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Haemophilia A and B are X-linked inherited bleeding disorders, resulting in the deficiency of clotting factor VIII and IX, respectively. Since the introduction of recombinant clotting factor concentrates in the early 1990s, the major safety concern for haemophilia therapy has been the development of inhibitory antibodies, or inhibitors. Over the recent past, new therapies for the treatment and prevention of bleeding have received regulatory approval or are under study.

We led the last large-scale exercise conducted by the Johns Hopkins Center for Health Security before the COVID-19 pandemic. Despite COVID-19, pandemic exercises are more necessary than ever to prevent the loss of hard-fought gains achieved during COVID-19, keep policymakers from assuming all pandemics will be like COVID-19, and encourage continued engagement from policymakers in strengthening health resilience rather than returning to a cycle of panic and neglect. Pandemic exercises can also advance new solutions necessary to effectively meet the challenge of a future pandemic. Over 2 decades, the Johns Hopkins Center for Health Security has developed and conducted 6 large-scale, high-level tabletop pandemic exercises. These exercises and others were designed to increase policy focus on the most critical needs in pandemic preparedness and heighten the urgency for making these changes in the near future. Pandemic experts and policymakers alike have highlighted the importance of exercises to ensure that all key actors involved in pandemic response-including the government, healthcare, public health, emergency response, and private business and industry sectors-understand both the best practices and policies to pursue before a pandemic and what to do once a pandemic occurs. These advance efforts can enhance planning, resource allocation, and coordination ahead of time and identify unique gaps and barriers. This commentary describes the approach we have developed to create and conduct such exercises and highlights key considerations that were important to successful outcomes.

Background: Screening for adverse childhood experiences (ACEs) and resilience in pregnancy is a promising practice for mitigating ACEs-related health complications. Yet, the best follow-up for pregnant patients with high ACEs and/or low resilience has not been established., Objective: This study evaluates referrals to and participation in an embedded health psychologist (EHP) intervention for pregnant patients with ACEs and/or low resilience., Materials and Methods: Patients in 3 Kaiser Permanente Northern California medical centers with ACEs who had also received resilience screening during standard prenatal care and who were participating in an EHP intervention were included (N = 910). The authors used multivariable logistic regression to examine whether ACEs (0, 1-2, 3+) and resilience (high vs low) were associated with referrals to and participation in EHP intervention. They also evaluated the impact of EHP intervention through clinician (N = 53) and patient (N = 51) surveys., Results: Patients with 3+ vs 0 ACEs were more likely to receive an EHP referral (adjusted odds ratio [aOR] = 2.89, 95% confidence interval [CI]: 1.93-4.33) and were more likely to participate in EHP intervention (aOR = 2.85, 95% CI: 1.87-4.36). Those with low vs high resilience were also more likely to receive an EHP referral (aOR = 1.86, 95% CI: 1.32-2.62) and participate in EHP (aOR = 1.71, 95% CI: 1.19-2.44). When ACEs and resilience were combined, those with high ACEs and low resilience had the greatest odds of referrals and participation. Patients and clinicians reported positive experiences with EHP intervention., Conclusion: Patients with higher ACEs and lower resilience scores were more likely to be referred to and participate in EHP intervention, suggesting that at-risk patients can be successfully linked with a health psychologist when accessible within obstetric care., Competing Interests: Conflicts of Interest None declared

Mass gatherings include a diverse range of events such as sporting competitions, religious ceremonies, entertainment activities, political rallies and cultural celebrations, which have important implications for population well-being. However, if not managed properly, these events can amplify health risks including those related to communicable diseases, and place undue strain on health systems in host countries and potentially in attendees' home countries, upon their return. The coronavirus disease 2019 (COVID-19) pandemic has provided a unique opportunity to evaluate the risk factors associated with mass gatherings and the effectiveness of applying mitigation measures during infectious disease emergencies. The pandemic has also allowed event organizers and health officials to identify best practices for mass gathering planning in host countries. To guide decisions about whether to hold, postpone, modify or cancel a mass gathering during the COVID-19 pandemic, the World Health Organization and its partners developed normative guidance and derivative tools promoting a risk-based approach to mass gathering planning. This approach involves three steps to guide decision-making around mass gatherings: risk evaluation, risk mitigation and risk communication. The approach was applied in the planning and execution of several mass gathering events, including the Tokyo 2020 and Beijing 2022 Olympic and Paralympic Games. Lessons identified from these large-scale international events offer insights into the planning and implementation of mass gathering events during a pandemic, and the broader impacts of such events on society. These lessons may also further inform and refine planning for future mass gatherings., ((c) 2024 The authors; licensee World Health Organization.)

