bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Bacterial Acetyl Coenzyme A Carboxylase Inhibitors with Antibiotic Efficacy In Vivo
Authors: Freiberg C. , Pohlmann J. , Nell P. G. , Endermann R. , Schuhmacher J. , Newton B. , Otteneder M. , Lampe T. , Häbich D. , Ziegelbauer K.
Published: July 2006

The pseudopeptide pyrrolidinedione antibiotics, such as moiramide B, have recently been discovered to target the multisubunit acetyl coenzyme A (acetyl-CoA) carboxylases of bacteria. In this paper, we describe synthetic variations of each moiety of the modularly composed pyrrolidinediones, providing insight into structure-activity relationships of biochemical target activity, in vitro potency, and in vivo efficacy. The novel derivatives showed highly improved activities against gram-positive bacteria compared to those of previously reported variants. The compounds exhibited a MIC
90
value of 0.1 μg/ml against a broad spectrum of
Staphylococcus aureus
clinical isolates. No cross-resistance to antibiotics currently used in clinical practice was observed. Resistance mutations induced by pyrrolidinediones are exclusively located in the carboxyltransferase subunits of the bacterial acetyl-CoA carboxylase, indicating the identical mechanisms of action of all derivatives tested. Improvement of the physicochemical profile was achieved by salt formation, leading to aqueous solubilities of up to 5 g/liter. For the first time, the in vitro activity of this compound class was compared with its in vivo efficacy, demonstrating a path from compounds weakly active in vivo to agents with significant efficacy. In a murine model of
S. aureus
sepsis, the 100% effective dose of the best compound reported was 25 mg/kg of body weight, only fourfold higher than that of the comparator molecule linezolid. The obvious improvements achieved by chemical derivatization reflect the potential of this novel antibiotic compound class for future therapy.
Phase II, Randomized, Double-Blind, Multicenter Study Comparing the Safety and Pharmacokinetics of Tefibazumab to Placebo for Treatment of
Staphylococcus aureus
Bacteremia
Authors: Weems J. John , Steinberg James P. , Filler Scott , Baddley John W. , Corey G. Ralph , Sampathkumar Priya , Winston Lisa , John Joseph F. , Kubin Christine J. , Talwani Rohit , Moore Thomas , Patti Joseph M. , Hetherington Seth , Texter Michele , Wenzel Eric , Kelley Violet A. , Fowler Vance G.
Published: July 2006

Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious
Staphylococcus aureus
infections. Sixty patients with documented
S. aureus
bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 μg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.
Antibiotic Coresistance in Extended-Spectrum-β-Lactamase-Producing
Enterobacteriaceae
and In Vitro Activity of Tigecycline
Authors: Morosini María-Isabel , García-Castillo María , Coque Teresa M. , Valverde Aránzazu , Novais Ângela , Loza Elena , Baquero Fernando , Cantón Rafael
Published: July 2006

The spread of extended-spectrum-β-lactamase (ESBL)-producing organisms, particularly those harboring the CTX-M-type enzymes, both in the hospital and in the community, is difficult to discontinue due to the successful mobilization and evolution of the genetic elements harboring ESBL genes and coresistance rates in these isolates. The activities of tigecycline against 285 non-clonally related isolates (172 from
Escherichia coli
, 84 from
Klebsiella
spp., 20 from
Enterobacter
spp., 5 from
Salmonella
spp., and 4 from
Citrobacter
spp.) expressing well-characterized ESBLs and recovered in our hospital and its community area of influence were comparatively assessed (CLSI microdilution). Susceptibility rates for meropenem, imipenem, tigecycline, amikacin, and piperacillin-tazobactam were 100%, 100%, 97.5%, 93.3%, and 93%, respectively. Tigecycline (mode MIC, 0.5 μg/ml; MIC
90
, 1 μg/ml) was 4- to 256-fold more active than doxycycline and minocycline (mode MIC range, 2 to 128 μg/ml). CTX-Ms were the most frequent ESBLs (61.4%), 65.8% in community and 58.6% in nosocomial isolates. CTX-M-9 (22%), CTX-M-14 (15.8%), and CTX-M-10 (14%) were the most represented derivatives. SHV and TEM variants constituted 22.8% and 15.8% of the ESBLs, respectively. Overall coresistance rates were as follows: gentamicin, 27.4%; tobramycin, 27.4%; amikacin, 6.7%; and chloramphenicol, 29.1%. Sulfonamide (61.7%), trimethoprim (52.3%), streptomycin (50.5%), and ciprofloxacin (37.2%) resistance levels were significantly (
P
< 0.001) associated with CTX-M-9 producers. No tigecycline resistance was observed, although seven
Klebsiella pneumoniae
isolates exhibited intermediate MICs (4 μg/ml). Tigecycline, lacking cross-resistance with other compounds, could represent an opportunity to reduce the intensity of selection for ESBL-producing organisms derived from the use of other antimicrobial agents. However, this in vitro promise requires support from clinical studies.
In Vitro Activities of Dalbavancin and 12 Other Agents against 329 Aerobic and Anaerobic Gram-Positive Isolates Recovered from Diabetic Foot Infections
Authors: Goldstein Ellie J. C. , Citron Diane M. , Warren Yumi A. , Tyrrell Kerin L. , Merriam C. Vreni , Fernandez Helen T.
Published: July 2006

