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

Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable traitlike measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD. © 2018 The Authors

Searches for neutrino counterparts of gravitational waves from the LIGO/Virgo third observing run with KM3NeT

International audienceThe KM3NeT neutrino telescope is currently being deployed at two different sites in the Mediterranean Sea. First searches for astrophysical neutrinos have been performed using data taken with the partial detector configuration already in operation. The paper presents the results of two independent searches for neutrinos from compact binary mergers detected during the third observing run of the LIGO and Virgo gravitational wave interferometers. The first search looks for a global increase in the detector counting rates that could be associated with inverse beta decay events generated by MeV-scale electron anti-neutrinos. The second one focuses on upgoing track-like events mainly induced by muon (anti-)neutrinos in the GeV--TeV energy range. Both searches yield no significant excess for the sources in the gravitational wave catalogs. For each source, upper limits on the neutrino flux and on the total energy emitted in neutrinos in the respective energy ranges have been set. Stacking analyses of binary black hole mergers and neutron star-black hole mergers have also been performed to constrain the characteristic neutrino emission from these categories

Searches for neutrino counterparts of gravitational waves from the LIGO/Virgo third observing run with KM3NeT

International audienceThe KM3NeT neutrino telescope is currently being deployed at two different sites in the Mediterranean Sea. First searches for astrophysical neutrinos have been performed using data taken with the partial detector configuration already in operation. The paper presents the results of two independent searches for neutrinos from compact binary mergers detected during the third observing run of the LIGO and Virgo gravitational wave interferometers. The first search looks for a global increase in the detector counting rates that could be associated with inverse beta decay events generated by MeV-scale electron anti-neutrinos. The second one focuses on upgoing track-like events mainly induced by muon (anti-)neutrinos in the GeV--TeV energy range. Both searches yield no significant excess for the sources in the gravitational wave catalogs. For each source, upper limits on the neutrino flux and on the total energy emitted in neutrinos in the respective energy ranges have been set. Stacking analyses of binary black hole mergers and neutron star-black hole mergers have also been performed to constrain the characteristic neutrino emission from these categories

Searches for neutrino counterparts of gravitational waves from the LIGO/Virgo third observing run with KM3NeT

International audienceThe KM3NeT neutrino telescope is currently being deployed at two different sites in the Mediterranean Sea. First searches for astrophysical neutrinos have been performed using data taken with the partial detector configuration already in operation. The paper presents the results of two independent searches for neutrinos from compact binary mergers detected during the third observing run of the LIGO and Virgo gravitational wave interferometers. The first search looks for a global increase in the detector counting rates that could be associated with inverse beta decay events generated by MeV-scale electron anti-neutrinos. The second one focuses on upgoing track-like events mainly induced by muon (anti-)neutrinos in the GeV--TeV energy range. Both searches yield no significant excess for the sources in the gravitational wave catalogs. For each source, upper limits on the neutrino flux and on the total energy emitted in neutrinos in the respective energy ranges have been set. Stacking analyses of binary black hole mergers and neutron star-black hole mergers have also been performed to constrain the characteristic neutrino emission from these categories

Searches for neutrino counterparts of gravitational waves from the LIGO/Virgo third observing run with KM3NeT

International audienceThe KM3NeT neutrino telescope is currently being deployed at two different sites in the Mediterranean Sea. First searches for astrophysical neutrinos have been performed using data taken with the partial detector configuration already in operation. The paper presents the results of two independent searches for neutrinos from compact binary mergers detected during the third observing run of the LIGO and Virgo gravitational wave interferometers. The first search looks for a global increase in the detector counting rates that could be associated with inverse beta decay events generated by MeV-scale electron anti-neutrinos. The second one focuses on upgoing track-like events mainly induced by muon (anti-)neutrinos in the GeV--TeV energy range. Both searches yield no significant excess for the sources in the gravitational wave catalogs. For each source, upper limits on the neutrino flux and on the total energy emitted in neutrinos in the respective energy ranges have been set. Stacking analyses of binary black hole mergers and neutron star-black hole mergers have also been performed to constrain the characteristic neutrino emission from these categories

Searches for neutrino counterparts of gravitational waves from the LIGO/Virgo third observing run with KM3NeT

International audienceThe KM3NeT neutrino telescope is currently being deployed at two different sites in the Mediterranean Sea. First searches for astrophysical neutrinos have been performed using data taken with the partial detector configuration already in operation. The paper presents the results of two independent searches for neutrinos from compact binary mergers detected during the third observing run of the LIGO and Virgo gravitational wave interferometers. The first search looks for a global increase in the detector counting rates that could be associated with inverse beta decay events generated by MeV-scale electron anti-neutrinos. The second one focuses on upgoing track-like events mainly induced by muon (anti-)neutrinos in the GeV--TeV energy range. Both searches yield no significant excess for the sources in the gravitational wave catalogs. For each source, upper limits on the neutrino flux and on the total energy emitted in neutrinos in the respective energy ranges have been set. Stacking analyses of binary black hole mergers and neutron star-black hole mergers have also been performed to constrain the characteristic neutrino emission from these categories