The effectiveness of bone anchored maxillary protraction (BAMP) in the management of class III skeletal malocclusion in children aged 11-14 years compared with an untreated control group: A multicentre two-arm parallel randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of bone anchored maxillary protraction (BAMP) in the management of class III skeletal malocclusion in children aged 11-14 years compared with an untreated control group in terms of perceived need for orthognathic surgery, skeletal and dental change, and psychological impact. DESIGN: A multicentre two-armed parallel randomised controlled trial. SETTING: Six UK hospital orthodontic units. METHODS: A total of 57 patients were randomly allocated into either the BAMP group (BAMPG) (n = 28) or a no treatment control group (CG) (n = 29). OUTCOMES: Data collection occurred at registration (DC1),18 months (DC2) and 3 years (DC3), where skeletal and dental changes were measured from lateral cephalograms and study models. Oral Aesthetic Subjective Impact Score (OASIS) and Oral Quality of Life (OHQOL) questionnaires were used to assess the psychological impact of treatment. RESULTS: The mean age was 12.9 ± 0.7 years and 12.6 ± 0.9 years in the BAMPG and CG, respectively. At DC2, the BAMPG achieved a class III ANB improvement of +0.6° compared with -0.7° in the CG (P = 0.004). The overjet improvement was +1.4 mm for the BAMPG and -0.2 mm for the CG (P = 0.002). There was no evidence of any other group differences for the other skeletal or dental cephalometric outcomes (P > 0.05) or the questionnaire data (OASIS P = 0.10, OHQOL P = 0.75). At DC2, the 18-month follow-up, 22% of the BAMPG achieved a positive overjet. At the 3-year follow-up (DC3), fewer patients in the BAMPG were perceived to need orthognathic surgery (48%) compared with 75% of patients in the CG (P = 0.04), with an odds ratio of 0.31 (95% confidence interval = 0.10-0.95). CONCLUSION: The BAMP technique did not show any social or psychological benefits; however, the skeletal class III improvement in ANB and the overjet change were sufficient to reduce the perceived need for orthognathic surgery by 27% compared with the CG.

Minimizing pain in deer antler removal: Local anaesthetics in ZnO nanoparticle based collagen dressings as a promising solution.

Antler removal in deer is a common practice for various purposes, including meat production and traditional medicine. However, the current industry practice using lidocaine as a local anesthetic has limitations, such as short duration of action and the potential for postoperative infections. In this study, we investigated the performance of a ZnO collagen nanocomposites loaded with local anesthetics to improve wound management and alleviate pain associated with antler removal in red deer. The research involved the preparation of collagen nanocomposites with local anesthetics and testing the drug release rates using in vitro drug release tests. Pharmacokinetic analysis was performed to evaluate the total drug release from the collagen matrix in red deer after velvet removal. Additionally, the analgesic efficacy of these collagen nanocomposite dressings was assessed after antler removal in red deer. Functionalized ZnO nanoparticles were incorporated into collagen fibers to enhance their mechanical stability and prolong drug release. The developed collagen nanocomposites aimed to slowly release local anesthetics and promote wound healing. The findings of this research could have significant implications for improving the pain management and wound healing associated with antler removal in deer. The results obtained from the in vitro drug release tests, pharmacokinetic analysis, and analgesic efficacy evaluations provide valuable insights into the understanding and development of novel approaches for antler removal procedures in red deer. The findings contribute to the advancement of knowledge in this field and lay the foundation for future implementation of improved techniques and protocols for antler removal.

Pain Mitigation Strategies for Disbudding in Goat Kids.

Pain mitigation strategies for disbudding in goat kids have gained significant attention in recent years because of growing concerns for animal welfare. Disbudding, the removal of horn buds in young goats, is a common practice to enhance safety and manage herd dynamics. However, the procedure will cause pain and distress if not managed effectively. This review covers the array of pain mitigation techniques currently available for disbudding, including the efficacy of these strategies in reducing pain and stress during the disbudding process, with specific attention to the potential toxicity associated with local anesthetics. The current best practice for disbudding on the farm suggests sedation/analgesia with an alpha-2 agonist, the placement of a two-point cornual nerve block, and then an NSAID for postoperative pain. In conclusion, this review offers recommendations for future research directions aimed at enhancing the welfare of young goats subjected to the disbudding procedure. These suggestions hold the promise of fostering significant improvements in the overall well-being of these animals.

