Polarity Sensitivity of Human Auditory Nerve Fibers Based on Pulse Shape, Cochlear Implant Stimulation Strategy and Array

Neural health is of great interest to determine individual degeneration patterns for improving speech perception in cochlear implant (CI) users. Therefore, in recent years, several studies tried to identify and quantify neural survival in CI users. Among all proposed techniques, polarity sensitivity is a promising way to evaluate the neural status of auditory nerve fibers (ANFs) in CI users. Nevertheless, investigating neural health based on polarity sensitivity is a challenging and complicated task that involves various parameters, and the outcomes of many studies show contradictory results of polarity sensitivity behavior. Our computational study benefits from an accurate three-dimensional finite element model of a human cochlea with realistic human ANFs and determined ANF degeneration pattern of peripheral part with a diminishing of axon diameter and myelination thickness based on degeneration levels. In order to see how different parameters may impact the polarity sensitivity behavior of ANFs, we investigated polarity behavior under the application of symmetric and asymmetric pulse shapes, monopolar and multipolar CI stimulation strategies, and a perimodiolar and lateral CI array system. Our main findings are as follows: (1) action potential (AP) initiation sites occurred mainly in the peripheral site in the lateral system regardless of stimulation strategies, pulse polarities, pulse shapes, cochlear turns, and ANF degeneration levels. However, in the perimodiolar system, AP initiation sites varied between peripheral and central processes, depending on stimulation strategies, pulse shapes, and pulse polarities. (2) In perimodiolar array, clusters formed in threshold values based on cochlear turns and degeneration levels for multipolar strategies only when asymmetric pulses were applied. (3) In the perimodiolar array, a declining trend in polarity (anodic threshold/cathodic threshold) with multipolar strategies was observed between intact or slight degenerated cases and more severe degenerated cases, whereas in the lateral array, cathodic sensitivity was noticed for intact and less degenerated cases and anodic sensitivity for cases with high degrees of degeneration. Our results suggest that a combination of asymmetric pulse shapes, focusing more on multipolar stimulation strategies, as well as considering the distances to the modiolus wall, allows us to distinguish the degeneration patterns of ANFs across the cochlea.

Dual-site blood culture yield and time to positivity in neonatal late-onset sepsis

ObjectiveTo determine whether culture yield and time to positivity (TTP) differ between peripheral and central vascular catheter-derived blood cultures (BCx) in neonatal intensive care unit (NICU) patients evaluated for late-onset sepsis.DesignSingle-centre, retrospective, observational study.SettingLevel IV NICU.ParticipantsThe study included infants >72 hours old admitted to NICU in 2007–2019 with culture-confirmed bacteraemia. All episodes had simultaneous BCx drawn from a peripheral site and a vascular catheter (‘catheter culture’).Main outcome measuresDual-site culture yield and TTP.ResultsAmong 179 episodes of late-onset bacteraemia (among 167 infants) with concurrently drawn peripheral and catheter BCx, the majority (67%, 120 of 179) were positive from both sites, compared with 17% (30 of 179) with positive catheter cultures only and 16% (29 of 179) with positive peripheral cultures only. 66% (19 of 29) of episodes with only positive peripheral BCx grew coagulase-negative Staphylococcus, while 34% (10 of 29) were recognised bacterial pathogens. Among 120 episodes with both peripheral and catheter BCx growth, catheter cultures demonstrated bacterial growth prior to paired peripheral cultures in 78% of episodes (93 of 120, p<0.001). The median TTP was significantly shorter in catheter compared with peripheral cultures (15.0 hours vs 16.8 hours, p<0.001). The median elapsed time between paired catheter and peripheral culture growth was 1.3 hours.ConclusionConcurrently drawn peripheral and catheter BCx had similar yield. While a majority of episodes demonstrated dual-site BCx growth, a small but important minority of episodes grew virulent pathogens from either culture site alone. While dual-site culture practices may be useful, clinicians should balance the gain in sensitivity of bacteraemia detection against additive contamination risk.

Blood Pressure Continuous Measurement through a Wearable Device: Development and Validation of a Cuffless Method

The present study aims to develop and validate a cuffless method for blood pressure continuous measurement through a wearable device. The goal is achieved according to the time-delay method, with the guiding principle of the time relation it takes for a blood volume to travel from the heart to a peripheral site. Inversely proportional to the blood pressure, this time relation is obtained as the time occurring between the R peak of the electrocardiographic signal and a marker point on the photoplethysmographic wave. Such physiological signals are recorded by using L.I.F.E. Italia’s wearable device, made of a sensorized shirt and wristband. A linear regression model is implemented to estimate the corresponding blood pressure variations from the obtained time-delay and other features of the photoplethysmographic wave. Then, according to the international standards, the model performance is assessed, comparing the estimates with the measurements provided by a certified digital sphygmomanometer. According to the standards, the results obtained during this study are notable, with 85% of the errors lower than 10 mmHg and a mean absolute error lower than 7 mmHg. In conclusion, this study suggests a time-delay method for continuous blood pressure estimates with good performance, compared with a reference device based on the oscillometric technique.

