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S Fuller

Publications and source records attributed to S Fuller.

At least 19 recordsLinked to original sources
PubMed2000

A conformational switch controlling HIV-1 morphogenesis.

Assembly of infectious human immunodeficiency virus type 1 (HIV-1) proceeds in two steps. Initially, an immature virus with a spherical capsid shell consisting of uncleaved Gag polyproteins is formed. Extracellular proteolytic maturation causes rearrangement of the inner virion structure, leading to the conical capsid of the infectious virus. Using an in vitro assembly system, we show that the same HIV-1 Gag-derived protein can form spherical particles, virtually indistinguishable from immature HIV-1 capsids, as well as tubular or conical particles, resembling the mature core. The assembly phenotype could be correlated with differential binding of the protein to monoclonal antibodies recognizing epitopes in the HIV-1 capsid protein (CA), suggesting distinct conformations of this domain. Only tubular and conical particles were observed when the protein lacked spacer peptide SP1 at the C-terminus of CA, indicating that SP1 may act as a molecular switch, whose presence determines spherical capsid formation, while its cleavage leads to maturation.

Animals↗
PubMed2000

The intact retroviral Env glycoprotein of human foamy virus is a trimer.

Electron microscopy of negatively stained human foamy virus particles provides direct evidence for the trimeric nature of intact Env surface glycoproteins. Three-dimensional image reconstruction reveals that the Env trimer is a tapering spike 14 nm in length. The spikes were often arranged in hexagonal rings which shared adjacent Env trimers.

Gene Products, env↗
PubMed1999

Epitopic overload at the site of injection may result in suppression of the immune response to combined capsular polysaccharide conjugate vaccines.

Capsular polysaccharide (CP) conjugate vaccines targeting a variety of bacterial infections are currently under development and clinical evaluation. The inclusion of multiple CP serotypes combined in a single injection is an important maneuver being evaluated. The combination of CP conjugate vaccines into a single multivalent injection may result in competition among the different components and adversely affect the immunogenicity of any individual conjugate. We observed a reduction of 30-90% in antibody responses to several serotypes in mice when immunogenicity of a 12-valent Escherichia coli (E. coli) lipopolysaccharide (LPS) conjugate vaccine was compared to the immunogenicity of each monovalent vaccine evaluated separately. A reduction of 30% was observed in the Staphylococcus aureus (S. aureus) type 8 CP antibodies when a type 8-rEPA conjugate was combined with a type 5-rEPA conjugate. S. aureus types 5 and 8-rEPA conjugates were combined with 100 micrograms of either rEPA (homologous) or diphtheria toxoid (DT) (heterologous) carrier proteins, and evaluated in rEPA or DT primed mice. The addition of the homologous protein resulted in a 64% reduction in type 5 CP antibodies. The heterologous protein did not affect the immunogenicity of the type 5. We postulate that the free protein competed with the conjugate and recruited most of the rEPA primed T cells. In the case of the DT conjugates, the DT targeted different populations of the T cells, thus interference was not observed. These data suggested that the epitopic load rather than the antigenic load at the site of injection caused reduced immunogenicity of the conjugates. We theorize that individual components of multivalent CP vaccines conjugated to the same carrier proteins would compete for a limited number of specific carrier protein primed T cells. This would result in one or more components being unavailable in eliciting a sufficient immune response. The use of multiple carrier proteins should be considered as an approach to reduce interference when multivalent conjugate vaccines are to be formulated into a single injection.

Animals↗
PubMed1999

Allergic reactions to 6-mercaptopurine during treatment of inflammatory bowel disease.

Hypersensitivity reactions to 6-mercaptopurine (6-MP) or azathioprine occur during the treatment of inflammatory bowel disease (IBD), raising significant diagnostic and therapeutic challenges. Charts of 591 patient with IBD treated with 6-MP in a single center were retrospectively reviewed. All allergic reactions were recorded along with results of rechallenge, desensitization, and subsequent course of IBD. Sixteen (2.7%) allergic reactions to 6-MP were noted, with fever being the most common (14 cases). Nine of these were rechallenged with 6-MP with recurrence of the same symptoms. Azathioprine was tried in six patients and in five the same symptoms recurred. Four patients underwent successful desensitization to either 6-MP or azathioprine; all four plus another patient who tolerated direct switch to azathioprine entered long-term remission. Among the remaining 11, 5 required surgery, 2 are well on methotrexate, and 4 have chronic symptoms while being treated with other medications. If an allergic reaction to 6-MP occurs during the treatment of IBD, direct switching to azathioprine is probably not justified. Instead, desensitization to either 6-MP or azathioprine should be attempted. Patients who can tolerate these medications after previous allergic reactions have improved outcomes compared with patients who resort to other forms of treatment.