Pharmacokinetics and efficacy of a novel long-acting bupivacaine formulation for cornual nerve block in calves.

Local anesthetics are commonly used in farm animals to provide analgesia for painful procedures but can cause adverse effects at high systemic concentrations. The pharmacokinetics and efficacy of a long-acting sucrose acetate isobutyrate (SAIB) bupivacaine formulation following cornual nerve block in calves were compared to lidocaine. Fourteen calves were randomly assigned to one of the treatment groups (i) 5% Bupivacaine-SAIB (BUP-SAIB), n = 7; or (ii) 2% lidocaine (LID), n = 7. Cornual nerve block was performed, and duration of effective analgesia was evaluated by nociceptive threshold testing using a hand-held pressure algometer. Blood samples were collected at various time points and plasma concentrations were analyzed by HPLC. Pharmacokinetic parameters were calculated using a non-compartmental model. The mechanical nociceptive thresholds showed that the novel formulation could desensitize the skin around the horn bud for 18.77 ± 8.88 h (range 8-36 h), compared to 0.79 ± 0.34 h (range 0.5-1.5 h) with lidocaine. The mean maximum plasma concentration (Cmax) of bupivacaine was 152.03 (SD 37.34) ng/mL and its Tmax was 0.39 (SD 0.13) h. The half-life of elimination was 32.79 ± 11.00 h and the rate of clearance was 0.12 ± 0.03 L h-1. No toxicity signs were seen after treatment in either group. The novel formulation produced long-lasting analgesia of several times greater duration than that produced by lidocaine. This study showed that the safety and efficacy of the SAIB formulation justifies further studies in a larger population of animals.

Effect of combinations of morphine, dexmedetomidine and maropitant on the electroencephalogram in response to acute electrical stimulation in anaesthetized dogs.

This study was conducted to compare the efficacy of combinations of morphine, dexmedetomidine and maropitant in preventing the changes in electroencephalographic (EEG) indices of nociception in anaesthetized dogs subjected to a noxious electrical stimulus. In a crossover study, eight healthy adult dogs were randomly allocated to four groups: Mor: morphine 0.6 mg/kg; Dex + Mor: morphine 0.3 mg/kg + dexmedetomidine 5 µg/kg; Maro + Mor: morphine 0.3 mg/kg + maropitant 1 mg/kg; and Dex + Maro + Mor: morphine 0.2 mg/kg + dexmedetomidine 3 µg/kg + maropitant 0.7 mg/kg. Following intramuscular administration of test drugs in a minimal anaesthesia model, a supramaximal electrical stimulus (50 V at 50 Hz for 2 s) was applied and the EEG data were recorded. There were significant increases (p < .05) in the poststimulus median frequency (F50) only in groups Mor and Maro + Mor. Dex + Mor group had a significantly lower change in F50 and F95 compared to all other treatment groups. There was no correlation of the changes in EEG frequencies with blood plasma concentration of the drugs during and after noxious stimulation. Combination of dexmedetomidine and morphine was most effective in abolishing the changes in EEG indices in response to a noxious stimulus indicating a supra-additive interaction between these two drugs.

Pharmacokinetics of morphine in combination with dexmedetomidine and maropitant following intramuscular injection in dogs anaesthetized with halothane.

