Actions of N-arachidonyl-glycine in a rat inflammatory pain model

<p>Abstract</p> <p>Background</p> <p>While cannabinoid receptor agonists have analgesic activity in inflammatory pain states they produce a range of side effects. Recently, it has been demonstrated that the arachidonic acid-amino acid conjugate, N-arachidonyl-glycine (NA-glycine) is effective in acute pain models.</p> <p>Results</p> <p>In the present study we examined the effect of NA-glycine in a rat model of inflammatory pain. Intrathecal administration of NA-glycine (70 – 700 nmol) and the pan-cannabinoid receptor agonist HU-210 (10 nmol) reduced the mechanical allodynia and thermal hyperalgesia induced by intraplantar injection of Freund's complete adjuvant (FCA). The actions of HU-210, but not NA-glycine were reduced by the cannabinoid CB₁receptor antagonist AM251. The cannabinoid CB₂receptor antagonist SR144528 also had no effect on the actions of NA-glycine. In contrast, N-arachidonyl-GABA (NA-GABA, 700 nmol) and N-arachidonyl-alanine (NA-alanine, 700 nmol) had no effect on allodynia and hyperalgesia. HU-210, but not NA-glycine produced a reduction in rotarod latency.</p> <p>Conclusion</p> <p>These findings suggest that NA-glycine may provide a novel non-cannabinoid receptor mediated approach to alleviate inflammatory pain.</p

Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development

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The Impact of Vulvar Lichen Sclerosus on Sexual Dysfunction

Background: Lichen sclerosus (LS) is a chronic inflammatory condition that is known to arise on the vulva. Many women with LS report vulvar pain, often affecting a patient's quality of life. In this study, the sexual function of LS patients, with and without pain, was compared to control populations. Materials and Methods: A case-control study to examine the relationship between LS and sexual dysfunction was conducted. A total of 335 women presenting to the gynecology clinic were included in the study: 197 women with biopsy confirmed LS were compared to two control groups (95 asymptomatic women were ?healthy? controls and 43 women had vulvovaginal candidiasis) on self-reported current health complaints, medical and surgical history and current symptoms such as pain and itching, type and frequency of sexual activity, and satisfaction with sexual activity. Results: Women with LS reported less frequent sexual activity than healthy controls (p=0.007) and Candida controls (p=0.04). Currently sexually active women with LS were significantly less likely to report vaginal intercourse (71.6%) than healthy controls (89.0%, p=0.003) or Candida controls (100%, p=0.0003), even though similar proportions of all three groups reported that vaginal intercourse was important. Satisfaction towards the quality of current sexual activity was significantly lower among women with LS compared with both the healthy and Candida control groups. 23.7% of women with LS reported that sexual activity was rarely or never satisfactory as compared with 0% of healthy controls (p<0.0001) and 6.5% of Candida controls (p=0.03). Conclusion: Women with LS have less frequent sexual activity and less satisfying sexual activity when compared with controls.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140128/1/jwh.2014.4805.pd

Insights into the pathogenesis of ulcerative colitis from a murine model of stasis-induced dysbiosis, colonic metaplasia, and genetic susceptibility

Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here by permission of American Physiological Society for personal use, not for redistribution. The definitive version was published in American Journal of Physiology-Gastrointestinal and Liver Physiology 310 (2016): G973-G988, doi:10.1152/ajpgi.00017.2016.Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflammatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis, offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically created blind self-filling (SFL) and self- emptying (SEL) ileal loops using wild-type (WT), IL-10 KO (IL10), and TLR4 KO (T4), and IL10/T4 double KO mice. After 5 weeks, loop histology, host gene/protein expression, and bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility oriented towards the loop end, whereas SEL remain empty. In wild type mice, SFL, but not SEL, develop pouch-like microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-/- deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. The inflammation associated with IL- 10-/- required TLR4, as animals lacking both pathways displayed little disease. Furthermore, germ-free IL10-/- mice conventionalized with SFL, but not SEL, microbiota populations develop severe colitis. These data support essential roles of stasis-induced, colon-like microbiota, TLR4- mediated colonic metaplasia, and genetic susceptibility in the development of pouchitis and possibly UC. However, these factors by themselves are not sufficient. Similarities between this model and human UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD and for identification of targets for novel preventative and therapeutic interventions.NIDDK DK42086 (DDRCC), UH3 DK083993, Leona and Harry Helmsley Trust (SHARE), R37 DK47722, T32 DK07074, F32 DK105728, Gastrointestinal Research Foundation of Chicago, Peter and Carol Goldman Family Research grant.2017-06-0