Adolescent↗
PubMed1998

Organization of HIV-1 capsid proteins on a lipid monolayer.

In an in vitro system that mimics the assembly of immature human immunodeficiency virus (HIV) particles, ordered arrays of HIV-1 capsid (CA) proteins encoded by the viral gag gene have been obtained by incubation of histidine-tagged capsid proteins (His-HIVCA) beneath lipid monolayers containing the nickel-chelating lipid, 1,2-di-O-hexadecyl-sn-glycero-3-(1'-2"-R-hydroxy-3'-N-(5-amino-1- carboxypentyl)iminodiacetic acid)propyl ether. The membrane-bound His-HIVCA proteins formed small crystalline arrays of primitive (p1) unit cells with dimensions of a = 74.2 A, b = 126.2 A, gamma = 89.3 degrees. The image-analyzed two-dimensional projection of His-HIVCA assemblies shows a cage-like lattice, consisting of hexamer and trimer units, surrounding protein-free cage holes. The hexamer-coordinated cage holes of 26.3-A diameter are spaced at 74. 2-A intervals: these distances, and the hexamer-trimer arrangement, are consistent with previous, lower resolution studies on immature HIV-1 virus particles produced in vivo. Additionally, HIV-1 matrix protein trimer unit structures align to the His-HIVCA trimer units such that residues previously shown to interact with the HIV-1 gp120/gp41 envelope protein complex are oriented toward the hexamer cage holes. Our results form a bridge between results from conventional methods for the analysis of HIV particle structure.

Capsid↗
PubMed1998

Biogeographic origins of goannas (Varanidae): a molecular perspective.

This project aims to clarify the phylogenetic relationships among the extant species of Varanus in order to elucidate the origins of Varanidae, using DNA sequences. Results obtained for a minimum of 662 nucleotides of 12S rRNA sequence data from each of 21 extant species of Varanus indicate that the Australian varanids form a single monophyletic clade and also suggest that within the Australian varanids, members of the subgenus Odatria (pygmy monitors) may from a clade separate from those in the subgenus Varanus (large monitors). The Asian species appear to be sister taxa to the Australian species, while the two African species investigated were most divergent, suggesting that the Varanidae are not Gondwanic in origin. Hypothesis testing analyses were performed and involved constraining the 12S sequence data according to previously described topologies and testing the difference using parametric and nonparametric statistics. The phylogeny generated using 12S sequence data was statistically different from previously described morphological trees, while there was some support for topologies based on chomosomal and immunological datasets. Overall, our results suggest that the Australian species may be derived from an Asian source and are, therefore, in agreement with the hypothesis based on the fossil record suggesting that Varanidae may be Asian in origin.

Animals↗
PubMed1998

Creation and maintenance of Helix, a Web based database of medical genetics laboratories, to serve the needs of the genetics community.

Helix (healthlinks.washington.edu/helix) is a web accessible database that serves as the main U.S. directory of laboratories offering genetic testing. The database was designed to address the previously unmet need for a centralized, continuously updated source of information about clinical and research genetic testing to keep pace with the rapid rate of gene discovery resulting from the Human Genome Project. The Helix project began in 1992 at the University of Washington and Children's Hospital and Regional Medical Center. It has evolved from a single user stand alone relational database to a fully Web enabled database queried and maintained via the web and linked to other web accessible genomic databases. As of February, 1998 it lists more than 500 diseases and 290 laboratories, with over 5,200 registered users making approximately 250 queries/day (90% via the Internet). We describe the iterative design, implementation, population and assessment of the database over a six year period.

Database Management Systems↗
PubMed1997

Structural analysis of membrane-bound retrovirus capsid proteins.

