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AIM: To determine if cats anaesthetised with alfaxalone have different recoveries to cats anaesthetised with a combination of ketamine and diazepam. METHODS: Anaesthesia for ovariohysterectomy was induced in cats with either alfaxalone (n=23) or a combination of ketamine and diazepam (n=22). All cats were premedicated with combinations of acepromazine and morphine. Recoveries were scored using a categorical grading scheme applied to 18 parameters over 60 minutes following extubation. The parameters scored covered movement, sensitivity to touch, sound and light, body position, sneezing and vocalisation. One person scored all recoveries and they were blinded to the induction drug used. Scores were compared between drugs at different times using the Kruskal–Wallis rank sum test. RESULTS: Recovery scores were not normally distributed. Analysis of the data using the Kruskal-Wallis rank sum test revealed that cats induced with alfaxalone showed an increase in recovery scores at 5 minutes for pawing at the head (p=0.001). No parameters differed significantly at 10 and 20 minutes. For cats anaesthetised with ketamine and diazepam there was an increase at 30 minutes in pacing, jerky sudden movements, unsettledness and increased sensitivity to touch at the surgical site and on the head (p≤0.01). At 60 minutes cats anaesthetised with ketamine and diazepam still showed an increase in unsettledness compared to those cats anaesthetised with alfaxalone (p=0.005). CONCLUSIONS: The results suggest that recoveries of cats following alfaxalone induction are significantly different to recoveries after induction with ketamine and diazepam. Overall, cats induced with ketamine and diazepam had more active and unsettled recoveries than alfaxalone over the 60-minute period observed. CLINICAL RELEVANCE: Cats recovering from alfaxalone anaesthesia have more settled recoveries than cats recovering from ketamine and diazepam anaesthesia. If a quiet settled recovery is desired following a surgical procedure, alfaxalone is likely to be a better choice than ketamine and diazepam. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate thermal nociceptive thresholds (TNTs) before and after inducing a standardized radiocarpal bone osteochondral fracture (OCF) in horses., Study Design: Prospective, controlled, randomized, masked study., Animals: A group of 10 Thoroughbred fillies aged 2 years., Methods: Skin temperature and TNTs were measured on the skin over the triceps brachii muscle in both the thoracic limbs before (week 0) and weekly (weeks 1-8) after unilateral arthroscopic induction of a radiocarpal OCF (n = 4) or sham surgery (n = 6) followed by a standardized exercise programme. The contralateral, non-operated thoracic limb was used as a control within each horse. Percentage thermal excursion (%TE) defined as %TE = 100 ∗ (TNT - skin temperature)/(cut-off temperature - skin temperature) was calculated. Data were analysed with a mixed-effects model followed by Dunnett's and Tukey's tests for within and between-limbs comparisons, respectively; p < 0.05 was considered significant., Results: Skin temperature in the control limb of OCF horses was significantly higher at week 7 than at week 0 (p = 0.0125). At week 1, TNTs and %TE values in operated limbs of OCF horses were significantly reduced compared with their baseline values at week 0 (p ≤ 0.0153) and their values in contralateral control limbs (p ≤ 0.0024) and operated limbs of sham-operated horses (p ≤ 0.0162). At week 2, TNTs and %TE values in operated limbs of OCF horses remained significantly reduced compared with values in operated limbs of sham-operated horses (p ≤ 0.0248)., Conclusions and Clinical Relevance: Creation of an OCF in a radiocarpal bone induced transitory (<2 weeks) ipsilateral heat hypersensitivity proximal to the surgery site (skin over the triceps brachii muscle) in horses. Surgically induced OCF may cause somatosensory abnormalities consistent with secondary thermal hyperalgesia., (Copyright © 2021 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

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%Δ 1, 2, 3, 10 were measured. Receiver operator characteristic (ROC) curves were generated and areas under ROC curve were calculated for PWTT%Δ 1, 2, 3 . A gray zone approach was used to identify the clinically inconclusive range. The area under the ROC curve for PWTT%Δ 3 was 0.91 (P = 0.001). Cutoff value for PWTT%Δ 3 was -2.5% (sensitivity: 86%, specificity: 90%). The gray zone for PWTT%Δ 3 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., (© Veterinary Emergency and Critical Care Society 2019.)

