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.

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.

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.

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.

Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain.

Ketorolac tromethamine, a nonnarcotic, prostaglandin synthesis-inhibiting analgesic, was compared with morphine sulfate for relief of moderate to severe postoperative pain. The 155 patient participants received single intramuscular doses of either ketorolac, 10, 30, or 90 mg, or morphine, 6 or 12 mg, administered in a double-blind, randomized fashion. Pain scores (verbal and visual analog) were recorded at baseline and assessed at 30 minutes and then hourly to 6 hours. Pain relief was rated at the same times. Ketorolac, 90 and 30 mg, was rated significantly better than morphine, 6 mg, at each assessment interval after 1 hour. Ketorolac, 90 and 30 mg, was rated similarly to morphine, 12 mg, for the first 3 hours and better than morphine, 12 mg, 4 hours after injection. There were no serious side effects reported. The only side effect reported in more than 3% of patients was 8% somnolence with morphine. This study shows ketorolac to be a safe and effective analgesic for relief of postoperative pain.

Intravenous ketorolac tromethamine versus morphine sulfate in the treatment of immediate postoperative pain.

Intravenous ketorolac tromethamine was compared with morphine sulfate for the relief of moderate to severe postoperative pain and for side effects in 125 women undergoing major abdominal gynecologic surgery. Patients were randomly assigned to receive an initial intravenous dose of ketorolac 10 mg, ketorolac 30 mg, morphine 2 mg, or morphine 4 mg, administered in a double-blind fashion. No other narcotics were administered in the 3 hours preceding the first dose of study drug. A second dose was administered on request, but no sooner than 15 minutes after the initial dose. Patients who required additional analgesia within the 6-hour observation period were remedicated with a backup analgesic and withdrawn from the study. Pain scores and side effect evaluations were performed at baseline, 30 minutes, 1 hour, and then hourly for up to 6 hours or until the subject terminated the study. No significant differences among the treatments were noted in terms of area under the time-effect curves for pain intensity differences or pain relief. In each treatment group, 70-80% of patients withdrew within 1 hour and approximately 90% within 3 hours of the initial drug dose because of inadequate analgesia. With the dosage regimens used, neither drug adequately controlled moderate to severe pain in the immediate postoperative period. Patients receiving ketorolac experienced significantly less drowsiness than those given morphine, and some subjects in each experienced nausea. No serious adverse effects were reported.

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.

Local or general anaesthetic in day case arthroscopy?

A series of 66 patients who have undergone arthroscopy of the knee using three local anesthetic techniques is presented. Over a similar period of time 70 patients had knee arthroscopy performed under general anaesthesia. In the local anaesthetic group the technique was successful in 50 cases, partially successful in 12 cases and totally unsatisfactory in 4 cases. In the general anaesthetic group all the procedures were successful. Local anaesthetic techniques were found to be satisfactory for diagnostic arthroscopy but general anaesthesia was better for operative procedures and was more acceptable to the surgeon and patient.

Diagnosis of Johne's disease in cattle using mesenteric lymph node biopsy: accuracy in clinical suspects.

Histopathological examination of biopsies of mesenteric lymph node obtained from the region of the terminal ileum proved to be a very accurate method of diagnosing Johne's disease in the living animal. Identical conclusions were reached in 100 clinical suspects following examination of either mesenteric lymph nodes alone, or a wider range of routine specimens including ileum, caecum, colon and ileocaecal lymph nodes. A method of obtaining biopsy specimens from mesenteric lymph nodes is described and is recommended when an early definitive diagnosis is required.

Bovine nasal granuloma in Victoria -- a search for the causative allergens.

Cows with nasal granuloma showed skin sensitivity to a range of environmental allergens while clinically normal control animals showed little sensitivity. The allergens producing the greatest number of positive reactions included the pollens of dock, capeweed, clover, paspalum, sorrel, rye grass, pepper tree and wattle, the spores of penicillium, cladosporium, botrytis and rye grass rust and extracts of sheep's wool and mite. It is likely that different allergens are important in different animals and in different regions and their importance in the aetiology of nasal granuloma probably depends on their presence in the inhaled air in high concentration for long periods.

Hypogammaglobulinaemia in foals: prevalence on Victorian studs and simple methods for detection and correction in the field.

The prevalence of hypogammaglobulinaemia in 82 young foals was determined. Twelve foals were considered clinically abnormal at birth and ten died within two weeks. All of these foals were hypogammaglobulinaemic. Seven (10%) of the other 70 apparently normal foals were hypogammaglobulinaemic despite having suckled normally. Three of these foals developed significant disease and one died at one month of age. Rapid detection of foals with low serum immunoglobulin levels was achieved by adapting the zinc sulphate turbidity test to partially evacuated blood collection tubes. This permitted test to be conducted on the stud or in the veterinarian's own laboratory. Plasma concentrated twofold by a freeze thaw technique was administered intravenously to supplement the immunoglobulin levels of two colostrum deprived foals. The simplicity of the concentration procedure eliminated the need for laboratory preparation of equine immunoglobulin.

Bovine nasal granuloma (atopic rhinitis) in Victoria. Experimental reproduction by the production of immediate type hypersensitivity in the nasal mucosa.

The Australian type of bovine nasal granuloma (bovine atopic rhinitis) was reproduced clinically, grossly and histopathologically in 7 of 9 experimental cattle by subjecting them to repeated acute episodes of immediate-type hypersensitivity on their nasal mucosa over periods of several months.

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.

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.