bluuebunny/crossref_metadata_2025 huggingface dataset:
Unitary IPSPs enhance hilar mossy cell gain in the rat hippocampus
Authors: Kerr Angharad M. , Capogna Marco
Published: November 2006

Mechanisms that control neuronal gain allow for adaptive rescaling to synaptic inputs of varying strengths or frequencies. Here, we show that unitary IPSPs (uIPSPs) modulate gain and unitary EPSP (uEPSP)‐action potential coupling in mossy cells (MCs) from rat hippocampal slices. Mossy fibre‐evoked uEPSCs were large, facilitated and were suppressed by the group II metabotropic glutamate agonist LY354740. Conversely, uIPSCs were smaller, depressed and were not affected by LY354740, but exerted strong inhibitory control over uEPSP‐action potential coupling. The IPSC reversal potential was determined by gramicidin perforated patch recordings to be −65.3 ± 5.0 mV, lying between the resting membrane potential (−75.3 ± 1.1 mV) and the action potential threshold (−56.5 ± 2.4 mV). When applied at theta frequency (10 Hz), uIPSPs increased the offset of the MC input–output response to depolarizing current injection, but also increased gain, maximal firing rate and the slope of the depolarization preceding action potentials. These effects were unchanged by the Ca2+ and HCN channel blockers mibefradil and ZD7288, respectively. The height and maximal slope of MC action potentials during tonic depolarization were also increased by uIPSPs, and the decay of uIPSP conductances injected by dynamic clamp at subthreshold membrane potentials was prolonged by TTX. Application of the muscarinic agonist pilocarpine mimicked the effect of IPSPs on MC maximal firing rate, and action potential height and slope, and this was reversed by the GABAA antagonist gabazine. Thus, uIPSPs can increase neuronal gain under hyperexcitable conditions, and this effect is probably due to the de‐inactivation of a TTX‐sensitive voltage‐dependent Na+ conductance.
Where Water Is Oxidized to Dioxygen: Structure of the Photosynthetic Mn
4
Ca Cluster
Authors: Yano Junko , Kern Jan , Sauer Kenneth , Latimer Matthew J. , Pushkar Yulia , Biesiadka Jacek , Loll Bernhard , Saenger Wolfram , Messinger Johannes , Zouni Athina , Yachandra Vittal K.
Published: November 2006

The oxidation of water to dioxygen is catalyzed within photosystem II (PSII) by a Mn
4
Ca cluster, the structure of which remains elusive. Polarized extended x-ray absorption fine structure (EXAFS) measurements on PSII single crystals constrain the Mn
4
Ca cluster geometry to a set of three similar high-resolution structures. Combining polarized EXAFS and x-ray diffraction data, the cluster was placed within PSII, taking into account the overall trend of the electron density of the metal site and the putative ligands. The structure of the cluster from the present study is unlike either the 3.0 or 3.5 angstrom–resolution x-ray structures or other previously proposed models.
Imaging the Sublimation Dynamics of Colloidal Crystallites
Authors: Savage J. R. , Blair D. W. , Levine A. J. , Guyer R. A. , Dinsmore A. D.
Published: November 2006

We studied the kinetics of sublimating crystals with single-particle resolution by experiments with colloidal spheres and by computer simulations. A short-range attraction between spheres led to crystallites one to three layers thick. The spheres were tracked with optical microscopy while the attraction was reduced and the crystals sublimated. Large crystallites sublimated by escape of particles from the perimeter. The rate of shrinkage was greatly enhanced, however, when the size decreased to less than 20 to 50 particles, depending on the location in the phase diagram. At this size, the crystallites transformed into a dense amorphous structure, which rapidly vaporized. The enhancement of kinetics by metastable or unstable phases may play a major role in the melting, freezing, and annealing of crystals.
Phytoplankton and Cloudiness in the Southern Ocean
Authors: Meskhidze Nicholas , Nenes Athanasios
Published: November 2006

The effect of ocean biological productivity on marine clouds is explored over a large phytoplankton bloom in the Southern Ocean with the use of remotely sensed data. Cloud droplet number concentration over the bloom was twice what it was away from the bloom, and cloud effective radius was reduced by 30%. The resulting change in the short-wave radiative flux at the top of the atmosphere was –15 watts per square meter, comparable to the aerosol indirect effect over highly polluted regions. This observed impact of phytoplankton on clouds is attributed to changes in the size distribution and chemical composition of cloud condensation nuclei. We propose that secondary organic aerosol, formed from the oxidation of phytoplankton-produced isoprene, can affect chemical composition of marine cloud condensation nuclei and influence cloud droplet number. Model simulations support this hypothesis, indicating that 100% of the observed changes in cloud properties can be attributed to the isoprene secondary organic aerosol.
FG-Rich Repeats of Nuclear Pore Proteins Form a Three-Dimensional Meshwork with Hydrogel-Like Properties
Authors: Frey Steffen , Richter Ralf P. , Görlich Dirk
Published: November 2006

Nuclear pore complexes permit rapid passage of cargoes bound to nuclear transport receptors, but otherwise suppress nucleocytoplasmic fluxes of inert macromolecules ≥30 kilodaltons. To explain this selectivity, a sieve structure of the permeability barrier has been proposed that is created through reversible cross-linking between Phe and Gly (FG)–rich nucleoporin repeats. According to this model, nuclear transport receptors overcome the size limit of the sieve and catalyze their own nuclear pore-passage by a competitive disruption of adjacent inter-repeat contacts, which transiently opens adjoining meshes. Here, we found that phenylalanine-mediated inter-repeat interactions indeed cross-link FG-repeat domains into elastic and reversible hydrogels. Furthermore, we obtained evidence that such hydrogel formation is required for viability in yeast.
Response to Comment on "Rapid Uplift of the Altiplano Revealed Through
13
C-
18
O Bonds in Paleosol Carbonates"
Authors: Eiler John , Garzione Carmala , Ghosh Prosenjit
Published: November 2006

