bluuebunny/crossref_metadata_2025 huggingface dataset:
Solder Creep-Fatigue Analysis by an Energy-Partitioning Approach
Authors: Dasgupta A. , Oyan C. , Barker D. , Pecht M.
Published: April 2008

This study explores the possibility of using a unified theory of creep-fatigue, similar to the Halford-Manson strain-range partitioning method, for examining the effect of cyclic temperature range on fatigue life, over a wide range of temperatures. Other investigators have attempted similar techniques before for solder fatigue analysis. The present study is different since it proposes an energy-partitioning technique rather than strain-partitioning to examine the dependence of solder fatigue behavior on temperature dependent changes in the relative amounts of plastic and creep strains. The solder microstructure also dictates creep behavior but is assumed to be a given invariant parameter in this study. In other words, this study is targeted at as-cast microstructures and does not address post-recrystallization behavior. A sample solder joint of axisymmetric configuration, commonly found in leaded through-hole mounting technology, is analyzed with the help of nonlinear finite element methods. The strain history is determined for constant-amplitude temperature cycling with linear loading and unloading, and with constant dwells at upper and lower ends of the cycle. Large-deformation continuum formulations are utilized in conjunction with a viscoplastic constitutive model for the solder creep-plasticity behavior. Relevant material properties are obtained from experimental data in the literature. The results show significant amounts of rachetting and shakedown in the solder joint. Detailed stress-strain histories are presented, illustrating the strain amplitude, mean strain and residual stresses and strains. For illustrative purposes, the hysteresis cycles are partitioned into elastic, plastic and creep components. Such partitioned histories are essential in order to implement either the Halford-Manson strain-range partitioning technique or the energy-based approach suggested here, for analyzing the creep-fatigue damage accumulation in solder material. This study also illustrates the role and utility of the finite element method in generating the detailed stress-strain histories necessary for implementing the energy partitioning approach for creep-fatigue damage evaluation. Solder life prediction is presented as a function of cyclic temperature range at a given mean temperature.
Stress Analysis and Thermal Characterization of a High Pin Count PQFP
Authors: Mertol A.
Published: April 2008

A three-dimensional finite element model of a high pin count plastic-quad-flat-pack (PQFP) has been developed by using ANSYS™ finite element simulation code [1]. The model has been used for both thermo-mechanical stress analysis during temperature cycling and thermal characterization of the package under forced air cooling. Parametric studies have been performed on two different molding compounds with and without a drop-in heat spreader. In addition, the model has been simplified by substituting the leadframe and molding compound with a single homogeneous material, reflecting both molding compound and the leadframe thermo-physical properties. Results from the molding compound parametric studies indicate a lower package stress if the molding compound with low thermal expansion coefficient is used. Comparisons of principal and von Mises stresses show that the simplified model, overall, underpredicts the stresses. Although both the simplified and detailed models predict almost the same value for junction-to-case resistance (θJC), calculated values are significantly lower than the measured θJC. In contrast to θJC, the predicted junction-to-ambient resistances (θJA) are in good agreement with the measured data.
Elasto-Plastic Large Deflection Analysis of a Copper Film
Authors: Lau J. H.
Published: April 2008

The ductility of a copper film has been determined by an elastoplastic large deflection finite element method. The effective stress and incremental plastic strain and pressure-deflection curves of the copper film have also been provided for a better understanding of its mechanical behavior. Furthermore, for engineering practice convenience, the ductility and effective stress of the copper film have been plotted as functions of measurable variables, i.e., applied pressure and deflection at the center of the bulge.
Electronic Materials and Structures for Multichip Modules
Authors: Charles H. K.
Published: April 2008

Multichip modules are rapidly becoming a major thrust in electronic packaging technology. Because of the high density and high performance nature of the electronic devices packaged in multichip modules, stringent new demands are being placed on materials, interconnect, and packaging structures. A systematic review of the materials and material structures for multichip modules is presented along with their associated physical and electronic properties. Particular emphasis is placed on new materials and their potential impact on multichip module packaging. Examples of their use in the fabrication of multichip modules and advanced chip-on-board systems are described.
A General Analytical Solution for Free Vibration of Rectangular Plates Resting on Fixed Supports and With Attached Masses
Authors: Singal R. K. , Gorman D. J.
Published: April 2008

A comprehensive analytical procedure based on the superposition method is described for establishing the free vibration frequencies and mode shapes of thin plates resting on rigid point supports and with attached masses. Effects of rotary inertia of the attached masses are incorporated into the analysis and are shown to be highly significant. Results of an extensive experimental program are reported and very good agreement is demonstrated between theory and experiment. The analytical procedure has application in numerous contemporary industrial problems, in particular, in the design of solar panels for space vehicles and in the field of electronic packaging.
Heat Pipes for Cooling High Flux/High Power Semiconductor Chips
Authors: North M. T. , Avedisian C. T.
Published: April 2008

