Salivary Antioxidant Profile in Patients with Systemic Sclerosis and Periodontitis.

Objective: The aim of the present study was to compare periodontal status and antioxidant profile in unstimulated saliva of systemic sclerosis (SSc) patients with periodontitis and systemically healthy periodontitis patients. Design: Twenty patients with established diagnoses of systemic sclerosis and periodontitis (SSc group) and 20 systemically healthy individuals with periodontitis (P group) were enrolled in the study. Clinical periodontal parameters (clinical attachment level (CAL), gingival recession (GR), periodontal probing depth (PPD), and gingival index (GI)) and concentration of uric acid (UA), superoxide dismutase (SOD), and glutathione peroxidase (GPX) in unstimulated saliva samples were assessed. Results: There were significantly higher mean values of CAL (4.8 ± 0.21 mm versus 3.18 ± 0.17 mm; p ≤ 0.001) and GR (1.66 ± 0.90 mm versus 0.46 ± 0.54 mm; p ≤ 0.001) in the SSc group when compared to the P group. Significantly higher level of GPX (p ≤ 0.001) and SOD (p ≤ 0.001) in unstimulated saliva was detected in the SSc group in comparison with the P group. The specific activity of UA did not significantly differ between the two groups (p = 0.083). Conclusion: The results may indicate higher periodontal destruction and antioxidant perturbations in unstimulated saliva of SSc patients with periodontitis compared to systemically healthy periodontitis patients.

Growth and Characterization of Graphene Layers on Different Kinds of Copper Surfaces.

Graphene films were grown by chemical vapor deposition on Cu foil. The obtained samples were characterized by Raman spectroscopy, ellipsometry, X-ray photoelectron spectroscopy and electron back-scatter diffraction. We discuss the time-dependent changes in the samples, estimate the thickness of emerging Cu2O beneath the graphene and check the orientation-dependent affinity to oxidation of distinct Cu grains, which also governs the manner in which the initial strong Cu-graphene coupling and strain in the graphene lattice is released. Effects of electropolishing on the quality and the Raman response of the grown graphene layers are studied by microtexture polarization analysis. The obtained data are compared with the Raman signal of graphene after transfer on glass substrate revealing the complex interaction of graphene with the Cu substrate.

Estimation of manual wheelchair-based activities in the free-living environment using a neural network model with inertial body-worn sensors.

Shoulder pain is common in manual wheelchair (MWC) users. Overuse is thought to be a major cause, but little is known about exposure to activities of daily living (ADLs). The study goal was to develop a method to estimate three conditions in the field: (1) non-propulsion activity, (2) MWC propulsion, and (3) static time using an inertial measurement unit (IMU). Upper arm IMU data were collected as ten MWC users performed lab-based MWC-related ADLs. A neural network model was developed to classify data as non-propulsion activity, propulsion, or static, and validated for the lab-based data collection by video comparison. Six of the participants' free-living IMU data were collected and the lab-based model was applied to estimate daily non-propulsion activity, propulsion, and static time. The neural network model yielded lab-based validity measures ≥0.87 for differentiating non-propulsion activity, propulsion, and static time. A quasi-validation of one participant's field-based data yielded validity measures ≥0.66 for identifying propulsion. Participants' estimated mean daily non-propulsion activity, propulsion, and static time ranged from 158 to 409, 13 to 25, and 367 to 609 min, respectively. The preliminary results suggest the model may be able to accurately identify MWC users' field-based activities. The inclusion of field-based IMU data in the model could further improve field-based classification.

Self-Monitoring of Balance Performance can Reduce the Rate of Falls Among Older Adults.

