Enteric dysfunctions in experimental Parkinson's disease: alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats

Parkinson's disease (PD) is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiological assay. Electrically and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, while acetylcholine levels were assayed in their incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors. As compared with control rats, at week 4 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate; impaired electrically evoked neurogenic cholinergic contractions; enhanced carbachol-induced contractions; decreased basal and electrically stimulated acetylcholine release from colonic tissues; decreased ChAT immunopositivity in the neuromuscular layer; unchanged density of HuC/D immunoreactive myenteric neurons; increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were detected also at week 8 post-6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate

Studies on the acylation of 4-(2-aminoethylthio)-7-nitrobenzofurazan: the role of bases in promoting the formation of fluorescent S-acyl derivatives through S–N Smiles rearrangement

The acylation of 4-(2-aminoethylthio)-7-nitrobenzofurazan has been investigated. Depending on the use of the base, a competitive Smiles rearrangement occurs during the acylation step leading to the formation of N-acyl and/or fluorescent S-acyl derivatives. The acylating agent also affects the ratio of N/S acylated isomers

Evidence for Factorization in Three-body B --> D(*) K- K0 Decays

Motivated by recent experimental results, we use a factorization approach to study the three-body B --> D(*) K- K0 decay modes. Two mechanisms are proposed for kaon pair production: current-produced (from vacuum) and transition (from B meson). The Bbar0 --> D(*)+ K- K0 decay is governed solely by the current-produced mechanism. As the kaon pair can be produced only by the vector current, the matrix element can be extracted from e+ e- --> K Kbar processes via isospin relations. The decay rates obtained this way are in good agreement with experiment. Both current-produced and transition processes contribute to B- --> D(*)0 K- K0 decays. By using QCD counting rules and the measured B- --> D(*)0 K- K0 decay rates, the measured decay spectra can be understood.Comment: 17 pages, 6 figure

Written information about individual medicines for consumers.

Medicines are the most common intervention in most health services. As with all treatments, those taking medicines need sufficient information: to enable them to take and use the medicines effectively, to understand the potential harms and benefits, and to allow them to make an informed decision about taking them. Written medicines information, such as a leaflet or provided via the Internet, is an intervention that may meet these purposes

Effects of Nitisinone on Oxidative and Inflammatory Markers in Alkaptonuria: Results from SONIA1 and SONIA2 Studies

Nitisinone (NTBC) was recently approved to treat alkaptonuria (AKU), but there is no information on its impact on oxidative stress and inflammation, which are observed in AKU. Therefore, serum samples collected during the clinical studies SONIA1 (40 AKU patients) and SONIA2 (138 AKU patients) were tested for Serum Amyloid A (SAA), CRP and IL-8 by ELISA; Advanced Oxidation Protein Products (AOPP) by spectrophotometry; and protein carbonyls by Western blot. Our results show that NTBC had no significant effects on the tested markers except for a slight but statistically significant effect for NTBC, but not for the combination of time and NTBC, on SAA levels in SONIA2 patients. Notably, the majority of SONIA2 patients presented with SAA > 10 mg/L, and 30 patients in the control group (43.5%) and 40 patients (58.0%) in the NTBC-treated group showed persistently elevated SAA > 10 mg/L at each visit during SONIA2. Higher serum SAA correlated with lower quality of life and higher morbidity. Despite no quantitative differences in AOPP, the preliminary analysis of protein carbonyls highlighted patterns that deserve further investigation. Overall, our results suggest that NTBC cannot control the sub-clinical inflammation due to increased SAA observed in AKU, which is also a risk factor for developing secondary amyloidosis. © 2022 by the authors

Comparison of synthetic jet actuators based on sharp-edged and round-edged nozzles

