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During the development of the sympathetic nervous system, signals from tropomyosin-related kinase receptors (Trks) and p75 neurotrophin receptors (p75) compete to regulate survival and connectivity. During this process, nerve growth factor (NGF)- TrkA signaling in axons communicates NGF-mediated trophic responses in signaling endosomes. Whether axonal p75 signaling contributes to neuronal death and how signaling endosomes contribute to p75 signaling has not been established. Using compartmentalized sympathetic neuronal cultures (CSCGs) as a model, we observed that the addition of BDNF to axons increased the transport of p75 and induced death of sympathetic neurons in a dynein-dependent manner. In cell bodies, internalization of p75 required the activity of JNK, a downstream kinase mediating p75 death signaling in neurons. Additionally, the activity of Rab5, the key GTPase regulating early endosomes, was required for p75 death signaling. In axons, JNK and Rab5 were required for retrograde transport and death signaling mediated by axonal BDNF-p75 in CSCGs. JNK was also required for the proper axonal transport of p75-positive endosomes. Thus, our findings provide evidence that the activation of JNK by p75 in cell bodies and axons is required for internalization to a Rab5-positive signaling endosome and the further propagation of p75-dependent neuronal death signals.

The study discussed here evaluated the presence of self-reported respiratory symptoms and their association with indoor bioaerosol concentrations over a year-long study in the El Paso, Texas, region. The authors collected air samples from homes to assess seasonal differences in bacterial and fungal bioaerosol concentrations. They distributed a health questionnaire to the participating homeowner during each seasonal air sampling. The authors used this questionnaire to assess whether the homeowners were suffering from specific symptoms prior to each sampling. Descriptive statistics and logistic regressions were conducted to model the relationship among 'high' reporters of symptoms, bioaerosols, and environmental factors. The authors collected evidence to support an association between indoor respirable bacterial concentrations and homeowners that reported at least eight respiratory symptoms (odds ratio [OR] = 1.10, p = .045). Smoking status, indoor humidity, and season also displayed associations with homeowners that reported at least eight respiratory symptoms (current smokers OR = 3.3, p = .042; indoor humidity OR = 1.5, p = .030; spring season OR = 7.2, p = .001; fall season OR = 3.4, p = .008). [ABSTRACT FROM AUTHOR]

Unlabelled: Calcitonin gene-related peptide (CGRP) and/or substance P (SP) immunoreactivity as well as isolectin B(4) (IB(4)) binding are commonly used to define peptidergic and non-peptidergic nociceptor populations, respectively. Although this demarcation is well supported in the mouse, there is accumulating evidence to suggest it is not so in the rat. Hence, this investigation was undertaken to evaluate and quantify the colocalization of the neuropeptides CGRP and SP with IB(4) binding sites and the transient receptor potential vanilloid subfamily type 1 (TRPV1) channel and to compare this colocalization between trigeminal (TG) and dorsal root ganglia (DRG) in adult rats. These findings illustrate that there is a substantial overlap ( approximately 45% in the DRG and approximately 30% in the TG) between peptidergic neurons (ie, CGRP- and SP-expressing) and neurons that bind IB(4) in rat sensory ganglia. However, there were also significant differences in the colocalization of these markers between the DRG and TG. For instance, in the DRG, significantly more CGRP-immunoreactive neurons also expressed IB(4) binding sites (44.5%) compared with the TG (27.5%). In contrast, significantly fewer CGRP-immunoreactive neurons in the DRG colocalized TRPV1 immunoreactivity (49.2%) compared with the TG (70%). Moreover, we directly assessed the colocalization of CGRP and IB(4) in the TG of rats and mice using a CGRP antibody that recognizes this peptide in both species. Thus, whereas only an approximately 10% overlap was observed in TG neurons of mouse, significantly greater overlap (approximately 35%) was observed in those of rat.Perspective: These data indicate that in adult rat sensory ganglia, there is not a clear distinction between the peptidergic and non-peptidergic nociceptor subclasses as a function of IB(4) binding. Furthermore, there are significant differences between the TG and DRG in the degree to which commonly utilized nociceptive neuronal markers are co-expressed. Taken together, the present findings dictate prudence when extrapolating experimental conclusions about the neurochemical classification of neurons between sensory ganglia or between species, including humans. [ABSTRACT FROM AUTHOR]

Whether Latinx families use youth mental health services (MHS) depends on complex influences of barriers and facilitators within and outside of the home. This research sought to shed light on caregiver strain as part of the equation focused on parental identification and responses to youth mental health needs. We examined multiple dimensions of caregiver strain as potential mediators between youth mental health symptom severity and psychological counseling utilization. The present sample consisted of 598 Latinx caregivers to youths ages 6-18 who provided information on youth internalizing and externalizing problems, caregiver strain, and youth psychological counseling service utilization within the last year. Our findings suggest that youth symptom severity (internalizing and externalizing problems) was generally positively associated with dimensions of caregiver strain. Youth symptom severity through objective and subjective internalized strain pathways were associated with greater odds of youth MHS utilization. In contrast, youth symptom severity through subjective externalized strain reduced the odds that Latinx caregivers would report utilizing youth MHS. These models only partially mediated the relationship between youth problems and service use. Findings suggest that Latinx caregivers may navigate conflicting sources of strain related to their child's mental health problem severity in ways that may differentially impact the odds that they access youth MHS. Along with addressing structural and systemic barriers to care, utilization of psychological counseling services may also be improved through interventions that help Latinx caregivers view youth services as avenues for addressing caregiver strain and providing psychoeducation that frames externalized strain within a mental health lens., Competing Interests: The authors have no relevant financial or non-financial interests to disclose., (Copyright: © 2024 Vázquez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aim: The aim of our study was to investigate skin conditions when wearing and removing a novel wireless non-adhesive cardiorespiratory monitoring device for neonates (Bambi-Belt) compared to standard adhesive electrodes., Study Design: This was a prospective study including preterm neonates requiring cardiorespiratory monitoring. Besides standard electrodes, the infants wore a Bambi Belt for 10 consecutive days. Their skin conditions were assessed using Trans Epidermal Water Loss (TEWL) and the Neonatal Skin Condition Score (NSCS) after daily belt and standard electrode removal. The ∆TEWL was calculated as the difference between the TEWL at the device's location (Bambi-Belt/standard electrode) and the adjacent control skin location, with a higher ∆TEWL indicating skin damage., Results: A total of 15 infants (gestational age (GA): 24.1-35.6 wk) were analyzed. The ΔTEWL significantly increased directly after electrode removal (10.95 ± 9.98 g/m 2 /h) compared to belt removal (5.18 ± 6.71 g/m 2 /h; F: 8.73, p = 0.004) and after the washout period (3.72 ± 5.46 g/m 2 /h vs. 1.86 ± 3.35 g/m 2 /h; F: 2.84, p = 0.09), although the latter did not reach statistical significance. The TEWL was not influenced by prolonged belt wearing. No significant differences in the NSCS score were found between the belt and electrode (OR: 0.69, 95% CI [0.17, 2.88], p = 0.6)., Conclusion: A new wireless non-adhesive device for neonatal cardiorespiratory monitoring was well tolerated in preterm infants and may be less damaging during prolonged wearing.

