Salmonella in captive and wild Tasmanian devils (Sarcophilus harrisii) in Tasmania.

Translocation of Tasmanian devils (Sarcophilus harrisii) is a common strategy for recovery of the species as carried out by the Save the Tasmanian Devil Program. Dasyurids including the endangered Tasmanian devil are well known to asymptomatically harbour the zoonotic bacteria Salmonella enterica in their intestinal tracts. Testing for Salmonella is a routine component of pretranslocation health testing, so a statewide microbiological survey of captive and wild devils was implemented in order to understand prevalence and common Salmonella serotypes, and inform decision-making when positive cultures are identified. This preliminary study identified a significantly higher proportion of Salmonella isolations in wild compared with captive devils. Mississippi and Typhimurium were the most common serotypes, followed by Lexington, Bovismorbificans, Kottbus and Amsterdam. Given the common finding of Salmonella in wild devils and the range of serotypes involved, in addition to numerous isolations in domestic species and humans, it is unlikely that the release of small numbers of captive devils to the wild in Tasmania poses a significant risk to the destination ecosystem. Ongoing monitoring of devils is required as the stress of acclimatisation could predispose devils to clinical disease. Appropriate personal protective attire is pertinent to protect personnel handling animals from this zoonotic infection.

Causes of mortality and severe morbidity requiring euthanasia in captive Tasmanian devils (Sarcophilus harrisii) in Tasmania.

BACKGROUND: Devil facial tumour disease (DFTD) is a contagious cancer causing marked population declines in wild Tasmanian devils. In response to this threat, a captive insurance population has been established. This study investigated causes of death in captive Tasmanian devils. METHODS: Clinical and laboratory records of captive Tasmanian devils held in seven Tasmanian captive facilities were analysed for cause of death or severe morbidity requiring euthanasia. RESULTS: Neoplasia was found to be the most common cause of mortality/severe morbidity, accounting for 27/63 of deaths. Cutaneous lymphoma was the most frequently observed tumour (10/27), at a higher incidence than previously reported. The most common cause of severe morbidity, following neoplasia, was leucoencephalomyelopathy, which caused severe, progressive hindlimb paresis and ataxia. CONCLUSION: Neoplasia, specifically cutaneous lymphoma, and degenerative neurological conditions are the most frequent causes of death in captive Tasmanian devils in Tasmania. Further work to determine the aetiologies of these conditions, as well as effective treatments, would be valuable.

Electrophysiological assessment methodology of sensory processing dysfunction in schizophrenia and dementia of the Alzheimer type.

Schizophrenia and Alzheimer's disease impacts on various sensory processings are extensively reviewed in the present publication. This article describes aspects of a research project whose aim is to delineate the neurobiology that may underlie Social Withdrawal in Alzheimer's disease, Schizophrenia and Major Depression. This is a European-funded IMI 2 project, identified as PRISM (Psychiatric Ratings using Intermediate Stratified Markers). This paper focuses specifically on the selected electrophysiological paradigms chosen based on a comprehensive review of all relevant literature and practical constraints. The choice of the electrophysiological biomarkers were fundamentality based their metrics and capacity to discriminate between populations. The selected electrophysiological paradigms are resting state EEG, auditory mismatch negativity, auditory and visual based oddball paradigms, facial emotion processing ERP's and auditory steady-state response. The primary objective is to study the effect of social withdrawal on various biomarkers and endophenotypes found altered in the target populations. This has never been studied in relationship to social withdrawal, an important component of CNS diseases.

High blood lead concentrations in captive Tasmanian devils (Sarcophilus harrisii): a threat to the conservation of the species?

BACKGROUND: The Tasmanian devil (Sarcophilus harrisii) is the world's largest extant marsupial carnivore. Since the emergence of devil facial tumour disease in 1996, the species has undergone a severe population decline. The insurance population (IP) was established in 2006 to build a disease-free captive population to maintain 95% of the wild Tasmanian devil genetic diversity for 50 years. Captive and semi-wild Tasmanian devils are fed with possum and wallaby meat provided by local hunters, who use lead ammunition. Lead ingestion can cause acute toxicity, including ataxia, coma and death, or chronic subclinical deleterious effects including decreased fertility. METHODS: We determined blood lead concentrations in 26 captive and 133 wild Tasmanian devils from various sites across Tasmania. RESULTS: Captive Tasmanian devils showed significantly higher blood lead concentrations than their conspecifics in the wild. In captivity, older animals had higher blood lead concentrations than young animals, which suggested regular exposure, as lead can accumulate in a living organism in the blood, soft tissues and bones. After a response measure was implemented by removing the heads and wounds containing lead from the diet, blood concentrations significantly decreased in animals at one of the captive study sites, supporting the suspicion of food as the source of lead. CONCLUSION: This study highlights the need to ensure meat fed to captive carnivores is not contaminated by lead, especially in the context of a conservation program breeding individuals in captivity, as for Tasmanian devils.

