bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacodynamic Model To Describe the Concentration-Dependent Selection of Cefotaxime-ResistantEscherichia coli
Authors: Olofsson Sara K. , Geli Patricia , Andersson Dan I. , Cars Otto
Published: November 2005

Antibiotic dosing regimens may vary in their capacity to select mutants. Our hypothesis was that selection of a more resistant bacterial subpopulation would increase with the time within a selective window (SW), i.e., when drug concentrations fall between the MICs of two strains. An in vitro kinetic model was used to study the selection of twoEscherichia colistrains with different susceptibilities to cefotaxime. The bacterial mixtures were exposed to cefotaxime for 24 h and SWs of 1, 2, 4, 8, and 12 h. A mathematical model was developed that described the selection of preexisting and newborn mutants and the post-MIC effect (PME) as functions of pharmacokinetic parameters. Our main conclusions were as follows: (i) the selection between preexisting mutants increased with the time within the SW; (ii) the emergence and selection of newborn mutants increased with the time within the SW (with a short time, only 4% of the preexisting mutants were replaced by newborn mutants, compared to the longest times, where 100% were replaced); and (iii) PME increased with the area under the concentration-time curve (AUC) and was slightly more pronounced with a long elimination half-life (T1/2) than with a shortT1/2situation, when AUC is fixed. We showed that, in a dynamic competition between strains with different levels of resistance, the appearance of newborn high-level resistant mutants from the parental strains and the PME can strongly affect the outcome of the selection and that pharmacodynamic models can be used to predict the outcome of resistance development.
Antichagasic Activity of Komaroviquinone Is Due to Generation of Reactive Oxygen Species Catalyzed by
Trypanosoma cruzi
Old Yellow Enzyme
Authors: Uchiyama Nahoko , Kabututu Zakayi , Kubata Bruno K. , Kiuchi Fumiyuki , Ito Michiho , Nakajima-Shimada Junko , Aoki Takashi , Ohkubo Kei , Fukuzumi Shunichi , Martin Samuel K. , Honda Gisho , Urade Yoshihiro
Published: November 2005

A novel potent trypanocidal diterpene, komaroviquinone, was reduced by
Trypanosoma cruzi
old yellow enzyme (TcOYE) to its semiquinone radical. The reductase activity in trypanosome lysates was completely immunoabsorbed by anti-TcOYE antibody. Since TcOYE is expressed throughout the
T. cruzi
life cycle, komaroviquinone is an interesting candidate for developing new antichagasic drugs.
Assessing the In Vitro Effectiveness of Antimicrobials against
Mycoplasma mycoides
subsp.
mycoides
Small-Colony Type To Reduce Contagious Bovine Pleuropneumonia Infection
Authors: Ayling R. D. , Bisgaard-Frantzen S. , March J. B. , Godinho K. , Nicholas R. A. J.
Published: November 2005

In vitro minimum inhibitory concentrations were determined for 21 antimicrobials against 41 isolates of
Mycoplasma mycoides
subsp.
mycoides
small-colony type, the cause of contagious bovine pleuropneumonia. Of the antimicrobials used most widely in Africa, oxytetracycline and tilmicosin were effective, while the isolates were resistant to tylosin. These results provide a baseline for monitoring antimicrobial resistance.
Cloning and Functional Analysis of the Gene Encoding the 33- to 36-Kilodalton Outer Membrane Protein Associated with Carbapenem Resistance in
Acinetobacter baumannii
Authors: Tomás Maria del Mar , Beceiro Alejandro , Pérez Astrid , Velasco David , Moure Rita , Villanueva Rosa , Martínez-Beltrán Jesús , Bou Germán
Published: November 2005

We investigated a multiresistant strain of
Acinetobacter baumannii
isolated in our hospital. Analysis of the N-terminal peptide sequence of the outer membrane proteins (OMPs) purified from the strain allowed us to clone and sequence the nucleotides of the gene encoding the 33- to 36-kDa OMP associated with carbapenem resistance in
A. baumannii
High Rate of Resistance to Quinupristin-Dalfopristin in
Enterococcus faecium
Clinical Isolates from Korea
Authors: Oh Won Sup , Ko Kwan Soo , Song Jae-Hoon , Lee Mi Young , Park Sulhee , Peck Kyong Ran , Lee Nam Yong , Kim Choon-Kwan , Lee Hyuck , Kim Shin-Woo , Chang Hyun-Ha , Kim Yeon-Sook , Jung Sook-In , Son Jun Seong , Yeom Joon-Sup , Ki Hyun Kyun , Woo Gun-Jo
Published: November 2005

We tested the in vitro susceptibilities of 603 enterococcal isolates from eight tertiary-care hospitals in Korea. The quinupristin-dalfopristin resistance rate in
Enterococcus faecium
was very high (25 isolates, 10.0%). It was suggested that both clonal spread and the sporadic emergence of quinupristin-dalfopristin-resistant isolates may explain the high prevalence of quinupristin-dalfopristin resistance in Korea.
THE EXTENDED VARIATIONAL PRINCIPLE FOR MEAN-FIELD, CLASSICAL SPIN SYSTEMS
Authors: KRITCHEVSKI E. , STARR S.
Published: November 2005