Background: 29% of older adults fall annually, resulting in the leading cause of accidental death. Fall prevention programs typically include exercise training and self-monitoring of physical activity has a positive effect on the self-efficacy and self-regulation of exercise behaviors. We assessed if self-monitoring of fall risk, without an intervention, impacts fall rates. Methods: Fifty-three older adults had open access to a balance measuring platform which allowed them to self-monitor their postural stability and fall risk using a simple 1-min standing balance test. 12-month retrospective fall history was collected and a monthly/bimonthly fall log captured prospective falls. Participants had access to self-monitoring for up to 2.2 years. Fall history and fall incidence rate ratios and their confidence intervals were compared between the periods of time with and without access to self-monitoring. Results: A 54% reduction in the number of people who fell and a 74% reduction in the number of falls was observed when participants were able to self-monitor their postural stability and fall risk, after normalizing for participation length. Further, 42.9% of individuals identified as having high fall risk at baseline shifted to a lower risk category at a median 34 days and voluntarily measured themselves for a longer period of time. Discussion: We attribute this reduction in falls to changes in health behaviors achieved through empowerment from improved self-efficacy and self-regulation. Providing older adults with the ability to self-monitor their postural stability and intuit their risk of falling appears to have modified their health behaviors to successfully reduce fall rates.

Facile Fabrication of Hybrid Carbon Nanotube Sensors by Laser Direct Transfer.

Ammonia is one of the most frequently produced chemicals in the world, and thus, reliable measurements of different NH3 concentrations are critical for a variety of industries, among which are the agricultural and healthcare sectors. The currently available technologies for the detection of NH3 provide accurate identification; however, they are limited by size, portability, and fabrication cost. Therefore, in this work, we report the laser-induced forward transfer (LIFT) of single-walled carbon nanotubes (SWCNTs) decorated with tin oxide nanoparticles (SnO2 NPs), which act as sensitive materials in chemiresistive NH3 sensors. We demonstrate that the LIFT-fabricated sensors can detect NH3 at room temperature and have a response time of 13 s (for 25 ppm NH3). In addition, the laser-fabricated sensors are fully reversible when exposed to multiple cycles of NH3 and have an excellent theoretical limit of detection of 24 ppt.

Rare germline variants in individuals diagnosed with schizophrenia within multiplex families.

An extensive catalog of common and rare genetic variants contributes to overall risk for schizophrenia and related disorders. As a complement to population genetics efforts, here we present whole genome sequences of multiple affected probands within individual families to search for possible high penetrance driver variants. From a total of 15 families diagnostically evaluated by a single research psychiatrist, we performed whole genome sequencing of a total of 61 affected individuals, called SNPs, indels, and copy number variants, and compared to reference genomes. In fourteen out of fifteen families, the schizophrenia polygenic risk score for each proband was within the control range defined by the Thousand Genomes cohort. In six families, each affected member carried a very rare or private, predicted-damaging, variant in at least one gene. Among these genes, variants in LRP1 and TENM2 suggest these are candidate disease-related genes when taken into context with existing population genetic studies and biological information. Results add to the number of pedigree sequences reported, suggest pathways for the investigation of biological mechanisms, and are consistent with the overall accumulating evidence that very rare damaging variants contribute to the heritability of schizophrenia.

Cerebrolysin after moderate to severe traumatic brain injury: prospective meta-analysis of the CAPTAIN trial series.

INTRODUCTION: This prospective meta-analysis summarizes results from the CAPTAIN trial series, evaluating the effects of Cerebrolysin for moderate-severe traumatic brain injury, as an add-on to usual care. MATERIALS AND METHODS: The study included two phase IIIb/IV prospective, randomized, double-blind, placebo-controlled clinical trials. Eligible patients with a Glasgow Coma Score (GCS) between 6 and 12 received study medication (50 mL of Cerebrolysin or physiological saline solution per day for ten days, followed by two additional treatment cycles with 10 mL per day for 10 days) in addition to usual care. The meta-analysis comprises the primary ensembles of efficacy criteria for 90, 30, and 10 days after TBI with a priori ordered hypotheses based on multivariate, directional tests. RESULTS: A total 185 patients underwent meta-analysis (mean admission GCS = 10.3, mean age = 45.3, and mean Baseline Prognostic Risk Score = 2.8). The primary endpoint, a multidimensional ensemble of functional and neuropsychological outcome scales indicated a "small-to-medium" sized effect in favor of Cerebrolysin, statistically significant at Day 30 and at Day 90 (Day 30: MWcombined = 0.60, 95%CI 0.52 to 0.66, p = 0.0156; SMD = 0.31; OR = 1.69; Day 90: MWcombined = 0.60, 95%CI 0.52 to 0.68, p = 0.0146; SMD = 0.34, OR = 1.77). Treatment groups showed comparable safety and tolerability profiles. DISCUSSION: The meta-analysis of the CAPTAIN trials confirms the safety and efficacy of Cerebrolysin after moderate-severe TBI, opening a new horizon for neurorecovery in this field. Integration of Cerebrolysin into existing guidelines should be considered after careful review of internationally applicable criteria.

