Showing papers by "McGill University published in 2002"

Functional profiling of the Saccharomyces cerevisiae genome.

Abstract: Determining the effect of gene deletion is a fundamental approach to understanding gene function. Conventional genetic screens exhibit biases, and genes contributing to a phenotype are often missed. We systematically constructed a nearly complete collection of gene-deletion mutants (96% of annotated open reading frames, or ORFs) of the yeast Saccharomyces cerevisiae. DNA sequences dubbed 'molecular bar codes' uniquely identify each strain, enabling their growth to be analysed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays. We show that previously known and new genes are necessary for optimal growth under six well-studied conditions: high salt, sorbitol, galactose, pH 8, minimal medium and nystatin treatment. Less than 7% of genes that exhibit a significant increase in messenger RNA expression are also required for optimal growth in four of the tested conditions. Our results validate the yeast gene-deletion collection as a valuable resource for functional genomics.

The draft genome of Ciona intestinalis : insights into chordate and vertebrate origins

Abstract: The first chordates appear in the fossil record at the time of the Cambrian explosion, nearly 550 million years ago. The modern ascidian tadpole represents a plausible approximation to these ancestral chordates. To illuminate the origins of chordate and vertebrates, we generated a draft of the protein-coding portion of the genome of the most studied ascidian, Ciona intestinalis. The Ciona genome contains approximately 16,000 protein-coding genes, similar to the number in other invertebrates, but only half that found in vertebrates. Vertebrate gene families are typically found in simplified form in Ciona, suggesting that ascidians contain the basic ancestral complement of genes involved in cell signaling and development. The ascidian genome has also acquired a number of lineage-specific innovations, including a group of genes engaged in cellulose metabolism that are related to those in bacteria and fungi.

Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder.

Abstract: ContextVarious anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder (ADHD), with varying methods, small samples, cross-sectional designs, and without accounting for stimulant drug exposure.ObjectiveTo compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls.Design, Setting, and ParticipantsCase-control study conducted from 1991-2001 at the National Institute of Mental Health, Bethesda, Md, of 152 children and adolescents with ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range, 4.5-19 years) recruited from the local community, who contributed 544 anatomic magnetic resonance images.Main Outcome MeasuresUsing completely automated methods, initial volumes and prospective age-related changes of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate nucleus of the brain were compared in patients and controls.ResultsOn initial scan, patients with ADHD had significantly smaller brain volumes in all regions, even after adjustment for significant covariates. This global difference was reflected in smaller total cerebral volumes (−3.2%, adjusted F1,280 = 8.30, P = .004) and in significantly smaller cerebellar volumes (−3.5%, adjusted F1,280 = 12.29, P = .001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F2,288 = 6.65; all pairwise comparisons Bonferroni corrected, −5.8%; P = .002) and cerebellar volumes (−6.2%, F2,288 = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F2,288 = 11.65) compared with controls (−10.7%, P<.001) and with medicated children with ADHD (−8.9%, P<.001). Volumetric abnormalities persisted with age in total and regional cerebral measures (P = .002) and in the cerebellum (P = .003). Caudate nucleus volumes were initially abnormal for patients with ADHD (P = .05), but diagnostic differences disappeared as caudate volumes decreased for patients and controls during adolescence. Results were comparable for male and female patients on all measures. Frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample (Pearson coefficients between −0.16 and −0.26; all P values were <.05).ConclusionsDevelopmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.

The antiphospholipid syndrome.

Abstract: The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the clinical association of antiphospholipid autoantibodies (aPL) with a syndrome of hypercoagulability that can affect any blood vessel, irrespective of type or size. Involvement of larger vessels, such as arteries or veins, manifests in the form of thrombosis or embolism, whereas involvement of smaller vessels, including capillaries, arterioles, and venules, manifests as thrombotic microangiopathy. Virtually any organ in the body, including the kidney, can be affected. Here, we review the basic principles and recent advances in our understanding of APS, and discuss the broad spectrum of renal diseases that have been observed in association with this syndrome. We also discuss the impact that APS may have on pre-existing renal disease as well as current recommendations for treatment of APS.

