Nucleotide sequencing reveals a novel DQB1-06 allele (DQB1*06013) with a silent mutation at codon 137.
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Alleles↗
Biomedical subjects
J M White
Publications and source records attributed to J M White.
Mutational analysis of the candidate internal fusion peptide of the avian leukosis and sarcoma virus subgroup A envelope glycoprotein.
The transmembrane subunit (TM) of the avian leukosis and sarcoma virus (ALSV) envelope glycoprotein (Env) contains a stretch of conserved hydrophobic amino acids internal to its amino terminus (residues 21 to 42). By analogy with similar sequences in other viral envelope glycoproteins, this region has been proposed to be a fusion peptide. We investigated the role of this region by changing each of three hydrophobic residues (Ile-21, Val-30, and Ile-39) to glutamatic acid and lysine in the ALSV subgroup A Env. Like wild-type (wt) Env, all six mutant Env proteins were proteolytically processed, oligomerized, and expressed at the cell surface in a form that bound Tva, the ALSV subgroup A receptor. Like wt Env, Ile21Glu, Ile21Lys, Va30Glu, and Val30Lys changed conformation upon binding Tva, as assayed by sensitivity to thermolysin. Ile39Glu and Ile39Lys were cleaved by thermolysin in both the absence and presence of Tva. Although incorporated into virus particles at approximately equal levels, all mutant Envs were compromised in their ability to support infection. The mutants at residues 21 and 30 showed levels of infection 2 to 3 orders of magnitude lower than that of wt Env. The mutants at residue 39 were noninfectious. Furthermore, none of the mutants displayed activity in a cell-cell fusion assay. Our results support the contention that residues 21 to 42 of ALSV subgroup A Env constitute its fusion peptide.
3T3 Cells↗
Dental lasers: have recent advances renewed interest?. Interview by Dan Marino.
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Dental Care↗
Activation of a retroviral membrane fusion protein: soluble receptor-induced liposome binding of the ALSV envelope glycoprotein.
It is not known how membrane fusion proteins that function at neutral pH, for example the human immunodeficiency virus envelope (Env) glycoprotein and intracellular fusion machines, are activated for target bilayer binding. We have addressed this question using a soluble oligomeric form of an avian retroviral Env glycoprotein (API) and soluble forms of its receptor. Binding of soluble receptor to API induces API to bind to liposomes composed of phosphatidylcholine and cholesterol at neutral pH. Liposome binding only occurs at fusion permissive temperatures (T > 20 degrees C), is complete between 2 to 5 min at 37 degrees C, and is stable to high salt, carbonate, and urea. Liposome binding is mediated by the ectodomain of the transmembrane subunit of API, and a mutant with a Val to Glu substitution in the Env fusion peptide (located in the ectodomain of the transmembrane subunit) shows significantly reduced liposome binding. Moreover, under conditions of equivalent binding to API, a mutant receptor that does not support infection (Zingler, K., and J.A.T. Young. 1996. J. Virol. 70:7510-7516) does not induce significant liposome binding. Our results indicate that a highly specific interaction between an avian retroviral Env and its receptor activates the retroviral glycoprotein for target bilayer binding at neutral pH in much the same way as low pH activates the influenza hemagglutinin. Our findings are discussed in terms of the mechanisms of viral and cellular fusion proteins that function at neutral pH.
3T3 Cells↗
Methadone-related overdose deaths in South Australia, 1984-1994. How safe is methadone prescribing?
OBJECTIVE: To assess the safety of prescribing of methadone tablets and syrup in South Australia by investigating overdose deaths of patients using prescribed methadone and non-patients using illegally obtained methadone. DESIGN: Surveillance study of deaths related to methadone overdose, 1984-1994. DATA SOURCES: Coroner's Office and the Therapeutic Goods Section of the South Australian Health Commission. RESULTS: Per capita prescription of methadone tablets for chronic pain in South Australia was the highest in Australia in 1994. A large increase in deaths, due mainly to methadone tablets prescribed for chronic pain, occurred in 1993-1994. Illegal diversion of methadone to non-patients was responsible for half of the deaths during these two years. Deaths from overdoses of methadone syrup prescribed in maintenance therapy for drug dependence declined from 1984 to 1994. The relative risk for patient deaths due to methadone tablets versus methadone syrup was estimated to be 7.29 (95% confidence limits, 2.15-31.48). Psychotropic drug combinations were present in 86% of deaths. CONCLUSION: The methadone syrup program for drug dependence remains relatively safe. Our data raise concerns about prescribing methadone tablets for chronic pain. Better prescriber education and accountability, patient assessment and supervision and advice to patients about concurrent use of alcohol and benzodiazepines are needed.
