The 2000 Ogura Lecture: Olfactory neural cells: An untapped diagnostic and therapeutic resource

Objective. This is an over-view of the cellular biology of upper nasal mucosal cells that have special characteristics that enable them to be used to diagnose and study congenital neurological diseases and to aid neural repair. Study Design: After mapping the distribution of neural cells in the upper nose, the authors' investigations moved to the use of olfactory neurones to diagnose neurological diseases of development, especially schizophrenia. Olfactory-ensheating glial cells (OEGs) from the cranial cavity promote axonal penetration of the central nervous system and aid spinal cord repair in rodents. The authors sought to isolate these cells from the more accessible upper nasal cavity in rats and in humans and prove they could likewise promote neural regeneration, making these cells suitable for human spinal repair investigations. Methods: The schizophrenia-diagnosis aspect of the study entailed the biopsy of the olfactory areas of 10 schizophrenic patients and 10 control subjects. The tissue samples were sliced and grown in culture medium. The ease of cell attachment to fibronectin (artificial epithelial basement membrane), as well as the mitotic and apoptotic indices, was studied in the presence and absence of dopamine in those cell cultures. The neural repair part of the study entailed a harvesting and insertion of first rat olfactory lamina propria rich in OEGs between cut ends of the spinal cords and then later the microinjection of an OEG-rich suspension into rat spinal cords previously transected by open laminectomy. Further studies were done in which OEG insertion was performed up to 1 month after rat cord transection and also in monkeys. Results: Schizophrenic patients' olfactory tissues do not easily attach to basement membrane compared with control subjects, adding evidence to the theory that cell wall anomalies are part of the schizophrenic lesion of neurones. Schizophrenic patient cell cultures had higher mitotic and apoptotic indices compared with control subjects. The addition of dopamine altered these indices enough to allow accurate differentiation of schizophrenics from control patients, leading to, possibly for the first time, an early objective diagnosis of schizophrenia and possible assessment of preventive strategies. OEGs from the nose were shown to be as effective as those from the olfactory bulb in promoting axonal growth across transected spinal cords even when added I month after injury in the rat. These otherwise paraplegic rats grew motor and proprioceptive and fine touch fibers with corresponding behavioral improvement. Conclusions. The tissues of the olfactory mucosa are readily available to the otolaryngologist. Being surface cells, they must regenerate (called neurogenesis). Biopsy of this area and amplification of cells in culture gives the scientist a window to the developing brain, including early diagnosis of schizophrenia. The Holy Grail of neurological disease is the cure of traumatic paraplegia and OEGs from the nose promote that repair. The otolaryngologist may become the necessary partner of the neurophysiologist and spinal surgeon to take the laboratory potential of paraplegic cure into the day-to-day realm of clinical reality.

Strange bedfellows: Green Hill Fort, archaeology and tourism

Green Hill Fort, Thursday Islalld was constructed between 1891-1893 to defend the Australian colonies against a feared Russian invasion. It retained an operational role until the 1920.'1 and played a minor role in World /t'ar 2. From 1954 to 1993 the site, but not the facilities, was used as a weather station. More recently it has been home ofthe Ton-es Strait Historical Society and Museum Association museum. It is a major attraction during the tourist season and an important local icon. For archaeologists it has sign~ficance as a relatively intact nineteenth-century military installation. Two 'Centenary of Federation' grants have proVided the impetus to undertake conservation and presentation works involving various task -spec~fic, archaeological activities. At the management level archaeologists play the lead role in the project. The project has demonstrated the value oJarchaeology and tourism joining forces. The danger ofa 'theme park 'presentation has been avoided. Technical accuracy and careful site planning has ensured a high degree ofaccuracy is retained. Provided these qualities can be assured then, it is argued, there is an opportunity for archaeology to be a majOl; long-term beneficiary. But to achieve that, the discipline must move from being entrenched in its academic mould and become Jar more receptive to the broader needs ofthe twentyfirst century.

Simulation of the micro-physics of rocks using LSMearth

The particle-based Lattice Solid Model (LSM) was developed to provide a basis to study the physics of rocks and the nonlinear dynamics of earthquakes (MORA and PLACE, 1994; PLACE and MORA, 1999). A new modular and flexible LSM approach has been developed that allows different microphysics to be easily included in or removed from the model. The approach provides a virtual laboratory where numerical experiments can easily be set up and all measurable quantities visualised. The proposed approach provides a means to simulate complex phenomena such as fracturing or localisation processes, and enables the effect of different micro-physics on macroscopic behaviour to be studied. The initial 2-D model is extended to allow three-dimensional simulations to be performed and particles of different sizes to be specified. Numerical bi-axial compression experiments under different confining pressure are used to calibrate the model. By tuning the different microscopic parameters (such as coefficient of friction, microscopic strength and distribution of grain sizes), the macroscopic strength of the material and can be adjusted to be in agreement with laboratory experiments, and the orientation of fractures is consistent with the theoretical value predicted based on Mohr-Coulomb diagram. Simulations indicate that 3-D numerical models have different macroscopic properties than in 2-D and, hence, the model must be recalibrated for 3-D simulations. These numerical experiments illustrate that the new approach is capable of simulating typical rock fracture behaviour. The new model provides a basis to investigate nucleation, rupture and slip pulse propagation in complex fault zones without the previous model limitations of a regular low-level surface geometry and being restricted to two-dimensions.