This was a retrospective cohort study of pregnant individuals in the Kaiser Permanente Northern California system who were screened for adverse childhood experiences and resilience as part of standard prenatal care at about 16 weeks of gestation. Overall, 14,625 pregnancies were included; 17.0% had newly identified depression; 9.8% had newly identified depression symptoms; and 8.9% had newly identified anxiety during the pregnancy with no known preexisting diagnosis. We found that adverse childhood experiences and low resilience were independently associated with newly identified depressive disorders, depression symptoms, and anxiety disorders during pregnancy. When adverse childhood experiences and resilience were modeled in combination, the greatest odds of each outcome occurred in individuals with a combination of four or more adverse childhood experiences and low resilience (vs no adverse childhood experiences and high resilience): depression adjusted odds ratio (aOR) 6.43 (95% CI, 5.23-7.90), depression symptoms aOR 9.49 (95% CI, 7.50-12.0), and anxiety disorder aOR 4.79 (95% CI, 3.81-6.02). Routine screening for adverse childhood experiences and resilience may identify individuals at risk of developing prenatal depression and anxiety, allowing faster resource linkage and potentially improved maternal and child outcomes., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Screening for adverse childhood experiences (ACEs) in prenatal and pediatric populations is recommended by the California ACEs Aware initiative and is a promising practice to interrupt ACEs in children and mitigate ACEs-related health complications in children and families. Yet, integrating ACEs screening into clinical practice poses several challenges., Objective: The objective of this report was to evaluate the Kaiser Permanente Northern California and Kaiser Permanente Southern California pilots and implementation of ACEs screening into routine prenatal (Kaiser Permanente Northern California) and pediatric (Kaiser Permanente Southern California) care., Materials and Methods: These pilots were evaluated and compared to identify common challenges to implementation and offer promising practices for negotiating these challenges. Evaluation methods included feedback from staff, clinicians, and patients, as well as comparisons of methods to overcome various barriers to screening implementation., Results: Implementing ACEs screening, like implementation of any new component of clinical care, takes careful planning, education, creation of content and workflows, and continuous integration of feedback from both patients and staff., Conclusion: This evaluation can serve as support for care teams who are considering implementing ACEs screening or who are already screening for ACEs. More research is needed regarding the relationship between ACEs and preventable and treatable health outcomes to improve health for patients and their families., Competing Interests: Conflict of InterestNone declared

Background: The optimal spontaneous breathing trial (SBT) duration is not known for children who are critically ill. The study objective was to evaluate extubation outcomes between cohorts exposed to a 1- or 2-h SBT., Methods: This was a retrospective cohort study of a quality improvement project database in a 24-bed pediatric ICU. The intervention was a respiratory therapist-driven SBT clinical pathway across 2 improvement cycles by using a 2- or 1-h SBT. The primary outcomes were extubation failure and rescue noninvasive ventilation in the first 48 h. Secondary outcomes included SBT results and process measures., Results: There were 218 and 305 encounters in the 2- and 1-h cohorts, respectively. Extubation failure (7.3 vs 8.5%; P = .62) and rescue noninvasive ventilation rates (9.3 vs 8.2%; P = .68) were similar. In logistic regression models, SBT duration was not independently associated with either primary outcome. Extubation after 1-h SBT failure was associated with significantly higher odds of rescue noninvasive ventilation exposure (odds ratio 3.94, 95% CI 1.3-11.9; P = .02). SBT results were not associated with odds of extubation failure. There were 1,072 (2 h) and 1,333 (1 h) SBTs performed. The 1-h SBT pass rate was significantly higher versus the 2-h SBT (71.4 vs 51.1%; P < .001). Among all failed SBTs, the top 3 reported failure modes were tidal volume ≤ 5 mL/kg (23.6%), breathing frequency increase > 30% (21%), and oxygen saturation < 92% (17.3%). When considering all failed SBTs, 75.5% of failures occurred before 45 min., Conclusions: A 1-h SBT may be a viable alternative to a 2-h version for the average child who is critically ill. Further, a 1-h SBT may better balance extubation outcomes and duration of invasive ventilation for the general pediatric ICU population., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Objective: Policy-makers and practitioners have a need to assess community resilience in disasters. Prior efforts conflated resilience with community functioning, combined resistance and recovery (the components of resilience), and relied on a static model for what is inherently a dynamic process. We sought to develop linked conceptual and computational models of community functioning and resilience after a disaster., Methods: We developed a system dynamics computational model that predicts community functioning after a disaster. The computational model outputted the time course of community functioning before, during, and after a disaster, which was used to calculate resistance, recovery, and resilience for all US counties., Results: The conceptual model explicitly separated resilience from community functioning and identified all key components for each, which were translated into a system dynamics computational model with connections and feedbacks. The components were represented by publicly available measures at the county level. Baseline community functioning, resistance, recovery, and resilience evidenced a range of values and geographic clustering, consistent with hypotheses based on the disaster literature., Conclusions: The work is transparent, motivates ongoing refinements, and identifies areas for improved measurements. After validation, such a model can be used to identify effective investments to enhance community resilience. (Disaster Med Public Health Preparedness. 2018;12:127-137).

