSM, which is better than the classical compressive NW-SE stress field model. In the central part of the Pyrenees, the agreement between earthquake fault-slip directions and the direction of shear stress from the local sources acting on the associated fault planes is compatible with the extensional stress field evidenced by recent investigations.
Abstract
Background
SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and ...respiratory insufficiency. A muscular dystrophy caused by mutations in the
LAMA2
gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness.
Methods
LAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age ≥ 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All examinations are adapted to the patient’s age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed.
Discussion
Our study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up.
Conclusion
Our natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD.
Trial registration
This study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017–3911) and is registered at
ClinicalTrial.gov
(
NCT04478981
).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Nemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired ...muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.
Idiopathic ventral herniation of the spinal cord is rarely seen as a cause of gradually increasing neurologic deficit. Its cause has never been clarified. It could be the result of a developmental ...disorder at 30- to 60-day gestational age. Neuropathologic analysis of herniated spinal cord tissue could probably support this hypothesis.
In a patient suffering from idiopathic ventral herniation of the spinal cord, a biopsy was performed in order to reduce the space-occupying effect. The biopsy was taken while intraoperative neuromonitoring was used. The patient recovered uneventfully without any additional deficit. Tissue analysis included histopathologic, immunohistochemical, and molecular examination (methylation profiling). The tissue did not appear as a normally functioning spinal cord; instead, a non-neoplastic glio-(neuronal) proliferation was found.
These findings support a developmental disorder as a cause for idiopathic ventral spinal cord herniation.
•A developmental abnormality might be considered as a cause for idiopathic spinal cord herniation•An aquired cause for idiopathic spinal cord herniation is very unlikely.•Idiopathic spinal cord herniation is a misnomer.
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