Evaluation of symptomatic drug effects in Alzheimer's disease: strategies for prediction of efficacy in humans.

In chronic diseases such as Alzheimer's disease (AD), the arsenal of biomarkers available to determine the effectiveness of symptomatic treatment is very limited. Interpretation of the results provided in literature is cumbersome and it becomes difficult to predict their standardization to a larger patient population. Indeed, cognitive assessment alone does not appear to have sufficient predictive value of drug efficacy in early clinical development of AD treatment. In recent years, research has contributed to the emergence of new tools to assess brain activity relying on innovative technologies of imaging and electrophysiology. However, the relevance of the use of these newer markers in treatment response assessment is waiting for validation. This review shows how the early clinical assessment of symptomatic drugs could benefit from the inclusion of suitable pharmacodynamic markers. This review also emphasizes the importance of re-evaluating a step-by-step strategy in drug development.

Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat.

RATIONALE: Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment. OBJECTIVES: The objective of the study was to investigate the effect of an AMPA positive modulator, CX691, (1) in three rodent models of learning and memory, (2) on neurochemistry in the dorsal hippocampus and medial prefrontal cortex following acute administration, and (3) on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat hippocampus following acute and sub-chronic administration. RESULTS: CX691 attenuated a scopolamine-induced impairment of cued fear conditioning following acute administration (0.1 mg/kg p.o.) and a temporally induced deficit in novel object recognition following both acute (0.1 and 1.0 mg/kg p.o.) and sub-chronic (bi-daily for 7 days) administration (0.01, 0.03, 0.1 mg/kg p.o.). It also improved attentional set-shifting following sub-chronic administration (0.3 mg/kg p.o.). Acute CX691 (0.1, 0.3 and 1.0 mg/kg, p.o.) increased extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex and dopamine in the medial prefrontal cortex. Sub-chronic administration of CX691 (0.1 mg/kg, p.o.) elevated BDNF mRNA expression in both the whole and CA(1) sub-region of the hippocampus (P < 0.05). CONCLUSIONS: Collectively, these data support the pro-cognitive activity reported for AMPA receptor positive modulators and suggest that these compounds may be of benefit in treating disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.

The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.

RATIONALE: Group II metabotropic glutamate receptors (mGluRs) comprise the mGluR2 and mGluR3 subtypes, the activation and modulation of which has been suggested to be beneficial for treating schizophrenia. Genetic association studies suggest limited association between mGluR2 and schizophrenia but some association between mGluR3 and schizophrenia. Conversely, pre-clinical studies suggest that mGluR2 may be responsible for mediating the antipsychotic activity of mGluR2/3 agonists, although to date, the role of mGluR3 has not been specifically assessed. OBJECTIVES: The aim of this study is to use recently generated mGluR3 and mGluR2 knockout mice to investigate which of the group II mGluRs mediates the actions of the mGluR2/3 agonist, LY379268, in two mouse models predictive of antipsychotic activity. MATERIALS AND METHODS: LY379268 (0.3-10 mg/kg SC), phencyclidine (PCP; 1-5 mg/kg IP), and amphetamine 1-10 mg/kg IP) were assessed on locomotor activity and behaviour in C57Bl/6J and transgenic mice. LY379268 was then assessed on PCP (5 mg/kg IP)- and amphetamine (2.5 mg/kg IP)-induced hyperactivity and behaviour in C57Bl/6J and transgenic mice. RESULTS: PCP (5 mg/kg)-evoked hyperactivity and behavioural alterations, i.e. circling, falling, stereotypy and ataxia, as well as amphetamine (2.5 mg/kg)-evoked hyperactivity, were dose-dependently attenuated by LY379268 (0.3-3 mg/kg) in C57Bl/6J mice. One milligram per kilogram of LY379268 reversed PCP-evoked hyperactivity and behavioural alterations in wild-type (WT) and mGluR3 knockout mice but not in mice lacking mGluR2. Similarly, 3 mg/kg LY379268 reversed amphetamine-evoked hyperactivity in WT and mGluR3 knockout mice but not in mice lacking mGluR2. CONCLUSION: The mGlu2 but not the mGlu3 receptor subtype mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.

Genetic screening for prey in the gut contents from a giant squid (Architeuthis sp.).

