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Enhancing endocannabinoid signaling is a potential therapeutic approach to treating anxiety disorders. Here the authors show that a compound leading to 'substrate-selective' inhibition of cyclooxygenase-2 (cox-2) increases endocannabinoid levels without affecting non-endocannabinoid lipids or prostaglandin synthesis. This compound decreased anxiety-like behaviors in mice via increased endocannabinoid signaling. Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro . However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chemistry and in vivo analytical and behavioral pharmacological approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacological strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential.

Fetal exposure to chorioamnionitis can impact the outcomes of the developing fetus both at the time of birth and in the subsequent neonatal period. Infants exposed to chorioamnionitis have a higher incidence of gastrointestinal (GI) pathology, including necrotizing enterocolitis (NEC); however, the mechanism remains undefined. To simulate the fetal exposure to maternal inflammation (FEMI) induced by chorioamnionitis, pregnant mice (C57BL/6J, IL-6−/−, RAG−/− or TNFR1−/−) were injected intraperitoneally on embryonic day (E)15.5 with lipopolysaccharide (LPS; 100 µg/kg body weight). Pups were delivered at term, and reared to postnatal day (P)0, P7, P14, P28 or P56. Serum and intestinal tissue samples were collected to quantify growth, inflammatory markers, histological intestinal injury, and goblet and Paneth cells. To determine whether FEMI increased subsequent susceptibility to intestinal injury, a secondary dose of LPS (100 µg/kg body weight) was given on P5, prior to tissue harvesting on P7. FEMI had no effect on growth of the offspring or their small intestine. FEMI significantly decreased both goblet and Paneth cell numbers while simultaneously increasing serum levels of IL-1β, IL-10, KC/GRO (CXCL1 and CXCL2), TNF and IL-6. These alterations were IL-6 dependent and, importantly, increased susceptibility to LPS-induced intestinal injury later in life. Our data show that FEMI impairs normal intestinal development by decreasing components of innate immunity and simultaneously increasing markers of inflammation. These changes increase susceptibility to intestinal injury later in life and provide novel mechanistic data to potentially explain why preterm infants exposed to chorioamnionitis prior to birth have a higher incidence of NEC and other GI disorders.

Condyloma acuminata (CA), lesions caused by strains of the human papilloma virus, are usually limited to anogenital and mucocutaneous regions. Though uncommon, isolated urinary CA lesions have been seen in some immunocompromised patients. We report a rare case of an immunocompetent 37-year-old female with innumerable bladder condylomas.

In this study of three strategies — hypothermia, machine perfusion, or both — for pretransplantation preservation of kidneys from brain-dead donors, hypothermia was found to be inferior to machine perfusion.

Introduction. We preliminarily assessed challenges to developing a telemedicine program at a specialty clinic in a public safety-net hospital serving a diverse population. Methods. Patients visiting a urology clinic were surveyed regarding potential follow-up telemedicine visits. A follow-up survey was performed during the COVID-19 pandemic to evaluate changing interest. Results. Our pre-COVID study population consisted of 498 patients, speaking 17 primary languages; primarily, the population had MediCal or no insurance coverage (56.8%). Most had the capability to take part in telemedicine video calls (73.1%), though significantly fewer had the confidence (45.9%) or interest (51%). There was a distinct drop in capability, confidence, and interest with increasing age but not with preferred language. During the COVID-19 pandemic, we noted increased interest in non-traditional visits (n=100), with 79% stating they would repeat a non-in-person visit. Conclusion. Increasing interest in non-traditional visits during the COVID-19 pandemic suggests patient interest and confidence may be malleable.

Patellar instability is a common orthopedic condition in the pediatric population. Many factors contribute to patellar instability, including trochlear dysplasia. However, patellar instability and its treatments are not well documented in the literature for patients with osteogenesis imperfecta. After medial patellofemoral ligament (MPFL) reconstruction, a 17-year-old male with osteogenesis imperfecta had a patellar dislocation that resulted in a patellar fracture. The patient subsequently had a revision of his MPFL reconstruction, and at 2½ years postoperation has had no episodes of recurrent patellar instability. The combination of bone fragility, trochlear dysplasia, and strength of the allograft used for MPFL reconstruction compared to the patient's bone strength led to dislocation and patellar fracture. Research into alternative methods for patellar fixation and postoperative physical therapy protocols for patients with osteogenesis imperfecta is needed. Special considerations must be made for this patient population.

The spinal cord is the gateway for sensory information from the body as it ascends to the brain, as well as a major motor output center of the nervous system. It is also a key location for sensory-motor integration, and a processing site for nociceptive information that eventually drives pain perception in the brain. Tremendous progress has been made in understanding spinal cord circuits using genetic and single cell sequencing approaches in mice. Recently, several groups have conducted single-nucleus and spatial sequencing studies in postmortem human spinal cord tissue. However, the spatial properties of spinal cord cellular diversity and potential sex differences that might be important for human physiology remain unexplored. We conducted deep single-nucleus sequencing on dissected lumbar dorsal and ventral spinal cord samples from 11 organ donors, including 6 females and 5 males, and anatomically annotated spinal cord cell types with 10X Xenium single-molecule spatial transcriptomics. We identified 34 spatially and genetically defined neuron classes, many of which have clearly recognizable conserved orthologs in the rodent spinal cord. We also identified sex specific cell types and states within multiple glial types, but not neurons, demonstrating sexual dimorphism at the transcriptomic cell-type level in the adult human spinal cord. The spatial and single-nucleus atlas resulting from our work build upon previous knowledge to better understand human spinal cord physiology and to identify drug targets for neurological diseases affecting the spinal cord, in particular pain.