Biological threat characterization (BTC) involves laboratory research conducted for the purpose of biological defense. BTC research is important for improving biological risk assessment and informing resource prioritization. However, there are also risks involved in BTC work, including potential for escape from the laboratory or the misuse of research results. Using a modified Delphi study to gather opinions from U.S. experts in biosecurity and biodefense, this analysis explores what principles and safeguards can maximize the benefits of BTC research and ensure that it is conducted safely and securely. Delphi participants were asked to give their opinions about the need for BTC research by the U.S. government (USG); risks of conducting this research; rules or guidelines that should be in place to ensure that the work is safe and accurate; components of an effective review and prioritization process; rules for when characterization of a pathogen can be discontinued; and recommendations about who in the USG should be responsible for BTC prioritization decisions. The findings from this research reinforce the need for BTC research at the federal level as well as a need for continued review and oversight of this research to maximize its effectiveness and reduce the risks involved. It also demonstrates the need for further discussion of what would constitute a "red line" for biothreat characterization research-research that should not be performed for safety, ethical, or practical reasons-and guidelines for when there is sufficient research in a given topic area so that the research can be considered completed., (© 2017 Society for Risk Analysis.)

Objectives: To evaluate trends in funding over the past 16 years for key federal public health preparedness and response programs at the US Department of Health and Human Services, to improve understanding of federal funding history in this area, and to provide context for future resource allocation decisions for public health preparedness., Methods: In this 2017 analysis, we examined the funding history of key federal programs critical to public health preparedness by reviewing program budget data collected for our annual examination of federal funding for biodefense and health security programs since fiscal year (FY) 2001., Results: State and local preparedness at the Centers for Disease Control and Prevention initially received $940 million in FY2002 and resulted in significant preparedness gains, but funding levels have since decreased by 31%. Similarly, the Hospital Preparedness Program within the Office of the Assistant Secretary for Preparedness and Response was funded at a high of $515 million in FY2003, but funding was reduced by 50%. Investments in medical countermeasure development and stockpiling remained relatively stable., Conclusions: The United States has made significant progress in preparing for disasters and advancing public health infrastructure. To enable continued advancement, federal funding commitments must be sustained.

Seven groups of 8-24 Beagle dogs, exposed to (239)PuO(2) aerosols by inhalation [mean initial lung depositions (ILD) of 0.0, 0.14, 0.63, 3.2, 13, 44 and 210 kBq] were observed throughout their lives to determine tissues at risk and dose-effect relationships. The mean average pulmonary retention half-time of (239)Pu was 1,192 days. Most (70%) of the plutonium recovered at death in dogs surviving >10 years after exposure was found in the thoracic lymph nodes with ∼15% in lung, ∼10% in liver and ∼2% in bone. Eight dogs at the highest exposure levels died from radiation pneumonitis prior to a minimal 3-year latency period after exposure for the observation of lung tumors, with the first succumbing 337 days after exposure. Of 108 plutonium-exposed Beagles with ILD <100 kBq, 51 (47%) had lung tumors with significantly increased incidence in those dogs with total lung dose of ≥1.1 Gy at death. The primary non-neoplastic effects observed were lymphopenia, atrophy and fibrosis of the thoracic lymph nodes, radiation pneumonitis and pulmonary fibrosis, and bacterial pneumonia. Lesions of the thoracic lymph nodes were observed in 98 of 108 exposed dogs, but there were no primary neoplasms of the lymph nodes. Bacterial pneumonia was observed in 13 plutonium-exposed dogs and was the most notable non-neoplastic cause of death, with survival nearly the same as that of controls. Setting of dose limits on the basis of detrimental effects commonly considers and differentiates between stochastic and deterministic effects, raising the question of whether the non-neoplastic effects found in this study were deterministic. The International Commission on Radiation Protection (ICRP), National Council on Radiation Protection & Measurements (NCRP), and similar organizations generally consider effects that increase in incidence and severity to meet the definition of deterministic. We demonstrated the radiation dose-related nature of effects such as pneumonitis and fibrosis graphically and lymphopenia numerically, rather than by quantified estimates. It is clear, however, that both incidence and severity increased with ILD and radiation dose and should be considered as deterministic effects.

Brain mapping has relied on a small number of routine chemical stains for many decades. The advent of immunomarkers has had a major impact on the ability to define homologous nuclei from one species to another. The first atlas to present a panel of immunomarkers was that of Paxinos et al. (1999a,b) in the adult rat brain. The markers used were parvalbumin, calbindin, calretinin, SMI32, tyrosine hydroxylase, and NADPH diaphorase (plus nissl and acetylcholinesterase). The 'signature' of a nucleus of interest in a new species can be tested against the findings in the rat. Since the pattern of immunomarkers seems to be conserved in mammalian evolution, such extrapolations can be made with reasonable confidence. A marmoset brain stained with a comprehensive set of immunomarkers has recently been published on the internet (Tokuno et al., 2009) and we are in the process of defining nuclear homologies in this brain by comparison with the same markers in the rat. In this article, we present an example (mapping the amygdala in the marmoset) which demonstrates the application of this immunomarker panel in defining homologies. The technique is particularly valuable in situations where little data on hodology or electrophysiology are available.