Results of an experimental study are reported which demonstrate the ability of heat pipes to simultaneously dissipate high heat fluxes and high total power at low surface temperatures. The application is to cooling high power density (and high total power) semiconductor chip modules. The two designs studied incorporate air or liquid cooling in the condenser sections. The air-cooled design consisted of a manifold base plate with a series of holes drilled in it each of which was lined with sintered copper powder which served as the wick. An array of wick lined tubes was attached normal to the plate and served as the condenser section. The other heat pipe was disk shaped and also had a sintered wick structure. Cooling water channels were placed over the entire periphery of the housing except in the region of heat input. Reported steady heat fluxes are up to 31 W/cm2 corresponding to total power dissipation of up to 1400 W for the water cooled heat pipe and up to 47 W/cm2 (900 W total power) for the air cooled heat pipe with surface temperatures under 100°C.
An Experimental and Finite Element Study of Thermal Fatigue Fracture of PbSn Solder Joints
Authors: Pao Yi-Hsin , Govila Ratan , Badgley Scott , Jih Edward
Published: April 2008

A solder joint specimen has been designed to determine the stress/strain hysteresis response and fracture behavior of 90 percent wtPb/10 percent wtSn solder alloy. The specimen consists of an Al2O3 beam and an Al 2024-T4 beam bonded together at the ends with solder. The specimen is subjected to thermal cycling to failure between 40°C to 140°C with a 10°C/min ramp rate and 10-minute hold times. Stress/strain hysteresis loops were experimentally determined as a function of thermal cycles. A method based on the stress relaxation data at hold times has been developed to determine the steady state creep parameters of the solder. A constitutive equation for the solder alloy based on elastic and creep deformation has been formulated and implemented in a finite element code, ABAQUS. Good agreement was obtained between the finite element model and the experimental results. In the thermal fatigue test, crack length versus number of thermal cycles was measured for two different shear strain ranges, and the fracture surface was examined with SEM. The SEM results show a combined transgranular and intergranular fracture. In addition, a significant amount of secondary cracks and voids were generated during thermal fatigue which led to material weakening. A thermal fatigue model based on the C* integral, the measured stress history, and creep properties was employed to model the fracture behavior.
Torsion of Elastically Coupled Plates With Applications to Electronic Packaging
Authors: Engel P. A. , Ling Yun
Published: April 2008

The coupling of a square base plate to another reinforcing plate is solved for torsional loads. Nondimensional analysis is carried out using thin plate theory. The distribution of connecting peripheral tie forces is shown to depend on the size ratio of the two plates, their rigidities, and the stiffness of the ties. Applications to twisted circuit cards with attached electronics modules are referred to.
Displacement-Limited Buckling of an Optical Fiber
Authors: King W. W.
Published: April 2008

Buckling of an optical fiber within a confining connector housing is analyzed under the restriction that the transverse deflection profile be shallow. Fibers with pinned ends and with clamped ends are treated. The three stages of buckling are discussed: sufficiently small transverse displacements that contact is not made with the housing wall; point contact with the wall; and finite-length contact with the wall. Explicit expressions for responses as functions of relative longitudinal displacement of ends are obtained for the first and third stages. For the second stage, longitudinal displacement and maximum fiber curvature are expressed in terms of buckling load. Except for a portion of the point-contact stage, contact with a confining wall causes more severe stresses in the fiber than would otherwise be the case.
Finite Element Method for Predicting Equilibrium Shapes of Solder Joints
Authors: Nigro N. J. , Heinrich S. M. , Elkouh A. F. , Zou X. , Fournelle R. , Lee Ping S.
Published: April 2008

This paper discusses the development and application of a finite element method for determining the equilibrium shapes of solder joints which are formed during a surface mount reflow process. The potential energy governing the joint formation problem is developed in the form of integrals over the joint surface, which is discretized with the use of finite elements. The spatial variables which define the shape of the surface are expressed in a parametric form involving products of interpolation (blending) functions and element nodal coordinates. The nodal coordinates are determined by employing the minimum potential energy theorem. The method described in this paper is very general and can be employed for those problems involving the formation of three dimensional joints with complex shapes. It is well suited for problems in which the boundary region is not known a priori (e.g., “infinite tinning” problems). Moreover, it enables the user to determine the shape of the joint in parametric form which facilitates meshing for subsequent finite element stress and thermal analyses.
Solder Joint Reliability of Surface Mount Connectors
Authors: Lau J. , Marcotte T. , Severine J. , Lee A. , Erasmus S. , Baker T. , Moldaschel J. , Sporer M. , Burward-Hoy G.
Published: April 2008

The solder joint reliability of five different surface mount connectors has been studied by eleven different experimental methods. A set of test methods and specifications for determining the reliability of the solder joints of surface mount connectors has been recommended.
The Effects of Inclined Free Edges on the Thermal Stresses in a Layered Beam
Authors: Yin Wan-Lee
Published: April 2008

