Allosteric modulators of the δ GABAA receptor subtype demonstrate a therapeutic effect in morphine-antinociceptive tolerance and withdrawal in mice.

The present study evaluated the effects of compounds targeting extrasynaptic δ subunit-containing γ-aminobutyric acid type A receptors (δ*-GABAARs) to interrogate the role of tonic inhibition in the development of antinociceptive tolerance caused by repeated morphine administration. We investigated the effect of subchronic or acute treatment with non-steroidal positive allosteric modulators (PAMs) of δ*-GABAARs, such as 2-261, on the morphine-antinociceptive tolerance. Mice were treated twice daily with morphine for 9 days and antinociception was measured using the hot water tail immersion test. Co-treatment with 2-261 and morphine prevented morphine-antinociceptive tolerance and acute administration of 2-261 on day 9 was sufficient to reverse the tolerance. Other compounds with activity at δ*-GABAARs also reversed morphine tolerance, whereas an enaminone that lacked activity at δ*-GABAARs did not. Acute administration of 2-261 did not cause an additive or synergistic antinociceptive effect when combined with an acute submaximal dose of morphine. We then used Cre/LoxP recombination to generate GABAA δ-subunit knockout mice to corroborate the pharmacological results. Observations of male δ-knockout mice demonstrated that the δ*-GABAARs was necessary for 2-261 modulation of both analgesic tolerance and somatic withdrawal symptoms produced by subchronic morphine. While female mice still benefited from the positive effects of 2-261, the δ-subunit was not necessary for these effects, highlighting a distinction of the different pathways that could have implications for some of the sex-related differences seen in human opioid-induced outcomes. Consequently, subtype-specific allosteric modulators of GABAARs may warrant further investigation as pharmacological targets to manage tolerance and withdrawal from opioids.

Hyperthyroid cats and their kidneys: a literature review.

Hyperthyroidism and chronic kidney disease (CKD) are common diseases of geriatric cats, and often occur concurrently. Thus, a thorough understanding of the influence of thyroid function on renal function is of significant value for all feline practitioners. Among other effects, hyperthyroidism causes protein catabolism and increases renal blood flow and glomerular filtration rate (GFR). These effects render traditional renal markers insensitive for the detection of CKD in cats with uncontrolled hyperthyroidism. Furthermore, the development of iatrogenic hypothyroidism with over treatment of hyperthyroidism can be detrimental to renal function and may negatively affect long-term survival. This review discusses important diagnostic considerations of feline hyperthyroidism, as well as key treatment modalities, with an emphasis on the use of radioiodine and the importance of post treatment monitoring of thyroid and renal parameters. In Australia, a common curative treatment for cats with benign hyperthyroidism (i.e. thyroid hyperplasia or adenoma) is a fixed dose of orally administered radioiodine, regardless of the serum total thyroxine concentration at the time of diagnosis. This review discusses the long term outcomes of this standard of care in comparison with current, relevant research literature from around the world. Finally, this review explores the use of symmetric dimethylarginine (SDMA) in assessing renal function before and after treatment in hyperthyroid cats. SDMA correlates well with GFR and creatinine in non-hyperthyroid cats, but our understanding of its performance in hyperthyroid cats remains in its infancy.

Update on feline alphaherpesvirus-1 seroprevalence in Victorian feral and owned cats.

The seroprevalence of feline alphaherpesvirus-1 (FHV-1) in feral cats in Victoria, Australia, was last assessed in 1981 when serum-virus-neutralising antibodies (VNAb) against FHV-1 were detected in 11% of the sampled population from two Victorian locations. In this current study, VNAb were assessed in serum from feral cats located in Phillip Island, Point Cook and Hattah in the Mallee region in Northern Victoria. In feral cats, the seroprevalence of VNAb to FHV-1 was highest in Point Cook at 24.6% (17/69), followed by Phillip Island at 16.7% (11/66) and Hattah where no feral cats had detectable VNAb to FHV-1 (0/12). In contrast, virus-neutralising antibodies were observed in 84.1% (37/44) of Victorian-owned cats. This higher seroprevalence in owned cats is likely due to the use of FHV-1 vaccines; however, the vaccination history of the cats was not known and the development of neutralising antibodies after infection or vaccination can vary. The results are useful for understanding FHV-1 exposure in feral and owned cats and are important background information in the context of any potential future use of FHV-1-vectored vaccines.

A clinical approach to multidrug-resistant urinary tract infection and subclinical bacteriuria in dogs and cats.