Tests of dalbavancin's in vitro activity against 209 aerobic and 120 anaerobic isolates from pretreatment diabetic foot infections showed an MIC
90
of ≤0.125 μg/ml against methicillin-susceptible
Staphylococcus aureus
(MSSA), methicillin-resistant
S. aureus
(MRSA), and 120 anaerobes (
Clostridium perfringens
, other clostridia,
Peptoniphilus asaccharolyticus
,
Finegoldia magna
, and
Anaerococcus prevotii
), compared to respective MIC
90
s for MSSA and MRSA of 0.5 and 1 μg/ml for vancomycin, 4 and 4 μg/ml for linezolid, 0.5 and 0.5 μg/ml for daptomycin, and 0.25 and >8 μg/ml for clindamycin.
Evolution of Drug Resistance in Different Sublineages of
Mycobacterium tuberculosis
Beijing Genotype
Authors: Mokrousov Igor , Jiao Wei Wei , Sun Gui Zhi , Liu Jia Wen , Valcheva Violeta , Li Mo , Narvskaya Olga , Shen A Dong
Published: July 2006

We compared the population structure and drug resistance patterns of the
Mycobacterium tuberculosis
strains currently circulating in the Beijing area of China. One hundred thirteen of 123 strains belonged to the Beijing family genotypes defined by spoligotyping. The Beijing genotype strains were further subdivided into old and modern sublineages on the basis of NTF locus analysis. A stronger association with resistance to the more recently introduced antituberculosis drugs has been observed for old versus modern strains of the Beijing genotype, suggesting that its different sublineages may differ in their mechanisms of adaptation to drug selective pressure.
Gene-Specific Effects of Antisense Phosphorodiamidate Morpholino Oligomer-Peptide Conjugates onEscherichia coliandSalmonella entericaSerovar Typhimurium in Pure Culture and inTissue Culture
Authors: Tilley Lucas D. , Hine Orion S. , Kellogg Jill A. , Hassinger Jed N. , Weller Dwight D. , Iversen Patrick L. , Geller Bruce L.
Published: July 2006

The objective was to improve efficacy of antisense phosphorodiamidate morpholino oligomers (PMOs) by improving their uptake into bacterial cells. Four different bacterium-permeating peptides, RFFRFFRFFXB, RTRTRFLRRTXB, RXXRXXRXXB, and KFFKFFKFFKXB (X is 6-aminohexanoic acid and B isβ -alanine), were separately coupled to two different PMOs that are complementary to regions near the start codons of a luciferase reporter gene (luc) and a gene required for viability (acpP). Luc peptide-PMOs targeted tolucinhibited luciferase activity 23 to 80% in growing cultures ofEscherichia coli. In cell-free translation reactions, Luc RTRTRFLRRTXB-PMO inhibited luciferase synthesis significantly more than the other Luc peptide-PMOs or the Luc PMO not coupled to peptide. AcpP peptide-PMOs targeted toacpPinhibited growth ofE. coliorSalmonella entericaserovar Typhimurium to various extents, depending on the strain. The concentrations of AcpP RFFRFFRFFXB-PMO, AcpP RTRTRFLRRTXB-PMO, AcpP KFFKFFKFFKXB-PMO, and ampicillin that reduced CFU/ml by 50% after 8 h of growth (50% inhibitory concentration [IC50]) were 3.6, 10.8, 9.5, and 7.5μ M, respectively, inE. coliW3110. Sequence-specific effects of AcpP peptide-PMOs were shown by rescuing growth of a merodiploid strain that expressedacpPwith silent mutations in the region targeted by AcpP peptide-PMO. In Caco-2 cultures infected with enteropathogenicE. coli(EPEC), 10 μM AcpP RTRTRFLRRTXB-PMO or AcpP RFFRFFRFFXB-PMO essentially cleared the infection. The IC50of either AcpP RTRTRFLRRTXB-PMO or AcpP RFFRFFRFFXB-PMO in EPEC-infected Caco-2 culture was 3 μM. In summary, RFFRFFRFFXB, RTRTRFLRRTXB, or KFFKFFKFFXB, when covalently bonded to PMO, significantly increased inhibition of expression of targeted genes compared to PMOs without attached peptide.
SCALAR WAVES IN A WORMHOLE TOPOLOGY
Authors: BUĞDAYCI NECMI
Published: July 2006

Global monochromatic solutions of the scalar wave equation are obtained in flat wormholes of dimensions (2+1) and (3+1). The solutions are in the form of infinite series involving cylindrical and spherical wave functions, and they are elucidated by the multiple scattering method. Explicit solutions for some limiting cases are illustrated as well. The results presented in this work constitute instances of solutions of the scalar wave equation in a space–time admitting closed time-like curves.
MASSLESS SPINNING TEST PARTICLES IN ALGEBRAICALLY SPECIAL VACUUM SPACE–TIMES
Authors: BINI DONATO , CHERUBINI CHRISTIAN , GERALICO ANDREA , JANTZEN ROBERT T.
Published: July 2006

The motion of massless spinning test particles is investigated using the Newman–Penrose formalism within the Mathisson–Papapetrou model extended to massless particles by Mashhoon and supplemented by the Pirani condition. When the "multipole reduction world line" lies along a principal null direction of an algebraically special vacuum space–time, the equations of motion can be explicitly integrated. Examples are given for some familiar space–times of this type in the interest of shedding some light on the consequences of this model.
ENTRAINMENT COEFFICIENT AND EFFECTIVE MASS FOR CONDUCTION NEUTRONS IN NEUTRON STAR CRUST: MACROSCOPIC TREATMENT
Authors: CARTER BRANDON , CHAMEL NICOLAS , HAENSEL PAWEL
Published: July 2006