E-cigarette use among adolescents is a national health epidemic spreading faster than researchers can amass evidence for risk and protective factors and long-term consequences associated with use. New technologies, such as machine learning, may assist prevention programs in identifying at risk youth and potential targets for intervention before adolescents enter developmental periods where e-cigarette use escalates. The present study utilized machine learning algorithms to explore a wide array of individual and socioecological variables in relation to patterns of lifetime e-cigarette use during early adolescence (i.e., exclusive, or with tobacco cigarettes). Extant data was used from 14,346 middle school students (Mage = 12.5, SD = 1.1; 6th and 8th grades) who participated in the Utah Prevention Needs Assessment. Students self-reported their substance use behaviors and related risk and protective factors. Machine learning algorithms examined 112 individual and socioecological factors as potential classifiers of lifetime e-cigarette use outcomes. The elastic net algorithm achieved outstanding classification for lifetime exclusive (AUC = .926) and dual use (AUC = .944) on a validation test set. Six high value classifiers were identified that varied in importance by outcome: Lifetime alcohol or marijuana use, perception of e-cigarette availability and risk, school suspension(s), and perceived risk of smoking marijuana regularly. Specific classifiers were important for lifetime exclusive (parent's attitudes regarding student vaping, best friend[s] tried alcohol or marijuana) and dual use (best friend[s] smoked cigarettes, lifetime inhalant use). Our findings provide specific targets for the adaptation of existing substance use prevention programs to address early adolescent e-cigarette use., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vázquez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A lack of validated measures to examine barriers to youth telepsychology services among Latinx families limits research that could identify targets for reducing mental health disparities. We developed and validated the Latinx Barriers to Accessing Telepsychology Services (Latinx BATS) questionnaire, a brief multidimensional measure for caregivers of youths. Participants included 511 Latinx caregivers of youths Ages 6-18 (English n = 275, Spanish n = 236) who completed the Latinx BATS and reported on telepsychology service utilization and youth mental health problems. Caregivers whose youths had clinically elevated mental health problems were more likely to report barriers to accessing youth telepsychology services compared to nonclinical youths. Commonly endorsed barriers included concerns that the child would be distracted and not get much benefit, and that providers would be unfamiliar with the family's culture or would not pick up on nuances and emotions. Loadings from an exploratory graph analysis returned four-factors: relational, acceptability, quality, and access concerns. Network centrality measures identified provider knowledge regarding community resources and Latinx culture as important targets for reducing barriers to youth telepsychology services. Confirmatory factor analyses were then conducted and found that the four-factor structure outperformed a single-factor solution. The four-factor structure was similar for the English and Spanish versions of the Latinx BATS, but the strength of item loadings varied across languages. Implications for the use of the Latinx BATS in research and clinical practice are discussed including specific strategies for reducing these obstacles to care among Latinx families. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

JNJ-10450232 (NTM-006) is a non-opioid, non-NSAID analgesic and antipyretic compound with structural similarity to acetaminophen. Preclinical models show comparable analgesia relative to acetaminophen and no evidence of hepatotoxicity associated with overdose. Moreover, it was safe and generally well tolerated in a First-in-Human Study. This single-dose, single-center, inpatient, randomized, double-blind study in moderate-to-severe acute pain following third molar extraction compared efficacy and safety of 250 mg and 1000 mg JNJ-10450232 (NTM-006), 1000 mg acetaminophen, and placebo during the 24 h following administration. While onset of action of 1000 mg JNJ-10450232 (NTM-006) was relatively slower compared with acetaminophen, its duration of action was sustained up to 24 h being superior beginning 7 h after administration. No clinically important differences among treatment groups in nature or severity of adverse events were observed and no serious adverse events were reported. Increased bilirubin, potentially due to UGT1A1 inhibition and ingestion of blood from oral surgery, was the most commonly reported adverse event and the only event reported by ≥ 5% of subjects across treatment groups. These data support further evaluation of JNJ-10450232 (NTM-006) for the treatment of moderate-to-severe pain. CLINICALTRIALS.GOV ID: NCT02209181., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Johnson & Johnson employed all authors at the time of the study, and each author has owned, or currently owns, Johnson & Johnson stock., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Research examining the effects of traumatic events on undocumented Latinx immigrants often focuses on assessing posttraumatic stress disorder or general psychological distress, which may obscure the field's understanding of how trauma exposure impacts other common mental health disorders (e.g., anxiety, depression). This study sought to assess the cumulative, individual, and timing effects of immigration-related traumatic events on anxiety and depressive symptoms among undocumented Latinx immigrants. Participants were 253 undocumented Latinx immigrants recruited using respondent-driven sampling who reported their history of immigration-related trauma exposure and symptoms of depression and anxiety. Results suggest that cumulative immigration-related trauma was significantly associated with increases in anxiety and depressive symptoms, τ = .26. Significant positive correlations were found for cumulative trauma at each point in the immigration process (i.e., before immigration, while in transit to the United States, and while living in the United States) such that increases in the number of events were associated with higher anxiety and depressive symptom levels, τ = .11-.29. Trauma frequency differed throughout the immigration process such that some events more commonly occurred before immigration or during transit to the United States, whereas others occurred while an individual resided in the United States. Random forest algorithms uncovered differences in the relative importance of individual traumatic events in explaining the variance of depressive, R 2 = .13, and anxiety symptoms, R 2 = .14. The findings highlight the importance of providing trauma-informed care when treating anxiety and depression among undocumented Latinx immigrants and considering multidimensional epidemiological approaches in assessing immigration-related trauma., (© 2023 International Society for Traumatic Stress Studies.)

JNJ-10450232 (NTM-006), a novel non-opioid, non-nonsteroidal anti-inflammatory drug with structural similarities to acetaminophen, demonstrated anti-pyretic and/or analgesic activities in preclinical models and humans and reduced potential to cause hepatotoxicity in preclinical species. Metabolism and disposition of JNJ-10450232 (NTM-006) following oral administration to rats, dogs, monkeys and humans are reported. Urinary excretion was the major route of elimination based on recovery of 88.6% (rats) and 73.7% (dogs) of oral dose. The compound was extensively metabolized based on low recovery of unchanged drug in excreta from rats (11.3%) and dogs (18.4%). Clearance is driven by O-glucuronidation, amide hydrolysis, O-sulfation and methyl oxidation pathways. The combination of metabolic pathways driving clearance in human is covered in at least one preclinical species despite a few species-dependent pathways. O-Glucuronidation was the major primary metabolic pathway of JNJ-10450232 (NTM-006) in dogs, monkeys and humans, although amide hydrolysis was another major primary metabolic pathway in rats and dogs. A minor bioactivation pathway to quinone-imine is observed only in monkeys and humans. Unchanged drug was the major circulatory component in all species investigated. Except for metabolic pathways unique to the 5-methyl-1H-pyrazole-3-carboxamide moiety, metabolism and disposition of JNJ-10450232 (NTM-006) are similar to acetaminophen across species., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Johnson & Johnson employed all authors at the time of the study, and each author has owned, or currently owns, Johnson & Johnson stock., (Copyright © 2023 Johnson & Johnson Consumer Inc. Published by Elsevier Inc. All rights reserved.)

JNJ-10450232 (NTM-006) is a new molecular entity that is structurally related to acetaminophen. A comprehensive non-clinical safety program was conducted to support first-in-human and clinical efficacy studies based on preclinical data suggesting that the compound has comparable or enhanced antinociceptive and antipyretic efficacy without causing hepatotoxicity at supratherapeutic doses. No hepatic toxicity was noted in a mouse model sensitive to acetaminophen hepatotoxicity or in rats, dogs, and non-human primates in 28-day repeat dose toxicity studies at and above doses/exposures at which acetaminophen is known to cause hepatotoxicity. In the 28-day toxicity studies, all treatment-related findings were monitorable and reversible. Methemoglobinemia, which was observed in dogs and to a lesser extent in rats, is also observed with acetaminophen. This finding is considered not relevant to humans due to species differences in metabolism. Thyroid hypertrophy and hyperplasia were also observed in dogs and were shown to be a consequence of a species-specific UGT induction also demonstrated with increased thyroid hormone metabolism. Indirect bilirubin elevation was observed in rats as a result of UGT1A1 Inhibition. JNJ-10450232 (NTM-006) had no toxicologically relevant findings in safety pharmacology or genotoxicity studies. Together, these data supported progressing into safety and efficacy studies in humans., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Johnson & Johnson employed all authors at the time of the study, and each author has owned, or currently owns, Johnson & Johnson stock., (Copyright © 2023. Published by Elsevier Inc.)