Clumped-isotope thermometry measurements of carbonate samples deposited in the Bolivian Altiplano as early as 28.5 million years ago and buried up to ∼5000 meters deep exhibit no relationship between burial depth and apparent temperature, and largely yield temperatures within error of plausible Earth-surface conditions. These results counter the predictions of Sempere
et al
. and support our previous conclusions regarding the uplift of the Altiplano.
Analysis of 12C(α, α′) using α condensate model wave function
Authors: Takashina M. , Sakuragi Y.
Published: November 2006

We analyze the inelastic scattering of the α+12 C system leading to the [Formula: see text] state in 12 C at incident energies of E α=139 MeV ~ 240 MeV using α condensate model wave function, and investigate the affection of the large nuclear radius of [Formula: see text] on the inelastic angular distribution. It is found that the oscillation pattern in inelastic angular distribution is sensitive to the extent of transition density rather than the nuclear radius of the excited state.
3α resonance excited states of 12C in a microscopic cluster model
Authors: Arai Koji
Published: November 2006

Three-alpha resonance excited states has been theoretically explored by means of the α+α+α microscopic cluster model. The resonance parameters is determined by employing the Complex Scaling Method (CSM). Our model space is extended by including higher partial waves than the RGM+CSM calculation by Pichler1. Our model has given the third 0+ state at 4~5MeV above the three-body threshold but the broad 0+ state, which was recently reported experimentally and overlapping with the 2+ state2, has not been localized between the second and the third 0+ states. On the other hands, our model has given the second 2+ state about 2MeV and the third at 4~5MeV.
Spin-orbit splittings in 13C and 13N with the nature of the Hoyle state in 12C
Authors: YAMADA Taiichi , HORIUCHI Hisashi , SCHUCK Peter
Published: November 2006

The spin-orbit splittings of 13 C and 13 N corresponding to the ground state and second 0+ state (Hoyle state) in 12 C are investigated within a 12 C +N model. The agreement of the calculated results with experiments suggests that the [Formula: see text] and [Formula: see text] states around Ex = 9 ~ 10 MeV in 13 C and 13 N can be interpreted as the spin-orbit partner with the [Formula: see text] configuration. We also discuss the positive parity states (including [Formula: see text]) of 13 C and 13 N around the [Formula: see text] threshold, indicating to have the configuration of the Hoyle state in 12 C plus a valence nucleon in sd shell.
2α + t cluster state in11B
Authors: Kawabata T. , Akimune H. , Fujita H. , Fujiwara M. , Hara K. , Hatanaka K. , Nakanishi K. , Shimbara Y. , Tamii A. , Yoshida H. P. , Yosoi M. , Fujita Y. , Itoh M. , Kanada-En'yo Y. , Kishi S. , Sakaguchi H. , Terashima S. , Yasuda Y. , Uchida M. , Wakasa T.
Published: November 2006

The cluster structures of the excited states in11B are studied by analyzing the isoscalar monopole and quadrupole strengths in the11B (d,d′) reaction at Ed= 200 MeV . The excitation strengths are compared with the predictions by the shell-model and antisymmetrized molecular-dynamics (AMD) calculations. It is found that the large monopole strength for the [Formula: see text] state at Ex= 8.56 MeV is well described by the AMD calculation and is an evidence for a developed 2α + t cluster structure.
Three-center cluster states in 11C and 11B
Authors: Kanada-En'yo Yoshiko
Published: November 2006

Structures of excited states in 11 C and 11 B were studied based on variational calculations after spin-parity projection in a framework of antisymmetrized molecular dynamics (AMD). The calculations systematically reproduce experimental data of the transition strengths such as Gamov-Teller(GT) and M1 transitions. A well-developed cluster structure of 2α+3 He (t) was found in the [Formula: see text] state of 11 C (11 B ). We assigned this state to the observed [Formula: see text] state at 8 MeV. The calculations reproduce the small [Formula: see text] which has been measured in the recent experiments. It was found that the [Formula: see text] state has a dilute cluster state, and its features are similar to those of the [Formula: see text] which is considered to be a gas state of three α clusters.
Non-adiabatic dynamics in the α+6He scattering and the nuclear breakup of 10Be
Authors: Ito Makoto
Published: November 2006

The α+6 He low-energy reactions and the structural changes of 10 Be in the microscopic α+α+N+N model are studied by the generalized two-center cluster model with the Kohn-Hulthén-Kato variation method. It is found that, in the inelastic scattering to the [Formula: see text] channel, characteristic enhancements are expected as the results of the parity-dependent non-adiabatic dynamics. In the positive parity state, the enhancement originates from the excited eigenstate generated by the resonance pole of the final channel, while that in the negative parity state is induced by the Landau-Zener level-crossing. The reaction mechanism in breakup of 10 Be into the 5 He +5 He and α+6 He continuums is also studied. The strong enhancement in the breakup of [Formula: see text] is discussed in connection with the non-adiabatic dynamics.
MICROSCOPIC DI–NUCLEON CONDENSATE WAVE FUNCTION
Authors: TOHSAKI AKIHIRO
Published: November 2006