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., (© Veterinary Emergency and Critical Care Society 2018.)

Objective: To compare the thermal nociceptive thresholds (TNTs) of dogs from three working/sport breeds., Study Design: Experimental prospective study., Animals: Thirty healthy adult dogs of mixed age, sex and reproductive status, 10 of each of three breeds: Harrier Hound, Greyhound and New Zealand Huntaway., Methods: On one day of each week for 4 weeks, unrestrained dogs were tested six times. TNTs were measured using a remotely activated device comprising a thermode attached to the thoracic limb, controlled by a microprocessor attached to the animal. Latency to exhibit behaviour indicative of nociception after initiation of heating and the temperature of the thermode at the point of behavioural response were measured. Linear mixed-effects models were fitted to the data, with dog included as a random effect, initial thermode temperature as a covariate and day, week and breed as fixed effects., Results: Initial thermode temperature significantly affected dogs' latency to respond (p < 0.001). Breed had a significant effect on both latency to respond and response temperature. Huntaways took longer to respond than Harriers or Greyhounds. For example, when the initial thermode temperature was 30 °C, Huntaways took 39.0 seconds to respond compared with 35.8 seconds for Harriers and 36.8 seconds for Greyhounds. Huntaways also responded at higher temperatures (mean±standard deviation: Huntaways 49.7±1.3 °C, Harriers 48.4±1.6 °C and Greyhounds 48.7±1.6 °C)., Conclusions and Clinical Relevance: Huntaways appeared to be less sensitive to thermal pain than the other breeds. Such information could be used by researchers and clinicians to better understand the generalizability of data gathered from a specific breed to the wider canine population or to tailor more effective pharmacological approaches to pain management in dogs., (Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: Dog breeds with the ABCB1-1Δ mutation have substantially truncated nonfunctional P-glycoprotein. Dogs homozygous for this mutation (mut/mut) are susceptible to the toxic adverse effects of ivermectin, loperamide, and vincristine. Anecdotal reports suggested ABCB1 mut/mut dogs showed increased depth and duration of acepromazine sedation., Hypothesis/objectives: That ABCB1 mut/mut dogs have increased depth and duration of sedation after acepromazine IV compared to normal dogs (nor/nor)., Animals: Twenty-nine rough-coated collies were divided into 3 groups of dogs based on their ABCB1 genotype: 10 mut/mut, 10 mut/nor, and 9 nor/nor., Methods: Dogs were given 0.04 mg/kg of acepromazine IV. Level of sedation, heart rate, respiratory rate, and blood pressure were recorded for 6 hours after acepromazine administration. Area under the curves (AUCs) of the normalized sedation score results were calculated and compared., Results: The median sedation scores for ABCB1 mut/mut dogs were higher than nor/nor dogs at all time points and were higher in mut/nor dogs for the first 2 hours. These differences were not found to be significant for any individual time point (P > .05). The median sedation score AUC for mut/mut dogs was significantly higher than nor/nor dogs (P = .028), but the AUC for mut/nor dogs was not (P = .45). There were no significant differences between groups for heart rate, respiratory rate, and blood pressure (P > .05)., Conclusions and Clinical Importance: In ABCB1 mut/mut dogs acepromazine dose rates should be reduced and careful monitoring performed during sedation., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Previous studies on transdermal methimazole have used pluronic lecithin organogel as the vehicle. This might not be the most suitable vehicle for a lipophilic drug, such as methimazole., Hypothesis/objectives: Once daily transdermal administration of a novel lipophilic formulation of methimazole is as safe and effective as oral carbimazole in treating hyperthyroidism in cats., Animals: Forty-five client-owned cats diagnosed with hyperthyroidism., Methods: Prospective study. Cats with newly diagnosed, untreated hyperthyroidism were treated with carbimazole (5 mg p.o., q12h) or methimazole (10 mg) applied to the inner pinnae q24h. Cats were examined after 0, 1, 4, 8, and 12 weeks of treatment. Clinical signs, body weight, systolic blood pressure, hematologic, serum biochemical and urine parameters, total serum thyroxine concentrations (TT4), and serum methimazole concentrations were recorded., Results: No significant differences between groups were detected at day 0. Both formulations were effective in treating hyperthyroidism. No significant differences were detected in thyroxine concentrations, body weight, blood pressure, heart rate, alkaline phosphatase, alanine aminotransferase, creatinine, urea, and urine specific gravity (USG) between groups. The serum methimazole concentrations correlated poorly with TT4-concentrations in both groups., Conclusions and Clinical Importance: In this 12-week trial, once daily application of a novel formulation of transdermal methimazole applied to the pinnae was as effective and safe as twice daily oral carbimazole in the treatment of cats with hyperthyroidism. This novel formulation and transdermal application could have practical advantages to some pet owners., (Copyright © 2011 by the American College of Veterinary Internal Medicine.)

