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Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long- lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here, we show that repeated general anesthesia in postnatal mice induces preferential apoptosis and subsequent loss of parvalbumin-positive inhibitory interneurons in the hippocampus. Each parvalbumin interneuron controls the activity of multiple pyramidal excitatory neurons, thereby regulating neuronal circuits and memory consolidation. Preventing the loss of parvalbumin neurons by deleting a proapoptotic protein, mitochondrial anchored protein ligase (MAPL), selectively in parvalbumin neurons rescued anesthesia- induced deficits in pyramidal cell inhibition and hippocampus-dependent long-term memory. Conversely, partial depletion of parvalbumin neurons in neonates was sufficient to engender long-lasting memory impairment. Thus, loss of parvalbumin interneurons in postnatal mice following repeated general anesthesia critically contributes to memory deficits in adulthood., Introduction Studies in rodents (1-4) and nonhuman primates (5, 6) have shown that prolonged or repeated, but not short-term (7-9), general anesthesia in juvenile animals leads to long-lasting memory impairment [...]

The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long- lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein rapamycin-insensitive companion of mTOR (Rictor) prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modeling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain., Introduction Chronic pain is a common (~20% of the world population) debilitating condition that can persist for years, severely affecting the quality of life of affected individuals and their families [...]

Realistic surgical simulation requires incorporation of the mechanical properties of soft tissue in mathematical models. In actual deformation of soft-tissue during surgical intervention, the tissue is subject to tension, compression, and shear. Therefore, characterization and modeling of soft-tissue in all these three deformation modes are necessary. In this paper we applied two types of pure shear test, unconfined compression and uniaxial tension test to characterize porcine liver tissue. Digital image correlation technique was used to accurately measure the tissue deformation field. Due to gravity and its effect on the soft tissue, a maximum stretching band was observed from the relative strain field on sample undergoing tension and pure shear test. The zero strain state was identified according to the position of this maximum stretching band. Two new constitutive models based on combined exponential/logarithmic and Ogden strain energy were proposed. The models are capable to represent the observed non-linear stress–strain relation of liver tissue for full range of tension and compression and also the general response of pure shear. [ABSTRACT FROM AUTHOR]

Advances in electrosurgical technology have promoted the use of electrocautery in many surgical procedures. Precise modeling of soft tissue deformation during electrocautery with electrosurgical generators can be a valuable tool in training simulators for surgical procedures. Coupling the visualization of electrocautery with the force feedback during an electrocautery process (to maintain optimal current) without causing necrosis is an important learning tool. Realistic simulation will provide surgeon trainees a method to practice electrocautery techniques prior to experimenting on live tissue as well as allow surgeons to gain a feel for electrocautery procedures. [ABSTRACT FROM AUTHOR]

The authors examined the electronic transport of a solid electrolyte resistive switch. Using element analysis and the temperature dependence of its electronic transport, they deduced that the conductive path is composed of Cu metal precipitated in the solid electrolyte film by an electrochemical reaction. Furthermore, they observed Coulomb blockade phenomena at 4 K when the switch was in the off state. Their observations and experimental results suggest that the metallic conductive path consists of metallic islands separated by tunneling barriers and that switching between the on and off states originates from modulation in the tunneling barriers. [ABSTRACT FROM AUTHOR]

Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long-lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here we showed that repeated general anesthesia in postnatal mice induces preferential apoptosis and subsequent loss of parvalbumin-positive inhibitory interneurons in the hippocampus. Each parvalbumin interneuron controls the activity of multiple pyramidal excitatory neurons, thereby regulating neuronal circuits and memory consolidation. Preventing the loss of parvalbumin neurons by deleting a pro-apoptotic protein MAPL (Mitochondrial Anchored Protein Ligase) selectively in parvalbumin neurons rescued anesthesia-induced deficits in pyramidal cell inhibition, and hippocampus-dependent long-term memory. Conversely, partial depletion of parvalbumin neurons in neonates was sufficient to engender long-lasting memory impairment. Thus, loss of parvalbumin interneurons in postnatal mice following repeated general anesthesia critically contributes to memory deficits in adulthood. [ABSTRACT FROM AUTHOR]

