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Abstract: Cannabidiol is the main nonpsychoactive component of marijuana. We examined the ability of in vivo and in vitro cannabidiol to interfere with the production of interleukin (IL)-12 and IL-10 by murine macrophages and to modulate macrophage chemotaxis. Cannabidiol added in vitro to peritoneal macrophages significantly increased IL-12 and decreased IL-10 production. The CB1 and CB2 receptor antagonists prevented this modulation. Macrophages from animals treated with cannabidiol at the dose of 30 mg kg−1 either orally or i.p. produced higher levels of IL-12 and lower levels of IL-10 in comparison to controls, and the CB receptor antagonists did not prevent these effects. Cannabidiol dose-dependently decreased fMLP-induced chemotaxis of macrophages, and the CB2 receptor antagonist prevented this decrease. [Copyright &y& Elsevier]

Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO signaling. We identified 2 pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding. [ABSTRACT FROM AUTHOR]

Abstract Objectives To evaluate immediate versus delayed surgical intervention on treatment outcomes in the management of congenital choanal atresia. Methods This study adhered to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines in reporting a systematic review of the literature. OVID Medline, EMBASE and Pubmed databases were searched using relevant key terms. Inclusion and exclusion criteria were designed to capture studies examining immediate versus delayed primary surgery for congenital choanal atresia. Timing of surgery was classified as immediate or delayed based on median age of intervention stratified by type of obstruction. Primary outcomes were primary treatment failure, respiratory function and mortality rates. Results A total of 2765 abstracts were identified and screened by 2 independent reviewers. Of the 688 articles reviewed in full text, 23 articles met the study criteria and were subjected to quality assessment. The full study assessment and quality control measures yielded 23 studies (representing 362 patients) for pooled patient-level analysis in the systematic review. Primary treatment failures occurred in 24.8% of patients that underwent immediate surgery and 42.6% of patients that underwent delayed surgery for bilateral choanal atresia (p = 0.01). There were no differences in mortality rates (5.6% vs 4.2%; p = 1.00) or qualitative measures of respiratory function. There were no difference in treatment outcomes for patients with unilateral choanal atresia (p > 0.05). Conclusions Through an analysis of pooled individual patient data, this systematic review of the literature demonstrated that there was significantly higher rates of treatment failure in patients that underwent delayed surgery for bilateral choanal atresia. Clinical trials and large prospective cohort studies investigating outcomes following immediate and delayed surgical intervention will provide further insight into treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The residency match is an important event in an aspiring physician's career. Otolaryngology -- Head and Neck Surgery (OTL-HNS) is a surgical specialty that has enjoyed high numbers of applicants to its residency programs. However, recent trends in Canada show a decline in first-choice applicants to several surgical fields. Factors thought to influence a medical student's choice include role models, career opportunities and work-life balance. The notion of perceived competitiveness is a factor that has not yet been explored. This study sought to compare competitiveness of OTL-HNS, as perceived by Canadian medical students to residency match statistics published yearly by CaRMS (Canadian Residency Matching Service), with the hope of informing future decisions of surgical residency programs. Methods: An electronic survey was created and distributed to all medical students enrolled in the 17 Canadian medical schools. After gathering demographic information, students were asked to rank what they perceived to be the five most competitive disciplines offered by CaRMS. They were also asked to rank surgical specialties from most to least competitive. Publically available data from CaRMS was then collected and analyzed to determine actual competitiveness of admissions to Canadian OTL-HNS residency programs. Results: 1194 students, from first to fourth year of medical school, completed the survey. CaRMS statistics over the period from 2008 to 2014 demonstrated that the five most competitive specialties were Plastic Surgery, Dermatology, Ophthalmology, Emergency Medicine and OTL-HNS. Among surgical disciplines, OTL-HNS was third most competitive, where on average 72% of students match to their first-choice discipline. When students were questioned, 35% ranked OTL-HNS amongst the top five most competitive. On the other hand 72%, 74% and 80% recognized Opthalmology, Dermatology and Plastic Surgery as being among the five most competitive, respectively. We found that fourth-year medical students were significantly more knowledgeable about the competitiveness of both OTL-HNS and Plastic Surgery compared to first-year students (p < 0.01). Conclusion: Overall, Canadian medical students may underestimate the competitiveness of OTL-HNS. Furthermore, competitiveness would appear to be a concept that resonates with medical students during the match process. [ABSTRACT FROM AUTHOR]