Application and Reliability of Accelerometer-Based Arm Use Intensities in the Free-Living Environment for Manual Wheelchair Users and Able-Bodied Individuals.

Arm use in manual wheelchair (MWC) users is characterized by a combination of overuse and a sedentary lifestyle. This study aimed to describe the percentage of daily time MWC users and able-bodied individuals spend in each arm use intensity level utilizing accelerometers. Arm use intensity levels of the upper arms were defined as stationary, low, mid, and high from the signal magnitude area (SMA) of the segment accelerations based on in-lab MWC activities performed by eight MWC users. Accelerometry data were collected in the free-living environments from forty MWC users and 40 sex- and age-matched able-bodied individuals. The SMA intensity levels were applied to the free-living data and the percentage of time spent in each level was calculated. The SMA intensity levels were defined as, stationary: ≤0.67 g, low: 0.671-3.27 g, mid: 3.27-5.87 g, and high: >5.871 g. The dominant arm of both MWC users and able-bodied individuals was stationary for most of the day and less than one percent of the day was spent in high intensity arm activities. Increased MWC user age correlated with increased stationary arm time (R = 0.368, p = 0.019). Five and eight days of data are needed from MWC users and able-bodied individuals, respectively, to achieve reliable representation of their daily arm use intensities.

Comparing supraspinatus to acromion proximity and kinematics of the shoulder and thorax between manual wheelchair propulsion styles: A pilot study.

BACKGROUND: Repetitive glenohumeral joint movement during manual wheelchair propulsion has been associated with shoulder pain in individuals with spinal cord injury. Clinical guidelines for shoulder health maintenance encourage semi-circular over arc propulsion to reduce loading frequency. This study aimed to determine the difference in estimated supraspinatus to acromion compression risk, and shoulder, thorax kinematics between (1) arc and semi-circular propulsion; and (2) self-selected and coached strategies. METHODS: Shoulder and thorax kinematics were captured during wheelchair propulsion, noting individually self-selected styles. Participants were then coached to perform the other style(s) of interest, arc and/or semi-circular. CT bone models of the humerus and scapula were animated using glenohumeral kinematics to estimate the minimum distance between the supraspinatus humeral attachment and the acromion. Compression risk was defined as the proportion of each propulsion phase where the minimum distance fell below 5 mm. Comparisons were made between conditions evaluating compression risk, minimum distances and kinematics at events throughout propulsion. FINDINGS: Ten individuals with spinal cord injury (9 male) participated. Arc and semi-circular propulsion did not significantly differ in compression risk or minimum distance across propulsion phases. Self-selected styles yielded lower compression risk and larger proximity values compared to coached styles. Glenohumeral horizontal abduction and thorax flexion differed between arc and semi-circular propulsion. Multiple glenohumeral and humerothoracic differences emerged between self-selected and coached conditions. INTERPRETATION: Supraspinatus compression was observed during both arc and semi-circular propulsion, suggesting risk may be unavoidable in this task. Self-selected styles yield less risk, likely related to coached style unfamiliarity.

Quality over quantity: skeletal loading intensity plays a key role in understanding the relationship between physical activity and bone density in postmenopausal women.

