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Biomedical subjects

Robert Anderson

Publications and source records attributed to Robert Anderson.

At least 19 recordsLinked to original sources
PubMed2005

ZDOCK and RDOCK performance in CAPRI rounds 3, 4, and 5.

We present an evaluation of the results of our ZDOCK and RDOCK algorithms in Rounds 3, 4, and 5 of the protein docking challenge CAPRI. ZDOCK is a Fast Fourier Transform (FFT)-based, initial-stage rigid-body docking algorithm, and RDOCK is an energy minimization algorithm for refining and reranking ZDOCK results. Of the 9 targets for which we submitted predictions, we attained at least acceptable accuracy for 7, at least medium accuracy for 6, and high accuracy for 3. These results are evidence that ZDOCK in combination with RDOCK is capable of making accurate predictions on a diverse set of protein complexes.

Algorithms↗
PubMed2005

Protein-Protein Docking Benchmark 2.0: an update.

We present a new version of the Protein-Protein Docking Benchmark, reconstructed from the bottom up to include more complexes, particularly focusing on more unbound-unbound test cases. SCOP (Structural Classification of Proteins) was used to assess redundancy between the complexes in this version. The new benchmark consists of 72 unbound-unbound cases, with 52 rigid-body cases, 13 medium-difficulty cases, and 7 high-difficulty cases with substantial conformational change. In addition, we retained 12 antibody-antigen test cases with the antibody structure in the bound form. The new benchmark provides a platform for evaluating the progress of docking methods on a wide variety of targets. The new version of the benchmark is available to the public at http://zlab.bu.edu/benchmark2.

Algorithms↗
PubMed2005

Comparison of postoperative pain in patients following photorefractive keratectomy versus advanced surface ablation.

PURPOSE: To compare postoperative pain associated with advanced surface ablation versus traditional photorefractive keratectomy (PRK). SETTING: Codet-Aris Vision Institute, Tijuana, Mexico. METHODS: This prospective double-masked randomized study included 56 eyes of 28 myopic patients who received traditional PRK in 1 eye and advanced surface ablation in the contralateral eye. For advanced surface ablation, removal of corneal epithelium was performed by incubating the cornea with 18% ethanol. Subsequently, the epithelium was removed by a surgical microsponge. For eyes treated by PRK, mechanical debridement of corneal epithelium was performed with a surgical blade. Excimer laser corneal ablation was performed using the Nidek EC-5000 excimer laser in all eyes. On postoperative days 1 and 3, patients were instructed to rate their pain via 3 pain measuring tools: (1) a global subjective rating; (2) a 100 mm visual analog scale (VAS); and (3) an 11-point numerical rating scale. RESULTS: All 28 patients completed postoperative questionnaires on day 1 and day 3. On postoperative day 1, all reported pain in both eyes. Using the global assessment rating, patients reported statistically significant more pain in eyes treated by advanced surface ablation (P = .0037; confidence interval [CI], 59%-92%). Furthermore, based on the 11-point numerical rating scale, mean pain scores were significantly higher in the advanced surface ablation treated eyes (P = .0121), while the VAS mean pain scores were marginally significantly higher (P = .0822). On postoperative day 3, 23 patients reported the presence of some pain, at least in 1 eye. Using the global assessment rating, 70% of the those who had pain reported more pain in the advanced surface ablation-treated eye (advanced surface ablation 16/23 versus PRK 7/23) (P = .0931; 95% CI, 47%-87%). In addition, on postoperative day 3, advanced surface ablation-treated eyes demonstrated slightly higher mean pain scores based on the 11-point numerical rating scale and on the VAS; however, mean differences were not statistically significant (P = .3494 and P = .3337, respectively). CONCLUSIONS: Advanced surface ablation was associated with statistically significantly more postoperative pain than PRK on postoperative day 1. A greater percentage of patients reported more pain in the advanced surface ablation-treated eyes on day 3. Refractive surgeons should consider the postoperative pain associated with advanced surface ablation when deciding on the type of epithelial debridement for their patients.

