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James Robinson

Publications and source records attributed to James Robinson.

46 records · Page 3Linked to original sources
PubMed2003

Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gp120 is sterically restricted on primary human immunodeficiency virus type 1.

Anti-human immunodeficiency virus type 1 (HIV-1) antibodies whose binding to gp120 is enhanced by CD4 binding (CD4i antibodies) are generally considered nonneutralizing for primary HIV-1 isolates. However, a novel CD4i-specific Fab fragment, X5, has recently been found to neutralize a wide range of primary isolates. To investigate the precise nature of the extraordinary neutralizing ability of Fab X5, we evaluated the abilities of different forms (immunoglobulin G [IgG], Fab, and single-chain Fv) of X5 and other CD4i monoclonal antibodies to neutralize a range of primary HIV-1 isolates. Our results show that, for a number of isolates, the size of the neutralizing agent is inversely correlated with its ability to neutralize. Thus, the poor ability of CD4i-specific antibodies to neutralize primary isolates is due, at least in part, to steric factors that limit antibody access to the gp120 epitopes. Studies of temperature-regulated neutralization or fusion-arrested intermediates suggest that the steric effects are important in limiting the binding of IgG to the viral envelope glycoproteins after HIV-1 has engaged CD4 on the target cell membrane. The results identify hurdles in using CD4i epitopes as targets for antibody-mediated neutralization in vaccine design but also indicate that the CD4i regions could be efficiently targeted by small molecule entry inhibitors.

Antibodies, Monoclonal↗
PubMed2002

HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.

The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.

Antibody Affinity↗
PubMed2002

Interactions of human antibodies, epitope exposure, antibody binding and neutralization of primary isolate HIV-1 virions.

OBJECTIVE: Development of an effective HIV vaccine has been limited because of the inherent structural properties of the HIV envelope on native virions and the failure of the immune system to respond in an effective manner. Identification of the interactions of human antibodies with virions resulting in neutralization will facilitate vaccine design. DESIGN: Combinations of human monoclonal antibodies (hMAb) were studied for binding to and neutralization of primary isolate virions. METHODS: Virion binding and neutralization were measured using primary isolate virions. RESULTS: Antibodies and combinations of antibodies to epitopes exposed upon CD4 binding (CD4i) and V3 loop antibodies resulted in additive binding and neutralization of R5X4 virus. Antibodies did not bind to or neutralize R5 virus as well. The combination of V3 loop antibody with 2G12 resulted in enhanced neutralization and binding to the R5X4 isolate but not the R5 isolate. Preincubation of the R5X4 isolate with F240, a non-neutralizing anti-gp41 antibody, significantly enhanced binding and neutralization by CD4i hMAb and 2F5. F240 also enhanced the binding of 2F5 to the R5 isolate and the neutralization of the R5 isolate mediated by 2G12. CONCLUSIONS: Neutralizing epitopes are obscured on intact primary isolate virions and are dynamically exposed upon ligand (CD4) interactions. Interestingly, a non-neutralizing antibody to gp41 also increased binding and neutralizing activity of some hMAb that poorly neutralized R5 virus. These data suggest that non-neutralizing epitopes may be appropriate targets for vaccine design and epitope exposure should be considered in the development of immunotherapeutic strategies for HIV.

Antibodies, Monoclonal↗
PubMed2002

Risperidone in children with autism and serious behavioral problems.

BACKGROUND: Atypical antipsychotic agents, which block postsynaptic dopamine and serotonin receptors, have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances. However, data on the safety and efficacy of atypical antipsychotic agents in children are limited. METHODS: We conducted a multisite, randomized, double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 17 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement (CGI-I) scale at eight weeks. RESULTS: A total of 101 children (82 boys and 19 girls; mean [+/-SD] age, 8.8+/-2.7 years) were randomly assigned to receive risperidone (49 children) or placebo (52). Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001). Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P<0.05 for each comparison). In two thirds of the children with a positive response to risperidone at eight weeks (23 of 34), the benefit was maintained at six months. CONCLUSIONS: Risperidone was effective and well tolerated for the treatment of tantrums, aggression, or self-injurious behavior in children with autistic disorder. The short period of this trial limits inferences about adverse effects such as tardive dyskinesia.

Adolescent↗
PubMed2002

Broadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexes.

HIV-1 entry into cells involves formation of a complex between gp120 of the viral envelope glycoprotein (Env), a receptor (CD4), and a coreceptor, typically CCR5. Here we provide evidence that purified gp120(JR-FL)-CD4-CCR5 complexes exhibit an epitope recognized by a Fab (X5) obtained by selection of a phage display library from a seropositive donor with a relatively high broadly neutralizing serum antibody titer against an immobilized form of the trimolecular complex. X5 bound with high (nM) affinity to a variety of Envs, including primary isolates from different clades and Envs with deleted variable loops (V1, -2, -3). Its binding was significantly increased by CD4 and slightly enhanced by CCR5. X5 inhibited infection of peripheral blood mononuclear cells by a selection of representative HIV-1 primary isolates from clades A, B, C, D, E, F, and G with an efficiency comparable to that of the broadly neutralizing antibody IgG1 b12. Furthermore, X5 inhibited cell fusion mediated by Envs from R5, X4, and R5X4 viruses. Of the five broadly cross-reactive HIV-1-neutralizing human monoclonal antibodies known to date, X5 is the only one that exhibits increased binding to gp120 complexed with receptors. These findings suggest that X5 could possibly be used as entry inhibitor alone or in combination with other antiretroviral drugs for the treatment of HIV-1-infected individuals, provide evidence for the existence of conserved receptor-inducible gp120 epitopes that can serve as targets for potent broadly cross-reactive neutralizing antibodies in HIV-1-infected patients, and have important conceptual and practical implications for the development of vaccines and inhibitors.

Antibodies, Monoclonal↗
PubMed2002

Folding pathway of apo-metallothionein induced by Zn2+, Cd2+ and Co2+.

Metal ion binding to the sulfhydryl groups of apometallothionein (apo-MT) causes both the formation of native metal-thiolate clusters and the folding of the polypeptide chain of each domain. Cd2+ and Zn2+ react with apo-MT to form metal-thiolate bonds in reactions that are complete within milliseconds and which are pH-dependent. Dual mixing experiments were conducted that involve the initial reaction of metal ion and apo-MT followed by mixing with 5,5'-N-dithio-bis(2-nitrobenzoate) or EDTA after 26 ms. They showed that structures had formed within the brief reaction period which were resistant to rapid reaction with reagents that interact with sulfhydryl groups or metal ions, respectively. It was concluded that native metallothionein domains had been constituted within this brief period. Apo-MT was also titrated with Co2+ to yield Co(n)-MT (n=1-7). Initially, Co2+ bound to independent, tetrahedral thiolate sites. Spectrophotometric analysis of the titration suggested that the independent Co(II) sites began to coalesce into clusters at n=4 (pH 7.2) or n=5 (pH 8.4). Back titration of free sulfhydryl groups (S) in Co(n)-MT (n=1-7) with iodoacetamide at pH 7.2 confirmed that clustering began at n=4. Upon conversion of these alkylated structures to the corresponding 113Cd2+ species 113Cd NMR spectroscopy established that the location of Co(II) in Co(n)-MT (n=1-3) was non-specific and that at n=4, the only observable structure was Co(II)4S11. The results suggest possible kinetic pathways of folding that are conceptually similar to those hypothesized for other small proteins.

Alkylation↗
PubMed2002

Tobacco use and quit behaviors among delinquent youth: a pilot study.

With rates of adolescent tobacco use steadily increasing over the past 20 years, assisting youth to quit, particularly those youth most susceptible to tobacco use, has become a national focus. The purpose of this pilot study was to examine and profile the smoking patterns of a small sample (n = 37) of juvenile offenders in Texas. In contrast to anecdotal reports, the sample group from this study did not differ clinically from the general population of adolescent tobacco users. Importantly, the study participants indicated previous attempts to stop smoking. The authors conclude that delinquent youth may be responsive to cognitive behavioral smoking cessation programs that also address the management of peer networks.

Adolescent↗
PubMed2002

A naturalistic study of risperidone treatment outcome using prognosis-adjusted discharge rates in New York State inpatients.

BACKGROUND: Information concerning the effectiveness of newer atypical antipsychotics is derived largely from controlled clinical trials of relatively short duration. Limited information is available concerning naturalistic outcome of patients selected for clinical treatment with atypical antipsychotics. This study evaluates 1-year discharge rates among all patients treated with risperidone within the New York State inpatient psychiatric hospital system during the calendar years 1994 and 1995 ("period of interest") relative to patients treated with all other antipsychotic medications. METHOD: Data from the Integrated Research Database at Nathan Kline Institute (Orangeburg, N.Y.) were used. This database maintains complete treatment records for all inpatients within the New York State psychiatric inpatient system along with demographic, diagnostic, admission, and discharge information. Patients were identified at admission or first change in antipsychotic during the period of interest, and 1-year outcome was determined. RESULTS: 2198 risperidone-treated patients were identified versus 3259 treated with other antipsychotics. Length of hospitalization prior to treatment initiation was the primary predictor of discharge rate for both risperidone and control groups. When adjustment was made for between-group difference in prognosis (dischargeability), patients treated with risperidone within 30 days of admission were less likely to be discharged than those treated with all other agents (including clozapine), whereas risperidone was more effective in patients who had been hospitalized for 90 days or more prior to switch from another antipsychotic to risperidone. CONCLUSION: When database information is utilized to evaluate treatment effectiveness, adjustment must be made for a priori differences in prognosis or dischargeability. With appropriate methodology, database studies may indicate which patient groups are most likely to benefit from newer atypical antipsychotic agents.

Adult↗
PubMedDate not supplied

Tibiofemoral kinematics of the anterior cruciate ligament (ACL)-deficient weightbearing, living knee employing vertical access open "interventional" multiple resonance imaging.

BACKGROUND: Our current understanding of tibiofemoral kinematics in the anterior cruciate ligament (ACL)-deficient knee is very limited. Using vertical open-access MRI, it is possible to accurately analyze tibiofemoral motion in patients with isolated rupture of the ACL. STUDY: Prospective cohort study. PURPOSE: To assess if ACL rupture alters normal knee weightbearing kinematics. METHODS: Tibiofemoral motion was assessed through the arc of flexion from 0 degrees to 90 degrees in 10 patients with isolated rupture of the ACL in one knee and a normal contralateral knee. Midmedial and midlateral sagittal images were analyzed in all positions of flexion in both knees to assess the tibiofemoral relationship. RESULTS: In the lateral compartment of the knee, the tibial plateau is persistently subluxed anteriorly throughout the arc of flexion from 0 degrees to 90 degrees (flexion facet center to posterior tibial cortex distance of 15.8 mm +/- 2.9 in ACL-deficient knees compared to 21.4 mm +/- 1.4 in normal knees at 0 degrees extension, P <.0001) when compared to normal knees. The medial tibiofemoral relationship is unchanged compared to normal knees. CONCLUSION: Rupture of the ACL changes tibiofemoral kinematics producing anterior subluxation of the lateral tibial plateau. CLINICAL SIGNIFICANCE: Altered kinematics may explain, at least in part, the increased incidence of secondary osteoarthritis in patients with ACL rupture.

Adult↗