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Mark A Miller

Publications and source records attributed to Mark A Miller.

51 records · Page 3Linked to original sources
PubMed2003

Competition of percolation and phase separation in a fluid of adhesive hard spheres.

Using a combination of Monte Carlo techniques, we locate the liquid-vapor critical point of adhesive hard spheres. We find that the critical point lies deep inside the gel region of the phase diagram. The (reduced) critical temperature and density are tau(c)=0.1133+/-0.0005 and rho(c)=0.508+/-0.01. We compare these results with the available theoretical predictions. Using a finite-size scaling analysis, we verify that the critical behavior of the adhesive hard sphere model is consistent with that of the 3D Ising universality class, the default for systems with short-range attractive forces.

Journal Article↗
PubMed2003

IL-12-assisted immunization generates CD4+ T cell-mediated immunity to Listeria monocytogenes.

Mice infected with virulent Listeria monocytogenes develop long-lived acquired immunity. We previously reported that acquired immunity to Listeria could also be elicited by immunizing mice with non-viable Listeria or listerial proteins/peptides in combination with IL-12. Here we show that this IL-12-assisted immunization strategy was effective in class I but not in class II MHC-deficient mice, suggesting that antigen-specific CD4(+) T cells are selectively generated using this adjuvant system. We have also evaluated the importance of endogenous production of IFN-gamma and IL-12 for the efficacy of IL-12-assisted immunization. IFN-gamma-deficient mice immunized with HKLM and IL-12 failed to produce effective Listeria-specific responses. In contrast, IL-12-deficient mice were able to generate protective antigen-specific T cell responses in response to immunization with HKLM and IL-12, indicating that exogenous IL-12 is sufficient to initiate a cytokine cascade that results in a potent T(H)1 response. IL-12-assisted immunization provides a model in which both the generation and effector mechanisms of anti-bacterial antigen-specific CD4(+) effector cells can be analyzed.

Adjuvants, Immunologic↗
PubMed2003

Early cement damage around a femoral stem is concentrated at the cement/bone interface.

This study aimed to improve understanding of the mechanical aspects of cemented implant loosening. After aggressive fatigue loading of stem/cement/femur constructs, micro-cracks and stem/bone micro-motions were quantified to answer three research questions: Are cracks preferentially associated with the stem/cement interface, the cement/bone interface or voids? Is cement damage dependent on axial position? Does cement damage correlate with micro-motion between the stem and the bone? Eight Charnley Cobra stems were implanted in cadaveric femora. Six stem/cement/femur constructs were subjected to "stair-climbing" loads for 300 kcycles at 2Hz. Loads were normalized by construct stiffness to avoid fracture. Two additional constructs were not loaded. Transverse sections were cut at 10mm intervals, stained with a fluorescent dye penetrant and examined using epi-fluorescence stereomicroscopy. Crack lengths and cement areas were recorded for 9 sections per specimen. Crack length-density was calculated by dividing summed crack length by cement mantle area. To isolate the effect of loading, length-density data were offset by the baseline length-density measured in the non-loaded specimens. Significantly more cracks were associated with the interdigitated area (35.1%+/-11.6%) and the cement/bone interface (31.0%+/-6.2%) than with the stem/cement interface (11.0%+/-5.2%) or voids (6.1%+/-4.8%) (p<0.05). Load-induced micro-crack length-density was significantly dependent on axial position, increasing proximally (p<0.001). Micro-motions were small, all stems rotated internally. Cement damage did not correlate with micro-motion.

Aged↗
PubMed2003

Application of circular statistics in the study of crack distribution around cemented femoral components.

Cemented stem constructs were loaded in cyclic fatigue using stair climbing loading and the resulting fatigue damage to the cement mantle was determined in terms of angular position of crack and crack length. Techniques from circular statistics were used to determine if the distribution of micro-cracks was uniform. With a designated orientation of 0 degrees -90 degrees -180 degrees -270 degrees indicating lateral-anterior-medial-posterior anatomic directions, the overall distribution of cracks was not uniform (p<0.05) with a mean crack direction in the postero-medial (249 degrees) quadrant of the mantle. The crack angular distribution for proximal (postero-medial; 251 degrees) and distal (antero-medial; 112 degrees) regions of the cement mantle was also different (p<0.025). These findings suggest that the location of cement damage depends on anatomic position and appears to correspond with the tensile stress field in the cement mantle.

Arthroplasty, Replacement, Hip↗
PubMed2003

Global illness and deaths caused by rotavirus disease in children.

