Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.

The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 + T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >65%, with a reduction in viability <45%, ex vivo. In memory CD4 + T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).

Electrocardiogram interpretation in the athlete.

The sudden death of a young athlete is a devastating event that impacts the lay public and medical community and has attracted efforts to screen for underlying cardiovascular diseases associated with sudden death in this population. Electrocardiography (ECG) screening has been shown to increase the sensitivity of finding structural heart diseases in competitive athletes. Recent research in diverse populations of athletes has led to refinements in ECG-interpretation standards designed to improve its diagnostic accuracy. This review summarizes relevant information regarding cardiovascular screening and ECG interpretation in athletes.

Towards an evidence-based process for the clinical interpretation of copy number variation.

The evidence-based review (EBR) process has been widely used to develop standards for medical decision-making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large-scale case-control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.

Role of Rho kinase isoforms in murine allergic airway responses.

Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses. Wildtype (WT) mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1(+/-) and ROCK2(+/-), respectively) were sensitised and challenged with ovalbumin. ROCK expression and activation were assessed by western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment. Compared with WT mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1(+/-) and ROCK2(+/-) mice, respectively, without changes in the other isoform. In WT lungs, ROCK activation increased after ovalbumin challenge and was sustained for several hours. This activation was reduced in ROCK1(+/-) and ROCK2(+/-) lungs. Airway responsiveness was comparable in WT, ROCK1(+/-), and ROCK2(+/-) mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in WT, but not ROCK1(+/-) or ROCK2(+/-) mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1(+/-) and ROCK2(+/-) versus WT mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1(+/-) mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses.

Experimental transmission of chronic wasting disease (CWD) of elk (Cervus elaphus nelsoni), white-tailed deer (Odocoileus virginianus), and mule deer (Odocoileus hemionus hemionus) to white-tailed deer by intracerebral route.

To compare clinical and pathologic findings of chronic wasting disease (CWD) in a natural host, 3 groups (n = 5) of white-tailed deer (WTD) fawns were intracerebrally inoculated with a CWD prion of WTD, mule deer, or elk origin. Three other uninoculated fawns served as controls. Approximately 10 months postinoculation (MPI), 1 deer from each of the 3 inoculated groups was necropsied and their tissues were examined for lesions of spongiform encephalopathy (SE) and for the presence of abnormal prion protein (PrP(d)) by immunohistochemistry (IHC) and Western blot (WB). The remaining deer were allowed to live until they developed clinical signs of the disease which began approximately 18 MPI. By 26 MPI, all deer were euthanatized on humane grounds. Obvious differences in clinical signs or the incubation periods were not observed between the 3 groups of deer given CWD. In 1 of 3 nonclinical deer euthanatized at 10 MPI, minimal microscopic lesions of SE were seen in the central nervous system (CNS) tissues, and PrP(d) was observed by IHC in tissues of all 3 deer. In the clinical deer, CNS lesions of SE and PrP(d) accumulations were more severe and extensive. It is concluded that the 3 sources of CWD prion did not induce significant differences in time to clinical disease or qualitative differences in signs or lesions in WTD. However, this observation does not imply that these CWD agents would necessarily behave similarly in other recipient species.

Assessment of potential human health risks posed by benzene in beverages.

A recent study by the U.S. Food and Drug Administration (FDA) indicated that some beverages contained benzene at levels above the federal drinking water standard of 5 parts per billion (ppb). In tests conducted by the FDA, Crystal Light Sunrise Classic Orange (CLSCO) was reported to contain benzene levels as high as 87.9 ppb. The purpose of the present study was to better characterize benzene concentrations in CLSCO and to quantify potential human health risks. Twenty-eight samples of CLSCO were obtained from retail stores in Houston, Tex., U.S.A. The mean benzene concentrations in 16 oz original and new formulation bottles were 90 and 0.18 ppb, respectively, while 64-oz bottles contained an average of 3.38 ppb. A variety of exposure scenarios were evaluated to determine potential health risks using both deterministic and probabilistic techniques. In the deterministic analyses, upper bound point estimate cancer risks ranged from 5.4E-6 to 8.7E-8, while hazard indices (HI) ranged from 0.28 to 0.00104. Probabilistic analyses were conducted to develop more realistic cancer risk estimates. In these analyses, the 50th and 95th percentile cancer risk estimates were 3.7E-6 and 8.0E-6, and the 50th and 95th percentile hazard indices were 0.19 and 0.42, respectively. In conclusion, all cancer risk estimates and noncancer hazards met the typical health risk benchmarks established by the U.S. regulatory agencies (1E-4 to 1E-6 for cancer and hazard indices less than 1.0).