The purpose of this study was to evaluate the pharmacokinetics of morphine in combination with dexmedetomidine and maropitant injected intramuscularly in dogs under general anaesthesia. Eight healthy dogs weighing 25.76 ± 3.16 kg and 3.87 ± 1.64 years of age were used in a crossover study. Dogs were randomly allocated to four groups: (1) morphine 0.6 mg/kg; (2) morphine 0.3 mg/kg + dexmedetomidine 5 µg/kg; (3) morphine 0.3 mg/kg + maropitant 1 mg/kg; (4) morphine 0.2 mg/kg + dexmedetomidine 3 µg/kg + maropitant 0.7 mg/kg. Blood samples were collected before, 15 and 30 min, and 1, 2, 3 4, 6 and 8 hr after injection of the test drugs. Plasma concentration of the drugs was determined by liquid chromatography-mass spectrometry. The elimination half-life (T1/2 ) of morphine was higher and the clearance rate (CL) was lower when combined with dexmedetomidine (T1/2  = 77.72 ± 20.27 min, CL = 119.41 ± 23.34 ml kg-1  min-1 ) compared to maropitant (T1/2  = 52.73 min ± 13.823 ml kg-1  min-1 , CL = 178.57 ± 70.55) or morphine alone at higher doses (T1/2  = 50.53 ± 12.55 min, CL = 187.24 ± 34.45 ml kg-1  min-1 ). Combining morphine with dexmedetomidine may increase the dosing interval of morphine and may have a clinical advantage.

Evaluation of analgesic interaction between morphine, dexmedetomidine and maropitant using hot-plate and tail-flick tests in rats.

OBJECTIVE: To determine if the combinations of morphine, dexmedetomidine and maropitant enhance the analgesic effect and decrease the dose of individual drugs in rats subjected to noxious thermal stimulation with hot-plate and tail-flick tests. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: A total of 96 male Sprague-Dawley rats. METHODS: The rats were randomly assigned to the following groups: 1) morphine (3 mg kg-1; Mor); 2) dexmedetomidine (10 µg kg-1; Dex); 3) maropitant (20 mg kg-1; Maro); 4) morphine (1.5 mg kg-1) + dexmedetomidine (5 µg kg-1; Mor + Dex); 5) dexmedetomidine (5 µg kg-1) + maropitant (10 mg kg-1; Dex + Maro); 6) morphine (1.5 mg kg-1) + maropitant (10 mg kg-1; Mor + Maro); 7) morphine (1 mg kg-1) + dexmedetomidine (3.5 µg kg-1) + maropitant (6.5 mg kg-1; Mor + Dex + Maro); and 8) normal saline (0.5 mL; saline), all injected intravenously. The tail-flick and hot-plate tests were performed before and 5, 15, 30, 45, 60, 90 and 120 minutes after the injection of the drugs. These variables were analysed with the effect-time area under the curve (AUC) analysis and a mixed linear model. RESULTS: Data were analysed in 94 rats. The rank order of the total analgesic effects of the treatment groups shown by AUC analysis was found to be Mor > Maro + Mor > Dex + Mor > Dex > Maro > Dex + Maro + Mor > Dex + Maro > saline for the hot-plate test, and Maro + Mor > Mor > Dex + Mor > Dex + Maro + Mor > Maro > Dex > Dex + Maro > saline for the tail-flick test. The mixed model analysis showed a significant difference between latencies of the group morphine + maropitant versus all other treatment groups in the tail-flick test (p < 0.0001) and morphine versus saline in the hot-plate test (p < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Morphine and maropitant appeared to show a supra-additive effect for analgesia in the tail-flick test. Clinical trials should be conducted to establish its use in treating pain.

Investigation of percentage changes in pulse wave transit time induced by mini-fluid challenges to predict fluid responsiveness in ventilated dogs.

OBJECTIVE: To investigate whether percentage changes in pulse wave transit time (PWTT%Δ) induced by mini-fluid challenges predict fluid responsiveness in mechanically ventilated anesthetized dogs. DESIGN: Prospective experimental trial. SETTING: University teaching hospital. ANIMALS: Twelve Harrier hounds. INTERVENTION: Each dog was anesthetized with propofol and isoflurane after premedication with acepromazine, mechanically ventilated, and had a fluid challenge. This was repeated 4 weeks later. The fluid challenge, 10 mL/kg of colloid administration over 13 minutes, consisted of 3 intermittent mini-fluid challenges (1 mL/kg of each over a minute) with a minute interval, and the remaining colloid administration (7 mL/kg) over 7 minutes. MEASUREMENTS AND MAIN RESULTS: Percentage change in velocity time integral of pulmonary arterial flow by echocardiography was calculated as an indication of change in stroke volume. Fluid responsiveness was defined as percentage change in velocity time integral ≥ 15% after 10 mL/kg colloid. Dogs responded on 14 fluid challenges and did not on 10. After 1, 2, 3, and 10 mL/kg of fluid challenge, PWTT%Δ1, 2, 3, 10 were measured. Receiver operator characteristic (ROC) curves were generated and areas under ROC curve were calculated for PWTT%Δ1, 2, 3 . A gray zone approach was used to identify the clinically inconclusive range. The area under the ROC curve for PWTT%Δ3 was 0.91 (P = 0.001). Cutoff value for PWTT%Δ3 was -2.5% (sensitivity: 86%, specificity: 90%). The gray zone for PWTT%Δ3 was identified as between -2.9% to -1.9% for which fluid responsiveness could not be predicted reliably in 6 out of 24 fluid challenges. CONCLUSIONS: In mechanically ventilated anesthetized dogs given a mini-fluid challenge of 3 mL/kg of colloid, PWTT%Δ could predict fluid responsiveness although the gray zone should be considered.