The therapeutic potential of dopamine modulators on the cardiovascular and renal systems

In the periphery, physiological dopamine increases renal blood flow, decreases renal resistance and acts on the kidney tubule to enhance natriuresis and diuresis. The loss of dopamine function may be involoved in the deterioration in kidney function associated with ageing and may have a role in the pathogenesis of hypertension and diabetes. Intravenous dopamine is used as a positive inotrope in the treatment of acute heart failure and cardiogenic shock and as a diuretic in renal failure. The clinical uses of dopamine are limited, as it must be given intravenously, and also has widespread effects. The levels of peripheral dopamine can be increased by the administration of L-dopa to increase synthesis, prodrugs to release dopamine (docarpamine, glu-dopa) or by inhibiting the breakdown of dopamine (nitecapone). Preliminary clinical trials suggest that docarpamine may be useful in patients with low cardiac output syndrome after cardiac surgery and in refractory cirrhotic ascites. Ibopamine is an agonist at dopamine D1 and D2 receptors, which may retard the progression of chronic renal failure. Gludopa is selective for the kidney thus avoiding widespread side effects. The early clinical studies with ibopamine as a diuretic in heart failure were favourable but the subsequent large mortality study showed that ibopamine increased mortality. Fenoldopam is a selective dopamine D1 receptor agonist. Intravenous fenoldopam may be useful in the treatment of hypertension associated with coronary artery bypass surgery or in hypertensive emergencies. Although our understanding of physiological and pathological roles of peripheral dopamine has been increasing rapidly in recent times, we still need more information to allow the design of clinically useful drugs that modify these roles. One priority is an orally-active selective dopamine D1 receptor agonist.

Biological determinants of extinction risk: why are smaller species less vulnerable?

It is becoming increasingly clear that species of smaller body size tend to be less vulnerable to contemporary extinction threats than larger species, but few studies have examined the mechanisms underlying this pattern. In this paper, data for the Australian terrestrial mammal fauna are used to ask whether higher reproductive output or smaller home ranges can explain the reduced extinction risk of smaller species. Extinct and endangered species do indeed have smaller litters and larger home ranges for their body size than expected under a null model. In multiple regressions, however, only litter size is a significant predictor of extinction risk once body size and phylogeny are controlled for. Larger litters contribute to fast population growth, and are probably part of the reason that smaller species are less extinction-prone. The effect of litter size varies between the mesic coastal regions and the and interior of Australia, indicating that the environment a species inhabits mediates the effect of biology on extinction risk. These results suggest that predicting extinction risk from biological traits is likely to be a complex task which must consider explicitly interactions between biology and environment.

MAX4 and RMS1 are orthologous dioxygenase-like genes that regulate shoot branching in Arabidopsis and pea

Shoot branching is inhibited by auxin transported down the stem from the shoot apex. Auxin does not accumulate in inhibited buds and so must act indirectly. We show that mutations in the MAX4 gene of Arabidopsis result in increased and auxin-resistant bud growth. Increased branching in max4 shoots is restored to wild type by grafting to wild-type rootstocks, suggesting that MAX4 is required to produce a mobile branch-inhibiting signal, acting downstream of auxin. A similar role has been proposed for the pea gene, RMS1. Accordingly, MAX4 and RMS1 were found to encode orthologous, auxin-inducible members of the polyene dioxygenase family.

Spatial and temporal changes in multiple hormone groups during lateral bud release shortly following apex decapitation of chickpea (Cicer arietinum) seedlings