We have developed a system for analysis of histidine-tagged (His-tagged) retrovirus core (Gag) proteins, assembled in vitro on lipid monolayers consisting of egg phosphatidylcholine (PC) plus the novel lipid DHGN. DHGN was shown to chelate nickel by atomic absorption spectrometry, and DHGN-containing monolayers specifically bound gold conjugates of His-tagged proteins. Using PC + DHGN monolayers, we examined membrane-bound arrays of an N-terminal His-tagged Moloney murine leukemia virus (M-MuLV) capsid (CA) protein, His-MoCA, and in vivo studies suggest that in vitro-derived His-MoCA arrays reflect some of the Gag protein interactions which occur in assembling virus particles. The His-MoCA proteins formed extensive two-dimensional (2D) protein crystals, with reflections out to 9.5 A resolution. The image-analyzed 2D projection of His-MoCA arrays revealed a distinct cage-like network. The asymmetry of the individual building blocks of the network led to the formation of two types of hexamer rings, surrounding protein-free cage holes. These results predict that Gag hexamers constitute a retrovirus core substructure, and that cage hole sizes define an exclusion limit for entry of retrovirus envelope proteins, or other plasma membrane proteins, into virus particles. We believe that the 2D crystallization method will permit the detailed analysis of retroviral Gag proteins and other His-tagged proteins.

Amino Acid Sequence↗
PubMed1997

Meeting clinician information needs by integrating access to the medical record and knowledge resources via the Web.

MINDscape is a web based integrated interface to diverse sources of clinical information including both patient specific information (electronic medical record) as well as medical knowledge (the "digital library") to provide "just in time" information at the point of care. It was developed at the University of Washington to meet clinical information needs both as identified locally and by a review of the literature. Beta testing by over 600 clinicians is in progress and medical centers wide access scheduled for Fall 1997. We describe the information needs we sought to meet and the ongoing evaluation approach we are taking to ensure the information needs of a diverse group of clinicians are met. The iterative evolution of the interface from prototype, to alpha to large scale beta testing is reported. Integration of information occurs at three levels: integration of information by patient, integration of information by provider, and integration of patient specific information with medical reference material and decision support tools.

Computer Communication Networks↗
PubMed1996

Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors.

PURPOSE: No increase in second tumor incidence was found in a previous analysis of women treated with chemotherapy for gestational trophoblastic tumors (GTT). More patient years at risk enabled a further analysis of the risk of second tumors to be performed in the 1,377 women treated in this until up to 1990. PATIENTS AND METHODS: Health questionnaires were returned on 93.3% of patients who successfully completed chemotherapy and were living in the United Kingdom. The remainder were flagged for death or developing further cancers by the Office of Population Census and Surveys and by the Thames Cancer Registry. Incidence density analysis was performed based on 15,279 person-years of observation available. Standardized incidence ratio (SIR) was used to estimate the relative risk (RR) of second tumors associated with the treatment. To calculate the expected number, the actual incidence rates observed by the Thames Cancer Registry during the same calendar period of observation were used. RESULTS: An overall 50% excess of risk (RR = 1.5; 95% confidence interval [CI], 1.1 to 2.1; P < .011) was observed: there were 37 second tumors, when 24.5 were expected. For specific second tumors, the risk was significantly increased for myeloid leukemia (RR = 16.6; 95% CI, 5.4 to 38.9), colon (RR = 4.6; 95% CI, 1.5 to 10.7), and breast cancer when the survival exceeded 25 years (RR = 5.8; 95% CI, 1.2 to 16.9). The risk was not significantly increased among the 554 women receiving single-agent therapy (RR = 1.3; 95% CI, 0.6 to 2.1). Leukemias only developed in patients receiving etoposide plus other cytotoxic drugs. CONCLUSION: This study suggests that there is a slight increased risk of second tumors after sequential or combination chemotherapy for GTT. This has become apparent since the introduction of etoposide and longer follow-up.

Adolescent↗
PubMed1996

Clinical trials: testing of adult chemical heating pad.

Chemical packs are recent innovations in the delivery of dry heat. Because these delivery systems do not have any mechanism for verifying temperature during application, research to determine their safety seems warranted. The purpose of this study was to measure the skin temperature of adults during a 30-minute application of the MediHeat adult heating pad (MH-AHP). Seventy-seven subjects received a 30-minute application of the MH-AHP to their backs while lying in both supine and prone positions. The mean skin temperature in both positions was 101 degrees F. There were significant differences, however, in minimum and maximum skin temperature between positions. Subjects in the prone position had significantly higher maximum skin temperature and significantly lower minimum skin temperature than subjects in the supine position. It is possible that the prone position allows for more air flow over the MH-AHP and that more heat was generated causing the higher maximum temperature. This explanation does not account for the lower minimum temperature. There were no significant differences in perception of heat between the positions at either 5 minutes or 30 minutes. Findings suggest that caution is necessary when applying heating devices that depend on air circulation for heat generation.

Adult↗
PubMed1995

Isolation of small, primitive human hematopoietic stem cells: distribution of cell surface cytokine receptors and growth in SCID-Hu mice.