Glucocorticoids affect bone mineral density and bone remodelling in OVX sheep: A pilot study.

The aim of this study was to validate the combination of ovariectomy and glucocorticoid treatment in sheep as a large animal model for osteoporosis by measuring the concentration of specific biomarkers in the blood of the sheep and measuring bone loss over five months. Aged Merino ewes were randomly allocated into four groups: control, ovariectomy (OVX), and two OVX groups receiving glucocorticoids-one group once-monthly for five months (OVXG), and the other for two months followed by no treatment for three months (OVXG2). Parameters measured were biochemical markers of bone turnover, areal bone mineral density, volumetric bone mineral density, and total and trabecular bone parameters. Ovariectomy increased the concentrations of bone resorption marker C-terminal telopeptides of type 1 collagen (CTx-1) and bone turnover marker serum osteocalcin (OC) concentrations in the OVX group compared to control sheep. The combination of ovariectomy and glucocorticoid treatment increased the concentrations of CTx-1 and decreased serum OC concentrations in the OVXG group compared to OVXG2. Femur and lumbar spine bone density were lower in experimentally treated groups when compared with the control group. Total and trabecular vBMD in the proximal tibia were significantly lower in the treatment groups when compared with the control group. A significant negative correlation between femoral bone density and CTx-1 was found. The results of this study suggest that the combination of OVX and glucocorticoids induces bone loss in a short period of time in sheep.

Toxicity and Pharmacokinetic Studies of Lidocaine and Its Active Metabolite, Monoethylglycinexylidide, in Goat Kids.

This study determined the convulsant plasma concentrations and pharmacokinetic parameters following cornual nerve block and compared the results to recommend a safe dose of lidocaine hydrochloride for goat kids. The plasma concentrations of lidocaine and monoethylglycinexylidide (MGX) were quantified using liquid chromatography-mass spectrometry. A total dose of 7 mg/kg body weight (BW) was tolerated and should therefore be safe for local and regional anesthesia in goat kids. The mean plasma concentration and mean total dose that produced convulsions in goat kids were 13.59 ± 2.34 µg/mL and 12.31 ± 1.42 mg/kg BW (mean ± S.D.), respectively. The absorption of lidocaine following subcutaneous administration was rapid with Cmax and Tmax of 2.12 ± 0.81 µg/mL and 0.33 ± 0.11 h, respectively. The elimination half-lives (t½λz) of lidocaine hydrochloride and MGX were 1.71 ± 0.51 h and 3.19 ± 1.21 h, respectively. Injection of 1% lidocaine hydrochloride (0.5 mL/site) was safe and effective in blocking the nerves supplying horn buds in goat kids.

Systems-based approaches enable identification of gene targets which improve the flavour profile of low-ethanol wine yeast strains.