Although the co-ordination of promotive root-sourced cytokinin (CK) and inhibitory shoot apex-sourced auxin (IAA) is central to all current models on lateral bud dormancy release, control by those hormones alone has appeared inadequate in many studies. Thus it was hypothesized that the IAA : CK model is the central control but that it must be considered within the relevant timeframe leading to lateral bud release and against a backdrop of interactions with other hormone groups. Therefore, IAA and a wide survey of cytokinins (CKs), were examined along with abscisic acid (ABA) and polyamines (PAs) in released buds, tissue surrounding buds and xylem sap at 1 and 4 h after apex removal, when lateral buds of chickpea are known to break dormancy. Three potential lateral bud growth inhibitors, IAA, ABA and cis-zeatin 9-riboside (ZR), declined sharply in the released buds and xylem following decapitation. This is in contrast to potential dormancy breaking CKs like trans-ZR and trans-zeantin 9-riboside 5'phosphate (ZRMP), which represented the strongest correlative changes by increasing 3.5-fold in xylem sap and 22-fold in buds. PAs had not changed significantly in buds or other tissues after 4 h, so they were not directly involved in the breaking of bud dormancy. Results from the xylem and surrounding tissues indicated that bud CK increases resulted from a combination synthesis in the bud and selective loading of CK nucleotides into the xylem from the root.

The coincidence of thrips and dispersed pollen in PNRSV-infected stonefruit orchards - a precondition for thrips-mediated transmission via infected pollen

Recent laboratory studies have demonstrated that Prunus necrotic ringspot virus (PNRSV) (family Bromoviridae) can be readily transmitted when thrips and virus-bearing pollen are placed together on to test plants. For this transmission mechanism to result in stonefruit tree infection in the field, PNRSV-bearing pollen must be deposited onto surfaces of stonefruit trees on which thrips also occur. In a previous paper, we demonstrated that almost all pollen in a PNRSV-infected Japanese plum orchard in southeastern Queensland was deposited onto flowers, whereas few grains occurred on leaves and none on stems. Here, we present results of our investigation of thrips species composition, distribution and abundance on stonefruit trees in the same study area as our previous pollen deposition study. We collected a total of 2010 adult thrips from 13 orchards during the 1989, 1991 and 1992 flowering seasons of which all but 14 were in the suborder Terebrantia. Most (97.4%) terebrantian thrips were of three species, Thrips imaginis, Thrips australis and Thrips tabaci. Thrips tabaci as well as species mixtures that included T imaginis, T australis and T tabaci have been shown to transmit PNRSV via infected pollen in laboratory tests. Adult thrips were frequently collected from flowers but rarely from leaves and never from stems. Large and significant differences in numbers of T imaginis, T australis and T tabaci adults in flowers occurred among orchards and between seasons. No factor was conclusively related to thrips numbers but flowers of late-flowering stonefruit varieties tended to hold more thrips than those of early-flowering varieties. Our results indicate that the common thrips species present on stonefruit trees in the Granite Belt are also ones previously shown to transmit PNRSV via infected pollen in the laboratory and that these thrips are concentrated in stonefruit flowers where most stonefruit pollen is deposited. These results contribute to mounting circumstantial evidence that stonefruit flowers may be inoculated with PNRSV via an interaction of thrips with virus-bearing pollen and that this transmission mechanism may be an important cause of new tree infections in the field.

Phenomenological turbulence and innovation in knowledge systems

Most considerations of knowledge management focus on corporations and, until recently, considered knowledge to be objective, stable, and asocial. In this paper we wish to move the focus away from corporations, and examine knowledge and national innovation systems. We argue that the knowledge systems in which innovation takes place are phenomenologically turbulent, a state not made explicit in the change, innovation and socio-economic studies of knowledge literature, and that this omission poses a serious limitation to the successful analysis of innovation and knowledge systems. To address this lack we suggest that three evolutionary processes must be considered: self-referencing, self-transformation and self-organisation. These processes, acting simultaneously, enable system cohesion, radical innovation and adaptation. More specifically, we argue that in knowledge-based economies the high levels of phenomenological turbulence drives these processes. Finally, we spell out important policy principles that derive from these processes.

Indirect evidence of density-dependent population regulation in Aponomma hydrosauri (Acari : Ixodidae), an ectoparasite of reptiles

The extent to which density-dependent processes regulate natural populations is the subject of an ongoing debate. We contribute evidence to this debate showing that density-dependent processes influence the population dynamics of the ectoparasite Aponomma hydrosauri (Acari: Ixodidae), a tick species that infests reptiles in Australia. The first piece of evidence comes from an unusually long-term dataset on the distribution of ticks among individual hosts. If density-dependent processes are influencing either host mortality or vital rates of the parasite population, and those distributions can be approximated with negative binomial distributions, then general host-parasite models predict that the aggregation coefficient of the parasite distribution will increase with the average intensity of infections. We fit negative binomial distributions to the frequency distributions of ticks on hosts, and find that the estimated aggregation coefficient k increases with increasing average tick density. This pattern indirectly implies that one or more vital rates of the tick population must be changing with increasing tick density, because mortality rates of the tick's main host, the sleepy lizard, Tiliqua rugosa, are unaffected by changes in tick burdens. Our second piece of evidence is a re-analysis of experimental data on the attachment success of individual ticks to lizard hosts using generalized linear modelling. The probability of successful engorgement decreases with increasing numbers of ticks attached to a host. This is direct evidence of a density-dependent process that could lead to an increase in the aggregation coefficient of tick distributions described earlier. The population-scale increase in the aggregation coefficient is indirect evidence of a density-dependent process or processes sufficiently strong to produce a population-wide pattern, and thus also likely to influence population regulation. The direct observation of a density-dependent process is evidence of at least part of the responsible mechanism.

