bluuebunny/crossref_metadata_2025 huggingface dataset:
Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite Instability
Authors: Markowitz Sanford , Wang Jing , Myeroff Lois , Parsons Ramon , Sun LuZhe , Lutterbaugh James , Fan Robert S. , Zborowska Elizabeth , Kinzler Kenneth W. , Vogelstein Bert , Brattain Michael , Willson James K. V.
Published: October 2006

Transforming growth factor-β (TGF-β) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-β receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-β-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.
Role of the Protein Chaperone YDJ1 in Establishing Hsp90-Mediated Signal Transduction Pathways
Authors: Kimura Yoko , Yahara Ichiro , Lindquist Susan
Published: October 2006

The substrate-specific protein chaperone Hsp90 (heat shock protein 90) from
Saccharomyces cerevisiae
functions in diverse signal transduction pathways. A mutation in
YDJ1
, a member of the DnaJ chaperone family, was recovered in a synthetic-lethal screen with Hsp90 mutants. In an otherwise wild-type background, the
ydj1
mutation exerted strong and specific effects on three Hsp90 substrates, derepressing two (the estrogen and glucocorticoid receptors) and reducing the function of the third (the tyrosine kinase p60

v-
src

). Analysis of one of these substrates, the glucocorticoid receptor, indicated that Ydj1 exerts its effects through physical interaction with Hsp90 substrates.
Muscle-Derived Neurotrophin-4 as an Activity-Dependent Trophic Signal for Adult Motor Neurons
Authors: Funakoshi Hiroshi , Belluardo Natale , Arenas Ernest , Yamamoto Yuji , Casabona Antonino , Persson Håkan , Ibáñez Carlos F.
Published: October 2006

The production of neurotrophin-4 (NT-4) in rat skeletal muscle was found to depend on muscle activity. The amounts of NT-4 messenger RNA present decreased after blockade of neuromuscular transmission with α-bungarotoxin and increased during postnatal development and after electrical stimulation in a dose-dependent manner. NT-4 immunoreactivity was detected in slow, type I muscle fibers. Intramuscular administration of NT-4 induced sprouting of intact adult motor nerves. Thus, muscle-derived NT-4 acted as an activity-dependent neurotrophic signal for growth and remodeling of adult motor neuron innervation. NT-4 may thus be partly responsible for the effects of exercise and electrical stimulation on neuromuscular performance.
A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase
Authors: Savitsky Kinneret , Bar-Shira Anat , Gilad Shlomit , Rotman Galit , Ziv Yael , Vanagaite Lina , Tagle Danilo A. , Smith Sara , Uziel Tamar , Sfez Sharon , Ashkenazi Maya , Pecker Iris , Frydman Moshe , Harnik Reli , Patanjali Sankhavaram R. , Simmons Andrew , Clines Gregory A. , Sartiel Adam , Gatti Richard A. , Chessa Luciana , Sanal Ozden , Lavin Martin F. , Jaspers N. G. J. , Taylor A. Malcolm R. , Arlett Colin F. , Miki Toru , Weissman Sherman M. , Lovett Michael , Collins Francis S. , Shiloh Yosef
Published: October 2006

A gene,
ATM
, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes.
ATM
, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial
ATM
complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3′ kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of
ATM
should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer.
Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA
Authors: Cases Olivier , Seif Isabelle , Grimsby Joseph , Gaspar Patricia , Chen Kevin , Pournin Sandrine , Müller Ulrike , Aguet Michel , Babinet Charles , Shih Jean Chen , De Maeyer Edward
Published: October 2006

Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males.
Transcriptional Activation by Tetracyclines in Mammalian Cells
Authors: Gossen Manfred , Freundlieb Sabine , Bender Gabriele , Müller Gerhard , Hillen Wolfgang , Bujard Hermann
Published: October 2006

A transcriptional transactivator was developed that fuses the VP16 activation domain with a mutant Tet repressor from
Escherichia coli
. This transactivator requires certain tetracycline (Tc) derivatives for specific DNA binding. Thus, addition of doxycycline to HeLa cells that constitutively synthesized the transactivator and that contained an appropriate, stably integrated reporter unit rapidly induced gene expression more than a thousandfold. The specificity of the Tet repressor-operator-effector interaction and the pharmacological characteristics of Tc's make this regulatory system well suited for the control of gene activities in vivo, such as in transgenic animals and possibly in gene therapy.
Rapid Accretion and Early Differentiation of Mars Indicated by
142
Nd/
144
Nd in SNC Meteorites
Authors: Harper Charles L. , Nyquist Laurence E. , Bansal Brij , Wiesmann Henry , Shih Chi-Yu
Published: October 2006

Small differences in the ratio of neodymium-142 to neodymium-144 in early formed mantle reservoirs in planetary bodies are the result of in situ decay of the extinct radionuclide samarium-146 and can be used to constrain early planetary differentiation and therefore the time scale of planetary accretion. The martian meteorite Nakhla (∼1.3 billion years old), the type sample of the nakhlite subgroup of the Shergottite-Nakhlite-Chassigny (SNC) meteorites, exhibits a 59 ± 13 parts per million excess in the ratio of neodymium-142 to neodymium-144 relative to normal neodymium. This anomaly records differentiation in the martian mantle before 4539 million years ago and implies that Mars experienced no giant impacts at any time later than 27 million years after the origin of the solar system.
Requirement of FGF-4 for Postimplantation Mouse Development
Authors: Feldman Benjamin , Poueymirou William , Papaioannou Virginia E. , DeChiara Thomas M. , Goldfarb Mitchell
Published: October 2006