Vascular Cognitive Impairment

Abstract: Cerebrovascular disease is the second most common cause of acquired cognitive impairment and dementia and contributes to cognitive decline in the neurodegenerative dementias. The current narrow definitions of vascular dementia should be broadened to recognise the important part cerebrovascular disease plays in several cognitive disorders, including the hereditary vascular dementias, multi-infarct dementia, post-stroke dementia, subcortical ischaemic vascular disease and dementia, mild cognitive impairment, and degenerative dementias (including Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies). Here we review the current state of scientific knowledge on the subject of vascular brain burden. Important non-cognitive features include depression, apathy, and psychosis. We propose use of the term vascular cognitive impairment, which is characterised by a specific cognitive profile involving preserved memory with impairments in attentional and executive functioning. Diagnostic criteria have been proposed for some subtypes of vascular cognitive impairment, and there is a pressing need to validate and further refine these. Clinical trials in vascular cognitive impairment are in their infancy but support the value of therapeutic interventions for symptomatic treatment.

Antiretroviral-Drug Resistance among Patients Recently Infected with HIV

Abstract: Background Among persons in North America who are newly infected with the human immunodeficiency virus (HIV), the prevalence of transmitted resistance to antiretroviral drugs has been estimated at 1 to 11 percent. Methods We performed a retrospective analysis of susceptibility to antiretroviral drugs before treatment and drug-resistance mutations in HIV in plasma samples from 377 subjects with primary HIV infection who had not yet received treatment and who were identified between May 1995 and June 2000 in 10 North American cities. Responses to treatment could be evaluated in 202 subjects. Results Over the five-year period, the frequency of transmitted drug resistance increased significantly. The frequency of high-level resistance to one or more drugs (indicated by a value of more than 10 for the ratio of the 50 percent inhibitory concentration [IC50] for the subject's virus to the IC50 for a drug-sensitive reference virus) increased from 3.4 percent during the period from 1995 to 1998 to 12.4 percent dur...

Applied Functional Data Analysis: Methods and Case Studies

Abstract: Introduction- Life Course Data in Criminology- The Nondurable Goods Index- Bone Shapes from a Paleopathology Study- Modeling Reaction Time Distributions- Zooming in on Human Growth- Time Warping Handwriting and Weather Records- How do Bone Shapes Indicate Arthritis?- Functional Models for Test Items- Predicting Lip Acceleration from Electromyography- Variable Seasonal Trend in the Goods Index- The Dynamics of Handwriting Printed Characters- A Differential Equation for Juggling

PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest.

Abstract: Mechanisms linking mitogenic and growth inhibitory cytokine signaling and the cell cycle have not been fully elucidated in either cancer or in normal cells. Here we show that activation of protein kinase B (PKB)/Akt, contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27. Akt transfection caused cytoplasmic p27 accumulation and resistance to cytokine-mediated G1 arrest. The nuclear localization signal of p27 contains an Akt consensus site at threonine 157, and p27 phosphorylation by Akt impaired its nuclear import in vitro. Akt phosphorylated wild-type p27 but not p27T157A. In cells transfected with constitutively active AktT308DS473D (PKBDD), p27WT mislocalized to the cytoplasm, but p27T157A was nuclear. In cells with activated Akt, p27WT failed to cause G1 arrest, while the antiproliferative effect of p27T157A was not impaired. Cytoplasmic p27 was seen in 41% (52 of 128) of primary human breast cancers in conjunction with Akt activation and was correlated with a poor patient prognosis. Thus, we show a novel mechanism whereby Akt impairs p27 function that is associated with an aggressive phenotype in human breast cancer. NOTE: In the version of the article initially published online, the abstract contained one extraneous sentence. This error has been corrected in the HTML and PDF versions. The abstract will appear correctly in the forthcoming print issue.

Mechanisms of action of arsenic trioxide.