Debridement↗
PubMed2005

Modulation of protective immunity, eosinophilia, and cytokine responses by selective mutagenesis of a recombinant G protein vaccine against respiratory syncytial virus.

Using an Escherichia coli-grown plasmid vector encoding a fragment of thioredoxin (Trx) fused to a central region (amino acids 128 to 229) of the respiratory syncytial virus (RSV) (Long strain) G protein, we employed site-directed mutagenesis to investigate the importance of selected amino acids to vaccine efficacy. Mice were immunized with a total of 10 wild-type or mutant Trx-G proteins and challenged intranasally with RSV. Striking differences in the induction of RSV G-protein-specific antibodies, protection against RSV challenge, cytokine RNA responses, and induction of RSV-associated eosinophilic inflammation were observed among the mutant proteins examined. Taken together, the results identify a critical role for specific amino acids in the induction of protective immunity and priming for eosinophilia against RSV.

Adjuvants, Immunologic↗
PubMed2005

Ethnicity, race, and baseline retinopathy correlates in the veterans affairs diabetes trial.

OBJECTIVE: The Veterans Affairs Diabetes Trial (VADT) cohort is enriched with approximately 20% Hispanics and 20% African Americans, affording a unique opportunity to study ethnic differences in retinopathy. RESEARCH DESIGN AND METHODS: Cross-sectional analyses on the baseline seven-field stereo fundus photos of 1,283 patients are reported here. Diabetic retinopathy scores are grouped into four classes of increasing severity: none (10-14), minimal nonproliferative diabetic retinopathy (NPDR) (15-39), moderate to severe NPDR (40-59), and proliferative diabetic retinopathy (60+). These four groups have also been dichotomized to none or minimal (10-39) and moderate to severe diabetic retinopathy (40+). RESULTS: The prevalence of diabetic retinopathy scores >40 was higher for Hispanics (36%) and African Americans (29%) than for non-Hispanic whites (22%). The difference between Hispanics and non-Hispanic whites was significant (P < 0.05). Similarly, the prevalence of diabetic retinopathy scores >40 was significantly higher in African Americans than in non-Hispanic whites (P < 0.05). These differences could not be accounted for by an imbalance in traditional risk factors such as age, duration of diagnosed diabetes, HbA(1c) (A1C), and blood pressure. Diabetic retinopathy severity scores were also significantly associated with increasing years of disease duration, A1C, systolic and diastolic blood pressure, the degree of microalbuminuria, fibrinogen, and the percentage of patients with amputations. There was no relationship between retinopathy severity and the percentage of people who had strokes or cardiac revascularization procedures. There was an inverse relationship between retinopathy severity and total cholesterol, triglycerides, and plasminogen activator inhibitor-1 as well as with smoking history. Diabetic retinopathy scores were not associated with age. CONCLUSIONS: In addition to many well-known associations with retinopathy, a higher frequency of severe diabetic retinopathy was found in the Hispanic and African-American patients at entry into the VADT that is not accounted for by traditional risk factors for diabetic retinopathy, and these substantial ethnic differences remain to be explained.

Adult↗
PubMed2004

Structure of a kinesin microtubule depolymerization machine.

With their ability to depolymerize microtubules (MTs), KinI kinesins are the rogue members of the kinesin family. Here we present the 1.6 A crystal structure of a KinI motor core from Plasmodium falciparum, which is sufficient for depolymerization in vitro. Unlike all published kinesin structures to date, nucleotide is not present, and there are noticeable differences in loop regions L6 and L10 (the plus-end tip), L2 and L8 and in switch II (L11 and helix4); otherwise, the pKinI structure is very similar to previous kinesin structures. KinI-conserved amino acids were mutated to alanine, and studied for their effects on depolymerization and ATP hydrolysis. Notably, mutation of three residues in L2 appears to primarily affect depolymerization, rather than general MT binding or ATP hydrolysis. The results of this study confirm the suspected importance of loop 2 for KinI function, and provide evidence that KinI is specialized to hydrolyze ATP after initiating depolymerization.