Fibroblast growth factors (FGFs) are thought to influence many processes in vertebrate development because of their diverse sites of expression and wide range of biological activities in in vitro culture systems. As a means of elucidating embryonic functions of FGF-4, gene targeting was used to generate mice harboring a disrupted
Fgf4
gene. Embryos homozygous for the null allele underwent uterine implantation and induced uterine decidualization but did not develop substantially thereafter. As was consistent with their behavior in vivo,
Fgf4
null embryos cultured in vitro displayed severely impaired proliferation of the inner cell mass, whereas growth and differentiation of the inner cell mass were rescued when null embryos were cultured in the presence of FGF-4 protein.
Molecular Basis of the
cauliflower
Phenotype in
Arabidopsis
Authors: Kempin Sherry A. , Savidge Beth , Yanofsky Martin F.
Published: October 2006

Genetic studies demonstrate that two
Arabidopsis
genes,
CAULIFLOWER
and
APETALA1
, encode partially redundant activities involved in the formation of floral meristems, the first step in the development of flowers. Isolation of the
CAULIFLOWER
gene from
Arabidopsis
reveals that it is closely related in sequence to
APETALA1
. Like
APETALA1
,
CAULIFLOWER
is expressed in young flower primordia and encodes a MADS-domain, indicating that it may function as a transcription factor. Analysis of the cultivated garden variety of cauliflower (
Brassica oleracea
var.
botrytis
) reveals that its
CAULIFLOWER
gene homolog is not functional, suggesting a molecular basis for one of the oldest recognized flower abnormalities.
Effects of Competition, Colonization, and Extinction on Rodent Species Diversity
Authors: Valone Thomas J. , Brown James H.
Published: October 2006

Analyses of long-term experimental data from the Chihuahuan desert revealed that species diversity of other rodents was higher on plots from which kangaroo rats (
Dipodomys
spp.) had been removed. The difference was due to consistently higher colonization and lower extinction probabilities of small granivorous rodents in the absence of competitively dominant kangaroo rats. The results of this ecosystem experiment demonstrate the importance of both competitive exclusion and metapopulation dynamics for biological diversity in a natural community.
Genetic Feminization of Brain Structures and Changed Sexual Orientation in Male
Drosophila
Authors: Ferveur Jean-François , Störtkuhl Klemens F. , Stocker Reinhard F. , Greenspan Ralph J.
Published: October 2006

The neural basis of sexual orientation in
Drosophila
was studied by the production of males with regionally feminized brains. Such flies express the female form of the sex determination gene
transformer
in a limited number of neurons under the control of
GAL4
enhancer trap inserts. This method facilitated the creation of lines with a stable pattern of feminization. In tests of sexual preferences, flies that were feminized in a portion of the antennal lobes or in a subset of the corpora pedunculata (mushroom bodies) courted both males and females. These two brain structures, both of which are involved in olfactory processing, may function in the recognition of sex-specific pheromones, in the control of sex-specific behaviors, or both.
PER Protein Interactions and Temperature Compensation of a Circadian Clock in
Drosophila
Authors: Huang Zuoshi J. , Curtin Kathryn D. , Rosbash Michael
Published: October 2006

The periods of circadian clocks are relatively temperature-insensitive. Indeed, the

per
L

mutation in the
Drosophila melanogaster
period gene, a central component of the clock, affects temperature compensation as well as period length. The
per
protein (PER) contains a dimerization domain (PAS) within which the

per
L

mutation is located. Amino acid substitutions at the

per
L

position rendered PER dimerization temperature-sensitive. In addition, another region of PER interacted with PAS, and the

per
L

mutation enhanced this putative intramolecular interaction, which may compete with PAS-PAS intermolecular interactions. Therefore, temperature compensation of circadian period in
Drosophila
may be due in part to temperature-independent PER activity, which is based on competition between inter- and intramolecular interactions with similar temperature coefficients.
Binding Strength Between Cell Adhesion Proteoglycans Measured by Atomic Force Microscopy
Authors: Dammer Ulrich , Popescu Octavian , Wagner Peter , Anselmetti Dario , Güntherodt Hans-Joachim , Misevic Gradimir N.
Published: October 2006

Measurement of binding forces intrinsic to adhesion molecules is necessary to assess their contribution to the maintenance of the anatomical integrity of multicellular organisms. Atomic force microscopy was used to measure the binding strength between cell adhesion proteoglycans from a marine sponge. Under physiological conditions, the adhesive force between two cell adhesion molecules was found to be up to 400 piconewtons. Thus a single pair of molecules could hold the weight of 1600 cells. High intermolecular binding forces are likely to form the basis for the integrity of the multicellular sponge organism.
A Regulatory Role for ARF6 in Receptor-Mediated Endocytosis
Authors: D'Souza-Schorey Crislyn , Li Guangpu , Colombo Maria I. , Stahl Philip D.
Published: October 2006

