Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly ...developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca2+ influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation and nociceptor sensitization by inflammatory mediators. Finally, peripherally restricted KOR agonists selectively reduce pain and itch behaviors, as well as mechanical hypersensitivity associated with a surgical incision. These experiments provide a rationale for the use of peripherally restricted KOR agonists for therapeutic treatment.
•KOR is expressed in peptidergic primary afferents in mouse and human•KOR is expressed in LTMRs that form circumferential and lanceolate endings•KOR signaling inhibits nociceptor sensitization and neurogenic inflammation•Peripherally selective KOR agonists inhibit nociception
Snyder et al. identify primary afferents that express the kappa opioid receptor in mouse and human and show that kappa opioid receptor signaling inhibits these cells in physiological and behavioral experiments.
ABSTRACT
We present the results of photometric and spectroscopic monitoring campaigns of the changing look AGN NGC 3516 carried out in 2018 to 2020 covering the wavelength range from the X-ray to the ...optical. The facilities included the telescopes of the CMO SAI MSU, the 2.3-m WIRO telescope, and the XRT and UVOT of Swift. We found that NGC 3516 brightened to a high state and could be classified as Sy1.5 during the late spring of 2020. We have measured time delays in the responses of the Balmer and He ii λ4686 lines to continuum variations. In the case of the best-characterized broad H β line, the delay to continuum variability is about 17 d in the blue wing and is clearly shorter, 9 d, in the red, which is suggestive of inflow. As the broad lines strengthened, the blue side came to dominate the Balmer lines, resulting in very asymmetric profiles with blueshifted peaks during this high state. During the outburst the X-ray flux reached its maximum on 2020 April 1 and it was the highest value ever observed for NGC 3516 by the Swift observatory. The X-ray hard photon index became softer, ∼1.8 in the maximum on 2020 April 21 compared to the mean ∼0.7 during earlier epochs before 2020. We have found that the UV and optical variations correlated well (with a small time delay of 1–2 d) with the X-ray until the beginning of 2020 April, but later, until the end of 2020 June, these variations were not correlated. We suggest that this fact may be a consequence of partial obscuration by Compton-thick clouds crossing the line of sight.
Abstract Background Buprenorphine/naloxone was approved by the FDA for office-based opioid maintenance therapy (OMT), with little long-term follow-up data from actual office-based practice. 18-Month ...outcome data on the office-based use of buprenorphine/naloxone (bup/nx) and the impact of socioeconomic status and other patient characteristics on the duration and clinical effects of bup/nx are reported. Methods This retrospective chart review and cross-sectional telephone interview provide treatment retention of opioid-dependent patients receiving bup/nx-OMT in an office-based setting. 176 opioid-dependent patients from two different socioeconomic groups (high and low SES) were begun on bup/nx, started intensive outpatient treatment, and followed-up after a minimum of 18 months (18–42 months) by telephone interview to assess treatment outcome. Results 110 subjects (67%) completed the interview, 77% remained on bup/nx with no difference in retention between high and low SES groups. Those on bup/nx at follow-up were more likely to report abstinence, to be affiliated with 12-step recovery, to be employed and to have improved functional status. Conclusions Bup/nx-OMT is a viable treatment option and when coupled with a required abstinence oriented addiction counseling program is effective in promoting abstinence, self-help group attendance, occupational stability, and improved psychosocial outcomes in both low SES and high SES patient populations over an 18–42-month period.
How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that ...transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can directly elicit AP firing in nociceptive as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory processing.
Background
The benefit of daily administration of Peanut (Arachis hypogaea) Allergen Powder‐dnfp (PTAH)—formerly AR101—has been established in clinical trials, but limited data past the first year of ...treatment are available. This longitudinal analysis aimed to explore the impact of continued PTAH therapeutic maintenance dosing (300 mg/day) on efficacy, safety/tolerability, and food allergy‐related quality of life.
Methods
We present a subset analysis of PALISADE‐ARC004 participants (aged 4–17 years) who received 300 mg PTAH daily for a total of ~1.5 (Group A, n = 110) or ~2 years (Group B, n = 32). Safety assessments included monitoring the incidence of adverse events (AEs), accidental exposures to food allergens, and adrenaline use. Efficacy was assessed by double‐blind, placebo‐controlled food challenge (DBPCFC); skin prick testing; peanut‐specific antibody assays; and Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM) scores.
Results
Continued maintenance with PTAH increased participants’ ability to tolerate peanut protein: 48.1% of completers in Group A (n = 50/104) and 80.8% in Group B (n = 21/26) tolerated 2000 mg peanut protein at exit DBPCFC without dose‐limiting symptoms. Immune biomarkers showed a pattern consistent with treatment‐induced desensitization. Among PTAH‐continuing participants, the overall and treatment‐related exposure‐adjusted AE rate decreased throughout the intervention period in both groups. Clinically meaningful improvements in FAQLQ and FAIM scores over time suggest a potential link between increased desensitization as determined by the DBPCFC and improved quality of life.
Conclusions
These results demonstrate that daily PTAH treatment for peanut allergy beyond 1 year leads to an improved safety/tolerability profile and continued clinical and immunological response.
Daily administration of Peanut (Arachis hypogaea) Allergen Powder‐dnfp (formerly AR101) beyond the 1‐year PALISADE trial (total treatment of ~1.5 or ~2 years) increased participants’ ability to tolerate peanut protein. This was paralleled by a pattern of immunomodulation consistent with desensitization and an improved safety/tolerability profile. Treatment beyond 1 year was associated with clinically meaningful improvements in self‐reported and caregiver‐reported food allergy‐related quality of life.