Phenomena such as pulsar frequency glitches are believed to be attributable to differential rotation of a current of "free" superfluid neutrons at densities above the "drip" threshold in the ionic crust of a neutron star. Such relative flow is shown to be locally describable by adaption of a canonical two-fluid treatment that emphasizes the role of the momentum covectors constructed by differentiation of action with respect to the currents, with allowance for stratification whereby the ionic number current may be conserved even when the ionic charge number Z is altered by beta processes. It is demonstrated that the gauge freedom to make different choices of the chemical basis determining which neutrons are counted as "free" does not affect their "superfluid" momentum covector, which must locally have the form of a gradient (though it does affect the "normal" momentum covector characterizing the protons and those neutrons that are considered to be "confined" in the nuclei). It is shown how the effect of "entrainment" (whereby the momentum directions deviate from those of the currents) is controlled by the (gauge-independent) mobility coefficient [Formula: see text], estimated in recent microscopical quantum mechanical investigations, which suggest that the corresponding (gauge-dependent) "effective mass" m⋆ of the free neutrons can become very large in some layers. The relation between this treatment of the crust layers and related work (using different definitions of "effective mass") intended for the deeper core layers is discussed.
Suppression of endogenous testosterone production attenuates the response to strength training: a randomized, placebo-controlled, and blinded intervention study
Authors: Kvorning Thue , Andersen Marianne , Brixen Kim , Madsen Klavs
Published: July 2006

We hypothesized that suppression of endogenous testosterone would inhibit the adaptations to strength training in otherwise healthy men. Twenty-two young men with minor experience with strength training participated in this randomized, placebo-controlled, double-blinded intervention study. The subjects were randomized to treatment with the GnRH analog goserelin (3.6 mg) or placebo (saline) subcutaneously every 4 wk for 12 wk. The strength training period of 8 wk, starting at week 4, included exercises for all major muscles [3–4 sets per exercise × 6–10 repetitions with corresponding 6- to 10-repetition maximum (RM) loads, 3/wk]. A strength test, blood sampling, and whole body DEXA scan were performed at weeks 4 and 12. Endogenous testosterone decreased significantly ( P < 0.01) in the goserelin group from 22.6 ± 5.5 (mean ± SD) nmol/l to 2.0 ± 0.5 ( week 4) and 1.1 ± 0.6 nmol/l ( week 12), whereas it remained constant in the placebo group. The goserelin group showed no changes in isometric knee extension strength after training, whereas the placebo group increased from 240.2 ± 41.3 to 264.1 ± 35.3 Nm ( P < 0.05 within and P = 0.05 between groups). Lean mass of the legs increased 0.37 ± 0.13 and 0.57 ± 0.30 kg in the goserelin and placebo groups, respectively ( P < 0.05 within and P = 0.05 between groups). Body fat mass increased 1.4 ± 1.0 kg and decreased 0.6 ± 1.2 kg in the goserelin and placebo groups, respectively ( P < 0.05 within and between groups). We conclude that endogenous testosterone is of paramount importance to the adaptation to strength training.
Prostaglandin E2is a potent inhibitor of epithelial-to-mesenchymal transition: interaction with hepatocyte growth factor
Authors: Zhang Aihua , Wang Mong-Heng , Dong Zheng , Yang Tianxin
Published: July 2006

Epithelial-to-mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of tubulointerstitial fibrosis. EMT is typically induced by transforming growth factor-β1(TGF-β1) and inhibited by hepatocyte growth factor (HGF). The present study was undertaken to evaluate the potential role of cyclooxygenase (COX)-2-derived PGE2in regulation of EMT in cultured Madin-Darby canine kidney (MDCK) cells, in the setting of HGF treatment. Exposure to 50 ng/ml HGF significantly induced COX-2 protein expression and PGE2release, whereas other growth factors, including epidermal growth factor, the insulin-like growth factor I protein, platelet-derived growth factor-BB, and TGF-β1, had no effects on COX-2 expression or PGE2release. COX-2 induction by HGF was preceded by activation of ERK1/2, and an ERK1/2-specific inhibitor, U-0126 (10 μM), completely abolished HGF-induced COX-2 expression. Exposure of MDCK cells to 10 ng/ml TGF-β1for 72 h induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and activation of α-smooth muscle actin. In contrast, treatment with 1 μM PGE2completely blocked EMT, associated with a significant elevation of intracellular cAMP and complete blockade of TGF-β1-induced oxidant production. cAMP-elevating agents, including 8-Br-cAMP, forskolin, and IBMX, inhibited EMT and associated oxidative stress induced by TGF-β1, but inhibition of cAMP pathway with Rp-cAMP, the cAMP analog, and H89, the protein kinase A (PKA) inhibitor, did not block the effect of PGE2. The effect of HGF on EMT was inhibited by ∼50% in the presence of a COX-2 inhibitor SC-58635 (10 μM). Therefore, our data suggest that PGE2inhibits EMT via inhibition of oxidant production and COX-2-derived PGE2partially accounts for the antifibrotic effect of HGF.
Odor-Driven Activity in the Olfactory Cortex of an In Vitro Isolated Guinea Pig Whole Brain With Olfactory Epithelium
Authors: Ishikawa Takahiro , Sato Takaaki , Shimizu Akira , Tsutsui Ken-Ichiro , de Curtis Marco , Iijima Toshio
Published: July 2006

