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PubMed2006

A model for building a standardized hand-off protocol.

BACKGROUND: The Joint Commission has made a "standardized approach to hand-off communications" a National Patient Safety Goal. METHOD: An interactive 90-minute workshop (hand-off clinic) was developed in 2005 to (1) develop a standardized process for the handoff, (2) create a checklist of critical patient content, and (3) plan for dissemination and training. CONCLUSION: To date, 7 of 10 residency programs have participated. Analysis of these protocols demonstrated that the hand-off process is highly variable and discipline-specific. Although all disciplines required a verbal handoff, because of competing demands, verbal communication did not always occur. In some cases, the transfer of professional responsibility was separated in time and space from the transfer of information. For example, in two cases, patient tasks were assigned to other team members to facilitate timely departure of a postcall resident (to meet resident duty-hour restrictions), but results were not formally communicated to anyone. The hand-off clinic facilitated the incorporation of "closed-loop" communication by requiring that follow-up on these tasks be conveyed to the on-call resident. DISCUSSION: This model for design and implementation can be applied to other health care settings.

Algorithms↗

PubMed2006

Statistical inference using the g or K point pattern spatial statistics.

Spatial point pattern analysis provides a statistical method to compare an observed spatial pattern against a hypothesized spatial process model. The G statistic, which considers the distribution of nearest neighbor distances, and the K statistic, which evaluates the distribution of all neighbor distances, are commonly used in such analyses. One method of employing these statistics involves building a simulation envelope from the result of many simulated patterns of the hypothesized model. Specifically, a simulation envelope is created by calculating, at every distance, the minimum and maximum results computed across the simulated patterns. A statistical test is performed by evaluating where the results from an observed pattern fall with respect to the simulation envelope. However, this method, which differs from P. Diggle's suggested approach, is invalid for inference because it violates the assumptions of Monte Carlo methods and results in incorrect type I error rate performance. Similarly, using the simulation envelope to estimate the range of distances over which an observed pattern deviates from the hypothesized model is also suspect. The technical details of why the simulation envelope provides incorrect type I error rate performance are described. A valid test is then proposed, and details about how the number of simulated patterns impacts the statistical significance are explained. Finally, an example of using the proposed test within an exploratory data analysis framework is provided.

Data Interpretation, Statistical↗

PubMed2000

The Logic and Realism of the Hypothesis of Exploitation Ecosystems.

Hypotheses on trophic dynamics in terrestrial ecosystems fall into two major categories: those in which plants are assumed to be invulnerable to their consumers and those in which the build-up of plant biomass is assumed to require top-down control of folivores. The hypothesis of exploitation ecosystems (EEH) belongs to the latter category and focuses particularly on the consequences of the high energetic costs of maintenance of endotherms. Carnivorous endotherms require relatively high prey densities in order to break even. Moreover, they are dependent on folivorous prey during the limiting season, at least at high latitudes. The endotherm branch of the grazing web is thus predicted to collapse from three-link trophic dynamics (carnivores → folivores → plants → inorganic resources) to two-link dynamics (folivores → plants → inorganic resources) along gradients of decreasing primary productivity. Consequently, the vegetation of cold and unproductive areas is predicted to be under intense winter grazing pressure, which prevents the accumulation of aboveground plant biomass and excludes erect woody plants. In the most extreme habitats (e.g., polar deserts and their high alpine counterparts), even folivorous endotherms are predicted to be absent, and the scanty vegetation is predicted to be structured by preemptive competition. Within temperature-determined productivity gradients, EEH is corroborated by biomass patterns, by patterns in the structure and dynamics of carnivore, folivore, and plant communities, and by experimental results. The general idea of top-down trophic dynamics is supported for other autotroph-based systems, too, but the relevance and sufficiency of the energy constraint in explaining patterns in trophic dynamics appears to be variable. Moreover, critical empirical evidence for or against the capacity of folivorous insects to regulate plant biomass has not yet been obtained. Another open question is the ability of boreal and temperate browsers, evolved in productive environments with intense predation pressure and abundance of forage, to prevent the regeneration of the least palatable tree species. There are, thus, many open questions waiting to be answered and many exciting experiments waiting to be conducted.

herbivory↗

PubMed2000

Homology modeling and characterization of IgE binding epitopes of mountain cedar allergen Jun a 3.

