Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cationic channel activated by painful stimuli such as capsaicin and noxious heat, and enriched in sensory neurons of the pain pathway. During inflammation, chemical mediators activate protein kinases (such as PKC) that phosphorylate TRPV1 and thereby enhance its function, with consequent increases in nociceptor sensitization. However, the causal relationships between TRPV1 phosphorylation and pathological pain remain unexplored. To directly investigate the roles of one specific TRPV1 phosphorylation event in vivo, we genetically altered a major PKC phosphorylation site, mouse TRPV1 S801, to alanine. The TRPV1 expression pattern in sensory neurons of S801A knock-in (KI) mice was comparable to that in WT controls. However, sensitization of capsaicin-mediated currents after the activation of PKC was substantially impaired in sensory neurons from KI mice. Thermal hyperalgesia induced by PMA or burn injury in KI was identical to WT. Inflammatory thermal hyperalgesia was only marginally attenuated in KI mice. In contrast, PMA-evoked nocifensive responses and sensitization of capsaicin responses were significantly attenuated in the hindpaws of KI mice. Ongoing pain from inflamed masseter muscle was also reduced in KI mice, and was further inhibited by the TRPV1 antagonist AMG9810. These results suggest that PKC-mediated phosphorylation of TRPV1 S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand, but not heat, in vivo. Further, this suggests that interference with TRPV1 S801 phosphorylation might represent one potential way to attenuate inflammatory pain, yet spare basal sensitivity and produce fewer side effects than more general TRPV1 inhibition.
Severe fetal pleural effusion and ascites in the second trimester are associated with poor prognosis. We present a case where long-term drainage of several pleural effusion by a double reverse pig tail stent was achieved. Although the ultimate outcome was successful, complications seen in this case include accidental placement of the proximal opening of the catheter, first into the myometrium, then between amnion and chorion; development of oligohydramnios; intrathoracic migration of the catheter. Review of the literature reveals a multitude of other complications associated with this procedure, specifically difficulties at the time of placement and failure of function due to obstruction, migration of the catheter, or removal by the fetus. It is important to consider these complications in the counseling and management of the patients. Ongoing research is required to further improve the design of the catheters.
Study ObjectiveAccess to naloxone is a priority for reducing opioid deaths. Although community members who complete naloxone training are able to administer nasal naloxone successfully and rapidly, little is known about the ability of community members to administer naloxone without training. The objective of this study was to assess the ability of untrained individuals to administer naloxone successfully in a simulated opioid overdose setting.DesignProspective single‐site open‐label randomized usability assessment.SettingScenario station at a large state fair during August and September 2017.ParticipantsA total of 207 healthy adults who were randomly assigned to administer naloxone using a nasal spray (NS) device (69 participants), an intramuscular (IM) kit (68 participants), or an improvised nasal atomizer (AT) kit (70 participants).InterventionParticipants were instructed to administer the device to a high‐fidelity mannequin in a public environment with distractions to mimic those that might be present in an actual overdose. No device instructions or administration materials were provided.Measurements and Main ResultsParticipants were assessed by trained study team members who directly observed all naloxone administrations using the predetermined end‐point criteria. Individual participant perceptions were evaluated immediately following the naloxone administration using a standardized questionnaire form. The primary outcome was successful administration, defined as administration within 7 minutes and without critical errors. Secondary outcomes were time to successful naloxone administration and ease of use of the device. The NS (66.7%, p<0.001) and IM (51.5%, p<0.001) devices had higher rates of successful administration than the improvised nasal AT device (2.9%). The NS device was administered more rapidly (median 16 sec) than the IM device (median 58 sec, p<0.001) or improvised nasal AT device (median 113 sec, p=0.012) devices, and it was the easiest to use.ConclusionIn this study of naloxone administration, participants administered the NS and IM devices more successfully than the AT device. The NS device was administered most rapidly and was easiest to use.
Plakophilin (PKP1) 1 is a member of the arm‐repeat family of catenins and acts as a structural component of desmosomes, which are important stabilizers of cell–cell adhesion. Besides this, PKP1 also occurs in a non‐junctional, cytoplasmic form contributing to post‐transcriptional regulation of gene expression. Moreover, PKP1 is expressed in the prostate epithelium but its expression is frequently downregulated in prostate cancers with a more aggressive phenotype. This observation may imply a tumour‐suppressive role of PKP1. We found that, in prostatic adenocarcinomas with PKP1 deficiency, the occurrence of T‐cells, B‐cells, macrophages and neutrophils were significantly increased. In a PKP1‐deficient prostatic cancer cell line expressing IL8, these levels were statistically meaningfully reduced upon PKP1 re‐expression. When analysing prostatic PKP1 knockdown cell lines, the mRNA and protein levels of additional cytokines, namely CXCL1 and IL6, were upregulated. The effect was rescued upon re‐expression of a PKP1 RNAi‐resistant form. The corresponding mRNAs were co‐precipitated with cytoplasmic PKP1, indicating that they are components of PKP1‐containing mRNA ribonucleoprotein particles. Moreover, the mRNA half‐lives of CXCL1, IL8 and IL6 were significantly increased in PKP1‐deficient cells, showing that these mRNAs were stabilized by PKP1. In an in vitro migration assay, the higher cytokine concentrations led to higher migration rates of THP1 and PBMC cells. This finding implies that PKP1 loss of expression in vivo correlates with the recruitment of immune cells into the tumour area to set up a tumour‐specific environment. One may speculate that this newly established tumour environment has tumour‐suppressive characteristics and thereby accelerates tumour progression and metastasis.
The enemy release hypothesis is often cited as a potential explanation for the success of introduced plants; yet, empirical evidence for enemy release is mixed. We aimed to quantify changes in herbivory and defense in introduced plants while controlling for three factors that might have confounded past studies: using a wide native range for comparison with the introduced range, measuring defense traits without determining whether they affect herbivore preferences, and not considering the effect of time since introduction. The first hypothesis we tested was that introduced plants will have evolved lower levels of plant defense compared to their source population. We grew South African (source) and Australian (introduced) beach daisies (Arctotheca populifolia) in a common‐environment glasshouse experiment and measured seven defense traits. Introduced plants had more ash, alkaloids, and leaf hairs than source plants, but were also less tough, with a lower C:N ratio and less phenolics. Overall, we found no difference in defense between source and introduced plants. To determine whether the feeding habits of herbivores align with changes in defense traits, we conducted preference feeding trials using five different herbivore species. Herbivores showed no overall preference for leaves from either group. The second hypothesis we tested was that herbivory on introduced plant species will increase through time after introduction to a new range. We recorded leaf damage on herbarium specimens of seven species introduced to eastern Australia and three native control species. We found no change in the overall level of herbivory experienced by introduced plants since arriving in Australia.ConclusionIn the field of invasion ecology, we need to rethink the paradigm that species introduced to a new range undergo simple decreases in defenses against herbivores. Instead, plants are likely to employ a range of defense traits that evolve in both coordinated and opposing ways in response to a plethora of different biotic and abiotic selective pressures.
We conducted a randomised, single-blind, placebo-controlled crossover study to assess the efficacy of a single i.v. dose of 20 mg dexamethasone as an anti-emetic in 31 patients receiving cancer chemotherapy. Patients receiving dexamethasone experienced significantly less nausea and vomiting (P less than 0.001 and P less than 0.01, respectively), and appetite and activity were normal in a majority of the treated group. Side effects were insignificant. We conclude that single-dose dexamethasone given i.v. at a dose of 20 mg is a safe and effective anti-emetic for patients receiving cancer chemotherapy excluding cisplatin.
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