We developed a new technique to isolate a whole guinea pig brain with an intact olfactory epithelium (OE) that enables us to access the ventral surface of the brain including olfactory areas with ease during natural odor stimulation. We applied odorants to OE and confirmed that odor-induced local field potentials (LFPs) could be induced in olfactory areas. In the olfactory bulb (OB) and the piriform cortex (PC), odor-induced LFPs consisted of a phasic initial component followed by a fast activity oscillation in the beta range (20 Hz). To understand the neural mechanisms of odor-induced responses especially in the anterior PC, we analyzed odor-induced LFPs, together with unit activity data. We confirmed that the initial component of odor-induced response has a characteristic temporal pattern, generated by a relatively weak direct afferent input, followed by an intra-cortical associative response, which was associated with a phasic inhibition. The beta oscillation might be formed by the repetition of these network activities. These electrophysiological data were consistent with the results of previous studies that used slice or in vivo preparations, suggesting that the olfactory neural network and activities of the brain are preserved in our new in vitro preparation. This study provides the basis for clarifying the sequence of neural activities underlying odor information processing in the brain in vitro following natural olfactory stimulation.
Management of Early Hemorrhage from Pancreatic Anastomoses after Pancreaticoduodenectomy
Authors: Wente Moritz N. , Shrikhande Shailesh V. , Kleeff Jörg , Müller Michael W. , Gutt Carsten N. , Büchler Markus W. , Friess Helmut
Published: July 2006

Background: Pancreatic surgery remains a challenge with considerable morbidity rates. The leading cause of emergency reexploration is early postoperative hemorrhage due to technical failure of hemostasis. Failure of hemostasis is usually tackled without difficulty, except when the bleeding arises from pancreatic anastomosis, since it poses a unique surgical challenge of preserving its integrity and also controlling the hemorrhage. The practical aspects and outcomes of management of this complication are unclear, with limited data. Methods: Data from 458 patients undergoing pancreaticoduodenectomy were analyzed. Early hemorrhage emanating from pancreatic anastomoses resulting in a relaparotomy was identified. Results: Eight patients (1.7%) had pancreatic anastomotic bleeding. The initial 2 patients underwent completion pancreatectomy, and the latter 6 patients underwent enterotomy with control of bleeding without disturbing the pancreatic anastomosis. The median interval between primary surgery and relaparotomy was 30.5 h, with a median overall hospital stay of 26.5 days; the 90-day mortality was zero. Based on these results, a step-by-step illustrated approach is described. Conclusions: This uncommon complication of early hemorrhage from pancreaticojejunostomy after pancreaticoduodenectomy can be successfully managed by an enterotomy without endangering the pancreatic anastomosis. By this approach, a completion pancreatectomy may be prevented and the integrity of the anastomosis preserved.
Irinotecan Combined with Infusional 5-Fluorouracil and High-Dose Leucovorin for the Treatment of Advanced Gastric Carcinoma as the First-Line Chemotherapy
Authors: Yilmaz Ugur , Oztop Ilhan , Alacacioglu Ahmet , Yaren Arzu , Tarhan Oktay , Somali Isil
Published: July 2006

Background: Because of insufficient activity and high toxicity of current chemotherapy regimens in advanced gastric cancer (AGC), there is a need for newer regimens. Methods: Twenty-five chemonaive patients with AGC have been treated with FOLFIRI regimen consisting of irinotecan 180 mg/m2 over 30 min on day 1 combined with leucovorin 200 mg/m2 over 2 h followed by 5-fluorouracil 400 mg/m2 as bolus and 600 mg/m2 as a 22-hour infusion on day 1 and 2. The treatment was administered every 14th day until progression or intolerable toxicity. Results: Twenty-five patients (17 male, 8 female; 22 patients with PS 0–1 and 3 patients with PS 2), median age 54 (range 25–77), received a total of 230 courses of chemotherapy (median 9; range 1–18). Objective responses were observed in 9 patients (36%), all being partial. Median progression-free survival, 1- and 2-year progression-free survival rates were 8.6 months, 28.4% and 15.3%, respectively. Median overall survival, 1- and 2-year overall survival rates were 11.6 months, 48.0% and 17.8%, respectively. As serious adverse events, grade 3–4 neutropenia was observed in 5 patients (20.0%), grade 3 diarrhea in 4 patients (16.0%). No treatment-related death occurred. Conclusion: FOLFIRI regimen is an active regimen with acceptable toxicity for the treatment of AGC.
Proteomic Analysis of Serum, Outflow Dialysate and Adsorbed Protein onto Dialysis Membranes (Polysulfone and PMMA) during Hemodialysis Treatment Using SELDI-TOF-MS
Authors: Ishikawa Isao , Chikazawa Yoshihiro , Sato Kazumasa , Nakagawa Masaru , Imamura Hidetsugu , Hayama Satoshi , Yamaya Hideki , Asaka Mitsuhiro , Tomosugi Naohisa , Yokoyama Hitoshi , Matsumoto Keiji
Published: July 2006

