Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Local adaptation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 397 records · Page 22Linked to original sources

[Competition for the promotion of essential generic drugs in Africa].

STATEMENT OF THE PROBLEM: in most sub-Saharan countries, an extensive economic crisis coupled with a low level of existing resources has put most pharmaceuticals beyond the reach of the general public. This situation was worsened by the devaluation of the Franc CFA in 1994. The supply of lowprice drugs and the improvement of rational drug use is now a priority. Unfortunately, essential generic drugs are little known and used in Africa. OBJECTIVE: 1. To improve the knowledge of and confidence in essential and generic drugs among providers, prescribers and consumers, through the participation of the general public in an incentive-based, creative competition; 2. To collect locally-adapted promotional material, to be used in the future promotion of essential and generic drugs in Africa. Design, setting and method: a competition was announced in June 1995, via various networks, in French-speaking Africa: the population was invited to create one or several items promoting essential generic drugs. These items included slogans, posters, songs and short plays. Over 550 entries were received before the deadline (15 October 1995), from 22 countries (mostly Sub-Saharan and French-speaking). The entries included 387 slogans, 94 posters, 22 plays, and various (photos, comic strips, songs, poems). RESULTS: 1. Greater awareness of essential generic drugs in Western Africa, through the publicity given to the competition; 2. Selection of a pool of approximately 200 promotional items, produced by the target populations, to be published in a catalog and distributed in African countries; 3. Insights into popular practices and representations of Western medications, and local re-interpretation of the concept. CONCLUSION: this public competition was effective at achieving three important goals: 1. Dynamic promotion (the competition was the opportunity for school projects, radio talkshows, etc. on generic drugs); 2. Re appropriation of a policy, thanks to a participative approach; 3. Analysis of the population's general comprehension of pharmaceuticals, through analysis of competition entries.

Advertising↗

Climate- and human-induced woody vegetation changes in Botswana and their implications for human adaptation.

For purposes of suggesting adaptive and policy options regarding the sustained use of forestry resources in Botswana, an analysis of the whole countrywide satellite data (showing the mean present distribution of vegetation in terms of species abundance and over all density) and the projection of vegetation cover changes using a simulation approach under different climatic scenarios were undertaken. The analysis revealed that changes in vegetation cover types due to human and natural causes have taken place since the first vegetation map was produced in 1971. In the southwest, the changes appear to be more towards an increasing prevalence of thorn trees; in the eastern part of the country where widespread bush encroachment is taking place, the higher population density suggests more human induced (agrarian-degradation) effects, while in the sparsely settled central Kalahari region, changes from tree savanna to shrubs may be indicative of the possible influence of climate with the associated effects of fires and local adaptations. Projection of future vegetation changes to about 2050 indicates degeneration of the major vegetation types due to the expected drying. Based on the projected changes in vegetation, current adaptive and policy arrangements are not adequate and as such a shift from the traditional adaptive approaches to community-based types is suggested. Defining forestry management units and adopting different management plans for the main vegetation stands that are found in Botswana are the major policy options.

Adaptation, Physiological↗

Allopatric combination of Fasciola hepatica and Lymnaea truncatula is more efficient than sympatric ones.

Parasites are capable of rapid evolutionary changes relative to their hosts, due to short life cycle, short generation time, and high fecundity. The direction of the evolution of parasite virulence can be studied in cross-transfer experiments, combining hosts and parasites from different localities, and comparing the outcome of established (sympatric and potentially locally adapted) and novel (allopatric) combinations of hosts and parasites. We aimed to compare the compatibility with snails hosts, the infectivity of metacercariae in rabbits and rats, and the fitness among different combinations (French-FF and Spanish-SS sympatries and allopatry-FS). The first isolate of Fasciola hepatica and its corresponding intermediate host, Lymnaea truncatula originated from Lugo's northwestern Spain. The second isolate of parasite and snail was collected in the Limoges area in central France. The Spanish snails were more susceptible to their sympatric trematode than the French snails. The Spanish flukes were more infective to intermediate hosts (snails) than the French flukes, but subsequent definitive hosts (rats or rabbits) infections remained similar. The estimated fitness was low in sympatric infections and highly similar (from 4.7 to 5.3). The fitness similarity corresponds, however, to different variations in life-history traits that could represent different strategies among the host-parasite local combinations. The infection rate in snails, metacercarial productivity, metacercarial infectivity, and the estimated fitness were better for allopatric combination (FS). The susceptibility data showed a higher efficiency of flukes in the allopatric snail population than in their local snail population. However, our results were obtained after one generation and from a single isolate and it remains to be determined if all allopatric fluke-snail isolates may present a better fitness. Nevertheless our results indicate that introduction of liver fluke-infected cattle should be monitored carefully, as it could result in the introduction of more efficient parasites.

