Revisiting the usefulness of thromboxane-A2 modulation in the treatment of bronchoconstriction in asthma.

Airway smooth muscle (ASM) is the effector cell in the bronchoconstrictory pathway. It is believed that the bronchoconstriction present in asthma is associated with changes in the airway milieu that affect ASM excitation-contraction coupling and Ca(2+)-handling. Asthmatics also react differently to ventilatory mechanical strain. Deep inspiration (DI), which produces bronchodilation in healthy individuals, is less effective in asthmatics, and even enhances bronchoconstriction in moderate to severely affected patients. Our laboratory has previously studied the mechanotransductory pathway of airway stretch-activated contractions (Rstretch) leading to DI-induced bronchoconstriction. We demonstrated the ability of agonists acting through thromboxane A2 (TxA2) receptors to amplify airway Rstretch responses. Despite the involvement of excitatory prostanoids in bronchoconstriction, clinical trials on treatments targeting TxA2-synthase inhibition and TP-receptor antagonism have produced mixed results. Studies in Western populations produced mostly negative results, whereas studies performed in Asian populations showed mostly positive outcomes. In this review, we discuss the role of TxA2-synthase inhibition and TP-receptor antagonism in the treatment of asthmatics. We present information regarding variations in study designs and the possible role of TP-receptor gene polymorphisms in previous study outcome discrepancies. Perhaps future studies should focus on asthmatic patients with DI-induced bronchoconstriction in particular, planting the seed for the individualized treatments for asthmatics.

Annotation of the Complete Genome Sequences of Bacteriophages Sara and Birdfeeder.

Sara is a siphovirus with a linear 17,362bp genome containing 25 genes. Birdfeeder is a podovirus with a circularly permuted 53,897bp genome containing 52 genes. Sara and Birdfeeder were isolated from environmental samples in Plattsburgh, NY, USA and Forest Hill, MD, USA, respectively, using Microbacterium foliorum NRRL B-24224.

Thromboxane prostanoid receptor activation amplifies airway stretch-activated contractions assessed in perfused intact bovine bronchial segments.

A deep inspiration (DI) produces bronchodilation in healthy individuals. Conversely, in asthmatics, DIs are less effective in producing bronchodilation and can cause more rapid airway renarrowing and even bronchoconstriction in moderate to severe asthmatics. It is noteworthy that the manner by which a DI is able to cause bronchoconstriction via a stretch-activated contraction (R(stretch)) is thought to correlate positively with airway inflammation. Asthmatic airway inflammation is associated with increased production of thromboxane A(2) (TxA(2)) and subsequent thromboxane prostanoid (TP) receptor activation, causing the heightened contractility of airway smooth muscle. In this study, we sought to investigate the effect of TxA(2) on airway R(stretch) by using bovine bronchial segments. In brief, these intact bronchial segments (2 mm in diameter) were dissected, side branches were ligated, and the tissues were mounted horizontally in an organ bath. R(stretch) was elicited by varying the transmural pressure under isovolumic conditions. Using a pharmacological approach, we showed a reduced R(stretch) response in tissues pretreated with indomethacin, a cyclooxygenase inhibitor, a result mimicked by pretreatment with the TP-selective receptor antagonist 4-(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoic acid (ICI 192605) and the selective p42/p44 mitogen-activated protein kinase inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD 95089) and by airway epithelial denudation. 9,11-Dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619), a TP receptor agonist, elicited enhanced R(stretch) responses in a dose-dependent manner. Pretreatment with 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809), a prostaglandin E (EP) receptor 1/prostaglandin D2 (DP)-selective receptor antagonist, and 9α,15R-dihydroxy-11.ß-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta-5Z,13E-dien-1-oic acid (AL 8810), a prostaglandin F (FP)-selective receptor antagonist, had no effect, suggesting EP, DP, and FP receptor activation is not involved in amplifying airway smooth muscle R(stretch). These data suggest a role for TP receptor activation and epithelial release of TxA(2) in amplifying airway R(stretch), thus providing novel insights into mechanisms regulating the DI-induced bronchoconstriction seen in asthmatics.

Prompting Paramedics: The Effect of Simulation on Paramedics' Identification of Learning Objectives.

INTRODUCTION: Simulation has emerged as a useful educational tool for the continued training of paramedics. Practicing paramedics are thought to learn through reflecting on their own actions in practice, and it is hoped that simulation could spur similar reflection, which could then lead to practice change. Despite this, there is limited data on how these practitioners use simulated experiences to set learning objectives. This study aimed to explore how simulation training affects self-identification of learning objectives in emergency medical services (EMS) providers (a.k.a. paramedics). METHODS: Paramedics (primary care and advanced care) participated in a 30-minute simulated learning session. All participants filled out pre-post surveys identifying their own learning objectives immediately before and after the simulation. An inductive qualitative analysis of these responses were conducted by two authors (EJ, TC) using an interpretive description approach, yielding a list of key themes commonly found in the learning objectives. Pre-post learning objectives were individually compared by the level of specificity as determined by the authorship team. Simple descriptive statistics were generated to describe the number of times that the paramedics' learning objectives became more or less specific, different, or same. RESULTS: Thirty-five paramedics who completed the simulation and survey were included. Four major themes emerged in the learning objectives: 1) assessment and diagnostic; 2) communication and collaboration; 3) integration of knowledge; and 4) treatment and management. After simulation, the learning objectives became more specific in 6 (17.1%), less specific in 3 (8.6%), different in 22 (62.9%), and remained same in 4 (11.4%). CONCLUSION: Simulation training shows promise in refining perceived learning needs. The results from this study offer insight into paramedics' self-identification of learning objectives and gaps pre-post simulation experiences. Understanding the underlying psychology of paramedics participating in simulation may help educators better understand how to guide reflection and continuous improvement.