New treatments are proposed for di-nucleon condensate based on the α condensate wave function. A beautiful mathematical structure is shown for the overlap.
STUDY OF THE TENSOR CORRELATION IN THE MEAN-FIELD-TYPE MODEL AND THE SHELL MODEL
Authors: SUGIMOTO SATORU
Published: November 2006

We study the effect of the tensor correlation using a mean-field-type model and a shell model. To treat the tensor correlation in a mean-field-type model, we introduce single-particle states with the parity and charge mixing considering the pseudoscalar and isovector characters of the pion, which mediates the tensor force. We study closed-shell and sub-closed-shell oxygen isotopes and find that a sizable attractive energy from the tensor force is obtained by introducing the parity and charge mixing. We also perform a shell model calculation up to two-particle–two-hole configurations. A large attraction energy is obtained for 16 O when we introduce single-particle wave functions with narrow widths.
EXTENDED THREE-BODY ANALYSIS OF 11LI WITH TENSOR AND PAIRING CORRELATIONS
Authors: MYO TAKAYUKI , KATŌ KIYOSHI , TOKI HIROSHI , IKEDA KIYOMI
Published: November 2006

We investigate the tensor and pairing correlations in 11 Li based on the 9 Li +n+n model. For 9 Li , we perform the configuration mixing with the shell model type wave function to introduce the core polarization caused by the tensor and pairing correlations. For 11 Li , we perform the coupled 9 Li +n+n calculation, in which the couplings between the correlations in 9 Li and the motion of the last two neutrons emerge Pauli-blocking for the p2 configuration of 11 Li and increases the s2 component to develop the halo structure.
t+t clustering in He-isotopes
Authors: Aoyama S. , Itagaki N. , Arai K. , Katō K. , Oi M.
Published: November 2006

t+t clustering in He isotopes is investigated by using two theoretical approaches. A role of the t+t cluster component in the ground state is examined with AMD triple-S, allowing the wider configuration space containing simultaneously the "t+t+valence neutrons" structure and "4 He +valence neutrons" structure. We understand the importance of the t + t component even for the ground state. Further, t + t resonances are investigated with RGM type approach. We obtained many t + t states as resonances near to t + t threshold.
NEUTRON-NEUTRON CORRELATIONS IN HALO NUCLEI
Authors:   For the LPC-CHARISSA-DEMON collaboration., ORR NIGEL
Published: November 2006

Work aimed at probing the spatial configuration of the valence neutrons in two-neutron halo nuclei using the technique of intensity interferometry is described. Following a brief review of the method and its application to our first measurements of the breakup of 6 He , 11 Li and 14 Be , the results of the analysis of a high statistics data set for 6 He are presented.
DECOMPOSITION OF GEOMETRIC CONSTRAINT SYSTEMS: A SURVEY
Authors: JERMANN CHRISTOPHE , TROMBETTONI GILLES , NEVEU BERTRAND , MATHIS PASCAL
Published: November 2006

Significant progress has been accomplished during the past decades about geometric constraint solving, in particular thanks to its applications in industrial fields like CAD and robotics. In order to tackle problems of industrial size, many solving methods use, as a preprocessing, decomposition techniques that transform a large geometric constraint system into a set of smaller ones.

In this paper, we propose a survey of the decomposition techniques for geometric constraint problems . We classify them into four categories according to their modus operandi, establishing some similarities between methods that are traditionally separated. We summarize the advantages and limitations of the different approaches, and point out key issues for meeting industrial requirements such as generality and reliability.
SOLVING SPATIAL CONSTRAINTS WITH GLOBAL DISTANCE COORDINATE SYSTEM
Authors: YANG LU
Published: November 2006

A systematic approach making use of distance geometry to solve spatial constraints is introduced. We demonstrate how to create the constraint equations by means of a relevant distance coordinate system. A short program is made (in Maple) which implements the algorithm producing automatically a complete set of constraint equations for a given point-plane configuration. The point-line-plane configurations are converted into point-plane ones beforehand.
NON-CARTESIAN MODELLING FOR ANALYSIS OF THE CONSISTENCY OF A GEOMETRIC SPECIFICATION FOR CONCEPTUAL DESIGN
Authors: SERRÉ PHILIPPE , ORTUZAR AUXKIN , RIVIÈRE ALAIN
Published: November 2006

In preliminary project phases, designers generally prefer to express their ideas via 2D or 3D sketches. The scientific problem covered in this paper is that of the analysis of the consistency of a 3D geometric specification. Since traditional geometric Cartesian modelling does not permit easy analysis of consistency, we will present two non-Cartesian modellings: either by exclusively using points, and Cayley-Menger determinants will enable the relations between mutual distances to be written, or by using points and vectors, and Gram determinants will enable the relations between scalar products to be written. Finally, we will present the advantages of these two modellings in order to analyse the overall consistency of a specification.
WELL-FORMED SYSTEMS OF POINT INCIDENCES FOR RESOLVING COLLECTIONS OF RIGID BODIES
Authors: SITHARAM MEERA
Published: November 2006

For tractability, many modern geometric constraint solvers recursively decompose an input geometric constraint system into standard collections of smaller, generically rigid subsystems or clusters. These are recursively solved and their solutions or realizations are recombined to give the solution or realization of the input constraint system.

Even for generically wellconstrained systems in 3D, and even when the shared objects between clusters in the decomposition are restricted to be points, it is a significant hurdle to find a wellformed system of shared object incidences that recombines a cluster decomposition. By wellformed we mean that the recombination system generically preserves the classification of the original, undecomposed system as a well, under or overconstrained system.

