Showing papers by "University of Toronto published in 1993"

Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

Abstract: Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.

Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

Abstract: Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

The Wilson disease gene is a putative copper transporting P–type ATPase similar to the Menkes gene

Abstract: Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. The gene (WD) has been mapped to chromosome 13 q14.3. On yeast artificial chromosomes from this region we have identified a sequence, similar to that coding for the proposed copper binding regions of the putative ATPase gene (MNK) defective in Menkes disease. We show that this sequence forms part of a P-type ATPase gene (referred to here as Wc1) that is very similar to MNK, with six putative metal binding regions similar to those found in prokaryotic heavy metal transporters. The gene, expressed in liver and kidney, lies within a 300 kb region likely to include the WD locus. Two WD patients were found to be homozygous for a seven base deletion within the coding region of Wc1. Wc1 is proposed as the gene for WD.

Differential T cell costimulatory requirements in CD28-deficient mice

Abstract: T cell receptor stimulation without costimulation is insufficient for the induction of an optimal immune response. It is thought that engagement of the CD28 molecule with its ligand B7 provides an essential costimulatory signal without which full activation of T cells cannot occur. A mouse strain with a defective CD28 gene was established. Development of T and B cells in the CD28-deficient mice appeared normal. However, T lymphocytes derived from CD28-/- mutant mice had impaired responses to lectins. Lectin stimulation did not trigger interleukin-2 (IL-2) production, IL-2 receptor alpha expression was significantly decreased, and exogenous IL-2 only partially rescued the CD28 defect. Basal immunoglobulin (Ig) concentrations in CD28-deficient mice were about one-fifth of those found in wild-type controls, with low titers of IgG1 and IgG2b but an increase in IgG2a. In addition, activity of T helper cells in CD28-/- mice was reduced and immunoglobulin class switching was diminished after infection with vesicular stomatitis virus. However, cytotoxic T cells could still be induced and the mice showed delayed-type hypersensitivity after infection with lymphocytic choriomeningitis virus. Thus, CD28 is not required for all T cell responses in vivo, suggesting that alternative costimulatory pathways may exist.

When More Pain Is Preferred to Less: Adding a Better End

Abstract: Subjects were exposed to two aversive experiences: in the short trial, they immersed one hand in water at 14 °Cfor 60 s; in the long trial, they im- mersed the other hand at 14 "C for 60 s, then kept the hand in the water 30 s longer as the temperature of the water was gradually raised to 15 °C, still pain- ful but distinctly less so for most sub- jects. Subjects were later given a choice of which trial to repeat. A significant majority chose to repeat the long trial, apparently preferring more pain over less. The results add to other evidence suggesting that duration plays a small role in retrospective evaluations of aver- sive experiences; such evaluations are often dominated by the discomfort at the worst and at the final moments of epi- sodes. you enjoying this?" or "Does it hurt?" This confidence could be unwarranted because two fallible mental processes separate retrospective assessments from the sequence of experiences that consti- tuted the original episode; an operation of memory and an act of evaluation. Some recent research has called into question the accuracy of people's mem- ories for their hedonic and affective ex- periences (Kent, 1985; Rachman & Eyrl, 1989; Thomas & Diener, 1990). This ar- ticle focuses on the process of evaluating

Autoencoders, Minimum Description Length and Helmholtz Free Energy

Abstract: An autoencoder network uses a set of recognition weights to convert an input vector into a code vector. It then uses a set of generative weights to convert the code vector into an approximate reconstruction of the input vector. We derive an objective function for training autoencoders based on the Minimum Description Length (MDL) principle. The aim is to minimize the information required to describe both the code vector and the reconstruction error. We show that this information is minimized by choosing code vectors stochastically according to a Boltzmann distribution, where the generative weights define the energy of each possible code vector given the input vector. Unfortunately, if the code vectors use distributed representations, it is exponentially expensive to compute this Boltzmann distribution because it involves all possible code vectors. We show that the recognition weights of an autoencoder can be used to compute an approximation to the Boltzmann distribution and that this approximation gives an upper bound on the description length. Even when this bound is poor, it can be used as a Lyapunov function for learning both the generative and the recognition weights. We demonstrate that this approach can be used to learn factorial codes.

