bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical Characterization of a Family of Brain Lipids That Induce Sleep
Authors: Cravatt Benjamin F. , Prospero-Garcia Oscar , Siuzdak Gary , Gilula Norton B. , Henriksen Steven J. , Boger Dale L. , Lerner Richard A.
Published: October 2006

A molecule isolated from the cerebrospinal fluid of sleep-deprived cats has been chemically characterized and identified as
cis
-9,10-octadecenoamide. Other fatty acid primary amides in addition to
cis
-9,10-octadecenoamide were identified as natural constituents of the cerebrospinal fluid of cat, rat, and human, indicating that these compounds compose a distinct family of brain lipids. Synthetic
cis
-9,10-octadecenoamide induced physiological sleep when injected into rats. Together, these results suggest that fatty acid primary amides may represent a previously unrecognized class of biological signaling molecules.
Association of Increased Spontaneous Mutation Rates with High Levels of Transcription in Yeast
Authors: Datta Abhijit , Jinks-Robertson Sue
Published: October 2006

Complex processes such as transcription, replication, repair, and recombination require changes in chromatin structure and the interactions of numerous trans-acting factors with DNA sequences, raising the possibility that these processes may be interrelated. Here the effect of transcription on the rate of spontaneous mutation in the yeast
Saccharomyces cerevisiae
was examined. With the use of a
lys2
frameshift allele under the control of a highly inducible promoter, the rate of spontaneous reversion was shown to increase when the mutant gene was highly transcribed. Thus, transcriptionally active DNA and enhanced spontaneous mutation rates are associated in yeast.
Correction of Radiation Sensitivity in Ataxia Telangiectasia Cells by a Truncated IκB-α
Authors: Jung Mira , Zhang Yin , Lee Sung , Dritschilo Anatoly
Published: October 2006

Cells from patients with ataxia telangiectasia (AT) are hypersensitive to ionizing radiation and are defective in the regulation of DNA synthesis. A complementary DNA that corrects the radiation sensitivity and DNA synthesis defects in fibroblasts from an AT group D patient was isolated by expression cloning and shown to encode a truncated form of IκB-α, an inhibitor of the nuclear factor kappa B (NF-κB) transcriptional activator. The parental AT fibroblasts expressed large amounts of the IκB-α transcript and showed constitutive activation of NF-κB. The AT fibroblasts transfected with the truncated IκB-α expressed normal amounts of the IκB-α transcript and showed regulated activation of NF-κB. These results suggest that aberrant regulation of NF-κB and IκB-α contribute to the cellular defect in AT.
Segregation in DNA Solutions Induced by Electric Fields
Authors: Mitnik L. , Heller C. , Prost J. , Viovy J. L.
Published: October 2006

DNA solutions subjected to an electric field exhibit an instability that leads to DNA segregation in aggregates tilted with regard to the field. With the use of epifluorescence videomicroscopy, the evolution of DNA patterns in capillaries as a function of DNA concentration, DNA size, field strength, and field frequency was studied. The field threshold for segregation was decreased when the frequency was lowered or when the DNA molecular weight or concentration was increased. Aggregation is attributed to an electrohydrodynamic instability triggered by the dipole-dipole interaction. This phenomenon explains the failure of earlier attempts to separate large DNA in capillaries.
A Salt-Sensitive 3′(2′),5′-Bisphosphate Nucleotidase Involved in Sulfate Activation
Authors: Murguia Jose Ramón , Bellés Jose María , Serrano Ramón
Published: October 2006

Overexpression of a yeast gene, HAL2, allows the cells to tolerate higher than normal extracellular salt concentrations. HAL2 encodes a 3′(2′)5′-bisphosphate nucleotidase that serves to remove the end products of sulfate transfer during cellular metabolism. The enzyme is inhibited by lithium and sodium and is activated by potassium. Metabolic systems that are sensitive to salt, as well as those governing osmolyte synthesis and ion transport, offer routes by which genetic engineering can be used to improve the tolerance of various organisms to salt.
Measurement of Lactose Repressor-Mediated Loop Formation and Breakdown in Single DNA Molecules
Authors: Finzi Laura , Gelles Jeff
Published: October 2006

In gene regulatory systems in which proteins bind to multiple sites on a DNA molecule, the characterization of chemical mechanisms and single-step reaction rates is difficult because many chemical species may exist simultaneously in a molecular ensemble. This problem was circumvented by detecting DNA looping by the lactose repressor protein of
Escherichia coli
in single DNA molecules. The looping was detected by monitoring the nanometer-scale Brownian motion of microscopic particles linked to the ends of individual DNA molecules. This allowed the determination of the rates of formation and breakdown of a protein-mediated DNA loop in vitro. The measurements reveal that mechanical strain stored in the loop does not substantially accelerate loop breakdown, and the measurements also show that subunit dissociation of tetrameric repressor is not the predominant loop breakdown pathway.
The Functional Significance of Arm Movements in Neonates
Authors: van der Meer A. L. H. , van der Weel F. R. , Lee D. N.
Published: October 2006

Arm movements made by newborn babies are usually dismissed as unintentional, purposeless, or reflexive. Spontaneous arm-waving movements were recorded while newborns lay supine facing to one side. They were allowed to see only the arm they were facing, only the opposite arm on a video monitor, or neither arm. Small forces pulled on their wrists in the direction of the toes. The babies opposed the perturbing force so as to keep an arm up and moving normally, but only when they could see the arm, either directly or on the video monitor. The findings indicate that newborns can purposely control their arm movements in the face of external forces and that development of visual control of arm movement is underway soon after birth.
Cooperative Organization of Inorganic-Surfactant and Biomimetic Assemblies
Authors: Firouzi A. , Kumar D. , Bull L. M. , Besier T. , Sieger P. , Huo Q. , Walker S. A. , Zasadzinski J. A. , Glinka C. , Nicol J. , Margolese D. , Stucky G. D. , Chmelka B. F.
Published: October 2006