A stress-function-based variational method is used to determine the thermal stresses in a layered beam with inclined free edges at the two ends. The stress functions are expressed in terms of oblique cartesian coordinates, and polynomial expansions of the stress functions with respect to the thickness coordinate are used to obtain approximate solutions. Severe interlaminar stresses act across end segments of the layer interfaces. Local concentration of such stresses may be significantly affected by the inclination angle of the end planes. Variational solutions for a two-layer beam show generally beneficial effects of free-edge inclination in dispersing the concentration of interlaminar stresses. The significance of these effects is generally not indicated by the power of the stress singularity as computed from an elasticity analysis of a bimaterial wedge.
Die Pad Anchoring Designs for Enhanced Adhesion Integrity in IC Packages
Authors: Nguyen L. T. , Michael M.
Published: April 2008

This paper describes mechanical means for enhancing the adhesion between the epoxy molding compound and the die and die pad in plastic packages. By introducing patterns of holes and slots along the periphery of the die pad, better anchoring between the plastic and the die and die pad is achieved. Interfacial delamination, as determined by scanning acoustic tomography, is minimized. The improved adhesion reduces wire bond fatigue failures and minimizes the risk of moisture accumulation under the die pad that often leads to plastic cracking during solder reflow. Higher packaging reliability can thus be achieved. Finite element modeling of the different design configurations yields stress profiles and deformation patterns which agree qualitatively with the experimental results.
Factors Affecting the Adhesion of Fluoropolymer Composites to Commercial Copper Foils
Authors: Jimarez L. J. , Matienzo L. J. , Mehta A. A.
Published: April 2008

Polytetrafluoroethylene (PTFE) films containing glass fillers have been shown to be promising materials in the development of high speed microelectronic packaging applications. Printed circuit board (PCB) manufacturing requires the use of copper foils that typically contain some surface modification for adhesion enhancement. The surface treatments of copper foils vary in composition and morphology. This study evaluates their chemical and physical characteristics before and after lamination to commercially available fluoropolymer dielectric films containing two different types of glass fillers. The peel strengths of the resulting interfaces are followed before and after PCB fabrication. The roles of surface composition, surface roughness, and fluoropolymer filler type are described in terms of the resulting adhesion of the metal/polymer interfaces.
Numerical Study of Flow and Heat Transfer for Circular Jet Impingement on the Bottom of a Cylindrical Cavity
Authors: Gavali S. , Karki K. , Patankar S. , Miura K.
Published: April 2008

A numerical study is presented for an axisymmetric laminar jet impingement on a confined disk, with the spent fluid being collected through an annual channel that is concentric with the nozzle. In this study, parametric variations were made of the dimensionless separation distance between the nozzle exit and the impingement surface, of the ratio of the diameter of the impingement surface to the nozzle diameter, and of the Reynolds number. The flow field is characterized by two recirculation zones, one adjacent to the nozzle exit and the other near the confining wall. The local heat transfer distribution on the impingement surface exhibits an off-axis maximum and a local minimum near the confining wall. The nozzle separation distance has an effect on surface heat transfer only for configurations with closet confinement. The thermal boundary condition on the impingement surface is found to have little effect on the total heat transfer.
An Experimental/Analytical Study of Strains in Encapsulated Assemblies
Authors: Guess T. R. , Burchett S. N.
Published: April 2008

A combined experimental and analytical study of strains that develop in encapsulated assemblies during casting, curing, and thermal excursions is described. The experimental setup, designed to measure in situ strains, consisted of thin, closed-end, metal tubes that were instrumented with strain gages and thermocouples before being over-potted with an encapsulant. Three epoxy-based materials were studied. After cure of the encapsulant, tube strains were measured over the temperature range of −55°C to 90°C. The thermal excursion experiments were then numerically modeled using finite element analyses and the results were compared to the experimental results. The predicted strains were overestimated (conservative) when a linear, elastic, temperature-dependent material model was assumed for the encapsulant and the stress free temperature was assumed to correspond to the cure temperature of the encapsulant. Very good agreement was obtained with the linear elastic calculations provided that the stress free temperature corresponded to the onset of the glassy-to-rubbery transition range of the encapsulant. Finally, very good agreement was obtained when a viscoelastic material model was utilized and a stress free temperature corresponding to the cure temperature was assumed.
Thermal Fatigue of Low-Temperature Solder Alloys in Insertion Mount Assembly
Authors: Seyyedi J.
Published: April 2008

Thermal fatigue resistance was investigated for insertion mount solder joints, manufactured with 58Bi-42Sn (wt. %), 43Sn-43Pb-14Bi, 52In-48Sn and 40In-40Sn-20Pb low-temperature alloys. Accelerated thermal cycling was used in conjunction with metallographic analysis to determine the fatigue resistance and to elucidate the failure mode for each solder composition. Additionally, the behavior of each solder alloy was compared to that of 63Sn-37Pb solder, tested under identical conditions. A two-phase microstructure with lamellar morphology was observed in 58Bi-42Sn, whereas a globular morphology was prevalent in the remaining alloys. The Bi-containing solders demonstrate fatigue resistance comparable to 63Sn-37Pb, but greater than the In-bearing alloys. These differences and microstructure changes prior to and during thermal fatigue testing are discussed.
Reliability of Postmolded IC Packages
Authors: Nguyen L. T.
Published: April 2008

This paper discusses the current reliability issues involved with typical postmolded IC packages. Four major topics are presented, namely, stress, moisture permeation and corrosion-related problems, adhesion, and outgassing impurities. As the trend moves toward higher lead count, with increasingly larger dies which require more power dissipation within smaller package outlines, stress reduction will become a main concern. Methods to quantify package stresses in situ are outlined, together with the advantages and drawbacks of various schemes for decoupling the silicon die from the molding compound. Since the typical molding compound is permeable to moisture, the package collects water during stringent qualification tests (autoclave, T/H, and HAST), and even under normal ambient conditions. Any ionic impurities in the molding compound will combine with the absorbed water to form an electrolytic pool. This increases the likelihood of corrosion in the presence of passivation defects or exposed metal lines. Device structures designed to follow moisture permeation and detect water-induced damage are discussed. The integrity of the interface between the molding compound and the device components is crucial to the long term reliability of the package. Delamination at the die interface produces complex stress profiles that can result in various defects ranging from metal line shift, passivation cracking, corner die chipping, to ball bond fatigue. Poor adhesion along the leads also opens potential paths for moisture ingress. The effects of assembly conditions and various adhesion enhancing schemes on the package integrity are evaluated. Finally, outgassing of halogenated (bromine and antimony oxide) byproducts added for flame retardancy during high temperature storage life testing results in ball bond degradation. The interaction yields typically porous intermetallic structures which grow in size with exposure time, leading ultimately to bond lifting. Possible reaction mechanisms are presented.
Thermomechanical Modeling of Direct Chip Interconnection Assembly
Authors: Buratynski E. K.
Published: April 2008

Efforts to model thermomechanical aspects of the Direct Chip Interconnection (DCI) assembly process are described. DCI is a method to simultaneously attach and electrically interconnect bare chips to a substrate using Anisotropic Conductive Adhesive Films (ACAF). Emphasis has been placed on describing the numerical procedure used in the analysis. The major components of the analysis include a calibration procedure to “numerically measure” anisotropic properties of the film, a curing model to capture “frozen-in” stresses, a global analysis that considers the overall assembly station but does not resolve details of the interconnection, and a local model, coupled to the global model, that resolves details about the interconnection. Typical results are shown to demonstrate the capabilities of the model.
Reducing Inter-Chip Temperature Differences in Computers Using Vortex Generators in Forced Convection
Authors: Garimella S. V. , Schlitz D. J.
Published: April 2008

Experiments were conducted to investigate methods of reducing inter-chip temperature differences in forced convective direct immersion cooling of semiconductor chips using a dielectric liquid (FC-77) as coolant. The experiments were conducted in a closed-loop flow facility with a 5 × 15 array of chips mounted on the bottom wall of a horizontal channel and with vortex generators installed on the opposite wall, upstream of the heated chip. Single, half delta-wing vortex generators of two heights, as well as a pair of counter-rotating vortex generators, were tested at different placement locations with respect to the heated chip. The channel height-based Reynolds number was varied from 1000 to 7500. Heat transfer coefficients and pressure drop measurements were obtained. The taller vortex generator placed 2.5 chip heights upstream of the heated chip was found to yield the best results. The increase in pressure drop due to each of the individual vortex generators was found to be negligible. The greatest enhancement in heat transfer of 17 percent was obtained at Reynolds numbers in the transitional flow regime.
Effect of Chip and Pad Geometry on Solder Joint Formation in SMT
Authors: Heinrich S. M. , Liedtke P. E. , Nigro N. J. , Elkouh A. F. , Lee P. S.
Published: April 2008

An analytical model of solder joint formation during a surface mount reflow process is developed for two-dimensional fillets whose flow may be restricted due to “finite” metallizations on a leadless component and the printed circuit board. Although these height and length constraints on the fillet geometry may result in obtuse contact angles, the solution is obtained in the form of an explicit integral, similar to that previously derived by the authors for the case of acute contact angles. This solution may also be recast into the form of elliptic integrals of the first and second kinds, thereby permitting one to evaluate the fillet geometry using mathematical tables or special function software, if desired, rather than resorting to a computer-based numerical quadrature. In addition an approximate zero-gravity solution is given by means of simple closed-form expressions relating the height, length, contact angles, and cross-sectional area of the fillet. Numerical results generated by implementing the “exact” integral solution for the joint profile are given in the form of dimensionless plots, relating fillet geometry to the solder properties (surface tension and density), amount of solder, chip height, and pad length. Also presented in dimensionless form are the approximate results from the zero-gravity model, which are independent of solder properties, yet are of sufficient accuracy for “small” joints. Because of their dimensionless nature, the results of the present paper may be of maximum utility to process engineers aiming to achieve desired joint geometries (e.g., to maximize fatigue life or to eliminate bridging problems), or to board designers responsible for selecting efficient footprint patterns to maximize board density. Models of solder joint formation, such as the one presented here, may be of most value when used in conjunction with stress analysis packages (e.g., finite element programs) and appropriate fatigue models. In this way an integrated approach to the design of solder joints and circuit boards may be taken, resulting in improved product reliability and performance.
Optimization of Extruded Type External Heat Sink for Multichip Module
Authors: Mertol A.
Published: April 2008

A three-dimensional finite element model of a multichip module (MCM) has been developed by using ANSYS™ finite element simulation code. The model has been used for thermal characterization of the module. In addition, optimum dimensions of an external heat sink, which maintains the specified device’s junction temperature within desired operating temperature limits, are determined as functions of air flow rate and power density of surrounding semiconductor devices. Parametric studies have been performed to study the effects of heat sink height, width and length on junction-to-ambient thermal resistance of a high power application specific integrated circuit (ASIC) device found in the MCM assembly. A set of curves are generated to select either heat sink dimensions or air speed for a given design requirements. Influence of the power output of surrounding devices on the thermal performance of the high power ASIC device is also assessed. The predicted results indicate that the ASIC device’s junction temperature as well as junction-to-ambient resistance increase as the power of the surrounding packages increases. This effect diminishes if a sufficiently large heat sink is used to cool the package.
Both Oral Metronidazole and Oral Vancomycin Promote Persistent Overgrowth of Vancomycin-Resistant Enterococci during Treatment of
Clostridium difficile
-Associated Disease
Authors: Al-Nassir Wafa N. , Sethi Ajay K. , Li Yuejin , Pultz Michael J. , Riggs Michelle M. , Donskey Curtis J.
Published: April 2008

For treatment of mild to moderate
Clostridium difficile
-associated disease (CDAD), oral metronidazole has been recommended as the preferred agent, in part due to concern that vancomycin may be more likely to promote colonization by vancomycin-resistant enterococci (VRE). We performed a prospective observational study to examine the effects of oral metronidazole or vancomycin treatment of CDAD on acquisition and concentration of VRE stool colonization. Before, during, and after 90 courses of CDAD therapy, stool samples were cultured for VRE, and the concentrations were quantified. Eighty-seven subjects (97%) had received antibiotics within the past month. For 56 treatment courses in which preexisting VRE colonization was present, metronidazole (
n
= 37 courses) and vancomycin (
n
= 19 courses), each promoted persistent VRE overgrowth during therapy, and the concentration decreased significantly in both groups by ∼2 weeks after completion of treatment (
P
<0.049). For 34 treatment courses in which baseline cultures were negative for VRE, new detection of VRE stool colonization occurred during 3 (14%) of the 22 courses of metronidazole and 1 (8%) of the 12 courses of vancomycin (
P
= 1.0). These results demonstrate that both oral metronidazole and oral vancomycin promote the overgrowth of VRE during treatment of CDAD. New CDAD treatments are needed that are less likely to disrupt the intestinal microflora and promote overgrowth of healthcare-associated pathogens.
A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in
Candida parapsilosis
,
Candida orthopsilosis
, and
Candida metapsilosis
Accounts for Reduced Echinocandin Susceptibility
Authors: Garcia-Effron Guillermo , Katiyar Santosh K. , Park Steven , Edlind Thomas D. , Perlin David S.
Published: April 2008

Candida parapsilosis
has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting.
C. parapsilosis
is part of a closely related group of organisms that includes the species
Candida orthopsilosis
and
Candida metapsilosis
. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other
Candida
species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the
C. parapsilosis
group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from
C. albicans
. Furthermore, clinical isolates of
C. albicans
and
C. glabrata
which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced
V
max
values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for
C. parapsilosis
group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of
Saccharomyces cerevisiae
. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the
C. parapsilosis
group accounts for the reduced susceptibility phenotype.
Prevalence of Serotype 19A
Streptococcus pneumoniae
among Isolates from U.S. Children in 2005-2006 and Activity of Faropenem
Authors: Critchley Ian A. , Jacobs Michael R. , Brown Steven D. , Traczewski Maria M. , Tillotson Glenn S. , Janjic Nebojsa
Published: April 2008

Of 393 isolates of
Streptococcus pneumoniae
from U.S. children collected in 2005-2006, nonvaccine serotypes accounted for 89.1%, with serotype 19A the most prevalent, representing 30.5% of all isolates. The MIC
90
of faropenem against serotype 19A isolates was 1 μg/ml, compared to ≥8 μg/ml against amoxicillin/clavulanate, cefdinir, cefuroxime axetil, and azithromycin.
Effect of Impaired Renal Function on the Pharmacokinetics of Tomopenem (RO4908463/CS-023), a Novel Carbapenem
Authors: Mallalieu Navita L. , Lennon Siân , Liu Mei , Kirkpatrick Christopher , Robson Richard , Luedin Eric , Davies Brian E.
Published: April 2008