The purpose of this article is to obtain a better understanding of the extended variational principle (EVP). The EVP is a formula for the thermodynamic pressure of a statistical mechanical system as a limit of a sequence of minimization problems. It was developed for disordered mean-field spin systems, spin systems where the underlying Hamiltonian is itself random, and whose distribution is permutation invariant. We present the EVP in the simpler setting of classical mean-field spin systems, where the Hamiltonian is non-random and symmetric. The EVP essentially solves these models. We compare the EVP with another method for mean-field spin systems: the self-consistent mean-field equations. The two approaches lead to dual convex optimization problems. This is a new connection, and it permits a generalization of the EVP.
TWO-PHOTON ABSORPTION AND EMISSION PROCESS
Authors: FAGNOLA FRANCO , QUEZADA ROBERTO
Published: November 2005

We analyze the two-photon absorption and emission process and characterize the stationary states at zero and positive temperature. We show that entangled stationary states exist only at zero temperature and, at positive temperature, there exists infinitely many commuting invariant states satisfying the detailed balance condition.
SMALL TIME ASYMPTOTICS FOR FLEMING–VIOT PROCESSES
Authors: XIANG KAI-NAN , ZHANG TU-SHENG
Published: November 2005

In this paper, a sample path large deviation for Fleming–Viot processes corresponding to the small time asymptotics is established. The rate function is identified as the energy functional of paths associated to the Bhattacharya metric, the intrinsic metric of Fleming–Viot processes.
IDENTIFYING TIME-CLUSTERING STRUCTURES IN LIGHTNING SEQUENCES
Authors: TELESCA LUCIANO , BERNARDI MARINA , ROVELLI CINZIA
Published: November 2005

Two years of lightning data, measured during 2002 and 2003 in an area of southern Italy, have been analyzed in order to reveal scaling behaviour in their time dynamics. We used the Allan Factor method to evidence the presence of time-clustering in the lightning data. We found that i) the sequence of lightning time-occurrences is characterized by two scaling regions, which reveal intra-cluster (inside an individual thunderstorm) and inter-cluster (among successive thunderstorms) time-clustering properties of lightning data. A crossover timescale is identified, which is connected with the mean duration of a thunderstorm. We investigated intra- and inter-cluster time-dynamics for the whole sequence as well as the sequence of only positive and only negative flashes. The negative lightning show a time-clustering feature stronger than that of the positive lightning.
Vasorelaxation in Space
Authors: Norsk Peter , Damgaard Morten , Petersen Lonnie , Gybel Mikkel , Pump Bettina , Gabrielsen Anders , Christensen Niels Juel
Published: November 2005

During everyday life, gravity constantly stresses the cardiovascular system in upright humans by diminishing venous return. This decreases cardiac output and induces systemic vasoconstriction to prevent blood pressure from falling. We therefore tested the hypothesis that entering weightlessness leads to a prompt increase in cardiac output and to systemic vasodilatation and that these effects persist for at least a week of weightlessness in space. Cardiac output and mean arterial pressure were measured in 8 healthy humans during acute 20-s periods of weightlessness in parabolic airplane flights and on the seventh and eighth day of weightlessness in 4 astronauts in space. The seated 1-G position acted as reference. Entering weightlessness promptly increased cardiac output by 29±7%, from 6.6±0.7 to 8.4±0.9 L min
−1
(mean±SEM;
P
=0.003), whereas mean arterial pressure and heart rate were unaffected. Thus, systemic vascular resistance decreased by 24±4% (
P
=0.017). After a week of weightlessness in space, cardiac output was increased by 22±8% from 5.1±0.3 to 6.1±0.1 L min
−1
(
P
=0.021), with mean arterial pressure and heart rate being unchanged so that systemic vascular resistance was decreased by 14±9% (
P
=0.047). In conclusion, entering weightlessness promptly increases cardiac output and dilates the systemic circulation. This vasorelaxation persists for at least a week into spaceflight. Thus, it is probably healthy for the human cardiovascular system to fly in space.
Joint Effects of Systolic Blood Pressure and Serum Cholesterol on Cardiovascular Disease in the Asia Pacific Region
Authors:   Asia Pacific Cohort Studies Collaboration
Published: November 2005

Background—

Although interest in multifactorial interventions for cardiovascular disease is increasing, data on the strength and shape of the joint effects of blood pressure and cholesterol levels on the risk of cardiovascular disease are scarce, confined primarily to coronary heart disease (CHD) mortality in early middle-aged Western populations.

Methods and Results—

This analysis included 29 cohorts from Asia (78% of the total 380 216 participants) and 7 from Australia and New Zealand, with a total of 2 547 447 person-years of observation. Stratified time-dependent Cox proportional-hazards analyses were used to regress time until first event against baseline systolic blood pressure (SBP) and total cholesterol levels. A total of 3079 CHD and 4247 stroke events occurred; stroke subtypes were confirmed by CT, MRI, or necropsy in 1471 (35%) stroke events. Usual values of SBP were strongly linearly associated with ischemic stroke, hemorrhagic stroke, and CHD. The slope of the association with SBP became steeper with decreasing levels of cholesterol for ischemic stroke (
P
=0.007) and CHD (
P
≤0.0001). For example, for the cholesterol groups of <4.75, 4.75 to 5.49, 5.50 to 6.24, and ≥6.25 mmol/L, each 10–mm Hg–higher systolic pressure was associated with 34% (95% CI, 30% to 37%), 28% (95% CI, 21% to 35%), 25% (95% CI, 18% to 32%), and 21% (95% CI, 13% to 27%) higher CHD risk, respectively. Adjustments for other leading cardiovascular risk factors made no appreciable differences in these results.