A model that makes use of the cooperative organization of inorganic and organic molecular species into three dimensionally structured arrays is generalized for the synthesis of nanocomposite materials. In this model, the properties and structure of a system are determined by dynamic interplay among ion-pair inorganic and organic species, so that different phases can be readily obtained through small variations of controllable synthesis parameters, including mixture composition and temperature. Nucleation, growth, and phase transitions may be directed by the charge density, coordination, and steric requirements of the inorganic and organic species at the interface and not necessarily by a preformed structure. A specific example is presented in which organic molecules in the presence of multiply charged silicate oligomers self-assemble into silicatropic liquid crystals. The organization of these silicate-surfactant mesophases is investigated with and without interfacial silicate condensation to separate the effects of self-assembly from the kinetics of silicate polymerization.
A Functionally Diverse Enzyme Superfamily that Abstracts the α Protons of Carboxylic Acids
Authors: Babbitt Patricia Clement , Mrachko Gregory T. , Hasson Miriam Sarah , Huisman Gjalt W. , Kolter Roberto , Ringe Dagmar , Petsko Gregory A. , Kenyon George L. , Gerlt John A.
Published: October 2006

Mandelate racemase and muconate lactonizing enzyme are structurally homologous but catalyze different reactions, each initiated by proton abstraction from carbon. The structural similarity to mandelate racemase of a previously unidentified gene product was used to deduce its function as a galactonate dehydratase. In this enzyme superfamily that has evolved to catalyze proton abstraction from carbon, three variations of homologous active site architectures are now represented: lysine and histidine bases in the active site of mandelate racemase, only a lysine base in the active site of muconate lactonizing enzyme, and only a histidine base in the active site of galactonate dehydratase. This discovery supports the hypothesis that new enzymatic activities evolve by recruitment of a protein catalyzing the same type of chemical reaction.
Absence of p350 Subunit of DNA-Activated Protein Kinase from a Radiosensitive Human Cell Line
Authors: Lees-Miller Susan P. , Godbout Roseline , Chan Doug W. , Weinfeld Michael , Day Rufus S. , Barron Geraldine M. , Allalunis-Turner Joan
Published: October 2006

The radiosensitive rodent mutant cell line
xrs
-5 is defective in DNA double-strand break repair and lacks the Ku component of the DNA-activated protein kinase, DNA-PK. Here radiosensitive human cell lines were analyzed for DNA-PK activity and for the presence of related proteins. The radiosensitive human malignant glioma M059J cell line was found to be defective in DNA double-strand break repair, but fails to express the p350 subunit of DNA-PK. These results suggest that DNA-PK kinase activity is involved in DNA double-strand break repair.
p53-Independent Expression of p21
Cip1
in Muscle and Other Terminally Differentiating Cells
Authors: Parker Susan B. , Eichele Gregor , Zhang Pumin , Rawls Alan , Sands Arthur T. , Bradley Allan , Olson Eric N. , Harper J. Wade , Elledge Stephen J.
Published: October 2006

Terminal differentiation is coupled to withdrawal from the cell cycle. The cyclin-dependent kinase inhibitor (CKI) p21
Cip1
is transcriptionally regulated by p53 and can induce growth arrest. CKIs are therefore potential mediators of developmental control of cell proliferation. The expression pattern of mouse p21 correlated with terminal differentiation of multiple cell lineages including skeletal muscle, cartilage, skin, and nasal epithelium in a p53-independent manner. Although the muscle-specific transcription factor MyoD is sufficient to activate p21 expression in 10T1/2 cells, p21 was expressed in myogenic cells of mice lacking the genes encoding MyoD and myogenin, demonstrating that p21 expression does not require these transcription factors. The p21 protein may function during development as an inducible growth inhibitor that contributes to cell cycle exit and differentiation.
Response of the Io Plasma Torus to Comet Shoemaker-Levy 9
Authors: McGrath M. A. , Hall D. T. , Matheson P. L. , Weaver H. A. , Trauger J. T. , Smith T. E. , Thomas N. , Gladstone R. , Schneider N. M. , Harris W. M. , Livengood T. A. , Prangé R. , Festou M. C.
Published: October 2006

Spectroscopic and imaging observations of the Io plasma torus were made in June and July 1994 in conjunction with the encounter of periodic comet Shoemaker-Levy 9 with Jupiter. Characteristic emissions from sulfur and oxygen ions showed a decline of about 30 percent in the extreme ultraviolet and an increase of about 40 percent in the far ultraviolet relative to preimpact observations. Changes in the extreme ultraviolet may be indicative of small changes in the torus electron temperature as a result of quenching of electrons by dust associated with the comet passage. However, no new emission features indicative of fragment dust within the torus were detected. The characteristic torus morphology seen in ground-based imaging was typical of that observed in the past.
Auroral Signature of Comet Shoemaker-Levy 9 in the Jovian Magnetosphere
Authors: Prangé R. , Engle I. M. , Clarke J. T. , Dunlop M. , Ballester G. E. , Ip W. H. , Maurice S. , Trauger J.
Published: October 2006