OBJECTIVE: Increasing physical activity (PA) is regularly cited as a modifiable target to improve health outcomes and quality of life in the aging population, especially postmenopausal women who exhibit low bone mineral density (BMD) and high fracture risk. In this cross-sectional study, we aimed to quantify real-world PA and its association with BMD in postmenopausal women. METHODS: Seventy postmenopausal women, aged 46 to 79 years, received a dual-energy X-ray absorptiometry scan measuring total hip BMD and wore bilateral triaxial accelerometers on the ankles for 7 days to measure PA in their free-living environment. Custom step detection and peak vertical ground reaction force estimation algorithms, sensitive to both quantity and intensity of PA, were used to calculate a daily bone density index (BDI) for each participant. Multiple regression was used to quantify the relationship between total hip BMD, age, step counts, and mean BDI over the span of 7 days of data collection. RESULTS: All participants completed the full 7 days of PA monitoring, totaling more than 7 million detected steps. Participants averaged 14,485 ±â€Š4,334 steps daily with mean peak vertical ground reaction force stepping loads of 675 ±â€Š121 N during daily living. Across the population, total hip BMD was found to be significantly correlated with objective estimates of mean BDI (r = 0.44), as well as participant age (r = 0.285). CONCLUSION: Despite having higher-than-expected PA, the low stepping loads observed in this cohort, along with half of the participants having low BMD measures, underscores the need for PA intensity to be considered in the management of postmenopausal bone health.

A Postural Assessment Utilizing Machine Learning Prospectively Identifies Older Adults at a High Risk of Falling.

Introduction: Falls are the leading cause of accidental death in older adults. Each year, 28.7% of US adults over 65 years experience a fall resulting in over 300,000 hip fractures and $50 billion in medical costs. Annual fall risk assessments have become part of the standard care plan for older adults. However, the effectiveness of these assessments in identifying at-risk individuals remains limited. This study characterizes the performance of a commercially available, automated method, for assessing fall risk using machine learning. Methods: Participants (N = 209) were recruited from eight senior living facilities and from adults living in the community (five local community centers in Houston, TX) to participate in a 12-month retrospective and a 12-month prospective cohort study. Upon enrollment, each participant stood for 60 s, with eyes open, on a commercial balance measurement platform which uses force-plate technology to capture center-of-pressure (60 Hz frequency). Linear and non-linear components of the center-of-pressure were analyzed using a machine-learning algorithm resulting in a postural stability (PS) score (range 1-10). A higher PS score indicated greater stability. Participants were contacted monthly for a year to track fall events and determine fall circumstances. Reliability among repeated trials, past and future fall prediction, as well as survival analyses, were assessed. Results: Measurement reliability was found to be high (ICC(2,1) [95% CI]=0.78 [0.76-0.81]). Individuals in the high-risk range (1-3) were three times more likely to fall within a year than those in low-risk (7-10). They were also an order of magnitude more likely (12/104 vs. 1/105) to suffer a spontaneous fall i.e., a fall where no cause was self-reported. Survival analyses suggests a fall event within 9 months (median) for high risk individuals. Conclusions: We demonstrate that an easy-to-use, automated method for assessing fall risk can reliably predict falls a year in advance. Objective identification of at-risk patients will aid clinicians in providing individualized fall prevention care.

Cellulose acetate/layered double hydroxide adsorptive membranes for efficient removal of pharmaceutical environmental contaminants.

The increasing amount of residual pharmaceutical contaminants in wastewater has a negative impact on both the environment and human health. In the present study, we developed new cellulose acetate/Mg-Al layered double hydroxide (Mg-Al LDH) nanocomposite membranes as an efficient method to remove pharmaceutical substances from wastewater. The morphology, porosity, surface properties and thermal stability of nanocomposite membranes containing various amounts of nanofiller were evaluated by scanning electron microscopy (SEM), X-ray microtomography (µCT), contact angle measurements and thermogravimetric analysis (TGA). The Mg-Al LDH nanofiller showed a high degree of exfoliation in the polymer matrix, evidenced by X-ray diffraction (XRD) and transmission electron microscopy (TEM). The hydrodynamic properties and adsorption capacity were evaluated with pure water and aqueous solutions of two common drugs, diclofenac sodium (DS) and tetracycline (TC), and the nanocomposite membranes showed an improved permeability compared with neat cellulose acetate. The membrane prepared with 4 wt.% Mg-Al LDH loading exhibited the highest water flux compared with the pure polymer one (529 vs 36 L·m-2·h-1) and a tenfold increase in adsorption capacity for DS. This enhancement is attributed to electrostatic interactions between the negatively charged drug molecule and positively charged Mg-Al LDH layers. Conversely, in the case of TC, the increase in adsorption capacity was smaller and was assigned to hydrogen bonding interactions between the drug molecule and the nanofiller.

