Showing papers by "University of Geneva published in 2004"

Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment.

Abstract: The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.

Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

Abstract: We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.

The Effects of Strontium Ranelate on the Risk of Vertebral Fracture in Women with Postmenopausal Osteoporosis

Abstract: background Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. methods To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. results New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events. conclusions Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.

The present moment in psychotherapy and everyday life

Abstract: PART I. Exploring the Present Moment PART II. Contextualizing the Present Moment PART III. Views from a Clinical Perspective APPENDIX. The Micro-Analytic Interview

Diagnosis and Treatment of Diabetic Foot Infections

Abstract: Benjamin A. Lipsky, Anthony R. Berendt, H. Gunner Deery, John M. Embil, Warren S. Joseph, Adolf W. Karchmer, Jack L. LeFrock, Daniel P. Lew, Jon T. Mader, Carl Norden, and James S. Tan Medical Service, Veterans Affairs Puget Sound Health Care System, and Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington; Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford, United Kingdom; Northern Michigan Infectious Diseases, Petoskey, Michigan; Section of Infectious Diseases, Department of Medicine, University of Manitoba, Winnipeg, Manitoba; Section of Podiatry, Department of Primary Care, Veterans Affairs Medical Center, Coatesville, Pennsylvania; Division of Infectious Diseases, Department of Medicine, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts; Dimensional Dosing Systems, Sarasota, Florida; Department of Medicine, Service of Infectious Diseases, University of Geneva Hospitals, Geneva, Switzerland; Department of Internal Medicine, The Marine Biomedical Institute, and Department of Orthopaedics and Rehabilitation, University of Texas Medical Branch, Galveston, Texas; Department of Medicine, New Jersey School of Medicine and Dentistry, and Cooper Hospital, Camden, New Jersey; and Department of Internal Medicine, Summa Health System, and Northeastern Ohio Universities College of Medicine, Akron, Ohio

Distant influences of amygdala lesion on visual cortical activation during emotional face processing.

Abstract: Emotional visual stimuli evoke enhanced responses in the visual cortex. To test whether this reflects modulatory influences from the amygdala on sensory processing, we used event-related functional magnetic resonance imaging (fMRI) in human patients with medial temporal lobe sclerosis. Twenty-six patients with lesions in the amygdala, the hippocampus or both, plus 13 matched healthy controls, were shown pictures of fearful or neutral faces in task-releant or task-irrelevant positions on the display. All subjects showed increased fusiform cortex activation when the faces were in task-relevant positions. Both healthy individuals and those with hippocampal damage showed increased activation in the fusiform and occipital cortex when they were shown fearful faces, but this was not the case for individuals with damage to the amygdala, even though visual areas were structurally intact. The distant influence of the amygdala was also evidenced by the parametric relationship between amygdala damage and the level of emotional activation in the fusiform cortex. Our data show that combining the fMRI and lesion approaches can help reveal the source of functional modulatory influences between distant but interconnected brain regions.

Bi-directional protein transport between the ER and Golgi.

Abstract: The endoplasmic reticulum (ER) and the Golgi comprise the first two steps in protein secretion. Vesicular carriers mediate a continuous flux of proteins and lipids between these compartments, reflecting the transport of newly synthesized proteins out of the ER and the retrieval of escaped ER residents and vesicle machinery. Anterograde and retrograde transport is mediated by distinct sets of cytosolic coat proteins, the COPII and COPI coats, respectively, which act on the membrane to capture cargo proteins into nascent vesicles. We review the mechanisms that govern coat recruitment to the membrane, cargo capture into a transport vesicle, and accurate delivery to the target organelle.

Light Signal Transduction in Higher Plants

Abstract: Plants utilize several families of photoreceptors to fine-tune growth and development over a large range of environmental conditions. The UV-A/blue light sensing phototropins mediate several light responses enabling optimization of photosynthetic yields. The initial event occurring upon photon capture is a conformational change of the photoreceptor that activates its protein kinase activity. The UV-A/blue light sensing cryptochromes and the red/far-red sensing phytochromes coordinately control seedling establishment, entrainment of the circadian clock, and the transition from vegetative to reproductive growth. In addition, the phytochromes control seed germination and shade-avoidance responses. The molecular mechanisms involved include light-regulated subcellular localization of the photoreceptors, a large reorganization of the transcriptional program, and light-regulated proteolytic degradation of several photoreceptors and signaling components.

Ferroelectricity at the Nanoscale: Local Polarization in Oxide Thin Films and Heterostructures

Abstract: Ferroelectric oxide materials have offered a tantalizing potential for applications since the discovery of ferroelectric perovskites more than 50 years ago. Their switchable electric polarization is ideal for use in devices for memory storage and integrated microelectronics, but progress has long been hampered by difficulties in materials processing. Recent breakthroughs in the synthesis of complex oxides have brought the field to an entirely new level, in which complex artificial oxide structures can be realized with an atomic-level precision comparable to that well known for semiconductor heterostructures. Not only can the necessary high-quality ferroelectric films now be grown for new device capabilities, but ferroelectrics can be combined with other functional oxides, such as high-temperature superconductors and magnetic oxides, to create multifunctional materials and devices. Moreover, the shrinking of the relevant lengths to the nanoscale produces new physical phenomena. Real-space characterization and manipulation of the structure and properties at atomic scales involves new kinds of local probes and a key role for first-principles theory.

