Background Niemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive, lethal, lysosomal disease characterized by progressive cerebellar ataxia and cognitive impairment. Although the NPC1 phenotype is heterogeneous with variable age of onset, classical NPC1 is a pediatric disorder. Currently there are no therapies approved by the FDA and therapeutics trials for NPC1 are complicated by disease rarity, heterogeneity, and the relatively slow rate of neurological decline. Thus, identification of disease relevant biomarkers is necessary to provide tools that can support drug development efforts for this devastating neurological disease. Methods Proximal extension assays (O-link® Explore 1536) were used to compare cerebrospinal fluid (CSF) samples from individuals with NPC1 enrolled in a natural history study and non-NPC1 comparison samples. Relative expression levels of 1467 proteins were determined, and candidate protein biomarkers were identified by evaluating fold-change and adjusted Kruskal–Wallis test p-values. Selected proteins were orthogonally confirmed using ELISA. To gain insight into disease progression and severity we evaluated the altered protein expression with respect to clinically relevant phenotypic aspects: NPC Neurological Severity Score (NPC1 NSS), Annual Severity Increment Score (ASIS) and age of neurological onset. Results This study identified multiple proteins with altered levels in CSF from individuals with NPC1 compared to non-NPC1 samples. These included proteins previously shown to be elevated in NPC1 (NEFL, MAPT, CHIT1, CALB1) and additional proteins confirmed by orthogonal assays (PARK7, CALB2/calretinin, CHI3L1/YKL-40, MIF, CCL18 and ENO2). Correlations with clinically relevant phenotypic parameters demonstrated moderate negative (p = 0.0210, r = -0.41) and possible moderate positive (p = 0.0631, r = 0.33) correlation of CSF CALB2 levels with age of neurological onset and ASIS, respectively. CSF CHI3L1 levels showed a moderate positive (p = 0.0183, r = 0.40) correlation with the concurrent NPC1 NSS. A strong negative correlation (p = 0.0016, r = -0.648) was observed between CSF CCL18 and age of neurological onset for childhood/adolescent cases. CSF CCL18 levels also showed a strong positive correlation (p = 0.0017, r = 0.61) with ASIS. Conclusion Our study identified and validated multiple proteins in CSF from individuals with NPC1 that are candidates for further investigation in a larger cohort. These analytes may prove to be useful as supportive data in therapeutic trials. Trial registrations NCT00344331, NCT00001721, NCT02931682.
The remains of a series of ditches at Lhanbryde are interpreted as the remains of a mill-lade system. The northern end of the lade subsequently contained the remains of a possible grain-drying kiln from which burnt oats and a sherd of pottery indicate an llth-to 13th-century date. The project was funded by the National Roads Directorate via Historic Scotland.
Prior to re-landscaping, an archaeological evaluation was undertaken in August 1998 of the area around the Wallace Memorial in Elderslie, Renfrewshire, which marks the reputed birthplace of Sir William Wallace. In addition to a 16th century structure, known as "Wallace's House", early map evidence suggested that there was a large rectilinear moated enclosure around the site with three rounded corner towers, only one of which now survives at the eastern corner in the garden of Moat House. Excavation across this moat revealed it to be a wide flat-bottomed ditch, with its inner edge faced by a battered and mortared rubble wall. Artefactual evidence and a radiocarbon date suggests that this enclosure was of medieval date. Unfortunately the majority of material recovered from the interior relates to the post-medieval re-use of the site.
Investigation prior to the construction of the bypass revealed features relating to various periods of activity. Pits were identified at several locations containing prehistoric pottery, while the northern and western perimeters of a Roman temporary camp were examined. The foundations of an Iron Age timber structure c. ten metres in diameter were excavated. Extensive excavation around the western entrance of the Roman temporary camp located a concentration of features including a spread of pits containing Neolithic pottery and chipped stone, four later prehistoric structures and Roman/Early Historic field ovens. Twenty-five Neolithic to Early Romano-British radiocarbon dates are reported. Includes separately authored reports on:
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