Conclusions—

In Asia-Pacific populations, there are hazards of increasing SBP at all cholesterol levels and hazards of increasing cholesterol at all levels of SBP, but the associations of SBP with CHD risk and ischemic stroke risk are slightly steeper among those with low cholesterol levels. The joint effects of SBP and total cholesterol on cardiovascular disease seem consistent across various Western and Asian populations.
Risk of High Blood Pressure Among Young Men Increases With the Degree of Immaturity at Birth
Authors: Johansson Stefan , Iliadou Anastasia , Bergvall Niklas , Tuvemo Torsten , Norman Mikael , Cnattingius Sven
Published: November 2005

Background—

Survivors of preterm birth constitute a new generation of young adults, but little is known about their long-term health. We investigated the association between gestational age (GA) and risk of high blood pressure (HBP) in young Swedish men and whether GA modified the risk of HBP; ie, whether HBP was related to being born small for gestational age (SGA).

Methods and Results—

This population-based cohort study included 329 495 Swedish men born in 1973 to 1981 who were conscripted for military service in 1993 to 2001. Multivariate linear- and logistic-regression analyses were performed. Main outcome measures were systolic and diastolic BPs at conscription. Linear-regression analyses showed that systolic BP increased with decreasing GA (regression coefficient −0.31 mm Hg/wk,
P
<0.001). Systolic and diastolic BPs both increased with decreasing birth weight for GA, but the association with systolic BP was most evident (regression coefficient −0.67 mm Hg per SD score in birth weight for GA,
P
<0.001). Compared with men born at term (GA, 37 to 41 weeks), the adjusted odd ratios (95% confidence intervals [CIs]) for high systolic BP (≥140 mm Hg) were as follows: moderately preterm (33 to 36 weeks), 1.25 (1.19 to 1.30); very preterm (29 to 32 weeks), 1.48 (1.30 to 1.68); and extremely preterm (24 to 28 weeks), 1.93 (1.34 to 2.76). Being SGA was associated only with an increased risk of high systolic BP among men born at 33 weeks or later. The risk estimates for high diastolic BP (≥90 mm Hg) increased with decreasing GA, but the risk reached significance only among men born moderately preterm.

Conclusions—

Preterm birth, a common pregnancy complication, is a risk factor for HBP in young men. The risk of high systolic BP associated with birth weight for GA is modified by GA, suggesting that perinatal contributions to BP elevation later in life may be induced by different biological pathways.
Turbulence and Gravity Waves within an Upper-Level Front
Authors: Koch Steven E. , Jamison Brian D. , Lu Chungu , Smith Tracy L. , Tollerud Edward I. , Girz Cecilia , Wang Ning , Lane Todd P. , Shapiro Melvyn A. , Parrish David D. , Cooper Owen R.
Published: November 2005

High-resolution dropwindsonde and in-flight measurements collected by a research aircraft during the Severe Clear-Air Turbulence Colliding with Aircraft Traffic (SCATCAT) experiment and simulations from numerical models are analyzed for a clear-air turbulence event associated with an intense upper-level jet/frontal system. Spectral, wavelet, and structure function analyses performed with the 25-Hz in situ data are used to investigate the relationship between gravity waves and turbulence. Mesoscale dynamics are analyzed with the 20-km hydrostatic Rapid Update Cycle (RUC) model and a nested 1-km simulation with the nonhydrostatic Clark–Hall (CH) cloud-scale model.

Turbulence occurred in association with a wide spectrum of upward propagating gravity waves above the jet core. Inertia–gravity waves were generated within a region of unbalanced frontogenesis in the vicinity of a complex tropopause fold. Turbulent kinetic energy fields forecast by the RUC and CH models displayed a strongly banded appearance associated with these mesoscale gravity waves (horizontal wavelengths of ∼120–216 km). Smaller-scale gravity wave packets (horizontal wavelengths of 1–20 km) within the mesoscale wave field perturbed the background wind shear and stability, promoting the development of bands of reduced Richardson number conducive to the generation of turbulence. The wavelet analysis revealed that brief episodes of high turbulent energy were closely associated with gravity wave occurrences. Structure function analysis provided evidence that turbulence was most strongly forced at a horizontal scale of 700 m.