Objectives: The report describes the strategic design, steps to full implementation and outcomes achieved by the Western Australian Data Linkage System (WADLS), instigated in 1995 to link up to 40 years of data from over 30 collections for an historical population of 3.7 million. Staged development has seen its expansion, initially from a linkage key to local health data sets, to encompass links to national and local health and welfare data sets, genealogical links and spatial references for mapping applications., Applications: The WADLS has supported over 400 studies with over 250 journal publications and 35 graduate research degrees. Applications have occurred in health services utilisation and outcomes, aetiologic research, disease surveillance and needs analysis, and in methodologic research., Benefits: Longitudinal studies have become cheaper and more complete; deletion of duplicate records and correction of data artifacts have enhanced the quality of information assets; data linkage has conserved patient privacy; community machinery necessary for organised responses to health and social problems has been exercised; and the commercial return on research infrastructure investment has exceeded 1000%. Most importantly, there have been unbiased contributions to medical knowledge and identifiable advances in population health arising from the research.

Purpose: The European Radiobiology Archives (ERA), together with corresponding Japanese and American databases, hold data from nearly all experimental animal radiation biology studies carried out between 1960 and 1998, involving more than 300,000 animals. The Federal Office for Radiation Protection, together with the University of Cambridge have undertaken to transfer the existing ERA archive to a web-based database to maximize its usefulness to the scientific community and bring data coding and structure of this legacy database into congruence with currently accepted semantic standards for anatomy and pathology., Methods: The accuracy of the primary data input was assessed and improved. The original rodent pathology nomenclature was recoded to replace the local 'DIS-ROD' (Disease Rodent) formalism with Mouse Pathology (MPATH) and Mouse Anatomy (MA) ontology terms. A pathology panel sampled histopathological slide material and compared the original diagnoses with currently accepted diagnostic criteria., Results: The overall non-systematic error rate varied among the studies between 0.26% and 4.41%, the mean error being 1.71%. The errors found have been corrected and the studies thus controlled have been annotated. The majority of the original pathology terms have been successfully translated into a combination of MPATH and MA ontology terms., Conclusions: ERA has the potential of becoming a world-wide radiobiological research tool for numerous applications, such as the re-analysis of existing data with new approaches in the light of new hypotheses and techniques, and using the database as an information resource for planning future animal studies. When the database is opened for new data it may be possible to offer long-term storage of data from recent and future animal studies.

Sterile neutrinos are attractive dark matter candidates. Their parameter space of mass and mixing angle has not yet been fully tested despite intensive efforts that exploit their gravitational clustering properties and radiative decays. We use the limits on gamma-ray line emission from the Galactic center region obtained with the SPI spectrometer on the INTEGRAL satellite to set new constraints, which improve on the earlier bounds on mixing by more than 2 orders of magnitude, and thus strongly restrict a wide and interesting range of models.

The monotremes are a unique group of living mammals, which diverged from the line leading to placental mammals at least 125 million years ago. We have examined the organization of pontine, inferior olivary, lateral reticular and vestibular nuclei in the brainstem of the short-beaked echidna (Tachyglossus aculeatus) to determine if the cyto- and chemoarchitecture of these nuclei are similar to that in placental mammals and marsupials. We have used Nissl staining in conjunction with enzyme-histochemistry for acetylcholinesterase, cytochrome oxidase and NADPH diaphorase as well as immunohistochemistry for non-phosphorylated neurofilament protein (SMI-32 antibody) and calcium binding proteins (parvalbumin, calbindin, calretinin). Homologies could be established between the arch shaped inferior olivary complex of the echidna and the principal, dorsal and medial accessory subdivisions of the therian inferior olivary complex. The pontine nuclei of the echidna included basilar and reticulotegmental components with similar cyto- and chemarchitectural features to therians and there were magnocellular and subtrigeminal components of the lateral reticular nucleus, also as seen in therians. Subdivisions and chemoarchitecture of the vestibular complex of the echidna were both similar to that region in rodents. In all three precerebellar nuclear groups studied and in the vestibular nucleus organization, the cyto- and chemoarchitecture of the echidna was very similar to that seen in therian mammals and no "primitive" or "reptilian" features were evident.