Axisymmetric synthetic jet actuators based on a loudspeaker and on two types of flanged nozzles were tested and compared experimentally. The first type of the nozzle was a sharp-edged circular hole. The second one had a special design with fillets at inner and outer nozzle exit and with a small step in the middle of the nozzle. The function of the step was to prevent the flow reattachment during the extrusion stroke. The actuators with the two types of nozzles were operated at resonance and were compared first qualitatively using a simple phase locked flow visualization. Then the hot-wire anemometer was used to measure velocity distributions along nozzle axis and velocity profiles at the nozzle exit. Comparison of the nozzles was based on evaluation of the characteristic velocity and integral quantities (volumetric, momentum, and kinetic energy fluxes). It was found out that these quantities, which were evaluated at the nozzle exit, differ substantially for both nozzles. On the other hand the velocity flow field in farther distances from the nozzle exit area did not exhibit such prominent differences

Detecting a stochastic gravitational wave background with the Laser Interferometer Space Antenna

The random superposition of many weak sources will produce a stochastic background of gravitational waves that may dominate the response of the LISA (Laser Interferometer Space Antenna) gravitational wave observatory. Unless something can be done to distinguish between a stochastic background and detector noise, the two will combine to form an effective noise floor for the detector. Two methods have been proposed to solve this problem. The first is to cross-correlate the output of two independent interferometers. The second is an ingenious scheme for monitoring the instrument noise by operating LISA as a Sagnac interferometer. Here we derive the optimal orbital alignment for cross-correlating a pair of LISA detectors, and provide the first analytic derivation of the Sagnac sensitivity curve.Comment: 9 pages, 11 figures. Significant changes to the noise estimate

Evaluation of commercially available fully automated and ELISA-based assays for detecting anti-SARS-CoV-2 neutralizing antibodies

Rapid and accurate measurement of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-specific neutralizing antibodies (nAbs) is paramount for monitoring immunity in infected and vaccinated subjects. The current gold standard relies on pseudovirus neutralization tests which require sophisticated skills and facilities. Alternatively, recent competitive immunoassays measuring anti-SARS-CoV-2 nAbs are proposed as a quick and commercially available surrogate virus neutralization test (sVNT). Here, we report the performance evaluation of three sVNTs, including two ELISA-based assays and an automated bead-based immunoassay for detecting nAbs against SARS-CoV-2. The performance of three sVNTs, including GenScript cPass, Dynamiker, and Mindray NTAb was assessed in samples collected from SARS-CoV-2 infected patients (n = 160), COVID-19 vaccinated individuals (n = 163), and pre-pandemic controls (n = 70). Samples were collected from infected patients and vaccinated individuals 2–24 weeks after symptoms onset or second dose administration. Correlation analysis with pseudovirus neutralization test (pVNT) and immunoassays detecting anti-SARS-CoV-2 binding antibodies was performed. Receiver operating characteristic (ROC) curve analysis was generated to assess the optimal threshold for detecting nAbs by each assay. All three sVNTs showed an excellent performance in terms of specificity (100%) and sensitivity (100%, 97.0%, and 97.1% for GenScript, Dynamiker, and Mindray, respectively) in samples collected from vaccinated subjects. GenScript demonstrated the strongest correlation with pVNT (r = 0.743, R2 = 0.552), followed by Mindray (r = 0.718, R2 = 0.515) and Dynamiker (r = 0.608, R2 = 0.369). Correlation with anti-SARS-CoV-2 binding antibodies was variable, but the strongest correlations were observed between anti-RBD IgG antibodies and Mindray (r = 0.952, R2 = 0.907). ROC curve analyses demonstrated excellent performance for all three sVNT assays in both groups, with an AUC ranging between 0.99 and 1.0 (p < 0.0001). Also, it was shown that the manufacturer's recommended cutoff values could be modified based on the tested cohort without significantly affecting the sVNT performance. The sVNT provides a rapid, low-cost, and scalable alternative to conventional neutralization assays for measuring and expanding nAbs testing across various research and clinical settings. Also, it could aid in evaluating actual protective immunity at the population level and assessing vaccine effectiveness to lay a foundation for boosters' requirements.Funding was provided by Qatar Foundation (Grant number: UREP28-173-3-057), Shenzhen Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, China, Qatar University (Grant number: RRC-2-032)