962 research outputs found
The validity of clinical diagnoses of dementia in a group of consecutively autopsied memory clinic patients
Background: Epidemiological studies show that up to 10 % of individuals aged 65 years and older suffer from dementia, most commonly from dementia of the Alzheimer Type (DAT) [1]. Clinicopathological studies are critical to our understanding of this disease and improving the accuracy of clinical diagnoses.Objectives: Our objectives were to examine the validity of clinical diagnoses of DAT, to determine the prevalence of different forms of dementia in this sample, and to investigate the relationship between age at death and polymorbidity.Subjects and method: Clinical data were available from 221 patients who had been examined at the Basel Memory Clinic between 1986 and 1996. From this population, 34 % (75 patients) were autopsied in the Department of Pathology, University Hospital Basel, and neuropathological examinations were additionally performed on 62 (83 %) of these patients. Clinical and neuropathological data were retrospectively compared.Results: 67.8 % of the neuropathologically examined patients received a definitive diagnosis of AD (Alzheimer's disease), vascular dementia (VaD) or mixed dementia (AD and VaD). AD alone or with other histopathological hallmarks of dementia was the most prevalent neuropathological diagnosis (63 %). VaD was deemed the only cause of dementia in only 4.8 % of patients. The sensitivity for DAT was 75.9 %, the specificity 60.6 %. Increasing age was associated with an increasing number of clinical and neuropathological diagnoses.Conclusion: The sensitivity and specificity of the clinical diagnoses of DAT found in our study are similar to previous reports (2-5). Older patients had more etiologies of their dementia than younger patients. This study reaffirms the need for internationally accepted criteria for clinical and neuropathological diagnoses, as well as further clinical-neuropathological investigations to further refine the clinical diagnostic proces
Structural insights into Legionella RidL-Vps29 retromer subunit interaction reveal displacement of the regulator TBC1D5
Legionella pneumophila can cause Legionnaires’ disease and replicates intracellularly in a distinct Legionella-containing vacuole (LCV). LCV formation is a complex process that involves a plethora of type IV-secreted effector proteins. The effector RidL binds the Vps29 retromer subunit, blocks retrograde vesicle trafficking, and promotes intracellular bacterial replication. Here, we reveal that the 29-kDa N-terminal domain of RidL (RidL2–281) adopts a “foot-like” fold comprising a protruding β-hairpin at its “heel”. The deletion of the β-hairpin, the exchange to Glu of Ile170 in the β-hairpin, or Leu152 in Vps29 abolishes the interaction in eukaryotic cells and in vitro. RidL2–281 or RidL displace the Rab7 GTPase-activating protein (GAP) TBC1D5 from the retromer and LCVs, respectively, and TBC1D5 promotes the intracellular growth of L. pneumophila. Thus, the hydrophobic β-hairpin of RidL is critical for binding of the L. pneumophila effector to the Vps29 retromer subunit and displacement of the regulator TBC1D5
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A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.
A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity
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Restoration of Topoisomerase 2 Function by Complementation of Defective Monomers in Drosophila
Type II topoisomerases are essential ATP-dependent homodimeric enzymes required for transcription, replication, and chromosome segregation. These proteins alter DNA topology by generating transient enzyme-linked double-strand breaks for passage of one DNA strand through another. The central role of type II topoisomerases in DNA metabolism has made these enzymes targets for anticancer drugs. Here, we describe a genetic screen that generated novel alleles of Drosophila Topoisomerase 2 (Top2). Fifteen alleles were obtained, resulting from nonsense and missense mutations. Among these, 14 demonstrated recessive lethality, with one displaying temperature-sensitive lethality. Several newly generated missense alleles carry amino acid substitutions in conserved residues within the ATPase, Topoisomerase/Primase, and Winged helix domains, including four that encode proteins with alterations in residues associated with resistance to cancer chemotherapeutics. Animals lacking zygotic Top2 function can survive to pupation and display reduced cell division and altered polytene chromosome structure. Inter se crosses between six strains carrying Top2 missense alleles generated morphologically normal trans-heterozygous adults, which showed delayed development and were female sterile. Complementation occurred between alleles encoding Top2 proteins with amino acid substitutions in the same functional domain and between alleles encoding proteins with substitutions in different functional domains. Two complementing alleles encode proteins with amino acid substitutions associated with drug resistance. These observations suggest that dimerization of mutant Top2 monomers can restore enzymatic function. Our studies establish the first series of Top2 alleles in a multicellular organism. Future analyses of these alleles will enhance our knowledge about the contributions made by type II topoisomerases to development