Multidrug-resistant bacteria are increasingly isolated from the urinary tract of pets, particularly those that suffer from concurrent conditions, have been hospitalised, or were treated with antimicrobials in the recent past. Many of the multidrug-resistant bacteria encountered are resistant to all commonly used oral antibiotics. This poses both a therapeutic dilemma in the individual pet and a threat to public health. This article begins with an overview of multidrug resistance in organisms that are commonly isolated from the urinary tract of pets. This is followed by a proposed clinical approach to managing multidrug-resistant urinary bacteria, which summarises current knowledge regarding appropriate sampling and analysis, reviews the current guidelines regarding appropriate antimicrobial use and discusses treatment options that might be considered. The article highlights several shortcomings of the current knowledge to be considered when planning future clinical research and developing policies.

Appraisal of the Australian Veterinary Prescribing Guidelines for antimicrobial prophylaxis for surgery in dogs and cats.

The Australian Veterinary Prescribing Guidelines for antimicrobial prophylaxis for surgery on dogs and cats are evidence-based guidelines for veterinary practitioners. Validation of these guidelines is necessary to ensure quality and implementability. Two validated tools, used for medical guideline appraisal, were chosen to assess the guidelines. The terminology from the GuideLine Implementability Appraisal (GLIA) and the Appraisal of Guidelines for Research and Evaluation version 2 (AGREE II) were adapted for use by veterinarians. A two-phase evaluation approach was conducted. In the first phase of the evaluation, the GLIA tool was used by two specialist veterinary surgeons in clinical practice. The results of this phase were then used to modify the guidelines. In the second phase, the AGREE II tool was used by 6 general practitioners and 6 specialists to appraise the guidelines. In phase 1, the specialist surgeons either agreed or strongly agreed that the guidelines were executable, decidable, valid and novel, and that the guidelines would fit within the process of care. The surgeons were neutral on flexibility and measurability. Additional clarity around one common surgical procedure was added to the guidelines, after which the surgeons agreed that the guidelines were sufficiently flexible. In phase 2, 12 veterinarians completed the assessment using the AGREE II tool. In all sections the scaled domain score was greater than 70%. The overall quality of the guidelines was given a global scaled score of 76%. This assessment has demonstrated that the guidelines for antimicrobial prophylaxis for companion animal surgery are valid and appear implementable.

Seven cases of probable endotoxin poisoning related to contaminated glutathione infusions.

We report seven cases of probable endotoxin poisoning linked to contaminated compounded glutathione. Five of the cases were using the infusions for treatment of Lyme disease highlighting the risks of using compounded sterile preparations for unapproved indications, especially if the quality of source products cannot be assured.

Primary radical therapy selection in high-risk non-metastatic prostate cancer.

As the incidence of prostate cancer rises, the detection and management of men with high-risk non-metastatic prostate cancer is becoming increasingly important. The benefits of radical treatment have been clearly shown in this group from a number of publications. The current mainstays of treatment are radical prostatectomy (with selective use of adjuvant radiation) and radical radiotherapy with concurrent androgen deprivation. The outcomes from these two approaches seem to be remarkably similar and are considered equally valid options for primary treatment. The choice of therapy is critically dependent on a number of factors, but ultimately left to the decision of the patients with advice from clinicians. Clinicians themselves, however, are known to be biased towards their particular skill set and experiences. Attempts at randomised comparisons between these two modalities have so far failed and are confounded by patient-clinician bias, the continual advances in therapy as well as the long natural history of the disease. In the lack of level 1 comparable evidence, this article explores the existing literature as to the key factors that should be considered in radical treatment selection for high-risk prostate cancer. These factors include disease aggressiveness, comorbidity and life expectancy, functional outcomes and the consequences of therapy failure with regards to salvage treatment. We propose that these factors may be useful in developing a decision guide for rationale radical therapy selection in the light of two apparently equally effective treatments. Ultimately, however, there is an urgent need for added clinical and biological markers that can provide a more precise approach to therapy selection.

Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed.

BACKGROUND: The aetiology of insulin resistance (IR) in naturally occurring canine hypothyroidism is poorly understood and likely multifactorial. Excess secretion of growth hormone (GH) by transdifferentiated pituitary cells may contribute to IR in some hypothyroid dogs, but although this has been demonstrated in experimental studies, it has not yet been documented in clinical cases. CASE REPORT: A 4-year-old male entire Samoyed presented with an 8-month history of pedal hyperkeratosis and shifting lameness, which had been unresponsive to zinc supplementation, antibiotics and glucocorticoid therapy. The dog also exhibited exercise intolerance and polydipsia of 12 and 2 months duration, respectively. On physical examination, obesity, poor coat condition, widened interdental spaces and mild respiratory stridor were noted. Initial laboratory test results revealed concurrent hypothyroidism and diabetes mellitus (DM). Further investigations showed IR, GH excess and a paradoxical increase of GH following stimulation with thyrotropin-releasing hormone. CONCLUSIONS: To the authors' knowledge, this is the first reported case that suggests that GH alterations may have clinical significance in naturally occurring hypothyroidism. Among other factors, hypothyroidism-induced GH excess should be considered as a possible cause of IR in patients suffering from hypothyroidism and concurrent DM. In such cases, DM may reverse with treatment of hypothyroidism, as was documented in this case.