Animals↗

Pleckstrin homology and phosphotyrosine-binding domain-dependent membrane association and tyrosine phosphorylation of Dok-4, an inhibitory adapter molecule expressed in epithelial cells.

Dok-like adapter molecules represent an expanding family of pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domain-containing tyrosine kinase substrates with negative regulatory functions in hematopoietic cell signaling. In a search for nonhematopoietic counterparts to Dok molecules, we identified and characterized Dok-4, a recently cloned member of the family. dok-4 mRNA was strongly expressed in nonhematopoietic organs, particularly the intestine, kidney, and lung, whereas both mRNA and protein were expressed at high levels in cells of epithelial origin. In Caco-2 human colon cancer cells, endogenous Dok-4 underwent tyrosine phosphorylation in response to pervanadate stimulation. In transfected COS cells, Dok-4 was a substrate for the cytosolic tyrosine kinases Src and Fyn as well as for Jak2. Dok-4 could also be phosphorylated by the receptor tyrosine kinase Ret but not by platelet-derived growth factor receptor-beta or IGF-IR. In both mammalian cells and yeast, Dok-4 was constitutively localized at the membrane in a manner that required both its PH and PTB domains. The PH and PTB domains of Dok-4 were also required for tyrosine phosphorylation of Dok-4 by Fyn and Ret. Finally, wild type Dok-4 strongly inhibited activation of Elk-1 induced by either Ret or Fyn. The attenuation of this inhibitory effect by deletion of the PH domain and its restoration by the addition of a myristoylation signal suggested an important role for constitutive membrane localization of Dok-4. In summary, Dok-4 is a constitutively membrane-localized adapter molecule that may function as an inhibitor of tyrosine kinase signaling in epithelial cells.

Adaptor Proteins, Signal Transducing↗

Losses of flicker sensitivity during dark adaptation: effects of test size and wavelength.

The losses of flicker sensitivity that occur during dark adaptation following extinction of a bleach depend greatly on the test stimuli that are used to measure those losses. Generally, the larger the test size is for a given test wavelength, the later is the loss of flicker sensitivity; for sufficiently large tests, losses become progressively more gradual. Similarly, the shorter the test wavelength is (between about 660 and 580 nm) for a given test size, the later is the loss of flicker sensitivity; for sufficiently short test wavelengths, losses become progressively more gradual. Although the pattern of flicker sensitivity loss as a function of test size is the same both foveally and parafoveally, foveal losses occur later and/or more gradually for a given test stimulus. The results suggest that losses of flicker sensitivity occur when spectrally antagonistic response(s) to the test are no longer adequate to maintain the flicker-response to that test. The results suggest also that the adequacy of such spectral antagonism depends on the local adaptation state of the retina, which becomes increasingly more light-adapted with increasingly large test size.

Adult↗

A proper study for mankind: Analogies from the Papionin monkeys and their implications for human evolution.