Impact of culture on commitment, satisfaction, and extra-role behaviors among Canadian ER physicians.

PURPOSE: The purpose of this paper is to explore the impact of hospital emergency department culture on the job satisfaction, patient commitment, and extra-role performance of Canadian emergency physicians. The conceptual model related four cultural archetypes from the competing valued model to the three outcome variables. DESIGN/METHODOLOGY/APPROACH: In total, 428 Canadian emergency physicians responded to a national survey. The conceptual model was tested via structural equation modeling via LISREL 8. FINDINGS: Culture had a relatively weak impact on the outcomes. Human resources culture related positively to job satisfaction while bureaucratic culture related positively to patient commitment. Patient commitment, but not job satisfaction strongly and positively related to extra-role behavior. A direct relationship between entrepreneurial culture and extra-role behavior emerged from an extended analysis. PRACTICAL IMPLICATIONS: Organizational culture seems to have more distal relationships with outcome variables and its influence is likely to be mediated by more proximal workplace variables. ORIGINALITY/VALUE: Of value by showing that a key modern leadership challenge is to create the kind of work culture that can become a source of competitive advantage through generating particular organizational outcomes valued by stakeholders.

Renal tubular-cell neoplasms in black-footed ferrets (Mustela nigripes)--38 cases.

Thirty-eight cases of renal tubular cell neoplasms were diagnosed in 184 captive, adult (>1-year-old), black-footed ferrets (Mustela nigripes) examined from 1985 to 1996. This prevalence (20.7%) is one of the highest reported for this neoplasm in a population of animals. These tumors rarely metastasized (1/38), and usually were incidental postmortem findings, associated clinical disease being present in only 3 (8%) of the 38 cases. The prevalence of renal tubular cell neoplasms found at postmortem examination increased linearly with age, up to 67% in ferrets >8 years old. Both males (prevalence = 19%) and females (prevalence = 24%) were affected. Multiple renal tumors were common, and seven ferrets (18.4% of affected animals) had bilateral tumors. The cause of this neoplastic syndrome could not be determined. Since most of the animals affected by this condition were in their postreproductive years of life, the impact of this neoplastic syndrome on the captive propagation of this species is negligible.

Comparison of two automated immunohistochemical procedures for the diagnosis of scrapie in domestic sheep and chronic wasting disease in North American white-tailed deer (Odocoileus virginianus) and mule deer (Odocoileus hemionus).

Two commercially available automated immunohistochemistry platforms, Ventana NexES and DakoCytomation Autostainer Universal Staining System, were compared for diagnosing sheep scrapie and cervid chronic wasting disease. Both automated platforms used the same antiprion protein monoclonal primary antibodies, but different platform-specific linker and amplification reagents and procedures. Duplicate sections of brainstem (at the level of the obex) and lymphoid tissue (retropharyngeal lymph node or tonsil) from the same tissue block were immunostained for the comparison. Examination of 1,020 tissues from 796 sheep revealed 100% concordance of results between the Ventana NexES and DakoCytomation platforms for diagnosing sheep scrapie from lymphoid tissue (103/103 positive; 405/405 negative) and brainstem (120/120 positive; 392/392 negative). Similarly, examination of 1,008 tissues from 504 white-tailed deer revealed 100% concordance between the Ventana NexES and DakoCytomation platforms for diagnosing chronic wasting disease from lymphoid tissue (104/104 positive; 400/400 negative) and brainstem (104/104 positive; 400/400 negative). Examination of 1,152 tissues from 482 mule deer revealed a concordance of 98.6% in lymphoid tissue and 99.9% in brainstem between the Ventana NexES and DakoCytomation platforms for diagnosing chronic wasting disease. The results indicate equivalence or near equivalence between the DakoCytomation and Ventana NexES autostainer platforms for identification of the disease-associated prion protein (PrPd)-positive and PrPd-negative brain and lymphoid tissues in sheep, white-tailed deer, and mule deer.