Adenosine diphosphate-ribosylation factor 6 (ARF6), ARF6 mutants, and ARF1 were transiently expressed in Chinese hamster ovary cells, and the effects on receptor-mediated endocytosis were assessed. Overexpressed ARF6 localized to the cell periphery and led to a redistribution of transferrin receptors to the cell surface and a decrease in the rate of uptake of transferrin. Similar results were obtained when a mutant defective in guanosine triphosphate hydrolysis was expressed. Expression of a dominant negative mutant, ARF6(T27N), resulted in an intracellular distribution of transferrin receptors and an inhibition of transferrin recycling to the cell surface. In contrast, overexpression of ARF1 had little or no effect on these parameters of endocytosis.
HST Imaging of Atmospheric Phenomena Created by the Impact of Comet Shoemaker-Levy 9
Authors: Hammel H. B. , Beebe R. F. , Ingersoll A. P. , Orton G. S. , Mills J. R. , Simon A. A. , Chodas P. , Clarke J. T. , De Jong E. , Dowling T. E. , Harrington J. , Huber L. F. , Karkoschka E. , Santori C. M. , Toigo A. , Yeomans D. , West R. A.
Published: October 2006

Hubble Space Telescope (HST) images reveal major atmospheric changes created by the collision of comet Shoemaker-Levy 9 with Jupiter. Plumes rose to 3000 kilometers with ejection velocities on the order of 10 kilometers second
-1
; some plumes were visible in the shadow of Jupiter before rising into sunlight. During some impacts, the incoming bolide may have been detected. Impact times were on average about 8 minutes later than predicted. Atmospheric waves were seen with a wave front speed of 454 ± 20 meters second
-1
. The HST images reveal impact site evolution and record the overall change in Jupiter's appearance as a result of the bombardment.
Mechanisms and Genes of Cellular Suicide
Authors: Steller Hermann
Published: October 2006

Apoptosis is a morphologically distinct form of programmed cell death that plays a major role during development, homeostasis, and in many diseases including cancer, acquired immunodeficiency syndrome, and neurodegenerative disorders. Apoptosis occurs through the activation of a cell-intrinsic suicide program. The basic machinery to carry out apoptosis appears to be present in essentially all mammalian cells at all times, but the activation of the suicide program is regulated by many different signals that originate from both the intracellular and the extracellular milieu. Genetic studies in the nematode
Caenorhabditis elegans
and in the fruit fly
Drosophila melanogaster
have led to the isolation of genes that are specifically required for the induction of programmed cell death. At least some components of the apoptotic program have been conserved among worms, insects, and vertebrates.
Synaptic Desensitization of NMDA Receptors by Calcineurin
Authors: Tong Gang , Shepherd Dawn , Jahr Craig E.
Published: October 2006

Desensitization is a phenomenon that is common to many ligand-gated ion channels but has been demonstrated only rarely with physiological stimulation. Numerous studies describe desensitization of the
N
-methyl-D-aspartate (NMDA) subtype of glutamate receptor by exogenous agonists, but whether synaptic stimulation causes desensitization has been unknown. Synaptic stimulation of NMDA receptors on rat hippocampal neurons resulted in desensitization that was prevented by intracellular 1,2-bis(
o
-aminophenoxy)ethane-
N,N,N′,N′
-tetraacetic acid (BAPTA), adenosine-5′-
O
-(3-thiotriphosphate) (ATP-γ-S), or inhibitors of phosphatase 2B (calcineurin), but not by inhibitors of phosphatases 1 and 2A or of tyrosine phosphatases. Synaptic NMDA receptors may fluctuate between phosphorylated and dephosphorylated forms, depending on the rate of synaptic stimulation and the magnitude of the associated influx of calcium through NMDA receptors.
Crystal Structure and Function of the Isoniazid Target of
Mycobacterium tuberculosis
Authors: Dessen Andréa , Quémard Annaïk , Blanchard John S. , Jacobs William R. , Sacchettini James C.
Published: October 2006

Resistance to isoniazid in
Mycobacterium tuberculosis
can be mediated by substitution of alanine for serine 94 in the InhA protein, the drug's primary target. InhA was shown to catalyze the β-nicotinamide adenine dinucleotide (NADH)-specific reduction of 2-
trans
-enoyl-acyl carrier protein, an essential step in fatty acid elongation. Kinetic analyses suggested that isoniazid resistance is due to a decreased affinity of the mutant protein for NADH. The three-dimensional structures of wild-type and mutant InhA, refined to 2.2 and 2.7 angstroms, respectively, revealed that drug resistance is directly related to a perturbation in the hydrogen-bonding network that stabilizes NADH binding.
Long-Lasting Neurotrophin-Induced Enhancement of Synaptic Transmission in the Adult Hippocampus
Authors: Kang Hyejin , Schuman Erin M.
Published: October 2006

The neurotrophins are signaling factors important for the differentiation and survival of distinct neuronal populations during development. To test whether the neurotrophins also function in the mature nervous system, the effects of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophic factor 3 (NT-3) on the strength of synaptic transmission in hippocampal slices were determined. Application of BDNF or NT-3 produced a dramatic and sustained (2 to 3 hours) enhancement of synaptic strength at the Schaffer collateral-CA1 synapses; NGF was without significant effect. The enhancement was blocked by K252a, an inhibitor of receptor tyrosine kinases. BDNF and NT-3 decreased paired-pulse facilitation, which is consistent with a possible presynaptic modification. Long-term potentiation could still be elicited in slices previously potentiated by exposure to the neurotrophic factors, which implies that these two forms of plasticity may use at least partially independent cellular mechanisms.
Demyelinating diseases
Authors: Love S
Published: October 2006