Fluctuations in ozone measured by the aircraft correlated highly with potential temperature fluctuations and the occurrence of turbulent patches at altitudes just above the jet core, but not at higher flight levels, even though the ozone fluctuations were much larger aloft. These results suggest the existence of remnant “fossil turbulence” from earlier events at higher levels, and that ozone cannot be used as a substitute for more direct measures of turbulence. The findings here do suggest that automated turbulence forecasting algorithms should include some reliable measure of gravity wave activity.
The Role of Deformation and Potential Vorticity in Southern Hemisphere Blocking Onsets
Authors: Dong Li , Colucci Stephen J.
Published: November 2005

The relative importance of interactions between deformation and potential vorticity (PV) as a block-onset mechanism is examined in 30 cases of atmospheric blocking over the Southern Hemisphere (SH). The blocking cases are diagnosed with a quasigeostrophic model for the u component of the geostrophic wind tendency. In this model, two mechanisms, the advection of the meridional gradient of PV and interactions between deformation and PV, can force the weakening of westerly flow or increasing easterly flow associated with blocking. The first forcing mechanism, which does not directly include deformation, indicates that the advection of equatorward increasing cyclonic PV (or equatorward decreasing anticyclonic PV) could force a local weakening of geostrophic westerlies or increasing easterlies. The second forcing mechanism, which represents the net effect of interactions between deformation and PV, indicates that eastward increasing PV embedded in a cyclonically sheared flow or equatorward increasing PV coincident with a stretching (diffluent) flow could each force a weakening in the westerlies.

While deformation is a distinct signature of blocking, it may not always actively participate in the formation of blocking. Advection and interaction contributions generally opposed each other in both the diagnosed blocking and nonblocking cases. Weakening westerlies associated with block onset would occur when one effect (usually the advection effect) contributes more negatively to the wind tendency than the opposing, positive contribution from the other effect. When deformation is actively involved in the formation of blocking, self-interactions between synoptic-scale PV and deformation and self-interactions between planetary-scale PV and deformation contribute more importantly than synoptic-to-planetary-scale interactions between PV and deformation fields to the weakening of westerlies associated with block onsets.
Stirring and Mixing in Two-Dimensional Divergent Flow
Authors: Lukovich Jennifer Verlaine , Shepherd Theodore G.
Published: November 2005

While stirring and mixing properties in the stratosphere are reasonably well understood in the context of balanced (slow) dynamics, as is evidenced in numerous studies of chaotic advection, the strongly enhanced presence of high-frequency gravity waves in the mesosphere gives rise to a significant unbalanced (fast) component to the flow. The present investigation analyses result from two idealized shallow-water numerical simulations representative of stratospheric and mesospheric dynamics on a quasi-horizontal isentropic surface. A generalization of the Hua–Klein Eulerian diagnostic to divergent flow reveals that velocity gradients are strongly influenced by the unbalanced component of the flow. The Lagrangian diagnostic of patchiness nevertheless demonstrates the persistence of coherent features in the zonal component of the flow, in contrast to the destruction of coherent features in the meridional component. Single-particle statistics demonstrate t2 scaling for both the stratospheric and mesospheric regimes in the case of zonal dispersion, and distinctive scaling laws for the two regimes in the case of meridional dispersion. This is in contrast to two-particle statistics, which in the mesospheric (unbalanced) regime demonstrate a more rapid approach to Richardson’s t3 law in the case of zonal dispersion and is evidence of enhanced meridional dispersion.
A Barotropic Envelope Rossby Soliton Model for Block–Eddy Interaction. Part IV: Block Activity and Its Linkage with a Sheared Environment
Authors: Luo Dehai
Published: November 2005

In this paper, a basic-state flow that has a linear, weak meridional shear is used as a mean flow condition to see if the blocking activity is related to the state of the zonal mean flow based upon the envelope soliton theory proposed in Part I. It is found that an isolated coherent structure similar to a dipole block can arise from the resonant interaction between preexisting planetary- and synoptic-scale waves, but its asymmetry, intensity, and persistence depend strongly upon the horizontal shear of the basic-state flow prior to block onset. The cyclonic shear of the basic-state flow not only plays an important role in preventing the eastward spread of block energy, but also provides a strong diffluent flow as a precursor of block flow. In such an environment, a high amplitude dipole anomaly is maintained and the deformed synoptic-scale eddies tend to deflect northward. But the anticyclonic shear of a basic-state flow plays a reverse role, which causes deformed eddies to deflect southward.

It is also found that positive westerly wind anomalies at both high and low latitudes and negative anomalies at middle latitudes are maintained by synoptic-scale eddies through the self-interaction of block. In this case, the zonal mean westerly wind is accelerated at high and low latitudes, and decelerated at middle latitudes. Only for a basic state with cyclonic shear is the meridional profile of the zonal mean wind during the onset of a dipole block in agreement with observations.

In addition, it can be shown by computing scatter diagrams of potential vorticity against streamfunction in different sheared environments that an eddy-induced isolated block can exhibit a local free-mode characteristic. Two approximately linear functional relationships between potential vorticity and streamfunction are found to be probably attributed to synoptic eddies.
Large-Scale Modes in a Rotating Atmosphere with Radiative–Convective Instability and WISHE
Authors: Fuchs Zeljka , Raymond David J.
Published: November 2005

A highly simplified parameterization of diabatic processes is applied to linearized equations on a equatorial beta plane. The diabatic processes include moist convection, cloud–radiation interactions (CRI), and wind-induced surface heat exchange (WISHE). The precipitation rate is assumed to increase linearly as the vertically averaged saturation deficit decreases.