The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1

Abstract: Many tyrosine kinases, including the receptors for hormones such as epidermal growth factor (EGF), nerve growth factor and insulin, transmit intracellular signals through Ras proteins. Ligand binding to such receptors stimulates Ras guanine-nucleotide-exchange activity and increases the level of GTP-bound Ras, suggesting that these tyrosine kinases may activate a guanine-nucleotide releasing protein (GNRP). In Caenorhabditis elegans and Drosophila, genetic studies have shown that Ras activation by tyrosine kinases requires the protein Sem-5/drk, which contains a single Src-homology (SH) 2 domain and two flanking SH3 domains. Sem-5 is homologous to the mammalian protein Grb2, which binds the autophosphorylated EGF receptor and other phosphotyrosine-containing proteins such as Shc through its SH2 domain. Here we show that in rodent fibroblasts, the SH3 domains of Grb2 are bound to the proline-rich carboxy-terminal tail of mSos1, a protein homologous to Drosophila Sos. Sos is required for Ras signalling and contains a central domain related to known Ras-GNRPs. EGF stimulation induces binding of the Grb2-mSos1 complex to the autophosphorylated EGF receptor, and mSos1 phosphorylation. Grb2 therefore appears to link tyrosine kinases to a Ras-GNRP in mammalian cells.

Orthogonal Array-Based Latin Hypercubes

Abstract: In this article, we use orthogonal arrays (OA's) to construct Latin hypercubes. Besides preserving the univariate stratification properties of Latin hypercubes, these strength r OA-based Latin hypercubes also stratify each r-dimensional margin. Therefore, such OA-based Latin hypercubes provide more suitable designs for computer experiments and numerical integration than do general Latin hypercubes. We prove that when used for integration, the sampling scheme with OA-based Latin hypercubes offers a substantial improvement over Latin hypercube sampling.

A Mouse Model of Greig Cephalopolysyndactyly Syndrome: The extra-toesJ Mutation Contains an Intragenic Deletion of the Gli3 Gene

Abstract: Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder affecting limb and craniofacial development. Recently, the human GLI3 gene has been proposed to be a candidate gene for GCPS. Here we describe the molecular characterization of extra-toes (Xt), which is a mouse model of GCPS. The Xt heterozygotes show craniofacial defects and a polydactyly phenotype similar to GCPS. We show that a deficiency of Gli3 expression in the XtJ mutant is due to a deletion within the 3' end of the gene. Furthermore, structures affected in the mouse mutant and human syndrome were found to correlate with expression domains of Gli3 in mouse. These results strongly suggest that the deficiency of GLI3 function leads to GCPS.

Exact exchange-only potentials and the virial relation as microscopic criteria for generalized gradient approximations.

Abstract: The information contained in the exact exchange potential of atoms as calculated in the optimized-potential model is used to analyze generalized approximations (GGA's) from a microscopic viewpoint. It is shown that the GGA recently introduced by Perdew and Wang [in Electronic Structure of Solids 1991, edited by P. Ziesche and H. Eschrig (Akademie Verlag, Berlin, 1991), Vol. 11] does not significantly improve the exchange potential given by the lowest-order gradient correction. This contrasts with its excellent reproduction of atomic exchange energies, which is shown to be mainly due to cancellation of local errors in the integrand of the virial relation for the exchange-energy functional. Utilizing this virial relation a GGA is constructed which reproduces atomic exchange potentials considerably better. This functional does not give as accurately total exchange energies, although it is superior to the second-order gradient expansion. It thus represents a balanced approach aiming at an overall improvement rather than focusing on the exchange energies only. It is concluded that the concept of GGA's due to its simple quasilocal-density dependence is not sufficiently flexible to accurately reproduce exchange potentials and exchange energies simultaneously. It seems that the criteria for judging and constructing approximate exchange functionals put forward in this work and the resulting GGA give a more realistic view of the overall capabilities of GGA's to represent the properties of the true exchange-energy functional, e.g., its functional derivatives, than previous GGA's.

Quantitative interpretation of magnetization transfer

Abstract: Magnetization transfer contrast (MTC) experiments using off-resonance irradiation have been performed with an agar gel model by systematically varying offset frequency, amplitude of the RF irradiation and gel concentration. The experimental results are shown to be quantitatively modelled by a two-pool system consisting of a liquid pool with a Lorentzian line shape and a small semisolid pool with a Gaussian lineshape. The fitted model yields physically realistic fundamental parameters with a T2 of the semisolid pool of 13 microseconds. Further analysis shows that the off-resonance irradiation MTC experiment had significant limitations in its ability to saturate the semisolid pool without directly affecting the liquid component.