Metabolic engineering has been vital to the development of industrial microbes such as the yeast Saccharomyces cerevisiae. However, sequential rounds of modification are often needed to achieve particular industrial design targets. Systems biology approaches can aid in identifying genetic targets for modification through providing an integrated view of cellular physiology. Recently, research into the generation of commercial yeasts that can produce reduced-ethanol wines has resulted in metabolically-engineered strains of S. cerevisiae that are less efficient at producing ethanol from sugar. However, these modifications led to the concomitant production of off-flavour by-products. A combination of transcriptomics, proteomics and metabolomics was therefore used to investigate the physiological changes occurring in an engineered low-ethanol yeast strain during alcoholic fermentation. Integration of 'omics data identified several metabolic reactions, including those related to the pyruvate node and redox homeostasis, as being significantly affected by the low-ethanol engineering methodology, and highlighted acetaldehyde and 2,4,5-trimethyl-1,3-dioxolane as the main off-flavour compounds. Gene remediation strategies were then successfully applied to decrease the formation of these by-products, while maintaining the 'low-alcohol' phenotype. The data generated from this comprehensive systems-based study will inform wine yeast strain development programmes, which, in turn, could potentially play an important role in assisting winemakers in their endeavour to produce low-alcohol wines with desirable flavour profiles.

Pharmacokinetics of Salicylic Acid Following Intravenous and Oral Administration of Sodium Salicylate in Sheep.

The pharmacokinetics of salicylic acid (SA) in sheep was evaluated following intravenous (IV) and oral administration of sodium salicylate (sodium salt of salicylic acid) at different doses. Six healthy sheep were administered sodium salicylate (SS) IV at doses of 10, 50, 100 and 200 mg/kg body weight and another six sheep were drenched with 100 and 200 mg/kg of SS orally. Both studies were randomised crossover trials. A one-week washout period between each treatment was allowed in both studies. Blood samples were collected at 0, 15, 30 min and 1, 2, 4 and 6 h after IV and oral SS administrations. Plasma SA concentrations were determined using high-performance liquid chromatography (HPLC) with diode array detection method. Pharmacokinetic variables were calculated in a non-compartmental model. The elimination half-life (T1/2 el) of SA after IV administration of 200 mg/kg SS was 1.16 ± 0.32 h. Mean bioavailability of SA was 64%, and mean T1/2 el was 1.90 ± 0.35 h, after 200 mg/kg of oral SS. The minimum plasma SA concentration (16.8 µg/mL) reported to produce analgesia in humans was achieved after IV administration of 100 and 200 mg/kg SS in sheep for about 0.17 h in this study. Experiments on pharmacokinetic⁻pharmacodynamics modelling are required to determine the actual effective plasma concentration range of SA in sheep.

A Novel Approach to Isolating Improved Industrial Interspecific Wine Yeasts Using Chromosomal Mutations as Potential Markers for Increased Fitness.

Wine yeast breeding programs utilizing interspecific hybridization deliver cost-effective tools to winemakers looking to differentiate their wines through the development of new wine styles. The addition of a non-Saccharomyces cerevisiae genome to a commercial wine yeast can generate novel phenotypes ranging from wine flavor and aroma diversity to improvements in targeted fermentation traits. In the current study we utilized a novel approach to screen isolates from an evolving population for increased fitness in a S. cerevisiae × S. uvarum interspecific hybrid previously generated to incorporate the targeted phenotype of lower volatile acidity production. Sequential grape-juice fermentations provided a selective environment from which to screen isolates. Chromosomal markers were used in a novel approach to identify isolates with potential increased fitness. A strain with increased fitness relative to its parents was isolated from an early timepoint in the evolving population, thereby minimizing the risk of introducing collateral mutations and potentially undesirable phenotypes. The evolved strain retained the desirable fermentation trait of reduced volatile acidity production, along with other winemaking traits of importance while exhibiting improved fermentation kinetics.

Evaluation of pulse pressure variation and pleth variability index to predict fluid responsiveness in mechanically ventilated isoflurane-anesthetized dogs.