Adult↗
ADAM 13: a novel ADAM expressed in somitic mesoderm and neural crest cells during Xenopus laevis development.
Embryonic development involves a series of cell adhesive interactions that provide mechanical and instructive information required for morphogenesis. The ADAMs family of membrane-anchored proteins, containing a disintegrin and metalloprotease domain, is well suited for participating in such developmental events. They encode not only a potential adhesive function, through an integrin-binding disintegrin domain, but also a potential antiadhesive function, through a zinc-dependent metalloprotease domain. In order to investigate the role of ADAMs in early development we cloned a cDNA encoding a novel member of the ADAM family from a Xenopus laevis neurula stage library. We call this cDNA, and the 915-amino-acid protein it encodes, ADAM 13, X-ADAM 13 RNA is expressed during embryogenesis from the midblastula stage through tadpole stage 45. X-ADAM 13 is localized to somitic mesoderm and cranial neural crest cells during gastrulation, neurulation, and in tail bud stages. Sequence analyses of the X-ADAM 13 metalloprotease and disintegrin domains indicate that the protein is likely to be involved in both proteolytic and cell-adhesive functions. The X-ADAM 13 sequence is most closely related to that of mouse meltrin alpha, which is implicated in myoblast fusion. Our data suggest that X-ADAM 13 may be involved in neural crest cell adhesion and migration as well as myoblast differentiation.
3T3 Cells↗
In vitro study of the effects of Nd:YAG laser probe parameters on bovine oral soft tissue excision.
BACKGROUND AND OBJECTIVES: Lasers are now used for intraoral, soft tissue procedures. The effects of Nd:YAG probes on cutting efficiency and temperature rise were evaluated in vitro. STUDY DESIGN/MATERIALS AND METHODS: Three hundred twenty-micron 400-microns, 500-microns, and 600-microns probes were used to ablate bovine gingiva, mucosa, and tongue at various power and frequency settings. Thermocouples positioned under the subjacent cortical bone measured temperature rise. Tissue samples were evaluated histologically. RESULTS: Mean pooled temperature rise was 1 degree C at 3 W and 1.4 degrees C at 5 W. Excision width ranged from 0..63 mm to 0.79 mm at tested settings, cutting depths from 0.19 mm to 0.49 mm, lateral and deep coagulation from 0.27 mm to 0.62 mm. CONCLUSION: Temperature rise in bone was related to increased power. Cutting efficiency of laser probes was not significantly improved by increased power. Probes of 320 to 500 microns provided efficient cutting at 3 W and 5 W, thus reducing the potential for unacceptable temperature rise in bone.
Animals↗
Effects of Nd: and Ho:yttrium-aluminium-garnet lasers on human dentine fluid flow and dental pulp-chamber temperature in vitro.
Dentine specimens were prepared from freshly extracted third molars and initial permeability measured. Each specimen was subjected to Nd:yttrium-aluminium-garnet (YAG) (1.06 or 1.32 microns wavelength) or Ho:YAG (2.10 microns wavelength) laser energy while temperatures in the pulp chambers were recorded. Permeability was again measured and the surfaces examined by scanning electron microscopy. Six crown segments were used for each laser variable and eight permeability measurements were taken before and eight after laser exposure, while temperature was recorded during treatment. All wavelengths reduced permeability but temperature rises were high enough to have caused pulpal damage, indicating that shorter treatment times and lower power settings may be necessary if used in vivo.
Aluminum Silicates↗
Neural network model of short-term horizontal disparity vergence dynamics.
We present a neural network model of short-term dynamics of the human horizontal vergence system (HVS) and compare its predictions qualitatively and quantitatively with a large variety of horizontal disparity vergence data. The model consists of seven functional stages, namely: (1) computation of instantaneous disparity; (2) generation of a disparity map; (3) conversion of the disparity into a velocity signal; (4) push-pull integration of velocity to generate a position signal; (5) conversion of the position signal to motoneuron/plant activity for each eye; (6) gating of velocity overdrive signal to motoneuron/plant system; and finally (7) discharge path for position cells. Closed-loop (normal binocular viewing) symmetric step and staircase disparity vergence data were collected from three subjects and model parameters were determined to quantitatively match each subject's data. The simulated closed-loop as well as open-loop (disparity clamped viewing) symmetric step, sinusoidal, pulse, staircase, square and ramp wave responses closely resemble experimental results either recorded in our laboratory or reported in the literature. Where possible, the firing pattern of the neurons in the model have been compared to actual cellular recordings reported in the literature. The model provides insights into neural correlates underlying the dynamics of vergence eye movements. It also makes novel predictions about the human vergence system.