Telomerase activity in canine osteosarcoma.

Appendicular osteosarcoma (OSA) is the most common primary bone tumour in dogs, and the prognosis with standard of care therapy of amputation and adjunctive chemotherapy is generally poor, with median survival times of 1 year. The ability of neoplastic cells to maintain their telomere length, by either telomerase activity or alternate methods, is an important step in tumour development and malignancy. The purpose of this study was to determine the presence of telomerase activity in canine OSA. To evaluate the frequency of alternative lengthening of telomeres in canine OSA, we have used the telomeric repeat amplification protocol in five canine cell lines and in six samples taken from clinical patients at the time of amputation. Our results reveal the presence of telomerase activity in 100% of canine OSA cell lines and 83% of clinical samples evaluated. This is in contrast to human OSA where 25-40% expression levels of telomerase are reported. Importantly, our results not only suggest that canine OSA may serve as a good model for aggressive telomerase-positive forms of human OSA but also that antitelomerase therapy strategies for treatment of canine OSA may be more successful than in the treatment of majority of human patients with OSA.

Chronic wasting disease.

Chronic wasting disease (CWD) is a unique transmissible spongiform encephalopathy (TSE) of mule deer (Odocoileus hemionus), white-tailed deer (O. virginianus), and Rocky Mountain elk (Cervus elaphus nelsoni). The natural history of CWD is incompletely understood, but it differs from scrapie and bovine spongiform encephalopathy (BSE) by virtue of its occurrence in nondomestic and free-ranging species. CWD has many features in common with scrapie, including early widespread distribution of disease-associated prion protein (PrP(d)) in lymphoid tissues, with later involvement of central nervous system (CNS) and peripheral tissues. This distribution likely contributes to apparent efficiency of horizontal transmission and, in this, is similar to scrapie and differs from BSE. Clinical features and lesions of CWD are qualitatively similar to the other animal TSEs. Microscopically, marked spongiform lesions occur in the central nervous system (CNS) after a prolonged incubation period and variable course of clinical disease. During incubation, PrP(d) can be identified in tissues by antibody-based detection systems. Although CWD can be transmitted by intracerebral inoculation to cattle, sheep, and goats, ongoing studies have not demonstrated that domestic livestock are susceptible via oral exposure, the presumed natural route of exposure to TSEs. Surveillance efforts for CWD in captive and free-ranging cervids will continue in concert with similar activities for scrapie and BSE. Eradication of CWD in farmed cervids is the goal of state, federal, and industry programs, but eradication of CWD from free-ranging populations of cervids is unlikely with currently available management techniques.

Novel genomic targets in oxidant-induced vascular injury.