The development and maintenance of chronic pain involves the reorganization of spinal nociceptive circuits. The mechanistic target of rapamycin complex 2 (mTORC2), a central signaling hub that modulates both actin-dependent structural changes and mTORC1-dependent mRNA translation, plays key roles in hippocampal synaptic plasticity and memory formation. However, its function in spinal plasticity and chronic pain is poorly understood. Here we show that pharmacological activation of spinal mTORC2 induces pain hypersensitivity, whereas its inhibition, using downregulation of the mTORC2-defining component Rictor, alleviates both inflammatory and neuropathic pain. Cell-type-specific deletion of Rictor showed that the selective inhibition of mTORC2 in a subset of excitatory neurons impairs spinal synaptic potentiation and alleviates inflammation-induced mechanical and thermal hypersensitivity, and nerve injury-induced heat hyperalgesia. The ablation of mTORC2 in inhibitory interneurons strongly alleviated nerve injury-induced mechanical hypersensitivity. Our findings reveal the role of mTORC2 in chronic pain and highlight its cell-type-specific functions in mediating pain hypersensitivity in response to peripheral inflammation and nerve injury., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Sensitization of spinal nociceptive circuits plays a crucial role in neuropathic pain. This sensitization depends on new gene expression that is primarily regulated via transcriptional and translational control mechanisms. The relative roles of these mechanisms in regulating gene expression in the clinically relevant chronic phase of neuropathic pain are not well understood. Here, we show that changes in gene expression in the spinal cord during the chronic phase of neuropathic pain are substantially regulated at the translational level. Downregulating spinal translation at the chronic phase alleviated pain hypersensitivity. Cell-type-specific profiling revealed that spinal inhibitory neurons exhibited greater changes in translation after peripheral nerve injury compared to excitatory neurons. Notably, increasing translation selectively in all inhibitory neurons or parvalbumin-positive (PV + ) interneurons, but not excitatory neurons, promoted mechanical pain hypersensitivity. Furthermore, increasing translation in PV + neurons decreased their intrinsic excitability and spiking activity, whereas reducing translation in spinal PV + neurons prevented the nerve injury-induced decrease in excitability. Thus, translational control mechanisms in the spinal cord, particularly in inhibitory neurons, play a role in mediating neuropathic pain hypersensitivity., Competing Interests: Declaration of Interests: Hien T. Zhao and Bethany Fitzsimmons are full-time employees and shareholders of Ionis Pharmaceutical, Inc. Other authors declare no competing interests.

Improving injury prediction accuracy and fidelity for mounted Warfighters has become an area of focus for the U.S. military in response to improvised explosive device (IED) use in both Iraq and Afghanistan. Although the Hybrid III anthropomorphic test device (ATD) has historically been used for crew injury analysis, it is only capable of predicting a few select skeletal injuries. The Computational Anthropomorphic Virtual Experiment Man (CAVEMAN) human body model is being developed to expand the injury analysis capability to both skeletal and soft tissues. The CAVEMAN model is built upon the Zygote 50 th percentile male human CAD model and uses a finite element modeling approach developed for high performance computing (HPC). The lower extremity subset of the CAVEMAN human body model presented herein includes: 28 bones, 26 muscles, 40 ligaments, fascia, cartilage and skin. Sensitivity studies have been conducted with the CAVEMAN lower extremity model to determine the structures critical for load transmission through the leg in the underbody blast (UBB) environment. An evaluation of the CAVEMAN lower extremity biofidelity was also carried out using 14 unique data sets derived by the Warrior Injury Assessment Manikin (WIAMan) program cadaveric lower leg testing. Extension of the CAVEMAN lower extremity model into anatomical tissue failure will provide additional injury prediction capabilities, beyond what is currently achievable using ATDs, to improve occupant survivability analyses within military vehicles.

Advancements in computational techniques have provided the ability to utilize detailed models in surgical training systems. The development of more complicated procedures coupled with reduced training time for medical residents has driven the need for accurate reality-based medical simulators. Extensive research has been conducted in the area of modeling general deformation of biological tissue; however few studies have focused on the physical properties of specific tool tissue interactions such as cutting. This paper presents a fracture mechanics based method to model the scalpel cutting of porcine liver by implementing a cohesive zone approach. Using in vivo cutting data, the parameters of the cohesive zone model are defined for the scalpel cutting process of soft biological tissues.

The advent of complex surgical procedures has driven the need for realistic surgical training simulators. Comprehensive simulators that provide realistic visual and haptic feedback during surgical tasks are required to familiarize surgeons with the procedures they are to perform. Complex organ geometry inherent to biological tissues and intricate material properties drive the need for finite element methods to assure accurate tissue displacement and force calculations. Advances in real-time finite element methods have not reached the state where they are applicable to soft tissue surgical simulation. Therefore a real-time, haptics-enabled simulator for probing of soft tissue has been developed which utilizes preprocessed finite element data (derived from accurate constitutive model of the soft-tissue obtained from carefully collected experimental data) to accurately replicate the probing task in real-time.

Advances in electrosurgical technology have promoted the use of electrocautery in many surgical procedures. Precise modeling of soft tissue deformation during electrocautery with electrosurgical generators can be a valuable tool in training simulators for surgical procedures. Coupling the visualization of electrocautery with the force feedback during an electrocautery process (to maintain optimal current) without causing necrosis is an important learning tool. Realistic simulation will provide surgeon trainees a method to practice electrocautery techniques prior to experimenting on live tissue as well as allow surgeons to gain a feel for electrocautery procedures.