Substance P activates Mas-related G protein-coupled receptors to induce itch.

BACKGROUND: Substance P (SP) is linked to itch and inflammation through activation of receptors on mast cells and sensory neurons. There is increasing evidence that SP functions through Mas-related G protein-coupled receptors (Mrgprs) in addition to its conventional receptor, neurokinin-1. OBJECTIVE: Because Mrgprs mediate some aspects of inflammation that had been considered mediated by neurokinin-1 receptor (NK-1R), we sought to determine whether itch induced by SP can also be mediated by Mrgprs. METHODS: Genetic and pharmacologic approaches were used to evaluate the contribution of Mrgprs to SP-induced scratching behavior and activation of cultured dorsal root ganglion neurons from mice. RESULTS: SP-induced scratching behavior and activation of cultured dorsal root ganglion neurons was dependent on Mrgprs rather than NK-1R. CONCLUSION: We deduce that SP activates MrgprA1 on sensory neurons rather than NK-1R to induce itch.

Peripheral NMDA Receptor/NO System Blockage Inhibits Itch Responses Induced by Chloroquine in Mice.

Intradermal administration of chloroquine (CQ) provokes scratching behavior in mice. Chloroquine-induced itch is histamine-independent and we have reported that the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is involved in CQ-induced scratching behavior in mice. Previous studies have demonstrated that activation of N-methyl-d-aspartate receptors (NMDARs) induces NO production. Here we show that NMDAR antagonists significantly decrease CQ-induced scratching in mice while a non-effective dose of an NMDAR agonist potentiates the scratching behavior provoked by sub-effective doses of CQ. In contrast, combined pre-treatment with sub-effective doses of an NMDAR antagonist, MK-801, and the NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), decreases CQ-induced scrat-ching behavior. While intradermal administration of CQ significantly increases the concentration of intradermal nitrite, the end product of NO metabolism, effective doses of intraperitoneal and intradermal MK-801 significantly decrease intradermal nitrite levels. Likewise, administration of an effective dose of L-NAME significantly decreases CQ-induced nitrite production. We conclude that the NMDA/NO pathway in the skin modulates CQ-induced scratching behavior.

Development of resistance to serotonin-induced itch in bile duct ligated mice.

Cholestatic itch can be severe and significantly impair the quality of life of patients. The serotonin system is implicated in cholestatic itch; however, the pruritogenic properties of serotonin have not been evaluated in cholestatic mice. Here, we investigated the serotonin-induced itch in cholestatic mice which was induced by bile duct ligation (BDL). Serotonin, sertraline or saline were administered intradermally to the rostral back area in BDL and sham operated (SHAM) mice, and the scratching behaviour was videotaped for 1 hour. Bile duct ligated mice had significantly increased scratching responses to saline injection on the seventh day after surgery. Additionally, serotonin or sertraline significantly induced scratching behaviour in BDL mice compared to saline at day 7 after surgery, while it did not induce itch at day 5. The scratching behaviour induced by serotonin or sertraline was significantly less in BDL mice compared to SHAM mice. Likewise, the locomotor activity of BDL or SHAM mice was not significantly different from unoperated (UNOP) mice on the fifth and seventh day, suggesting that the scratching behaviour was not affected by motor dysfunctions. Our data suggest that despite the potentiation of evoked itch, a resistance to serotonin-induced itch is developed in cholestatic mice.

Are itch and scratching the nausea and vomiting of skin?

The physiologic similarities between itch and nausea may not be evident initially, but they share the role of repelling irritants and toxins from the body by inducting scratching and vomiting, respectively. In addition, itch and nausea frequently occur together in certain conditions such as uraemia. Here we show that the mechanisms underlying itch and nausea overlap and that advances in either field may influence the identification of novel drug targets, particularly for itch.

Mixed reality based teleoperation and visualization of surgical robotics.

Surgical robotics has revolutionized the field of surgery, facilitating complex procedures in operating rooms. However, the current teleoperation systems often rely on bulky consoles, which limit the mobility of surgeons. This restriction reduces surgeons' awareness of the patient during procedures and narrows the range of implementation scenarios. To address these challenges, an alternative solution is proposed: a mixed reality-based teleoperation system. This system leverages hand gestures, head motion tracking, and speech commands to enable the teleoperation of surgical robots. The implementation focuses on the da Vinci research kit (dVRK) and utilizes the capabilities of Microsoft HoloLens 2. The system's effectiveness is evaluated through camera navigation tasks and peg transfer tasks. The results indicate that, in comparison to manipulator-based teleoperation, the system demonstrates comparable viability in endoscope teleoperation. However, it falls short in instrument teleoperation, highlighting the need for further improvements in hand gesture recognition and video display quality.

