Ketogenic diet mitigates opioid-induced hyperalgesia by restoring short-chain fatty acids-producing bacteria in the gut.

ABSTRACT: Opioids are commonly prescribed to patients with chronic pain. Chronic opioid usage comes with a slew of serious side effects, including opioid-induced hyperalgesia (OIH). The patients with long-term opioid treatment experience paradoxical increases in nociceptive hypersensitivity, namely, OIH. Currently, treatment options for OIH are extremely lacking. In this study, we show that the ketogenic diet recovers the abnormal pain behavior caused by chronic morphine treatment in male mice, and we further show that the therapeutic effect of the ketogenic diet is mediated through gut microbiome. Our 16S rRNA sequencing demonstrates that chronic morphine treatment causes changes in mouse gut microbiota, specifically a decrease in short-chain fatty acids-producing bacteria, and the sequencing data also show that the ketogenic diet rescues those bacteria in the mouse gut. More importantly, we show that supplementation with short-chain fatty acids (butyrate, propionate, and acetate) can delay the onset of OIH, indicating that short-chain fatty acids play a direct role in the development of OIH. Our findings suggest that gut microbiome could be targeted to treat OIH, and the ketogenic diet can be used as a complementary approach for pain relief in patients with chronic opioid treatment. We only used male mice in this study, and thus, our findings cannot be generalized to both sexes.

Standardised Tool for the Assessment of Bruxism.

OBJECTIVE: This paper aims to present and describe the Standardised Tool for the Assessment of Bruxism (STAB), an instrument that was developed to provide a multidimensional evaluation of bruxism status, comorbid conditions, aetiology and consequences. METHODS: The rationale for creating the tool and the road map that led to the selection of items included in the STAB has been discussed in previous publications. RESULTS: The tool consists of two axes, specifically dedicated to the evaluation of bruxism status and consequences (Axis A) and of bruxism risk and etiological factors and comorbid conditions (Axis B). The tool includes 14 domains, accounting for a total of 66 items. Axis A includes the self-reported information on bruxism status and possible consequences (subject-based report) together with the clinical (examiner report) and instrumental (technology report) assessment. The Subject-Based Assessment (SBA) includes domains on Sleep Bruxism (A1), Awake Bruxism (A2) and Patient's Complaints (A3), with information based on patients' self-report. The Clinically Based Assessment (CBA) includes domains on Joints and Muscles (A4), Intra- and Extra-Oral Tissues (A5) and Teeth and Restorations (A6), based on information collected by an examiner. The Instrumentally Based Assessment (IBA) includes domains on Sleep Bruxism (A7), Awake Bruxism (A8) and the use of Additional Instruments (A9), based on the information gathered with the use of technological devices. Axis B includes the self-reported information (subject-based report) on factors and conditions that may have an etiological or comorbid association with bruxism. It includes domains on Psychosocial Assessment (B1), Concurrent Sleep-related Conditions Assessment (B2), Concurrent Non-Sleep Conditions Assessment (B3), Prescribed Medications and Use of Substances Assessment (B4) and Additional Factors Assessment (B5). As a rule, whenever possible, existing instruments, either in full or partial form (i.e. specific subscales), are included. A user's guide for scoring the different items is also provided to ease administration. CONCLUSIONS: The instrument is now ready for on-field testing and further refinement. It can be anticipated that it will help in collecting data on bruxism in such a comprehensive way to have an impact on several clinical and research fields.

Research routes on awake bruxism metrics: Implications of the updated bruxism definition and evaluation strategies.

BACKGROUND: With time, due to the poor knowledge on it epidemiology, the need to focus on awake bruxism as a complement of sleep studies emerged. OBJECTIVE: In line with a similar recent proposal for sleep bruxism (SB), defining clinically oriented research routes to implement knowledge on awake bruxism (AB) metrics is important for an enhanced comprehension of the full bruxism spectrum, that is better assessment and more efficient management. METHODS: We summarised current strategies for AB assessment and proposed a research route for improving its metrics. RESULTS: Most of the literature focuses on bruxism in general or SB in particular, whilst knowledge on AB is generally fragmental. Assessment can be based on non-instrumental or instrumental approaches. The former include self-report (questionnaires, oral history) and clinical examination, whilst the latter include electromyography (EMG) of jaw muscles during wakefulness as well as the technology-enhanced ecological momentary assesment (EMA). Phenotyping of different AB activities should be the target of a research task force. In the absence of available data on the frequency and intensity of wake-time bruxism-type masticatory muscle activity, any speculation about the identification of thresholds and criteria to identify bruxers is premature. Research routes in the field must focus on the improvement of data reliability and validity. CONCLUSIONS: Probing deeper into the study of AB metrics is a fundamental step to assist clinicians in preventing and managing the putative consequences at the individual level. The present manuscript proposes some possible research routes to advance current knowledge. At different levels, instrumentally based and subject-based information must be gathered in a universally accepted standardised approach.

Bruxism and oro-facial pain not related to temporomandibular disorder conditions: Comorbidities or risk factors?