Background: The expression profiles of solid tumor models in rodents have been only minimally studied despite their extensive use to develop anticancer agents. We have applied RNA expression profiling using Affymetrix U95A GeneChips to address fundamental biological questions about human tumor lines., Methods: To determine whether gene expression changed significantly as a tumor increased in size, we analyzed samples from two human colon carcinoma lines (Colo205 and HCT-116) at three different sizes (200 mg, 500 mg and 1000 mg). To investigate whether gene expression was influenced by the strain of mouse, tumor samples isolated from C.B-17 SCID and Nu/Nu mice were also compared. Finally, the gene expression differences between tissue culture and in vivo samples were investigated by comparing profiles from lines grown in both environments., Results: Multidimensional scaling and analysis of variance demonstrated that the tumor lines were dramatically different from each other and that gene expression remained constant as the tumors increased in size. Statistical analysis revealed that 63 genes were differentially expressed due to the strain of mouse the tumor was grown in but the function of the encoded proteins did not link to any distinct biological pathways. Hierarchical clustering of tissue culture and xenograft samples demonstrated that for each individual tumor line, the in vivo and in vitro profiles were more similar to each other than any other profile. We identified 36 genes with a pattern of high expression in xenograft samples that encoded proteins involved in extracellular matrix, cell surface receptors and transcription factors. An additional 17 genes were identified with a pattern of high expression in tissue culture samples and encoded proteins involved in cell division, cell cycle and RNA production., Conclusions: The environment a tumor line is grown in can have a significant effect on gene expression but tumor size has little or no effect for subcutaneously grown solid tumors. Furthermore, an individual tumor line has an RNA expression pattern that clearly defines it from other lines even when grown in different environments. This could be used as a quality control tool for preclinical oncology studies.

Background: Molecular characterization has contributed to the understanding of the inception, progression, treatment and prognosis of cancer. Nucleic acid array-based technologies extend molecular characterization of tumors to thousands of gene products. To effectively discriminate between tumor sub-types, reliable laboratory techniques and analytic methods are required., Results: We derived mRNA expression profiles from 21 human tissue samples (eight normal kidneys and 13 kidney tumors) and two pooled samples using the Affymetrix GeneChip platform. A panel of ten clustering algorithms combined with four data pre-processing methods identified a consensus cluster dendrogram in 18 of 40 analyses and of these 16 used a logarithmic transformation. Within the consensus dendrogram the expression profiles of the samples grouped according to tissue type; clear cell and chromophobe carcinomas displayed distinctly different gene expression patterns. By using a rigorous statistical selection based method we identified 355 genes that showed significant (p < 0.001) gene expression changes in clear cell renal carcinomas compared to normal kidney. These genes were classified with a tool to conceptualize expression patterns called "Functional Taxonomy". Each tumor type had a distinct "signature," with a high number of genes in the categories of Metabolism, Signal Transduction, and Cellular and Matrix Organization and Adhesion., Conclusions: Affymetrix GeneChip profiling differentiated clear cell and chromophobe carcinomas from one another and from normal kidney cortex. Clustering methods that used logarithmic transformation of data sets produced dendrograms consistent with the sample biology. Functional taxonomy provided a practical approach to the interpretation of gene expression data.