The objective of this study was to assess the impact of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite in humans. Thirty-two subjects were enrolled in an open-label, two-center study. Subjects were evenly assigned to one of four groups, based on creatinine clearance ranges of ≥80, 50 to 79, 30 to 49, and <30 ml/min. The drug was given as a single 1,500-mg constant-rate intravenous infusion over 60 min. There were no safety concerns with increasing renal dysfunction. Renal impairment had a significant impact on exposure of both tomopenem and its metabolite. Mean (± standard deviation) areas under the curve for tomopenem increased with decreasing renal function, from 191 ± 35.2 to 1,037 ± 238 μg·h/ml. The maximum concentration of drug in plasma (
C
max
) increased with a maximum difference of 44% between the severe and normal groups. In contrast, the corresponding increase in
C
max
of the metabolite was much higher, at 174%. Total body clearance was linearly correlated with creatinine clearance (
R
2
= 0.97;
P
< 0.0001). Renal clearance for tomopenem decreased with increasing severity of disease, with mean values decreasing from 4.63 ± 0.89 to 0.59 ± 0.19 liters/h. The results of this study indicated a strong correlation between the creatinine clearance and total clearance of tomopenem. While renal impairment appeared to have a significant effect on the pharmacokinetics of tomopenem, an even greater effect was seen on the elimination of the inactive metabolite.
In Vitro Activity of Telavancin against Resistant Gram-Positive Bacteria
Authors: Krause Kevin M. , Renelli Marika , Difuntorum Stacey , Wu Terry X. , Debabov Dmitri V. , Benton Bret M.
Published: April 2008

The in vitro activity of telavancin was tested against 743 predominantly antimicrobial-resistant, gram-positive isolates. Telavancin was highly active against methicillin-resistant staphylococci (MIC
90
, 0.5 to 1 μg/ml), streptococci (all MICs, ≤0.12 μg/ml), and VanB-type enterococci (all MICs, ≤2 μg/ml). Time-kill studies demonstrated the potent bactericidal activity of telavancin.
Comparative Surveillance Study of Telavancin Activity against Recently Collected Gram-Positive Clinical Isolates from across the United States
Authors: Draghi Deborah C. , Benton Bret M. , Krause Kevin M. , Thornsberry Clyde , Pillar Chris , Sahm Daniel F.
Published: April 2008

Telavancin is an investigational, rapidly bactericidal lipoglycopeptide antibiotic that is being developed to treat serious infections caused by gram-positive bacteria. A baseline prospective surveillance study was conducted to assess telavancin activity, in comparison with other agents, against contemporary clinical isolates collected from 2004 to 2005 from across the United States. Nearly 4,000 isolates were collected, including staphylococci, enterococci, and streptococci (pneumococci, beta-hemolytic, and viridans). Telavancin had potent activity against
Staphylococcus aureus
and coagulase-negative staphylococci (MIC range, 0.03 to 1.0 μg/ml), independent of resistance to methicillin or to multiple agents. Telavancin activity was particularly potent against all streptococcal groups (MIC
90
s, 0.03 to 0.12 μg/ml). Telavancin had excellent activity against vancomycin-susceptible enterococci (MIC
90
, 1 μg/ml) and was active against VanB strains of vancomycin-resistant enterococci (MIC
90
, 2 μg/ml) but less active against VanA strains (MIC
90
, 8 to 16 μg/ml). Telavancin also demonstrated activity against vancomycin-intermediate
S. aureus
and vancomycin-resistant
S. aureus
strains (MICs, 0.5 μg/ml to 1.0 μg/ml and 1.0 μg/ml to 4.0 μg/ml, respectively). These data may support the efficacy of telavancin for treatment of serious infections with a wide range of gram-positive organisms.
In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Studies of the Mode of Action in
Staphylococcus aureus
Authors: Robertson Gregory T. , Bonventre Eric J. , Doyle Timothy B. , Du Qun , Duncan Leonard , Morris Timothy W. , Roche Eric D. , Yan Dalai , Lynch A. Simon
Published: April 2008

Rifamycins have proven efficacy in the treatment of persistent bacterial infections. However, the frequency with which bacteria develop resistance to rifamycin agents restricts their clinical use to antibiotic combination regimens. In a program directed toward the synthesis of rifamycins with a lower propensity to elicit resistance development, a series of compounds were prepared that covalently combine rifamycin and quinolone pharmacophores to form stable hybrid antibacterial agents. We describe mode-of-action studies with
Staphylococcus aureus
of CBR-2092, a novel hybrid that combines the rifamycin SV and 4
H
-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed that CBR-2092 has rifampin-like effects on RNA synthesis in rifampin-susceptible strains and quinolone-like effects on DNA synthesis in rifampin-resistant strains. Studies of mutant strains that exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting rifampin resistance. In contrast to quinolone comparator agents, no strains with altered susceptibility to CBR-2092 were found to exhibit changes consistent with altered efflux properties. The combined data indicate that CBR-2092 may have potential utility in monotherapy for the treatment of persistent
S. aureus
infections.
Hemolysin of Uropathogenic
Escherichia coli
Evokes Extensive Shedding of the Uroepithelium and Hemorrhage in Bladder Tissue within the First 24 Hours after Intraurethral Inoculation of Mice
Authors: Smith Yarery C. , Rasmussen Susan B. , Grande Kerian K. , Conran Richard M. , O'Brien Alison D.
Published: April 2008