Mixed reality guided root canal therapy.

Root canal therapy (RCT) is a widely performed procedure in dentistry, with over 25 million individuals undergoing it annually. This procedure is carried out to address inflammation or infection within the root canal system of affected teeth. However, accurately aligning CT scan information with the patient's tooth has posed challenges, leading to errors in tool positioning and potential negative outcomes. To overcome these challenges, a mixed reality application is developed using an optical see-through head-mounted display (OST-HMD). The application incorporates visual cues, an augmented mirror, and dynamically updated multi-view CT slices to address depth perception issues and achieve accurate tooth localization, comprehensive canal exploration, and prevention of perforation during RCT. Through the preliminary experimental assessment, significant improvements in the accuracy of the procedure are observed. Specifically, with the system the accuracy in position was improved from 1.4 to 0.4 mm (more than a 70% gain) using an Optical Tracker (NDI) and from 2.8 to 2.4 mm using an HMD, thereby achieving submillimeter accuracy with NDI. 6 participants were enrolled in the user study. The result of the study suggests that the average displacement on the crown plane of 1.27 ± 0.83 cm, an average depth error of 0.90 ± 0.72 cm and an average angular deviation of 1.83 ± 0.83°. Our error analysis further highlights the impact of HMD spatial localization and head motion on the registration and calibration process. Through seamless integration of CT image information with the patient's tooth, our mixed reality application assists dentists in achieving precise tool placement. This advancement in technology has the potential to elevate the quality of root canal procedures, ensuring better accuracy and enhancing overall treatment outcomes.

Surgical navigation with a head-mounted tracking system and display.

We present the design of a self-contained head-mounted surgical navigation system, which consists of an optical tracking system and an optical see-through head-mounted display (HMD). While the current prototype is bulky, we envision a more compact solution via the eventual integration of the tracking camera(s) into the HMD goggles. Rather than attempting to accurately overlay preoperative models onto the field of view, we adopted a simpler approach of displaying a small "picture-in-picture" virtual view in the HMD. We believe this approach will provide suitable assistance for some image-guided procedures, such as tumor resection, while improving the ergonomics by reducing the need for the surgeon to look away from the patient to view an external monitor. We report the results of initial experiments performed with this system, while preparing for a more clinically realistic study.

Metal ion specificities for folding and cleavage activity in the Schistosoma hammerhead ribozyme.

The effects of various metal ions on cleavage activity and global folding have been studied in the extended Schistosoma hammerhead ribozyme. Fluorescence resonance energy transfer was used to probe global folding as a function of various monovalent and divalent metal ions in this ribozyme. The divalent metals ions Ca(2+), Mg(2+), Mn(2+), and Sr(2+) have a relatively small variation (less than sixfold) in their ability to globally fold the hammerhead ribozyme, which contrasts with the very large difference (>10,000-fold) in apparent rate constants for cleavage for these divalent metal ions in single-turnover kinetic experiments. There is still a very large range (>4600-fold) in the apparent rate constants for cleavage for these divalent metal ions measured in high salt (2 M NaCl) conditions where the ribozyme is globally folded. These results demonstrate that the identity of the divalent metal ion has little effect on global folding of the Schistosoma hammerhead ribozyme, whereas it has a very large effect on the cleavage kinetics. Mechanisms by which the identity of the divalent metal ion can have such a large effect on cleavage activity in the Schistosoma hammerhead ribozyme are discussed.

Improvement in dynamic range limitation of swept source optical coherence tomography by true logarithmic amplification.

We previously demonstrated, with both theoretical and experimental studies, the dynamic range limitation with spectral domain optical coherence tomography (OCT) relative to time domain OCT. A significant portion of this limitation was due to the difference of analog/digital conversion. In this paper, a new method of true logarithmic amplification is discussed theoretically and tested experimentally to increase the dynamic range of a swept source OCT. With the current experimental setup, an increase of the dynamic range by about 6 dB was obtained.

Can Mixed-Reality Improve the Training of Medical Procedures?