A diagnosis of demyelination carries important therapeutic and prognostic implications. In most cases the diagnosis is made clinically, and involvement of the histopathologist is largely confined to postmortem confirmation and clinicopathological correlation. However, every now and then, accurate diagnosis of the presence or cause of demyelination before death hinges on the histopathological assessment. Recognition of demyelination depends on an awareness of this as a diagnostic possibility, and on the use of appropriate tinctorial and immunohistochemical stains to identify myelin, axons and inflammatory cells. In biopsy specimens, the critical distinction is usually from ischaemic or neoplastic disease, and the types of demyelinating disease most likely to be encountered are multiple sclerosis, acute-disseminated encephalomyelitis, progressive multifocal leucoencephalopathy and extrapontine myelinolysis. Interpretation of the pathology has to be made in the context of the clinical, radiological and biochemical findings. Freezing of a small amount of fresh tissue allows for later virological studies, and electron microscopy is occasionally helpful for demonstration of viral particles.
YANG–MILLS GRAVITY IN FLAT SPACE–TIME I: CLASSICAL GRAVITY WITH TRANSLATION GAUGE SYMMETRY
Authors: HSU JONG-PING
Published: October 2006

We formulate and explore the physical implications of a new translation gauge theory of gravity in flat space–time with a new Yang–Mills action, which involves quadratic gauge curvature and fermions. The theory shows that the presence of an "effective Riemann metric tensor" for the motions of classical particles and light rays is probably the manifestation of the translation gauge symmetry in flat physical space–time. In the post-Newtonian approximation of the tensor gauge field produced by the energy–momentum tensor, the results are shown to be consistent with classical tests of gravity and with the quadrupole radiations of binary pulsars.
BLACK HOLE ENTROPY IN STRING THEORY: GOING BEYOND BEKENSTEIN AND HAWKING
Authors: DABHOLKAR ATISH
Published: October 2006

In this talk I summarize some recent progress in string theory in understanding the entropy of a class of black holes including corrections to the Bekenstein–Hawking formula. The quantum corrected entropy is in precise numerical agreement with the logarithm of the number of microstates once quantum corrections are correctly taken into account.
ON THE RELATION BETWEEN BPS SOLUTIONS IN 4D AND 5D
Authors: BEHRNDT KLAUS , CARDOSO GABRIEL LOPES , MAHAPATRA SWAPNA
Published: October 2006

We discuss the explicit dictionary between general stationary four- and five-dimensional supersymmetric solutions in N = 2 supergravity theories with cubic prepotentials. All these solutions are completely determined in terms of the same set of harmonic functions and attractor equations. We discuss various examples like black holes and black rings in Taub-NUT space–time. Then we consider corrections to the four-dimensional solutions associated with more general prepotentials and comment on analogous corrections on the 5D side.
QUANTUM GEOMETRY AND THE BIG BANG
Authors: SINGH PARAMPREET
Published: October 2006

Loop quantum cosmology provides a new paradigm on the genesis of our universe in which the classical expanding branch is joined via a quantum geometric bridge to a classical contracting branch. The evolution between two phases of our universe is non-singular and deterministic, which is a direct manifestation of incorporating non-perturbative quantum geometric features of loop quantum gravity. Using analytical and numerical techniques, details of the quantum nature of big bang can be quantified and reliable physical predictions can be made. The quantum description can also be well approximated by an effective theory which leads to ρ2 modifications to the Friedmann equation in the Planck regime.
Radiation-induced gastric epithelial apoptosis occurs in the proliferative zone and is regulated by p53, bak, bax, and bcl-2
Authors: Przemeck S. M. C. , Duckworth C. A. , Pritchard D. M.
Published: October 2006

Unlike the small intestine and colon where γ-radiation-induced apoptosis has previously been well characterized, the response of murine gastric epithelium to γ-radiation has not been investigated in detail. Apoptosis was therefore assessed on a cell positional basis in gastric antral and corpus glands from adult male mice following γ-radiation. Maximum numbers of apoptotic cells were observed in both antrum and corpus at 48 h and at radiation doses greater than 12 Gy. However, the number of apoptotic cells observed in the gastric epithelium was much lower than observed in the small intestine or colon after similar doses of radiation. Hematoxylin and eosin, caspase 3 immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling detected similar numbers and cell positional distributions of apoptotic cells, hence hematoxylin and eosin was used for subsequent studies. The highest numbers of apoptotic cells were observed at cell positions 5–6 in the antrum and cell positions 15–18 in the corpus. These distributions coincided with the distributions of PCNA-labeled proliferating cells, but not with the distributions of H+-K+-ATPase-labeled parietal cells or TFF2-labeled mucous neck cells. Decreased numbers of apoptotic gastric epithelial cells were observed in p53-null, bak-null, and bax-null mice compared with wild-type counterparts 6 and 48 h after 12 Gy γ-radiation. Significantly increased numbers of apoptotic gastric epithelial cells were observed in bcl-2-null mice compared with wild-type littermates 6 h after 12 Gy γ-radiation. Radiation therefore induces apoptosis in the proliferative zone of mouse gastric epithelium. This response is regulated by the expression of p53, bak, bax, and bcl-2.
H2O2 activates redox- and 4-aminopyridine-sensitive Kv channels in coronary vascular smooth muscle
Authors: Rogers Paul A. , Chilian William M. , Bratz Ian N. , Bryan Robert M. , Dick Gregory M.
Published: October 2006