Aims: Alterations in the profiling of peptides and proteins in the serum, outflow dialysate and adsorbed protein on the dialysis membrane were investigated. Methods: Alterations in the protein profiling of routine hemodialysis using polysulfone (TS-UL) and PMMA (moderate flux membrane of polymethylmethacrylate: BK-U) in 8 patients and that of adsorption onto polysulfone and PMMA membranes in 4 patients were evaluated by SELDI-TOF-MS and ProteinChip array. Mass-to-charge ratios (m/z) between 2,000 and 120,000 were analyzed. Results: The protein with a relative intensity of m/z 11,730 measured by SELDI-TOF-MS was present in a small amount in the outflow dialysate and in a large amount in adsorption (identified as β2-microglobulin) onto PMMA membrane. Unexpectedly, 68 molecular masses of peptides that were adsorbed more onto polysulfone than onto PMMA membrane were observed. There were more peptides less than m/z 11,730 adsorbed onto polysulfone membrane than onto PMMA membrane. Dominant peaks, m/z 6,629 and 6,431 adsorbed onto polysulfone membrane were identified as apolipoprotein CI and truncated apolipoprotein CI, respectively. 37 proteins with molecular weights larger than m/z 11,730 showed greater filtration through PMMA membrane than through polysulfone membrane. 149 molecular masses that were adsorbed onto PMMA or more onto PMMA membrane than onto polysulfone membrane were observed. Conclusion: This experiment suggests that membrane adsorption is an important mechanism for the removal of middle-molecular-weight proteins by hemodialysis using not only PMMA membrane but also polysulfone membrane. Adsorption of peptide or protein onto a dialysis membrane may depend not only on the membrane material, but also on the peptide or protein.
Four-Dimensional Data Assimilation and Balanced Dynamics
Authors: Neef Lisa J. , Polavarapu Saroja M. , Shepherd Theodore G.
Published: July 2006

The problem of spurious excitation of gravity waves in the context of four-dimensional data assimilation is investigated using a simple model of balanced dynamics. The model admits a chaotic vortical mode coupled to a comparatively fast gravity wave mode, and can be initialized such that the model evolves on a so-called slow manifold, where the fast motion is suppressed. Identical twin assimilation experiments are performed, comparing the extended and ensemble Kalman filters (EKF and EnKF, respectively). The EKF uses a tangent linear model (TLM) to estimate the evolution of forecast error statistics in time, whereas the EnKF uses the statistics of an ensemble of nonlinear model integrations.

Specifically, the case is examined where the true state is balanced, but observation errors project onto all degrees of freedom, including the fast modes. It is shown that the EKF and EnKF will assimilate observations in a balanced way only if certain assumptions hold, and that, outside of ideal cases (i.e., with very frequent observations), dynamical balance can easily be lost in the assimilation. For the EKF, the repeated adjustment of the covariances by the assimilation of observations can easily unbalance the TLM, and destroy the assumptions on which balanced assimilation rests. It is shown that an important factor is the choice of initial forecast error covariance matrix. A balance-constrained EKF is described and compared to the standard EKF, and shown to offer significant improvement for observation frequencies where balance in the standard EKF is lost. The EnKF is advantageous in that balance in the error covariances relies only on a balanced forecast ensemble, and that the analysis step is an ensemble-mean operation. Numerical experiments show that the EnKF may be preferable to the EKF in terms of balance, though its validity is limited by ensemble size. It is also found that overobserving can lead to a more unbalanced forecast ensemble and thus to an unbalanced analysis.
Very Early Formation of Big, Liquid Drops Revealed by ZDR in Continental Cumulus
Authors: Knight Charles A.
Published: July 2006

Examination of the early radar echo histories of several vigorous, cumulus clouds in northeast Colorado and northwest Kansas, with sensitive, dual-polarization radar, reveals the formation of millimeter-sized water drops at about the same time that the conventional, first precipitation echo (from ice) forms aloft. The early, positive ZDR values appear in the vicinity of the 0°C level (the radar data do not specify height accurately) and soon extend both above and below it. Positive ZDR is found within and to the upwind side of the updraft, separate from the conventional first precipitation echoes, which appear first at higher altitude, generally downwind of the updraft core, and have no significantly positive ZDR. Big, liquid drops were not expected this early in the formation of continental cumulus. The early presence of supercooled water drops larger than cloud droplets may be a significant factor in the glaciation of these clouds.

The kind of early radar coverage illustrated here would be a priceless adjunct to aircraft studies of precipitation formation in cumulus. Microphysical data from aircraft must be interpreted with numerical models in order to deduce (or verify) the processes, and such models require the kind of early data illustrated here, both for initialization and verification.
Parameterization of Pressure Perturbations in a PBL Mass-Flux Model
Authors: Lappen Cara-Lyn , Randall David A.
Published: July 2006

In a companion paper, the authors presented a boundary layer parameterization that was based on the mass-flux concept and included an internally consistent representation of the vertical flux of horizontal momentum. In the present paper, the authors show how the framework of that model can be used to determine the perturbation pressure field, by solving the anelastic pressure equation. The pressure covariances needed to close the parameterization can then be diagnosed. Tests show very encouraging agreement of the pressure statistics with results obtained from large-eddy simulations.
Estimating Open-Ocean Barotropic Tidal Dissipation: The Hawaiian Ridge
Authors: Zaron Edward D. , Egbert Gary D.
Published: July 2006