Involvement of the neurokinin-2 receptor in airway smooth muscle stretch-activated contractions assessed in perfused intact bovine bronchial segments.

The airway response to deep inspirations (DIs) in asthmatics has been shown to be ineffective in producing bronchodilation and can even cause bronchoconstriction. However, the manner by which a DI is able to cause bronchoconstriction remains ambiguous. We sought to investigate the pathway involved in this stretch-activated contraction and whether this contraction is intrinsic to airway smooth muscle (ASM). In brief, intact bovine bronchial segments were dissected, and side branches were ligated and then mounted horizontally in an organ bath. Intraluminal pressure was measured under isovolumic conditions. Instantaneously opening and then closing the tap on a column of fluid 5 to 30 cm high evoked a sudden increase in intraluminal pressure (equivalent to the height of the column of fluid) followed by a stress relaxation response of the ASM. When tissues were stimulated with carbachol (10(-8) M) or serotonin (10(-7) M) for 10 min, and the consequent agonist-evoked pressure response was dissipated manually, the response to the same transmural stretch was accompanied by a slowly developing and prolonged increase in intraluminal pressure. This stretch-activated response was significantly diminished by the stretch-activated cation channel blocker gadolinium (10(-3) M), the L-type Ca2+ channel blockers nifedipine (2 x 10(-6) M), diltiazem (10(-5) M), and verapamil (10(-5) M), the sensory neurotoxin capsaicin (10(-5) M), and the neurokinin (NK)(2) receptor antagonists MEN 10376 ([Tyr(I),d-Trp(6,8,9),Lys(10)]-NKA(4-10)) (10(-5) M) and SR48968 (N-[(2S)-4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide) (3 x 10(-6) M). These results show the ability of isolated airways to exhibit stretch-activated contractions and suggest a role for stretch-activated cation channels, sensory afferent neurons, the neurotransmitter NKA, and L-type Ca(2+) channels in these isolated airway responses.

Cannabinoid hyperemesis syndrome presentation to the emergency department: A two-year multicentre retrospective chart review in a major urban area.

OBJECTIVE: Cannabinoid hyperemesis syndrome (CHS) is a paradoxical side effect of cannabis use. Patients with CHS often present multiple times to the emergency department (ED) with cyclical nausea, vomiting, and abdominal pain, and are discharged with various misdiagnoses. CHS studies to date are limited to case series. The objective was to examine the epidemiology of CHS cases presenting to two major urban tertiary care centre EDs and one urgent care centre over a 2-year period. METHODS: Using explicit variables, trained abstractors, and standardized abstraction forms, we abstracted data for all adults (ages 18 to 55 years) with a presenting complaint of vomiting and/or a discharge diagnosis of vomiting and/or cyclical vomiting, during a 2-year period. The inter-rater agreement was measured using a kappa statistic. RESULTS: We identified 494 cases: mean age 31 (+/-11) years; 36% male; and 19.4% of charts specifically reported cannabis use. Among the regular cannabis users (>three times per week), 43% had repeat ED visits for similar complaints. Moreover, of these patients, 92% had bloodwork done in the ED, 92% received intravenous fluids, 89% received antiemetics, 27% received opiates, 19% underwent imaging, 8% were admitted to hospital, and 8% were referred to the gastroenterology service. The inter-rater reliability for data abstraction was kappa=1. CONCLUSIONS: This study suggests that CHS may be an overlooked diagnosis for nausea and vomiting, a factor that can possibly contribute to unnecessary investigations and treatment in the ED. Additionally, this indicates a lack of screening for CHS on ED history, especially in quantifying cannabis use and eliciting associated symptoms of CHS.

Self-Inflicted Nailgun-Induced Penetrating Penile Injury: Case Report and Discussion.

Penetrating penile injuries occur mostly in industrial/work accidents, automobile accidents, or as a result of sexual curiosity and attempts at self-expression/mutilation. In this case report, the authors describe an accidental nailgun injury to the penis of a 46-year-old man. We discuss the management of such injuries in the emergency department, including the utility of a dorsal penile block for regional anesthesia. Although exceptionally rare, familiarity with penetrating lower urinary tract injuries may reduce their long-term repercussions on genitourinary and sexual health.

L-type Ca(2+) channels, Ca(2+)-induced Ca(2+) release, and BK(Ca) channels in airway stretch-induced contraction.

Resistance arteries constrict in response to mechanical stress. This response is myogenic in nature, and reliant on membrane depolarization, activation of L-type Ca(2+) channels, Ca(2+)-induced Ca(2+)-release and large conductance Ca(2+)-dependent K(+) channels (BK(Ca)). Airway smooth muscle is also affected by mechanical stress: a deep inspiration produces a bronchodilation in healthy individuals, but bronchoconstriction in moderate to severe asthmatics. In this study, our objective was to investigate the regulation of this airway stretch-activated contractile response (R(stretch)), and explore its similarities to the vascular myogenic response. Using a pharmacological approach in intact bovine bronchial segments cannulated horizontally in an organ bath, we showed the ability of carbachol (2-carbamoyloxyethyl-trimethyl-azanium), KCl, neurokinin-A, and U46619 (9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z, 13E-dien-1-oic acid) to generate R(stretch) in a concentration-dependent manner. R(stretch) was significantly reduced by nifedipine, ryanodine, and iberiotoxin, suggesting that it possesses characteristics similar to those of the vascular smooth muscle myogenic response, such as a role for membrane depolarization, L-type Ca(2+) channel, ryanodine receptors and BK(Ca) channel activation. This study demonstrates a novel role for the L-type Ca(2+) channel in airway smooth muscle and provides new insights into possible mechanisms regulating the deep inspiration-induced bronchoconstriction seen in asthmatics.