The Jun a 3 protein from mountain cedar (Juniperus ashei) pollen, a member of group 5 of the family of plant pathogenesis-related proteins (PR-proteins), reacts with serum IgE from patients with cedar hypersensitivity. We used the crystal structures of two other proteins of this group, thaumatin and an antifungal protein from tobacco, both approximately 50% identical in sequence to Jun a 3, as templates to build homology models for the allergen. The in-house programs EXDIS and FANTOM were used to extract distance and dihedral angle constraints from the Protein Data Bank files and determine energy-minimized structures. The mean backbone deviations for the energy-refined model structures from either of the templates is <1 A, their conformational energies are low, and their stereochemical properties (determined with PROCHECK) are acceptable. The circular dichroism spectrum of Jun a 3 is consistent with the postulated beta-sheet core. Tryptic fragments of Jun a 3 that reacted with IgE from allergic patients all mapped to one helical/loop surface of the models. The Jun a 3 models have features common to aerosol allergens from completely different protein families, suggesting that tertiary structural elements may mediate the triggering of an allergic response.

Allergens↗

PubMed1995

Local nasal immunotherapy for birch allergic rhinitis with extract in powder form.

BACKGROUND: Traditional subcutaneous immunotherapy has been proved effective in birch pollenosis. It has, however, some drawbacks as systemic reactions, which are rare but important. Local nasal immunotherapy (LNIT) represents a potential safer route of allergen administration. OBJECTIVE: To study the clinical efficacy and safety of local nasal immunotherapy by means of an extract in powder form as treatment of birch allergic rhinitis. METHODS: Thirty birch allergic patients have been selected on the basis of a positive history, skin test, radioallergosorbent test assay (RAST) and specific nasal challenge. Two 15 patient groups were randomly assigned to the active treatment or to the placebo one. Treatment lasted 22 weeks (14 for the build-up phase and eight for maintenance period) and symptoms were recorded during the treatment and the birch pollen season. RESULTS: The clinical efficacy of LNIT is suggested by a significant reduction of medication score only in the treated group during the pollen season, although the symptom score was significantly lower in the treated group for 1 week only. Moreover, a significant increase of specific nasal threshold dose was observed after treatment only in the active treated group. Mild adverse reaction to LNIT, limited to the upper respiratory tract, were reported during the treatment in the active group, but they did not interfere with LNIT schedule. No asthmatic or systemic reaction were observed. CONCLUSIONS: This study indicates that LNIT with allergen in powder form has proven clinically effective in the treatment of birch allergic rhinitis. Further studies are needed to establish whether this treatment can be considered a real alternative to the traditional subcutaneous immunotherapy in birch allergic rhinitis.

Administration, Intranasal↗

PubMed2003

Carbon dynamics and land-use choices: building a regional-scale multidisciplinary model.

Policy enabling tropical forests to approach their potential contribution to global-climate-change mitigation requires forecasts of land use and carbon storage on a large scale over long periods. In this paper, we present an integrated modeling methodology that addresses these needs. We model the dynamics of the human land-use system and of C pools contained in each ecosystem, as well as their interactions. The model is national scale, and is currently applied in a preliminary way to Costa Rica using data spanning a period of over 50 years. It combines an ecological process model, parameterized using field and other data, with an economic model, estimated using historical data to ensure a close link to actual behavior. These two models are linked so that ecological conditions affect land-use choices and vice versa. The integrated model predicts land use and its consequences for C storage for policy scenarios. These predictions can be used to create baselines, reward sequestration, and estimate the value in both environmental and economic terms of including C sequestration in tropical forests as part of the efforts to mitigate global climate change. The model can also be used to assess the benefits from costly activities to increase accuracy and thus reduce errors and their societal costs.

Carbon↗

PubMedDate not supplied

Medical expert systems based on causal probabilistic networks.