The generalized inverse of a regional model is used to estimate barotropic tidal dissipation along the Hawaiian Ridge. The model, based on the linear shallow-water equations, incorporates parameterizations for the dissipation of energy via friction in the bottom boundary layer and form drag due to internal waves generated at topographic slopes. Sea surface height data from 364 orbit cycles of the Ocean Topography Experiment (TOPEX)/Poseidon satellite mission are used to perform inversions at eight diurnal and semidiurnal tidal frequencies. It is estimated that the barotropic M2 tide loses energy at a rate of 19 GW, of which 88% is lost within 250 km of the ridge, presumably via conversion to the internal or baroclinic tide. Uncertainty in the assumed model error and wave drag in the forward model suggest that M2 dissipation values from 18 to 25 GW are consistent with the altimetric observations. Other barotropic tidal constituents are estimated to lose a total of 5.7 GW. The spatial distribution of barotropic dissipation along the ridge is similar to that inferred from three-dimensional primitive equation models, and it is largely insensitive to details of assumed model and data errors. Dissipation at semidiurnal frequencies is most intense at the French Frigate Shoals with lesser, but significant, contributions at other sites. Diurnal tidal dissipation is concentrated to the east of the French Frigate Shoals, at the Gardner Pinnacles. Further work with three-dimensional models will be necessary to determine the fate of the energy that is removed from the barotropic tide.
Persistent Near-Diurnal Internal Waves Observed above a Site of M2 Barotropic-to-Baroclinic Conversion
Authors: Carter Glenn S. , Gregg Michael C.
Published: July 2006

Near-diurnal internal waves were observed in velocity and shear measurements from a shipboard survey along a 35-km section of the Kaena Ridge, northwest of Oahu. Individual waves with upward phase propagation could be traced for almost 4 days even though the ship transited approximately 20 km. Depth–time maps of shear were dominated by near-diurnal waves, despite the fact that Kaena Ridge is a site of considerable M2 barotropic-to-baroclinic conversion. Guided by recent numerical and observational studies, it was found that a frequency of ½M2 (i.e., 24.84-h period) was consistent with these waves. Nonlinear processes are able to transfer energy within the internal wave spectrum. Bicoherence analysis, which can distinguish between nonlinearly coupled waves and waves that have been independently excited, suggested that the ½M2 waves were nonlinearly coupled with the dominant M2 internal tide only between 525- and 595-m depth. This narrow depth range corresponded to an observed M2 characteristic emanating from the northern edge of the ridge. The observations occurred in close proximity to the internal tide generation region, implying a rapid transfer of energy between frequencies. Strong nonlinear interactions seem a likely mechanism. Nonlinear transfers such as these could complicate attempts to close local single-constituent tidal energy budgets.
The Morality of Value- and Purpose-Rationality
Authors: Rutgers Mark R. , Schreurs Petra
Published: July 2006

Max Weber's distinction between purpose- and value-rationality is almost universally accepted in administrative theory. Its precise meaning is, however, unclear. In this article, more insight into the nature of Weber's distinction is claimed by approaching it from a (neo-) Kantian perspective. It is claimed that the Kantian contrast between autonomy and heteronomy of the will and the distinction between absolute and relative ends is at the heart of Weber's distinction. This implies that the distinction has paradoxical underpinnings as it is rooted in a moral context that does not fit Weber's sociological approach.
Emergent Accountability in State–Local Relations
Authors: O'Connell Lenahan
Published: July 2006

Applying Kearns's concept of the “accountability environment, ” this study of a reform of solid waste policy finds that the relationship between the state and local jurisdictions can best be described as structured by mechanisms of emergent accountability. After distinguishing hierarchical from emergent accountability, the author tests the following hypothesis: Under a structure of emergent accountability, progress toward a stated goal will be partial, as initial success plateaus short of full attainment. The findings support the hypothesis. It is recommended that future research on accountability relate the structure of the accountability environment to the level of outcomes achieved.
Enchantment, Weak Ontologies, and Administrative Ethics
Authors: Howe Louis E.
Published: July 2006

The article contributes to an enlivening of ethical discourse by employing the notion of weak ontology. Weak ontologies insist that fundamental sources of inspiration, or “ontostories, ” are indispensable to a vital ethics, even as it admits that every onto-story is contestable. The article considers powerful perspectives that militate against implementing weak ontology: liberalism's conception of the neutral framework and Max Weber's characterization of the modern world as disenchanted. The article argues that these two perspectives contribute to a nay-saying ethic and a negative form of governance because the disenchanted world they describe is too hard to love. The article ends with an examination of an ethical perspective that seeks to overturn the disenchantment story by cultivating a nontheistic experience of enchantment.
The Principle of Least Interest
Authors: Sprecher Susan , Schmeeckle Maria , Felmlee Diane
Published: July 2006

Data from a longitudinal sample of dating couples (some of whom married) were analyzed to test the aspect of Waller’s (1938) principle of least interest that states that unequal emotional involvement between romantic partners has implications for relationship quality and stability. Both members of the couples were asked multiple times over several years which partner, if either, was more emotionally involved. Perceptions of unequal emotional involvement were common and tended to remain stable over time. Less emotionally involved partners perceived themselves as having more control over the continuation of their relationships. Equal emotional involvement was associated with greater relationship satisfaction and stability. Concurrent and retrospective perceptions of relative emotional involvement were associated with several aspects of relationship breakup within the subsample of those who broke up during the study. Perceptions of emotional involvement have many implications for dating couples, including being linked to relationship satisfaction and other outcomes.
Ethical Climates and Contextual Predictors of Whistle-Blowing
Authors: Rothwell Gary R. , Baldwin J. Norman
Published: July 2006