To estimate the global illness and deaths caused by rotavirus disease, we reviewed studies published from 1986 to 2000 on deaths caused by diarrhea and on rotavirus infections in children. We assessed rotavirus-associated illness in three clinical settings (mild cases requiring home care alone, moderate cases requiring a clinic visit, and severe cases requiring hospitalization) and death rates in countries in different World Bank income groups. Each year, rotavirus causes approximately 111 million episodes of gastroenteritis requiring only home care, 25 million clinic visits, 2 million hospitalizations, and 352,000-592,000 deaths (median, 440,000 deaths) in children <5 years of age. By age 5, nearly every child will have an episode of rotavirus gastroenteritis, 1 in 5 will visit a clinic, 1 in 65 will be hospitalized, and approximately 1 in 293 will die. Children in the poorest countries account for 82% of rotavirus deaths. The tremendous incidence of rotavirus disease underscores the urgent need for interventions, such as vaccines, particularly to prevent childhood deaths in developing nations.

Child, Preschool↗
PubMed2002

Structural genomics of the Thermotoga maritima proteome implemented in a high-throughput structure determination pipeline.

Structural genomics is emerging as a principal approach to define protein structure-function relationships. To apply this approach on a genomic scale, novel methods and technologies must be developed to determine large numbers of structures. We describe the design and implementation of a high-throughput structural genomics pipeline and its application to the proteome of the thermophilic bacterium Thermotoga maritima. By using this pipeline, we successfully cloned and attempted expression of 1,376 of the predicted 1,877 genes (73%) and have identified crystallization conditions for 432 proteins, comprising 23% of the T. maritima proteome. Representative structures from TM0423 glycerol dehydrogenase and TM0449 thymidylate synthase-complementing protein are presented as examples of final outputs from the pipeline.

Cloning, Molecular↗
PubMed2002

Role of the low-affinity binding site in electron transfer from cytochrome C to cytochrome C peroxidase.

The interaction of yeast iso-1-cytochrome c (yCc) with the high- and low-affinity binding sites on cytochrome c peroxidase compound I (CMPI) was studied by stopped-flow spectroscopy. When 3 microM reduced yCc(II) was mixed with 0.5 microM CMPI at 10 mM ionic strength, the Trp-191 radical cation was reduced from the high-affinity site with an apparent rate constant >3000 s(-1), followed by slow reduction of the oxyferryl heme with a rate constant of only 10 s(-1). In contrast, mixing 3 microM reduced yCc(II) with 0.5 microM preformed CMPI *yCc(III) complex led to reduction of the radical cation with a rate constant of 10 s(-1), followed by reduction of the oxyferryl heme in compound II with the same rate constant. The rate constants for reduction of the radical cation and the oxyferryl heme both increased with increasing concentrations of yCc(II) and remained equal to each other. These results are consistent with a mechanism in which both the Trp-191 radical cation and the oxyferryl heme are reduced by yCc(II) in the high-affinity binding site, and the reaction is rate-limited by product dissociation of yCc(III) from the high-affinity site with apparent rate constant k(d). Binding yCc(II) to the low-affinity site is proposed to increase the rate constant for dissociation of yCc(III) from the high-affinity site in a substrate-assisted product dissociation mechanism. The value of k(d) is <5 s(-1) for the 1:1 complex and >2000 s(-1) for the 2:1 complex at 10 mM ionic strength. The reaction of horse Cc(II) with CMPI was greatly inhibited by binding 1 equiv of yCc(III) to the high-affinity site, providing evidence that reduction of the oxyferryl heme involves electron transfer from the high-affinity binding site rather than the low-affinity site. The effects of CcP surface mutations on the dissociation rate constant indicate that the high-affinity binding site used for the reaction in solution is the same as the one identified in the yCc*CcP crystal structure.

Binding Sites↗
PubMed2002

Fatigue crack growth rate does not depend on mantle thickness: an idealized cemented stem construct under torsional loading.

Retrieval studies indicate that cemented stem loosening in femoral components of total hip replacement can initiate at the stem-cement interface. The etiology of the crack propagation process from the stem-cement interface is not well understood, but cracks are typically associated with thin cement mantles. In this study, a combination of experimental and computational methods was used to investigate the fatigue crack propagation process from the stem-PMMA cement interface using a novel torsional loading model. Constructs with thin (1 mm), medium (3 mm) or thick (7 mm) cement mantles were evaluated. Crack growth was stable for all cases and the rate of crack growth diminished with increasing crack length. Crack growth rate did not depend on mantle thickness (p > 0.05) over the first 1 mm of crack length, but cracks in thin mantles reached the full thickness of the mantle in the fewest number of loading cycles. The fracture mechanics-based finite element models indicated decreased stress intensity factors with increasing crack length and were consistent with the experimental findings. When combined with a fatigue crack growth Paris-law for PMMA cement, the finite element models provided reasonable predictions of the crack growth process.