Animals↗
PubMed2004

Towards an in vitro model for acute hemorrhagic conjunctivitis: cytokine-mediated vascular endothelial cell activation triggered by enterovirus type 70 infection.

BACKGROUND: Little is known of the pathogenetic mechanisms of enterovirus type 70 (EV70), a causative agent of acute hemorrhagic conjunctivitis. However, virus- or cytokine-induced perturbation of vascular endothelial cells are potential triggering events. OBJECTIVE: To determine whether EV70 infection of human umbilical vascular endothelial cells (HUVECs) and human corneal epithelial cells (HCEs) causes the release of vasoactive cytokines, capable of triggering vascular endothelial cell activation. STUDY DESIGN: Susceptibility of cultured HUVECs and HCEs to EV70 was tested by observing the appearance of cytopathic effect or immunoprecipitation of viral protein in infected cells. The culture fluids from the virus-infected cells were tested for their ability to stimulate the expression of intercellular adhesion molecule-1 (ICAM-1) on uninfected HUVECs. Anti-cytokine antibodies were used to identify ICAM-1-activating cytokine(s). RESULTS: Both HUVECs and HCEs were susceptible to EV70 infection. Culture fluids from EV70-infected HUVECs and HCEs stimulated ICAM-l expression on uninfected HUVECs, which was completely blocked by anti-interleukin-1alpha (IL-1alpha) antibody but not by interleukin-1beta (IL-1beta) or anti-tumor necrosis factor alpha (TNFalpha) antibodies. CONCLUSION: This study provides the first evidence of EV70 infection of both HCEs and HUVECs, and furthermore, identifies IL-1alpha as the predominant endothelial cell-activating factor produced by EV70-infected cells. Since endothelial cell activation is often an initiating step towards vascular permeability and/or inflammation, the perturbation of endothelial cell function through EV70 induced IL-1alpha is thus a potential contributory factor in the pathogenesis of EV70-associated hemorrhagic conjunctivitis.

Antibodies↗
PubMed2004

A strategy for treatment of Epstein-Barr virus-positive Hodgkin's disease by targeting interleukin 12 to the tumor environment using tumor antigen-specific T cells.

Adoptive immunotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T cells (CTL) is effective for the prophylaxis and treatment of EBV-induced lymphoma in hematopoietic stem cell recipients. However, in EBV-positive Hodgkin's disease (HD) the efficacy of adoptively transferred EBV-specific CTL may be limited by tumor-derived immunosuppressive factors, such as T-cell growth factor (TGF) beta, interleukin (IL)13 and the chemokine TARC. Local delivery of IL12 to tumor sites by tumor-specific CTL could provide direct antitumor effects and overcome the CTL-inhibitory effects of the Th2 tumor environment while avoiding the systemic toxicity of recombinant IL12. EBV-specific CTL transduced with a retrovirus vector expressing the p40 and p35 subunits of IL12 as a single molecule (Flexi-IL12), produced IL12 following antigenic stimulation. This resulted in an elevated production of Th1 cytokines, including interferon gamma and tumor necrosis factor alpha, and a reduction in the Th2 cytokines IL4 and IL5. Flexi-IL12-transduced CTL resisted the antiproliferative and anticytotoxic effects of exogenous TGFbeta, likely by antagonizing the TGFbeta-induced downregulation of the Th1 transcriptional factor T-bet. In addition, Flexi-IL12-transduced CTL demonstrated a proliferative advantage in the presence of inhibitory supernatants from HD-derived cell lines. Tumor-specific, Flexi-IL12-transduced EBV-specific CTL should have a functional advantage over unmodified CTL, particularly in the presence of the adverse Th2 cytokine environment produced by Hodgkin tumor cells.

Antigens, Neoplasm↗
PubMed2004

Deinococcus frigens sp. nov., Deinococcus saxicola sp. nov., and Deinococcus marmoris sp. nov., low temperature and draught-tolerating, UV-resistant bacteria from continental Antarctica.