Experimental Evidence of Time Delay Induced Death in Coupled Limit Cycle Oscillators
Experimental observations of time delay induced amplitude death in a pair of
coupled nonlinear electronic circuits that are individually capable of
exhibiting limit cycle oscillations are described. In particular, the existence
of multiply connected death islands in the parameter space of the coupling
strength and the time delay parameter for coupled identical oscillators is
established. The existence of such regions was predicted earlier on theoretical
grounds in [Phys. Rev. Lett. 80, 5109 (1998); Physica 129D, 15 (1999)]. The
experiments also reveal the occurrence of multiple frequency states, frequency
suppression of oscillations with increased time delay and the onset of both
in-phase and anti-phase collective oscillations.Comment: 4 aps formatted RevTeX pages; 6 figures; to appear in Phys. Rev. Let
Ab initio simulations of liquid NaSn alloys: Zintl anions and network formation
Using the Car-Parrinello technique, ab initio molecular dynamics simulations
are performed for liquid NaSn alloys in five different compositions (20, 40,
50, 57 and 80 % sodium). The obtained structure factors agree well with the
data from neutron scattering experiments. The measured prepeak in the structure
factor is reproduced qualitatively for most compositions. The calculated and
measured positions of all peaks show the same trend as function of the
composition.\\ The dynamic simulations also yield information about the
formation and stability of Sn clusters (Zintl anions) in the liquid. In our
simulations of compositions with 50 and 57 % sodium we observe the formation of
networks of tin atoms. Thus, isolated tin clusters are not stable in such
liquids. For the composition with 20 % tin only isolated atoms or dimers of tin
appear, ``octet compounds'' of one Sn atom surrounded by 4 Na atoms are not
observed.Comment: 12 pages, Latex, 3 Figures on reques
Effect of hydrogen on ground state structures of small silicon clusters
We present results for ground state structures of small SiH (2 \leq
\emph{n} \leq 10) clusters using the Car-Parrinello molecular dynamics. In
particular, we focus on how the addition of a hydrogen atom affects the ground
state geometry, total energy and the first excited electronic level gap of an
Si cluster. We discuss the nature of bonding of hydrogen in these
clusters. We find that hydrogen bonds with two silicon atoms only in SiH,
SiH and SiH clusters, while in other clusters (i.e. SiH,
SiH, SiH, SiH, SiH and SiH) hydrogen is bonded
to only one silicon atom. Also in the case of a compact and closed silicon
cluster hydrogen bonds to the cluster from outside. We find that the first
excited electronic level gap of Si and SiH fluctuates as a function
of size and this may provide a first principles basis for the short-range
potential fluctuations in hydrogenated amorphous silicon. Our results show that
the addition of a single hydrogen can cause large changes in the electronic
structure of a silicon cluster, though the geometry is not much affected. Our
calculation of the lowest energy fragmentation products of SiH clusters
shows that hydrogen is easily removed from SiH clusters.Comment: one latex file named script.tex including table and figure caption.
Six postscript figure files. figure_1a.ps and figure_1b.ps are files
representing Fig. 1 in the main tex
The Coupled Electron-Ion Monte Carlo Method
In these Lecture Notes we review the principles of the Coupled Electron-Ion
Monte Carlo methods and discuss some recent results on metallic hydrogen.Comment: 38 pages, 6 figures, Lecture notes for the International School of
Solid State Physics, 34th course: "Computer Simulation in Condensed Matter:
from Materials to Chemical Biology", 20 July-1 August 2005 Erice (Italy). To
appear in Lecture Notes in Physics (2006
Boxy/peanut/X bulges, barlenses and the thick part of galactic bars: What are they and how did they form?
Bars have a complex three-dimensional shape. In particular their inner part
is vertically much thicker than the parts further out. Viewed edge-on, the
thick part of the bar is what is commonly known as a boxy-, peanut- or X- bulge
and viewed face-on it is referred to as a barlens. These components are due to
disc and bar instabilities and are composed of disc material. I review here
their formation, evolution and dynamics, using simulations, orbital structure
theory and comparisons to observations.Comment: 21 pages, 7 figures, invited review to appear in "Galactic Bulges",
E. Laurikainen, R. Peletier, D. Gadotti, (eds.), Springe
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