Human CD34+ cells were subfractionated into three size classes using counterflow centrifugal elutriation followed by immunoadsorption to polystyrene cell separation devices. The three CD34+ cell fractions (Fr), Fr 25/29, Fr 33/37, and Fr RO, had mean sizes of 8.5, 9.3 and 13.5 microns, respectively. The majority of cells in the large Fr RO CD34+ cell population expressed the committed stage antigens CD33, CD19, CD38, or HLA-DR and contained the majority of granulocyte-macrophage colony-forming units (CFU-GM), burst-forming units-erythroid (BFU-E), and CFU-mixed lineage (GEMM). In contrast, the small Fr 25/29 CD34+ cells were devoid of committed cell surface antigens and lacked colony-forming activity. When seeded to allogeneic stroma, Fr RO CD34+ cells produced few CFU-GM at week 5, whereas cells from the Fr 25/29 CD34+ cell population showed a 30- to 55-fold expansion of myeloid progenitors at this same time point. Furthermore, CD34+ cells from each size fraction supported ontogeny of T cells in human thymus/liver grafts in severe combined immunodeficient (SCID) mice. Upon cell cycle analyses, greater than 97% of the Fr 25/29 CD34+ cells were in G0/G1 phase, whereas greater proportions of the two larger CD34+ cell fractions were in active cell cycle. Binding of the cytokines interleukin (IL)-1 alpha, IL-3, IL-6, stem cell factor (SCF), macrophage inhibitory protein (MIP)-1 alpha, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage (GM)-CSF to these CD34+ cell populations was also analyzed by flow cytometry. As compared with the larger CD34+ cell fractions, cells in the small Fr 25/29 CD34+ cell population possessed the highest numbers of receptors for SCF, MIP1 alpha, and IL-1 alpha. Collectively, these results indicate that the Fr 25/29 CD34+ cell is a very primitive, quiescent progenitor cell population possessing a high number of receptors for SCF and MIP1 alpha and capable of yielding both myeloid and lymphoid lineages when placed in appropriate in vitro or in vivo culture conditions.

Animals↗
PubMed1995

Informatics and medical libraries: changing needs and changing roles.

Medical librarians play a crucial role in the evolution of institutional information policy. As information professionals, they share many similarities with their medical informatics counterparts. Both groups emphasize information delivery to the point of decision making; both groups serve as curators of institutional knowledge bases. If the term "publication" encompasses the delivery of clinical information relevant to individuals or populations, both librarians and medical informaticians have an immediate interest in the nature of biomedical publishing, particularly in areas of intellectual ownership, confidentiality, distribution, and access. Both groups also have been early leaders in applying information technology to solve pressing knowledge-management problems, and both groups have a strong commitment to educating colleagues in the effective use of information. Although the challenges faced by librarians and medical informaticians are sometimes different, the evolution of information technology and new forms of biomedical communication suggest that there is now a greater convergence between the two disciplines.

Artificial Intelligence↗
PubMed1995

The organization of the digital library.

As digital information proliferates and the difficulties of managing it threaten to overwhelm traditional publication and information delivery processes, new visions of a digital library are forming. Exactly what a digital library is and how it is to be organized have not yet been determined, and bibliographic organization of digital information has not been sufficiently addressed. Bibliography is the systematic description or classification of writings or publications considered as material objects. In today's digital world, such material objects may no longer be relevant, but the need for systematic description remains. The important issue is not whether digital bibliography is needed but, instead, whether or not existing bibliographic techniques are appropriate for this new media. A second issue is the location of the responsibility for a new digital bibliography. Does it rest with medical informaticians, often the producers of this new digital information, or with librarians, traditionally the classifiers of information? Developments in both medical informatics and medical librarianship indicate a need for greater collaboration between these specialties in order to achieve their common purpose--the creation, classification, and dissemination of scholarly information.

Bibliography of Medicine↗
PubMed1995

Educating physicians to use the digital library.

Skill in creating, finding, managing, and using biomedical information is a vital component of modern medical practice. Medical schools recognize the revolutionary implications of computing technology and use a number of different strategies to integrate "informatics education" into their curricula. In many institutions, leadership for this effort rests with the health sciences library and/or the department of medical informatics. Examples are presented of how nine medical schools have implemented informatics education; no single informatics-education strategy prevails, and these schools' strategies do not exhaust the possibilities. Informatics education programs will require better planning and integration in the future because of the need to keep pace with curriculum reform, the changing context of medical practice, and the speed of technological innovation.

Education, Medical↗