This paper's theme is that analogies drawn from the cercopithecine tribe Papionini, especially the African subtribe Papionina (baboons, mangabeys, and mandrills), can be a valuable source of insights about the evolution of the human tribe, Hominini, to complement homologies found in extant humans and/or African apes. Analogies, involving a "likeness of relations" of the form "A is to B, as X is to Y," can be usefully derived from nonhomologous (homoplastic) resemblances in morphology, behavior, ecology, or population structure. Pragmatically, the papionins are a fruitful source of analogies for hominins because they are phylogenetically close enough to share many basic attributes by homology, yet far enough that homoplastic modifications of these features are easily recognized as such. In "The Seedeaters," an analogy between Theropithecus among baboons and Australopithecus africanus among hominines was the source of a widely discussed (and often misrepresented) diet-based scenario of hominin origins that explained previously unassociated hominin apomorphies, interpreted basal hominins as nonhuman rather than prehuman primates, and accommodated a basal hominin adaptive radiation of at least two lines. Current usage recognizes an even more extensive evolutionary radiation among the basal hominins, originating no earlier than about 7 ma, with multiple lineages documented or inferred by 2.5 ma. Although multilineage clades (especially the Paranthropus clade) within this complex are widely recognized, and emerge from sophisticated, parsimony-based analyses, it is suspected that in many cases, developmental or functional homoplasies are overwhelming the phylogenetic signal in the data. The papionin analogy (specifically the splitting of the traditional, morphology-based genera Cercocebus and Papio mandated by molecular evidence) illustrates the power of these factors to produce erroneous cladograms. Moreover, the rapid deployment of basal hominins across varied African habitats was an ideal scenario for producing morphologically undetectable homoplasy. There seems to be no foolproof way to distinguish, a priori, homologous from homoplastic resemblances in morphology, but one pragmatic strategy is to severely censor the datset, retaining only resemblances or differences (often apparently trivial ones) that cannot be reasonably explained on the basis of functional resemblance or difference, respectively. This strategy may eliminate most morpological data, and leave many fossil taxa incertae sedis, but this is preferable to unwarranted phylogenetic confidence. Another source of phylogenetic uncertainty is the possibility of gene-flow by occasional hybridization between hominins belonging to ecologically and adaptively distinct species or even genera. Although the evidence is unsatisfactorily sparse, it suggests that among catarrhines generally, regardless of major chromosomal rearrangements, intersterility is roughly proportional to time since cladogenetic separation. On a papionin analogy, especially the crossability of Papio hamadryas with Macaca mulatta and Theropithecus gelada, crossing between extant hominine genera is unlikely to produce viable and fertile offspring, but any hominine species whose ancestries diverged less than 4 ma previously may well have been able to produce hybrid offspring that could, by backcrossing, introduce alien genes with the potential of spreading if advantageous. Selection against maladaptive traits would maintain adaptive complexes against occasional genetic infiltration, and the latter does not justify reducing the hybridizing forms to a conspecific or congeneric rank. Whether reticulation could explain apparent parallels in hominin dentition and brain size is uncertain, pending genetic investigation of these apparently complex traits. Widespread papionin taxa (such as Papio baboons and species-groups of the genus Macaca), like many such organisms, are distributed as a "patchwork" of nonoverlapping but often parapatric forms (allotaxa). Morphologically diagnosable, yet not reproductively isolated, most allotaxa would be designated species by the phylogenetic species concept, but subspecies by the biological species concept, and use of the term "allotaxa" avoids this inconsistency. A line of contact between allotaxa typically coincides with an ecotone, with neighboring allotaxa occupying similar econiches in slightly different habitats, and often exhibiting subtle, adaptive, morphological differences as well as their defining differences of pelage. "Hybrid zones," with a wide variety of internal genetic structures and dynamics, typically separate parapatric allotaxa. Current models attribute the formation and maintenance of allotaxa to rapid pulses of population expansion and contraction to and from refugia, driven by late Neogene climatic fluctuations. An overall similarity in depth of genetic diversity suggests that papionin taxa such as Papio baboons, rather than extant humans, may present the better analogy for human population structure of the "prereplacement" era. Neandertals and Afro-Arabian "premodern" populations may have been analogous to extant baboon (and macaque) allotaxa: "phylogenetic" species, but "biological" subspecies. "Replacement," in Europe, probably involved a rapidly sweeping hybrid zone, driven by differential population pressure from the "modern" side. Since the genetic outcome of hybridization at allotaxon boundaries is so variable, the problem of whether any Neandertal genes survived the sweep, and subsequent genetic upheavals, is a purely empirical one; if any genes passed "upstream" across the moving zone, they are likely to be those conferring local adaptive advantage, and markers linked to these. In general, extant papionin analogies suggest that the dynamics and interrelationships among hominin populations now known only from fossils are likely to have been more complex than we are likely to be able to discern from the evidence available, and also more complex than can be easily expressed in conventional taxonomic terminology.

