Biomedical subjects

Peter Hunt

Publications and source records attributed to Peter Hunt.

15 recordsLinked to original sources

PubMed2006

Interruption of enfuvirtide in HIV-1 infected adults with incomplete viral suppression on an enfuvirtide-based regimen.

Many antiretroviral drugs continue to exert an anti-human immunodeficiency virus (HIV) benefit in the presence of drug resistance mutations. The degree to which enfuvirtide exerts continued antiviral activity in the presence of incomplete viral suppression has not been defined. To address this question, 25 subjects interrupted enfuvirtide while remaining on a stable background regimen. Enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV-1 RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals. These data indicate that enfuvirtide has measurable antiviral activity in the setting of incomplete viral suppression. Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined.

Adult↗

PubMed2006

Rate of viral evolution and risk of losing future drug options in heavily pretreated, HIV-infected patients who continue to receive a stable, partially suppressive treatment regimen.

BACKGROUND: Many treatment-experienced, HIV-infected patients who have limited therapeutic options for complete viral suppression continue to receive a partially suppressive treatment regimen pending the availability of at least 2 new antiretroviral drugs. The major risk of this approach is ongoing viral evolution and the loss of future drug options. METHODS: Antiretroviral-treated subjects with incomplete viral suppression were sampled from a clinic-based cohort. Inclusion criteria were receipt of a stable treatment regimen for > or = 120 days, a plasma HIV RNA load of > 500 copies/mL, and > or = 1 resistance mutation. Phenotypic and genotypic resistance testing was performed every 4 months. RESULTS: The 106 patients who were eligible for the study had a median of 3 observations during a median of 11.3 months. An estimated 23% and 18% developed at least 1 new nucleoside analogue and 1 new protease inhibitor mutation at 1 year, respectively. An estimated 30% lost the phenotypic equivalent of 1 susceptible drug at 1 year. A lower number of total mutations at baseline was a significant predictor of developing a new nucleoside analogue mutation (P=.01). At 1 year, the probability that an existing mutation would become undetectable using population-based sequencing was 32%. There was a higher rate of change at nonresistance codons than at codons known to be associated with drug resistance. CONCLUSIONS: Heavily pretreated patients with HIV infection who remain on a partially suppressive regimen have a measurable risk of losing future drug options, particularly those patients who have few baseline mutations. Resistance mutations vary over time, which suggests that the results of any single resistance test may not be representative of all mutations selected by a given treatment regimen.

Anti-HIV Agents↗

PubMed2006

Neutralizing antibody responses against autologous and heterologous viruses in acute versus chronic human immunodeficiency virus (HIV) infection: evidence for a constraint on the ability of HIV to completely evade neutralizing antibody responses.

Acute human immunodeficiency virus (HIV) infection is associated with the rapid development of neutralization escape mutations. The degree to which viral evolution persists in chronic infection has not been well characterized, nor is it clear if all patients develop high-level neutralization antibody escape. We therefore measured neutralizing antibody responses against autologous and heterologous viruses in a cohort of acutely and chronically infected subjects (n = 65). Neutralizing antibody responses against both autologous virus and heterologous viruses were lower among individuals with acute infection than among those with chronic infection. Among chronically infected individuals, there was a negative correlation between the level of neutralizing antibodies against autologous virus and the level of viremia. In contrast, there was a positive correlation between the level of neutralizing antibodies against a panel of heterologous viruses and the level of viremia. Viral evolution, as defined by the presence of higher neutralizing titers directed against earlier viruses than against contemporaneous viruses, was evident for subjects with recent infection but absent for those with chronic infection. In summary, neutralizing antibody responses against contemporaneous autologous viruses are absent in early HIV infection but can be detected at low levels in chronic infection, particularly among those controlling HIV in the absence of therapy. HIV replication either directly or indirectly drives the production of increasing levels of antibodies that cross-neutralize heterologous primary isolates. Collectively, these observations indicate that although HIV continuously drives the production of neutralizing antibodies, there may be limits to the capacity of the virus to evolve continuously in response to these antibodies. These observations also suggest that the neutralizing antibody response may contribute to the long-term control of HIV in some patients while protecting against HIV superinfection in most patients.

Acute Disease↗

PubMed2006

The periodontal prosthesis mode of transition to an implant-supported dentition.

In recent years, implant-supported reconstructions have become a welcome alternative to dentures for those who have lost their natural dentition. While the benefits of the final implant-supported reconstruction may be obvious, the planning and execution of therapy to achieve this result may be bewildering to many dentists. Four main modes of transfer have evolved: an uncontrolled or "haphazard" transition; the traditional "dentures first" mode, an immediate transition, and a staged transition. This article proposes an additional mode of transition called periodontal prosthesis, which has the potential to make the transition process smoother and more predictable while providing optimal retention of alveolar supporting structures and generating optimal esthetics.

Dental Implantation, Endosseous↗

PubMed2006

Immediate transition to an implant-supported dentition.