Core outcome domains for chronic pain clinical trials: IMMPACT recommendations

Objective. To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment. Methods. Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia. governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain. Conclusions. There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy. (C) 2003 International Association for the Study of Pain.

Biochemical and molecular studies using human autopsy brain tissue

The use of human brain tissue obtained at autopsy for neurochemical, pharmacological and physiological analyses is reviewed. RNA and protein samples have been found suitable for expression profiling by techniques that include RT-PCR, cDNA microarrays, western blotting, immunohistochemistry and proteomics. The rapid development of molecular biological techniques has increased the impetus for this work to be applied to studies of brain disease. It has been shown that most nucleic acids and proteins are reasonably stable post-mortem. However, their abundance and integrity can exhibit marked intra- and intercase variability, making comparisons between case-groups difficult. Variability can reveal important functional and biochemical information. The correct interpretation of neurochemical data must take into account such factors as age, gender, ethnicity, medicative history, immediate ante-mortem status, agonal state and post-mortem and post-autopsy intervals. Here we consider issues associated with the sampling of DNA, RNA and proteins using human autopsy brain tissue in relation to various ante- and post-mortem factors. We conclude that valid and practical measures of a variety of parameters may be made in human brain tissue, provided that specific factors are controlled.

Warranty and optimal reliability improvement through product development

For products sold with warranty, the warranty servicing cost can be reduced by improving product reliability through a development process. However, this increases the unit manufacturing cost. Optimal development must achieve a trade-off between these two costs. The outcome of the development process is uncertain and needs to be taken into account in the determination of the optimal development effort. The paper develops a model where this uncertainty is taken into account. (C) 2003 Elsevier Ltd. All rights reserved.

Developmental anomalies in the tooth plates and jaw bones of lungfish

Lungfish of the tooth-plated lineage, both fossil and living, may be affected by alterations in the permanent tooth plates and associated jaw bones as they grow. In a few taxa, the unusual structures may be so common that they must be considered as normal for those species, or as a variation of the normal condition. In others the condition is rare, affecting only a few individuals. Variations, or anomalies, may appear in the growing tissues of the lungfish tooth plate at any time in the life cycle, although they usually appear early in development. Once the changes appear, they persist in the dentition. The altered structures include divided or intercalated ridges, short ridge anomaly, changes in the shape, number and position of cusps, pattern loss, and fused ridges or cusps. Criteria used to distinguish alteration from normal conditions are the incidence of the character in the population, the associated changes in the jaw bone, and the position of the altered structure in the tooth plate. The occurrence of similar changes across a wide range of different species suggests that they may have a genetic cause, especially when they are a rare occurrence in most taxa, but common enough to be a part of the normal variation in others. Prevalence of related anomalies throughout the history of the group suggests that dipnoans of the tooth-plated lineage are closely related, despite significant differences in morphology, microstructure, and function of the denfitions.

A rapid method for determining recent sunscreen use in field studies

The role of sunscreens in preventing skin cancer and melanoma is the focus of ongoing research. Currently, there is no objective measure which can be used in field studies to determine whether a person has applied sunscreen to their skin, and researchers must use indirect assessments such as questionnaires. We sought to develop a rapid, non-invasive method for identifying sunscreen on the skin for use in epidemiological studies. Our basic method is to swab the skin, elute any residues which have been adsorbed onto the swab by rinsing in ethanol, and submit the eluted washings for spectrophotometric analysis. In a controlled study, we applied 0.1 ml of sunscreen to a 50 cm(2) grid on both forearms of 21 volunteers. Each forearm was allocated one of 10 different sunscreen brands. The skin was swabbed after intervals of 20 min, 1 h, 2 h and 4 h. In a field study conducted among 12 children aged 2-4 years attending a child care centre, sunscreen was applied to the faces of half the children. Swabs were then taken from the face and back of all children without knowledge of sunscreen status. In the controlled study, sunscreen was clearly detectable up to 2 h after application for all brands containing organic sunscreen, and marginally detectable at 4 h. In the field study, this method correctly identified all children with and without sunscreen. We conclude that spectrophotometric analysis of skin swabs can reliably detect the presence of sunscreen on the skin for up to 2 It after application. (C) 2002 Elsevier Science B.V. All rights reserved.