JNJ-10450232 (NTM-006) is a new molecular entity that comprises structural similarities to acetaminophen and provides comparable analgesia in animals and humans without causing the hepatotoxicity associated with acetaminophen overdose in preclinical models. This double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of JNJ-10450232 (NTM-006) following single (50-6000 mg) and multiple (250-2500 mg twice daily for 8 days) doses in healthy male volunteers. JNJ-10450232 (NTM-006) was absorbed within 1-3 h, except at high doses at which C max was delayed and bimodal, while increases in AUC were more than dose proportional. CL/F and Vd/F decreased approximately 3-fold with increasing single doses up to 6000 mg and multiple doses up to 1000 mg, resulting in similar t ½ values that ranged from 8 to 10 h across doses. JNJ-10450232 (NTM-006) was generally safe and well tolerated, and no dose-limiting toxicities were observed. Transient increases in indirect bilirubin were noted at post-baseline timepoints due to UGT1A1 inhibition, without any evidence of adverse hepatic effects. Macular rash and generalized erythema were the most common drug-related adverse events after multiple doses., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: giant cell tumor (GCT) is a benign intramedullary bone tumor that frequently arises at the ends of long bones. After the distal femur and proximal tibia, the distal radius is the third most affected site with particularly aggressive tumors. Our objective is the presentation of the clinical case of a patient diagnosed with distal radius GCT classified in grade III of Campanacci who received a treatment adjusted to her economic possibilities., Case Report: a 47-year-old female, without economic solvency and with some medical service. Treatment included block resection, reconstruction with distal fibula autograft, and radiocarpal fusion with blocked compression plate. Eighteen months later, the patient had good grip strength (80% on the healthy side) and had fine motor function in the hand. The wrist presented stability with pronation of 85o, supination of 80o, flexion-extension of 0o and a score of 6.7 in the DASH functional outcomes assessment questionnaire. His radiological evaluation five years after his surgery continued with no evidence of local recurrence and pulmonary involvement., Conclusion: the result in this patient, together with the published data, indicate that the block tumor resection technique, plus distal fibula autograft and arthrodesis with blocked compression plate provide an optimal result of functionality for the grade III distal radial tumor at low cost.

Objective: To systematically identify novel pharmacological strategies for preventing or treating post-traumatic stress disorder (PTSD) by leveraging large-scale analysis of real-world observational data., Methods: Using a self-controlled study design, the association between 1399 medications and the incidence of PTSD across four US insurance claims databases covering commercially insured, Medicare eligible, and Medicaid patients was examined. A validated algorithm for identifying PTSD in claims data was used, and medications were identified by their RxNorm ingredient. Medications used to treat PTSD or its symptoms (e.g., antidepressants, antipsychotics) were excluded. Medications associated with ≥30% reduction in risk of PTSD in ≥2 databases were identified., Results: A total of 137,182,179 individuals were included in the analysis. Fifteen medications met the threshold criteria for a potential protective effect on PTSD; six were categorized as "primary signals" while the remaining nine were considered "potential signals". The primary signals include a beta blocker that has been previously studied for PTSD, and five medications used to treat attention-deficit/hyperactivity disorder. The potential signals include four medications used to treat substance use disorders and five medications used to treat sleep disorders., Discussion: The medications identified in this analysis provide targets for further research in studies that are designed to examine specific hypotheses regarding these medications and the incidence of PTSD. This work may aid in discovering novel therapeutic approaches to treat PTSD, wherein new and effective treatments are badly needed., (© 2021 The Authors. Psychiatric Research and Clinical Practice published by Wiley Periodicals LLC on behalf of American Psychiatric Association.)

Aim: The new modality of virtual classes undertaken by dental students can have negative effects on psychological health and / or academic performance. The objective of this study was to determine the relationship between stress and depression in the social academic environment in dentistry students at the Científica del Sur University in 2020., Materials and Methods: The study was descriptive, observational, cross-sectional, and prospective. 108 students from 6th to 10th cycle of Dentistry at the Universidad Científica del Sur participated and were evaluated by means of a questionnaire with the SISCO Inventory to measure academic stress. The BECK scale (BID II) was also used for the evaluation of depression., Results: Students in the 6th term presented a greater probability of stress and depression. The age group most affected was students between 19 and 22 years of age. The p value for the relationship between academic stress and depression was p <0.001., Conclusion: There are statistically significant differences between academic stress and depression in students from the 6th to the 10th term of the Stomatology career at the Universidad Científica del Sur., Competing Interests: Conflicto de intereses: Los autores declaran no tener conflicto de intereses

Adolescents with a history of child maltreatment experience increased risk for psychopathology that sets them on a trajectory towards a range of difficulties in adulthood. Various factors influence caregivers' decisions to seek mental health services (MHS) that could improve developmental outcomes. The present study applied a machine learning algorithm, elastic net, to a sample of 878 adolescent-caregiver dyads from the Longitudinal Studies of Child Abuse and Neglect. Analyses simultaneously examined a large number of factors to determine their ability to discriminate between caregivers who perceived a need for MHS and those who did not, as well as caregivers who utilized MHS and those who did not. Results highlight family demographics, chronic parental stressors, youth psychopathology, and exposure to recent adversities as good classifiers of caregiver perceived need for (77.6%; sensitivity = .77; specificity = .78) and utilization of (71%; sensitivity = .71; specificity = .71) adolescent MHS. Elastic net identified adolescent clinical externalizing and internalizing problems, and parental stress related to child(ren)'s behavior as high value classifiers of both outcomes. Youth living with non-kin caregivers were also significantly more likely to utilize MHS. Findings highlight the importance of assessing clinical need, stress related to child(ren)'s behavior, and caregiver kinship in understanding the likelihood that at-risk families will seek adolescent MHS., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Rheumatoid arthritis (RA) patients are at increased risk for developing cardiovascular disease, including right heart failure. The evaluation of right ventricle (RV) using the relationship between tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic pressure (RVSP) is of clinical prognostic relevance. Mild echocardiographic pulmonary hypertension (ePH) has been associated with worse RV function. The aim of this study was to evaluate RV function as measured by TAPSE to RVSP ratio in rheumatoid arthritis patients compared to matched healthy controls., Method: A case-control study with 67 RA patients aged 40 to 75 years that fulfilled the 2010 ACR/EULAR criteria and 45 matching controls was included. A transthoracic echocardiogram was performed to all patients. TAPSE was measured as the distance traveled from end-diastole to end-systole. RVSP was calculated using the modified Bernoulli equation. Comparisons were done using Chi-square and Mann-Whitney's U test or Student's t test., Results: Patients with RA had significantly reduced ventricular function (TAPSE 23 [21-25] vs 25 [23-26], p = 0.033) and TAPSE/RVSP ratio was significantly lower in RA-patients than controls (TAPSE to RVSP ratio 0.809 [0.67-1.01] vs 0.933 [0.79-1.11], p = 0.009). RA-patients with mild ePH had similar RV function, evaluated by TAPSE, in comparison to RA-patients with normal RVSP., Conclusion: RA-patients had worse RV function measured by TAPSE and worse TAPSE/RVSP ratio than controls. Also, RA-patients with mild ePH had reduced right ventricular-pulmonary arterial coupling in comparison with patients with RA and normal RVSP. These echocardiographic findings could justify aggressive treatment for these patients and assess their evolution. Key Points • Right ventricular (RV) function and RV coupling with the pulmonary artery (RV-PA coupling) were worse in patients with RA in comparison to healthy controls. • Values of right ventricular systolic pressure (RVSP) were similar between RA-patients and non-RA controls. • Prevalence of normal RVSP, mild echocardiographic pulmonary hypertension (ePH), and pulmonary hypertension was similar between RA-patients and non-RA matched controls •Patients with RA and mild ePH had reduced RV-PA coupling in comparison with RA-patients with normal RVSP.