Causal probabilistic networks (CPNs) offer new methods by which you can build medical expert systems that can handle all types of medical reasoning within a uniform conceptual framework. Based on the experience from a commercially available system and a couple of large prototype systems, it appears that CPNs are now an attractive alternative to other methods. A CPN is an intensional model of a domain, and it is therefore conceptually much closer to qualitative reasoning systems and to simulation systems than to rule-based or logic-based systems. Recent progress in Bayesian inference in networks has yielded computationally efficient methods. The inference method used follows the fundamental axioms of probability theory, and gives a sound framework for causal and diagnostic (deductive and abductive) reasoning under uncertainty. Experience with the prototypes indicates that it may be possible to use decision theory as a rational approach to test planning and therapy planning. The way in which knowledge is acquired and represented in CPNs makes it easy to express 'deep knowledge' for example in the form of physiological models, and the facilities for learning make it possible to make a smooth transition from expert opinion to statistics based on empirical data.

Artificial Intelligence↗

PubMed2003

Governance and the loss of biodiversity.

Most of the world's biodiversity occurs within developing countries that require donor support to build their conservation capacity. Unfortunately, some of these countries experience high levels of political corruption, which may limit the success of conservation projects by reducing effective funding levels and distorting priorities. We investigated whether changes in three well surveyed and widespread components of biodiversity were associated with national governance scores and other socio-economic measures. Here we show that governance scores were correlated with changes in total forest cover, but not with changes in natural forest cover. We found strong associations between governance scores and changes in the numbers of African elephants and black rhinoceroses, and these socio-economic factors explained observed patterns better than any others. Finally, we show that countries rich in species and identified as containing priority areas for conservation have lower governance scores than other nations. These results stress the need for conservationists to develop and implement policies that reduce the effects of political corruption and, in this regard, we question the universal applicability of an influential approach to conservation that seeks to ban international trade in endangered species.

Animals↗

PubMed2001

Decision analysis for small, asymptomatic intracranial arteriovenous malformations.

OBJECT: Asymptomatic intracranial arteriovenous malformations (AVMs) represent a clinically challenging problem because of the complex decision making that must be undertaken prior to beginning any type of treatment. In addition, the relative infrequency of these lesions means that there is relatively little experience reported in the literature. The authors use a decision-analysis technique to model the considerations that go into determining the treatment of these lesions in an effort to quantify the various risks and overall benefits conferred by the following three treatment strategies: observation/natural history, microsurgery, and stereotactic radiosurgery. METHODS: The authors conducted a thorough literature search to elucidate the risks and outcomes associated with each treatment option. These values were used to build and run a comprehensive Markov model to determine a base-case analysis. All of the input variables were also subjected to sensitivity analysis to identify the most influential input variables and the crossover points in which favored strategies changed. The base-case analysis suggested that microsurgery was the favored treatment option because this hypothetical cohort accumulated 21.53 quality-adjusted life years (QALYs) over the course of the model compared with the 16.97 QALYs and 16.40 QALYs for stereotctic radiosurgery and observation, respectively. Sensitivity analysis demonstrated that overall major neurological morbidity and mortality were the most influential input variables both perioperatively and during the radiosurgical "latent" period (that is, up to 2 years posttreatment). The maximum acceptable perioperative combined major neurological morbidity and mortality rate was 6.8%. The latent period combined major neurological morbidity and mortality would need to be 0.7% to make radiosurgery favorable in this analysis. CONCLUSIONS: Results of this decision analysis model suggest that microsurgery in the hands of experienced cerebrovascular surgeons, who can expect a less than 6.8% combined rate of major neurological morbidity and mortality, offers patients a greater overall quality of life over time.

Algorithms↗

PubMedDate not supplied

Pollen and spores in the air of a hospital out-patient ward.

BACKGROUND: Aerobiological studies of interest to the allergy specialist are routinely carried out using information from outdoor traps. However, most of our time is spent indoors and it is often the content of this air that is responsible for allergic phenomena. MATERIAL AND METHODS: The air of a hospital outpatient ward was analyzed using two portable volumetric aerobiological traps, one at floor level and the other at a height of 1 meter. Both spores and pollen grains were counted and their values were compared with those outside the building. RESULTS AND CONCLUSIONS: Twenty types of pollen grains were found. Their concentrations ranged from 2.7 and 25.1 grains/m3, with the most frequent being (in order) grasses, evergreen oak (holm and cork oaks), water plantain, and olive. Twenty two different types of spores were found with concentrations of between 175.0 and 1395.8 spores/m3 and the most frequent were Cladosporium, Ustilago and basidiospores. No significant differences were found between the floor level and the meter-high measurements. Comparison with outdoor levels showed that the three most abundant pollen types were correlated, with a ratio of 30:1 between indoor and outdoor levels. For the spores and fungi propagules, the indoor:outdoor ratio was highly variable, depending on the type. Thus, for Aspergillus-Penicillium spores, the concentration was even higher indoors than outdoors, although for most types, lower levels were found indoors, with a mean outdoor:indoor ratio of 4:1. We argue that this relationship reflects the presence of indoor spore sources. Rainfall was correlated with a decline in pollen levels and a rise in spore levels.