Previously, we demonstrated that coronary vasodilation in response to hydrogen peroxide (H2O2) is attenuated by 4-aminopyridine (4-AP), an inhibitor of voltage-gated K+ (KV) channels. Using whole cell patch-clamp techniques, we tested the hypothesis that H2O2 increases K+ current in coronary artery smooth muscle cells. H2O2 increased K+ current in a concentration-dependent manner (increases of 14 ± 3 and 43 ± 4% at 0 mV with 1 and 10 mM H2O2, respectively). H2O2 increased a conductance that was half-activated at −18 ± 1 mV and half-inactivated at −36 ± 2 mV. H2O2 increased current amplitude; however, the voltages of half activation and inactivation were not altered. Dithiothreitol, a thiol reductant, reversed the effect of H2O2 on K+ current and significantly shifted the voltage of half-activation to −10 ± 1 mV. N-ethylmaleimide, a thiol-alkylating agent, blocked the effect of H2O2 to increase K+ current. Neither tetraethylammonium (1 mM) nor iberiotoxin (100 nM), antagonists of Ca2+-activated K+ channels, blocked the effect of H2O2 to increase K+ current. In contrast, 3 mM 4-AP completely blocked the effect of H2O2 to increase K+ current. These findings lead us to conclude that H2O2 increases the activity of 4-AP-sensitive KV channels. Furthermore, our data support the idea that 4-AP-sensitive KV channels are redox sensitive and contribute to H2O2-induced coronary vasodilation.
Aging alters the skeletal response to disuse in the rat
Authors: Perrien Daniel S. , Akel Nisreen S. , Dupont-Versteegden Esther E. , Skinner Robert A. , Siegel Eric R. , Suva Larry J. , Gaddy Dana
Published: October 2006

Disuse has been shown to cause a rapid and dramatic loss of skeletal mass and strength in the load-bearing bones of young and mature animals and humans. However, little is known about the skeletal effects of disuse in aged mammals. The present study was designed to determine whether the skeletal effects of disuse are maintained with extreme age. Fischer 344/Brown Norway male rats (6 and 32 mo old) were hindlimb suspended (HS) or housed individually for 2 wk. Trabecular volume and microarchitecture in the proximal tibia were significantly decreased by HS only in young rats. HS significantly reduced cortical bone mineral density and increased cortical porosity only in old rats by inducing new pore formation. Cortical pore diameter was also increased in old rats, regardless of loading condition. Ex vivo osteogenic and adipogenic cultures established from each group demonstrated that age and HS decreased osteoblastogenesis. Age, but not HS, decreased sensitivity to endogenous bone morphogenetic protein stimulation, as measured by treatment with exogenous Noggin. Adipocyte development increased with age, whereas HS suppressed sensitivity to peroxisome proliferator-activated receptor-γ-induced differentiation. Serum insulin-like growth factor I levels were reduced with HS in young rats and with age in control and HS rats. These results suggest that the site of bone loss due to disuse is altered with age and that the loss of osteogenic potential with disuse in the old rats may be due to the combined effects of decreased insulin-like growth factor I levels and sensitivity, as well as diminished bone morphogenetic protein production.
Nutzen und Risiko der Hormonersatztherapie – ein Update
Authors: Schmidt M. , Kimmig R.
Published: October 2006

Die Hormonersatztherapie (HRT) mit Östrogenen und Gestagenen wird seit mehr als 40 Jahren zur Behandlung klimakterischer Beschwerden eingesetzt. Die HRT mit Östrogenen oder als kombinierte Östrogen-Gestagen-Therapie kann als wirkungsvolle Behandlung von vasovegetativen Symptomen sowie von Beschwerden der urogenitalen Atrophie angesehen werden. In den letzten Jahren sind hinsichtlich der Risiken der HRT vermehrt Bedenken erhoben worden, die zu einem Sinneswandel bei Ärzten und Patientinnen geführt haben. Auslöser für diesen Sinneswandel waren im Wesentlichen drei grosse internationale Studien: die Heart and Estrogen/Progestin Replacement Study, die Women’s Health Initiative Study und die One Million Women Study. Ziel dieser Arbeit ist es, den aktuellen Stand der teils kontrovers geführten Diskussion zu Nutzen und Risiken der HRT aufzuzeigen.
Alternative Therapiemöglichkeiten im Klimakterium
Authors: Reinhard-Hennch Bettina , Strowitzki Thomas , von Hagens Cornelia
Published: October 2006

Fragestellung: İbersicht über alternative Therapiemöglichkeiten im Klimakterium. Methoden: Literaturrecherche in Cochrane Library und Medline (1966–2006) nach Stichwörtern, zu naturheilkundlicher Intervention im Klimakterium und in Originalarbeiten oder Reviews, die zusätzlich gefunden wurden. Ergebnisse: Die Gesamtdaten zeigen, dass Cimicifuga, eventuell auch Phytoöstrogene, Hopfen und Salbei klimakterische Beschwerden, insbesondere Hitzewallungen, beeinflussen können. Johanniskraut kann moderate depressive Verstimmungen lindern. Für Phytoöstrogene gibt es Hinweise zur Knochenprotektion und Risikoreduktion von Herzerkrankungen. Zum Einfluss des Lebensstils auf Hitzewallungen gibt es keine eindeutigen Aussagen, Studien belegen eine präventive Wirksamkeit auf Knochen und Herz/Kreislauf. Schlussfolgerung: Lebensstil, Cimicifuga und Phytoöstrogene sind eine Option zur Linderung von Wechseljahresbeschwerden und Prävention chronischer Alterserkrankungen. Phytoöstrogene und Cimicifuga können bei Brustkrebspatientinnen nicht empfohlen werden.
Is Overactivity the Core Feature of Hypomania in Bipolar II Disorder?
Authors: Benazzi Franco
Published: October 2006

