Although the source of embryonic stem (ES) cells presents ethical concerns, their use may lead to many clinical benefits if differentiated cell types can be derived from them and used to assemble functional organs. In pancreas, insulin is produced and secreted by specialized structures, islets of Langerhans. Diabetes, which affects 16 million people in the United States, results from abnormal function of pancreatic islets. We have generated cells expressing insulin and other pancreatic endocrine hormones from mouse ES cells. The cells self-assemble to form three-dimensional clusters similar in topology to normal pancreatic islets where pancreatic cell types are in close association with neurons. Glucose triggers insulin release from these cell clusters by mechanisms similar to those employed in vivo. When injected into diabetic mice, the insulin-producing cells undergo rapid vascularization and maintain a clustered, islet-like organization.

Animals↗

PubMed2001

Bone marrow cells regenerate infarcted myocardium.

Myocardial infarction leads to loss of tissue and impairment of cardiac performance. The remaining myocytes are unable to reconstitute the necrotic tissue, and the post-infarcted heart deteriorates with time. Injury to a target organ is sensed by distant stem cells, which migrate to the site of damage and undergo alternate stem cell differentiation; these events promote structural and functional repair. This high degree of stem cell plasticity prompted us to test whether dead myocardium could be restored by transplanting bone marrow cells in infarcted mice. We sorted lineage-negative (Lin-) bone marrow cells from transgenic mice expressing enhanced green fluorescent protein by fluorescence-activated cell sorting on the basis of c-kit expression. Shortly after coronary ligation, Lin- c-kitPOS cells were injected in the contracting wall bordering the infarct. Here we report that newly formed myocardium occupied 68% of the infarcted portion of the ventricle 9 days after transplanting the bone marrow cells. The developing tissue comprised proliferating myocytes and vascular structures. Our studies indicate that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease.

Animals↗

PubMed2001

Do facial averageness and symmetry signal health?

We investigated whether the attractive facial traits of averageness and symmetry signal health, examining two aspects of signalling: whether these traits are perceived as healthy, and whether they provide accurate health information. In Study 1, we used morphing techniques to alter the averageness and symmetry of individual faces. Increases in both traits increased perceived health, and perceived health correlated negatively with rated distinctiveness (a converse measure of averageness) and positively with rated symmetry of the images. In Study 2, we examined whether these traits signal real, as well as perceived, health, in a sample of individuals for whom health scores, based on detailed medical records, were available. Perceived health correlated negatively with distinctiveness and asymmetry, replicating Study 1. Facial distinctiveness ratings of 17-year-olds were associated with poor childhood health in males, and poor current and adolescent health in females, although the last association was only marginally significant. Facial asymmetry of 17-year-olds was not associated with actual health. We discuss the implications of these results for a good genes account of facial preferences.

Journal Article↗

PubMed2001

Imai technique for management of the coronary arteries arising from a solitary sinus in discordant ventriculo-arterial connections.

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Child, Preschool↗

PubMed2001

Changes in attitudes and practices of optometrists in their management of diabetic retinopathy after the release of NHMRC guidelines. National Health and Medical Research Council.

The purpose of this study was to document attitudes and practices of Australian optometrists in their management of diabetic retinopathy prior to the release of the National Health and Medical Research Council (NHMRC) Clinical Practice Guidelines for the Management of Diabetic Retinopathy and at two time points following their release. A self-administered questionnaire was mailed to a stratified random sample of 500 Australian optometrists at the three time points. The same sample was used for the first two surveys and a new random sample was drawn for the second follow-up survey. The response to the three questionnaires was 86%, 80% and 84%, respectively. More than 90% of optometrists reported receiving a copy of the guidelines and 82% reported receiving the supplementary Retinopathy Chart. Fifty-seven per cent reported having read the guidelines at least once in entirety and 65% reported that they refer to the Retinopathy Chart at least monthly in their clinical practice. There was a significant decrease in the number of optometrists who reported that patient unwillingness to be dilated and their fear of precipitating angle closure glaucoma were moderate or major barriers to performing dilated ophthalmoscopy. Concomitantly, the percentage of optometrists who reported that they often or always perform dilated ophthalmoscopy on new patients with diabetes increased significantly from 74.5% (95% confidence limit = 70.2, 78.8) to 81.5% (95% confidence limit = 77.5, 85.5). There have been some significant changes in the self-reported management practices of optometrists in relation to diabetic retinopathy since the release of the NHMRC guidelines and Retinopathy Chart.

Attitude to Health↗

PubMed2001

Changes in management of diabetic retinopathy by Australian ophthalmologists as a result of the NHMRC clinical guidelines.