Here we motivate, formally state and give an efficient, greedy algorithm to find such a wellformed system for a general constraint system, when the shared objects in the cluster decomposition are restricted to be points. Our solution relies on an interesting new matroid structure underlying collections of rigid clusters with shared points.
Dietary nitrate increases gastric mucosal blood flow and mucosal defense
Authors: Petersson Joel , Phillipson Mia , Jansson Emmelie Å. , Patzak Andreas , Lundberg Jon O. , Holm Lena
Published: November 2006

Salivary nitrate from dietary or endogenous sources is reduced to nitrite by oral bacteria. In the acidic stomach, nitrite is further reduced to bioactive nitrogen oxides, including nitric oxide (NO). In this study, we investigated the gastroprotective role of nitrate intake and of luminally applied nitrite against provocation with diclofenac and taurocholate. Mucosal permeability (51Cr-EDTA clearance) and gastric mucosal blood flow (laser-Doppler flowmetry) were measured in anesthetized rats, either pretreated with nitrate in the drinking water or given acidified nitrite luminally. Diclofenac was given intravenously and taurocholate luminally to challenge the gastric mucosa. Luminal NO content and nitrite content in the gastric mucus were determined by chemiluminescence. The effect of luminal administration of acidified nitrite on the mucosal blood flow was also investigated in endothelial nitric oxide synthase-deficient mice. Rats pretreated with nitrate or given nitrite luminally had higher gastric mucosal blood flow than controls. Permeability increased more during the provocation in the controls than in the nitrate- and nitrite-treated animals. Dietary nitrate increased luminal NO levels 50 times compared with controls. Nitrate intake also resulted in nitrite accumulation in the loosely adherent mucous layer; after removal of this mucous layer, blood flow was reduced. Nitrite administrated luminally in endothelial nitric oxide synthase-deficient mice increased mucosal blood flow. We conclude that dietary nitrate and direct luminal application of acidified nitrite decrease diclofenac- and taurocholate-induced mucosal damage. The gastroprotective effect likely involves a higher mucosal blood flow caused by nonenzymatic NO production. These data suggest an important physiological role of nitrate in the diet.
High-intensity exercise acutely decreases the membrane content of MCT1 and MCT4 and buffer capacity in human skeletal muscle
Authors: Bishop David , Edge Johann , Thomas Claire , Mercier Jacques
Published: November 2006

The regulation of intracellular pH during intense muscle contractions occurs via a number of different transport systems [e.g., monocarboxylate transporters (MCTs)] and via intracellular buffering (βmin vitro). The aim of this study was to investigate the effects of an acute bout of high-intensity exercise on both MCT relative abundance and βmin vitro in humans. Six active women volunteered for this study. Biopsies of the vastus lateralis were obtained at rest and immediately after 45 s of exercise at 200% of maximum O2 uptake. βmin vitro was determined by titration, and MCT relative abundance was determined in membrane preparations by Western blots. High-intensity exercise was associated with a significant decrease in both MCT1 (−24%) and MCT4 (−26%) and a decrease in βmin vitro (−11%; 135 ± 3 to 120 ± 2 μmol H+·g dry muscle−1·pH−1; P < 0.05). These changes were consistently observed in all subjects, and there was a significant correlation between changes in MCT1 and MCT4 relative abundance ( R2 = 0.92; P < 0.05). In conclusion, a single bout of high-intensity exercise decreased both MCT relative abundance in membrane preparations and βmin vitro. Until the time course of these changes has been established, researchers should consider the possibility that observed training-induced changes in MCT and βmin vitro may be influenced by the acute effects of the last exercise bout, if the biopsy is taken soon after the completion of the training program. The implications that these findings have for lactate (and H+) transport following acute, exhaustive exercise warrant further investigation.
Sex differences in left ventricular function and β-receptor responsiveness following prolonged strenuous exercise
Authors: Scott Jessica M. , Esch Ben T. A. , Haykowsky Mark J. , Isserow Saul , Koehle Michael S. , Hughes Bevan G. , Zbogar Dominik , Bredin Shannon S. D. , McKenzie Don C. , Warburton Darren E. R.
Published: November 2006

Sex differences in neuroendocrine and metabolic responses to prolonged strenuous exercise (PSE) have been well documented. The aim of this investigation was to examine sex differences in left ventricular function and cardiac β-receptor responsiveness following a single bout of PSE. Nine male and eight female triathletes were examined during three separate sessions: before, immediately after, and 24 h following a half-ironman triathlon using dobutamine stress echocardiography. Steady-state graded infusions of dobutamine were used to assess β-receptor responsiveness. Slopes calculated from linear regressions between dobutamine doses and changes in heart rate and contractility for each participant were used as an index of β-receptor responsiveness. Despite no change in preload, fractional area change decreased from baseline after the race in both men and women, with a greater decrease in men [men: 54.1% (SD 2.1) to 50.7% (SD 3.4) vs. women: 55.4% (SD 2.7) to 53.3% (SD 2.5); P < 0.05]. The amount of dobutamine necessary to increase heart rate by 25 beats/min [men: 29.6 μg·kg−1·min−1 (SD 6.6) to 42.7 μg·kg−1·min−1 (SD 12.9) vs. women: 23.5 μg·kg−1·min−1 (SD 4.0) to 30.0 μg·kg−1·min−1 (SD 7.8); P < 0.05] and contractility by 10 mmHg/cm2 [men: 20.9 μg·kg−1·min−1 (SD 5.1) to 37.0 μg·kg−1·min−1 (SD 11.5) vs. women: 22.6 μg·kg−1·min−1 (SD 6.4) to 30.7 μg·kg−1·min−1 (SD 7.2); P < 0.05] was greater in both men and women postrace. However, the amount of dobutamine required to induce these changes was greater in men, reflecting larger β-receptor alterations in male triathletes following PSE relative to women. These data suggest that following an acute bout of PSE, male triathletes demonstrate an attenuated chronotropic and inotropic response to β-adrenergic stimulation compared with female triathletes.
Uncoupling of upper airway motor activity from phrenic bursting by positive end-expired pressure in the rat
Authors: Lee Kun-Ze , Fuller David D. , Tung Li-Chu , Lu I-Jung , Ku Li-Chi , Hwang Ji-Chuu
Published: November 2006