The electrodynamic interaction of the dust and gas comae of comet Shoemaker-Levy 9 with the jovian magnetosphere was unique and different from the atmospheric effects. Early theoretical predictions of auroral-type processes on the comet magnetic field line and advanced modeling of the time-varying morphology of these lines allowed dedicated observations with the Hubble Space Telescope Wide Field Planetary Camera 2 and resulted in the detection of a bright auroral spot. In that respect, this observation of the surface signature of an externally triggered auroral process can be considered as a "magnetospheric active experiment" on Jupiter.
The Fragment R Collision: W. M. Keck Telescope Observations of SL9
Authors: Graham James R. , de Pater Imke , Jernigan J. Garrett , Liu Michael C. , Brown Michael E.
Published: October 2006

The W. M. Keck telescope was used to observe the impact of comet Shoemaker-Levy 9 (SL9) fragment R at a wavelength of 2.3 micrometers on 21 July 1994. The data showed three outbursts. The first flash lasted about 40 seconds and was followed 1 minute after its peak by a second flash that lasted about 3 minutes. A third, longer lasting flare began 6 minutes after the first flash and lasted for 10 minutes. At its maximum brightness, the flare outshone Jupiter. The two short flashes are probably associated with the initial meteor trail and the subsequent fireball, respectively. The bright flare occurred when the impact site rotated into view. These data show that the explosion ejected material at least 1300 kilometers above the visible cloud tops. The luminosity of the impact site during the long bright flare was probably maintained by the release of gravitational potential energy, as this material fell back onto the lower atmosphere.
Control of IκB-α Proteolysis by Site-Specific, Signal-Induced Phosphorylation
Authors: Brown Keith , Gerstberger Susan , Carlson Louise , Franzoso Guido , Siebenlist Ulrich
Published: October 2006

IκB-α inhibits transcription factor NF-κB by retaining it in the cytoplasm. Various stimuli, typically those associated with stress or pathogens, rapidly inactivate IκB-α. This liberates NF-κB to translocate to the nucleus and initiate transcription of genes important for the defense of the organism. Activation of NF-κB correlates with phosphorylation of IκB-α and requires the proteolysis of this inhibitor. When either serine-32 or serine-36 of IκB-α was mutated, the protein did not undergo signal-induced phosphorylation or degradation, and NF-κB could not be activated. These results suggest that phosphorylation at one or both of these residues is critical for activation of NF-κB.
DNA Topoisomerase and Recombinase Activities in Nae I Restriction Endonuclease
Authors: Jo Kiwon , Topal Michael D.
Published: October 2006

Nae I endonuclease must bind to two DNA sequences for cleavage. Examination of the amino acid sequence of Nae I uncovered similarity to the active site of human DNA ligase I, except for leucine 43 in Nae I instead of the lysine essential for ligase activity. Changing leucine 43 to lysine 43 (L43K) changed Nae I activity: Nae I-L43K relaxed supercoiled DNA to yield DNA topoisomers and recombined DNA to give dimeric molecules. Interruption of the reactions of Nae I and Nae I-L43K with DNA demonstrated transient protein-DNA covalent complexes. These findings imply coupled endonuclease and ligase domains and link Nae I endonuclease to the topoisomerase and recombinase protein families.
Assessment of the Cardiff nephrectomy cut-up protocol with total blocking of the renal sinus: effect on tumour staging and practical issues
Authors: Soilleux E J , Roberts I S D
Published: October 2006

Aim:To evaluate the effects on detection of vascular invasion and workload of a new standard dissection protocol for examining nephrectomy specimens for renal cell carcinoma.

Methods:Using 192 consecutive renal cell carcinoma nephrectomy specimens, the incidence of vascular invasion and number of tissue blocks per tumour were compared before and after introduction of the new protocol.

Results:The Cardiff protocol increased the percentage of tumours staged as T3b (renal sinus or hilar vein invasion) from 37.7% to 55.7% cases (p<0.001), with an increase from 9.1% to 21.7% of those staged as T3b due to renal sinus vein invasion alone (p<0.01). A small, but significant, permanent increase in workload was observed from an average of 11.7 to 13.4 blocks per case (p<0.001).

Conclusions:This protocol is suitable for use in routine practice to evaluate pathological prognostic determinants important for clinical management, while causing only a small increase in workload.
EFFECTS OF A MIXED VECTOR–SCALAR SCREENED COULOMB POTENTIAL FOR SPINLESS PARTICLES
Authors: DE CASTRO ANTONIO S.
Published: October 2006

The problem of a spinless particle subject to a general mixing of vector and scalar screened Coulomb potentials in a two-dimensional world is analyzed and its bounded solutions are found. Some unusual results, including the existence of a bona fide solitary zero-eigenmode solution, are revealed for the Klein–Gordon equation. The cases of pure vector and scalar potentials, already analyzed in previous works, are obtained as particular cases.
AXIAL VECTOR CURRENT MATRIX ELEMENTS AND QCD SUM RULES
Authors: PASUPATHY J. , SINGH RITESH K.
Published: October 2006

The matrix element of the isoscalar axial vector current, [Formula: see text], between nucleon states is computed using the external field QCD sum rule method. The external field induced correlator, [Formula: see text], is calculated from the spectrum of the isoscalar axial vector meson states. Since it is difficult to ascertain, from QCD sum rule for hyperons, the accuracy of validity of flavor SU(3) symmetry in hyperon decays when strange quark mass is taken into account, we rely on the empirical validity of Cabbibo theory to determine the matrix element [Formula: see text] between nucleon states. Combining with our calculation of [Formula: see text] and the well-known nucleon β-decay constant allows us to determine [Formula: see text] occurring in the Bjorken sum rule. The result is in reasonable agreement with experiment. We also discuss the role of the anomaly in maintaining flavor symmetry and validity of OZI rule.
QUANTUM GEOMETRY AND ITS IMPLICATIONS FOR BLACK HOLES
Authors: BOJOWALD MARTIN
Published: October 2006

