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Abstract Background The clinical diagnosis of encephalitis is often difficult and identification of a causative organism is infrequent. The encephalitis syndrome may herald the emergence of novel pathogens with outbreak potential. Individual treatment and an effective public health response rely on identifying a specific pathogen. In Australia there have been no studies to try to improve the identification rate of encephalitis pathogens. This study aims to review the diagnostic assessment of adult suspected encephalitis cases. Methods A retrospective clinical audit was performed, of all adult encephalitis presentations between July 1998 and December 2007 to the three hospitals with adult neurological services in the Hunter New England area, northern New South Wales, Australia. Case notes were examined for evidence of relevant history taking, clinical features, physical examination, laboratory and neuroradiology investigations, and outcomes. Results A total of 74 cases were included in the case series. Amongst suspected encephalitis cases, presenting symptoms and signs included fever (77.0%), headache (62.1%), altered consciousness (63.5%), lethargy (32.4%), seizures (25.7%), focal neurological deficits (31.1%) and photophobia (17.6%). The most common diagnostic laboratory test performed was cerebrospinal fluid (CSF) analysis (n = 67, 91%). Herpes virus polymerase chain reaction (n = 53, 71.6%) and cryptococcal antigen (n = 46, 62.2%) were the antigenic tests most regularly performed on CSF. Neuroradiological procedures employed were computerized tomographic brain scanning (n = 68, 91.9%) and magnetic resonance imaging of the brain (n = 35, 47.3%). Thirty-five patients (47.3%) had electroencephalograms. The treating clinicians suspected a specific causative organism in 14/74 cases (18.9%), of which nine (12.1%) were confirmed by laboratory testing. Conclusions The diagnostic assessment of patients with suspected encephalitis was not standardised. Appropriate assessment is necessary to exclude treatable agents and identify pathogens warranting public health interventions, such as those transmitted by mosquitoes and those that are vaccine preventable. An algorithm and guidelines for the diagnostic workup of encephalitis cases would assist in optimising laboratory testing so that clinical management can be best tailored to the pathogen, and appropriate public health measures implemented.

Abstract Background Outbreak investigation is a core function of public health agencies. Suboptimal outbreak investigation endangers both public health and agency reputations. While audits of clinical medical and nursing practice are conducted as part of continuous quality improvement, public health agencies rarely make systematic use of structured audits to ensure best practice for outbreak responses, and there is limited guidance or policy to guide outbreak audit. Methods A framework for prioritising which outbreak investigations to audit, an approach for conducting a successful audit, and a template for audit trigger questions was developed and trialled in four foodborne outbreaks and a respiratory disease outbreak in Australia. Results The following issues were identified across several structured audits: the need for clear definitions of roles and responsibilities both within and between agencies, improved communication between agencies and with external stakeholders involved in outbreaks, and the need for development of performance standards in outbreak investigations - particularly in relation to timeliness of response. Participants considered the audit process and methodology to be clear, useful, and non-threatening. Most audits can be conducted within two to three hours, however, some participants felt this limited the scope of the audit. Conclusion The framework was acceptable to participants, provided an opportunity for clarifying perceptions and enhancing partnership approaches, and provided useful recommendations for approaching future outbreaks. Future challenges include incorporating feedback from broader stakeholder groups, for example those of affected cases, institutions and businesses; assessing the quality of a specific audit; developing training for both participants and facilitators; and building a central capacity to support jurisdictions embarking on an audit. The incorporation of measurable performance criteria or sharing of benchmark performance criteria will assist in the standardisation of outbreak investigation audit and further quality improvement.

Abstract Background A storm-related disaster in New South Wales, Australia in June 2007 caused infrastructure damage, interrupted essential services, and presented major public health risks. We investigated household disaster preparedness and information sources used before and during the disaster. Methods Rapid cluster survey of 320 randomly selected households in Newcastle and Lake Macquarie, New South Wales, Australia. Results 227 households (71%) responded to the survey. By the day before the storm, 48% (95%CI 40–57%) of households were aware of a storm warning, principally through television (67%; 58–75%) and radio (57%; 49–66%) announcements. Storm preparations were made by 42% (28–56%) of these households. Storm information sources included: radio (78%; 68–88%); family, friends, colleagues and neighbours (50%; 40–60%); and television (41%; 30–52%). Radio was considered more useful than television (62%; 51–73% vs. 29%; 18–40%), even in households where electricity supply was uninterrupted (52%; 31–73% vs. 41%; 20–63%). Only 23% (16–30%) of households were aware that the local government-operated radio network has a designated communication role during disasters. A battery-operated household radio and appropriate batteries were available in 42% (34–50%) of households, while only 23% (16–29%) had all of: a torch, battery-operated radio, appropriate batteries, mobile phone, emergency contact list and first aid equipment. Conclusion Broadcast media are important information sources immediately before and during disasters. Health services should promote awareness of broadcast networks' disaster role, especially the role of radio, and encourage general household disaster preparedness. A rapid cluster survey conducted shortly after a natural disaster provided practical, robust information for disaster planning.