One cause of preventable death is a lack of proper skills for providing critical care. The conventional course taught to non-medical individuals involves instructions of advanced emergency procedures routinely limited to a verbal block of instructions in a standardized presentation (for example, an instructional video).In the present study, we evaluate the benefits of using an OST-HMD for training of caregivers in an emergency medical environment. A rich user interface was implemented that provides 3D visual aids including images, text and tracked 3D overlays corresponding to each task that needs to be performed. A user study with 20 participants is conducted which involves training of two tasks where each subject performs one task with the HMD and the other with standard training. Two evaluations were performed, with the first immediately after the training followed by a second one three weeks later. Our results indicate that using a mixed reality HMD is more engaging, improves the time-on-task, and increases the confidence level of users in providing emergency and critical care.

Brief communication: MRGPRX2, atopic dermatitis and red man syndrome.

Vancoymycin causes red man syndrome, an itchy erythematous eruption involving the face, neck and upper torso. Atopic dermatitis also manifests itch and erythema, and staphylococcus δ-toxin contributes to this process. The antibiotic and toxin each provoke mast cell degranulation but the mechanism had not been understood. We have determined that these compounds evoke degranulation via interaction with the same receptor, MRGPRX2, on mast cells. A receptor antagonist inhibits this process. Antagonists of this receptor may have therapeutic potential.

Peripheral Mechanisms of Itch.

A multitude of exogenous environmental stimuli and endogenous molecular and cellular components interface directly or indirectly with the free nerve endings of sensory nerves in the skin. Environmental stimuli include substances derived from the microbiome and materials, such as allergens, that otherwise come in contact with the skin. Endogenous stimuli include components of or mediators derived from the epidermal barrier, keratinocytes, mast cells, and additional resident and skin-homing immune cells. The sensation of itch is ultimately provoked by mediators that interact with and activate pruriceptors on the sensory nerve fibers. These peripheral fibers convey signals from the skin to the dorsal root and trigeminal ganglia and on to the spinal cord and brain where central processing of the itch sensation occurs. A discussion of the nature and sources of itch stimuli and receptors in the periphery form the basis of this chapter. The development of drugs that target these processes is in the process of revolutionizing therapeutic approaches to itch.

Evidence for the involvement of nitric oxide in cholestasis-induced itch associated response in mice.

Cholestasis is a major systemic disorder associated with distressing pruritus (itch). Nitric oxide (NO) is a neurotransmitter, assumed to be involved in pruritus. Based on over-production of NO in cholestatic liver diseases, this project aimed to investigate involvement of NO in cholestasis-related itch in mice. To achieve this, cholestasis was induced by bile duct ligation (BDL). Our results showed that BDL mice elicited significant itch on fifth and seventh day after the procedure. This scratching behavior was inhibited by intraperitoneal (IP) treatment of mice with non-selective NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME; 3mg/kg) and inducible NOS (iNOS) inhibitor aminoguanidine (AG; 100mg/kg). The inhibitory effects of l-NAME and AG were reversed by pretreatment with l-arginine (100mg/kg). Administration of l-NAME, AG and l-arginine per se, in BDL and SHAM mice did not produce scratching behaviors. In addition, intradermal injection of l-arginine at dose of 300 nmol/site significantly increased itch in BDL mice. Furthermore, nitrite levels in skin and serum of BDL animals significantly increased after 7 d of operation and administration of NOS inhibitors decreased this enhancement. l-arginine injection reversed the effects of NOS inhibitors on reduction of nitrite levels in the skin and serum of BDL mice. Finally, cutaneous iNOS expression increased in BDL mice 7 d after surgery. Taken together, our study showed for the first time that BDL, as a model of acute cholestasis in rodents, induces NO over-production by activating NOS enzymes, especially iNOS, which contribute to pruritus.

Dual action of neurokinin-1 antagonists on Mas-related GPCRs.

The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2. An unrelated tripeptide NK-1R antagonist has dual activity on MRGPRX2. This tripeptide both suppresses itch in mice and inhibits degranulation from the LAD-2 human mast cell line elicited by basic secretagogue activation of MRGPRX2. Antagonists of Mrgprs may fill the void left by the failure of NK-1R antagonists.

Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs.

Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch. We show that the cysteine protease cathepsin S activates MrgprC11 and evokes receptor-dependent scratching in mice. In contrast to its activation of conventional protease-activated receptors, cathepsin S-mediated activation of MrgprC11 did not involve the generation of a tethered ligand. We demonstrate further that different cysteine proteases selectively activate specific mouse and human Mrgpr family members. This expansion of our understanding by which proteases interact with G-protein-coupled receptors (GPCRs) redefines the concept of what constitutes a protease-activated receptor. The findings also implicate proteases as ligands to members of this orphan receptor family while providing new insights into how cysteine proteases contribute to itch.