General relativity successfully describes space–times at scales that we can observe and probe today, but it cannot be complete as a consequence of singularity theorems. For a long time, there have been indications that quantum gravity will provide a more complete, non-singular extension which, however, was difficult to verify in the absence of a quantum theory of gravity. By now there are several candidates which show essential hints as to what a quantum theory of gravity may look like. In particular, loop quantum gravity is a non-perturbative formulation which is background independent, two properties which are essentially close to a classical singularity with strong fields and a degenerate metric. In cosmological and black hole settings, one can indeed see explicitly how classical singularities are removed by quantum geometry: there is a well-defined evolution all the way down to, and across, the smallest scales. As for black holes, their horizon dynamics can be studied showing characteristic modifications to the classical behavior. Conceptual and physical issues can also be addressed in this context, providing lessons for quantum gravity in general. Here, we conclude with some comments on the uniqueness issue often linked to quantum gravity in some form or another.
THE BLACK HOLE HORIZON AS A DYNAMICAL SYSTEM
Authors: 't HOOFT GERARD
Published: October 2006

Interactions between outgoing Hawking particles and ingoing matter are determined by gravitational forces and Standard Model interactions. In particular, the gravitational interactions are responsible for the unitarity of the scattering against the horizon, as dictated by the holographic principle, but the Standard Model interactions also contribute, and understanding their effects is an important first step towards a complete understanding of the horizon's dynamics. The relation between in- and outgoing states is described in terms of an operator algebra. In this contribution, in which earlier results are rederived and elaborated upon, we first describe the algebra induced on the horizon by U(1) vector fields and scalar fields, including the case of an Englert–Brout–Higgs mechanism, and a more careful consideration of the transverse vector field components.

We demonstrate that, unlike classical black holes, the quantized black hole has on its horizon an imprint of its (recent) past history, i.e., quantum hair. The relation between in- and outgoing states depends on this imprint. As a first step towards the inclusion of non-Abelian interactions, we then compute the effects of magnetic monopoles both in the in-states and in the out-states. They completely modify, and indeed simplify, our algebra.
MAXIMAL SUPERGRAVITIES AND THE E10 COSET MODEL
Authors: KLEINSCHMIDT AXEL , NICOLAI HERMANN
Published: October 2006

The maximal rank hyperbolic Kac–Moody algebra 𝔢10 has been conjectured to play a prominent role in the unification of duality symmetries in string and M-theory. We review some recent developments supporting this conjecture.
Mechanism of glucocorticoid regulation of the intestinal tight junction barrier
Authors: Boivin Michel A. , Ye Dongmei , Kennedy John C. , Al-Sadi Rana , Shepela Chris , Ma Thomas Y.
Published: October 2006

A defective intestinal epithelial tight junction (TJ) barrier has been proposed as an important pathogenic factor contributing to the intestinal inflammation of Crohn's disease. Glucocorticoids are first-line therapeutic agents for the treatment of moderate to severe Crohn's disease. Glucocorticoid treatment has been shown to induce retightening of the intestinal TJ barrier defect in Crohn's disease patients. However, the mechanisms that mediate the glucocorticoid therapeutic action on intestinal TJ barrier function remain unknown. The aim of this study was to elucidate the mechanism of glucocorticoid modulation of the intestinal epithelial TJ barrier using an in vitro model system. Filter-grown Caco-2 intestinal epithelial cells were used as an in vitro model to examine the effects of glucocorticoids on basal intestinal epithelial TJ barrier function and on TNF-α-induced disruption of the TJ barrier. Glucocorticoids (prednisolone and dexamethasone) did not have a significant effect on baseline Caco-2 TJ barrier function but prevented the TNF-α-induced increase in Caco-2 TJ permeability. The glucocorticoid protective effect against the TNF-α-induced increase in Caco-2 TJ permeability required activation of the glucocorticoid receptor (GR) complex. The activation of the GR complex resulted in GR complex binding to the glucocorticoid response element (GRE) site on DNA and activation of a GR-responsive promoter. Glucocorticoids inhibited the TNF-α-induced increase in myosin light chain kinase (MLCK) protein expression, a key process mediating the TNF-α increase in intestinal TJ permeability. The glucocorticoid inhibition of the TNF-α-induced increase in MLCK protein expression was due to the binding of the GR complex to a GRE binding site on the MLCK promoter region suppressing the TNF-α-induced activation. Glucocorticoids inhibit the TNF-α-induced increase in Caco-2 TJ permeability. The prednisolone protective action was mediated by binding of activated GR complex to the GRE site on the MLCK promoter, suppressing the TNF-α-induced increase in MLCK gene activity, protein expression, and subsequent opening of the intestinal TJ barrier.
Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure
Authors: Graham H. K. , Trafford A. W.
Published: October 2006