OBJECTIVE: To evaluate whether pulse pressure variation (PPV) and pleth variability index (PVI) are more accurate than central venous pressure (CVP) for predicting fluid responsiveness in mechanically ventilated isoflurane-anesthetized dogs after premedication with acepromazine. DESIGN: Prospective experimental trial. SETTING: University teaching hospital. ANIMALS: Twelve Harrier hound dogs. INTERVENTIONS: Each dog was anesthetized and had a fluid challenge performed. This was repeated 4 weeks later for a total of 24 fluid challenges. After premedication with intramuscular acepromazine, anesthesia was induced with propofol and maintained with isoflurane. The dogs were mechanically ventilated with constant settings. The fluid challenge consisted of 10 mL/kg of 6% hydroxyethyl starch intravenously over 13 minutes. MEASUREMENTS AND MAIN RESULTS: Before and after the fluid challenge, PPV, PVI, CVP, and other hemodynamics were recorded. Change in velocity time integral of pulmonary arterial blood flow by echocardiography was calculated as an indication of change in stroke volume. A fluid responder was defined as an increase in velocity time integral ≥ 15%. Receiver operator characteristic (ROC) curves were used to determine cutoff values. Areas under ROC curve were calculated and compared. Dogs responded on 14 fluid challenges and did not on 10. Cutoff values for PPV and PVI were 11% (sensitivity 79%; specificity 80%) and 9.3% (sensitivity 86%; specificity 70%), respectively. The areas under the ROC curve of PPV [0.85, 95% confidence interval (CI): 0.70-1.00, P = 0.038] and PVI (0.84, 95% CI: 0.68-1.00, P = 0.043) were significantly higher than CVP (0.56, 95% CI: 0.32-0.81). CONCLUSIONS: PPV and PVI predicted fluid responsiveness more accurately than CVP and may be useful to guide fluid administration in mechanically ventilated isoflurane-anesthetized dogs after premedication with acepromazine.

Comparison of electroencephalographic changes in response to acute electrical and thermal stimuli with the tail flick and hot plate test in rats administered with opiorphin.

BACKGROUND: The objective of this study was to compare the changes in the electroencephalogram (EEG) in response to noxious stimuli with tail flick and hot plate responses of rats administered opiorphin. METHODS: Female Sprague -Dawley rats (n = 8 per group) randomly received intravenous (IV) injection of morphine (1 mg/kg,) or opiorphin (2 mg/kg,) or saline (0.5 ml,) in each of the three testing methods (EEG, tail flick and hot plate). Each type of test (n = 24 per test) was conducted in different population of rats on separate occasions. The tail flick and hot plate latencies were recorded until 5 min after test drug administration to conscious rats. The EEG was recorded in anaesthetised rats subjected to noxious thermal and electrical stimuli after test drug administration. At the end of 5 min in each of the testing methods rats were administered naloxone subcutaneously (SC) (1 mg/kg) and the test procedure was repeated. RESULTS: There was no significant increase in the median frequency and spectral edge frequency (F50 & F95) of EEG, indicators of nociception, of morphine and opiorphin groups after noxious stimulation. Noxious stimuli caused a significant increase in both F50 and F95 of the saline group. An injection of naloxone significantly increased the F50, thus blocking the action of both opiorphin and morphine. There was a significant increase in the tail flick latency after administration of opiorphin and morphine as compared to the baseline values. Rats of morphine group spent significantly longer on the hot plate when compared to those of the opiorphin and saline groups. There was no significant difference in the hot plate latencies of opiorphin and saline groups. CONCLUSION: The results of this study suggest that the analgesic effect of opiorphin occurs at the spinal level and it is not as effective as morphine at supraspinal level. It may be due to rapid degradation of opiorphin or limited ability of opiorphin to cross the blood brain barrier or a higher dose of opiorphin is required for its action in the brain. Pharmacokinetic/pharmacodynamics studies along with in vivo penetration of opiorphin in the cerebrospinal fluid are required for further evaluation of opiorphin analgesia.

Sustained-Release Injectable Hydrogel Formulations for Administration of Sodium Salicylate in Broiler Chickens.