Air Microbiology↗

PubMed2003

[Anatomy and uses of the mature leaves of three species of Sabal (Arecaceae) of the Yucatan, México].

This paper describes the leaf anatomy of Sabal mauritiiformis (Karst.) Griseb. & H. Wendl., Sabal mexicana Mart. and Sabal yapa Wright ex Becc., three of the four most representative species of the Yucatán Península, in Mexico. These species are locally used: in the roofing of traditional homes, as food (fruits and apical buds), and in the production of hats, brooms and handicrafts. Leaf samples were collected in secondary growth of lower montane rainforest in the state of Quintana Roo and in two home gardens in the state of Yucatán. Herbarium samples were obtained, and samples of blade and petiole were fixed in formaline-acetic acid-alcohol. Cross incisions were made on the blade and petiole, and were dyed with safranin and toluidine blue O. The results show that S. mauritiiformis and S. yapa are morphologically alike: both are tall, slim palm trees; the leaf in S. mauritiiformis is a shorter palm-like structure compared with the other two species. The shape of the main nerve, as seen in cross section, is rectangular in the three species. The hastula in the three species is acuminate and adaxial. The foliar anatomic structure is similar in the three species, although there are some differences. The adaxial an abaxial epidermis of the blade consist of one layer and, superficially, the anticlinal walls are straight; the stomata are intercostal, of the tetracytic type, present on both surfaces in S. mexicana and S. yapa and only on the abaxial surface on S. mauritiiformis. The hypodermis is one layer thick in S. yapa and in S. mexicana and two layers thick in S. mauritiiformis. In the three species the palisade parenchyma consists of several undefined strata as the cells are similar-in shape and size--to the cells in the spongy parenchyma, so there is no marked difference between these strata and the spongy parenchyma seems almost continuous. Both fibrous and vascular bundles are distributed between the hypodermis and the palisade parenchyma; the fiber bundles can be found towards the abaxial surface while the vascular and fiber bundles are located towards the adaxial surface. The fibers, in the three species, are elongated, with the pointed tips, undivided and unseptated. One to three wide vessels of metaxilem can be seen in the vascular bundles, those in S. yapa being the widest in diameter. The vascular bundles are surrounded by thick fiber sheaths which come in pairs. The anatomic structure of the petiole is similar to that of the blade, and is characterized by the many vascular and fiber bundles dispersed in the parenchymatous tissue, and which are very resistant. The histological structure of the blade and petiole reflects strength and flexibility, qualities which make these plants adequate in the construction of roofs for rural housing and other buildings.

Arecaceae↗

PubMed2006

[Elaboration and validation of an index for preeclampsia diagnosis].

OBJECTIVE: To build a consistent and valid preeclampsia diagnosis index (IDP) for its Spanish acronyms. PATIENTS AND METHOD: The study was done in a Gyneco-Obstetrics Hospital and a Family Medicine Unit from March 2000 to February 2001. Fifty items were chosen from the literature, with a design to validate diagnostic tests, which were assessed by family doctors and gyneco-obstetricians in regard to their appearance and content validity. Concurrent criterion validity. Golden standard: Two gyneco-obstetricians diagnosed pre-eclampsia (hypertension and proteinuria). Simultaneously a family doctor (in an independent and blinded way) questioned, examined and recorded laboratory data of 219 preeclamptic patients and 251 non preeclamptic patients. RESULTS: Preeclampsia diagnosis index is an additive index with 21 clinical and paraclinical parameters weighted according to their individual diagnostic capacity. It has two parts: The first one with 82% (95%CI 80-84) sensitivity; 93% (95%CI 91-95) specificity; the second one with 86% (95%CI 83-89) sensitivity; 75% (95%CI 65-85) specificity. CONCLUSIONS: Preeclampsia diagnosis index is easily applied and has immediate results, which makes easier the physician's decisions.