Thanatochemical Study of Glycated Hemoglobin in Diabetic Status Assessment

Background and objectives. In forensic medicine, the postmortem determination of glycated hemoglobin (HbA1c) helps identify undiagnosed cases of diabetes or cases with uncontrolled glycemic status. In order to contribute to the solidification of thanatochemistry, both globally and especially nationally, we aimed to determine this biomarker postmortem, for the first time in our institution, in order to identify undiagnosed pre-mortem diabetics, as well as those with inadequate glycemic control. Materials and Methods. Our research consisted of analyzing a total number of 180 HbA1c values, 90 determinations from the peripheral blood and 90 from the central blood. The determination of HbA1c was performed by means of a fully automatic analyzer (HemoCue HbA1c 501), certified by the National Glycohemoglobin Standardization Program (NGSP)/Diabetes Control and Complications Trial (DCCT) and calibrated according to the standards developed by the International Federation of Clinical Chemistry (IFCC). According to ADA criteria, HbA1c values can provide us with the following information about the diagnosis of diabetes: normal 4.8–5.6%; prediabetes 5.7–6.4%; diabetes ≥ 6.5%. Results. A considerable number of cases with an altered glycemic status (cases that had HbA1c values equal to or greater than 5.7%) were identified—51% demonstrable by peripheral blood determinations and 41% by central blood determinations. Notably, 23 people with diabetes (25%) were identified by analyzing the peripheral blood; 18 other people with diabetes (20%) were identified by analyzing the central blood. Conclusions. Our study managed to confirm the antemortem diagnosis of DM using a simple point-of-care analyzer and applying standardized and certified criteria on HbA1c levels measured postmortem. We also identified a considerable number of cases with DM in patients with no antemortem history of glucose imbalance—at least 20% more cases. Although the two different sites used for blood collection showed a strong statistical correlation, it seems that the peripheral site could have a higher sensibility in detecting postmortem altered glycemic status.

Non-neuronal Role of Acetylcholinesterase in Bone Development and Degeneration

Acetylcholinesterase (AChE), an enzyme catalyzing the degradation of acetylcholine, plays an important suppressive role in the cholinergic regulation by terminating the action of acetylcholine. The expression of acetylcholinesterase and other cholinergic components is not restricted to only brain and nerve tissues but can also be found in non-neuronal tissues like the immune system and bone tissue. Primary identification of these components has been achieved. However, the information about their specific functions and underlying molecular mechanisms in bone remains scattered. Here, the physiological process of bone development, homeostasis, and degeneration are introduced. Next, the cholinergic system and its expression in bone tissue is documented. Among them, special attention goes to AChE, as the structure of this enzyme suggests diverse binding affinities, enabled by a peripheral site and a catalytic site. The peripheral site supports the non-enzymatic function of AChE in non-neuronal systems. Based on recent studies, the non-neuronal roles of acetylcholinesterase, both enzymatically and non-enzymatically, in bone development, homeostasis and degeneration are summarized briefly together with potential mechanisms to support these functions. We conclude that AChE may be a potential therapeutic target for bone diseases like osteoporosis.

Advances in the Development of Reactivators for the Treatment of Organophosphorus Inhibited Cholinesterase

Abstract:: Organophosphorus Compounds (OPCs) are used as pesticides to control pest, as chemical weapons in military conflict and unfortunately in the terrorist attack. These compounds are irreversible inhibitors of acetylcholinesterase, resulting in the accumulation of acetylcholine that leads to severe health complications which may be ended with the death of the victim. Current antidotes used for reactivation of organophosphorus inhibited acetylcholinesterase (OP-AChE) are not able to cross the blood-brain barrier efficiently, therefore being incapable to reactivate OP-AChE of the central nervous system. Due to limitations with current antidotes, there is an urgent need for new effective antidotes that could be included in the treatment regimen of OP poisoning. In this direction, comprehensive work has been done to improve the permeability of existing antidotes using a variety of strategies that include synthesis of oxime bonded to peripheral site binding moiety via an alkyl, aryl, or heteroatom-containing linker, synthesis of sugar oximes, and prodrug of 2-PAM, incorporating fluorine and chlorine in the structure of charged oximes. Other classes of compounds such as the mannich base, N-substituted hydroxyimino acetamide, alkylating agents, have been investigated for reactivation of OP-AChE. This review comprises the development of various classes of reactivators with the aim of either enhancing blood-brain permeability of existing antidotes or discovering a new class of reactivators.

New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer’s Disease Treatment

New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics.