bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinically Relevant Genotype Interpretation of Resistance to Didanosine
Authors: Marcelin Anne-Geneviève , Flandre Philippe , Pavie Juliette , Schmidely Nathalie , Wirden Marc , Lada Olivier , Chiche Dan , Molina Jean-Michel , Calvez Vincent
Published: April 2005

We analyzed the didanosine (ddI) arm of the randomized, placebo-controlled Jaguar trial in order to define a genotypic score for ddI associated with virologic response. In this arm, 111 patients experiencing virologic failure received ddI in addition to their current combination therapy for 4 weeks. The impact of mutations in the reverse transcriptase gene on the virologic response to ddI was studied in univariate analysis. Genotypic score was constructed using step-by-step analyses first including only mutations associated to poorer virologic response (scored as +1), while secondarily, mutations associated to a better response (scored as −1) were also eligible. Eight mutations were associated with a reduced response to ddI, M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F, and K219Q/E, and two mutations were associated with a better response, K70R and M184V/I. The best prediction of the virologic response to ddI was obtained with a composite score comprising mutations added and subtracted (set II, M41L + T69D + L74V+ T215Y/F + K219Q/E − K70R − M184V/I;P= 4.5 × 10−9) and by comparing that to only mutations added (set I, M41L + T69D + L74V + L210W + T215Y/F + K219Q/E;P= 1.2 × 10−7). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log10copies/ml when they were ranked as having a genotypic score II of −2, −1, or 0 or 1 and 2 mutations or more, respectively. In conclusion, we developed and validated a genotypic score, taking into account mutations negatively and positively impacting the virologic response to ddI.
Molecular Characterization of MexL, the Transcriptional Repressor of the
mexJK
Multidrug Efflux Operon in
Pseudomonas aeruginosa
Authors: Chuanchuen Rungtip , Gaynor Jared B. , Karkhoff-Schweizer RoxAnn , Schweizer Herbert P.
Published: April 2005

The
Pseudomonas aeruginosa mexJK
efflux operon is constitutively expressed in mutants with defects in the upstream
mexL
gene, which encodes a repressor of the TetR family. MexL and a MexL
A47D
mutant protein were purified from
Escherichia coli
as fusion proteins with carboxy-terminal hexahistidine tags. Native polyacrylamide gel electrophoresis and size exclusion chromatography revealed that MexL is a tetramer in solution. MexL and MexL
A47D
oligomerization was confirmed using a genetic approach, and the MexL
A47D
mutant protein was not impaired in multimerization. Gel mobility shift and footprinting assays demonstrated that MexL, but not MexL
A47D
, binds specifically to the 94-bp
mexL-mexJ
intergenic region to sequences located between positions −84 and −20 from the
mexJ
initiation codon. MexL protected about 60 nucleotides on each strand, and the protected regions overlapped almost perfectly, a finding consistent with MexL regulating the expression of both
mexL
and
mexJK
, which was ascertained by gene fusion analyses. The protected region contains predicted −10 and −35 promoter sequences for both
mexL
and
mexJ
, with partially overlapping −10 regions. The
mexL
promoter assignment was verified by mapping the
mexL
transcription start site, and the
mexJ
promoter was localized to the predicted regions using
lacZ
fusions. The MexL-protected region contains two inverted GTATTT repeats, and their location in the protected region and overlap with the
mexL
and
mexJ
promoter sequences strongly support a role in MexL binding.
Evaluation by Monte Carlo Simulation of the Pharmacokinetics of Two Doses of Meropenem Administered Intermittently or as a Continuous Infusion in Healthy Volunteers
Authors: Krueger Wolfgang A. , Bulitta Jurgen , Kinzig-Schippers Martina , Landersdorfer Cornelia , Holzgrabe Ulrike , Naber Kurt G. , Drusano George L. , Sörgel Fritz
Published: April 2005

Meropenem is a broad-spectrum carbapenem antibacterial agent. In order to optimize levels in plasma relative to the MICs, the ideal dose level and dosage regimen need to be determined. The pharmacokinetics of meropenem were studied in two groups, each comprising eight healthy volunteers who received the following doses: 500 mg as an intravenous infusion over 30 min three times a day (t.i.d.) versus a 250-mg loading dose followed by a 1,500 mg continuous infusion over 24 h for group A and 1,000 mg as an intravenous infusion over 30 min t.i.d. versus a 500-mg loading dose followed by a 3,000-mg continuous infusion over 24 h for group B. Meropenem concentrations in plasma and urine were determined by liquid chromatography-mass spectrometry/mass spectrometry and high-performance liquid chromatography with UV detection, respectively. Pharmacokinetic calculations were done by use of a two-compartment open model, and the data were extrapolated by Monte Carlo simulations for 10,000 simulated subjects for pharmacodynamic evaluation. There were no significant differences in total clearance and renal clearance between group A and group B or between the intermittent treatment and the continuous infusion. The analyses of the probability of target attainment by MIC for the high- and low-dose continuous infusions were robust up to MICs of 4 mg/liter and 2 mg/liter, respectively. The corresponding values for intermittent infusions were only 0.5 mg/liter and 0.25 mg/liter. When these observations were correlated with MICs obtained from the MYSTIC database, intermittent infusion results in adequate activity against two of the most common nosocomially acquired pathogens,
Klebsiella pneumoniae
and
Enterobacter cloacae
. However, against
Pseudomonas aeruginosa
, the evaluation shows a clear advantage of high-dose therapy administered as a continuous infusion. We believe that in the empirical therapy situation, the continuous-infusion mode of administration is most worth the extra efforts. We conclude that clinical trials for evaluation of the continuous infusions of meropenem in critically ill patients are warranted.
Behavior of Thymidylate Kinase toward Monophosphate Metabolites and Its Role in the Metabolism of 1-(2′-Deoxy-2′-Fluoro-β-
l
-Arabinofuranosyl)-5-Methyluracil (Clevudine) and 2′,3′-Didehydro-2′,3′-Dideoxythymidine in Cells
Authors: Hu Rong , Li Ling , Degrève Bart , Dutschman Ginger E. , Lam Wing , Cheng Yung-Chi
Published: April 2005