To study the complex interaction between oxidative injury and the pathogenesis of vascular disease, vascular gene expression was examined in male Sprague-Dawley rats given 35 or 70 mg/kg allylamine, a synthetic amine converted to acrolein and hydrogen peroxide within the vascular wall. Vascular lesions and extensive vascular remodeling, coupled to increased production of 8-epi-PGF2alpha, nuclear localization of NFkappaB, and alterations in glutathione homeostasis, were observed in animals treated with allylamine for up to 20 days. Transcriptional profiling, immunohistochemistry, and in situ hybridization showed that genes involved in adhesion and extracellular matrix (ECM) (alpha(1) integrin, collagen), cytoskeletal rearrangements (alpha-smooth muscle actin, alpha-tropomyosin), and signal transduction (NFkappaB, osteopontin, and LINE) were altered by oxidant treatment. To evaluate mechanisms of gene dysregulation, cultured aortic smooth muscle cells were challenged with allylamine or its metabolites and processed for molecular analysis. These agents increased formation of reactive oxygen species and elicited changes in gene expression similar to those observed in vivo. Oxidative stress and changes in gene expression were inhibited by N-acetyl cysteine, a precursor of glutathione. These results indicate that genes along the ECM-integrin-cytoskeletal axis, in addition to LINE, are molecular targets in oxidant-induced vascular injury.

Chronic wasting disease of cervids.

Chronic wasting disease (CWD) has recently emerged in North America as an important prion disease of captive and free-ranging cervids (species in the deer family). CWD is the only recognized transmissible spongiform encephalopathy (TSE) affecting free-ranging species. Three cervid species, mule deer (Odocoileus hemionus), white-tailed deer (O. virginianus), and Rocky Mountain elk (Cervus elaphus nelsoni), are the only known natural hosts of CWD. Endemic CWD is well established in southern Wyoming and northern Colorado, and has been present in this 'core area' for two decades or more. Apparently CWD has also infected farmed cervids in numerous jurisdictions, and has probably been endemic in North America's farmed deer and elk for well over a decade. Several free-ranging foci distant to the Colorado-Wyoming core area have been discovered since 2000, and new or intensified surveillance may well identify even more foci of infection. Whether all of the identified captive and free-ranging foci are connected via a common original exposure source remains undetermined. Some of this recently observed 'spread' may be attributable to improved detection or natural movements of infected deer and elk, but more distant range extensions are more likely caused by movements of infected captive deer and elk in commerce, or by some yet unidentified exposure risk factor. Research on CWD over the last 5 years has resulted in a more complete understanding of its pathogenesis and epidemiology. CWD is infectious, transmitting horizontally from infected to susceptible cervids. Early accumulation of PrP(CWD) in alimentary tract-associated lymphoid tissues during incubation suggests agent shedding in feces or saliva as plausible transmission routes. Residual infectivity in contaminated environments also appears to be important in sustaining epidemics. Improved tests allow CWD to be reliably diagnosed long before clinical signs appear. Implications of CWD are not entirely clear at this time. Natural transmission to humans or traditional domestic livestock seems relatively unlikely, but the possibility still evokes public concerns; impacts on wildlife resources have not been determined. Consequently, where CWD is not known to occur surveillance programs and regulations that prevent or reduce the likelihood that CWD will be introduced into these jurisdictions should be encouraged. Where CWD is known to occur, affected jurisdictions are conducting surveillance to estimate and monitor trends in geographic distribution and prevalence, managing deer and elk populations in attempts to limit spread, and developing and evaluating techniques for further controlling and perhaps eradicating CWD. Programs for addressing the challenges of CWD management will require interagency cooperation, commitment of funds and personnel, and applied research. Chronic wasting disease (CWD) is perhaps the most enigmatic of the naturally occurring prion diseases. Although recognized as a transmissible spongiform encephalopathy (TSE) since the late 1970s (Williams and Young 1980, 1982), interest in and concern about CWD has only recently emerged. CWD most closely resembles scrapie in sheep in most respects, but recent media and public reaction to CWD has been more reminiscent of that afforded to bovine spongiform encephalopathy (BSE) less than a decade ago. Yet, with the exception of transmissible mink encephalopathy (TME), CWD is the rarest of the known animal TSEs: fewer than 1,000 cases have been diagnosed worldwide, and all but two of these occurred in North America. CWD is unique among the TSEs in that it affects free-living species (Spraker et al. 1997; Miller et al. 2000). The three natural host species for CWD, mule deer (Odocoileus hemionus), white-tailed deer (O. virginianus), and Rocky Mountain elk (Cervus elaphus nelsoni), are all in the family Cervidae and native to North America. Like scrapie, CWD is contagious: epidemics are self-sustaining in both captive and free-ranging cervid populations (Miller et al. 1998, 2000). The geographic extent of endemic CWD in free-ranging wildlife was initially thought to be quite limited and its natural rate of expansion slow; however, recent investigations have revealed that CWD has been inadvertently spread much more widely via market-driven movements of infected, farmed elk and deer. Both the ecological and economic consequences of CWD and its spread remain to be determined; moreover, public health implications remain a question of intense interest. Here, we review current understanding of CWD, its implications, and its management.