The cardiac extracellular matrix (ECM) maintains the structural and mechanical integrity of the myocardium. We determined the alterations in the composition of the ECM coincident with the transition from compensated left ventricular (LV) hypertrophy (LVH) to symptomatic congestive heart failure (CHF) and the mechanisms underlying such changes. Heart failure was induced in ferrets by aortic banding. Myocardial collagen content was assessed by HPLC and histological analysis. Matrix metalloproteinase (MMP) activity and tissue inhibitor of metalloproteinase (TIMP) expression were evaluated using gelatin zymography and Western blotting, respectively. LV free wall thickness increased by 29% in asymptomatic LVH and was associated with a 20% increase in interstitial fibrosis ( P < 0.05). CHF was coincident with increased plasma angiotensin II levels (149 ± 48, 40 ± 19, and 5.6 ± 1 pg/ml for CHF, LVH, and sham, respectively; P < 0.01, CHF vs. sham and LVH), ventricular dilatation (LV internal diameter = 15 ± 0.4 vs. 9 ± 0.1 mm, P < 0.05), increased active MMP-9 (3.0- and 2.2-fold increase over sham and LVH, respectively, n = 5–10 animals per group, P < 0.01), and reduced myocardial total collagen content (3.5 ± 0.4, 2.6 ± 0.3, and 2.2 ± 0.3% in sham, LVH, and CHF, respectively, P < 0.05). In CHF the distribution of collagen was markedly altered, becoming punctate in nature. No difference in MMP-2 activity, TIMP-1, TIMP-2, TIMP-3, or TIMP-4 expression, or collagen cross-linking was found at any time. The present work demonstrates structural reorganization and loss of collagen from cardiac ECM during the transition to decompensated CHF. The enhanced MMP-9 activity coincident with the transition to CHF provides potential therapeutic opportunities for managing the progression from asymptomatic LVH to symptomatic CHF.
Vasoconstriction seen in coronary bypass grafts during handgrip in humans
Authors: Momen Afsana , Gahremanpour Amir , Mansoor Ather , Kunselman Allen , Blaha Cheryl , Pae Walter , Leuenberger Urs A. , Sinoway Lawrence I.
Published: October 2006

In animal studies, sympathetically mediated coronary vasoconstriction has been demonstrated during exercise. Human studies examining coronary artery dynamics during exercise are technically difficult to perform. Recently, noninvasive transthoracic Duplex ultrasound studies demonstrated that 1) patients with left internal mammary artery (LIMA) grafts to the left anterior descending artery can be imaged and 2) the LIMA blood flow patterns are similar to those seen in normal coronary arteries. Accordingly, subjects with LIMA to the left anterior descending artery were studied during handgrip protocols as blood flow velocity in the LIMA was determined. Beat-by-beat analysis of changes in diastolic coronary blood flow velocity (CBV) was performed in six male clinically stable volunteers (60 ± 2 yr) during two handgrip protocols. Arterial blood pressure (BP) and heart rate (HR) were also measured, and an index of coronary vascular resistance (CVR) was calculated as diastolic BP/CBV. Fatiguing handgrip performed at [40% of maximal voluntary contraction (MVC)] followed by circulatory arrest did not evoke an increase in CVR ( P = not significant). In protocol 2, short bouts of handgrip (15 s) led to increases in CVR (18 ± 3% at 50% MVC and 20 ± 8% at 70% MVC). BP was also increased during handgrip. Our results reveal that in conscious humans, coronary vasoconstriction occurs within 15 s of onset of static handgrip at intensities at or greater than 50% MVC. These responses are likely to be due to sympathetic vasoconstriction of the coronary circulation.
Acute and conditioned hypoxic tolerance augmented by endothelial nitric oxide synthase inhibition in mice
Authors: Song Michael Y. , Zwemer Charles F. , Whitesall Steven E. , D'Alecy Louis G.
Published: October 2006

To identify a possible role for nitric oxide (NO) in acute hypoxic tolerance (HT) we measured hypoxic survival time (HST), effect of hypoxic conditioning (HC), and survival following hypoxic conditioning while blocking or mimicking the action of nitric oxide synthase (NOS). To inhibit NOS, CD-1 mice were given supplemental endogenous NOS inhibitor asymmetrical dimethylarginine (ADMA) or a synthetic NOS inhibitor Nω-nitro-l-arginine (l-NNA), both of which nonselectively inhibit three of the isoforms of NOS [inducible (iNOS), neuronal (nNOS), and endothelial NOS (eNOS)]. ADMA (10 mg/kg ip) or saline vehicle was given 5 min before HST testing. l-NNA was given orally at 1 g/l in drinking water with tap water as the control for 48 h before testing. Both ADMA and l-NNA significantly increased HST and augmented the HC effect on HST. Neither the nNOS selective inhibitor 7-nitroindazole (7-NI) nor the iNOS selective inhibitor N-{[3-(aminomethyl)phenyl]methyl}-enthanimidamide (1400W) had a statistically significant effect on HST or HT. The NO donor, 3-morpholinosydnoeimine, when given alone did not significantly decrease HT, but it did mitigate the increased HT effect of l-NNA. These data confirm that acute hypoxic conditioning increases HT and that NOS inhibition by endogenous (ADMA) and a synthetic NOS inhibitor (l-NNA) further increases HT, whereas iNOS and nNOS inhibition does not, suggesting that it is the inhibition of eNOS that mediates enhancement of HT.
Allowing for Missing Data at Highly Polymorphic Genes when Testing for Maternal, Offspring and Maternal-Fetal Genotype Incompatibility Effects
Authors: Hsieh Hsin-Ju , Palmer Christina G.S. , Sinsheimer Janet S.
Published: October 2006