Condyloma acuminata (CA), lesions caused by strains of the human papilloma virus, are usually limited to anogenital and mucocutaneous regions. Though uncommon, isolated urinary CA lesions have been seen in some immunocompromised patients. We report a rare case of an immunocompetent 37-year-old female with innumerable bladder condylomas. Keywords: Condyloma acuminata, Bladder, Human papilloma virus, Immunocompetent Insan papilloma virusu suslarinin neden oldugu kondiloma akuminata (CA) lezyonlari, genellikle anogenital ve mukokutanoz bolgelerle sinirlidir. Bagisiklik sistemi baskilanmis bazi hastalarda nadir de olsa izole uriner CA lezyonlari gorulmustur. Bu calismada, sayisiz mesane kondilomlu ve immunokompetan olan 37 yasinda bir kadina ait nadir bir olgu sunulmustur. Anahtar Kelimeler: Kondiloma akuminata, Mesane, insan papilloma virusu, immunokompetan

Abstract Peripheral sensory neurons are characterized by their size, molecular profiles, and physiological responses to specific stimuli. In mouse, the peptidergic and non-peptidergic subsets of nociceptors are distinct and innervate different lamina of the spinal dorsal horn. The unique molecular signature and neuroanatomical organization of these neurons supports a labeled line theory for certain types of nociceptive stimuli. However, long standing evidence supports the polymodal nature of nociceptors in many species. We have recently shown that the peptidergic marker, CGRP, and the non-peptidergic marker, P2X3R, show largely overlapping expression at the mRNA level in human dorsal root ganglion (DRG). Herein, our aim was to assess the protein distribution of nociceptor markers, including their central projections, in the human DRG and spinal cord. Using DRGs obtained from organ donors, we observed that CGRP and P2X3R were co-expressed by approximately 33% of human DRG neurons and TrpV1 was expressed in ~60% of human DRG neurons. In the dorsal spinal cord, CGRP, P2X3R, TrpV1 and Nav1.7 protein stained the entirety of lamina II, with only P2XR3 showing a gradient of expression. This was confirmed by measuring the size of the substantia gelatinosa using Hematoxylin and Eosin staining of adjacent sections. Our findings are consistent with the known polymodal nature of most primate nociceptors and indicate that the central projection patterns of nociceptors are different between mice and humans. Elucidating how human nociceptors connect to subsets of dorsal horn neurons will be important for understanding the physiological consequences of these species differences. Competing Interest Statement The authors have declared no competing interest. Footnotes * SS - sis150030atutdallas.edu, IS - ishwarya.sankaranarayananatutdallas.edu, VJ - vxj090020atutdallas.edu, AC - acervantesatorgan.org, JCR – jreeseatorgan.org, TJP – theodore.priceatutdallas.edu * The authors declare no conflicts of interest * The data that support the findings of this study are available on request to the corresponding author.

Background: In vascular smooth muscle cells (VSMCs), LRRC8A volume regulated anion channels (VRACs) are activated by inflammatory and pro-contractile stimuli including tumor necrosis factor alpha (TNFα), angiotensin II and stretch. LRRC8A physically associates with NADPH oxidase 1 (Nox1) and supports its production of extracellular superoxide (O2-·). Methods and Results: Mice lacking LRRC8A exclusively in VSMCs (Sm22α-Cre, KO) were used to assess the role of VRACs in TNFα signaling and vasomotor function. KO mesenteric vessels contracted normally to KCl and phenylephrine, but relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) was enhanced compared to wild type (WT). 48 hours of ex vivo exposure to TNFα (10ng/ml) markedly impaired dilation to ACh and SNP in WT but not KO vessels. VRAC blockade (carbenoxolone, CBX, 100 µM, 20 min) enhanced dilation of control rings and restored impaired dilation following TNFα exposure. Myogenic tone was absent in KO rings. LRRC8A immunoprecipitation followed by mass spectroscopy identified 35 proteins that interacted with LRRC8A. Pathway analysis revealed actin cytoskeletal regulation as the most closely associated function of these proteins. Among these proteins, the Myosin Phosphatase Rho-Interacting protein (MPRIP) links RhoA, MYPT1 and actin. LRRC8A-MPRIP co-localization was confirmed by confocal imaging of tagged proteins, Proximity Ligation Assays, and IP/western blots which revealed LRRC8A binding at the second Pleckstrin Homology domain of MPRIP. siLRRC8A or CBX treatment decreased RhoA activity in cultured VSMCs, and MYPT1 phosphorylation at T853 was reduced in KO mesenteries suggesting that reduced ROCK activity contributes to enhanced relaxation. MPRIP was a target of redox modification, becoming oxidized (sulfenylated) after TNFα exposure. Conclusions: Interaction of Nox1/LRRC8A with MPRIP/RhoA/MYPT1/actin may allow redox regulation of the cytoskeleton and link Nox1 activation to both inflammation and vascular contractility.Competing Interest StatementThe authors have declared no competing interest.