Six Gram-positive, non-motile, UV- and draught-tolerant bacteria were isolated from antarctic soil and rock samples. The pink to orange cocci grew well on oligotrophic medium PYGV (pH 7.5) at 9-18 degrees C. They tolerated 0-10% NaCl, were aerobic to facultatively anaerobic and contained ornithine in their cell wall (type A3beta, Orn-Gly2). The lipid profiles of four strains were found to be typical for those of D. radiodurans. Major fatty acids were 16:1cis9, 15:1cis9, 17:1cis9 and i17:1cis9, the respiratory quinone of three strains was MK-8. Comparative 16S rDNA gene sequencing revealed phylogenetic relationships to the Deinococcus clade, especially to D. radiopugnans. The levels of 16S rRNA gene sequence similarity and DNA-DNA hybridisation data showed the six isolates represented new taxa. Phenotypic properties supported the description of three new species which were different from the eight known Deinococcus species and particularly from D. radiopugnans. Soil isolate AA-692T (DSM 12807T) is the type strain of Deinococcus frigens sp. nov., with AA-752 (DSM 15993) and AA-829 (DSM 15994) as additional strains from soil. The endolithic isolate AA-1444T, Deinococcus saxicola sp. nov., (DSM 15974T) came from antarctic sandstone, and Deinococcus marmoris sp. nov. (isolate AA-63T [DSM 12784T]) as well as AA-69 (DSM 15951) were isolated from antarctic marble.

Anaerobiosis↗
PubMed2003

A single amino acid substitution in a recombinant G protein vaccine drastically curtails protective immunity against respiratory syncytial virus (RSV).

Recent studies have indicated a dominant T cell epitope located approximately between amino acids 184 and 203 on the respiratory syncytial virus (RSV) G protein. Using an Escherichia coli-grown plasmid vector encoding a fragment of thioredoxin (Trx) fused to a central region (amino acids 128-229) of the RSV G protein, we employed site-directed mutagenesis to investigate the importance of selected amino acids on vaccine efficacy. By changing two amino acids Arg 188 and Lys 192 to alanine, the ability of the Trx-G 128-229 fusion protein to protect mice against RSV challenge was virtually abolished. Mice immunized with the double mutant protein showed low levels of neutralizing antibodies and no pulmonary eosinophilic infiltrate, in contrast to that observed in mice immunized with wild type protein prior to RSV challenge. While less effective than the double mutant, mutation of either Arg 188 or Lys 192 to Ala drastically impaired the ability of immunized Trx-G 128-229 to induce neutralizing antibodies and to elicit pulmonary eosinophilia associated with RSV challenge. Despite low levels of virus-neutralizing antibodies, G protein-specific antibodies were detected by Western blotting in the sera from mice immunized with either of the single mutants (Arg 188 or Lys 192) but not the double mutant. Finally, immunization of mice with truncated forms of the Trx-G protein, showed partial protection against RSV challenge with Trx-G 128-188 but not with Trx-G 189-229. Taken together, the results indicate an important role for Arg 188 and Lys 192 in the induction of protective immunity and priming for eosinophilia against RSV. Furthermore, while the dominant protective linear epitope on the RSV G protein requires an intact sequence around Arg 188, there are additional, but less potent, protective epitopes upstream of Arg 188.

Amino Acid Substitution↗
PubMed2003

Prediction of resource use during acute pediatric illnesses.