Dopamine D4 receptors elevated in schizophrenia

Abstract: Although the biological basis of schizophrenia is not known, possible causes include genetic defects, viruses, amines, brain structure and metabolism, neuroreceptors, and G proteins. The hypothesis of dopamine overactivity in schizophrenia is based on the fact that neuroleptics block dopamine D2 receptors in direct relation to their clinical antipsychotic potencies. Moreover, dopamine D2 or D2-like receptors are elevated in postmortem schizophrenia brain tissue. This elevation, however, is only found in vivo using [11C]methylspiperone but not [11C]raclopride. The dopamine D4 receptor gene has not yet been excluded in schizophrenia because the 21 gene variants of D4 have not yet been tested. Because the link between D1 and D2 receptors is reduced in schizophrenia tissue, we tested whether one component of this link was sensitive to guanine nucleotide. We report here that the binding of [3H]raclopride to D2 receptors in schizophrenia was not sensitive to guanine nucleotide. This finding permitted analysis of data on the binding of [3H]emonapride to the D2, D3 and D4 receptors. We conclude that the combined density of D2 and D3 receptors (labelled by [3H]raclopride) is increased by only 10% in schizophrenia brain, as found by Farde et al., but that it is the density of dopamine D4 receptors which is sixfold elevated in schizophrenia. These findings resolve the apparent discrepancy, mentioned above, wherein the density of [11C]methylspiperone-labelled sites (D2, D3 and D4), but not that of [11C]raclopride-labelled sites (D2 and D3), was found elevated in the schizophrenia striatum.

Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies.

Abstract: Five or more dopamine receptor genes are expressed in brain However, the pharmacological similarities of the encoded D1-D5 receptors have hindered studies of the localization and functions of the subtypes To better understand the roles of the individual receptors, antibodies were raised against recombinant D1 and D2 proteins and were shown to bind to the receptor subtypes specifically in Western blot and immunoprecipitation studies Each antibody reacted selectively with the respective receptor protein expressed both in cells transfected with the cDNAs and in brain By immunocytochemistry, D1 and D2 had similar regional distributions in rat, monkey, and human brain, with the most intense staining in striatum, olfactory bulb, and substantia nigra Within each region, however, the precise distributions of each subtype were distinct and often complementary D1 and D2 were differentially enriched in striatal patch and matrix compartments, in selective layers of the olfactory bulb, and in either substantia nigra pars compacta or reticulata Electron microscopy demonstrated that D1 and D2 also had highly selective subcellular distributions In the rat neostriatum, the majority of D1 and D2 immunoreactivity was localized in postsynaptic sites in subsets of spiny dendrites and spine heads in rat neostriatum Presynaptic D1 and D2 receptors were also observed, indicating both subtypes may regulate neurotransmitter release D1 was also present in axon terminals in the substantia nigra These results provide a morphological substrate for understanding the pre- and postsynaptic functions of the genetically defined D1 and D2 receptors in discrete neuronal circuits in mammalian brain

Analysis and synthesis of facial image sequences using physical and anatomical models

Abstract: An approach to the analysis of dynamic facial images for the purposes of estimating and resynthesizing dynamic facial expressions is presented. The approach exploits a sophisticated generative model of the human face originally developed for realistic facial animation. The face model which may be simulated and rendered at interactive rates on a graphics workstation, incorporates a physics-based synthetic facial tissue and a set of anatomically motivated facial muscle actuators. The estimation of dynamical facial muscle contractions from video sequences of expressive human faces is considered. An estimation technique that uses deformable contour models (snakes) to track the nonrigid motions of facial features in video images is developed. The technique estimates muscle actuator controls with sufficient accuracy to permit the face model to resynthesize transient expressions. >

Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons.