Phasic bursting in the hypoglossal nerve can be uncoupled from phrenic bursting by application of positive end-expired pressure (PEEP). We wished to determine whether similar uncoupling can also be induced in other respiratory-modulated upper airway (UAW) motor outputs. Discharge of the facial, hypoglossal, superior laryngeal, recurrent laryngeal, and phrenic nerves was recorded in anesthetized, ventilated rats during stepwise changes in PEEP with a normocapnic, hyperoxic background. Application of 3- to 6-cmH2O PEEP caused the onset inspiratory (I) UAW nerve bursting to precede the phrenic burst but did not uncouple bursting. In contrast, application of 9- to 12-cmH2O PEEP uncoupled UAW neurograms such that rhythmic bursting occurred during periods of phrenic quiescence. Single-fiber recording experiments were conducted to determine whether a specific population of UAW motoneurons is recruited during uncoupled bursting. The data indicate that expiratory-inspiratory (EI) motoneurons remained active, while I motoneurons did not fire during uncoupled UAW bursting. Finally, we examined the relationship between motoneuron discharge rate and PEEP during coupled UAW and phrenic bursting. EI discharge rate was linearly related to PEEP during preinspiration, but showed no relationship to PEEP during inspiration. Our results demonstrate that multiple UAW motor outputs can be uncoupled from phrenic bursting, and this response is associated with bursting of EI nerve fibers. The relationship between PEEP and EI motoneuron discharge rate differs during preinspiratory and I periods; this may indicate that bursting during these phases of the respiratory cycle is controlled by distinct neuronal outputs.
Flat Dosing of Carboplatin Is Justified in Adult Patients with Normal Renal Function
Authors: Ekhart Corine , de Jonge Milly E. , Huitema Alwin D.R. , Schellens Jan H.M. , Rodenhuis Sjoerd , Beijnen Jos H.
Published: November 2006

Purpose: The Calvert formula is a widely applied algorithm for the a priori dosing of carboplatin based on patients glomerular filtration rate (GFR) as accurately measured using the 51Cr-EDTA clearance. Substitution of the GFR in this formula by an estimate of creatinine clearance or GFR as calculated by formulae using serum creatinine (SCR; Cockcroft-Gault, Jelliffe, and Wright) is, however, routine clinical practice in many hospitals. The goal of this study was to validate this practice retrospectively in a large heterogeneous adult patient population.

Experimental Design: Concentration-time data of ultrafilterable platinum of 178 patients (280 courses, 3,119 samples) with different types of cancer receiving carboplatin-based chemotherapy in conventional and high doses were available. Data were described with a linear two-compartment population pharmacokinetic model. Relations between SCR-based formulae for estimating renal function and carboplatin clearance were investigated.

Results: None of the tested SCR-based estimates of renal function were relevantly related to the pharmacokinetic variables of carboplatin. Neither SCR (median, 51; range, 18-124 μmol/L) nor the estimated GFR using the three different formulae was related to carboplatin clearance.

Conclusions: Our data do not support the application of modifications of the Calvert formula by estimating GFR from SCR in the a priori dosing of carboplatin in patients with relatively normal renal function (creatinine clearance, >50 mL/min). For targeted carboplatin exposures, the original Calvert formula, measuring GFR using the 51Cr-EDTA clearance, remains the method of choice. Alternatively, in patients with normal renal function, a flat dose based on the mean population carboplatin clearance should be administered.
Antileukemic Activity of Lysophosphatidic Acid Acyltransferase-β Inhibitor CT32228 in Chronic Myelogenous Leukemia Sensitive and Resistant to Imatinib
Authors: La Rosée Paul , Jia Taiping , Demehri Shadmer , Härtel Nicolai , de Vries Peter , Bonham Lynn , Hollenback David , Singer Jack W. , Melo Junia V. , Druker Brian J. , Deininger Michael W.
Published: November 2006

Purpose: Lysophosphatidic acid acyltransferase (LPAAT)-β catalyzes the conversion of lysophosphatidic acid to phosphatidic acid, an essential component of several signaling pathways, including the Ras/mitogen-activated protein kinase pathway. Inhibition of LPAAT-β induces growth arrest and apoptosis in cancer cell lines, implicating LPAAT-β as a potential drug target in neoplasia.

Experimental Design: In this study, we investigated the effects of CT32228, a specific LPAAT-β inhibitor, on BCR-ABL-transformed cell lines and primary cells from patients with chronic myelogenous leukemia.

Results: CT32228 had antiproliferative activity against BCR-ABL-positive cell lines in the nanomolar dose range, evidenced by cell cycle arrest in G2-M and induction of apoptosis. Treatment of K562 cells with CT32228 led to inhibition of extracellular signal-regulated kinase 1/2 phosphorylation, consistent with inhibition of mitogen-activated protein kinase signaling. Importantly, CT32228 was highly active in cell lines resistant to the Bcr-Abl kinase inhibitor imatinib. Combination of CT32228 with imatinib produced additive inhibition of proliferation in cell lines with residual sensitivity toward imatinib. In short-term cultures in the absence of growth factors, CT32228 preferentially inhibited the growth of granulocyte-macrophage colony-forming units from chronic myelogenous leukemia patients compared with healthy controls.