The monotremes (echidnas and platypus) have been claimed by some authors to show 'avian' or 'reptilian' features in the gross morphology and microscopic anatomy of the cerebellum. We have used Nissl staining in conjunction with enzyme histochemistry to acetylcholinesterase and cytochrome oxidase and immunohistochemistry to non-phosphorylated neurofilament protein (SMI-32 antibody), calcium binding proteins (parvalbumin, calbindin and calretinin) and tyrosine hydroxylase to examine the cyto- and chemoarchitecture of the cerebellar cortex and deep cerebellar nuclei in the short-beaked echidna. Immunoreactivity for non-phosphorylated neurofilament (SMI-32 antibody) was found in the deep cerebellar nuclei and in Purkinje cells of most regions except the nodule. Purkinje cells identified with SMI-32 immunoreactivity were clearly mammalian in morphology. Parvalbumin and calbindin immunoreactivity was found in Purkinje cells with some regional variation in staining intensity and in Purkinje cell axons traversing cerebellar white matter or terminating on Lugaro cells. Calbindin immunoreactivity was also present in inferior olivary complex neurons. Calretinin immunoreactivity was found in pontocerebellar fibers and small cells in the deep granule cell layer of the ansiform lobule. We found that, although the deep cerebellar nuclei were much less clearly demarcated than in the rodent cerebellum, it was possible to distinguish medial, interposed and lateral nuclear components in the echidna. As far as we can determine from our techniques, the cerebellum of the echidna shows all the gross and cytological features familiar from the cerebellum of therian mammals., (Copyright 2007 S. Karger AG, Basel.)

While much of the language used to express the concepts of radiation protection works effectively, there are many ill-chosen names and phrases and much jargon that permeate our professional speech and writing. From the oxymoron "internal exposure" to the "snarl word" "decay," there is much room for improvement. This essay identifies many of the problems and suggests solutions. We examine the kinds of confusions that can result from using familiar words with unfamiliar meanings and the need for neology. We offer insights into specific and unambiguous naming of physical quantities and explore the seemingly unlimited kinds of "dose." We disaggregate exposure from irradiation following intakes, and unmask units like "gram rad per microcurie hour." We call for a definition of radiation weighting factor that doesn't result in a violation of the law of conservation of energy. We examine the subtleties of distinguishing between radiation and radioactive materials. Some words, such as "exposure," have multiple meanings, while at other times there are different words or phrases with the same meaning, such as "critical level" and "decision level" or "detection level" and "minimum detectable amount." Sometimes phrases are used whose meaning is unclear or not agreed upon, such as "lower limit of detection." Sometimes there are words that are simply not apt, such as "disintegration" applied to the emission of a subatomic particle from a nucleus.

Animal experiments have contributed a great deal to our information on effects and risks arising from exposure to radionuclides. This applies, in particular, to alpha-emitting radionuclides where information from man is limited to thorotrast, 224Ra and 226Ra. The late C.W. Mays was the first to suggest that animal data in conjunction with epidemiological data could allow estimates of human risks for radionuclides - predominantly from actinides - where information in man is scarce. The 'International Radiobiology Archives of Long-term Animal Studies' were created through the combined efforts of European, American and Japanese scientists and aim to safeguard the large amount of existing data on long-term animal experiments and make them available for, among others, an improved assessment of risks from alpha-emitting radionuclides. This paper summarizes the structure of the archives and reviews their present status and future plans. It also demonstrates the extensive information available in these archives on alpha-emitting radionuclides which is suitable for further analysis. Also, the structure of the animal archives could - in a slightly modified form - accommodate the epidemiological data available on 224Ra and thorotrast and, thus, facilitate a direct comparison of data from man, dogs and rodents.

Single-strand conformational polymorphism (SSCP) analysis and direct sequencing methods were used to examine lung tumors derived from a cohort of beagle dogs with inhalational exposures to 239PuO2. These exposures were done at Pacific Northwest Laboratories where 18-month-old beagle dogs were given 239PuO2 by single-dose inhalation and allowed to live out their life-spans. Formalin-fixed paraffin-embedded blocks of tissues from 25 dogs exposed to 239PuO2 by aerosol inhalation which later developed lung tumors were available for this study. Two of 25 tumors had mutations within exon 1 of K-ras detected by SSCP analysis. Both mutations were GGT to GAT transitions at codon 12 confirmed by direct sequencing experiments. One was an adenocarcinoma from the medium-high exposure group and the other was a broncheolo-alveolar carcinoma from the medium-low exposure group. The rate of K-ras mutations in plutonium-induced lung tumors described herein (8%) was greater than previously described in canine plutonium-induced lung tumors (0%), but was less than that which we have described in spontaneous canine lung cancer (16%), less than that reported for human spontaneous non-small cell lung cancer (13-36%) and less than that described in rats with spontaneous lung cancer (40%) or lung tumors following 239Pu inhalation exposure (46%).