Genes can be associated with disease through an individual’s inherited genotype, the maternal genotype or the interaction between these two. When the gene is highly polymorphic, it is more difficult to identify the gene’s functional role than for less polymorphic loci, because different alleles at the locus may be associated with the disease through separate and joint effects from maternal and offspring genotypes. Family-based studies are used to test genetic associations because of their robustness to population stratification. However, parental genotype data are often missing, and omitting incompletely genotyped families is inefficient. Methods have been proposed to accommodate incomplete families in family-based association studies. They are not easily generalized to allow simultaneous examination of offspring allelic, maternal allelic and maternal-fetal genotype (MFG) incompatibility effects. Since many MFG incompatibility effects occur through matching between maternal and offspring’s genotypes, we present an identity-by-state (IBS) framework to incorporate incomplete families in the MFG test when modeling genetic effects produced by a polymorphic gene. Using simulations, we examine the MFG test’s performance with incomplete parental genotype data and an IBS framework. The MFG test using the IBS framework is immune to population stratification and efficiently uses information from incomplete families.
Long-Term Efficacy and Safety of Celecoxib in Alzheimer’s Disease
Authors: Soininen Hilkka , West Christine , Robbins Jeffery , Niculescu Liviu
Published: October 2006

Background/Aims: Cyclooxygenase-2 (COX-2) may play an important role in the neuropathology of Alzheimer’s disease (AD). The efficacy and safety of celecoxib (200 mg bid), a COX-2 selective inhibitor, were assessed in patients ≧50 years with established mild-to-moderate AD to determine whether treatment was effective in retarding deterioration of cognitive function. Methods: This was a 52-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The primary efficacy end points were the change from baseline to week 52 in the Alzheimer’s Disease Assessment Scale-Cognitive Behavior (ADAS-cog) composite score and the week 52 Clinician’s Interview-Based Impression of Change Plus (CIBIC+). Results: At 52 weeks, change in ADAS-cog scores from baseline was similar for placebo and celecoxib 200 mg bid groups (5.00 and 4.39, respectively). CIBIC+ scores were also similar (4.83 and 4.92). Two extension studies were conducted but were terminated early based on these efficacy results. Safety data from all 3 studies indicated that celecoxib was generally well-tolerated. Conclusion: Celecoxib 200 mg bid did not slow the progression of AD in this study, and the occurrence of adverse events was as expected for an elderly population with a complex chronic medical condition.
Serum Trefoil Factors in Patients with Inflammatory Bowel Disease
Authors: Grønbæk Henning , Vestergaard Else Marie , Hey Henrik , Nielsen Jens Nederby , Nexø Ebba
Published: October 2006

Background: Trefoil factors (TFF1–3) play a critical role in mucosal protection and repair in the gastrointestinal tract. The aims of the present study were to examine associations between serum TFF1–3 and clinical and biochemical markers reflecting disease activity and to examine changes in TFF1–3 in patients with inflammatory bowel disease (IBD) before and during high-dose prednisolone treatment and tapering.Methods: Serum concentrations of TFF1–3 were quantified in 48 ulcerative colitis (UC) and 50 Crohn’s disease (CD) patients with little or moderate activity. Additionally, serum TFF concentrations were determined in patients with severe activity in colon IBD (4 UC and 6 CD) before and during prednisolone treatment with 7 healthy subjects as controls. Results: Median concentrations of TFF1, TFF2, and TFF3 were significantly increased in IBD patients compared with healthy controls (p < 0.01). TFF3 concentrations correlated with clinical and biochemical parameters of disease activity in UC patients. In addition, a trend towards reduction in TFF concentrations during treatment with prednisolone and concomitant clinical and biochemical remission was observed. Conclusions: The present data support the concept that trefoil peptides are upregulated and may play a role in IBD mucosal protection and repair. In UC patients, TFF3 levels were increased in active disease levels correlated with disease activity indices. Due to a large variation, serum TFFs are not a potential marker for disease activity.
Epidemiological Features of Degenerative Brain Diseases as They Occurred in Yaounde Referral Hospitals over a 9-Year Period
Authors: Kengne Andre Pascal , Dzudie Anastase , Dongmo Louis
Published: October 2006

Objective and Methods: It was the aim of this study to determine the relative prevalence and characteristics of degenerative disorders of the main central nervous system in Cameroon. Medical files of neurological consultations of the two main teaching hospitals of Yaounde were considered for a 9-year period ranging from 1993 to 2001. Clinical and epidemiological data were recorded for each patient. Results: Degenerative brain disorders accounted for 3.9% of consultations during the study period. Of the 84 patients received for degenerative disorders, 62 (73.8%) were men. Their age ranged from 9 to 84 years, with a mean of 54.16 years. The main degenerative diseases recorded were the following: Parkinson disease (48.8%), chorea (20.2%), dementia (19%) and amyotrophic lateral sclerosis (12%). Conclusion: Degenerative brain disorders are not rare in our setting. The appropriate diagnosis and management in this environment may be compromised by the prohibitive cost of diagnostic facilities and the lack of qualified personnel.
Metabolic Syndrome and Cognitive Function: A Population-Based Follow-Up Study in Elderly Women
Authors: Komulainen Pirjo , Lakka Timo A. , Kivipelto Miia , Hassinen Maija , Helkala Eeva-Liisa , Haapala Irja , Nissinen Aulikki , Rauramaa Rainer
Published: October 2006