Abstract Background To determine patterns of childhood lead exposure in a community living near a lead and zinc smelter in North Lake Macquarie, Australia between 1991 and 2002. Methods An analysis of serial blood lead levels (BLL) of children less than 13 years of age in North Lake Macquarie participating in voluntary blood lead screening. Distance to the smelter and soil lead concentration of the child's place of residence was calculated. Categorical analysis of BLL by residential distance from smelter, residential soil lead concentration, age and year of sample was calculated. Linear regression models were fit for blood lead levels against residential distance from smelter, the log of residential soil lead concentration, age and year of BLL sample. Results Geometric mean BLLs were statistically significantly higher for distances less than 1.5 kilometres from the smelter and for residential soil lead concentrations greater than 300 ppm. Yearly BLLs since 1995 were statistically significantly lower than for preceding years, with an average decrease of 0.575 μg/dL per year since 1991. BLLs are statistically significantly higher for children whose age is 1 to 3 years old. Linear regression modelling of BLL predicted a statistically significant decrease in BLL of 3.0831 μg/dL per kilometre from the smelter and a statistically significant increase in BLL of 0.25 μg/dL per log of lead in residential soil. The model explained 28.2% of the variation in BLL. Conclusion Residential distance to the smelter, log of residential soil lead concentration, child's age and year of BLL sample are statistically significant factors for predicting elevated BLLs in children living near a North Lake Macquarie lead smelter.

Detection and quantification of the amorphous phase of etoricoxib bulk drug substances, a selective cycloogenase-2 inhibitor used for the treatment of osteoarthritis, rheumatoid arthritis, and dental pain, was carried out using modulated differential scanning calorimetry (MDSC), dynamic mechanical analysis (DMA), and Raman spectroscopy. Detection of amorphous content in pharmaceutical powders by DMA is a special application of dynamic mechanical spectroscopy. DMA was found to be a sensitive technique, able to detect the presence of an amorphous phase in a crystalline phase at concentrations as low as 0.5%. The limit of detection (LOD) determined for DMA was 2.5%. In comparison, Raman spectroscopy and MDSC had LOD values of 2% and 5% amorphous, respectively., (Copyright © 2011 Wiley Periodicals, Inc.)

We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.

The physical stability of bulk active pharmaceutical ingredients (API) is of significant scientific and regulatory concern. Carrying out physical stability testing on lots with varying rates of hydrate conversion can potentially lead to erroneous conclusions if these rate differences remain unknown and unstudied. The lot dependency of etoricoxib's rate of hemihydrate conversion was investigated and a quick discriminatory technique was developed to qualitatively assess relatively slow to rapidly converting lots. This novel technique was also used to screen potential parameters affecting the hydrate conversion rate such as particle size/surface area, amorphous content, and initial hemihydrate content. Based on qualitative X-ray powder diffraction (XRPD) and quantitative Raman data, significant effects on the rate of hydration were observed with the addition of small amounts of amorphous etoricoxib. Furthermore, it was found that the presence of hemihydrate also increased the rate of conversion by seeding anhydrous etoricoxib. This suggests that the initial presence of the hydrate form can cooperatively accelerate conversion. A better understanding of the factors affecting hydrate conversion rates resulted in the appropriate selection of storage conditions for both the bulk API and the formulated product.

A series of non-amide-linked 6-substituted-2-naphthamidine urokinase plasminogen activator (uPA) inhibitors are described. These compounds possess excellent binding activities and selectivities with significantly improved pharmacokinetic profiles versus previously described amide-linked inhibitors.