Early Experience Alters Brain Function and Structure

Abstract: Objective. To investigate the effects of early experience on brain function and structure. Methods. A randomized clinical trial tested the neu- rodevelopmental effectiveness of the Newborn Individ- ualized Developmental Care and Assessment Program (NIDCAP). Thirty preterm infants, 28 to 33 weeks' ges- tational age (GA) at birth and free of known develop- mental risk factors, participated in the trial. NIDCAP was initiated within 72 hours of intensive care unit admission and continued to the age of 2 weeks, corrected for pre- maturity. Control (14) and experimental (16) infants were assessed at 2 weeks' and 9 months' corrected age on health status, growth, and neurobehavior, and at 2 weeks' corrected age additionally on electroencephalogram spec- tral coherence, magnetic resonance diffusion tensor im- aging, and measurements of transverse relaxation time. Results. The groups were medically and demograph- ically comparable before as well as after the treatment. However, the experimental group showed significantly better neurobehavioral functioning, increased coherence between frontal and a broad spectrum of mainly occipital brain regions, and higher relative anisotropy in left in- ternal capsule, with a trend for right internal capsule and frontal white matter. Transverse relaxation time showed no difference. Behavioral function was improved also at 9 months' corrected age. The relationship among the 3 neurodevelopmental domains was significant. The re- sults indicated consistently better function and more ma- ture fiber structure for experimental infants compared with their controls. Conclusions. This is the first in vivo evidence of en- hanced brain function and structure due to the NIDCAP. The study demonstrates that quality of experience before term may influence brain development significantly. Pe- diatrics 2004;113:846 - 857; preterm infants, NIDCAP, neu- robehavior, spectral coherence, diffusion tensor imaging, transverse relaxation time, Bayley Scales of Infant Devel- opment, APIB.

Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide

Abstract: Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase ( MGMT ) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival ( P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation ( P = 0.002; Fisher’s exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor ( P = 0.017; Cox regression). Conclusions: This prospective clinical trial identifies MGMT -methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O -6-benzylguanine, a noncytotoxic substrate of this enzyme.

The biogenesis of multivesicular endosomes

Abstract: Recent progress has been made in our understanding of the molecular mechanisms that regulate the biogenesis of multivesicular transport intermediates in the degradation pathway that leads to lysosomes. Here, we discuss recent work that uncovers some of the mechanisms that cause both membrane invagination within these newly forming intermediates and the detachment of these intermediates from early endosomal membranes.

Quantum Cryptography Protocols Robust against Photon Number Splitting Attacks for Weak Laser Pulse Implementations

Abstract: We introduce a new class of quantum key distribution protocols, tailored to be robust against photon number splitting (PNS) attacks. We study one of these protocols, which differs from the original protocol by Bennett and Brassard (BB84) only in the classical sifting procedure. This protocol is provably better than BB84 against PNS attacks at zero error.

Hand Hygiene among Physicians: Performance, Beliefs, and Perceptions

Abstract: The authors questioned physicians on their beliefs about hand-washing before examining a patient and observed their actual hand-washing practices. Predictors of adherence include being an internist...

The HUPO PSI's molecular interaction format--a community standard for the representation of protein interaction data.

Abstract: A major goal of proteomics is the complete description of the protein interaction network underlying cell physiology. A large number of small scale and, more recently, large-scale experiments have contributed to expanding our understanding of the nature of the interaction network. However, the necessary data integration across experiments is currently hampered by the fragmentation of publicly available protein interaction data, which exists in different formats in databases, on authors' websites or sometimes only in print publications. Here, we propose a community standard data model for the representation and exchange of protein interaction data. This data model has been jointly developed by members of the Proteomics Standards Initiative (PSI), a work group of the Human Proteome Organization (HUPO), and is supported by major protein interaction data providers, in particular the Biomolecular Interaction Network Database (BIND), Cellzome (Heidelberg, Germany), the Database of Interacting Proteins (DIP), Dana Farber Cancer Institute (Boston, MA, USA), the Human Protein Reference Database (HPRD), Hybrigenics (Paris, France), the European Bioinformatics Institute's (EMBL-EBI, Hinxton, UK) IntAct, the Molecular Interactions (MINT, Rome, Italy) database, the Protein-Protein Interaction Database (PPID, Edinburgh, UK) and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING, EMBL, Heidelberg, Germany).

Cornelia de Lange syndrome is caused by mutations in NIPBL , the human homolog of Drosophila melanogaster Nipped-B

Abstract: Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.