The present study reports thanatosis behavior in Hippocampus reidi seahorses. We observed two different types of tonic immobility during seahorse handling, both in the laboratory and in field studies. In the former, the seahorses assumed a stretched posture, and in the latter, pointed their heads towards their bellies and curled their tails in a spiral towards their abdomen. The displays lasted 124 ± 100 s ( n = 3) in the laboratory and 155 ± 7.07 s ( n = 5) in the field. Camouflage is the seahorses primary defense from predators and our observations suggest that thanatosis is a secondary strategy that could be more effective than retaliation or escaping predators, due to the fact that seahorses lack teeth and have limited swimming ability. The responses caused by fear occurred after manipulation, allowing for the conclusion that the seahorse H. reidi may use thanatosis as a secondary defense strategy under major stress events. [ABSTRACT FROM AUTHOR]

Trismus refers to any condition inducing limited mouth opening and may present as a result of acquired or congenital pathology. We present the case of a newborn who presented with severe, congenital trismus due to brainstem dysgenesis. We describe the course of his investigations, and a multidisciplinary approach to the management of his care and follow-up. To our knowledge, this is one of the earliest reported cases of congenital trismus attributable to brainstem dysgenesis. A literature review was conducted to provide an overview of the differential pathogenesis as it presents in congenital cases and discuss the complexity of managing congenital trismus due to brainstem dysgenesis in a neonate and infant. [ABSTRACT FROM AUTHOR]

This work analyzes an original parallel robot that consists of a set of non-coaxial discs rotating about parallel axes. The robot is specifically designed to make a tool like a plasma torch perform trajectories with sharp turns at controlled velocity. A typical task consists in cutting rectangular holes in plates using a plasma torch. An under determined inverse kinematics problem determines the motion of the motors that yields the desired motion of the end effector; it is solved by performing a pseudo-dynamic analysis with a general purpose multibody solver. Two different solution procedures are proposed; the corresponding results are compared and discussed. The locally optimal solution resulting from both approaches minimizes linear combinations of quadratic forms related to the weighted kinetic coenergy of the robot components. [ABSTRACT FROM AUTHOR]