Background: Recent studies found that overactivity (increased goal-directed activities) may be as important as mood change (elevated and/or irritable mood) for the diagnosis of mania/hypomania (on family history and psychometric grounds), questioning DSM-IV-TR criteria always requiring mood change and listing overactivity among the other symptoms. The aim of the study was to find out if overactivity was at least as important as mood change for the diagnosis of hypomania. Sampling and Methods: A consecutive sample of 137 bipolar II disorder (BP-II) and 76 major depressive disorder remitted outpatients were interviewed with the Structured Clinical Interview for DSM-IV by a senior clinical and research psychiatrist in a private practice. Patients were asked if they had had hypomanic symptoms and episodes, and which were the most common hypomanic symptoms during the various episodes. The study aim had not been planned when variables were collected for different study goals. Results: Overactivity was the most common hypomanic symptom in BP-II, more common than elevated mood, and had the strongest association with BP-II among all the hypomanic symptoms (overactivity odds ratio = 15.4, elevated mood odds ratio = 12.6). Three factors were found: an ‘elevated mood’ factor including elevated mood and increased self-esteem; a ‘mental activation’ factor including racing/crowded thoughts, and a ‘behavioral activation’ factor including overactivity. There was no relationship between overactivity and mood change. Irritable mood was not associated with overactivity and elevated mood. BP-II was present in 21.6%of patients without a history of overactivity, and in 81.0% of patients with a history of overactivity. BP-II was present in 25.0% of patients without elevated mood, and in 63.3% of patients with elevated mood. As a predictor of BP-II, overactivity had a sensitivity of 90.5%, a specificity of 61.8%, and a positive predictive value of 81.0% (elevated mood: 72.2, 82.8, and 88.3%, respectively). Five or more hypomanic symptoms had the most balanced combination of sensitivity (82.4%) and specificity (85.5%) for BP-II, and a positive predictive value of 91.1%. Overactivity was present in 89.5% of patients with a history of ≧5 hypomanic symptoms, while elevated mood was present in 76.6%. Conclusions: Theresults seem to support the view that overactivity may be a core feature of hypomania, suggesting the upgrading of overactivity to a stem criterion for hypomania.
Long-Term Cost of Stroke Subtypes among Medicare Beneficiaries
Authors: Lee Won Chan , Christensen Michael C. , Joshi Ashish V. , Pashos Chris L.
Published: October 2006

Background and Purpose: The economic impact of hemorrhagic stroke, including subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH), has not been well characterized compared to the more prevalent ischemic stroke (IS). Methods: Patients diagnosed with SAH, ICH or IS in 1997 were identified in a 5% national random sample of all Medicare beneficiaries. Medical care patterns and associated Medicare reimbursements were analyzed from one year prior to the index event through four years following that event. Results: 11,430 patients were identified with SAH (n = 342), ICH (n = 1,957) or IS (n = 9,131). Average Medicare expenditures, from the initial event through four years, were USD 48,327 for SAH, USD 38,023 for ICH and USD 39,396 for IS. Conclusions: Long-term healthcare costs of SAH and ICH are substantial. With the expected increase in the elderly population over the coming decades, these results emphasize the need for effective preventive and acute medical care.
Hereditary Angioedema Associated with Heterozygous Factor V Leiden Mutation in a Patient with Purpura Fulminans
Authors: Celikel S. , Buyukasik Y. , Karakaya G. , Kalyoncu A.F.
Published: October 2006

Background: Hereditary angioedema (HAE) is an autosomal dominant, quantitative or functional defect of the C1 esterase inhibitor. The main role of the C1 esterase inhibitor is to regulate the activation of the complement system, the contact phase of the intrinsic coagulation system. On the other hand, factor V Leiden is the most common cause of primary and recurrent venous thromboembolism and displays a strong interaction with oral contraceptives. Here we report the case of a patient with HAE associated with the factor V Leiden mutation who had purpura fulminans when put on an oral contraceptive therapy. Case: A 42-year-old woman presented to the emergency room with a history of livid skin changes on her legs during a flight. On physical examination, the vital signs were normal, but there were edemas in her legs. The livid skin changes tended to increase, eventually leading to skin necrosis on the next day. She had a history of a similar episode two months before and experienced both episodes of necrotic skin lesions just after she had been put on a hormone replacement therapy due to irregular menstruations. She also had a history of recurrent angioedema attacks since her childhood, triggered by stress and physical stimulants such as pressure and heat. Subsequent investigations revealed heterozygous factor V mutation, activated protein C resistance and reduced C1 inhibitor levels. Conclusion: Thrombosis is a multifactorial disease. The coexistence of multiple hereditary and acquired factors eases its occurrence. Women with HAE should be screened for the factor V Leiden mutation before pregnancy or the start of a hormone replacement therapy.
Thiol-Related Genes in Diabetic Complications
Authors: Liang Mingyu , Pietrusz Jennifer L.
Published: October 2006

Objective—

Our laboratory and others have found that deficiencies in cellular thiols may be importantly involved in the development of diabetic complications. However, the role for specific thiol-related genes in diabetic complications is unclear.