The modeled modes are Matsuno’s normal modes, that is, Kelvin waves, mixed Rossby–gravity waves, Rossby waves, and inertio–gravity waves, and an additional mode called here a slow moisture mode. All of the Matsuno modes are damped and remain stable even when CRI and WISHE are turned on. Their phase speeds do not vary much from Matsuno’s adiabatic values except for very long wavelength Kelvin and Rossby modes, for which the phase speeds are reduced compared to the adiabatic values. The slow moisture modes are stationary and unstable under CRI, while WISHE causes them to propagate. Under CRI and WISHE together the slow moisture modes are unstable and eastward propagating for long wavelengths and slowly moving relative to the mean flow for short wavelengths. The dispersion relations of the slow moisture modes are one of nearly constant or decreasing frequency with increasing wavenumber. The most important model parameter is the tropospheric moisture relaxation time scale, which is chosen to be 1 day.

The model failed to explain the observed phase speeds of convectively coupled Matsuno modes. Following Mapes, the authors suggest that other dynamics, more realistic than the one including only the first baroclinic mode, may be responsible for these modes.
Momentum Flux Spectrum of Convectively Forced Gravity Waves: Can Diabatic Forcing Be a Proxy for Convective Forcing?
Authors: Chun Hye-Yeong , Song In-Sun , Horinouchi Takeshi
Published: November 2005

The momentum flux of convectively forced internal gravity waves is calculated using explicitly resolved model-simulated gravity wave data. The momentum flux in a control simulation with nonlinearity and cloud microphysical processes is compared with that in quasi-linear dry simulations with either diabatic forcing or nonlinear forcing. It is found that the momentum flux induced by either of these two sources is significantly different from each other and also from the momentum flux in the control simulation. This is because the spectral distribution and magnitude of each wave source are significantly different and the cancellation of the momentum flux by cross-correlation terms between the two sources cannot be included in the momentum flux by a single source. This suggests that a parameterization of convectively forced gravity waves must take into account nonlinear forcing as well as diabatic forcing in order to qualitatively and quantitatively represent the reference-level momentum flux spectrum.
Principal Component Analysis of Doppler Radar Data. Part I: Geometric Connections between Eigenvectors and the Core Region of Atmospheric Vortices
Authors: Harasti Paul R. , List Roland
Published: November 2005

This is the first in a three-part series of papers that present the first applications of principal component analysis (PCA) to Doppler radar data. Although this novel approach has potential applications to many types of atmospheric phenomena, the specific goal of this series is to describe and verify a methodology that establishes the position and radial extent of the core region of atmospheric vortices. The underlying assumption in the current application is that the streamlines of the nondivergent component of the horizontal wind are predominantly circular, which is a characteristic often observed in intense vortices such as tropical cyclones.

The method employs an S2-mode PCA on the Doppler velocity data taken from a single surveillance scan and arranged sequentially in a matrix according to the range and azimuth coordinates. Part I begins the series by examining the eigenvectors obtained from such a PCA applied to a Doppler velocity model for a modified, Rankine-combined vortex, where the ratio of the radius of maximum wind to the range from the radar to the circulation center is varied over a wide range of values typically encountered in the field. Results show that the first two eigenvectors within the eigenspace of range coordinates represent over 99% of the total variance in the data. It is also demonstrated that the coordinates of particular cusps in the curves of the eigenvector coefficients plotted against their indices are geometrically related to both the position of circulation center and the radius of maximum wind.
Venous Thrombosis: The Role of Genes, Environment, and Behavior
Authors: Rosendaal Frits R.
Published: November 2005

Over the last decade we have witnessed an avalanche of newly identified risk factors for venous thrombosis. This has advanced our knowledge of its etiology, because more determinants have been described and because the underlying concepts have received a new and broader understanding.

Venous thrombosis is a common multicausal disease occurring as the result of interacting genetic, environmental and behavioral risk factors. Some of these have been known since medieval times, such as the increased risk of thrombosis during immobilization in pregnancy and after childbirth (although retained milk of the breast-feeding mother was seen as the primary cause for the latter). Pregnancy and puerperium still cause thrombosis, as do exogenous hormones in oral contraceptives and hormonal replacement therapy. Furthermore, the immobilization in the puerperium of the old days translates directly to situations of immobilization in current times, such as prolonged travel in airplanes or excessive electronic gaming.

While pedigrees with abundant thrombosis were observed in the early 1900s, the first cause of heritable thrombophilia (antithrombin deficiency) was discovered in 1965, with the subsequent identification of deficiencies of protein C and protein S in the early 1980s. These were uncommon and strong risk factors, whereas the more recently discovered genetic variants are common and weak, and cause disease only in the presence of other factors.
A Unique Activating Mutation in JAK2 (V617F) Is at the Origin of Polycythemia Vera and Allows a New Classification of Myeloproliferative Diseases
Authors: Vainchenker William , Constantinescu Stefan N.
Published: November 2005