Immediate implant placement and loading is becoming increasingly acceptable. However, to be successful, very careful case selection is required, and even if this is achieved, the clinical situation that develops as soon as the natural teeth are removed may prove much less adequate for implant stability, positioning, and survival than anticipated. It makes sense to "over engineer" a case and to place more implants rather than fewer to ensure adequate support during the critical early phase of therapy, particularly when the implants are loaded at the time of placement. It also should be appreciated that immediate transition induces gross changes that can make it difficult to predict the final esthetic outcome.

Crowns↗

PubMed2006

A randomized pilot study comparing combination therapy plus enfuvirtide versus a treatment interruption followed by combination therapy plus enfuvirtide.

Most individuals with multidrug-resistant HIV who switch to a new therapeutic regimen containing a single fully effective agent experience incomplete viral suppression. We postulated that interruption of antiretroviral therapy prior to the introduction of such a regimen would improve long-term virological outcomes. Thirty, three-class experienced, enfuvirtide-naive individuals with detectable drug-resistant viraemia were randomized to an immediate enfuvirtide/optimized-background treatment regimen or a 16-week treatment interruption followed by enfuvirtide/optimized-background treatment regimen. The median CD4+ T-cell count and viral load at study entry were 39 cells/mm and 4.72 log10 copies RNA/ml, respectively. There was no evidence of any virological or immunological benefit associated with the interruption. In multivariate analysis, only the baseline phenotypic susceptibility score was predictive of treatment response at week 48 (P=0.009). Only 40% of individuals had evidence of a shift in drug-resistance genotype during the interruption. In summary, interrupting therapy prior to initiating salvage therapy in patients with advanced disease did not result in an improved virological response to enfuvirtide. The collective predictive activity of an enfuvirtide-containing regimen was important in predicting treatment response.

Anti-HIV Agents↗

PubMed2005

Substituting c-Jun N-terminal kinase-3 (JNK3) ATP-binding site amino acid residues with their p38 counterparts affects binding of JNK- and p38-selective inhibitors.

c-Jun N-terminal kinase (JNK) activation is linked to the aberrant cell death in several neurodegenerative disorders, including Parkinson's and Alzheimer's disease. The sequence similarity among the JNK isoforms and fellow MAP kinase family member p38 has rendered the challenge of producing JNK3-specific inhibitors difficult. Using the crystal structure of JNK3 complexed with JNK inhibitors, potential compound-interacting amino acid residues were mutated to the corresponding residues in p38. The effects of these mutations on the kinetic parameters with three compounds were examined: a JNK3- (vs. p38-) selective inhibitor (SP 600125); a p38-selective inhibitor (Merck Z); and a potent combined JNK3 and p38 inhibitor (Merck Y). The data confirm the role of the JNK3 residues Ile-70 and Val-196 in both inhibitor and ATP-binding. Remarkably, the Ile-70-Val and Val-196-Ala mutations caused an increase and decrease, respectively, in the binding affinity of the p38-specific compound, Merck Z, of 10-fold. The Ile-70-Val effect may be due to the increased capacity of the active site to accommodate Merck Z, whereas the Val-196-Ala mutant may induce an unfavourable conformational change. Conservative mutations of the Asn-152 and Gln-155 residues inactivated the JNK3 enzyme, possibly interfering with protein folding in a critical hinge region of the protein.

Adenosine Triphosphate↗

PubMed2005

Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit.

We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.

Animals↗

PubMed2004

Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load.

Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation "set point" is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10,000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.

Adult↗

PubMed2004

Development and application of a salmonid EST database and cDNA microarray: data mining and interspecific hybridization characteristics.

We report 80,388 ESTs from 23 Atlantic salmon (Salmo salar) cDNA libraries (61,819 ESTs), 6 rainbow trout (Oncorhynchus mykiss) cDNA libraries (14,544 ESTs), 2 chinook salmon (Oncorhynchus tshawytscha) cDNA libraries (1317 ESTs), 2 sockeye salmon (Oncorhynchus nerka) cDNA libraries (1243 ESTs), and 2 lake whitefish (Coregonus clupeaformis) cDNA libraries (1465 ESTs). The majority of these are 3' sequences, allowing discrimination between paralogs arising from a recent genome duplication in the salmonid lineage. Sequence assembly reveals 28,710 different S. salar, 8981 O. mykiss, 1085 O. tshawytscha, 520 O. nerka, and 1176 C. clupeaformis putative transcripts. We annotate the submitted portion of our EST database by molecular function. Higher- and lower-molecular-weight fractions of libraries are shown to contain distinct gene sets, and higher rates of gene discovery are associated with higher-molecular weight libraries. Pyloric caecum library group annotations indicate this organ may function in redox control and as a barrier against systemic uptake of xenobiotics. A microarray is described, containing 7356 salmonid elements representing 3557 different cDNAs. Analyses of cross-species hybridizations to this cDNA microarray indicate that this resource may be used for studies involving all salmonids.