This article presents the results of a study that investigates ethical climate theory and eight contextual predictors of willingness to blow the whistle and frequency of whistle-blowing on seven forms of misconduct. Although three of the ethical climates investigated demonstrate relationships with whistle-blowing intentions and actions, the ethical climates generally fail to predict whistle-blowing consistently. Instead, supervisory status emerges as the most consistent predictor of intentions and behaviors. Contrary to popular belief, civilian status also demonstrates significant negative relationships with whistle-blowing. Police are less inclined than civilian employees to maintain a code of silence.
Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death
Authors: Fritzsching Benedikt , Oberle Nina , Pauly Eva , Geffers Robert , Buer Jan , Poschl Johannes , Krammer Peter , Linderkamp Otwin , Suri-Payer Elisabeth
Published: July 2006

Most CD4+CD25hiFOXP3+ regulatory T cells (Tregs) from adult peripheral blood express high levels of CD45RO and CD95 and are prone to CD95L-mediated apoptosis in contrast to conventional T cells (Tconvs). However, a Treg subpopulation remained consistently apoptosis resistant. Gene microarray and 6-color flow cytometry analysis including FOXP3 revealed an increase in naive T-cell markers on the CD95L-resistant Tregs compared with most Tregs. In contrast to Tregs found in adult humans, most CD4+CD25+FOXP3+ T cells found in cord blood are naive and exhibit low CD95 expression. Furthermore, most of these newborn Tregs are not sensitive toward CD95L similar to naive Tregs from adult individuals. After short stimulation with anti-CD3/CD28 monoclonal antibodies (mAbs), cord blood Tregs strongly up-regulated CD95 and were sensitized toward CD95L. This functional change was paralleled by a rapid up-regulation of memory T-cell markers on cord blood Tregs that are frequently found on adult memory Tregs. In summary, we show a clear functional difference between naive and memory Tregs that could result in different survival rates of those 2 cell populations in vivo. This new observation could be crucial for the planning of therapeutic application of Tregs.
Cell cycle related proteins in hyperplasia of usual type in breast specimens of patients with and without breast cancer
Authors: Tafuri Luciene SA , Rocha Gislene FS , Gobbi Helenice
Published: July 2006

Background

Hyperplasia of usual type (HUT) is a common proliferative lesion associated with a slight elevated risk for subsequent development of breast cancer. Cell cycle-related proteins would be helpful to determine the putative role of these markers in the process of mammary carcinogenesis. The aim of this study was to analyze the expression of cell cycle related proteins in HUT of breast specimens of patients with and without breast cancer, and compare this expression with areas of invasive carcinomas.

Results

Immunohistochemical evaluation was performed using antibodies against cell cycle related proteins ER, PR, p53, p21, p63, and Ki-67 in hyperplasia of usual type (HUT) in specimens of aesthetic reduction mammaplasty (ARM), in specimens of mammaplasty contralateral to breast cancer (MCC), and in specimens of invasive mammary carcinomas (IMC) presenting HUT in the adjacent parenchyma. The results showed that the immunoexpression of ER, PR, p21, p53, p63, and KI-67 was similar in HUT from the three different groups. The p63 expression in myoepithelial cells showed discontinuous pattern in the majority of HUT, different from continuous expression in normal lobules. Nuclear expression of p53 and p21 was frequently higher expressed in IMC and very rare in HUT. We also found cytoplasmic expression of p21 in benign hyperplastic lesions and in neoplastic cells of IMC.

Conclusion

Our data failed to demonstrate different expression of cell cycle related proteins in HUT from patients with and without breast cancer. However, we found discontinuous expression of p63 in myoepithelial cells around HUT adjacent to carcinomas and cytoplasmic expression of p21 in epithelial cells of hyperplastic foci. Further studies are needed to determine how these subgroups relate to molecular abnormalities and cancer risk.
Conservation of alternative polyadenylation patterns in mammalian genes
Authors: Ara Takeshi , Lopez Fabrice , Ritchie William , Benech Philippe , Gautheret Daniel
Published: July 2006

Background

Alternative polyadenylation is a widespread mechanism contributing to transcript diversity in eukaryotes. Over half of mammalian genes are alternatively polyadenylated. Our understanding of poly(A) site evolution is limited by the lack of a reliable identification of conserved, equivalent poly(A) sites among species. We introduce here a working definition of conserved poly(A) sites as sites that are both (i) properly aligned in human and mouse orthologous 3' untranslated regions (UTRs) and (ii) supported by EST or cDNA data in both species.

Results

We identified about 4800 such conserved poly(A) sites covering one third of the orthologous gene set studied. Characteristics of conserved poly(A) sites such as processing efficiency and tissue-specificity were analyzed. Conserved sites show a higher processing efficiency but no difference in tissular distribution when compared to non-conserved sites. In general, alternative poly(A) sites are species-specific and involve minor, non-conserved sites that are unlikely to play essential roles. However, there are about 500 genes with conserved tandem poly(A) sites. A significant fraction of these conserved tandems display a conserved arrangement of major/minor sites in their 3' UTR, suggesting that these alternative 3' ends may be under selection.

Conclusion

This analysis allows us to identify potential functional alternative poly(A) sites and provides clues on the selective mechanisms at play in the appearance of multiple poly(A) sites and their maintenance in the 3' UTRs of genes.
Impact of the clinical context on the 14-3-3 test for the diagnosis of sporadic CJD
Authors: Cuadrado-Corrales Natividad , Jiménez-Huete Adolfo , Albo Carmen , Hortigüela Rafael , Vega Luz , Cerrato Laura , Sierra-Moros Maríajosé , Rábano Alberto , de Pedro-Cuesta Jesús , Calero Miguel
Published: July 2006

Background

The 14-3-3 test appears to be a valuable aid for the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) in selected populations. However, its usefulness in routine practice has been challenged. In this study, the influence of the clinical context on the performance of the 14-3-3 test for the diagnosis of sCJD is investigated through the analysis of a large prospective clinical series.