BACKGROUND: Significant resources are used for acute illnesses in children. Identifying predictors of resource use can focus interventions to reduce this use. OBJECTIVE: To determine the relative effects of maternal, infant, social milieu, and demographic characteristics, the mother-child interaction, and perception of illness severity on the use of resources during acute illnesses in children. DESIGN: At the 2-week and 6-, 15-, and 24-month well-child care visits of a cohort of mother-infant dyads, the mother-well-child interaction was assessed by using the Biringen Emotional Availability Scales, and data were gathered regarding maternal depression and sense of competence, infant temperament, maternal social support, the home environment, and demographic characteristics. At each of the cohort's 1983 ill-child care visits during 30 months of follow-up, the mother-ill-child interaction was assessed by using the Emotional Availability Scales, and mothers and pediatricians independently assessed illness severity using the Acute Illness Observation Scales. Resources used during the illnesses-over-the-counter and prescription medications, tests, hospitalizations, follow-up visits, and the emergency department-were assessed. SETTING: A hospital primary care center and an urban and a suburban private practice. Patients Between February 1, 1995, and March 30, 1998, a consecutive sample of 380 dyads were asked to enroll at the 2-week well-child care visit; 316 (83.2%) consented, and complete data were available for analysis of 243 dyads. MAIN OUTCOME MEASURES: A path analytic framework using a structural equation model assessed the presence and strength of predictive relationships between demographic, maternal, infant, and social milieu data, the Biringen Emotional Availability Scales, and the Acute Illness Observation Scales and the main outcome measure, resource use. RESULTS: Three variables predicted greater mean resource use during each acute illness episode: a less optimal mother-child interaction (beta = -.53), lower scores for parenting sense of competence (beta = -.26), and greater perception of illness severity by mothers (beta =.33). By using the coefficient of determination (R2), these 3 predictors account for 55% of the reliable variance in resource use during acute illnesses. CONCLUSION: The quality of the mother-child interaction, maternal sense of competence, and maternal assessment of severity of the illness are major predictors of resource use during acute pediatric illnesses, and should be important foci of interventions to reduce resource use.

Acute Disease↗
PubMed2003

Construction of adeno-associated virus packaging plasmids and cells that directly select for AAV helper functions.

Recombinant adeno-associated virus type 2 (rAAV) has promise for use as a gene therapy vector. Potential problems in the production of rAAV stocks are both the limited amount of recombinant virus that is produced by traditional methods and the possibility of wild-type replication competent adeno-associated virus (wtAAV) contamination. The presence of these contaminants is largely dependent upon the helper plasmid used. Whilst wtAAV is not a pathogen, the presence of these contaminants is undesirable as they may affect experiments concerning the biology of rAAV. Additionally as protocols using rAAV with altered tropism are becoming more prevalent, it is important that no recombination be permitted that may cause the creation of a replication competent AAV with modified (targeting) capsids. Many experimental protocols require the generation of large amounts of high titre rAAV stocks. We describe the production of several AAV helper plasmids and cell lines designed to achieve this goal. These plasmids possess split AAV rep and cap genes to eliminate the production of wtAAV and they possess a selection mechanism which is operatively linked to expression from the AAV cap gene. This allows positive selection of those cells expressing the highest level of the structural capsid proteins and therefore those cells which yield the highest amount of rAAV.

CD4 Antigens↗
PubMed2003

Activation of vascular endothelial cells by IL-1alpha released by epithelial cells infected with respiratory syncytial virus.

Although pulmonary inflammation is a serious, sometimes life-threatening, consequence of respiratory syncytial virus (RSV) infection, the mechanisms involved are not well understood. Since the process of inflammation is initiated by a complex series of events including the activation of specific adhesion molecules on vascular endothelium, we searched for endothelial cell-activating factors released from RSV-infected epithelial cells. We demonstrate here that vascular endothelial cells exposed to culture supernatants from RSV-infected pulmonary epithelial A549 cells are activated to express increased cell surface ICAM-1, and to a lesser extent, VCAM-1 and E-selectin. IL-1alpha was identified as the predominant endothelial cell-activating factor by pretreating epithelial cell supernatants with anti-IL-1alpha antibody. The preferential upregulation of endothelial ICAM-1 (relative to VCAM-1 and E-selectin) by RSV-infected epithelial cell supernatants was replicated by recombinant IL-1alpha thus confirming IL-1alpha as a major endothelial cell-activating cytokine released by RSV-infected epithelial cells. Il-1alpha mediated endothelial cell activation is thus a likely contributory event in the initiation of leukocyte inflammation associated with RSV infection.