Background: DBA/1 mice arthritis models have contributed to our understanding of human rheumatoid arthritis (RA) and spondyloarthritis (SpA) pathogenesis, as well as the exploration of therapeutic targets for treatment. Quantitative polymerase chain reaction (qPCR) is an indispensable tool in molecular research, which requires reference gene validation to obtain consistent and reliable results., Objective: To determine the stability of candidate reference genes for qPCR in the joint of collagen-induced arthritis (CIA) and spontaneous arthritis (SpAD) DBA/1 mice., Methods: The expression of eleven commonly used reference genes (ACTB, B2M, EF1a, GAPDH, HMBS, HPRT, PPIB, RPL13A, SDHA, TBP, and YWHAZ) was assessed by qPCR and the data were compared using delta-Ct methods and the geNorm, NormFinder, and RefFinder software packages. Genes identified as stable in each model were used for the quantification of inflammatory cytokines RESULTS: The gene stabilities differed between the two arthritis models in the DBA/1 mice. EF1a and RPL13A were the best reference genes for SpAD, while RPL13A and TBP were the best for the CIA. These genes allowed the data normalization for the quantification of the inflammatory cytokines in both models; these results showed an increase in the expression of IL-1B, IL-12B, IL-17A, and IL-6 in the inflamed joints. The use of different primer sequences for the same reference gene resulted in different relative quantification values., Conclusion: This study demonstrates that commonly used reference genes may not be suitable for arthritic tissues from DBA/1 mice, and strengthening the principle that meticulous validation of reference genes is essential before each experiment to obtain valid and reproducible qPCR data for analysis or interpretation.

Background: Observational data may inform novel drug development programs by identifying previously unappreciated, clinical benefits of existing drugs. Several preclinical and clinical studies have suggested emergent therapeutic utility of drugs acting on the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, including the antidementia drug memantine., Methods: Using a self-controlled cohort study design, the association of exposure to the NMDA receptor antagonist memantine with the incidence of all observed disease outcomes in four US administrative claims databases, spanning from January 2000 through January 2019, was assessed. The databases used in this study were the IBM MarketScan ® Commercial Database (CCAE), the IBM MarketScan ® Multi-State Medicaid Database (MDCD), the IBM MarketScan ® Medicare Supplemental Database (MDCR), and the Optum ©  De-Identified Clinformatics ® Data Mart Database. Outcomes were defined according to the unique Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) classification system codes and required a diagnosis on two or more distinct dates. Of 20,953 outcomes assessed, only those for which memantine was associated with a ≥ 50% reduction in risk in two or more databases were included. A meta-analysis with random effects was used to pool data across the databases., Results: Overall, 312,336 patients were exposed to memantine during the study. After removing conditions related to dementia and memory loss, 60 outcomes met the threshold criteria. Results fell into five disease categories: mental disorders, substance use disorders, pain, gastrointestinal and colon disorders, and demyelinating disease. The bulk of findings fell into the first two groups, with 28 outcomes related to mental disorders and 24 related to substance use disorders., Conclusion: The present results confirm that NMDA receptor antagonism may have broader therapeutic utility than previously recognized. Further observational and clinical research may be warranted to explore the therapeutic benefit of NMDA antagonists for the outcomes found in this study.

The development of microarray patches for vaccine application has the potential to revolutionise vaccine delivery. Microarray patches (MAP) reduce risks of needle stick injury, do not require reconstitution and have the potential to enhance immune responses using a fractional vaccine dose. To date, the majority of research has focused on vaccine delivery with little characterisation of local skin response and recovery. Here we study in detail the immediate local skin response and recovery of the skin post high density MAP application in 12 individuals receiving 3 MAPs randomly assigned to the forearm and upper arm. Responses were characterised by clinical scoring, dermatoscopy, evaporimetry and tissue viability imaging (TiVi). MAP application resulted in punctures in the epidermis, a significant transepidermal water loss (TEWL), the peak TEWL being concomitant with peak erythema responses visualised by TiVi. TEWL and TiVi responses reduced over time, with TEWL returning to baseline by 48 h and erythema fading over the course of a 7 day period. As MAPs for vaccination move into larger clinical studies more variation of individual subject phenotypic or disease propensity will be encountered which will require consideration both in regard to reliability of dose delivery and degree of inherent skin response.

[This corrects the article DOI: 10.1038/s41541-020-00222-2.]., (© The Author(s) 2020.)

We evaluated vaccination against Streptococcus pyogenes with the candidate vaccine, J8-DT, delivered by a high-density microarray patch (HD-MAP). We showed that vaccination with J8-DT eluted from a coated HD-MAP (J8-DT/HD-MAP), induced similar total IgG responses to that generated by vaccination with J8-DT adjuvanted with Alum (J8-DT/Alum). We evaluated the effect of dose reduction and the number of vaccinations on the antibody response profile of vaccinated mice. A reduction in the number of vaccinations (from three to two) with J8-DT/HD-MAP induced comparable antibody responses to three vaccinations with intramuscular J8-DT/Alum. Vaccine-induced protection against an S. pyogenes skin challenge was assessed. J8-DT/HD-MAP vaccination led to a significant reduction in the number of S. pyogenes colony forming units in skin (92.9%) and blood (100%) compared to intramuscular vaccination with unadjuvanted J8-DT. The protection profile was comparable to that of intramuscular J8-DT/Alum. J8-DT/HD-MAP induced a shift in the antibody isotype profile, with a bias towards Th1-related isotypes, compared to J8-DT/Alum (Th2 bias). Based on the results of this study, the use of J8-DT/HD-MAP should be considered in future clinical development and control programs against S. pyogenes . Furthermore, the innate characteristics of the technology, such as vaccine stability and increased coverage, ease of use, reduction of sharp waste and the potential reduction of dose may be advantageous compared to current vaccination methods., Competing Interests: Competing interestsThe authors of this manuscript have read the journal’s policy and have the following competing interests: A.H.F., P.F., C.M.J.F., C.W., S.B.B., A.D. and S.M. are paid employees of Vaxxas Pty Ltd., (© The Author(s) 2020.)