Animals↗

Gut ischaemia.

Intestinal mucosal injury that results from local ischaemia can be detected by early increases in gut permeability, followed by later morphological, histological, and biochemical abnormalities. Local adaptive mechanisms (for example increased oxygen extraction) can cope with reductions in blood flow of up to 50%, as may occur during episodes of septic shock or cardiac tamponade. Why then does hypoxic injury develop? The peculiar vascular anatomy of the villi allows for oxygen short circuiting to occur at their base, when blood flow is low. Although overall oxygen extraction efficiency may be high, regional hypoxia at the villus tip may, paradoxically occur. The severity of reperfusion injury depends on the duration of preceding hypoxia. Free radical generation through the hypoxanthine xanthine oxidase system is important in mediating cellular damage. In addition, luminal aggressive factors (for example, pancreatic proteases) may cause mucosal damage, as suggested by earlier studies. More recent studies in pigs suggests that pancreatic duct ligation merely delays, but does not prevent development of gut reperfusion injury. Enteral nutrition should benefit patients with the ischaemic intestine because in comparison with total parental nutrition, it stimulates regional blood flow, and attenuates mucosal injury. There are no randomised trials to verify this, but use of tonometry to monitor local ischaemia may help resolve the issue.

Animals↗

The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice.

OBJECTIVE: Cells of adaptive immunity have been implicated in atherogenesis. Though substantial information is available on immune cells in atherosclerotic lesions of the lamina intima, cells in the lamina adventitia have received less attention. METHODS AND RESULTS: The composition of immune cells in the innominate artery and abdominal aorta was examined in young, adult, and old apolipoprotein (apo) E(-/-) and wild-type mice on standard mouse chow. In the innominate artery of apoE(-/-) mice, adventitial T cells increased at 32, 52, and 78 weeks exceeding those of the intima by 6-, 24-, and 85-fold. Single T cells dominated in young mice, later T/B cell clusters emerged, and lymphoid-like structures reminiscent of inflammatory follicles formed preferentially in the abdominal aorta of old mice. Follicles contained organized sets of immune response-regulating cells: Interdigitating dendritic cells, T cell effectors, proliferating B cells, and plasma cells. Adventitial T cell inflammation was associated with a marked increase in transcripts of the chemokine MIP-1alpha in the aorta but not in spleen or liver. CONCLUSIONS: Adventitial lymphocyte infiltration and formation of inflammatory follicle-like structures in the abdominal aorta of old apoE(-/-) mice point to the adventitia as a site of local adaptive immune reactions during atherogenesis in hyperlipidemic mice.

Age Factors↗

Effect of heart rate on regulative features of the cortical activity-flow coupling.

OBJECTIVE: Heart rate plays an important role in compensatory conditions of arterial pressure changes. Very little information, however, exists on its role in the dynamic adjustment of stimulated organ perfusion. We studied the influence of heart rate on the activity-flow coupling mechanism which adapts local cerebral blood flow in accordance with cortical activity. Since it does not affect heart rate or arterial blood pressure by itself, the commonly observed heart rate variability in test conditions was used to compare the flow response between different heart rate groups. For evaluation under stable heart rate conditions we performed a short test paradigm with a transcranial Doppler technique with the necessary high time resolution. METHODS: 168 healthy young volunteers (24 +/- 3 years of age) were grouped according to their heart rate in decade steps from 60 to 100 beats/min (mean: 82 +/- 9 beats/min). The visually evoked flow velocity responses in the posterior cerebral artery were evaluated according to a control system approach. Peak systolic and end diastolic data were evaluated separately. RESULTS: A correlation analysis between heart rate and baseline flow velocity as well as each of the control system parameters, i.e. gain, attenuation, rate time and natural frequency, revealed no significance. The flow responses did not differ among the heart rate groups as concluded from an ANOVA test. DISCUSSION: The increase in heart rate and the possible stress factors responsible for this seem to be of no relevance in regulative features of the activity-flow coupling. The almost identical time course of flow velocity responses among the groups showing a heart rate difference of up to 50% indicates an integrative principle in flow regulation supporting simplified concepts of flow adaptation.

Adult↗

An intraspecific comparative analysis of character divergence between sympatric species.

