BackgroundJanus kinase 3 (JAK3) is a member of the membrane-associated non-receptor tyrosine kinase protein family and is considered predominantly expressed in hematopoietic cells. We previously identified JAK3 as a differentially expressed gene in granulosa cells (GC) of bovine preovulatory follicles. The present study aimed to further investigate JAK3 regulation, to identify protein binding partners and better understand its mode of action in bovine reproductive cells.ResultsGC were obtained from small follicles (SF), dominant follicles at day 5 of the estrous cycle (DF), and ovulatory follicles, 24 h following hCG injection (OF). RT-PCR analyses showed greatest expression of JAK3 in GC of DF, while JAK3 expression was downregulated in OF (P < 0.0001). In addition, there was a 5- and 20-fold reduction of JAK3 steady-state mRNA levels in follicular walls, respectively at 12 and 24 hours post-hCG as compared to 0 h (P < 0.05). Similarly, JAK3 expression was downregulated by the endogenous LH surge. These results were confirmed in western blot analysis showing weakest JAK3 protein amounts in OF as compared to DF. Yeast two-hybrid screening of a DF-cDNA library resulted in the identification of JAK3 partners in GC that were confirmed by co-immunoprecipitation and included leptin receptor overlapping transcript-like 1 (LEPROTL1), inhibin beta A (INHBA) and cyclin-dependent kinase inhibitor 1B (CDKN1B). In functional studies using bovine endometrial cells, JAK3 increased phosphorylation of STAT3 and cell viability, while the addition of JANEX-1 inhibited JAK3 actions.ConclusionThese results support a physiologically relevant role of JAK3 in follicular development and provide insights into the mode of action and function of JAK3 in reproductive tissues.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0280-5) contains supplementary material, which is available to authorized users.

BackgroundBuprenorphine is a potent lipophilic opioid analgesic that is largely used in the multimodal treatment of acute pain. Simbadol (buprenorphine hydrochloride) is the first and only FDA-approved high-concentration formulation of buprenorphine for use in cats. The aim of this study was to evaluate the analgesic efficacy of carprofen in combination with one of two commercial formulations of buprenorphine (Simbadol and Vetergesic, 1.8 mg/mL and 0.3 mg/mL, respectively) in dogs undergoing ovariohysterectomy. Twenty-four dogs were included in a randomized, prospective, controlled, clinical trial. Patients were randomly divided into 2 groups as follows. Dogs were premedicated with acepromazine (0.02 mg/kg) and either 0.02 mg/kg of Vetergesic or Simbadol intramuscularly (Vetergesic group – VG; Simbadol group – SG, respectively; n = 12/group). General anesthesia was induced with propofol and maintained with isoflurane in 100% oxygen. Carprofen (4.4 mg/kg SC) was administered after induction of anesthesia. Heart rate, respiratory rate, blood pressure, pulse oximetry, pain scores using the Glasgow Composite Pain Scale Short Form (CMPS-SF), sedation scores using a dynamic interactive visual analogue scale and adverse events were evaluated before and after ovariohysterectomy by an observer who was unaware of treatment administration. If CMPS-SF scores were ≥ 5/20, dogs were administered rescue analgesia (morphine 0.5 mg/kg IM). Statistical analysis was performed using linear mixed models and Fisher’s exact test (p < 0.05).ResultsPain and sedation scores and physiological parameters were not significantly different between treatments. Three dogs in VG (25%) and none in SG (0%) required rescue analgesia (p = 0.109). Adverse effects (i.e. vomiting and melena) were observed in two dogs in SG and were thought to be related to stress and/or nonsteroidal anti-inflammatory drug toxicity.ConclusionsThe administration of buprenorphine with carprofen preoperatively provided adequate postoperative analgesia for the majority of dogs undergoing OVH without serious adverse events. Prevalence of rescue analgesia was not significantly different between groups; however, it could be clinically relevant and explained by a type II error (i.e. small sample size). Future studies are necessary to determine if analgesic efficacy after Simbadol and Vetergesic is related to individual variability or pharmacokinetic differences.