A model system was developed to investigate the effects of DNA alkylating agents on cellular gene expression. The cytomegalovirus immediate-early promoter (CMV) and the mouse mammary tumor virus promoter (MMTV) were coupled separately to the luciferase reporter gene and stably expressed in cultured cells. The change in luciferase activity was used as a measure of gene expression inhibition. Seven well-characterized DNA alkylating agents of varied DNA adduct-forming ability were evaluated in this system. The major groove binders/intercalators (that form guanine adducts) increased CMV-luciferase activity above background, while minor groove binders (that form adenine adducts) all decreased it. The MMTV-luciferase activity was remarkably different to the CMV-luciferase activity and was inhibited to the greatest extent by the minor groove alkylators. One of these, a polybenzamide with spatially separated alkylating groups, inhibited gene expression to a greater extent than inhibition of general DNA or RNA synthesis.

Irreversible inhibitors of the epidermal growth factor receptor (EGFR) are showing promise in clinical trials. This report is the first to show that inhibition of the EGFR tyrosine kinase by an irreversible binder synergizes with cisplatin, at least in EGFR-overexpressing tissue culture cell lines in vitro. Unlike previous synergies demonstrated between ErbB2 blockade and DNA-damaging drugs, the synergy between the irreversible EGFR inhibitor and cisplatin does not appear to involve the repair of DNA-cisplatin adducts. Given the current clinical data, this combination may be of more than theoretical interest.

The enantiomers of the previously reported racemic 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl] indoline (amino-seco-CI-TMI) were prepared via resolution of a precursor by chiral HPLC. The only detectable product isolated from reaction of the racemic compound with calf thymus DNA, followed by thermal cleavage, was shown by mass spectrometry and two-dimensional NMR spectroscopy to be the adenine N3 adduct. Polyacrylamide gel electrophoresis assays with the racemate and with each enantiomer also showed adenine to be the only site of alkylation. While the racemic amino compound exhibited sequence selectivity identical to that of the previously characterized phenol analogue, the enantiomers exhibited distinctly different sequence selectivities, allowing the (+) enantiomer to be assigned the "natural" S configuration. The (+)-(S) enantiomer is 3-fold more cytotoxic than the (-)-(R) enantiomer (IC(50) values of 240 and 700 nM, respectively, in AA8 cells, after exposure for 4 h).

Both 5-hydroxy- and 5-amino-seco-CBI-TMI minor groove alkylators are very potent cytotoxins. The patterns of alkylation of the two enantiomers of both compounds were compared on a section of the gpt gene. All of the compounds alkylated only at adenines, with the amino compounds being slightly more selective. Consensus alkylation sequences for both S (natural) enantiomers were identical, but for the R (unnatural) enantiomers these varied slightly. The consensus sequences suggest that the S enantiomers bind lying in the 3'-->5' direction from the alkylated adenine, but there was no clear indication of which direction the R enantiomers lie on the DNA. Both S enantiomers were 10- to 100-fold more efficient alkylators than the R enantiomers, and the amino compounds were somewhat more efficient than the corresponding phenols. The S enantiomers were more cytotoxic then the R in both the phenol and amino series. The large amounts of end-labelled DNA required for this work was obtained by first end-labelling appropriate primer oligonucleotides, then amplifying by PCR. Compared with other methods in use, this is a simple and flexible one-step procedure for the preparation of labelled DNA of any sequence. An improvement in the synthesis of 5-hydroxy-seco-CBI-TMI is reported.

Total pancreatic RNA from the holocephalan species Callorhyncus milii (elephantfish) was used to make cDNA as a template for the polymerase chain reaction. Three redundant primers based on the known amino acid sequence of elephantfish insulin were used to amplify a fragment of proinsulin comprising truncated B-chain, complete C-peptide, and complete A-chain. Whereas the C-peptide/A-chain junction contained the expected dibasic cleavage site (-Lys-Arg-), the B-chain/C-peptide junction was found to contain only a single Arg, the first such site to be unequivocally associated with the proteolytic processing of a proinsulin to insulin. Examination of the flanking sequences around this site shows that a typical endocrine/neuroendocrine PC3 conversion enzyme should still be able to cleave, as the general requirements for precursor processing at a monobasic site are satisfied, notably a basic residue (Lys) at the -4 position. An acidic residue (in this case Asp) at the +1 position, which is seen in all known proinsulins, is maintained. The corresponding genomic DNA fragment of elephantfish proinsulin was also amplified by PCR, revealing a 402-bp intron at the conserved IVS-2 position within the C7 codon., (Copyright 1997 Academic Press. Copyright 1997 Academic Press)