Cell Line↗
PubMed2003

Manipulation of cell surface macromolecules by flaviviruses.

Cell surface macromolecules play a crucial role in the biology and pathobiology of flaviviruses, both as receptors for virus entry and as signaling molecules for cell-cell interactions in the processes of vascular permeability and inflammation. This review examines the cell tropism and pathogenesis of flaviviruses from the standpoint of cell surface molecules, which have been implicated as receptors in both virus-cell as well as cell-cell interactions. The emerging picture is one that encompasses extensive regulation and interplay among the invading virus, viral immune complexes, Fc receptors, major histocompatibility complex antigens, and adhesion molecules.

Animals↗
PubMed2003

Expression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission.

Many solid tumours have been shown to lack expression of either of the immune co-stimulatory molecules CD80 (B7.1) or CD86 (B7.2), which is thought to be one of the ways in which tumours may escape immune recognition. We have examined the surface expression of CD80, CD86, human leucocyte antigen (HLA) class I and II, CD11a, CD54, and CD58 on the blast cells from patients with acute myeloid leukaemia (AML) at presentation. CD80 was only rarely expressed on AML blasts and, in those leukaemic cells expressing CD80, the level of expression was low. In contrast, expression of CD86 was detected on the AML blasts in more than half of the samples tested and, in some cases, the level of expression was equivalent to that of mature monocytes and activated B lymphocytes. The percentage of leukaemic blasts expressing CD86 was higher in the M4 and M5 French-American-British (FAB) types, and expression of CD11a and HLA class II was higher in the M4 FAB type. There was no difference in expression of CD80, CD54, CD58, or HLA Class I between different FAB subgroups. There was no significant difference in duration of first remission with expression of CD80, CD86, CD11a, CD54 or HLA class II. However, when expression of CD80 and CD86 were considered together, a significantly longer duration of remission was found. We suggest that these molecules may play a role in immunosurveillance, resulting in prolonged remission in some patients treated for AML.

Acute Disease↗
PubMed2003

Surgeon training and complications in total ankle arthroplasty.

BACKGROUND: This study assessed the problems with initial use of ankle arthroplasty by surgeons who were trained by observing the surgeon/inventor (group I), who have completed a structured, hands-on surgical training course (group II), or who were trained during a 1-year foot and ankle fellowship (group III). MATERIALS AND METHODS: The perioperative records of the first 10 cases of nine surgeons were reviewed. We evaluated the 6-month-postoperative standing mortise and lateral radiographs for evidence of syndesmosis union and accuracy of tibial component implantation. Three surgeons were each in group I, group II, and group III. Average patient age at time of surgery was similar. Ankle arthritis was classified as rheumatoid arthritis (RA) or osteoarthritis (OA) as follows: group I (7 RA, 23 OA), group II (7 RA, 23 OA), and group III (3 RA, 27 OA). RESULTS: In group I, there were nine intraoperative complications, four postoperative wound dehiscences, and three postoperative deep infections. Radiographic evaluation of the 26 cases with adequate postoperative roentgenograms revealed that 10/26 (38%) had a delayed union of the syndesmosis. In group II, there were six intraoperative complications and two postoperative wound problems: an early anterior wound problem and a delayed lateral wound breakdown. Radiographic evaluation of the 26 cases with adequate postoperative roentgenograms revealed that 13/26 (50%) had a delayed union of the syndesmosis. In group III, there were four intraoperative complications and four postoperative wound problems--all healed with local supportive care with one requiring lateral hardware removal. Radiographic evaluation of the 26 cases with adequate postoperative roentgenograms revealed that 5/30 (17%) had a delayed union of the syndesmosis. The initial series from these three groups are statistically indistinguishable with respect to rates of complications, revisions, or malalignment. CONCLUSION: No identified training method had a statistically demonstrable positive impact on preparing surgeons for performing total ankle replacement. Some of these findings are likely generic for total ankle replacements and not restricted to any class or design of implant. Surgeon initial use of total ankle replacement needs to be done with caution and serious consideration.

Adult↗