Myeloproliferative disorders (MPDs) are heterogeneous diseases that occur at the level of a multipotent hematopoietic stem cell. They are characterized by increased blood cell production related to cytokine hypersensitivity and virtually normal cell maturation. The molecular pathogenesis of the MPDs has been poorly understood, except for chronic myeloid leukemia (CML), where the Bcr-Abl fusion protein exhibits constitutive kinase activity. Since some rare MPDs are also related to a dysregulated kinase activity, a similar mechanism was thought to be likely responsible for the more frequent MPDs. We investigated the mechanisms of endogenous erythroid colony formation (EEC) by polycythemia vera (PV) erythroid progenitor cells and found that EEC formation was abolished by a pharmacological inhibitor of JAK2 as well as an siRNA against JAK2. JAK2 sequencing revealed a unique mutation in the JH2 domain leading to a V617F substitution in more than 80% of the PV samples. This mutation in the pseudokinase autoinhibitory domain results in constitutive kinase activity and induces cytokine hypersensitivity or independence of factor-dependent cell lines. Retroviral transduction of the mutant JAK2 into murine HSC leads to the development of an MPD with polycythemia. The same mutation was found in about 50% of patients with idiopathic myelofibrosis (IMF) and 30% of patients with essential thrombocythemia (ET). Using different approaches, four other teams have obtained similar results. The identification of the JAK2 mutation represents a major advance in our understanding of the molecular pathogenesis of MPDs that will likely permit a new classification of these diseases and the development of novel therapeutic approaches.
POEMS Syndrome
Authors: Dispenzieri Angela
Published: November 2005

POEMS syndrome is defined by the presence of a peripheral neuropathy (P), a monoclonal plasma cell disorder (M), and other paraneoplastic features, the most common of which include organomegaly (O), endocrinopathy (E), skin changes (S), papilledema, edema, effusions, ascites, and thrombocytosis. Virtually all patients will have either sclerotic bone lesion(s) or co-existent Castleman’s disease. Not all features of the disease are required to make the diagnosis, and early recognition is important to reduce morbidity. Other names for the syndrome include osteosclerotic myeloma, Crow-Fukase syndrome, or Takatsuki syndrome. Because the peripheral neuropathy is frequently the overriding symptom and because the characteristics of the neuropathy are similar to that chronic inflammatory demyelinating polyneuropathy (CIDP), patients are frequently misdiagnosed with CIDP or monoclonal gammopathy of underdetermined significance (MGUS)-associated peripheral neuropathy. Not until additional features of the POEMS syndrome are recognized is the correct diagnosis made and effective therapies initiated. Clues to an early diagnosis include thrombocytosis and sclerotic bone lesions on plain skeletal radiographs. Therapies that may be effective in patients with CIDP and MGUS-associated peripheral neuropathy (intravenous gammaglobulin and plasmapheresis) are not effective in patients with POEMS. Instead, the mainstays of therapy for patients with POEMS include irradiation, corticosteroids, and alkylator-based therapy, including high-dose chemotherapy with peripheral blood stem cell transplantation.
Fetal Globin Induction—Can It Cure β Thalassemia?
Authors: Perrine Susan P.
Published: November 2005

The β thalassemias are one of a few medical conditions in which reactivation of a gene product that is expressed during fetal life can functionally replace a deficiency of essential proteins expressed at a later developmental stage. The fetal globin genes are present and normally integrated in hematopoietic stem cells, and at least one fetal gene appears accessible for reactivation, particularly in β° thalassemia. However, rapid cellular apoptosis from α globin chain precipitation, and relatively low levels of endogenous erythropoietin (EPO) in some β+ thalassemia patients contribute to the anemia in β thalassemia syndromes.

In clinical trials, three classes of therapeutics have demonstrated proof-of-principle of this approach by raising total hemoglobin levels by 1–4 g/dL above baseline in thalassemia patients: EPO preparations, short chain fatty acid derivatives (SCFADs), and chemotherapeutic agents. Although thalassemic erythrocytes survive only for a few days, the magnitude of these responses is similar to those induced by rhu-EPO in anemic conditions of normal erythrocyte survival. New oral therapeutic candidates, which stimulate both fetal globin gene expression and erythropoiesis, and combinations of therapeutics with complementary molecular actions now make this gene-reactivation approach feasible to produce transfusion independence in many patients. Development of the candidate therapeutics is hindered largely by costs of drug development for an orphan patient population.
Inherited Risk Factors for Venous Thrombosis
Authors: Cushman Mary
Published: November 2005

Venous thrombosis occurs as a consequence of genetic and environmental risk factors. Since the discovery of factor V Leiden, the most common genetic risk factor, there has been intense interest in clarifying the roles of genes and the environment with thrombosis risk. The translation of this risk information to clinical practice is a challenging one in the setting of a rapidly expanding knowledge base that includes application of genetic medicine. There are benefits, but also potential harms, of testing for inherited disorders associated with thrombosis. This paper reviews inherited risk factors for thrombosis and discuss clinical applications of testing.
Protective effect of leptin against ischemia-reperfusion injury in the rat small intestine
Authors: Hacioglu Alper , Algin Cem , Pasaoglu Ozgul , Pasaoglu Ercument , Kanbak Gungor
Published: November 2005

Background

The small intestine is extremely sensitive to ischemia-reperfusion (I/R) injury and a range of microcirculatory disturbances which contribute to tissue damage. Previous studies have shown that leptin plays an important physiological role in the microvasculature. The aim of this study was to evaluate the protective effects of leptin in I/R – induced mucosal injury in the small intestine.