Abstract: Arsenic trioxide has shown substantial efficacy in treating both newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL). As a single agent, it induces complete remissions, causing few adverse effects and only minimal myelosuppression. These successes have prompted investigations to elucidate the mechanisms of action underlying these clinical responses. Substantial data show that arsenic trioxide produces remissions in patients with APL at least in part through a mechanism that results in the degradation of the aberrant PML-retinoic acid receptor alpha fusion protein. Studies have also investigated concerns about the toxicity and potential carcinogenicity of long-term exposure to environmental arsenic. Arsenic apparently affects numerous intracellular signal transduction pathways and causes many alterations in cellular function. These actions of arsenic may result in the induction of apoptosis, the inhibition of growth and angiogenesis, and the promotion of differentiation. Such effects have been observed in cultured cell lines and animal models, as well as clinical studies. Because arsenic affects so many cellular and physiological pathways, a wide variety of malignancies, including both hematologic cancer and solid tumors derived from several tissue types, may be susceptible to therapy with arsenic trioxide. These multiple actions of arsenic trioxide also highlight the need for additional mechanistic studies to determine which actions mediate the diverse biological effects of this agent. This information will be critical to realizing the potential for synergy between arsenic trioxide and other chemotherapeutic agents, thus providing enhanced benefit in cancer therapy.

The experimental evolution of specialists, generalists, and the maintenance of diversity

Abstract: Environmental heterogeneity may be a general explanation for both the quantity of genetic variation in populations and the ecological niche width of individuals. To evaluate this hypothesis, I review the literature on selection experiments in heterogeneous environments. The niche width usually – but not invariably – evolves to match the amount of environmental variation, specialists evolving in homogeneous environments and generalists evolving in heterogeneous environments. The genetics of niche width are more complex than has previously been recognized, particularly with respect to the magnitude of costs of adaptation and the putative constraints on the evolution of generalists. Genetic variation in fitness is more readily maintained in heterogeneous environments than in homogeneous environments and this diversity is often stably maintained through negative frequency-dependent selection. Moreover environmental heterogeneity appears to be a plausible mechanism for at least two well-known patterns of species diversity at the landscape scale. I conclude that environmental heterogeneity is a plausible and possibly very general explanation for diversity across the range of scales from individuals to landscapes.

Circulating levels of IGF-1 directly regulate bone growth and density

Abstract: IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1‐deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in

Competition, concentration and their relationship: An empirical analysis of the banking industry

Abstract: This article examines competitive conditions and market structure in the banking industry, and investigates their interrelationship. Competition is measured using the Panzar–Rosse model. In order to distinguish competitive behaviour on local, national and international markets, for each country, three subsamples are taken: small or local banks, medium-sized banks and large or international banks. For all 23 countries considered, estimations indicate monopolistic competition, competition being weaker in local markets and stronger in international markets. Subsequently, a relationship for the impact of the market structure on competition is derived and tested empirically, providing support for the conventional view that concentration impairs competitiveness.

Unmyelinated tactile afferents signal touch and project to insular cortex

Abstract: There is dual tactile innervation of the human hairy skin: in addition to fast-conducting myelinated afferent fibers, there is a system of slow-conducting unmyelinated (C) afferents that respond to light touch. In a unique patient lacking large myelinated afferents, we found that activation of C tactile (CT) afferents produced a faint sensation of pleasant touch. Functional magnetic resonance imaging (fMRI) analysis during CT stimulation showed activation of the insular region, but not of somatosensory areas S1 and S2. These findings identify CT as a system for limbic touch that may underlie emotional, hormonal and affiliative responses to caress-like, skin-to-skin contact between individuals.

The BABAR detector

Abstract: BABAR, the detector for the SLAC PEP-II asymmetric e+e- B Factory operating at the upsilon 4S resonance, was designed to allow comprehensive studies of CP-violation in B-meson decays. Charged particle tracks are measured in a multi-layer silicon vertex tracker surrounded by a cylindrical wire drift chamber. Electromagentic showers from electrons and photons are detected in an array of CsI crystals located just inside the solenoidal coil of a superconducting magnet. Muons and neutral hadrons are identified by arrays of resistive plate chambers inserted into gaps in the steel flux return of the magnet. Charged hadrons are identified by dE/dx measurements in the tracking detectors and in a ring-imaging Cherenkov detector surrounding the drift chamber. The trigger, data acquisition and data-monitoring systems, VME- and network-based, are controlled by custom-designed online software. Details of the layout and performance of the detector components and their associated electronics and software are presented.