Although sympatric character divergence between closely related species has been described in a wide variety of taxa, the evolutionary processes responsible for generating these patterns are difficult to identify. One hypothesis that can explain sympatric differences is ecological character displacement: the sympatric origin of morphologically divergent phenotypes in response to selection caused by interspecific competition. Alternatively, populations may adapt to different conditions in allopatry, with sympatric distributions evolving through selective colonization and proliferation of ecologically compatible phenotypes. In this study, I characterize geographic variation within two sibling species of rocky-shore gastropods that have partially overlapping distributions in central California. In sympatry, both Nucella emarginata and N. ostrina show significant differences in shell shape and shell ornamentation that together suggest that where the two species co-exist, divergent phenotypes arose as an evolutionary consequence of competition. To examine the evolutionary origins of divergent characters in sympatry, I used a comparative method based on spatial autocorrelation to remove the portion of the phenotypic variance among populations that is explained by genetic distance (using mitochondrial DNA sequences and allozyme frequency data). Because the remaining portion of the phenotypic variance represents the independent divergence of individual populations, a significant sympatric difference in the corrected dataset provides evidence of true character displacement: significant sympatric character evolution that is independent of population history. After removal of genetic distance effects in Nucella, shell shape differences remain statistically significant in N. emarginata, providing evidence of significant sympatric character divergence. However, for external shell ornamentation in both species and shell shape in N. ostrina, the significance of sympatric differences is lost in the corrected dataset, indicating that colonization events and gene flow have played important roles in the evolutionary history of character divergence in sympatry. Although the absence of a widely dispersing planktonic larva in the life cycle of Nucella will promote local adaptation, the results here indicate that once advantageous traits arise, demographic processes, such as recurrent gene flow between established populations and extinction and recolonization, are important factors contributing to the geographic pattern of sympatric character divergence.

Animals↗

Effects of increased muscle mass on mouse sagittal suture morphology and mechanics.

The purpose of this study is to test predicted form-function relationships between cranial suture complexity and masticatory muscle mass and biomechanics in a mouse model. Specifically, to test the hypothesis that increased masticatory muscle mass increases sagittal suture complexity, we measured the fractal dimension (FD), temporalis mass, and temporalis bite force in myostatin-deficient (GDF8(-/-)) mice and wild-type CD-1 mice (all male, 6 months old). Myostatin is a negative regulator of muscle mass, and myostatin-deficient mice show a marked increase in muscle mass compared to normal mice. We predicted that increased sagittal suture complexity would decrease suture stiffness. The data presented here demonstrate that increased suture complexity (measured as FD) was observed in a hypermuscular mouse model (GDF8(-/-)) with significantly increased temporalis muscle mass and bite forces. Hypermuscular mice were also found to possess suture connective tissue that was less stiff (i.e., underwent more displacement before failure occurred) when loaded in tension. By decreasing stiffness, suture complexity apparently helps to dissipate mechanical loads within the cranium that are related to chewing. These results suggest that cranial suture connective tissue locally adapts to functional demands of the biomechanical suture environment. As such, cranial sutures provide a novel model for studies in connective tissue mechanotransduction.

Animals↗

Attempt to classify glial cells by means of their process specialization using the rabbit retinal Müller cell as an example of cytotopographic specialization of glial cells.

The rabbit retinal Müller cell is one of the most widely studied glial cell types, and it has all forms of contacts that a glial cell can express, viz. 1) to a (ventricular) fluid space, 2) to a mesenchymal borderline (basal lamina), and 3) to neuronal compartments. This cell demonstrates the local adaptation of cell processes to the microenvironment with which they are in contact. Summarizing available data on Müller cells and other glial cell types, it is concluded that the structure with which the process is in contact determines the type of glial cell process that develops. The type I process has microvilli, desmosome-like junctions, and high Na+,K+-ATPase activity; this type of process is in direct contact with a fluid such as cerebrospinal fluid. The type II endfoot-bearing process contains gliofilaments and has a high K+ conductivity; this type of process is covered by a basal lamina and is in contact with mesenchyme. The type III sheath-bearing process insulates neuronal compartments and expresses suitable membrane properties for glia-neuronal communication. Since structurally similar processes have been shown to have similar physiological properties, a new systematic classification of glial cells is proposed, based on the presence or absence of defined types of cell processes. This approach is believed to provide new insights into the function of neuroglia in both the central and peripheral nervous systems, in vertebrates and invertebrates, and even during ontogenetic development.