Methods and Results—

We began the present study by systematically determining the expression level of 11 thiol-related genes in three tissues from rats with streptozotocin-induced diabetes. Several thiol-related genes were found to exhibit diabetes-associated, time-dependent differential expression. Thioredoxin 2, a mitochondrion-specific thioredoxin whose role in diabetes was unknown, was suppressed in the aorta from rats with two weeks of diabetes. When thioredoxin 2 expression in human umbilical vein endothelial cells was knocked-down by small interfering RNA, high-ambient glucose-elicited substantial injurious effects (n=5 to 9,
P
<0.05), including increases in cytosolic cytochrome c (by 2.2±0.6-fold), lipid peroxidation (by 40±8%), fibronectin expression (by 35±7%), and oxidized glutathione, and decreases in endothelial nitric oxide synthase expression (by 79±15%), basal accumulation of nitrite/nitrate (by 68±16%), total free thiols (by 42±8%), and glutathione (by 6±1%). In the absence of thioredoxin 2 knockdown, high-ambient glucose did not have significant effects on any of these measurements. The effect of thioredoxin 2 knockdown appeared to be associated with increases in glucose consumption and glucose transporter 1 expression.

Conclusion—

These results provided the first expression profile of thiol-related genes in a model of diabetes and demonstrated a novel role for endogenous thioredoxin 2 in protecting cells against high ambient glucose.
Extracellular Matrix–Bound Angiopoietin-Like 4 Inhibits Endothelial Cell Adhesion, Migration, and Sprouting and Alters Actin Cytoskeleton
Authors: Cazes Aurélie , Galaup Ariane , Chomel Clémence , Bignon Marine , Bréchot Nicolas , Le Jan Sébastien , Weber Holger , Corvol Pierre , Muller Laurent , Germain Stéphane , Monnot Catherine
Published: October 2006

Angiopoietin-like 4 (ANGPTL4) is a secreted protein that belongs to the angiopoietin family and is involved in angiogenesis and metabolism regulation. We previously reported the induction of
angptl4
by hypoxia in endothelial cells and in human ischemic tissues from peripheral artery disease. We here observed in a mouse model of hindlimb ischemia that the mRNA upregulation in the vessels correlates with the accumulation of the full-length protein in ischemic tissues. We then investigated its functions in endothelial cells. In response to hypoxia, endogenous ANGPTL4 accumulates in the subendothelial extracellular matrix (ECM). Although the secreted protein undergoes proteolysis leading to truncated fragments present in the medium, only full-length ANGPTL4 interacts with the ECM. Competition and direct binding assays indicate that the strong interaction of ANGPTL4 with the ECM is heparin/heparan sulfate proteoglycan dependent. The balance between matrix-associated and soluble forms of ANGPTL4 points to the role of the ECM in the regulation of its bioavailability. The angiogenic function of the ECM-bound full-length protein was investigated using either the form associated with the conditioned ECM from ANGPTL4-transfected HEK293 cells or the purified immobilized protein. We show that matrix-associated and immobilized ANGPTL4 limit the formation of actin stress fibers and focal contacts in the adhering endothelial cells and inhibit their adhesion. Immobilized ANGPTL4 also decreases motility of endothelial cells and inhibits the sprouting and tube formation. Altogether, these findings show that hypoxic endothelial cells accumulate ANGPTL4 in the ECM, which in turn negatively regulates their angiogenic capacities through an autocrine pathway.
Oxyhemoglobin-Induced Suppression of Voltage-Dependent K
+
Channels in Cerebral Arteries by Enhanced Tyrosine Kinase Activity
Authors: Ishiguro Masanori , Morielli Anthony D. , Zvarova Katarina , Tranmer Bruce I. , Penar Paul L. , Wellman George C.
Published: October 2006

Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) has devastating consequences. Oxyhemoglobin (oxyhb) has been implicated in SAH-induced cerebral vasospasm as it causes cerebral artery constriction and increases tyrosine kinase activity. Voltage-dependent, Ca
2+
-selective and K
+
-selective ion channels play an important role in the regulation of cerebral artery diameter and represent potential targets of oxyhb. Here we provide novel evidence that oxyhb selectively decreases 4-aminopyridine sensitive, voltage-dependent K
+
channel (K
v
) currents by ≈30% in myocytes isolated from rabbit cerebral arteries but did not directly alter the activity of voltage-dependent Ca
2+
channels or large conductance Ca
2+
-activated (BK) channels. A combination of tyrosine kinase inhibitors (tyrphostin AG1478, tyrphostin A23, tyrphostin A25, genistein) abolished both oxyhb-induced suppression of K
v
channel currents and oxyhb-induced constriction of isolated cerebral arteries. The K
v
channel blocker 4-aminopyridine also inhibited oxyhb-induced cerebral artery constriction. The observed oxyhb-induced decrease in K
v
channel activity could represent either channel block, or a decrease in K
v
channel density on the plasma membrane. To explore whether oxyhb altered trafficking of K
v
channels to the plasma membrane, we used an antibody generated against an extracellular epitope of K
v
1.5 channels. In the presence of oxyhb, staining of K
v
1.5 on the plasma membrane surface was markedly reduced. Furthermore, oxyhb caused a loss of spatial distinction between staining with K
v
1.5 and the general anti-phosphotyrosine antibody PY-102. We propose that oxyhb-induced suppression of K
v
currents occurs via a mechanism involving enhanced tyrosine kinase activity and channel endocytosis. This novel mechanism may contribute to oxyhb-induced cerebral artery constriction following SAH.
The Calcium Paradoxon of Renin Release
Authors: Grünberger Christian , Obermayer Birgit , Klar Jürgen , Kurtz Armin , Schweda Frank
Published: October 2006