Arthroplasty, Replacement, Hip↗
PubMed2002

Morbidity, mortality, and healthcare burden of nosocomial Clostridium difficile-associated diarrhea in Canadian hospitals.

OBJECTIVE: To assess the healthcare burden, morbidity, and mortality of nosocomial Clostridium difficile-associated diarrhea (N-CDAD) in Canadian hospitals. DESIGN: Laboratory-based prevalence study. SETTING: Nineteen acute-care Canadian hospitals belonging to the Canadian Hospital Epidemiology Committee surveillance program. PATIENTS: Hospitalized patients in the participating centers. METHODS: Laboratory-based surveillance was conducted for C. difficile toxin in stool among 19 Canadian hospitals from January to April 1997, for 6 continuous weeks or until 200 consecutive diarrhea stool samples had been tested at each site. Patients with N-CDAD had to fulfill the case definition. Data collected for each case included patient demographics, length of stay, extent of diarrhea, complications of CDAD, CDAD-related medical interventions, patient outcome, and details of death. RESULTS: We found that 371 (18%) of 2,062 tested patients had stools with positive results for C difficile toxin, of whom 269 (13%) met the case definition for nosocomial CDAD. Of these, 250 patients (93%) had CDAD during their hospitalization, and 19 (7%) were readmitted because of CDAD (average readmission stay, 13.6 days). Forty-one patients (15.2%) died, of whom 4 (1.5% of the total) were considered to have died directly or indirectly of N-CDAD. The following N-CDAD-related morbidity was noted: dehydration, 3%; hypokalemia, 2%; gastrointestinal hemorrhage requiring transfusion, 1%; bowel perforation, 0.4%; and secondary sepsis, 0.4%. The cost of N-CDAD readmissions alone was estimated to be a minimum of $128,200 (Canadian dollars) per year per facility. CONCLUSION: N-CDAD is a common and serious nosocomial infectious complication in Canada, is associated with substantial morbidity and mortality, and imposes an important financial burden on healthcare institutions.

Aged↗
PubMedDate not supplied

Adjuvanticity of an IL-12 fusion protein expressed by recombinant deltaG-vesicular stomatitis virus.

The remarkable immunomodulatory and adjuvant properties of rIL-12 have been well described. Many early studies documenting the adjuvanticity of IL-12 were performed using the murine model of Listeria monocytogenes infection. In this report, we describe the construction of an attenuated recombinant vesicular stomatitis virus (VSV-deltaG) that encodes a single-chain IL-12 fusion protein (IL-12F), and the use of this virus as an expression vector to produce large quantities of IL-12F. VSV-expressed IL-12F (vIL-12F) was then co-administered to mice along with a poorly immunogenic listerial antigen preparation as a vaccine regimen and the resulting immune responses were monitored. The vIL-12F was found to have adjuvant properties similar to those observed for rIL-12. Co-administration of vIL-12F and listerial antigen elicited powerful cell-mediated immune responses that conferred long-lived protective listerial immunity. These studies demonstrated that VSVdeltaG-IL12F-infected cells secrete bioactive single-chain IL-12, and laid the foundation for studies using VSVdeltaG-IL12F as a vector for delivery of IL-12F in vivo.

Adjuvants, Immunologic↗
PubMedDate not supplied

Amphiphilic conjugates of human brain natriuretic peptide designed for oral delivery: in vitro activity screening.

Congestive heart failure (CHF) is a complex syndrome involving altered neurohormonal levels and impaired cardiac and renal function. In recent years, intravenous administration of exogenous human brain-type natriuretic peptide (hBNP) has become an important therapy in treating patients with acutely decompensated CHF. However, reports during the past year suggest that hBNP could play a prominent role in the chronic treatment of CHF patients as well. We are currently developing conjugates of hBNP suitable for oral delivery to provide a patient-friendly treatment option for chronic heart failure patients. In this report, we present in vitro activity results obtained from hBNP conjugates featuring a variety of rationally designed amphiphilic oligomers. Mapping studies revealed that the hydrophobic/hydrophilic balance of the oligomer impacted the regioselectivity of conjugation. Additionally, the regiochemistry and extent of conjugation had a significant impact on activity. Many monoconjugates retained activity comparable to native peptide and are currently under evaluation in subsequent in vivo screens.

Administration, Oral↗