Assessment of gait kinetics in post-menopausal women using tri-axial ankle accelerometers during barefoot walking.

BACKGROUND: Physical activity (PA) interventions, designed to increase exposure to ground reaction force (GRF) loading, are a common target for reducing fracture risk in post-menopausal women with low bone mineral density (BMD). Unfortunately, accurate tracking of PA in free-living environments and the ability to translate this activity into evaluations of bone health is currently limited. RESEARCH QUESTION: This study evaluates the effectiveness of ankle-worn accelerometers to estimate the vertical GRFs responsible for bone and joint loading in post-menopausal women at a range of self-selected walking speeds during barefoot walking. METHODS: Seventy women, at least one year post-menopause, wore Actigraph GT3X + on both ankles and completed walking trials at self-selected speeds (a minimum of five each at fast, normal and slow walking) along a 30 m instrumented walkway with force plates and photocells to measure loading and estimate gait velocity. Repeated measures correlation analysis and step-wise mixed-effects modelling were performed to evaluate significant predictors of peak vertical GRFs normalized to body weight (pVGRFbw), including peak vertical ankle accelerations (pVacc), walking velocity (Velw) and age. RESULTS: A strong repeated measures correlation of r = 0.75 (95%CI [0.71-0.76] via 1000 bootstrap passes) between pVacc and pVGRFbw was observed. Five-fold cross-validation of mixed-model predictions yielded an average mean-absolute-error (MAE[95%CI]) and root-mean-square-error (RMSE) rate of 5.98%[5.61-6.42] and 0.076 [0.069-0.082] with a more complex model (including Velw,) and 6.80%[6.37-7.54] and 0.087BW[0.081-0.095] with a simpler model (including only pVacc), when comparing accelerometer-based estimations of pVGRFbw to force plate measures of pVGRFbw. Age was not found to be significant. SIGNIFICANCE: This study is the first to show a strong relationship among ankle accelerometry data and high fidelity lower-limb loading approximations in post-menopausal women. The results provide the first steps necessary for estimation of real-world limb and joint loading supporting the goals of accurate PA tracking and improved individualization of clinical interventions.

Pseudospin Symmetry and Microscopic Origin of Shape Coexistence in the

Lifetime measurements of excited states of the light N=52 isotones ^{88}Kr, ^{86}Se, and ^{84}Ge have been performed, using the recoil distance Doppler shift method and VAMOS and AGATA spectrometers for particle identification and gamma spectroscopy, respectively. The reduced electric quadrupole transition probabilities B(E2;2^{+}→0^{+}) and B(E2;4^{+}→2^{+}) were obtained for the first time for the hard-to-reach ^{84}Ge. While the B(E2;2^{+}→0^{+}) values of ^{88}Kr, ^{86}Se saturate the maximum quadrupole collectivity offered by the natural valence (3s, 2d, 1g_{7/2}, 1h_{11/2}) space of an inert ^{78}Ni core, the value obtained for ^{84}Ge largely exceeds it, suggesting that shape coexistence phenomena, previously reported at N≲49, extend beyond N=50. The onset of collectivity at Z=32 is understood as due to a pseudo-SU(3) organization of the proton single-particle sequence reflecting a clear manifestation of pseudospin symmetry. It is realized that the latter provides actually reliable guidance for understanding the observed proton and neutron single particle structure in the whole medium-mass region, from Ni to Sn, pointing towards the important role of the isovector-vector ρ field in shell-structure evolution.

Safety assessment in Child A cirrhotic patients treated with Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with Ribavirin.