Conclusion: These data establish LPAAT-β as a potential drug target for the treatment of BCR-ABL-positive leukemias.
Peroxisome Proliferator-Activated Receptor γ Is Highly Expressed in Pancreatic Cancer and Is Associated With Shorter Overall Survival Times
Authors: Kristiansen Glen , Jacob Juliane , Buckendahl Ann-Christin , Grützmann Robert , Alldinger Ingo , Sipos Bence , Klöppel Günter , Bahra Marcus , Langrehr Jan M. , Neuhaus Peter , Dietel Manfred , Pilarsky Christian
Published: November 2006

Purpose: Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that has been implicated in carcinogenesis and progression of various solid tumors, including pancreatic carcinoma. We aimed to clarify the expression patterns of PPARγ in pancreatic ductal carcinomas and to correlate these to clinicopathologic variables, including patient survival.

Experimental Design: Array-based expression profiling of 19 microdissected carcinomas and 14 normal ductal epithelia was conducted. Additionally, Western blots of pancreatic cancer cell lines and paraffinized tissue of 129 pancreatic carcinomas were immunostained for PPARγ. For statistical analysis, Fisher's exact test, χ2 test for trends, correlation analysis, Kaplan-Meier analysis, and Cox's regression were applied.

Results: Expression profiles showed a strong overexpression of PPARγ mRNA (change fold, 6.9; P = 0.04). Immunohistochemically, PPARγ expression was seen in 71.3% of pancreatic cancer cases. PPARγ expression correlated positively to higher pT stages and higher tumor grade. Survival analysis showed a significant prognostic value for PPARγ, which was found to be independent in the clinically important subgroup of node-negative tumors.

Conclusions: PPARγ is commonly up-regulated in pancreatic ductal adenocarcinoma and might be a prognostic marker in this disease. Both findings corroborate the importance of PPARγ in tumor progression of pancreatic cancer.
Identification of the Decay-Accelerating Factor CD55 as a Peanut Agglutinin–Binding Protein and Its Alteration in Non–Small Cell Lung Cancers
Authors: Higuchi Mitsunori , Endo Yuichi , Suzuki Hiroyuki , Osuka Fumihiko , Shio Yutaka , Fujiu Koichi , Kanno Ryuzo , Oishi Akio , Fujita Teizo , Gotoh Mitsukazu
Published: November 2006

Purpose: Peanut agglutinin (PNA) recognizes tumor-associated carbohydrates. In this study, we aimed to identify the core protein harboring PNA-binding sugars in the human lung and to explore the relationship with the pathology of primary non–small cell lung cancers (NSCLC).

Experimental Design: PNA lectin blotting was used to detect PNA-binding proteins in the microsomal fraction of lung tissue from 24 patients with NSCLC. The 55- to 65-kDa core peptide PNA-binding protein was characterized by enzymatic treatment and identified by immunoprecipitation and affinity chromatography. The expression level and increase in size of the 55- to 65-kDa PNA-binding protein/decay-accelerating factor (DAF) were compared between normal and tumor regions of the tumor tissue by Western blotting and quantitative PCR.

Results: The 55- to 65-kDa PNA-binding protein was observed in human lung. This was a glycosylphosphatidylinositol-anchored membrane protein carrying O-linked carbohydrates. This core protein was identified as DAF, one of the complementary regulatory proteins. DAF was enlarged to 65 to 75 kDa in NSCLC tumor lesions due to sialylation in the sugar moiety. At the transcription level, DAF levels were significantly lower in tumor regions, suggesting its down-regulation in NSCLC cells.

Conclusions: DAF was identified as a new PNA-binding protein in the human lung. The down-regulation and heavy sialylation of DAF was associated with pathology in NSCLC, and these alterations make this protein a potential marker for NSCLC.
Effect of Chemotherapy on Skeletal Health in Male Survivors from Testicular Cancer and Lymphoma
Authors: Brown Janet E. , Ellis Sue P. , Silcocks Paul , Blumsohn Aubrey , Gutcher Sandra A. , Radstone Clare , Hancock Barry W. , Hatton Matthew Q. , Coleman Robert E.
Published: November 2006

Purpose: There are concerns over the late effects of cancer therapy, including accelerated bone loss leading to increased risk of osteoporosis. Treatment-related bone loss is well recognized in breast and prostate cancer, due to overt hypogonadism, but there has been little evaluation of the skeletal effects of chemotherapy alone in adults. This study assesses the extent of bone loss due to previous chemotherapy in men.

Experimental Design: The bone mineral density (BMD) of men who had received previously chemotherapy with curative intent for lymphoma or testicular cancers was compared with that of an age-matched population of men from a cancer control population that had not received chemotherapy. BMD was measured by dual-energy X-ray scanning. Additionally, measurement of sex hormones and the bone turnover markers N-telopeptide fragment of type I collagen and bone-specific alkaline phosphatase were done. All statistical tests were two sided.

Results: One hundred fifteen chemotherapy-treated patients and 102 cancer controls were recruited. There was no statistical difference in BMD between the chemotherapy and control groups at either spine or hip and the mean BMD values in both groups were no lower than that of a reference population. There were no significant differences in estradiol, luteinizing hormone, and testosterone, but follicle-stimulating hormone values were significantly higher in the chemotherapy group (P = 0.011). The mean values of NH2-terminal telopeptide fragment of type I collagen and bone-specific alkaline phosphatase were within the reference ranges.