l
-Nucleoside analogs are a new class of antiviral and anticancer agents, several of which are currently used in the clinic. The phosphorylation of these agents to the triphosphate form is thought to be important for exertion of their pharmacological activities. 1-(2′-Deoxy-2′-fluoro-β-
l
-arabinofuranosyl)-5-methyluracil (
l
-FMAU; Clevudine) is a thymidine analog that is currently under phase III clinical trials as an anti-human hepatitis B virus agent. We examined the behavior of its monophosphate metabolite with human recombinant thymidylate kinase (TMPK) and showed that
l
-FMAU monophosphate (
l
-FMAUMP) is a poorer substrate than its
d
-configuration anomer (
d
-FMAUMP). The phosphorylation efficiency of
l
-FMAUMP is similar to that of the monophosphate of 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), an anti-human immunodeficiency virus analog, both of which are approximately 1% TMP. To clarify the role of human TMPK in the phosphorylation of
l
-FMAUMP to the diphosphate metabolite in cells, a Tet-On inducible human TMPK cell line system was established. In this system, the expression of TMPK is closely regulated in response to various concentrations of doxycycline. When the cells were treated with
l
-FMAU or d4T, the amounts of the diphosphate and triphosphate metabolites of these analogs were increased, in accordance with an increase in human TMPK activity in cells. In conclusion, this is the first demonstration of the behavior of TMPK toward
l
-FMAUMP. This study indicates that human TMPK can phosphorylate
l
-FMAUMP and play a critical role in
l
-FMAU metabolism in cells.
Seven Novel Variants of the Staphylococcal Chromosomal Cassette
mec
in Methicillin-Resistant
Staphylococcus aureus
Isolates from Ireland
Authors: Shore Anna , Rossney Angela S. , Keane Conor T. , Enright Mark C. , Coleman David C.
Published: April 2005

Methicillin-resistant
Staphylococcus aureus
(MRSA) isolates recovered in Irish hospitals between 1971 and 2002 were characterized using multilocus sequence typing (MLST) (
n
= 130) and SCC
mec
typing (
n
= 172). Where atypical SCC
mec
typing results were obtained, PCR amplification of entire SCC
mec
elements, analysis of amplimer mobility, and nucleotide sequencing were undertaken. MLST revealed that 129/130 isolates had the same genotypes as internationally spread MRSA clones, including ST239, ST247, ST250, ST5, ST22, ST36, and ST8. A novel genotype, ST496, was identified in one isolate. Half of the isolates (86/172) had SCC
mec
type I, IA, II, III, or IV. The remaining 86 isolates harbored novel SCC
mec
variants in three distinct genetic backgrounds: (i) 74/86 had genotype ST8 and either one of five novel SCC
mec
II (IIA, IIB, IIC, IID, and IIE) or one of two novel SCC
mec
IV (IVE and IVF) variants; (ii) 3/86 had genotype ST239 and a novel SCC
mec
III variant; (iii) 9/86 had a novel SCC
mec
I variant associated with ST250. SCC
mec
IVE and IVF were similar to SCC
mec
IVc and IVb, respectively, but differed in the region downstream of
mecA
. The five SCC
mec
II variants were similar to SCC
mec
IVb in the region upstream of the
ccr
complex but otherwise were similar to SCC
mec
II, except for the following regions: SCC
mec
IIA and IID had a novel
mec
complex, A.4 (Δ
mecI
-IS
1182-
Δ
mecI-mecR1-mecA-
IS
431mec
); SCC
mec
IIC and IIE had a novel
mec
complex, A.3 (IS
1182
-Δ
mecI
-
mecR1-mecA-
IS
431mec
); SCC
mec
IID and IIE lacked pUB110; SCC
mec
IIC and IIE lacked a region of DNA between Tn
554
and the
mec
complex; and SCC
mec
IIB lacked Tn
554
. This study has demonstrated a hitherto-undescribed degree of diversity within SCC
mec
.
Prevalence and Characterization of Invasive Isolates of
Streptococcus pyogenes
with Reduced Susceptibility to Fluoroquinolones
Authors: Powis Jeff , McGeer Allison , Duncan Carla , Goren Ryan , de Azavedo Joyce C. S. , Bast Darrin J. , Pong-Porter Sylvia , Mazzulli Tony , Green Karen , Willey Barbara , Low Donald E.
Published: April 2005

Fluoroquinolone susceptibility testing was performed on invasive group A streptococcus isolates from 1992-1993 and 2003 from Ontario, Canada. None were nonsusceptible to levofloxacin. Two of 153 (1.3%) from 1992-1993 and 7 of 160 (4.4%) from 2003 had a levofloxacin MIC of 2 μg/ml; all nine had
parC
mutations, and eight were serotype M6.
Discovery of Small-Molecule Human Immunodeficiency Virus Type 1 Entry Inhibitors That Target the gp120-Binding Domain of CD4
Authors: Yang Quan-en , Stephen Andrew G. , Adelsberger Joseph W. , Roberts Paula E. , Zhu Weimin , Currens Michael J. , Feng Yaxiong , Crise Bruce J. , Gorelick Robert J. , Rein Alan R. , Fisher Robert J. , Shoemaker Robert H. , Sei Shizuko
Published: April 2005

The interaction between human immunodeficiency virus type 1 (HIV-1) gp120 and the CD4 receptor is highly specific and involves relatively small contact surfaces on both proteins according to crystal structure analysis. This molecularly conserved interaction presents an excellent opportunity for antiviral targeting. Here we report a group of pentavalent antimony-containing small molecule compounds, NSC 13778 (molecular weight, 319) and its analogs, which exert a potent anti-HIV activity. These compounds block the entry of X4-, R5-, and X4/R5-tropic HIV-1 strains into CD4+cells but show little or no activity in CD4-negative cells or against vesicular stomatitis virus-G pseudotyped virions. The compounds compete with gp120 for binding to CD4: either immobilized on a solid phase (soluble CD4) or on the T-cell surface (native CD4 receptor) as determined by a competitive gp120 capture enzyme-linked immunosorbent assay or flow cytometry. NSC 13778 binds to an N-terminal two-domain CD4 protein, D1/D2 CD4, immobilized on a surface plasmon resonance sensor chip, and dose dependently reduces the emission intensity of intrinsic tryptophan fluorescence of D1/D2 CD4, which contains two of the three tryptophan residues in the gp120-binding domain. Furthermore, T cells incubated with the compounds alone show decreased reactivity to anti-CD4 monoclonal antibodies known to recognize the gp120-binding site. In contrast to gp120-binders that inhibit gp120-CD4 interaction by binding to gp120, these compounds appear to disrupt gp120-CD4 contact by targeting the specific gp120-binding domain of CD4. NSC 13778 may represent a prototype of a new class of HIV-1 entry inhibitors that can break into the gp120-CD4 interface and mask the gp120-binding site on the CD4 molecules, effectively repelling incoming virions.
Synthesis and Estrogenic Activity Screening of Some 6,9-Disubstituted Estradiol Derivatives
Authors: Sakač Marija N. , Penov Gaši Katarina M. , Popsavin Mirjana , Djurendić Evgenija A. , Andrić Silvana , Kovačević Radmila M.
Published: April 2005

Oxidation of estradiol dipropionate (1) with chromium(VI) oxide-3,5-dimethylpyrazole complex yielded 9α-hydroxy-6-oxoestra-1,3,5(10)-triene-3,17β-diyl dipropionate (2) and 6-oxoestra-1,3,5(10)-triene-3,17β-diyl dipropionate (3). Dehydration of compound 2 with phosphorus(V) oxide or acetic anhydride gave 6-oxoestra-1,3,5(10),9(11)-tetraene-3,17β-diyl dipropionate (5). Reduction of compounds 2 and 5 with sodium borohydride afforded 3,6β,9α-trihydroxyestra-1,3,5(10)-triene-17β-yl propionate (4) and 3,6β-dihydroxyestra-1,3,5(10),9(11)-tetraene-17β-yl propionate (6), respectively. The action of thionyl chloride on compound 2 yielded 6-hydroxyestra-1,3,5(10),6,8-pentaene-3,17β-diyl dipropionate (7). Biological tests in vivo of these compounds showed a moderate antiestrogenic activity of compound 4.
Primary local orbital amyloidosis: biochemical identification of the immunoglobulin light chain κIII subtype in a small formalin fixed, paraffin wax embedded tissue sample
Authors: Kaplan B , Martin B M , Cohen H I , Manaster J , Kassif Y , Rehany U , Livneh A
Published: April 2005

Background:Amyloidosis refers to a heterogeneous group of disorders associated with the deposition of chemically distinct amyloid fibril proteins. Precise determination of chemical amyloid type has diagnostic, therapeutic, and prognostic relevance. Although immunohistochemical techniques are used routinely to determine the amyloid type, the results can be negative or inconclusive, so that biochemical characterisation is often required. The development and application of new biochemical microtechniques suitable for examination of extremely small tissue samples is essential for precise identification of the deposited amyloid proteins.

Aims:To investigate biochemically the amyloid proteins present in a formalin fixed paraffin wax embedded orbital tissue from a patient with localised orbital amyloidosis in whom immunohistochemistry was not helpful in the determination of amyloid type.

Methods:Extraction of amyloid proteins from fixed tissue and their identification was carried out by a recently developed microtechnique. An extremely small tissue sample was dewaxed and extracted with formic acid. The extracted material was analysed using electrophoresis, western blotting, and amino acid sequencing.

Results:Biochemical examination of the extracted proteins showed the presence of immunoglobulin (Ig) derived amyloid proteins, which were composed of the N-terminal fragments of the Ig light chain κIII subtype (AL-κIII) (16, 8, and 3 kDa).

Conclusions:This is the first chemically proved AL case reported in association with primary localised orbital amyloidosis. The biochemical microtechnique used was useful in achieving a precise diagnosis of amyloid disease, in a case where the results of routine immunohistochemical examination of amyloid were inconclusive.
Mesoporous tantalum oxide photocatalysts for Schrauzer-type conversion of dinitrogen to ammonia
Authors: Yue Chaoyang , Trudeau Michel L , Antonelli David
Published: April 2005

Mesoporous tantalum oxide, Fe3+-doped mesoporous tantalum oxide, and bis(toluene) titanium reduced mesoporous tantalum oxide were used for the first time as Schrauzer-type photocatalysts for the conversion of dinitrogen to ammonia. The materials were characterized by XRD, TEM, XPS, and nitrogen absorption before and after catalytic runs. The results showed low to moderate activities depending on the composition. In contrast to previously studied Ti catalysts, Fe doping and heat pretreatment were not prerequisites for photocatalytic activity, but did improve the turnover rates by up to a factor of two. The optimal Fe loading for the tantalum oxides was found to be 1 wt% and the optimal heating condition at 300 °C for 3 h. Increased surface area and heat treatment were also found to improve activities. Contrary to our expectations, reduction of the mesostructure with bis(toluene) titanium had little effect on the catalytic activity. In spite of the dramatically higher surface areas of the mesoporous tantalum oxides as compared with bulk titanias used previously in this process, the overall catalytic activities were still less than those obtained in the Schrauzer system. This suggests that the increase in diffusion and surface area offered by the mesoporous structure is offset by the smaller crystalline domain sizes in the walls of the structure, leading to poor electron-hole separation and a reduction in catalytic efficiency. Key words: mesoporous, Schrauzer, ammonia, photocatalysis, tantalum oxide.
AN ALGORITHMIC MODEL FOR HETEROGENEOUS HYPER-CLUSTERS: RATIONALE AND EXPERIENCE
Authors: CAPPELLO FRANCK , FRAIGNIAUD PIERRE , MANS BERNARD , ROSENBERG ARNOLD L.
Published: April 2005

A formal model of hyperclusters of processors—that is, clusters of clusters of … of clusters of processors—is formulated. The model characterizes a hypercluster ℋ via a suite of parameters that expose the computational and communicational powers of ℋ's constituent processors and networks. The hyperclusters studied enjoy heterogeneity along three orthogonal axes. (1) The processors that populate a hypercluster may differ in computational powers (speed of computation and memory access). (2) The clusters comprising a hypercluster are organized hierarchically and are interconnected via a hierarchy of networks of possibly differing bandwidths and speeds. (3) The clusters at each level of the hierarchy may differ in sizes. The resulting HiHCoHP model is rather detailed, exposing architectural features such as the bandwidth and transit costs of both networks and their ports. The algorithmic tractability of the model is demonstrated by reviewing two case studies that use the model to study heterogeneous clusters (HNOWs, for short). The first study develops an algorithm for the trigger-broadcast problem in HNOWs, in which a broadcast "triggers" personalized computations at each node of the cluster. The algorithm is predictably efficient in general and is actually optimal in special circumstances. The second study develops an asymptotically optimal algorithm for sharing a large "bag of tasks" within an HNOW.
THERMAL CONDUCTIVITY OF SUPERFLUID NEUTRON STARS
Authors: SHAHZAMANIAN M. A. , YAVARY H.
Published: April 2005

The components of the diffusive thermal conductivity tensor of superfluid neutron stars are calculated by using anisotropic energy gap for 3p2 pairing and approximation collision integrals at temperatures where [Formula: see text]. The contribution from neutron–neutron collisions is taken into account. Nonrelativistic effects for pairing will be studied. A comparison with the corresponding relativistic case is also made.
DYNAMICAL DERIVATION OF BODE'S LAW
Authors: BASS R. W. , DEL POPOLO A.
Published: April 2005

In a planetary or satellite system, idealized as n small bodies in an initially coplanar with concentric orbits around a large central body obeying the Newtonian point-particle mechanics, resonant perturbations will cause a dynamical evolution of the orbital radii except for cases with highly specific mutual relationships. In particular, the most stable situation can be achieved only when each planetary orbit is roughly twice as far from the Sun as the preceding one. This has been empirically observed by Titius (1766) and Bode (1778). By reformulating the problem as a hierarchical sequence of (unrestricted) 3-body problems and considering only the gravitational interactions among the central body and the body of interest and the adjacent outer body in the orbits, it is proved that the resonant perturbations from the outer body will destabilize the inner body (and vice versa) unless its mean orbital radius is a unique and specific multiple of β, the distal multiplier, of the inner body. In this way a sequence of concentric orbits can each stabilize the adjacent inner orbit, and since the outermost orbit is already tied to the collection of the inner orbits by conservation of total angular momentum, the entire configuration is stabilized.
THREE POSITIVE PERIODIC SOLUTIONS OF NONLINEAR DIFFERENTIAL EQUATIONS WITH PERIODIC COEFFICIENTS
Authors: LIU YUJI , GE WEIGUO , GUI ZHANJI
Published: April 2005

We establish the existence of at least three positive periodic solutions to the second order differential equation with periodic coefficients [Formula: see text] where f is continuous with f(t + T, x) = f(t,x) for (t,x) ∊ R × R and T > 0, p, q are continuous and T-periodic with p > 0 and q ≥ 0. We accomplish this by making growth assumptions on f, which can apply to many more cases than those discussed in recent works. An example to illustrate the main result is given.
Differential regulation of fatty acid elongation enzymes in brown adipocytes implies a unique role forElovl3during increased fatty acid oxidation
Authors: Jakobsson Andreas , Jörgensen Johanna A. , Jacobsson Anders
Published: April 2005

The expression of the Elovl3 gene, which belongs to the Elovl gene family coding for microsomal enzymes involved in very long-chain fatty acid (VLCFA) elongation, is dramatically increased in mouse brown adipose tissue upon cold stimulation. In the present study, we show that the cold-induced Elovl3 expression is under the control of peroxisome proliferator-activated receptor-α (PPARα) and that this regulation is part of a fundamental divergence in the regulation of expression for the different members of the Elovl gene family. In cultured brown adipocytes, a mixture of norepinephrine, dexamethasone, and the PPARα ligand Wy-14643, which rendered the adipocytes a high oxidative state, was required for substantial induction of Elovl3 expression, whereas the same treatment suppressed Elovl1 mRNA levels. The nuclear liver X receptor (LXR) has been implicated in the control of fatty acid synthesis and subsequent lipogenic processes in several tissues. This regulation is also exerted in part by sterol regulatory element-binding protein (SREBP-1), which is a target gene of LXR. We found that stimulation of Elovl3 expression was independent of LXR and SREBP-1 activation. In addition, exposure to the LXR agonist TO-901317 increased nuclear abundance of LXR and mature SREBP-1 as well as expression of the elongases Lce and Elovl1 in a lipogenic fashion but repressed Elovl3 expression. A functional consequence of this was seen on the level of esterified saturated fatty acids, such as C22:0, which was coupled to Elovl3 expression. These data demonstrate differential transcriptional regulation and concomitantly different functional roles for fatty acid elongases in lipid metabolism of brown adipocytes, which reflects the metabolic status of the cells.
A mathematical model of rat distal convoluted tubule. II. Potassium secretion along the connecting segment
Authors: Weinstein Alan M.
Published: April 2005

A simulation of the rat distal convoluted tubule (DCT) is completed with a model of the late portion, or connecting tubule (CNT). This CNT model is developed by relying on a prior cortical collecting duct (CCD) model (Weinstein AM. Am J Physiol Renal Physiol 280: F1072–F1092, 2001), and scaling up transport activity of the three cell types to a level appropriate for DCT. The major difference between the two tubule segments is the lower CNT water permeability. In early CNT the luminal solution is hypotonic, with a K+ concentration less than that of plasma, and it is predicted that osmotic equilibration requires the whole length of CNT, to end with a nearly isotonic fluid, whose K+ concentration is severalfold greater than plasma. With respect to potassium secretion, early CNT conditions are conducive to maximal fluxes, whereas late conditions require the capacity to transport against a steep electrochemical gradient. The parameter dependence for K+ secretion under each condition is different: maximal secretion depends on luminal membrane K+ permeability, but the limiting luminal K+ concentration does not. However, maximal secretion and the limiting gradient are both enhanced by greater Na+ reabsorption. While higher CNT water permeability depresses K+ secretion, it favors Na+ reabsorption. Thus in antidiuresis there is a trade-off between enhanced Na+-dependent K+ secretion and the attenuation of K+ secretion by slow flow. When the CNT model is configured in series with the early DCT, thiazide diuretics promote renal K+ wasting by shifting Na+ reabsorption from early DCT to CNT; they promote alkalosis by shifting the remaining early DCT Na+ reabsorption to Na+/H+ exchange. This full DCT is suitable for simulating the defects of hyperkalemic hypertension, but the model offers no suggestion of a tight junction abnormality that might contribute to the phenotype.
Percutaneous Mitral Valve Repair for Chronic Ischemic Mitral Regurgitation
Authors: Daimon Masao , Shiota Takahiro , Gillinov A. Marc , Hayase Motoya , Ruel Marc , Cohn William E. , Blacker Steven J. , Liddicoat John R.
Published: April 2005

Background—

Although surgical annuloplasty is the standard repair for ischemic mitral regurgitation (IMR), its application is limited by high morbidity and mortality. Using 2D and real-time 3D echocardiography in an ovine model of chronic IMR, we evaluated the geometric impact and short-term efficacy of a percutaneous transvenous catheter-based approach for mitral valve (MV) repair using a novel annuloplasty device placed in the coronary sinus.

Methods and Results—

Six sheep developed IMR 8 weeks after induced posterior myocardial infarction. An annuloplasty device optimized to reduce anterior-posterior (A-P) mitral annular dimension and MR was placed percutaneously in the coronary sinus. Mitral annular A-P and commissure-commissure dimensions and MV tenting area (MVTa) in 3 parallel A-P planes (medial, central, and lateral) were assessed by real-time 3D echocardiography with 3D software. The annuloplasty device reduced MR jet area from 5.4±2.6 to 1.3±0.9 cm
2
(
P
<0.01), mitral annular A-P dimension in both systole and diastole (24.3±2.5 to 19.7±2.4 mm;
P
<0.03; 31.0±3.9 to 24.7±2.1 mm;
P
<0.001), and MVTa at mid systole in all 3 planes (153±46 to 93±24 mm
2
,
P
<0.01; 140±47 to 88±23 mm
2
,
P
<0.03; and 103±23 to 87±26 mm
2
,
P
<0.03).

