Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: A prospective observational study

Background: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. Methods: In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with =2 clinical signs/symptoms of NP-C were considered ''suspected NP-C'' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI =70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. Results: In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores =70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients. Conclusion: This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion–transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management

Reconceptualizing informal work practices: Some observations from an ethnic minority community in urban UK

Whilst paid informal work has been conceptualized as a form of paid employment imbued with solely economic motivations, this article critically argues that such a market‐­oriented reading fails to take into account alternative explanations for the existence of informal work practices. Using evidence from 50 interviews conducted within a Pakistani urban community in a northern UK city, this article, uses a mixed‐embeddedness perspective to highlight the importance of predominantly socially and culturally driven motives in the decision to engage in informal work. The findings highlight that participation in informal work, whilst a product of marginalization due to certain institutional and structural factors, is also driven by a range of non‐monetary motives—a result of certain socially embedded work relations between ethnic minority workers and their employers. It is this social embeddedness of the employer–employee relationship in the Pakistani ethnic minority community that explains the continuation of informal work practices in the face of prevailing laws and regulations. The findings add weight to the understanding of informal work as being about more than just economics and constraints, offering these ethnic minority workers opportunities, even status, and giving them agency in an otherwise disempowered situation

Ceramiche egee e di tipo egeo lungo I versanti adriatico e ionico della Peninsolo italiana: situazioni a confronto

Sintesi delle analisi archeometriche delle ceramiche in varie parti d'Italia, con illustrate le zone egee di provenienza e i centri di produzione locali