A Study of the Frequency of Self-Mutilation in a Community Sample of Adolescents

Abstract: Currently little research exists examining self-mutilation (SM) in community samples of adolescents, despite tentative findings suggesting that self-harming behaviors, including SM may be increasing. The present study provides a comprehensive review of previous literature on the frequency of SM as well as preliminary epidemiological data concerning the frequency of SM in a community sample of high schools students. The relationship between SM, anxiety, and depressive symptomatology was also assessed. Four hundred and forty students from two schools, an urban and a suburban high school, were given a screening measure designed to assess for SM. Students who indicated that they hurt themselves on purpose also participated in a follow-up interview. Based on interviews it was found that 13.9% of all students reported having engaged in SM behavior at some time. Girls reported significantly higher rates of SM than did boys (64 vs. 36%, respectively). Self-cutting was found to be the most common type of SM, followed by self-hitting, pinching, scratching, and biting. Finally, students who self-mutilate reported significantly more anxiety and depressive symptomatology than students who did not self-mutilate. Results are also presented concerning demographic information and patterns of SM behavior.

Estimating carbon accumulation rates of undrained mires in Finland–application to boreal and subarctic regions:

Abstract: Equations based on empirical relationships of peat physical properties were used to estimate the average long-term apparent rate of carbon accumulation (LORCA) in Finnish mire vegetation regions. The results were generalized to the boreal and subarctic regions. Analyses of 1302 dated peat cores were used to infer carbon accumulation for each mire vegetation region of Finland. The area-weighted LORCA for Finnish undrained mire areas was 18.5 g m 2 yr 1 and the total carbon sink 0.79 Tg yr 1 (1 Tg = 1012g). The total carbon pool of Finnish undrained mires was estimated as 2257 Tg. The aapa-mire region included 80% of the total net accumulation rate of carbon and 85% of the total carbon reservoirs of Finnish undrained mires. LORCA was signi” cantly higher in the raised-bog region, 26.1 g m 2 yr 1, compared with the aapa-mire region, 17.3 g m 2 yr 1, and bogs generally had a higher LORCA 20.8 g m 2 yr 1, than fens 16.9 g m 2 yr 1. The total C sink for boreal and subarctic mires was estimated at 66 Tg yr 1 whi...

Automatic "pipeline" analysis of 3-D MRI data for clinical trials: application to multiple sclerosis

Abstract: The quantitative analysis of magnetic resonance imaging (MRI) data has become increasingly important in both research and clinical studies aiming at human brain development, function, and pathology. Inevitably, the role of quantitative image analysis in the evaluation of drug therapy will increase, driven in part by requirements imposed by regulatory agencies. However, the prohibitive length of time involved and the significant intra- and inter-rater variability of the measurements obtained from manual analysis of large MRI databases represent major obstacles to the wider application of quantitative MRI analysis. We have developed a fully automatic "pipeline" image analysis framework and have successfully applied it to a number of large-scale, multi-center studies (more than 1000 MRI scans). This pipeline system is based on robust image processing algorithms, executed in a parallel, distributed fashion. This paper describes the application of this system to the automatic quantification of multiple sclerosis lesion load in MRI, in the context of a phase III clinical trial. The pipeline results were evaluated through an extensive validation study, revealing that the obtained lesion measurements are statistically indistinguishable from those obtained by trained human observers. Given that intra- and inter-rater measurement variability is eliminated by automatic analysis, this system enhances the ability to detect small treatment effects not readily detectable through conventional analysis techniques. While useful for clinical trial analysis in multiple sclerosis, this system holds widespread potential for applications in other neurological disorders, as well as for the study of neurobiology in general.

Modeling elasticity in crystal growth.

Abstract: A new model of crystal growth is presented that describes the phenomena on atomic length and diffusive time scales. The former incorporates elastic and plastic deformation in a natural manner, and the latter enables access to time scales much larger than conventional atomic methods. The model is shown to be consistent with the predictions of Read and Shockley for grain boundary energy, and Matthews and Blakeslee for misfit dislocations in epitaxial growth.