Conclusions—

Percutaneous coronary sinus–based mitral annuloplasty reduces chronic IMR by reducing mitral annular A-P diameter and MVTa. This suggests the potential clinical application of a new nonsurgical therapeutic approach in patients with IMR.
Hospital Volume and Selection of Valve Type in Older Patients Undergoing Aortic Valve Replacement Surgery in the United States
Authors: Schelbert Erik B. , Vaughan-Sarrazin Mary S. , Welke Karl F. , Rosenthal Gary E.
Published: April 2005

Background—

Hospital volume has been linked to quality of care. The relation between hospital volume and recommended use of bioprosthetic valves in older patients undergoing aortic valve replacement (AVR) is unknown.

Methods and Results—

We identified 80 470 patients aged ≥65 years undergoing isolated AVR (with or without bypass surgery) in 1045 US hospitals during 1999–2001 from Medicare Part A files.
International Classification of Diseases, Ninth Revision, Clinical Modification
codes were used to identify patients undergoing bioprosthetic valve (35.21) or mechanical valve (35.22) AVR. The sample was categorized into deciles on the basis of the valve surgery volume of the hospital. Generalized estimating equations determined the relative risk of receiving a bioprosthetic valve in different volume deciles, with adjustment for age, gender, race, comorbidity, and other factors. Bioprosthetic valve use increased (
P
<0.001) from 44% in 1999 to 52% in 2001 and with age (from 36% in patients aged 65 to 69 years to 60% in patients aged ≥90 years). Rates were directly related (
P
<0.001) to volume, rising from 28% in the 1st decile to 68% in the 10th decile. With the use of generalized estimating equations, the relative risk of bioprosthetic valve use, relative to the 1st decile, progressively increased from 1.2 (95% CI, 1.1 to 1.4) in the 2nd decile to 2.3 (95% CI, 1.9 to 2.7) in the 10th decile.

Conclusions—

Hospital volume was a strong predictor of bioprosthetic valve use in older patients undergoing AVR. The lower use of bioprosthetic valves in low-volume hospitals is at odds with recent guidelines recommending bioprosthetic valves in patients aged ≥65 years. These findings further support the use of volume as a marker of hospital quality.
37°C: From the Inside of a Being to the Thin Line of Life
Authors: Tratnik Polona
Published: April 2005

An observer entering the installation 37°C becomes a part of the inside of an organism. This is a warm and dark environment in which living human skin cells are displayed. The aim of the project is to confront observers with a fragile boundary between life and death, to envelop them within the presence of life. Life does not have clear demarcations. On the precarious edge, it can either slip into death or come back to life. The author's work seeks to present the experience of such intermediary states of existence.
The Historic Search for Red Sprites: Art Meets Science in Lightning's Angels
Authors: McLeish Peter
Published: April 2005

Sprites are fleeting, luminous shapes that shoot into the upper atmosphere during large thunderstorms as lightning simultaneously reaches down to Earth. For at least a century, scientists have attempted to confirm and explain the existence of sprites with visual images and data. The author's series Lightning's Angels supplements the documentation of sprites by exploring the properties of this natural phenomenon through digitally enhanced oil portraits set to music and displayed in a large scale multimedia format, such as at a planetarium.
Investigating the Fault Tolerance of Neural Networks
Authors: Tchernev Elko B. , Mulvaney Rory G. , Phatak Dhananjay S.
Published: April 2005

Particular levels of partial fault tolerance (PFT) in feedforward artificial neural networks of a given size can be obtained by redundancy (replicating a smaller normally trained network), by design (training specifically to increase PFT), and by a combination of the two (replicating a smaller PFT-trained network). This letter investigates the method of achieving the highest PFT per network size (total number of units and connections) for classification problems. It concludes that for nontoy problems, there exists a normally trained network of optimal size that produces the smallest fully fault-tolerant network when replicated. In addition, it shows that for particular network sizes, the best level of PFT is achieved by training a network of that size for fault tolerance. The results and discussion demonstrate how the outcome depends on the levels of saturation of the network nodes when classifying data points. With simple training tasks, where the complexity of the problem and the size of the network are well within the ability of the training method, the hidden-layer nodes operate close to their saturation points, and classification is clean. Under such circumstances, replicating the smallest normally trained correct network yields the highest PFT for any given network size. For hard training tasks (difficult classification problems or network sizes close to the minimum), normal training obtains networks that do not operate close to their saturation points, and outputs are not as close to their targets. In this case, training a larger network for fault tolerance yields better PFT than replicating a smaller, normally trained network. However, since fault-tolerant training on its own produces networks that operate closer to their linear areas than normal training, replicating normally trained networks ultimately leads to better PFT than replicating fault-tolerant networks of the same initial size.
Equity in the Courts of Merchants
Authors: Donahue Charles
Published: April 2005