PURPOSE: To document changes in management of diabetic retinopathy by Australian ophthalmologists after release of the National Health and Medical Research Council (NHMRC) clinical guidelines. METHODS: Self-administered questionnaires were mailed to Australian ophthalmologists prior to release of the NHMRC guidelines for the management of diabetic retinopathy, and at one and 2.5 years after release of the guidelines. The questionnaires elicited information about current management practices in relation to diabetic retinopathy RESULTS: The response rate for the baseline and two follow-up surveys was 82%, 81%, and 80%, respectively. More than 85% of the ophthalmologists responded that the guidelines were useful in improving management, were easy to understand, and were already part of their routine clinical practice. A relatively small percentage (12%) felt that the guidelines made recommendations that were not practical or feasible. Contrary to the NHMRC guidelines, at the second follow-up survey, only 50% of the ophthalmologists said that they would almost never perform fluorescein angiography in eyes with mild non-proliferative diabetic retinopathy. The change from baseline to the second follow-up in the percentage of ophthalmologists who would perform cataract surgery after treating clinically significant macular oedema (as advised by the NHMRC guidelines) was statistically significant (baseline = 83.7%, 95% confidence limit = 80.4, 87.0; second follow up = 90.4, 95% confidence limit = 87.3, 93.5). CONCLUSIONS: Distribution of the printed NHMRC Clinical Practice Guidelines: Management of Diabetic Retinopathy and full colour Retinopathy Chart resulted in a significant change in the recommended order of treatment of clinically significant macular oedema. However no significant change in the use of fluorescein angiography was documented.

Australia↗

PubMed2001

Diabetic retinopathy: effects of national guidelines on the referral, examination and treatment practices of ophthalmologists and optometrists.

OBJECTIVE: To investigate the changes in referral, examination and treatment practices for diabetic retinopathy by ophthalmologists and optometrists following the release of national guidelines. METHODS: A two-page self-administered questionnaire was mailed to all Australian ophthalmologists and a random sample of 500 Australian optometrists prior to and 1 year after release of the National Health and Medical Research Council of Australia (NHMRC) clinical practice guidelines for the management of diabetic retinopathy. The questionnaires elicited information about current practice related to the management of patients with diabetic retinopathy. RESULTS: Of the 464 contactable ophthalmologists who responded to the baseline survey, 374 (80.6% response) completed the follow-up survey The response rate for the contactable optometrists was 80.1% (310 of 384). There were almost no significant changes in management practices from baseline to follow up. For example, the percentage of ophthalmologists who reported that they were often or almost always confident in detecting moderate retinal thickening near the macula remained nearly identical from baseline to follow up (80.2% vs 79.1 %). The rate was also similar from baseline to follow up for optometrists (31.1% vs 28.8%). The one area in which ophthalmologists reported significant changes in management towards agreement with the NHMRC guidelines was use of angiography; they were less likely to manage their patients this way (20.4% vs 14.2% with laser and 48.9% vs 38.4% without laser for increasing level of severity in clinical signs; both P < 0.05). CONCLUSIONS: The NHMRC guidelines for diabetic retinopathy have been successfully distributed to ophthalmologists and optometrists in Australia. However, the mere provision of the guidelines has had little impact on management practices. It will be important to determine if ongoing dissemination and implementation strategies not only increase awareness of health-care practitioners to the guidelines, but also change behaviours.

Adolescent↗

PubMed2001

Theoretical and practical considerations in the psychological and educational assessment of the student with intractable epilepsy: dynamic assessment as an adjunct to static assessment.

Assessing the student with intractable epilepsy requires skill not only in evaluating cognitive problems, but also detecting seizures and discovering how to adapt instruction to minimize their negative impact on learning. Ironically, assessment efforts are seen as compromised by the occurrence of seizures during testing, when determining how seizure events may interfere with learning and the instructional modifications that are necessary to cope with them, should be a key part of assessment. A dual approach to assessment is recommended that combines the identification of cognitive deficits with an evaluation of how recurring seizures may prevent the student from engaging in instruction. Without also evaluating the student's response to instruction, teaching to specific cognitive needs is limited by insufficient knowledge about how to keep the student involved in instruction when seizures occur. Static assessment evaluates cognitive functioning at the time of testing, without changing the way that the student learns and responds. By engaging the student in teaching/learning sessions, dynamic assessment explores how the student best learns despite cognitive deficits and the disruptive effect of seizures. This paper includes a description of the authors'experience in using dynamic assessment as an adjunct to static assessment in evaluating a student with intractable epilepsy.

Child↗

PubMed2001

Attractiveness of facial averageness and symmetry in non-western cultures: in search of biologically based standards of beauty.