Evaluation of methodologies for small area life expectancy estimation.

STUDY OBJECTIVE: To evaluate methods for calculating life expectancy in small areas, for example, English electoral wards. DESIGN: The Monte Carlo method was used to simulate the distribution of life expectancy (and its standard error) estimates for 10 alternative life table models. The models were combinations of Chiang or Silcocks methodology, 5 or 10 year age intervals, and a final age interval of 85+, 90+, or 95+. SETTING: A hypothetical small area experiencing the population age structure and age specific mortality rates of English men 1998-2000. PARTICIPANTS: Routine mortality and population statistics for England. MAIN RESULTS: Silcocks and Chiang based models gave similar estimates of life expectancy and its standard error. For all models, life expectancy was increasingly overestimated as the simulated population size decreased. The degree of overestimation depended largely on the final age interval chosen. Life expectancy estimates of small populations are normally distributed. The standard error estimates are normally distributed for large populations but become increasingly skewed as the population size decreases. Substitution methods to compensate for the effect of zero death counts on the standard error estimate did not improve the estimate. CONCLUSIONS: It is recommended that a population years at risk of 5000 is a reasonable point above which life expectancy calculations can be performed with reasonable confidence. Implications are discussed. Within the UK, the Chiang methodology and a five year life table to 85+ is recommended, with no adjustments to age specific death counts of zero.

Transmissible spongiform encephalopathies in non-domestic animals: origin, transmission and risk factors.

The transmissible spongiform encephalopathies (TSEs), scrapie and bovine spongiform encephalopathy (BSE), are serious diseases of domestic animals. Although not as significant in terms of numbers of animals affected or geographical distribution, TSEs also affect non-domestic animals. Transmissible mink encephalopathy (TME) was the first TSE to be identified in non-domestic animals. This disease of captive mink (Mustela vison) is very rare and is associated with exposure through feed contaminated by a TSE agent. The second TSE to be identified in non-domestic animals was chronic wasting disease (CWD) of deer and elk. This disease is not known to be associated with feedstuffs contaminated with the agent of CWD, but the natural route of exposure appears to be oral, possibly through direct interaction between animals or through environmental contamination. Over the last five years, the known distribution of CWD across North America has expanded, increasing concerns over the impact of this disease on populations of free-ranging cervids and the viability of game farming industries. Concurrent with the epidemic of BSE, a variety of non-domestic ruminants and felid species were also affected in the United Kingdom, presumably through exposure to the agent in contaminated feed. These examples illustrate that when non-domestic animals are held in captivity, they depend upon feeds supplied by their caretakers and may show degrees of susceptibility to infectious agents in feeds which vary from those of domestic species. Although humans have less influence over exposure of free-ranging species to infectious agents, monitoring these populations for diseases may be important for managing the health of these animals. It is important to institute or continue surveillance for an entire range of infectious diseases, including TSEs, in free-ranging and captive non-domestic species. Study of diseases in these species may provide important information about infectious agents of concern for domestic animals and humans.

Chronic wasting disease in deer and elk in North America.