Electrophysiological Correlates of Rapid Spatial Orienting Towards Fearful Faces

Abstract: We investigated the spatio-temporal dynamic of attentional bias towards fearful faces. Twelve participants performed a covert spatial orienting task while recording visual event-related brain potentials (VEPs). Each trial consisted of a pair of faces (one emotional and one neutral) briefly presented in the upper visual field, followed by a unilateral bar presented at the location of one of the faces. Participants had to judge the orientation of the bar. Comparing VEPs to bars shown at the location of an emotional (valid) versus neutral (invalid) face revealed an early effect of spatial validity: the lateral occipital P1 component (~130 ms post-stimulus) was selectively increased when a bar replaced a fearful face compared to when the same bar replaced a neutral face. This effect was not found with upright happy faces or inverted fearful faces. A similar amplification of P1 has previously been observed in electrophysiological studies of spatial attention using non-emotional cues. In a behavioural control experiment, participants were also better at discriminating the orientation of the bar when it replaced a fearful rather than a neutral face. In addition, VEPs time-locked to the face-pair onset revealed a C1 component (~90 ms) that was greater for fearful than happy faces. Source localization (LORETA) confirmed an extrastriate origin of the P1 response showing a spatial validity effect, and a striate origin of the C1 response showing an emotional valence effect. These data suggest that activity in primary visual cortex might be enhanced by fear cues as early as 90 ms post-stimulus, and that such effects might result in a subsequent facilitation of sensory processing for a stimulus appearing at the same location. These results provide evidence for neural mechanisms allowing rapid, exogenous spatial orienting of attention towards fear stimuli.

Chromosome 21 and down syndrome: from genomics to pathophysiology.

Abstract: The sequence of chromosome 21 was a turning point for the understanding of Down syndrome. Comparative genomics is beginning to identify the functional components of the chromosome and that in turn will set the stage for the functional characterization of the sequences. Animal models combined with genome-wide analytical methods have proved indispensable for unravelling the mysteries of gene dosage imbalance.

Path integration in mammals

Abstract: It is often assumed that navigation implies the use, by animals, of landmarks indicating the location of the goal. However, many animals (including humans) are able to return to the starting point of a journey, or to other goal sites, by relying on self-motion cues only. This process is known as path integration, and it allows an agent to calculate a route without making use of landmarks. We review the current literature on path integration and its interaction with external, location-based cues. Special importance is given to the correlation between observable behavior and the activity pattern of particular neural cell populations that implement the internal representation of space. In mammals, the latter may well be the first high-level cognitive representation to be understood at the neural level.

Global judgments of subjective well-being: Situational variability and long-term stability.

Abstract: Subjective well-being (SWB) is an important indicator of quality oflife. SWB can be conceptualized as a momentary state (e.g., mood) aswell as a relatively stable trait (e.g., life satisfaction). Thevalidity of self-reported trait aspects of SWB has been questioned byexperimental studies showing that SWB judgments seem to be stronglycontext dependent. Particularly, momentary mood seems to have a stronginfluence on global SWB judgments. To explore the ecological validity ofthese conclusions a non-experimental longitudinal self-reportstudy with three occasions of measurement was conducted(N = 249). The associations between momentarymood ratings and global judgments of SWB (life satisfaction,satisfaction with life domains, frequency and intensity of emotions) aswell as personality ratings (self-esteem, optimism, neuroticism,extraversion) were analyzed in a multistate-multitrait-multiconstructmodel. This model takes (a) measurement error, (b) occasion-specificdeviations, and (c) stable interindividual differences into account. Itis shown that the variability in global SWB judgments and personalityratings is relatively small and much smaller than the variability inmood. Furthermore, the occasion-specific associations between moodstates, on the one hand, and global SWB and personality ratings, on theother hand, are relatively small and inconsistent. All global SWB andpersonality variables are more strongly related to mood on the traitlevel than on the occasion-specific deviation level. Therefore, incontrast to experimental studies, occasion-specific mood effects do notseem to be inherently important in ecological measurement settings.

Physicochemical Parameters Associated with Nanoparticle Formation in the Salting-Out, Emulsification-Diffusion, and Nanoprecipitation Methods

Abstract: Purpose. The aim of this work was to relate the physicochemical properties of the aqueous and organic phases used for nanoparticle (NP) preparation to the formation of NP produced by salting-out, emulsification-diffusion, and nanoprecipitation. Methods. Methacrylic acid copolymer and poly(vinyl alcohol) (PVAL) were selected as NP polymer and emulsifying agent, respectively. Salting-out and emulsification-diffusion NP batches were prepared modifying the PVAL content in the aqueous phase. For nanoprecipitation, NP were produced with variation of the polymer content and type of solvent in the organic phase. Results. For salting-out and emulsification-diffusion, NP formation was discussed in terms of the emulsification theory. The nanoemulsion obtained during NP preparation was visualized by scanning electron microscopy. Aqueous and organic phases used for NP preparation were characterized by their viscosity and surface tension. NP characteristics such as particle mean size, residual surfactant, suspendability in water after freeze-drying, and morphology were explained in terms of these properties. For nanoprecipitation, NP formation was analyzed considering the diffusion-stranding phenomenon. Conclusions. NP formation by salting-out and emulsification-diffusion was related to PVAL chain interactions at the droplet interface (e.g., reduction in the interfacial tension, mechanical sta- bilization, and steric stabilization) and in the bulk solution (hy- drodynamic stabilization). For nanoprecipitation, χsolvent-water and Δδsolvent-water of the organic phase solvents were well related to the NP characteristics.