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To characterize the orofacial abnormalities in patients with rheumatoid arthritis (RA) and compare them with those in a reference population., Methods: The study included 30 RA patients and 30 consecutive patients in an odontology clinic in whom RA was ruled out. Patients underwent a clinical dental examination which included: 1) clinical and radiographic abnormalities of the temporomandibular joint; 2) biomechanical craniocervical analysis; 3) state of dentition and treatment needs; 4) periodontal status; 5) oral hygiene status; and 6) facial pain, which was compared among study groups. In addition, the association between the variables studied was determined through correlation tests., Results: Patients with RA showed a higher prevalence of temporomandibular abnormalities, both clinical (100.0% vs. 60.0%, P<.001) and radiographic, including erosions (50.0% vs. 16.0%, P=.010), compared with individuals in the control group. Likewise, patients with RA had a greater number of missing teeth (6.9±5.7 vs. 3.0±2.0, P=.001), more caries (13.4±5.4 vs. 4.9±6.5, P=.001), periodontitis (1.3±0.9 vs. 0.8±0.8, P=.015), poorer oral hygiene (43.3% vs. 13.3%, P=.005) and greater facial pain (66.7% vs. 20.0%, P <.001). The cephalometric analysis of Rocabado showed differences in the craniocervical angle and hyoid triangle between RA and controls. Significant correlations were obtained between oral and temporomandibular abnormalities., Conclusions: Patients with RA showed a greater orofacial deterioration, which reflects the importance of multidisciplinary care, including periodic dental examination., (Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Monoacylglycerol lipase (MAGL) has emerged as an attractive drug target because of its important role in regulating the endocannabinoid 2-arachidonoylglycerol (2-AG) and its hydrolysis product arachidonic acid (AA) in the brain. Herein, we report the discovery of a novel series of diazetidinyl diamide compounds 6 and 10 as potent reversible MAGL inhibitors. In addition to demonstrating potent MAGL inhibitory activity in the enzyme assay, the thiazole substituted diazetidinyl diamides 6d-l and compounds 10 were also effective at increasing 2-AG levels in a brain 2-AG accumulation assay in homogenized rat brain. Furthermore, selected compounds have been shown to achieve good brain penetration after oral administration in an animal study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Though sex differences in chronic pain have been consistently described in the literature, their underlying neural mechanisms are poorly understood. Previous work in humans has demonstrated that men and women differentially invoke distinct brain regions and circuits in coping with subjective pain unpleasantness. The goal of the present work was to elucidate the molecular mechanisms in the basolateral nucleus of the amygdala (BLA) that modulate hyperalgesic priming, a pain plasticity model, in males and females. We used plantar incision as the first, priming stimulus and prostaglandin E 2 (PGE 2 ) as the second stimulus. We sought to assess whether hyperalgesic priming can be prevented or reversed by pharmacologically manipulating molecular targets in the BLA of male or female mice. We found that administering ZIP, a cell-permeable inhibitor of aPKC, into the BLA attenuated aspects of hyperalgesic priming induced by plantar incision in males and females. However, incision only upregulated PKCζ/PKMζ immunoreactivity in the BLA of male mice, and deficits in hyperalgesic priming were seen only when we restricted our analysis to male Prkcz -/- mice. On the other hand, intra-BLA microinjections of pep2m, a peptide that interferes with the trafficking and function of GluA2-containing AMPA receptors, a downstream target of aPKC, reduced mechanical hypersensitivity after plantar incision and disrupted the development of hyperalgesic priming in both male and female mice. In addition, pep2m treatment reduced facial grimacing and restored aberrant behavioral responses in the sucrose splash test in male and female primed mice. Immunofluorescence results demonstrated upregulation of GluA2 expression in the BLA of male and female primed mice, consistent with pep2m findings. We conclude that, in a model of incision-induced hyperalgesic priming, PKCζ/PKMζ in the BLA is critical for the development of hyperalgesic priming in males, while GluA2 in the BLA is crucial for the expression of both reflexive and affective pain-related behaviors in both male and female mice in this model. Our findings add to a growing body of evidence of sex differences in molecular pain mechanisms in the brain., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Aims: To assess the effect of physical exercise (PE) on the histological and transcriptional characteristics of proteoglycan-induced arthritis (PGIA) in BALB/c mice., Methods: Following PGIA, mice were subjected to treadmill PE for ten weeks. The tarsal joints were used for histological and genetic analysis through microarray technology. The genes differentially expressed by PE in the arthritic mice were obtained from the microarray experiments. Bioinformatic analysis in the DAVID, STRING, and Cytoscape bioinformatic resources allowed the association of these genes in biological processes and signalling pathways., Results: Arthritic mice improved their physical fitness by 42.5% after PE intervention; it induced the differential expression of 2,554 genes. The bioinformatic analysis showed that the downregulated genes (n = 1,371) were significantly associated with cellular processes that mediate the inflammation, including Janus kinase-signal transducer and activator of transcription proteins (JAK-STAT), Notch, and cytokine receptor interaction signalling pathways. Moreover, the protein interaction network showed that the downregulated inflammatory mediators interleukin (IL) 4, IL5, IL2 receptor alpha (IL2rα), IL2 receptor beta (IL2rβ), chemokine ligand (CXCL) 9, and CXCL12 were interacting in several pathways associated with the pathogenesis of arthritis. The upregulated genes (n = 1,183) were associated with processes involved in the remodelling of the extracellular matrix and bone mineralization, as well as with the processes of aerobic metabolism. At the histological level, PE attenuated joint inflammatory infiltrate and cartilage erosion., Conclusion: Physical exercise influences parameters intimately linked to inflammatory arthropathies. Research on the effect of PE on the pathogenesis process of arthritis is still necessary for animal and human models. Cite this article: Bone Joint Res. 2020;9(1):36-48., (© 2020 Author(s) et al.)

The aim of the study was to describe the oral health and orofacial function of Mexican patients with rheumatoid arthritis (RA) and their association with clinical and radiological aspects of the disease. Patients with RA received a complete odontological exam, which also included a clinical and radiographic assessment of the temporomandibular joint (TMJ). The rheumatologic assessment included detailed profiling of the disease and serological and radiographic parameters. The study included 62 RA patients; the median (min-max) age was 51 (18-72) years old and 8.5 (1-39) years of disease duration. The 63.6% of the patients had DAS28 ≥ 3.2, and a median (min-max) of Sharp/van der Heijde score (SvdHS) of 41 (0-214). 98.3% of the patients presented caries, which were severe in 53.3% of the cases. The 73.8% of the patients were missing teeth due to caries, with a median (min-max) of 4 (0-32) teeth missing per patient. Oral hygiene was classified as bad in 49.1% of patients and only 15.3% of them had a healthy periodontium. The TMJ function was abnormal in 98.4% of the patients and 62.9% of them presented moderate or severe TMJ disorder (TMD). The radiographic damage of the TMJ correlated positively with the SvdHS. No correlations were found between disease activity or structural progression and orofacial variables, including periodontitis. There are severe oral and orofacial health problems in RA patients despite having medical attention for their disease. Multidisciplinary management remains an area of opportunity for both the medical specialists and the health system in our country.

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain., Competing Interests: All authors were employees of Janssen Research and Development at the time the research was conducted., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Physical exercise (PE) is recommended for Rheumatoid Arthritis (RA), but the molecular and biological mechanisms that impact the inflammatory process and joint destruction in RA remain unknown. The objective of this study was to evaluate the effect of PE on the histological and transcriptional changes in the joints of adjuvant-induced arthritis (AIA) rat model. AIA rats were subjected to PE on a treadmill for eight weeks. The joints were subjected to histological and microarray analysis. The differentially expressed genes (DEGs) by PE in the arthritic rats were obtained from the microarray. The bioinformatic analysis allowed the association of these genes in biological processes and signaling pathways. PE induced the differential expression of 719 genes. The DEGs were significantly associated with pathogenic mechanisms in RA, including HIF-1, VEGF, PI3-Akt, and Jak-STAT signaling pathways, as well as response to oxidative stress and inflammatory response. At a histological level, PE exacerbated joint inflammatory infiltrate and tissue destruction. The PE exacerbated the stressed joint environment aggravating the inflammatory process, the hypoxia, and the oxidative stress, conditions described as detrimental in the RA joints. Research on the effect of PE on the pathogenesis process of RA is still necessary for animal models and human., Competing Interests: The authors declare no conflict of interest.