The use of two 'micro-scale' dynamic mechanical testing techniques for determining the viscoelastic properties of very small microcrystalline cellulose compacts ( approximately 20 mg) is reported. The first method is a simple tensile 'stretching' test, and the second is a dynamic version of the three-point beam-bending technique. For both approaches the storage (elastic) and loss (viscous) moduli could be readily determined for compacts of a wide range of porosities. The experimentally determined storage moduli were consistently one order of magnitude greater than the corresponding loss moduli indicating a dominating elastic response for the microcrystalline cellulose compacts. The moduli determined using the oscillating three-point beam-bending technique were slightly lower than expected and this was attributed to sample anisotropy and imperfect sample alignment/friction during testing. The moduli obtained using the simple dynamic tension tests were practically identical to complex moduli values reported for much larger specimens, and it appears that this technique is well suited to measuring the dynamic mechanical properties of very small pharmaceutical powder compacts.

Differential scanning calorimetry (DSC) is frequently the pharmaceutical thermal analysis technique of choice because of its ability to provide detailed information about both the physical and energetic properties of a substance. This review provides an up-to-date overview of the applications of DSC in the drug development process. It should serve as a broad introduction to those starting work in this area, and also as a valuable reference for those already practising in this field.

To determine the effect of temperature on the water vapor sorption behavior of some amorphous pharmaceutical sugars, aqueous solutions of sucrose, lactose, trehalose, and raffinose were freeze-dried using a conventional laboratory lyophilizer. The amorphous sugars formed were stored for several months at 5, 30, and 50 degrees C and at a range of relative humidities (0-90% RH). After equilibration the extent of water vapor sorption was determined gravimetrically, and the presence of any crystalline material was determined. A significant amount of water was sorbed by each of the amorphous sugars even at moderate humidities. In every system studied, lowering the storage temperature at any given relative humidity caused an increased quantity of water to be sorbed. This indicated the predominance of an exothermic water vapor sorption process. Spontaneous crystallization of all the sugars occurred at elevated RHs, and the onset of crystallization did not necessarily coincide with attainment of the water content of the final crystalline forms(s) or the reduction of the sugars' glass transition temperature to ambient conditions. Notably, the amorphous and crystalline forms of some sugars were able to coexist in a quasi-equilibrium state under certain temperature and humidity conditions.

Purpose: To evaluate a simple calorimetric method for estimating the fragility of amorphous pharmaceutical materials from the width of the glass transition region., Methods: The glass transition temperature regions of eleven amorphous pharmaceutical materials were characterized at six different heating and cooling rates by differential scanning calorimetry (DSC)., Results: Activation energies for structural relaxation (which are directly related to glass fragility) were estimated from the scan rate dependence of the glass transition temperature, and correlations between the glass transition widths and the activation energies were examined. The expected correlations were observed, and the exact nature of the relationship varied according to the type of material under consideration., Conclusions: The proposed method of determining the fragility of amorphous materials from the results of simple DSC experiments has some utility, although "calibration" of the method for each type of materials is necessary. Further work is required to establish the nature of the relationships for a broad range of amorphous pharmaceutical materials.

Selected examples from three series of isomeric (alkylthio)-1,2,4-triazoles were prepared and examined for anticonvulsant activity versus strychnine-, maximal-electroshock-, pentylenetetrazole-, and 3-mercaptopropionic-acid-induced seizures in mice. A number of 5-aryl-3-(alkylthio)-4H-1,2,4-triazoles were selective antagonists of strychnine-induced convulsions. The isomeric 3-aryl-5-(alkylthio)- and 5-aryl-3-(alkylthio)-1H-1,2,4-triazoles were essentially inactive as anticonvulsants. The most potent antagonist of strychnine-induced convulsions was 5-(2-fluorophenyl)-4-methyl-3-(methylthio)-4H-1,2,4-triazole (3s), while the most selective antagonist was 5-(3-fluorophenyl)-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3aa). The anticonvulsant profiles of these 4H-1,2,4-triazoles suggested that they were acting functionally like glycine receptor agonists. Since it has recently been postulated that compounds possessing glycine-agonist-like properties might be useful in the treatment of spasticity, we examined 5-phenyl-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3c) in an in vivo model of spasticity. In this regard, 3c reduced the occurrence of hyperreflexia in rats that had received spinal transections 5-10 weeks previously. While triazole 3c appeared to possess glycine-agonist-like properties in vivo, it did not displace [3H]strychnine binding from rat brain stem/spinal cord membranes in vitro. On the other hand, 3c enhanced muscimol-stimulated 36Cl influx in a rat cerebellar membrane preparation, indicating a possible interaction of these triazoles with the GABAA receptor.