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Recent advances in high-resolution structural studies of protein amyloids have revealed parallel in-register cross-β-sheets with periodic arrays of closely spaced identical residues. SHP099 in vivo What do these structures tell us about the mechanisms of action of common amyloid-promoting factors, such as heparan sulfate (HS), nucleic acids, polyphosphates, anionic phospholipids, and acidic pH?Defects in the HEXB gene which encodes the β-subunit of β-hexosaminidase A and B enzymes, cause a GM2 gangliosidosis, also known as Sandhoff disease, which is a rare lysosomal storage disorder. link2 The most common form of the disease lead to quickly progressing mental and motor decline in infancy; however there are other less severe forms with later onset that can also involve lower motor neurons. The diagnosis of this disease is based on low serum β-hexosaminidases A and B levels and confirmed using genetic test. We report two siblings with compound heterozygous HEXB mutations whose phenotype was extremely mild consisting in stuttering in both cases associated to mild proximal weakness in one of the cases, broadening the clinical spectrum of late onset Sandhoff disease.Disorders of the neuromuscular junction (NMJ) comprise a spectrum of rare diseases causing muscle fatigability and weakness, leading to life-long effects on quality of life. We established the Dutch-Belgian registry for NMJ disorders, based on a unique combination of patient- and physician-reported information. Information on natural course, disease burden, prevalence of complications and comorbidity is collected through patient-reported standardized questionnaires and verified using medical documentation. Currently, the registry contains information of 565 Myasthenia Gravis (MG) patients and 38 Lambert-Eaton myasthenic syndrome (LEMS) patients, constituting approximately 25% (MG) and 80% (LEMS) of patients in the Netherlands. This is a very large registry, with the highest participation rate per capita. In addition to confirming many disease characteristics previously described in the literature, this registry provides several novel insights. The reported rate of potentially corticosteroid-related comorbidity, including hypertension, heart disease, osteoporosis and type 2 diabetes was high, emphasizing the need to commence corticosteroid-sparing immune suppressive treatment as soon as possible. The reported rate of other auto-immune diseases is far higher than previously expected 27% of MG and 38% of LEMS patients, and a surprisingly high number of MG patients (47%) is unaware of their antibody status. In conclusion, this registry provides a valuable collection of information regarding MG and LEMS disease course. Continuous collection of annual follow-up data will provide further longitudinal insights in disease burden, course and treatment effect.Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory vasculopathy characterized by systemic vasculitis, early-onset stroke and livedo racemosa. We report a family cohort of 3 patients with ADA2 compound heterozygous mutation p.[Thr360Ala] and [Gly383Ser]. Two of them had progressive involvement of the peripheral nervous system in the fourth decade, both after stroke. In one patient, clinical and neurophysiological studies showed progression of mononeuritis multiplex to chronic axonal sensorimotor polyneuropathy, nerve biopsy had features of small vessel vasculitic neuropathy, and muscle biopsy disclosed neurogenic atrophy with reinnervation. The second patient presented with progressive sensory symptoms of the lower limbs and chronic axonal sensorimotor polyneuropathy in nerve conduction studies. These two patients had absent plasma ADA2 activity. The third patient had no neurological affection despite low, but not absent, plasma ADA2 activity. Patients were started on a tumor necrosis factor (TNF) inhibitor, which has presumed benefits for the vasculitic phenotype of DADA2.This study aims to investigate intra-rater reliability and construct validity of the Facioscapulohumeral Dystrophy Composite Outcome Measure (FSHD-COM), in childhood FSHD. Participants included eighteen children with FSHD, and matched healthy controls. Reliability data were collected from 15 participants with FSHD over two testing sessions. Validity data were collected from all participants. Participants with FSHD completed; the FSHD-COM (and modified pediatric version), Motor Function Measure-32 (MFM-32), FSHD Severity Scales, Performance of the Upper Limb 2.0, Pediatric Quality of Life™ Neuromuscular Module and pediatric FSHD Health-Index Questionnaire. Both versions of the FSHD-COM showed excellent intra-rater reliability (ICC1,2 > 0.99, lower 95%CI > 0.98) with a Minimal Detectable Change (MDC95%) of ≤14.5%. The FSHD-COM had robust and widespread correlations with other related outcome measures. The FSHD-COM versions and 6 min walk test effectively discriminated between children with and without FSHD; the MFM-32 and 10 m walk/run test did not. Ceiling effects were not observed on either version of the FSHD-COM. Reliability and validity findings in this childhood FSHD study concord with estimates in adults. Both versions of the FSHD-COM were effective in discriminating disease in children with mild FSHD symptoms. The FSHD-COM has the potential to be a useful measure of function across the life span.We report the case of a 16-year-old Spanish boy with cerebellar and spinal muscular atrophy, spasticity, psychomotor retardation, nystagmus, ophthalmoparesis, epilepsy, and mitochondrial respiratory chain (MRC) deficiency. Whole exome sequencing (WES) uncovered three variants (two of them novel) in a compound heterozygous in EXOSC8 gene (NM_181503.3c.[390+1delG];[628C>T;815G>C]) that encodes the exosome complex component RRP43 protein (EXOSC8). In order to assess the pathogenicity of these variants, expression experiments of RNA and protein for EXOSC8 were carried out. The c.[390+1delG] variant produces the elimination of exon 7 (r.[345_390del]; p.[Ser116LysfsTer27]) and a decrease of the RNA expression in relation to the other allele (p.[Pro210Ser;Ser272Thr]). Furthermore, total mRNA expression is reduced by 30% and the protein level by 65%. EXOSC8 is an essential protein of the exosome core, a ubiquitously expressed complex responsible for RNA processing and degradation. Recessive mutations in EXOSC8 cause pontocerebellar hypoplasia type 1C (PCH1C), and currently, only two homozygous variants in this gene have been described. However, unlike PCH1C-affected individuals with EXOSC8 variants, our patient presents a normal supratentorial cerebral tissue (neither corpus callosum hypoplasia nor hypomyelination) with a less severe phenotype and longer survival. In conclusion, our data expand both genetic and phenotypic spectrum associated with EXOSC8 variants.