An increase in the free intracellular calcium concentration promotes exocytosis in most secretory cells. In contrast, renin release from juxtaglomerular (JG) cells is suppressed by calcium. The further downstream signaling cascades of this so called “calcium paradoxon” of renin secretion have been incompletely defined. Because cAMP is the main intracellular stimulator of renin release, we hypothesized that calcium might exert its suppressive effects on renin secretion via the inhibition of the calcium-regulated adenylate cyclases AC5 and AC6. In primary cultures of JG cells, calcium-dependent inhibitors of renin release (angiotensin II, endothelin-1, thapsigargin) suppressed renin secretion, which was paralleled by decreases in intracellular cAMP levels [cAMP]. When [cAMP] was clamped by membrane permeable cAMP derivates, renin release was not suppressed by any of the calcium liberators. Additionally, both endothelin and thapsigargin suppressed cAMP levels and renin release in isoproterenol or forskolin-pretreated As4.1 cells, a renin-producing cell line that expresses AC5 and AC6. The calcium-dependent inhibition of intracellular cAMP levels and renin release was prevented by small interfering RNA-mediated knockdown of AC5 and/or AC6 expression, underlining the functional significance of these AC isoforms in renin-producing cells. Finally, in isolated perfused mouse kidneys, angiotensin II completely inhibited the stimulation of renin secretion induced by adenylate cyclase activation (isoproterenol) but not by membrane permeable cAMP analogs, supporting the conclusion that the suppressive effect of calcium liberators on renin release is mediated by inhibition of adenylate cyclase activity.
The Stroke–Thrombolytic Predictive Instrument
Authors: Kent David M. , Selker Harry P. , Ruthazer Robin , Bluhmki Erich , Hacke Werner
Published: October 2006

Background and Purpose—

Many patients with ischemic stroke eligible for recombinant tissue plasminogen activator (rt-PA) are not treated in part because of the risks and benefits perceived by treating physicians. Therefore, we aimed to develop a Stroke-Thrombolytic Predictive Instrument (TPI) to aid physicians considering thrombolysis for stroke.

Methods—

Using data from 5 major randomized clinical trials (n=2184) testing rt-PA in the 0- to 6-hour window, we developed logistic regression equations using clinical variables as potential predictors of a good outcome (modified Rankin Scale score ≤1) and of a catastrophic outcome (modified Rankin Scale score ≥5), with and without rt-PA. The models were internally validated using bootstrap re-sampling.

Results—

To predict good outcome, in addition to rt-PA treatment, 7 variables significantly affected prognosis and/or the treatment-effect of rt-PA: age, diabetes, stroke severity, sex, previous stroke, systolic blood pressure, and time from symptom onset. To predict catastrophic outcome, only age, stroke severity, and serum glucose were significant; rt-PA treatment was not. For patients treated within 3 hours, the median predicted probability of a good outcome with rt-PA was 42.9% (interquartile range [IQR]=18.6% to 64.7%) versus 25.3% (IQR=9.8% to 46.2%) without rt-PA; the median predicted absolute benefit was 12.5% (IQR=5.1% to 21.0%). The median probability for a catastrophic outcome, with or without, rt-PA was 15.2% (IQR=8.0% to 31.2%). The area under the receiver-operator characteristic curve was 0.788 for the model predicting good outcome and 0.775 for the model predicting bad outcome.

Conclusions—

The Stroke-TPI predicts good and bad functional outcomes with and without thrombolysis. Incorporated into a usable tool, it may assist in decision-making.
Additional Outcomes and Subgroup Analyses of NXY-059 for Acute Ischemic Stroke in the SAINT I Trial
Authors: Lees Kennedy R. , Davalos Antonio , Davis Stephen M. , Diener Hans-Christoph , Grotta James , Lyden Patrick , Shuaib Ashfaq , Ashwood Tim , Hardemark Hans-Goran , Wasiewski Warren , Emeribe Ugochi , Zivin Justin A.
Published: October 2006

Background and Purpose—

NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. We conducted analyses on additional end points and sensitivity analyses to confirm our findings.

Methods—

We randomized 1722 patients with acute ischemic stroke to a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The primary outcome was disability at 90 days, as measured by the modified Rankin Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5 (bed-bound, requiring constant care). Additional and exploratory analyses included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments of activities of daily living by Barthel index; and National Institutes of Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days.

Results—

NXY-059 significantly improved the distribution of the mRS disability score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test
P
=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01 to 1.42). The benefit was not attributable to any specific baseline characteristic, stratification variable or subgroup interaction. Neurological scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89;
P
=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI, 1.22, 1.98;
P
<0.0001; OR, 1.27; 95% CI, 1.01, 1.59;
P
=0.02).

Conclusions—

NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. Benefit on neurological scores and activities of daily living was detectable early but not significant at 90 days; however, our trial was underpowered to measure effects on the neurological examination. The benefit on disability is not confounded by interactions and is supported by other outcome measures.