cost 0.2 % to 58.01 % of the average monthly salary of the patient. In 2014, the least affordable drugs for patients with COPD were drugs from the inhaled corticosteroids group: Flixotide nebules, Nebufluzone and Pulmicort, the cost of which varied from 19.86% to 58.01%, which can be afforded only by patients with incomes above the average. The most affordable drug is a short-acting β 2-agonist-salbutamol (Ca.s. 0.43-15.70%). ConClusions: Ukraine faces a rather difficult situation for patients with COPD. Drugs recommended by GOLD are presented insufficiently, and a large number of drugs available in the market are not readily available to patients.

JAK3 is a member of the membrane‐associated non‐receptor tyrosine kinase protein family and is considered predominantly expressed in hematopoietic cells. We previously identified JAK3 as a differentially expressed gene in granulosa cells (GC) of bovine preovulatory follicles. This study aimed to further investigate JAK3 mRNA and protein regulation and to identify its binding partners in GC of bovine dominant follicles. GC were obtained from small follicles (SF), dominant follicles at day 5 of the estrous cycle (DF), and ovulatory follicles, 24 hours following hCG injection (OF). RT‐PCR analyses showed greatest expression of JAK3 in GC of DF, while the weakest expression was in OF (P < 0.0001). There was a 5‐ and 20‐fold reduction of JAK3 steady‐state mRNA levels in follicular walls, respectively at 12 and 24 hours post‐hCG as compared to 0 hour (P < 0.05). These results were confirmed in western blot analysis showing weakest JAK3 protein levels in OF as compared to DF. Yeast two‐hybrid screening of a DF‐cDNA library resulted in the identification of 23 JAK3 partners in GC. Moreover, the amount of phosphorylated STAT3 in GC was greatest in SF and DF as compared to OF while the opposite was observed for non‐phosphorylated STAT3. In functional studies using bovine endometrial cells, we discovered that phosphorylation of STAT3 (pSTAT3) in a bovine endometrial cell line was increased by JAK3 while inhibition of JAK3 by JANEX‐1 decreased the amount of pSTAT3. In the same study, we showed that JAK3 increased endometrial cell proliferation as well. We found a similar effect of JAK3 on STAT3 phosphorylation using an immortalized murine granulosa cell line. These results support a physiologically relevant role of JAK3 in follicular development and provide insights into the mode of action and function of JAK3 in reproductive tissues.Support or Funding InformationThis work was supported in part by internal funds from Université de Montréal to KN and by a Discovery Grant from Natural Sciences and Engineering Research Council of Canada (NSERC) to JGL.

moderate to severe asthma. Methods: Two literature reviews were conducted to retrieve economic evaluations (1) on moderate to severe asthma treatment and (2) on PM in asthma to identify key parameters for the development of the decision tree. The economic impact of PM testing to guide the choice of treatment for uncontrolled moderate to severe asthma can be assessed from a provincial Ministry of Health (MoH) or a societal perspective over a 1-year period. Asthma exacerbations were the main efficacy parameter considered and costs included were treatments, resource utilization, administration, follow-up and productivity loss. Values were extracted from literature and governmental publications. The model was tested in an applied context, using the blood type-E immunoglobulin (IgE) assay to guide treatment with omalizumab compared with no testing (omalizumab for all). Results: When tested, total cost reduction was -$8,811 and -$9,225 from a MoH and a societal perspective respectively for a total QALY gain of 0.06 per patient, which lead to a dominant strategy for IgE testing compared to no testing. According to deterministic analysis results, IgE testing remains a dominant strategy over no testing in all scenarios tested. However, parameters with the greatest impact on base-case ICURs were the prevalence of allergic asthma and the cost of omalizumab. ConClusions: The global economic model can help estimating on a similar basis the economic impact of several technologies using PM testing to guide the treatment of uncontrolled moderate to severe asthma.