Many uropathogenic
Escherichia coli
(UPEC) strains produce both hemolysin (Hly) and cytotoxic necrotizing factor type 1 (CNF1), and the loci for these toxins are often linked. The conclusion that Hly and CNF1 contribute to urovirulence is supported by the results of epidemiological studies associating the severity of urinary tract infections (UTIs) with toxin production by UPEC isolates. Additionally, we previously reported that mouse bladders and rat prostates infected with UPEC strain CP9 exhibit a more profound inflammatory response than the organs from animals challenged with CP9
cnf
1
and that CNF1 decreases the antimicrobial activities of polymorphonuclear leukocytes. More recently, we created an Hly mutant, CP9Δ
hlyA
1
::
cat
, and showed that it was less hemolytic and destructive for cultured bladder cells than CP9 was. Here we evaluated the relative effects of mutations in
hlyA
1
or
cnf
1
alone or together on the pathogenicity of CP9 in a mouse model of ascending UTI. To do this, we constructed an
hlyA
1
-complemented clone of CP9Δ
hlyA
1
::
cat
and an
hlyA
1
cnf
1
CP9 double mutant. We found that Hly had no influence on bacterial colonization of the bladder or kidneys in single or mixed infections with the wild type and CP9Δ
hlyA
1
::
cat
but that it did provoke sloughing of the uroepithelium and bladder hemorrhage within the first 24 h after challenge. Finally, we confirmed that CNF1 expression induces bladder inflammation and, in particular, as shown in this study, submucosal edema. From these data, we speculate that Hly and CNF1 may be largely responsible for the signs and symptoms of cystitis in humans infected with toxigenic UPEC.
Cholesterol Depletion ReducesHelicobacter pyloriCagA Translocation and CagA-Induced Responses in AGS Cells
Authors: Lai Chih-Ho , Chang Yun-Chieh , Du Shin-Yi , Wang Hung-Jung , Kuo Chun-Hsien , Fang Shih-Hua , Fu Hua-Wen , Lin Hui-Hao , Chiang Ann-Shyn , Wang Wen-Ching
Published: April 2008

Infection withHelicobacter pylori cagA-positive strains is associated with gastritis, ulcerations, and gastric cancer. CagA is translocated into infected epithelial cells by a type IV secretion system and can be tyrosine phosphorylated, inducing signal transduction and motogenic responses in epithelial cells. Cellular cholesterol, a vital component of the membrane, contributes to membrane dynamics and functions and is important in VacA intoxication and phagocyte evasion duringH. pyloriinfection. In this investigation, we showed that cholesterol extraction by methyl-β-cyclodextrin reduced the level of CagA translocation and phosphorylation. Confocal microscope visualization revealed that a significant portion of translocated CagA was colocalized with the raft marker GM1 and c-Src during infection. Moreover, GM1 was rapidly recruited into sites of bacterial attachment by live-cell imaging analysis. CagA and VacA were cofractionated with detergent-resistant membranes (DRMs), suggesting that the distribution of CagA and VacA is associated with rafts in infected cells. Upon cholesterol depletion, the distribution shifted to non-DRMs. Accordingly, the CagA-induced hummingbird phenotype and interleukin-8 induction were blocked by cholesterol depletion. Raft-disrupting agents did not influence bacterial adherence but did significantly reduce internalization activity in AGS cells. Together, these results suggest that delivery of CagA into epithelial cells by the bacterial type IV secretion system is mediated in a cholesterol-dependent manner.
The Phenolic Glycolipid ofMycobacterium tuberculosisDifferentially Modulates the Early Host Cytokine Response but Does Not in Itself Confer Hypervirulence
Authors: Sinsimer Daniel , Huet Gaelle , Manca Claudia , Tsenova Liana , Koo Mi-Sun , Kurepina Natalia , Kana Bavesh , Mathema Barun , Marras Salvatore A. E. , Kreiswirth Barry N. , Guilhot Christophe , Kaplan Gilla
Published: April 2008

Mycobacterium tuberculosispossesses a diversity of potential virulence factors including complex branched lipids such as the phenolic glycolipid PGL-tb. PGL-tb expression by the clinicalM. tuberculosisisolate HN878 has been associated with a less efficient Th1 response and increased virulence in mice and rabbits. It has been suggested that the W-Beijing family is the only group ofM. tuberculosisstrains with an intactpks1-15gene, required for the synthesis of PGL-tb and capable of producing PGL-tb. We have found that some strains with an intactpks1-15do not produce PGL-tb while others may produce a variant of PGL-tb. We examined the early host cytokine response to infection with these strains in vitro to better understand the effect of PGL-tb synthesis on immune responses. In addition, we generated a PGL-tb-producing H37Rv in order to determine the effect of PGL-tb production on the host immune response during infection by a strain normally devoid of PGL-tb synthesis. We observed that PGL-tb production by clinicalM. tuberculosisisolates affected cytokine production differently depending on the background of the strain. Importantly, while ectopic PGL-tb production by H37Rv suppressed the induction of several pro- and anti-inflammatory cytokines in vitro in human monocytes, it did not lead to increased virulence in infected mice and rabbits. Collectively, our data indicate that, while PGL-tb may play a role in the immunogenicity and/or virulence ofM. tuberculosis, it probably acts in concert with other bacterial factors which seem to be dependent on the background of the strain.
Helicobacter pylori
VacA Subdomain Required for Intracellular Toxin Activity and Assembly of Functional Oligomeric Complexes
Authors: Ivie Susan E. , McClain Mark S. , Torres Victor J. , Algood Holly M. Scott , Lacy D. Borden , Yang Rong , Blanke Steven R. , Cover Timothy L.
Published: April 2008