Fishes as integrators of benthic and pelagic food webs in lakes

Abstract: Studies of lake ecosystems generally focus on pelagic food chains and processes. Recently, there has been an emerging recognition of the importance of benthic production and processes to whole-lake ecosystems. To examine the extent to which zoobenthos contribute to higher trophic level production in lakes, we synthesized diet data from 470 fish populations (15 species) and stable isotope data from 90 fish populations (11 species), all of which are common inhabitants of north-temperate lakes. Across all species considered, zoobenthos averaged 50% of total prey consumption. Indirect consumption of zoobenthos (i.e., feeding on zoobenthos-supported fishes) contributed another 15%, for a total of 65% reliance on benthic secondary production. Stable isotopes provided estimates of mean zoobenthivory ranging from 43% to 59%. For most fish species, consumption of zoobenthos was highly variable among populations. The overwhelming concern of ecologists with pelagic food chains and processes contrasts sharply with our finding that benthic secondary production plays a central role in supporting higher trophic level production. This extensive zoobenthivory can subsidize fish populations, leading to apparent competition and otherwise altering trophic dynamics and ecosystem processes in the pelagic zone. We argue for a more integrated view of lake ecosystems that recognizes the duality of benthic and pelagic production pathways. Food web models that explicitly consider energy flow from pelagic and benthic sources will provide a more realistic energy flow template for understanding the regulation of lake ecosystem functioning.

Electrodynamics of Magnetars: Implications for the Persistent X-Ray Emission and Spin-down of the Soft Gamma Repeaters and Anomalous X-Ray Pulsars

Abstract: We consider the structure of neutron star magnetospheres threaded by large-scale electrical currents and the effect of resonant Compton scattering by the charge carriers (both electrons and ions) on the emergent X-ray spectra and pulse profiles. In the magnetar model for the soft gamma repeaters (SGRs) and anomalous X-ray pulsars (AXPs), these currents are maintained by magnetic stresses acting deep inside the star, which generate both sudden disruptions (SGR outbursts) and more gradual plastic deformations of the rigid crust. We construct self-similar force-free equilibria of the current-carrying magnetosphere with a power-law dependence of magnetic field on radius, ∝ r-(2+p), and show that a large-scale twist of field lines softens the radial dependence of the magnetic field to p < 1. The spin-down torque acting on the star is thereby increased in comparison with an orthogonal vacuum dipole. We comment on the strength of the surface magnetic field in the SGR and AXP sources, as inferred from their measured spin-down rates, and the implications of this model for the narrow measured distribution of spin periods. A magnetosphere with a strong twist [B/Bθ = O(1) at the equator] has an optical depth ~1 to resonant cyclotron scattering, independent of frequency (radius), surface magnetic field strength, or charge/mass ratio of the scattering charge. When electrons and ions supply the current, the stellar surface is also heated by the impacting charges at a rate comparable to the observed X-ray output of the SGR and AXP sources, if Bdipole ~ 1014 G. Redistribution of the emerging X-ray flux at the cyclotron resonance will strongly modify the emerging pulse profile and, through the Doppler effect, generate a nonthermal tail to the X-ray spectrum. We relate the sudden change in the pulse profile of SGR 1900+14 following the 1998 August 27 giant flare to an enhanced optical depth at the electron cyclotron resonance resulting from a sudden twist imparted to the external magnetic field during the flare. The self-similar structure of the magnetosphere should generate frequency-independent profiles; more complicated pulse profiles may reflect the presence of higher multipoles, ion cyclotron scattering, or possibly nonresonant Compton scattering of O-mode photons by pair-loaded currents.

Five-Year Risk of Cardiac Mortality in Relation to Initial Severity and One-Year Changes in Depression Symptoms After Myocardial Infarction

Abstract: Background— Although previous research demonstrated an independent link between depression symptoms and cardiac mortality after myocardial infarction (MI), depression was assessed only once, and a dose-response relationship was not evaluated. Methods and Results— We administered the Beck Depression Inventory to 896 post-MI patients during admission and at 1 year. Five-year survival was ascertained using Medicare data. We observed a significant long-term dose-response relationship between depression symptoms during hospitalization and cardiac mortality. Results remained significant after control for multiple measures of cardiac disease severity. Although 1-year scores were also linked to cardiac mortality, most of that impact was explained by baseline scores. Improvement in depression symptoms was associated with less cardiac mortality only for patients with mild depression. Patients with higher initial scores had worse long-term prognosis regardless of symptom changes. Conclusions— The level of depression...

Environmental Enrichment Reverses the Effects of Maternal Separation on Stress Reactivity

Abstract: Postnatal maternal separation increases hypothalamic corticotropin-releasing factor (CRF) gene expression and hypothalamic-pituitary-adrenal (HPA) and behavioral responses to stress. We report here that environmental enrichment during the peripubertal period completely reverses the effects of maternal separation on both HPA and behavioral responses to stress, with no effect on CRF mRNA expression. We conclude that environmental enrichment leads to a functional reversal of the effects of maternal separation through compensation for, rather than reversal of, the neural effects of early life adversity.

Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase perk and phosphorylation of the translation initiation factor eif2alpha

Abstract: Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little is known about the mechanism by which hypoxia induces a global downregulation of protein synthesis. A critical step in the regulation of protein synthesis in response to stress is the phosphorylation of translation initiation factor eIF2alpha on Ser51, which leads to inhibition of new protein synthesis. Here we report that exposure of human diploid fibroblasts and transformed cells to hypoxia led to phosphorylation of eIF2alpha, a modification that was readily reversed upon reoxygenation. Expression of a transdominant, nonphosphorylatable mutant allele of eIF2alpha attenuated the repression of protein synthesis under hypoxia. The endoplasmic reticulum (ER)-resident eIF2alpha kinase PERK was hyperphosphorylated upon hypoxic stress, and overexpression of wild-type PERK increased the levels of hypoxia-induced phosphorylation of eIF2alpha. Cells stably expressing a dominant-negative PERK allele and mouse embryonic fibroblasts with a homozygous deletion of PERK exhibited attenuated phosphorylation of eIF2alpha and reduced inhibition of protein synthesis in response to hypoxia. PERK(-/-) mouse embryo fibroblasts failed to phosphorylate eIF2alpha and exhibited lower survival after prolonged exposure to hypoxia than did wild-type fibroblasts. These results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2alpha and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.

Delirium predicts 12-month mortality.

Abstract: Background Delirium has not been found to be a significant predictor of postdischarge mortality, but previous research has methodologic limitations including small sample sizes and inadequate control of confounding. This study aimed to determine the independent effects of presence of delirium, type of delirium (incident vs prevalent), and severity of delirium symptoms on 12-month mortality among older medical inpatients. Methods A prospective, observational study of 2 cohorts of medical inpatients was conducted with patients 65 years or older: 243 patients had prevalent or incident delirium, and 118 controls had no delirium. Baseline measures included presence of delirium and/or dementia, severity of delirium symptoms, physical function, comorbidity, and physiological and clinical severity of illness. Mortality during the 12 months after enrollment was analyzed with the Cox proportional hazards model with adjustment for covariates. Results The unadjusted hazard ratio of delirium with mortality was 3.44 (95% confidence interval, 2.05-5.75); the adjusted hazard ratio was 2.11 (95% confidence interval, 1.18-3.77). The effect of delirium was sustained over the entire 12-month period after adjustment for covariates and was stronger among patients without dementia. Among patients with dementia, there was a weak, nonsignificant effect of delirium on survival. After adjustment for covariates, mortality did not differ between patients with incident and prevalent delirium, but among patients with delirium without dementia, greater severity of delirium symptoms was associated with higher mortality. Conclusions Delirium is an independent marker for increased mortality among older medical inpatients during the 12 months after hospital admission. It is a particularly important prognostic marker among patients without dementia.

Cognitive modulation of pain: how do attention and emotion influence pain processing?

Abstract: There have been anecdotal accounts for centuries of people apparently experiencing little or no pain in situations that most of us would find excruciating. Yet, western medicine has given little credence to a patient’s ability to modify pain. Instead, we focus on the pharmacological control of pain. For this reason, the vast majority of research on pain control has concentrated on peripheral and spinal cord mechanisms of opioid and anti-inflammatory analgesic therapy. Nevertheless, researchers are beginning to recognize that a variety of pain modulatory mechanisms exist in the nervous system, and these modulatory systems can be accessed either pharmacologically or through contextual and/or cognitive manipulation (Fields, 2000). Variables such as attentional state, emotional context, hypnotic suggestions, attitudes, expectations or anesthesia-induced changes in consciousness now have been shown to alter both pain perception and forebrain pain transmission in humans. These techniques, at times, preferentially alter sensory and/or affective aspects of pain perception, and the associated modulation of pain-evoked neural activity occurs in limbic and/or sensory brain regions, suggesting multiple endogenous pain-modulatory systems. This paper compares the modulatory influences of two principal cognitive variables, attention and emotion, on pain perception and addresses possible neural mechanisms underlying each of these influences.