Methods

Forty rats were divided into 5 groups (n = 8). Group I was subjected to a sham operation. Following mesenteric ischemia in group II (control); physiologic saline 1 cm3, in group III; leptin 100 μg/kg, and physiologic saline 1 cm3, in group IV;NG-L-arginine methyl ester (L-NAME) 20 mg/kg, and physiologic saline 1 cm3, in group V; leptin 100 μg/kg, L-NAME 20 mg/kg, and physiologic saline 1 cm3were given intra-peritoneally. In these groups, an I/R procedure was performed by occlusion of the superior mesenteric artery for 45 min followed by 120 min reperfusion. After reperfusion, the small intestines were resected for malondialdehyde (MDA) and nitric oxide (NO) concentration and histopathologic properties. Mucosal lesions were scored between 0 and 5. Tissue MDA and NO concentration and histopathologic grades were compared statistically.

Results

Tissue MDA level significantly increased (P< 0.05), tissue NO level significantly decreased in group V animals, compared to group III animals respectively (P< 0.001). Histopathologically, intestinal injury significantly decreased in the leptin treated ischemic group.

Conclusion

Leptin can be used safely in mesenteric occlusive diseases, since it induces NO formation and release in mesenteric vessels.
Opportunistic screening for iron-deficiency in 6–36 month old children presenting to the paediatric emergency department
Authors: Pusic Martin V , Dawyduk Brenda J , Mitchell David
Published: November 2005

Background

The Complete Blood Count (CBC) is a test frequently performed on children presenting to the Pediatric Emergency Department (PED), usually for the evaluation of an infectious illness. The CBC also allows for screening for Iron-deficiency Anemia. This study aims to determine the prevalence of a low Mean Cell Volume (MCV) in children having a CBC performed during a PED visit and whether physicians acted upon the abnormal value.

Methods

We present a retrospective cohort study. We reviewed the PED charts of all children 6–36 months of age who had a CBC performed during a 4-month period and the red blood cell mean cell volume was low. Our main outcome variable was whether or not the possible iron deficiency was addressed through documentation of either iron therapy or further investigation.

Results

938 children had a CBC performed during the two periods. Of these, 78 (8%) had an abnormal MCV or Hemoglobin with no previously identified explanation. Physicians documented either treatment or follow-up investigations in 27 cases (35%, 95% CI: 24–46%). Factors associated with the physician documenting either treatment or investigation plan were the following: hemoglobin level (OR 12.6; 95%CI: 4.0, 39) and age ≤ 18 months (OR 4.2; 95%CI: 1.4, 13).

Conclusion

Children who have had a CBC in the PED can be screened for iron deficiency at no additional cost. Physicians may be under-utilizing this information.
Evaluating changeability to improve fruit and vegetable intake among school aged children
Authors: Nanney Marilyn S , Haire-Joshu Debra , Elliott Michael , Hessler Kimberly , Brownson Ross C
Published: November 2005

Background

The purposes of this paper are two fold. First, to describe an approach used to identify fruits and vegetables to target for a child focused dietary change intervention. Second, to evaluate the concept of fruit and vegetable changeability and feasibility of applying it in a community setting.

Methods

Steps for identifying changeable fruits and vegetables include (1) identifying a dietary database (2) defining geographic and (3) personal demographics that characterize the food environment and (4) determining which fruits and vegetables are likely to improve during an intervention. The validity of these methods are evaluated for credibility using data collected from quasi-experimental, controlled design among 7–9 year old children (n = 304) participating in a tutoring or mentoring program in St. Louis, MO. Using a 28-item food frequency questionnaire, parents were asked to recall for their child how often foods were eaten the past 7 days. This questionnaire was repeated eight months later (response rate 84%). T-test analyses are used to determine mean serving differences from baseline to post test.

Results

The mean serving differences from baseline to post test were significant for moderately eaten fruits (p < .001), however, not for vegetables (p = .312). Among the intervention group, significantly more children ate grapes (p < .001), peaches (p = .022), cantaloupe (p < .001), and spinach (p = .044) at post testing – all identified as changeable with information tailored to participants.

Conclusion

Data driven, food focused interventions directed at a priority population are feasible and practical. An empirical evaluation of the assumptions associated with these methods supports this novel approach. However, results may indicate that these methods may be more relevant to fruits than vegetables. This process can be applied to diverse populations for many dietary outcomes. Intervention strategies that target only those changeable fruits and vegetables are innovative and warrant further study.
Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism
Authors: Hakimi Parvin , Johnson Mark T , Yang Jianqi , Lepage David F , Conlon Ronald A , Kalhan Satish C , Reshef Lea , Tilghman Shirley M , Hanson Richard W
Published: November 2005

Background

The metabolic function of PEPCK-C is not fully understood; deletion of the gene for the enzyme in mice provides an opportunity to fully assess its function.

Methods

The gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-C) was deleted in mice by homologous recombination (PEPCK-C-/- mice) and the metabolic consequences assessed.

Results

PEPCK-C-/- mice became severely hypoglycemic by day two after birth and then died with profound hypoglycemia (12 mg/dl). The mice had milk in their stomachs at day two after birth and the administration of glucose raised the concentration of blood glucose in the mice but did not result in an increased survival. PEPCK-C-/- mice have two to three times the hepatic triglyceride content as control littermates on the second day after birth. These mice also had an elevation of lactate (2.5 times), β-hydroxybutyrate (3 times) and triglyceride (50%) in their blood, as compared to control animals. On day two after birth, alanine, glycine, glutamine, glutamate, aspartate and asparagine were elevated in the blood of the PEPCK-C-/- mice and the blood urea nitrogen concentration was increased by 2-fold. The rate of oxidation of [2-14C]-acetate, and [5-14C]-glutamate to 14CO2 by liver slices from PEPCK-C-/- mice at two days of age was greatly reduced, as was the rate of fatty acid synthesis from acetate and glucose. As predicted by the lack of PEPCK-C, the concentration of malate in the livers of the PEPCK-C-/- mice was 10 times that of controls.