Animals↗

Fast robust automated brain extraction.

An automated method for segmenting magnetic resonance head images into brain and non-brain has been developed. It is very robust and accurate and has been tested on thousands of data sets from a wide variety of scanners and taken with a wide variety of MR sequences. The method, Brain Extraction Tool (BET), uses a deformable model that evolves to fit the brain's surface by the application of a set of locally adaptive model forces. The method is very fast and requires no preregistration or other pre-processing before being applied. We describe the new method and give examples of results and the results of extensive quantitative testing against "gold-standard" hand segmentations, and two other popular automated methods.

Algorithms↗

Sequence diversity of human caliciviruses recovered from children with diarrhea in Mendoza, Argentina, 1995-1998.

Human caliciviruses were detected by EIA and/or RT-PCR in stool specimens from children with diarrhea treated at out- or in-patient facilities between 1995 and 1998 in Mendoza, Argentina. Mexico virus-like strains detected by primers NV36/51 were transiently prevalent in 1995/1996. Significantly more human caliciviruses were detected when primers were designed from contemporaneously circulating strains. Nucleotide sequences of a highly conserved region in the RNA polymerase gene of 10 selected human caliciviruses were determined. Eight strains were Norwalk-like viruses and two strains were Sapporo-like viruses. Seven of the eight Norwalk-like viruses also were positive by the recombinant Mexico virus antigen EIA. The seven Mexico virus EIA-positive strains revealed two patterns in the RNA polymerase sequences: two strains were closest to Mexico virus and the other five strains were closest to Lordsdale virus. One of the five "Lordsdale" viruses was found to be a naturally occurring recombinant between the Mexico virus and Lordsdale human calicivirus genetic clusters [Jiang et al., (1999b) Archives of Virology 144:2377-2387]. The Mexico virus EIA-negative strain had 73-77% nucleotide identity with the closest related Norwalk-like viruses, indicating it might belong to a new genetic cluster of the Norwalk-like virus genus. The two Sapporo-like viruses were distinct genetically; one belonged to the Houston/90 or Parkville cluster and the other to a new cluster. Some strains appeared to have short periods of prevalence and locally adapted primer pairs significantly increased detection rates. The finding of high diversity of circulating strains, including recombinant strains and strains with previously unrecognized genetic identities, highlights a need for studies of human caliciviruses in these children and other populations.

Amino Acid Sequence↗

Impact of geographical origin on mating behaviour in two species of Biomphalaria (Planorbidae: Gastropoda).

Studies of inbreeding and outcrossing have traditionally concentrated on matings within populations. The influence of geographical origin on mate choice in animals from different populations has received less attention. We investigated whether planorbid snails mated preferentially within their own population or with snails from other populations. Snails from three Biomphalaria pfeifferi strains and three B. glabrata strains were allowed to mate with conspecifics in the laboratory. We recorded their matings at night using time-lapse video. When they could choose between sympatric and allopatric snails, Biomphalaria snails significantly preferred the former: snails of each population mated more often with sympatric than with allopatric snails. This tendency to avoid outcrossing may indicate that, in some species, local adaptations can be more valuable than genetic novelties. Copyright 1999 The Association for the Study of Animal Behaviour.

Journal Article↗

Sharable representation of clinical guidelines in GLIF: relationship to the Arden Syntax.