Adult↗

PubMed2006

Orangutan leaf-carrying for nest-building: toward unraveling cultural processes.

We report an empirical study on leaf-carrying, a newly discovered nest-building technique that involves collecting nest materials before reaching the nest site. We assessed whether leaf-carrying by rehabilitant orangutans on Kaja Island, Central Kalimantan, owes to cultural influences. Findings derive from ca 600 h observational data on nesting skills and nesting associations in Kaja's 42 resident rehabilitants, which yielded 355 nests and 125 leaf-carrying cases by 34 rehabilitants. Regional contrasts with 14 other communities (7 rehabilitant, 7 wild) indicated cultural influences on leaf-carrying on Kaja. Association data showed exceptional social learning opportunities for leaf-carrying on Kaja, with residents taking differential advantage of these opportunities as a function of development, experience, and social position. Juvenile males with basic nesting skills were most influenced by social input. Most (27) leaf-carriers had probably learned leaf-carrying when caged and 7 probably learned it on Kaja. Social priming was probably the main impetus to leaf-carrying on Kaja, by simply prompting observers to copy when leaf-carrying associates collected nesting materials, what they collected, and where they used their collected materials. Implications concern acquisition processes and ontogenetic schedules that orchestrate sets of features-needs or interests, cognitive abilities, social preferences-which enable cultural transmission.

Animals↗

PubMed2001

Predicting days of high allergenic risk during Betula pollination using weather types.

The aim of this study was to build up a picture of the influence of meteorological conditions on pollen and pollinosis, taking account of weather types, pollen concentrations in the air and pollinosis symptoms, with the aim of preventing allergic responses. The study took place in Burgundy from 1996 to 1998, during the pollination of the birch (Betula), which is the most important arborean allergen in this region. We used daily pollen data from four Hirst volumetric traps, identified weather types by Bénichou's classification, and obtained data on the occurrence of rhinitis, conjunctivitis, asthma and coughing from a sample of 100 patients. These data were analysed by multiple-component analysis. The results show that pollen dispersal is favoured by windy conditions, low relative humidity, precipitation below 2 mm and temperatures above 6 degrees C. Such weather also favours pollinosis, but other particular meteorological situations, even if they do not assist pollen dispersal, can act directly on the development of symptoms: a decrease of temperature (3 degrees C) led to the development of rhinitis and conjunctivitis, while strong winds were associated with many cases of conjunctivitis and asthma, owing to the irritant effect of cold or wind; asthma was favoured by temperature inversions with fog, probably because such weather corresponds to high levels of pollution, which act on bronchial hyperreactivity. Because the weather types favouring pollination and pollinosis are predicted by the meteorological office, this can constitute a tool for reducing the effect of high-risk allergenic days.

Asthma↗

PubMed2004

[Relationship between urban green-land landscape patterns and air pollution in the central district of Yichang city].

In this paper, four types of landscape structures and their green-land landscape patterns, including the landscapes of dominant green-land patch pattern, even green-land patch pattern, dominant wooded corridor pattern and building or concrete covering pattern (control) in the central district of Yichang city in Hubei Province, were analyzed respectively on the basis of landscape ecological theory. The atmospheric noise and the contents of SO2, NOx and total suspension particle (TSP) of the landscapes were monitored respectively by comparative method. The results showed that the landscape of building or concrete covering pattern (control) was mostly composed of woodless corridors and building or concrete covering patches with the tiptop green-land fragmentation index (18.125 3 ind x hm(-2)) and only had 1.00% green-land coverage, which had a relatively higher atmospheric noise and the highest TSP content in the landscape. The landscape of dominant green-land patch pattern had the highest green-land coverage (up to 43.59%) dominated by great green-land patches and the least fragmentation index (0.453 9 ind x hm(-2)), in which, the atmospheric noise weakened by 28.12% and the TSP content reduced significantly by 86.42%, comparing to the control. The landscape of even green-land patch pattern had the relatively lower green-land coverage (11.34%) and fragmentation index (2.751 1 ind x hm(-2)), which was mainly composed of the middle or small green-land patches and wooded corridors with a regular distribution. In the landscape, the TSP content reduced obviously by 46.62% of the control, while the effect of dust retention was only 53.95% of that in the landscape of dominant green-land patch pattern. In the landscape of dominant wooded corridor pattern, which was a traffic center and turned into a main pollution resource in the city, there were a relatively higher green-land fragmentation index (6.870 0 ind x hm(-2)) and the highest wooded corridor density (0.844 3 hm x hm(-2)) with only 6.13% green-land coverage, and the atmospheric noise and the TSP and NOx content increased by 21.47%, 5.08% and 9.06%, respectively, comparing to control. It was obvious that the greater the average area of the green-land patch and the lower the fragmentation index of green-land patches, the more effective the green-land on purifying air pollution.