Methods

Six hundred seventy-two Spanish patients with clinically suspected sCJD were analyzed. Clinical classification at sample reception according to the World Health Organization's (WHO) criteria (excluding the 14-3-3 test result) was used to explore the influence of the clinical context on the pre-test probabilities, and positive (PPV) and negative (NPV) predictive values of the 14-3-3 test.

Results

Predictive values of the test varied greatly according to the initial clinical classification: PPV of 98.8%, 96.5% and 45.0%, and NPV of 26.1%, 66.6% and 100% for probable sCJDi (n = 115), possible sCJDi (n = 73) and non-sCJDi (n = 484) cases, respectively. According to multivariate and Bayesian analyses, these values represent an improvement of diagnostic certainty compared to clinical data alone.

Conclusion

In three different contexts of sCJD suspicion, the 14-3-3 assay provides useful information complementary to clinical and electroencephalographic (EEG) data. The test is most useful supporting a clinical impression, whilst it may show deceptive when it is not in agreement with clinical data.
Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis
Authors: Pakozdi Angela , Amin Mohammad A , Haas Christian S , Martinez Rita J , Haines G Kenneth , Santos Lanie L , Morand Eric F , David John R , Koch Alisa E
Published: July 2006

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of bone and cartilage, which is mediated, in part, by synovial fibroblasts. Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes responsible for matrix degradation. Macrophage migration inhibitory factor (MIF) is a cytokine that induces the production of a large number of proinflammatory molecules and has an important role in the pathogenesis of RA by promoting inflammation and angiogenesis.

In the present study, we determined the role of MIF in RA synovial fibroblast MMP production and the underlying signaling mechanisms. We found that MIF induces RA synovial fibroblast MMP-2 expression in a time-dependent and concentration-dependent manner. To elucidate the role of MIF in MMP-2 production, we produced zymosan-induced arthritis (ZIA) in MIF gene-deficient and wild-type mice. We found that MMP-2 protein levels were significantly decreased in MIF gene-deficient compared with wild-type mice joint homogenates. The expression of MMP-2 in ZIA was evaluated by immunohistochemistry (IHC). IHC revealed that MMP-2 is highly expressed in wild-type compared with MIF gene-deficient mice ZIA joints. Interestingly, synovial lining cells, endothelial cells, and sublining nonlymphoid mononuclear cells expressed MMP-2 in the ZIA synovium. Consistent with these results, in methylated BSA (mBSA) antigen-induced arthritis (AIA), a model of RA, enhanced MMP-2 expression was also observed in wild-type compared with MIF gene-deficient mice joints. To elucidate the signaling mechanisms in MIF-induced MMP-2 upregulation, RA synovial fibroblasts were stimulated with MIF in the presence of signaling inhibitors. We found that MIF-induced RA synovial fibroblast MMP-2 upregulation required the protein kinase C (PKC), c-jun N-terminal kinase (JNK), and Src signaling pathways. We studied the expression of MMP-2 in the presence of PKC isoform-specific inhibitors and found that the PKCδ inhibitor rottlerin inhibits MIF-induced RA synovial fibroblast MMP-2 production. Consistent with these results, MIF induced phosphorylation of JNK, PKCδ, and c-jun. These results indicate a potential novel role for MIF in tissue destruction in RA.
Insulin Gene Variable Number of Tandem Repeats (INS VNTR) Genotype and Metabolic Syndrome in Childhood Obesity
Authors: Santoro Nicola , Cirillo Grazia , Amato Alessandra , Luongo Caterina , Raimondo Paolo , D’Aniello Antonietta , Perrone Laura , Miraglia del Giudice Emanuele
Published: July 2006

Objective: The insulin variable number of tandem repeats (VNTR) polymorphism located in the insulin gene promoter (INS VNTR) has been associated with insulin levels in obese children. Hyperinsulinemia is a pivotal factor in the development of metabolic syndrome, an emerging complication in childhood obesity. With the present study, we aimed to test the associations between INS VNTR and the metabolic syndrome in juvenile-onset obesity.

Subjects and Methods: We screened for the INS VNTR in 320 obese children (152 girls; mean age, 11.2 ± 2.3 yr; mean z-score body mass index, 3.6 ± 1.1). All of them underwent a standard oral glucose tolerance test; baseline measurements included blood pressure and plasma lipid and fasting insulin levels. By using the data derived from the oral glucose tolerance test, the whole-body insulin sensitivity and the insulinogenic index were calculated.

Results: The prevalence of metabolic syndrome reached 39%. No differences in INS VNTR genotype distribution were observed between obese subjects and 200 lean, age- and sex-matched children (P = 0.7). Among obese subjects, the prevalence of the metabolic syndrome was significantly higher in subjects with the I/I genotype (P = 0.006); the risk for developing the metabolic syndrome was significantly higher in subjects carrying the I/I genotype (odds ratio, 2.5; 95% confidence interval, 1.5–3.9). Obese subjects homozygous for the class I allele showed higher insulin levels and insulinogenic index but lower whole-body insulin sensitivity.

Conclusions: We conclude that the I variant of the insulin promoter, when expressed in homozygotes, can predispose obese children to develop the metabolic syndrome.