Giant squids (Architeuthis sp.) remain mysterious; they have evaded observation and are rarely taken from their deep sea habitat. Information on the diet of Architeuthis is scarce due to the limited number of specimens with morphologically recognizable remains in their digestive tracts. We explored the use of polymerase chain reaction (PCR)-based methods for detection of DNA in the prey remains and amorphous slurry from an Architeuthis gut sample. The DNA region amplified varied in size, allowing separation of fish and squid components. Sequence comparisons identified fish prey as Macruronus novaezelandiae. Isolation of Architeuthis DNA from an ingested tentacle and the presence of chitin fragments indicate cannibalism occurs in giant squid. Denaturing gradient gel electrophoresis was used to screen for less common DNA types, revealing a high frequency of PCR-generated false alleles, but no additional prey species.

Characterization of glutamate-gated chloride channels in the pharynx of wild-type and mutant Caenorhabditis elegans delineates the role of the subunit GluCl-alpha2 in the function of the native receptor.

Glutamate-gated chloride (GluCl) channels are the site of action of the anthelmintic ivermectin. Previously, the Xenopus laevis oocyte expression system has been used to characterize GluCl channels cloned from Caenorhabditis elegans. However, information on the native, pharmacologically relevant receptors is lacking. Here, we have used a quantitative pharmacological approach and intracellular recording techniques of C. elegans pharynx to characterize them. The glutamate response was a rapidly desensitizing, reversible, chloride-dependent depolarization (EC(50) = 166 microM), only weakly antagonized by picrotoxin. The order of potency of agonists was ibotenate > L-glutamate > kainate = quisqualate. Ivermectin potently and irreversibly depolarized the muscle (EC(50) = 2.7 nM). No further depolarization was seen with coapplication of maximal glutamate during the maximal ivermectin response, indicating that ivermectin depolarizes the muscle by the same ionic mechanism as glutamate (i.e., chloride). The potency of ivermectin on the pharynx was greater than at any of the GluCl subunits expressed in X. laevis oocytes. This effect of ivermectin was abolished in the mutant avr-15, which lacks a functional GluCl-alpha2 subunit. However, a chloride-dependent, nondesensitizing response to glutamate persisted. Therefore, the GluCl-alpha2 subunit confers ivermectin sensitivity and a high-affinity desensitizing glutamate response on the native pharyngeal GluCl receptor.

Physiological and pharmacological studies on nematodes.

Classical transmitters and neuroactive peptides act as transmitters or modulators within the central and peripheral nervous systems of nematodes, for example Ascaris suum and Caenorhabditis elegans. Acetylcholine (ACh) and gamma-aminobutyric acid (GABA) are respectively the excitatory and inhibitory transmitters onto somatic body wall muscle while 5-hydroxytrypamine (5-HT) is the excitatory transmitter onto pharyngeal muscle. 5-HT also reduces ACh-induced contractions of somatic muscle and this action of 5-HT is mediated through activation of adenylate cyclase while that on pharyngeal muscle is mediated through inositol phosphate activation. Glutamate, dopamine and octopamine also have transmitter roles in nematodes. Neuroactive peptides of the RFamide family can excite somatic muscle, for example, AF-1 (KNEFIRFamide), AF-2 (KHEYLRFamide), AF-3 (AVPGVLRFamide) and AF-4 (GDVPGVLRFamide) or inhibit and relax this muscle, for example, PF-1 (SDPNFLRFamide), PF-2 (SADPNFLRFamide) and PF-4 (KPNlRFamide). In addition PF-3 (AF-8) (KSAYMRFamide) has a biphasic action on pharyngeal muscle, excitation followed by inhibition while AF-1 only inhibits this muscle. The peptide effects can be either pre- or postsynaptic or both and are likely to be mediated through second messenger systems. In addition these peptides modulate the action of classical transmitters, particularly ACh.

The effect of methadone prescribing in a clinic setting on the criminal activity of drug users.

The objective was to examine the impact of clinic attendance and methadone prescribing on drug user criminality. Fifty-four consecutive attenders at a Drug Problem Clinic were interviewed by questionnaire. An objective assessment of the criminality on 49(91%) of the above was made by examining their conviction details, before and after clinic attendance. Seventy-seven per cent strongly agreed that fewer criminal charges had been preferred since attendance at the clinic had begun and drugs prescribed. No statistically significant difference was found in the conviction numbers for the group as a whole: mean 3.9 (before) to 3.2 (after): p = 0.24, or for the females in particular: mean 2.8 (before) to 5.9 (after): p = 0.97. There was, however, a significant drop in the number of convictions amongst the males: mean 4.3 (before) to 2.5 (after): p = 0.02. This study confirms an association between methadone maintenance therapy in a clinic setting and a reduction in criminality amongst males.

Polyol-combinant saliva stimulants and oral health in Veterans Affairs patients--an exploratory study.

