4-(8-Eth­oxy-2,3-dihydro-1H-cyclo­penta­[c]quinolin-4-yl)butane-1-peroxol

In the title mol­ecule, C18H23NO3, the hydro­per­oxy­butyl substituent is nearly fully extended, with the four torsion angles in the range 170.23 (10)–178.71 (9)°. The O—O distance in the hydro­peroxide group is 1.4690 (13) Å. This group acts as an inter­molecular hydrogen-bond donor to a quinoline N atom. This results in dimeric units about the respective inversion centers, with graph-set notation R 2 2(18)

Superconducting properties of (formula presented)

We present the low-temperature electronic transport properties of the intermetallic commonly known as (formula presented) In contrast to the much simpler (formula presented)-type structure of the 39-K superconductor (formula presented) (formula presented) forms a complex structure-type that is nearly unique in nature. The structure has 110.5 atoms per unit cell and a stoichiometry (formula presented) Polycrystalline (formula presented) is superconducting below (formula presented) with a critical magnetic field (formula presented) Isotopically pure (formula presented) samples have an enhanced (formula presented) Hall-effect measurements suggest that the material is intrinsically compensated. © 2002 The American Physical Society

Orexin-A measurement in narcolepsy : A stability study and a comparison of LC-MS/MS and immunoassays

Background: Orexin-A and-B are neuropeptides involved in sleep-wake regulation. In human narcolepsy type 1, this cycle is disrupted due to loss of orexin-producing neurons in the hypothalamus. Cerebrospinal fluid (CSF) orexin-A measurement is used in the diagnosis of narcolepsy type 1. Currently available immunoassays may lack specificity for accurate orexin quantification. We developed and validated a liquid chromatography mass spectrometry assay (LC-MS/MS) for CSF orexin-A and B. Methods: We used CSF samples from narcolepsy type 1 (n = 22) and type 2 (n = 6) and non-narcoleptic controls (n = 44). Stable isotope-labeled orexin-A and-B internal standards were added to samples before solid-phase extraction and quantification by LC-MS/MS. The samples were also assayed by commercial radioimmunoassay (RIA, n = 42) and enzymatic immunoassay (EIA, n = 72) kits. Stability of orexins in CSF was studied for 12 months. Results: Our assay has a good sensitivity (10 pmol/L = 35 pg/mL) and a wide linear range (35-3500 pg/mL). Added orexin-A and-B were stable in CSF for 12 and 3 months, respectively, when frozen. The median orexin-A concentration in CSF from narcolepsy type 1 patients was <35 pg/mL (range <35-131 pg/mL), which was lower than that in CSF from control individuals (98 pg/mL, range <35-424 pg/mL). Orexin-A concentrations determined using our LC-MS/MS assay were five times lower than those measured with a commercial RIA. Orexin-B concentrations were undetectable Conclusions: Orexin-A concentrations measured by our LC-MS/MS assay were lower in narcolepsy type 1 patients as compared to controls. RIA yielded on average higher concentrations than LC-MS/MS.Peer reviewe

Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103

Orexins are neuropeptides that regulate the sleep-wake cycle and feeding behaviour. QRFP is a newly discovered neuropeptide which exerts similar orexigenic activity, thus playing an important role in energy homeostasis and regulation of appetite. The exact expression and signalling characteristics and physiological actions of QRFP and its receptor GPR103 are poorly understood. Alzheimerâ €™ s disease (AD) patients experience increased nocturnal activity, excessive daytime sleepiness, and weight loss. We hypothesised therefore that orexins and QRFP might be implicated in the pathophysiology of AD. We report that the down-regulation of hippocampal orexin receptors (OXRs) and GPR103 particularly in the cornu ammonis (CA) subfield from AD patients suffering from early onset familial AD (EOFAD) and late onset familial AD (LOAD). Using an in vitro model we demonstrate that this downregulation is due to to Aβ-plaque formation and tau hyper-phosphorylation. Transcriptomics revealed a neuroprotective role for both orexins and QRFP. Finally we provide conclusive evidence using BRET and FRET that OXRs and GPR103 form functional hetero-dimers to exert their effects involving activation of ERK 1/2. Pharmacological intervention directed at the orexigenic system may prove to be an attractive avenue towards the discovery of novel therapeutics for diseases such as AD and improving neuroprotective signalling pathways

Synthesis, Characterisation, and Preliminary In Vitro Studies of Vanadium(IV) Complexes with a Schiff Base and Thiosemicarbazones as Mixed Ligands

[VO(sal‐L‐tryp)(H2O)] (1, sal‐L‐tryp = N‐salicylidene‐L‐tryptophanate) was used as a precursor to produce the new complexes [VO(sal‐L‐tryp)(MeATSC)]·1.5C2H5OH [2, MeATSC = 9‐Anthraldehyde‐N(4)‐methylthiosemicarbazone], [VO(sal‐L‐tryp)(N‐ethhymethohcarbthio)]·H2O [3, N‐ethhymethohcarbthio = (E)‐N‐ethyl‐2‐(4‐hydroxy‐3‐methoxybenzylidene)hydrazinecarbothioamide] and [VO(sal‐L‐tryp)(acetylethTSC)]·C2H5OH {4, acetylethTSC = (E)‐N‐ethyl‐2‐[1‐(thiazol‐2‐yl)ethylidene]hydrazinecarbothioamide} by reaction with the respective thiosemicarbazone. The chemical and structural properties of these ligands and complexes were characterised by elemental analysis, ESI‐MS, FTIR, UV/Vis, ESR and 1H and 13C NMR spectroscopy and X‐ray crystallography. Dimethyl sulfoxide (DMSO) and [D6]DMSO solutions of 1–4 were oxidised in air to produce vanadium(V) species, which were verified by ESI‐MS and 51V NMR spectroscopy. The anticancer properties of 2–4 were examined with three colon cancer cell lines, HTC‐116, Caco‐2 and HT‐29, and noncancerous colonic myofibroblasts, CCD18‐Co. Compounds 2–3 exhibited less inhibitory effects in the CCD‐18Co cells, which indicates a possible cytotoxic selectivity towards colon cancer cells. In general, compounds that exhibit antiproliferative activity to cancer cells but do not affect noncancerous cells may have a potential in chemotherapy