Averageness and symmetry are attractive in Western faces and are good candidates for biologically based standards of beauty. A hallmark of such standards is that they are shared across cultures. We examined whether facial averageness and symmetry are attractive in non-Western cultures. Increasing the averageness of individual faces, by warping those faces towards an averaged composite of the same race and sex, increased the attractiveness of both Chinese (experiment 1) and Japanese (experiment 2) faces, for Chinese and Japanese participants, respectively. Decreasing averageness by moving the faces away from an average shape decreased attractiveness. We also manipulated the symmetry of Japanese faces by blending each original face with its mirror image to create perfectly symmetric versions. Japanese raters preferred the perfectly symmetric versions to the original faces (experiment 2). These findings show that preferences for facial averageness and symmetry are not restricted to Western cultures, consistent with the view that they are biologically based. Interestingly, it made little difference whether averageness was manipulated by using own-race or other-race averaged composites and there was no preference for own-race averaged composites over other-race or mixed-race composites (experiment 1). We discuss the implications of these results for understanding what makes average faces attractive. We also discuss some limitations of our studies, and consider other lines of converging evidence that may help determine whether preferences for average and symmetric faces are biologically based.

Adolescent↗

PubMed2001

Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development.

Mammalian cells harbor three highly homologous and widely expressed members of the ras family (H-ras, N-ras, and K-ras), but it remains unclear whether they play specific or overlapping cellular roles. To gain insight into such functional roles, here we generated and analyzed H-ras null mutant mice, which were then also bred with N-ras knockout animals to ascertain the viability and properties of potential double null mutations in both loci. Mating among heterozygous H-ras(+/-) mice produced H-ras(-/-) offspring with a normal Mendelian pattern of inheritance, indicating that the loss of H-ras did not interfere with embryonic and fetal viability in the uterus. Homozygous mutant H-ras(-/-) mice reached sexual maturity at the same age as their littermates, and both males and females were fertile. Characterization of lymphocyte subsets in the spleen and thymus showed no significant differences between wild-type and H-ras(-/-) mice. Analysis of neuronal markers in the brains of knockout and wild-type H-ras mice showed that disruption of this locus did not impair or alter neuronal development. Breeding between our H-ras mutant animals and previously available N-ras null mutants gave rise to viable double knockout (H-ras(-/-)/N-ras(-/-)) offspring expressing only K-ras genes which grew normally, were fertile, and did not show any obvious phenotype. Interestingly, however, lower-than-expected numbers of adult, double knockout animals were consistently obtained in Mendelian crosses between heterozygous N-ras/H-ras mice. Our results indicate that, as for N-ras, H-ras gene function is dispensable for normal mouse development, growth, fertility, and neuronal development. Additionally, of the three ras genes, K-ras appears to be not only essential but also sufficient for normal mouse development.

Animals↗

PubMed2000

Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen.

Standard cell culture systems impose environmental oxygen (O(2)) levels of 20%, whereas actual tissue O(2) levels in both developing and adult brain are an order of magnitude lower. To address whether proliferation and differentiation of CNS precursors in vitro are influenced by the O(2) environment, we analyzed embryonic day 12 rat mesencephalic precursor cells in traditional cultures with 20% O(2) and in lowered O(2) (3 +/- 2%). Proliferation was promoted and apoptosis was reduced when cells were grown in lowered O(2), yielding greater numbers of precursors. The differentiation of precursor cells into neurons with specific neurotransmitter phenotypes was also significantly altered. The percentage of neurons of dopaminergic phenotype increased to 56% in lowered O(2) compared with 18% in 20% O(2). Together, the increases in total cell number and percentage of dopaminergic neurons resulted in a ninefold net increase in dopamine neuron yield. Differential gene expression analysis revealed more abundant messages for FGF8, engrailed-1, and erythropoietin in lowered O(2). Erythropoietin supplementation of 20% O(2) cultures partially mimicked increased dopaminergic differentiation characteristic of CNS precursors cultured in lowered O(2). These data demonstrate increased proliferation, reduced cell death, and enhanced dopamine neuron generation in lowered O(2), making this method an important advance in the ex vivo generation of specific neurons for brain repair.

Animals↗

PubMed2000

Stem cells--hype and hope.

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Aging↗

PubMed2000

Stem cells and the cellular organization of the brain.

The modern field of neuroscience emerged in the hands of neuroanatomists at the end of the last century. They recognized that information flows through arrays of cells and that the structure of the cells shapes the passage of information through the brain. In the middle of this century, the role of ion flux in the movement of information along axons was established. The electron microscope and the microelectrode helped to explain information transfer at the synapse, and study of the modulation of synaptic strength is currently a major area of neuroscience research. The origin of the many types of neuron seen by the early anatomists remains enigmatic, but the solution to this mystery is now emerging. The identification of stem cells and of the mechanisms that control their differentiation into distinct neuron types will contribute to a new understanding of both the origin of neuronal types and neuronal circuits. The current enthusiasm for stem cells is stimulated by interest from both the academic and nonacademic communities. These enthusiasts recognize a simple truth, that the cells are smart; they are the agents that control cell number and type in the brain. They create the structure that generates the higher order brain function. If these premises are true, then in the new century our understanding of the nervous system will be transformed by the facts of stem cell biology. J. Neurosci. Res. 59:298-300, 2000. Published 2000 Wiley-Liss, Inc.

Animals↗