A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In the Valley of Tehuacan-Cuicatlan, Cyrtocarpa procera and Bursera morelensis are located and are used in traditional medicine. In this research, several biological properties were evaluated. The methanol extracts of C. procera (MeCp) and B. morelensis (MeBm) were obtained by maceration. The antibacterial activities of the extracts were evaluated by the Kirby-Baüer disc-diffusion method. The wound healing activity was evaluated by histopathological analysis. Both extracts had a bacteriostatic effect in the Staphylococcus aureus (MeCp MIC = 0.25 mg/mL and MeBm MIC = 1 mg/mL) and the Vibrio cholerae (MeCp MIC = 1 mg/mL and MeBm MIC = 4 mg/mL). Both extracts demonstrated a wound healing efficacy similar to the reference standard (Recoveron). They also showed a high antioxidant capacity (MeCp SC 50 = 5.75  μ g/mL and MeBm SC 50 = 4.27  μ g/mL). These results are related to the concentration of phenols (MeCp = 166 and MeBm = 236.6 mg GAe/g) and flavonoids of MeCp = 16 and MeBm = 22  μ g Qe/g. Both extracts, acting in a similar way in microorganisms that cause infection thanks to their antioxidant activity, favor the healing of wounds. This is the first study in which the biological properties of these two species are compared.

Systemic lupus erythematosus (SLE) is a perplexing and potentially severe disease, the pathogenesis of which is yet to be understood. SLE is considered to be a multifactorial disease, in which genetic factors, immune dysregulation, and environmental factors, such as ultraviolet radiation, are involved. Recently, the description of novel genes conferring susceptibility to develop SLE even in their own (monogenic lupus) has raised the interest in DNA dynamics since many of these genes are linked to DNA repair. Damage to DNA induces an inflammatory response and eventually triggers an immune response, including those targeting self-antigens. We review the evidence that indicates that patients with SLE present higher levels of DNA damage than normal subjects do and that several proteins involved in the preservation of the genomic stability show polymorphisms, some of which increase the risk for SLE development. Also, the experience from animal models reinforces the connection between DNA damage and defective repair in the development of SLE-like disease including characteristic features such as anti-DNA antibodies and nephritis. Defining the role of DNA damage response in SLE pathogenesis might be strategic in the quest for novel therapies.

Background: Injection using needle and syringe (N&S) is the most widely used method for vaccination, but requires trained healthcare workers. Fear of needles, risk of needle-stick injury, and the need to reconstitute lyophilised vaccines, are also drawbacks. The Nanopatch (NP) is a microarray skin patch comprised of a high-density array of microprojections dry-coated with vaccine that is being developed to address these shortcomings. Here we report a randomised, partly-blinded, placebo-controlled trial that represents the first use in humans of the NP to deliver a vaccine., Methods: Healthy volunteers were vaccinated once with one of the following: (1) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg haemagglutinin (HA) per dose), applied to the volar forearm (NP-HA/FA), n = 15; (2) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg HA per dose), applied to the upper arm (NP-HA/UA), n = 15; (3) Fluvax® 2016 containing 15 µg of the same H1N1 HA antigen injected intramuscularly (IM) into the deltoid (IM-HA/D), n = 15; (4) NPs coated with excipients only, applied to the volar forearm (NP-placebo/FA), n = 5; (5) NPs coated with excipients only applied to the upper arm (NP-placebo/UA), n = 5; or (6) Saline injected IM into the deltoid (IM-placebo/D), n = 5. Antibody responses at days 0, 7, and 21 were measured by haemagglutination inhibition (HAI) and microneutralisation (MN) assays., Findings: NP vaccination was safe and acceptable; all adverse events were mild or moderate. Most subjects (55%) receiving patch vaccinations (HA or placebo) preferred the NP compared with their past experience of IM injection with N&S (preferred by 24%). The antigen-vaccinated groups had statistically higher HAI titres at day 7 and 21 compared with baseline (p < 0.0001), with no statistical differences between the treatment groups (p > 0.05), although the group sizes were small. The geometric mean HAI titres at day 21 for the NP-HA/FA, NP-HA/UA and IM-HA/D groups were: 335 (189-593 95% CI), 160 (74-345 95% CI), and 221 (129-380 95% CI) respectively. A similar pattern of responses was seen with the MN assays. Application site reactions were mild or moderate, and more marked with the influenza vaccine NPs than with the placebo or IM injection., Interpretation: Influenza vaccination using the NP appeared to be safe, and acceptable in this first time in humans study, and induced similar immune responses to vaccination by IM injection., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Migraine is considered a neurovascular disorder, but its pathophysiological mechanisms are not yet fully understood. Adenosine has been shown to increase in plasma during migraine attacks and to induce vasodilation in several blood vessels; however, it remains unknown whether adenosine can interact with the trigeminovascular system. Moreover, caffeine, a non-selective adenosine receptor antagonist, is included in many over the counter anti-headache/migraine treatments., Methods: This study used the rat closed cranial window method to investigate in vivo the effects of the adenosine A 2A receptor antagonists with varying selectivity over A 1 receptors; JNJ-39928122, JNJ-40529749, JNJ-41942914, JNJ-40064440 or JNJ-41501798 (0.3-10 mg/kg) on the vasodilation of the middle meningeal artery produced by either CGS21680 (an adenosine A 2A receptor agonist) or endogenous CGRP (released by periarterial electrical stimulation)., Results: Regarding the dural meningeal vasodilation produced neurogenically or pharmacologically, all JNJ antagonists: (i) did not affect neurogenic vasodilation but (ii) blocked the vasodilation produced by CGS21680, with a blocking potency directly related to their additional affinity for the adenosine A 1 receptor., Conclusions: These results suggest that vascular adenosine A 2A (and, to a certain extent, also A 1 ) receptors mediate the CGS21680-induced meningeal vasodilation. These receptors do not appear to modulate prejunctionally the sensory release of CGRP. Prevention of meningeal arterial dilation might be predictive for anti-migraine drugs, and since none of these JNJ antagonists modified per se blood pressure, selective A 2A receptor antagonism may offer a novel approach to antimigraine therapy which remains to be investigated in clinical trials.

Background and Aims: This double-blind (DB), randomized, placebo-controlled, sequential-group, multiple-ascending dose, phase 1 study evaluated safety, pharmacokinetics and pharmacodynamics of JNJ-39439335 in healthy men (part 1), and in participants with knee osteoarthritis (part 2)., Methods: Both parts 1 and 2 consisted of screening (upto 21 days), 21-day DB treatment phase [eight participants/group: JNJ-39439335 (part 1: 2-50 mg; part 2: 10-50 mg): n=6; placebo: n=2] and follow-up (total study duration ~10 weeks)., Results: Plasma concentrations and systemic exposure of JNJ-39439335 increased in slightly higher than dose-proportional fashion (steady-state reached by day 14). Renal excretion of JNJ-39439335 was negligible. Marked dose-related increases in pharmacodynamic heat pain assessments were observed in JNJ-39439335-treated participants, which persisted throughout the treatment with no signs of tolerance with repeated dosing. No effect on pharmacodynamic cold pain or mechanical pain assessments were seen. Effects on pharmacodynamic capsaicin-induced flare assessments in JNJ-39439335-treated participants versus placebo were consistent with effects observed with single-dose, and did not demonstrate tolerance with multiple dosing. In participants with knee osteoarthritis, significant improvements versus placebo were observed in a stair-climbing-induced pain model. All JNJ-39439335-treated participants reported ≥1 treatment-emergent adverse events (TEAE); most common (≥50% incidence) TEAEs in part 1 were feeling hot (79%), thermohypoesthesia (71%), paresthesia (58%) and feeling cold (50%), and in part 2, were minor thermal burns (50%)., Conclusions: JNJ-39439335 (doses 2-50 mg) was well-tolerated, and associated with acceptable multiple-dose pharmacokinetic profile. JNJ-39439335 demonstrated sustained pharmacodynamic effects (heat pain perception, heat pain latency, capsaicin-induced flare), and an efficacy signal in participants with osteoarthritis pain., Implications: Given the efficacy signal observed and the unique safety profile, larger phase 2 studies are needed to better understand the potential of JNJ-39439335 in the treatment of chronic pain. Analgesic efficacy of lower doses administered over a longer period of time and improved patient counseling techniques to reduce the minor thermal burns can be explored to minimize the adverse events.