Conclusions: The absence of accelerated bone loss following chemotherapy is reassuring and suggests that standard dose cytotoxic chemotherapy has no lasting clinically important direct effects on bone metabolism.
Classification of Breast Cancer Using Genetic Algorithms and Tissue Microarrays
Authors: Dolled-Filhart Marisa , Rydén Lisa , Cregger Melissa , Jirström Karin , Harigopal Malini , Camp Robert L. , Rimm David L.
Published: November 2006

Purpose: A multitude of breast cancer mRNA profiling studies has stratified breast cancer and defined gene sets that correlate with outcome. However, the number of genes used to predict patient outcome or define tumor subtypes by RNA expression studies is variable, nonoverlapping, and generally requires specialized technologies that are beyond those used in the routine pathology laboratory. It would be ideal if the familiarity and streamlined nature of immunohistochemistry could be combined with the rigorously quantitative and highly specific properties of nucleic acid–based analysis to predict patient outcome.

Experimental Design: We have used AQUA-based objective quantitative analysis of tissue microarrays toward the goal of discovery of a minimal number of markers with maximal prognostic or predictive value that can be applied to the conventional formalin-fixed, paraffin-embedded tissue section.

Results: The minimal discovered multiplexed set of tissue biomarkers was GATA3, NAT1, and estrogen receptor. Genetic algorithms were then applied after division of our cohort into a training set of 223 breast cancer patients to discover a prospectively applicable solution that can define a subset of patients with 5-year survival of 96%. This algorithm was then validated on an internal validation set (n = 223, 5-year survival = 95.8%) and further validated on an independent cohort from Sweden, which showed 5-year survival of 92.7% (n = 149).

Conclusions: With further validation, this test has both the familiarity and specificity for widespread use in management of breast cancer. More generally, this work illustrates the potential for multiplexed biomarker discovery on the tissue microarray platform.
Novel D761Y and Common Secondary T790M Mutations in Epidermal Growth Factor Receptor–Mutant Lung Adenocarcinomas with Acquired Resistance to Kinase Inhibitors
Authors: Balak Marissa N. , Gong Yixuan , Riely Gregory J. , Somwar Romel , Li Allan R. , Zakowski Maureen F. , Chiang Anne , Yang Guangli , Ouerfelli Ouathek , Kris Mark G. , Ladanyi Marc , Miller Vincent A. , Pao William
Published: November 2006

Purpose: In patients whose lung adenocarcinomas harbor epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations, acquired resistance to the tyrosine kinase inhibitors (TKI) gefitinib (Iressa) and erlotinib (Tarceva) has been associated with a second-site EGFR mutation, which leads to substitution of methionine for threonine at position 790 (T790M). We aimed to elucidate the frequency and nature of secondary EGFR mutations in patients with acquired resistance to TKI monotherapy.

Experimental Design: Tumor cells from patients with acquired resistance were examined for secondary EGFR kinase domain mutations by molecular analyses.

Results: Eight of 16 patients (50% observed rate; 95% confidence interval, 25-75%) had tumor cells with second-site EGFR mutations. Seven mutations were T790M and one was a novel D761Y mutation found in a brain metastasis. When combined with a drug-sensitive L858R mutation, the D761Y mutation modestly reduced the sensitivity of mutant EGFR to TKIs in both surrogate kinase and cell viability assays. In an autopsy case, the T790M mutation was found in multiple visceral metastases but not in a brain lesion.

Conclusions: The T790M mutation is common in patients with acquired resistance. The limited spectrum of TKI-resistant mutations in EGFR, which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and KIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.
Clozapine-Induced Effuso-Constrictive Pericarditis
Authors: Rathore S. , Masani N.D. , Callaghan P.O.
Published: November 2006

Clozapine is a widely used antipsychotic medication and is effective against both positive and negative symptoms of schizophrenia. However, clozapine use should be monitored closely due to its side effects profile. The main side effects include cardiorespiratory symptoms, seizures and agranulocytosis. We report a case of effuso-constrictive pericarditis soon after being started on clozapine therapy, whose symptoms improved after discontinuation of clozapine. The literature is reviewed and importance of monitoring is discussed.
Morphologic Alteration Induced by Short-Term Smoke Exposure in Rats
Authors: Işık A. Cemal Ümit , Yardımcı Serdar , Güven Cengiz , Avunduk Mustafa C. , Civelek Şenol
Published: November 2006

Background: It is a well-established fact that cigarette smoking causes degenerative, inflammatory, and respiratory diseases in humans.Because many factors such as air pollution and harsh working conditions can easily be eliminated in animal studies, we conducted this study to identify the effect of tobacco on rat trachea. Methods: 24 male Wistar rats were divided randomly into an experimental and a control group. The experimental group of rats was exposed to cigarette smoke for 2 h each day over a duration of 60 consecutive days and the control group was treated in an identical fashion yet exposed only to room air. A morphometric study was performed on tracheal specimens taken from 22 rats (10 smoke-exposed rats and 12 control rats). Results: Our results show that many of the morphological changes of the tracheal epithelium were found in the experimental group and significant quantitative differences were observed between the two groups. Loss of cilia, basal cell hyperplasia, goblet cell hyperplasia and an increased number of subepithelial inflammatory cells were observed by light microscopic examination of the trachea of experimental rats. We found very high levels of plasma thiocyanate after exposure to smoke in the experimental group, but no increase in the control group. Conclusions: The oxidants contained tobacco which could play an important role in the development of these structural and functional abnormalities in the trachea after smoke exposure. In addition, smoking can recruit inflammatory cells to the trachea.
Left Ventricular Diastolic Function in Hemodialysis Patients: Role of Preload Increase Maneuver on Tissue Doppler Imaging Evaluation
Authors: Freitas Valéria C. , Danzmann Luiz C. , Torres Marco R.
Published: November 2006