Aim Muscle injuries and extensive exercise are associated with cyclo-oxygenase dependent formation of inflammatory prostaglandins. Since the effect of topical administration of non-steroidal anti-inflammatory drugs ( NSAIDs) on local cyclo-oxygenase is unknown, the present exploratory, open label, non-randomized study set out to measure exercise induced release of prostaglandins before and after epicutaneous administration of diclofenac. Methods Microdialysis was used to determine the local interstitial concentration of PGE2 and 8-iso- PGF2α as well as diclofenac concentrations in the vastus lateralis under rest, dynamic exercise and during recovery in 12 healthy subjects at baseline and after a treatment phase applying a total of seven plasters medicated with 180 mg of diclofenac epolamine over 4 days. Results At baseline PGE2 concentrations were 1169 ± 780 pg ml−1 at rest and 1287 ± 459 pg ml−1 during dynamic exercise and increased to 2005 ± 1126 pg ml−1 during recovery. After treatment average PGE2 concentrations were 997 ± 588 pg ml−1 at rest and 1339 ± 892 pg ml−1 during exercise. In contrast with the baseline phase no increase in PGE2 concentrations was recorded during the recovery period after treatment ( PGE2 1134 ± 874 pg ml−1). 8-iso- PGF2α was neither affected by exercise nor by treatment with diclofenac. Local and systemic concentrations of diclofenac were highly variable but comparable with previous clinical pharmacokinetic studies. Conclusions We can hypothesize an effect of topical diclofenac epolamine plaster on limiting the increase of local concentrations of the pro-inflammatory prostaglandin PGE2 induced in the muscle of healthy human subjects following standardized physical exercise. No effect of diclofenac treatment on 8-iso- PGF2α concentrations was observed, mainly since isoprostane is produced by a free radical-catalyzed lipid peroxidation mechanism independent of cyclo-oxygenases. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To review the outcomes of supraglottoplasty performed in children with severe laryngomalacia at a pediatric university teaching hospital and to determine if these outcomes are influenced by gender, age at time of supraglottoplasty, or medical comorbidities. Methods: Retrospective chart review of children who underwent supraglottoplasty for severe laryngomalacia between 2001 and 2010 at the Children's Hospital of Eastern Ontario in Ottawa, Canada. Statistical significance was obtained using 2-tailed Fisher's exact test. The outcome measures were resolution of laryngomalacia symptoms or persistence of laryngomalacia symptoms with or without additional surgery. Results: Among 26 post-primary supraglottoplasty patients, 46.2% had resolution and 53.8% had persistence, including 19.2% with partial improvement and 34.6% requiring revision supraglottoplasty and/or tracheostomy. Resolution was present in 35.7% of males and 58.3% of females (p =0.43); in 33.3% of all patients ≤2 months old and 52.9% of all patients >2 months old (p =0.43); and in 50.0% of non-comorbid patients ≤2 months old and 80.0% of non-comorbid patients >2 months old (p =0.52). 71.4% of persistence cases were found in comorbid patients. 83.3% of comorbid patients had persistence, compared to 28.6% of non-comorbid patients (p =0.008). Of the 3 patients with overlapping comorbid categories, 2 required at least 2 revision supraglottoplasties and ultimately required a tracheostomy. Conclusions: Persistence of laryngomalacia symptoms post-primary supraglottoplasty was not associated with gender or age at time of surgery, and was more commonly found in children with comorbidities. Patients with coexisting medical conditions appear to require more aggressive surgical management, beyond one revision supraglottoplasty. [Copyright &y& Elsevier]

Pediatric tonsillitis is encountered frequently across specialties, and while high quality guidelines exist, there is persistent evidence of care which is not evidence based, including antibiotic overprescribing and surgical practice variability. Quality indicators (QIs) can be utilized for initiatives to improve the quality of care and subsequent patient outcomes. We sought to develop pediatric tonsillitis QIs that are applicable across specialties and that cover aspects of both diagnosis and the spectrum of management options. A guideline-based approach to QI development was employed. Candidate indicators (CIs) were extracted from international guidelines deemed high quality by two reviewers and evaluated by an eleven-member expert panel consisting of otolaryngology – head & neck surgeons, a pediatrician and a family physician. The final QIs were selected utilizing a modified RAND/UCLA appropriateness methodology. Twenty-six CIs were identified after initial literature review. After the first round of evaluations, the panel agreed on thirteen candidate indicators as appropriate QIs. A subsequent expert panel meeting provided a platform to discuss areas of disagreement, discuss any recently published research, and to brainstorm additional CIs not identified from the guideline extraction. Following the second round of evaluations, the expert panel agreed upon sixteen QIs as appropriate measures of high-quality care. This study proposes sixteen QIs developed through a multidisciplinary lens to guide practitioners in the diagnosis and management of pediatric tonsillitis. These QIs can be used to improve transparency, accountability, and provide objective data to assist future quality improvement initiatives. [ABSTRACT FROM AUTHOR]