INTRODUCTION: Bruxism has historically been of particular interest to the field of dentistry, primarily due to the inferred damage it may cause to the dentition and supporting periodontal structures. The definition of bruxism itself has undergone multiple changes over time. In addition, the effects of bruxism as it relates to oro-facial pain conditions has remained a debatable topic. PURPOSE: To review the available literature relating to bruxism and non-temporomandibular disorder (TMD) pain conditions. METHODS: A literature search was conducted with the assistance of an expert librarian. The following databases were reviewed: PubMed, MEDLINE, EMBASE and Google Scholar. For additional references, articles were also retrieved by hand search from the selected papers. Any articles that were not published in English, or the focus were related to temporomandibular disorders were excluded. CONCLUSIONS: While bruxism and certain headache conditions do tend to occur together frequently, evidence relating to any clear common pathophysiological mechanism has yet to be fully elucidated. Robust evidence as it relates to the relationship between bruxism and other non-TMD oro-facial pains is also lacking.

Biomechanics and Derangements of the Temporomandibular Joint.

The human temporomandibular joint, is a ginglymo-arthrodial joint. The articular disk serves as a fibrous, viscoelastic structure that allows force distribution and smooth movement of the joint in its normal arrangement during mandibular movements. Most studies suggest that in the normal disk position the posterior band is located at the 12'o clock position within the glenoid fossa in the closed mouth posture. When the biomechanics of the joint is altered, the disk may be displaced creating an abnormal relationship between the disk, condyle, and the eminence that is often referred to as an internal derangement. This article reviews the various presentations of internal derangements.

Optical calibration of the SuperCam instrument body unit spectrometers.

The SuperCam remote sensing instrument on NASA's Perseverance rover is capable of four spectroscopic techniques, remote micro-imaging, and audio recording. These analytical techniques provide details of the chemistry and mineralogy of the rocks and soils probed in the Jezero Crater on Mars. Here we present the methods used for optical calibration of the three spectrometers covering the 243-853 nm range used by three of the four spectroscopic techniques. We derive the instrument optical response, which characterizes the instrument sensitivity to incident radiation as a function of a wavelength. The instrument optical response function derived here is an essential step in the interpretation of the spectra returned by SuperCam as it converts the observed spectra, reported by the instrument as "digital counts" from an analog to digital converter, into physical values of spectral radiance.

Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology.

LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.

A Pre-Existing Myogenic Temporomandibular Disorder Increases Trigeminal Calcitonin Gene-Related Peptide and Enhances Nitroglycerin-Induced Hypersensitivity in Mice.

Migraine is commonly reported among patients with temporomandibular disorders (TMDs), especially myogenic TMD. The pathophysiologic mechanisms related to the comorbidity of the two conditions remain elusive. In the present study, we combined masseter muscle tendon ligation (MMTL)-produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like hypersensitivity in mice. Facial mechanical allodynia, functional allodynia, and light-aversive behavior were evaluated. Sumatriptan, an FDA-approved medication for migraine, was used to validate migraine-like hypersensitivity. Additionally, we examined the protein level of calcitonin gene-related peptide (CGRP) in the spinal trigeminal nucleus caudalis using immunohistochemistry. We observed that mice with MMTL pretreatment have a prolonged NTG-induced migraine-like hypersensitivity, and MMTL also enabled a non-sensitizing dose of NTG to trigger migraine-like hypersensitivity. Systemic injection of sumatriptan inhibited the MMTL-enhanced migraine-like hypersensitivity. MMTL pretreatment significantly upregulated the protein level of CGRP in the spinal trigeminal nucleus caudalis after NTG injection. Our results indicate that a pre-existing myogenic TMD can upregulate NTG-induced trigeminal CGRP and enhance migraine-like hypersensitivity.

Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity.

Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8+ effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.

Burning Mouth Syndrome.

Burning mouth syndrome (BMS) is a chronic disorder for which a definitive etiopathology is not known. The BMS patient often experiences a continuous burning pain in the mouth without any clinical signs. This confusing condition can create frustration for both patient and practitioner. Ultimately, it is important for the practitioner who treats head and face pain to become knowledgeable in the recognition of the many complexities and various presentations associated with BMS. In doing so, the practitioner can be better prepared to help patients cope with this confounding disorder and gain a better quality of life.

Assessment of the Orofacial Pain Patient.

The diagnostic process of pain in the oral, facial, and head region is often perceived as more difficult due the numerous, extensively innervated structures located in this area. To successfully manage the patient with these pain presentations, it is critical for the clinician to spend ample time procuring a good medical and dental history. A systematic approach to the physical examination will ensure that sufficient data are acquired without overlooking potentially important contributing factors. The use of adjunctive laboratory tests and imaging studies should be based on the findings in the history and examination.

Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers.

Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate.

Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors.

The epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harbouring activating mutations in the EGFR kinase, but resistance arises rapidly, most frequently owing to the secondary T790M mutation within the ATP site of the receptor. Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternative mechanisms of action. Here we describe the rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor. The crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays. However, as a single agent it is not effective in blocking EGFR-driven proliferation in cells owing to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state. We observe marked synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization, rendering the kinase uniformly susceptible to the allosteric agent. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR(L858R/T790M) and by EGFR(L858R/T790M/C797S), a mutant that is resistant to all currently available EGFR TKIs. More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors.

EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor.

Non-small cell lung cancer patients carrying oncogenic EGFR mutations initially respond to EGFR-targeted therapy, but later elicit minimal response due to dose-limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets EGFR-activating mutations arising de novo and upon resistance acquisition, while sparing wild-type (WT) EGFR. EGF816 potently inhibited the most common EGFR mutations L858R, Ex19del, and T790M in vitro, which translated into strong tumor regressions in vivo in several patient-derived xenograft models. Notably, EGF816 also demonstrated antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 treatment led to minimal inhibition of WT EGFR and was well tolerated. In single-dose studies, EGF816 provided sustained inhibition of EGFR phosphorylation, consistent with its ability for irreversible binding. Furthermore, combined treatment with EGF816 and INC280, a cMET inhibitor, resulted in durable antitumor efficacy in a xenograft model that initially developed resistance to first-generation EGFR inhibitors via cMET activation. Thus, we report the first preclinical characterization of EGF816 and provide the groundwork for its current evaluation in phase I/II clinical trials in patients harboring EGFR mutations, including T790M.

CRITICAL APPRAISAL. Sleep Bruxism and Sleep-Disordered Breathing.

Sleep bruxism (SB) is a repetitive jaw muscle activity with clenching or grinding of the teeth during sleep. SB is characterized by what is known as rhythmic masticatory muscle activity (RMMA). RMMA is the laboratory polysomnographic finding that differentiates SB from other oromandibular movements seen during sleep. Most often RMMA episodes are associated with sleep arousal. Some patients will report similar complaints related to both SB and sleep disordered breathing (SDB). There are some reports that would suggest that SB is a result of SDB. It has has been postulated that SB is a compensatory mechanism to re establish muscle tone of the upper airway. While these disorders do in fact often present concomitantly, the relationship between the two is yet to be fully elucidated. This Critical Appraisal reviews 3 recent publications with the intent to better define what relationships may exists between SDB and SB. While the current evidence appears to support the notion that these are often concomitant disorders, it also makes clear that evidence to support the hypothesis that SDB is causative for SB is currently lacking.

Planetary geochemical investigations using Raman and laser-induced breakdown spectroscopy.

An integrated Raman spectroscopy and laser-induced breakdown spectroscopy (LIBS) instrument is a valuable geoanalytical tool for future planetary missions to Mars, Venus, and elsewhere. The ChemCam instrument operating on the Mars Curiosity rover includes a remote LIBS instrument. An integrated Raman-LIBS spectrometer (RLS) based on the ChemCam architecture could be used as a reconnaissance tool for other contact instruments as well as a primary science instrument capable of quantitative mineralogical and geochemical analyses. Replacing one of the ChemCam spectrometers with a miniature transmission spectrometer enables a Raman spectroscopy mineralogical analysis to be performed, complementing the LIBS chemical analysis while retaining an overall architecture resembling ChemCam. A prototype transmission spectrometer was used to record Raman spectra under both Martian and Venus conditions. Two different high-pressure and high-temperature cells were used to collect the Raman and LIBS spectra to simulate surface conditions on Venus. The resulting LIBS spectra were used to generate a limited partial least squares Venus calibration model for the major elements. These experiments demonstrate the utility and feasibility of a combined RLS instrument.

Trigger point injections for headache disorders: expert consensus methodology and narrative review.

OBJECTIVE/BACKGROUND: To review the existing literature and describe a standardized methodology by expert consensus for the performance of trigger point injections (TPIs) in the treatment of headache disorders. Despite their widespread use, the efficacy, safety, and methodology of TPIs have not been reviewed specifically for headache disorders by expert consensus. METHODS: The Peripheral Nerve Blocks and Other Interventional Procedures Special Interest Section of the American Headache Society over a series of meetings reached a consensus for nomenclature, indications, contraindications, precautions, procedural details, outcomes, and adverse effects for the use of TPIs for headache disorders. A subcommittee of the Section also reviewed the literature. RESULTS: Indications for TPIs may include many types of episodic and chronic primary and secondary headache disorders, with the presence of active trigger points (TPs) on physical examination. Contraindications may include infection, a local open skull defect, or an anesthetic allergy, and precautions are necessary in the setting of anticoagulant use, pregnancy, and obesity with unclear anatomical landmarks. The most common muscles selected for TPIs include the trapezius, sternocleidomastoid, and temporalis, with bupivacaine and lidocaine the agents used most frequently. Adverse effects are typically mild with careful patient and procedural selection, though pneumothorax and other serious adverse events have been infrequently reported. CONCLUSIONS: When performed in the appropriate setting and with the proper expertise, TPIs seem to have a role in the adjunctive treatment of the most common headache disorders. We hope our effort to characterize the methodology of TPIs by expert opinion in the context of published data motivates the performance of evidence-based and standardized treatment protocols.