We developed injectable hydrogels for the slow release of analgesic drugs in birds as an in vivo model of pharmacokinetics in wild avian species. Hydrogels loaded with sodium salicylate (NaSA) were injected subcutaneously in Ross broiler chickens. The hydrogels were made by dissolving sodium alginate and NaSA in water at 2 different concentrations (low, LALG; high, HALG) and then adding calcium chloride. In vitro drug release studies were performed by swelling the hydrogels in water and analyzing serial samples by ultraviolet-visible (UV-Vis) spectroscopy. Dried hydrogel films of the same formulations of the two alginate concentrations then were dissolved in sterile water for the in vivo pharmacokinetic study conducted in 18 chickens divided into 3 groups of 6 birds. Each of the 2 resultant NaSA hydrogel solutions were filtered with 0.2-µm syringe filters before injecting at a NaSA dose of 150 mg/kg SC in the respective LALG or HALG groups. The control group was injected SC with the same dose of NaSA dissolved in water. Pharmacokinetics parameters calculated by the compartmental and noncompartmental approaches were compared among the 3 groups by the Kruskal-Wallis test. Results of in vitro studies showed that both hydrogels released 80% of the drug during the first 3.5 hours. Results of the pharmacokinetic study indicated that NaSA concentrations remained above the minimum effective concentration (MEC) for analgesia in humans for 24 ± 8.9 (LALG) to 26 ± 4 (HALG) hours for the hydrogel formulations compared to 10 ± 5.6 hours for the aqueous formulation. These hydrogel formulations may have potential in providing long-term analgesia in avian species, but need further evaluation with pharmacodynamic or pharmacokinetic/pharmacodynamic modeling studies.

Effect of choline chloride premedication on xylazine-induced hypoxaemia in sheep.

OBJECTIVE: To determine the anti-inflammatory efficacy of choline in vivo and in vitro and to investigate the anti-inflammatory mechanisms of choline. STUDY DESIGN: Randomized, controlled studies. ANIMALS: In vivo trials used 16 Romney sheep. In vitro experiments utilized RAW 264.7 mouse macrophage cells. METHODS: Hypoxaemia induced in 16 sheep by intravenous (IV) injection of 50 µg kg-1 xylazine, an α-2 agonist, was measured in sheep at 0, 1 and 4 minutes using arterial blood gas analysis with and without 50 mg kg-1 IV choline chloride premedication. Cell culture studies used enzyme-linked immunosorbent assay to measure the release of tumour necrosis factor (TNF-α) from lipopolysaccharide (LPS) stimulated macrophages with and without choline chloride premedication. TNF-α release was compared to thalidomide suppressed and untreated cells. RESULTS: Choline premedication in sheep mitigated a reduction in arterial partial pressure of oxygen (PaO2) but did not prevent development of clinically significant hypoxaemia. Decrease in mean PaO2 of choline treated sheep was 6.36 kPa (47.7 mmHg) compared to 9.81 kPa (73.6 mmHg) in control sheep. In vitro studies demonstrate that choline administered concurrent with LPS activation did not significantly suppress TNF-α expression but that treatment of cells with choline 10 minutes prior to LPS activation did significantly suppress TNF-α expression. Choline pretreated cells expressed 23.99 ± 4.52 ng mg-1 TNF-α while LPS only control cells expressed 33.83 ± 3.20 ng mg-1. CONCLUSIONS: Choline is able to prevent macrophage activation in vitro when administered prior to LPS activation and may reduce hypoxaemia in sheep developing pulmonary oedema after xylazine administration. This effect requires premedication with choline. CLINICAL RELEVANCE: Pharmacological manipulation of autonomic inflammatory responses holds promise for the treatment of inflammation. However, the complex cellular mechanisms involved in this reflex means that an adequate therapy should approach multiple pathways and mechanisms of the inflammatory response.

Whole transcriptome RNAseq analysis of Oenococcus oeni reveals distinct intra-specific expression patterns during malolactic fermentation, including genes involved in diacetyl metabolism.

We report the first whole transcriptome RNAseq analysis of the wine-associated lactic acid bacterium Oenococcus oeni using a combination of reference-based mapping and de novo transcript assembly in three distinct strains during malolactic fermentation in Cabernet Sauvignon wine. Two of the strains (AWRIB551 and AWRIB552) exhibited similar transcriptomes relative to the third strain (AWRIB419) which was dissimilar by comparison. Significant intra-specific variation for genes related to glycolysis/gluconeogenesis, purine metabolism, aminoacyl-tRNA biosynthesis, ABC transporters and phosphotransferase systems was observed. Importantly, thirteen genes associated with the production of diacetyl, a commercially valuable aroma and flavour compound, were also found to be differentially expressed between the strains in a manner that correlated positively with total diacetyl production. This included a key strain-specific gene that is predicted to encode a l-lactate dehydrogenase that may enable l-lactic acid to be utilised as a precursor for the production of diacetyl. In conjunction with previous comparative genomic studies of O. oeni, this study progresses the understanding of genetic variations which contribute to the phenotypes of this industrially-important bacterium.