Helicobacter pylori
VacA is a secreted pore-forming toxin that is comprised of two domains, designated p33 and p55. The p55 domain has an important role in the binding of VacA to eukaryotic cell surfaces. A total of 111 residues at the amino terminus of p55 (residues 312 to 422) are essential for the intracellular activity of VacA, which suggests that this region may constitute a subdomain with an activity distinct from cell binding. To investigate the properties of this subdomain, a small deletion mutation (targeting aspartic acid 346 and glycine 347) was introduced into the
H. pylori
chromosomal
vacA
gene. Similar to wild-type VacA, the VacA Δ346-347 mutant protein was proteolytically processed, secreted, and bound to eukaryotic cells. However, VacA Δ346-347 did not cause cell vacuolation or membrane depolarization, and it was impaired in the ability to assemble into large water-soluble oligomeric structures. Interestingly, VacA Δ346-347 was able to physically interact with wild-type VacA to form mixed oligomeric complexes, and VacA Δ346-347 inhibited wild-type vacuolating activity in a dominant-negative manner. These data indicate that the assembly of functional oligomeric VacA complexes is dependent on specific sequences, including amino acids 346 and 347, within the p55 amino-terminal subdomain.
Effective flexural stiffness of slender structural concrete columns
Authors: Tikka Timo K. , Mirza S. Ali
Published: April 2008

The CSA A23.3 standard permits the use of a moment-magnifier approach for the design of slender reinforced concrete and composite steel–concrete columns. This approach is strongly influenced by the effective flexural stiffness (EI), which varies due to the nonlinearity of the concrete stress–strain curve and the cracking along the column length, among other factors. The EI equations given in the CSA standard are approximate when compared with the EI values computed from the axial load – bending moment – curvature relationships. This study was conducted to determine the influence of a full range of variables on EI used for the design of slender reinforced concrete and composite steel–concrete columns, and also to examine the existing CSA EI equations. Over 27 000 isolated concrete columns, each with a different combination of specified variables, in symmetrical single-curvature bending were simulated to generate the stiffness data. Two new design equations to compute EI of structural concrete columns were then developed from the simulated stiffness data and are proposed as an alternative to the existing CSA design equations for EI.
Developing a project knowledge management framework for tunnel construction: lessons learned in Taiwan
Authors: Tserng H. Ping , Chang Chin-Hsiang
Published: April 2008

Knowledge, particularly in the form of experience, can provide a competitive advantage in the construction industry. Knowledge organization (KO) systems developed in the library, information, and computer sciences are excellent for delivering knowledge services. However, it is difficult for these systems to judge how suitable (not just relevant) any of the retrieved knowledge will be in practice. This study puts forward a directional experience ontology (DExOntology) framework, which makes use of KO characteristics to set up problem-topic ontology, but augments the retrieved knowledge documents (KwDocs) in the knowledge bank with additional “orientation” from weighted attributes determined by domain experts, thus bridging the gap between existing KO systems and practical requirements. The goal is a mechanism that delivers knowledge, especially in the domain of practical experience, more efficiently and effectively than simple information retrieval searches. The study finds that the DExOntology framework significantly improves both the relevancy and suitability of the retrieved knowledge, making it a more useful system for construction industry practitioners to use in the field.
Seismic assessment of rainscreen stucco systems
Authors: Kharrazi Mehdi H.K. , Taylor Graham W. , Ventura Carlos E.
Published: April 2008

This paper evaluates the comparative and absolute in-plane seismic performance of rainscreen and nonrainscreen stucco exterior cladding systems for residential wood frame construction in British Columbia. In this study, an experimental program including quasi-static and dynamic tests was implemented, comprised of 18 (in-plane) quasi-static tests and two dynamic tests. The principal parameters investigated in this study were type of strapping, type and length of strapping fastener, and type and length of lath fastener. All rainscreen specimens were constructed with a 20 mm air space. The overall conclusion is that both rainscreen and nonrainscreen stucco comply with the code requirements addressing the permissible drifts. Therefore, both stucco systems were found to improve the structural behaviour when used as the lateral resisting system of residential wood frame buildings. This paper concludes with recommendations for seismic refinements to current construction practices.