Clinical guidelines are intended to improve the quality and cost effectiveness of patient care. Integration of guidelines into electronic medical records and order-entry systems, in a way that enables delivery of patient-specific advice at the point of care, is likely to encourage guidelines acceptance and effectiveness. Among the methodologies for modeling guidelines and medical decision rules, the Arden Syntax for Medical Logic Modules and the GuideLine Interchange Format version 3 (GLIF3) emphasize the importance of sharing encoded logic across different medical institutions and implementation platforms. These two methodologies have similarities and differences; in this paper we clarify their roles. Both methods can be used to support sharing of medical knowledge, but they do so in complementary situations. The Arden Syntax is suitable for representing individual decision rules in self-contained units called Medical Logic Modules (MLMs), which are usually implemented as event-driven alerts or reminders. In contrast, GLIF3 is designed for encoding complex multistep guidelines that unfold over time. As a consequence, GLIF3 has several mechanisms for complexity management and additional constructs that may require overhead unnecessary for expressing simple alerts and reminders. Unlike the Arden Syntax, GLIF3 encourages a top-down process of guideline modeling consisting of three levels that are created in order: Level 1 comprises a human-readable flowchart of clinical decisions and actions. Level 2 comprises a computable specification that can be verified for logical consistency and completeness; and Level 3 comprises an implementable specification that includes information required for local adaptation of guideline logic as well as for mapping guideline variables onto institutional medical records. A major emphasis of the current GLIF3 development process has been to create the computable specification that formally represents medical decision and eligibility criteria. We based GLIF3's formal expression language on the Arden Syntax's logic grammar, making the necessary extensions to the Arden Syntax's data structures and operators to support GLIF3's object-oriented data model. We discuss why the process of generating a set of MLMs from a GLIF-encoded guideline cannot be automated, why it can result in information loss, and why simple medical rules are best represented as individual MLMs. We thus show that the Arden Syntax and GLIF3 play complementary roles in representing medical knowledge for clinical decision support.

Computer Simulation↗

Toward a representation format for sharable clinical guidelines.

Clinical guidelines are being developed for the purpose of reducing medical errors and unjustified variations in medical practice, and for basing medical practice on evidence. Encoding guidelines in a computer-interpretable format and integrating them with the electronic medical record can enable delivery of patient-specific recommendations when and where needed. Since great effort must be expended in developing high-quality guidelines, and in making them computer-interpretable, it is highly desirable to be able to share computer-interpretable guidelines (CIGs) among institutions. Adoption of a common format for representing CIGs is one approach to sharing. Factors that need to be considered in creating a format for sharable CIGs include (i) the scope of guidelines and their intended applications, (ii) the method of delivery of the recommendations, and (iii) the environment, consisting of the practice setting and the information system in which the guidelines will be applied. Several investigators have proposed solutions that improve the sharability of CIGs and, more generally, of medical knowledge. These approaches can be useful in the development of a format for sharable CIGs. Challenges in sharing CIGs also include the need to extend the traditional framework for disseminating guidelines to enable them to be integrated into practice. These extensions include processes for (i) local adaptation of recommendations encoded in shared generic guidelines and (ii) integration of guidelines into the institutional information systems.

Computer Simulation↗

Late Pleistocene human population bottlenecks, volcanic winter, and differentiation of modern humans.

The "Weak Garden of Eden" model for the origin and dispersal of modern humans (Harpending et al., 1993) posits that modern humans spread into separate regions from a restricted source, around 100 ka (thousand years ago), then passed through population bottlenecks. Around 50 ka, dramatic growth occurred within dispersed populations that were genetically isolated from each other. Population growth began earliest in Africa and later in Eurasia and is hypothesized to have been caused by the invention and spread of a more efficient Later Stone Age/Upper Paleolithic technology, which developed in equatorial Africa. Climatic and geological evidence suggest an alternative hypothesis for Late Pleistocene population bottlenecks and releases. The last glacial period was preceded by one thousand years of the coldest temperatures of the Later Pleistocene (approximately 71-70 ka), apparently caused by the eruption of Toba, Sumatra. Toba was the largest known explosive eruption of the Quaternary. Toba's volcanic winter could have decimated most modern human populations, especially outside of isolated tropical refugia. Release from the bottleneck could have occurred either at the end of this hypercold phase, or 10,000 years later, at the transition from cold oxygen isotope stage 4 to warmer stage 3. The largest populations surviving through the bottleneck should have been found in the largest tropical refugia, and thus in equatorial Africa. High genetic diversity in modern Africans may thus reflect a less severe bottleneck rather than earlier population growth. Volcanic winter may have reduced populations to levels low enough for founder effects, genetic drift and local adaptations to produce rapid population differentiation. If Toba caused the bottlenecks, then modern human races may have differentiated abruptly, only 70 thousand years ago.

Animals↗