Objective: Tissue Doppler imaging (TDI) has recently been proposed as a relatively preload-independent method to evaluate left ventricular diastolic function. We sought to investigate the higher-accuracy of TDI to assess diastolic function in end-stage renal disease (ESRD) patients on hemodialysis (HD) associated with a preload increase maneuver. Methods: Thirty-two consecutiveESRD patients (16 female, ages 48.8 ± 17.5 years, 14 ≤45 and 18 >45 years old) were evaluated. Measurements of E, A velocities and the E/A ratio from transmitral inflow pulsed wave Doppler, and E’, A’ velocities and the E’/A’ ratio from TDI were obtained 1 h before and 1 h after HD at baseline and with a preload increase maneuver. Results: The E/A ratio changed significantly in all patients aged >45 before and after HD with the preload increase maneuver. The E’/A’ ratio increased in all subjects with the preload increase maneuver before HD but did not change with the maneuver after HD in the euvolemic state in all patients. Conclusion: In ESRD patients on routine HD, TDI evaluation associated with a preload increase maneuver proved to be a more accurate method to identify diastolic dysfunction when the evaluation is performed in euvolemic patients after HD.
Microanatomy of Milk Ducts in the Nipple
Authors: Taneri Ferit , Kurukahvecioglu Osman , Akyurek Nalan , Tekin Ercument H. , İlhan Mustafa N. , Cifter Cagatay , Bozkurt Sukru , Dursun Ayse , Bayram Orhan , Onuk Erhan
Published: November 2006

The aim of this study was to determine number and diameter of milk ducts in the nipple and to investigate the possible influences of age, breast weight, and diameter of the nipple on the number of ducts. Two hundred and twenty-six carcinoma mastectomy specimens were weighed and the nipple diameters measured. The number of ducts was counted in histological cross sections. Mean diameter of the nipple and mean breast weight were 13.9 mm and 844.6 g, respectively. There was a small but statistically significant positive correlation between nipple diameter and number of milk ducts (rho = 0.158; p = 0.01), but no correlation with breast weight. The mean number of ducts in the nipple duct bundle was 17.5. This is significantly higher than the number of ducts reported to open on the nipple surface. This discrepancy could reflect duct branching within the nipple or the presence of some ducts which do not reach the nipple surface. Smaller breast ducts (diameter <0.5 mm) represent nearly 50% of the nipple ducts and could be a challenge to the ductoscopy technology.
Increased Plasma Oxidized Phospholipid:Apolipoprotein B-100 Ratio With Concomitant Depletion of Oxidized Phospholipids From Atherosclerotic Lesions After Dietary Lipid-Lowering
Authors: Tsimikas Sotirios , Aikawa Masanori , Miller Francis J. , Miller Elizabeth R. , Torzewski Michael , Lentz Steven R. , Bergmark Claes , Heistad Donald D. , Libby Peter , Witztum Joseph L.
Published: November 2006

Background—

Oxidized phospholipids (OxPL) are pro-inflammatory. We evaluated whether changes in plasma levels of OxPL associated with apolipoprotein B-100 (apoB-100) reflect changes in OxPL content in atherosclerotic plaques during dietary-induced atherosclerosis progression and regression.

Methods and Results—

OxPL content was measured in plasma and immunohistochemically in aortic plaques with antibody E06 in cynomolgus monkeys and New Zealand White rabbits at baseline, after a high-fat/high-cholesterol diet and after reversion to normal chow. The OxPL/apoB ratio, representing the content of OxPL on individual apoB-100 particles, and Total apoB-OxPL (OxPL/apoB multiplied by plasma apoB levels), reflecting the OxPL content on all apoB-100 particles, were measured. Total apoB-OxPL plasma levels increased 3-fold (
P
<0.0001) during hypercholesterolemia and decreased ≈75% (
P
<0.0001) during reversion to normocholesterolemia. In contrast, OxPL/apoB levels decreased significantly (
P
<0.0001) during hypercholesterolemia and increased significantly (
P
=0.0002) during reversion to normocholesterolemia. Immunostaining revealed that during atherosclerosis progression OxPL co-localized with apoB-100, whereas during regression OxPL virtually disappeared.

Conclusion—

In the setting of overall reduction of plasma OxPL levels after dietary lipid-lowering, increases in the OxPL/apoB ratio reflect reduced content of OxPL in atherosclerotic plaques. These data suggest that changes in the OxPL/apoB ratio may reflect early atherosclerosis regression.
Saving History? Egyptian Hagiography in Its Space and Time
Authors: van Minnen Peter
Published: November 2006

Egyptian hagiography, just as other kinds of hagiography, originates in a certain time and place. The problem is that we can rarely pin down what part of the evidence is early and what evidence derives from later developments. We also often do not know where exactly the evidence comes from. In this paper, I will first discuss some of the problems this poses in dealing with Egyptian hagiography as a source of history, then I will argue that it is a kind of history after all: from about 400, when Egyptian hagiography takes off, it consistently provides a totalizing explanation for what had happened in the course of the fourth century: people had turned from paganism to Christianity, but no one had taken much notice while it happened. Egyptian hagiography does not build on authentic memory of what had happened in the fourth century, but amounts to an imaginative explanation-after-the-fact, largely inspired by the Bible and other literature.