This paper had its origins in a study of Benvenuto Stracca's De mercatura. The purpose of the study was to determine whether there was anything in that work that supported the notion that there was a system of customary mercantile law in operation in Italy in Stracca's time. The answer to that question proved to be a rather resounding 'no', and the arguments that lead to that conclusion will be published elsewhere. In the process of examining Stracca's sources, much information appeared about how the jurists of the fourteenth, fifteenth and early sixteenth centuries did deal with mercantile matters and, in particular, the way in which they manipulated the concept of equity to achieve what they deemed to be just results in such cases. Limitations of space allowed consideration of only a couple of procedural examples intheprevious paper. The story, it seemed to me, deserved consideration in its own right. What follows, then, is a fuller consideration of the use of equity by the commentators in their handling of mercantile cases, beginning, as the previous paper did, with Stracca's general remarks on the topic.
Diagnosis of Frontal Instabilities over the Southern Ocean
Authors: Patoux Jérôme , Hakim Gregory J. , Brown Robert A.
Published: April 2005

The development of three fronts over the Southern Ocean is described using SeaWinds-on-QuikSCAT scatterometer surface winds and an attribution technique to partition the wind field in three components: nondivergent and irrotational components at the scale of the front, and the remaining harmonic component (or environmental flow) induced by the synoptic-scale flow. The front and the environment in which the front is embedded are analyzed separately.

A frontal wave is shown to develop out of the first front when the large-scale alongfront stretching decreases, the environmental flow becomes frontolytic, and a connection with the upper levels is established. In the second case, the stretching remains relatively strong and no frontal wave develops. The third front exhibits a developing wave but is not in a favorable configuration with the upper levels; the frontal wave does not deepen significantly.
Numerical Study of a Typhoon with a Large Eye: Model Simulation and Verification
Authors: Zhang Qing-Hong , Chen Shou-Jun , Kuo Ying-Hwa , Lau Kai-Hon , Anthes Richard A.
Published: April 2005

Typhoon Winnie (1997) was the fourth supertyphoon in the western North Pacific in 1997. In its mature stage, an outer eyewall, consisting of deep convection with a diameter of 370 km, was observed by satellite and radar. Within this unusually large outer eyewall existed an inner eyewall, which consisted of a ring of shallow clouds with a diameter of ∼50 km. In this study, Typhoon Winnie is simulated using a nested-grid version of the fifth-generation Pennsylvania State University–National Center for Atmospheric Research (PSU–NCAR) Mesoscale Model (MM5) with an inner grid length of 9 km. The model reproduces an outer cloud eyewall with a diameter of ∼350 km. The simulated radar reflectivity and hourly precipitation are verified with satellite microwave, infrared, and cloud brightness temperature images.

Analysis of the model results indicates that the large outer eyewall in many ways possesses the structure of a typical hurricane eyewall. This includes strong tangential winds and radial inflow outside the eyewall as well as an extremely large horizontal wind shear right at the eyewall. The outer eyewall is characterized with a ring of high vorticity (RHV). This RHV is closely related to a ring of high convergence (RHC). This RHC is caused by organized convective systems along the eyewall. The eye simulated by Winnie is characterized by a broad region of warm, dry slowly sinking air.

The factors determining the diameter of eyes in tropical cyclones are discussed by considering the scale of the environmental angular momentum and the maximum kinetic energy achieved by parcels of air originating in the environment and reaching the radius of maximum wind. It is hypothesized that the formation of a large eye is favored by large circulations in which parcels of air are drawn in toward the center of the storm from great distances, and trajectories of air in Winnie that support this hypothesis are shown.
Influence of a Hailstreak on Boundary Layer Evolution
Authors: Segele Zewdu T. , Stensrud David J. , Ratcliffe Ian C. , Henebry Geoffrey M.
Published: April 2005

Severe thunderstorms developed on 20 June 1997 and produced heavy precipitation, damaging winds, and large hail over two swaths in southeastern South Dakota. Calculations of fractional vegetation coverage (scaled from 0 to 1) based upon composite satellite data indicate that, within the hailstreak region, vegetation coverage decreased from 0.50 to near 0.25 owing to the damaging effects of hail on the growing vegetation. The northern edge of the larger hailstreak was located a few kilometers south of Chamberlain, South Dakota, a National Weather Service surface observation site. Hourly observations from Chamberlain and several nearby surface sites in South Dakota are averaged over 7 days both before and after this hail event. These observations illustrate that the late-afternoon (nighttime) temperatures are 2°C higher (2°C lower) near the hailstreak after the event than before the event. Similarly, daily average dewpoint temperatures after the event are 2.6°C lower near the hailstreak. These changes are consistent with the influences of a recently devegetated zone on changes to the surface energy budget.

To explore how these hailstreaks further affected the evolution of the planetary boundary layer in this region, two model simulations are performed using the fifth-generation Pennsylvania State University–National Center for Atmospheric Research (PSU–NCAR) Mesoscale Model (MM5). In the control run, climatology is used for the land surface characteristics, and hence the simulation is independent of the hailstreaks. In the hailstreak simulation (HSS), the fractional vegetation coverage and soil moisture in the hailstreak regions are modified to reflect the likely conditions within the hailstreaks. Two different days are simulated: one with low surface wind speeds and one with stronger surface wind speeds. For the low surface wind speed case, the HSS simulation produces a sea-breeze-like circulation in the boundary layer by midmorning. For the stronger surface wind speed case, this sea-breeze-like circulation does not develop in the HSS, but the simulated low-level temperatures are modified over a larger area. These results suggest that to capture and reasonably simulate the evolution of boundary layer structures, there is a need for routine daily updates of land surface information. Hailstreaks also are important to consider in the future as the focus for observational studies on nonclassical mesoscale circulations.
Use of Cellular and Plasma Apheresis in the Critically Ill Patient: Part II: Clinical Indications and Applications
Authors: Linenberger Michael L. , Price Thomas H.
Published: April 2005