The present study investigates superficial in vivo dosimetry (IVD) by means of a previously proposed electron paramagnetic resonance (EPR) dosimetry system aiming at measuring and verifying total doses delivered by complex radiotherapy treatments. In view of novel regulatory requirements in Germany, differences between measured and planned total doses to the EPR dosimeters are analyzed and compared to reporting thresholds for significant occurrences.

EPR dosimeters, each consisting of one lithium formate monohydrate (LFM) and one polycrystalline l-alanine (ALA) pellet, were attached to the surface of an anthropomorphic head phantom. Three head and neck treatments with total target doses ranging from 30 to 64Gy were fully delivered to the phantom by helical tomotherapy. During each treatment, eight EPR dosimeters were placed at distinct spots (i) within or next to the planning target volume (PTV), (ii) near to organs at risk including the parotids and the lenses, (iii) at the thyroid lying out-of-field. EPotal doses delivered by complex IMRT treatments. EPR-IVD in combination with helical tomotherapy is suitable to reliably detect local dose deviations at superficial dosimeter spots in the order of current national reporting thresholds for significant occurrences (i.e. 10%/4Gy).

The results of this proof of principle study suggests that superficial EPR-IVD is applicable in a wide dose range and in various irradiation conditions - being a valuable tool for monitoring cumulative total doses delivered by complex IMRT treatments. EPR-IVD in combination with helical tomotherapy is suitable to reliably detect local dose deviations at superficial dosimeter spots in the order of current national reporting thresholds for significant occurrences (i.e. 10%/4Gy).

Metallic hip implants (MHI) are common in elderly patients. For pelvic cancers radiotherapy, conventional approaches consist of MHI avoidance during treatment planning, which leads, especially in case of bilateral MHI, to a decreased quality or increased complexity of the treatment plan. The aim of this study is to investigate the necessity of using avoidance sectors (AvSe) using a 2-arcs coplanar pelvic volumetric modulated arc-therapy (VMAT) planning.

We evaluated (1) The dose calculation error of a static 6MV open beam traversing a MHI; (2) The magnitude of an error's decrease within the planning target volume (PTV) for a 360° VMAT treatment without AvSe as compared to the static open beam; (3) The dosimetric influence of MHI misalignment generated by patient's repositioning rolls during image-guided radiotherapy (IGRT).

(1) In the static 6MV beam configuration, for distances between 0.5cm and 6cm from the MHI, the median (maximum, number of points) dose calculation error was -1.55% (-2.5%, 11); (2) Compared to the static open beam, in the 360° VMAT treatment without AvSe a simulated error was decreased by a factor of 4.4/2.4 (median/minimum); (3) MHI anterior-posterior misalignment exceeding 0.6cm, resulted in error at PTV surface of >2%.

A standard 2 coplanar arcs 360° VMAT treatment, with dedicated artifact reduction algorithms applied, decreased the error of static beam traversing MHI, in patients presenting a bilateral MHI and might be used to treat the pelvic region without MHI avoidance.

A standard 2 coplanar arcs 360° VMAT treatment, with dedicated artifact reduction algorithms applied, decreased the error of static beam traversing MHI, in patients presenting a bilateral MHI and might be used to treat the pelvic region without MHI avoidance.As a specialised branch of archaeology requiring specific field and laboratory methodologies, the contributions of archaeobotany have often been overlooked by the ecological research community. Developments in the fields of botany, chemistry, and ancient DNA analyses have greatly increased the potential for archaeobotany to contribute to topical questions relating to the Anthropocene and landscape transformations. link3 We review the role of archaeobotany in identifying and describing past arable land use. Analytical techniques are illustrated with examples at both local and regional scales, demonstrating how archaeobotany can provide unique details of the wide array of past subsistence and land-use strategies. These data and their potential should be better recognised as important information that could underpin models seeking to evaluate or predict the effects of socioenvironmental interactions.