Genetically modified mice have provided insights into the progression and pathology of Alzheimer's disease (AD). Here, we have examined two mouse models of AD: the rTg4510 mouse, which overexpresses mutant human Tau gene, and the APP/PS1 mouse, which overexpresses mutant human genes for amyloid precursor protein and presenilin 1. Both models exhibit deficits in hippocampal function, but comparative analyses of these deficits are sparse. We used extracellular field potential recordings in hippocampal slices to study basal synaptic transmission (BST), paired-pulse facilitation (PPF), and long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapses in both models. We found that 6-7, but not 2-3-month-old rTg4510 mice exhibited reduced pre-synaptic activation (fiber volley (FV) amplitude, ∼50%) and field excitatory post-synaptic potential (fEPSP) slope (∼40%) compared to wild-type controls. In contrast to previous reports, BST, when controlled for FV amplitude, was not altered in rTg4510. APP/PS1 mice (2-3 mo and 8-10 mo) had unchanged FV amplitude compared to wild-type controls, while fEPSP slope was reduced by ∼34% in older mice, indicating a deficit in BST. PPF was unchanged in 8-10-month-old APP/PS1 mice, but was reduced in 6-7-month-old rTg4510 mice. LTP was reduced only in older rTg4510 and APP/PS1 mice. Our data suggest that BST deficits appear earlier in APP/PS1 than in rTg4510, which exhibited no BST deficits at the ages tested. However, FV and synaptic plasticity deficits developed earlier in rTg4510. These findings highlight fundamental differences in the progression of synaptic pathology in two genetically distinct models of AD.

Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), an enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. In order to determine the role of KMO in the phenotype of mouse models of HD, we have developed a potent and selective KMO inhibitor termed CHDI-340246. We show that this compound, when administered orally to transgenic mouse models of HD, potently and dose-dependently modulates the Kyn pathway in peripheral tissues and in the central nervous system. The administration of CHDI-340246 leads to an inhibition of the formation of 3-OH-Kyn and Quin, and to an elevation of Kyn and Kynurenic acid (KynA) levels in brain tissues. We show that administration of CHDI-340246 or of Kyn and of KynA can restore several electrophysiological alterations in mouse models of HD, both acutely and after chronic administration. However, using a comprehensive panel of behavioral tests, we demonstrate that the chronic dosing of a selective KMO inhibitor does not significantly modify behavioral phenotypes or natural progression in mouse models of HD.

Introduction: The study examined the behavior of vasculature in conditions of eliminated cardiac function using mathematical modeling. In addition, we addressed the question of whether the stretch-recoil capability of veins, at least in part accounts for the slower response to simulated cardiac arrest. Methods: In the first set of computational experiments, blood flow and pressure patterns in veins and arteries during the first few seconds after cardiac arrest were assessed via a validated multi-scale mathematical model of the whole cardiovascular system, comprising cardiac dynamics, arterial and venous blood flow dynamics, and microcirculation. In the second set of experiments, the effects of stretch-recoil zones of venous vessels with different diameters and velocities on blood velocity and dynamic pressure analyzed using computational fluid dynamics (CFD) modeling. Results: In the first set of experiments, measurement of changes in velocity, dynamic pressure, and fluid flow revealed that the venous system responded to cardiac arrest more slowly compared to the arteries. This disparity might be due to the intrinsic characteristics of the venous system, including stretch-recoil and elastic fiber composition. In the second set of experiments, we attempted to determine the role of the stretch-recoil capability of veins in the slower response to cardiac arrest. During the second set of experiments, we found that this recoil behavior increased dynamic pressure, velocity, and blood flow. The enhancement in dynamic pressure through combining the results from both experiments yielded a 15-40% increase in maximum dynamic pressure due to stretch-recoil, depending on vein diameter under normal conditions. Conclusion: In the situation of cardiac arrest, the vein geometry changes continue, promoting smooth responses of the venous system. Moreover, the importance of such vein behavior in blood displacement may grow as the pressure on the venous side gradually decreases with time. Our experiments suggest that the driving force for venous return is the pressure difference that remains within the venous system after the energy coming from every ventricular systole spent to overcome the resistance created by arterial and capillary systems.

Diverse representation in clinical trials is an important goal in the testing of a medical, diagnostic, or therapeutic intervention. To date, the desired level of trial equity and inclusivity has been unevenly achieved.

Surgical injury can frequently lead to chronic pain. Despite the obvious importance of this problem, the first publications on chronic pain after surgery as a general topic appeared only a decade ago. This study tests the hypothesis that chronic postsurgical pain was, and still is, represented insufficiently.

Local and volatile anesthetics are widely used for surgery. It is not known whether anesthetics impinge on the orchestrated events in spontaneous resolution of acute inflammation. Here we investigated whether a commonly used local anesthetic (lidocaine) and a widely used inhaled anesthetic (isoflurane) impact the active process of resolution of inflammation.