Combined analyses of data on 260 life-span beagle dogs that inhaled 238PuO2 at the Inhalation Toxicology Research Institute (ITRI) and at Pacific Northwest National Laboratory (PNNL) were conducted. The hazard functions (age-specific risks) for incidence of lung, bone and liver tumors were modeled as a function of cumulative radiation dose, and estimates of lifetime risks based on the combined data were developed. For lung tumors, linear-quadratic functions provided an adequate fit to the data from both laboratories, and linear functions provided an adequate fit when analyses were restricted to doses less than 20 Gy. The estimated risk coefficients for these functions were significantly larger when based on ITRI data compared to PNNL data, and dosimetry biases are a possible explanation for this difference. There was also evidence that the bone tumor response functions differed for the two laboratories, although these differences occurred primarily at high doses. These functions were clearly nonlinear (even when restricted to average skeletal doses less than 1 Gy), and evidence of radiation-induced bone tumors was found for doses less than 0.5 Gy in both laboratories. Liver tumor risks were similar for the two laboratories, and linear functions provided an adequate fit to these data. Lifetime risk estimates for lung and bone tumors derived from these data had wide confidence intervals, but were consistent with estimates currently used in radiation protection. The dog-based lifetime liver tumor risk estimate was an order of magnitude larger than that used in radiation protection, but the latter also carries large uncertainties. The application of common statistical methodology to data from two studies has allowed the identification of differences in these studies and has provided a basis for common risk estimates based on both data sets.

Beagle dogs exposed to 238PuO2 aerosols (136 dogs, 13-22 per group, mean initial lung depositions of 0.0, 0.13, 0.68, 3.1, 13, 52 and 210 kBq) were observed throughout life to determine tissues at risk and dose-effect relationships. The pulmonary retention of 238Pu was represented by the sum of two exponentially decreasing components of the initial lung deposition; about 84% cleared with a 174-day half-time; the half-time of the remainder was 908 days. The average percentages of final body burden found in lung, skeleton, liver and thoracic lymph nodes in the 30 longest-surviving dogs (mean survival 14 years) were 1, 46, 42 and 6%, respectively. Of 116 beagles exposed to plutonium, 34 (29%) developed bone tumors, 31 (27%) developed lung tumors, and 8 (7%) developed liver tumors. Although lungs accumulated a higher average radiation dose than skeleton, more deaths were due to bone tumors than to lung tumors. Deterministic effects included radiation pneumonitis, osteodystrophy, hepatic nodular hyperplasia, lymphopenia, neutropenia and sclerosing tracheobronchial lymphadenitis. Hypoadrenocorticism was also observed in a few dogs. Increased serum alanine aminotransferase, indicative of liver damage, was observed in groups with > or =3.1 kBq initial lung deposition. Estimates of cumulative tissue dose in a human exposed to airborne 238PuO2 for 50 years at a rate of one annual limit on intake each year were derived based on a comparison of the data on metabolism for humans and beagles. The 50-year dose estimates for humans are an order of magnitude lower than doses at which increased incidence of neoplasia was observed in these dogs, whereas the projected doses to humans from 50-year exposure at the annual limit of intake are of similar magnitude to those at which deterministic effects were seen in the beagles.

The incidence of invasive meningococcal disease in Australia has increased over the past decade, and in April 1997 the National Health and Medical Research Council published guidelines for management of patients with meningococcal disease and their contacts. These guidelines emphasise the need for immediate intravenous antibiotic treatment of patients with suspected meningococcal disease, before transfer to hospital or lumbar puncture. When possible, blood for culture should be collected before antibiotic therapy, if this does not delay treatment.

Hypoadrenocorticism, known as Addison's disease in humans, was diagnosed in six beagles after inhalation of at least 1.7 kBq/g lung of 238PuO2. Histological examination of adrenal gland specimens obtained at necropsy revealed marked adrenal cortical atrophy in all cases. Autoradiographs showed only slight alpha-particle activity. Although the pathogenesis of adrenal cortical atrophy in these dogs is unclear, there is evidence to suggest an autoimmune disorder linked to damage resulting from alpha-particle irradiation to the lymphatic system.

The distribution and effects of inhaled 239Pu(NO3)4 deposited in the liver of dogs were studied in five groups of 20 beagles exposed to initial lung depositions ranging from 1.0 to 520 Bq g(-1) lung. Following life-span observations, the liver contained 40 +/- 1% of the final body deposition of plutonium, second only to the skeleton. The liver-to-skeleton ratio of deposited plutonium for total organ was 0.8, or 3.5 when expressed on a per-gram basis. There was no effect of exposure level on liver-to-skeleton ratios. Autoradiographs showed that the dose rate delivered to parenchymal cells was higher than evident from radiochemical analysis of the whole organ. Elevated levels of serum liver enzymes were observed in groups with mean liver concentrations of 1.3 Bq g(-1) and liver doses of 3 Gy or higher. Nodular hyperplasia of liver and bile-duct hyperplasia were observed. Liver tumors, principally of bile-duct epithelium, were late-occurring and were observed at lower exposure levels at which life span was not shortened by lung or bone tumors.