Comparison of fMRI motion correction software tools.

Motion correction of fMRI data is a widely used step prior to data analysis. In this study, a comparison of the motion correction tools provided by several leading fMRI analysis software packages was performed, including AFNI, AIR, BrainVoyager, FSL, and SPM2. Comparisons were performed using data from typical human studies as well as phantom data. The identical reconstruction, preprocessing, and analysis steps were used on every data set, except that motion correction was performed using various configurations from each software package. Each package was studied using default parameters, as well as parameters optimized for speed and accuracy. Forty subjects performed a Go/No-go task (an event-related design that investigates inhibitory motor response) and an N-back task (a block-design paradigm investigating working memory). The human data were analyzed by extracting a set of general linear model (GLM)-derived activation results and comparing the effect of motion correction on thresholded activation cluster size and maximum t value. In addition, a series of simulated phantom data sets were created with known activation locations, magnitudes, and realistic motion. Results from the phantom data indicate that AFNI and SPM2 yield the most accurate motion estimation parameters, while AFNI's interpolation algorithm introduces the least smoothing. AFNI is also the fastest of the packages tested. However, these advantages did not produce noticeably better activation results in motion-corrected data from typical human fMRI experiments. Although differences in performance between packages were apparent in the human data, no single software package produced dramatically better results than the others. The "accurate" parameters showed virtually no improvement in cluster t values compared to the standard parameters. While the "fast" parameters did not result in a substantial increase in speed, they did not degrade the cluster results very much either. The phantom and human data indicate that motion correction can be a valuable step in the data processing chain, yielding improvements of up to 20% in the magnitude and up to 100% in the cluster size of detected activations, but the choice of software package does not substantially affect this improvement.

Abstractionist and processing accounts of implicit learning.

Five experiments evaluated the contributions of rule, exemplar, fragment, and episodic knowledge in artificial grammar learning using memorization versus hypothesis-testing training tasks. Strings of letters were generated from a biconditional grammar that allows different sources of responding to be unconfounded. There was no evidence that memorization led to passive abstraction of rules or encoding of whole training exemplars. Memorizers instead used explicit fragment knowledge to identify the grammatical status of test items, although this led to chance performance. Successful hypothesis-testers classified at near-perfect levels by processing training and test stimuli according to their rule structure. The results support the episodic-processing account of implicit and explicit learning.

Evaluating the relationship between explicit and implicit knowledge in a sequential reaction time task.

Can knowledge underlying a simple perceptual-motor skill be unconscious? Three experiments (a) trained participants on a 4-choice reaction time (RT) task in which the stimulus on each trial was determined by a repeating 12-element sequence and (b) studied the extent to which participants' knowledge of this sequence was implicit, that is, unavailable for conscious access. Participants proved via an indirect test to have acquired knowledge of the sequence, because their RTs increased when the sequence was changed. To evaluate whether this knowledge was consciously accessible, participants were asked to perform an "objective" free-generation or recognition test of sequence knowledge. Results show that sequence knowledge is fully accessible on these objective tests. Moreover, it is demonstrated in this procedure that old-new recognition cannot be explained by unconscious attribution of perceptual-motor fluency. The question is raised whether distinct implicit (procedural) and explicit (declarative) forms of knowledge are acquired when participants learn a perceptual-motor skill.

Abstraction processes in artificial grammar learning.

Four experiments explored the extent the extent to which abstract knowledge may underlie subjects' performance when asked to judge the grammaticality of letter strings generated from an artificial grammar. In Experiment 1 and 2 subjects studied grammatical strings instantiated with one set of letters and were then tested on grammatical and ungrammatical strings formed either from the same or a changed letter-set. Even with a change of letter-set, subjects were found to be sensitive to a variety of violation of the grammar. In Experiments 3 and 4, the critical manipulation involved the way in which the training strings were studied: an incidental learning procedure was used for some subjects, and others engaged in an explicit code-breaking task to try to learn the rules of the grammar. When strings were generated from a biconditional (Experiment 4) but not from a standard finite-state grammar (Experiment 3), grammaticality judgements for test strings were independent of their surface similarity to specific studied strings. Overall, the results suggest that transfer in this simple memory task is mediated at least to some extent by abstract knowledge.