Recently, we have shown that the non-psychoactive cannabinoid compound cannabidiol (CBD) induces apoptosis of glioma cells in vitro and tumor regression in vivo. The present study investigated a possible involvement of caspase activation and reactive oxygen species (ROS) induction in the apoptotic effect of CBD. CBD produced a gradual, time-dependent activation of caspase-3, which preceded the appearance of apoptotic death. In addiction, release of cytochrome c and caspase-9 and caspase-8 activation were detected. The exposure to CBD caused in glioma cells an early production of ROS, depletion of intracellular glutathione and increase activity of glutathione reductase and glutathione peroxidase enzymes. Under the same experimental condition, CBD did not impair primary glia. Thus, we found a different sensitivity to the anti-proliferative effect of CBD in human glioma cells and non-transformed cells that appears closely related to a selective ability of CBD in inducing ROS production and caspase activation in tumor cells.

We evaluated the ability of cannabidiol (CBD) to impair the migration of tumor cells stimulated by conditioned medium. CBD caused concentration-dependent inhibition of the migration of U87 glioma cells, quantified in a Boyden chamber. Since these cells express both cannabinoid CB1 and CB2 receptors in the membrane, we also evaluated their engagement in the antimigratory effect of CBD. The inhibition of cell was not antagonized either by the selective cannabinoid receptor antagonists SR141716 (CB1) and SR144528 (CB2) or by pretreatment with pertussis toxin, indicating no involvement of classical cannabinoid receptors and/or receptors coupled to Gi/o proteins. These results reinforce the evidence of antitumoral properties of CBD, demonstrating its ability to limit tumor invasion, although the mechanism of its pharmacological effects remains to be clarified.

Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC(50) of 25 microM. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and alpha-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.

In the present work we investigated on rat splenocytes long-term interactions between opioid and cannabinoid drugs in terms of a common regulation of cAMP intracellular pathway. Both morphine and the synthetic cannabinoid compound CP-55,940 inhibited in a concentration-dependent manner the intracellular cAMP level in splenocytes stimulated by forskolin. The in vitro combination of submaximal concentrations of the two drugs did not yield any additive effect on the inhibition induced by the two drugs. In splenocytes taken from rats chronically treated with CP-55,940 (0.2 mg/kg i.p., twice a day for 4.5 days) or morphine (5 mg/kg s.c., twice a day for 6.5 days) and in vitro exposed to either CP-55,940 or morphine, it was found a desensitisation and cross-desensitisation to the inhibitory effects on cAMP production induced by the two drugs. Binding experiments on the cannabinoid receptors level in spleen coronal sections after in vivo chronic administration of morphine, revealed that there was no changes in the binding of [H3]-CP-55,940. Thus, these results strengthen the hypothesis of cAMP as part of the common intracellular pathway shared by opiates and cannabinoids at immune cell level.

In the present work, we investigated in the rat the possibility of functional interaction between opiate and cannabinoid systems at immune level comparatively with the central nervous system (CNS). Moderate analgesic doses of the synthetic cannabinoid compound CP-55,940 (0.2 mg/kg, i.p.) and morphine (5 mg/kg, s.c.) significantly inhibited the ConA-induced splenocyte proliferation and natural killer (NK) cytolytic activity. The acute co-administration of the two drugs resulted in an enhancement of antinociception while they did not yield any additive inhibition of the immune parameters. The CB1 cannabinoid receptor antagonist N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 3 mg/kg, i.p.) and the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethhyl bicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 3 mg/kg, i.p.) did not block the central nor the immune effects of morphine; similarly, the opioid receptor antagonist naloxone did not attenuate CP-55,940-induced effects. Animals tolerant to CP-55,940-induced (0.2 mg/kg, i.p.; twice a day for 4 days) or morphine-induced analgesia (5 mg/kg, s.c.; twice a day for 6 days) also developed tolerance to their acute immunosuppressive effects. Concomitantly, animals became cross-resistant to the immunosuppressive effects while an asymmetric cross-tolerance developed for analgesia. Our data demonstrated the existence of an interaction between cannabinoids and opiates at the immune level that differs from the interaction present in the CNS.