Aged canines exhibit central neuropathological changes strikingly similar to those seen in patients with Alzheimer's disease. In this study, brain tissue from pure bred beagles raised in a controlled environment were examined for Alzheimer-like pathology. The mean age of the animals was 15.6 years. The incidence of plaques among these 29 dogs was 65.5%. Of the 19 samples that demonstrated Alzheimer-like pathology, 18 were characterized as diffuse and one as neuritic. Plaque density was found to be independent of age. Plaque numbers were highest in the perirhinal cortex and the adjacent temporal cortex. Familial influence on plaque development is supported by congruence within 15 of the 16 litters examined (p < 0.001). In this environmentally controlled group the diffuse plaques were rarely converted to the dense neuritic plaques found in Alzheimer's disease.

Evidence is presented of gradients between nasal and temporal areas of the cat's retina in the properties of their ganglion cell populations. Mean ganglion cell size is greater in temporal retina than in nasal retina, partly because the alpha- and beta-cells of temporal retina are distinctly bigger than their counterparts in nasal retina, and partly because more medium-sized cells, and fewer small cells, are to be found in temporal retina. This high proportion of medium-sized ganglion cells may reflect a high proportion of beta-cells or of the medium sized gamma-cells described by Stone and Clarke ('80). Several of these differences can be related to prior morphological, electrophysiological, and behavioural observations in the cat, and similar differences have been reported in several other mammalian species. Evidence is presented that, in the cat, at least some of these differences are less marked near the vertical meridian of the retina than more temporally or nasally. The present results may therefore, be evidence of a nasal-temporal gradient in retinal structure and funtion common to many mammals, and distinct from previously recognised gradients in ganglion cell properties related to the area centralis and visual streak specialisations.

The retinal distribution of ipsilaterally and contralaterally projecting ganglion cells has been determined in the rabbit using both degeneration and horseradish peroxidase tracing techniques. Contralaterally projecting ganglion cells are present throughout the retinas, while ipsilaterally projecting ganglion cells are confined to a 3.0-3.5 mm wide strip adjacent to the temporal retinal margin. Thus, in this temporal strip both ipsilaterally and contralaterally projecting cells intermingle, while at more nasal locations all ganglion cells project contralaterally. Each of the contra- and ipsilaterally projecting populations comprises ganglion cells with soma diameters representing the full range present in the rabbit retina. However, a relatively large proportion of the ipsilaterally projecting ganglion cells have large somata (greater than or equal to 20 micrometer). Large ganglion cells are most numerous in the rabbit's temporal retina and have previously been described as reaching their peak density at the large cell node, just above the temporal end of the visual streak (Provis 1979). The large cell node lies immediately temporal to the nasal border of the strip of retina in which ipsilaterally projecting cells are located. It is possible that this specialization in the region of retina which observes the binocular visual field plays a particular role in binocular vision for the rabbit.

The relationship between neuronal death and the formation of patterned connections was studied in the facial neuromuscular system of foetal, neonatal, and adult mice. The facial neuromuscular system was selected because two large, widely separated, facial muscles (the nasolabial and posterior auricular muscles) are innervated by clearly separated parts of the facial motor nucleus in the adult mouse. The number of motorneurones in the facial nucleus was counted in Nissl-stained sections at different stages of development. Over 6400 neurones were present in the facial nucleus at day 17 p.c. (post-coitum). After day 17 p.c. the number of neurones fell rapidly and only 2000 cells remain in the adult nucleus. This represents a loss of 68%, most of which occurs between days 18 and 20 p.c. Neurones with pyknotic nuclei are seen on day 17 p.c. and are most numerous on day 18 p.c. This leads us to believe that the fall in neurone numbers is due to cell death. Indirect evidence provided by acetylcholinesterase histochemistry (time of earliest reaction in the facial muscles) and horseradish peroxide (HRP) tracing studies (time of earliest transport) indicate that facial motorneurone axons innervate the facial musculature before the period of cell death: diffuse acetylcholinesterase activity first appeared in the auricular muscles at day 15 p.c. and in the nasolabial muscles at day 17 p.c.; retrograde transport of HRP from the auricular and nasolabial muscles to the facial nucleus cannot be reliably demonstrated before day 17 p.c. We assessed the topography of early facial neuromuscular innervation by making HRP injections into nasolabial and posterior auricular muscles of embryonic and neonatal mice. Injections of HRP at day 17 p.c. (the day before cell loss commenced) showed that the nasolabial muscle and posterior auricular muscles were innervated by the same subnuclei of the facial nucleus as in the adult--except that there was a small number (1-5%) of labelled cells located in parts of the nucleus not consistent with the adult innervation pattern. These data indicate that, except for a small number of neurones, topographically organized connections in the facial neuromuscular system are established before the period of cell death. We conclude that motoneurone cell death does not play a major role in the establishment of topographically organized connections in this system.

The topographic organization of the facial nucleus motoneurons in the rat was investigated with the horseradish peroxidase retrograde tracing method using tetramethyl benzidine as a chromogen. Facial muscles were 'represented' on the facial nucleus in an orderly fashion. For example, the motoneurons supplying the rostral (nasolabial) muscles are laterally placed, whereas those supplying the caudal (auricular) muscles are medially placed. Notable findings in this study are: (i) the relatively unremarkable size of the nasolabial (vibrissal) muscle representation; there does not seem to be an increase in size of this part of the nucleus, commensurate with the specialized sensory functions of the vibrissal area of the face and (ii) the neurons supplying the posterior belly of the digastric are found in the suprafacial nucleus which lies about 1 mm dorsal to the main facial nucleus.

An indirect estimate of the extent of branching of the olivary axons in the cerebellum in a marsupial (Trichosurus vulpecula) was carried out. The cells in the inferior olivary nuclear complex (IOC) of both sides were estimated (mean = 57,200), as were the cerebellar Purkinje cells (mean = 881,300). Assuming that all climbing fibers arise from IOC cells and that each Purkinje cell receives a climbing fiber input, each IOC cell sends climbing fiber terminals to 15 Purkinje cells.

This paper presents an atlas of the rat brain based on horizontal sections stained for acetylcholinesterase (AChE). Fourteen labeled photographs from sections at 0.5 mm intervals are presented. The atlas is intended for use with male rats 250-300 g in weight. It was constructed using the flat-skull position (lambda and bregma in same horizontal plane). Either the interaural midline or bregma can serve as the reference zero point. We have found the stain for AChE to be a useful general purpose stain for identifying brain nuclei and tracts.

The olivocerebellar projection has been studied in the rat using the horseradish peroxidase (HRP) retrograde tracing technique. All regions of the cerebellum, except for the flocculonodular lobe, were injected with small volumes of HRP. The overall organization of the rat olivocerebellar projection is similar in all major respects to that found in other mammals. For example, in the rat Crus 1 and Crus 2 receive afferents from the principal olive, medial part of the rostral dorsal olive, the rostral medial olive, the dorsal cap and the ventrolateral outgrowth which agrees with studies in the cat. The most notable difference between the present study and studies in other mammals is the finding of a projection in the rat from the dorsomedial cell column to all regions of the cerebellar hemispheres, except for the paraflocculus.

The direct projections of the spinal cord onto the cerebellar cortex were traced using Nauta method following the placement of cervical or thoracic spinal cord hemisections in six brush-tailed possums. Degenerating fibres reached the cerebellum via typically placed dorsal and ventral spinocerebellar tracts. Although complete differentiation of the terminations of ventral and dorsal tracts was not possible, it was found that the dorsal tract terminates mainly in the ipsilateral anterior lobe ermis and in the pyramis and paraflocculus of the ipsilateral posterior lobe. The ventral tract ends almost entirely in the anterior lobe with the majority of fibres terminating contralateral to the side of the hemisection. Within the anterior lobe, degenerating fibers were distributed fairly symmetrically about the midline in five sagittal rows. Three such rows were found in the posterior lobe. The relatively small number of rows in the anterior lobe (five) may be a characteristic feature of marsupials when compared with eutherian mammals.

The principal findings of this report on the morphology and electrophysiology of the possum optic nerve are: (i) There are about 230,000 fibres in the optic nerve. This fibre count, based on electron microscopy, is slightly less than a previously reported estimate of the total number of ganglion cells in the possum retina. (ii) The majority (greater than 98%) of the fibres of the optic nerve are myelinated axons of retinal ganglion cells. The diameters of these fibres range from 0.4--4.6 micrometer (axon diameter range: 0.3--3.8 micrometer) and the frequency distribution of the fibre diameters (and axon diameters) is positively skewed and unimodal. (iii) The antidromic compound action potential of the possum optic nerve shows four negative peaks following stimulation of the optic chiasm. These peaks are associated with four conduction latency groups of fibres which have been designated t1, t2, t3 and t4 in order of increasing conduction latency. (iv) The mean peak conduction velocities of the fibres in the conduction latency groups are 13.1 ms-1 (t1), 8.1 ms-1 (t2), 5.7 ms-1 (t3) and 3.1 ms-1 (t4). (v) There is no direct correlation between the frequency distribution of fibre (or axon) diameters as measured by electron microscopy of transverse sections of fixed optic nerve and the conduction latency groups. (vi) The reconstruction of the possum optic nerve compund action potential on the basis of either axon or fibre diameter frequency distribution does not provide an acceptable, indirect correlation between the morphology and the electrophysiology of this optic nerve.