Agriculture↗

PubMed2000

Impact to lung health of haze from forest fires: the Singapore experience.

OBJECTIVE: From late July to the beginning of October 1997, countries of Southeast Asia experienced severe smoke haze pollution from uncontrolled forest fires mainly in the Indonesian states of Kalimantan and Sumatra. In Singapore, the impact of the 1997 haze was felt in the period from the end of August to the first week of November 1997 as a result of prevailing winds. METHODOLOGY: The Ministry of the Environment monitors ambient air quality by a country-wide telemetric air quality monitoring and management network, with 15 stations located throughout the island, linked via a public telephone network to a central control station at the Environment Building. The monitoring methods used are the United States Environmental Protection Agency (USEPA) reference methods. The Pollutant Standards Index (PSI) developed by the USEPA is used for the reporting of daily air pollution concentrations. Intervals on the PSI scale are related to the potential health effects of the daily measured concentrations of the five major air pollutants: sulfur dioxide, particulate matter (PM10), nitrogen dioxide, ozone and carbon monoxide. Public sector health facilities which come under the Ministry of Health, have computerized patient care systems which enable the routine ongoing surveillance of disease conditions for the period of the haze. Attention during the period of the haze was focused on conditions related to health effects of the haze. Data sources for the monitoring of the lung health effects of the haze included morbidity from public sector outpatient care facilities, accidents and emergency departments, public sector inpatient care facilities and national mortality data. RESULTS: Findings from the health impact of the haze showed that there was a 30% increase in outpatient attendance for haze-related conditions. An increase in PM10 levels from 50 microg/m3 to 150 microg/m3 was significantly associated with increases of 12% of upper respiratory tract illness, 19% asthma and 26% rhinitis. Supplementary findings from scanning the electron microscopic sizing of the haze particles showed that 94% of the particles in the haze were below 2.5 microm in diameter. This was consistent with emissions from combustion sources originating over 500 km from Singapore. This has been of some concern because particles smaller than 2.5 microm in diameter can easily bypass normal body defence metabolism and penetrate deeply into the alveoli of the lungs. During the same period, there was also an increase in accident and emergency attendance for haze-related conditions. There was no significant increase in hospital admissions or in mortality. CONCLUSION: The present study found that the health effects from the 1997 smoke haze in Singapore were generally mild.

Air Pollutants↗

PubMed2002

Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus.