Abstract: To examine the role of Ca2+ in early neuronal death, we studied the impact of free intracellular calcium concentration ([Ca2+]i) on survivability in populations of cultured mouse spinal neurons We asked whether early neurotoxicity was triggered by Ca2+ influx, whether elevated [Ca2+]i was a predictive indicator of impending neuronal death, and whether factors other than [Ca2+]i increases influenced Ca2+ neurotoxicity We found that when neurons were lethally challenged with excitatory amino acids or high K+, they experienced a biphasic [Ca2+]i increase characterized by a primary [Ca2+]i transient that decayed within minutes, followed by a secondary, sustained, and irreversible [Ca2+]i rise that indicated imminent cell death We showed that in the case of glutamate-triggered neurotoxicity, processes triggering eventual cell death required Ca2+ influx, and that neurotoxicity was a function of the transmembrane Ca2+ gradient Fura-2 Ca2+ imaging revealed a "ceiling" on measurable changes in [Ca2+]i that contributed to the difficulty in relating [Ca2+]i to neurotoxicity We found, by evoking Ca2+ influx into neurons through different pathways, that the chief determinants of Ca2+ neurotoxicity were the Ca2+ source and the duration of the Ca2+ challenge When Ca2+ source and challenge duration were taken into account, a statistically significant relationship between measured [Ca2+]i and cell death was uncovered, although the likelihood of neuronal death depended much more on Ca2+ source than on the magnitude of the measured [Ca2+]i increase Thus, neurotoxicity evoked by glutamate far exceeded that evoked by membrane depolarization with high K+ when [Ca2+]i was made to increase equally in both groups The neurotoxicity of glutamate was triggered primarily by Ca2+ influx through NMDA receptor channels, and exceeded that triggered by non-NMDA receptors and Ca2+ channels when [Ca2+]i was made to rise equally through these separate pathways The greater neurotoxicity triggered by NMDA receptors was related to some attribute other than an ability to trigger greater [Ca2+]i increases as compared with other Ca2+ sources We hypothesize that this represents a physical colocalization of NMDA receptors with Ca(2+)-dependent rate-limiting processes that trigger early neuronal degeneration

Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene.

Abstract: Mice with the recessive motheaten (me) or the allelic viable motheaten (mev) mutations express a severe autoimmune and immunodeficiency syndrome. We have shown that the basic defect in these mice involves lesions in the gene which encodes haematopoietic cell phosphatase (HCP). These mice thus provide excellent models for investigating the roles of phosphatases in haematopoiesis and the nature of the genetic and cellular events linking impaired haematopoiesis to severe immunodeficiency and expression of systemic autoimmunity.

Situated information spaces and spatially aware palmtop computers

Abstract: article in this issue) will further these abilities and cause the generation of short-range and global electronic information spaces to appear lhroughout our everyday environments. How will this information be organized, and how will we interact with it? Wherever possible, we should look for ways of associating electronic information with physical objects in our environment. This raeans that our information spaces will be 3D. The SemNet system [4] is an example of a tool that offers users access to large, complicated 3D information spaces. Our goal is to go a step further by grounding and situating the information in a physical context to provide additional understanding of the organization of the space and to improve user orientation. As an example of ubiquitous computing and situated information spaces, consider a fax machine. The electronic data associated with a fax machine should be collecl:ed, associated , and colocated with [he physical device (see Figure 1). This means that your personal electronic phone book, a log of your incoming and outgoing calls, and fax messages could be accessible by browsing a situated 3D electronic information space surrounding the fax machine. The information would be organized by the layout of the physical device. Incoming calls would be located near 1:he earpiece of the hand receiver while outgoing calls would be situated near the mouthpiece. The phone, book could be found near the keypad. A log of the outgoing fax messages would be found near the fax paper feeder while a log of the incoming faxes would be located at the paper dispenser tray. These logical information hot spots on the physical device can be moved and customized by users according to their personal organizations. The key idea is that the physical object anchors the information, provides a logical means of partitioning and organizing the associated information space, and serves as a retrieval cue for users. A major design requirement of situated information spaces is the ability for users to visualize, browse, and manipulate the 3D space using a ,.RoE.ALL-portable, palmtop computer. That is, instead of a large fixed display on a desk, we want a small, mobile display to act as a window onto the information space. Since the information spaces will consist of multimedia data, the display of the palmtop should be able to handle all forms of data including text, graphics, video, and audio. Moreover, the desire to merge the physical and …

A hypervariable segment in the human dopamine receptor D4 (DRD4) gene

Abstract: The human dopamine D4 receptor contains a novel polymorphism within the putative third cytoplasmic loop of the protein. The polymorphism is characterized by a varying number of direct imperfect 48-bp repeats in the gene. Pharmacological characterization has suggested that this receptor is the site through which the atypical neuroleptic clozapine exerts its antipsychotic action and that some polymorphic variants display different pharmacological properties. Further analysis of the repeat region using innovative technologies indicates that the alleles vary not only in the number of repeats (2-8 or 10 repeat units) but also in the sequence of the repeats and the order in which they appear. In 178 unrelated chromosomes we have identified 19 different repeats in 25 different haplotypes coding for 18 different predicted amino acid sequences, making this one of the most variable functional proteins currently described.

Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice.

Abstract: Beginning at the time of insulitis (7 wk of age), CD4+ and CD8+ mature thymocytes from nonobese diabetic (NOD) mice exhibit a proliferative unresponsiveness in vitro after T cell receptor (TCR) crosslinking. This unresponsiveness does not result from either insulitis or thymic involution and is long lasting, i.e., persists until diabetes onset (24 wk of age). We previously proposed that it represents a form of thymic T cell anergy that predisposes to diabetes onset. This hypothesis was tested in the present study by further investigating the mechanism responsible for NOD thymic T cell proliferative unresponsiveness and determining whether reversal of this unresponsiveness protects NOD mice from diabetes. Interleukin 4 (IL-4) secretion by thymocytes from > 7-wk-old NOD mice was virtually undetectable after treatment with either anti-TCR alpha/beta, anti-CD3, or Concanavalin A (Con A) compared with those by thymocytes from age- and sex-matched control BALB/c mice stimulated under identical conditions. NOD thymocytes stimulated by anti-TCR alpha/beta or anti-CD3 secreted less IL-2 than did similarly activated BALB/c thymocytes. However, since equivalent levels of IL-3 were secreted by Con A-activated NOD and BALB/c thymocytes, the unresponsiveness of NOD thymic T cells does not appear to be dependent on reduced IL-2 secretion. The surface density and dissociation constant of the high affinity IL-2 receptor of Con A-activated thymocytes from both strains are also similar. The patterns of unresponsiveness and lymphokine secretion seen in anti-TCR/CD3-activated NOD thymic T cells were also observed in activated NOD peripheral spleen T cells. Exogenous recombinant (r)IL-2 only partially reverses NOD thymocyte proliferative unresponsiveness to anti-CD3, and this is mediated by the inability of IL-2 to stimulate a complete IL-4 secretion response. In contrast, exogenous IL-4 reverses the unresponsiveness of both NOD thymic and peripheral T cells completely, and this is associated with the complete restoration of an IL-2 secretion response. Furthermore, the in vivo administration of rIL-4 to prediabetic NOD mice protects them from diabetes. Thus, the ability of rIL-4 to reverse completely the NOD thymic and peripheral T cell proliferative defect in vitro and protect against diabetes in vivo provides further support for a causal relationship between this T cell proliferative unresponsiveness and susceptibility to diabetes in NOD mice.

A framework for the robust estimation of optical flow

Abstract: The authors consider the problem of robustly estimating optical flow from a pair of images using a new framework based on robust estimation which addresses violations of the brightness constancy and spatial smoothness assumptions. They also show the relationship between the robust estimation framework and line-process approaches for coping with spatial discontinuities. In doing so, the notion of a line process is generalized to that of an outlier process that can account for violations in both the brightness and smoothness assumptions. A graduated non-convexity algorithm is presented for recovering optical flow and motion discontinuities. The performance of the robust formulation is demonstrated on both synthetic data and natural images. >

Drug-Related Hospital Admissions

Abstract: OBJECTIVE:To review and summarize studies reporting rates of drug-related hospital admissions.DATA SOURCES:Manual and computerized literature searches using MEDLINE, Index Medicus, and International Pharmaceutical Abstracts as databases (key words: Drug, drug-related, or iatrogenic; admission, hospital admission, or hospitalization; and ADR or adverse drug reaction). References from retrieved articles were searched to locate further studies.STUDY SELECTION:Included were English-language studies of humans admitted to the hospital because of medications. Problems investigated were admissions prompted by adverse drug reactions (ADRs) when drugs were used by the patient and admissions resulting from a patient's noncompliant or unintentionally inappropriate drug use. Excluded were cases involving drug abuse, alcoholism, suicide attempts, intoxication, or inadequate prescribing.DATA SYNTHESIS:Between 1966 and 1989, ADR rates from 49 hospitals or groups of hospitals in a variety of international settings were pu...