Chronic wasting disease (CWD) has emerged as an important disease of wildlife in North America. The disease is a unique member of the transmissible spongiform encephalopathies (TSEs) or prion diseases, which naturally affect only a few species. Of the TSEs, CWD is the only one found in free-ranging species. However, interest in CWD has recently grown, by association with the better-known TSEs such as variant Creutzfeldt-Jakob disease of humans and bovine spongiform encephalopathy. Knowledge of the geographic distribution of CWD, though still limited, has greatly improved since the mid-1990s as a result of surveillance in free-ranging deer and elk and in commercially owned Rocky Mountain elk (Cervus elaphus nelsoni), and the disease has now been found in multiple areas of the plains and Rocky Mountain foothills of western North America. Studies of the biology and natural history of CWD over recent years have resulted in a better understanding of the pathogenesis and epidemiology of the disease. Early involvement of the lymphoid tissues of the alimentary tract during the incubation period of CWD suggests plausible routes for agent exit from an infected individual, such as in faeces or saliva. Chronic wasting disease is laterally transmitted and environmental contamination may play an important role in local maintenance of the disease. Studies on the epidemiology of CWD have led to the development of models to help explain the history of CWD and to simulate future impacts on deer and elk populations. Diagnostic tests have been improved, allowing diagnosis early in the incubation period, long before the appearance of clinical disease. Surveillance techniques and programmes have been developed and instituted by wildlife management agencies for free-ranging deer and elk and by state and federal agricultural agencies for privately-owned elk. During the 1990s, perceptions of TSEs have altered dramatically; perhaps most remarkably, the goal of global eradication of all prion diseases is now being discussed.

Emerging infectious diseases in wildlife.

The processes which give rise to emerging infectious diseases of wildlife can be categorised as follows: ecosystem alterations of anthropogenic or natural origin; movement of pathogens or vectors, via human or natural agency; and changes in microbes or in the recognition of emerging pathogens due to advances in the techniques of epidemiology. These are simplistic divisions because factors influencing the emergence of diseases of wild animals generally fall into more than one category. Mycoplasmosis among passerines is related to habitat changes and artificial feeding resulting in increased bird densities and subsequent disease transmission. The origin of this strain of Mycoplasma gallisepticum is not known. Hantavirus infections in rodents have emerged due to human-induced landscape alterations and/or climatic changes influencing population dynamics of hantavirus reservoir hosts, with disease consequences for humans. Movement of pathogens or vectors is a very important process by which diseases of wildlife expand geographic range. Although the origin of caliciviruses of rabbits and hares is somewhat obscure, their movement by humans, either deliberately or accidentally, has greatly expanded the distribution of these viruses. Rabies is an ancient disease, but geographic expansion has occurred by both natural and anthropogenic movements of wild animals. Human movement of amphibians may explain the distribution of the highly pathogenic chytrid fungus around the world. Newly recognised paramyxoviruses may reflect both changes in these pathogens and the development of techniques of identification and classification. Many more such examples of emerging diseases will arise in the future, given the extensive alterations in landscapes world-wide and movements of animals, vectors and pathogens. Those who study and diagnose diseases of wildlife must be alert for emerging diseases so that the impact of such diseases on wild animals, domestic animals and humans can be minimised.

Deposition patterns of disease-associated prion protein in captive mule deer brains with chronic wasting disease.

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) in captive and free-ranging cervids in the USA; its origin is obscure. Archival formalin-fixed and paraffin-embedded specimens of 16 captive mule deer brains with CWD were analyzed using immunocytochemistry for the disease-associated prion protein (PrP). The most prominent pattern of PrP deposition were plaque-like structures, a substantial proportion of which were florid plaques surrounded by a rim of spongiform vacuoles. The percentage of florid plaques was highly variable according to region, ranging from 0% to 52.7%. The highest percentage was observed in the medulla and basal ganglia, the lowest in the cerebral cortex. Only three brains contained no florid plaques. There were also punctate synaptic-type and perivascular deposits, particularly in areas of severe spongiform change, and subpial and subependymal plaque-like deposits, whereas cerebellar involvement was mild. Thus, CWD brain pathology prominently features florid PrP plaques, as does variant Creutzfeldt-Jakob disease (vCJD), but differs in other characteristics from vCJD.