Background/aims: Transient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have been evaluated in clinical studies for their analgesic effects. Mavatrep, a potent, selective, competitive TRPV1 receptor antagonist has demonstrated pharmacodynamic effects consistent with target engagement at the TRPV1 receptor in a previous single-dose clinical study. The current study was conducted to evaluate the analgesic effects of a single dose of mavatrep., Methods: In this randomized, placebo- and active-controlled, 3-way crossover, phase 1b study, patients with painful knee osteoarthritis were treated with a single-dose of 50mg mavatrep, 500mg naproxen twice-daily, and placebo. Patients were randomized to 1 of 6 treatment sequences. Each treatment sequence included three treatment periods of 7 days duration with a 7 day washout between each treatment period. The primary efficacy evaluation was pain reduction measured by the 4-h postdose sum of pain intensity difference (SPID) based on the 11-point (0-10) Numerical Rating Scale (NRS) for pain after stair-climbing (PASC). The secondary efficacy evaluations included 11-point (0-10) NRS pain scores entered into the Actiwatch between clinic visits, the Western Ontario and McMaster Universities Arthritis Index subscales (WOMAC) questionnaire, and use of rescue medication. Safety and tolerability of single oral dose mavatrep were also assessed., Results: Of 33 patients randomized, 32 completed the study. A statistically significantly (p<0.1) greater reduction in PASC was observed for mavatrep versus placebo (4-h SPID least square mean [LSM] [SE] difference: 1.5 [0.53]; p=0.005 and 2-h LSM [SE] difference of PID: 0.7 [0.30]; p=0.029). The mean average daily current pain NRS scores were lower in the mavatrep and naproxen treatment arm than in the placebo arm (mavatrep: 7 day mean [SD], 3.72 [1.851]; naproxen: 7 day mean [SD], 3.49 [1.544]; placebo: 7 day mean [SD], 4.9 [1.413]). Mavatrep showed statistically significant improvements as compared with placebo on the WOMAC subscales (pain on days 2 [p=0.049] and 7 [p=0.041], stiffness on day 7 [p=0.075]), and function on day 7 [p=0.077]). The same pattern of improvement was evident for naproxen versus placebo. The mean (SD) number of rescue medication tablets taken during the 7-day treatment period was 4.2 (6.49) for mavatrep treatment, 2.8 (5.42) for naproxen, and 6.3 (8.25) for placebo treatment. All patients that received mavatrep reported at least 1 treatment emergent adverse event (TEAE). Feeling cold (79%), thermohypoesthesia (61%), dysgeusia (58%), paraesthesia (36%), and feeling hot (15%) were the most common TEAEs in the mavatrep group. Total 9% patients receiving mavatrep experienced minor thermal burns. No deaths or serious AEs or discontinuations due to AEs occurred., Conclusion: Overall, mavatrep was associated with a significant reduction in pain, stiffness, and physical function when compared with placebo in patients with knee osteoarthritis. Mavatrep's safety profile was consistent with its mechanism of action as a TRPV1 antagonist., Implications: Further studies are required to evaluate whether lower multiple doses of mavatrep can produce analgesic efficacy while minimizing adverse events, as well as the potential for improved patient counselling techniques to reduce the minor thermal burns related to decreased heat perception., Trial Registration: 2009-010961-21 (EudraCT Number)., (Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

This double-blind, randomized, placebo-controlled, sequential group, phase 1 study was designed to assess in healthy men, the safety, tolerability, pharmacokinetics, and translational pharmacodynamics of JNJ-39439335 (mavatrep), a transient receptor potential vanilloid subtype 1 antagonist; it was preceded by a translational preclinical study which assessed the ability of JNJ-39439335 to block capsaicin-induced flare in rats, providing predictive pharmacokinetic and pharmacodynamic data that informed the subsequent phase 1 clinical study. The clinical study consisted of 2 parts: part 1 assessed pharmacokinetics and pharmacodynamics, including heat pain detection threshold and heat pain tolerance, of JNJ-39439335, and part 2 assessed pharmacodynamic effect of JNJ-39439335 on capsaicin-induced flare and sensory testing on naïve and UVB-sensitized skin in humans. Plasma concentrations of JNJ-39439335 peaked at approximately 2 to 4 hours postdose, then declined multiexponentially, with a prolonged terminal phase (half-life: 30-86 hours). Renal clearance of JNJ-39439335 was negligible. JNJ-39439335 treatment resulted in clear, consistent dose-related increases in heat pain detection threshold, heat pain tolerance, and heat pain latency. JNJ-39439335 reduced the capsaicin-induced flare area and flare intensity, with complete blocking observed in the 50-mg dose group at 144 hours postdose. This was consistent with the capsaicin flare results observed with JNJ-39439335 in rats. The most common adverse events observed in the clinical study were related to increases in body temperature after JNJ-39439335 treatment; these were predominately mild to moderate in severity with no evidence of exposure dependence up to 225 mg. JNJ-39439335 was well tolerated at single doses up to 225 mg, recommending its suitability for further clinical development., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Alterations in tissue oxygen pressure contribute to a number of diseases, including rheumatoid arthritis (RA). Low partial pressure of oxygen, a condition known as hypoxia, is a relevant feature in RA since it is involved in angiogenesis, inflammation, apoptosis, cartilage degradation, energy metabolism, and oxidative damage. Therefore, alterations in hypoxia-related signaling pathways are considered potential mechanisms of disease pathogenesis. The objective of this review is to highlight and update our current knowledge of the role of hypoxia in the pathogenesis of RA. We describe the experimental evidence that RA synovial tissue exists in a hypoxic state, as well as the origin and involvement of synovial hypoxia in different aspects of the pathogenic process.

This study aimed to determine the prevalence of musculoskeletal (MSK) pain and rheumatic diseases in the Raramuri population (also known as Tarahumaras) who are an indigenous group in the northern state of Chihuahua in Mexico. We used the Community-Oriented Program for Control of Rheumatic Diseases (COPCORD) methodology. An analytical cross-sectional study was conducted including indigenous Raramuri aged ≥18 years from communities settled in Chihuahua City. Subjects with positive MSK pain were evaluated by primary care physicians and rheumatologists. Demographic and occupational factors such as gender and job type associated with rheumatic disease were investigated. A total of 380 indigenous Raramuri (mean age 33.6 ± 13.1 years; 37.9 % male) were interviewed. Seventy-six individuals (20 %) reported MSK pain in the last 7 days. Pain intensity was reported as "severe" and "the most severe" in 30 % of the cases. Fifty-six individuals (14.7 %) reported pain in the past and 86 (22.6 %) had either past or current pain. The prevalence of rheumatic diseases was 10.5 %. Diagnosed diseases were osteoarthritis (6.6 %), low back pain (1.6 %), spondyloarthritis (0.8 %), rheumatoid arthritis (0.5 %), non-specific arthritis (0.5 %), rheumatic regional pain syndromes (0.3 %), and fibromyalgia (0.3 %). Rheumatic disease was associated with the following variables: age (odds ratio (OR) 1.04, 95 % confidence interval (CI) 1.02-1.08; p = 0.006), family history of rheumatic symptoms (OR 6.9; 95 % CI 2.6-18.7; p < 0.001), and Health Assessment Questionnaire-Disability Index (OR 28.9; 95 % CI 2.8-289.7; p < 0.001). A high prevalence of non-traumatic MSK pain suggests the need for a rheumatic disease prevention program in the Raramuri people in Chihuahua, Mexico.