Abbreviations: AE, adverse event; ARC004, PALISADE Follow‐on Study; DBPCFC, double‐blind placebo‐controlled food challenge; FAIM, Food Allergy Independent Measure; FAQLQ, Food Allergy Quality of Life Questionnaire; MWD, mean wheal diameter; PALISADE, Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization in Children and Adults; PTAH, Peanut (Arachis hypogaea) Allergen Powder‐dnfp; QoL, quality of life; SPT, skin prick test.
Abstract
In this third paper of the series reporting on the reverberation mapping campaign of active galactic nuclei with asymmetric H
β
emission-line profiles, we present results for 15 ...Palomar–Green quasars using spectra obtained between the end of 2016–2021 May. This campaign combines long time spans with relatively high cadence. For eight objects, both the time lags obtained from the entire light curves and the measurements from individual observing seasons are provided. Reverberation mapping of nine of our targets has been attempted for the first time, while the results for six others can be compared with previous campaigns. We measure the H
β
time lags over periods of years and estimate their black hole masses. The long duration of the campaign enables us to investigate their broad-line region (BLR) geometry and kinematics for different years by using velocity-resolved lags, which demonstrate signatures of diverse BLR geometry and kinematics. The BLR geometry and kinematics of individual objects are discussed. In this sample, the BLR kinematics of Keplerian/virialized motion and inflow is more common than that of outflow.
We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer.
Cohorts of patients with ...metastatic cancer having failed prior therapy entered a phase I trial of rhuMAb VEGF administered by a 90-minute intravenous infusion at doses from 0.1 to 10.0 mg/kg on days 0, 28, 35, and 42. Patients underwent pharmacokinetic sampling on day 0 and had serum samples obtained during the subsequent 28 days. Response assessment was carried out on days 49 and 72.
Twenty-five patients with a median Eastern Cooperative Oncology Group performance status of 0 were accrued. There were no grade III or IV adverse events definitely related to the antibody. There were three episodes of tumor-related bleeding. Infusions of rhuMAb VEGF were well tolerated without significant toxicity. Grades I and II adverse events possibly or probably related to study drug included asthenia, headache, and nausea. Pharmacokinetics revealed a linear profile with a half-life of 21 days. There were no objective responses, though 12 patients experienced stable disease over the duration of the study.
rhuMAb VEGF was safely administered without dose-limiting toxicity at doses ranging up to 10 mg/kg. Multiple doses of rhuMAb VEGF were well tolerated, and pharmacokinetic studies indicate that doses of > or = 0.3 mg/kg have a half-life similar to that of other humanized antibodies. Subsequent trials will explore rhuMAb VEGF alone and in combination chemotherapy.
ABSTRACT
We report the results of long-term reverberation mapping campaigns of the nearby active galactic nuclei (AGNs) NGC 4151, spanning from 1994 to 2022, based on archived observations of the ...FAST Spectrograph Publicly Archived Programs and our new observations with the 2.3 m telescope at the Wyoming Infrared Observatory. We reduce and calibrate all the spectra in a consistent way, and derive light curves of the broad H β line and 5100 Å continuum. Continuum light curves are also constructed using public archival photometric data to increase sampling cadences. We subtract the host galaxy contamination using Hubble Space Telescope imaging to correct fluxes of the calibrated light curves. Utilizing the long-term archival photometric data, we complete the absolute flux-calibration of the AGN continuum. We find that the H β time delays are correlated with the 5100 Å luminosities as $\tau _{\rm H\beta }\propto L_{5100}^{0.46\pm 0.16}$. This is remarkably consistent with Bentz et al. (2013)’s global size–luminosity relationship of AGNs. Moreover, the data sets for five of the seasons allow us to obtain the velocity-resolved delays of the H β line, showing diverse structures (outflows, inflows, and discs). Combining our results with previous independent measurements, we find the measured dynamics of the H β broad-line region (BLR) are possibly related to the long-term trend of the luminosity. There is also a possible additional ∼1.86 yr time lag between the variation in BLR radius and luminosity. These results suggest that dynamical changes in the BLR may be driven by the effects of radiation pressure.
Abstract Background Celiac disease is a chronic inflammatory condition with wide ranging effects on individual’s lives caused by a combination of symptoms and the burden of adhering to a gluten-free ...diet (GFD). Objectives To further understand patients’ experience of celiac disease, the impact it has on health-related quality of life (HRQOL), and to develop a conceptual model describing this impact. Methods Adults with celiac disease on a GFD reporting symptoms within the previous 3 months were included; patients with refractory celiac disease and confounding medical conditions were excluded. A semistructured discussion guide was developed exploring celiac disease symptoms and impact on patients’ HRQOL. An experienced interviewer conducted in-depth interviews. The data set was coded and analyzed using thematic analysis to identify concepts, themes, and the inter-relationships between them. Data saturation was monitored and concepts identified formed the basis of the conceptual model. Results Twenty-one participants were recruited, and 32 distinct gluten-related symptoms were reported and data saturation was reached. Analysis identified several themes impacting patients’ HRQOL: fears and anxiety, day-to-day management of celiac disease, physical functioning, sleep, daily activities, social activities, emotional functioning, and relationships. The conceptual model highlights the main areas of impact and the relationships between concepts. Conclusions Both symptoms and maintaining a GFD have a substantial impact on patient functioning and HRQOL in adults with celiac disease. The conceptual model derived from these data may help to design future patient-reported outcomes as well as interventions to improve the quality of life in an individual with celiac disease.
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