Objective: To test the hypothesis that metabolic syndrome predicts cognitive impairment, and to examine the association of single metabolic risk factors with cognitive functioning. Methods: Weperformed a 12-year follow-up study in a population-based sample of 101 women aged 60–70 years at baseline. Metabolic syndrome wasdefined by the National Cholesterol Education Program criteria (≧3 out of 5 risk factors). Global cognitive function was measured by the Mini-Mental State Examination both at baseline and follow-up. A detailed neuropsychological evaluation for memory and cognitive speed was performed at follow-up. Results: The prevalence of metabolic syndrome increased from 13% at baseline to 49% at follow-up (p < 0.001). Women with metabolic syndrome at baseline had a 4.27 (95% confidence interval: 1.02–17.90; p = 0.047) times higher risk of poor memory at follow-up after adjustment for age, education and depression. The increasing number of metabolic risk factors was associated with worsening of memory at follow-up (p = 0.034 for linear trend). Women with low baseline levels of high-density lipoprotein (HDL) cholesterol were more likely to have poor memory at follow-up than those with higher HDL levels (p = 0.028). The risk of having poor memory increased by 46.5% (95% confidence interval: 15–66%; p = 0.008) with 1 SD decrease in HDL cholesterol level. Conclusion: In elderly women, metabolic syndrome may be an important contributor to worsening of memory, which is an essential part of mild cognitive impairment.
Neuropsychological Performance Is Associated With Vascular Function in Patients With Atherosclerotic Vascular Disease
Authors: Moser David J. , Robinson Robert G. , Hynes Stephanie M. , Reese Rebecca L. , Arndt Stephan , Paulsen Jane S. , Haynes William G.
Published: October 2006

Objective—

We previously reported preliminary data (N=14) demonstrating a significant and positive relationship between forearm vascular function and neuropsychological performance in individuals with atherosclerotic vascular disease (AVD). The current study was conducted to confirm and extend those findings in a much larger, nonoverlapping sample.

Methods and Results—

Participants were 82 individuals with AVD, with no history of stroke, cardiac surgery, or dementia. Forearm vascular function was measured before and after brachial artery infusion of vasoactive agents (acetylcholine, nitroprusside, verapamil). Neuropsychological functioning was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status. Statistical analysis included multiple regression and partial correlations, controlling for education. Vascular function was significantly and positively associated with neuropsychological performance [R
2
change=0.116, F change (3,74)=3.72,
P
=0.015]. Follow-up analyses indicated that smooth muscle function was the aspect of vascular function most strongly associated with neuropsychological performance. Individual vascular risk factors were not significantly associated with neuropsychological performance when controlling for vascular function.

Conclusions—

Better vascular function is significantly associated with better neuropsychological performance in individuals with AVD. It is possible that this relationship exists in healthy elderly individuals as well, although this cannot be determined based on the existing data, because a healthy comparison group was not studied. With additional research, measures of vascular function might be useful in the early identification of individuals who are at greatest risk for developing vascular cognitive impairment.
Obligatory Role of Cardiac Nerves and α
1
-Adrenergic Receptors for the Second Window of Ischemic Preconditioning in Conscious Pigs
Authors: Kudej Raymond K. , Shen You-Tang , Peppas Athanasios P. , Huang Cheng-Hsiung , Chen Wei , Yan Lin , Vatner Dorothy E. , Vatner Stephen F.
Published: October 2006

We tested the hypothesis that cardiac nerves may mediate ischemic preconditioning. Pigs were chronically instrumented to measure aortic, left atrial and left ventricular pressures, and regional myocardial function (wall thickening). Hemodynamic variables, area at risk, and tissue blood flows (radioactive microspheres) were similar among groups. Myocardial infarct size following 60 minutes coronary artery occlusion and 4 days reperfusion, expressed as a fraction of the area at risk, was 42±4.0%, in innervated pigs and similar in pigs with regional cardiac denervation (CD, 41±2.5%). Infarct size in innervated pigs during the first window of preconditioning (first window) was markedly reduced (6±1.8%,
P
<0.01), as it was in the second window of preconditioning (second window) (16±3.3%,
P
<0.01). Although infarct size was still reduced in pigs with CD and first window preconditioning (9±1.8%,
P
<0.01), the protective effects of second window were abrogated in pigs with CD resulting in an infarct size of 38±5.6%. In another group of innervated pigs during pharmacological α
1
-adrenergic receptor (AR) blockade, infarct size was also not reduced during the second window (48±3.2%). Additionally, Western blot analysis of inducible nitric oxide synthase and cyclooxygenase-2 proteins demonstrated significant (
P
<0.05) upregulation following the second window in innervated pigs, but not in pigs with CD or α
1
-AR blockade. Thus, the mechanism of protection during the second window, but not the first window, appears to be dependent on cardiac nerves and α
1
-AR stimulation.
Long-Term Effect of Intra-Arterial Thrombolysis in Stroke
Authors: Nedeltchev Krassen , Fischer Urs , Arnold Marcel , Ballinari Pietro , Haefeli Tobias , Kappeler Liliane , Brekenfeld Caspar , Remonda Luca , Schroth Gerhard , Mattle Heinrich P.
Published: October 2006

Background and Purpose—

Thrombolysis has been shown to improve the 3-month outcome of patients with ischemic stroke, but knowledge of the long-term effect of thrombolysis is limited.

Methods—

The present study compares the long-term outcome of stroke patients who were treated with intra-arterial thrombolysis (IAT) using urokinase with the outcome of patients treated with aspirin. The modified Rankin Scale (mRS) was used to assess the outcome; 173 patients treated with IAT and 261 patients treated with aspirin from the Bernese Stroke Data Bank were eligible for the study. A matching algorithm taking into account patient age and stroke severity on admission (as measured by the National Institute of Health Stroke Scale [NIHSS]) was used to assemble an IAT and an aspirin group.