Apheresis is the process of separating the blood and removing or manipulating a cellular or plasma component for therapeutic benefit. Such procedures may be indicated in the critical care setting as primary or adjunctive therapy for certain hematologic, neurologic, renal, and autoimmune/rheumatologic disorders. In part I of this series, the technical aspects of apheresis were described and the physiologic rationale and clinical considerations were discussed. This review highlights the pathophysiologic basis, specific clinical indications, and treatment parameters for disorders that more commonly require management in the intensive care unit. The choice of plasma or cellular apheresis in these cases is guided by wellaccepted, evidence-based clinical treatment guidelines. For some disorders, such as liver failure, severe sepsis, and multiple-organ dysfunction syndrome, apheresis treatment approaches remain experimental. Ongoing studies are investigating the potential utility of conventional plasma exchange, ex vivo plasma manipulation, and newer technologies for these and other disorders in severely ill patients.
Dexmedetomidine in the Treatment of Withdrawal Syndromes in Cardiothoracic Surgery Patients
Authors: Baddigam Krishna , Russo Pierantonio , Russo JoAnne , Tobias Joseph D.
Published: April 2005

Dexmedetomidine (Precedex, Abbott Laboratories, Abbott Park, IL) is an• 2adrenergic agonist that possesses a high ratio of specificity for the• 2versus the• 1receptor. It is currently approved for the provision of sedation during mechanical ventilation in adults. Given previous experience with clonidine for the treatment of substance withdrawal and the preliminary anecdotal experience with dexmedetomidine, it appears that dexmedetomidine may be a useful agent for treatment of substance withdrawal in the intensive care setting. The authors present their experience with the use of dexmedetomidine to control withdrawal behavior in 3 patients following cardiothoracic surgery. Previous reports regarding the use of dexmedetomidine to treat withdrawal and its potential application in this clinical arena are reviewed.
Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim
Authors: Möller Christine , Alfredsson Jessica , Engström Maria , Wootz Hanna , Xiang Zou , Lennartsson Johan , Jönsson Jan-Ingvar , Nilsson Gunnar
Published: April 2005

Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)–only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) and FOXO3a. SCF treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEK/MAPK) and phosphatidylinositol 3 (PI3)–kinase pathways in this process. Overexpression of phosphorylation-deficient FOXO3a caused an up-regulation of Bim and induced mast cell apoptosis even in the presence of SCF. Mast cell apoptosis induced by the phosphorylation-deficient FOXO3a was attenuated in bim–/– mast cells. Because apoptosis is abnormally reduced in bim–/– mast cells, these data provide evidence that Akt-mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.
Quadratic regression analysis for gene discovery and pattern recognition for non-cyclic short time-course microarray experiments
Authors: Liu Hua , Tarima Sergey , Borders Aaron S , Getchell Thomas V , Getchell Marilyn L , Stromberg Arnold J
Published: April 2005

Background

Cluster analyses are used to analyze microarray time-course data for gene discovery and pattern recognition. However, in general, these methods do not take advantage of the fact that time is a continuous variable, and existing clustering methods often group biologically unrelated genes together.

Results

We propose a quadratic regression method for identification of differentially expressed genes and classification of genes based on their temporal expression profiles for non-cyclic short time-course microarray data. This method treats time as a continuous variable, therefore preserves actual time information. We applied this method to a microarray time-course study of gene expression at short time intervals following deafferentation of olfactory receptor neurons. Nine regression patterns have been identified and shown to fit gene expression profiles better than k-means clusters. EASE analysis identified over-represented functional groups in each regression pattern and each k-means cluster, which further demonstrated that the regression method provided more biologically meaningful classifications of gene expression profiles than the k-means clustering method. Comparison with Peddada et al.'s order-restricted inference method showed that our method provides a different perspective on the temporal gene profiles. Reliability study indicates that regression patterns have the highest reliabilities.

Conclusion

Our results demonstrate that the proposed quadratic regression method improves gene discovery and pattern recognition for non-cyclic short time-course microarray data. With a freely accessible Excel macro, investigators can readily apply this method to their microarray data.
Detection of target DNA using fluorescent cationic polymer and peptide nucleic acid probes on solid support
Authors: Raymond Frédéric R , Ho Hoang-Anh , Peytavi Régis , Bissonnette Luc , Boissinot Maurice , Picard François J , Leclerc Mario , Bergeron Michel G
Published: April 2005

Background

Nucleic acids detection using microarrays requires labelling of target nucleic acids with fluorophores or other reporter molecules prior to hybridization.

Results

Using surface-bound peptide nucleic acids (PNA) probes and soluble fluorescent cationic polythiophenes, we show a simple and sensitive electrostatic approach to detect and identify unlabelled target nucleic acid on microarray.

Conclusion

This simple methodology opens exciting possibilities for applied genetic analysis for the diagnosis of infections, identification of genetic mutations, and forensic inquiries. This electrostatic strategy could also be used with other nucleic acid detection methods such as electrochemistry, silver staining, metallization, quantum dots, or electrochemical dyes.