Animals↗

PubMed2004

Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding.

Gamma-secretase performs the final processing step in the generation of amyloid-beta (Abeta) peptides, which are believed to be causative for Alzheimer's disease. Presenilins (PS) are required for gamma-secretase activity and the presence of two essential intramembranous aspartates (D257 and D385) has implicated this region as the putative catalytic centre of an aspartyl protease. The presence of several key hydrogen-bonding residues around the active site of classical aspartyl proteases led us to investigate the role of both the critical aspartates and two nearby conserved hydrogen bond donors in PS1. Generation of cell lines stably overexpressing the D257E, D385E, Y256F and Y389F engineered mutations has enabled us to determine their role in enzyme catalysis and binding of a transition state analogue gamma-secretase inhibitor. Here we report that replacement of either tyrosine residue alters gamma-secretase cleavage specificity, resulting in an increase in the production of the more pathogenic Abeta42 peptide in both cells and membranous enzyme preparations, without affecting inhibitor binding. In contrast, replacement of either of the aspartate residues precludes inhibitor binding in addition to inactivation of the enzyme. Together, these data further incriminate the region around the intramembranous aspartates as the active site of the enzyme, targeted by transition state analogue inhibitors, and highlight the roles of individual residues.

Amyloid Precursor Protein Secretases↗

PubMed2004

A technique for performing antegrade selective cerebral perfusion without interruption of forward flow or cannula relocation for pediatric aortic arch reconstruction.

New technology and advances in extracorporeal bypass circuitry and surgical techniques have drastically improved outcomes in infants with congenital heart defects. Hypothermia with circulatory arrest has fallen out of favor in many institutions over the last decade in part from data implicating even short circulatory arrest times to long-term neurologic sequelae. Implementing continuous cerebral perfusion techniques for aortic arch reconstruction is desirable in ameliorating neurologic complications because long-term survival of complex defects can be more routinely achieved. Many centers have implemented alternative means of alleviating cerebral ischemic periods by incorporating selective antegrade or retrograde cerebral perfusion techniques. The incidence of post-operative neurologic events is low when alternative cerebral perfusion techniques are used. Many techniques used to perform continuous cerebral perfusion involve brief periods of circulatory arrest, usually for perfusion cannula repositioning. Herein we describe a technique for performing continuous antegrade cerebral perfusion without a need to interrupt forward flow.

Aorta, Thoracic↗

PubMed2002

Programs-that-work: CDC's guide to effective programs that reduce health-risk behavior of youth.

In response to requests from educators for effective programs that reduce health-risk behavior among youth, the Centers for Disease Control and Prevention initiated "Programs-That-Work" (PTW) in 1992 to identify health education programs with credible evidence of effectiveness. CDC identified as PTW two programs to reduce tobacco use and eight programs to reduce sexual risk behaviors. Eligible programs undergo a two-step external review to examine quality of the research evidence and the extent to which the programs are practical for use by health educators. If CDC identifies a programs as a PTW on the basis of external review, the program is packaged and made available for dissemination to education and youth agencies. Communities ultimately make the decision about adopting a program, and CDC does not require their use. Thousands of educators have sought information about PTW through the CDC web site, informational brochures, and training.

Adolescent↗

PubMedDate not supplied

Molecular transformations as a way of finding and exploiting consistent local QSAR.

The idea of a "transformation", making a small change to a chemical structure, for instance removing or replacing a substituent, is familiar to chemists. We suggest two ways of representing a transformation in silico, as a substructure descriptor difference vector, and as the set of atoms remaining once a maximum common substructure is eliminated. Such transformations can be filtered sensibly, and it is easy to compare one transformation to another. These representations have two applications. First, we can use these methods to automatically organize and display sets of closely related compounds such that any consistent local QSAR in a data set can be easily seen, the T-ANALYZE application. Second, we can suggest to a chemist how to change a molecule "on hand" to a more active one based on local QSAR for that activity, the T-MORPH application.

Journal Article↗

PubMedDate not supplied

Issues in maintenance and repairs of wheelchairs: A pilot study.

In this pilot study, we assessed wheelchair durability and its effect on user satisfaction. Specifically, we examined the characteristics of the participants' wheelchairs, the types of maintenance and repairs completed, and whether the participants' satisfaction was affected by problems with their wheelchairs. A convenience sample of 130 participants who used wheelchairs as their primary means of mobility was recruited. Participants completed a questionnaire about their wheelchairs, the maintenance and repair history, and their satisfaction levels. Results showed that 26% of the participants had completed a wheelchair repair in the past 6 months, 16% had completed general maintenance, and 27% had completed tire repairs. Neither hours of wheelchair use nor wheelchair age affected repair or maintenance frequency. Participants were generally satisfied with their wheelchairs. Better understanding of wheelchair maintenance and repair issues will guide improvements in wheelchair design and enhance the community participation of individuals who use wheelchairs.

Adult↗