Scalable Preparation and Differential Pharmacologic and Toxicologic Profiles of Primaquine Enantiomers

Hematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) activity is the major limitation of primaquine (PQ), the only antimalarial drug in clinical use for treatment of relapsing Plasmodium vivax malaria. PQ is currently clinically used in its racemic form. A scalable procedure was developed to resolve racemic PQ, thus providing pure enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. These enantiomers were compared for antiparasitic activity using several mouse models and also for general and hematological toxicities in mice and dogs. (+)-(S)-PQ showed better suppressive and causal prophylactic activity than (−)-(R)-PQ in mice infected with Plasmodium berghei. Similarly, (+)-(S)-PQ was a more potent suppressive agent than (−)-(R)-PQ in a mouse model of Pneumocystis carinii pneumonia. However, at higher doses, (+)-(S)-PQ also showed more systemic toxicity for mice. In beagle dogs, (+)-(S)-PQ caused more methemoglobinemia and was toxic at 5 mg/kg of body weight/day given orally for 3 days, while (−)-(R)-PQ was well tolerated. In a novel mouse model of hemolytic anemia associated with human G6PD deficiency, it was also demonstrated that (−)-(R)-PQ was less hemolytic than (+)-(S)-PQ for the G6PD-deficient human red cells engrafted in the NOD-SCID mice. All these data suggest that while (+)-(S)-PQ shows greater potency in terms of antiparasitic efficacy in rodents, it is also more hematotoxic than (−)-(R)-PQ in mice and dogs. Activity and toxicity differences of PQ enantiomers in different species can be attributed to their different pharmacokinetic and metabolic profiles. Taken together, these studies suggest that (−)-(R)-PQ may have a better safety margin than the racemate in human

Sleep, vigilance, and thermosensitivity

The regulation of sleep and wakefulness is well modeled with two underlying processes: a circadian and a homeostatic one. So far, the parameters and mechanisms of additional sleep-permissive and wake-promoting conditions have been largely overlooked. The present overview focuses on one of these conditions: the effect of skin temperature on the onset and maintenance of sleep, and alertness. Skin temperature is quite well suited to provide the brain with information on sleep-permissive and wake-promoting conditions because it changes with most if not all of them. Skin temperature changes with environmental heat and cold, but also with posture, environmental light, danger, nutritional status, pain, and stress. Its effect on the brain may thus moderate the efficacy by which the clock and homeostat manage to initiate or maintain sleep or wakefulness. The review provides a brief overview of the neuroanatomical pathways and physiological mechanisms by which skin temperature can affect the regulation of sleep and vigilance. In addition, current pitfalls and possibilities of practical applications for sleep enhancement are discussed, including the recent finding of impaired thermal comfort perception in insomniacs

Deficient sustained attention to response task and P300 characteristics in early Huntington’s disease

Evidence for the extent and nature of attentional impairment in premanifest and manifest Huntington’s disease (HD) is inconsistent. Understanding such impairments may help to better understand early functional changes in HD and could have consequences concerning care for HD patients. We investigated attentional control in both early and premanifest HD. We studied 17 early HD subjects (mean age: 51 years), 12 premanifest HD subjects (mean age: 43 years), and 15 healthy controls (mean age: 51 years), using the sustained attention to response task (SART), a simple Go/No-go test reflecting attentional and inhibitory processes through reaction time (RT) and error rates. Simultaneously recorded EEG yielded P300 amplitudes and latencies. The early HD group made more Go errors (p < 0.001) and reacted slower (p < 0.005) than the other groups. The RT pattern during the SART was remarkably different for early HD subjects compared to the other two groups (p < 0.005), apparent as significant post-error slowing. P300 data showed that for early HD the No-go amplitude was lower than for the other two groups (p < 0.05). Subjects with early HD showed a reduced capacity to effectively control attention. They proved unable to resume the task directly after having made an error, and need more time to return to pre-error performance levels. No attentional control deficits were found for the premanifest HD group

Recognition and diagnosis of sleep disorders in Parkinson's disease

Contains fulltext : 109296.pdf (publisher's version ) (Open Access)Sleep disturbances are among the most frequent and incapacitating non-motor symptoms of Parkinson's disease (PD), and are increasingly recognized as an important determinant of impaired quality of life. Here we review several recent developments regarding the recognition and diagnosis of sleep disorders in PD. In addition, we provide a practical and easily applicable approach to the diagnostic process as a basis for tailored therapeutic interventions. This includes a stepwise scheme that guides the clinical interview and subsequent ancillary investigations. In this scheme, the various possible sleep disorders are arranged not in order of prevalence, but in a 'differential diagnostic' order. We also provide recommendations for the use of sleep registrations such as polysomnography. Furthermore, we point out when a sleep specialist could be consulted to provide additional diagnostic and therapeutic input. This structured approach facilitates early detection of sleep disturbances in PD, so treatment can be initiated promptly

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor

Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023