Spondyloarthritis comprise a group of inflammatory rheumatic diseases characterized by its association to HLA-B27 and the presence of arthritis and enthesitis. The pathogenesis involves both an inflammatory process and new bone formation, which eventually lead to ankylosis of the spine. To date, the intrinsic mechanisms of the pathogenic process have not been fully elucidated, and our progress is remarkable in the identification of therapeutic targets to achieve the control of the inflammatory process, yet our ability to inhibit the excessive bone formation is still insufficient. The study of new bone formation in spondyloarthritis has been mostly conducted in animal models of the disease and only few experiments have been done using human biopsies. The deregulation and overexpression of molecules involved in the osteogenesis process have been observed in bone cells, mesenchymal cells, and fibroblasts. The signaling associated to the excessive bone formation is congruent with those involved in the physiological processes of bone remodeling. Bone morphogenetic proteins and Wnt pathways have been found deregulated in this disease; however, the cause for uncontrolled stimulation remains unknown. Mechanical stress appears to play an important role in the pathological osteogenesis process; nevertheless, the association of other important factors, such as the presence of HLA-B27 and environmental factors, remains uncertain. The present review summarizes the experimental findings that describe the signaling pathways involved in the new bone formation process in spondyloarthritis in animal models and in human biopsies. The role of mechanical stress as the trigger of these pathways is also reviewed., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Background: Rheumatic diseases (RDs) represent a global problem for health care systems and patients. Community Oriented Program for Control of Rheumatic Diseases (COPCORD) is a low-cost screening tool for detecting musculoskeletal (MSK) pain and RDs., Objective: The aim of this study was to examine the pattern of MSK pain and RDs in clinic population in Chihuahua City, Mexico., Methods: A cross-sectional study was conducted in 7 primary health clinics using the COPCORD methodology in subjects older than 18 years. People with MSK pain not induced by trauma (positive cases) were evaluated by primary care physicians and rheumatologists., Results: The study included 1006 individuals with a mean age of 46.0 (SD, 15.8) years; 751 (74.7%) were women. Musculoskeletal pain in the previous 7 days was reported by 571 individuals (56.75%; 95% confidence interval [CI], 53.8%-60.1%), and 356 cases (35.4%; 95% CI, 32.5%-38.4%) were COPCORD positive. The mean pain intensity in visual analog scale was 6.62 (SD, 2.4). The most common painful joint was the knee (54.7%; 95% CI, 51.1%-59.0%). Two hundred eighty subjects with MSK pain (49.0%) previously sought medical attention, and 375 (65.7%) were under treatment. Functional impairment was reported by 69.8% of the COPCORD-positive subjects. The prevalence of RDs was 21.4% (95% CI, 18.9%-23.8%). The most prevalent disease was osteoarthritis (10.3%; 95% CI, 8.6%-12.4%), followed by regional pain syndromes (5.5%; 95% CI, 4.1%-7.0%), rheumatoid arthritis (1.4%; 95% CI, 0.8%-2.2%), and mechanical low-back pain (1.4%; 95% CI, 0.7%-2.2%)., Conclusions: Musculoskeletal pain is an important problem that affects our community. The data provided in this study will be presented to the local authorities to help in the development of prevention strategies.

Spiral ganglion neurons (SGNs) faithfully encode acoustic waves from hair cells to the cochlear nucleus (CN) using voltage-dependent ion channels. A sizable portion of our knowledge on SGN functions have been derived from pre-hearing neurons. In post-hearing SGNs, the mechanisms of how they encode the massive sound information without delay and precisely are largely unknown. Mature SGNs are housed in the central bony labyrinth of the cochlea, protected by a well-insulated myelin sheath, making it a technical feat to isolate viable neurons for rigorous functional electrophysiology. Recently, we have overcome the previous intractable hindrance in SGN functional analyses. We provide a step-by-step user-friendly protocol with practical applications, including patch-clamp recordings and imaging by using cultured SGNs.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease whose pathogenic mechanisms remain to be elucidated. The oxidative stress and antioxidants play an important role in the disease process of RA. The study of oxidants and antioxidants biomarkers in RA patients could improve our understanding of disease pathogenesis; likely determining the oxidative stress levels in these patients could prove helpful in assessing disease activity and might also have prognostic implications. To date, the usefulness of oxidative stress biomarkers in RA patients is unclear and the evidence supporting them is heterogeneous. In order to resume and update the information in the status of oxidants and antioxidants and their connection as biomarkers in RA, we performed a systematic literature search in the PubMed database, including clinical trials published in the last five years using the word combination "rheumatoid arthritis oxidative stress". In conclusion, this review supports the fact that the oxidative stress is an active process in RA pathogenesis interrelated to other better known pathogenic elements. However, some controversial results preclude a definite conclusion.

Introduction: Undernutrition is a recognized public health problem in Mexican children and cryptosporidiosis is probably a factor contributing to this problem. However, it remains a neglected and poorly attended infection in Mexico. This study aimed to determine the prevalence of Cryptosporidium parvum and to establish its association with the nutritional status in schoolchildren of northwestern Mexico., Methodology: A total of 405 schoolchildren between 6 and 13 years of age were included in this study. Weight-for-age (W/A), height-for-age (H/A) and body mass index-for-age (BMI/A) Z scores were calculated. The Faust technique was used to detect intestinal parasites in stool samples and C. parvum coproantigen was detected by enzyme-linked immunosorbent assay (ELISA)., Results: The overall prevalence of C. parvum was 28.4%. Some of the study children were C. parvum free (n = 86) and some were C. parvum infected (n = 77). The prevalences of risk of undernutrition found in both groups of children for H/A, W/A, and BMI/A Z scores were 18%, 21% and 28%, respectively. Weight, ZW/A, and ZH/A were significantly higher in the C. parvum-free group compared to the C. parvum-infected group (p ≤ 0.05). The children with cryptosporidiosis were 2.7 times more likely to be at risk of undernutrition by W/A Z score and 2.9 times more likely to be at risk of undernutrition by ZH/A than were the C. parvum-free children., Conclusions: Cryptosporidiosis may be a contributing factor to childhood undernutrition in northwestern Mexico. The proper authorities must implement control and prevention measurements in Mexico and other developing countries.

Monoacylglycerol lipase (MGL) is a ubiquitously expressed enzyme that catalyzes the hydrolysis of monoacylglycerols (MGs) to yield FFAs and glycerol. MGL contributes to energy homeostasis through the mobilization of fat stores and also via the degradation of the endocannabinoid 2-arachidonoyl glycerol. To further examine the role of MG metabolism in energy homeostasis, MGL(-/-) mice were fed either a 10% (kilocalories) low-fat diet (LFD) or a 45% (kilocalories) high-fat diet (HFD) for 12 weeks. Profound increases of MG species in the MGL(-/-) mice compared with WT control mice were found. Weight gain over the 12 weeks was blunted in both diet groups. MGL(-/-) mice were leaner than WT mice at both baseline and after 12 weeks of LFD feeding. Circulating lipids were decreased in HFD-fed MGL(-/-) mice, as were the levels of several plasma peptides involved in glucose homeostasis and energy balance. Interestingly, MGL(-/-) mice had markedly reduced intestinal TG secretion following an oral fat challenge, suggesting delayed lipid absorption. Overall, the results indicate that global MGL deletion leads to systemic changes that produce a leaner phenotype and an improved serum metabolic profile., (Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.)

Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.