The experiments strongly suggested that the reason why Purkinje cells die so easily after global brain ischemia relates to deficiencies in aldolase C and EAAT4 that allow them to survive pathologically intense synaptic input from the inferior olive after the restoration of blood flow. This conclusion is based on: (a) the remarkably tight correspondence between the regional absence of aldolase C and EAAT4 in Purkinje cells and the patterned loss of Purkinje cells after a bout of global brain ischemia; (b) the necessity of the olivocerebellar pathway for the ischemic death of Purkinje cells; and (c) the build-up of pathologically synchronous and high-frequency burst activity within the inferior olive during recovery from ischemia. Indeed, the correspondence between the absence of aldolase C and EAAT4 to sensitivity to ischemia could be demonstrated for zones of Purkinje cells as small as two neurons. A second finding was that Purkinje cells are not uniformly sensitive to transient ischemia, since they die most frequently in zones where aldolase C and EAAT4 are absent. One implication of the experiment is that factors beyond the unique synaptic and membrane properties of Purkinje cells play an important role in determining this neuron's high sensitivity to ischemia. The data strongly imply that two properties of Purkinje cells that make them susceptible to ischemic death are their reduced capability to sequester glutamate and reduced ability to generate energy during anoxia. The patterned death of Purkinje cells is sufficient to induce a form of audiogenic myoclonus, as determined with a neurotoxic dose of ibogaine. Ibogaine-induced myoclonus is recognized behaviorally as a reduced ability to habituate to a startle stimulus and resembles the myoclonic jerk of rats during recovery from a prolonged bout of global brain ischemia. Commonalities of ischemia and ibogaine-induced neurodegeneration are the intricately striped Purkinje cell loss in the posterior lobe and a nearly complete deafferentation of the lateral aspect of the fastigial nucleus from the cerebellar cortex, in particular the dorsolateral protuberance. Thus, the data point strongly to a cerebellar contribution to audiogenic myoclonus. Single-neuron electrophysiology experiments in monkeys have demonstrated that the evoked activity in the deep cerebellar nuclei occurs too late to initiate the startle response (60) and electromyography of the postischemic myoclonus of rats corroborates this view (see Chapter 31) (20). However, the nearly complete loss of GABAergic terminals in the dorsolateral protuberance after Purkinje cell death would be expected to dramatically increase its tonic firing and the background excitation of the brain-stem structures that it innervates. The fastigial nucleus innervates a large number of autonomic and motor structures in the brainstem and diencephalon, including the ventrolateral nucleus of the thalamus and the gigantocellular reticular nucleus in the medulla--structures that have been implicated in human posthypoxic myoclonus (6, 7). We propose that the posthypoxic myoclonic jerk of rats is, at least in part, due to disinhibition of the fastigial nucleus produced by patterned Purkinje cell death in the vermis. The argument is as follows: the loss of GABAergic inhibition in the fastigial nucleus after ischemia leads to diaschisis of the motor thalamus and reticular formation which, in turn, is responsible for enhanced motor excitability and myoclonus. That the audiogenic myoclonus after global brain ischemia in the rat gradually resolves over a period of 2 to 3 weeks is consistent with this view, as restoration of background excitability after CNS damage in rats has been documented to occur within this time-frame (61). Our view brings together the physiologic finding that posthypoxic myoclonus appears to originate in the sensory-motor cortices and/or reticular formation with the consistent anatomical finding of Purkinje cell loss after ischemia, and explains the puzzle of Marsden's unique cases of myoclonus associated with coeliac disease (1). Moreover, our argument is consistent with findings both in rats (62, 63) and humans (64) that damage to the vermis impairs the long-term habituation of the startle reflex. It remains to be determined whether the pathologically enhanced startle responses after vermal damage resemble brain-stem reticular or cortical myoclonus at the electrophysiologic level of analysis. What is the purpose of the regional expression of aldolase C and EAAT4 in Purkinje cells? The close correspondence between the spatial distribution of aldolase C and the parasagittal anatomy of the cerebellum (48) has led to the view that aldolase C may help specify connectivity during development. While the present experiments do not address this issue, they underscore the fact that aldolase plays a fundamental role in metabolism. Because Purkinje cells have a repressed expression of aldolase A (31), whatever role the absence of aldolase C may play during development comes at the price of metabolic frailty later in adulthood. From another point of view, aldolase C and EAAT4 appear to confer upon Purkinje cells the ability to survive their own climbing fiber. Indeed, climbing fibers form a distributed synapse that synchronously releases glutamate (or aspartate) at all levels of the dendritic tree simultaneously (65, 66). Such synchronous activation triggers calcium influx throughout the Purkinje cell dendrites at a magnitude that is unparalleled in the nervous system (12), and, thus, places an extraordinarily high metabolic demand on the Purkinje cell. The apparently reduced level of aldolase in a subpopulation of Purkinje cells provides the condition for energy failure and death during anoxia so long as the climbing fibers are intact or when climbing fiber activation is pharmacologically enhanced under normoxic conditions, such as after ibogaine (53-56). Lastly, the argument that diaschisis produced by patterned cerebellar degeneration leads to thalamo-cortical and reticular hyperexcitability agrees with C. David Marsden and his colleagues' bold demonstration of an inhibitory influence of cerebellar cortex on motor cortex in humans (67). Our anatomic data indicate that the spatially distinct zones of Purkinje cells, which are killed by global brain ischemia, may be the origin of such inhibition.

Amino Acid Transport System X-AG↗