Genetic association and characterization of FSTL5 in isolated clubfoot

ACKNOWLEDGEMENTS: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 (E.Boerwinkle). We thank H. Hobbs and J. Cohen for contributing control samples for replication genotyping, Nadav Ahituv for sharing RNA-seq data for both bat and mouse embryonic limb buds, Tommy Hyatt for designing the custom genotyping assay, and members of the UT Southwestern Transgenic Core facility, including John Ritter, Mylinh Nguyen, and Robert Hammer. Publicly available mouse embryonic expression analysis results were provided online at https://oncoscape.v3.sttrcancer.org/atlas.gs.washington.edu.mouse.rna/landing (24). The authors acknowledge the contributions and support of the Center for Excellence in Clubfoot Research at Scottish Rite for Children, including Shawne Faulks and Kristhen Atala. Fstl5 mutant rats were produced by the NIH Mutant Rat Resource at UT Southwestern Medical Center (R24RR03232601, R24OD011108, R01HD036022, and (5R01HD053889). This study was supported by funding from the Scottish Rite for Children Research Fund (J.J.R.), Shriners Hospital for Children (J.T.H), and the National Institutes of Health award R01HD043342 (J.T.H.).Peer reviewedPostprin

Facemasks, Hand Hygiene, and Influenza among Young Adults: A Randomized Intervention Trial

Limited vaccine availability and the potential for resistance to antiviral medications have led to calls for establishing the efficacy of non-pharmaceutical measures for mitigating pandemic influenza. Our objective was to examine if the use of face masks and hand hygiene reduced rates of influenza-like illness (ILI) and laboratory-confirmed influenza in the natural setting. A cluster-randomized intervention trial was designed involving 1,178 young adults living in 37 residence houses in 5 university residence halls during the 2007–2008 influenza season. Participants were assigned to face mask and hand hygiene, face mask only, or control group during the study. Discrete-time survival models using generalized estimating equations to estimate intervention effects on ILI and confirmed influenza A/B infection over a 6-week study period were examined. A significant reduction in the rate of ILI was observed in weeks 3 through 6 of the study, with a maximum reduction of 75% during the final study week (rate ratio [RR] = 0.25, [95% CI, 0.07 to 0.87]). Both intervention groups compared to the control showed cumulative reductions in rates of influenza over the study period, although results did not reach statistical significance. Generalizability limited to similar settings and age groups. Face masks and hand hygiene combined may reduce the rate of ILI and confirmed influenza in community settings. These non-pharmaceutical measures should be recommended in crowded settings at the start of an influenza pandemic

Two-Photon Fluorescence Microscopy Imaging of Cellular Oxidative Stress Using Profluorescent Nitroxides

A range of varying chromophore nitroxide free radicals and their nonradical methoxyamine analogues were synthesized and their linear photophysical properties examined. The presence of the proximate free radical masks the chromophore’s usual fluorescence emission, and these species are described as profluorescent. Two nitroxides incorporating anthracene and fluorescein chromophores (compounds 7 and 19, respectively) exhibited two-photon absorption (2PA) cross sections of approximately 400 G.M. when excited at wavelengths greater than 800 nm. Both of these profluorescent nitroxides demonstrated low cytotoxicity toward Chinese hamster ovary (CHO) cells. Imaging colocalization experiments with the commercially available CellROX Deep Red oxidative stress monitor demonstrated good cellular uptake of the nitroxide probes. Sensitivity of the nitroxide probes to H2O2-induced damage was also demonstrated by both one- and two-photon fluorescence microscopy. These profluorescent nitroxide probes are potentially powerful tools for imaging oxidative stress in biological systems, and they essentially “light up” in the presence of certain species generated from oxidative stress. The high ratio of the fluorescence quantum yield between the profluorescent nitroxide species and their nonradical adducts provides the sensitivity required for measuring a range of cellular redox environments. Furthermore, their reasonable 2PA cross sections provide for the option of using two-photon fluorescence microscopy, which circumvents commonly encountered disadvantages associated with one-photon imaging such as photobleaching and poor tissue penetration