Conclusion

We conclude that PEPCK-C is required not only for gluconeogenesis and glyceroneogenesis but also for cataplerosis (i.e. the removal of citric acid cycle anions) and that the failure of this process in the livers of PEPCK-C-/- mice results in a marked reduction in citric acid cycle flux and the shunting of hepatic lipid into triglyceride, resulting in a fatty liver.
Using a Module-based Laboratory To Incorporate Inquiry into a Large Cell Biology Course
Authors: Howard David R. , Miskowski Jennifer A.
Published: November 2005

Because cell biology has rapidly increased in breadth and depth, instructors are challenged not only to provide undergraduate science students with a strong, up-to-date foundation of knowledge, but also to engage them in the scientific process. To these ends, revision of the Cell Biology Lab course at the University of Wisconsin-La Crosse was undertaken to allow student involvement in experimental design, emphasize data collection and analysis, make connections to the “big picture,” and increase student interest in the field. Multiweek laboratory modules were developed as a method to establish an inquiry-based learning environment. Each module utilizes relevant techniques to investigate one or more questions within the context of a fictional story, and there is a progression during the semester from more instructor-guided to more open-ended student investigation. An assessment tool was developed to evaluate student attitudes regarding their lab experience. Analysis of five semesters of data strongly supports the module format as a successful model for inquiry education by increasing student interest and improving attitude toward learning. In addition, student performance on inquiry-based assignments improved over the course of each semester, suggesting an improvement in inquiry-related skills.
Students Investigating the Antiproliferative Effects of Synthesized Drugs on Mouse Mammary Tumor Cells
Authors: Hammamieh Rasha , Anderson Margery , Carr Katharine , Tran Christine N. , Yourick Debra L. , Jett Marti
Published: November 2005

The potential for personalized cancer management has long intrigued experienced researchers as well as the naïve student intern. Personalized cancer treatments based on a tumor's genetic profile are now feasible and can reveal both the cells' susceptibility and resistance to chemotherapeutic agents. In a weeklong laboratory investigation that mirrors current cancer research, undergraduate and advanced high school students determine the efficacy of common pharmacological agents through in vitro testing. Using mouse mammary tumor cell cultures treated with “unknown” drugs historically recommended for breast cancer treatment, students are introduced to common molecular biology techniques from in vitro cell culture to fluorescence microscopy. Student understanding is assessed through laboratory reports and the successful identification of the unknown drug. The sequence of doing the experiment, applying logic, and constructing a hypothesis gives the students time to discover the rationale behind the cellular drug resistance assay. The breast cancer experiment has been field tested during the past 5 yr with more than 200 precollege/undergraduate interns through the Gains in the Education of Mathematics and Science program hosted by the Walter Reed Army Institute of Research.
Pore-pressure detection sensitivities tested with time-lapse seismic data
Authors: Kvam Øyvind , Landrø Martin
Published: November 2005

In an exploration context, pore-pressure prediction from seismic data relies on the fact that seismic velocities depend on pore pressure. Conventional velocity analysis is a tool that may form the basis for obtaining interval velocities for this purpose. However, velocity analysis is inaccurate, and in this paper we focus on the possibilities and limitations of using velocity analysis for pore-pressure prediction. A time-lapse seismic data set from a segment that has undergone a pore-pressure increase of 5 to 7 MPa between the two surveys is analyzed for velocity changes using detailed velocity analysis. A synthetic time-lapse survey is used to test the sensitivity of the velocity analysis with respect to noise. The analysis shows that the pore-pressure increase cannot be detected by conventional velocity analysis because the uncertainty is much greater than the expected velocity change for a reservoir of the given thickness and burial depth. Finally, by applying amplitude-variation-with-offset (AVO) analysis to the same data, we demonstrate that seismic amplitude analysis may yield more precise information about velocity changes than velocity analysis.
Central nervous system lymphoma associated with mycophenolate mofetil in lupus nephritis
Authors: Dasgupta N , Gelber A C , Racke F , Fine D M
Published: November 2005

Lymphomas, both within and outside the central nervous system, are uncommon among patients with systemic lupus erythematosus (SLE). We describe a 58-year old Korean woman with SLE who presented with acute headache and confusion in the setting of prednisone and mycophenolate mofetil (MMF) therapy used to treat focal proliferative and membranous lupus nephritis. Three-dimensional brain magnetic resonance imaging (MRI) showed two peripherally (‘ring’) enhancing lesions within the basal ganglia, bilaterally, with associated mass effect and subfalcine herniation. A brain biopsy revealed an Epstein-Barr virus (EBV)-positive diffuse large B cell lymphoma. This is the first description of CNS lymphoma in a patient treated with MMF for lupus nephritis. While intracerebral lymphoma in the immunocompromised patient with lupus is rare, this disorder should be considered in the differential diagnosis of new-onset neurological symptoms among such patients.