Convergence, Ocular↗
CHOP-based chemotherapy is as effective as alternating PEEC/CHOP chemotherapy in a randomised trial in high-grade non-Hodgkin's lymphoma. Scotland and Newcastle Lymphoma Group.
The aim of this study was to test whether survival for patients with high-grade non-Hodgkin's lymphoma (NHL) can be improved with a non-cross-resistant regimen as compared to a CHOP-based regimen. This is a multicentre study comprising 325 adult patients, median age 58 years, with high-grade non-Hodgkin's lymphoma: patients of any age and performance status were eligible provided they were able to receive the drugs in the regimens. Patients were randomised to either B-CHOP-M (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisolone and methotrexate) or PEEC-M (methylprednisolone, vindesine, etoposide, chlorambucil and methotrexate) alternating with B-CHOP-M. At a median follow-up of 9 years, there was no significant difference in overall survival or disease-free survival between the two arms. Toxicities for the two regimens were equivalent. This study confirms that for relatively unselected patients with high-grade non-Hodgkin's lymphoma, an alternating multidrug regimen does not improve upon the results obtained with B-CHOP-M.
Adult↗
Polio eradication: surveillance implications for the United Kingdom.
The requirements for certification of elimination of wild virus poliomyelitis will pose particular problems for some industrialized countries, such as the United Kingdom, where there has been no case detected for at least a decade. Systems of surveillance of poliomyelitis have been reviewed and potential weaknesses identified. When oral polio vaccine is routinely used, the rate of vaccine-associated cases provides an indication of the likelihood that if they occurred, wild virus cases would be detected. Acute flaccid paralysis surveillance was done for 3 years, but rates were lower than reported elsewhere and were accepted for certification purposes. Alternative techniques, such as surveillance of polioviruses, either in clinical samples or from the environment, may be developed in such countries. The ability to identify enteroviruses and to distinguish between wild and vaccine strains of polioviruses will give assurance that silent transmission of wild viruses is unlikely.
Disease Notification↗
Biochemical and molecular characterization of bovine fertilin alpha and beta (ADAM 1 and ADAM 2): a candidate sperm-egg binding/fusion complex.
Fertilin alpha and beta (previously known as PH-30 alpha and beta) are sperm surface proteins implicated in sperm-egg binding and membrane fusion. In this work we report the purification, characterization, and cloning of the bovine homologues of fertilin alpha and beta. Immunofluorescence and Western blotting, using polyclonal antibodies made against guinea pig fertilin, identified likely bovine fertilin alpha and beta homologues. These candidates were purified under nondenaturing conditions using lectin and ion-exchange chromatography and were subjected to amino acid sequence analysis. Degenerate oligonucleotides made from bovine N-terminal protein sequences and from guinea pig fertilin sequences were used to isolate clones encoding bovine fertilin alpha and beta from a bovine testis cDNA library. The predicted proteins have the same domain organization as guinea pig fertilin alpha and beta: pro, metalloprotease-like, disintegrin-like, and cysteine-rich domains, followed by an EGF-like repeat, a transmembrane domain, and a cytoplasmic tail. In contrast to the reported sequence of guinea pig fertilin alpha, the mature, proteolytically processed bovine fertilin alpha subunit contains a complete disintegrin-like domain, and a potential amphipathic beta strand, which may be involved in sperm-egg fusion. Gradient sedimentation experiments suggest that the fertilin alpha/beta heterodimer may be present on the sperm surface as a higher-order oligomer.
ADAM Proteins↗
Structure-based identification of an inducer of the low-pH conformational change in the influenza virus hemagglutinin: irreversible inhibition of infectivity.