Spatiotemporal Mapping Techniques Show Clozapine Impairs Neurogenic and Myogenic Patterns of Activity in the Colon of the Rabbit in a Dose-Dependent Manner.

Background: Clozapine, an antipsychotic used in treatment-resistant schizophrenia, has adverse gastrointestinal effects with significant associated morbidity and mortality. However, its effects on defined patterns of colonic contractile activity have not been assessed. Method: We used novel radial and longitudinal spatiotemporal mapping techniques, combined with and monitoring of ambient lumen pressure, in ex vivo preparations of triply and of singly haustrated portions of rabbit colon. We identified the contractile patterns of mass peristalses, fast phasic, and ripple contractions and directly qualified the effects of clozapine, at concentrations of 10 µmol/L, 20 µmol/L, and 30 µmol/L, and of norclozapine, the main metabolite of clozapine, on contractile patterns. The effects of carbachol, serotonin and naloxone on clozapine-exposed preparations were also determined. Tetradotoxin was used to distinguish neurogenic from myogenic contractions. Results: At 10 µmol/L, clozapine temporarily abolished the longitudinal contractile components of mass peristalsis, which on return were significantly reduced in number and amplitude, as was maximal mass peristaltic pressure. These effects were reversed by carbachol (1 µmol/L) and to some extent by serotonin (15 µmol/L). At 10 µmol/L, myogenic ripple contractions were not affected. At 20 µmol/L, clozapine had a similar but more marked effect on mass peristalses with both longitudinal and radial components and corresponding maximal pressure greatly reduced. At 30 µmol/L, clozapine suppressed the radial and longitudinal components of mass peristalses for over 30 min, as well as ripple contractions. Similar dose-related effects were observed on addition of clozapine to the mid colon. At 20 µmol/L, norclozapine had opposite effects to those of clozapine, causing an increase in the frequency of mass peristalsis with slight increases in basal tone. These slightly augmented contractions were abolished on addition of clozapine. Concentrations of norclozapine below 20 µmol/L had no discernible effects. Conclusion: Clozapine, but not norclozapine, has potent effects on the motility of the rabbit colon, inhibiting neurogenic contractions at lower concentrations and myogenic contractions at higher concentrations. This is the likely mechanism for the serious and life-threatening gastrointestinal complications seen in human clozapine-users. These effects appear to be mediated by cholinergic and serotonergic mechanisms. Spatiotemporal mapping is useful in directly assessing the effects of pharmaceuticals on particular patterns of gastrointestinal motility.

Analgesic effects of morphine and butorphanol in broiler chickens.

OBJECTIVE: To evaluate analgesic efficacies of morphine and butorphanol in lame broiler chickens. STUDY DESIGN: Double blind, randomized, controlled experimental study. ANIMALS: In study 1, 36 lame and 36 sound chickens. In study 2, 48 lame and 48 sound chickens. METHODS: Sound and lame chickens were gait scored and randomly assigned into four groups: sound-drug, sound-placebo, lame-drug, and lame-placebo in study 1. In study 2, an additional lame and sound handling control group was included. Chickens in drug groups were injected with either morphine or butorphanol 2 mg kg-1 intravenously. Chickens in placebo groups were injected with an equal volume of normal saline. All birds underwent an obstacle course (OC) and latency-to-lie (LTL) test before injection and at 30 minutes and 2 hours after injection, to assess their walking ability and their standing ability. The time taken to finish the OC and the standing time in the LTL test were recorded. Friedman tests with Dunn's correction were used to identify significant differences. RESULTS: Lame chickens finished the OC faster (mean ± standard deviation 36 ± 8 c.f. 69 ± 18 seconds) after the injection of butorphanol. Morphine caused sedation with an increase in time taken to finish the OC, even in sound chickens. In the lame handling control and placebo groups the OC times increased and the LTL times decreased with each observation. CONCLUSION: Intravenous butorphanol (2 mg kg-1) may be analgesic in chickens for up to 2 hours. Morphine caused sedation.