An exploratory study investigated the root caries incidence in Department of Veterans Affairs patients with exposed root surfaces. For a period of six to 30 months, the subjects were systematically assigned to groups which used chewable dragees or chewing gums that contained either xylitol or sorbitol as bulk sweeteners. The mean treatment time was 1.8 years (standard deviation = 0.8). The consumption levels of both polyols was up to 8.5 g daily, used typically in five episodes during a 16-hour period. The subjects were examined every six months in connection with their standard scheduled visits at the Veterans Affairs Medical Center. The risk for a root-surface lesion in the xylitol group was only 19% of that for a surface in the sorbitol group (relative risk, 0.19; 95% confidence interval, 0.06-0.62; p < or = 0.0065). Simultaneous study in periodontal patients showed that both polyols significantly reduced the gingival index scores, and slightly (but not significantly) reduced the plaque index scores. Collectively, both studies suggest that frequent daily consumption of chewable, saliva-stimulating products containing essentially nonfermentable or slowly fermentable dietary carbohydrate sweeteners (xylitol and sorbitol) may have an oral-health-improving effect in Department of Veterans Affairs Medical Center patients. It is necessary to evaluate if these procedures would be efficacious in larger and expanded patient cohorts.

Saliva stimulants and the oral health of geriatric patients.

Root-surface caries (RSC) has been recognized as a specific and important dental disease. Significant advances have been made in the pathology and microbiology of RSC, and the need to standardize the guidelines for recording RSC data has been recognized. Researchers have emphasized the increasing impact RSC will have on the geriatric population, especially since the methods to treat and prevent this disease are limited. The purpose of this study was to investigate the possibility of limiting RSC in a Veterans Administration (VA) patient population, using polyol-containing saliva stimulants that were voluntarily consumed by residents of a VA Medical Center (VAMC) over a period of from six to 30 months. Another aim was to study the effect of this program on the gingival health of periodontal patients.

Fractures of the distal femur in the elderly treated with a carbon fibre supracondylar plate.

The use of a contoured supracondylar carbon fibre plate in 22 patients with a fracture of the lower femur is reported. The patients were all elderly (mean age 80.6 years) and three patients in the study died of unrelated medical causes. Of the 19 surviving patients, in 17 the fracture united (89 per cent). The supracondylar plate was technically simple to use and the authors feel that it represents a significant advantage over existing implants for this difficult fracture.

The structure of the insertions of the tendons of biceps brachii, triceps and brachialis in elderly dissecting room cadavers.

The terminal portions of the tendon of brachialis, and the distal tendons of biceps brachii and triceps, were compared by routine histology. All tendons came from elderly dissecting room cadavers. There were pronounced quantitative differences between the 3 tendons in (1) the thickness of the attachment-zone fibrocartilage, (2) the thickness of cortical calcified tissue, and (3) the percentage of bone to marrow. There was significantly more uncalcified fibrocartilage at the attachment of biceps than at the other sites, reflecting greater range of movement of the tendon at this site. The thickness of cortical calcified tissue and the percentage of bone to marrow were significantly greater at the attachment of brachialis than either biceps or triceps. The large quantities of bone at the attachment of brachialis may be related more to the importance of the coronoid process in buttressing the elbow joint than to any special requirement for large amounts of calcified tissue at the tendon attachment. Near its attachment zone, the biceps tendon splits into superficial and deep laminae that are distinct from the macroscopic subdivision of this tendon. It is suggested that the lamination may facilitate the movements of pronation and supination. In support of this, the deep portion of the superficial lamina contained fibrocartilage where it rubbed against the attachment-zone of the deep lamina. In one body, the fibrocartilage of the biceps attachment-zone was subject to degenerative changes, including cell clumping and matrix fissuring.

Carbon-fibre reinforced plates for problem fractures.

We report our experience with carbon-fibre reinforced plastic (CFRP) plates in the management of 19 problem fractures complicated by either infection, nonunion, comminution or contamination. The combination offers secure fixation without inhibition of callus formation.

Quantitative differences in the histology of the attachment zones of the meniscal horns in the knee joint of man.

The attachment zones of the meniscal horns of 7 dissecting room cadavers were examined by routine histology. All the knees were devoid of gross pathological change and no discoid menisci were included. Significant differences are reported in the thickness of the zones of uncalcified fibrocartilage and cortical calcified tissue (calcified fibrocartilage and underlying lamellar bone) and in the percentage of bone:bone marrow. There was a thicker zone of uncalcified fibrocartilage and a greater quantity of calcified tissue at the horns of the lateral than the medial meniscus. The differences in uncalcified fibrocartilage were largely attributable to the posterior horns, but the variations in calcified tissue mainly reflected differences between the anterior horns. It is suggested that the greater mobility of the lateral meniscus and the blending of its anterior horn with the anterior cruciate ligament are important factors accounting for the quantitative differences in the meniscal attachment zones.