Past efforts to employ a structure-based approach to design an inhibitor of the fusion-inducing conformational change in the influenza virus hemagglutinin (HA) yielded a family of small benzoquinones and hydroquinones. The most potent of these, tert-butyl hydroquinone (TBHQ), inhibits both the conformational change in HA from strain X:31 influenza virus and viral infectivity in tissue culture cells with 50% inhibitory concentrations in the micromolar range (D. L. Bodian, R. B. Yamasaki, R. L. Buswell, J. F. Stearns, J. M. White, and I. D. Kuntz, Biochemistry 32:2967-2978, 1993). A new structure-based inhibitor design search was begun which involved (i) the recently refined crystal structure (2.1-A resolution) of the HA ectodomain, (ii) new insights into the conformational change, and (iii) improvements in the molecular docking program, DOCK. As a result, we identified new inhibitors of HA-mediated membrane fusion. Like TBHQ, most of these molecules inhibit the conformational change. One of the new compounds, however, facilitates rather than inhibits the HA conformational change. Nonetheless, the facilitator, diiodofluorescein, inhibits HA-mediated membrane fusion and, irreversibly, infectivity. We further characterized the effects of inhibitors from both searches on the conformational change and membrane fusion activity of HA as well as on viral infectivity. We also isolated and characterized several mutants resistant to each class of inhibitor. The implications of our results for HA-mediated membrane fusion, anti-influenza virus therapy, and structure-based inhibitor design are discussed.
Antiviral Agents↗
Patterns of symptom complaints in methadone maintenance patients.
AIM: Not all maintenance patients respond to methadone in the same manner, and many complain of withdrawal symptoms during the 24-hour inter-dosing interval (i.e. the dose does not 'hold'). The persistence of these complaints are a source of concern as they may signal unsanctioned drug use and poor treatment outcome. This study examined the prevalence and profile of symptom complaints in methadone maintenance patients who report that their methadone dose does not 'hold'. DESIGN: In the first phase, a cross-sectional survey of 114 methadone patients examined a range of symptoms including direct opioid effects and withdrawal. Phase 2 involved a comparison of the temporal pattern of symptom complaints between patients who reported the oral dose not 'holding' and those who did not. SETTING: Participants in this study were enrolled in the South Australian Public Methadone Maintenance Program. MEASUREMENTS: In Phase 1, a checklist of 21 commonly reported symptom complaints associated with methadone maintenance treatment was administered. In Phase 2, this checklist was modified to include only those symptoms that changed in the 24-hour inter-dosing interval. The checklist was administered eight times over this period. Further data were collected using the Morphine Benzedrine Group Scale of the Addiction Research Centre Inventory, a measure of positive opioid effect. FINDINGS: In Phase 1, it was found that approximately one-third of the sample reported that the methadone dose was consistently inadequate in preventing withdrawal symptoms for the entire inter-dosing interval. They could not be differentiated by demographic, health, other drug use or treatment characteristics. In Phase 2, despite having a higher oral methadone dose, patients reporting that their daily dose did not 'hold' experienced a smaller degree of opioid effect, and a greater intensity of opioid withdrawal, during the 24-hour period. CONCLUSION: These data demonstrate that there is a change in pharmacodynamic response over the 24-hour period for all methadone patients, but the degree of change is greater in a subgroup of patients. Charting symptom presentation throughout the inter-dosing interval can aid in identifying those patients who are experiencing difficulties with their treatment regime.
Adult↗
ADAMs in fertilization and development.
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Amino Acid Sequence↗
Chromosomal assignment of four testis-expressed mouse genes from a new family of transmembrane proteins (ADAMs) involved in cell-cell adhesion and fusion.
A new gene family of multidomain membrane proteins (ADAMs) that include A Disintegrin And Metalloprotease domain comprises an increasing number of identified members. Two members of this family, fertilin alpha and fertilin beta, form a heterodimeric protein that is required for sperm-egg fusion. Most recently, it has been shown that a third family member, meltrin alpha, is involved in myoblast fusion (Yagami-Hiromasa et al., 1995, Nature 377: 652-656). Using restriction fragment length polymorphism analysis of a DNA panel from an interspecific backcross, we have determined the chromosomal locations of four mouse genes of this family that are expressed in testis: fertilin alpha, fertilin beta, ADAM 4, and ADAM 5. These genes have been given the locus symbols Ftna (fertilin alpha), Ftnb (fertilin beta), Adam4 (ADAM 4), and Adam5 (ADAM 5). They were mapped to chromosomes 5, 14, 9, and 8, respectively, revealing a dispersed localization. Human chromosome locations of these genes are predicted on the basis of the mapping results using the information provided by comparative linkage maps. Because all four of these ADAM genes are expressed in testis and fertilin alpha and beta have been found to be important for fertilization, we compared their chromosomal locations with known mouse mutations affecting spermatogenesis and fertility.
ADAM Proteins↗