Results—

One hundred and forty-four patients treated with IAT and 147 patients treated with aspirin could be matched and included in the comparative analysis. The median NIHSS score was 14 in each group. At 2 years, 56% of the patients treated with IAT and 42% of the patients treated with aspirin achieved functional independence (mRS, 0 to 2;
P
=0.037). Clinical outcome was excellent (mRS, 0 to 1) in 40% of the IAT and in 24% of the aspirin patients (
P
=0.008). Mortality was 23% and 24%, respectively.

Conclusions—

The present study provides evidence for a sustained effect of IAT when assessed 2 years after the stroke.
Humor Comprehension and Appreciation: An fMRI Study
Authors: Bartolo Angela , Benuzzi Francesca , Nocetti Luca , Baraldi Patrizia , Nichelli Paolo
Published: October 2006

Humor is a unique ability in human beings. Suls [A two-stage model for the appreciation of jokes and cartoons. In P. E. Goldstein & J. H. McGhee (Eds.), The psychology of humour. Theoretical perspectives and empirical issues. New York: Academic Press, 1972, pp. 81–100] proposed a two-stage model of humor: detection and resolution of incongruity. Incongruity is generated when a prediction is not confirmed in the final part of a story. To comprehend humor, it is necessary to revisit the story, transforming an incongruous situation into a funny, congruous one. Patient and neuroimaging studies carried out until now lead to different outcomes. In particular, patient studies found that right brain-lesion patients have difficulties in humor comprehension, whereas neuroimaging studies suggested a major involvement of the left hemisphere in both humor detection and comprehension. To prevent activation of the left hemisphere due to language processing, we devised a nonverbal task comprising cartoon pairs. Our findings demonstrate activation of both the left and the right hemispheres when comparing funny versus nonfunny cartoons. In particular, we found activation of the right inferior frontal gyrus (BA 47), the left superior temporal gyrus (BA 38), the left middle temporal gyrus (BA 21), and the left cerebellum. These areas were also activated in a nonverbal task exploring attribution of intention [Brunet, E., Sarfati, Y., Hardy-Bayle, M. C., & Decety, J. A PET investigation of the attribution of intentions with a nonverbal task. Neuroimage, 11, 157–166, 2000]. We hypothesize that the resolution of incongruity might occur through a process of intention attribution. We also asked subjects to rate the funniness of each cartoon pair. A parametric analysis showed that the left amygdala was activated in relation to subjective amusement. We hypothesize that the amygdala plays a key role in giving humor an emotional dimension.
Event-related Potential Signatures of Relational Memory
Authors: Hannula Deborah E. , Federmeier Kara D. , Cohen Neal J.
Published: October 2006

Various lines of evidence suggest that memory for the relations among arbitrarily paired items acquired prior to testing can influence early processing of a probe stimulus. The event-related potential experiment reported here was designed to explore how early in time memory for a previously established face-scene relationship begins to influence processing of faces, under sequential presentation conditions in which a preview of the scene can promote expectancies about the to-be-presented face. Prior to the current work, the earliest component documented to be sensitive to memory for the relations among arbitrarily paired items was the late positive complex (LPC), but here relational memory effects were evident as early as 270–350 msec after face onset. The latency of these relational memory effects suggests that they may be the precursor to similar effects observed in eye movement behavior. As expected, LPC amplitude was also affected by memory for face-scene relationships, and N400 amplitude reflected some combination of memory for items and memory for the relations among items.
Neuroanatomic Organization of Sound Memory in Humans
Authors: Kraut Michael A. , Pitcock Jeffery A. , Calhoun Vince , Li Juan , Freeman Thomas , Hart John
Published: October 2006

The neural interface between sensory perception and memory is a central issue in neuroscience, particularly initial memory organization following perceptual analyses. We used functional magnetic resonance imaging to identify anatomic regions extracting initial auditory semantic memory information related to environmental sounds. Two distinct anatomic foci were detected in the right superior temporal gyrus when subjects identified sounds representing either animals or threatening items. Threatening animal stimuli elicited signal changes in both foci, suggesting a distributed neural representation. Our results demonstrate both category- and feature-specific responses to nonverbal sounds in early stages of extracting semantic memory information from these sounds. This organization allows for these category-feature detection nodes to extract early, semantic memory information for efficient processing of transient sound stimuli. Neural regions selective for threatening sounds are similar to those of nonhuman primates, demonstrating semantic memory organization for basic biological/survival primitives are present across species.
Why You Think Milan is Larger than Modena: Neural Correlates of the Recognition Heuristic
Authors: Volz Kirsten G. , Schooler Lael J. , Schubotz Ricarda I. , Raab Markus , Gigerenzer Gerd , von Cramon D. Yves
Published: October 2006

When ranking two alternatives by some criteria and only one of the alternatives is recognized, participants overwhelmingly adopt the strategy, termed the recognition heuristic (RH), of choosing the recognized alternative. Understanding the neural correlates underlying decisions that follow the RH could help determine whether people make judgments about the RH's applicability or simply choose the recognized alternative. We measured brain activity by using functional magnetic resonance imaging while participants indicated which of two cities they thought was larger (Experiment 1) or which city they recognized (Experiment 2). In Experiment 1, increased activation was observed within the anterior frontomedian cortex (aFMC), precuneus, and retrosplenial cortex when participants followed the RH compared to when they did not. Experiment 2 revealed that RH decisional processes cannot be reduced to recognition memory processes. As the aFMC has previously been associated with self-referential judgments, we conclude that RH decisional processes involve an assessment about the applicability of the RH.