BACKGROUND: In our country, the national program for hepatitis C virus treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir was approved for patients with stage four of liver fibrosis and stage three associated with specific comorbidities. Our aim was to analyze the characteristics associated with the presence of adverse events in patients receiving this antiviral regimen, with ribavirin in cirrhotic patients. METHODS: We prospectively studied a cohort of adults with hepatitis C virus infection with Child A cirrhosis, treated for 12 weeks with ombitasvir/paritaprevir/ritonavir/dasabuvir and ribavirin, which have been followed in an infectious diseases tertiary-care hospital. RESULTS: We included 137 adult patients diagnosed with compensated cirrhosis, hepatitis C virus genotype 1b infected, 82 (60%) previously treated. We recorded 201 adverse events in 98 (71.5%) patients, with a median number of events per patient of one. The intensity of adverse events was classified as mild, moderate and severe in 50%, 36% and 14% of cases, respectively. Forty-five (22%) episodes required medical intervention. The most frequently reported adverse events were pruritus 34(35%), asthenia 22(22%) and insomnia 15(15%). The presence of severe adverse events was associated with the presence of comorbidities (p = 0.01, OR : 9.5, 95% CI : 1.2-74.3) and with the presence of associated medication (p = 0.02, OR : 3.9, 95% CI : 1.08-14.2). At the end of current treatment, 136 (99.2%) patients had undetectable viral load. CONCLUSION: We found a high number of adverse events, but most of them were mild or moderate and only one quarter of them required medical intervention. Only severe adverse events were associated with comorbidities and associated medication.

Shell Evolution towards

The level structure of the neutron-rich ^{77}Cu nucleus is investigated through ß-delayed γ-ray spectroscopy at the Radioactive Isotope Beam Factory of the RIKEN Nishina Center. Ions of ^{77}Ni are produced by in-flight fission, separated and identified in the BigRIPS fragment separator, and implanted in the WAS3ABi silicon detector array, surrounded by Ge cluster detectors of the EURICA array. A large number of excited states in ^{77}Cu are identified for the first time by correlating γ rays with the ß decay of ^{77}Ni, and a level scheme is constructed by utilizing their coincidence relationships. The good agreement between large-scale Monte Carlo shell model calculations and experimental results allows for the evaluation of the single-particle structure near ^{78}Ni and suggests a single-particle nature for both the 5/2_{1}^{-} and 3/2_{1}^{-} states in ^{77}Cu, leading to doubly magic ^{78}Ni.

The discovery of benzoxazine sulfonamide inhibitors of NaV1.7: Tools that bridge efficacy and target engagement.

The voltage-gated sodium channel NaV1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of NaV1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat NaV1.7 versus human NaV1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse NaV1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement.

Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators.

Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.

Single Residue Substitutions That Confer Voltage-Gated Sodium Ion Channel Subtype Selectivity in the NaV1.7 Inhibitory Peptide GpTx-1.

There is interest in the identification and optimization of new molecular entities selectively targeting ion channels of therapeutic relevance. Peptide toxins represent a rich source of pharmacology for ion channels, and we recently reported GpTx-1 analogs that inhibit NaV1.7, a voltage-gated sodium ion channel that is a compelling target for improved treatment of pain. Here we utilize multi-attribute positional scan (MAPS) analoging, combining high-throughput synthesis and electrophysiology, to interrogate the interaction of GpTx-1 with NaV1.7 and related NaV subtypes. After one round of MAPS analoging, we found novel substitutions at multiple residue positions not previously identified, specifically glutamic acid at positions 10 or 11 or lysine at position 18, that produce peptides with single digit nanomolar potency on NaV1.7 and 500-fold selectivity against off-target sodium channels. Docking studies with a NaV1.7 homology model and peptide NMR structure generated a model consistent with the key potency and selectivity modifications mapped in this work.

Inhibition of Inactive States of Tetrodotoxin-Sensitive Sodium Channels Reduces Spontaneous Firing of C-Fiber Nociceptors and Produces Analgesia in Formalin and Complete Freund's Adjuvant Models of Pain.

While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported "compound 52" aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund's adjuvant (CFA) model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors.